Bohomolets anaesthesiology basic
Upcoming SlideShare
Loading in...5
×
 

Bohomolets anaesthesiology basic

on

  • 1,594 views

 

Statistics

Views

Total Views
1,594
Views on SlideShare
1,594
Embed Views
0

Actions

Likes
2
Downloads
34
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft Word

Usage Rights

CC Attribution-ShareAlike LicenseCC Attribution-ShareAlike License

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Bohomolets anaesthesiology basic Bohomolets anaesthesiology basic Document Transcript

  • MINISTRY OF PUBLIC HEALTH OF UKRAINE NATIONAL O.O. BOGOMOLETS MEDICAL UNIVERSITYCHAIR OF ANAESTHESIOLOGY AND INTENSIVE THERAPY “Affirmed” Head of the Chair of Anaesthesiology and Intensive Therapy Professor F.S. Glumcher “____” _________ 2009 STUDY GUIDE FOR PRACTICAL WORK FOR TEACHERS AND STUDENTSCLASSES IN ANAESTHESIOLOGY AND INTENSIVE THERAPY THEME: «ANAESTHESIOLOGY: BASIC ASPECTS» Kyiv 2009 1
  • 1. Theme Actual Significance Anaesthesiology is unique in that it requires a working familiarity with mostother specialties, including surgery and its subspecialties, internal medicine,pediatrics, and obstetrics as well as clinical pharmacology, applied physiology, andbiomedical technology. There are a lot of special considerations in different fieldsof Surgery. The purposes of this topic is to familiarize students with features ofanaesthesia in some special fields.2. Educational purposes of practical classThe Core Topics are:1. The Practice of Anesthesiology2. The History of Anesthesia3. Preoperative Evaluation of Patients (Preoperative History, PhysicalExamination, Laboratory Evaluation, ASA Physical Status Classification,Informed Consent)3. Inhalation Anesthetics3.1. Pharmacokinetics of Inhalation Anesthetics. Theories of Anesthetic Action3.2. Clinical Pharmacology of Inhalation Anesthetics3.2.1. Nitrous Oxide3.2.2. Halothane3.2.3. Sevoflurane3.3. Nonvolatile Anesthetic Agents3.3.1. Pharmacokinetics3.3.2. Barbiturates3.3.3. Benzodiazepines3.3.4. Opioids3.3.5. Ketamine3.3.6. Propofol3.3.7. Neuromuscular Blocking Agents (Neuromuscular Transmission, Distinctionsbetween Depolarizing and Nondepolarizing Blockade)4. Spinal, Epidural, and Caudal Blocks4.1. The Role of Neuraxial Anesthesia in Anesthetic Practice4.2. Mechanism of Action (Somatic Blockade, Autonomic Blockade,Cardiovascular Manifestations, Pulmonary Manifestations, GastrointestinalManifestations, Urinary Tract Manifestations)4.3. Spinal Anesthesia4.3.1. Specific Technique for Spinal Anesthesia4.3.2. Factors Influencing Level of Block4.3.3. Spinal Anesthetic Agents4.4. Epidural Anesthesia4.4.1. Factors Affecting Level of Block4.4.2. Epidural Anesthetic Agents4.4.3. Failed Epidural Blocks 2
  • 4.5. Caudal Anesthesia4.6. Complications of Neuraxial Blocks (High Neural Blockade, Cardiac Arrestduring Spinal Anesthesia, Urinary Retention, Inadequate Anesthesia or Analgesia,Intravascular Injection, Total Spinal Anesthesia, Subdural Injection, Backache,Postdural Puncture Headache, Neurological Injury, Spinal or Epidural Hematoma,Meningitis and Arachnoiditis, Epidural Abscess, Systemic Toxicity, TransientNeurological Symptoms, Lidocaine Neurotoxicity)5. Peripheral Nerve Blocks5.1. Advantages and Disadvantages5.2. Choice of Anesthetic5.3. Placement of the Block3. Contents of a theme The Practice of Anesthesiology The Greek philosopher Dioscorides first used the term anesthesia in the firstcentury AD to describe the narcotic-like effects of the plant mandragora. The termsubsequently was defined in Baileys An Universal Etymological EnglishDictionary (1721) as "a defect of sensation" and again in the EncyclopediaBritannica (1771) as "privation of the senses." The present use of the term todenote the sleeplike state that makes painless surgery possible is credited to OliverWendell Holmes in 1846. In the United States, use of the term anesthesiology todenote the practice or study of anesthesia was first proposed in the second decadeof the twentieth century to emphasize the growing scientific basis of the specialty.Although the specialty now rests on a scientific foundation that rivals any other,anesthesia remains very much a mixture of both science and art. Moreover, thepractice of anesthesiology has expanded well beyond rendering patients insensibleto pain during surgery or obstetric delivery (Table 1). The specialty is unique inthat it requires a working familiarity with most other specialties, including surgeryand its subspecialties, internal medicine, pediatrics, and obstetrics as well asclinical pharmacology, applied physiology, and biomedical technology. Theapplication of recent advances in biomedical technology in clinical anesthesiacontinues to make anesthesia an exciting and rapidly evolving specialty. Asignificant number of physicians applying for residency positions inanesthesiology already have training and certification in other specialties.Table 1. Definition of the Practice of Anesthesiology, Which Is the Practice ofMedicine. 3
  • Assessment of, consultation for, and preparation of, patients for anesthesia.Relief and prevention of pain during and following surgical, obstetric, therapeutic,and diagnostic procedures.Monitoring and maintenance of normal physiology during the perioperativeperiod.Management of critically ill patients.Diagnosis and treatment of acute, chronic, and cancer-related pain.Clinical management and teaching of cardiac and pulmonary resuscitation.Evaluation of respiratory function and application of respiratory therapy.Conduct of clinical, translational, and basic science research.Supervision, teaching, and evaluation of the performance of both medical andparamedical personnel involved in perioperative care.Administrative involvement in health care facilities, organizations, and medicalschools necessary to implement these responsibilities. The History of Anesthesia Anesthetic practices date from ancient times, yet the evolution of thespecialty began in the mid-nineteenth century and only became firmly establishedless than six decades ago. Ancient civilizations had used opium poppy, cocaleaves, mandrake root, alcohol, and even phlebotomy (to the point ofunconsciousness) to allow surgeons to operate. It is interesting that the ancientEgyptians used the combination of opium poppy (morphine) and hyoscyamus(hyoscyamine and scopolamine); a similar combination, morphine andscopolamine, is still used parenterally for premedication. Regional anesthesia inancient times consisted of compression of nerve trunks (nerve ischemia) or theapplication of cold (cryoanalgesia). The Incas may have practiced local anesthesiaas their surgeons chewed coca leaves and spat saliva (presumably containingcocaine) into the operative wound. Surgical procedures were for the most partlimited to caring for fractures, traumatic wounds, amputations, and the removal ofbladder calculi. Amazingly, some civilizations were also able to performtrephination of the skull. A major qualification for a successful surgeon was speed.The evolution of modern surgery was hampered not only by a poor understandingof disease processes, anatomy, and surgical asepsis but also by the lack of reliableand safe anesthetic techniques. These techniques evolved first with inhalationanesthesia, followed by local and regional anesthesia, and finally intravenousanesthesia. The development of surgical anesthesia is considered one of the mostimportant discoveries in human history.Inhalation Anesthesia 4
  • Because the invention of the hypodermic needle did not occur until 1855, thefirst general anesthetics were destined to be inhalation agents. Ether (really diethylether, known at the time as "sulfuric ether" because it was produced by a simplechemical reaction between ethyl alcohol and sulfuric acid) was originally preparedin 1540 by Valerius Cordus, a 25-year-old Prussian botanist. Ether was used by themedical community for frivolous purposes ("ether frolics") and was not used as ananesthetic agent in humans until 1842, when Crawford W. Long and William E.Clark used it independently on patients. However, they did not publicize thisdiscovery. Four years later, in Boston, on October 16, 1846, William T.G. Mortonconducted the first publicized demonstration of general anesthesia using ether. Thedramatic success of that exhibition led the operating surgeon to exclaim to askeptical audience: "Gentlemen, this is no humbug!" Chloroform was independently prepared by von Leibig, Guthrie, andSoubeiran in 1831. Although first used by Holmes Coote in 1847, chloroform wasintroduced into clinical practice by the Scottish obstetrician Sir James Simpson,who administered it to his patients to relieve the pain of labor. Ironically, Simpsonhad almost abandoned his medical practice after witnessing the terrible despair andagony of patients undergoing operations without anesthesia. Joseph Priestley produced nitrous oxide in 1772, but Humphry Davy firstnoted its analgesic properties in 1800. Gardner Colton and Horace Wells arecredited with having first used nitrous oxide as an anesthetic in humans in 1844.Nitrous oxides lack of potency (an 80% nitrous oxide concentration results inanalgesia but not surgical anesthesia) led to clinical demonstrations that were lessconvincing than those with ether. Nitrous oxide was the least popular of the three early inhalation anestheticsbecause of its low potency and its tendency to cause asphyxia when used alone.Interest in nitrous oxide was revived in 1868 when Edmund Andrews administeredit in 20% oxygen; its use was, however, overshadowed by the popularity of etherand chloroform. It is ironic that nitrous oxide is the only one of these agents still incommon use today. Chloroform initially superseded ether in popularity in manyareas (particularly in the United Kingdom), but reports of chloroform-relatedcardiac arrhythmias, respiratory depression, and hepatotoxicity eventually causedmore and more practitioners to abandon it in favor of ether. Even after the introduction of other inhalation anesthetics (ethyl chloride,ethylene, divinyl ether, cyclopropane, trichloroethylene, and fluroxene), etherremained the standard general anesthetic until the early 1960s. The only inhalationagent that rivaled ethers safety and popularity was cyclopropane (introduced in1934). However, both are highly combustible and have since been replaced by thenonflammable potent fluorinated hydrocarbons: halothane (developed in 1951;released in 1956), methoxyflurane (developed in 1958; released in 1960), enflurane 5
  • (developed in 1963; released in 1973), and isoflurane (developed in 1965; releasedin 1981). New agents continue to be developed. One such agent, desflurane (releasedin 1992), has many of the desirable properties of isoflurane as well as the rapiduptake and elimination characteristics of nitrous oxide. Sevoflurane, another agent,also has low blood solubility, but concerns about potentially toxic degradationproducts delayed its release in the United States until 1994.Local and Regional Anesthesia The origin of modern local anesthesia is credited to Carl Koller, anophthalmologist, who demonstrated the use of topical cocaine for surgicalanesthesia of the eye in 1884. Cocaine had been isolated from the coca plant in1855 by Gaedicke and later purified in 1860 by Albert Neimann. In 1884 thesurgeon William Halsted demonstrated the use of cocaine for intradermalinfiltration and nerve blocks (including the facial nerve, the brachial plexus, thepudendal nerve, and the posterior tibial nerve). August Bier is credited withadministering the first spinal anesthetic in 1898; he used 3 mL of 0.5% cocaineintrathecally. He was also the first to describe intravenous regional anesthesia (Bierblock) in 1908. Procaine was synthesized in 1904 by Alfred Einhorn and within ayear was used clinically as a local anesthetic by Heinrich Braun. Braun was alsothe first to add epinephrine to prolong the action of local anesthetics. FerdinandCathelin and Jean Sicard introduced caudal epidural anesthesia in 1901. Lumbarepidural anesthesia was described first in 1921 by Fidel Pages and again in 1931by Achille Dogliotti. Additional local anesthetics subsequently introducedclinically include dibucaine (1930), tetracaine (1932), lidocaine (1947),chloroprocaine (1955), mepivacaine (1957), prilocaine (1960), bupivacaine (1963),and etidocaine (1972). Ropivacaine and levobupivacaine, an isomer ofbupivacaine, are newer agents with the same duration of action as bupivacaine butless cardiac toxicity.Intravenous Anesthesia Intravenous anesthesia followed the invention of the hypodermic syringe andneedle by Alexander Wood in 1855. Early attempts at intravenous anesthesiaincluded the use of chloral hydrate (by Oré in 1872), chloroform and ether(Burkhardt in 1909), and the combination of morphine and scopolamine(Bredenfeld in 1916). Barbiturates were synthesized in 1903 by Fischer and vonMering. The first barbiturate used for induction of anesthesia was diethylbarbituricacid (barbital), but it was not until the introduction of hexobarbital in 1927 thatbarbiturate induction became a popular technique. Thiopental, synthesized in 1932by Volwiler and Tabern, was first used clinically by John Lundy and Ralph Watersin 1934, and remains the most common induction agent for anesthesia.Methohexital was first used clinically in 1957 by V.K. Stoelting and is the only 6
  • other barbiturate currently used for induction. Since the synthesis ofchlordiazepoxide in 1957, the benzodiazepines—diazepam (1959), lorazepam(1971), and midazolam (1976)—have been extensively used for premedication,induction, supplementation of anesthesia, and intravenous sedation. Ketamine wassynthesized in 1962 by Stevens and first used clinically in 1965 by Corssen andDomino; it was released in 1970. Ketamine was the first intravenous agentassociated with minimal cardiac and respiratory depression. Etomidate wassynthesized in 1964 and released in 1972; initial enthusiasm over its relative lackof circulatory and respiratory effects was tempered by reports of adrenalsuppression after even a single dose. The release of propofol, diisopropylphenol, in1989 was a major advance in outpatient anesthesia because of its short duration ofaction.Neuromuscular Blocking Agents The use of curare by Harold Griffith and Enid Johnson in 1942 was amilestone in anesthesia. Curare greatly facilitated tracheal intubation and providedexcellent abdominal relaxation for surgery. For the first time, operations could beperformed on patients without having to administer relatively large doses ofanesthetic to produce muscle relaxation. These large doses of anesthetic oftenresulted in excessive circulatory and respiratory depression as well as prolongedemergence; moreover, they were often not tolerated by frail patients. Other neuromuscular blocking agents (NMBAs)—gallamine,decamethonium, metocurine, alcuronium, and pancuronium—were soonintroduced clinically. Because the use of these agents was often associated withsignificant side effects, the search for the ideal NMBA continued. Recentlyintroduced agents that come close to this goal include vecuronium, atracurium,pipecuronium, doxacurium, rocuronium, and cis-atracurium. Succinylcholine wassynthesized by Bovet in 1949 and released in 1951; it has become a standard agentfor facilitating tracheal intubation. Until recently, succinylcholine remainedunparalleled in its rapid onset of profound muscle relaxation, but its occasionalside effects continued to fuel the search for a comparable substitute. Mivacurium, anewer short-acting nondepolarizing NMBA, has minimal side effects, but it stillhas a slower onset and longer duration of action than succinylcholine. Rocuroniumis an intermediate-acting relaxant with a rapid onset approaching that ofsuccinylcholine. Rapacuronium, the most recently released NMBA, finallycombined succinylcholines rapid onset and short duration of action with animproved safety profile. However, the manufacturer of rapacuronium voluntarilywithdrew it from the market due to several reports of serious bronchospasm.Opioids Morphine was isolated from opium in 1805 by Sertürner and subsequentlytried as an intravenous anesthetic (see above). The morbidity and mortality initially 7
  • associated with high doses of opioids in early reports caused many anesthetists toavoid opioids and favor pure inhalation anesthesia. Interest in opioids in anesthesiareturned following the synthesis of meperidine in 1939. The concept of balancedanesthesia was introduced in 1926 by Lundy and others and evolved to consist ofthiopental for induction, nitrous oxide for amnesia, meperidine (or any opioid) foranalgesia, and curare for muscle relaxation. In 1969, Lowenstein rekindled interestin opioid anesthesia by reintroducing the concept of high doses of opioids ascomplete anesthetics. Morphine was initially employed, but fentanyl, sufentanil,and alfentanil were all subsequently used as sole agents. As experience grew withthis technique, its limitations in reliably preventing patient awareness andsuppressing autonomic responses during surgery were realized. Remifentanil is anew rapidly metabolized opioid that is broken down by nonspecific plasma andtissue esterases. Preoperative Evaluation of Patients No one standard anesthetic meets the needs of all patients. Rather, ananesthetic plan should be formulated that will optimally accommodate the patientsbaseline physiological state, including any medical conditions, previousoperations, the planned procedure, drug sensitivities, previous anestheticexperiences, and psychological makeup. Inadequate preoperative planning anderrors in patient preparation are the most common causes of anestheticcomplications. To help formulate the anesthetic plan, a general outline forassessing patients preoperatively is an important starting point. This assessmentincludes a pertinent history (including a review of medical records), a physicalexamination, and any indicated laboratory tests. Classifying the patients physicalstatus according to the ASA scale completes the assessment. Anesthesia andelective operations should not proceed until the patient is in optimal medicalcondition. Assessing patients with complications may require consultation withother specialists to help determine whether the patient is in optimal medicalcondition for the procedure and to have the specialists assistance, if necessary, inperioperative care. Following the assessment, the anesthesiologist must discusswith the patient realistic options available for anesthetic management. The finalanesthetic plan is based on that discussion and the patients wishes (reflected in theinformed consent; see below).The Preoperative History The preoperative history should clearly establish the patients problems aswell as the planned surgical, therapeutic, or diagnostic procedure. The presenceand severity of known underlying medical problems must also be investigated aswell as any prior or current treatments. Because of the potential for druginteractions with anesthesia, a complete medication history including use of anyherbal therapeutics should be elicited from every patient. This should include theuse of tobacco and alcohol as well as illicit drugs such as marijuana, cocaine, and 8
  • heroin. An attempt must also be made to distinguish between true drug allergies(often manifested as dyspnea or skin rashes) and drug intolerances (usuallygastrointestinal upset). Detailed questioning about previous operations andanesthetics may uncover prior anesthetic complications. A family history ofanesthetic problems may suggest a familial problem such as malignanthyperthermia. A general review of organ systems is important in identifyingundiagnosed medical problems. Questions should emphasize cardiovascular,pulmonary, endocrine, hepatic, renal, and neurological function. A positiveresponse to any of these questions should prompt more detailed inquiries todetermine the extent of any organ impairment.Physical Examination The history and physical examination complement one another: Theexamination helps detect abnormalities not apparent from the history and thehistory helps focus the examination on the organ systems that should be examinedclosely. Examination of healthy asymptomatic patients should minimally consist ofmeasurement of vital signs (blood pressure, heart rate, respiratory rate, andtemperature) and examination of the airway, heart, lungs, and musculoskeletalsystem using standard techniques of inspection, eg, auscultation, palpation, andpercussion. An abbreviated neurological examination is important when regionalanesthesia is being considered and serves to document any subtle preexistingneurological deficits. The patients anatomy should be specifically evaluated whenprocedures such as a nerve block, regional anesthesia, or invasive monitoring areplanned; evidence of infection over or close to the site or significant anatomicabnormalities may contraindicate such procedures. The importance of examining the airway cannot be overemphasized. Thepatients dentition should be inspected for loose or chipped teeth and the presenceof caps, bridges, or dentures. A poor anesthesia mask fit should be expected insome edentulous patients and those with significant facial abnormalities.Micrognathia (a short distance between the chin and the hyoid bone), prominentupper incisors, a large tongue, limited range of motion of the temporomandibularjoint or cervical spine, or a short neck suggests that difficulty may be encounteredin tracheal intubation.Laboratory Evaluation Routine laboratory testing for healthy asymptomatic patients is notrecommended when the history and physical examination fail to detect anyabnormalities. Such routine testing is expensive and rarely alters perioperativemanagement; moreover, abnormalities often are ignored—or result in unnecessarydelays. Nonetheless, because of the current litigious environment in the UnitedStates, many physicians continue to order a hematocrit or hemoglobin 9
  • concentration, urinalysis, serum electrolyte measurements, coagulation studies, anelectrocardiogram, and a chest radiograph for all patients. To be valuable, performing a preoperative test implies that an increasedperioperative risk exists when the results are abnormal and a reduced risk existswhen the abnormality is corrected. The usefulness of a screening test for diseasedepends on its sensitivity and specificity as well as the prevalence of the disease.Sensitive tests have a low rate of false-negative results, whereas specific tests havea low rate of false-positive results. The prevalence of a disease varies with thepopulation tested and often depends on sex, age, genetic background, and lifestylepractices. Testing is therefore most effective when sensitive and specific tests areused in patients in whom the abnormality might be expected. Accordingly,laboratory testing should be based on the presence or absence of underlyingdiseases and drug therapy as suggested by the history and physical examination.The nature of the procedure should also be taken into consideration. Thus, abaseline hematocrit is desirable in any patient about to undergo a procedure thatmay result in extensive blood loss and require transfusion. Testing fertile women for an undiagnosed early pregnancy may be justifiedby the potentially teratogenic effects of anesthetic agents on the fetus; pregnancytesting involves detection of chorionic gonadotropin in urine or serum. Routinetesting for AIDS (detection of the HIV antibody) is highly controversial. Routinecoagulation studies and urinalysis are not cost effective in asymptomatic healthypatients.ASA Physical Status Classification In 1940, the ASA established a committee to develop a "tool" to collect andtabulate statistical data that would be used to predict operative risk. The committeewas unable to develop such a predictive tool, but instead focused on classifying thepatients physical status, which led the ASA to adopt a five-category physicalstatus classification system for use in assessing a patient preoperatively. A sixthcategory was later added to address the brain-dead organ donor. Although thissystem was not intended to be used as such, the ASA physical status generallycorrelates with the perioperative mortality rate. Because underlying disease is onlyone of many factors contributing to perioperative complications, it is not surprisingthat this correlation is not perfect. Nonetheless, the ASA physical statusclassification remains useful in planning anesthetic management, particularlymonitoring techniques.Informed Consent The preoperative assessment culminates in giving the patient a reasonableexplanation of the options available for anesthetic management: general, regional,local, or topical anesthesia; intravenous sedation; or a combination thereof. Theterm monitored anesthesia care (previously referred to as local standby) is now 10
  • commonly used and refers to monitoring the patient during a procedure performedwith intravenous sedation or local anesthesia administered by the surgeon.Regardless of the technique chosen, consent must always be obtained for generalanesthesia in case other techniques prove inadequate. If any procedure is performed without the patients consent, the physicianmay be liable for assault and battery. When the patient is a minor or otherwise notcompetent to consent, the consent must be obtained from someone legallyauthorized to give it, such as a parent, guardian, or close relative. Although oralconsent may be sufficient, written consent is usually advisable for medicolegalpurposes. Moreover, consent must be informed to ensure that the patient (orguardian) has sufficient information about the procedures and their risks to make areasonable and prudent decision whether to consent. It is generally accepted thatnot all risks need be detailed—only risks that are realistic and have resulted incomplications in similar patients with similar problems. It is generally advisable toinform the patient that some complications may be life-threatening. The purpose of the preoperative visit is not only to gather importantinformation and obtain informed consent, but also to help establish a healthydoctor–patient relationship. Moreover, an empathically conducted interview thatanswers important questions and lets the patient know what to expect has beenshown to be at least as effective in relieving anxiety as some premedication drugregimens. Inhalation Anesthetics The course of general anesthesia can be divided into three phases: (1)induction, (2) maintenance, and (3) emergence. Inhalation anesthetics areparticularly useful in the induction of pediatric patients in whom it may be difficultto start an intravenous line. In contrast, adults usually prefer rapid induction withintravenous agents, although the nonpungency and rapid onset of sevoflurane havemade inhalation induction practical for adults. Regardless of the patients age,anesthesia is often maintained with inhalation agents. Emergence dependsprimarily upon the pulmonary elimination of these agents. Because of their unique route of administration, inhalation anesthetics haveuseful pharmacological properties not shared by other anesthetic agents. Forinstance, exposure to the pulmonary circulation allows a more rapid appearance ofthe drug in arterial blood than does intravenous administration. The study of therelationship between a drugs dose, tissue concentration, and elapsed time is calledpharmacokinetics (how a body affects a drug). The study of drug action, includingtoxic responses, is called pharmacodynamics (how a drug affects a body). After ageneral description of the pharmacokinetics and pharmacodynamics of inhalationanesthetics, this chapter presents the clinical pharmacology of individual agents.Pharmacokinetics of Inhalation Anesthetics 11
  • Although the mechanism of action of inhalation anesthetics remains unknown, it isassumed that their ultimate effect depends on attainment of a therapeutic tissueconcentration in the central nervous system. There are many steps, however,between the administration of an anesthetic from a vaporizer and its deposition inthe brain.Factors Affecting Inspiratory Concentration (FI)The fresh gas leaving the anesthesia machine mixes with gases in the breathingcircuit before being inspired by the patient. Therefore, the patient is not necessarilyreceiving the concentration set on the vaporizer. The actual composition of theinspired gas mixture depends mainly on the fresh gas flow rate, the volume of thebreathing system, and any absorption by the machine or breathing circuit. Thehigher the fresh gas flow rate, the smaller the breathing system volume, and thelower the circuit absorption, the closer the inspired gas concentration will be to thefresh gas concentration. Clinically, these attributes translate into faster inductionand recovery times.Theories of Anesthetic Action General anesthesia is an altered physiological state characterized byreversible loss of consciousness, analgesia of the entire body, amnesia, and somedegree of muscle relaxation. The multitude of substances capable of producinggeneral anesthesia is remarkable: inert elements (xenon), simple inorganiccompounds (nitrous oxide), halogenated hydrocarbons (halothane), and complexorganic structures (barbiturates). A unifying theory explaining anesthetic actionwould have to accommodate this diversity of structure. In fact, the various agentsprobably produce anesthesia by different methods (agent-specific theory). Forexample, opioids are known to interact with stereospecific receptors, whereasinhalation agents do not have a predominant structure–activity relationship (opiatereceptors may mediate some minor inhalation anesthetic effects). There does not appear to be a single macroscopic site of action that is sharedby all inhalation agents. Specific brain areas affected by various anestheticsinclude the reticular activating system, the cerebral cortex, the cuneate nucleus, theolfactory cortex, and the hippocampus. Anesthetics have also been shown todepress excitatory transmission in the spinal cord, particularly at the level of thedorsal horn interneurons that are involved in pain transmission. Differing aspectsof anesthesia may be related to different sites of anesthetic action. For example,unconsciousness and amnesia are probably mediated by cortical anesthetic action,whereas the suppression of purposeful withdrawal from pain may be related tosubcortical structures such as the spinal cord or brain stem. One study in ratsrevealed that removal of the cerebral cortex did not alter the potency of theanesthetic! 12
  • At a microscopic level, synaptic transmission is much more sensitive togeneral anesthetic agents than axonal conduction, though small-diameter nerveaxons may be vulnerable. Both presynaptic and postsynaptic mechanisms areplausible. The unitary hypothesis proposes that all inhalation agents share a commonmechanism of action at the molecular level. This is supported by the observationthat the anesthetic potency of inhalation agents correlates directly with their lipidsolubility (Meyer–Overton rule). The implication is that anesthesia results frommolecules dissolving at specific lipophilic sites. Of course, not all lipid-solublemolecules are anesthetics (some are actually convulsants), and the correlationbetween anesthetic potency and lipid solubility is only approximate. Neuronal membranes contain a multitude of hydrophobic sites in theirphospholipid bilayer. Anesthetic binding to these sites could expand the bilayerbeyond a critical amount, altering membrane function (critical volume hypothesis).Although this theory is probably an oversimplification, it explains an interestingphenomenon: the reversal of anesthesia by increased pressure. Laboratory animalsexposed to elevated hydrostatic pressure develop a resistance to anesthetic effects.Perhaps the pressure is displacing a number of molecules from the membrane,increasing anesthetic requirements. Anesthetic binding might significantly modify membrane structure. Twotheories suggest disturbances in membrane form (the fluidization theory ofanesthesia and the lateral phase separation theory); another theory proposesdecreases in membrane conductance. Altering membrane structure could produceanesthesia in a number of ways. For instance, electrolyte permeability could bechanged by disrupting ion channels. Alternatively, hydrophobic membraneproteins might undergo conformational changes. In either event, synaptic functioncould be inhibited. General anesthetic action could be due to alterations in any one of severalcellular systems including ligand-gated ion channels, second messenger functions,or neurotransmitter receptors. For example, many anesthetics enhance alfa-aminobutyric acid (GABA) inhibition of the central nervous system. Furthermore,GABA receptor agonists appear to enhance anesthesia, whereas GABA antagonistsreverse some anesthetic effects. There appears to be a strong correlation betweenanesthetic potency and potentiation of GABA receptor activity. Thus, anestheticaction may relate to hydrophobic binding to channel proteins (GABA receptors).Modulation of GABA function may prove to be a principal mechanism of actionfor many anesthetic drugs.Minimum Alveolar Concentration 13
  • The minimum alveolar concentration (MAC) of an inhaled anesthetic is thealveolar concentration that prevents movement in 50% of patients in response to astandardized stimulus (eg, surgical incision). MAC is a useful measure because itmirrors brain partial pressure, allows comparisons of potency between agents, andprovides a standard for experimental evaluations. Nonetheless, it should beconsidered a statistical average with limited value in managing individual patients,particularly during times of rapidly changing alveolar concentrations (eg,induction). MAC can be altered by several physiological and pharmacological variables.One of the most striking is the 6% decrease in MAC per decade of age, regardlessof volatile anesthetic. MAC is relatively unaffected by species, sex, or duration ofanesthesia. Surprisingly, MAC is not altered after hypothermic spinal cordtransection in rats, leading to the hypothesis that the site of anesthetic inhibition ofmotor responses lies in the spinal cord.Clinical Pharmacology of Inhalation AnestheticsNitrous OxidePhysical Properties Nitrous oxide (N2O; laughing gas) is the only inorganic anesthetic gas inclinical use . It is colorless and essentially odorless. Although nonexplosive andnonflammable, nitrous oxide is as capable as oxygen of supporting combustion.Unlike the potent volatile agents, nitrous oxide is a gas at room temperature andambient pressure. It can be kept as a liquid under pressure because its criticaltemperature lies above room temperature. Nitrous oxide is a relatively inexpensiveanaesthetic, however, concerns regarding its safety have led to continued interestin alternatives such as xenon.Effects on Organ SystemsCardiovascularThe circulatory effects of nitrous oxide are explained by its tendency to stimulatethe sympathetic nervous system. Even though nitrous oxide directly depressesmyocardial contractility in vitro, arterial blood pressure, cardiac output, and heartrate are essentially unchanged or slightly elevated in vivo because of itsstimulation of catecholamines. Myocardial depression may be unmasked inpatients with coronary artery disease or severe hypovolemia. The resulting drop inarterial blood pressure may occasionally lead to myocardial ischemia. Constrictionof pulmonary vascular smooth muscle increases pulmonary vascular resistance,which results in an elevation of right ventricular end-diastolic pressure. Despitevasoconstriction of cutaneous vessels, peripheral vascular resistance is notsignificantly altered. Because nitrous oxide increases endogenous catecholamine 14
  • levels, it may be associated with a higher incidence of epinephrine-inducedarrhythmias.RespiratoryNitrous oxide increases respiratory rate (tachypnea) and decreases tidal volume asa result of central nervous system stimulation and, perhaps, activation ofpulmonary stretch receptors. The net effect is a minimal change in minuteventilation and resting arterial CO2 levels. Hypoxic drive, the ventilatory responseto arterial hypoxia that is mediated by peripheral chemoreceptors in the carotidbodies, is markedly depressed by even small amounts of nitrous oxide. This hasserious implications in the recovery room, where low arterial oxygen tensions inpatients may go unrecognized.CerebralBy increasing CBF and cerebral blood volume, nitrous oxide produces a mildelevation of intracranial pressure. Nitrous oxide also increases cerebral oxygenconsumption (CMRO2). Levels of nitrous oxide below MAC provide analgesia indental surgery and other minor procedures.NeuromuscularIn contrast to other inhalation agents, nitrous oxide does not provide significantmuscle relaxation. In fact, at high concentrations in hyperbaric chambers, nitrousoxide causes skeletal muscle rigidity. Nitrous oxide is probably not a triggeringagent of malignant hyperthermia.RenalNitrous oxide appears to decrease renal blood flow by increasing renal vascularresistance. This leads to a drop in glomerular filtration rate and urinary output.HepaticHepatic blood flow probably falls during nitrous oxide anesthesia, but to a lesserextent than with the other volatile agents.GastrointestinalSome studies have suggested that nitrous oxide is a cause of postoperative nauseaand vomiting, presumably as a result of activation of the chemoreceptor triggerzone and the vomiting center in the medulla. Other studies, particularly in children,have failed to demonstrate any association between nitrous oxide and emesis.Contraindications 15
  • Although nitrous oxide is insoluble in comparison with other inhalation agents, itis 35 times more soluble than nitrogen in blood. Thus, it tends to diffuse into air-containing cavities more rapidly than nitrogen is absorbed by the bloodstream. Forinstance, if a patient with a 100-mL pneumothorax inhales 50% nitrous oxide, thegas content of the pneumothorax will tend to approach that of the bloodstream.Because nitrous oxide will diffuse into the cavity more rapidly than the air(principally nitrogen) diffuses out, the pneumothorax expands until it contains 100mL of air and 100 mL of nitrous oxide. If the walls surrounding the cavity arerigid, pressure rises instead of volume. Examples of conditions in which nitrousoxide might be hazardous include air embolism, pneumothorax, acute intestinalobstruction, intracranial air (tension pneumocephalus following dural closure orpneumoencephalography), pulmonary air cysts, intraocular air bubbles, andtympanic membrane grafting. Nitrous oxide will even diffuse into tracheal tubecuffs, increasing the pressure against the tracheal mucosa.Because of the effect of nitrous oxide on the pulmonary vasculature, it should beavoided in patients with pulmonary hypertension. Obviously, nitrous oxide is oflimited value in patients requiring high inspired oxygen concentrations.Drug InteractionsBecause the relatively high MAC of nitrous oxide prevents its use as a completegeneral anesthetic, it is frequently used in combination with the more potentvolatile agents. The addition of nitrous oxide decreases the requirements of theseother agents (65% nitrous oxide decreases the MAC of the volatile anesthetics byapproximately 50%). Although nitrous oxide should not be considered a benigncarrier gas, it does attenuate the circulatory and respiratory effects of volatileanesthetics in adults. Nitrous oxide potentiates neuromuscular blockade, but less sothan the volatile agents. The concentration of nitrous oxide flowing through avaporizer can influence the concentration of volatile anesthetic delivered. Forexample, decreasing nitrous oxide concentration (ie, increasing oxygenconcentration) increases the concentration of volatile agent despite a constantvaporizer setting. This disparity is due to the relative solubilities of nitrous oxideand oxygen in liquid volatile anesthetics. The second gas effect was discussedearlier.HalothanePhysical PropertiesHalothane is a halogenated alkane. The carbon–fluoride bonds are responsible forits nonflammable and nonexplosive nature. Thymol preservative and amber-colored bottles retard spontaneous oxidative decomposition. Halothane is the leastexpensive volatile anesthetic, and because of its safety profile (see below),continues to be used worldwide. 16
  • Effects on Organ SystemsCardiovascularA dose-dependent reduction of arterial blood pressure is due to direct myocardialdepression; 2.0 MAC of halothane results in a 50% decrease in blood pressure andcardiac output. Cardiac depression—from interference with sodium–calciumexchange and intracellular calcium utilization—causes an increase in right atrialpressure. Although halothane is a coronary artery vasodilator, coronary blood flowdecreases, due to the drop in systemic arterial pressure. Adequate myocardialperfusion is usually maintained, as oxygen demand also drops. Normally,hypotension inhibits baroreceptors in the aortic arch and carotid bifurcation,causing a decrease in vagal stimulation and a compensatory rise in heart rate.Halothane blunts this reflex. Slowing of sinoatrial node conduction may result in ajunctional rhythm or bradycardia. In infants, halothane decreases cardiac output bya combination of decreased heart rate and depressed myocardial contractility.Halothane sensitizes the heart to the arrhythmogenic effects of epinephrine, so thatdoses of epinephrine above 1.5 mg/kg should be avoided. This phenomenon maybe a result of halothane interfering with slow calcium channel conductance.Although organ blood flow is redistributed, systemic vascular resistance isunchanged.RespiratoryHalothane typically causes rapid, shallow breathing. The increased respiratory rateis not enough to counter the decreased tidal volume, so alveolar ventilation dropsand resting PaCO2 is elevated. Apneic threshold, the highest PaCO2 at which apatient remains apneic, also rises because the difference between it and restingPaCO2 is not altered by general anesthesia. Similarly, halothane limits the increasein minute ventilation that normally accompanies a rise in PaCO2. Halothanesventilatory effects are probably due to central (medullary depression) andperipheral (intercostal muscle dysfunction) mechanisms. These changes areexaggerated by preexisting lung disease and attenuated by surgical stimulation.The increase in PaCO2 and the decrease in intrathoracic pressure that accompanyspontaneous ventilation with halothane partially reverse the depression in cardiacoutput, arterial blood pressure, and heart rate described above. Hypoxic drive isseverely depressed by even low concentrations of halothane (0.1 MAC).Halothane is considered a potent bronchodilator, as it often reverses asthma-induced bronchospasm. In fact, halothane may be the best bronchodilator amongthe currently available volatile anesthetics. This action is not inhibited bypropranolol, a beta-adrenergic blocking agent. Halothane attenuates airwayreflexes and relaxes bronchial smooth muscle by inhibiting intracellular calciummobilization. Halothane also depresses clearance of mucus from the respiratorytract (mucociliary function), promoting postoperative hypoxia and atelectasis. 17
  • CerebralBy dilating cerebral vessels, halothane lowers cerebral vascular resistance andincreases CBF. Autoregulation, the maintenance of constant CBF during changesin arterial blood pressure, is blunted. Concomitant rises in intracranial pressure canbe prevented by establishing hyperventilation prior to administration of halothane.Cerebral activity is decreased, leading to electroencephalographic slowing andmodest reductions in metabolic oxygen requirements.NeuromuscularHalothane relaxes skeletal muscle and potentiates nondepolarizing neuromuscular-blocking agents (NMBA). Like the other potent volatile anesthetics, it is atriggering agent of malignant hyperthermia.RenalHalothane reduces renal blood flow, glomerular filtration rate, and urinary output.Part of this decrease can be explained by a fall in arterial blood pressure andcardiac output. Because the reduction in renal blood flow is greater than thereduction in glomerular filtration rate, the filtration fraction is increased.Preoperative hydration limits these changes.HepaticHalothane causes hepatic blood flow to decrease in proportion to the depression ofcardiac output. Hepatic artery vasospasm has been reported during halothaneanesthesia. The metabolism and clearance of some drugs (eg, fentanyl, phenytoin,verapamil) appear to be impaired by halothane. Other evidence of hepatic cellulardysfunction includes sulfobromophthalein (BSP) dye retention and minor livertransaminase elevations.Biotransformation and Toxicity Postoperative hepatic dysfunction has several causes: viral hepatitis,impaired hepatic perfusion, preexisting liver disease, hepatocyte hypoxia, sepsis,hemolysis, benign postoperative intrahepatic cholestasis, and drug-inducedhepatitis. Halothane hepatitis is extremely rare (1 per 35,000 cases). Patientsexposed to multiple halothane anesthetics at short intervals, middle-aged obesewomen, and persons with a familial predisposition to halothane toxicity or apersonal history of toxicity are considered to be at increased risk. Signs includeincreased serum alanine and aspartate transferase, elevated bilirubin (leading tojaundice), and encephalopathy.The hepatic lesion seen in humans—centrilobular necrosis—also occurs in ratspretreated with an enzyme inducer (phenobarbital) and exposed to halothane under 18
  • hypoxic conditions (FIO2 < 14%). This halothane hypoxic model implies hepaticdamage from reductive metabolites or hypoxia. More recent evidence points to an immune mechanism. For instance, somesigns of the disease indicate an allergic reaction (eg, eosinophilia, rash, fever) anddo not appear until a few days after exposure. Furthermore, an antibody that bindsto hepatocytes previously exposed to halothane has been isolated from patientswith halothane-induced hepatic dysfunction. This antibody response may involveliver microsomal proteins that have been modified by trifluoroacetic acid as thetriggering antigens (trifluoroacetylated liver proteins such as microsomalcarboxylesterase).ContraindicationsIt is prudent to withhold halothane from patients with unexplained liverdysfunction following previous exposure. Because halothane hepatitis appears toaffect primarily adults and children past puberty, some anesthesiologists chooseother volatile anesthetics in these patients. There is no compelling evidenceassociating halothane with worsening of preexisting liver disease.Halothane should be used with great caution in patients with intracranial masslesions because of the possibility of intracranial hypertension.Hypovolemic patients and some patients with severe cardiac disease (aorticstenosis) may not tolerate halothanes negative inotropic effects. Sensitization ofthe heart to catecholamines limits the usefulness of halothane when exogenousepinephrine is administered or in patients with pheochromocytoma.Drug InteractionsThe myocardial depression seen with halothane is exacerbated by beta-adrenergic-blocking agents (eg, propranolol) and calcium channel-blocking agents (eg,verapamil). Tricyclic antidepressants and monoamine oxidase inhibitors have beenassociated with fluctuations in blood pressure and arrhythmias, although neitherrepresents an absolute contraindication. The combination of halothane andaminophylline has resulted in serious ventricular arrhythmias.SevofluranePhysical PropertiesLike desflurane, sevoflurane is halogenated with fluorine. Sevoflurane combines asolubility in blood slightly greater than desflurane. Nonpungency and rapidincreases in alveolar anesthetic concentration make sevoflurane an exellent choicefor smooth and rapid inhalation inductions in pediatric and adult patients. In fact,inhalation induction with 4–8% sevoflurane in a 50% mixture of nitrous oxide and 19
  • oxygen can be achieved in approximately 1–3 min. Likewise, its low bloodsolubility results in a rapid fall in alveolar anesthetic concentration upondiscontinuation and a more rapid emergence compared with isoflurane (althoughnot an earlier discharge from the postanesthesia care unit). As with desflurane, thisfaster emergence has been associated with a greater incidence of delirium in somepediatric populations, which can be successfully treated with 1.0–2.0 mkg/kg offentanyl. Sevofluranes modest vapor pressure permits the use of a conventionalvariable bypass vaporizer.Effects on Organ SystemsCardiovascularSevoflurane mildly depresses myocardial contractility. Systemic vascularresistance and arterial blood pressure decline slightly less than with isoflurane ordesflurane. Because sevoflurane causes little, if any, rise in heart rate, cardiacoutput is not maintained as well as with isoflurane or desflurane. There is noevidence associating sevoflurane with coronary steal syndrome. Sevoflurane mayprolong the QT interval, the clinical significance of which is unknown.RespiratorySevoflurane depresses respiration and reverses bronchospasm to an extent similarto that of isoflurane.CerebralSimilar to isoflurane and desflurane, sevoflurane causes slight increases in CBFand intracranial pressure at normocarbia, although some studies show a decrease incerebral blood flow. High concentrations of sevoflurane (> 1.5 MAC) may impairautoregulation of CBF, thus allowing a drop in CBF during hemorrhagichypotension. This effect on CBF autoregulation appears to be less pronounced thanwith isoflurane. Cerebral metabolic oxygen requirements decrease, and seizureactivity has not been reported.NeuromuscularSevoflurane produces adequate muscle relaxation for intubation of childrenfollowing an inhalation induction.RenalSevoflurane slightly decreases renal blood flow. Its metabolism to substancesassociated with impaired renal tubule function (eg, decreased concentrating ability)is discussed below. 20
  • HepaticSevoflurane decreases portal vein blood flow, but increases hepatic artery bloodflow, thereby maintaining total hepatic blood flow and oxygen delivery.Biotransformation and ToxicityThe liver microsomal enzyme P-450 (specifically the 2E1 isoform) metabolizessevoflurane at a rate one-fourth that of halothane (5% versus 20%), but 10 to 25times that of isoflurane or desflurane and may be induced with ethanol orphenobarbital pretreatment. The potential nephrotoxicity of the resulting rise ininorganic fluoride (F–) was discussed earlier. Serum fluoride concentrationsexceed 50 mmol/L in approximately 7% of patients who receive sevoflurane, yetclinically significant renal dysfunction has not been associated with sevofluraneanesthesia. The overall rate of sevoflurane metabolism is 5%, or 10 times that ofisoflurane. Nonetheless, there has been no association with peak fluoride levelsfollowing sevoflurane and any renal concentrating abnormality. Most studies have not associated sevoflurane with any detectablepostoperative impairment of renal function that would indicate toxicity or injury.Nonetheless, some clinicians recommend that fresh gas flows be at least 2 L/minfor anesthetics lasting more than a few hours and that sevoflurane not be used inpatients with preexisting renal dysfunction.Contraindications Contraindications include severe hypovolemia, susceptibility to malignanthyperthermia, and intracranial hypertension.Drug Interactions Like other volatile anesthetics, sevoflurane potentiates NMBAs. It does notsensitize the heart to catecholamine-induced arrhythmias. Nonvolatile Anesthetic Agents General anesthesia is not limited to the use of inhalation agents. Numerousdrugs that are administered orally, intramuscularly, and intravenously augment orproduce an anesthetic state within their therapeutic dosage range. Preoperativesedation, the topic of this chapters case study, is traditionally accomplished byway of oral or intravenous routes. Induction of anesthesia in adult patients usuallyinvolves intravenous administration, and the development of EMLA (eutectic[easily melted] mixture of local anesthetic) cream, LMX (plain lidocaine cream 4%and 5%), and 2% lidocaine jelly has significantly increased the popularity ofintravenous inductions in children. Even maintenance of general anesthesia can beachieved with a total intravenous anesthesia technique. This chapter begins with a 21
  • review of the pharmacological principles of pharmacokinetics andpharmacodynamics and how they apply to this class of drugs. The clinicalpharmacology of several anesthetic agents is presented: barbiturates,benzodiazepines, opioids, ketamine, etomidate, propofol, and droperidol.Pharmacokinetics Pharmacokinetics is defined by four parameters: absorption, distribution,biotransformation, and excretion. Elimination implies drug removal by bothbiotransformation and excretion. Clearance is a measurement of the rate ofelimination.Absorption There are many possible routes of systemic drug absorption: oral,sublingual, rectal, inhalation, transdermal, subcutaneous, intramuscular, andintravenous. Absorption, the process by which a drug leaves its site ofadministration to enter the bloodstream, is affected by the physical characteristicsof the drug (solubility, pKa, and concentration) and the site of absorption(circulation, pH, and surface area). Absorption differs from bioavailability, whichis the fraction of unchanged drug that reaches the systemic circulation. Forinstance, nitroglycerin is well absorbed by the gastrointestinal tract. It has lowbioavailability when administered orally, as it is extensively metabolized by theliver before it can reach the systemic circulation and the myocardium (first-passhepatic metabolism). Because the veins of the mouth drain into the superior vena cava, sublingualor buccal drug absorption bypasses the liver and first-pass metabolism. Rectaladministration is an alternative to oral medication in patients who areuncooperative (eg, pediatric patients) or unable to tolerate oral ingestion. Becausethe venous drainage of the rectum bypasses the liver, first-pass metabolism is lesssignificant than with small intestinal absorption. Rectal absorption can be erratic,however, and many drugs cause irritation of the rectal mucosa. Transdermal drug administration has the advantage of prolonged andcontinuous absorption with a minimal total drug dose. The stratum corneum servesas an effective barrier to all but small, lipid-soluble drugs (eg, clonidine,nitroglycerin, scopolamine). Parenteral injection includes subcutaneous, intramusclular, and intravenousroutes of administration. Subcutaneous and intramuscular absorption depends ondiffusion from the site of injection to the circulation. The rate of diffusion dependson the blood flow to the area and the carrier vehicle (solutions are absorbed fasterthan suspensions). Irritating preparations can cause pain and tissue necrosis.Intravenous injection completely bypasses the process of absorption, because thedrug is placed directly into the bloodstream. 22
  • Distribution Distribution plays a key role in clinical pharmacology because it is a majordeterminant of end-organ drug concentration. A drugs distribution dependsprimarily on organ perfusion, protein binding, and lipid solubility. After absorption, a drug is distributed by the bloodstream throughout thebody. Highly perfused organs (the vessel-rich group) take up a disproportionatelylarge amount of drug compared with less perfused organs (the muscle, fat, andvessel-poor groups). Thus, even though the total mass of the vessel-rich group issmall, it can account for substantial initial drug uptake. As long as a drug is bound to a plasma protein, it is unavailable for uptakeby an organ regardless of the extent of perfusion to that organ. Albumin oftenbinds acidic drugs (eg, barbiturates), whereas alfa1-acid glycoprotein (AAG) bindsbasic drugs (local anesthetics). If these proteins are diminished or if the protein-binding sites are occupied (eg, other drugs), the amount of free drug available fortissue uptake is increased. Renal disease, liver disease, chronic congestive heartfailure, and malignancies decrease albumin production. Trauma (includingsurgery), infection, myocardial infarction, and chronic pain increase AAG levels. Availability of a drug to a specific organ does not ensure uptake by thatorgan. For instance, the permeation of the central nervous system by ionized drugsis limited by pericapillary glial cells and endothelial cell tight junctions, whichconstitute the blood–brain barrier. Lipid-soluble, nonionized molecules pass freelythrough lipid membranes. Other factors, such as molecular size and tissue binding—particularly by the lung—can also influence drug distribution. After the highly perfused organs are saturated during initial distribution, thegreater mass of the less perfused organs continue to take up drug from thebloodstream. As plasma concentration falls, some drug leaves the highly perfusedorgans to maintain equilibrium. This redistribution from the vessel-rich group isresponsible for termination of effect of many anesthetic drugs. For example,awakening from the effects of thiopental is not due to metabolism or excretion butrather to redistribution of the drug from brain to muscle. As a corollary, if the lessperfused organs are saturated from repeated doses of drug, redistribution cannotoccur and awakening depends to a greater extent on drug elimination. Thus, rapid-acting drugs such as thiopental and fentanyl will become longer acting afterrepeated administration or when a large single dose is given.Biotransformation Biotransformation is the alteration of a substance by metabolic processes.The liver is the primary organ of biotransformation. The end products ofbiotransformation are usually—but not necessarily—inactive and water soluble.The latter property allows excretion by the kidney. 23
  • Metabolic biotransformation can be divided into phase I and phase IIreactions. Phase I reactions convert a parent drug into more polar metabolitesthrough oxidation, reduction, or hydrolysis. Phase II reactions couple (conjugate) aparent drug or a phase I metabolite with an endogenous substrate (eg, glucuronicacid) to form a highly polar end product that can be eliminated in the urine.Although this is usually a sequential process, phase I metabolites may be excretedwithout undergoing phase II biotransformation, and a phase II reaction can precedea phase I reaction. Hepatic clearence is the rate of elimination of a drug as a result of liverbiotransformation. More specifically, clearance is the volume of plasma cleared ofdrug per unit of time and is expressed as milliliters per minute. The hepaticclearance depends on the hepatic blood flow and the fraction of drug removed fromthe blood by the liver (hepatic extraction ratio). Drugs that are efficiently clearedby the liver have a high hepatic extraction ratio, and their clearance isproportionate to hepatic blood flow. On the other hand, drugs with a low hepaticextraction ratio are poorly cleared by the liver, and their clearance is limited by thecapacity of the hepatic enzyme systems. Therefore, the effect of liver disease ondrug pharmacokinetics depends on the drugs hepatic extraction ratio and thediseases propensity to alter hepatic blood flow or hepatocellular function.Excretion The kidney is the principal organ of excretion. Non–protein-bound drugsfreely cross from plasma into the glomerular filtrate. The nonionized fraction ofdrug is reabsorbed in the renal tubules, whereas the ionized portion is excreted inurine. Thus, alterations in urine pH can alter renal excretion. The kidney alsoactively secretes some drugs. Renal clearance is the rate of elimination of a drugfrom kidney excretion. Renal failure changes the pharmacokinetics of many drugsby altering protein binding, volumes of distribution, and clearance rates.Relatively few drugs depend on biliary excretion, as they are usually reabsorbed inthe intestine and are consequently excreted in the urine. Delayed toxic effects fromsome drugs (eg, fentanyl) may be due to this enterohepatic recirculation.The lungs are responsible for excretion of volatile agents, such as inhalationanesthetics.BarbituratesMechanisms of Action Barbiturates depress the reticular activating system—a complexpolysynaptic network of neurons and regulatory centers—located in the brain stemthat controls several vital functions, including consciousness. In clinicalconcentrations, barbiturates preferentially affect the function of nerve synapses 24
  • rather than axons. They suppress transmission of excitatory neurotransmitters (eg,acetylcholine) and enhance transmission of inhibitory neurotransmitters (eg, alfa-aminobutyric acid [GABA]). Specific mechanisms include interfering withtransmitter release (presynaptic) and stereoselectively interacting with receptors(postsynaptic).PharmacokineticsAbsorption In clinical anesthesiology, barbiturates are most frequently administeredintravenously for induction of general anesthesia in adults and children with anintravenous line. Exceptions include rectal thiopental or methohexital for inductionin children and intramuscular pentobarbital or secobarbital for premedication of allage groups.Distribution The duration of action of highly lipid-soluble barbiturates (thiopental,thiamylal, and methohexital) is determined by redistribution, not metabolism orelimination. For example, although thiopental is highly protein bound (80%), itsgreat lipid solubility and high nonionized fraction (60%) account for maximalbrain uptake within 30 s. If the central compartment is contracted (eg, hypovolemicshock), if the serum albumin is low (eg, severe liver disease), or if the nonionizedfraction is increased (eg, acidosis), higher brain and heart concentrations will beachieved for a given dose. Subsequent redistribution to the peripheral compartment—specifically, the muscle group—lowers plasma and brain concentration to 10%of peak levels within 20–30 min. This pharmacokinetic profile correlates withclinical experience—patients typically lose consciousness within 30 s and awakenwithin 20 min. Induction doses of thiopental depend on body weight and age.Lower induction doses in elderly patients is a reflection of higher peak plasmalevels because of slower redistribution. In contrast to the rapid initial distributionhalf-life of a few minutes, the elimination half-life of thiopental ranges from 3–12h. Thiamylal and methohexital have similar distribution patterns, whereas lesslipid-soluble barbiturates have much longer distribution half-lives and durations ofaction. Repetitive administration of barbiturates saturates the peripheralcompartments, so that redistribution cannot occur and the duration of actionbecomes more dependent on elimination.Biotransformation Biotransformation of barbiturates principally involves hepatic oxidation toinactive water-soluble metabolites. Because of greater hepatic extraction,methohexital is cleared by the liver three to four times more rapidly than thiopentalor thiamylal. Although redistribution is responsible for the awakening from asingle dose of any of these lipid-soluble barbiturates, full recovery of psychomotor 25
  • function is more rapid following use of methohexital due to its enhancedmetabolism.Excretion High protein binding decreases barbiturate glomerular filtration, whereashigh lipid solubility tends to increase renal tubular reabsorption. Except for the lessprotein-bound and less lipid-soluble agents such as phenobarbital, renal excretionis limited to water-soluble end products of hepatic biotransformation. Methohexitalis excreted in the feces.Effects on Organ SystemsCardiovascular Induction doses of intravenously administered barbiturates cause a fall inblood pressure and an elevation in heart rate. Depression of the medullaryvasomotor center vasodilates peripheral capacitance vessels, which increasesperipheral pooling of blood and decreases venous return to the right atrium. Thetachycardia is probably due to a central vagolytic effect. Cardiac output is oftenmaintained by a rise in heart rate and increased myocardial contractility fromcompensatory baroreceptor reflexes. Sympathetically induced vasoconstriction ofresistance vessels may actually increase peripheral vascular resistance. However,in the absence of an adequate baroreceptor response (eg, hypovolemia, congestiveheart failure, adrenergic blockade), cardiac output and arterial blood pressure mayfall dramatically due to uncompensated peripheral pooling and unmasked directmyocardial depression. Patients with poorly controlled hypertension areparticularly prone to wide swings in blood pressure during induction. Thecardiovascular effects of barbiturates therefore vary markedly, depending onvolume status, baseline autonomic tone, and preexisting cardiovascular disease. Aslow rate of injection and adequate preoperative hydration attenuate these changesin most patients.Respiratory Barbiturate depression of the medullary ventilatory center decreases theventilatory response to hypercapnia and hypoxia. Barbiturate sedation typicallyleads to upper airway obstruction; apnea usually follows an induction dose. Duringawakening, tidal volume and respiratory rate are decreased. Barbiturates do notcompletely depress noxious airway reflexes, and bronchospasm in asthmaticpatients or laryngospasm in lightly anesthetized patients is not uncommonfollowing airway instrumentation. Laryngospasm and hiccuping are more commonafter use of methohexital than after thiopental. Bronchospasm following inductionwith thiopental may be due to cholinergic nerve stimulation (which would bepreventable by pretreatment with atropine), histamine release, or direct bronchialsmooth muscle stimulation. 26
  • Cerebral Barbiturates constrict the cerebral vasculature, causing a decrease in cerebralblood flow and intracranial pressure. The drop in intracranial pressure exceeds thedecline in arterial blood pressure, so that cerebral perfusion pressure (CPP) isusually increased. (CPP equals cerebral artery pressure minus the greater ofcerebral venous pressure or intracranial pressure.) The decrease in cerebral bloodflow is not detrimental, as barbiturates induce an even greater decline in cerebraloxygen consumption (up to 50% of normal). Alterations in cerebral activityand oxygen requirements are reflected by changes in the electroencephalogram(EEG), which progresses from low-voltage fast activity with small doses to high-voltage slow activity and electrical silence (suppression) with very large doses ofbarbiturate (a bolus of 15–40 mg/kg of thiopental followed by an infusion of 0.5mg/kg/min). This effect of barbiturates may protect the brain from transientepisodes of focal ischemia (eg, cerebral embolism) but probably not from globalischemia (eg, cardiac arrest). Furthermore, doses required for EEG suppressionhave been associated with prolonged awakening, delayed extubation, and the needfor inotropic support. The degree of central nervous system depression induced by barbituratesranges from mild sedation to unconsciousness, depending on the doseadministered. Some patients relate a taste sensation of garlic or onions duringinduction with thiopental. Unlike opioids, barbiturates do not selectively impair theperception of pain. In fact, they sometimes appear to have an antianalgesic effectby lowering the pain threshold. Small doses occasionally cause a state ofexcitement and disorientation that can be disconcerting when sedation is theobjective. Barbiturates do not produce muscle relaxation, and some induceinvoluntary skeletal muscle contractions (eg, methohexital). Relatively small dosesof thiopental (50–100 mg intravenously) rapidly control most grand mal seizures.Unfortunately, acute tolerance and physiological dependence on the sedative effectof barbiturates develop quickly. Table 2. Uses and Dosages of Commonly Used Barbiturates 27
  • Agent Use Route Concentration Dose (mg/ (%) kg)Thiopental, Induction IV 2.5 3–6thiamylal Sedation IV 2.5 0.5–1.5Methohexital Induction IV 1 1–2 Sedation IV 1 0.2–0.4 Induction Rectal 10 25 (children)Secobarbital, Premedication Oral 5 2–41pentobarbital IM 2–41 Rectal 3 suppository1Maximum dose is 150 mgRenalBarbiturates reduce renal blood flow and glomerular filtration rate in proportion tothe fall in blood pressure.HepaticHepatic blood flow is decreased. Chronic exposure to barbiturates has opposingeffects on drug biotransformation. Induction of hepatic enzymes increases the rateof metabolism of some drugs (eg, digitoxin), whereas combination with thecytochrome P-450 enzyme system interferes with the biotransformation of others(eg, tricyclic antidepressants). The induction of aminolevulinic acid synthetasestimulates the formation of porphyrin (an intermediary in heme synthesis), whichmay precipitate acute intermittent porphyria or variegate porphyria in susceptibleindividuals.ImmunologicalAnaphylactic and anaphylactoid allergic reactions are rare. Sulfur-containingthiobarbiturates evoke mast cell histamine release in vitro, whereas oxybarbituratesdo not. For this reason, some anesthesiologists prefer methohexital over thiopentalor thiamylal in asthmatic or atopic patients.Drug Interactions 28
  • Contrast media, sulfonamides, and other drugs that occupy the same protein-binding sites as thiopental will increase the amount of free drug available andpotentiate the organ system effects of a given dose.Ethanol, opioids, antihistamines, and other central nervous system depressantspotentiate the sedative effects of barbiturates. The common clinical impression thatchronic alcohol abuse is associated with increased thiopental requirements lacksscientific proof.BenzodiazepinesMechanisms of Action Benzodiazepines interact with specific receptors in the central nervoussystem, particularly in the cerebral cortex. Benzodiazepine–receptor bindingenhances the inhibitory effects of various neurotransmitters. For example,benzodiazepine-receptor binding facilitates GABA–receptor binding, whichincreases the membrane conductance of chloride ions. This causes a change inmembrane polarization that inhibits normal neuronal function. Flumazenil (animidazobenzodiazepine) is a specific benzodiazepine–receptor antagonist thateffectively reverses most of the central nervous system effect of benzodiazepines.PharmacokineticsAbsorptionBenzodiazepines are commonly administered orally, intramuscularly, andintravenously to provide sedation or induction of general anesthesia. Diazepam andlorazepam are well absorbed from the gastrointestinal tract, with peak plasmalevels usually achieved in 1 and 2 h, respectively. Although oral midazolam hasnot been approved by the U.S. Food and Drug Administration, this route ofadministration has been popular for pediatric premedication. Likewise, intranasal(0.2–0.3 mg/kg), buccal (0.07 mg/kg), and sublingual (0.1 mg/kg) midazolamprovide effective preoperative sedation.Table 3. Uses and Doses of Commonly Used Benzodiazepines. 29
  • Agent Use Route1 Dose (mg/kg)Diazepam Premedication Oral 0.2–0.52 Sedation IV 0.04–0.2 Induction IV 0.3–0.6Midazolam Premedication IM 0.07–0.15 Sedation IV 0.01–0.1 Induction IV 0.1–0.4Lorazepam Premedication Oral 0.053 IM 0.03–0.053 Sedation IV 0.03–0.0431 IV, intravenous; IM, intramuscular.2Maximum dose 15 mg.3Not recommended forchildrenIntramuscular injection of diazepam is painful and unreliable. In contrast,midazolam and lorazepam are well absorbed after intramuscular injection, withpeak levels achieved in 30 and 90 min, respectively. Induction of generalanesthesia with midazolam requires intravenous administration of the drug.DistributionDiazepam is quite lipid soluble and rapidly penetrates the blood–brain barrier.Although midazolam is water soluble at low pH, its imidazole ring closes atphysiological pH, causing an increase in its lipid solubility. The moderate lipidsolubility of lorazepam accounts for its slower brain uptake and onset of action.Redistribution is fairly rapid for the benzodiazepines (the initial distribution half-life is 3–10 min) and, like the barbiturates, is responsible for awakening. Althoughmidazolam is frequently used as an induction agent, none of the benzodiazepinescan match the rapid onset and short duration of action of thiopental. All threebenzodiazepines are highly protein bound (90–98%).BiotransformationThe benzodiazepines rely on the liver for biotransformation into water-solubleglucuronide end products. The phase I metabolites of diazepam arepharmacologically active.Slow hepatic extraction and a large Vd result in a long elimination half-life fordiazepam (30 h). Although lorazepam also has a low hepatic extraction ratio, its 30
  • lower lipid solubility limits its Vd, resulting in a shorter elimination half-life (15h). Nonetheless, the clinical duration of lorazepam is often quite prolonged due toa very high receptor affinity. In contrast, midazolam shares diazepams Vd, but itselimination half-life (2 h) is the shortest of the group because of its high hepaticextraction ratio.ExcretionThe metabolites of benzodiazepine biotransformation are excreted chiefly in theurine. Enterohepatic circulation produces a secondary peak in diazepam plasmaconcentration 6–12 h following administration. Renal failure may lead toprolonged sedation in patients receiving midazolam due to the accumulation of aconjugated metabolite.Effects on Organ SystemsCardiovascularThe benzodiazepines display minimal cardiovascular depressant effects even atinduction doses. Arterial blood pressure, cardiac output, and peripheral vascularresistance usually decline slightly, whereas heart rate sometimes rises. Midazolamtends to reduce blood pressure and peripheral vascular resistance more thandiazepam. Changes in heart rate variability during midazolam sedation suggestdecreased vagal tone (ie, drug-induced vagolysis).RespiratoryBenzodiazepines depress the ventilatory response to CO2. This depression isusually insignificant unless the drugs are administered intravenously or inassociation with other respiratory depressants. Although apnea may be lesscommon after benzodiazepine induction than after barbiturate induction, evensmall intravenous doses of diazepam and midazolam have resulted in respiratoryarrest. The steep dose–response curve, slightly prolonged onset (compared withthiopental or diazepam), and high potency of midazolam necessitate carefultitration to avoid overdosage and apnea. Ventilation must be monitored in allpatients receiving intravenous benzodiazepines, and resuscitation equipment mustbe immediately available.CerebralBenzodiazepines reduce cerebral oxygen consumption, cerebral blood flow, andintracranial pressure but not to the extent the barbiturates do. They are veryeffective in preventing and controlling grand mal seizures. Oral sedative dosesoften produce antegrade amnesia, a useful premedication property. The mildmuscle-relaxant property of these drugs is mediated at the spinal cord level, not atthe neuromuscular junction. The antianxiety, amnesic, and sedative effects seen at 31
  • low doses progress to stupor and unconsciousness at induction doses. Comparedwith thiopental, induction with benzodiazepines is associated with a slower loss ofconsciousness and a longer recovery. Benzodiazepines have no direct analgesicproperties.Drug InteractionsCimetidine binds to cytochrome P-450 and reduces the metabolism of diazepam.Erythromycin inhibits metabolism of midazolam and causes a 2- to 3-foldprolongation and intensification of its effects. Heparin displaces diazepam fromprotein-binding sites and increases the free drug concentration (200% increaseafter 1000 units of heparin).The combination of opioids and diazepam markedly reduces arterial blood pressureand peripheral vascular resistance. This synergistic interaction is particularlypronounced in patients with ischemic or valvular heart disease.Benzodiazepines reduce the minimum alveolar concentration of volatileanesthetics as much as 30%.Ethanol, barbiturates, and other central nervous system depressants potentiate thesedative effects of the benzodiazepines.OpioidsMechanisms of ActionOpioids bind to specific receptors located throughout the central nervous systemand other tissues. Four major types of opioid receptor have been identified : mu (μ,with subtypes μ -1 and μ -2), kappa (κ), delta (δ), and sigma (σ). Although opioidsprovide some degree of sedation, they are most effective at producing analgesia.The pharmacodynamic properties of specific opioids depend on which receptor isbound, the binding affinity, and whether the receptor is activated. Although bothopioid agonists and antagonists bind to opioid receptors, only agonists are capableof receptor activation. Agonists–antagonists (eg, nalbuphine, nalorphine,butorphanol, and pentazocine) are drugs that have opposite actions at differentreceptor types.Table 4. Classification of Opioid Receptors. 32
  • Receptor Clinical Effect Agonists Μ Supraspinal analgesia (μ -1) Morphine Respiratory depression (μ -2) Met-enkephalin2 Physical dependence β -endorphin2 Muscle rigidity Fentanyl Κ Sedation Morphine Spinal analgesia Nalbuphine Butorphanol Dynorphin2 Oxycodone Δ Analgesia Leu-enkephalin2 Behavioral β-endorphin2 Epileptogenic Σ Dysphoria Pentazocine Hallucinations Nalorphine Respiratory stimulation Ketamine?1 Note: The relationships among receptor, clinical effect, and agonist are more complex thanindicated in this table. For example, pentazocine is an antagonist at μ -receptors, a partial agonistat κ-receptors, and an agonist at σ -receptors.2Endogenous opioid. Endorphins, enkephalins, and dynorphins are endogenous peptides that bindto opioid receptors. These three families of opioid peptides differ in their proteinprecursors, anatomic distributions, and receptor affinities. Opiate–receptor activation inhibits the presynaptic release and postsynapticresponse to excitatory neurotransmitters (eg, acetylcholine, substance P) fromnociceptive neurons. The cellular mechanism for this neuromodulation mayinvolve alterations in potassium and calcium ion conductance. Transmission ofpain impulses can be interrupted at the level of the dorsal horn of the spinal cordwith intrathecal or epidural administration of opioids. Modulation of a descendinginhibitory pathway from the periaqueductal gray through the nucleus raphe magnusto the dorsal horn of the spinal cord may also play a role in opioid analgesia.Although opioids exert their greatest effect within the central nervous system,opiate receptors have also been isolated from somatic and sympathetic peripheralnerves.Pharmacokinetics 33
  • Absorption Rapid and complete absorption follows the intramuscular injection ofmorphine and meperidine, with peak plasma levels usually reached after 20–60min. Oral transmucosal fentanyl citrate absorption (fentanyl "lollipop") is aneffective method of producing analgesia and sedation and provides rapid onset (10min) of analgesia and sedation in children (15–20 mkg/kg) and adults (200–800mkg). The low molecular weight and high lipid solubility of fentanyl also allowtransdermal absorption (the fentanyl patch). The amount of fentanyl releaseddepends primarily on the surface area of the patch but can vary with local skinconditions (eg, blood flow). Establishing a reservoir of drug in the upper dermisdelays systemic absorption for the first few hours. Serum concentrations offentanyl reach a plateau within 14–24 h of application (peak levels occur later inelderly patients than in young adult patients) and remain constant for up to 72 h.Continued absorption from the dermal reservoir accounts for a prolonged fall inserum levels after patch removal. A high incidence of nausea and variable bloodlevels have limited the acceptance of fentanyl patches for postoperative relief ofpain.Experimental studies have explored the possibility of an inhalation delivery ofliposome-encapsulated fentanyl.DistributionThe distribution half-lives of all of the opioids are fairly rapid (5–20 min). The lowfat solubility of morphine slows passage across the blood–brain barrier, however,so that its onset of action is slow and its duration of action is prolonged. Thiscontrasts with the high lipid solubility of fentanyl and sufentanil, which allows arapid onset and short duration of action. Interestingly, alfentanil has a more rapidonset of action and shorter duration of action than fentanyl following a bolusinjection, even though it is less lipid soluble than fentanyl. The high nonionizedfraction of alfentanil at physiological pH and its small Vd increase the amount ofdrug available for binding in the brain. Significant amounts of lipid-soluble opioidscan be retained by the lungs (first-pass uptake) and later diffuse back into thesystemic circulation. The amount of pulmonary uptake depends on prioraccumulation of another drug (decreases), a history of tobacco use (increases), andcoincident inhalation anesthetic administration (decreases). Redistributionterminates the action of small doses of all of these drugs, whereas larger dosesmust depend on biotransformation to adequately lower plasma levels.BiotransformationMost opioids depend primarily on the liver for biotransformation. Because of theirhigh hepatic extraction ratio, their clearance depends on liver blood flow. The 34
  • small Vd of alfentanil is responsible for a short elimination half-life (1.5 h).Morphine undergoes conjugation with glucuronic acid to form morphine 3-glucuronide and morphine 6-glucuronide. Meperidine is N-demethylated tonormeperidine, an active metabolite associated with seizure activity. The endproducts of fentanyl, sufentanil, and alfentanil are inactive.The unique ester structure of remifentanil, an ultrashort-acting opioid with aterminal elimination half-life of less than 10 min, makes it susceptible to rapidester hydrolysis by nonspecific esterases in blood (red cells) and tissue in amanner similar to esmolol. Biotransformation is so rapid and so complete that theduration of a remifentanil infusion has little effect on wake-up time. Itscontext/sensitive half-time (the time required for the plasma drug concentration todecline by 50% after termination of an infusion) is approximately 3 min regardlessof the duration of infusion. This lack of drug accumulation following repeatedboluses or prolonged infusions differs from other currently available opioids.Extrahepatic hydrolysis also implies the absence of metabolite toxicity in patientswith hepatic dysfunction. Patients with pseudocholinesterase deficiency have anormal response to remifentanil.Excretion The end products of morphine and meperidine biotransformation areeliminated by the kidneys, with less than 10% undergoing biliary excretion.Because 5–10% of morphine is excreted unchanged in the urine, renal failureprolongs its duration of action. The accumulation of morphine metabolites(morphine 3-glucuronide and morphine 6-glucuronide) in patients with renalfailure has been associated with narcosis and ventilatory depression lasting severaldays. In fact, morphine 6-glucuronide is a more potent and longer-lasting opioidagonist than morphine. Similarly, renal dysfunction increases the chance of toxiceffects from normeperidine accumulation. Normeperidine has an excitatory effecton the central nervous system, leading to myoclonic activity and seizures that arenot reversed by naloxone. A late secondary peak in fentanyl plasma levels occursup to 4 h after the last intravenous dose and may be explained by enterohepaticrecirculation or mobilization of sequestered drug. Metabolites of sufentanil areexcreted in urine and bile. The main metabolite of remifentanil is eliminatedrenally but is several thousand times less potent than its parent compound, and thusis unlikely to produce any noticeable opioid effects. Even severe liver disease doesnot affect the pharmacokinetics or pharmacodynamics of remifentanil.Effects on Organ SystemsCardiovascular In general, opioids do not seriously impair cardiovascular function.Meperidine tends to increase heart rate (it is structurally similar to atropine),whereas high doses of morphine, fentanyl, sufentanil, remifentanil, and alfentanil 35
  • are associated with a vagus-mediated bradycardia. With the exception ofmeperidine, the opioids do not depress cardiac contractility. Nonetheless, arterialblood pressure often falls as a result of bradycardia, venodilation, and decreasedsympathetic reflexes, sometimes requiring vasopressor (eg, ephedrine) support.Furthermore, meperidine and morphine evoke histamine release in someindividuals that can lead to profound drops in systemic vascular resistance andarterial blood pressure. The effects of histamine release can be minimized insusceptible patients by slow opioid infusion, adequate intravascular volume, orpretreatment with H1 and H2 histamine antagonists.Intraoperative hypertension during opioid anesthesia, particularly morphine andmeperidine, is not uncommon. It is often attributable to inadequate anestheticdepth and can be controlled with the addition of vasodilators or volatile anestheticagents. The combination of opioids with other anesthetic drugs (eg, nitrous oxide,benzodiazepines, barbiturates, volatile agents) can result in significant myocardialdepression.Respiratory Opioids depress ventilation, particularly respiratory rate. Resting PaCO2increases and the response to a CO2 challenge is blunted, resulting in a shift of theCO2 response curve downward and to the right. These effects are mediatedthrough the respiratory centers in the brain stem. The apneic threshold—thehighest PaCO2 at which a patient remains apneic—is elevated, and hypoxic driveis decreased. Gender differences may exist in these effects, with womendemonstrating more respiratory depression. Morphine and meperidine can causehistamine-induced bronchospasm in susceptible patients. Opioids (particularlyfentanyl, sufentanil, and alfentanil) can induce chest wall rigidity severe enough toprevent adequate ventilation. This centrally mediated muscle contraction is mostfrequent after large drug boluses and is effectively treated with neuromuscularblocking agents. Opioids can effectively blunt the bronchoconstrictive response toairway stimulation such as occurs during intubation.CerebralThe effects of opioids on cerebral perfusion and intracranial pressure appear to bevariable. In general, opioids reduce cerebral oxygen consumption, cerebral bloodflow, and intracranial pressure, but to a much lesser extent than barbiturates orbenzodiazepines. These effects presume a maintenance of normocarbia by artificialventilation; however, there are some reports of mild—and usually transient—increases in cerebral artery blood flow velocity and intracranial pressure followingopioid boluses in patients with brain tumors or head trauma. Because opioids alsotend to produce a mild decrease in mean arterial pressure, the resulting fall in CPPmay be significant in some patients with abnormal intracranial elastance. Anysmall rise in intracranial pressure that opioids may cause must be compared with 36
  • the potentially large increases in intracranial pressure during intubation in aninadequately anesthetized patient. The effect of most opioids on the EEG isminimal, although high doses are associated with slow δ-wave activity. High dosesof fentanyl may rarely cause seizure activity; however, some cases may actually besevere opioid-induced muscle rigidity. EEG activation has been attributed tomeperidine. Stimulation of the medullary chemoreceptor trigger zone is responsible for ahigh incidence of nausea and vomiting. Physical dependence is a significantproblem associated with repeated opioid administration. Unlike the barbiturates orbenzodiazepines, relatively large doses of opioids are required to render patientsunconscious. Regardless of the dose, however, opioids do not reliably produceamnesia. Intravenous opioids have been the mainstay of pain control for more thana century. The relatively recent use of opioids in epidural and subdural spaces hasrevolutionized pain management.Table 5. Uses and Doses of Common Opioids.Agent Use Route1 Dose2Morphine Premedication IM 0.05–0.2 mg/kg Intraoperative anesthesia IV 0.1–1 mg/kg Postoperative analgesia IM 0.05–0.2 mg/kg IV 0.03–0.15 mg/kgMeperidine Premedication IM 0.5–1 mg/kg Intraoperative anesthesia IV 2.5–5 mg/kg Postoperative analgesia IM 0.5–1 mg/kg IV 0.2–0.5 mg/kgFentanyl Intraoperative anesthesia IV 2–150 mkg/kg Postoperative analgesia IV 0.5–1.5 mkg/kgSufentanil Intraoperative anesthesia IV 0.25–30 mkg/kgAlfentanil Intraoperative anesthesia Loading dose IV 8–100 mkg/kg Maintenance infusion IV 0.5–3 mkg/kg/minRemifentanil Intraoperative anesthesia Loading dose IV 1.0 mkg/kg Maintenance infusion IV 0.5–20 mkg/kg/min Postoperative analgesia/sedation IV 0.05–0.3 mkg/kg/min 37
  • 1IM, intramuscular; IV, intravenous.2Note: The wide range of opioid doses reflects a large therapeutic index and depends uponwhich other anesthetics are simultaneously administered. For obese patients, dose should bebased on ideal body weight or lean body mass, not total body weight. Tolerance can developrapidly (ie, within 2 h) during IV infusion of opioids, necessitating higher infusion rates. Dosecorrelates with other variables besides body weight that need to be considered (eg, age). Therelative potencies of fentanyl, sufentanil, and alfentanil are estimated to be 1:9:1/7. Unique among opioids, meperidine and structurally similar sameridine havelocal anesthetic qualities when administered into the subarachnoid space.Meperidines clinical use has been limited by classic opioid side effects (nausea,sedation, and pruritus), which may not be as pronounced with sameridine.Intravenous meperidine (25 mg) has been found to be the most effective opioid fordecreasing shivering.GastrointestinalOpioids slow gastric emptying time by reducing peristalsis. Biliary colic mayresult from opioid-induced contraction of the sphincter of Oddi. Biliary spasm,which can mimic a common bile duct stone on cholangiography, is effectivelyreversed with the pure opioid antagonist naloxone. Patients receiving long-termopioid therapy (for cancer pain, for example) usually become tolerant to most ofthe side effects, except constipation because of the decreased gastrointestinalmotility.Endocrine The stress response to surgical stimulation is measured in terms of thesecretion of specific hormones, including catecholamines, antidiuretic hormone,and cortisol. Opioids block the release of these hormones more completely thanvolatile anesthetics. This is particularly true of the more potent opioids such asfentanyl, sufentanil, alfentanil, and remifentanil. In particular, patients withischemic heart disease may benefit from attenuation of the stress response.Drug InteractionsThe combination of opioids—particularly meperidine—and monoamine oxidaseinhibitors may result in respiratory arrest, hypertension or hypotension, coma, andhyperpyrexia. The cause of this dramatic interaction is not understood.Barbiturates, benzodiazepines, and other central nervous system depressants canhave synergistic cardiovascular, respiratory, and sedative effects with opioids. 38
  • The biotransformation of alfentanil, but not sufentanil, may be impaired followinga 7-day course of erythromycin, leading to prolonged sedation and respiratorydepressionKetamineMechanisms of Action Ketamine has multiple effects throughout the central nervous system,including blocking polysynaptic reflexes in the spinal cord and inhibitingexcitatory neurotransmitter effects in selected areas of the brain. In contrast to thedepression of the reticular activating system induced by the barbiturates, ketaminefunctionally "dissociates" the thalamus (which relays sensory impulses from thereticular activating system to the cerebral cortex) from the limbic cortex (which isinvolved with the awareness of sensation). Although some brain neurons areinhibited, others are tonically excited. Clinically, this state of dissociativeanesthesia causes the patient to appear conscious (eg, eye opening, swallowing,muscle contracture) but unable to process or respond to sensory input. Ketaminehas been demonstrated to be an N-methyl-D-aspartate receptor (a subtype of theglutamate receptor) antagonist. The existence of specific ketamine receptors andinteractions with opioid receptors has been postulated.PharmacokineticsAbsorptionKetamine is administered intravenously or intramuscularly. Peak plasma levels areusually achieved within 10–15 min after intramuscular injection.DistributionKetamine is more lipid soluble and less protein bound than thiopental; it is equallyionized at physiological pH. These characteristics, along with a ketamine-inducedincrease in cerebral blood flow and cardiac output, lead to rapid brain uptake andsubsequent redistribution (the distribution half-life is 10–15 min). Once again,awakening is due to redistribution to peripheral compartments.BiotransformationKetamine is biotransformed in the liver to several metabolites, some of which (eg,norketamine) retain anesthetic activity. Induction of hepatic enzymes may partiallyexplain the development of tolerance in patients who receive multiple doses ofketamine. Extensive hepatic uptake (hepatic extraction ratio of 0.9) explainsketamines relatively short elimination half-life (2 h).Excretion 39
  • End products of biotransformation are excreted renally.Effects on Organ SystemsCardiovascularIn sharp contrast to other anesthetic agents, ketamine increases arterial bloodpressure, heart rate, and cardiac output. These indirect cardiovascular effects aredue to central stimulation of the sympathetic nervous system and inhibition of thereuptake of norepinephrine. Accompanying these changes are increases inpulmonary artery pressure and myocardial work. For these reasons, ketamineshould be avoided in patients with coronary artery disease, uncontrolledhypertension, congestive heart failure, and arterial aneurysms. The directmyocardial depressant effects of large doses of ketamine, probably due toinhibition of calcium transients, are unmasked by sympathetic blockade (eg, spinalcord transection) or exhaustion of catecholamine stores (eg, severe end-stageshock). On the other hand, ketamines indirect stimulatory effects are oftenbeneficial to patients with acute hypovolemic shock.RespiratoryVentilatory drive is minimally affected by the customary induction doses ofketamine, although rapid intravenous bolus administration or pretreatment withopioids occasionally produces apnea. Ketamine is a potent bronchodilator, makingit a good induction agent for asthmatic patients. Although upper airway reflexesremain largely intact, patients at increased risk for aspiration pneumonia should beintubated. The increased salivation associated with ketamine can be attenuated bypremedication with an anticholinergic agent.CerebralConsistent with its cardiovascular effects, ketamine increases cerebral oxygenconsumption, cerebral blood flow, and intracranial pressure. These effects precludeits use in patients with space-occupying intracranial lesions. Myoclonic activity isassociated with increased subcortical electrical activity, which is not apparent onsurface EEG. Undesirable psychotomimetic side effects (eg, illusions, disturbingdreams, and delirium) during emergence and recovery are less common in childrenand in patients premedicated with benzodiazepines. Of the nonvolatile agents,ketamine may be the closest to being a "complete" anesthetic as it inducesanalgesia, amnesia, and unconsciousness.Drug InteractionsNondepolarizing neuromuscular blocking agents are potentiated by ketamine. Thecombination of theophylline and ketamine may predispose patients to seizures.Diazepam attenuates ketamines cardiostimulatory effects and prolongs its 40
  • elimination half-life. Propranolol, phenoxybenzamine, and other sympatheticantagonists unmask the direct myocardial depressant effects of ketamine. Ketamineproduces myocardial depression when given to patients anesthetized withhalothane or, to a lesser extent, other volatile anesthetics. Lithium may prolong theduration of action of ketamine.PropofolMechanisms of ActionThe mechanism by which propofol induces a state of general anesthesia mayinvolve facilitation of inhibitory neurotransmission mediated by GABA.PharmacokineticsAbsorptionPropofol is available only for intravenous administration for the induction ofgeneral anesthesia and for moderate to deep sedation.DistributionThe high lipid solubility of propofol results in an onset of action that is almost asrapid as that of thiopental (one-arm-to-brain circulation time). Awakening from asingle bolus dose is also rapid due to a very short initial distribution half-life (2–8min). Most investigators believe that recovery from propofol is more rapid and isaccompanied by less hangover than recovery from methohexital, thiopental, oretomidate. This makes it a good agent for outpatient anesthesia. A lower inductiondose is recommended in elderly patients because of their smaller Vd. Women mayrequire a higher dose of propofol than men and appear to awaken faster.BiotransformationThe clearance of propofol exceeds hepatic blood flow, implying the existence ofextrahepatic metabolism. This exceptionally high clearance rate (10 times that ofthiopental) probably contributes to relatively rapid recovery after a continuousinfusion. Conjugation in the liver results in inactive metabolites that are eliminatedby renal clearance. The pharmacokinetics of propofol do not appear to be affectedby moderate cirrhosis. Use of propofol infusion for long-term sedation of childrenwho are critically ill or young adult neurosurgical patients has been associated withcases of lipemia, metabolic acidosis, and death.ExcretionAlthough metabolites of propofol are primarily excreted in the urine, chronic renalfailure does not affect clearance of the parent drug. 41
  • Effects on Organ SystemsCardiovascularThe major cardiovascular effect of propofol is a decrease in arterial blood pressuredue to a drop in systemic vascular resistance (inhibition of sympatheticvasoconstrictor activity), cardiac contractility, and preload. Hypotension is morepronounced than with thiopental but is usually reversed by the stimulationaccompanying laryngoscopy and intubation. Factors exacerbating the hypotensioninclude large doses, rapid injection, and old age. Propofol markedly impairs thenormal arterial baroreflex response to hypotension, particularly in conditions ofnormocarbia or hypocarbia. Rarely, a marked drop in preload may lead to a vagallymediated reflex bradycardia. Changes in heart rate and cardiac output are usuallytransient and insignificant in healthy patients but may be severe enough to lead toasystole, particularly in patients at the extremes of age, on negative chronotropicmedications, or undergoing surgical procedures associated with the oculocardiacreflex. Patients with impaired ventricular function may experience a significantdrop in cardiac output as a result of decreases in ventricular filling pressures andcontractility. Although myocardial oxygen consumption and coronary blood flowdecrease to a similar extent, coronary sinus lactate production increases in somepatients. This indicates a regional mismatch between myocardial oxygen supplyand demand.RespiratoryLike the barbiturates, propofol is a profound respiratory depressant that usuallycauses apnea following an induction dose. Even when used for conscious sedationin subanesthetic doses, propofol infusion inhibits hypoxic ventilatory drive anddepresses the normal response to hypercarbia. As a result, only properly trainedpersonnel should use this technique. Propofol-induced depression of upper airwayreflexes exceeds that of thiopental and can prove helpful during intubation orlaryngeal mask placement in the absence of paralysis. Although propofol can causehistamine release, induction with propofol is accompanied by a lower incidence ofwheezing in asthmatic and nonasthmatic patients compared with barbiturates oretomidate and is not contraindicated in asthmatic patients.CerebralPropofol decreases cerebral blood flow and intracranial pressure. In patients withelevated intracranial pressure, propofol can cause a critical reduction in CPP (< 50mm Hg) unless steps are taken to support mean arterial blood pressure. Propofoland thiopental probably provide a similar degree of cerebral protection during focalischemia. Unique to propofol are its antipruritic properties. Its antiemetic effects(requiring a blood propofol concentration of 200 ng/mL) make it a preferred drugfor outpatient anesthesia. Induction is occasionally accompanied by excitatoryphenomena such as muscle twitching, spontaneous movement, opisthotonus, or 42
  • hiccupping possibly due to subcortical glycine antagonism. Although thesereactions may occasionally mimic tonic–clonic seizures, propofol appears to havepredominantly anticonvulsant properties (ie, burst suppression), has beensuccessfully used to terminate status epilepticus, and may be safely administered toepileptic patients. Propofol decreases intraocular pressure. Tolerance does notdevelop after long-term propofol infusions.Drug InteractionsNondepolarizing neuromuscular blocking agents may be potentiated by previousformulations of propofol, which contained Cremophor. Newer formulations do notshare this interaction.Fentanyl and alfentanil concentrations may be increased by concomitantadministration of propofol. Some clinicians administer a small amount ofmidazolam (eg, 30 mkgg/kg) prior to induction with propofol; they believe thecombination produces synergistic effects (eg, faster onset and lower total doserequirements). However, this technique of "coinduction" has questionable efficacy.Neuromuscular Blocking Agents Skeletal muscle relaxation can be produced by deep inhalational anesthesia,regional nerve block, or neuromuscular blocking agents (commonly called musclerelaxants). In 1942, Harold Griffith published the results of a study using a refinedextract of curare (a South American arrow poison) during anesthesia. Musclerelaxants rapidly became a routine part of the anesthesiologists drug arsenal. AsGriffith noted, it is important to realize that neuromuscular junction blockingagents produce paralysis, not anesthesia. In other words, muscle relaxation doesnot ensure unconsciousness, amnesia, or analgesia. This chapter reviews theprinciples of neuromuscular transmission and presents the mechanisms of action,physical structures, routes of elimination, recommended dosages, and side effectsof several muscle relaxants.Neuromuscular Transmission The region of approximation between a motor neuron and a muscle cell isthe neuromuscular junction. The cell membranes of the neuron and muscle fiberare separated by a narrow (20-nm) gap, the synaptic cleft. As a nerves actionpotential depolarizes its terminal, an influx of calcium ions through voltage-gatedcalcium channels into the nerve cytoplasm allows storage vesicles to fuse with theterminal membrane and release their contents of acetylcholine (ACh). The AChmolecules diffuse across the synaptic cleft to bind with nicotinic cholinergicreceptors on a specialized portion of the muscle membrane, the motor end-plate.Each neuromuscular junction contains approximately 5 million of these receptors,but activation of only about 500,000 receptors is required for normal musclecontraction. 43
  • Distinctions between Depolarizing and Nondepolarizing BlockadeNeuromuscular blocking agents are divided into two classes: depolarizing andnondepolarizing. This division reflects distinct differences in the mechanism ofaction, response to peripheral nerve stimulation, and reversal of block.Mechanism of ActionSimilar to ACh, all neuromuscular blocking agents are quaternary ammoniumcompounds whose positively charged nitrogen imparts an affinity to nicotinic AChreceptors. Whereas most agents have two quaternary ammonium atoms, a few haveone quaternary ammonium cation and one tertiary nitrogen that is protonated atphysiological pH.Depolarizing muscle relaxants very closely resemble ACh and therefore readilybind to ACh receptors, generating a muscle action potential. Unlike ACh, however,these drugs are not metabolized by acetylcholinesterase, and their concentration inthe synaptic cleft does not fall as rapidly, resulting in a prolonged depolarization ofthe muscle end-plate.Continuous end-plate depolarization causes muscle relaxation because opening ofthe lower gate in the perijunctional sodium channels is time limited. After theinitial excitation and opening , these sodium channels close and cannot reopenuntil the end-plate repolarizes. The end-plate cannot repolarize as long as thedepolarizing muscle relaxant continues to bind to ACh receptors; this is called aphase I block. After a period of time, prolonged end-plate depolarization can causeionic and conformational changes in the ACh receptor that result in a phase IIblock, which clinically resembles that of nondepolarizing muscle relaxants.Nondepolarizing muscle relaxants bind ACh receptors but are incapable ofinducing the conformational change necessary for ion channel opening. BecauseACh is prevented from binding to its receptors, no end-plate potential develops.Neuromuscular blockade occurs even if only one alfa-subunit is blocked. Thus, depolarizing muscle relaxants act as ACh receptor agonists, whereasnondepolarizing muscle relaxants function as competitive antagonists. This basicdifference in mechanism of action explains their varying effects in certain diseasestates. For example, conditions associated with a chronic decrease in ACh release(eg, muscle denervation injuries) stimulate a compensatory increase in the numberof ACh receptors within muscle membranes. These states also promote theexpression of the immature (extrajunctional) isoform of the ACh receptor, whichdisplays low channel conductance properties and prolonged open-channel time.This up-regulation causes an exaggerated response to depolarizing musclerelaxants (with more receptors being depolarized), but a resistance tonondepolarizing relaxants (more receptors that must be blocked). In contrast,conditions associated with fewer ACh receptors (eg, down-regulation in 44
  • myasthenia gravis) demonstrate a resistance to depolarizing relaxants and anincreased sensitivity to nondepolarizing relaxants. Spinal, Epidural, and Caudal Blocks Spinal, caudal, and epidural blocks were first used for surgical procedures atthe turn of the twentieth century. These central blocks were widely used prior tothe 1940s until increasing reports of permanent neurological injury appeared.However, a large-scale epidemiological study conducted in the 1950s indicatedthat complications were rare when these blocks were performed skillfully withattention to asepsis and when newer, safer local anesthetics were used. Aresurgence in the use of central blocks ensued, and today they are once againwidely used in clinical practice. Spinal, epidural, and caudal blocks are also known as neuraxial anesthesia.Each of these blocks can be performed as a single injection or with a catheter toallow intermittent boluses or continuous infusions. Neuraxial anesthesia greatlyexpands the anesthesiologists armamentarium, providing alternatives to generalanesthesia when appropriate. They may also be used simultaneously with generalanesthesia or afterward for postoperative analgesia and for the management ofacute and chronic pain disorders. Neuraxial techniques have proved to be extremely safe when managed well;however, there is still a risk for complications. Adverse reactions andcomplications range from self-limited back soreness to debilitating permanentneurological deficits and even death. The practitioner must therefore have a goodunderstanding of the anatomy involved, be thoroughly familiar with thepharmacology and toxic dosages of the agents employed, diligently employ steriletechniques, and anticipate and quickly treat physiological derangements.The Role of Neuraxial Anesthesia in Anesthetic Practice Almost all operations below the neck can be performed under neuraxialanesthesia. However, because intrathoracic, upper abdominal, and laparoscopicoperations can significantly impair ventilation, general anesthesia withendotracheal intubation is also necessary. Some clinical studies suggest that postoperative morbidity—and possiblymortality—may be reduced when neuraxial blockade is used either alone or incombination with general anesthesia in some settings. Neuraxial blocks mayreduce the incidence of venous thrombosis and pulmonary embolism, cardiaccomplications in high-risk patients, bleeding and transfusion requirements,vascular graft occlusion, and pneumonia and respiratory depression followingupper abdominal or thoracic surgery in patients with chronic lung disease.Neuraxial blocks may also allow earlier return of gastrointestinal functionfollowing surgery. Proposed mechanisms include amelioration of the 45
  • hypercoagulable state associated with surgery, sympathectomy-mediated increasesin tissue blood flow, improved oxygenation from decreased splinting, enhancedperistalsis, and suppression of the neuroendocrine stress response to surgery. Forpatients with coronary artery disease, a decreased stress response may result in lessperioperative ischemia and reduced morbidity and mortality. The increasing use ofperioperative beta-blockade to reduce perioperative cardiac complications,however, may minimize or eliminate the potential advantage of neuraxialanesthesia in this setting. Reduction of parenteral opioid requirements maydecrease the incidence of atelectasis, hypoventilation, and aspiration pneumonia.Postoperative epidural analgesia may also significantly reduce the time untilextubation and reduce the need for mechanical ventilation after major abdominalor thoracic surgery.The Sick Elderly Patient Anesthesiologists are all too familiar with situations in which a consultant"clears" a sick elderly patient with significant cardiac disease for surgery "underspinal anesthesia." But is a spinal anesthetic really safer than general anesthesia forsuch a patient? A spinal anesthetic with no intravenous sedation may reduce thelikelihood of postoperative delirium or cognitive dysfunction, which is sometimesseen in the elderly. Unfortunately, some, if not most, patients require somesedation during the course of the procedure, either for comfort or to facilitatecooperation. And is spinal anesthesia always safer for a patient with severecoronary artery disease or a decreased ejection fraction? Ideally an anesthetictechnique in such a patient should not involve either hypotension (which decreasesmyocardial perfusion pressure) or hypertension or tachycardia (which increasemyocardial oxygen consumption), and should not require large fluid infusion(which can precipitate congestive heart failure). Unfortunately, a spinal anestheticis often associated with hypotension and bradycardia, which may be rapid in onsetand is sometimes profound. Moreover, treatment may require rapid administrationof intravenous fluid, vasopressors, and/or an anticholinergic, which can cause fluidoverload (when the vasodilatation wears off), rebound hypertension, andtachycardia. The slower onset of hypotension and bradycardia following epiduralanesthesia may give the anesthesiologist more time to correct hemodynamicchanges, although they still occur. Some clinicians avoid epidural anesthesia inelderly patients who may have spinal stenosis, fearing the mass effect of the bolusof anesthetic might compromise spinal cord perfusion. General anesthesia, on theother hand, also poses potential problems for patients with cardiac compromise.Most general anesthetics are cardiac depressants and many cause vasodilatation.Deep anesthesia can readily cause hypotension, whereas light anesthesia relative tothe level of stimulation causes hypertension and tachycardia. Insertion of alaryngeal mask airway causes less of a stress response than endotrachealintubation, but deeper levels of general anesthesia are still required to blunt theresponse to surgical stimulation. 46
  • Thus arguments can be made for and against neuraxial and regionalanesthesia in this setting. Perhaps then it is not the technique that is critical asmuch as the careful execution of whatever anesthetic technique is planned.The Obstetric Patient Neuraxial anesthesia has had a great impact in obstetrics. Currently, epiduralanesthesia is widely used for analgesia in women in labor and during vaginaldelivery. Cesarean section is most commonly performed under epidural or spinalanesthesia. Both blocks allow a mother to remain awake and experience the birthof her child. Large population studies in Great Britain and in the United Stateshave shown that regional anesthesia for cesarean section is associated with lessmaternal morbidity and mortality than is general anesthesia. This may be largelydue to a reduction in the incidence of pulmonary aspiration and failed intubation.Mechanism of Action The principal site of action for neuraxial blockade is the nerve root. Localanesthetic is injected into CSF (spinal anesthesia) or the epidural space (epiduraland caudal anesthesia) and bathes the nerve root in the subarachnoid space orepidural space, respectively. Direct injection of local anesthetic into CSF for spinalanesthesia allows a relatively small dose and volume of local anesthetic to achievedense sensory and motor blockade. In contrast, the same local anestheticconcentration is achieved at nerve roots only with much higher volumes andquantities of local anesthetic with epidural and caudal anesthesia. Moreover, theinjection site (level) for epidural anesthesia must generally be close to the nerveroots that must be anesthetized. Blockade of neural transmission (conduction) inthe posterior nerve root fibers interrupts somatic and visceral sensation, whereasblockade of anterior nerve root fibers prevents efferent motor and autonomicoutflow.Somatic Blockade By interrupting the transmission of painful stimuli and abolishing skeletalmuscle tone, neuraxial blocks can provide excellent operating conditions. Sensoryblockade interrupts both somatic and visceral painful stimuli, whereas motorblockade produces skeletal muscle relaxation. The effect of local anesthetics onnerve fibers varies according to the size of the nerve fiber, whether it ismyelinated, and the concentration achieved and the duration of contact. Spinalnerve roots contain varying mixtures of these fiber types. Smaller and myelinatedfibers are generally more easily blocked than larger and unmyelinated ones. This,and the fact that the concentration of local anesthetic decreases with increasingdistance from the level of injection, explains the phenomenon of differentialblockade. Differential blockade typically results in sympathetic blockade (judgedby temperature sensitivity) that may be two segments higher than the sensory block 47
  • (pain, light touch), which in turn is usually two segments higher than the motorblockade.Autonomic Blockade Interruption of efferent autonomic transmission at the spinal nerve roots canproduce sympathetic and some parasympathetic blockade. Sympathetic outflowfrom the spinal cord may be described as thoracolumbar, whereas parasympatheticoutflow is craniosacral. Sympathetic preganglionic nerve fibers (small, myelinatedB fibers) exit the spinal cord with the spinal nerves from T1 to the L2 level andmay course many levels up or down the sympathetic chain before synapsing with apostganglionic cell in a sympathetic ganglia. In contrast, parasympatheticpreganglionic fibers exit the spinal cord with the cranial and sacral nerves.Neuraxial anesthesia does not block the vagus nerve (tenth cranial nerve). Thephysiological responses of neuraxial blockade therefore result from decreasedsympathetic tone and/or unopposed parasympathetic tone.Cardiovascular Manifestations Neuraxial blocks typically produce variable decreases in blood pressure thatmay be accompanied by a decrease in heart rate and cardiac contractility. Theseeffects are generally proportional to the degree (level) of the sympathectomy.Vasomotor tone is primarily determined by sympathetic fibers arising from T5 toL1, innervating arterial and venous smooth muscle. Blocking these nerves causesvasodilation of the venous capacitance vessels, pooling of blood, and decreasedvenous return to the heart; in some instances, arterial vasodilation may alsodecrease systemic vascular resistance. The effects of arterial vasodilation may beminimized by compensatory vasoconstriction above the level of the block. A highsympathetic block not only prevents compensatory vasoconstriction but alsoblocks the sympathetic cardiac accelerator fibers that arise at T1–T4. Profoundhypotension may result from vasodilation combined with bradycardia anddecreased contractility. These effects are exaggerated if venous return is furthercompromised by a head-up position or by the weight of a gravid uterus.Unopposed vagal tone may explain the sudden cardiac arrest sometimes seen withspinal anesthesia. Deleterious cardiovascular effects should be anticipated and stepsundertaken to minimize the degree of hypotension. Volume loading with 10–20mL/kg of intravenous fluid for a healthy patient will partially compensate for thevenous pooling. Left uterine displacement in the third trimester of pregnancy helpsminimize physical obstruction to venous return. Despite these efforts, hypotensionmay still occur and should be treated promptly. Fluid administration can beincreased, and autotransfusion may be accomplished by placing the patient in ahead-down position. Excessive or symptomatic bradycardia should be treated withatropine, and hypotension should be treated with vasopressors. Direct alfa- 48
  • adrenergic agonists (such as phenylephrine) increase venous tone and producearteriolar constriction, increasing both venous return and systemic vascularresistance. Ephedrine has direct beta-adrenergic effects that increase heart rate andcontractility and indirect effects that also produce some vasoconstriction. Ifprofound hypotension and/or bradycardia persist despite these interventions,epinephrine (5–10 mkg intravenously) should be administered promptly.Pulmonary Manifestations Clinically significant alterations in pulmonary physiology are usuallyminimal with neuraxial blocks because the diaphragm is innervated by the phrenicnerve with fibers originating from C3–C5. Even with high thoracic levels, tidalvolume is unchanged; there is only a small decrease in vital capacity, which resultsfrom a loss of the abdominal muscles contribution to forced expiration. Phrenicnerve block may not occur even with total spinal anesthesia as apnea often resolveswith hemodynamic resuscitation, suggesting that brain stem hypoperfusion isresponsible rather than phrenic nerve block. The concentration of local anesthetic,even with a cervical sensory level, is reported to be below that required to blockthe large A-alfa fibers of the phrenic nerve.Patients with severe chronic lung disease may rely upon accessory muscles ofrespiration (intercostal and abdominal muscles) to actively inspire or exhale. Highlevels of neural blockade will impair these muscles. Similarly, effective coughingand clearing of secretions require these muscles for expiration. For these reasons,neuraxial blocks should be used with caution in patients with limited respiratoryreserve. These deleterious effects need to be weighed against the advantages ofavoiding airway instrumentation and positive-pressure ventilation. For surgicalprocedures above the umbilicus, a pure regional technique may not be the bestchoice for patients with severe lung disease. On the other hand, these patients maybenefit from the effects of thoracic epidural analgesia (with dilute local anestheticsand opioids) in the postoperative period, particularly following upper abdominal orthoracic surgery. Thoracic or upper abdominal surgery is associated with decreaseddiaphragmatic function postoperatively (from decreased phrenic nerve activity)and decreased functional residual capacity (FRC), which can lead to atelectasis andhypoxia via ventilation/perfusion mismatch. Some evidence suggests thatpostoperative thoracic epidural analgesia in high-risk patients can improvepulmonary outcome by decreasing the incidence of pneumonia and respiratoryfailure, improving oxygenation, and decreasing the duration of mechanicalventilatory support.Gastrointestinal Manifestations Sympathetic outflow originates at the T5–L1 level. Neuraxial block–inducedsympathectomy allows vagal tone dominance and results in a small, contracted gutwith active peristalsis. This can provide excellent operative conditions for some 49
  • laparoscopic procedures when used as an adjunct to general anesthesia.Postoperative epidural analgesia has been shown to hasten return ofgastrointestinal function.Hepatic blood flow will decrease with reductions in mean arterial pressure fromany anesthetic technique. For intraabdominal surgery, the decrease in hepaticperfusion is related more to surgical manipulation than to anesthetic technique.Urinary Tract Manifestations Renal blood flow is maintained through autoregulation, and there is littleclinical effect upon renal function from neuraxial blockade. Neuraxial anesthesia atthe lumbar and sacral levels blocks both sympathetic and parasympathetic controlof bladder function. Loss of autonomic bladder control results in urinary retentionuntil the block wears off. If no urinary catheter is anticipated perioperatively, it isprudent to use the shortest acting and smallest amount of drug necessary for thesurgical procedure and limit the amount of intravenous fluid administration (ifpossible). The patient should be monitored for urinary retention to avoid bladderdistention following neuraxial anesthesia.Metabolic and Endocrine ManifestationsSurgical trauma produces a neuroendocrine response via a localized inflammatoryresponse and activation of somatic and visceral afferent nerve fibers. This responseincludes increases in adrenocorticotropic hormone, cortisol, epinephrine,norepinephrine, and vasopressin levels as well as activation of the renin–angiotensin–aldosterone system. Clinical manifestations include intraoperative andpostoperative hypertension, tachycardia, hyperglycemia, protein catabolism,suppressed immune responses, and altered renal function. Neuraxial blockade canpartially suppress (during major invasive surgery) or totally block (during lowerextremity surgery) this stress response. By reducing catecholamine release,neuraxial blocks may decrease perioperative arrhythmias and possibly reduce theincidence of ischemia. To maximize this blunting of the neuroendocrine stressresponse, neuraxial block should precede incision and extend into thepostoperative period.Spinal Anesthesia Spinal anesthesia blocks nerve roots as they course through the subarachnoidspace. The spinal subarachnoid space extends from the foramen magnum to the S2in adults and S3 in children. Injection of local anesthetic below L1 in adults and L3in children helps avoid direct trauma to the spinal cord. Spinal anesthesia is alsoreferred to a subarachnoid block or intrathecal injection.Spinal Needles 50
  • Spinal needles are commercially available in an array of sizes (16–30gauge), lengths, and bevel and tip designs. All should have a tightly fittingremovable stylet that completely occludes the lumen to avoid tracking epithelialcells into the subarachnoid space. Broadly, they can be divided into either sharp(cutting)-tipped or blunt-tipped needles. The Quincke needle is a cutting needlewith end injection. The introduction of blunt tip (pencil-point) needles hasmarkedly decreased the incidence of postdural puncture headache; in general thesmaller the gauge needle the lower the incidence of headache. The Whitacre andother pencil-point needles have rounded points and side injection. The Sprotte is aside-injection needle with a long opening. It has the advantage of more vigorousCSF flow compared with similar gauge needles. However, this can lead to a failedblock if the distal part of the opening is subarachnoid (with free flow CSF), theproximal part is not past the dura, and the full dose of medication is not delivered.Spinal CathetersVery small subarachnoid catheters are currently no longer approved by the U.S.Food and Drug Administration (FDA). The withdrawal of these catheters wasprompted by their association with cauda equina syndrome. Larger cathetersdesigned for epidural use are associated with relatively high complication rateswhen placed subarachnoid.Specific Technique for Spinal AnesthesiaThe midline, paramedian, or prone approach can be used for spinal anesthesia. Aspreviously discussed, the needle is advanced from skin through the deeperstructures until two "pops" are felt. The first is penetration of the ligamentumflavum and the second is penetration of the dura–arachnoid membrane. Successfuldural puncture is confirmed by withdrawing the stylet to verify free flow of CSF.With small-gauge needles (< 25 g), particularly in the presence of low CSFpressure (eg, a dehydrated patient), aspiration may be necessary to detect CSF. Ifinitially free flow occurs but then CSF cannot be aspirated after attaching thesyringe, the needle may have moved. Persistent paresthesia or pain upon injectionshould alert the clinician to withdraw and redirect the needle.Factors Influencing Level of Block A lot of factors that have been shown to affect level of neural blockadefollowing spinal anesthesia. The most important determinants are baricity, positionof the patient during and immediately after injection, and drug dosage. In general,the higher the dosage or site of injection, the higher the level of anesthesiaobtained. Moreover, migration of the local anesthetic cephalad in CSF depends onits specific gravity relative to CSF (baricity). CSF has a specific gravity of 1.003–1.008 at 37°C. A hyperbaric solution of local anesthetic is denser (heavier) thanCSF, whereas a hypobaric solution is less dense (lighter) than CSF. The localanesthetic solutions can be made hyperbaric by the addition of glucose or 51
  • hypobaric by the addition of sterile water. Thus, with a head-down position, ahyperbaric solution spreads cephalad and a hypobaric anesthetic solution movescaudad. A head-up position causes a hyperbaric solution to settle caudad and ahypobaric solution to ascend cephalad. Similarly, in a lateral position, a hyperbaricspinal solution will have a greater effect on the dependent (down) side, whereas ahypobaric solution will achieve a higher level on the nondependent (up) side. Anisobaric solution tends to remain at the level of injection. Anesthetic agents aremixed with CSF (at least 1:1) to make their solutions isobaric. Other factorsaffecting the level of neural blockade include the level of injection and the patientsheight and vertebral column anatomy. The direction of the needle bevel orinjection port may also play a role; higher levels of anesthesia are achieved if theinjection is directed cephalad than if the point of injection is oriented laterally orcaudad. Hyperbaric solutions tend to move to the most dependent area of the spine(normally T4–T8 in the supine position). With normal spinal anatomy, the apex ofthe thoracolumbar curvature is T4. In the supine position, this should limit ahyperbaric solution to produce a level of anesthesia at or below T4. Abnormalcurvatures of the spine, such as scoliosis and kyphoscoliosis, have multiple effectson spinal anesthesia. Placing the block becomes more difficult because of therotation and angulation of the vertebral bodies and spinous processes. Finding themidline and the interlaminar space may be difficult. The paramedian approach tolumbar puncture may be preferable in patients with severe scoliosis andkyphoscoliosis, particularly if there is associated degenerative joint disease. Theparamedian approach is easiest for spinal anesthesia at the L5–S1 level. In theTaylor approach, a variant of the standard paramedian approach describedpreviously, the needle enters 1 cm medial and 1 cm inferior to the posteriorsuperior iliac spine and is directed cephalad and toward the midline. Reviewingradiographs of the spine before attempting the block may be useful. Spinalcurvature affects the ultimate level by changing the contour of the subarachnoidspace. Previous spinal surgery can similarly result in technical difficulties inplacing a block. Correctly identifying the interspinous and interlaminar spaces maybe difficult at the levels of previous laminectomy or spinal fusion. The paramedianapproach may be easier, or a level above the surgical site can be chosen. The blockmay be incomplete, or the level may be different than anticipated, due topostsurgical anatomic changes. CSF volume inversely correlates with level of anesthesia. Increasedintraabdominal pressure or conditions that cause engorgement of the epiduralveins, thus decreasing CSF volume, are associated with higher blocks. This wouldinclude conditions such as pregnancy, ascites, and large abdominal tumors. Inthese clinical situations, higher levels of anesthesia are achieved with a given doseof local anesthetic than would otherwise be expected. For spinal anesthesia on aterm parturient, the dosage of anesthetic can be reduced by one-third comparedwith a nonpregnant patients. Age-related decreases in CSF volume are likely 52
  • responsible for the higher anesthetic levels achieved in the elderly for a givendosage of spinal anesthetic. Severe kyphosis or kyphoscoliosis can also beassociated with a decreased volume of CSF and often results in a higher thanexpected level, particularly with a hypobaric technique or rapid injection.Conflicting opinion exists as to whether increased CSF pressure caused bycoughing or straining, or turbulence on injection has any effect on the spread oflocal anesthetic in the CSF.Spinal Anesthetic AgentsMany local anesthetics have been used for spinal anesthesia in the past, but only afew are currently in use. There is renewed interest in some older medicationsbecause of reports documenting an increased incidence of transient neurologicalsymptoms with 5%lidocaine (see Complications of Neuraxial Anesthesia). Onlypreservative-free local anesthetic solutions are used. Addition of vasoconstrictors(alfa-adrenergic agonists) and opioids may enhance the quality and/or prolong theduration of spinal anesthesia. Vasoconstrictors include epinephrine (0.1–0.2 mg)and phenylephrine (1–2 mg). Both agents appear to decrease the uptake andclearance of local anesthetics from CSF and may have weak spinal analgesicproperties. Clonidine and neostigmine also have spinal analgesic properties, butexperience with them as additives for spinal anesthesia is limited. Hyperbaric bupivacaine and tetracaine are two of the most commonly usedagents for spinal anesthesia. Both are relatively slow in onset (5–10 min) and havea prolonged duration (90–120 min). Although both agents produce similar sensorylevels, spinal tetracaine generally produces more motor blockade than theequivalent dose of bupivacaine. Addition of epinephrine to spinal bupivacaineprolongs its duration only modestly. In contrast, epinephrine can prolong theduration of tetracaine anesthesia by more than 50%. Phenylephrine also prolongstetracaine anesthesia but has no effect on bupivacaine spinal blocks. Ropivacainehas also been used for spinal anesthesia, but experience with it is more limited. A12-mg intrathecal dose of ropivacaine is roughly equivalent to 8 mg ofbupivacaine, but it appears to have no particular advantages for spinal anesthesia.Lidocaine and procaine have a rapid onset (3–5 min) and short duration of action(60–90 min). There are conflicting data as to whether their duration is prolongedby vasoconstrictors; any effect appears to be modest. Although lidocaine for spinalanesthesia has been used worldwide, some caution its use in light of thephenomenon of transient neurological symptoms (TNS) and cauda equinasyndrome (see below). Some experts suggest that lidocaine can be safely used as aspinal anesthetic if the total dose is limited to 60 mg and diluted to 2.5% or lesswith an opioid and/or CSF prior to injection. Repeat doses following an initial"failed" block should be avoided as perhaps should the use of epinephrine withlidocaine. 53
  • Hyperbaric spinal anesthesia is more commonly used than the hypobaric orisobaric techniques. The level of anesthesia is then dependent on the patientsposition during and immediately following the injection. In the sitting position,"saddle block" can be achieved by keeping the patient sitting for 3–5 minfollowing injection so that only the lower lumbar nerves and sacral nerves areblocked. If the patient is moved from a sitting position to a supine positionimmediately after injection, the agent will move more cephalad to the dependentregion defined by the thoracolumbar curve, as full protein binding has not yetoccurred. Hyperbaric anesthetics injected intrathecally with the patient in a lateraldecubitus position are useful for unilateral lower extremity procedures. The patientis placed laterally with the extremity to be operated on in a dependent position. Ifthe patient is kept in this position for about 5 min following injection, the blockwill tend to be denser and achieve a higher level on the operative dependent side.If regional anesthesia is chosen for surgical procedures involving hip or lowerextremity fracture, hypobaric spinal anesthesia can be useful because the patientneed not lie on the fractured extremityEpidural Anesthesia Epidural anesthesia is a neuraxial technique offering a range of applicationswider than the typical all-or-nothing spinal anesthetic. An epidural block can beperformed at the lumbar, thoracic, or cervical level. Sacral epidural anesthesia isreferred to as a caudal block and is described at the end of this chapter. Epiduraltechniques are widely used for operative anesthesia, obstetric analgesia,postoperative pain control, and chronic pain management. It can be used as asingle shot technique or with a catheter that allows intermittent boluses and/orcontinuous infusion. The motor block can range from none to complete. All thesevariables are controlled by the choice of drug, concentration, dosage, and level ofinjection. The epidural space surrounds the dura mater posteriorly, laterally, andanteriorly. Nerve roots travel in this space as they exit laterally through theforamen and course outward to become peripheral nerves. Other contents of theepidural space include fatty connective tissue, lymphatics, and a rich venous(Batsons) plexus. Recent fluoroscopic studies have suggested the presence of septaor connective tissue bands. Epidural anesthesia is slower in onset (10–20 min) andmay not be as dense as spinal anesthesia. This can be manifested as a morepronounced differential block or a segmental block, a feature that can be usefulclinically. For example, by using relatively dilute concentrations of a localanesthetic combined with an opioid, an epidural can block the smaller sympatheticand sensory fibers and spare the larger motor fibers, providing analgesia withoutmotor block. This is commonly employed for labor and postoperative analgesia.Moreover, a segmental block is possible because the anesthetic is not spreadreadily by CSF and can be confined close to the level at which it was injected. A 54
  • segmental block is characterized by a well-defined band of anesthesia at certainnerve roots; nerve roots above and below are not blocked. This can be seen with athoracic epidural that provides upper abdominal anesthesia while sparing cervicaland lumbar nerve roots. Epidural anesthesia and analgesia is most often performed in the lumbarregion. The midline or paramedian approach can be used. Lumbar epiduralanesthesia can be used for any procedure below the diaphragm. Because the spinalcord typically terminates at the L1 level, there is an extra measure of safety inperforming the block in the lower lumbar interspaces, particularly if an inadvertentdural puncture occurs. Thoracic epidural blocks are technically more difficult to accomplish thanlumbar blocks because of greater angulation and marked overlapping of thespinous processes at the vertebral level. Moreover, the potential risk of spinal cordinjury with inadvertent dural puncture, although small with good technique, maybe greater than that at the lumbar level. Thoracic epidural blocks can beaccomplished with either a midline or paramedian approach. Rarely used forprimary anesthesia, the thoracic epidural technique is most commonly used forintra- and postoperative analgesia. Single shot or catheter techniques are used formanagement of chronic pain. Infusions via an epidural catheter are very useful forproviding analgesia and may obviate or shorten postoperative ventilation forpatients with underlying lung disease and following chest surgery. Cervical blocks are usually performed with the patient sitting, with the neckflexed, using the midline approach. Clinically, they are used primarily formanagement of pain.Epidural NeedlesThe standard epidural needle is typically 17–18 gauge, 3 or 3.5 inches long, andhas a blunt bevel with a gentle curve of 15–30° at the tip. The Tuohy needle ismost commonly used. The blunt, curved tip helps push away the dura after passingthrough the ligamentum flavum instead of penetrating it. Straight needles without acurved tip (Crawford needles) may have a higher incidence of dural puncture butfacilitate passage of an epidural catheter. Needle modifications include winged tipsand introducer devices set into the hub designed for guiding catheter placement.Epidural Catheters Placing a catheter into the epidural space allows for continuous infusion orintermittent bolus techniques. In addition to extending the duration of the block, itmay allow a lower total dose of anesthetic to be used, and, therefore, decrease thehemodynamic insults if incremental initial dosing is used. 55
  • Epidural catheters are useful for intraoperative epidural anesthesia and/orpostoperative analgesia. Typically, a 19- or 20-gauge catheter is introducedthrough a 17- or 18-gauge epidural needle. When using a curved tipped needle, thebevel opening is directed either cephalad or caudad, and the catheter is advanced2–6 cm into the epidural space. The shorter the distance the catheter is advanced,the more likely it is to become dislodged. Conversely, the further the catheter isadvanced, the greater the chance of a unilateral block, due to the catheter tip eitherexiting the epidural space via an intervertebral foramen or coursing into theanterolateral recesses of the epidural space. After advancing the catheter thedesired depth, the needle is removed, leaving the catheter in place. The cathetercan be taped or otherwise secured along the back. Catheters have either a singleport at the distal end or multiple side ports close to a closed tip. Some have a styletfor easier insertion. Spiral wire-reinforced catheters are very resistant to kinking.The spiral or spring tip is associated with fewer, less intense paresthesias and maybe associated with a lower incidence of inadvertent intravascular insertion.Activating an Epidural The quantity (volume and concentration) of local anesthetic needed forepidural anesthesia is very large compared with that needed for spinal anesthesia.Significant toxicity can occur if this amount is injected intrathecally orintravascularly. Safeguards against this include the epidural test dose andincremental dosing. This is true whether the injection is through the needle orthrough an epidural catheter. A test dose is designed to detect both subarachnoid and intravascularinjection. The classic test dose combines local anesthetic and epinephrine, typically3 mL of 1.5%lidocaine with 1:200,000 epinephrine (0.005 mg/mL). The 45 mg oflidocaine, if injected intrathecally, will produce spinal anesthesia that should berapidly apparent. Some clinicians have suggested use of lower doses of localanesthetic, as unintended injection of 45 mg of intrathecal lidocaine can bedifficult to manage in areas such as labor rooms. The 15 mkg dose of epinephrine,if injected intravascularly, should produce a noticeable increase in heart rate (20%or more) with or without hypertension. Unfortunately, epinephrine as a marker ofintravenous injection is not ideal. False positives can occur (a uterine contractioncausing pain or an increase in heart rate coincident to test dosing) as well as falsenegatives (patients taking beta-blockers). A 25% or more increase in T-waveamplitude on the electrocardiograph (ECG) has been suggested to be a morereliable sign of intravascular injection. Both fentanyl and larger doses of localanesthetic without epinephrine have been advocated as intravenous injection testdoses. Simply aspirating prior to injection is insufficient to avoid inadvertentintravenous injection; most experienced practitioners have encountered false-negative aspirations through both a needle and a catheter. 56
  • Incremental dosing is a very effective method of avoiding seriouscomplications. If aspiration is negative, a fraction of the total intended localanesthetic dose is injected, typically 5 mL. This dose should be large enough formild symptoms of intravascular injection to occur but small enough to avoidseizure or cardiovascular compromise. This is particularly important for laborepidurals that are to be used for cesarean section. If the initial labor epidural boluswas delivered through the needle and then the catheter was inserted, it may beerroneously assumed that the catheter is well positioned because the patient is stillcomfortable from the initial bolus. If the catheter was inserted intravascularly, orhas since migrated intravascularly, systemic toxicity will likely result if the fullanesthetic dose is injected. Catheters can migrate intrathecally or intravascularlyfrom an initially correct epidural position anytime after initial placement. Somecases of "catheter migration" may represent delayed recognition of an improperlypositioned catheter.If a clinician uses an initial test dose, is diligent about aspirating prior to eachinjection, and always uses incremental dosing, significant systemic toxicity orinadvertent intrathecal injections are rare.Factors Affecting Level of BlockFactors affecting the level of epidural anesthesia may not be as predictable as withspinal anesthesia. In adults, 1–2 mL of local anesthetic per segment to be blockedis a generally accepted guideline. For example, to achieve a T4 sensory level froman L4–L5 injection would require about 12–24 mL. For segmental or analgesicblocks, less volume is needed. The dose required to achieve the same level of anesthesia decreases withage. This is probably a result of age-related decreases in the size or compliance ofthe epidural space. Although there is little correlation between body weight andepidural dosage requirements, patient height affects the extent of cephalad spread.Thus, shorter patients may require only 1 mL of local anesthetic per segment to beblocked, whereas taller patients generally require 2 mL per segment. Although lessdramatic than with spinal anesthesia, spread of epidural local anesthetics tends tobe partially affected by gravity. The lateral decubitus, Trendelenburg, and reverseTrendelenburg positions can be used to help achieve blockade in the desireddermatomes. Injection in the sitting position appears to deliver more localanesthetic to the larger L5–S1 and S2 nerve roots; patchy anesthesia or sparing ofthose dermatomes is sometimes encountered with lumbar epidural anesthesia. Additives to the local anesthetic, particularly opioids, tend to have a greatereffect on the quality of epidural anesthesia than on the duration of the block.Epinephrine in concentrations of 0.005 mg/mL prolongs the effect of epidurallidocaine, mepivacaine, and chloroprocaine more than that of bupivacaine,levobupivacaine, etidocaine, and ropivacaine. In addition to prolonging the 57
  • duration and improving the quality of block, epinephrine decreases vascularabsorption and peak systemic blood levels of epidurally administered localanesthetics. Phenylephrine generally is less effective than epinephrine as avasoconstrictor for epidural anesthesia.Epidural Anesthetic Agents The epidural agent is chosen based on the desired clinical effect, whether itis to be used as a primary anesthetic, for supplementation of general anesthesia, orfor analgesia. The anticipated duration of the procedure may call for a short- orlong-acting single shot anesthetic or the insertion of a catheter. Commonly usedshort- to intermediate-acting agents for surgical anesthesia include lidocaine,chloroprocaine, and mepivacaine. Long-acting agents include bupivacaine,levobupivacaine, and ropivacaine. Levobupivacaine, the S-enantiomer ofbupivacaine, is less toxic than bupivicaine but is no longer available in the UnitedStates. Only preservative-free local anesthetic solutions or those specificallylabeled for epidural or caudal use are employed. Following the initial 1–2 mL per segment bolus (in fractionated doses),repeat doses delivered through an epidural catheter are either done on a fixed timeinterval, based on the practitioners experience with the agent, or when the blockdemonstrates some degree of regression. Once some regression in sensory levelhas occurred, one-third to one-half the initial activation dose can generally safelybe reinjected. It should be noted that chloroprocaine, an ester with rapid onset, shortduration, and extremely low toxicity, may interfere with the analgesic effects ofepidural opioids. Previous chloroprocaine formulations with preservatives,specifically bisulfite and ethylenediaminetetraacetic acid (EDTA), proved to beproblematic when inadvertently injected in a large volume intrathecally. Bisulfitepreparations of chloroprocaine were believed to cause neurotoxicity, whereasEDTA formulations were associated with severe back pain (presumably due tolocalized hypocalcemia). Current preparations of chloroprocaine are preservativefree and without these complications. Some experts believe the local anesthetics,when injected in very large doses intrathecal, may have been at least partlyresponsible for neurotoxicity.Bupivacaine, an amide local anesthetic with a slow onset and long duration ofaction, has a high potential for systemic toxicity. Surgical anesthesia is obtainedwith a 0.5% or 0.75% formulation. The 0.75% concentration is not recommendedfor obstetric anesthesia. Its use in the past for cesarean section was associated withseveral reports of cardiac arrest resulting from inadvertent intravenous injection.The difficulty in resuscitation and the resultant high mortality rate result from thehigh protein binding and lipid solubility of bupivacaine, which causes the agent toaccumulate in the cardiac conduction system leading to refractory reentrant 58
  • arrhythmias. Very dilute concentrations of bupivacaine (eg, 0.0625%) arecommonly combined with fentanyl and used for analgesia for labor andpostoperative pain. The S-enantiomer of bupivacaine, levobupivacaine, appears tobe primarily responsible for the local anesthetic action on nerve conduction but notthe systemic toxic effects. Ropivacaine, a mepivacaine analogue introduced andmarketed as a less toxic alternative to bupivacaine, is roughly equal to or slightlyless than bupivacaine in potency, onset, duration, and quality of block. It mayexhibit less motor block at lower concentrations while maintaining a good sensoryblock.Failed Epidural Blocks Unlike spinal anesthesia, in which the end point is usually very clear (freeflowing CSF) and the technique is associated with a very high success rate,epidural anesthesia is critically dependent on detection of a more subjective loss ofresistance (or hanging drop). Also, the more variable anatomy of the epidural spaceand less predictable spread of local anesthetic in it make epidural anesthesiainherently less predictable. Misplaced injections of local anesthetic can occur in a number of situations.In some young adults, the spinal ligaments are soft and either good resistance isnever appreciated or a false loss of resistance is encountered. Similarly, entry intothe paraspinous muscles during an off-center midline approach may cause a falseloss of resistance. Other causes of failed epidural anesthesia (such as intrathecal,subdural, and intravenous injection) are discussed in the section of this chapter oncomplications. Even if an adequate concentration and volume of an anesthetic weredelivered into the epidural space, and sufficient time was allowed for the block totake effect, some epidural blocks are not successful. A unilateral block can occur ifthe medication is delivered through a catheter that has either exited the epiduralspace or coursed laterally. The chance of this occurring increases as the distancethe catheter is threaded into the epidural space increases. When unilateral blockoccurs, the problem may be overcome by withdrawing the catheter 1–2 cm andreinjecting it with the patient turned with the unblocked side down. Segmentalsparing, which may be due to septations within the epidural space, may also becorrected by injecting additional local anesthetic with the unblocked segmentdown. The large size of the L5, S1, and S2 nerve roots may prevent adequatepenetration of local anesthetic and is thought to be responsible for sacral sparing.The latter is particularly a problem for surgery on the lower leg; in such cases,elevating the head of the bed and reinjecting the catheter can sometimes achieve amore intense block of these large nerve roots. Patients may complain of visceralpain despite a seemingly good epidural block. In some cases (eg, traction on theinguinal ligament and spermatic cord), a high thoracic sensory level may alleviatethe pain; in other cases (traction on the peritoneum), intravenous supplementation 59
  • with opioids or other agents may be necessary. Visceral afferent fibers that travelwith the vagus nerve may be responsible.Caudal Anesthesia Caudal epidural anesthesia is one of the most commonly used regionaltechniques in pediatric patients. It may also be used in anorectal surgery in adults.The caudal space is the sacral portion of the epidural space. Caudal anesthesiainvolves needle and/or catheter penetration of the sacrococcygeal ligamentcovering the sacral hiatus that is created by the unfused S4 and S5 laminae. Thehiatus may be felt as a groove or notch above the coccyx and between two bonyprominences, the sacral cornua. Its anatomy is more easily appreciated in infantsand children. The posterior superior iliac spines and the sacral hiatus define anequilateral triangle. Calcification of the sacrococcygeal ligament may make caudalanesthesia difficult or impossible in older adults. Within the sacral canal, the duralsac extends to the first sacral vertebra in adults and to about the third sacralvertebra in infants, making inadvertent intrathecal injection more common ininfants. In children, caudal anesthesia is typically combined with general anesthesiafor intraoperative supplementation and postoperative analgesia. It is commonlyused for procedures below the diaphragm, including urogenital, rectal, inguinal,and lower extremity surgery. Pediatric caudal blocks are most commonlyperformed after the induction of general anesthesia. The patient is placed in thelateral or prone position with one or both hips flexed, and the sacral hiatus ispalpated. After sterile skin preparation, a needle or intravenous catheter (18–23gauge) is advanced at a 45° angle cephalad until a pop is felt as the needle piercesthe sacrococcygeal ligament. The angle of the needle is then flattened andadvanced. Aspiration for blood and CSF is performed, and, if negative, injectioncan proceed. Some clinicians recommend test dosing as with other epiduraltechniques, although many simply rely on incremental dosing with frequentaspiration. Tachycardia (if epinephrine is used) and/or increasing size of the Twaves on ECG may indicate intravascular injection. Clinical data have shown thatthe complication rate for "kiddie caudals" is very low. Complications include totalspinal and intravenous injection causing seizure or cardiac arrest. Intraosseousinjection has also been reported to cause systemic toxicity. A dosage of 0.5–1.0 mL/kg of 0.125–0.25%bupivacaine (or ropivacaine)with or without epinephrine can be used. Opioids may also be added (eg, 50–70mkg/kg of morphine), although they are not recommended for outpatients becauseof the risk of delayed respiratory depression. The analgesic effects of the blockextend for hours into the postoperative period. Pediatric outpatients can safely bedischarged home even with mild residual motor block and without urinating, asmost children will urinate within 8 h. 60
  • Repeated injections can be accomplished via repeating the needle injectionor via a catheter left in place and covered with an occlusive dressing after beingconnected to extension tubing. Higher epidural anesthesia/analgesia can beaccomplished with epidural catheters threaded cephalad into the lumbar or eventhoracic epidural space from the caudal approach in infants and children. Atechnique has been described using a nerve stimulator to determine the level towhich the catheter has been threaded. More commonly fluoroscopy is used.Smaller catheters are technically difficult to pass due to kinking. Cathetersadvanced into the thoracic epidural space have been used to achieve T2–T4 blocksfor ex-premature infants undergoing inguinal hernia repair. This is achieved usingchloroprocaine 1 mL/kg as an initial bolus and incremental doses of 0.3 mL/kguntil the desired level is achieved. For adults undergoing anorectal procedures, caudal anesthesia can providedense sacral sensory blockade with limited cephalad spread. Furthermore, theinjection can be given with the patient in the prone jackknife position, which isused for surgery. A dose of 15–20 mL of 1.5–2.0%lidocaine with or withoutepinephrine is usually effective. Fentanyl 50–100 mkg may also be added. Thistechnique should be avoided in patients with pilonidal cysts because the needlemay pass through the cyst track and can potentially introduce bacteria into thecaudal epidural space. Although no longer commonly used for obstetric analgesia,a caudal block can be useful for the second stage of labor in situations in which theepidural is not reaching the sacral nerves, or when repeated attempts at epiduralblockade have been unsuccessful.Complications of Neuraxial BlocksThe complications of epidural, spinal, or caudal anesthetics range from thebothersome to the crippling and life-threatening. Broadly, the complications can bethought of as those resulting from physiological excessive side effects, placementof the needle (or catheter), and drug toxicity.Table 6.Complications of Neuraxial Anesthesia.Adverse or exaggerated physiological responses Urinary retention High block Total spinal anesthesia Cardiac arrest Anterior spinal artery syndrome Horners syndromeComplications related to needle/catheter placement 61
  • Trauma Backache Dural puncture/leak Postdural puncture headache Diplopia Tinnitus Neural injury Nerve root damage Spinal cord damage Cauda equina syndrome Bleeding Intraspinal/epidural hematoma Misplacement No effect/inadequate anesthesia Subdural block Inadvertent subarachnoid block Inadvertent intravascular injection Catheter shearing/retention Inflammation Arachnoiditis Infection Meningitis Epidural abscessDrug toxicity Systemic local anesthetic toxicity Transient neurological symptoms Cauda equina syndromeHigh Neural Blockade High levels of neural blockade can occur readily with either spinal orepidural anesthesia. Administration of an excessive dose, failure to reduce standarddoses in selected patients (eg, the elderly, pregnant, obese, or very short), orunusual sensitivity or spread of local anesthetic may be responsible. Patients oftencomplain of dyspnea and have numbness or weakness in the upper extremities.Nausea with or without vomiting often precedes hypotension. Once it is recognized 62
  • patients should be reassured, oxygen supplementation may need to be increased,and bradycardia and hypotension should be corrected. Spinal anesthesia ascending into the cervical levels causes severehypotension, bradycardia, and respiratory insufficiency. Unconsciousness, apnea,and hypotension resulting from high levels of spinal anesthesia are referred to as a"high spinal" or "total spinal." It can also occur following attemptedepidural/caudal anesthesia if there is inadvertent intrathecal injection (see below).Severe sustained hypotension with lower sensory blocks can also lead to apneathrough medullary hypoperfusion. Anterior spinal artery syndrome has beenreported following neuraxial anesthesia, presumably due to prolonged severehypotension together with an increase in intraspinal pressure. Treatment of an excessively high neuraxial block involves maintaining anadequate airway and ventilation and supporting the circulation. When respiratoryinsufficiency becomes evident, in addition to supplemental oxygen, assistedventilation, intubation, and mechanical ventilation may be necessary. Hypotensioncan be treated with rapid administration of intravenous fluids, a head-downposition, and aggressive use of vasopressors. Epinephrine should be used early ifephedrine or phenylephrine is insufficient. Dopamine infusion may be helpful.Bradycardia should be treated early with atropine. Ephedrine or epinephrine canalso increase heart rate. If respiratory and hemodynamic control can be readilyachieved and maintained after high or total spinal anesthesia, surgery may proceed.Apnea is often transient, and unconsciousness may leave the patient amnesticwithout adverse recall.Cardiac Arrest during Spinal Anesthesia Examination of data from the ASA Closed Claim Project identified severalcases of cardiac arrest during spinal anesthesia. Because many of the reportedcases predated the routine use of pulse oximetry, many physicians believedoversedation and unrecognized hypoventilation and hypoxia were the causes.However, large prospective studies continue to report a relatively high incidence ofcardiac arrest in patients having received a spinal anesthetic, perhaps as high as1:1500. Many of the arrests were preceded by bradycardia and occurred in younghealthy patients. A recent examination of this problem identified vagal responsesand decreased preload as key factors and suggests that patients with high baselinevagal tone are at risk. Prophylactic volume expansion is recommended, as is earlyand aggressive vagolytic (atropine) treatment of bradycardia followed byephedrine and epinephrine if necessary.Urinary Retention Local anesthetic block of S2–S4 root fibers decreases urinary bladder toneand inhibits the voiding reflex. Epidural opioids can also interfere with normalvoiding. These effects are most pronounced in male patients. Urinary bladder 63
  • catheterization should be used for all but the shortest acting blocks. If a catheter isnot present postoperatively, close observation for voiding is necessary. Persistentbladder dysfunction can also be a manifestation of serious neural injury asdiscussed below.Inadequate Anesthesia or Analgesia As with other regional anesthesia techniques, neuraxial blocks are "blind"techniques that rely on indirect signs of correct needle placement. It is notsurprising that they are associated with a small but significant failure rate that isusually inversely proportional to the clinicians experience. The end point forspinal anesthesia (CSF flow) is much more obvious than loss of resistance. Failuremay still occur even when CSF is obtained during spinal anesthesia. Movement ofthe needle during injection, incomplete entry of the needle opening into thesubarachnoid space, subdural injection, or loss of potency of the local anestheticsolution may be responsible. Commercially prepared tetracaine solutions may losepotency when stored for prolonged periods at high temperatures.Intravascular Injection Inadvertent intravascular injection of the local anesthetic for epidural andcaudal anesthesia can produce very high serum levels. Extremely high levels oflocal anesthetics affect the central nervous system (seizure and unconsciousness)and the cardiovascular system (hypotension, arrhythmia, and cardiovascularcollapse). Because the dosage of medication for spinal anesthesia is relativelysmall, this complication is seen primarily with epidural and caudal blocks. Localanesthetic may be injected directly into a vessel through a needle or later through acatheter that has entered a blood vessel (vein). The incidence of intravascularinjection can be minimized by carefully aspirating the needle (or catheter) beforeevery injection, using a test dose, always injecting local anesthetic in incrementaldoses, and close observation for early signs of intravascular injection (tinnitus,lingual sensations). The local anesthetics vary in their toxicity. Chloroprocaine isthe least toxic because it is broken down very rapidly; lidocaine, mepivacaine,levobupivacaine, and ropivacaine are intermediate in toxicity; and bupivacaine ismost toxic.Total Spinal Anesthesia Total spinal anesthesia can occur following attempted epidural/caudalanesthesia if there is inadvertent intrathecal injection. Onset is usually rapidbecause the amount of anesthetic required for epidural and caudal anesthesia is 5–10 times that required for spinal anesthesia. Careful aspiration, use of a test dose,and incremental injection techniques during epidural and caudal anesthesia canhelp avoid this complication. In the event of an inadvertent large subarachnoidinjection, particularly of lidocaine, consideration should be given to "subarachnoid 64
  • lavage" by repeated withdrawal of 5 mL of CSF and replacement withpreservative-free normal saline.Subdural Injection As with inadvertent intravascular injection and because of the larger amountof local anesthetic administered, inadvertent subdural injection of local anestheticduring attempted epidural anesthesia is much more serious than during attemptedspinal anesthesia. A subdural injection of epidural doses of local anestheticproduces a clinical presentation similar to that of high spinal anesthesia, with theexception that the onset may be delayed for 15–30 min. The spinal subdural spaceis a potential space between the dura and the arachnoid containing a small amountof serous fluid. Unlike the epidural space, the subdural space extendsintracranially, so that anesthetic injected into the spinal subdural space can ascendto higher levels than epidural medications. As with high spinal anesthesia,treatment is supportive and may require intubation, mechanical ventilation, andcardiovascular support. The effects generally last from one to several hours.Backache As a needle passes through skin, subcutaneous tissues, muscle, andligaments it causes varying degrees of tissue trauma. A localized inflammatoryresponse with or without reflex muscle spasm may be responsible for postoperativebackache. It should be noted that up to 25–30% of patients receiving only generalanesthesia also complain of backache postoperatively and a significant percentageof the general population has chronic back pain. Postoperative back soreness orache is usually mild and self-limited, although it may last for a number of weeks. Iftreatment is sought, acetaminophen, nonsteroidal antiinflammatory medication,and warm or cold compresses should suffice. Although backache is usually benign,it may be an important clinical sign of much more serious complications, such asepidural hematoma and abscess (see below).Postdural Puncture Headache Any breach of the dura may result in a postdural puncture headache (PDPH).This may follow a diagnostic lumbar puncture, a myelogram, a spinal anesthetic,or an epidural "wet tap" in which the epidural needle passed through the epiduralspace and entered the subarachnoid space. Similarly, an epidural catheter mightpuncture the dura at any time and result in PDPH. An epidural wet tap is usuallyimmediately recognized as CSF dripping from the needle or aspirated from anepidural catheter. However, PDPH can follow use of a seemingly uncomplicatedepidural anesthetic and may be the result of just the tip of the needle scratchingthrough the dura. Typically, PDPH is bilateral, frontal or retroorbital, and occipitaland extends into the neck. It may be throbbing or constant and associated withphotophobia and nausea. The hallmark of PDPH is its association with bodyposition. The pain is aggravated by sitting or standing and relieved or decreased by 65
  • lying down flat. The onset of headache is usually 12–72 h following the procedure;however, it may be seen almost immediately. Untreated, the pain may last weeks,and in rare instances has required surgical repair.Neurological Injury Perhaps no complication is more perplexing or distressing than persistentneurological deficits following an apparently routine neuraxial block in which anepidural hematoma or abscess is ruled out. The nerve roots or spinal cord may beinjured. The latter may be avoided if the neuraxial blockade is performed below L1in adults and L3 in children.Spinal or Epidural Hematoma Needle or catheter trauma to epidural veins often causes minor bleeding inthe spinal canal although this is usually benign and self-limiting. A clinicallysignificant spinal hematoma can occur following spinal or epidural anesthesia,particularly in the presence of abnormal coagulation or bleeding disorder. Theincidence of such hematomas has been estimated to be about 1:150,000 forepidural blocks and 1:220,000 for spinal anesthetics. The vast majority of reportedcases have occurred in patients with abnormal coagulation either secondary todisease or pharmacological therapies. Some have emphasized the association witha technically difficult or bloody block. It should be noted that many hematomashave occurred immediately after the removal of an epidural catheter. Thus,insertion and removal of an epidural catheter are risk factors. Neuraxial anesthesiais best avoided in patients with coagulopathy, significant thrombocytopenia,platelet dysfunction, or those who have received fibrinolytic/thrombolytic therapy.Meningitis and ArachnoiditisInfection of the subarachnoid space can follow neuraxial blocks as the result ofcontamination of the equipment or injected solutions, or as a result of organismstracked in from the skin. Indwelling catheters may become colonized withorganisms that then track deep, causing infection. Fortunately, these are rareoccurrences.Epidural AbscessSpinal epidural abscess (EA) is a rare but potentially devastating complication ofneuraxial anesthesia. The reported incidence varies widely from 1:6500 to1:500,000 epidurals. Most cases in the literature are isolated case reports. Severalprospective studies, including over 140,000 blocks, have failed to report one EA.EA can occur in patients who did not receive regional anesthesia; risk factors insuch cases include back trauma, injecting drug use, and neurosurgical procedures.Most reported anesthesia-related cases involve epidural catheters. In one reported 66
  • series, there was a mean of 5 days from catheter insertion to the development ofsymptoms, although presentation can be delayed for weeks.Systemic ToxicityAbsorption of excessive amounts of local anesthetics can produce very high toxicserum levels (see Intravascular Injection). Excessive absorption from epidural orcaudal blocks is rare if the maximum safe dosage of local anesthetic is notexceeded.Transient Neurological SymptomsFirst described in 1993, transient neurological symptoms (TNS), also referred to astransient radicular irritation, are characterized by back pain radiating to the legswithout sensory or motor deficits, occurring after the resolution of spinal block andresolving spontaneously within several days. It is most commonly associated withhyperbaric lidocaine (incidence up to 11.9%), but has also been reported withtetracaine (1.6%), bupivacaine (1.3%), mepivacaine, prilocaine, procaine, andsubarachnoid ropivacaine. There are also case reports of TNS following epiduralanesthesia. The incidence of this syndrome is highest among outpatients (earlyambulation) after surgery in the lithotomy position and lowest among inpatients inpositions other than lithotomy. There is a paucity of reports of TNS followingspinal lidocaine for cesarean section. The pathogenesis of TNS is believed torepresent concentration-dependent neurotoxicity of local anesthetics.Lidocaine NeurotoxicityCauda equina syndrome (CES) was associated with the use of continuous spinalcatheters (prior to their withdrawal) and 5%lidocaine. CES is characterized bybowel and bladder dysfunction together with evidence of multiple nerve rootinjury. There is lower motor neuron type injury with paresis of the legs. Sensorydeficits may be patchy, typically occurring in a peripheral nerve pattern. Pain maybe similar to that of nerve root compromise. Animal studies suggest that pooling or"maldistribution" of hyperbaric solutions of lidocaine can lead to neurotoxicity ofthe nerve roots of the cauda equina. However, there are reports of CES occurringafter uneventful single-shot lidocaine spinals. CES has also been reportedfollowing epidural anesthesia. Animal data suggest that the extent of histologicalevidence of neurotoxicity following repeat intrathecal injection is lidocaine=tetracaine > bupivacaine > ropivacaine. Peripheral Nerve Blocks Advancement in needle delivery devices, safer local anesthetics, anddevelopment of indwelling catheters for postoperative perineural infusion have ledto a transformation in regional anesthesia; the focus has shifted from providing 67
  • intraoperative regional anesthesia to providing intraoperative anesthesia andpostoperative regional analgesia. Fundamental to the success of regional anesthesia is the correct positioningof the needle tip in the perineural sheath, prior to injection of local anesthetic. Inthe past, this was accomplished either by eliciting a paresthesia with the needle tipor, in the case of an axillary nerve block, by using the transarterial approach. Eitherout of fear of persistent paresthesias or arterial injury, or because of advancementof the specialty and development of newer technologies, anesthesiologists todaycommonly employ a nerve stimulator to help define needle tip location. The use ofnerve stimulators is not risk free, as morbidities have been reported with thesedevices, leaving providers in search of the optimal tool. Other technologies that arebeing studied are ultrasound, Doppler, and sensory nerve stimulation. Currently thebest way to establish needle tip location is based on a motor response to nervestimulation; a motor response at approximately 0.5 mA indicates that the needle isin the appropriate position and local anesthetic can be injected. The choice of anesthesia is determined by patient comorbidities and byobtaining an informed consent that includes understanding all available optionsand their risks and benefits. Important considerations in discussing anestheticchoices include the suitability of the technique for the type of surgery, thesurgeons preference, the experience of the anesthesiologist, and the physiologicaland mental state of the patient. The use of peripheral nerve blocks is increasing; they are being used as theprimary and sole anesthetic technique to facilitate painless surgery, supplementedwith monitored anesthesia care (moderate sedation) or with a "light" generalanesthetic, with the airway protected with a laryngeal mask airway (LMA), orinstituted preoperatively but primarily for postoperative analgesia. Patient satisfaction is improved, there is less cognitive impairment withregional anesthesia compared to general anesthesia (particularly in elderlypatients), and there is new evidence that peripheral nerve blocks (regionalanesthesia) are less immunosuppressive than general anesthesia. Althoughperipheral nerve blocks are not risk free, they offer an excellent alternative forpatients in whom postoperative nausea and vomiting are a problem, who are at riskfor development of malignant hyperthermia, or who are hemodynamicallycompromised or too ill to tolerate general anesthesia. The disadvantages of peripheral nerve blocks, although uncommon, includethe toxicity of local anesthetics, chronic paresthesias and nerve damage, and,depending on the nerves being anesthetized (interscalene block, supraclavicularblock, etc), respiratory failure due to phrenic nerve blockade, and seizures due tointraarterial injections. 68
  • When discussing the use of peripheral nerve blocks to facilitate a regionalanesthetic compared to a general anesthetic, the risks and benefits of bothtechniques must be discussed with the patient so that the patient may make aninformed choice.ContraindicationsMost contraindications to peripheral nerve blockade using local anesthetics arerelative, in that many patients are not good candidates for either regional or generalanesthesia and, therefore, the physician must decide which is safest and advise thepatient accordingly:Uncooperative patient, Bleeding diathesis, Infection, Localanesthetic toxicity, Peripheral neuropathy. Regional anesthetics require relatively cooperative patients and, therefore,pediatric patients, combative patients, and demented patients can present achallenge to the anesthesiologist. Many peripheral nerve blocks in pediatricpatients are performed after general anesthesia is induced. In adult patients,however, there is some concern about performing peripheral nerve blocks in ananesthetized patient who cannot respond to an intraneuronal injection, placing thepatient at increased risk for an adverse event. Furthermore, in demented orcombative patients, even if regional anesthesia can be induced, general anesthesiamay also be required to ensure that the patient remains still for the surgicalprocedure. If general anesthesia is induced, it could be argued that if there is noreduction in postoperative pain as a result of using a peripheral nerve block, thenadditional risks should not be assumed by also using a regional anesthetictechnique. Bleeding diastasis induced with an anticoagulant or resulting from a geneticdefect (hemophilia) or an acquired defect (disseminated intravascular coagulation)increases the risks associated with regional anesthesia. A hematoma within aperipheral nerve sheath increases the risk of ischemic nerve damage and, in acircumferential extremity (ankle) field block, may lead to limb or digit ischemia. Bloodstream infection is also a relative contraindication to regionalanesthesia. Most anesthesiologists will perform a single-shot peripheral nerveblock if indicated; however, if the patient is truly bacteremic, placement of acatheter for delivery of postoperative anesthesia/analgesia should be given carefulconsideration and should possibly be avoided, as these catheters serve as a nidusfor infection. All patients are at risk of local anesthetic toxicity if local anestheticsare injected into the intravascular space. Some blocks, however, require such alarge volume of local anesthetic to be effective that if multiple nerves are to beblocked, the risk of local anesthetic toxicity is simply too great. Examples includebilateral axillary blocks for bilateral hand procedures and multiple thoracicintercostal nerve blocks for flail chest. 69
  • Finally, patients with a preexisting peripheral neuropathy may be atincreased risk of permanent nerve damage, or if a defect is in a contralateral nerve,blockade of an ipsilateral nerve may be of concern, eg, an interscalene block in apatient with contralateral phrenic nerve paralysis.Choice of Anesthetic Local anesthetics are discussed elsewhere, but when performing a block, theanesthesiologist must weigh the toxicity of the agent to be used and thecharacteristics of individual local anesthetics such as time to onset and duration ofaction, degree of sensory versus motor block, and the cardiac toxicity of largevolumes of local anesthetics delivered into the perineural sheath.Placement of the Block Because performing peripheral nerve blocks is time consuming and becauseoperating room turnover time is critical, the procedure is often performed in theholding area or in a specially designed procedure room, ie, block room. Althoughregional anesthesia is relatively safe, patients undergoing a regional anestheticmust have adequate monitoring, meeting American Society of Anesthesiologists(ASA) guidelines, and must be in an environment that allows delivery ofsupplemental oxygen (nasal cannula or face mask) with necessary resuscitationequipment available. The greatest immediate risk of nerve blocks is systemic toxicity frominadvertent intravascular injection. Delayed toxicity can follow the initial injectionwhen rapid or excessive amounts of local anesthetics are absorbed systemically.Peak blood levels occur at various times after the block. A high index of suspicionis required to detect early signs of systemic toxicity. In addition to aspiration of thesyringe, many clinicians always use a 3 mL test dose of local anesthetic with1:200,000 (5 mkg/mL) or 1:400,000 (2.5 mkg/mL) epinephrine to detectintravascular placement of a needle or catheter. An abrupt increase in heart rategreater than 20% over baseline is generally indicative of an intravascular injection.Incremental dosing (5 mL injections at a time) with frequent intermittent aspirationhelps minimize the risk of intravascular injection. The "immobile needle"technique is often used to prevent needle movement during injection: intravenoustubing is attached between the needle and syringe such that the needle can beeasily stabilized in the correct position and is not readily displaced by injection. Anassistant usually aspirates with the syringe and injects when asked to do so,allowing the operator to use one hand for palpation and the other to control theneedle. Good surgical anesthesia is obtained only when local anesthetic is injected inclose proximity to the nerve or nerves that are to be blocked. Common localanesthetic solutions that are used for surgical anesthesia include lidocaine 1.5–2%,mepivacaine 2%, bupivacaine 0.5%, levobupivacaine 0.5%, or ropivacaine 0.5%. 70
  • More dilute solutions are used for postoperative analgesia. Injection techniquesinclude use of a field block, reliance on fixed anatomic relationships, elicitation ofparesthesias, and use of a nerve stimulator.Premedication Premedication with small doses of a benzodiazepine and/or opioid helpsreduce anxiety and raise the pain threshold. The degree of sedation variesaccording to practitioner, but in general only light sedation is desirable when theelicitation of paresthesias is to be used for nerve localization. Use of a nervestimulator allows deeper sedation. Supplemental oxygen should generally beadministered to all patients via nasal cannula or face mask to reduce the incidenceof hypoxemia following sedation.Field Block A single injection or multiple injections of a relatively large volume of localanesthetic in the general location of cutaneous nerves produces a field block. Thesuperficial cervical plexus block is an example of a field block. Field blocks arealso commonly used to supplement axillary brachial plexus and ankle blocks.Surgeons often use field blocks for minor, superficial operations. The techniquemay also be used to supplement patchy peripheral nerve blocks or when the levelof a neuraxial block begins to recede. When a large volume of local anesthetic is tobe injected, use of a dilute concentration and addition of epinephrine (1:200,000 [5mkg/mL] or 1:400,000 [2.5 mkg/mL]) help reduce systemic absorption and thelikelihood of systemic toxicity.Fixed Anatomic Relationships Some nerve block techniques rely on a constant anatomic relationship tolocate correct needle position. High in the axilla, the brachial plexus is always inclose association with the axillary artery in the axillary sheath. As described later,in the transarterial technique of a brachial plexus block, the artery is located andlocal anesthetic is injected just above and below it. Similarly, themusculocutaneous nerve can be blocked as it travels in the body of thecoracobrachialis muscle; injection of coracobrachialis muscle can therefore beused to supplement axillary or interscalene brachial plexus anesthesia. Intercostalnerves travel in a neurovascular bundle on the undersurface of the inferior borderof each rib. The nerve maintains an inferior position in the bundle; from superior toinferior the order is vein, artery, and nerve (VAN). Each intercostal nerve cantherefore be blocked by an injection at the inferior border of the corresponding rib.Similarly, the femoral nerve has a constant position in a neurovascular bundle as ittravels in the femoral canal. The femoral nerve is always lateral to the artery; fromlateral to medial the order is nerve, artery, vein, empty space, and lymphatics.Elicitation of Paresthesias 71
  • When a needle makes direct contact with a sensory nerve, a paresthesia iselicited in its area of sensory distribution. With this technique, it is important toascertain that the needle is making contact with the nerve rather than penetrating it,and that the injection is in proximity to the nerve (perineural) rather than within itssubstance (intraneural). The high pressures generated by a direct intraneuralinjection can cause hydrostatic (ischemic) injury to nerve fibers. A perineuralinjection may produce a brief accentuation of the paresthesia, whereas anintraneural injection produces an intense, searing pain that serves as a warning toimmediately terminate the injection and reposition the needle. Pain intensity andduration help differentiate between accentuation and intraneural injection. Use ofblunt bevel (B-bevel) needles appears to reduce the small incidence of nervetrauma associated with peripheral nerve blocks. B-bevel needles have a less blunttip and smaller cutting edge than regular needles. This design helps push nervesaside upon contact, instead of piercing them. Many clinicians also believe that theblunt tip provides better feedback, allowing better appreciation of tissue planes andpenetration of fascial compartments.Nerve Stimulation Low-level electrical current applied from the tip of a needle can elicitspecific muscle contractions when the needle is in close proximity to a motornerve. One lead of a low-output nerve stimulator is attached to a needle and theother lead is grounded elsewhere on the patient. Lower current is required whenthe negative lead is attached to the exploring needle. The special needles that areused are insulated and permit current flow only at the tip for precise localization ofnerves, whereas the nerve stimulators used deliver a linear, constant current outputof 0.1–6.0 mA. Muscle contractions occur and increase in intensity as the needleapproaches the nerve and diminish when the needle moves away. Moreover, theevoked contractions require much less current as the needle approaches the nerve.Optimal positioning produces evoked contractions with 0.5 mA or less, butsuccessful blocks can often be obtained with needle positions that producecontractions with as much as 1 mA. Characteristically, the evoked response rapidlydiminishes (fades) after injection of 1–2 mL of local anesthetic. Transientaugmentation may be observed before extinction of the motor response because theionic anesthetic solutions transiently facilitate conduction of the current. Key Concepts • An anesthetic plan should be formulated that will optimally accommodate the patients baseline physiological state, including any medical conditions, previous operations, the planned procedure, drug sensitivities, previous anesthetic experiences, and psychological makeup. • Inadequate preoperative planning and errors in patient preparation are the most common causes of anesthetic complications. 72
  • • Anesthesia and elective operations should not proceed until the patient is in optimal medical condition.• To be valuable, performing a preoperative test implies that an increased perioperative risk exists when the results are abnormal and a reduced risk exists when the abnormality is corrected.• The intraoperative anesthesia record serves many purposes. It functions as a useful intraoperative monitor, a reference for future anesthetics for that patient, and a tool for quality assurance.• The study of the relationship between a drugs dose, tissue concentration, and elapsed time is called pharmacokinetics (how a body affects a drug). The study of drug action, including toxic responses, is called pharmacodynamics (how a drug affects a body).• The greater the uptake of anesthetic agent, the greater the difference between inspired and alveolar concentrations, and the slower the rate of induction.• Three factors affect anesthetic uptake: solubility in the blood, alveolar blood flow, and the difference in partial pressure between alveolar gas and venous blood.• General anesthesia is an altered physiological state characterized by reversible loss of consciousness, analgesia of the entire body, amnesia, and some degree of muscle relaxation.• Nonpungency and rapid increases in alveolar anesthetic concentration make sevoflurane an excellent choice for smooth and rapid inhalation inductions in pediatric and adult patients• Non–protein-bound drugs freely cross from plasma into the glomerular filtrate. The nonionized fraction of drug is reabsorbed in the renal tubules, whereas the ionized portion is excreted in urine.• The plasma concentration of a drug with long half-lives may still fall rapidly if distribution accounts for the vast majority of the decline and elimination is a relatively insignificant contributor. Therefore, the rate of clinical recovery from a drug cannot be predicted by its half-lives alone.• Although apnea may be less common after benzodiazepine induction than after barbiturate induction, even small intravenous doses of diazepam and midazolam have resulted in respiratory arrest. Ventilation must be monitored in all patients receiving intravenous benzodiazepines, and resuscitation equipment must be immediately available.• The accumulation of morphine metabolites (morphine 3-glucuronide and morphine 6-glucuronide) in patients with renal failure has been associated with narcosis and ventilatory depression lasting several days. 73
  • • Opioids (particularly fentanyl, sufentanil, and alfentanil) can induce chest wall rigidity severe enough to prevent adequate ventilation.• The stress response to surgical stimulation is measured in terms of the secretion of specific hormones, including catecholamines, antidiuretic hormone, and cortisol. Opioids block the release of these hormones more completely than volatile anesthetics.• In sharp contrast to other anesthetic agents, ketamine increases arterial blood pressure, heart rate, and cardiac output. These indirect cardiovascular effects are due to central stimulation of the sympathetic nervous system and inhibition of the reuptake of norepinephrine.• Spinal, epidural, and caudal blocks are also known as neuraxial anesthesia. Each of these blocks can be performed as a single injection or with a catheter to allow intermittent boluses or continuous infusions.• Performing a lumbar (subarachnoid) puncture below L1 in an adult (L3 in a child) avoids potential needle trauma to the cord.• The principal site of action for neuraxial blockade is the nerve root.• Neuraxial blocks typically produce variable decreases in blood pressure that may be accompanied by a decrease in heart rate and cardiac contractility.• Deleterious cardiovascular effects should be anticipated and steps undertaken to minimize the degree of hypotension. Volume loading with 10–20 mL/kg of intravenous fluid for a healthy patient will partially compensate for the venous pooling.• Excessive or symptomatic bradycardia should be treated with atropine, and hypotension should be treated with vasopressors.• Major contraindications to neuraxial anesthesia are patient refusal, bleeding diathesis, severe hypovolemia, elevated intracranial pressure, infection at the site of injection, and severe stenotic valvular heart disease or ventricular outflow obstruction.• For epidural anesthesia, a sudden loss of resistance is encountered as the needle penetrates the ligamentum flavum and enters the epidural space. For spinal anesthesia, the needle is advanced further through the epidural space and penetrates the dura–subarachnoid membranes as signaled by free flowing cerebrospinal fluid.• Epidural anesthesia is a neuraxial technique offering a range of applications wider than the typical all-or-nothing spinal anesthetic. An epidural block can be performed at the lumbar, thoracic, or cervical level.• Epidural techniques are widely used for operative anesthesia, obstetric analgesia, postoperative pain control, and chronic pain management. 74
  • • The quantity (volume and concentration) of local anesthetic needed for epidural anesthesia is very large compared with spinal anesthesia. Significant toxicity can occur if this amount is injected intrathecally or intravascularly. Safeguards against this include the epidural test dose and incremental dosing.• Caudal epidural anesthesia is one of the most commonly used regional techniques in pediatric patients.• The greatest immediate risk of nerve blocks is systemic toxicity from inadvertent intravascular injection. Delayed toxicity can follow the initial injection when rapid or excessive amounts of local anesthetics are absorbed systemically.• Good surgical anesthesia is obtained only when local anesthetic is injected in close proximity to the nerve or nerves that are to be blocked.• A perineural injection may produce a brief accentuation of the paresthesia, whereas an intraneural injection produces an intense, searing pain that serves as a warning to immediately terminate the injection and reposition the needle. 75