Anaesthesia online edition 2013


Published on

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

  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Anaesthesia online edition 2013

  1. 1. 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
  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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  29. 29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  36. 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
  37. 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
  38. 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
  39. 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
  42. 42. “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
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. 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
  51. 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
  52. 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
  53. 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
  55. 55. “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
  56. 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
  57. 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
  58. 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
  59. 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
  60. 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
  61. 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
  62. 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
  63. 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
  64. 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
  65. 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
  66. 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
  67. 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
  68. 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