Anaesthesia online edition 2013
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Anaesthesia online edition 2013



This book contains the results of research, conducted by Prof.

This book contains the results of research, conducted by Prof.
L.N. Rao and his co-research workers from 1964 onwards.



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Anaesthesia online edition 2013 Anaesthesia online edition 2013 Document Transcript

  • NEURO PHYSIOLOGICAL BASIS OF THE GENERALANAESTHETIC TECHNIQUES AND MECHANISM OF ANAESTHETIC COMPLICATIONS IN PERI OPERATIVE PERIOD BY PROF. L.N.RAO, M.D., D.A., MAMS (Prof. NARAHARI RAO LAKKARAJU) Retired Professor of Anaesthesiology Ex-President of Indian Society of Anaesthesiology (National) Retired Commissioner Medical Services (APVVP), Government of Andhra Pradesh, India Phone : +91 9247417620 E-mails : 1) 2) 2
  • 1st Edition : Consisting of only Complimentary copies Published in : April 2012 Edition : 2nd Online Edition 2013 Printers : NEW HYDERABAD PRESS & ARTS 2nd Floor, Jamal Market, Chatta Bazar, Hyderabad. A.P. India. Cell: 9700698068, 9052442440 E-mail: 3
  • GENERAL NOTE (ABOUT THE BOOK) 1. Inspiration to write this book (about the results of intensive investigation into basic principles ofAnaesthesiology starting from 1964) is purely due to the divine force called parameswara, Allah the great, Lord Jesus Christ etc. 2. One of the greatest psychological books in the world (Bhagavat Gita), gives us following message.“Yogasthah kuru karmani sangam tyaktva Dhanunjaya ……..” It means all human beings should act without attachment to their work, because He, (the Lord) has allotted the duties to them. They should not worry about the success or failure of the work etc., etc., etc. Hence the authors feel that whether this book succeeds or it fails to achieve it’s purpose is immaterial. We are only doing our duty and nothing else. 3. This Edition of the book (which is only for providing complimentary copies to the anaesthesiologists and others is dedicated to Mrs. Sethu Laxmi, an anesthesiologist of South India (In Tamilnadu, India). She was murdered by the relatives of a patient who died in peri-operative period, (consequent to a peri anaesthetic complication). May her soul rest in peace. 4. Anaesthetic complications (as indicated by our research) are due to the patient’s personality factor (P-factor) and anaesthesiologist has no role in the causation of such complications (of course, he has to understand (P) factor and treat the cndition to prevent catastrophy). 5. This book contains the results of research, conducted by Prof. L.N. Rao and his co-research workers from 1964 onwards. 6. This book is divided into 3 sections. 4
  • SECTION-I Deals with neurophysiological factors which produce ideal operating conditions, (when general anaesthetic techniques are used). Present concepts (about the fundamentals of the speciality), and results of research for more than 25 years are dealt with, in detail (for the purpose of highlighting the results of the research, the research papers are also printed). SECTION-II Deals with patients personality factor (P-Factor) which, in fact, causes all anaesthetic complications in peri-operative period in vulnerable patients (this is the results of our research). (The present concepts of anaesthetic complications are also discussed). Method of treatment is also suggested. SECTION III Contains summary/conclusions/acknowledgments. 7. Author prays god that, information provided, in this book, forms a nidus for further research in the basic principles in Anaesthesiology so that the speciality of Anaesthesiology becomes a broad based and independent speciality (like medicine/ surgery/gynecology etc) as desired by Dr.Haggard at the time of inauguration of the journal “ANAESTHESIOLOGY” in 1940". (refer the introduction). (PROF. L.N. RAO) 5
  • P R O L O G U E In the month of March, 2012, results of National Survey of American Society of Anaesthesiologists concerning the impact of peri-operative catastrophe, on the life of American anaesthesiologists concerned were published. They were published inAnaesth.Analg. (Vol.114) pages 596 to 603. (2012). More than 500 Anaesthesiologists responded. Results of the survey is given below: 1. 70% of the members were feeling guilty or serious. They were still re-living the event (which happened on the day of catastrophe in peri- operative period). 2. 88% said they required more time to recover emotionally from the event. 3. 19% accepted that they did not fully recover. 4. 12% thought of changing their career. Prof. L.N. Rao was in the process of printing this book when we read the survey on-line. Our 1st impression (about the survey) was to express sympathy to the American Society of Anaesthesiologists who had significant impact on them. After a while, he also started wondering, why peri-operative catastrophe should occur at all in a developed and affluent country like U.S.A. If this survey was carried out in India or in any other developing country, he could have taken it lightly. Much later, it dawned on him that, peri-operative catastrophe could still occur in a highly developed country (with all the gadgets to monitor every aspect of vital functions of the patient), because patients in U.S.A. (highly developed country) and India (a developing country), would react in a similar way, (when they are being operated under any of the techniques of Anaesthesia). 6
  • When we think about the catastrophe, it immediately gives us an impression that some unexpected situation developed in peri- operative period, and “event managers”, (the surgeon and his staff and Anaesthesiologist and his staff) could not deal with the situation. Hence the peri-operative catastrophe occured. In normal course of events, when a patient is posted for surgery (minor, major, elective or emergency), every aspect of his/her vital functions are studied in detail and both the parties (surgical personnel and anaesthesiology personnel) would be more than familiar with the patients fitness for surgery and anaesthesia and probable risk factor would be known to them. Catastrophe in peri operative period could happen when some unknown factor works against the patients’ welfare in peri operative period, because, the anaesthesiologists would not know how to deal with the unknown factor. We, in this book, indicated some unknown factors (mostly concerned with vulnerable patients) which could cause anesthetic complications in peri-operative period. We strongly feel that a thorough study about such factors might give the anaesthesiologists a document to understand such factors and if treatment is scientifically provided, peri operative catastrophes may be avoided. This is only a suggestion and we wish that, those who read this book get advantage from our experience. PROF. L.N. RAO 7
  • C O N T E N T S SECTION-I Deals with the research into the fundamentals of Anaesthesiology, Papers published, results obtained, and the special research paper (which is based on the results obtained during research). Page Nos. A) Introduction 12 B) Evolution of Anaesthesiology as a speciality. 18 C) The necessity of research into the fundamentals of Anaesthesiology. 22 D) Research papers published (about fundamentals of Anaesthesiology) or presented to a gathering of Anaesthesiologists. 27 - 122 D-1: RAO L.N. et all, increased afferent activity (vagal, splanchnic etc) leading to hyperventilation syndrome. Ind. J. Aneasth. 14, 226-232, 1966. 27 D-2: P.S.R.K. HARNATH, A. KRISHNAMOORTHY, L.N. RAOAND K. SESHGIRI RAO, passage of gallamine from blood into the liquor space in man and in dog., Brit. J. Pharmacol., 48, 640-645, 1973. 28 D-3: L.N. RAO AND H. VENKATAKRISHNA BHATT, Role of Thiopentone, Nitrous oxide, relaxant anaesthesia in causing the syndrome of post operative paralysis in man. Derr Anesthetist, 24, 73-77, 1975. 41 D-4: L.N. RAO, T.N. PRAHLAD AND H. VENKATAKRISHNA BHATT, Central Nervous effects of hyperventilation-a preliminary report, Ind. J. Medical Sciences, 23, 665-670, 1969. 55 8
  • D-5: L.N. RAO AND H. VENKATAKRISHNA BHATT, Vagal activity in canine: A possible connection to hyperventilation syndrome. Anesthesia and Analgesia, 49, 351-354, 1970. 66 D-6: L.N. RAO, Patho-Physiological changes during artificial over ventilation, XXIV congresso societa Italiana. Anesthesia E Rianimazione (International symposium on non operative resuscitation and Intensive care) (Book) (Vol-I) pages 694-702, 1971. 75 D-7: L.N. RAO, Factors affecting awareness in patients during and after general anesthetic techniques. (Research paper presented at I.S.A.(National) at its annual conference at Lakhnow, U.P. India. In December 1910. 98 E) Results of Investigations into the fundamentals of anesthesiology. 118 -120 F) Special Research Paper (Result of Research for 25 years). F-1: Letter from InternationalAnesthesia Research Society (accepting the abstract of the papers) for their annual conference in 2011. 121 Note: Since visa to visit Canada (Vancouvre) was denied due to lack of time to process the visa papers Prof. Rao could not present the paper in their annual conference in 2011. Hence, This Research Paper (F2) is Printed in this book for information to all the anesthesiologists about the contents of the paper. Titled “NEURO PHYSIOLOGICAL BASIS OF REVERSIBLE DEPRESSION OF C.N.S. DURING GENERALANAESTHETIC TECHNIQUES”. 122 9
  • SECTION – II RELATIONSHIP OF ANAESTHETIC COMPLICATIONS WITH PATIENT’S PERSONALITY FACTOR (P-FACTOR) A) Commonly observed complications in peri-operative period. 135 B) Interaction with patients pre-operative phase, and post operative phases. 136 C) Study of concerned literature (about complications in patients – (Due to their personality). 140 D) Mechanism of the development of “Shock Syndrome” in some vulnerable patients. (an anaesthetic complication) 144 E) Papers published in journals/books (including those Articles which were presented at various gatherings of Indian Society of Anaesthesiologists). 147-232 E-1: L.N. RAO, G. ACHUTARAMAIAH AND K. GURUMOORTHY, Clinical Signs of Neurogenic stress in surgical patients during and after an operative procedure. Ind. J. Anesth. 23, 112-116, 1975. 147 E-2: L.N. RAO, The “Syndrome of depressed vital functions in the post operative period in the man: Role of neuro humors in its causation”. This is a chapter 29, in the book “NEUROHUMORAL CORRELATES OF BEHAVIOUR” Edited by Dr. Sharada Subramanyam. 1977., Thomson Press (India) Ltd., Publication Division, pages 234-243, Faridabad, Haryana, India. 159 10
  • E-3: L.N. RAO AND H. VENKATAKRISHNA BHATT, Stress response during surgery and anesthesia, International surgery, 57, 294-298, 1972. 175 E-4: L.N. RAO AND H. VENKATAKRISHNA BHATT, Syndrome of post operative depression of vital functions in poor risk patients: its treatment. Int. J. Clinicl. Pharmacol. Toxicology & Therapy, 19, 18-22, 1981. 189 E-5: L. N. RAO, J.G. CHAR, H. VENKATAKRISHNA BHATT AND HARI NARAYANA, Psychosomatic factors involved in the development of bleeding tendency in the post operative period. A Case report. Ind. J. Anesth. 23, 293-296, 1972. 203 E-6: L.N. RAO, Neurophysiological basis of the syndrome of post operative depression of vital functions in some operated patients under general anesthetic techniques., (This research paper was presented at Southern Zone conference at Hyderabad. A.P. India in 2009). (It was a conference of I.S.A. (National) for South Zone Members.) 211 E-7: L.N. RAO, Neurophysiological factors which lead to awareness in patients during surgery under general anesthetic techniques. 222 (This research paper was presented to the I.S.A. Branch of Andhra Pradesh (India) on the occasion of their annual conference in the year 2010, NELLORE. A.P., INDIA). SECTION – III A) SUMMARY AND CONCLUSION 233 B) ACKNOWLEDGMENTS 237 C) EPILOGUE 238 D) In praise of “IGNORANCE” 239 11
  • INTRODUCTION Dr. Howard, W. Haggard in his inaugural address to the founding fathers of prestigious journal of Anaesthesiology in 1940 (in U.S.A.) clearly outlined the criteria for medical/surgical and allied specialities. (for the purpose of recognition as an individual speciality). He told the organizers of the journal that any speciality which does not fulfill the three criteria (given below) cannot claim to be a separate and individual speciality because without fulfilling these criteria, the persons who are practicing the speciality are treated only as skilled workers, and they cannot be considered as specialists, even when they are highly successful in their work pattern. Following are the criteria for becoming specialists in independent/broad based specialties, in various disciplines of medical sciences. 1.1 The persons (workers) practicing such a speciality should have intellectual as well as manual occupation, when they are treating the patients like medical/surgical specialties as well as allied specialties. 1.2 The speciality (to which such individuals belong to) should have fundamentals which should be easily understood by medical/ surgical fraternity thereby they should get prestige/recognition from the members of medical/surgical faculty as specialists purely on the basis of understanding of the fundamentals of their speciality. Neurophysiology & Anaesthesia 12
  • 1.3 General public who are ultimate beneficiaries (due to the use of such a speciality as a part of their treatment) should understand the fundamentals of the speciality concerned. 2. He clarified his remarks further about the type of fundamentals of a speciality which is regarded as a satisfactory one, (if it fits to the following criteria). 2.1 In case of medical speciality common person is told about the disease process and the type of treatment required by the patient, for temporary or permanent cure. The common man easily understands the fundamentals of medical speciality and he reconciles to the situation even when the patient dies during medical treatment. 2.2 In a similar way a common person understands the need of an operation and also he understands the possible complications, when surgery is done, which rarely ends up in death of the person during or after the operation. Hence he reconciles to the situation because he understands the principles of surgery and does not blame the surgeon, unless gross evidence is presented about the surgeon’s negligence during surgery or when his care was bad in the post operative period. 2.3 Anaesthesiologist did not so far develop such a clear picture about it’s fundamentals so that common man understands it. Hence the difficulty is in calling it a broad based speciality or independent speciality. Neurophysiology & Anaesthesia 13
  • FUNDAMENTALS OFANAESTHESIOLOGY (AS ON TODAY) WHEN COMPARED TO SURGERY OR MEDICAL SPECIALITIES 3.1 Anaesthesiology as a speciality has revolutionized its techniques in the later half of 20th Century and unimaginable situation has now developed in which anaesthetic techniques are used to operate grossly ill patients with derangements of vital functions of the body specially due to severe disease of kidneys, heart, liver and other vital organs. Patients with end stage renal disease, gross electrolyte imbalance and those patients who are associated with severe restriction of blood supply to the head or the heart are successfully anaesthetized. Anaesthesia is successfully provided to beating heart surgery. 3.2 Anaesthsiologist in the role of consultant to help the seriously ill patients during and after surgery (and in I.C.U.) is highly respected consultant and every doctor in the medical fraternity knows his contribution and respects him for the same. However situation differs and a confused atmosphere ensues when a fatality occurs in peri-operative period (1 hr. before surgery to 48 hours or more after surgery). All persons in the operating team speculate that technique of anaesthesia could be one of the main factors in the causation of the fatality (or the complication in peri-operative period). 3.3 Main reason for such a situation is due to the fact that signs and symptoms of the abuse of anaesthetic drugs are exactly similar to the signs and symptoms in a patients who develops anaesthetic complication in peri-operative period, leading to paralysis and coma in the operated patients in the post operative period. Neurophysiology & Anaesthesia 14
  • 3.4 Hospital administrators, judicial officers and other investigating officers (investigating the cause of complication/ catastrophe occurring in post-operative period), like to exclude primarily the abuse of anaesthetic drugs as the causatory factor because patient who develops complication or dies in peri- operative period, was in comatic condition with paralysis of respiratory and other muscles with no sensation (of any type) during the complication/or when fatality occurred. 3.5 Common persons including close relatives of the person (who died in the peri-operative period) do not understand the basic fundamentals of anaesthesiology. Since patient was found to be deeply unconscious, with paralysis of respiratory and other muscles with analgesia and reflex suppression, present when the patient died, common man thinks that anaesthetist has used excessive dose of anaesthetic drugs (abuse of anaesthetic drugs) and anaesthesiologist’s explanation (about his innocence) would not be believed by them. In under developed and developing countries usually 30% to 40% of operating units are in semi urban and rural areas and they are not equipped with respiratory care units. Hence, people misunderstands the role of anaesthesiologist, (in rural areas), when they see the anaesthetist struggling to keep the patient alive in peri-operative period (by using artificial ventilation and other supportive measures) and when they see that surgeon disappears from the scene, only to visit the patient periodically, they suspect that anaesthetist was the main culprit because they feel that he abused the anaesthetic drugs and his negligence has caused the fatality in the patient operated upon and he is now trying to eliminate excessive anaesthetic drugs from the body of the affected patient, used by him during the operation. Neurophysiology & Anaesthesia 15
  • 3.5 In the well developed countries such a situation does not cause much concern to the anaesthesiologist because comatic and paralyzed patients in peri-operative period are routinely treated in respiratory care units (in post operative ward). Hence Anaesthesiologists of U.S.A., Canada, Japan, European countries etc., do not face this problem seriously. In developing and under developed countries only urban areas have respiratory care units attached to the operating unit. Hence in most of operating units, in semi urban and rural areas, anaesthetists are exposed to harassment and recently one lady anaesthetist in south India was murdered by patient’s relatives (when the operated patient died in a comatose condition in peri-operative period). 3.6 Under such circumstances it is necessary that fundamentals of Anaesthesiology are studied carefully and role of anaesthesiologist in such a situation is rationalized. By this step (by rationalizing the fundamentals of anaesthesiology) it becomes easy for common man to understand the speciality better (similar to that of medicine and surgery). Once they understand the fundamental principles, they would not harass the anaesthetic staff (when fatality occurs in peri-operative period). 3.7 As on today the fundamentals of anaesthesiology (with regards to the reason for the operated patient to get paralysis and comatic condition in peri operative period) are confused and contradictory. Tremendous success of general anaesthetic techniques is due to the use of skeletomuscular relaxants (with some adjuvants) but unfortunately anaesthetists explain to the patient’s relatives (relatives of affected patient who is paralysed Neurophysiology & Anaesthesia 16
  • in the post operative period) that skeletomuscular relaxant drugs which helped the patient earlier by producing ideal operating conditions are now paralyzing the patient in the post operative period. Such a blame to the same drug to cause peri operative complications in the post operative period is unfortunate because the actual meaning of the statement of the anaesthesiologist would be understood by the relatives is that the good drug used during surgery has turned poisonous in the post operative period. Hence patient’s relatives do not agree with the anaesthetist’s explanation and they would harass him/her for abuse of the anaesthetic drugs during operation period. ***** Neurophysiology & Anaesthesia 17
  • SECTION-I (B) EVOLUTION OFANAESTHESIOLOGY AS A SPECIALITY 1. It appears that many dentists and others tried to invent a process of pain relief during dental surgery in the middle of 19th Century (in the year 1846) (or about that time). One dentist succeeded to show to the world that pain during surgery could be relieved by using diethyl ether as a pain relieving agent. Many others also claimed that they had discovered this fact earlier but failed to get their claim recognized. Some persons in fact, suffered during such controversy and they were harassed for their claim. Unfortunately the anaesthesiologist working in semi-urban and rural areas of many parts of the world even today, are being harassed for a different reason. He/she is being harassed for practicing the speciality of anaesthesiology in semi-urban and rural areas in under developed or developing countries, for his inability to convince the relatives of patients, (who developed anaesthetic complication) that anaesthesiologists is innocent and that such a complication developed in spite of his best efforts to use the anaesthetic drugs as per rules. He fails to convince the public that he did not abuse the anaesthetic drugs (because signs and symptoms of anaesthetic complications are exactly similar to those which appear in patients who developed complications, when anaesthetist abused anaesthetic drugs). 2. Next stage of the development of anaesthesiology is the intervening period that is from the introduction of diethyl ether (as an anaesthetic drug) to the period when skeletomuscular relaxant drugs were introduced into the specialty. During this period, anaesthetic techniques were an artistic way of inducing Neurophysiology & Anaesthesia 18
  • pain relief by selected individuals, who could produce anaesthesia successfully for short operative procedures, by using diethylether in addition to other anaesthetic drugs (as adjuvants), specially the drugs like chloroform, Ethylchloride,ACE mixtures (mixture of chloroform, diethylether with a preservative) etc. During this period anaesthesia was an art rather than a scientific procedure. 1st and 2nd Hyderabad Commissioners reported that Chloroform could safely be used during surgery, where as most of the anaesthetists failed to use Chloroform safely because of its cardiac toxicity. Hence it remained as such an art, practiced by few gifted individuals until skeletomuscular drugs were introduced into the speciality of anaesthesiology in the middle of 20th Century. 3. Important developments took place after 1942 when rapid expansion of anaesthetic services took place and large number of persons (known as anaesthetists) (anaesthesiologists or anaesthetic technicians), who using skeletomuscular relaxants, (short acting and long acting types of skeletomuscular relaxant drugs) provided anaesthetic services to various operative procedures and by the end of 20th Century anaesthetic services become so common that operating units in various countries in the world increased tremendously. Millions of operations under general anesthetic techniques are carried out every day in the entire globe. Such a success in the anaesthetic techniques was possible, only because of the induction of skeletomuscular relaxants into the speciality of anaesthesiology in the middle of 20th Century. Neurophysiology & Anaesthesia 19
  • 4. As stated earlier, from the date of introduction of skeletomuscular relaxants into anaesthetic practice, and upto this day billions of operations were carried out in patients whose age group ranged from few hours of life to 90 years of age or more, (most of them successfully). However, in small number of operated patients anaesthetic complications started developing in peri operative period (One hour before surgery to 48 hours or more in post operative period). During anaesthetic complications patients continued to be unconscious with depression of vital functions (paralysis of all muscles etc.), in addition to the occurrence of coma in the affected patient. Aanesthesiologits became a confused lot of persons. They started explaining the cause of the post operative paralysis in operated patients to be associated with the continued action of skeletomuscular relaxant drugs on C.N.S. In the post operative period. Hence terms like “central nervous action of curare”, “clinical syndrome of incomplete reversal”, and “a stage of apparent recurarization” were used to describe the anaesthetic complications which develops in the peri operative period and continues into the post operative period. Some others speculated that effect of antidote to curare (drugs like neostigmine or its equivalent drugs) wears off prematurely, leaving the skeletomuscular relaxant drugs to act unopposed on CNS thereby leading to the paralytic condition of the patient under comatose conditions. At this stage, it is necessary to point out that anaesthesiologists even now believe that skeletomuscular relaxant drugs not only act on the periphery (on neuro muscular junction), producing paralysis of respiratory and other muscles but also act on CNS causing analgesia, unawareness during surgery, reflex suppression etc., Neurophysiology & Anaesthesia 20
  • thereby causing satisfactory conditions for safe surgery. They (anaesthesiologists) feel that if anaesthetic complication develops in peri operative period, it was due to the continued action of skeletomuscular drug on CNS in the post operative period and ventilatory support (as well as support of other vital functions) in the post operative ward with ventilator therapy was enough to treat such complications. This explanation and satisfaction with ventilatory support to the affected patients appear to be doing injustice to the speciality and to the anaesthesiologists because 30% to 40% of operative units in semi urban and rural areas of the world (specially in under developed and developing world) do not have respiratory care units attached to post operative ward. When a patient is paralyzed in post operative ward in rural areas anaesthesiologist has to struggles to keep the patient alive by squeezing the ambu bag or any other device available for keeping up satisfactory ventilatory function of the affected patient (in addition to other supportive measures to keep him alive). Such an act, on the part of anaesthetist therefore appears to the patient’s relatives that anesthesiologist was irresponsible and had abused the anaesthetic drugs during anaesthetic procedure, and caused the anaesthetic complication in the peri operative period. Such a situation undermines the image of the anaesthesiologist concerned and he is harassed by the patient’s relatives. 5. Author therefore feel that research on fundamentals of Anaesthesiology has to be vigorous so that anaesthesiologist could claim to be specialist and not a skilled technician. ***** Neurophysiology & Anaesthesia 21
  • SECTION-I (C) NECESSITY OF RESEARCH INTO THE FUNDAMENTALS OF THE SPECIALITY OF ANAESTHESIOLOGY 1. As stated earlier (in the introduction) the fundamentals of Anaesthesiology (if at all any fundamental principles exist for the speciality) are not clear enough to be understood by doctor fraternity (surgeons, physicians etc) and the common man, who is the ultimate beneficiary, of surgery carried out on them under regional or general anaesthetic techniques. He does not understand it’s basic principles and it appears that main reason for non development of the clarity of fundamentals of anaesthesia appears to be the financial gains (for anaesthetizing patients), with the help of skeletomuscular relaxants and getting away with the consequences like post operative paralysis and comatic condition in the post operative period by ventilating him (with other support to vial functions) for 4 to 10 hours or more and send the patient back to his original ward (after he is alright). This statement may appear harsh but it appears to be true because many changes in the techniques of anaesthesia were introduced to make anaesthetic procedures convenient and safe, when operations are carried out in sitting position, head low position, lithotomy position, prone position etc. However, no anaesthesiologist carried out research to find out the main basis of various factors which produced ideal operating conditions and nobody tried to find out the reason why some operated patients develope coma and paralysis in the post operative period. This situation (lack of research to find out the mechanism which Neurophysiology & Anaesthesia 22
  • produced ideal operating conditions) (as well as various post operative complication) could be due to the speculation by the anaesthesiologist that skeletomuscular relaxant drugs act on CNS to cause areflexia, analgesia, reflex relaxation of diaphragm and other respiratory muscles etc., including occasional complication during surgery and in the post operative period. Because of such a speculation they blame the skeletomuscular relaxant drugs for their prolonged action on CNS, (for causing post operative depression of vital functions) when an occasional (operated) patient fails to recover from anaesthesia for 4 to 10 hours or more in the post operative period. Scientifically their argument is not convincing because it is now known that skeletomuscular relaxant drugs do not act on CNS. Hence common man believes that anaesthesiologist has abused the anaesthetic drugs (during the procedure of anaesthesia) and hence, the patient developed coma and paralysis in the post operative period. 2. Awareness during surgery even when anaesthetic technique is continuing, is another anaesthetic complication for which so far no scientific explanation is available. At present anaesthesiologist speculates that awareness during surgery was due to light stage of anaesthesia and vigorous titration of anaesthetic drugs would prevent the incidence of awareness during surgery. They feel that light stage of anaesthesia was due to carelessness of anaesthesiologist (who relaxed in his duties during anaesthetic procedure). In under developed and developing countries, patients (who claim to be aware during surgery) are approaching family courts (its public grievance cell) to award compensation to the affected patients who claim to be Neurophysiology & Anaesthesia 23
  • affected functionally by awareness during surgery (such patients express dissatisfaction with the operative procedure thinking that operation was not satisfactorily done and their inability to work efficiently in the post surgical period was due to the ineffective surgery). 3. Some patients are observed to loose their memory temporarily and in some rare cases, such a loss of memory is prolonged for few weeks. During this period, they behave abnormally and act as if they are different personalities in the post operative period. 4. Apart from such complications, analysis of the currently believed fundamentals lead to the following un-answered questions about the very basis of the speciality of anaesthesiology. (a) What is the mechanism by which a patient undergoing operative procedure (under general anaesthetic technique) is unaware during surgery and anaesthesia. Anaesthesiologists believe that loss of proprioception (due to the paralysis of skeletal and respiratory muscles) leads to a situation in which CNS is deprived of proprioception (roughly 15% to 20% of all peripheral impulses), thereby depressing the activity of CNS. They, therefore speculate that unconsciousness ensues, purely due to the loss of proprioception. However, their speculation cannot be true because tactile sensation, sensation from bones and joints, sensation from the viscera of abdomen, chest, head and neck etc is still intact and sensation is transmitted through autonomic nervous system (which is about 80% of the total sensation of the Neurophysiology & Anaesthesia 24
  • body). Such sensory information reaches midbrain and the giant cells of ascending reticulo alerting system (ARS) in the midbrain receives such sensory information to cause intense activity of various neurons of CNS. Hence CNS cannot be depressed due to the lack of proprioception only. (unless ARS is depressed, cerebral (cortical) cells are active and keep the other neurons of various lobes active so that functions of CNS are not depressed. (b) Consciousness in an individual depends on the activity of cerebral cortical neurons in CNS, and the activity of cortical neurons depend upon ascending reticulo alerting system (ARS). Activity of ARS depends upon the volley of peripheral afferents (which are mentioned in para (a)); The (Axons of ARS) directly arbourise (connect) with the dendrides (inter connecting neurons), of cerebral cortex so that during the activity of ARS, Acetyl Choline (and probably other neuro humors) are released. (Acetylcholine is the main transmitter of Cholinergic system). As long as ARS is intact and is receiving information from periphery, cerebral cortical neurons would be active to keep up the consciousness of the individual. Hence it is necessary to find out under what conditions, ARS stops its activity (and also stops producing cholinergic transmitting hormones), to produce unawareness during surgery under general anaesthetic techniques. (c) What is the cause of the development of areflexia, unawareness during surgery, analgesia and reflex relaxation of respiratory muscles. (including diaphragm) Neurophysiology & Anaesthesia 25
  • (d) Why some patients develop behavioural changes in post anaesthetic period, in addition to the loss of memory in the immediate/delayed post anaesthetic period. (e) What is the mechanism, which causes “shock syndrome” in some patients during spinal or general anaesthetic techniques in peri operative period. (during or after surgery, which is the main anaesthetic complication in some patients). (refer the article “Clinical Signs of neurogenic stress” in Section II”. Page - 136 5. Our research team therefore looked into all these aspects of the fundamentals of the speciality of anaesthesiology, which includes the reason for some vulnerable patients to get “shock syndrome” during all forms of anaesthetic techniques. ***** Neurophysiology & Anaesthesia 26
  • RESEARCH PAPER RAO L.N., RAMA RAO K.R. AND SQ. LEADER BHALLA “Increased afferent activity (vagal, splanchnic etc) leading to hyperventilation syndrome during surgery under general anaesthesia” Indian Journal of Anaesthesia, 1966, Vol. 14, Pages 226-232 NOTE: REPRINT NOT AVAILABLE In this Article Prof. L.N. Rao in 1966, after intense study of Neurophysiology put forward the theory that vagus, (Due to receptor activity during IPPV) causes ideal operating conditions during G.A. D1 27
  • RESEARCH PAPER PASSAGE OF GALLAMINE FROM BLOOD INTO THE LIQUOR SPACE IN MAN AND IN DOG BY: PROF. P.S.R.K. HARNATH, A. KRISHNAMURTHY, PROF. L.N. RAO, AND K. KRISHNAMURTHY RAO KURNOOL (P.O.) A.P. INDIA British Journal of Pharmacology 1973, 48, 640-645 SPECIAL NOTE BY PROF. L.N. RAO Please see Table-I of the paper which gives the correct picture of concentration of gallamine in patients at the time of recovery. It is obvious that 10 to 25% or more of gallamine concentration (when compared to the paralysing concentration) is present at the time of recovery of patient from anaesthesia. D2 28
  • PASSAGE OF GALLAMINE FROM BLOOD INTO THE LIQUOR SPACE IN MAN AND IN DOG P.S.R.K. HARANATH,A. KRISHNAMURTY, L.N. RAO AND K. SESHAGIRIRIRAO Department of Pharmacology and Anaesthesiology, Kurnool Medical College, Kurnool 518002, A.P., India. SUMMARY: 1. Patients receiving an intravenous injection of 2-3.8 mg/kg gallamine showed gallamine-like activity in their lumbar c.s.f. collected 15 and 70-100 min after the injection. The activity assayed on acetylcholine contractions of frog rectus muscle was equivalent to between 0.1 and 0.75 µg/ml gallamine. 2. In anaesthetized dogs an intravenous injection as well as an intravenous infusion of gallamine led to the appearance of gallamine-like activity in the cisternal c.s.f. and, on perfusion of the cerebral ventricles, in the effluent collected from the cisterna magna. 3. After an intravenous injection of 1 mg/kg the activity in the cisternal c.s.f. corresponded to between 0.2 and 1 µg/ml and in the effluent to between 130 and 175 ng/min during the first 15 min perfusion and then declined. 4. On intravenous infusion of gallamine at a rate of 10 (µg/kg)/min for 2 h the cisternal c.s.f. showed a uniform of gallamine-like activity corresponding to between 0.4 and 0.67 µg/ml during the infusion. In the cisternal effluent the gallamine-like acitivity rose initially to between 20 and 90 ng/min but declined before the infusion was ended. Neurophysiology & Anaesthesia D2 - 30
  • 5. The intravenous injection of gallamine caused respiratory paralysis but did not affect arterial blood pressure; it s intravenous infusion caused no respiratory paralysis and did not affet arterial blood pressure. INTRODUCTION: Muscle relaxants like tubocurarine and gallamine, which are quaternary ammonium compouinds, are expected either not to pass from blood into cerebrospinal fluid (c.s.f.) or to do so with difficulty. Previous reports on the passage of muscle relaxants from blood into c.s.f. have been contradictory. The passage of tubocurarine into c.s.f. was reported by Mahfouz (1949) and Dal Santo (1964). but Cohen (1963) did not detect tubocurarine in the c.s.f. in animal and human experiments after intravenous administration of tubocurarine. Recently definite evidence was obtained in man and dog for its passage into the liquor space. The lumbar c.s.f. of patients who had received an intravenous injection of tubocurarine was found to exert tubocurarine-like activity when assayed on the frog rectus muscle contracted by acetycholine. Similary, tubocurarine-like acitivity was detected in thecisternal c.s.f. as well as in the effluent collected during perfusion of different parts of the liquor space after an intravenous injection and during an intravenous infusion of tubocurarine (Devasankaraiah Haranath & Krishnaurty, 1973). On the other hand, Dal Santo (1972) who studied the urinary excretion and the distribution of labelled (14 C)-gallamine inected intravenously into anaesthetized dogs, found no significant radioactivity in the c.s.f. In the present experiments the passage of gallamine from blood into the liquor space was studied in man and dogs with Neurophysiology & Anaesthesia 31
  • the methods used by Devasankaraiah et al. (1973) in their experiments with tubocurarine. In patients, lumbar c.s.f. was examined for gallamine-like activity after intravenous injection of gallamine, and in anaesthetized dogs cisternal c.s.f. and cisternal effluent collected during persufion of the cerebral ventricles were examined for such activity after intravenous injection or during intravenous infusion of gallamine. METHODS: Clinical procedures Six male patients (33.1 to 50 kg), who were schedule for surgery, were given atropine 0.6 mg as preanaesthetic medi- cation. Anaesthesia was induced by intravenous thiopentobarbitone sodium (150 to 250 mg). Gallamine (2 to 3.8 mg/kg) was then injected intravenously. As it produced immediate respiratory arrest the trachea was intubated, con- nected to a Boyle’s apparatus and controlled respiration was applied. Anaesthesia was maintained with nitrous oxide and oxygen. Supplemental doses of gallamine were administered when necessary. Three samples are obtained by the lumbar puncture, one before and two at different times after the in- jection of gallamine. At the same time blood samples were obtained in syringes containing 0.1 ml of heparin 5%. Animal experiments: Dogs weighing 6-16 kg were used. They were anaesthetized with intravenous pentobarbitone sodium (30 mg/kg). The ex- perimental procedures for recording arterial blood pressure and respiration were the same as those described by Devasankaraiah et al. (1973). The cerebral ventricles were perfused from alateral ventricle to cisterna magna according to the method described for casts by Bhattacharya & Feldberg (1958). The rate of Neurophysiology & Anaesthesia 32
  • perfusion was 0.1 ml/mi, and the perfusion fluid was artificial c.s.f. of the following composition (g/litre): NaCI 8.1; KCI 0.25; CaC12 0.14; MgC12 0.11; NaHCO3 1.76; NaH2 PO4 0.072; urea 0.13; glucose 0.61. Gallamine solutions were either injected in- travenously or infused intravenously at a rate of 0.4 ml/min with a slow infusion pump. BIOASSAY: The samples of c.s.f. effluent or plasma were assayed bio- logically for gallamine-like activity on acetylcholine-induced contractions of frog rectus muscle as described for curare by Burn (1952) and with the modification given by Devasankaraiah et al. (1973). The preparation was usually sensitive to 0.5 µg of gallamine. Control samples of c.s.f. and of plasma potentiated the acetylcholine-induced contractions of the frog rectus muscle. As the potentiating effect of plasma was strong, the values ob- tained for the gallamine for the gallamine concentrations of plasma are probably too low. DRUGS: In clinical administration Flaxedil brand of gallamine solu- tions in vials (40 mg/ml) was used. For the experiments on dogs, gallamine triethiodide (Flasedil) supplied through the courtesy of May & Baker was used. RESULTS: Clinical Studies As shown in Table 1, samples of lumbar c.s.f. withdrawn from six patients during an operation 15 min after an intravenous in- jection of 2 to 3.8 mg/kg gallamine exerted gallamine-like ac- tivity on the frog rectus muscle equivalent to between 0.15 and Neurophysiology & Anaesthesia 33
  • 0.6 µg/ml. The activity of a second sample withdrawn at the end of the operation 70 to 110 min after the injection was about the same whether it had been necessary during this time to give additonal injections of smaller amounts of gallamine or not. The Table aslo shows that the gallamine concentration in plasma collected 15 min after the injection varied widely from patient to patient (between) 0.6 and 40 µg/ml) and decreased in plasma collected 70 to 110 min after the injection. Table 1. Gallamine-like effect (expressed in terms of gallamine µg/ml) in lumbar c.s.f. collected from six male patients after its intraenous injection Patient . Weight Dose of gallamine Gallamine conc. (µg/ml) No. (Kg.) given (mg/kg) 15 min 70-110 min 1. 50.0 3.2 0.31 (0.6) 2. 36.3 3.3 0.6 (40.0) 0.75 (8.0) 3. 33.1 3.8 0.15 (2.5) 0.2 4. 40.0 3.0 0.5 (10.0) 5. 42.7 2.8 + 0.2 (20.0) 0.1 (3.3) 0.9 at 25’ 0.9 at 75’ 6. 40.0 2.0 + 0.3 (15.0) 0.35 (13.5) 2.0 at 15’ The figures in brackets refer to plasma concentration of gallamine (µg/ml) Experiments on dogs: Intravenous injection of gallamine: An intravenous injection of gallamine (1 mg/kg) produced immediate respiratory arrest and artifical ventilation was applied. Respiration began to recover within 10 min but artificial ventilation was continued for 40 to 50 min to ensure adequate oxygenation. The arterial blood pressure did not chane during this time. Neurophysiology & Anaesthesia 34
  • As seen from Table 2 and 3, the gallamine concentration in plasma was maximal 15 min after the injection when it was between 0.7 and 6.7 µg/ml. It then declined. Table 2 gives the gallamine-like acitivity of samples showed gallamine-like acivity corresponding to between 0.2 and 1 µg/ml. The peak concentration was obtained either in the 30 or in the 60 min sample. Table 2. Concentration of gallamine in consecutive samples of cisternal c.s.f. and plasma of anaesthetized dogs after intravenous inection of 1 mg/kg gallamine. Gallamine concentration (µg/ml) Expt. Weight c.s.f. plasma No. (Kg.) 15 min 30 min 60 min 15 min 30 min 60 min 1. 6 0.33 0.4 0.2 1.67 2. 12 04 0.33 1.0 3.0 0.5 nil 3. 13 0.33 056 033 075 0.75 0.3 In Expt. 2 of the Table, a fourth sample of c.s.f. (not includeed in the Table) was collected 120 min after the injection. It no longer exerted gallamine-like acitivity although a plasma sample collected at this time showed gallamine acivity corresponding to 1 µg/ml. Table 3 give the gallamine-like acivity in the cisternal effluent colected during perfusion of the cerebral ventricles. In all three experiments the output of gallamine was maximal in the sample collected during the first 15 min after the gallamine injection when it was between 130 and 175 ng/min and declined to between 27 and 68 ng/min in the second 15 min sample, but in the third 30 min sample a further decline occurred in only one of the three experiments. Neurophysiology & Anaesthesia 35
  • TABLE 3. Output of gallamine in ng/min in cisternal effluent on perfu- sion from lateral ventricle, and its plasma concentration in anaethetized dogs after intravenous injetion of 1 mg/kg gallamine Expt. Weight Gallamine output in effluent (ng/min) Plasma gallamine concn. (µg/ml) No. (Kg.) 0-15 min 16-30 min 31-60 min 15 min 30 min 60 min 4. 10 130 27 27 0.7 0.5 0.4 2. 10 175 63 67 1.4 1.0 0.7 3. 14 130 68 18 6.7 2.0 1.33 Intraenous infusion of gallamine: A continuous intravenous infusion of gallamine for 2 h at a rate of 10 (µg/kg)/ min din not affet arterial blood pressure nor did it depress respiration; there was in fact some slight increase in the respiratory amplitude as illustrated in Figure 1. As seen from the results of Tables 4 and 5, the concentration of gallamine in samples of plasma collected during the 2 h infu- sion varied greatly from dog to dog. Larger dogs had hihger plasma gallamine concentration than smaller dogs, proportional to the total infused per minute. In the same dog, the plasma Neurophysiology & Anaesthesia 36
  • Fig. 1. Recrod of respiration and blood pressure from a dog (6 kg) under pentobarb itone anaesthesia. At the black dot gallamine i.v. infusion at 10 (µg/kg)/min was started. Records taken at the time noted under each panel after commencement of infusion. (Time 1 min.) Table 4. Concentration of gallamine in consecutive half hourly or hourly samples of cisternal c.s.f. and plasma obtained from anaesthetized dogs during continuous instravenous infusion of 10 (µg/kg)/min gallamine. Gallamine concentration (µg/ml) Expt. Weight c.s.f. plasma No. (Kg.) 30 min 60 min 120 min 30 min 60 min 120 min 7 12.0 0.5 0.63 0.4 0.5 0.4 8 12.7 0.5 0.5 0.6 0.8 0.75 0.25 9 16.0 0.5 0.5 0.67 1.8 1.5 1.25 concentration of gallamine showed some fluctuations in the samples collected different times of the infusion being higher initially in three, and lower in two of the dogs than at the end of the infusion. During the infusion gallamine-like activity appeared in the cisternal c.s.f.As shown in Table 4, the activity was nearly the same in all three dogs and in the samples collected 30, 60 or 120 min after the beginning of the gallamine infusion. As seen from the results of Table 5, gallamine-like acitivity appeared also in the cisternal effluent when the cerebral ventricles were perfused during the infusion. The output of gallamine ranged from 20 to 90 ng/min and declined during the 2 h infusion. TABLE 5. Output of gallamine n ng/min in cisternal effluent on perfu- sion from lateral ventricle of anaesthetized dogs during intravenous infusion of gallamine, 10 (µg/kg)/min Neurophysiology & Anaesthesia 37
  • Expt. Weight Gallamine output in Plasma gallamine concn. effluent (ng/min) (µg/ml) No. (Kg.) 0-15min 16-30min 31-60min 61-120min 15min 30min 60min 120min 10. 7.5 90 40 40 30 1.0 0.75 1.0 0.68 11. 6.0 90 60 54 34 0.5 0.5 0.67 1.012 12. 15.0 25 55 20 30 2.0 2.9 3.3 3.3 DISCUSSION: The present experiments show that after the intravenous administration of gallamine the lumbar c.s.f. obtained from anaesthetized patients and the cisternal c.s.f. obatined from anaesthetized dogs or, on perfusion of their cerebral ventricles, the cisternal effluent exerted gallamine-like acitivity when tested o the acetylcholine-induced contraction of the frog rectus muscle. These findings agree with the results obtained by Devasankaraiah et al. (1973) in similar studies with tubocurarine and suggest that gallamine itself, or if not, a derivative of it which has re- tained its biological activity, passed from the blood into the li- quor space. The appearance of gallamine-like activity in the c.s.f. of patients was obtained with doses of gallamine (2-3.8 mg/kg) which are of the order (3.5 mg/kg) used in clinical anaesthetic practice and are therefore of clinical interest. It is not possible from the data available to give the reason why Dal Santo (1972) in his studies in anaesthetized dogs onthe urinary excretion and distribution in the body of (14C)-gallamine could not detect any radioactivity in the cisternal c.s.f. after an intravenous injection of a trace dose of 50 µCi gallamine equivalent to 50x106 counts/min, particularly since in a previ- ous similar study (1964) with (14C)-dimethy1-(+)-tubocurarine injected intravenously in a trace dose equivalent to 25x106 counts/ min he could detect up to 20x10-5 of the injected amount in the cisternal c.s.f. In his experiments with labelled gallamine about 7 samples of c.s.f. were collected in 7 hours. In the present experiments gallamine-like acivity was detected only in those Neurophysiology & Anaesthesia 38
  • samples of c.s.f. collected during the first hour after a single intravenous injection of gallamine, because a sample collected after the second hour no longer exerted such activity. It is possible that in the experiments of Dal Santo collection of the samples of c.s.f. started too late after the injection of the labelled gallamine, at a time when the gallamine that had passed into the c.s.f. had disappeared, or if a derivative, had passed into the c.s.f. that it was one which did not contain radio-active carbon. In the past, the passage of quaternary ammonium compounds across the blood-c.s.f. barrier has been doubtful. The present findings with gallamine and the earlier ones with tubocurarine by Mahfouz (1949) Dal Santo (1964) and Devasankaraiah et al. (1973) however suggest that this barrier is not absolute and that small amounts of these muscle relaxants pass into the c.s.f. Neither hypoxia nor a fall in blood pressure, nor histamine release accounts for this passage, because in the experiments on dogs with intravenous infusion of gallamine the appearance of gallamine-like activity in the c.s.f., or in the effluent on perfu- sion of the cerebral ventricles, occurred without changes in respiration or blood pressure and gallamine, unlike (+)- tubocurarine, does not release histamine. The finding that 15 min after an intravenous injection of gallamine, gallamine-like activity was detected in the lumbar c.s.f. of patients and in the cisternal c.s.f. of dogs, sugest that the gallamine passes equally well into the spinal and cerebral c.s.f. space. On the other hand, the gallamine-like activity found in the cisternal c.s.f. may well have passed, partly at least, from the cerebral ventricles into the subarachnoid space. This con- clusion is based on the finding that on perfusion of the cerebral ventricles the highest values for gallamine-like activity were found in the first 15 min samples after an intravenous injection of gallamine and decreased steeply in the second 15 min sample, whereas in the cisternal c.s.f. the highest values were found not Neurophysiology & Anaesthesia 39
  • in the first sample collected 15 min but in the second one collected 30 min after the injection, or there was a slight decrease only in the second sample. The concentration of gallamine in c.s.f. was always less than in plasma, but a fixed ratio of the two concentrations cannot be given from the results obtained. This is due to the fact that on account of the strong potentiating effect which plasma exerts on the acetylcholine-induced contractions of the frog rectus muscle the values obtained for plasma concentrations were too low and did not give the true concentrations of gallamine in plasma. This work was supported by a grant in aid frm the Indian Council of Medical Research, which is gratefully acknowledged. REFERENCES: BHATTACHARYA, B.K. & FELDBERG, W. (1958). Perfusion of cerebral ventricles: effects of drugs on outflow from cisterna and aqueduct. Br. J. Pharmac. Chemother., 13, 156-162. BURN, J.H. (1952). Practical Pharmacology, pp. 5-7-. Oxford: Blackwell. COHEN, E.N. (1963). Blood-brain barrier to d-tubocurarine. J. Pharmacol., 141, 356-362. DAL SANTO, G. (1964). Kinetics of distribution of radioactive-labelled muscle relaxants. I. Investigation with [14C]-dimethyl tubocurarine. Anaesthesiology, 25, 788-800. DAL SNATO, G. (1972). Kinetics of ditribution of radioactive labelled muscle relaxants. IV. Urinary elimination of single dose of [14C]-gallamine. Br. J. Anaesth., 44, 321-329. DEVASNAKARAIAH, G., HARANATH, P.S.R.K. & KRISHNAMURTY, A. (9173). Passage of intravenously administered tubocurarine into the liquor space in man and dog. Br. J. Pharmac., 47, 787-798. MAHFOUZ, M. (1949). The fate of tubocurarine in the body. Br. J. Pharmac. Chemother., 4, 295-303. (Received August 10, 1972) ***** Neurophysiology & Anaesthesia 40
  • “ROLE OF THIOPENTONE, NITROUS OXIDE AND RELAXANT ANAESTHESIA IN CAUSING THE SYNDROME OF POST-OPERATIVE PARALYSIS IN MAN” L.N. Rao and H. Venkatakrishna-Bhatt** Departments of Anaesthesiology and Pharmacology, Kurnool Medical College, Kurnool 518002 (Andhra Pradesh), India Received: November 6, 1973 -------------------------------------------------------------------------- * This investigation was supported by a research grant from State Medical Research Council of Government of Andhra Pradesh, Hyderabad 500 029. (India). ** At present working as Research Officer, Division of Medical and Industrial Toxicology, National Institute of Occupational Health, Asarva, Opposite to New Mental Hospital, Ahmedabad 380016 (Gujarat) India. --------------------------------------------------------------------------- Summary: Forty-seven patients undergoing elective/ emergency surgery were investigated for the recovery pattern by numerically scoring the state of consciousness, skeletomus- cular tone, respiration and blood pressure after the neuromsucular transmission at the level of thenar muscles returned to normalcy. Anaethesia in them consisted of thiopentone induction and pas- sive ventilation with nitrous oxide and oxygen mixtures (4½:2½l) with consequent changes in PaCO2 (22.0 to 90 mm Hg) after using 0.43 to 0.68 mg/kg d-tubocurarine or 2.3 to 3.8 mg/kg gallamine. In this series twelve patients were selected at random and biological assay of cerebrospinal fluid in them for curare/ gallamine after 15 min anaesthesia and at the recovery phase was carried out on frog rectus muscle. All the patients recov- ered satisfactorily and did not present clinical signs of de- pression of central nervous system, even though twelve pa- tients, in whom concentration of d’tc/gallamine was moni- tored at 15 mts. of its, IV administration and later again moni- tored at the end of anaesthesia revealed that d’tc or gallamine concentration (at the time of their recovery from anaesthesia) Neurophysiology & Anaesthesia D3 - 43
  • was still high in plasma and C.S.F. Inspite of containing signifi- cant quantity (10% to 25%) or more of paralysing dose of d’tc or gallamine, such patients recovered normally, these 12 patients had the presene of curare (ranging from 0.05 to 0.33 µg/ml) and gallamine (from 0.1 to 0.75 µg/ml) in the cerebrospinal fluid. this study therefore indicates that thiopentone, nitrous oxide and relaxant type of anaesthesia does not cause clinical syndrome of post-operative paralysis even when such a technique of anaesthesia is administered in poor-risk patients with associated changes in acid-base balance, electrolytes etc. Significant quan- tities of skeletomsucular relaxant drug (used during the tech- nique) when found in cerebrospinal fluid and in plasma (refer table-I of the research paper “Passage of gallamine from blood to the liquor space in man & in dog” printed in this book), did not induce post-operative paralysis in man. ***** Some patients present a clinical syndrome of post-operative paralysis [1] which is presumed to be due to electrolyte imbalance, metabolic acidosis, antibiotic therapy, hypercapnia and hypo-porteinaemia (due to prolongation of neuromuscular block in poor-risk patients) [2-8]. More recently it has been stated that when a high concentration of the relaxant drug is available at the mynoeural junction at the end of an anaesthetic ptocedure neuromuscular block continues inspite of administration of neo- stigmine [9] and that the action of muscle relaxant could outlast that of neostigmine [10]. However it is observed that neuromsucular transmission need not be depressed on all occa- sions in patients in whom the syndrome of post-operative pa- ralysis characterized by depressed level of consciousness, hyotonia of skeletal muscles and apnoea is present in the post- operative period [11,13]. Moreover patients who are the potential subjects for developing such a syndrome in the Neurophysiology & Anaesthesia 44
  • postosugrical period (such as intestinal obstruction of some du- ration) cannot be experimnetally made to manifest the same by the administration of relaxant drugs preopoeratively [12]. It is also observed that the level of consciousness, skeletomuscular tone and respiratory efficiency could be improved by dehydra- tion therapy [11,14]. These observations, therefore, sugest that depression of the level of consciousness, skeletomuscular tone and respiration in the postanaesthetic phase need not be due to peripheral factors only (cntinued or abnromal action of drugs at the myoneural junction), and that depression of the central ner- vous system could coexist in them. Foster [15] postulated such a possibility in some patients in whom hypokalaemia was present. However, definite proof that a low serum potassium level can casue depression of the central nervous system in such situa- tions is lacking. Since recent studies reveal that commonly used skeletomuscular relaxant drugs penetrate the blood -cerebrospi- nal fluid barrier freely during anaesthesia in man [16,17], prob- ably due to a change of the blood-brain barrier during hyperven- tilation techniques [18], it is interesting to study the role of the anaesthetic technique itself in contributing to postoperative de- pression of the level of consciousness, keletomusucular tone and respiration etc. MATERIALS AND METHODS Forty-seven adult patients of both sexes undergoing various elective or mergency surgical procedures were studied for the pattern of recovery from balanced anaesthetic proceduresAmodi- fication of the postanaesthetic score chart devised by Aldrete [19] was used. This enables a quantitative estimation to be made of the state of skeltomuscular tone, consciousness, respiratory efficiency etc. The pateints were anaestehtized with 250 to 400 mg thiopentone (2.5% - May & Baker, India). Orotracheal intu- bation was facilitated by injection of a single dose of tubocurarine Neurophysiology & Anaesthesia 45
  • 0.43 to 0.68 mg/kg (Burroughs Wellcome India) or gallamine 2.0 to 3.8mg/kg (May & Baker, India). As a premeidation, only atropine sulphate 0.6 mg (E. Merck) was intravenously admin- istered prior to thiopentone. Passive manual ventilation was maintained with a mixture of oxygen 2.51/min and nitrous ox- ide 4.51/min using a closed circuit Boyle apparatus (Indian Oxy- gen Company). By inclusion or exclusion of the Mark III soda- lime absorber, and by regulation of the tidal volume, force and rate of ventilation, PaCO2 levels were adjusted to lie between 22.0 and 90.0 mm Hg. After 45 to 90 min of anaesthesia (asso- ciated withthe anticipated time of surgery), venous blood was drawn from wrist veins (after warming the writst to 40º C with hot packs) into paraffin and the pH immediately estimated. The carbon-dioxide content was estimated with Van Slyke’s manormetric apparatus (Gallenkepm, London) and PaCO2 was calculated by solving the Henderson Hasselbalch equation, as suggested by Woolmer [20]. Twelve patients were selected at random from the series and curare/gallamine-like activity in blood and cerebrospinal fluid was biologically assayed by the method of Burn [21]. The samples of blood and cerebrospinal fluid were collected at, 15 min after intravenous administration of tubocurarine/gallamine, and at the end of anaestehtic proce- dure [16, 17]. At the end of surgery, anaesthesia was stopped and residual action of tubocurarine or gallamine was reversed by using neostigmine 2.5 to 5.0 mg with atropine 1.2 mg. The exant dose of neostigmine was calculated with the help of pe- ripheral nerve stimulator (Meditronics Corporation -Ahmedaad, India) [22], which allows stimulation at rates of 30 to over 300/ sec. As soon as nitrous oxide was cut off, neostigmine 2.5 mg with atropine 1.2 mg was injected intravenously and ulanar nerve was stimulated at the elbow at twitch and tatanic rates. The state of neuromuscular transmission was judged by the activity of thenar and hypothenar muscles (little and ring fingers) and if necesary neostigmine 2.5 mg was again administered. At the Neurophysiology & Anaesthesia 46
  • end of 15 min after the termination of anaetehsia, skeletomus- cular tone was assessed by the patient’s ability to show wrinkes in the forehead inaddition to his ability to move the limbs. Out of 10 points (two each for satisfactory recovery of conscious- ness, skeletomuscular tone, respiration, blood pressure and skin colour), scoring of 7 points was considered to be an indication of normal recovery of the patient under observation because changes in blood pressue and skin colour were not related to the direct or indirect efects of tubocurarine or gallamine. If a sub- ject could breath deeply (by expanding the chest during such efforts) when asked, it was considered that he has recovered normal respiratory activity. The level of consciousness was judged by his ability to open the eye-lids, show his tongue etc. when asked to do so. RESULTS: In all 47 patients, (Table 1) the score was more than 7 out of 10 points by 15th minute after termination of anaesthesia. How- ever it was 9 out of 10 in many patients, irrespective of the grossly poor-risk nature of such cases, indicating that recovery from neu- romuscular relaxant drugs, thiopentone and nitrous oxide ana- esthesia was complete at the time of scoring. Hypocapinic, isocapnic and hypercapnic type of passive ventilation did not affect the recovery pattern at the end of anaesthetic procedure. In the 12 patients in whom biologial assay for tubocurarine or gallamine-like activity was carried out in blood and cerebrospi- nal fluid, it was noted that both drugs penetrated the blood-cere- brospinal fluid barrier and were found in cerebospinal fluid in concentrations as high as 0.05 to 0.33 µg/ml of tubocurarine and 0.1 to 0.75µg/ml of gallamine at the end of anaesthetic procedure [16,17]. However their presence in plasma and cere- brospinal fluid during and after the anaesthetic procedure, did not influence the pattern of recovery because in all patients the Neurophysiology & Anaesthesia 47
  • score was seven or more points. Presence of 10 to 25% or more of paralysing dose of relaxant drugs (dtc or gallamine), in blood & csf (at the time of recovery (16,17) did not affect the recovery pattern in them (refer table-I of the reference article listed as 17) (which is printed in this book). Even though clinically and according to the method of scor- ing all the patients recovered normally, they were found asleep unless they were disturbed by questioning or by other means of stimuli. They did not take any interest in the surroundings but responded intelligently to simple commands and never indicated a retardation of recent memory. DISCUSSION: The cerebral autoregulation is complete in awake man [23] and has been shown to be intact during thiopentone, tubocurarine and nitrous oxide anaethesia [24] withthe result that changes in blood pressure and oxygen tension within physiological limits do not influence the cerebral vascular flow [24,25]. Even when the cerebrovascular flow is reduced during the technique of hypocapnic ventilation [26], “the perfusion pressure” at all points in the cerebral cortex is increased inspite of less total perfused volume [27,28], thus making perfusion pattern of the entire cortex uniform by cutting of regional imbalances [29]. These facts (about the need based changes in the pattern of perfusion of central nervous system under different conditions of ventila- tion and blood pressure changes) could possibly explain the observation that passive ventilation with low levels of PaCO2 keeps up satisfactory oxidative metabolism of brain in rats and dogs [30,31] and man [32]. Since passive ventilation with PaCO2 between 22.0 and 90 mm Hg did not appear to affect the pattern of recovery in the 47 patients in this study, the innocuous natue of such a technique [33] is confirmed clinically. Neurophysiology & Anaesthesia 48
  • Talbe 1: Score rate in 47 Patients during recovery phase S. Risk Operation PaCO2 Score rate at (+) presence of No. (class) (mm Hg) time of recoverya muscle relaxant 1 3 Gastroenterostomy 30 8/10 +Gallamine in CSF (Carcinoma stomach duodenal stenosis) 2 1 Laparotomy and release, of adhesions 28 9/10 --- 3 3 Laparotomy-drainage of pus and closure 32 9/10 --- 4 1 Laparotomy 23.9 8/10 --- 5 2 Repair of ventral hernia 25.6 6/10 --- 6 5 Choledochojujunnstomy for carcinoma 35 7/10 --- of gall bladder 7 6 Ileo-ileal anastomosis for intestinal 26 7/10 +Tubocurarine in CSF obstruction due to adhesions 8 5 L.S.C.S. 30 8/10 +Tubocurarine in CSF 9 5 L.S.C.S. 32 7/10 --- 10 5 Appendectomy 34 8/10 --- 11 1 Appendectomy 40 9/10 +Tubocurarine in CSF 12 1 Appendectomy 32 9/10 +Tubocurarine in CSF 13 2 Gastronenterostomy 33 8/10 +Gallamine in CSF 14 2 Gastronenterostomy 34 8/10 +Gallamine in CSF 15 1 Marsapalisation of hydatid cyst 32 8/10 --- 16 1 Radical masterctomy 26.2 8/10 --- 17 1 Gastronenterostomy --- 8/10 +Tubocurarine in CSF 18 1 Gastronenterostomy and appendectomy 23.9 7/10 --- 19 1 Urethrolithotomy 24.6 8/10 --- 20 1 Pyelolithotomy 29.6 8/10 --- 21 1 Vagotomy and gastro-jejunostomy 34 9/10 +Tubocurarine in CSF 22 1 Vagotomy and gastro-jejunostomy 23.9 9/10 --- 23 1 Vagotomy and gastro-jejunostomy 22 7/10 --- 24 1 Urethrolithotomy 43.5 9/10 --- 25 2 Vagotomy and gastro-jejunostomy 29 9/10 --- 26 3 Ventral hernia (repair) 24.7 9/10 --- 27 2 Gastroenterostomy 90.5 8/10 --- 28 2 Gastroenterostomy 25 9/10 --- 29 3 Enteroenterostomy for T.B. strictures 32.5 9/10 --- 30 2 Laparotomy & resection of gastric ulcer 23.9 8/10 --- and gastro-jejunostomy 31 2 Gastro-jejunostomy and appendectomy 26.4 9/10 --- 32 1 Nephrolithotomy 22 9/10 +Gallamine in CSF 33 2 Laparotomy 23.1 9/10 --- 34 2 Vagotomy and gastro-jejunostomy 41 9/10 --- 35 3 Gastro-jejunostomy and ileotransverse 23 9/10 --- colostomy 36 2 Gastro-jejunostomy and vagotomy 23 9/10 --- 37 2 Freyer postectomy 45 9/10 --- 38 2 Carcinoma Rt. Kidney exploration 26.4 9/10 --- 39 1 Gastro-jejunostomy and appendectomy 58.4 9/10 --- 40 5 Laparotomy 52 9/10 --- 41 1 Freyer prostectomy 52.8 9/10 --- 42 5 Laparotomy 60 9/10 --- 43 1 Gastro-jejunostomy and vagotomy 38 9/10 --- 44 1 Gastro-jejunostomy 64 9/10 --- 45 3 Laparotomy and enteroenterostomy 24 8/10 +Gallamine in CSF 46 6 Intestinal obstruction releasing of 54 9/10 --- 47 7 Intestinal obstructin releasing of 22 9/10 --- contracting band Preoperative risk was classified according to the regulations accepted by American Society of Anesthesiologists. Score estimated 15 min after the end of anaesthesia. & in plasma & in plasma & in plasma & in plasma Neurophysiology & Anaesthesia 49
  • It is thus far argued that alterations in the electroencephalographic pattern indicate cerebral hypoxia due to changes in cerebral vas- cular flow during such techniques. However, evidence is now presented suggesting that changes in electroencephalographic pattern are not reliable indicators of cerebral anaerobiosis[32]. Even though the question of passage of tubocurarine and gallamine across the blood-cerebrospinal fluid barrier and its action at the central nervous system is controversial [34-42], attempts were made in this study to record the recovery pattern in patients who exhitibed significant concentration of such drugs in plasma and cerebrospinal fluid at the time of termination of anaesthesia [16,17] so that the role of central nervous action of tubocurarine and gallamine in causing depression of vital func- tions in postopeartive period (such as areflexia, depression of consciousness, hypotonia of skeletal muscles etc.) could be assessed. However, it was found clinically and by the method of scoring, hardly signs of nervous depression were present in patients who exhibited significant quantities of tubocurarine gallamine-like activity in the plasma and csf (cerebrospinal fluid) at the end of operation. The type of score chart used in this study, though not mathematical and exacting, was helpful to determine quantitatively the recovery pattern of various vital functions in the postoperative period similar to Apgar score chart used for neonates. A significant number of patients in this study were undergoing emergency or life saving surgery and derangements in electrolytes, body water and acid-base balance were to be ex- pected. However, in none of these was the score less than 7 out of 10 and in a few of them the score was a shigh as 9 suggesting that recovery from the effects of non-depolarisation block could satisfactorily takes places in patients suffering from serious illness. These observations, therefore suggest that technique of anaesthesia which is generally used for major Neurophysiology & Anaesthesia 50
  • surgical procedures (thiopentone induction, nitrous oxide ana- esthesia, skeletomuscular paralysis with tubocurarine or its equivalents and passive ventilation with mild to moderate degreee of change in PaCO2), does not per se cause the syndrome of postoperative depression of vital functions in man. Only side effects of such a technique could be the irresistible desire to sleep (when undisturbed) in the immediate post-anes- thetic period in patients who were exposed to such techniques, and this could be due to the action of tubocurarine or gallamine on the central nervous system [43]. REFERENCES: 1. Brechner, V.L.: Clinical syndrome of incomplete neuromuscular block reversal: Doctor look at your patient. Anesth. Analg. 50, 876 (1971). 2. Scurr, C.F.: Carbon-dioxide retension simulating curarizaiton. Br. Med. J. 1954/I, 565 3. Hunter, A.R.: Neostigmine resistant curarization. Br. Med. J. 1956/II, 919. 4. Foldes, F.F.: Neuromscular blocking agents in man. Clin. Pharmacol. 1, 345 (1960) 5. Brookes, D.K., Feldman, SA.: Metabolic acidosis (a new approach to neostigmine resistant curarization). Anesthesia 17, 161 (1962). 6. Bush, G.H., Baraka, A.: Factors afecting the termination of curarization in human subjects. Brit. J. Anaesth. 36, 356 (1964). 7. Corrado, A.P.: Respiratory depression due to antibiotics: Calcium in treatment. Anesth. Anagl. 42, l (1963). 8. Baraka, A.: The influence of carbon dioxide on the neuromuscular block caused by tubocurarine chloride in the human subjects. Brit. J. Anaesth. 36, 272 (1964). 9. Baraka, A.: Irreversible tubocurarine neuromscular block in the human. Brit. J. Anaesth. 39, 891 (1967). 10.Hannington-Kiff, P.g.: Residual poost-operative paralysis. Proc. J. Soc. Med. 63, 73 (1970). Neurophysiology & Anaesthesia 51
  • 11.Rao, L.N., Venkatakrishna-Bhatt, H.: Stress response during surgery and anesthesia in man: Its possible connection with the syndrome of depressed vital functions in the post-surgical period. Indian J. Anaesth. 19, 365 (1971). 12.Wylie, W.D., Churchill-Davidson, H.C.: In: A Practice of Anaesthesia. 2nd Edition. P. 757. London: Llyod-Luke 1966. 13.Churchill-Davidson, H.C.: In: Recent Advanes in Anesthesia and Analgesia. 9th Edition. Edited by C.L. Hewer. P. 98. London. Churchill 1963. 14.Sikh, S.S., Agarwal, G., Branhbutt, P. Rai, P.: Recurarization and prolonged unconsciousness. Indian J. Anaesth. 20, 91 (1970). 15.Foster, P.A.: Potassium depletion and central action of curare. Br. J.Anaesth. 28, 488 (1956). 16.Devasankaraiah, G., Haranath, P.S.R.K., Krishnamurthy, A.: Passage of intravenously administered tubocurarine into the liquor space in man and dog. Brit. J. Pharmacol. 47, 787 (1973). 17.Haranath, P.S.R.K., Krishnamurthy, A., Rao, L.N., Seshagiri Rao, K.: Passage of intravenously administered gallamine into the liquor spae in man and dog. Brit. J. Pharmacol. 48, 640 (1973). 18.Rangachary, S.S., Roth, A.D., Andrew, W.N., Mark, H.V.: Alterations of blood brain barrier with hyperventilation. J. Neurosurg. 26, 614 (1965). 19.Aldrete, J.A.: Personal communication (1971). 20.Woolmer, R.: The measurement of pH and PCO2. In: Modern Trends in Anaesthesia. Edited by F.T. Evans and T.C. Gray. 2, 31 - 55. London: Butterworths 1962. 21.Burn, J.H. : Practical Pharmacology. P. 5 - 7. Oxoford: Blackwell 1952. 22.Bhatia, M.T., Shah, G.H.: Clinical trial with indigenous nerve stimulator. Indian J. Anaesth. 18, 244 (1970). 23.Lassen, N.A.: Cerebral blood flow and oxygen consumption in man. Physiol. Rev. 39, 183 (1959). 24.Smith, A.L., Neigh, J.L., Hoffman, J.C., Wollman, H.: Effects of general anesthesia on autoregulation of cerebral blood flow in man. J. appl. Physiol. 29, 665 (1970). 25.Kogure, K., Scheinberg, P., Fujishima, M., busto, R., Reinmuth, O.M.: Effects of hypoxia on cerebral oxygen autoregulation. Amer. J. Physiol. 219, 1393 (1970). Neurophysiology & Anaesthesia 52
  • 26.Kety, S.S., Schmidt, C.F.: The effects of active and passive hyperventilation on cerebral blood flow, cerebral oxygen consumption, cardiac output and blood pressure of normal young man. J. clin. Invest. 25, 107 (1946). 27.Ehrenfeld, W.K. Hamilton, F.N., Larson, C.P. Jr., Hickey, R.F., Severinghaus, J.w.: effects of carbon-dioxide and systemic hypertension on down stream cerebral arterial pressue during carotid endo-arterectomy. Surgery 67, 87 (1970). 28.Fouracade, H.F., Larson, C.P. Jr., Ehrenfold, W.K., Hikcey, R.F. Nowton, T.H. : The effects of carbon-dioxide and systemic hypertension on central perfusion pressure during carotid endarterectomy. Anesthesiology 33, 383 (1970). 29.Wilkinson, I.M.S., Brown, D.R.: The influence of anaesthesia and of arterial hypocapnia on regional blood flow in normal human cerebral hemisphere. Brit. J. Anaesth. 42, 472 (1970). 30.Cain, S.M.: An attempt to demonstrate cerebral anoxia during hypervenitlation of anesthetized dogs. Amer. J. Physiol. 204, 323 (1967). 31.Miller,A.T. (Jr.), Curtin, K.E., Shen, A.L., Suiter, C.K. : Brain oxygenation in the rat during hyperventilation with air and with low oxygen mixtues. Amer. J. Physiol. 219, 798 (1970). 32.Allexander, S.C., Cohen, P.J., Woolman, H., Smith, T.C., Revich, M., Vander Mollen, R.A.: Cerebral carbohydrate metabolism during hyocapnia in man.: Studies during nitrous oxide anesthesia. Anesthesiology 26, 624 (1965). 33.Editorial. Brit. J. Anaesth. 41, 563 (1969). 34.Mahfouz, M.: The fate of tubocurarine in the body. Brit. J. Pharmacol. 4, 295 (1949). 35.Dalsanto, G.: Kinetics of distribution of radioactive labelled muscle relaxants. I. Investigation with C14 dimethyl d-tubocurarine. Anesthesiology 25, 788 (1966). 36.Dripps, R.D.: Abnormal respiratory responses to various “curare” drugs during surgical anaesthesia: Incidence, etiology and treatment. Ann. Surg. 137, 145 (1958). 37.Cohen, e.N.: Blood brain barrier to d-tubocurarine. J. Pharmacol. 141, 356 (1963). 38. Carmichael, e.a., Feldberg, W., Fleischauer, K.: The effects of tubocurarine perfused through different parts of the cerebral ventricles. J. Physiol. (Lond.) 175, 303 (1964). Neurophysiology & Anaesthesia 53
  • 39.Whitacer, R.J., Fisher, A.J.: Clinical observations on use of curare in anesthesia. Anesthesiology. 6. 124 (1945). 40.Dripps R.D., Severinghaus. J.W.: General anesthesia and respiations. Physiol. Rev. 35, 741 (1955). 41.Smith. S.M., Brown, H.O, Toman, J.E.P., Goodman, L.S.: The lack of central effects of d-tubocurarine. Anesthesiology 8, 1 (1947). 42.Churchill-Davidson, H.C.: Richardson, A.t.: Myasthenia crisis, therapeutic use of d-tubocurarine. Lancer 1953/I, 1221. 43.Haranath, P.S.R.K. Shyamala Kumari, S.: Sleep induced by small doses of tubocurarine injected into cerebral ventricles in dogs. Brit. J. Pharmacol. 49. 23 (1973). Dr. L. Narahari Rao, M.D., D.A., Professor and Head Department of Anaesthesiology Kurnool Medical College, Kurnool 518002 (Andra Pradesh) India ***** Neurophysiology & Anaesthesia 54
  • “CENTRAL NERVOUS EFFECTS OF HYPERVENTILATION A PRELIMINARY REPORT” L.N. Rao, T.N. Prahlad AND H. Venkatakrishna Bhatt 1). Abstract in Biological abstract Vol. 51. No. 20 Oct. 15, 1970. No. 113229. 2) Abstracted in Excerpta Medica (Physiology) Vol. 23, Nol. 23, Dec. 1970. Abstract No. 7262 Reprinted frm “Indian Journal of Medical Sciences” Vol. 23, No. 12, December 1969, pp 665-670 56
  • “CENTRAL NERVOUS EFFECTS OF HYPERVENTILATION A PRELIMINARY REPORT” L.N. Rao, T.N. Prahlad and H. Venkatakrishna Bhatt Despite the fact that Bonwill5 and Beridge4 utilized the technique of active hyperventilation for painless surgical procedures, it’s use for similar purposes (to induce analgesia during various surgical procedures) is now associated with the possibilities of hypoxemic changes in persons exposed to such techniques and thus a controversy exists about the safety of its application. However, a critical review of the entire problem reveals that such a controversy stems from the fact that the ex- act mode of causation of analgesia during such techniques is not known even today. Benjami Lee3 attributed the occurance of analgesia during hyperventilation to be a form of hypnotism whereas present day anesthetists ascribe it to the cerebral ef- fects of hyperventilation, which, in turn are believed to be due to a reduced cerebral blood flow. Many authors associate a direct or indirect role for hypocapnia to be the cause for analgesia and other aspects of the yperventilation syndrome (Bonvellet & Dell6 , Cluttonbrock7 , Gray & Geddes8 , Sugioka & Davis22 , Robinson & Gray17 , and Allen & Morris2 ). This study therefore aims to create conditons in which chances of hypocapnia and cerebral hypoxemic conditions are minimized so as to evaluate various factors causing generalized analgesia during voluntary hyperventilation. _____________________________________________________ 1. Professor of Anesthsiology. 2. Department of Anesthsiology. 3. Department of Pharmacology. Kurnool Medical College, Kurnool, Anadhra Pradesh, India. Received for publication, November 9, 1968. Neurophysiology & Anaesthesia D4 - 57
  • MATERIALS & METHODS 25 volunteers (8 doctors and the rest, surgical patients) were selected to undergo active hyperventilation (rates of breathing 25 to 30/minute) for varying periods (10 to 30 minutes) while they breathed (through a Magill’s circuit) a mixture of 2 per cent carbon dioxide and 98 per cent oxygen which was de- livered at a flow rate of 20 litres/minute (the capafcity of the reservoir bag being 6 liters). The average values of minute vol- umes in these cases ranged between 25 to 30 litres/minute. The fully opened expiratory valve allowed minimal instrumental re- sistance to breathing and patients did not feel exhausted even after 30 minutes. Pain threshold resonse was elicited in them prior to, during and after a phase of hyperventilation which lasted for 10 to 30 minutes by the following method:- A disc 4 cm x 2.5 cm with blunt projections (6 mm long) underneath the central portion of the disc, was placed over the shin of tibia. The proijections were so blunt (due to fine polish) that they did not elicit any other sensation than touch on the skin. Prior to the application of the disc, 5 per cent lignocaine ointment was applied locally to minimize touch sensation also so that the patients felt only deep pressure sense over the shin of the tibia. A sphygmomanometer cuff was then applied over the disc and the mercury pressure raised in such a way that the per- son concerned cried or showed other evidence of intolerable bone pain. This was termed the pain threshold response. Later, the same process of eliciting the pain threshold resonse was re- peated 2 to 3 times during hyperventilation and in 13 cases the post-hyperventilatory pain threshold response (1 to 8 minutes after cessation of hyperventilation) was elicited to exclude the influence of distracting elements on the pain threshold response during hyperventilation. Neurophysiology & Anaesthesia 58
  • RESULTS Out of 25 volunteers, 4 were termed unpredictable because of wide fluctuations between any two consecutive recordings of the pain threshold response in the pre-hyperventilatory, during hyperventilation, or in the post-hyperventilatory phase. 21 of these patients were found to be associated with constant values during these phases: all of them did show significant evi- dence of a raise in pain threshold resonse during hypervenitlation (Figs. 1 & 2). Four out of these 21 cases did present further evidence of the hyperventilation syndrome (apnea or respira- tory irregularrity pattern after a phase of hyperventilation). In 13 cases, the pain threshold resonse was recorded in the post- hyperventilatory phase (1 to 8 minutes after cessatin of such attempts) only to exclude distracting influences affecting the pain threshold response levels during active hyperventilation. Except in one case, the rest did show evidence of a sustained rise in the pain threshold response (Fig. 2). One patient, who complained of abdominal pain before Neurophysiology & Anaesthesia 59
  • Fig. 1:- Record of pain threshold response with 2% Co2 in O2, prior to and during voluntary hyperventilation. Case X exhibited apnoea of 10 to 20 seconds in ost-hyperventilatory phase. Case Y exibited waxing and waning type of respirations immediately after hyperventilation. Fig. 2:- Record of pain threshold resonse prior to, during and after hypervenitlation. Interrupted lines indicate the record of pain thresh- old obtained after hyperventilation. Case A was drowsy for a short time after hyperventilation. The abdominal pain of which he complained earlier was stated to have abated after hyperventilation. Case B was apneic after hyperventilation and started breathing only when asked. However waxing and waning type of respiration continued for sometime afterwards. hyperventilation, volunteered that it had abated. To rule out the possibility of ischemic pain influencing these patients, the mercury pressure was raised upto 300 mm/Hg in a few of these patients but they did not wince or show any other evidence of pain perception. Neurophysiology & Anaesthesia 60
  • DISCUSSION Bonvallet & Dell6 and Gray & Geddes8 observed that hypocapnia induces general analgesia during hyperventilation (due to generalised reduction of the activity of the reticular sys- tem). Robinson18 , however, felt that hypocapnia, instead of de- pressing the reticular system directly (as was origfinally believed by B onvallet & Dell6 ) might interfere with the glycolytic en- zyme activity so as to influence the cellular utilization of glu- cose and consequent depression of the activity of central cells. Others ascribed an indirect role for hypocapnia in causing vari- ous aspects of the hyperventilation syndrome. Clutton-brock7 suggested that cerebral vascular flow, which was found to be reduced by 32 per cent due to hyperventilation by Kety & Schmidt10 possibly due to hypocapnia, results in cerebral hy- poxemia and therefore generalised analgesia develops during hyperventilation. Sugioka & Davis22 and Allen & Morris2 pro- duced some evidence of cerebral hypoxemia during passive hy- perventilation. Studdard20 , however, noted that, in spite of an effective control of alveolar CO2 tension during hyperventila- tion, EEG slowing did occur, revealing that such a change in the EEG is unrelated to PaCO2 levels but is a direct sequel of such a techniquje and most probably due to hypoxemia (due to cere- bral vasoconstriction). The obvious deduction from these views is that cerebral vaso-constriction, which may or may not be realted to PaCO2 level during hyperventilation, should disap- pear if vasodilation is induced by various methods (for instance with the use of amyl nitrite). Though Clutton-b rock7 stated that administration of amyl nitrite during hyperventilation reduced the pain threshold, Robinson & Gray17 could not confirm these results. Our experience inthis study brings out an as yet unex- plored aspect of the hyperventilation syndrome in that even when 2 per cent CO2 was added into the breathing mixtures, the pain Neurophysiology & Anaesthesia 61
  • threshold response was persistently raised during and after hyperventilation. In this study we cannot rule out the possibility of cerebral vascular constriction in spite of the presence of 2 per cent CO2 in the breathing mixtures because these vessles might still constrict under the influence of central nervous factors as was originally postulated by Rao et al16 . The point, however, is whether such a change in cerebral vascular tone could cause temporary or permanent hypoxemic change in the central nervous sytem inducing (as is now widely believed) some of the beneficial aspects of the hyperventilation syndrome (for instance analgesia). The clinical observation that such patients (who are exposed to these techniques of hyperventilation for any length of time) recover immediately and are oriented better than others exosed to other techniques of anesthesia for similar surgery, strongly suggests that it might not be so. Similarly, in spite of 98 per cent O2 in the breathing mixtures (paCO2 in cerebral vessels might be around 700 mm/Hg), the pain thresho9ld resonse was persistently raised which contnued into the immediate post-hyperventilatory phase, thereby indicating that cerebral hypoxemia might not be the cause of analgesia during hyperventilation. At this stage, it is worthwhile to point out that slowing of the EEG is not a specific phenomenon suggestive of low paCO2 , high pH or cerebral hypoxemia during hyperventilation. Hughes et al9 could not record any delta wave activity in the EEG during upper abdominal surgery in spite of paCO2 levels as low as 12 to 14 mm/Hg. Similarly Kinnel11 could not find any evidence of slower EEG waves during upper abdominal surgery in sptie of the occurence of hypocapnia, unless extradural block was si- multaneously given. It is now shown that EEG slowing could be produced by somatic afferentation at slow rates and such afferentation is found to be frequency dependent (Riotback19 Neurophysiology & Anaesthesia 62
  • and Pampeiano12 ). Vagoaortic nerves are, however, found to be independent of frequency and afferentation in them even at fast rates is found to cause slowing of EEG activity (Padel & Dell13 ). Even mechnical irritation of the larynx is found to cause this change in the EEG tracing (Vanreeth & Capon23 ). On the basis of the fact that vagal afferentation significantly increased dur- ing hyperventilation, (Adrian1 ) it is highly likely that slow EEG waves observed during hyperventilation might be vagally ori- ented and might not indicate hypoxemic conditions during the same period. Similarly, on the basis of recent evidence that va- gal afferentation could produce significant changes in cardio- vascular, respiratory and skeletomuscular systems (Rao & Bhatt14 ) it could be pointed out that the entire hyperventilation syndrome (namely analgesia, hypotonia of the skeletal muscles, anea, EEG changes and various changes in cardiovascular tone) is a neurophysiological phenomenon in which vagal and other afferentations have a dominant role to induce its various param- eters through the central nervous system (Rao et al16 , and Rao15 ). In 25 valunteers, the pain threshold resonse was eicited prior to, during and after a phase of active hyperventilation (10 to 30 minutes) during which the person cncerned was breathing 2 per cent CO2 : 98 percent O2 through a Magill’s circuit (total flow rate 20 litres/minute). 21 cases whose records were considered as predictable have shown evidence of a rise in the pain threshold response during active hyperventilation. In 13 cases, the pain threshold response was recorded after 1 to 8 minutes of cessation of hyperentilation and it was found that except in one case they did show evidence of sustenance of the raised pain threshold response. These results indicate that hypocapnia might not be the cause of analgesia during hyperventilation. Neurophysiology & Anaesthesia 63
  • ACKNOWLEDGEMENT This investigation was carried out with the aid of a State Medical Research Grant from the Government of Andhra Pradesh, India. We are grateful to Profressor T.C. Gray of the Liverpool University, for his helpful suggestions. We are equally obliged to the Superintendent, Government Genral Hospital, for permitting us to experiment on human volunteers from various wards. REFERENCES 1. Adrain, E.D.: Afferent Impulses in Vagus and Their Effects on Respiration. J. Physiol. (Lond.) 79:332, 1933. 2. Allen, G.D. and Morris L.E.: Central Nervous Effects of Hyperventilation During Anesthesia. Brit. . Anesth. 34: 296, 1962. 3. Benjamin, Lee.: Quoted by 21. 4. Berridge, W.A.: Quoted by 21. 5. Bonwill: Quoted by 21 6. Bonvallet, M and Dell, P.: Proceedings the Societe d’Electro encephalographicc et des Sciences Connexes de Longue Francaise. Electroencepha. Clin. Neurophysil. 8: 170, 1956. 7. Clutton-brock, J.: The Cerebral Effects of Over-ventilation. Brit. J. Anesth. 29: 111, 1957. 8. Gray, T.C. and Geddes, I.C.: Hyperventilation for Maintenance of Anesthesia. Lancet. 1: 4, 1959. 9. Hughes, J.R., King, D.B., Cutter, .N. and Markello, R.: EEG in Hyperventilation and Lightly Anesthetized Patients. Electroenceph. Clin. Neurophysiol. 14: 274, 1962. 10.Kety, S.S. and Schmidt, C.F.: The Effect of Active and Passive Hyperventilation on Cerebral Blood Flow, Cerebral Oxygen Consumption, Cardiac Output and Blood Pressure of NormalYoung Men. J. Clin. Invest. 25: 107, 1946. 11.Kennel, J.D.: The Influence of Afferent Block in Hyperventilation Anesthesia. Anesthesia 17: 58, 1962. 12.Pompeiano, O. and Swett, J.E.: EEG and Behavioural Manifestations Arch. Ital. Biol. 100: 311, 1962. Neurophysiology & Anaesthesia 64
  • 13.Padel, Y. and Dell, P.: Effects Bulbaires et Reticulaires des Stimulations Endormantes Dutronc Vago-aortique. J. Physiol. (Paris) 57: 269, 1965. 14.Rao, L.N. and Venkatakrishna Bhatt, H.: Skeletomuscular, Respiratory and Cardiovascular Responses to Bilateral Vagal Stimulation - Its Significance in Clinical Practive. Anesth. Analg. (In Press). 15. Rao L.N.: Apnoea During and After Hyperventilation Ind. J. Anesth. 15: 23, 1967. 16.Rao, L.N., Ramarao, K.R. and Bhalla: S.K.: Increased Afferentation in Vagal Splanchnic etc. Leading to Hyperventilation Syndrome During Surgery under General Anesthesia. Ind. J. Anesth. 14: 226 1966. 17.Robinson, J.S. and Gray T.C.: Observations on the Cerebral Effects of Passive Hyperventilation. Brit. J. Anesth. 33: 62, 1961. 18.Robinson, J.S.: Hyperventilation - Modern Trends in Anesthesia Edn. F.T. Evans and T.C. Gray, Vol II, Butterwoth, P. 82, 1962. 19.Riotback, A.L.: Electrical Phenomena in the Cerebral Cortex During the Extinction of Orientation and Conditioned Reflexes, in Jasper, H.H. and Smirnov, G.D. The Moscow Colloquium of Electroencephalography of Higher Nervous Activity. Electroenceph. Clin. Neurophysiol. Suppl. 13: 91, 1960 20.Studdard, J.C.: Electroencephalographic Activity During Voluntarily Controlled Alveolar Hyperventilation. Brit. J. Anesth. 39: 2, 1967, 21.Sykes, S.: Essays on 100 years of Anesthesia. Vol. II. Livingstone Ltd., P. 67, 1961. 22.Vanreeth, P.C. and Capon. A.: Sleep Induced by Stimulation of the LaryngealRegion. Electroenceph. Clin. Neurophysiol. 17: 725, 1963. ***** Neurophysiology & Anaesthesia 65
  • RESEARCH PAPER “VAGAL ACTIVITY IN CANINES: A Possible Connection to Hyperventilation Syndrome” BY: PROF. L.N. RAO M.D. DA AND H. VENKATAKRISHNA BHATT, M.SC. KURNOOL (P.O.) A.P. INDIA. ANAESTHESIA, ANALGESIA Current research, 1970, 49, 351-354 Reprint from: ANAESTHESIAAND ANALGESIA Vol. 49, 351 - 354, 1970 D5 66
  • “VAGAL ACTIVITY IN CANINES” A Possible Connection to Hyperventilation Syndrome L.N. RAO, M.D., D.A. H. VENKATAKRISHNA-BHATT, M.Sc., Kurnool (P.O.) Andhra Pradesh, India* *Department of Anesthesiology and Pharmacology, Kurnool Medical College, Kurnool (P.O.) Andhra Pradesh, India. This investigation was supported by a grant from State Medical Research, government of Andhra Pradesh, India. Reprinted from Anesthesia and Analgesia - Current Researchs, MAY-JUNE, 1970 During artifical ventilation, afferent impulses in the vagus nerves are directly proportional to the amount of pulmonary stretch1 . Some investigators believe the increased volume of the afferent impulses contribute substantially to changes in the skeletomuscular, respiratory, and cardiovascular systems which occur during artificial ventilation. Aserinsky and Debias2 obsrved that pulmonary stretch- receptor activity during hyperventilation eliminates the oculocardiac reflex. Daly and Hazzledine3 noted that hyperven- tilation reduces or eliminates the ability to produce bradycardia when the carotid body is stimulated. Dermkesian and Lamb4 stated that pulmonary stretch-receptor activity induced by breathholding and artifical ventilation effects a vagal response characterized by bradycardia and even cardiac arrest. They noted that 1.2 mg. of atropine was effective in preventing such re- sponses. Downes5 and Katz and Wolf6 indicated that hypotonia during hyperventilation is a reflex phenomenon which is prob ably mediated through vagal impulses. Rudomin7,8 observed that laryngeal reflexes are depressed during artifical ventilation or during electrical stimulation of the vagi. Siker9 attributed post Neurophysiology & Anaesthesia D5 - 67
  • anesthetic respirartory depression and apnoea to vagal influence on the respiratory center. Robson10 stated that at least in the ini- tial phase of artifical ventilation the synchronization observed between inspiratory neuronal discharge and the respirator is caused by stretch phenomena. In spite of the evidence put forth by these investigators that stretch-receptor activity may be one of the most important fac- tors in the hyperventilation syndrome, many clinical scientists reject this theory. The present study was undertaken as an at- tempt to elucidate the possible role of the vagus nerves during artificial ventilation. The object of the study was to induce low- intensity stimulation of the cervical vagi in anaesthetized dogs, with the hope of evoking the skeletomuscular, respiratory, and cardiovascular changes typical of the hyperventilation syndrome. METHODS Bilateral stimulation of the vagus nerves was performed 48 times in 8 anaesthetized dogs of the both sexes weighing 7.5 to 10.5 kg. Chloralose (110 mg./kg.) was administered intrave- nously, and anesthesia was maintained with doses of 25 mg./kg. every 30 minutes. A tracheotomy was performed, and respira- tions were recorded on a kymograph using Mary’s tambour. Blood pressue in the left femoral artery was recorded on the same kymograph. A hole in the right femur was drilled just proxmial to the condyles, and the femur was stabilized with a supporting rod attached to the ergographic stand.The tibia, proximal to the ankle, was anchored to the isometric lever mounted on the ergographic stand. Patellar-tendon reflex was elicited using an electrically- driven hammer, powered by 4 to 6 volts of direct current and Neurophysiology & Anaesthesia 68
  • tapping at the rate of six times per minute. Bilateral stimulation of the vagus nerves was accomplished by placing both cervical vagi in the groove provided for the nerve stimulation. Four to 6 volts of direct current were fed into an induction coil, and the resultant high-frequency, alternative current was fed into the nerve stimulator. Usually, the period of stimulation was 30 to 60 seconds. In a few cases, 0.6 mg. of atropine was administered intravenously so that peripheral ef- fects, such as bradycardia and subsequent hypotension, were prevented. Later experiments, using only stimulation of the central ends of cut vagi, were performed to determine whether or not there was any difference in results. RESULTS Bilateral vagal stimulation resulted in the depression or elimination of the patellar reflex and in the cessation of respira- tory activity (figure). There was severe bradycardia and hypoten- sion. (When the central ends of cut vagi were stimulated). When atropine had been administered prior to stimulation, there was no bradycardia, but hypertension was observed.Apnea persisted throughout the phase of stimulation and, in some cases, more than 20 to 30 seconds into the poststimulatory phase. The patel- lar reflex was reduced 75 percent during stimulation, and, in a few cases, it disappeared completely. However, it reappeared instantaneouslyu with cessation of stimulation, and its magni- tude increased during the poststimulatory phase, returning to normal within a few seconds. The administration of atropine prior to stimulation did not prevent apnoea or depression of the patellar reflex. Neurophysiology & Anaesthesia 69
  • FIG. Record of respiration, blood pressure, and patellar reflex in dog under cholralose anesthesia. Arrow indicates point where 0.6 mg. of atropine was administered intravenously. White dot shows where both vagi were cut. Bar shows period of stimulation. Time-marks stand for one-half minute. Stimulation of the ends of cut vagi produced the same results as those observed during stimulation of the intact vagi. DISCUSSION The purpose of this study was to investigate the possibility that impulses from the vagus nerves influence skeltomuscular tone because we11,12 have postulated that hyhpotonia and other aspects of the hyperventilation syndrome could be mediated through vagal impulses. There is no evidence in the literature to suport this theory of vagal influence on skeletomuscular tone during hyperventilation, but an indirect referrence to such a pos- sibility emanates from the work of Bonvallet and Dell13 . These investigators demonstrated that afferent impulses frm the vagus nerves stimulate the ventral parts of the bulbar-reticular system, Neurophysiology & Anaesthesia 70
  • which in turn controls the skeletomuscular tone through the descending bullbospinal tracts by influenceing gamma-fiber activity.14,15. The type of output current fed into the nerve stimulator by means of an induction coil will undoubtedly be familiar to physi- ologists who have used it in similar circumstances. It cannot be presumed that the pattern of affernet impulses in vagi elicited by this method is similar to that which is observed in vagi dur- ing artificial ventilation. In addition, it cannot be assumed that similar effects would occur in human beings. Nevertheless, the present study does suggest that afferent impulses in vagi, which are proportional to the amount of pumonary stretch during artificial ventilation, can produce changes in the skeletomuscular tone during hyperventilation. (The primary advantage of hyperventilation lies in this possibil- ity). The role of stretch-receptor activity in hyperventilation is further emphasized by the fact that hypotonia of skeletal muscles during hyperventilation is independent of hypocarbia5,6 . Recently Rudomin7,8 demonstrated that depressed laryngeal reflexes (another major advantage of hyperventilation) result from affer- ent impulses which are activated by artifical ventilation or by electrical stimulation of the vagus nerves. The preceding facts add weight to the theory11 that changes occuring in the skeltomuscular tone during hyperventilation are part of a neuro- physiologic factor rather than a biochemical phenomenon. Changes in other vital funtions, such as respiration and blood pressure, were studied in order to demonstrate that simultaneous changes in these vital funtions could be induced during the phase of vagal stimulation. The partial restoration of blood pressure Neurophysiology & Anaesthesia 71
  • during vagal stimulation16 cannot readily be explained, but it could have resulted from activation of the Bainbridge reflex, brought about by a pooling of blood in the great veins during severe bradycardia. The present investigation cannot provide conclusive proof that the hyperventilation syndrome is a neurophysiologic phe- nomenon, but it does point strongly to such a possibility. This study reveals that the hypotonia and apnoea which occur during huyperventilation could have been caused by afferent impulses from the vagus nerves. Other mainifestations of the hyperventi- lation syndrome which may be influenced by such afferent im- pulses include the depressed laryngeal reflexes and the pattern of slow wave sleep that appears on electroencephalograhic records taken during hyperventilation. SUMMARY Bilateral stimulation of the vagus nerves was performed 48 times in 8 dogs of both sexes under chloralose anaesthesia. In every instance, vagal stimulation resulted in apnoea and depresion of the patellar-tendon reflex. During the period of stimulation, bradycardia and hypotension were observed. On the other hand, hypertension was observed when the peripheral ef- fects were blocked by adminsitering 0.6 mg. of atropine intra- venously or when the central ends of cut vagi were stimulated. Other parameters such as patellar reflex and respiratory rhythm, were not altered by blockage of peripheral effects. There is a discussion of the significance of afferent impulses in vagi in relation to changes in skeltomuscular tone (represented by the patellar reflex), respiration, and blood pressure during hyperventilation. Neurophysiology & Anaesthesia 72
  • ACKNOWLEDGMENT We are thankful to Professor P.S.R.K. Haranth, M.D. D.Sc., for the facilities and encouragement. Generic and Trade Names of Drugs Chloralose Atropine REFERENCES: 1. Adrian, E.D.: Afferent Impulses in Vagus and Their Effect on Respiration. J. Physiol. (London) 79:332-358 (October 6) 1933. 2. Aserinsky, E. and Debias, P.: Suppression of Oculocardiac Reflex by Means of Respiratory Movements. Physiologist 4: page 5 (August) 1961. 3. Daly, D.M. and Hazzledine, J.L.: The effects of Artifically Induced Hyperventilation on the Primary Cardiac Reflex Resonse to Stimulation of the Carotid Bodies in the Dog. J. Physiol.(London) 168: 872-889 (October) 1963. 4. Dermkesian, G,. and Lamb, L.E.: Syncope in Population Healthy Young Adults. JAMA 168: 1200-1207 (November 1) 1958. 5. Downes. H.: Hyperventilation and Abdominal Reflex Inhibition in the Rat. Anesthesiology 24: 615-619 (September-October) 1963. 6. Katz., R.L. and Wolf. C.E.: Neuromuscular and Elecromyographic Studies in Mna: Effects of Hyperventilation, Carbon Dioxide Inhalation and d-Tubocurarine.Anesthesiology 25: 781-787 (November-December) 1964. 7. Rudomin. P.: Recurrent Laryngeal Nerve Discharges Produced by Cutaneous and Vagal Afferent Stimulation. Acta Physiol. Lat. Amer. 15: 964-981 (September 5) 1967. 8. Rudomin P.: Presynaptic Inhibition INduced by Vagal Afferent Volley. J. Neurophysiol. 30: 964-981 (September 5) 1967. 9. Siker, E.s.: Postanesthetic Respiratory Depression. Anesth. & Analg. 44: 2530259 (March-April) 1965. 10.Robson, G.J.: Respiratory Centres and Their Responses. In: Evans, F.T. and Gray, T.C. editors: Modern Trends of Anesthesia, vol. 3. London, butterworth, 1967, p. 42-53. 11.Rao, L.N. Ramarao, K.R. and Bhalla S.K.: Increased Afferent Activity (Vagal, Splanchnic, etc.) Leading to Hyperventilation Syndrome. Indian J. Anaesth. 14: 226-232 (August) 1966. Neurophysiology & Anaesthesia 73
  • 12.Rao, L.N.,: Apnoea During and Immediately After Hyperventilation: A Reoreintation. Indian J. Anaesth. 15: 238-244 (November) 1967. 13. Bonveallet, M. and Dell, P.: bulbar Control of the Arousing System. In: Jouvet, M., editor: Intgernational Symposium on the Anatomical and Physiological Basis of Sleep, Lyons, France, September 9-11, 1963. Electroenceph. Clin. Neurophysioil. 17: 440-448 (October) 1964. 14.Magoun, H.W. and Rhines, R.: Inhibitory Mechanism inthe Bulbar Reticular Formation. J. Neurophysiol. 9: 165-171 (May) 1946. 15.Granit, R. and Kaada, B.R.: Influence of Stimulation of Central Nervous Structures on Muscle Spindles in Cat. Acta Physiol. Scand. 27: 130-160, 1952. 16.Zanchetti, A.: Brain Stem Mechanisms of Sleep. Anesthesiology 28: 81-99 (January-February) 1967. **** Neurophysiology & Anaesthesia 74
  • RESEARCH PAPER (The Reprint is from a book) “ON VENTILATORY THERAPY AND NON OPERATIVE RESUSCITATION” Conducted by Italiana (Italian) Anaesthesia Society (Anesia E Rianimazione). They conducted an international conference in 1971 and the articles presented are in the form two b ooks (Vol. I & Vol. II) Prof. L.N. Rao, Presented a paper which is in the Ist volume of the book. D6 75
  • Reprint from A book containing papers presented to the conference (which was international) ATTI XXIV CONGRESSO SOCIETA ITALIANA ANESTESIA E RIANIMAZIONE L.N. RAO, MD, DA. PATHOPHYSIOLOGICAL CHANGES DURING ARTIFICIAL OVERVENTILATION A New conecept about their pathogenesis (da pag. 694 a pag. 702) D6 76
  • L.N. RAO, MD, DA PATHOPHYSIOLOGICAL CHANGES DURING ARTIFICIAL OVERVENTILATION 1) Abstract in Biological abstract Vol. 53, No. 37275 of 1972, 2) Mentioned in Indicus Medicus of 1973. 77
  • PATHOPHYSIOLOGICAL CHANGES DURING ARTIFICIAL OVERVENTILATION L.N. RAO, M.D., D.A. Even though few surgeons around 1880 used active overventilation techniques to mitigate pain during minor surgi- cal procedures88 , it appears that the techniques of short termed or prolonged ventilation are better studied in relation to their various beneficial and complicating aspects only since a decade, because of the immense importance of such techniques in the supportive therapy of patients suffering with acute respiratory failure. Various results of exetnsive study of artifical overventi- lation by respiratory physiologists, anaesthesiolgoists and other physicians dealing wth respiratory problems in patients exposed to such artificial ventilatory techniques are now available. But it could be categorically stated that they did not so far succeed in isolating basic factors which contribute to such a diversified change in various vital functions of the body during artifical over-ventilation. The commonly observed sequelae of artifical over-ventilation (short-termed as well as prolonged one) are pre- sented in the accompanyting table. Their classification is how- ever new and is purposely used by the author to explain their aetiology and pathogenesis on group basis rather than individual ones because various neurophysiological factors are involved in their causation. ____________________________________________________ *Professor of Anesthesiology Kurnool Medical College, Kurnool, (A.P.) India. Neurophysiology & Anaesthesia 78
  • IMPORTANT CHANGES IN VITAL FUNCTIONS OBSERVED DUR- ING ARTIFICIAL OVERVENTILATION Group-1. Changes in mechanics of respiration and its sequelae. 1. Increase in airway resistance1, 61. 2. Decrease in pulmonary compliance1-3, 34. 3. Arterial hypoxaemia occuring during the phase of artificial ventilation 1-7, 34, 81. 4. Gross picture of hypoventilation of alveoli developing in cases of prolonged mechanical ventilation, inspite of manifold rise in minute volume 2,3,34,81. Group-II: Changes in respiration, general reflex activity and level of consciousness. 1. Level of consciousness is depressed with or without E.E.G. changes. pattern of slow wave sleep 15, 17-21. 2. General supression of snesory reflex activity including a rise in pain threshold 14-16. 3. Hypotonia of skeletal muscles 22, 23. 4. Depression of laryngeal reflexes 24, 25. 5. Apnoea or depressed respiratory pattern occuring during or after overventilation 8-11, 58. 6. Changes in human reaction time12. 7. Changes in flicker fusion tests13. Group-III: Changes in Cardiovasular state and reginal blood flow. 1. Cardiac output decreased.87 . 2. Peripheral resistance decreased 28-30. 3. Cerebrovascular flow decreased31. Neurophysiology & Anaesthesia 79
  • Group-IV: Changes in acid-base state, body water and bleeding time. 1. Occurance of lactacedemia32,33. 2. Increase in extracelluar fluid content during prolonged mechanical ventilation 2,3, 34,81. 3. Development of Gastro-intestinal haemorrhages3 . It is immediately obvious from the table that artifical overventilation caused diversified changes in almost all vital functions of the body, though many of these changes may not be obvious in a single patient subjected to such techniques. A review of literature about their pathogenesis reveals that even today conflicting and contradictory veiws are often expressed about the same. It may threrefore be pointed out at this stage that such a situation has been allowed to develop merely because of the fact that almost all the clinicians and respiratory physiologists, concerned with the study of these fundamental problems, have presumed that alteratins in CO2 content of the body (due to techniques of artificial overventilation) has directly or indirectly (through a change in cardiovascular system and regional blood flow) resulted in various cardiovascular, respira- tory, skeletomuscular, E.E.G. and other changes in persons ex- posed to such techniques. Under such circumstances author, at- tempted to study the basic problems of artificial overventilation on altogether different line16, 58-61, 86 , and noted that current neu- rophysiological facts suggested that aetiology and pathogenesis of various changes in vital functions observed during artificial overventilation, could satisfactorily be explained on the basis of a neurophysiological phenomenon rather than a biochemical one. Neurophysiology & Anaesthesia 80
  • THE CONCEPT BASED ON NEUROPHYSIOLOGICAL CORRELATION OF CLINICAL OBSERVATIONS The basic neurophysiological factor contributing to such diversified changes in vital functions could therefore be the alteration of the activity of the neurones of brain-stem (and other related structures of C.N.S.), consequent to the increased recep- tor activity in the lungs, setting up volley of afferents in vagosympathetic trunk and posterior nerve roots during the phase of overventilation (voluntary or passive): ADRIAN43 , in 1933 demonstrated a linear relationship between volleys of vagal afferents and lung volumes in dogs during artifical overventila- tion. WIDDICOMBE38 , later suspected that apart from «stretch receptor» Activity leading to the type of vagal afferent volleys described by Adrian, other type of receptors might have casued afferentation in nonmedullated (fine) vagal fibres which con- ducted at slower rates than others and were resistant to cooling upto 1°C. Coleridge44 et al. recently demonstrated such recep- tors to be situated in various lobes of the lung and that they are stimulated at much higher lung volumes during artifical over- ventilation. They also observed that the stimulation of such «high threshold inflation receptors» by natural (overventilation) or artifical means (by capsaicin) resulted in various cardiovascular and respiratory sequelae akin to those observed during artificial overventilation. Paintal and his colleagues 46,47 , later demon- strated yet another type of receptors (J. receptors) whicv are stimulated during active exercise and occasionally during artifical overventilation, which in turn cause inhibition of monsynaptic reflexes. More recently SELLICK and WIDDICOMBE45 , desxcribed the existance of irritation receptors in the lungs which are stimu- Neurophysiology & Anaesthesia 81
  • lated by artifical overinflation of the lungs. The facts that all these types of receptors are activated with varying lung volumes is very important in clinical conditions because, for varitety of reasons, grossly increased minute volumes are often used to ven- tilate during balanced anaesthetic techniques4-7 , or when non- operative resuscitation therapy is induced in some needy pa- tients.2, 3,34,81 In spite of the fact that such a great possibility of the activation of various receptors (stretch receptors, high thresh- old inflation receptors, J. receptors and irritatin receptors) exists during the techniques of short-termed and prolonged artificial ventilatory technques, (due to significant increase in lung vol- umes), most of the clinical physiologists do not consider this possibility seriously, while explaining the mechanism of various pathophysiological changes occuring during such techniques. Their basis for such a disregard for receptor activity is the ob- servation that Hering-Breuer reflex is less developed in humans when compareed to other mammals40,41 . It is however, necessary to point out, at this stage that even though higher development of C.N.S. in man has introduced certain restraint on the com- monly observed respiratory reflexes which are so far found to be brisk in experimental animals, conditions prevalent in humans while short-termed or prolonged artificial ventilatory tech- niques are needed are far different when compared to those observed during health, thereby necessitating a closer analy- sis of such conditions. It is a common knowledge that short- termed or prolonged ventilation is initiated in persons in whom the entire respiratory apparatus is deranged because of the use of skeletomuscular relaxant drugs or disease process. During surgery under general anaesthesia, patient is made un- conscious (with hypnotic) and he is paralysed with realaxant drugs. Patient is intubated with endotracheal tube Neurophysiology & Anaesthesia 82
  • and positive pressure ventilation (I.P.P.V.) is instituted. Under such circumstances higher centres in CNS would not be exercising and restraining the respiratory reflexes, specially when irritation receptors and other receptors are stimulated by endo tracehal tube and intermittant positive pressure ventilation (I.P.P.V.) is setup. This single aspect of the altered respiratory physiology induces a situation in which great amount of volume changes of the lungs could take place without the initial opposing actions of diaphragm or other respiratory muscles of the thoracic cage by higher centres in CNS. Under such circumstances it is unrealistic to assume that the resultant receptor activity (due to such an increase in lung volumes) does not influence the higher centres in C.N.S. in man. Such views (about the receptor activity influcening the C.N.S. during such techniques) are strengthened by the observation of various research workers who stated that receptor activity in man has a dominant role in inducing changes in skeletomuscular tone, respiratory rhythem and pattern, laryngeal reflexes and other reflex patterns of the body 39,42,48,96,97. With regards to the observed change in mechanics of breath- ing with corresponsing changes in blood gases, it is now known that apart from a change in airway resistance and pulmonary compliance a state of generalised hypoventilation of lungs develops in cases of prolonged mechanical ventilation2,3,34,81, the exact cause of which is so far not known. But the following experimental and neurophysiological facts indicate that recep- tor ativity from the lungs and thoracic cage has a dominant role to play in causing observed changes, in pulmonary mechanics and blood gases. Robson in 1967 observed that artifical over- ventilation results in inhibition of inspiratory neuronal activity while hyperactivity of expiratory neurones takes place with the Neurophysiology & Anaesthesia 83
  • simultaneous development of apnoea with a relaxed diaphragm. From the work of GILL and KUNO50 , it could be surmised that such a diaphragmatic relaxation during artificial overventi- lation might be due to the observed expiratory neuronal hyperactivity. Experimentally SEARS49 confirmed that vagal afferentation (low intensity stimulation of cervical vagii) resulted in inibition of a inspiratory neurones with hyperactivity of expi- ratory ones with a relaxed diaphragm. The clinical confirmation of this neuronal change influencing the technique comes from the observation of ROBSON48 , who revealed that the synchronisatin of the respirator with that of the neuronal activity, in the initial phases of artificial ventilation in a curarized patient was based on stretch information rather than the coincident biochemical changes. Basing on these neurophysiological facts it appears that various changes in the breathing pattern and bronchomotor tone during artificial ventilation might be the sequalae of the recep- tor activity inducing continued expiratory phase of the respira- tory cycle. This possibility is strenthened by the observations of COLEBACH and his COLLEAGUES51,52,76 , who noted that when cer- vical end of cut vagii were stimulated bilaterally increase in air- way resistance with significant reduction of pulmonary compli- ance occured. Basing on such possibilities RAO61 and his COLLAEGUES, COLEBACHAND and his COLLEAGUES51 , postulated that during aritificial ventilation, the absence of periodic «Pulling effect» of the throcic cage and intercostal muscles coupled with increased bronchomotor tone (due to expiratory activity of the respiratory phase continuing), results in gross increase in air- way resistance. They also attributed the observed changes in blood-gases during artificial overventilation to such a change in the bronchomotor tone, because, it is now known that changes in bronchomotor tone affet both the airway resitance and Neurophysiology & Anaesthesia 84
  • pulmonary compliance76 , thus contributing to alveolar hypoventilation57 . It is also known that size of alveolus varies greatly through- out the lung parenchyma56 . Similary, it is possible that a great variation in the size of the lumen of finer airways exists because WILSON90 , stated that design of tracheobronchial tree is so ar- ranged that minimum of etnropy is produced with maximum of efficiency. Due to these factors (continued expiratory phase of the respiratory cycle; size of the finer airways and alveoli vary- ing throughout the lung parenchma), any change in the rate of inflation and inflation pressures (during artificial overventila- tion) will not be felt uniformly by the finer airways91 , and ac- cording to the gas laws55 , the group of alveoli depending upon the finest airways for their ventilation will suffer the maximum (due to such change in mechanics of respiration). This aspet of the technique of artificial respiration becomes important from the fact that such constricted airways cannot be adequately wid- ened by artificial means54,76 . It therefore becomes obvious that changes in ventilation/perfusion ratios occur during such tech- niques, thereby inducing changes in the composition of blood gases during short-termed artificial overventilation. Simulta- neous alterations in cardiac output87 , (due to causes to be dis- cussed later) become additive26,27 to such changes in ventila- tion/perfusion ratios thereby aggrevating the alveoler- arterial gradients for O2 during the techniques. These views of the author are strengthened by the fact that in cases wherein artificial overventilation is kept up for a short period hypoventilation of alveoli is relatively minimal and the change in the blood gases is noted ony in PaO2 levels whereas PaCO2 appears to be well below the physiological limits. In later phase Neurophysiology & Anaesthesia 85
  • of mechnical ventilation, however, (as in the case of the patients who are ventilated mechanically for 10 to 15 days) greater num- ber of alveoli collapse permanently thus increasing the v.d./vt. ratios with gross increase in anatomical dead space. (Greater percentage of collapsed alveoli being present compared to the functioning ones) thus contributing to a rise in PaCO2 also and creating a picture of grossly inefficient ventilation inspite of greatly increased minute volumes and rate of respirations. With regard to the occurance of apnoea, changes in pain threshold and E.E.G. pattern of slow wave sleep during artifical overventilation, RAO et al.16,58,59,60 , similarly observed that receptor activity might induce changes in the activity of the brainstrem neurones thus inducing such changes in the pain threshold, E.E.G. pattern and respiration. (This is purely a neu- rophysiological phenomena). SALMOIRAGHI and BURN92 , stated that diminution or absence of neuronal traffic in the brainstem reticular formation occurs during artificial respiration.Thier views when studied in the light of the observation of BRIDENBAUGH11 , BAINTON8 , ROBSON48 , and SEARS49 , reveal that occurance of apnoea during or immediately after artifical overventilation is again a part of a neurophysi- ological phenomenon. It could similary be stated that the E.E.G. and behavioural manifestations of sleep recorded during volun- tary or pasive overventilation, might be receptor orientated in whose causation, vagal and other afferents from lungs and thoracic cage have a dminant role to play. This possibility is strengthened by the recent observations that coincident hypocapnoea is not the cause for E.E.G. changes during such techniques37 .As early as 1932 it was demonstrated that stimula- Neurophysiology & Anaesthesia 86
  • tion of sinus nerves induces behavioural and skeletomuscular pattern of sleep69,70 . Later it is revealed that stimulation of cervical vagus itself (by electrical means) causes E.E.G. manifestation of slow wave sleep67,68 . Mere mechanical iirtation of the larynx is recently shown to induce the same result in E.E.G.93 . Since it is now known that vagal afferents as well as somatic and other visceral afferents could influence various neurones of the brainstem which have a controlling influence on the skeleal muscular tone and pain threshold in addition to induce skeletomsucular, behavioural or E.E.G. manifestations of physiological sleep67-70 , it is highly likely that changes observed in these paramenters during artificial overventilation are receptor oriented16,59,60 . Under such circumstances it is likely that various changes observed in human reaction time12 , flicker fusion tests13-80 , E.E.G. pattern17-21 , pain threshold14-16 , and skeletomuscular tone22,23 , might only indicate such a change in the acitivity of C.N.S. due to the influence of receptor activity and they therefore need not indicate a phase of cerebral hypoxaemia (as is so far believed to be). These views are strenghthened by the recent investigations that such techniques of artifical overventilation in fact protect an ischaemic brain from further damage35,98 rather than inducing it hypoxic, probably by making the cerebral flow uniform36 . (which was not earlier uniform). With regards to the mechanism of changes in cardiovascular system, it could be similarly stated that receptor activity has a dominant role in its causation. As early as 1965 COLERIDGE44 , and her colleagues postulated that stimulation of «high thresh- old inflation receptors» caused various cardiovascular and res- piratory changes akin to those observed during artificial over Neurophysiology & Anaesthesia 87
  • ventilation. Recent experimental evidence28-30 , confirms such views because bilateral vagotomy or section of vagosympathetic trunks in thorax reduces or abolishes various changes in cardiac output and peripheral resistance during the techniques of artifical respiration thereby revealing that mere changes in PaCO2 need not be directly related to such changes in cardiovascular system. Since changes in vascular flow to structures like kidney could take place under the influence of C.N.S. during many techniques of anaesthesia77,94 (which need not normally induce hypoxic changes in the kidney unless complicated by hypotension or hypoxaemia) it is likely that changes in cerebrovascular flow, on a same analogy might not induce hypoxic changes in CNS. These views are strengthened by the record observations which indicate that the techniques of artificial overventilation are inocceous78,80,98 , and that cerebral oxygenation during hyperven- tilation is sufficient to maintain normal oxidative meabolism73 . Finally, it is relevant to discuss the exact mechanism of the occurance of lactacedaemia, retention of body water and development of bleeding tendencies during such techniques of artificial overventilation. The foregoing discussion, when studied in the light of the observation of BISHOP75 , who stated that pressure breathing is a physiological stress, which is primarily due to the pulmonary receptor activity, reveals that such afferents in vagosympathetic nerves and probably others from the thoracic cage to stimulate, hypothalamus and other higher centres in the C.N.S. such a way that various products of stress response are liberated73,82 , which incluce aldosterone, ACTH and Catecholamine production. It is therefore possible that lactacedaemia and development of bleeding tendencies in Neurophysiology & Anaesthesia 88
  • some patients who are exposed to prolonged ventilatory techniques reflects this phase of stress response, because it is now proved beyond doubt that catecholamines can prodeuce both these changes in the body79,83-83,95 . Of course, aldosterone pro- duction in excessive quantities is already recorded to occur in patients who are subjected to prolonged mechnical ventilation which inturn induces water retention in them81 . All these aspects of altered physiology, therefore, only indicate that such changes in lactic acid content in the body need not reflect hypoxic changes during the techniques of artificial over ventilation. S U M M A R Y Since the current opinions about the exact mechanism of various pathophysiological changes are controversial and are often contradictory, the author basing on his clinical and experimental experiences, correlated the currently known neurophysiological facts and thus evolved a concept about their causation. He believes that various pathophysiological changes occuring during short-termed and prolonged ventilatory tech- niques are different constituents of a neurophysiological phe- nomenon, which occurs primarily due to the increased receptor activity from the lungs and thoracic cage. Since the activity of the neurones of C.N.S. is changed due to vagosympathetic afferents and in the posterior nerve roots during such techniques, ACTH, aldosterone and catecholamines are liberated which induce changes in acid base balance, bleeding time, and body water. Neurophysiology & Anaesthesia 89
  • R I A S S U N T O Poiche le opinioni correnti circa l’esatto meccanismo di vari cambiamenti patofisiologici sono controverse e spesso anche contraddittorie, l’Autore, basandosi sulle sue esperienze cliniche e sperimentali, ha messo in correlazione i fattori neurofisiologici attualmente noti elaborandone un concetto circa la loro causa. L’Autore e convinto che vari cambiamenti patofisiologici che si manfiestano nel corso di brevi o prolungate tecniche di ventilazione sono costituenti diverse di un fenomeno neurofisiologico causato principalmente dal-l’aumentata attivita ricettiva dai polmoni e dalla gabbia toracica. Dato che l’attivita del S.N.S. e cambiata a causa di apporti vagosimpatici nelle radici del nervo posteriore, durante queste tecniche vengono liberati ACTH, aldosterone e catecolamine, che provocano cambiamenti nell’equilibrio acido-base, «bleeding time» e liquido fisiologico. ACKNOWLEDGMENT While crystalizing these views, the author had been associated with Brig. K.R. Rama, Rao, Prof. P.S.R.K. Harnath and Shri H. Venkata Krishna Bhatt, whose help and construc- tive criticism is gratefully acknowledged. The secretarial help of Shri G. Seshanna has been of immense value during the preparation of this manuscript. Part of the work, presented in this paper, was supported by the funds from the Andhra Pradesh State Medical Research Committee. Neurophysiology & Anaesthesia 90
  • B I B L I O G R A P H Y 1. GOLD, M.I, HAN, Y,K. & HELRICH, M. Pulmonary mechanics during anaestheisa. III: Influenced of intermittent positive pressure and relation in blood gases, «Anesth. Analg.», 45, 631-640, 1966. 2. BUSHNELL, L.S., PONTOPPIDAN, H., HEDLEY-WHYTE, J., and BENDIXEN, H.H., Efficiency of different types of ventilation in long term respiratory care, mechnical versus spontaneous, «Anaesth. Analg.» 45, 696-702, 1966. 3. PONTOPPIDAN, H.HEDLEY-WHYTE, J., BENDIXEN H.H., LAVER, M.B., & RADFORD, E.P., Ventilation and oxygen requiremtns during prolonged artifial ventilation in patients with respiratory failure, «New. Eng. J. Med.», 273, 401-409, 1965. 4. SLATER, E.M., NILSSON, S.E., LEAKE, D.L. PARRY, W.K., LAVER, M.B., HEDLEY-WHYTE, J., and BENDIXEN, H.H., Arterial oxygen tension measurements during nitrous oxide-O2 anaesthesia, «Anaesthesiology», 26, 642, 647, 1965. 5. HEDLEY-WHYTE, LAVER, M.B., and BENDIXEN, H.H., Effect of changes in tidal ventilation on physiological shunting, «Amer. J. Physiol.», 206, 291-297, 1964. 6. NUNN, J.F. BERGMAN, N.A., & COLEMAN, A.J., Factors influcening the arterial PO2 during anaesthesia with artifical ventilation, «Brit. J.Anaesth.» 36, 743-744, 1964. 7. SYKES, M.K. YOUNG, W.E., and ROBINSON, B.E. Oxygenation during Anesthesia with controlled ventilation, «Brit. J. Anaesth.» 37, 314, 325. 1965. 8. BAINTON, C.R. and MITCHELL, R.A., Post hyperventilation apnoea in awake man, «J. Appl. Physiol.» 21, 411, 1966. 9. FINK, B.R. HANKS, E.C., HOLADAY, D.A. and NGAI, S.H. Monitoring of ventilation by integrated diapharagmatic electrogram, determination of CO2 threshld in anaesthetised man, «J. Amer. Med. Assn.», 172, 1367-1373, 1960. 10.FINK, B.R. Influence of cerebral activity on wakefulness and on regulation of breathing, «J. Appl. Physiol.», 16, 15-20, 1961. 11.BRIDENBAUGH, P.O, CHURRCHILL-DAVIDSON, H.C., & CHURNER, M.D, Efforts of CO2 n actions of d.t.c. and Gallamine, «Anaesth, Analg.», 45, 804, 1966. Neurophysiology & Anaesthesia 91
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  • 70.SPYCHALA, V., Intersuchungen iber vagetative Bee influssung der Muskeleigumreflexe, «Ztchr. Ges. Exper. Med.», 83, 199-202, 1932. 71.SCHWWITZER, A., AND WRIGHT, S., Effects on the knee Jerk of stimulation of the central end of the vagus and various changes in the circulation and respiration, «J. Physiol.», 88, 459-475, 1937. 72.EVANS, M.H., MCPHERSON, The effect of electrical stimulation of visceral afferent fibres on monosynaptic and polysynpatic reflex responses, «J. Physiol.», 150, 105-113, 1960. 73.CAIN, S.M., A attempt to demonstrate cerebral anoxia during hyperventilation of aneasthetized dogs, «Amer. J. Physiol.», 204, 323-326, 1963. 74.MCCANN, S.M., Effect of hypothalamic leisons on adreno-cortical response to stress in rats, «Amer. J. Physiol.», 175, 13-20- 1953. 75.BISHOP, B., Abdominal muscles and diaphragm activity and cavity pressure breathing, «J. Appl. Physiol.», 18, 37-42, 1963. 76.OSLEN, C.R., DEKOCK, M.A., COLEBATCH, H.J.H., Stability of airways during reflex bronchoconstriction, «J. Appl. Physiol.», 23, 23-26, 1967. 77.MILES, B.A., AND DE WARDNER, H.E., Renal vasco constriction produced by ether and cycloproane anaesthesia, «J. Physiol.», 118, 140-144, 1952. 78.Editorial, «Brit. J. Anaesth.», 41, 563, 1969. 79.GREENE, N.M., Effect of epinephrine in lactate and pyruvate and excess lactate in humans, «J. Lab. Clin. Med.», 58, 682-686, 1961. 80.WHITWAN, J.G., BOETTNER, RB., GILGER, A.P., AND LITTELL, A.S., Hyperventilation brain damage and flicker, «Brit. J. Anaesth.», 38, 846-851, 1966. 81.SLADEN, A., LAVER, M.B., AND PONTOPPIDAN, H., Pulmonary complications and water retention in prolonged mechnical ventilation, «New, Eng. J. Med.», 279, 448-453, 1968. 82.REDGATE, E.S AND GELLHORN, E., Nature of sympathoadrenal discharge under conditions of excitation of central autonomic structures, «Amer. J. Physiol.», 174, 475-480, 1953. 83.GENTON, E., KERN, F., JR., AND VONKULLA, K.N., Fibrinolysis induced by pressor amines, «Amer. J., Med.», 31, 564, 1961. 84.BIGGS, R MCFARLANE, R.G., AND PILING, J., Observations on fibrinolysis: experimental acitivity produced by excersise or adrenaline, «Lancet», 1, 402-405, 1947. Neurophysiology & Anaesthesia 96
  • 85.BIGS, R., AND MCFARLANE, R.G., Human coagulation and its disorder, in «Blackwell scientific publications», Oxofrd, pp. 147-158, 1957. 86.RAO, L.N., RAMA, RAO, K.R., BHALLA, S.K., AND PANDE, J.N., Peripherally evoked central nervoes responses during surgery under general anaesthesia; a clinico neurophysiological correlation, «Ind. J. Anaesth.», 15, 81-87, 1967. 87.THEY, R.A., MILDE, J.H., AND MICHENFELDER, J.D., Effect of hypocapnoea on cariac output during anaesthesia, «Anesthesiology», 27, 778, 1966. 88.SYKES, S.W., «Essays on 1st 100 years of Anaesthesia», Volume II, Chapter 5, «Natural Anaesthesia», Livingston, London, pp. 67-79, 1961. 89.GRANIT, R., AND KAADA, B.R., Inflluence of stimulation of central nervous structures on muscle spindles in Cat., «Acta Physiol. Scand.», 27, 130-160, 1952. 90.WILSON, T.A, Design of bronchial tree, « Nature», 213, 668-669, 1967. 91.COMROE, J.R., FORRESTER, R.E., DUBIOS, A.B., BRISCOES, W.A., AND CARLSON, E., The lung, 2nd edition «Year Book» publications, U.S.A., 1962. 92. SALMOIRAGHI, C.C., AND BURNS, B.D., Notes on mechnism of rhythmic respiration, «J. Neurophysiuol.», 23, 14-16, 1960. 93.REETH, P.C., VAN AND CAON, A., Sommeil provoque chez le lap in par des stimulations profonde, Cephaliques et cervicales, «Compt. Rend.», 255, 3050-3052, 1962. 94.BAYLISS, L.E., AND BROWN, A., The part played by real nerves in the production of water diuresis in the hypophysectomised and decerebrate Dogs, «J. Physiol.», 98, 190-206, 1940. 95.IRVING, M.H., The sympatho adreanl factor in haemorrhagic shock, «Ann. Roy. Col. Surg. », 42, 367-386, 1968. 96.ASERINSKY, E., AND DEBIAS, P., Suppression of occulo cardiac reflex by means of respiratory movement, Physilogist», 4, 5, 1961. 97.DALY, D.K., AND HAZZLEDINE, J.L., The effects of artificially induced hyperventilation onthe primary cardiac reflex response to stimulation of the caroted bodies in the Dog, «J. Physiol.», 168, 872-889, 1963. 98.MILLAR, A.T. JR., CURTIN, K.E., SHEN, A.L, AND SAITER, C.K., Brain oxygenation in rat during hyperventilation with air and with low O2 mixtures, «Amer. J. Physiol.», 219, 7098-801, 1970 ***** Neurophysiology & Anaesthesia 97
  • RESEARCH PAPER PRESENTED TO ISA (NATIONAL) (Anaesthetist’s Annual Meeting at Luckhnow, UP, India in 1910) “FACTORS AFFECTRING AWARENESS IN PATIENTS DURING AND AFTER GENERAL ANAESTHETIC TECHNIQUES” BY: PROF. L.N. RAO, M.D., DA (Invited to present the paper as a guest faculty to I.S.A. (National) at Luckhnow in 1910) D7 98
  • FACTORS AFFECTRING AWARENESS IN PATIENTS DURINGAND AFTER GENERAL ANAESTHETIC TECHNIQUES BY: PROF. L.N. RAO # 16-9-749/48, Old Malakpet, Hyderabad-36. A.P. (India). ------------------------------------------------------------------------- Introduction: After the introduction of skeletouscular relax- ant drugs into the anaesthetic practice a revolution has occured in the filed of techniques of anestheisa, called as balanced anes- thetic techniques (1.2.72)Anesthesiologists are now able to anes- thetize a neonate to senior citizens of 90yrs or more. Surgery could be safely done in supine, prone, head up and trendelenburg positions for 30 min of surgery to 30 hrs or more with safety. Anestheologists, world over believe that anesthesiology is a clini- cal pharmacology. They attribute the revolutionary success in anesthesiology, strating in the later part of 20th centruy, to the introduction of skeletomuscular relaxant drugs. they believe that skeletomuscular relaxant drugs directly (through blocking prop- rioception) or indirectly (through their action on the synapses of C.N.S.) cause unawareness in the patient and cause ideal oper- ating conditions necessary for any type of surgery carried out on various organs of the body in different positions for prolonged periods. They (3 to 8, 17, 80) also firmly believe that skeleto- muscular relaxant drugs, due to variety of conditions in some patients, continue to act on the brain as well as neuro muscular juncitons there by keeping the patient unaware in the post op- erative period also. Such patients are comatose with absence of reflexes and respiration. Their msucles are completely paralyzed. In short, their vital functions are fully depressed upto 4-8 hrs or more in the post operative period. Hence it is necessary fo find out various factors which cause unawareness during surgery and factors which cause unawareness in the post operative period, Neurophysiology & Anaesthesia 99
  • as well as causes which are responsible to cause awareness during surgery in some patients even when anesthetic techniques are continuing in them. ***** FACTORS CAUSING UNAWARENESS IN PATIENT DURING SURGERY: 1. Role of skeletomuscular relaxant drugs in causing unaware- ness in patients during surgery under general anaesthetic thecniques. 1(A). Smith et al (9) experimented on human volunteer to note the central nervous efects of dtc. And noted that even when the volunteer received 2½ times the paralyzing dose of dtc., C.N.S. was not affected. Harnath et al. (10) injected 500 micro- grams of dtc. into the carotid artery of unanesthetized dogs and noted that respiration and muscle tone in the dogs were normal. Later they infused 30 micrograms/min of dtc. into the carotid artery of ananesthetized dogs for some time and found that dogs only slept for some time but no peripheral effects (muscle tone and respiration) were noted in them. Harnath and Shamala Kumari (11) reported that perfusion of lateral ventricals with 10 nanograms/min of dtc. in unanaesthetized dogs increased neu- ronal discharge in occipital lobes and resulted in restlessness in dogs but no peripheral effects were noted. Others (47,48,49) injected larger dose of dtc. into intra cerebroventricular system and found that dogs developed convulsions. 1(B). Devashankaraya et al (12) Harnath et al (13) and Rao and Bhatt(14) conducted experiments on patients getting oper- ated under balanced anesthetic techniques. Patients were anaes- Neurophysiology & Anaesthesia 100
  • thetized routinely and they were paralyzed with bolus dose of 30 mg of dtc. or gallamine (in the dosage of 2.0 - 3.8 mg/kg body weight). They were intubated and artifical ventilation was instituted. Concentration of dtc. or gallamine was assayed bio- logically at 15th min (which is paralyzing dose) and at the end of operation (60-110 min of surgery) in C.S.F. and in the blood of the patients who underwent surgery. dtc. and gallamine was present in C.S.F. and the blood in all the patients at the 15th min and at the end of the surgery. Most important finding was that blood concentration of dtc. and gallamine which was present in C.S.F. and in blood at the end of surgery and anaesthetisa, was very high (10% to 25% of the concentration present at the 15th min of the administration of the drug). Inspite of such a heavy concentration of the drug, patients recovered normally from an- esthetic procedure(14). 1(C) It appears from these experiments that, skeletomuscular relaxant drugs do not have action on C.N.S., because, presence of high quantity of skeletomuscular relaxant drugs in the blood and C.S.F. (at the time of recovery) did not depress C.N.S. in the post operative period. Hence it becomes necessary to find out the role of other factors which cause depression of C.N.S. so that unawareness in the patient during surgery (as well as developement of ideal operating conditions in the patients during surgery) would be attributed to such factors during anesthesia. OTHER FACTORS WHICH COULD CAUSE UNAWARENESS IN PATIENTS DURING SURGERY AND WHICH COULD PRODUCE IDEAL OPERATION CONDITIONS (BY DEPRESSION OF C.N.S.) 2(A). Fowweather et al (81) were the 1st persons who Neurophysiology & Anaesthesia 101
  • included all signs and symptoms of over breathing (active or passive) into the term “Hyper ventilation syndrome”. In depth study of literature concerning the artificial ventilation revealed that large number of scientists carried out research on hyper- ventilation to study the possibility of hypoxia of the brain causing unawareness and other aspects of hyperventilation syn- drome. Cain (18) in 1962 reversed such trend (to link cerebral hypoxia with various aspects of hyperventilation syndrome) when he showed that cerebral excess lactate was not sufficiently present in the brain of hyper ventilated animals to prove cerebral hypoxaemia to cause hyper ventilation syndrome. This observa- tion was confirmed by Wilkinson et al (73) who indicated that normal human brain contained large amount of variation in blood flow in various parts of the brain. Others stated that during hy- perventilation, the regional variation of blood flow disappears and entire brain gets uniform blood supply, due to intact auto regulation (77,78,79). Hence unawareness in patients during surgery is not due to cerebral hypoxia. 2(B). Since I.P.P.V. is the common mode of inflation (during artifical ventilation in curarized patients) the work of Bishop and his colleagues becomes releveant to the anesthesiologists. Bishop et al (19,20,21) experimneted about the pressure breathing (interposing positive and negative pressues in the breathing circuits). They found that pressure breathing (I.P.P.V.) was the main cause of the relaxed diaphragm and other respiratory muscles. Further it was established that such a change in the activity of respiratory muscles was reflex in nature be- cause bilateral vagotomy abolished the changes in the activity of respiratory muscles. Adrian(24) demonstrated that afferent vollyes in vagus nerve were directly proportional to the lung Neurophysiology & Anaesthesia 102
  • volumes during artifical respiration. Rao and Bhatt(22) Schwitzer and Wright(63) stimulated vagus nerve and observed that respi- ratory activity and skeltomuscular activity was depressed or stopped completely during such a stimulation. Various physi- ologists (25-29, 62,75) showed the existance of pulmonary re- ceptors for inflation, deflation and irritation of pulmonary paranchyma and treaceo bronchial tree. Stimulation of such re- ceptors resulted in large increase in afferent volleys in vagal nerves. I.P.P.V. (artificial ventilation using pressure to inflate the lungs) would lead to significant increase in the stimuli in vagal nerves (emanating from the lungs) which travel at fast rate towards C.N.S. and influence various synapses of C.N.S. to cause various aspects of hyperventilation syndrome (22,24,46,50,51). They (vagal nerves carrying stimuli from the lungs during I.P.P.V.) could cause behavioural and skeleto mus- cular pattern of sleep (31 to 34, 87), abolition of occulocardiac reflex (35) and abolition of the effects of stimulation on carotid body on the heart (30,36). Downes(37) & Katz and Wolf(38) revealed that hypotonia of skeletal muscles during artifical ven- tilation was reflex phenomenon. Rudamin (40) observed that laryngeal reflexes were abolished by artifical ventilation. Deshpande & Devanadan(29) indicated that monosynaptic re- flexes are inhibited when “J” receptors in the lungs are stimu- lated. Bon Vallet and Dell(41), Magoun & Rhines(42), Granit and Kada(43) & Rao & Bhatt (22,50) demonstrated that vagal nerves when they are stimulated lead to the control of skeleto muscular tone. Rao (44) & Siker (45) observed that apnoea dur- ing & immediately after hyper ventilation is due to vagal affer- ents from pulmonary receptors. Robson(83) revealed that syn- chronization of respiratory muscles with a ventilator is stretch receptor oriented phenomenon. Neurophysiology & Anaesthesia 103
  • 2(C). These experimental results indicate that no single factor is responsible to produce the revolutionary change in anaesthesiology, specially during balanced anesthetic techniques. Introduction of skeleto muscular drugs into anesthesiology enabled anesthesiologists to paralyze the patient so that artificial ventilation could be initiated in them (with out resistance) through endotracheal tube. Gases like N2O and O2 mixtures could be pumped into them under pressure. The resultant pressure ventila- tion (I.P.P.V.) helps the patients to be unaware during surgery with absence of reflex activity, loss of respiratory and other muscles tone including draphragm. Hence it apears that introduction of skeleto muscular relaxant drugs really revolutionized the anesthetic techniques because a profoundly relaxed patient alows other events (like I.P.P.V. etc.) in him without resistance. Because of I.P.P.V., pulmonary receptors are stimulated to send large no. of vagal af- ferents to C.N.S. which act on various neurons of C.N.S. thereby causing unawareness in patients as well as producing various ben- eficial effects of general anesthetic techniques. It may be mentioned at this stage that, some amount of skeleto muscular relaxant drugs which pass the blood brain barier (as seen in references 12th & 13th) cause sleep pattern in patients in the post operative period and they have no further effect on C.N.S. Even during the sleep (when undisturbed) they wakeup to respond to simple commands including showing the tongue and opening the eyes etc. (when asked to do so), indicating that C.N.S. returned to normalcy in the imme- diate post operatie period. (C.N.S. was depressed during IPPV for reasons given in the special paper printed in Sect. I). 3. OTHER FACTORS WHICH CAUSE CHANGES IN AWARENESS DURING SURGERY AND IN POST OPERATIVE PERIOD As stated above the patient undergoing surgery with general anesthetic techniques are unaware of surgery and they returned Neurophysiology & Anaesthesia 104
  • to normalcy by 10 - 15 min after the cessation of anesthetic pro- cess (as indicated by their response to simple commands like opening the mouth when asked to do so, putting out the tongue when asked and to open the eyes etc.) However some patients (0.1-0.2%) are found to be aware during the surgery itself even when geneal anesthetic techniques with I.P.P.V. are continuing (read the reason for their awareness in Section II). SECONDLY an occational patient may not recover from an- esthetic effects in the post-operative period for 4 - 8 hrs. or more needing ventilatory therapy. Since such patients are found to be comatose with apnoea, areflexia, and atonia of skeletal as well as respiratory muscles, an impression is created among the sur- geons and patient’s relatives that, the anesthesiologist has used large doses of anesthetic drugs in the concerned patient so that he is still suffering with the effects of large quantity of drugs used during anesthetic techniques. Hence they feel that patient is having apnoea, coma and depression of other vital functions in the post-operative period, (as a result of the effect of the an- aesthetic drugs used during anesthetic techniques). Lastely It is a fact to state that not much knowledge is now available about the patients who become aware during surgery itself.Anesthesi- ologist feel that patient develops awareness due to light stage of anesthesia.This assumption is untrue because skeleto muscular relaxant drugs do not act on C.N.S. and normally no other drugs are used exessively during the anesthetic techniques (except the periodic administration of skeleto muscular relaxant drugs - when necessary). Hence this study was carried out to find out the ex- act cause of awareness during surgery, (unawareness during sur- gery which in some patients reverses back to become awareness during surgery) as well as the cause of coma in some operated patients in post operative period. The cause of unawareness dur- ing surgery is already discussed. Hence further study involves to find out the causes of awareness during surgery and comatic conditions in the post operative period. Neurophysiology & Anaesthesia 105
  • 3(A). Wang(53) and Overman and Wang(54) found a correla- tion between sensory stimulation and survival rates of dogs who were subjected to hypovolumic stress. They observed that the stimulation of sensory nerves during the induction of haemorragic shock caused death in dogs at a residual blood volume which normally would have been compatible with their survival (if sensory nerve was not simultaneously stimulated). They also noted that if severe injuries were induced in chronically dener- vated limbs of the dogs, they survived at residual blood vol- umes which were lethal to others in whom nerve supply to the limbs was normal. This experiment reveals the result of neuro- genic stress on body function. 3(B) Grant & Reeves(55) stated that tachycardia and hypoten- sion if observed in human beings for limbs injury ndicates hypovolumia where as similar signs if seen in a case of abdomi- nal injury might be compatable with normal blood volume in him (inspite of signs and symptoms of hypovolumia in him). They therefore felt that neurogenic stress in some unkonwn way controls the outcome of stressful situation because some sus- ceptible individuals might hyper react to such stressful condi- tions. They also noted that morbidity or motality increased dur- ing stressful conditions, specially in Vulnerable persons.. 3(C) Rocco & Vandum (56), Vandom et al (57) and Folkow et al (58) showed that manipulation of abdominal contents un- der general anestheisa caused changes in pulse rate, pulse pres- sure and blood pressure in patients which culd be abolished by simultaneously use of local or regional blocks. Vandom (57) and his colleagues in 1962 revealed further that, even though every patient produced stress reaction leading to changes in circula- Neurophysiology & Anaesthesia 106
  • tion up to some extent, poor risk patients (who, because of long period of suffering and who became cachetic with changes in protein content, body water and elcrolytes etc.). They reacted maximally to the surgical stress which increased the mortality rates in them. they also stated that such an increase in morbidity and mortality rates were directly related to the hyper reactive nature of poor risk patients to the surgical stress. Folkow et al (58) further revealed that circulatory changes in humans during abdominal surgery was mainly due to the stimulation of adrenaergic nerves (as a part of stress response). According to Weiner et al (59), stimulation of adrenergic nerves lead to the stimulation of hypothalamus (Redgate(60) & Gelhorn (61) lead- ing to release of biologically active amines (like epinephrine, Norepinephrine, dopamine etc.) 4. NEUROGENIC STRESS OF SURGERY CAUSING AWARENESS DURING SURGERY AS WELLAS THE COMATIC CONDITION IN PATIENTS IN POST-OPERATIVE PERIOD. 4(A) It is known that stress of any type could in addition to other side effects, released stress products (sympathetic amines like epinephrine, norepinephrine etc.). It is now weidely believed that modern techniques of balanced anestehteic states do not cause significant amount of stress. However, it is noted that poor risk patients & those persons who are scared of surgery and ap- prehensive towards the surgical/anesthetic procedures, do re- lease significant amount of stress products. Rao & Bhatt (66) & Rao L.N. (52) investigated the Norepinephrine concentration in patients, prior to, during opearative procedures and also in the post operative period. they observed wide variatins in concen- trations of norepinephrine in 3 types of anaesthesia even when Neurophysiology & Anaesthesia 107
  • they were operated for similar surgial procedures. IN this con- nection, the work of Bowman & Nott(68) and Naess & Sirnes(69) was found to be relevant because they indicated that Norepi- nephrine when present in significant quantity initially enhances the activity of neuro muscular transmission, but they found that after sometime, it prolongs the failure of neuro muscular trans- mission at the level of neuro muscular junctin so that after the lag period, the norepinephrine acts like a neuro muscular block- ing agent (like d’tc. or gallamine) but it’s effect would be for a prolonged period. Similar observations were made by Bowman & Raper(70) and Ellis & Beckett(82). Paton & Zamis (16) and others(68,69,70,84,85,86) who emphasized that though initially Norepinephrine facilitate nervous tissue, it, in the second phase of its acitivity (after 20-30 min) depresses the functional units of C.N.S.) leading to the comatic and paralytic condition in the patient in the post-operative period. 4(B). In the study of Rao(52) and Rao & Bhatt(66), large amounts of norepinephrine were released by some patients even before operation was started. Some patients similarly released large quantities of norepinephrine during the surgery and in post operative period. Hence, large and un-physiological levels of Noreinephrine would cross the blood brain barrier and in it’s second phase of activity cause depression of central synopses in C.N.S. (76,84,85,86) thereby producing the syndrome of con- tinued unconsciousness in addition to the depression of other vital functions. So far, the anesthesiologists (3 to 8, 17, 80) world over blamed the skeleto muscular relaxant drugs for the syn- drome of depressed vital functions in the post-anesthetic period which is not correct because evidence was put forward earlier refer 1(C), that skeleto muscular relaxant drugs do not act on C Neurophysiology & Anaesthesia 108
  • C.N.S. Rao et al. (14, 52,66,67,71) studied the aspet of post- operative complication in some vulnerable patients (during ex- periments in patients undergoing surgery). They concluded that hyper reactive nature of some vulnerable patients lead to the accumulation of nor-adrenaline in C.N.S. Since coma and para- lytic condition in surgical patients is due to such accumilation of noradrenaline in C.N.S. Rao & Bhatt (71) treated the patients (affected) by the post-operative paralysis by extraction therapy. Unlike the action of skeleto muscular relaxants, adrenaline & other symathatomimetic amines act for prolonged period (4 - 8 hrs or more) such drugs (sympathomimetic drugs) are partially metabolized but they have to be forced out through kidney with extraction therapy. However, during such a period of the post- operative depression of vital functions, the affected patients have to be on a ventilator and their vital functions are to be main- tained in a respiratory care unit. Sime 30-40% of operating units in under developed and developing countries or in rural areas with no infrastructure to attend to such cases with a standby ventilator, the anesthesiologists in those operating units have to be taught the neuro physiological mechanism which causes the syndrome in the post operative period. They should be told to maintain respiratory function of the affected patients for 2 - 4 hrs or more by anestehtic machine, or ambubag or other meth- ods at his disposal. they have to be taught in addition, the ex- traction therapy which includes dehydrating the patients with suitable solution, with simultaneous infusion of I.V. Fluids to compensate the loss in body fluids & electrolytes during dehyderation therapy. Atropine + Neostigmine(71) (or other equivalent drugs) should be used periodically to increase Neurophysiology & Anaesthesia 109
  • acethylecholine levels in C.N.S. till vital functions are restored to normalcy. 4(C). In this connection, we have found out that awareness during surgery is also due to the patient’s factor. The central synapses, which control the activity of C.N.S. and which were earlier depressed by pulmonary receptor oriented vagal affer- ents (during I.P.P.V. Under balanced anesthetic techniques), are stimulated to restore the normal activity by stress products (noredrenaline etc.) in some vulnerable individuals by stimulat- ing (ARS). However, after the initial phase, the stress product would produce complete depression of C.N.S. in the second phase of it’s activity. Such patients would present the syndrome of depressed vital functions in their post-operative period. It is necessary to understand at this stage that even though both con- ditions (awareness during surgery and the syndrome of depres- sion of vital functions in the post-operatie period) are inter-re- lated (to the action of stress products on the body of a sensitive patient who hyper reacted to neurogenic stress of surgery), it need not be presumed that a patient who is aware during sur- gery, would also get the syndrome of the depressed vital funcitons in the post-operative period. CONCLUSION: Since 1942, specially during the last 25yrs, surgery of patients with diseases of kidneys, heart, lungs, brain etc. associated with gross changes in electrolytes, metabolic disturbances, circulatory & respiratory failure, beame pssible purely due to miraculous developments in the field of Anesthe- siology. Consultant anesthesiologist is now a respected member of medical faculty. However lack of knowledge of the develop Neurophysiology & Anaesthesia 110
  • ments in basic sciences which have a great role in the field of anesthesiology resulted in a situation, when, even a senior most anesthesiologist is humiliated because he is unable to explain the reasons under which intra-operative complication (aware- ness during surgery) and post-operative complication (post- operative paralytic conditions in some operated patients) occur during and after surgery under anesthetic techniques. This situ- ation is due to the fact that anesthesiology (as a spciality) is not a clinical pharmacology. It is infact a clinical neurophysiology in which three factors are imortant. First factor is the inability of skeleto muscular relaxant drugs to act on C.N.S. second factor is the role of I.P.P.V. in which unawareness is caused in patients during surgery (including other beneficial effects) by I.P.P.V. Third factor is the patients factor (P-factor) which is respon- sible to produce the stress products in some vulnerable patients thereby causing awareness during surgery as well as pot-opera- tive paralytic condition with coma in some operated patients. P- factor is also responsible to cause many other types of compli- cations in peri operative period. REFERENCES: 1. Neff, W., Mayer, E.C., and Porales, M, Nitrous oxide & oxygen anesthesia with curare relaxant, Cal. Med. 66,67, 1947. 2. Mushin W.w. and Rendel Baker L. Pethidine as supplement to N2O anesthesia, Brit. M.J. 2, 472, 1947. 3. Foster, P.A., Potassium depletion & centarl action of curare, Brit. Aaesthesth., 28, 488, 1956. 4. Huter. A.R. Neostigmine resistant curarization, Brit. Med. J. 2, 919-20, 1956. 5. Brechner. V.L. Clinical syndrome of incomplete neuro-muscular block reversal: Doctor look at your patient, Anaesth Analg. 50, 876-78, 1971. Neurophysiology & Anaesthesia 111
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  • Editor, “Neuro humumoral correleates of behaviour”, Thomson press (India) Ltd. Faridabad, haryana, India. 234-43, 1977. 53.Wang S.C. The importance of afferent nervous factors in experimental traumatic shock: the effect of chronic deafferentation, Amer. J. Physiol. 148, 547-56, 1947. 54.Overman R.R. and Wang S.C. The contributory role of afferent nervous factors in experimental shock: Sublethal haemorrhag and sciatic nerve stimulation, Amer. J. Physiol. 48, 289-95, 1947. 55.Grant, R.T. and Reeve E.B. as reported by R.P. Harboadr in Evans F.T. & Gray T.C. Editor, Modern Trends in anesthesia Vol.-I, Butterworths, London, Page 163, 1958. 56.Rocco A.G. and Vandam L.D., Change in circulation consequent to manipulations during abdominal surgery, J.a.M.A. 164, 14-8, 1957. 57.Vandam L.D. Scheveizer H.J. and Kubota, Circulatory response to intra abdominal manipulations during etheranesthesia, Circulatory response to intra abdominal manipulations during etheaneshtesia, Circ. Res. 11, 287-95, 1962. 58.Folkow B. Gelin L.E., Stenburg K. cardiovascular action during abdominal surgery Ann. Surg. 156, 905-13, 1972. 59.Weiner N., Gloutier G. Bjur R., and Peffer R.I., Modification of norepinephrine syntehsis in intact issues by drugs and during short term adrenergic nerve stimulation, Pharmacol. Rev. 24, 203-21, 1972. 60.Redgate E.Sl, and Gelhorn E, Nature of sympatho adrenal discharge under condition of excitation of central nervous structures, Amer. J. Physiol. 174, 475-80, 1953. 61.Gelhorn E. Physiological foundations of neurology & psychiatry, University of Minnesota Pres, Minneaspolis, 1953. 62.Kostreva D.r., Juperku E.J., Hess G.L. Coon R.L., & Kampine J.P., Pulmonary afferentitzer activity recorded from sympathetic nerves, J.Appl. Physiol. 39(Vol.-I), 37-40, 1975. 63.Schveitzer A. & Wright S Effects on Kneejerk of stimulation of the central end of vagus & of various changes in the circulation & respiration. J. Physiol. 88, 459-75, 1937. 64.Chase M.H. & Naka Mura Y. inhibition of the mesentric reflex by vegal afferents, Experentia, 24, 918-19, 1968. 65.Evans mH. & MvPharson. The effects of the electrical stimulation of visceral afferents fibers on monosynaptic & polysynaptic reflexes responses, J. Physiol. 150, 105-113, 1960. Neurophysiology & Anaesthesia 115
  • 66.Rao L.N. & Venkata Krishna Bhatt H., Stress response during surgery & anesthesia: Indicated by concentration of norepinephrine in plasma of surgical patients, International surgery, 57, 295-98, 1972. 67.Rao L.N. Peripherally evoked cental nervous resonses during surgery under general anesthesia: A clicnico neuro physological correlation, Ind. J. Anesthesia. 15, 81-3, 1967. 68.Bowman W.C., & Nott M.W., Actions of sympathomimitic amines & their antagonists on skeletol muscles, reviews, 21, 27-72, 1969. 69.Naess K. Sirnes T.b., Synergetic effect of adrenaline & d’tubocurarine on neuro muscular transmission. Acta. Physiol. Scandinev. 29, 293-306, 1953. 70.Bowman W.C. & Raper C. Effects of symathomimitic amines on neuro muscular transmission. Britt. J. Pharmacol. Chemother. 27, 313-31, 1966. 71.Rao L.N. & Venkata Krishna Bhatt H., syndrome of post-operative depression of vital functions in poor risk patients: its treatment, International. J. Pharma & toxicol. 19, 18-22, 1981. 72.Lundy J.s., Balanced anesthesia Minn. Medi. 9, 399, 1926. 73.Wilkinson I.M.S. & Brown D.R.G. The influence of anesthesia & arterial hypocaponea on regional blood flow in normal human cerebral hemisphere. Brit. J. Anaesth. 42, 472-82, 1970. 74.Trendlen Berg G.U., Editorial, Anesthesiology, 25, 259-261, 1964. 75.Tomori Z. & Widdicomb J.G. Muscular brochomoter & cardiac reflexes elicited by mehcanically stimulation of respiratory tract. J. Physiol. 200, 25-50, 1969. 76.Lundberg A., Adrenaline & transmission in the sympathetic ganglion of the cat. Acta. Physiol. Scandinev. 26, 252-63, 1952. 77.Kogure K. Scheinburg P., Fugishima H., Busto R. & Reinmuth O.K. Effects of hypoxia on cereral auto regulation. Amer. J. Physiol. 219, 1393-96, 1970. 78.Lassen N.A., Cerebral blood flow & O2 consumption in Man, Physiol. Rev. 39, 183-238, 1959. 79.Millar AT Jr., Curtain K.E. Shen A.l. & Suiter c.K. Brain oxygenatin in rat during hyperventilation with air & with low O2 mixtures. Amer. J. Physiol. 219, 798-801, 1970. 80.Baraka A., Irversible tubocurarine neuro muscular blocks in the human being, Brit. J. Anaesth. 39, 891-94, 1967. Neurophysiology & Anaesthesia 116
  • 81.Fowweather F.S. Davidson C.C. & Ellis L Spontaneous hyper ventilation tetaney, Brit. Med. J. 2, 373-75, 1940. 82.Ellis S., & Bektt, S.B., Depression of neuro muscular transmission by Norepinephrine, Fed. Proc. 14, 336, 1955. 83.Robson, G.J. Respiratory centers & their responses-evans FT & Gray T.C. editors modern trends in Anesthesia, Vol. 3 London, Butterwoth, 42-53, 1967. 84.Rothbeller AB, effects of catecholamines on central nervous system. Pharma. Rev. 11, 195, 494-547. 85.Burn J.H. relation of adrenaline to acetyle choline in the nervous system. Physiol. Rev. 25, 789-99, 1945. 86.Abraham V.C. & Pickford. M. observations on central anatagnism between adrenaline & acetyle choline J. Physiol. 196, 131, 712-18. 87.Jouvet, M. Neurology of status of sleep, Physiol. Rev. 47, 117-163, 1967. ***** Neurophysiology & Anaesthesia 117
  • SECTION - I (E) RESULTS OF INVESTIGATIONS INTO THE FUNDAMENTALS OF ANAESTHESIOLOGY 1. Skeleto muscular relaxant drugs act only at the neuro muscular junction and cause paralysis of skeletal and respiratory muscles. 2. Such drugs produce R.E.M. Type of sleep (when injected into carotid artery), hence they have no role in producing ideal operating conditions in patients (when they are used to anaesthetise the patients during surgery). Following are the details. a) They do not cause any change in the activity of CNS (except producing bouts of REM type of sleep), even when they are present in blood and CSF of patients, (10% to 25% or more of paralyzing concentration of the drug at the time of recovery from anaesthesia). Patients do recover normally). b) They can not cause the syndrome of depressed vital functions in the post operative period. Because they have no capability to cause paralysis and coma in the patients in post operative period. c) Since they do not depressed CNS, (directly) they cannot cause a areflexia, analgesia, reflex relaxation of diaphragm and other respiratory muscles (which are necessary to produce ideal operating condition during general anaesthetic techniques). They can only produce light stage of sleep (REM sleep in patients in the immediate post operative period but any disturbance in the patients causes activity in them (who was sleeping earlier). Neurophysiology & Anaesthesia 118
  • 3. Higher faculty, normally existing in a awake individual would nnot continue to restrain respiratory reflexes in patients who receive thiopentone or its equivalent drugs, N2O and oxygen, relaxant anaesthesia. This phenomenon is revealed by fact that irritant receptor which are stimulated by endotracheal intubation in a patient causes changes in blood pressure, pulse rate, etc., hence it is highy likely that during thiopentone, N2O, oxygen, relaxant anaesthesia all other receptors present in the tracheobronchial tree and lung-parenchyma are actively stimulated during pressure ventilation (I.P.P.V.) (which is a part of general anaesthetic technique). Hence I.P.P.V. stimulates inflation receptors, deflation receptors, stretch receptors, type J receptors, and irritation receptors. When patients are operated under general anaesthesia. I.P.P.V., therefore leads to large volley of afferents in vagal nerves which act on various neurones of CNS (during I.P.P.V.). Such vagal afferents therefore modify the activity of various neurones of central nervous system causing ideal operating conditions during general anaesthetic techniques (please read our special research paper in section I (F-2) on this subject). 4. Ideal operating conditions, produced during general anaesthetic techniques are therefore due to the reversible depession of CNS. 5. Unawareness occurring during general anaesthetic techniques, is again due to vagal nerves, acting through trigonal area of vagal and glossopharynged nerves (neurons of vagal and glossopharyngeal nerves coupled with adjacent neurons of CNS in the floor of 4th ventricle). (Previously these neurons were called Neurophysiology & Anaesthesia 119
  • bulbar part of mesentic reticular formation). Vagal nerves stop the activity of the ascending reticulo alerting system (ARS), (which is called activating system). Hence unawareness in a human being (who is anaesthetized during I.P.P.V.) is due to the vagal activity which strengthens deactivating system present in trigonal projections of IX and X nerves (coupled with neurons adjoining the vagal trigones) (which was earlier called bulbar reticular formation). Hence patients are unaware during IPPV (due to the activity of deactivating system which is strengthened by vagal afferents. In addition, Vagal nerves, acting through deactivating mechanism existing in bulbar reticular formation (and with the help of magoun and rhynes area of medualla, hypothalamus, thalamus etc.) cause areflexia, reflex relaxation of diaphragm and other respiratory muscles, including apnoea and analgesia, because all the neurons concerning these functions are a part of deactivating mechanism. ***** Neurophysiology & Anaesthesia 120
  • Fwd: IARS 2011 Annual Meeting - Abstract Author Disclosure Notification - Second Reminder! 1 message __________________________________________________________________ narahari <> Mon, May 2, 2011 at 8:22 PM To: -----------forward message---------- Date: 2011/4/29 Subject: IARS 2011 Annual Meeting - Abstract Author Disclosure Notifica- tion - Second Reminder! To: “” <> Cc: “” <> Dear Dr. Lakkaraju, The IARS Abstract Submission System has identified you as a co-author on an accepted abstract submission for the IARS. 2011 Annual Meeting, May 21-24, 2011, in Vancouver, Canada. Our system shows that you have still not completed you disclosure; we will need this completed prior to the meeting and presenation of the post. The system is now closed and you can no longer enter your information online so wel will need you to complete the attached form and either scan and email it back to or fax it back to 415-296-6901. We will enter this into the system on the backend for you. Please note - If you are the co-author on multiple submissions we do not need multiple disclosures. Please fill-in and return only one completed disclosure statement. Note: We are unalbe to enter disclosures without legible names written on the top portion of the form. If you received this email before and sent your disclosure, but did not complete this section, we are contacting you again to send one that w can enter. Please return the completed form no later than Friday, May 6, 2011. Congratulations again on the acceptance of your abstract for the IARS 2011 Annaul Meeting, we hope to see you in Vancouver! Sincerely, ****************** Meetings Department International Anesthesia Research Society Phone (415) 2966900 / Fax (415) 296-6901 Neurophysiology & Anaesthesia F1 - 121
  • FINAL RESEARCH PAPER (PAPER BASED ON RESEARCH FOR 25 YEARS ON GENERALANAESTHETIC TECHNIQUES) NEUROPHYSIOLOGY IS THE BACK BONE OF ANAESTHESIALOGY By: PROF. L.N. RAO NOTE: This paper was to be presented at annual conference of International Anaesthesia research society in may 2011. He could not presented it because visa to Canada was not given F2 122
  • NEUROPHYSIOLOGICAL BASIS OF REVERSIBLE DEPRESSION OF C.N.S. DURING GENERAL ANAESTHETIC TECHNIQUES INTRODUCTION After introduction of skeleto muscular relaxant drugs into the speciality of anaesthesiology, a revolutinary success is achieved in the methodology of general anaesthetic techniques. Hence anaesthesiologists world ever, speculate that various beneficial actions of general anaesthetic techniques (which cause unaware- ness during surgery and produce ideal operating conditions) could be due to the reversible depressin of C.N.S. during such techniques, due to skelto muscular relaxant drugs acting periph- erally on neuro muscular junction and centrally on C.N.S. How- ever, experimental evidences do not support such a possibility because Dr. Smith et al (1) did not find evidence of the involve- ment of C.N.S. in a volunteer, who received 2½ times the para- lyzing dose of d’tubocurarine (dtc). the volunteer (in spite of large dose of d’tc) (administered IV) retained signs of active function of C.N.S. in him. Harnath et al. (2,37) injected dtc. & various other drugs with dissimilar action into the carotid artery of unanesthetised dogs & found that all the drugs injected in them caused sleep (R.E.M. type of sleep), thereby indicating that sleep, caused with variety of drugs (with dissimilar action) in unanesthetised dogs, was a non-specific phenomenon. They also injected 500 micrograms of dtc. in unanesthetised dogs (into the carotid artery & found that, apart from sleep peripheral ef- fect in such dogs (depression of respiration and changes in muscle tone etc.) did not develope in them (37). dtc in smaller doses when infused in some dogs produced irritability in them Neurophysiology & Anaesthesia 123
  • without producing peripheral effects (no paralysis of respira- tory and skeleto muscular tone). Other scientists (3 & 4), when they administered higher doses of dtc found such dogs irritable & some dogs had sceizures. These experiments clearly indicated that dtc caused only non specific type of sleep in unanesthetised dogs & higher doses caused irritation of C.N.S. rather than the depression of C.N.S. secondly the sleep produced by dtc. in ex- perimental animals (as well as in patients inthe immediate post- operative period), appears to be similar to the sleep produced by the administration of sleep dose of Thiopentone sodium (or other hypnotic drugs), which is commonly used to produce sleep be- fore the start of general anaesthesia (with skeleto muscular drugs). It is a well known fact that surgery (major or minor) cannot be done with only thiopentone. Hence sleep produced by skeleto muscular relaxant drugs is not enough even for minor surgery, thereby indicating that ideal operating conditions in a patient, for major surgery, are not produced by dtc. or by other relaxant drugs alone. PRELIMINARY INVESTIGATIONS ABOUT SKELETO MUSCULAR RELAXANT DRUGS IN PATIENTS UNDER GOING VARIOUS SURGICAL PROCEDURES Hence further research was carried out in patients who were subjected to various surgical procedures under general an- aesthetic techniques (5,6,7). Aim of the study was to find out factors (other than skeleto muscular relaxant drugs) which could cause ideal operating conditions (reflex relaxation of diaphragm and other respiratory muscles, areflexia, analgesia etc). during general anaesthetic techniques. This study, also aims to find out whether large percentage of paralyzing concentration of skeleto Neurophysiology & Anaesthesia 124
  • muscular drugs, when present in blood and C.S.F. of patients, at the time of recovery from anaestethesia, acting on CNS could modify the recovery pattern of patients (after general anaesthetic techniques). After the use of a hypnotic drug, gallamine (one of the relaxant drugs) or dtc was administered as a bolus dose (30 mg of dtc. or 3.0-3.8 mg of gallamine per Kg of body weight) (ad- ministered I.V.). After starting the surgery, concentration of dtc or gallamine was monitored in them at 15th min. of the adminis- tration of such drugs, in the plasma and CSF of the patients. (it is termed a paralyzing dose). Again at the end of 70-110 min. of surgery, the plasma and csf concentration of these drugs was monitored, (6 patients were given d’tc and 6 patients were given gallamine in the doses mentioned above) and such concentra- tion of relaxant drugs (collected at the time of recovery from anaesthesia) was termed as concentation of relaxant drugs at the time of recovery. (Recovery concentration). RESULTS: It was found that in patients in whom d’tc or gallamine were given for producing ideal operating conditions, 10-25% or more of the paralyzing dose of the drugs, (paralyzing dose of the drug is that which was found at the 15th min. of the admin- istration of the drugs in plasma and csf) was present at the time of recovery. However in this study the patients, (in whom 10- 25% or more of paralyzing dose of the relaxant drug was found at the time of recovery) did not have any difference in their re- covery pattern when compared to other patients in whom the Neurophysiology & Anaesthesia 125
  • drugs like d’tc. or gallamine were routinely used to produce ideal operating conditions. This study therefore confirmed that results of animal experimentals (wherein it was demonstrated that skeleto muscular relaxant drugs do not depress C.N.S.) were aslo applicable to human beings because, when large quantity of d’tc or gallamine (more than 10-25% of paralysing dose) were present on the blood and in C.S.F. of the patients (at the time of recovery), they did not cause depression of C.N.S. in them. In fact all such patiens, after stoppage of anaesthetic procedure, responded to simle commands like opening the eyes, pulling out the tongue etc. (when asked to do so) indicating that their C.N.S., in immediate post operative period, was normally active. Only observation was that such patients sleep for a while, when they are not disturbed. This type of sleep could be ascribed to the nonspecific reaction to relaxant drugs (as seen in animal experiments). This study hence, reveals that, analgesia, areflexia and reflex suppresion of diaphragm (and other respiratory muscles) during general anaesthetic techniques are not due to the action of skeleto muscular drugs on C.N.S. because there is no evi- dence that these drugs act on C.N.S., because even when 10 to 25% or more of paralysing dose of relaxant dosgs was present t the time of recovery (in the blood and C.S.F.), C.N.S. was not depressed in the patients. It was normally active by 10 or 15 minutes of stoppage of anaesthesia. Neurophysiology & Anaesthesia 126
  • CURRENT CONCEPTS ABOUT RESPIRATORY PHYSIOLOGY Review of literature, (specially respiratory physiology & neurophysiology) revealed that all type of pulmonary receptors are stimulated during I.P.P.V. (8-11) (due to volume changes in lungs during I.P.P.V.), there by sending large number of afferent volleys (through the vegal nerves) which reach C.N.S. at fast rates (12-14). Squealae of stimulation of vagal nerves in animal experiments by the physiologists revealed that they (vagal nerves when stimulated) caused behavioural and skeletomuscular pat- tern of sleep (15-21). Reflex relaxation of diaphragm and other respiratory muscles (23,24,35), abolition of largyngeal reflexes (25,26) etc. In this connection, it is believed that development of higher faculties in human brain caused absence of Hering breuere reflex and other respiratory reflexes in man. Hence physi- ologists, and anaesthesiologists feel that respiratory reflex re- sponses in humans could not be the same as seen in animals. In this connection, it is necessary to point out that, an unconscious and fully relaxed patient, does not retain higher faculties to re- strain such reflexes during general anaesthetic techniques with I.P.P.V. The fact that during thiopentone, N2O:O2 relaxant ana- esthesia, significant changes in blood presure and pulse rates occur during endotracheal intubation. (due to the stimulation of irritant receptors in the trachea), indicates that an unconscious human patient acts similar to the animals (specially about his/ her response to reflexes elicitated by stimulation of irritation and other receptors of tracheo bronchial tree and pulmonary paranchyma). Hence insertion of endotrachealtube and I.P.P.V. would stimulate various receptors in a human being which would be Neurophysiology & Anaesthesia 127
  • similar to the experimental animals specially when the patient is unconscious with thiopentone etc. Hence, it becomes necessary to explore the result of various afferent impulses in vagal nerves (due to the stimulation of receptors in the lungs during I.P.P.V., (specially their ability to reversibly depress C.N.S. in patients during I.P.P.V.) THE NEUROPHYSIOLOGICAL MECHANISM WHICH CAUSES DEPRESSION OF C.N.S. DUE TO VAGALAFFERENTS DURING I.P.P.V. (DURING GENERALANAESTHETIC TECHNIQUES) According to the neurophysiologists C.N.S. has two ma- jor systems (mechanism) which are termed asAscending reticulo alerting system (A.R.S.) (activating mechanism) which keeps the neurons of cerebral cortex lobes actively functioning and its anatagonist the de-activating system (de-activating mechanism) which stops the activity of A.R.S. periodically, to give CNS rest needed. The main constituent of reticulo alerting mechanism (ARS) is in the cholinergic system (measencephalic reticular formation in the brain stem with the associated active involve- ment of pons and other neurons of cholinergic system in CNS (27-32). (Even though some physiologist revealed that someother neuro-humours take part in the cholinergic system, Acetylcho- line appears to be the main neuro-humour which acts as the neuro transmitter of cholinergic system). The afferent stimuli from periphery as well as the internal organs of the body (36) (tactilesensation, sensation from skin, bones, joints and internal organs of the chest, abdomen and the brain) which are transmit- ted by autonomic nervous system are the motive force of the mesencephalic reticular formation and other neurons of activat- ing system (ARS) in the CNS (36). Under the influence of such Neurophysiology & Anaesthesia 128
  • afferents, ARS in the cholinergic system produces large quan- tity of acetylcholine (possibly other neuro humours) which acti- vate the neurons of the cerebral contex in CNS. In this connec- tion, it is accepted by physiologists that ascending reticular for- mation (activating mechanism), whose cells are in the midbrain, is necessary for initiating the activity of cortical neurons of C.N.S. (good analogy in this context is a car battery which starts firing of self motor of an automobile). Due to some reason, if ARS (activating mechanism) does not function, the neurons of cere- bral cortex (which are periodically stopped from functioning by deactivating mechanism) do not start functioning. (Even when normal and healthy state of cortical neurons is present). Hence cortical neurons in the cerebrum requires ARS (and acetylcho- line) to start spontaneous and repetitive firing of cerebral corti- cal neurons to keep the person conscious (27-32). The other sys- tem called deactivating mechanism is situated in bulbar reticu- lar formation in the brain (which is situated in the trigonal area of vagal and glossoharyngeal nerves and other neurons adjoin- ing trigones in the floor of fourth ventrical) (17,19,33). Physi- ologists experimentally proved that bulbar reticular formation is connected with magoun and rhynes area in the medulla as well as with thalamus, hypothalamus and prefrontal region etc. It is further learned that all these neurons in C.N.S. function as a single functional unit. Respiratory centre is observed to be lo- cated close to this functional unit. It is also learnt that vagal nerves (when stimulated during I.P.P.V.), act on all these units of deactivating mechanism, there by causing unawareness in patients during I.P.P.V. (due to suppression of the activity of ARS) as well as apnoea, areflexia and other con- stituents of ideal operating condition (due to their action on other neurons close to them). Secondly during I.P.P.V. huge volley of afferents in vagus stimulate the deactivating system which vir- Neurophysiology & Anaesthesia 129
  • tually shuts down the activity of ARS and stops the activity of cerebral cortical neurons. It is also learnt that deactivating sys- tem stops the peripheral sensory stimuli (afferents) reaching mesenchephalic reticular formation and other neurons connected to ARS (34). Hence during I.P.P.V., ARS and other supporting systems are stopped, thereby leading to the reversible depres- sion of cerebral cortical neurons in C.N.S. (due to the action of deactivating system which is strengthened by vagal afferents). Hence the patient during surgery with I.P.P.V. becomes unaware of surgery. DICUSSION: Basing on the experimental evidences of various physi- ologists, it is obvious that reversible depression of certain neu- rons in CNS which occurs in modern techniques of general ana- esthesia (in which I.P.P.V. is the main factor in the paralyzed patient), is purely due to the afferents in vagal nerves which acting through bulbar reticular formation (Trigones of IX and X nerves and as well as the adjoining neurons in fourth ventricate of C.N.S.), strenthens the deactivating system leading to un- awareness in the patients during the techniques in which I.P.P.V. is used. Patient is also apnoeic, areflexic, atonic and has analge- sia, etc. purely due to reversible depression of neurones specific to those neurons of central nervous system.As soon as I.P.P.V. is stopped, all these neurones in CNS recover from the depression and the patient becomes normal and active (with in 5-10 min. in the post operative period) because after stoppage of I.P.P.V. reticulo alerting system (ARS) becmes active and produces neuro humours, specially Acetycholine which is necessary for normal activity of various cortical neurons of CNS (which were stopped functioning during I.P.P.V.) Hence in Neurophysiology & Anaesthesia 130
  • patients, CNS becomes normal within 5-10 min of cessation of I.P.P.V. and he/she responds to simple commands like opening the mouth and putting out the tongue (when asked to do so). Some patients even answer the questions like telling his name etc. (However, patients sleep for sometime, when they are not disturbed). SUMMARY AND CONCLUSION: Basing on the above facts it is clear that present tech- niques of general anaestheisa are based on an interplay between activating and deactivating mechanism in C.N.S. and the main cause of such an interplay of these mechanisms in C.N.S. is the I.P.P.V. in a well relaxed patient. The patient who is receiving I.P.P.V. initiates & strengthens the deactivating system to stop ARS. Skeleto muscular relaxant drugs only help the anesthesi- ologists to pin down the patient to the operation table and to intubate him with an endotraceal tube as well as to institute pres- sure ventialtion in him (without any resistance). Artificial ventilation (I.P.P.V.) with O2 and other gases act as a means to produce ventilatory support and to provide sufficient O2 to the patient as well as helping to produce ideal opearting conditions in him, (which are produced by deactivating systems). Patient is unware of surgery and has analgesia, areflexia, reflex depres- sion of respiraotry muscles (including diaphragm), only due to the strengthening of deactivating system by the vagal afferents (due to the effect of pulmonary receptors during I.P.P.V.) REFERENCES: 1. Smith, S.M. Brown, H.O., Toman, J.E.P. & Goodman C.S., the lack of central effects of d’tubocurarine, Anesthesiology, 1947, 8, 8-14. Neurophysiology & Anaesthesia 131
  • 2. Harnath, P.S.R. Sunanda Bai, K. & Venkatakrishna Bhatt H., Intracarotid injections and infusion of cholinominitic drugs and their anatagonists in conscious dogs, Brit. J. Pharmac. Chemother. 1967, 29, 42-54. 3. Salama, S., & Sright, S., action of d’tubocurarine chloride on the central nervous system of the cat. Brit. J. Pharmac. Chemother. 1950. 548-61. 4. Feldburg, W. Sherwood, S.L. injections of drugs into lateral vertial of the cat. J. Physiol. Lond. 1954. 123, 148-67. 5. Devashankaraiah, G. Harnath. P.S.R.K. & Krishnamurthy A., passage of dtc. from blood into liquor spaces in dogs and man, Brit. J. Pharmacol. 1873, 47, 787-93. 6. Harnath, P.S.R.K. Krishna Murthy A., Rao L.N & Sheshagiri Rao K. passage of gallamine from blood into liquor spaces in man and dog. Brit. J. Pharmacol. 1973, 48, 640-45. 7. Rao L.N. & Venkata Krishna Bhatt H., Role of theophentone, Nitrous oxide and relaxant anaesthesia in causing the syndrome of post operative paralysis in man. Derr Anesthetists 1975, 24, 73-77. 8. Coleride, H.M. Coleridge J.C.G. & Luck, J.C., Pulmonary afferent fibers of small diameter stimulated by capsicum & by hyperinflation of lungs. J. Physiol. (Lond.) 1965, 179, 248-65. 9. Sellick H., & Widdicomb J.G., Vagal deflation and inflation reflexes mediated by lung irritation receptors. QJL. Exp. Physiol. 1970, 153-63. 10.Paintal A.S. Mechanism of stimulation of tyoe “J” Pulmonary receptors, J. Physiol. (Lond.) 1969, 203, 511-33. 11. Deshpande S.S., Devanandan M.S. Reflex inhabitation of monosynaptic reflexes by type “J” pulmonary endings J. Physiol. (Lond.), 1969, 206, 345-57. 12.Adrian E.D. Afferent impulses in Vagus & their effect on respiration, J. Physiol. (Lond.) 1933, 179, 248-62. Neurophysiology & Anaesthesia 132
  • 13.Rao L.N. Rama Rao K.R. & Balla S.K., increased afferent activity (vagal, splanchnic etc.) leading to hyperventilation syndrome during surgery under-general anaesthesia, Ind. J. Anesth. 1966, 14, 226-32. 14.Rao L.N. Pathophysiological changes during aritificial over ventilation, A. Curadi Ruggeio Rizzi editor symposium Internationnazionaie, Remimazione. E. Theraphiea intesnsive extra chirarurgiche, Asiago (Vicenza) Italia, 27, Guingo-Luglio 1971, pages 694-702. 15.Robinson, J.S. & Gray T.C. obervation on cerebral effets on passive ventilation Brit. J. Anesth. 1961, 33, 62-8 16.Hughes, J.R. King, B.D. Cutter J.A., & Markello R., the E.E.G. In hyperventilated lightly anaesthetized patients, electro encephal. Clin. Neurophysiol. 1962, 14, 274-76. 17.Bonvallet M. & Dell P., Bulbar control of the arousal system, electro encephal. Clin. Neurophysiol. 1964. 17, 440-41 18.Bonvallet M. & Dell P., Reflections on mechanism of action of hyperventilation on E.E.G. electro Enchephal. Clin. Neurophysiol. 1956. 8, 170-76. 19.Moruzi G. Berluchi G. Maffei L., Strato G., Hypnogenic brainstem mechanism antonists to reticular alerting system, Electro encephal. Clin. neurophysiol. 1964, 17, 448-52. 20.Geddes I.C. & Gray T.C. Hyperventilation for maintenance of anaesthesia 1959, Lancet 2, 4-8. 21.Jouvet, M. Neurology status of sleep, Physiol. Rev. 1967, 47, 117-63. 22.Bollem A.R., Electro-encephologram in anaesthesia, 1962, 348, 90-96. 23.Downes H., Hyperventilation & abdominal reflex inhibition in the rat, Anesthesiology 1963, 24, 615-18. 24.Katz R.L. & Wolf C.E. Neuromuscular & electromyo-graphics studies in man: effects of hyperventilation, Co2 inhalation & dtc., anesthesiology, 1964. 25, 781-86. 25.Rudamin P. Presynaptic inhibition induced by vagal afferent volleys, J. Neurophysiol. 1967, 30, 964-81. Neurophysiology & Anaesthesia 133
  • 26.Rudamin P. Primary afferent depolarization produced by vagal visceral afferents, Experentia, 1967, 23, 117-19. 27.Libet B., Central activation in consciousness and unconsciousness, Prospect. Biol. Med. 1965, 9, 77-9. 28.Krenjevic C.K. Central cholinergic pathways. Fed. Proc. 1969, 25, 113-19. 29.Szerb J.C. cortical acetylecholine release and electroencephalogram arousal, J. Physiol. (Lond.) 1967, 192, 329-40. 30.Bradley P.B. Dhawan B.N. & Worstencract J.H. Pharmacological properties of cholinergic neurons in the medulla & pons of the cat, J. Physiol. (Lond.) 1966, 153, 658-702. 31. Bradely P.B. Dray A.B., short latency excitation of brain stem neurons in the rat by acetylcholine, Brit. J. Pharma. Chemother., 1972, 45, 372-75. 32.Kanai T. & Szerb J.C. Mescncephalic reticular alerting system & corticular acetylecholine out put 1965, nature: 205, 80-4. 33.Magoun H.W., & Rhines R., inhibitory mechanism in the bulbar reticular formation, J. Neurophysiol. 1964, 9, 165-71. 34.Salmoirraghi G.C. & Burns B.D. notes on mechanism of rhythmic respiration, J. Neuronphysiol. 1960, 23, 14-6. 35.Rao L.N. & Venkatakrishna Bhatt H., Vagal activity in canines: its possible relationship with hyperventilation syndrome, Anesth. Analg. 1970, 49, 351-54. 36.Dafney N., Nental E., & Fieldman S., effects of afferent stimuli from parts of the body, Electroencephal. Clin. Neurophysiol. 1965, 19, 256-63. 37.Harnath P.S.R.K. sleep & central cholinergic mechanism in editor Sharada Subramanyam, Neuro humoural correlates of behaviour 1977. Thampsompress (India) Ltd. Publication Division Fareedbad, Haryana, India. Pages 134-39. ***** Neurophysiology & Anaesthesia 134
  • SECTION-II PATIENT’S PERSONALITY FACTOR (P.FACTOR): IT’S ROLE IN CAUSING COMPLICATIONS AND CATASTROPHIES IN PERI OPERATIVE PERIOD SECTION-II (A): Commonly observed complications in peri operative period: Type-1: Awareness during surgery in patients who are undergoing surgery even when general anaesthesia is continuing (read the article in section II of the book). Page - 211 Type-2: Delayed recovery of patients who were operated under generalanaesthesia(for4to8hoursormoreinpostoperativeperiod) (read the article in section II of the book). Page - 200 Type-3: Patients after general or regional anaesthesia develop severe hypo-tension, tachycardia and unresponsive nature of vasculature to the normally used Vasopressors. Such a complication is similar to that which was seen in soldiers of Vietnam War. The soldiers in that war exhibited “Shock Syndrome” after minor injuries in which no blood loss occurred in them. Hence, patients who developed similar clinical picture during or after minor surgery are called the patients with “Shocks Syndrome” (or vaso constrictive vascular failure), which developes after any form of anaesthesia. Type-4: Patients after general or regional anaesthesia who developed “Shock Syndrome” even though, the surgery was minor. Such patients also develope pulmonary aedema. (due to Neurophysiology & Anaesthesia 135
  • pulmonary vasoconstriction). Hence, they are called vaso constrictive pulmonary failure type of patients. Type-5: Other complications which occur in some patients in the immediate or delayed post operative period. a) Transient loss of memory in the immediate or delayed post operative period. b) Abnormal behavioural tendencies in some vulnerable patients in post operative period. SECTION II (B): INTER ACTION WITH PATIENTS IN PRE OPERATIVE PHASE AND POST OPERATIVE PHASE 1.0 During our study (during research project which started from 1964), we noticed various neurophysiological factors in vulnerable patients who caused all types of complications in peri operative period. We understood during the course of study that some vulnerable patients hyper react to the surgical stress and result of their hyper reaction to surgery causes all type of complications. We have printed various articles published or presented during gatherings of anaesthesiologists in India about the mechanism of these complications. We also reprinted in this book facts about the stress response (the details of which are not readily known). Prof. L.N. RAO, one of the authors provided such information in the form of a chapter (chapter 29) in a book by the name “NEURO HUMOURAL CORRELATES OF BEHAVIOUR” which is in response to a circular from physiologists to clinicians in 1992 for participation in a satellite Neurophysiology & Anaesthesia 136
  • symposium on the subject (BEHAVIOUR) (as a part of the international conference of physiologists in 1974). the book is edited by famous Indian physiologists Dr. Sharada Subramanyam. The chapter 29 in the book mentioned is reprinted in this book in the published articles (section 2 of the book). 2. To understand the factors which caused various complications, we selected at random 50 thousand patients and our team of research workers interacted with them in pre operative and post operative phases. Such patients also were interacted at the time of their discharge from the hospital by our team of research workers. Whenever possible, our team interacted with their family members also including their spouses at home. They were asked about their reaction to trivial incidents in life, their sex life, their suitability with their spouses and their adjustment with their spouses as well as other members of the joint family. Finally we questioned them in the post operative period whether they were aware and heard the discussion between the surgeon and other members who were present in the operation theater (even when the surgery was going on and patient was anaesthetized). During the period of 10 years of study, out of 50 thousand patients selected at random, we found only 10 thousand patients were intelligent enough to understand our questionnaire. They were intelligent and also ready to reveal their private life as much as possible so that their intimate information about the personality could be gauged by our team of research workers. The remaining patients out of 50 thousand could not understand our Neurophysiology & Anaesthesia 137
  • questionnaire. Hence, they were only observed about their reaction to various aspects of the life in the hospital, in the preoperative and post operative periods only. They were also observed about their feelings particularly about their colleagues (patients who developed complications during or after surgery). It was observed that significant member of such patients developed “shock syndrome” type of complications, with or without pulmonary aedema. More than 100 patients developed type-3 or type-4 complications which was treated and patients were discharged from the hospital. 3.0 Results of our study are given below: a) 90% of the 10,000 subjects, who understood our questionare and positively interacted with our team workers were found to be normal in all respects. b) Some patients (among them) answered with hesitancy that too after repeated questioning that they did not have sexual happiness with their spouses (females dominate in this category), (they also blamed the joint family system for their failure to get sexual pleasures due to improper atmosphere). They also blamed many members of his/her family to make their lives unhappy. Since no alternative was available to them, they got accustomed to the situation and were trying to live as normal as possible. c) A small number of these patients had vague pains in the abdomen, head and neck, pelvic organs, with low back pain etc. this information was more in childless couples and less in others (who had children). d) Some patients (among the rest of 40 thousand patients) when asked at the time of pre-anaesthetic check-up, their reaction Neurophysiology & Anaesthesia 138
  • to stress and strain in their lives, they answered in a bizarre manner and it was obvious that significant number of such patients had psychiatric tendencies (which were latent but such tendencies could erupt into severe emotional upsets at any time). e) Patients coming to pre-anaesthetic check-up for hysterectomy, interval tubectomy (tubectomy carried out after a lapse of few months or years after the birth of a child). And in male patients who came for vasectomy (in family planning camps) were having more psychiatric tendencies than other patients. f) A group of persons (males and females) complained that their unpleasantness in their lives was the destiny and they blamed the joint family system for the same. g) 0.1 to 0.2 percent of them complained that doctors were inefficient in finding the cause of chronic pain in their abdomen, head, neck, and pelvic region as well as low back pain (they spent considerable money for investigations and they were told that they were normal in all respects).They were irritable, cachetic and hyper reacted to trivial nature of problems in lives. h) Our study gave us an impression that good number of persons in he society could at any time explode into highly emotional situations purely due to a latent tendency of psychiatric attitude in life. i) Summarily we could understand that normalcy in their life style in the society does not guarantee an emotion free life when situation becomes against them. Hence, our experience with them (more than 50 thousand patients in 10 years) was as an index to their emotional upsets in life in which such patients developed Neurophysiology & Anaesthesia 139
  • more than hundred cases of shock syndrome with or without pulmonary aedema. Fortunately, we could treat them and send them back to their respective homes. SECTION (C): STUDY OF LITERATURE CONCERNING THE COMPLICATIONS IN PERI OPERATIVE PERIOD. 1.0 Soldiers fighting in Vietnam War in 20th Century, some times, exhibited severe “Shock syndrome”, which is categorized by severe hypo-tension, with very feeble or absent pulse, dizziness or unconsciousness, even when they did not have any blood loss (due to very minor injury). Even though all the above symptoms and signs suggested severe blood loss with major injury, they received only minor injuries (with no blood loss) and on investigation their body contained normal blood volume. It appears that great amount of fear, severe anxiety and highly unfavourable circumstances, do cause major changes in the vital functions in some susceptible individuals leading to hypo-tension, absent pulse (pulse pressure less than 5mm of mercury is not palpable), unconsciousness etc, indicating as if the person concerned suffered severe trauma with large amount of blood loss.All these symptoms categorize him into “shock syndrome”, whereas the investigations found that he had normal blood in the body and his fear of general atmosphere in the battle field has caused the “shock syndrome”. 2. In our series of study some patients who were highly anxious, and either suffered with chronic pain for long time or bodily disfunction were called as poor risk patients by surgeons. Neurophysiology & Anaesthesia 140
  • Such patients are observed to be cachectic with altered body fluid, body proteins, electrolytes etc. Some others who were highly anxious and who faced surgery for trauma or any other emergency surgery also are classified as poor risk patients. Both the group of patients (who are poor risk types) would hyper react to trivial matters to get shock syndrome (during minor surgery under any form of anaesthesia) or when they face very unfavourable circumstances in their lives. 3. During the study, we observed many patients coming up for minor surgery and some others for emergency surgery to go into shock syndrome in the peri operative period similar to the soldiers of Vietnam War. Such complications were observed after spinal or general anaesthesia, even when surgery was uncomplicated. In 1975 we published three cases out of many others who developed shock syndrome with or without pulmonary aedema (please refer the paper title “Clinical signs of neurogenic stress in surgical patients”) in section II among the published articles (printed in this book) to indicate many other cases who presented similar complications. In our study we observed and treated more than hundred complication of these types in more than 10 years. 4.0 Out of the 3 cases, two patients developed “shock syndrome” during or after surgery when spinal anaesthesia was given. 1 case is more interesting because, she was operated 1 month earlier for removal of non cancerous body tumor on the leg bone (Tibia). Surgery for 4 ½ hours and general anaesthesia were uneventful. After 1 month, she was reposted for surgery, when the surgeon intended to fill up the gap in the leg bone Neurophysiology & Anaesthesia 141
  • (tibia) by a turn graft which was minor procedure (when compared to the 1st operation carried on her). However, during 2nd operation (turn graft) she developed “shock syndrome”, with pulmonary aedema. 5. In all the cases, signs and symptoms of shock syndrome are given below in detail. a) They would be pulse-less (pulse pressure was less than 5mm of mercury – so it could not be felt). b) Systolic blood pressure would fluctuate between 70 to 80 mm of mercury in spite of the efforts of anaesthesilogist to bring up blood pressure by the conventional cardio vascular therapy. Blood vessels in their body do not respond to such treatment (blood vessels were insensitive to vaso pressor drugs and other drugs administered during hypo-tension). c) On the advice of Cardiologist, Professor of Psychiatry (late) Dr.Neelkant Rao Yadav was called in and on his advice the 3 cases were given Vasodilator-cum-Central sedative drug like chlorpromazine. It was slowly administered with all the care so that further hypo-tension does not occur in them. During such a treatment other supportive therapy including oxygen and other fluids to support the circulation were given. In the course of 30 to 60 minutes pulse pressure improved and it could be felt. During next 60 minutes systolic blood pressure improved to 100mm of mercury. Meanwhile, after administration of 25mg of chlorpromazine was given I.M., it was observed in next 2 hours that patients were conscious and and blood pressure was satisfactory because even though the diastolic pressure was same, systolic pressure improved to 100mm to 110mm of mercury.After Neurophysiology & Anaesthesia 142
  • 5 to 6 hours of such treatment patient was declared to be normal and was sent to the I.C.U. Attached to the cardio vascular ward for observation and treatment. 6.0 All the three cases before their discharge from the hospital – were inter acted by our research staff. Following are the details of information obtain from the patients. a) ‘M’, the 1st woman (in the article mentioned) had two sons. Her husband forced her to get “interval tubectomy” done so that he (her husband) could bring up the family reasonably well. However, she wanted one more child (preferably a female child) before tubectomy was done. Hence she became phychotic and developed “shock syndrome” after spinal anaesthesia. Incidentally she developedamnesia for all events in the immediate post operative period, which lasted 10 days (after which she became normal). b) ‘P’ the third patient quoted in the article was posted for abdominal hysterectomy under spinal anaesthesia. She had only one son and she did not like to get uterus removed. She wanted one more child. However, her husband, on doctor’s advice (because of chronic cervicities, which may develop Carcinoma of cervix any time) forced her to consent for hysterectomy. She however resisted the operation and it was postponed after tubal ligation under spinal anaesthesia. c) ‘V’ the woman quoted as 2nd case in the article, with stood well during 1st operation (which was 1 month before and it lasted for 4 ½ hours with lot of blood loss). After 1st operation she learnt that a gap of 6" was produced in the leg bone (tibia) during 1st operation. Surgeon wanted, during 2nd operation, to fill up Neurophysiology & Anaesthesia 143
  • the gap by a “turn graft”, which according to her may or may not succeed. Secondly, many of her friends and relatives told her that the removed part of the leg tumor could be cancerous and she may be bed ridden for long period. Under these circumstances (with the rumors of a failure of further surgery and the possibility of her tumor (removed earlier) could be cancerous), she became highly emotional with psychotic behaviour. She therefore presented the shock syndrome with the addition of pulmonary aedema during 2nd operation. SECTION – II (D) MECHANISM OF DEVELOPMENT OF “SHOCK SYNDROME” IN SOME VULNERABLE PATIENTS 1.0 When we analyze the development of the “shock syndrome” presented by vulnerable patients (discussed in the research paper consisting three operated cases), it becomes obvious that, patient’s personality factor (P. factor) caused the following changes in the vital functions of the patients (vulnerable ones), before getting operated. (operation for them was a serious event during which they reacted very seriously). a) Since the patients who are vulnerable are maladjusted to the society and with their own family members, they are always on “stress mode” in life with latent psychiatric tendencies. This change in their personality leads to the constant production of stress products (constant release of micro amounts of sympathatomimitic amines all the times) since blood vessels in the body are chronically exposed to micro levels of such drugs, blood vessels in the body become insensitive to the action of usual resuscitation drugs in them (more over, such patients always Neurophysiology & Anaesthesia 144
  • have great deal of vaso constriction in their tissues). Hence hypotension occurs during “shock syndrome” purely due to stagnant circulation,Vaso dialatation in the vessels of the muscles and Vaso constriction in other tissues of the body. In such a situation (specially with hypotension, stagnant circulation with insensitive nature of the vascular bed in the body, conventional drugs used to bring up blood pressure in normal course of treatment would fail to bring back normal blood pressure. b) Treatment adapted by psychologist in such a situation is to slowly decrease the intense vaso constriction in the body with drugs like chlorpromazine or equivalent drugs, so that stagnant circulation becomes dynamic. Psychiatrist also uses central sedation so that production of noradrenaline is stopped. Such a treatment (given slowly and cautiously helps the patient by treating psychiatric tendency as well as reduction of the production of noradrenaline and its co-generators. After central sedation, production of sympathatomimitic amines are slowly cut down with the result that Vaso dialatation of the muscles is stopped. Hence the psychiatric treatment succeeds in such patients. c) Occurrence of pulmonary aedema and exudation of watery discharge through endotracheal tubes in some patients during or after surgery (rarely in delayed post operative period) is due to the intense Vaso constriction in the pulmonary vessels during the shock syndrome”) accompanied by Vaso dialatation of the vessels of the musculature). Hence pulmonary vessels push the plasma from the blood vessels into extra vascular tissue in the pulmonary parenchyma, thereby not only pulmonary aedema develops but also watery Neurophysiology & Anaesthesia 145
  • exudation (which is in fact the plasma from the vessels which is pushed out into extra vascular tissues), hence, waterly discharge takes place through the endtracheal tube. 2. SUMMARY OF THE SURVEY OF THE PATIENTS BY OUR TEAM Our research interaction with the patients in three phases (two days prior to the operation, during pre anaesthetic check- up and in the post operative period) was started from 1969 and lasted for more than 10 years (in which period 50 thousand cases were selected at random for interaction). During this period following complications occurred in them. We attribute the development of complications in them in the peri operative period to the patient’s personality factors (P-factors). a) More than 100 “shock syndrome” type of complications were treated among all patients coming to our hospital. All of them became normal and were discharged. b) More than 141 patients developed the syndrome of post operative depression of vital functions in them (delayed recovery). They were treated successfully by extraction therapy (read the concerned article in the international journal of clinical pharmacology in section II, printed in this book). c) We thought that 10 thousand intelligent patients could be studied for awareness during surgery. however, roughly 1 in 3 thousand patients replied that they heard the discussions in the operation theater but they did not understand it’s importance. Hence, they only told this to the team that they did not take it seriously. ***** Neurophysiology & Anaesthesia 146
  • Reprinted from the Indian Journal of Anaethesia, Vol. 23, No. 2. May 1975. Editor: S. PRAMANIK, MB, DA., FFARCS (ENG.) CLINICAL SIGNS OF NEUROGENIC STRESS IN SURGICAL PATIENTS DURING AND AFTER AN OPERATIVE PROCEDURE By: PROF. L.N. RAO M.D. D.A. AND DR. J. ACHUTARAMAIAH M.B.B.S. D.A. AND DR. K. GURUMURTHY M.B.B.S., D.A. Department of Anesthesiology, Kurnool Medical College, Kurnool (A.P.) 148
  • CLINICAL SIGNS OF NEUROGENIC STRESS IN SURGICAL PATIENTS DURING AND AFTER AN OPERATIVE PROCEDURE By: PROF. L.N. RAO M.D. D.A. AND DR. J. ACHUTARAMAIAH M.B.B.S. D.A. AND DR. K. GURUMURTHY M.B.B.S., D.A. Department of Anesthesiology, Kurnool Medical College, Kurnool (A.P.) --------------------------------------------------------------------------- It is generally believed that changes occurring in the general condition of the patient as observed by changes in respira- tory, cardiovascular and central nervous systems during or after anaesthesia and surgery have a direct or indirect relation- ship with the anaesthetic drugs/techniques used. A decade ear- lier Vandam and co-workers (Rocco & Vandam, 1957 and Vandam et al., 1962) have suggested that surgery itself in cer- tain type of patients results in excessive stress reaction during commonly used anaesthetic techniques. However, this aspect did not elicit enough interest and no further efforts were made to study the effects of such an increase in stress in suscep- tible individuals as regards various vital functions during or at the end of surgery and anaesthesia. Rao and Bhatt (1972) ob- served that wide variation in stress respons (neurogenic stress) existed in different individuals. They also noted that the abnor- mal sensitivity of the individual to the operative and post-opera- tive stress has a direct relationship with some operative and post- operative complications (Rao et al., 1972). Neurophysiology & Anaesthesia 149
  • The case reports now presented bring out clinical signs of stress response as observed in many sensitive patients. Since, the exact mechanism of changes in vital functions of such patients is obscure, the therapy which was beneficial in them suggests a possible explanation for their altered respiratory, circulatory and behavioural functions during such a period. CASE REPORTS CASE-1. ‘M’ a female patients, aged about 25 years, was oper- ated upon for non-puerperal ligation of fallopian tubes in Mass Tubectomy Camp held in Government General Hos- pital, Kurnool in 1969 under mid-spinal analgesia. She behaved normally during anaesthesia and surgery but was found to be excited and apprehensive in the immediate post- operative period. Blood pressure and pulse were however normal and she was sedated with 200 mg. of phenobarbi- tone given i.m. which quietened her for the next 12 hours. After that period she was found to be hypotensive (BP 60 to 70 mm. of Hg systolic) with tahycardia (pulse 140 to 160/ min.) and tachypnoea (rate between 60 to 70/min., Her behaviour was abnormal and she was repeatedly shout- ing that she will never survive the post-surgical period. She became uncontrollable and administration of 60 mg. mephetine (i.v.) and a drip of noradrenalin (16 microgram per milliliter) could not maintain BP more than 70 mm of Hg systolic. In fact, after such an infusion cardiac irregularity developed. Because of the behavioural pattern, it became necessary to take the advice of a psychiatric consultant who advised heavy sedatin with Neurophysiology & Anaesthesia 150
  • tranquilizers. Chlorpromazine was therefore administered. (12.5 mg. i.v. and 25 mg. i.m., every four hours). Within a few hours of such treatment BP and pulse rate became nor- mal and she made uneventful recovery. Later on it was found- out that she was against the operative procedure, but her husband and mother-in-law forced her to get operated. She had two sons and she was very much keen to have a female child before getting operated. CASE - 2. In August, 1973, ‘V’ a female, aged about 25 years, was subjected to turn graft (involving the rotation of lower end of femur so as to fill-up the gap in the upper part of leg (a gap of 6” between tibia and femur) She was earlier admitted in July, 1973, for osteoclastoma of upper end of right tibia. It was excised by the same surgeon under general anaesthesia (incidentally, type of general anaesthesia and anaesthetist were also same for both the surgical sessions). Anaesthesia on both occasions consisted of thiopentone induction (250 mg. of 2.5% soln.) orotracheal intubation after using 75 mg. succinylcholine, N2O, O2 and ether in Magill’s semiclosed system. On the first occasion surgery lasted for 4½ hours. Defective functioning of tourniquet led to profuse bleeding. However, at no time hypotension occurred. During subsequent operation a month later when ‘turn graft’ was done severe hypotension was observed during the operation even though blood-loss was much less than the previous occasion. Significant aspect of this operation was the fact that hypotension so observed was refractory to blood transfusion and other steps at resuscitation. As soon as the op- eration was completed and anaesthesia stopped, the patient re- gained consciousness and she started crying in pain. Neurophysiology & Anaesthesia 151
  • No signs of cerebral ischaemia (inspite of continued hypoten- sion) were present. Meanwhile she appeared unusually existed and respirations were asthmatic in nature (bronchoconstrictive type with extensive wheeze with accessory muscles working). Respiratory rate was between 60 to 70/min. She was restless, excited and could not tolerate the mask for administration of oxygen and hence assistance of respiration was very difficult. During such period BP and pulse were unrecordable. Very soon, signs of pulmonary oedema were obvious. Nasotracheal intuba- tion was done and IPPV was maintained with Bird MK 7 respi- rator with difficulty because she was restless and did not readily accept IPPV. Administration of 12.5 mg of chlorpromazine i.v. and 37.5 mg of chlorpromaxine i.m. resulted in quietening ef- fect and within next four hours BP became recordable and pul- monary oedema disappeared. Meanwhile she was found to be fully conscious and cooperative. Respiratory rate and rhythm were normal. Blood pressure and pulse improved further within the next six hours, when IPPV was discontinued. She made an uneventful recovery and was discharged 10 days later. No signs of cerebral hypoxia was present either in the immediate or in the delayed post-surgical phase. CASE - 3. ‘P’a female patient aged about 30 years suffering from chronic cervicitis was posted for total abdominal hysterectomy on 01/12/1973. Pre-operative examination revealed her to be in good health with 12 Gm of haemoglobin, blood urea nitrogen 2 mg/100 ml. ESR 12 mm/1st hour and all the systems normal clinically. Midspinal analgesia was given in right lateral position with Neurophysiology & Anaesthesia 152
  • 1.8 ml. of 5% lignocaine (heavy) in L2 - L3 interspace with head down tilt (5°). As soon as she was brought back to the supine position, 5% dextrose drip was started and within ten minutes of spinal analgesia blood pressure was found to be vary- ing between 69 and 80 mm of Hg systolic. Administration of 15 mg of inj mehentine i.v. and 15 mg. i.m. with 0.3 mg. of atropine could partially improve the hypoten- sion. Meanwhile surgery was allowed to start and within next 10 minutes it was found that she was pulseless with stagnant circulatory system as evidenced by engorged veins throughout the body. At this stage noradrenaline drip (8 micrograms/ml) at a rapid rate, intravenous administration of 8 mg. of betacortil and 100% oxygen did not improve her condition. One unit of compatible blood (300 ml.) was rapidly transfused with steep head down tilt. Even then no improvement of circulation re- sulted. Meanwhile, further surgery, after abdominal sterilization of both fallopian tubes, was abandoned and abdomen was closed. All through she was answering to questions and breathing spon- taneously. But after 2 hours of spinal analgesia she was found to be sluggish in responses to questions and pulmonary oedema developed. However, blood pressure varied between 50 and 60 mm Hg systolic and no signs of cerebral hypoxia were present (as evident by corneal, conjunctival, and pupillary reflexes). No peripheral or central cyanosis was evident. It was therefore de- cided to institute IPPV with Bird Mk 8 respirator, after orotracheal intubation. Chlorpromazine 12.5 mg i.v. (very slowly) and 37.5 mg. i.m. was administered after stopping noradrenaline drip. The urine out put which was nil during the period of hypotension improved significantly within the next 30 to 60 minutes and pulse volume Neurophysiology & Anaesthesia 153
  • also improved though BP was between 60 and 70 mm Hg systolic. Pulmonary oedema, which persisted for one hour after starting the IPPv also disappeared at this stage. Within next eight hours pulse rate settled down to 100-120/min. and BP improved to 80-100 mm Hg systolic without recourse to any vasopressor drug. She was extubated after 20 hours of spinal analgesia when all her vital functions were normal. However within the next few hours she developed behavioural changes (excitement and agitation with hypotension (60 to 80 mm of Hg systolic) both of which were corrected by administration of chlorpromazine (25 mg intramuscularly every six hours). This routine continued for the next three days when she was later switched over to chlordiazepoxide (Zepoxine 10 mg. 8 hourly) and later discharged from the hospital after 10 days. After such a stormy episode of hypotension and pulmonary oedema a detailed case history revealed that she was a psychiat- ric patient who was treated with electroconvulsive therapy for emotional imbalance. SALIENT FEATURES OF THE CASES PRESENTED All the three cases presented share the following features. 1. All of them had past history of emotional upset. Case 1 was unwilling to get tubal ligation and was repeatedly telling this to the staff in the post-operative phase. Case 2 was operated one month before and since then she was found to be unusually apprehensive and agitated. Case 3 had psychiatric treatment for agitation (manifested by occasional fits) for which electrocon- vulsive therapy was given twice before. 2. All these patients were found to be unresponsive to vasopressors, blood transfusion and corticosteroids during the Neurophysiology & Anaesthesia 154
  • period of hypotension (during or after surgical procedures). Inspite of these aspects of circulatory derangements they were never found to be cyanotic. They also maintained minimal level of consciousness throughout the phase of hypotension and were free from signs and symptoms of cerebral hypoxia in the post- operative phase even after prolonged phase of hypotension (lasting for 6 to 12 hours). (As judged by pupillary signs). 3. Urinary excretion in these cases ceased during the phase of hypotension (probably due to intense renal vascular constric- tion) but started profusely when chlorpromazine was given (within one hour of its administration intravenously). Since uri- nary secretion was good after such a therapy, inspite of con- tained hypotension (BP between 50 and 70- mm Hg systolic) it is possible that chlorpromazine induced renal vasodilatation and thus producing diuresis. DISCUSSION Neurogenic stress (due to injury, operative or psychic trauma) has been shown to cause stimulation of hypothalamus (McMann, 1953; Porter. 1952, Redgate & Gellhorn, 1653; Gellhorn, 1957 and Gellhorn et al., 1946) causing changes in cardio vascular system (Rocco Vandam, 1957 and Vandam et al., 1962). Since it is now shown that different persons vary differently in pre- senting stress response to surgery under general anaesthesia (Rao & Bhatt, 1972) it is likely that some susceptible individuals (ab- normally emotional types) react to pre-operative apprehension, operative and anaesthetic stress and post-operative anxiety in such a way that higher centres (mainly hypothalamus) induce gross alteration of vital functions of the body during operative and post-operative phases (Rao and Bhatt, 1972). Since pro- Neurophysiology & Anaesthesia 155
  • longed use of catecholamines results in cardiovascular crisis (during its administration) similar to that observed in the cases presented (Yard and Nickerson, 1956; Freedom et al., 1941 and Irving, 1968), it is likely that they suffered from sympathetic overactivity consequent to the constant hypothalamic stimula- tion resulting in the unusual type of cardiovascular crises ob- served in them. It is now shown that stimulation of sympathetic system is associated with intense vasodilatation in some tissues (skeletal muscle) in addition to constriction of arterioles and venules of others tissues of the body (Balard et al. 1970, Aboud and Eckstein, 1966 a & b). Since pulmonary vessels also share the vasoconstrictive response of vasculature of the skin, kidney, liver etc. (during neurogenic stress), it is likely that fluids are actively driven out of both the systems (systemic and pulmo- nary circulations) into extravascular tissues resulting in pulmo- nary oedema. The efficacy of treatment (by the use of chlorpro- mazine, a potent central nervous depressant drug) would there- fore indicate the possibility that all the cases suffered from sym- pathetic overactivity consequent to the excessive stimulation of hypothalamus (as a result of neurogenic stress). Although there might be other forms of clinical manifestations of stress response due to surgery and anaesthesia, it is possible that vasoconstric- tive cardiovascular crises or vaso constrictive pulmonary crises (leading to pulmonary oedema) could occasionally develop in some patients which if diagnosed timely, could be effectively treated on the line suggested. It could be appropriate to mention that such patients are always on defensive mode with minimal secretion of catecholamines. Hence, constant supply of minimal quantity of noradrenaline, causes refractory stage in the blood vessels, when cardiovascular stimulants are given to raise blood for and pulse pressure during emergency (when Neurophysiology & Anaesthesia 156
  • hypotension and absence of pulse is noticed in such patients). (Hence patients personality factor (P-factor) should also be considerate the time of diagnosis of their condition as well as at the time of their treatment). ACKNOWLEDGMENT The gracious help of Dr Neelakanta Raj Yadav, Professor of Psychiatry, Kurnool Medical College is gratefully acknowledged. Dr. Subba Rao, Additional Professor of Obstetrics and Gynaecology, are similarly thanked for giving permission to re- port the cases from their respective units. We are also grateful to Dr. K.B. Krishna Mohan. Superintendent of the Hospital for per- mitting us to report the cases. REFERENCES 1. Aboud, F.M. Eckstein, J.W. (1966) Active reflex vasoditation in man. Fed. Prov. 24, 1611. 2. Aboud, F.M. and Eckstein, J.W. (1966): Comparative changes in segmental vascular resistance in response to nerve stimulation and to norepinephrine. Cir. Res. 20, 263. 3. Balard, D.R., Aboud F.M. and Mayer, H.e. (1970): Release of humoral vasodilator substance during neurogenic vasodilatation. Amer. J. Physiol, 160, 1451. 4. Freeman, N. E. Freedman, H. and Miller, C.C. (1941): Production of shock by the prolonged continuous injection of adrenaline in unanaesthetised dog. Amer. J Physiol, 131, 545. 5. Gellhorn, E. Cortell, R. and Murpey, J. P. (1946): “Are mass discharges characteristic of central antunomic structures?” Amer J. Physiol, 136, 376. 6. Gellhorn, E. (1957): Autonomic imbalance & hypothalamus. Minneopolis, University of Minnesota Press 11a-139. Neurophysiology & Anaesthesia 157
  • 7. Irving, M.H. (1968): Sympathoadrenal factor in haemorragic shock. Ann. Roy. Coll. Surg. 42, 367. 8. McCann, S.M. (1953): effet of hypothalamic lesions on adrenal cortical response to stress in rats, Amer. J. Physiol. 143, 13. 9. Rao, L.N. and Venkatakrishna Bhatt., H. (1972): Stress response during surgery and anaesthesia as indicated by norepinephrine concentration in plasma of surgical patients. Int. Surg, 57, 294. 10. Rao L.N. and Venkatakrishna Bhatta. H. (1971): Stress response during surgery and anaesthesia in man: its possible connection with the syndrome of depressed vital functious in post-surgical period (preliminary report). Ind. Anaesth. 19, 365. 11. Rao, L.N., Char, J.g. and Venkatakrishna Bhatt. H. (1972): Psychosomatic factors involved in the development of bleeding tendency in post-operative period - A case report. Ind. J. Anaesth., 20, 293. 12. Redgate, E.S. and Gellhorn, E. (1953): Nature of sympathoadrenal discharge under conditions of excitation of central autonomic structures. Amer. J. Physiol. 143, 475. 13. Rocco, A.g. and Vandam, L.D. (1957): Changes in circulation consequent to manipulations during abdominal surgery J.A.M.A., 164, 64. 14. Vandam, L.D. Schweize, H.J. and Kubota, F. (1962): Circulatory response to intra-abdominal maniulations during ether anaesthesia in man. Cir. Res. 11, 287 15. Vard, A.C. and Nickerson, M. (1956): Shock produced in dogs by infusion of norepinephrine. Fedr. Pro. 15, 502. ***** Neurophysiology & Anaesthesia 158
  • RERINT FROM NEUROPHYSIOLOGY BOOK The Book contains collection of Research Papers presented to the Satellite symposium on “BEHAVIOUR” held at Chennai in 1974, in Connection with the International Conference of Physiologists in 1974. Edited by: PROF. SARADA SUBRAMANYAM Chapter 29 is written by: PROF. L.N. RAO MD, DA Kurnool (PO), A.P. India. E2 SECTION II 159
  • CHAPTER - 29 THE SYNDROME OF DEPRESSED VITAL FUNCTIONS IN THE POST OPERATIVE PERIOD IN MAN: ROLE OF NEUROHUMOURS IN ITS CAUSATION Prof. L.N. Rao Prof. and Head of the Department of Anaesthesiology, Kurnool Medical College, Kurnool, A.P., India. ------------------------------------------------------------------ INTRODUCTION: AFTER the introduction of skeleto muscular relaxants into anaesthetic practice in 1942, it became possible to induce ideal operating conditions, by using different drugs or techniques to achieve them, without causing depression of cardio-vascular system. The resultant technique of balanced anaesthesia (Lundy, 1926, Neff et al., 1947 and Mushin et al., 1947), which is used extensively today (with some minor modifications in actual ap- plication of the technique) aims to induce sensory and motor reflex suppression and unconsciousness in the patients, with the use of thiopentone, halothane (or their equivalents) for induc- tion of anaesthesia, and artificial ventilation with N2 O,-O2 mix- tures keeping iso or hypo capnic levels of PCO2 in them after using paralysing doses of d’tc, gallamine or their equivalents. Even though, such techniques are of use in patients ranging in age groups of 9 days to 90 years without side effects, (Editorial Brit. J., Anaesth., 1969), it is observed that some patients ap- pear to present a syndrome of depressed vital functions in the immediate or delayed post operative phase. So far, such a syn- drome of post operative depression of vital functions was thought to be directly related to the effects of skelletomuscular relaxant Neurophysiology & Anaesthesia 161
  • drugs, used during such techniques in the immediate or delayed post operative phase and hence terms like ‘Central Nervous ac- tion of Curare’, ‘Neostigmine resisteant Curarization’, ‘Clinical syndrome of incomplete reversal’ and ‘a stage of apparent re- curarization’ were used by different research workers (Foster, 1956; Hunter, 1956; brechner, 1971; Feldman, 1959; Jenkins, 1961; Shah and Patel, 1967; Way et al, 1967; and Sikh et al., 1970). The syndrome is characterized by various levels of de- pression of consciousness, respiratory depression or apnoea, absence or depression of behavioural response to painful stimuli, hypotonia or atonia of skeletal muscles and depression of protective reflex activity. Some specialists believe that higher concentration of curare or its equivalents contribute to such a syndrome and that effect of antidotes to curare (like neostigmine) could wear off prematurely leaving the relaxant drug to act unopposed, thereby leading to loss of proprioception (Baraka, 1964 and 67; Hannington-Kiff, 1970). However, in our Institution such views could not be confirmed because it was recently found that presence of 10 to 25 percent of the paralys- ing doses of d’tc or gallamine, when found in plasma and C.S.F. after isocapnic, hypocapnic and hypercapnic ventilation, did not cause abnormal recovery in surgical patients who were operated for 70 to 110 minutes under thiopentine, N2O and relaxant type of anaesthesia (Devashankariah et al., 1973; Harnath et al., 1973; Rao and Bhatt, 1975 and Rao, 1976). The poineering work of Churchill-Davidson (1963, 67), Wyly and Chruchill-Davidson (1966, 1972), Vandam and his Colleagues (1962) and Folkow et al. (1962), therefore formed the basis for further work to explore the possible role of surgical stress itself (its neurogenic part) in causing the syndrome. Neurophysiology & Anaesthesia 162
  • Effects of Neurogenic Stress on Body Functions It is kown that stress of any type could, in addition to other side effects, activate sympatho-adrenal axis therby causing the release of significant amounts of catecholamines into the tissues (Redgate and Gellhorn, 1953; and Gellhorn, 1957). When such a stress is of neurogenic type (for instance without haemorrage and asphyxia during surgery and anaesthesia), it is shown that activation of posterior hypothalamus and medulla in CNS causes release of noradranaline from post-ganglionic nerve endings of sympathetic nervous system (Gellhorn et al., 1946 and Gellhorn, 1953). The fact that srugery itself (its neurogenic part) is a strong stressor agent is revealed by the release of sig- nificant quantities of corticosteriods, free cortisol, free fatty acid, ACTH and noradrenaline into circulation. (Hardy et al, 1959, Hume; 1962; Plumpton and Besser, 1969; Miller and Morris, 1961; Lewis, 1963; Oyame and Takaguchi, 1970 and Clark et al., 1970). Even skin incision is reported to cause changes in lung and chest wall compliance (Maxworthy and Roorback, 1966). manipulation of abdominal contents under general anes- thesia was shown to cause lowering of pulse pressure, blood pressure and pulse rates (Rocco and Vandam, 1957; Vandam et al., 1962, Folkow et al., 1962), which could be abolished by simultaneous use of local or regional blocks (Flokow et al., 1962). Vandam and his colleages (1962) further observed that even though every patient produced these changes during manipula- tion of abdominal structures, up to some extent, poor risk pa- tients (who, because of chronic background of suffering, be- come cachectic with changes in protein content, body water, elec- trolytes etc.) reacted to such a stress maximally and increased morbidity and mortality in them were directly related to their hyper-reactive nature to surgical stress (its neurogenic part). Use Neurophysiology & Anaesthesia 163
  • of different types of anaesthetic drugs did not diminish their hyper-reaction to surgical stress. Folkow et al., 1962, revealed that changes in pulse rate, pulse pressure and blood pressure during srugery of the abdomen, were due to the stimulation of adrenergic nerves. These observations, suggest that sensory stimulation from the field of operation in susceptible individu- als (due to chronic background of suffering) could induce in- creased morbidity and mortality in them. Such a possibility is further strengthened by the earlier work of Wang (1947) and Overman and Wang (1947) who found a correlation between the sensory stimulation and survival rate of dogs, subjected to hypovolaemic stress. They observed that stimulation of sensory nerves during induction of haemorrhagic shock caused death in dogs at a residual blood volume, which normally would have been compatible with their survival, if sensory nerve was not stimultaneously stimulated. They also noted that, if severe inju- ries were induced in chronically denervated limbs of the dogs, they survived at resideual blood volumes, (which were lethal in others), (with intact nerve supply). These facts, about the role of sensory nerve stimulation and survival rates in man and dogs, during neurogenic and hypovolaemic stress respectively, when studied in the light of the observations of Grant and Reeves (1958) who stated that tachycardia, vasoconstriction and hypo-tension, if observed in a person with a limb injury indicates hypovolaemia, whereas similar signs, if seen in a case of abdominal injury might be compatible with normal blood vol- ume in him, this fact indicates that neurogenic stress in some unknown way controls the outcome of stressful situations and that some susceptible individuals who hyperreact to such stress may die in spite of various measures of resuscitation. (with signs of cordiac and pulmonary failure). Neurophysiology & Anaesthesia 164
  • Further Investigations by Us Since neurogenic stress (like preoperative apprenension, operative trauma) (unassociated with haemorrhage or asphyxia) and post-operative pain or apprehension could activate CNS as a whole and posterior hypothalamus in particular (Gellhorn et al, 1946; de Groot and Harris 1950; McCann 1953 and Redgate and Gellhorn, 1953) with the resultant release of significant quan- tities of noradrenaline from post-ganglionic nerve endings (Gellhorn, 1953 and Trendelenburg, 1964), noradrenaline con- centrations were estimated in plasma of surgical patients sub- jected to various types of operative procedures prior to, during and immediately after completion of surgery under different an- aesthetic techniques (Rao and Bhatt, 1972). Even though C.S.F. estimation of noradrenaline during such stiuations could have been more informative, samples could not be taken from such patients, because of technical reasons (inability to obtain the same during and after operations). Tables 1 and 2 indicate that every patients reacted differently to similar type of sensory stimuli (due to surgical trauma under similar techniques of anaesthe- sia). Poor risk patients, those coming up for elective or emer- gency surgery in cachectic conditions (consequent to chronic sufering), when subjected to various minor or major surgical procedures, resulted in maximum response of noradrenaline pro- duction in peripheral blood. Such investigations concerning the neurohumoral sequelae of stress response, therefore, confirm the observations of Vandam and his colleagues (1962) about the hyper-reactive nature of poor risk type of patients. They also suggest that release of abnormal quantities of stress products (noradrenaline and other biogenic amines) could have a great role in causing observed increase in mortality and morbidity in such susceptible patients who produce large quantities of stress products (Rao and Bhatt, 1972). Neurophysiology & Anaesthesia 165
  • The Mechanism About the Causation of the Syndrome Since adrenergic nerves carry painful sensations from abdominal and thoracic contents, their stimulation during srugery results in the release of stress products, some of which, like noradrenaline or its precursor dopamine etc., are biologically active and hence cause various effects on vital functions of the body. Since Weiner et al., 1972 demonstrated that stimulation of adrenergic nerve leads to large synthesis and turn over of noradrenaline in the affected tissues, and since neurogenic stress causes stimulation of hypothalamus (Redgate and Gellhorn, 1953); and Gellhorn, 1957) it is likely that neurogenic stress of surgical procedures (not associated with significant blood loss or asphyxia) results in the release of significant quantities of noradrenaline or other types of biologically active amines into CNS. Moreover, the large and unphysiological levels of noradrenaline which are shown to be released in peripheral circulation in some susceptible patients (Rao and Bhatt, 1972) could also be released in CNS also and lead to signs and symptoms of their action on CNS. It is therefoe likely that depressed level of consciousness, susppression of sensory and motor reflex activity and respiratory depression in patients which are manifested in the syndrome of post-operative depression of vital functions could be due to the depression of spontaneous acivity of cerebral cortical neurones, depression of cholinergic central synapses, toxic paralysis of central synapses and TABLE 1: CASES STUDIES WITH NOREPINEPHRINE CONCENTRATIONS IN PLASMA AT VARIOUS STAGES (Norepinehrine concentration is expressed as µm/Liter of plasma). (Contd on next page) Neurophysiology & Anaesthesia 166
  • Case Nature of Operation Preoperative Preanesthetic After During During Later Remarks No. Induction Maximal Recovery Part of Postoperative Phase 2. Hemicolectomy for T.B. of large intestine --- --- 50 100 --- --- --- 4. Laparotomy for stab injury fo the abdomen --- 8 8 10 7.4 --- --- 5. Partial gastrectomy for gastric ulcer --- 10 --- 12 10.0 --- --- 7. Intestinal obstruction (in grave physical status, excessive gangrene of the bowel). --- 6 --- 7.5 --- --- --- 9. -- do -- --- 50 --- 25 --- --- --- 11. Hemicolectomy 12.5 20 --- 50 100.0 --- --- 12. Exploratory laparotomy --- --- --- 30 --- --- --- 13. Excision of dermoid cyst (arising from lesser sac of peritoneum) 30.0 --- --- 20 40.0 --- --- 15. Partial gastrectomy --- --- --- 30 20.0 --- --- 17. Exploratory laprotomy --- --- 10 --- 40.0 --- --- 19. Abdominal vagotomy and gatroenterostomy --- --- --- 20 30.0 --- --- 20. Exploratory laparotmy --- 10 --- 20 10.0 --- --- 21. Abdominal perineal resection for carinoma After using of the rectum --- 10 --- 15 20.0 50.0 halothane. 24. Gastroenterostomy --- 30 --- 20 10 --- --- 25. Partial gastrectomy --- 50 --- 20 --- 50 --- 26. Exploratory laparotomy --- 20 --- 30 --- --- --- 27. Partial gastrectomy --- 5 --- 35 40 --- --- 28. Exploratory laparotomy --- 20 --- --- 5 --- --- 29. Herniorrhaphy 50 20 --- 30 --- --- --- 30. Excision of hydrocele sac --- 10 --- 50 --- --- --- 31. Herniorrhaphy --- 4 2 <2 --- --- --- 32. Excision of varicose veins --- <2 --- 4 --- --- --- 33. Gastroenterostomy --- 2 --- 15 --- --- --- 34. Gastrectomy --- 20 --- 15 --- --- --- 35. Gastroenterostomy --- 10 --- 50 --- --- --- 36. Exploratory laparotomy and closure of perforated gastric ulcer --- 3 --- 2 3 --- --- 37. Exploratory laparotomy and Hemicolectomy <2 <2 --- 40 50 --- --- Neurophysiology&Anaesthesia167
  • TABLE 2. NOREPINEPHRINE CONCENTRATION IN PATIENTS WHEN SUBJECTED TO SIMILAR SURGICAL PROCEDURES UNDER 3 TYPES OF ANESTHESIA. (Norepinephrine concentration is expressed as µg/Liter of plasma). Type of operation Case No. Types of Prior to During After Remarks Anesthesia Operation Operation Operation 1. Exploratory 4 G.A. 8 10 7.4 --- laparatomy and 12 G.A. --- 30 --- --- minor abdominal 15 G.A. 30 20 40.0 --- surgical 17 G.A. 10 40 --- --- procedure 20 G.A. 10 20 10.0 --- 26 G.A. 20 30 --- --- 28 G.A. 20 --- 5.0 --- 36 L.A. 3 2 3.0 G.A. had to be given later. 2.Partial 5 G.A. 10 12 10.0 --- gastrectomy 13 G.A. --- 30 20.0 --- 25 G.A. 50 20 50.0 --- 27 G.A. 5 35 40.0 --- 34 S.A. 20 15 --- G.A. had to be given later 3. Gastroenterostomy 19 G.A. 15 20 30.0 --- 24 G.A. 30 20 10.0 --- 33 S.A. 2 2 --- --- 35 S.A. 10 50 --- --- 4.Hemicolectomy 2 G.A. --- 50 100.0 --- 11 G.A. 20 50 --- --- 37 L.A. 1 40* 50 *G.A. had to be given later 5.Excision of 7 G.A. 6 7.5 --- --- gangrenous large bowel. 9 G.A. 50 25.0 100.0 --- 6.Abdominal perineal resection of sigmoid 21 G.A. 20 *15.0 *After using halothane colon 7.Herniorrhaphy 29 S.A. 50 30.0 --- --- (Inguinal) 31 S.A. 4 <2.0 --- --- 8.Plication of 30 S.A. 10 50.0 --- --- hydrocele sac 9.Excision of varicose veins of the legs. 32 S.A. 1 2.0 --- --- Neurophysiology & Anaesthesia 168
  • depression of respiratory centre, primarily due to the action of the stress products (noradrenaline or other biogenic amines on these structures) (Krnjevic and Phillis, 1963; burn, 1945; Abraham and Pickford, 1956; Rothballer, 1959; Hoff and Breckenbridge, 1950; Krivoy et al., 1953). Even thoug Churhill- Davidson (1963) and Rao and Bhatt (1971) observed that neu- romuscular transmission in patients affected by such a syndrome improves with neostigmine therapy, large number of others re- corded altered neuromuscular transmission at the myoneural junction. The latter group of workers speculate that loss of prop- rioception in such patients is due to the continued action of nondepolarizers at the myoneural junction was the main cause of the syndrome inthe immediate or delayed post-operative pe- riod (Scurr, 1954; Hunter, 1956; bush and Baraka, 1964; Baraka 1964 and 1967; Folds, 1960 Corado, 1963; Way et al., 1967; Feldman, 1959; Shah and Patel, 1967, Sikh et al., 1970 and Brechner, 1971). However, it is well knwon that physiuologists throughout the world use gallamine in experimental animals to immobilize them on the table because it does not interfere with reflex activity or sensorium in them (Brahmayya Shastry per- sonal communication). Moreover, administration of 2½ times the pralysing dose of curare in a volunteer did not cause depres- sion of CNS or loss of sensorium in him (Smith et al., 1947). These facts, therefore indicate that loss of proprioception in sur- gical patients cannot be the cause of the depression of various vital functions in the post-operative period and that depression of CNS in such patients could be due to large quantity of noradrenaline in CNS itself (accumulated during stress leading to the development of the syndrome). Depressed neuromuscu- lar transmission observed by the scientist in their series of cases could be due to the action of noradrenaline, (which is rleased Neurophysiology & Anaesthesia 169
  • during neurogenic stress of surgery) on the sensitized neuromuscular junction (which was earlier depressed by d’tc), because, it is shown that noradrenaline acts as a nondepolarisor type of blocking agent on a sensitized neuromuscular junction (Bowman and Raper, 1966; Ellis and Beckett, 1955; Paton and Zaimis, 1950; Naess and Sirnes, 1953), by hyper-polarizing the muscle fibre membrane which spreads to the end plate region also (Bowman and Nott 1969). CONCLUSION: Based on these clinical, experimental and neurophysiologi- cal facts, it is confirmed that syndrome of depression of vital functions in the immediate or delayed post-operative period in surgical patients is due to the hyper-reactive nature of some patients to surgical stress. Stimulation of hypothalamus and other centres of central adrenergic system during such a stress results in the production of noradrenaline and other types of biologi- cally active amines in CNS, as well as peripheral blod, resulting in the mainfestation of various clinical signs of the syndrome. Dehydration therapy suggested by Rao and Bhatt, therefore aims to wash off the accumulated prodeucts of stress response from CNS, thereby restoring vital functions to normally. ACKNOWLEDGMENT This study was possible because of the support from Prof. P.S.R.K. Haranath, Prof. Sadasivudu and Shri H.V.K. Bhatt of the Departments of Pharmacology and Biochemistry. I am grate- ful to them for all that they have doen in this project. ***** Neurophysiology & Anaesthesia 170
  • REFERENCES: ABRAHAM, VC. AND PICKFORD, J.: Observations on Central anatagonism between adrenaline and acetyle Choline, J. Physiol. (Lond.) 131, 712-718 (1956). BARAKA A. : Irreversible tubo-curratine-neuro muscular block inthe human, Brit. J. Anaesth. 39, 891-894 (1967) BARAKA, A., : The influence of Carbondioxide on neuromuscular block caused by tubo-curarine chloride in the human subjects, Brit. J. Anaesth., 36, 272-278 (1964). BOWMAN, W.c., and Nott, M.W.: Actions of sympathetic amines and their antagonists on skelletal muscles, Pharmacol. Rev., 21, 27-74 (1969) BOWMAN, W.C. AND RAPER, C.: Effects of sympathetic amines on neuro- muscular transmission. Brit. J. Pharmacol, Chemotherap., 27, 313-331 (1966). BRECHNER, V.L.: Clinical Syndrome of incomplete neuro-muscular block reversal: Doctor Look at your patient, Anaesth. Anag, 50, 876-878 (1971). BUSH, G.H., BARAKA A.: Factors affecting the termination of curarization in human subjects, Brit. J. Anaesth., 36, 356 (1964). BURN, J.H.: The relation of adrenaline to acetycholine in the nervous system, Physiuol. Rev., 25, 789-799 (1945). CHURCHILL-DAVIDSON, H.C.: in Hewer, C.L., Editor, Recent advances of Anaesthesia and Anagesia, J & A. Churchill, London, 1963, pp. 97-98. CLARKE, R.S.J., JHONSTON, H. AND SHERIDAN, B.: The influence of anaesthesia and surgery on plasma cortisol, Insulin and free fatty acids., Birt. J.Anaesth. 42, 295-299 (1970) CORRADO, A.P.: Respiratory depression due to Antibiotics: Calcium in treatment, Anaesth. Anag., 42, 1-11 (1963). DE GROOT, J. AND HARRIS, G.W.: Hypothalmic Control of the anterior pituitary gland and blood lymphocytes, J. Physiol. (Lond)., 111, 335-346 (1950). DEVASANKARAIAH, G., HARNATH, P.S.R.K. AND KRISHNAMURTHY A.: Passage of ‘dtc’ from blood into and liquor spaces in dog and man, Brit. J. Pahrmacol., 47, 787-793 (19973). Editorial, Brit. J. Anaesth., 41, 563 (1969). ELLIS, S. AND BECKETT, S.B.: Depression of neuro-muscular transmission by norepinephine, Fed. Proc., 14, 336 (1955). FELDMAN, S.A.L. An interesting case of recurarization Brit. J. Anaesth., 31, 461-463 (1959). Neurophysiology & Anaesthesia 171
  • FOSTER, P.A.: Potassium depletion and the central action of Curare, Brit. J. Anaesth. 28, 488-502 (1956). FOLDS, F.: Neuromuscular blocking agents in man, Clin. Pharmacol. Ther., 1, 345-395 (1960). FOLKOW, B., GELIN, L.E., LINDELL, S.E., STENBERG, K. AND THOREN, O.: Cardiovascular actions during abd. surgery,Ann. Surg., 156, 905-913 (1962). GELLHORN, E.: Autonomic imbalance and hypothalamus, University of Minnosota Press, Minneopolis, pp. 119-139 (1957). GELLHONR, E.: Physuiologial foundation of Neurology and Psychiatry University of Minnesota Press, Minneopolis (1953). GELLHORN, E., CORTELL, R., AND MURPHY, J.P.: Are mass discharges characteristics of central autonomic structures?, Amer. J. Physiol. 146, 376-385 (1946). GRANT, R.T. AND REEVE, E.B.: as reported by R.P. Harboard in Evants, FT. and Gray, T.C. Editors, Modern trends in Anaestheisa Vol. I, Butterworths, London (1958), 163. HANNINGTON-KIFF, J.G.: Residual ost operatie paralysis, Proc. Ro. Soc. Med., 63, 73-76 (1970). HARNATH, P.S.R.K., KRISHNAMURHTY, A., RAO, L.N. AND SESHAGIRI RAO, K.: Pasage of Gallamine from blood into liquor spaces in man and dog, Brit. J. Pharmacol., 48, 640-645 (1973). HARDY, J., CARTER, T., AND TURNER, M.: Catecholamine Metabolism,Ann. Surg., 150, 666-683 (1959). HOFF, H.E., BRECKENSB RIDGE, C.G. and Cunningham.: Adrenaline Apnoea in medullary animals, Amer. J. Physiol. 160, 485-489 (1950). HUNTER, A.R.: Neostigmine resistant curarization, Brit. Med., J., 2, 919-920 (1956). HUME.: in Seeley, S.F. and Weisinger, J.R. Editors, Federation proeedings of Amer. Soc. of Exp. Biology, Washington, D.c., 1962, pp 87-98. KRNJEVIC, K. AND PHILLIS, J.W.: Action of certain amines on cerebral cortical neurones, Brit. J. Pharmacol. Chemothe., 20, 471-490 (1963). KRIVOY, W.A, HART, E.R. AND MARRAZZZI, A.S.: Inhibition of phrenic respiratory potentials by adrenaline and other sympathetic amines, Fed. Proc. 12, 337-338 (1953). LEWIS, R.N. : Plasma hydrocortisone concentrations in relation to Anaesthesia and surgery, Brit. J. Anaesth., 35, 84-90, 1963. Neurophysiology & Anaesthesia 172
  • LUNDY, J.S.: Balanced Anesthesia, Minn. Med., 9, 399 (1926). MAXWORTHY, J.F. (JR.) AND ROORBACK, E.: Chest and lung compliance change with stress, Anaesth. Analg. 45, 340-347 (1966). MCCANN, S.M. : Effect of Hypothalamic leisions on adreno cortical response to stress in rats, Amr. J. Physiol. 175, 13-20 (1953). MILLAR, R.A. AND MORRIS, M.E.: Sympatho-adrenal responss during general anaesthesia in dogs and man, Canad. Anaesth. Soc. J., 8, 856-863 (1961). MUSHIN, W.W. AND RENDELBAKBER, L.: Pethedine as a supplement to N20 Anaesthesia, Brit. Med., J., 2, 472 (1947). NAES, K. AND SIRNES, T.B.: Synergistic effect of adrenaline and d’-tubocurarine on neuromuscular tranmissions, Acta Physiol. Scand., 29, 293-306 (1953). NEFF, W., MAYER, E.C. AND PORALES, M.: Nitrous Oxide and Oxygen anaesthesia with Curare relaxant, Calif. Med. 66, 67 (1947). O. VERMAN, R.R. AND WANG, S.C.: The contributory role of afferent nervous factors in exeprimental shock: Sublethal haemorrage and sciatic nerve stimulation, Amer. J. Physiol. 148, 289-295 (1947). OYAMA, T. AND TAKIGUCHI, M.: Plasma levels of ACTH and Cortisol in man during halothane anaesthesia and surgery, Anaesth. Analg., 49, 363-366 (1970). PATON, W.D.M. ZAIMIS, E.J.: Actions and clinical assessment of drugs which produce neuromuscular block, Lancet, 2, 568-570 (1950). PLUMPTON, F.S. AND BESSOR, G.M.: The adreno cortical response to surgery and insulin induced hypoglycaemia in corticosteroid treated and normal subjects, Brit. J. Surg., 56, 216-219 (1969). RAO, L.N.: Pattern of recovery from balanced aneasthetic technique: its relationship with plasma and C.S.F. levels of dtc/gallamine in the immediate post operative period, Ind., J. Anaesth. (In press, 1976). RAO, L.N. AND H.V. BHATT.: Role of therpentone Nitrous oxide and relaxant anaesthesia in causing the syndrome of post operative paralysis in man, Der. Anaesth. 24, 73-77 (1975). RAO, L.N. AND VENKATAKRISHNA BHATT, H.: Stress response during surgery and anaesthesia.: indicated by norepinehrine concentrations in the plasma of surgical patients, Int. Surg., 57, 294-298 (1972). RAO, L.N. AND VENKATAKRISHNA BHATT, H.: Stress response during surgery and anaesthesia in man: Its possible connection with the syndrome of depressed vital functions in the ost surgical period (preliminary Report). Ind. J. Anaesth., 19, 365-376 (1971). Neurophysiology & Anaesthesia 173
  • REDGATE, E.S. AND GELLHORN, E.: Nature of sympathoadrenal discharge under condtions of excitation of central autonomic structures, Amer. J. Physiol. 174, 475-480 (1953). ROCCO, A. G. AND VANDAM, L.D.: Changes in circulation consequent to manipulation during abdominal surgery, J.A.M.A., 164, 14-18 (1957). ROTHBALLER, A.B.: Effect of Catecholamines on central nervous system, Pharmacol. Rev., 11, 494-547 (1959). SCURR, C.F.: Carbondioxide retention simulating curarization, Brit. Me. J., 1, 565-566 (1954). SHAH, B.M. AND PATEL, R.A.:Aproblem case of recurarization, Ind. J.Anaesth., 15, 203-204 (1967). SIKH, S.S., AGARWAL, G., BRANBUTT, P. AND RAI, P.: Recurarization and prolonged unconsciousness, Ind. J. Anaesth., 20, 91-95 (1970). SMITH, S.M., BROWN, H.O, TOMAN, J.E.PO., AND GOODMAN, L.S.: The lack of central effects of d-tubocurarine, Anaesthesiology, 8, 1-14 (1947). TRENDELENBRUG, G.U.: Editorial, Anaesthesiolgoy, 25, 259-261 (1964). VANDAM, L.D., SCHWEIZER, H.J. AND KUBOTA.: Circulaotry response to intra-abdominal manipulations during ether anaesthesia, Circ. Res., 11, 287-295 (1962). WAY, W.L, KATZUNG, B.G. AND LARSON, C.P. JR. : Recurarization with quinidine, J.a.M.a., 200, 153-154 (1967). WANG, S.C.: The Importance of the afferent nervous factors in experimental traumatic shock: The effect of chronic deafferentation, Amer. J. Physiol., 148, 547-556 (1947). WEBER H.: Uber Anasthesie durch adrenalin, Verh. Dtsch. Ges. Inn. Med., 21 616-619 (1904). WEINER, N., GLOUTIER, G. BJUR, R. AND PEFFER, R.I.: Modification of Norepinephric synthesis in intact tissues by drugs and during short term adrenergic nerve stimulation, Pharmacol. Rev., 24, 203-221 (1972). WYLIE, W.D. AND CHURCHILL-DAVIDSON in “A practice of Anaesthesia,” 3rd edition, LLoyd Luke, Lond. pp 775-899 (1972). WYLIE, W.D. AND CHURCHILL-DAVIDSON, H.C.: A Practice of Anaesthesia, LLoyd-Luke, London, 2nd edition, pp 735-777 (1966). ***** Neurophysiology & Anaesthesia 174
  • A Reprint from International Surgery - Vol. 57, 1972, 295-298 “Stress Response During Surgery and Anesthesia” Indicated by Norepinephrine Concentration in Plasma of Surgical Patients L. NARAHARI RAO, M.D., D.A. AND H. VENKATAKRISHNA BHATT, M.SC., KURNOOL (P.O.), ANDHRA PRADESH, INDIA. --------------------------------------------------------------------------------- Accepted for publication Aug. 25, 1971. Frm the Departments of anesthesiology (Dr. Rao) and Pharmacology (Dr. Bhatt) Kurnool Medical College, Andhra Pradesh. Reprint requests to Dr. Rao. Supported by the State Medical Research Council of the Government of Andhra Pradesh. Stress Response During Surgery and Anesthesia/Rao et al. --------------------------------------------------------------------------------- 176
  • Catecholamine production is a part of stress response1 2 . Its concentration increased during anesthesia in animals and man and is further increased by surgical traum3 12 . However, these investigators thought surgical stress was a homogeneous entity and did not consider the possibility of different individuals presenting grossly variable forms of stress. Further, they did not consider the possibility that type (surface surgery or that involving body cavities), site (surgery of limbs or that of abdominal organs) and magnitude (major or minor surgical procedures) of surgical trauma might induce variable types of stress response in different individuals. Type and magnitude of surgery are directly related to changes in adrenocorticotrophic hormone production13 chest and lung compliance14 and tension of oxygen in arterial blood15 . Increased morbidity and mortality in poor-risk patients is due to their hypersensitivity to the neurogenic component of surgical procedures16 17 . In this study we observed the type of response presented by different indi- viduals to similar types of surgery and anesthesia. It was pre- sumed that changes in norepinephrine concentration in plasma of the patients were directly proportional to the severity of surgical stress, because the neurogenic component of stress in- duces significant changes in the concentration of norepinephrine in peripheral blood1 2 . MATERIAL AND METHODS Samples of peripheral venous blood from forearm veins were collected from 37 patients (30 poor-risk and seven healthy adults of both sexes) who were subjected to elective or emer- gency surgery. Samples were taken during the preoperative phase Neurophysiology & Anaesthesia 177
  • (12 to 24-hours before surgery), preanesthetic phase (30 minutes to 24-hours before surgery), early operative phase (within 10 to 15-minutes after the start of surgery), during maximal surgery and in the immediate postsurgical phase (or immediately after recovery from anesthesia). In a few patients who exhibited unstable vital functions in the postoperative phase, samples were also collected in the delayed posteperative period (6 to 24-hours) after surgery). Eight milliliters of venous blood so collected were drawn into a syringe containing heparin and immediately transferred into a test tube containing 0.04 ml of hearin and 5 µg of ascorbic acid per milliliter of blood. the samples was immediately cnetrifuged and stored at 0 C. Plasma so obtained was assayed without further treatment for norepinephrine and epinephrine concentrations on pithed rat blood pressure and on sensitized rat uterus respectively.18 To pre- vent other biologically active amines from influeencing the re- sults, all samles were alkalinized and brought back to the original pH so that the absence of biologially active amines in the sample confirmed the presence of norepinephrine in the sample. As a further precaustion, antagonists like phentolamine (Regitine®) were always used to abolish the presor response elicited earlier by the plasma sample on pithed rat blood pressure. Table 1 Concentration of Epinepherine and Norepinephrine in Cases Subjected to Major Surgical Procedures Under General Anaesthesia (Concentrations of Epinephrine and Norepinephrine are expressed as µg/Liter of Plasma). (Contd on next page) Neurophysiology & Anaesthesia 178
  • Table 1 Concentration of Epinepherine and Norepinephrine in Cases Subjected to Major Surgical Procedures Under General Anaesthesia (Concentrations of Epinephrine and Norepinephrine are expressed as µg/Liter of Plasma). Case No. Nature of Operation Earlier than Surgery During Surgery During Recovery Epinephrine Norepinephrine Epinephrine Norepinephrine Epinephrine Norepinephrine 4 Abdomen injury - exploratory laparotomy <5 8 10 10 <5 7.4 5 Partial gastrectomy <5 10 <5 12 50 10 7 Intestinal obstruction (Resection of large intestine) <5 6 <5 7.5 --- --- 9 do <5 50 <5 25 <5 100 12 Exploratory laparotomy <5 30 --- --- 13 Partial gastrectomy <5 30 <5 20 15 Laparotomy and resection of large cyst in lesser sac <5 30 <5 20 50 40 Neurophysiology&Anaesthesia179
  • As a rule, patients who had had significant hemorrhage were excluded from this study. They were anesthetized with 250 to 400 mg of thiopentone sodium (after injection of 0.6 mg of atropine hydrochloride as premedicatin 30 minutes before induction of anesthesia) and they were intubated orotracheally after intravenous administration of 50 to 100 mg of succinyl dicholine chloride (Scoline®, Glaxo, India). Anesthesia was maintained in a closed circuit with controlled leakage by means of a Mark III absorber of the Boyle’s apparatus (Indian Oxygen Company), using a high flow rate of 9 liters per minute (nitrou oxide and oxygen in a ratio of 6:3). Paralyzing doses of d-tubocurarine were always used and no inhaling agent was added to the breathing mixture. Anesthesia was terminated with the hlep of 2.5 to 5 mg of neostigmine sulfate after administering 1.0 mg of atropine intravenously. During some part of the surgical procedure, venous blood samples from wrist veins were drawn into paraffinized syrnges. Carbon dioxide content in the sample was derived using Van Slyke’s volumetric apparatus. The pH was measured with a Cam- bridge pH meter and paCO2 was later calculated by the Henderson-Hasselbalch equation. It was noted in this study that venous blood samples from wrist veins do not reflect the true state of paCO2 of arterial blood during anesthesia, as has been claimed,19 because, in spite of the use of PaCO2 absorption tech- nique with a high flow of gases, paCO2 levels could not be re- duced lower than 24mm Hg. In fact, in some patients values around 40mm Hg were recorded and these patients were not included in this series. Neurophysiology & Anaesthesia 180
  • Some patients who were relatively healthy were subjected to regional analgesia, e.g., spinal and field block surgial procedures were done. Some of them, however, became uncon- trollable and ultimately general anesthesia had to be induced by the above techniques. RESULTS: 1. The earlier part of the study (Table 1) revealed that production of epiniphrine did not keep pace with the phase to phase changes in norepinephrine. Catecholamines were measures in 17 cases and in three cases epinephrine appeared to increase (compared to preanesthetic levels). Two of these were explained by the excitement associated with stormy recoveries. The other case was associated with execessive blood loss in the preoperative phase due to a stab njury of the abdomen. 2. Norepinephrine production was significantly high in almost all phases of investigztion (Tables 2 and 3). The marked increae in concentration in the preoperative and preanesthetic phases in some patients might be due to apprehension. Surgery itself, although it contribues to significant increased in norepinephrine levels, did not induce unifrom responses in all individuals subjected to similar surgery under a similar form of anesthesia. 3. The type of anesthesia (general, spinal or local) did not have a modifying influence over norepinephrine production during almost all phases studied, because in realtively healhty Neurophysiology & Anaesthesia 181
  • individuals exposed to various surgical procedures under spinal or local anesthesia techniques, norepinephrine production was equally varied. DISCUSSION: Wang and Overman20,21 observed that stimulation of the sensory nerve caused death in animals at residual blood volumes which would have been compatible with survival if they were subjected to graded hemorrhage only. Coversely, when reflex vasoconstrictioon of the traumatized extremity was pre- vented by chronic deafferentation, the animals survived at residual blood volumes which were not compatible with sur- vival of animals that had traumatized limbs with intact nerve suplies. Grant and Reeves22 stated that even though signs and symptoms of hemorrhage in the case of limb injury and abdomi- nal injury are the same, such signs do not entirely disappear when normal blood volume is resstored after abdominal injury. These facts indicate that the neurogenic component of stress plays a major role in causing changes in blood volume and other vital functions of the body. Vandam et al16,17 noted that cardiovascular changes to graded surgical trauma occur under commonly used anesthesia procedures and that such changes were greatest in poor-risk patients. TABLE 2. CASES STUDIED WITH NOREPINEPHRINE CONCENTRATION IN PLASMA AT VARIOUS STAGES (Norepinephrine concentration is expressed as µg/Liter of plasma). (Contd. on next page) Neurophysiology & Anaesthesia 182
  • Case Nature of Operation Preoperative Preanesthetic After During During Later Remarks No. Induction Maximal Recovery Part of Postoperative Phase 2. Hemicolectomy for T.B. of large intestine --- --- 50 100 --- --- --- 4. Laparotomy for stab injury fo the abdomen --- 8 8 10 7.4 --- --- 5. Partial gastrectomy for gastric ulcer --- 10 --- 12 10.0 --- --- 7. Intestinal obstruction (in grave physical status, excessive gangrene of the bowel). --- 6 --- 7.5 --- --- --- 9. -- do -- --- 50 --- 25 --- --- --- 11. Hemicolectomy 12.5 20 --- 50 100.0 --- --- 12. Exploratory laparotomy --- --- --- 30 --- --- --- 13. Excision of dermoid cyst (arising from lesser sac of peritoneum) 30.0 --- --- 20 40.0 --- --- 15. Partial gastrectomy --- --- --- 30 20.0 --- --- 17. Exploratory laprotomy --- --- 10 --- 40.0 --- --- 19. Abdominal vagotomy and gatroenterostomy --- --- --- 20 30.0 --- --- 20. Exploratory laparotmy --- 10 --- 20 10.0 --- --- 21. Abdominal perineal resection for carinoma After using of the rectum --- 10 --- 15 20.0 50.0 halothane. 24. Gastroenterostomy --- 30 --- 20 10 --- --- 25. Partial gastrectomy --- 50 --- 20 --- 50 --- 26. Exploratory laparotomy --- 20 --- 30 --- --- --- 27. Partial gastrectomy --- 5 --- 35 40 --- --- 28. Exploratory laparotomy --- 20 --- --- 5 --- --- 29. Herniorrhaphy 50 20 --- 30 --- --- --- 30. Excision of hydrocele sac --- 10 --- 50 --- --- --- 31. Herniorrhaphy --- 4 2 <2 --- --- --- 32. Excision of varicose veins --- <2 --- 4 --- --- --- 33. Gastroenterostomy --- 2 --- 15 --- --- --- 34. Gastrectomy --- 20 --- 15 --- --- --- 35. Gastroenterostomy --- 10 --- 50 --- --- --- 36. Exploratory laparotomy and closure of perforated gastric ulcer --- 3 --- 2 3 --- --- 37. Exploratory laparotomy and Hemicolectomy <2 <2 --- 40 50 --- --- __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________________ Neurophysiology&Anaesthesia183
  • TABLE 3. NOREPINEPHRINE CONCENTRATION IN PATIENTS WHEN SUBJECTED TO SIMILAR SURGICAL PROCEDURES UNDER 3 TYPES OF ANESTHESIA. (Norepinephrine concentration is expressed as µg/Liter of plasma). Type of operation Case No. Types of Prior to During After Remarks Anesthesia Operation Operation Operation 1. Exploratory 4 G.A. 8 10 7.4 --- laparatomy and 12 G.A. --- 30 --- --- minor abdominal 15 G.A. 30 20 40.0 --- surgical 17 G.A. 10 40 --- --- procedure 20 G.A. 10 20 10.0 --- 26 G.A. 20 30 --- --- 28 G.A. 20 --- 5.0 --- 36 L.A. 3 2 3.0 G.A. had to be given later. 2.Partial 5 G.A. 10 12 10.0 --- gastrectomy 13 G.A. --- 30 20.0 --- 25 G.A. 50 20 50.0 --- 27 G.A. 5 35 40.0 --- 34 S.A. 20 15 --- G.A. had to be given later 3. Gastroenterostomy 19 G.A. 15 20 30.0 --- 24 G.A. 30 20 10.0 --- 33 S.A. 2 2 --- --- 35 S.A. 10 50 --- --- 4.Hemicolectomy 2 G.A. --- 50 100.0 --- 11 G.A. 20 50 --- --- 37 L.A. 1 40* 50 *G.A. had to be given later 5.Excision of 7 G.A. 6 7.5 --- --- gangrenous large bowel. 9 G.A. 50 25.0 100.0 --- 6.Abdominal perineal resection of sigmoid 21 G.A. 20 *15.0 *After using halothane colon 7.Herniorrhaphy 29 S.A. 50 30.0 --- --- (Inguinal) 31 S.A. 4 <2.0 --- --- 8.Plication of hydrocele sac 30 S.A. 10 50.0 --- --- 9.Excision of varicose veins of the legs. 32 S.A. 1 2.0 --- --- Neurophysiology & Anaesthesia 184
  • Gelhorn and Redgate1,2 showed that neurogenic stress induced sympathetic overactivity with predominance of norepinephrine which is presumed to be liberated from the terminal granules.23 Our study in the initial phases aimed to demonstrate that the concentration of epinephrine in the peripheral blood did not sig- nificantly change, thereby proving that asphyxia and hypovalemia (which are known to produce epinephrine predomnantly2 24 ) did not influence these results. Price et al11 , while discussing the possible role of the adrenal medulla in liberating various neuro- hormones during gnereal anesthesia, stated that the observed increase in norepinephrine levels reflected a phase of sympa- thetic overactivity and that the adrenal medulla did not partici- pate to any extent in man. Their views about the inactive role of the adrenal medulla can be extended to surgical stress also, es- pecially its neurogenic component. Since current balanced an- esthesia techniques are ineffective in stopping most noxious stimuli that inffluence the central nervous system,5 26 it is likely that the hypothalamus, medulla oblongata and spinal cord are activated by noxious stimuli whose hyperactivity leads to the production of high levels of norepinephrine in the peripheral blood.1 2 Our study, however, indicated a grossly increased level of norepinephrine in some patients, which could partially be explained by the fact that samples from the forearm veins give hihger readings of norepinephrine than wrist veins.27 Since most of the cases studied had prolonged histories of suffering (being poor-risk cases), it is possible that they were hypersensitive to surgical stress.16 17 Similarly, it is also likely that higher concen- tration of norepinehrine observed might be because bioassay reesults are always higher than fluorometric methods.24 Since our primary aim was to measure the production of stress response in different individuals, limitatins in the interpretation Neurophysiology & Anaesthesia 185
  • of results and the fact that fluorometric methods are more specific than bioassay methods did not handicap our investiga- tions. Our (TABLE 3.) study indicated that individuals do react differently to similar surgical procedures under similar types of anesthesia and confirmed the views of Vandam et al.16 17 SUMMARY: In order to study the stress response produced by individuals under various forms of anesthesia, norepinephrine was estimated in 37 patients by bioassay on pithed rat blood pressure. Blood samples were taken from the patients in the preoperative, operative and postoperative phases. On a few occasions, when epinephrine was alos estimated, it was revealed that its produc- tion was not significant under these conditions of study. Norepinephrine levels were persistenly higher in all phases, indicating significant stress response to surgery and anesthesia. Poor-risk patients who were subjected to elective or emergency surgery exhibited a maximum concentration in peripheral blood. REFERENCES: 1. Gelhorn, E: Autonomic imbalance and hypothalamus. University of Minnesota Pres: Mineapolis, 119-139, 1957. 2. Redgate, ES, and Glehorn, E: Nature of sympathoadrenal discharge under conditons of excitation of central autonomic structures. Amer J. Phsiol. 174: 475, 1953. 3. Brewster, WR, Isaacs, JP, and Waino-Anderson, T: Depresant effects of ether on myocardium of the dog and its modification by reflex release of epiniphrine and norepinephrine. Amer J. Physiol. 171:37, 1952. 4. Dobkin, AB, et al: The neuroendocrine and metabolic effects of anaesthesia associated with accute hypoxia and acute hypercapnoea. Canad Anaesth. Soc. J. 14:442, 1967. Neurophysiology & Anaesthesia 186
  • 5. Dobkin AB, Byles, PH, and Neville, JF Jr.: Neuroendocrine and metabolic effects of general anesthesia during spontaneous breathing, controlled breating mild hypoxia and mild hypercarbia. Canad Anaesth. Soc. J. 13:130, 1966. 6. Dobkin, AB, Byles, PH<and Neville, JF Jr.: Neuroendocrine and and mtabolic effects of general anaestheisa an d graded haemorrhage. Canad Anaesth. Soc. J 13:453, 1966. 7. Hamelberg, W, et al: Catecholamine levels during light and deep anesthesia, Anesthesioil. 21:297, 1960. 8. Hardy, JD, Carter, T, and Turner, M: Catecholamine metabolism. Ann Surg. 150:666, 1959. 9. Hume: In Federation Proceedin gs of american Society of Experimnetal biology: Washington D.C.: Ed. Huxley, SE. & Weesigner, I.R.: 87-98, 1962. 10.Miller, RA, and Morris, ME: Symptho-adrenal responses during general anesthesia in man. Canad Anaesth. Soc. J 8:356, 1961. 11.Price, HL, et al: Sympatho-Adrenal responses to general anestehsia in man and their relation to hemodynamics., Anesthesiology 20:563, 1959. 12.Richardson, JA, Woods, EF, and Richardson, Ak: Plasma concentrations of epinephrine and norepinephrine during Anesthesia. J. Pharma. Expt. Ther 119:378, 1957. 13.Plumpton, FA, and Beser, GM: The adrenocoritcal responses to surgery and insulin-induced hypoglycaemia in corticosteroid treated and normal subjects. Birt. J. Surg. 56:216, 1969. 14.Muxworhty, JF Jr., and Roorbach, E: Chest and lung compliance change with stress. Anaesth Analg. 45:340, 1966. 15.Slater, EM, et al: Arterial oxygenation measuremnets during N2 O-O2 anesthesia. Anesthesiology. 26:642, 1965. 16.Rocco, AG, and Vandam, LD: Changes in circulation consequent to manipulation during abdominal surgery. JAMA 164:14, 1957. 17.Vandam, LD, Schweizer, HJ, and Kubota: Circulatory respone to intraabdominal manipulators during ether anesthesia in man. Cir. Res. 11:287, 1962. 18.Gaddam, JH, Peart, WS, and Vogt, M: The estimation of adrenaline and allied substances in blood. J. Physiol. (Lond). 108:467, 1949. 19.Woolmer, R: The measurement of pH and PaCO2 in “Modern Trends in Anaesthesia” : II, Ed. Evans, FT, and Gray TC, Buttersworths: London: 31-55, 1962. Neurophysiology & Anaesthesia 187
  • 20.Wang, SC: The importance of the afferent nervous factor n experimental shock: the effects of chronic denervation. Amer J. Physiol. 148:547, 1947. 21.Overman, RR, and Wang, SC: The contributory role of afferent nervous factos in experimental shock: Sublethal hemorrhage and sciatic nerve stimulation, Amer J. Physiol. 148:289, 1947. 22.Grant, RT, and Reeves, EB: Rep Ser Med. Res. Comm. No. 277 as reported by R.P. Harpboard n Modern Trands of Anaesthesia: I, Edited by Evans, F.T., and Gray, T.C.: 141:166, Buttersorth, London, 1958. 23.Trendelendburg, AK: The norepinephrine stores and their functional comparrtments. Anesthesiology. 25:259, 1964. 24.Watts, DT, and Westfall, V: Studies on blood catecholamine levels during hemorrhagic shock in dogs. Proc. Soc. Exptl. Biol. N.Y., 115:601, 1964. 25.Loder, RE: Inadequacy of general anesthesia for abdominal operation: A possible solution. Lancet 2:466, 1957. 26.Rao, LN, et al: Peripherally evoked central nervous responses during surgery under general anaesthesia:Aclinico-neurophysiological coorelation. Indian J Anaesth. 15:81, 1967. 27.Price, HL: Estimation of epinephrine and norepinephrine concentrations in human plasma by the trihydroxyindole method. Pharmacol. Rev. 11:273, 1959. ***** Neurophysiology & Anaesthesia 188
  • Neurophysiology & Anaesthesia 190
  • International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 19, No. 1 - 1981 (pp. 18-22). “SYNDROME OF POSTOPERATIVE DEPRESSION OF VITAL FUNCTIONS IN POOR-RISK PATIENTS: ITS TREATMENT” L.N. RAO** AND H. VENKATAKRISHNA-BHATT** **Department of Anaesthesiology and Intensive Care, Gandhi Medical College, Hyderabad. and ***Division of Medical and Industrial Toxicology, National Institue of Occupational Health, Meghani Nagan, Ahmedabad, India. --------------------------------------------------------------------------------------------- * Project was carried out at Kurnool Medical College, Kurnool 518002, Andhra Pradesh, India. ** Present address: Department of Anaesthesiology, Gandhi Medical College, Hyderabad 500 001, Andhra Pradesh, India. *** Presdent Address: Division of Medial and Industrial Toxicology, National Institue of Occupational Health, Ahmedabad, 380 016, Gujarat, India. --------------------------------------------------------------------------------------------- Abstract.: Loss of proprioception due to depressed neuromuscular transmitter following cotinued action of skeletomuscular relaxant drugs may not be the main cause of stupor, respiratory depression, and suprression of motor and senosry reflex activity in the immediate or delayed post-opera- tive period in surgical patients. Those with a chronic history of suffering (termed poor-risk types because of other associated derangements in electrolytes, body water, etc.), hyper-react to surgical stress as well as postoperative pain and apprehension. This leads to the release of large quantities of stess products (noradrenalin and its cognates) into the central nervous system (CNS), thus inducing a phase of depression of the cerebral cor- tex and other vulnerable parts of the CNS in such a way that the stupor analgesic stage is induced in the affected persons (called the “syndrome of post-operative depression of vital functions”). Treatment of such a syndrome thus involved removal of the stress Neurophysiology & Anaesthesia 191
  • products from the CNS as well as from peripheral circulation by exraction therapy (20% mannitol administration), coupled with udicious use of atropine and neostigmine to stimulate the CNS itself, i.e., the production of acetylcholine in the mesencephalic reticulo-activating system. Key Words: post-operative depresion - poor-risk patients- vital functions. Poor-risk patients, suffering frm ulcerative colitis, intenstinal tuberculosis, or chronic or sub-acute intestinal obstructin, whether or not associated with changes in electrolytes, blood volume, or body water, often react negatively to surgery and anaesthesia (Rocco et al. 1957, Vandum et al. 1962). They present a syndrome of depression of consciousness (up to various levels), areflexia, atonia of skeletal muscles, and respiratory depression in the post-surgical phase, irrespective of the type of general anaesthesia and anaesthetic drugs administered [Rao et al. 1971a]. Moreover they sometimes acquire a bleeding tendency [Rao et al. 1971b]. Current concepts about its etiology The various complications of the syndrome of depressed vital functions during the postoperative period are generally believed to develop due to the following factors: residual action of muscle relaxant drugs that resist the attempts to reverse their action at myoneural junction. [Hunter 1956]; breakdown of the blood brain barrier to muscle relaxants, re- sulting in profound depression of CNS [Foster 1956]; carbondioxide accumulation in the post-anaesthetic phase, simulating the continued action of relaxant drugs [Scurr 1954]; Neurophysiology & Anaesthesia 192
  • cumulative action of antibiotics used in surgery, (carotid 63), changes in acid base state and body-water, contributing to an abnormal action of muscles relaxants [Brooks et al. 1962]; and hypoxia of CNS occuring at the time of balanced anaesthetic techniques and alleged to be due to hyperventilation as a result of the reduced cerebrovascular flow [Kety et al. 1946.]. Clinical evaluatin of such concepts: A preliminary clinical study to evaluate these concepts was carried out in poor-risk patients and low-wage groups of sub- jects undergoing surgery who gave their written consent to the experiment. Balanced anaesthetic techniques were administered by the modified method of Suwa and Yamamura [1970, Rao et al.1975] so that severe hypocapnia was avoided in spite of artificial ventilation. The incidence of post-operative depression of vital functions was similar after general anaesthesia (when balanced anaesthetic techniques were usually associated with mild to moderate hypocapnia) and after hypervenilatory tech- niques in patients, irrespective of paCO2 levels and concentra- tion of d-tubocurarine/gallamine in plasma at the time of recov- ery from anaesthesia [Rao et al. 1975, 1976, Rao 1977a]. Fur- thermore, the neuromuscular transmission was normal in the thenar and hypothenar muscles in most of the patients who de- veloped the syndrome [Rao et al. 1971a]. To find which causal role surgical trauma plays in this, plasma norepinephrine was estimated in 37 patients prior to, during, and after surgical pro- cedures [Rao et al. 1972], Rocco et al. 1957]. the type of surgery (major or minor) and the type of anaethesia (spinal, local, or general) did not induce uniform stress response, as indicated by norepinephrine plasma levels in different groups of poor-risk patients. It was also observed that compared to other types of patients, poor-risk types reacted maximally to surgery in all phases, irrespective of the trivial nature of the surgery. Since Neurophysiology & Anaesthesia 193
  • Table 1 Patients who were treated in the immediate postoperative period between January 1970 to November 1974. (Total 141 Cases). Particulars Type Dehydration Dehydration Remarks therapy only therapy and drugs (1-2 hours) (atropine & neostigmine 4 to 12 hours) 1. General Surgical a. Intestinal obstruction (24 to 240 hours) Emergency 15 10 --- b. Perforation of intestine Emergency 25 15 --- c. Hemicolectomy for cancer surgery Elective 6 4 --- d. Intestinal apendectomy Elective 1 --- --- e. Rectosigmoidectomy for cancer surgery Elective 2 4 --- f. Surgery of strangulated hernia with resection of intestinal loops Elective 10 2 --- g. Exploratory laparotomy with minor surgery in the intestines Elective 4 2 --- h. Exploratory laparotomy with drainage of pus and in pelvic fossa Emergency --- 1 --- II. Gynecologic surgery a. Abdominal hysterectomy and vaginal hysterectomy Elective 20 6 --- III. Neurosurgery These cases not receive relaxants except at the time of intubation (50 to 100 mg scoline) a. Laminectomy Elective 2 1 IV. Orthopaedics a. Surgery on the long bones Elective 2 1 As above V. Urology a. Nephrectomy Elective 2 2 --- b. Prostatotomy Elective 2 --- --- VI. ENT surgery a. Mastoidectomy Emergency 2 --- No relaxants used except 50 to 100 mg scoline at the time of intubation. Neurophysiology & Anaesthesia 194
  • areflexia, continued unconsciousness, and respiratory depression in affected patients could not be shown to be due to continued action of drugs like d-tubocurarine [Rao et al. 1975, Rao 1977a], it was assumed that the development of the syndrome was caused by the hyperactive nature of the poor-risk patients reacting to surgery [Rocco et al. 1957, Vandum et al. 1962]. the underlying cause may have been the accumulation of toxic by products of stress resonse (norepinephrine and other biogenic amines) in the CNS, leading to the depression of brain activity in the postoperatie period [Rao et al. 1971a, 1976, Rao 1977b]. TREATMENT: Once clinical signs of the syndrome were established (e.g., depressed level of consciousness even though the patients may make some efforts to open the eyes, etc., when asked; respira- tory depression even after administration of 2.5 to 5.0 mg neostigmine; hypo- or atonia of skeletal muscles; and sluggish reaction to painful stimuli), efforts were made to wash off toxic by-products (products of stress response) from the CNS by extraction therapy. Simultaneous efforts were made to build up the acetylcholine content in the CNS [Haranath et al. 1972] (with the use of atropine and neostimine). The pattern of treatment was therefore evolved by trial and error processes on the following lines: 20% mannitol solution in a dosage of 1.5 mg/kg body weight was rapidly administered by intravenous drip (transfused within 30min) with simultaneous infusion of 5% dextrose solution (1 litre) to avoid severe dehyderation. Neurophysiology & Anaesthesia 195
  • urethal catheter was applied to measure urinary secretion after emptying the bladder; 2 hrs after mannitol administration, 1.0 mg atropine and 1.5 mg neostigmine were administered within a period of 10 min and response (in the form of improvement of consciousness level, skeltomuscular tone, and respiration) was carefully noted; after 4 hrs (if the patient did not recover), further doses of 0.6 mg atropine and 1.5 mg neostigmine were repeated; all the time endotracheal intubation and IPPV were maintained, and the patient was ventilated with mixtures rich in oxygen (40 to 60% O2 in air); after 8 hrs of IPPV and extraction therapy, if patient still suffered from the syndrome, another infusion of 300 ml mannitol solution was given with simultaneous infusion of 5% dextrose; if necessary, last doses of atropine (0.6 mg) and neostigmine (2.5 mg) were administered at the end of 10 to 12 hrs of IPPV. Our experience in a study with 141 patients who developed the syndrome (see Table 1) revealed that while many cases improved with the dehydration therapy alone, some cases had to be treated for 4 to 12 hrs. Large quantities of urine output; i.e., 600 to 1500 ml, enhanced the recovery rate. DISCUSSION: Evidence shows that consciousness was maintained inthe cerebral cortex according to the high degree of spontaneous and repetitive firing of cortical neurons [Libel 1965] and that such activity of cerebral neurons (spontaneous and repetitive firing) Neurophysiology & Anaesthesia 196
  • is trigered byh acetylcholine in the ascending cholinrgic system [Krnjevic 1969, Szerb 1967, Bradley 1960]. Kanai and Szerb [1965] observed that stimulation of mesencephalic reticular formation at 100/s scaused increased release of acetylcholine at various areas of the cerebral cortex. Therefore, retension of consciousness and remaining unconscious seem to depend upon EEG activation, which is directly related to activation of cholinergic neurons of the CNS (Bradley et al. 1966, 1972).Ad- ministration of atropine and neostigmine enables release and increased production of free acetylcholine in the CNS [Bhattacharya et al. 1958, Polak 1965, Katz 1967]. Ever since the introduction of balanced anaesthesia during surgery, there were doubts about the role of neostigmine in causing normal state after anaesthetic procedures. Katz in 1967 revealed that, at least in part, the dramatic recovery of alertness of surgical patients when neostigmine had been administered was due to central stimulation. It is now known that the CNS is depressed during balanced anaesthetic states due to vagosympathetic afferents from the lungs during artificial overventilation [Rao et al. 1966, 1970, 1975, 1977]. The patients could be brought back to normal by the use of doxapragm [Siker 1965] and micoren. Nonspecific stimuli such as squeezing the Achiulles tendon or moving the endotracheal tube itself occasionally restarts respiratory efforts after a phase of artifical ventilation [Robson 1967], probably by increasing the efferent traffic in the CNS which was suppressed during artificial ventilation [Salimorrhagi et al. 1960]. Since concentration of acetylcholine increased during alert states [Haranath et al. 1973], it is likely that administration of neostigmine and atropine provided a good stimulus for making the patient alert after balanced anaesthetic states. However, if the CNS was grossly depressed by the Neurophysiology & Anaesthesia 197
  • cumulative action of stress products such as noradrenalin and other biogenic amines (Weber 1904, Rothballer 1959, Abraham et al. 1956, Burn 1945], administration of atropine and neostigmine which cross the blood-brain barrier with some difficulty [Haranath et al. 1972] will not be sufficient to restore the activity of CNS to a normal state. It is known that when large amounts of catecholamines accumulate in the body, the kidney is the main site of exretion [Burn 1945]. Hence exraction therapy becomes necessary to wash out the accumulated products of stress response. Intermittent administration of atropine and neostigmine was necessary to build up large amounts of acetylcholine inthe CNS so that, as a follows-up to extraction therapy, the CNS could be triggered to normal activity [Rao 1977b, Rao et al. 1977]. for the author: DR. MED. L.N. RAO, M.D., D.A., Professor and Head of the Department Anaesthesiology and Intensive Care, Gandhi Medical College, Hyderabad 500 001. Andra Pradesh India Neurophysiology & Anaesthesia 198
  • REFERENCES: Abraham V C, Pickford M 1956 Observations on central antagonism between adrenaline and acetylcholine. J. Physiol. (london) 131, 712. Bhattacharya B K, Feldberg W 1958 Perfusion of cerebral ventricles: Assay of pharmaccologically active substances in the effluent from cisterna and acqueduct. Brit. J. Pharmac. Chemother. 13, 163 Burn J H 1945 Relation of adrenaline to acetylcholine in the nervous system. Physiol. Rev. 25, 789. Bradley P B, Dray A B 1972 Short latency excitation of brian stem neurons in the rat by acetylcholine. Brit. J. Pharmac. 45, 372 Bradley P B, Dhawan N, Wolstencraft J H 196 Pharmacological propertiee of cholinergic neurones in the medulla nad pons of the cat. . Phsiol. (Londn). 183, 658. Bradley P B Elecrophysiological basis of evidence relating to the role of adrenaline in the central nervous system. In: Adrenergic Mechanisms Brookes D K, Feldman A S 1962 Metabolic acidosis (a new aporach to the neostigmine resistant curarization). Anaesthetisa 17, 161 Corrado A P 1963 Respiratory depression due to antibiotics; calcium in treatment. Anaesth. Analg. 1, 43 Foster P A 1956 Potassium depletion and central action of curare. Brit. J. Anaesth. 28, 488. Haranth P S R K, Venkatakrishna-Bhatt H 1972 Effects of eserine and neostigmine on the relase of acetylcholine into the perfused cerebral ventricles in unanaesthetized dogs. Indian J. Med. Res. 60, 1682 Haranath P S R K, Venkatakrishna-Bhatt H 1973 Release of acetylcholine from the perfused cerebral ventricles of unanaesthetized dogs during sleep and waking. Jap. J. Physiol. 23, 241 Hunter A R 1956 Neostigmine-resistant curarization. Brit. Med. J. 2, 919 Kanai T, Szerb J C 1965 Mesencephalic reticular activating system and cortical acetylcholine output. Nature 205, 80 Katz R L 1967 D-tubocrarine, edrophonium and neostigmine. Anaesthesiology 28, 327 Kety S S Schemidt S P 1946 The effect of active and passive hyperventilation on cerebral blood flow, cerebral oxygen consumption, cardiac output and blood pressure of normal young man. J. Clin. Invest. 25, 107 Neurophysiology & Anaesthesia 199
  • Krnjevick K 1969 Central cholinergic pathways. Fedn. Proc. 28, 113 Libet B 1965 Cortical activation in consciousness and unconsciousness, Perspect. Biol. Med. 9, 77 Polak R L 1965 Effect of hyoscine on the output of acetylcholine into perfused cerebral ventricles of the cat. J. Physiol. (London) 181, 317 Rao L N, Venkatrishna-Bhatt H 1971a Stress response during surgery and aneasthetisa in man: Its possible connection with the syndrome of depressed vital functions in the post-surgical period (a preliminary report). Indian J. Anaesth. 19, 365 Rao L N, Venkatakrishna-Bhatt Acquired bleeding tendency during and after an operative procedure: Its relationship with stress response. Indian J. Anaesth. 19, 63 Rao L N, Venkatakrishna-Bhatt H 1975 Role of thiopentone, nitrous oxide and muscle relaxants in causing the post-operative praralysis in man. Anaesthetist 24, 73 Rao L N, Venkatakrishna-Bhatt H 1976 Syndrome of depressed vital functions in the immediate post-operative period of surgical patients; Some aspects of its pathogenesis, Europ. J. Intensive Care Med. 2, 41 Rao L N 1977a Pattern of recovery from balanced anaesthetic techniques: Its relationship with plasma and CSF levels of d-tubocurarine/gallamine in immediate post-operative period. Asian Arch. Anaesth. Resus. 7, 52 Rao L N, Venkatakrishna-Bhatt H 1972 Stress response during surgery and anaesthesia: Indicated by norepinephrine concentrations in plasma of surgical patients. International Surg. 57, 294 Rao L N, 1977 The syndrome of depression of vital functions in the post-operative period in man: Role of neurohumours in its causation. In: Neurohumoural correlates of Behaviour, Sub-rahmanyam S. (ed.) p. 234-243, Thompson Press (India) Ltd. Publication Division, Faridabad Rao L N, Rama-Rao K R, Bhalla S K 1966 Increased afferent activity (vagal, splanchnic etc.) leading to hyperventilation syndrome during surgery under general anaesthesia. Indian J. Anaesth. 14, 226 Rao L N, 1967 Apnoea during and immediately after hyperventilation: A reoreintation Indian. J. Anaeth. 15, 238 Rao L N, Venkatakrishna-Bhatt H, Prahlad T N 1969 Central nervous effects of hyperventilation: A preliminary report, Indian J. Med. Sc. 23, 665 Rao L N, Venkatakrishna-Bhatt H 1970 Vagal activity in Canines: A possible connection to hyperventilation syndrome. Anaesth. Analg. 49, 351 Neurophysiology & Anaesthesia 200
  • Rao L N, Venkatakrishna-Bhatt H 1975 Changes in the activity of central nervous system during balanced anaesthetic states. Indian J. Med. Sc. 29, 257 Rao L N, Raghavendra Rao P 1977 Mechanism of beneficial effects of hyperventilation during balanced anaesthetic techniques: An alternate theory. Asian Arch. of Anaeth. Resus. 7, 27 Rao L N, Venkatakrishna-Bhatt H 1977 Mechanism of toxicity of surgical stress in poor-risk patients. Asian Arch. Anaesth. Resus. 7, 41 Robson J G 1967 The respiratory centres and their responses. In: Modern Trends in Anaesthesia, Evans F.T. Gray T.C. (eds.) 3, p. 42-55, butterworths, London Rocco A G, Vandum L D 1957 Changes in circulation consequent to manipulation during abdominal surgery. J. Am. Med. Assn. 164, 14 Rothballer A B 1959 Effects of catecholamines on the CNS. Pharmacol. Rev. 11, 494 Salimorrhagi G C, Burns B D 1960 Notes on the mechanism of rhythmic respiration. J. Neurophysiol. 23, 14 Scurr C F 1954 Carbon-dioxide reterntion simulating curarization. Brit. Med. J. 1, 565 Siker E S 1965 Post-anaesthetic respiratory depression. Anaesth. Analg. 44, 253 Suwa K, Yamamura H 1970 The effect of gas inflow on the regulation of CO2 levels with hyperventilation during anaesthesia. Anaesthesiology 23, 440 Szerb J C 1967 Cortical acetylcholine release and electroence-phalographic arousal. J. Physiol. (Lond.) 192, 329 Vandum L D , Schweizer H J, Kubota L 1962 Circulatory response to intraabdominal manipulation during ether anaesthesia in man. Cir. Res. 11, 287 Weber H 1904 Uber Anaesthesie durch Adrenalin. Verl. dtsch. Ges. int. Med. 21, 616 Vane J R, Wolstenholme G E W, O’Connor M (ed.) 1960 p 410-420, Churchill, London. ***** Neurophysiology & Anaesthesia 201
  • Reprinted from the Indian Journal of Anaethesia, Vol. 20, No. 3. August, 1972 Editor: S. PRAMANIK, MB, DA., FFARCS (ENG.) PSYCHOSOMATIC FACTORS INVOLVED IN THE DEVELOPMENT OF BLEEDING TENDENCY IN THE POST-OPERATIVE PERIOD - A CASE REPORT By L.N. RAO, MD, DA, Professor of Anaesthesiology, J.G. CHAR, MBBS, Postgraduate student in Anaesthesiology, H. VENKATAKRISHNA BHATT, M.SC., Assistant Research Officer AND P. HARINARAYANA, MS, Additional Professor of Surgery Kurnool Medical College, Kurnool, Andhra Pradesh E5 SECTION II 203
  • PSYCHOSOMATIC FACTORS INVOLVED IN THE DEVELOPMENT OF BLEEDING TENDENCY IN THE POST-OPERATIVE PERIOD - A CASE REPORT By L.N. RAO, MD, DA, Professor of Anaesthesiology, J.G. CHAR, MBBS, Postgraduate student in Anaesthesiology, H. VENKATAKRISHNA BHATT, M.SC., Assistant Research Officer AND P. HARINARAYANA, MS, Additional Professor of Surgery Kurnool Medical College, Kurnool, Andhra Pradesh --------------------------------------------------------------------------- Episodes of acquired bleeding tendency development during or immediately after surgical procedures are now well docu- mented (Rao and Venkatakrishna Bhatt, 1971 : Ganesiah, 1965; Manchanda et al., 1966; Narang et all., 1966 ; Sonan, 1966 and Davidson et al., 1969). It is however, a fact to state that episodes of bleeding tendency development in the later period of post-operative phase are rare. Rao and Venkatakrishna Bhatt (1971) reported two cases of such acquired bleeding tendency developing after 72 hours of post-operative period but they did not investigate as to evaluate the possible factors invovled in its causatin. This case is therefore presented by us only to indicate the possible role of psychosomatic factors involved in the causation of the bleeding tendency in the post-operative period. Neurophysiology & Anaesthesia 204
  • CASE REPORT Miss A., aged 12 years was admitted in the Government General Hospital, Kurnool on 14-03-1971 with the complaint of pain abdomen of 3 months’ duration. Investigations revealed that she had subacute intestinal obstruction and hence she was subjected to exploratory laparotomy on 19-03-1971. Her pre-operative checkup revealed her to be in moderate general conditon with no signs and symptoms of gross dehydration. She was not anaemic and daily urine output was normal. She however, gave history that she passed blood stained urine after admission into the ward and hence she was referred to the gynaecology department for checkup to exclude her attainment of menarche, Gynaecologists, however, over-ruled such a possibility and the episodes of blood stained urine could not be explained, because analysis of urne and other examinations pertaining to urogenital system did not indicate any abnormality. During the exploratory laparotomy it was noticed that a few constricting bands narrowed the large intestine with proximal dilatationThe bands were, therefore resected and abdomen closed in layers. The entire procedure of anaesthesia and surgery which lasted for 45 minutes was uneventful and 300 mil. of compatible blood was transfused towards the end of operative procedure. She later developed urticaria on the upper arm through which she was transfused which cleared up completely on administration of an antihistamine (Avil). Her next 48 hours of post-operative progress was uneventful. Neurophysiology & Anaesthesia 205
  • After 72 hours of operation, however, she developed mild hypotension which was immediately corrected by rapid infusion of dextravan in 5% glucose. After further 24 hours she developed oliguria with frank haematuria. However, no haemolysis was found in blood and no haemolysed blood in urine though plenty of red blood corpuscles were found in the latter. Remote possibility of incompatible blood transfusion on the day of operation was excluded by repeating blood grouping and cross- matching of the left-over sample of blood.At this stage, though, routine investigations like bleeding and coagulation time, were within normal limits, specific tests for evaulating the type of coagulation defect (described in appendix) revealed that fibrinogen level in her was less than 150 mg/ml. of blood and that no circulating fibrinolysins could be detected. Bassing on our earlier work (Rao and Venkatakrishna Bhatt, 1971), it was decided to investigate for the possible involvement of psycho- somatic factors aggravating the post-operative stress in her which could have explained the occurrence of such bleeding tendency in her. Hence, noradrenaline concentrations in peripheral blood was estimated by the method of bioassay on pithed rat blood pressure (Shipley and Tilden, 1971; Muschol and Vogt, 1958). It was found that its level was grossly unphysiologiccal being 20 mg/1 of plasma. at the time she was conscious and her respiratory excursions were normal with blood pressure within normal limits. She was found to be associated with kidney shutdown for a period of 48 hours only to suddenly go over to the phase of polyurea with secretion of 1,100 ml./24 hours. After further 24 hours she died of peripheral vascular failure. Neurophysiology & Anaesthesia 206
  • DISCUSSION Though Rao and Venkatakrishna Bhatt (1971) observed that two out of 15 cases in their series manifested bleeding tenden- cies in the delayed post-operative period, such reports are rare and pathogenesis of such a tendency developing in delayed post-operative period is not quite clear. Rao and Venkatakrishna Bhatt (1971) reported that some patients react differently to the stress of surgery and anaesthesia. Their results are concurrent with the views of Vandam and colleagues (1957, 1962) that poor risk patients have increased morbidity and mortality rates because of their hypersensitivity to neurogenic stress. Hence we investigated this case for the possible abnormal response to the post-operative stress which could account for the kidney shut- down and the development of bleeding tendency during the de- layed post-operative period. The results of various investiga- tions revealed that defibrinogenation has occurred in her (for details of investigation see appendix). Since it is known that excessive catecholamine production leads, in the initial phases to hypercoagulability of blood, followed by depletion of fibrinogen concentration of blood with the final results of the development of hypocoagugility (Levy and Blattberge, 1964). We estimated the plasma concentration of noradrenaline and noted that it was very high. As early as 1946, Gelhorn and his his colleagues (1953, 1957) observed that neurogenic stress (for instance fear, apprehension and post-operative pain) results in the activation of posterior hypothalamus with the resultant hy- peractivity of sympathetic system without the active participa- tion of adrenal gland. The high concentration of noradrenaline estimated in this case therefore strengthens the possiblity that she was in an abnormal state of cnetral nervous system and Neurophysiology & Anaesthesia 207
  • contributed to some of the changes in vital functions observed. It is known that during neurogenic stress posterior hypothala- mus is stimulated and it is likely that the kidney shutdown in the post-operative phase in this patient is a part of the sympathetic overactivity during such hyperactive phase of the posterior hy- pothalamus. These possibilities when studied with the results of the investigations, reveal that anxiety, apprehension, and pain could cause in post operative haemorrhage and kidney shut down in suscetible individuals and it is therefore suggested that better management of the post-operative phase in necessary to avoid such complications. APPENDIX I. Method of rough estimation of fibrinogen in plasma: Test I : Clot observation test. (Abner 1963): 5 ml of patient’s blood is placed in a clean dry test tube. The test is positive if no clot forms within 5-10 min. or a clot is formed immediately but lysis within next 30 min. (the fibrinogen level may be assumed to be less than 150 mg/100 ml. of blood). Test II : Qualitative fibrinogen estimation test. In this rapid diagnositc test, one ml. of patient’s blood is added to a test tube containing 0.1 ml. of topical throm- bin. The test is positive if a clot does not form or takes more than 30 seconds to do so. Test III : Qualitative fibrinolysin test. Place equal parts of unclotted blood and normal clotted blood in a test tube. If clot and lysis occurs then it shows that fibrinolysis are circulating in the blood of the patient. Neurophysiology & Anaesthesia 208
  • II. Results of investigations: Test I : Positive. Test II : Positive Test III : Negative III. Inference: Fibrogenenopaenia. (fibrinogen level being less than 150 mg/100 ml. of blood but no circulating fibrinolysins). ACKNOWLEDGEMENT Authors thank the Superintendent of the General Hospital for permitting them to publish this paper and Professor P.S.R.K. Haranath for the laboratory facilities. REFERENCES 1. Rao, L.N. and Venkatkrishna Bhatt, H. (1971): Acquired bleeding tendency during and after an operative procedure: Ind. J. Anaesth., 19, 63. 2. Ganeshiah (1965): Acute defibrinogenopaenia post-operative (fatal). Ar. Fores Med. J., 21,225. 3. Manchanda, R.L. Keshwani, R.K., Rajender Sing and Nayer, H.M. (1966): Defibvrinogenation syndrome. An occasional surgical emergecy. Ind. J. Surg., 28, 331. 4. Sonan, D.P. (1966): Spontaneous fibrinolysis. Ind. J. Anaesth., 14, 46. 5. Davidson, J.F., McGregor, I.A. and McNicol, G.P. (1966): Acute failure of homeostasis during intra-oral carcinoma: Its treatment with aminocaproic acid. Br. J. Plastic Surg. 22, 117. 6. Narang, R.S. Gurubachan Sing and Saini, V.K. (1966): Fibrinolysis. A cause of abnormal bleeding episodes in cardiopulmonary surgery. Ind. J Anaesth.14, 51 7. Vandam, L.D. Schwitzer, H.C. and Kubota (1962): Circulatory response to intra-abdominal manipulation during ether anaesthesia in man. Cir. Zes. 11, 287. Neurophysiology & Anaesthesia 209
  • 8. Rcco, A.G. and Vandam, L.D. (1957): Changes in circulation consequent to manipulation during abdominal surgery J.A.M.A., 14, 1641. 9. Levy, M.N. and Blattberge (1964): Blood factors in shock. Ed. Hershey, S.G., London, J. and A. Churchill Ltd., pp. 65-77. 10.Gelhorn, E. (1957): Anatomic imbalance and hypothalamus. Minneapolis, University of Minnesota Press, pp. 119-139. 11.Redgate, E.S. and Gelhorn, E. (1953): Sympathoadrenal discharge under conditions of excitation of central anatomic structures. Amer. J. Physiol., 174, 475. 12.Abner, H. (1963): Obstetric anaesthsia for special problems. Anesth. & Analg. 42, 680. 13.Shipley, R.E. and Tilden, J.H. (1947): A pithed rat blood pressure suitable for assaying pressor substances. Proc. Soc. Expil. Biol. Med., 64, 453-455. 14.Muscholl, E. and Vogt. M. (1958): The action of reserpine on the peripheral sypathetic system. J. Physiol. (Lond.), 141, 132-155. ***** Neurophysiology & Anaesthesia 210
  • NEUROHYSIOLOGICAL BASIS OF THE SYNDROME OF POST-OPERATIVE DEPRESSION OF VITAL FUNCTIONS IN SOME OPERATED PATIENTS UNDER GENERAL ANAESTHETIC TECHNIQUES BY DR.L.N.RAO, MD HYDERABAD - 500 036. ANDHRA PRADESH, INDIA ------------------------------------------------------------- INTRODUCTION After the introduction of skeletomuscular relaxant drugs into the specialty of anaesthesiology a revolution has occurred in the general anaesthetic techniques and now it is possible to anaesthetize safely a neonate to elderly patients (90 years and above) without compromising the safety pattern in them. Because of such a success in the matter of general anaesthetic techniques, anaesthesiologists, world over speculate, that the revolutionary progress in the field of general anaesthesia (in short time of 30 to 40 years) is due to skeletomuscular relaxant drugs acting peripherally on neuro muscular junction andcentrally on cerebral cortex with the result that ideal operating conditions are produced in an unaware patient under general anaesthetic techniques. Operated patients normally recover from the effects of anaesthesia with in 5-10 min. of termination of surgery when the effect of anaesthesia wears off. However, they continue to sleep for more time when they are not disturbed. Occasionally some patients are found comatose with paralytic conditions developed in them in the post-operative period, often needing 4-8 hrs. or more of ventilatory support for their survival. Anaesthesiologists, world over, believe that under certain Neurophysiology & Anaesthesia 212
  • conditions biological life of skeletomuscular relaxant drugs is prolonged and such drugs (whose action is extended) continue to act on C.N.S., thereby causing post-operative paralytic condition with coma in some operated patients. Hence terms like “Central nervous action of curare” (1), “Neostigmine resistant curarization” (2), “Clinical syndrome of incomplete reversal” (3), “a stage of apparent recurarization” (4-10, 12, 14) etc are used to describe the syndrome of depressed vital functions in the post-operative period of affected patients purely on the basis of the speculation that continued action of relaxant drugs on C.N.S. is the cause of the syndrome. Some others indicated that antidote to curare (drugs like neostigmine or its equivalent drugs) wears off pre-maturely, leaving the skeletomuscular relaxant drugs to act unopposed on C.N.S, in the post-operative period. Thereby leading to the paralytic condition and coma. (They also feel that relaxant drugs continue to act on C.N.S. in post-operative period to cause coma in them). Intensive research about this problem (about the exact cause of coma with paralytic condition in some operated patients in post-operative period) was carried out in many centers in the world but it appears that the study about this problem (developing in some operated patients) is now sluggish or absent because it is observed that the affected patients normally recover from the above mentioned syndrome with ventilatory therapy in the post-operative period for 4 to 10 Hrs. or more. Hence research in this aspect is now sluggish because senior anesthesiologists who mould the minds of juniors feel that intense research about the cause of developing the above mentioned syndrome in some operated patients is unnecessary because ventilatory support would keep them alive any way. However, at this stage it may not be out of place to mention that only highly developed countries like U.S.A., Canada, Japan, U.K, European countries etc., are having respiratory therapy units (with critical care facilities) in 100% of operating units. In the rest of the world specially in the Neurophysiology & Anaesthesia 213
  • developing and underdeveloped countries operating units in semi- urban and rural areas do not have facilities for critical care therapy with ventilators. In India all operating units in the cities and some district hospitals have such facilities but the operating units in rural areas do not have a standby ventilator with trained personnel to help the anesthesiologist for the treatment of critically ill patients (such operating units are approximately in 30-40% of the rural areas in India). Hence anaesthesiologist himself has to struggle to keep the patient alive by using all methods of respiratory therapy available in the operating unit. Under such circumstances, surgeon, as well as patients relatives have a feeling that the anaesthesiologist must have used large quantity of anaesthetic drugs during anaesthetic procedure (abuse of such drugs) to cause coma and paralytic condition in the patient in the post-operative period. They also feel that the anaesthesiologist with the help of a nurse, and ward boy, is now struggling to wash off the excessive drugs given during surgery and he is struggling to keep the patient alive washing off excess of anaesthetic drugs abused during anaesthesia. Such a situation severely undermines the image of the anaesthesiologist concerned and some times a senior anaesthesiologist also comes under the cloud because he cannot satisfactorily explain to the surgeon and the patient’s relatives why the patient did not recover satisfactorily in the post operative period. An anesthesiologist was murdered in Tamilnadu (rural part of south India) by the relatives of the affected patient, thinking that she has abused anaesthetic drugs, which caused anaesthetic complication. Hence this research project aims to find out factors which cause delayed recovery from anaesthesia and other anaesthetic complications including neuro physiological mechanism which causes anaesthetic complications in peri operative period (one hour before surgery to 48 Hrs or more after surgery). ***** Neurophysiology & Anaesthesia 214
  • As early as 1947 Dr.Smith et al injected 2 ½ times the paralyzing dose of d’tubocurarine (dtc) into a volunteer and noted that such a large does of dtc did not stop the functioning of C.N.S. in the volunteer (11). Later on, experiments in dogs and patients revealed that dtc and gallamine do not effect C.N.S. because in conscious dogs, intracarotid injections of dtc only produced bouts R.E.M. type of sleep (when observed for some time) and they did not produce depression of C.N.S., as evident by the lack of peripheral effects (16) in such dogs (they had normal respiration, muscle tone etc.). In patients undergoing surgery for 70-110 min. presence of 10-25% or more of paralyzing dose of d’tc or gallamine in C.S.F and plasma of patients (at the time of recovery) did not affect their normal recovery pattern during hypo carbia, hypercarbia etc (18). During the period of this project work, many emergency cases were operated upon (patients who had varying levels of calcium and electrolytes). None of such patients had delayed recovery from anaesthesia. Hence it could be concluded that presence of significant amount of skeletomuscular relaxant drugs in C.S.F. and plasma at the time of recovery from anaesthetic do not affect the C.N.S., (as seen in the patients who recovered normally from anaesthetic process even when such patients had more than 10-25% of paralyzing does of skeletomuscular relaxants in C.s.F and plasma at the time of recovery (13,15,18)). It was observed in animal experiments that administration of dtc and many other drugs dissimilar in action in conscious dogs resulted in R.E.M. sleep only (16) thereby indicating that sleep observed in them was a non-specific phenomenon. In the case of human beings also similar pattern of sleep develops in the immediate post operative period (after Neurophysiology & Anaesthesia 215
  • various types of surgery under general anaesthetic techniques). However, it is observed that such patients (after 5-10 min. of termination of anaesthetic procedure) respond to simple commands like opening the eyes, putting out the tongue (when asked) and telling their name (when asked to do so) thereby indicating that presence of large concentration of skeletomuscular relaxant drugs in their blood and C.s.F. at the time of recovery in the post-operative period does not depress the C.N.S. (because they responded to simple commands after 5 to 10 min. of termination of anaesthetic procedure). NEURO PHYSIOLOGICAL MECHANISM WHICH CAUSES POST-OPERTIVE PARALYTIC CONDITIONS (INCLUDING COMA) IN SOME OPERATED PATIENTS Surgeons of U.S.A.(23-25) after learning that some soldiers in the battle field went into shock syndrome with minor injuries even when they had full blood volumes in them, experimented the effect of neurogenic stress in patients operated under anaesthesia. They observed that manipulation of abdominal contents under anaesthesia caused circulatory changes in the patients experimented. They found that such changes in circulation could be prevented by blocking the nerves in the relevant portion of the abdomen. Later hume (17) found that nor-adrenaline levels in urine of operated patients under anaesthesia increased, prior to during and after an operative procedure. Basing on these facts Rao and Bhatt (18-22) monitored the neurogenic stress, (as indicated by nor-adrenaline concentration in plasma of the patients) prior to, during operation and in the post operative period. Dr.Folkow (24), Dr.Rocco et al Neurophysiology & Anaesthesia 216
  • (23) Dr.VAndom et al(25) categorized some patients as poor risk types because they had long period of suffering with pain, or body dis-function. Such patients were found to have cachexia, changes in body fluid content, changes in body proteins, electrolytes etc. They observed that such patients (poor risk types), hyper reacted to any stress and strain in life, specially to the neurogenic stress of the surgery. Higher morbidity ad mortality rates in them (after an operative procedure) were due to their hyper reactivity to the neurogenic stress of the surgery. Rao & Bhatt (19-22) confirmed their observations in that poor risk patients and highly apprehensive patients not only reacted maximally to surgical stress but also reacted adversely in the pre and post operative period. RELATIONSHIP OF STRESS RESPONSE IN VULNERABLE PATIENTS TO THE CAUSATION OF COMAAND PARALYTIC CONDITION IN THE POST OPERATIVE PERIOD Physiologists after experiments in animals indicated that nor-adrenaline (which is the main constituent of stress product) acts on nervous tissue both at the peripheral and central level. Rathballer (26) experimented with all sympathomimitic amines and stated that all such amines when given by any route for sufficient time (subcutaneously, intramuscualarly or intravenously in experimental animals) leads to the accumulation of such amines in C.N.S. causing stupor-analgesia in them. Other physiologists agreed with his finding and stated that nor- adrenaline is bi-phasic in its action. In the 1st phase it enhances Neurophysiology & Anaesthesia 217
  • the neuromuscular transmission at the peripheral level as well as it stimulates various neurons of C.N.S. In the 2nd phase of its activity (after 20-30 min. of its 1st phase of activity), it depresses the neuromuscular transmission at the peripheral level and causes gross depression of C.N.S. causing stupor analgesia in experimental animals. In the human beings the state of stupor analgesia takes the form of coma and paralytic condition in the operated patients (who are affected by the accumulation of nor-adrenaline in their C.N.S, due to hyper reaction to surgical stress (Hence depressant action of noradrenaline continues its action in the post operative period). Effective therapy in such situations (to recover consciousness and general activity in the affected patients), is the extraction therapy suggested by Rao and Bhatt (22). It helps the patient by extracting accumulated nor-adrenaline in C.N.S. by extracting the excessive nor-adrenaline from C.N.S. and same is excreted through the kidneys. CONCLUSION 1. Some patients who are exposed to long periods of pain and suffering with bodily discomfort become chachectic with changes in body fluid content, body proteins and electrolytes; they hyper react to neurogenic stress of surgery. Hence such patients are called poor risk types. 2. Some other patients coming up for surgery of trauma or emergency surgery (who are highly apprehensive to surgery and anaesthesia), also hyper react to neurogenic stress of surgery. (during elective and emergency surgery). Neurophysiology & Anaesthesia 218
  • 3. Both these groups of patients, hyper react to neurogenic stress of surgery and produce significant levels of nor-adrenaline in plasma and in C.N.S. (as a part of the stress product), due to hyper re-action to stress of surgery, excessive concentration of noradrenaline is produced in C.N.S. which may or may not be in C.S.F. In our series of cases of coma with paralysis in post operative period only 1 to 2% of cases had trace of noradrenaline in C.S.F. Rest of the cases did not contain any quantity of Nor- adrenaline in C.S.F. However, during treatment of such patients we found that their urine contained significant quantity of noradrenaline. 4. Nor-adrenaline initially (in its 1st phase of its activity) causes stimulation of nervous tissue (both peripheral as well as at central level) but within a short time (20-30 min.), it changes its activity pattern to that of depression of the nervous issue as a whole (peripherally and centrally) thereby causing coma and paralytic condition in post-operative phase of operated patients, leading to coma and paralytic condition in some vulnerable operated patients. REFERENCES: 1. Foster P.A., potassium depletion and the central action of curarie, Brit J.Anaesth., 1956:28488-502. 2. Hunter A.R. neostigmine resistant curarization, Brit. Med. J. 2, 1956:919-20. 3. Brechner V.L., clinical syndrome of incomplete neuromuscular block reversal; Doctor look at your patient, Anesth. Analg. 1971: 50:876-78. Neurophysiology & Anaesthesia 219
  • 4. Feldman, S.A.L. an interesting case of recurarization, Brit J.Anaesth., 1959:28:461-63. 5. Sha B.M. & Patel R.A., a problem case of recurarization Ind J.Anesth., 1967:15203-4. 6. Way W.L. Katzung, B.G., & Larson C.P.J., recurarization with quinidine J.A.M.A., 1967:200153-4. 7. Sikh S.S., Agarwal, G.Branbutt P., & Rao P. recurarization and prolonged unconsciousness, Ind J.Anaesh., 1970:2091-5. 8. Scurr C.F., Carbondoxide retention simulating curarization, Brit Med J(1) 1954565-66. 9. Baraka,A. influence of carbondioxide on neuromuscular block caused by d’tubocurarine chloride in human subjects Brit. J.Anaesth., 1964:36:272-78 10. Baraka A., irreversible tubocurorine neuromuscular block in the human, Brit J., Anaesth., 1967:39:891-94. 11. Smith S.M.Brown, H.O., Toman, J.E.P., & Goodman C.S., the lack of central effects of d’tubocurarine, anesthesiology, 1947:8:8-14. 12. Bush G.H. & Baraka A., factors affecting the termination of curarization in human subjects, Brit J.Anaesth., 1964:3635-6. 13. Devashankaraiah G. Harnath P.S.R.K. & Krishna MurthyA., passage of “d’tc” from blood into liquor spaces in dog & man, Brit J. Pharmacol 1973:47:787-93. 14. Hannington-Kiff J.G., residual post-operatie paralysis, Proc. Roy. Soc,Med., 19706373-6. 15. Harnath, P.S.R.K., Krishna Murthy A. Rao L.N. & Sheshagiri Rao K., passage of gallamine from blood into liquor spaces in man and dog, Brit J.Pharmocol., 1973:48640-45. 16. Harnath, P.S.R.K., Sleep & central cholinergic mechanism’s in Sharada Subramanyam Editor neuro humural correlates of behaviour 1977, Thompson press (India) Ltd., Publication Division, Faridabad, Haryana, India pages 134-139. Neurophysiology & Anaesthesia 220
  • 17. Hume, in Seeley S.F. & Weisinger, J.R., Editors federation proceedings of Amer. Soc., Exp. Biol., Washington D.C., 1962:pages:87-98. 18. Rao L.N. and Venkata Krishna Bhatt, H., Role of thiopentone, N2O, relaxant anaesthesia in causing the syndrome of post-operative paralysis in man, Derr anesthetist 1975:2473-7. 19. Rao L.N. & Venkata Krishna Bhatt., H., stress response during surgery and anaesthesia as indicated by nor-epinephrine concentration in plasma of surgical patients, Int. Surg 197257294-98. 20. Rao L.N. & Venkata Krisha Bhatt H., stress response during surgery and anaesthesia in man its possible connection with the syndrome of depressed vital functions in the post surgical period, Ind. J.Anesth. 1971:19:365-76. 21. Rao L.N., the syndrome of depressed vital functions in the post-operative period in man role of neurohumours in its causation, in Sharada Subramanyam Editor “neuro humural correlates of behaviour” 1977, Thompson press (India) Ltd., Publication Division, Faridabad, Haryana, India pages 234-243. 22. Rao L.N. & Venkatakrishna Bhatt H., syndrome of post operative depression of vital functions in poor risk patients: in its treatmet, Int, J.Clin. Pharma & Toxicol 1981:19:18-22. 23. Rocco A.G., & Vendom L.D., changes in circulation, consequent to manipulation during abdominal surgery, J.A.M.A. 1957:16414-8. 24. Folkow B., Gellen L.E., Lindol S.E., Stenburg K. & Thoren O., cardiovascular action during abdominal surgery, Ann Surg., 1962156905-13. 25. Vandom, L.D., Schweizer H.J. & Kubota. Circulatory response to intra abdominal manipulations during either anaesthesia, Circ. Res. 19062:11:287-95. 26. Rothballer A.B., effect of catichol amines on central nervous system, Pharmocol. Rev., 1959:11:494-47. ***** Neurophysiology & Anaesthesia 221
  • RESEARCH PAPER “NEUROPHYSIOLOGICAL FACTORS WHICH LEAD TO AWARENESS IN PATIENTS DURING SURGERY UNDER GENERALANAESTHETIC TECHNIQUES” BY DR.L.N.RAO, MD HYDERABAD - 500 036. ANDHRA PRADESH, INDIA. NOTE: Presented to the Annual Conference of Indian Society of Anaesthetists, (at their annual conference of andhra pradesh branch of I.S.A. (national) in the year 2010 E7 SECTION II 222
  • “NEUROPHYSIOLOGICAL FACTORS WHICH LEAD TO AWARENESS IN PATIENTS DURING SURGERY UNDER GENERALANAESTHETIC TECHNIQUES” BY DR.L.N.RAO, MD HYDERABAD - 500 036. ANDHRA PRADESH, INDIA. ----------------------------------------------------------------------- INTRODUCTION: After the introduction of relaxant drugs into the specialty of anaesthesiology, a revolutionary progress occurred in general anaesthetic techniques. Surgery in neonates and senior citizen of 90 years, and above, is possible in any suitable position with the safety factor intact during and after surgery, possibly due to I.P.P.V. during general anaesthetic techniques (1,2,3). Normally patients during operations are unaware during surgery. However some patients (0.1 to 0.2%) of operated patients are found to be aware during surgery, even when techniques of general anaesthesia are continuing in them. Hence this study is to find out the conditions in which a person, becomes aware during surgery, in spite of the techniques of general anaesthesia continuing. ***** Neurophysiology & Anaesthesia 223
  • NEUROPHYSIOLOGY OF CONSCIOUSNESS (AWARENESS TO THE SURROUNDINGS) An individual is conscious (aware & active) when his/her neurons of cerebral cortex are firing upon with spontaneous and repetitive pattern of firing. (4-9). For such firing of cerebral cortical neurons in the pattern of spontaneous and repetitive pattern, large amount of acetylcholine (and possibly other neuro- humours) which are neurotransmitters of cholinergic neurons of C.N.S., are required. Life of acetylcholine (which is the main neurotransmitter of cholinergic system) is very brief because it’s half life is only few minutes after which it is metabolized by cholyne esterase. Hence if a person has to be conscious (aware of his surroundings and reacting to his surrounding factors), acetylcholine (and probably other neuro-humours) have to be produced continuously and that too in large quantity (adequate quantity to keep the neurons of the cerebral cortex in spontaneous and repetitive pattern of firing). This becomes necessary because acetylcholine cannot be stored (because it’s half life is only few minutes). Acetylcholine which is the main neurotransmitter of cholinergic system in C.N.S. is produced in mescenchephalic reticular formation (6-9) in the brain stem of C.N.S. Other cholinergic neurons of C.N.S. (4,5,6,7), like pons etc. in C.N.S. have supportive role only in producing acetylcholine and keeping the consciousness intact. The motive force for the production of acetylcholine and other neuro-hormones of cholinergic system (by mescenchephalic reticular formation and other neurons of cholinergic system) is the inflow of large volley of afferent impulses from periphery (tactile sensation, sensation from joints, Neurophysiology & Anaesthesia 224
  • muscles and sensation from internal organs of the abdomen and chest) (9). Stimuli from pons and other neurons of cholinergic system in the brain, form a secondary role to help the mescenchephalic reticular formation. The process of activity of cortical neurons is like the activity of starting the automobile by the self motor and the reticulo alerting system (ARS) (which is also called by Neurophysiologists as reticulo activating mechanism in C.N.S.) carries out this function (of starting the activity of neurons of cerebral nervous system). After starting the activity of cerebral cortical neurons, such neurons continue to act (firing of such neurons spontaneously and repetitively), until this activity of cortical neurons is stopped periodically by the deactivating mechanism. The deactivating mechanism exists in bulbar reticular formation of brain stem in C.N.S. (bulbar reticular formation is called projections of Vagus and glosso phased nerves and neurons surrounding the trigones) The process of stopping the activity of cerebral cortical neurons (deactivating mechanism) is strenthened by some areas of medulla (magoun and rhynes area), thalamus, hypothalamus and prefrontal area of C.N.S. (11-13,25). Normally deactivating mechanism depresses the ascending reticulo alerting system (A.R.S.) in the C.N.S. so that patient sleeps (takes rest) periodically (in the form of repeating the cycles of activating and de-activating pattern of cerebral cortical activity in 24 Hrs). IMPORTANCE OF DEACTIVATING MECHANISM DURING ANAESTHETIC TECHNIQUES: As stated earlier deactivating mechanism existing in neurons of Trigones of Vagus and glasso pharyngeal nerves Neurophysiology & Anaesthesia 225
  • (which area was earlier called bulbar reticular formation of brain stem) (11-13,25), which is helped by medulla (Magoun and Rhynes area) thalamus, hypothalamus and prefrontal area of C.N.S. Vagal afferents during I.P.P.V., during anaesthesia (due to large volume changes in the lungs during IPPV) (1-3) strengthen the deactivating mechanism, such a way that during general anaesthetic techniques with I.P.P.V. reticulo alerting system (ARS) is depressed continuously leading to the complete stoppage of the activity of cerebral cortical neurons in C.N.S., leading to the reversible depression of brain activity during I.P.P.V. Hence the depression of C.N.S. is due to the over action of de- activating system during I.P.P.V. which causes unawareness during surgery as well as other benefits of general anaesthetic techniques such as areflexia, Analgesia and reflex depression of diaphragm and other respiratory muscles.(apnoea occurs partly due to paralysis of respiratory muscles but mainly due to the inhibitory reflexes to the diaphragm and other respiratory muscles from CNS, so that diaphrahm and other respiratory muscles relax during I.P.P.V.). FACTORS ACTING ON C.N.S. IN VULNERABLE PATIENTS TO CAUSE AWARENESS DURING SURGERY WITH I.P.P.V. Apart from Reticulo alerting system (ARS) and its antagonist, (the inhibitory mechanism), there is yet another important mechanism in C.N.S., which affects the activity to Reticulo alerting system (ARS) (15-18). Such a mechanism is calledAdrenergic system. Normally adrenergic system does not Neurophysiology & Anaesthesia 226
  • interfere with the activity of reticulo alerting mechanism but in some patients with psychosomatic back ground (due to long history of pain and mental or physical disability) Adrenergic system acts to make, cerebral cortical cells of such persons extra sensitive to situations, which, they feel are harmful to patients safety. Nor-adrenaline stimulates ARS thereby cortex become hyperactive during surgical stress so that awareness is maintained even when deactivating mechanism is still acting on them. Stress of any type (anger, apprehension or suffering with pain for long time or due to body dis-function), leads to stimulation of ARS by stress products thereby increasing the activity of cerebral cortical neurons (as a hyper guardedness of C.N.S.). awareness during surgery therefore is an extra guarding mechanism against harmful situations (surgical stress is treated as an enemy action (extra guarding action of cerebral cortical cells is against an enemy). Since the action of nor- Adrenaline on the C.N.S. is on the cerebral cortical neurons directly the action of Adrenergic transmitters and its co-generators occurs on following lines in a patient who is reacting to stress of any kind described above (to guard the patient from harmful conditions like surgical stress etc., which is treated as an enemy action). Neurophysiology & Anaesthesia 227
  • SUMMARY OF ACTION OF NORADRENALINE IN VULNERABLE PATIENTS (AT THE LEVEL OF C.N.S.) a) When small quantity of noradrenaline is produced in the body (as a stress response) in a conscious person, it only stimulates the nervous tissue (both at the neuro-muscular junction and at the level of neurons of C.N.S.), thereby leading to irritability, and a feeling of uneasiness in such a conscious individual. In our survey of patients who came to operation theatre we found many patients to be having psychiatric tendencies with maladjustments to their pattern of living. We feel that such patients are getting minimal quantities of sympathotomimitic amines released (on a continuous basis), so that their tissues become sensitive to its presence and react abnormally in an unfavourable condition. (b) During I.P.P.V.when the vulnerable individual is unaware during surgery (under general anaesthetic techniques), the sympathotomimitic amines act on cortical neurons directly in a psychotic type of patient and stimulates them even when they are depressed by I.P.P.V. Hence, as an extra precaution to protect person against the stress of surgery, (an enemy) neuronal activity at the level of cerebral cortex leads to awareness in such a patient undergoing surgery even when the anaesthetic techniques are continuing with I.P.P.V. Neurophysiology & Anaesthesia 228
  • PATIENTS WHO ARE VULNERABLE TO GET AWARENESS DURING SURGERY: After reviewing the pioneer work of surgeons of U.S.A. (Rocco & Vandom (18), Vandom et al (19) and Folkow et al (20), Rao and Bhatt monitored the concentration of noraderenaline in 27 patients (21, 22) undergoing surgery with I.P.P.V. (as an index of stress response during general anaesthesia). American Surgeons (mentioned above) indicated that patients who experienced long period of painful conditions in the body could be categorized as poor risk types with cachexia, with changes in body fluid content, body proteins etc. Such patients are found to hyper react to neurogenic stress of surgery (which was responsible to cause higher rates of mortality and morbidity in them), Rao & Bhatt monitored noraderenaline concentration in the blood of patients who had history of long period of suffering with pain (poor risk patients) and some others who were highly apprehensive of the surgical/anaesthetic procedures in peri operative period. They observed in the poor risk and highly apprehensive patients that concentration of stress products (as indicated by nor- aderenaline concentration in their blood) varied widely in pre-operative phase, during operation, and during post- operative phase. (21, 22) Secondly, type of surgery (major or minor), and the type of anaesthesia (local, regional or general anaesthesia) did not induce a uniform type of stress response. Lastly it was observed that poor risk and highly apprehensive patients reacted maximally in all the three phases of surgery, irrespective of the type of surgery carried out. Basing on their hyper reactive response to surgical stress (as indicated by blood levels of noradrenaline) (it is expected that noradrenaline is similarly produced (as a stress response) in C.N.S. also) (due to the hyper reactive response to surgical stress). Neurophysiology & Anaesthesia 229
  • CONCLUSION AND SUMMARY American surgeons mentioned above, after experimental evidence stated that poor risk and apprehensive patients reacted maximally to neurogenic stress of surgery with the result that they had higher morbidity and mortality rate in them (when compared to other patients who underwent similar surgical procedures). In the study of Rao & Bhatt (21, 22) they found that such patients produced significant levels of nor-epinephrine in pre-operative and post operative phases in the blood irrespective of type of surgery and anaesthesia. (Noradrenaline is therefore expected to be produced in significant quantity even in C.N.S.). Hence noradrenaline acting on ARS and neurons of the cerebral cortex restarts their activity (activity of cortical cells was suppressed during I.P.P.V.). This action takes place only in velnerable patients and all the rest of patients do not get this type of special action on cortical neurones of CNS. Hence, normally except few vulnerable patients, rest of patients do not wake up during surgery. Only in vulnerable patients cortical neurones are stimulated during IPPV (as a part of surgery) and it leads to the awareness during surgery in spite of general anaesthetic techniques continuing. The awareness so developed could be categorized as hyper guarding action towards unfamiliar events (stress of surgery etc). Neurophysiology & Anaesthesia 230
  • REFERENCES: 1. Rao L.N., Rama Rao K.R. and Bhalla S.K. increased afferent activity (vagal, splanchnic etc.) leading to hyperventilation syndrome during surgery under general anaesthesia, Ind. J.Anesth, 1966 14:226-32. 2. Rao L.N., Pathophysiological changes during artificial over ventilation in: A curadi Ruggirorizzi Editor, symposium internationazionale, reanemazione. E.Therapia intensive extra chirarugiche,Asiago (Vicenza), Italia, 27, Giugnoluglio, 1971: pages 694-702. 3. Rao L.N., & Venkatakrishna Bhatt H, vegal activity in canines:A possible connection to hyper ventilation syndrome, Anaesth.Analg., 1970:49:351-54. 4. Libet B, Central activation in consciousness and un-consciousness, prosp. Biol., Med., 1965:9:77-9. 5. Krnjikic K., Centralcholinergic, pathways, Fed.Proc. 1969:25:113-19 6. Szerb,J.C.Cortical acetyle choline release and lectroencephalogram arousal, J.Physiol (Lond) 1967:192:329-35.Bradley P.B., Dhawan, B.N. & Wolstencraft J.H., Pharmacological properties of cholinergic neurons in medulla and pons of the cat J.Physiol (Lond) 1966:183:658-702. 7. Bradley P.B. & Dray, A.B. shortlatency excitation of brain stem neurons in the rat by acetyle choline Brit J.Pharma. Chemotherp. 1972:45:372-75. 8. Kanai T., & Szerb, J.C., Mesenchaphalic reticular alerting system & cortical acetylecholine output, 1965:nature:205:80-4. 9. Dafney N., Bental E. & Fieldman S., effect of afferent stimuli from various parts of the body, Electroencephal. Clin.Neurophysiol, 1965:19:256-63. 10. Magoun HW & Rhines R., inhibitory mechanism in the bulbar reticular formation, Jneurophysiol., 1964:9:165-71. 11. Bonvallet H & Dell P., Bulbar control of arousal system, electroencephal. Clin.Neurophysiol., 1964:17:440-41. 12. Moruzzi G., Berluchi, G., Maffei L and Strata Hypnogenic brain mechanism antagnostic to reticular alerting system, Electroencephal. Clin.Neurophysiol., 1964:17:448-52. 13. Bowman W.C. & Raper C., effects of symptathetic amines neuro muscular transmission, Brit J.Pharmocol. Chemother., 1966:27:313-31. 14. Paton, W.D.M. & Jaimies, E.J. Actions & clinical assessment of drugs which produce neuro muscular block, Lancet 2, 1950:pages:568-70. Neurophysiology & Anaesthesia 231
  • 15. Rothballer A.B. effects of Catecholamines on Central Nervous System, Pharma. Rev., 1959:11:494-547. 16. Burn, J.H. relationship of adrenaline to acetylcholine in Central Nervous System, Physiol. Rev. 194525:789-99 17. Abraham V.C. & Pickford M. observation on central antagonism between adrenaline & acetylcholine, J.Physiol (Lond), 1956131712-18. 18. Rocco A.G. & Vandom L.D. changes in circulation, consequent to manipulation during abdominal surgery, J.A.M.A., 1957:16414-8. 19. Vandom L.D., Schweizer H.J. & Kubota, circulatory response to intra abdominal manipulations during ether anaesthesia, Circ. Res. 1962: 11287-95. 20. Folkow B, Gellen L.E. Lindell, SE Stenburg K & Thoren O, Cardio-vascular action during abdominal surgery, Ann. Surg 1962:156:905-13. 21. Rao L.N. The syndrome of depressed vital functions in post operative period Role of neuro hormones causation in editor Sharada Subramanyam, Neurohumural co-relates of behaviour, publication division, Thompson press (India) Ltd., Fareedabad, Haryana, India 1977:pages 234-243. 22. Rao L.N. & Venkatakrishna Bhatt H, Stree response during surgery & anaesthesia as indicated by concentration of nor-epinephrine in plasma of surgical patients, Int Surg., 197257295-98. 23. Rao L.N. & Venkatakrishna Bhatt H, syndrome of post operative depression of vital functions in poor risk patients, its treatment, Int. J.Clin. Pharma. Thera & Toxi 1981:19:18-22. 24. Salmoirraghi G.C. & Burns B.D. notes on mechanism of fhythmic respiration J. Neurophysiol, 1960:23:14-6. 25. Bowman W.C. & Nott, M.W. actions of sympathetic amines & their antagonists on skeletal muscles, Pharma. Rev. 1969:21:27-72. 26. Nass K & Sirness T.B. synergic effects of adrenaline & d’tubocurorine on nerve transmission, Acta Physiol. Scandinev. 1953:29293-96. ***** Neurophysiology & Anaesthesia 232
  • SECTION-III SUMMARY AND CONCLUSION Anaesthesiology is a specialty by its own right. Even though, started in the middle of 19th Century it gained tremendous momentum around 1846 AD. Earlier to that, only nerve blocks and spinal anaestheitc techniques were practiced in a limited way to help minor surgery. Since 1846, diethylether, chloroform etc were used successfully by a few gifted individuals. Their use was limited in time and area of surgery in a patient because of technical reasons. Since 1942 or so it became very easy to paralyze the patient and intubate him with ease. Soon after there was a controversy about cerebral vaso constriction causing ischaemia of CNS and beneficial effects of general anaesthesia were attributed to hypocarbia during hyper ventilation (in the beginning when d’dubocuranine was introduced). As stated earlier anaesthesiology and enthusiasm to hyper ventilate the patient were synonymous. However in the next 2 to 3 decades it became clear that beneficial aspects with IPPV, during general anaesthesia could be produced in a patient even with isocarbia or mild hyper carbia. Various circuits are evolved so that CO2 wash out was minimized and today, it could be conveniently proclaimed that, nearly a million operations under general anaesthetic techniques are performed in a month (according to unofficial statistics) in the globe. Anaesthetic techniques, got modified to suit every type of surgery and it could be safely stated that the progress in Anaesthesiology was faster than most of other specialties in the field of medical science during the span of 25 to 30 years in later part of 20th century. Neurophysiology & Anaesthesia 233
  • The chronology of the progress and successful application of anaesthetic techniques to suit every surgeon (to make surgery successful) gave rise to a sort of euphoria and the anaesthesiologist believed that skeletomuscular relaxant drugs were miraculous drugs, which not only provide paralysis of respiratory and other muscles but also areflexia, reflex relaxation of diaphragm, analgesia etc so that further research into the mechanism under which ideal conditions for surgery during surgery under general anaesthesia was not seriously considered necessary. Some occasional patient, whose recovery from anaesthesia was delayed, is treated with ventilator therapy for few hours (until such a time he becomes normal). Hence no serious attempt was made to find out the cause of such a delayed recovery from anaesthesia. Some anaesthetists, speculated that under special circumstances, biological life span of skeletomuscular drugs was extended and that skeleto muscular relaxant drugs continued their action on CNS causing delayed recovery. Hence ventilator therapy for 4 to 10 hours or more in such patients (who did not recover), was used and further efforts to investigate the actual case of delayed recovery were sluggish or absent. However things began to happen further. Since exact mechanism of beneficial action of skeletal muscular relaxant drugs was not known anaesthesiologists are not at all in a position to understand why some patients were aware during surgery. Since this problem came upto the surface, next problem, which they could not answer (which is the basic one for the specialty of anaesthesiology itself), was about the exact mechanism which causes the patients during general anaesthetic techniquesunaware of surgery. This fundamental question coud not be answered Neurophysiology & Anaesthesia 234
  • because skeleto muscular drugs do not act on CNS. Loss of proprioception which is due to muscle paralysis is only 15% to 20% of the total stimuli reaching CNS from periphery. (Tactile sensation, sensation from bones and joints, sensation from viscera of abdomen, throat, head neck etc. is about 80% which is intact during the use of relaxant drugs). Hence loss of proprioception cannot depress CNS. Anaesthesiologists are therefore at a loss to explain how beneficial effects of general anaesthetic techniques occur during general anaesthesia. If it is due to depression of CNS, causing areflexia, reflex suppression of diaphragm and other respiratory muscles, analgesia etc., the mechanism which depresses CNS during general anaesthetic has to be found out (which is so far not done). During our research into the fundamentals of anaesthesiology, we came to the conclusion about many aspects of basic frame work (about the specialty of anaesthesiology). They are given below. 1) Apart from relaxation of skeletal muscles and pinning down the patient to the operation table, the relaxant durgs do not play any other role, specially they do not produce any of the ideal conditions for surgeory. 2) They allow the anaesthesiologist to intubate the patient with an endotracheal tube (without resistance) thereby allowing IPPV to be started in the patient. 3) IPPV in it’s turn prodeces unawareness in the patient so that patients are comfortable during surgery and they do not know the extent of surgery and the time taken to operate on them. 4) 10 to 25% or more of the paralyzing concentration of skeleto muscular relaxant drugs are present in the plasma and CSF of the patient, (who is operated upon), at the time of recovery Neurophysiology & Anaesthesia 235
  • from anaesthesia. Even then patients do recover normally and do not have any delay in recovery in the post anaesthetic period. 5) IPPV strenghthens the deactivating mechanism which not only stops the reticulo alerting system (ARS) (activating system) and causes reversible depression of CNS, thereby ideal operating conditions are produced. 6) Our research has indicated that IPPV causes an interplay between activating and deactivating systems (in adition to act on respiratory centre) to cause unawareness in a patient during surgery in addition to cause apnoea, areflexia, analgesia etc to facilitate surgical procedures. 7). All the above facts indicate that anaesthesiology is in fact clinical neurophysiology. Use of drugs only helps to start IPPV interplay of activating and deactivating systems in CNS, (which cause unawareness in the patient) is purely neurophysiological phenomena. Hence it could be safely called an extension of clinical neuro physiology. 8) Anaesthetic complications are not related to the continued action of relaxant drugs (as it is so far believed) on CNS in the post operative period. 9) Some patients are found to be vulnerable to hyperact to the stress of surgery during local, spinal and general anaesthesia. 10) In some patients who are not properly adjusted in life, continuous release of stress products are taking place which act on various tissues to produce anaesthetic complications during and after surgery under any type of anaesthesia (regional or general). Hence patients personality factor (P-factor) is the main cause for anaesthetic complications and occasional fatality in some patients, in the peri operative period. 11) Knowledge of psychiatric sciences appear to be necessary for a successful anaesthesiologist. Neurophysiology & Anaesthesia 236
  • SECTION - III (B) ACKOWLEDGEMENTS Entire project starting from 1964 and continuing for 25 to 30 years would not have been possible without the active help of Major General K.Rama Rao (when Dr.L.N.Rao was a Major in the Armed Forces) and later by Dr.(Prof.) P.S.R.K. Harnah, Prof and Head of the department, Pharmacology and Principal Kurnool Medical college, Kurnool, AP, India (later he retired as Director Medical Education, Government of AP India). We are highly indebted to Dr.H.V.Bhatt (PHD) who was a scientist in pharmacology department of Kurnool Medical College. He extended all help during the research project. We are equally indebted to the Superintendents of Kurnool general hospital, Kurnool, Supdt. Osmania General Hospital, Hyderabad and Gandhi Hospital, Hyderabad for permitted the research project to continue in their hospitals.(originally started in Kurnool). Most important aspect of this project is to bring out the role of psychiatrist, as a co-physician in the surgical team (apart from Cardiologist and general physician). He is extremely thankful to Prof. (Late) Neelkant RaoYadav, who in fact taught Dr. L.N.Rao (one of the authors) about the close relationship of Anaesthesiology and psychiatry. Neurophysiology & Anaesthesia 237
  • E P I L O G U E This book is the outcome of many views of anaesthesiologists, who though thought correctly but did not dare to voice their opinion that anaesthetic complications in perioperative period are due to a third but an unknown factor (1st factor is the anaesthesiologist himself, 2nd one is the technique and the drugs used by him and the third factor...........?) Prof. L.N. Rao heard this unspoken truth for nearly 40 years and tried his best to find out the nature of the 3rd yet unknown factor. In the next 10 years of life, he found out that P-factor causes all the complications in peri operatie period. When he tried to present a paper on P-factor (The unknown factor which is infact patient’s personality or P-factor) his abstract was rejected, At Luckhnow in 2010 (annual conference). Hence all the details of this unknown factor (P-factor), with its potency to cause catastrophy in peri operative period, is given in this book written by Prof. L.N. Rao. (He not only evolved P-factor but as well saved many patients by the knowledge of complexity of P-factor), ***** 238
  • IN PRIASE OF IGNORANCE 1. Ignorance is the Natural human condition. 2. Even those who claim to be familiar with medical/surgical/ and other subjects of interest to humanity are less ignorant than others: They only know infinite decimal part of the subject concerned. 3. Ignorance coupled with intelligence is a stimulus for imagination and it acts as a spur to further study of the subject concerned. 4. Ignorance coupled with rigidity in observing rules and conventions stops further enquiry because it stops also finding the proper reason, why a person dares to put forward new concepts. It also prevents the recognition of Innovators, who are trying to build abridge to cross the sea of ignorance. 5. Innovators are usually so far ahead from the intelligentsia that they are hardly visible: They can be seen by the dust raised by them (during their innovative methods). 6. Ignorant persons and intelligentsia mistake the cloud of dust, raised by innovators as a disturbance to their beliefs. (Own firm beliefs on the subject). They try to clear the dust by all means so that innovators are eliminated completely: Divine power occasionally, intervenes to help the innovators to make the intelligentsia to understand the work of Innovators. (that was the way of life in the past, its is now in the present and would continue in future). 7. All great innovations in the world (by far seen by humanity) are due to divine intervention only: They have come up in spite of opposition by intelligentsia (opposing them all the time). It is believed that for one new idea which is accepted by intelligentsia many other ideas are buriedpermanently. (Extraced from the editorial of May & June issue of American Journal “Anaesthesiology” in the year 1964). (Suitably modified) 239
  • PROF.. L.N.RAO was born on 8th July 1932.After obtaining M.B.B.S. degree in 1956, he became the 1st Post Graduate in Anaesthesiology from AIIMS in 1961. He was professor of Anaesthesiology from 1964 onwards and presided over ISA (National) proceedings of 1987 at Kolkatta. He, retired from A.P. Government Service as Commissioner Medical Services (APVVP), Government of A.P. in 1988. Throughout his career as a Professor of Anaesthesiology (later as a consultant anaesthetist and medical administrator), he was not satisfied with the presently believed fundamentals of Anaesthesiology. He, with his research colleagues carried out intensive research into it’s fundamentals. His first publication was in 1966 in Ind. J. Anaesth. in which he postulated that vagal nerves (during IPPV) cause hyperventilation syndroe. He now with the coauthership of Dr. M.V.R. Sharma, has written this book, (which is the result of 25 years of Research into fundamental of Anaesthesiology. His aim of writing this book was to see status of Anaesthesiologists is not affected even after his association with the anaesthetic complication in peri operative period because Prof. Rao now provides evidence to indicate that anaesthetic complications in the peri operative period are not due to the abuse of drugs (during anaesthesia): They (complications) are due to patient’s personality factor (P-factor). 240