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Home , Anesthetic, Inhalational anesthetic

13 The Effects of Agents on Cardiac Function

MICHAEL K. LOUSHIN, MD

CONTENTS

INTRODUCTION INDUCTION SEQUENCE INHALATIONALANESTHETICS INTRAVENOUS PHYSIOLOGIC EFFECTS OF ACUPUNCTURE ANESTHESIA AND TEMPERATURE REGULATION MYOCARDIAL PRECONDITIONING WITH INHALATIONAL AND INTRAVENOUS ANESTHETICS HEART TRANSPLANT SUMMARY COMPANION CD MATERIAL REFERENCES

1. INTRODUCTION 2. ANESTHESIA INDUCTION SEQUENCE Today, anesthesia is considered necessary for many types of A typical general anesthesia induction sequence for an adult surgeries and procedures. In general, anesthesia may provide is as follows: after establishing intravenous access and place- analgesia, amnesia, hypnosis, and muscle relaxation. The depth ment of standard American Society of Anesthesiologists (1) of administered anesthesia can vary from minimal to monitors, a patient is preoxygenated with 100% oxygen. An general anesthesia (Table 1). General anesthesia typically induction dose of intravenous such as , causes significant alterations in hemodynamics, especially dur- an , and a are administered (seeJPEG 1, ing induction of anesthesia. Importantly, both inhalational and on the Companion CD and description at end of chapter). After intravenous anesthetics can affect cardiovascular performance; the patient is rendered unconscious and anesthetized, direct this includes effects on cardiac output, heart rate, systemic is performed, and the trachea intubated with an vascular resistance, cardiac conduction system, myocardial endotracheal tube. After confirmation of endotracheal intuba- contractility, coronary flow, or blood . Yet, the tion, the patient is placed on an anesthesia ventilator and next choice of inhalational and intravenous anesthetics is typically ventilated with a combination of anesthetic , air, and associated with the patient's underlying cardiovascular status, oxygen (see JPEG 2, on the Companion CD and description at such as the presence of and hypovolemia. The end of chapter). Note, if a total intravenous anesthetic tech- primary goal of this chapter is to make commonly employed nique (such as propofol and opioid infusion) is chosen, anes- methodologies and anesthetics more familiar to the reader, with thetic gases are not administered. particular attention to the potential influences on the cardiovas- The cardiovascular effects of most anesthetics cular system. typically become evident during and immediately following induction. Maintaining cardiovascular stability requires care- From: Handbook c~f Cardiac Anatomy, Physiology, and Devices Edited by: P. A. laizzo © Humana Press Inc., Totowa, NJ ful titration of medications, knowledge of clinical and basic

171 172 PART II1: PHYSIOLOGY AND ASSESSMENT/ LOUSHIN

Table 1 Continuum of Depth of Sedation Definition of General Anesthesia and Levels of Sedation/Analgesia Moderate Minimal sedation sedation~analgesia Deep General (anxiolysis) ("conscious sedation") sedation~analgesia anesthesia Responsiveness Normal response to Purposeful response to Purposeful response following Unarousable even with verbal stimulation verbal or tactile stimulation repeated or painful stimulation painful stimulus Airway Unaffected No intervention required Intervention may be required Intervention often required Spontaneous ventilation Unaffected Adequate May be inadequate Frequently inadequate Cardiovascular function Unaffected Usually maintained Usually maintained May be impaired Excerpted from ASA Standards, Guidelines and Statements, 2003, of the American Society of Anesthesiologists. A copy of the full text can be obtained from ASA, 520 N. Northwest Highway, Park Ridgewood, IL 60068-2573. Table 2 F CI Minimal Alveolar Concentration (MAC) NmN I I of Inhalational Anesthetics F C -- C H MAC % Vapor ] ] Agent (% of l atmosphere) (at 20°C) I I F Br 6.0 680 0.75 243 Halothane 1.2 240 2.0 160 F H F Nitrous oxide 105 I I I 70 H C--O--C C--F I I I F CI F nitrous oxide is frequently utilized. After placement of Ameri- can Society of Anesthesiologists monitors, a high concen- Isoflurane tration of halothane or sevoflurane along with oxygen is administered via a face mask. After the patient becomes F H F unconscious, a peripheral intravenous catheter is placed, and I t I a similar adult general anesthesia and airway management H--C OmC CmF sequence follows. I Direct laryngoscopy and endotracheal intubation can often I I stimulate the upper and lower airways, which in turn may cause F F F significant changes in blood pressures and heart rate if airway Desflurane responses are not blunted. Commonly, titration of anesthetics and administration is used to blunt these airway and F I associated sympathetic responses. F FmC--F 3. INHALATIONAL ANESTHETICS I I Commonly used inhalational anesthetics include nitrous 0 C H H--C oxide, isoflurane, desflurane, halothane, and sevoflurane I I (Fig. 1). Each of these inhalational anesthetics has a specific H F C--F minimum alveolar concentration (MAC) at which general I anesthesia is considered induced (Table 2). MAC is defined as Sevofiurane F the minimum alveolar concentration of an inhaled anesthetic required to prevent movement in 50% of patients in response Fig. 1. Chemical structure of commonly administered inhalational to a surgical incision. It is important to note that infants have anesthetics. a higher MAC than adults, and pregnant women and elderly patients have lower MAC requirements. MAC is additive, that is, the 0.5 MAC of nitrous oxide and science in physiology and , and diligent monitor- the 0.5 MAC of isoflurane result in 1 MAC total anesthesia. ing of vital signs (JPEG 3). More specifically, the brain anesthetic is Typically, induction of general anesthesia in children by dependent on factors such as inspired (F~) and alveolar (FA) placement of an intravenous catheter for preinduction may be concentration of anesthetic . The brain (F~) concentration traumatic to the child or difficult because of noncooperation. of anesthetic is dependent on FA and F~: Instead, initial mask induction with halothane, sevoflurane, or Fl <"-" FA ~ FB CHAPTER 13 / ANESTHESIAAND CARDIOVASCULAREFFECTS 173

Table 3 Cardiovascular Effects of Inhalational Anesthetics Heart Blood Systemic Cardiac Sensitize Coronary rate pressure vascular resistance output to epinephrine dilation Desflurane + - - - 0/- 0/+ + Halothane 0 - - 0/- - +++ + Isoflurane + ..... 0/+ ++ Sevoflurane 0 - - - 0/- 0/+ 0 Nitrous oxide + 0 0 0 0 0 0, no change; +, increased; ++, more increased; +++, most increased; -, decreased; --~ more decreased; ---, most decreased.

Anesthetic uptake is determined by its blood solubility, car- Volatile anesthetics may also cause specific cardiac dys- diac output, and the difference between alveolar and venous rhythmias. Specifically, volatile anesthetics have been reported partial pressure (2). The greater the uptake of anesthetic gas, the both to slow the rate of sinoatrial node discharge and to increase slower is the rate of induction. Inhalational anesthetics with ventricular and His bundle conduction times (11), which may lower blood:gas solubility (i.e., desflurane and sevoflurane) increase the development of nodal rhythms. Further, volatile will cause faster induction and emergence from general anes- anesthetics may increase ventricular automaticity by altering thesia. potassium and calcium ion channels (11). It has been reported that halothane increases the incidence of 3.1. Blood Pressure ventricular dysrhythmias, especially when coadministered with and Systemic Vascular Resistance epinephrine; in contrast, the coadministration of epinephrine All volatile anesthetics (e.g., isoflurane, desflurane, sevo- with isoflurane, desflurane, or sevoflurane has minimal effects flurane, and halothane) cause dose-dependent effects on car- on increasing the incidence of ventricular dysrhythmias (12- diovascular function. For example, these agents cause a dose- 14). Furthermore, halothane may blunt the reflex increases in dependent decrease in mean arterial blood pressure (3-6). The heart rates that typically accompany decreases in blood pres- relative decrease in mean arterial blood pressure is considered sure; it may also slow conduction from the sinoatrial node, to be caused by decreases in systemic vascular resistance, resulting in junctional ventricular rhythms. myocardial contractility, sympathetic output, or a combination Sevoflurane and desflurane are also known to blunt sympa- of these. In particular, isoflurane, desflurane, and sevoflurane thetic baroreflex sensitivity partially. Importantly, isoflurane cause greater decreases in systemic vascular resistance com- is well known to cause significant decreases in systemic vas- pared to halothane (Table 3). Further, increasing doses of hal- cular resistances and thus in blood pressure. Yet, the baro- othane result in small changes in system vascular resistance (7), receptor response remains partially intact, and cardiac output and decreases in mean arterial pressure. Yet, halothane admin- is maintained relatively stable with isoflurane via associated istration is associated with decreases in cardiac output. increases in heart rate. In general, volatile anesthetics decrease systemic vascular resistance by causing peripheral , thus increasing 3.3. Coronary Blood Flow blood flow to cutaneous and tissues (3). It should In general, volatile anesthetics cause a dose-dependent coro- be noted that nitrous oxide causes a minimal alteration of sys- nary vasodilation, with isoflurane having a greater effect than temic vascular resistance when administered alone. halothane (15,16). Increasing the concentration of isoflurane 3.2. Cardiac Conduction System and Heart Rate increases coronary blood flow and this has the potential to cause "coronary steal" syndrome (17,18). Coronary steal is caused by Baroreceptors located near the aortic root, carotid arteries, vasodilation of healthy coronary arteries and shunting of blood and other sites detect changes in arterial blood pressures which from myocardium at risk to areas not at risk; in coronary artery then influences cardiovascular function. A typical barorecep- disease, areas at ischemic risk for myocardial ischemia have tor reflex from the carotid artery includes the afferent (cranial coronary arteries that are already maximally vasodilated. nerve IX) and efferent (cranial nerve X) nerves. An increase in Desflurane and sevoflurane have not been associated with coro- arterial blood pressure is detected by the baroreceptors, caus- nary steal syndrome (19,20). Nevertheless, the exact clinical ing a reflex decrease in the heart rate. A decrease in arterial significance of coronary steal in humans is generally consid- blood pressure causes a reflex tachycardia to maintain cardiac ered somewhat unresolved. output and perfusion. Importantly, volatile anesthetics cause dose-dependent decreases in baroreceptor reflex activi- 3.4. Contractility and Cardiac Output ties (8): hence, hemodynamic compensatory responses are Volatile anesthetics depress myocardial contractility by attenuated by volatile anesthetics (9,10). It is common that inducing alterations of calcium ion flux (21). The mechanism alterations in hemodynamics caused by volatile anesthetics of negative inotropic effects of volatile anesthetics include: may require administrations of other pressor medications to decreased free Ca 2+, decreased Ca 2÷ release from sarcoplasmic offset the attenuation of these normal physiological protective reticulum, and/or altered contractile protein response to Ca 2+ functions. (21,22). Halothane diminishes myocardial contractility more 174 PART II1: PHYSIOLOGY AND ASSESSMENT/ LOUSHIN than isoflurane, desflurane, and nitrous oxide. Isoflurane and dioprotection against injury associated with ischemia and sevoflurane cause minimal change in contractility and thus reperfusion (25-28). The mechanism of cardioprotection allow for better maintained systemic cardiac output (22). seems to be similar to ischemic preconditioning first described Because of the better cardiovascular stability following either by Murray et al. (29) and thus likely involves the mitochon- isoflurane or sevoflurane administration compared to halothane, drial potassium (KATP)channel (30). the former agents are utilized frequently in patients with con- genital heart defects or depressed myocardial function. 3.7. Future Inhalational Anesthetics Because of the simultaneous stimulation of the sympathetic Xenon was first used as an anesthetic gas in humans by , the myocardial depressant effects of nitrous Cullen and Gross in 1951 (31). Xenon, an inert gas, has many oxide are usually not evident in healthy individuals. Yet, in a properties that make it an ideal anesthetic gas. It has very low compromised and failing myocardium, its depressant effects on toxicity and is nonexplosive and nonflammable. The MAC of contractility become much more evident. More specifically, xenon is approx 70%. Its very low blood-to-gas solubility par- nitrous oxide has been associated with sympathomimetic tition coefficient (0.115) provides for fast onset and emer- effects because it increases plasma catecholamines, mydriasis, gence from anesthesia (32). Preliminary clinical studies with and vasoconstriction of both systemic and pulmonary circula- xenon have shown minimal adverse effects on the cardiovas- tions (23). When nitrous oxide is administered with opioids cular system and general hemodynamics parameters (32-34). such as , the sympathomimetic effects are abolished. More specifically, xenon has been shown to induce minimal Therefore, the combined administration of nitrous oxide and effects on alterations in heart rates, coronary blood flows, left opioids may result in a significant overall decrease in mean ventricular pressures, and/or atrioventricular conduction times arterial pressure and cardiac output. (35). However, factors that may limit the use of xenon as an The abrupt increase in a patient's desflurane concentration anesthetic gas are its cost and unique delivery system; xenon has been associated with a significant increase in sympathetic must be extracted from the atmosphere, and the process is output, resulting in increased heart rate and mean arterial pres- expensive. Nevertheless, special breathing and delivery sys- sure. A proposed mechanism for this sympathetic stimulation is tems are in development. that it is caused by airway and lung irritation with a high con- All volatile anesthetics may trigger centration of desflurane (24). A smaller increase in sympathetic in susceptible patients. Malignant hyperthermia is an inherited output is commonly associated with isoflurane administration, pharmacogenetic disorder that affects skeletal muscle and is whereas sevoflurane, because of lack of airway irritation with characterized by a hypermetabolic response when exposed to a its administration, is not associated with any increase in sympa- triggering agent such as volatile anesthetics and succinylcho- thetic output, even with a very rapid increase in concentration. line. Disregulation of the ryanodine receptor, the calcium Because of the favorable airway properties of sevoflurane, it is release channel of sarcoplasmic reticulum, is involved in the used frequently for induction of anesthesia in chil- unregulated release of calcium from this storage site. Signs dren. Importantly, a high concentration of sevoflurane (4-8%) and symptoms of malignant hyperthermia include sympathetic for rapid mask induction is well tolerated in children. hyperactivity, elevated carbon dioxide production, muscle rigidity, hyperthermia, metabolic acidosis, dysrhythmias, and 3.5. Pulmonary Blood Flow hyperkalemia. Treatment of malignant hyperther-mia requires Volatile anesthetics are potent ; in some removal of the triggering agent, intravenous administration of cases, they have been used for the treatment of status asthma- dantrolene, and management of the associated symptoms. ticus. In general, it is considered that volatile anesthetics may 4. INTRAVENOUS ANESTHETICS cause a mild decrease in pulmonary vascular resistance, whereas with nitrous oxide, they can cause a significant increase in pul- 4.1. monary vascular resistance. In patients with congenital heart In general, barbiturates cause central nervous system inhibi- defects (i.e., intracardiac shunts, single ventricle, transposition tion (depression) by enhancing the effects of ,/-aminobutyric of great arteries, tetralogy of Fallot), the properties of select acid (GABA) (36). Barbiturates bind to the GABA receptor volatile anesthetics may be critical in offering better cardio- complex, which increases chloride channel activity, causing vascular stability. Administration of nitrous oxide in patients subsequent inhibition of the central nervous system. The GABA with preexisting pulmonary artery hypertension may exacer- receptor complex has binding affinities for GABA, barbitu- bate the strain on the right heart by increasing pulmonary rates, , propofol, and (23). vascular resistance. The elevated pulmonary vascular resis- Thiopental (3-5 mg/kg) and (1.5-2 mg/kg) are tance may also result in right-to-left intracardiac shunting in common barbiturates used for induction of general anesthesia susceptible patients (i.e., those with ventriculoseptal defect). (Fig. 2). After intravenous injection of thiopental or methohexi- Volatile anesthetics may also diminish the degree of hypoxic tal, anesthesia is induced rapidly, within seconds. The duration pulmonary vasoconstriction, which may result in hypoxia. of induced anesthesia after a single bolus dose of intravenous is short (approx 5 min) because of rapid redistribu- 3.6. Cardioprotection/Preconditioning tion from the brain to other tissues, such as muscle and adipose. The potential for myocardial preconditioning with volatile Importantly, intraarterial injection of thiopental can result in anesthetics has been extensively studied. Importantly, halo- severe vasospasm, which may lead to thrombosis, tissue injury, genated volatile anesthetics have been shown to provide car- or gangrene. If intraarterial injections do occur, counteractive CHAPTER 13 /ANESTHESIA AND CARDIOVASCULAR EFFECTS 175 H• O Thiopental H O Methohexital N CH2CH3 N CH2CH = OH2 S 0 i N \~O i~(3 cH2)2CH3 IN \\/ HCC~CCH2CH31 CH3 O OH3

Fig. 2. Chemical structure of thiopental and methohexital.

measures such as sympathetic nerve blocks or administration of Table 4 papaverine, , or may be initiated Cardiovascular Effects of Intravenous Anesthetics to decrease arterial vasospasm. Heart Blood Systemic" Cardiac Administration of barbiturates is typically associated with rate pressure vascular resistance output decreases in mean arterial pressure, which result from both Thiopental + - - + induced vasodilation and decreased myocardial contractility ++ ++ + ++ (Table 4). Barbiturates have been shown to cause dose-related Propofol 0/- ..... myocardial depression, which is not as pronounced as that 0 0/- 0 0 associated with volatile anesthetics. Barbiturates may cause a Fentanyl 0/- 0 0 0 slight depression of carotid and aortic baroreceptors; there- 0/- 0/- 0/- 0 0 0 0 0 fore, a decrease in mean arterial pressure leads to reflex tachy- Methohexital ++ - - 0/- cardia. If intravenous barbiturates are administered slowly, Meperidine ++ 0/- 0]- 0/+ relative hemodynamic stability can be maintained (37). In contrast, a rapid infusion of barbiturates, especially in hypo- 0, no change; +, increased; ++, more increased; +++, most increased; volemic patients, may result in significant hypotension. Sub- -, decreased; --, more decreased; ---, most decreased. sequently, typical increases in heart rates on barbiturate administration are not present if the baroreceptor reflexes are not intact, as in heart transplant patients or in isolated heart preparations. Importantly, barbiturates do not generally sensi- minimal change in blood pressure and systemic vascular resis- tize the myocardium to the potential arrhythmic effects of tance. Therefore, coadministration of and nitrous administered catecholamines. oxide is not associated with significant decreases in cardiovas- cular function (39); thus, it is employed in patients for whom 4.2. Benzodiazepines such concerns may be justified. Benzodiazepines are considered to produce central nervous system depression by binding to the GABA receptor complex 4.3. Opioids and ultimately increasing chloride channel activity. Benzodiaz- Opioids are commonly administered as adjuncts to epines, such as midazolam and diazepam, are often adminis- anesthesia. Opioids currently used in clinical practice include tered as adjuncts to anesthesia for sedation, amnesia, and fentanyl, morphine, meperidine, , and anxiolysis. Benzodiazepines themselves do not have (Table 5). All opioids exert their effect by interacting with properties. However, they possess properties opioid receptors (mu~, mu 2, kappa, or delta) (Table 6); they are and hence are utilized in acute management of seizures. adjuncts to help blunt sympathetic responses to noxious stimuli. Interestingly, the acute administration of benzodiazepines Overall, opioids cause minimal changes in cardiac output and is not associated with significant changes in hemodynamic blood pressure. Yet, opioids will generally cause bradycardia parameters; blood pressure, heart rate, and systemic vascular by increasing vagal tone. resistance are fairly well maintained. However, systemic vas- Typically, at very high doses, opioids may have the follow- cular resistance decreases in a dose-related fashion (38), but ing effects on hemodynamics: inhibition of the autonomic ner- a typical dose required for sedation and anxiolysis in adults vous system, direct myocardial depression, and/or induced ( 1-2 mg iv) usually is not associated with any significant he- histamine release. More specifically, one in vitro study of modynamic alteration. human atrial myocardium found that fentanyl, remifentanil, More specifically, induction of anesthesia with midazolam and sufentanil did not modify inotropic effects; (0.2-0.3 mg/kg iv) is associated with a decrease in systemic caused negative inotropy by affecting calcium regulation (40). vascular resistance, but with a minimal effect on cardiac output; However, it has also been reported that opioids such as fenta- the baroreceptor reflex remains intact, and a decrease in mean nyl may depress rat myocardial contractility by affecting cal- arterial pressure results in a responsive increase in heart rate. It cium regulation (41). Finally, it is considered that morphine has been reported that diazepam elicits even fewer cardiovascu- may cause decreases in mean arterial pressures by causing lar effects than midazolam. At most, diazepam may cause a histamine release and bradycardia. 176 PART IIh PHYSIOLOGY AND ASSESSMENT/LOUSHIN

Table 5 Opioid Agonists Commonly Used in Clinical Practice Heart Blood System rate pressure vascular resistance Contractili~ Histamine Meperidine ++ - - +/- ++ Morphine 0/- - - - ++ Fentanyl 0/- 0 0 0 0 Alfentanil - 0/- - 0/- 0 Sufentanil - 0/- 0/- 0/- 0 Remifentanil - 0 0 0 0

O, no change: +, increased; ++, more increased; +++, most increased; -, decreased; - -, more decreased; - - -, most decreased.

Table 6 o Opioid and Opioid Receptors Mu Delta Kappa receptor deceptor receptor Morphine +++ +? + Fentanyl +++ Sufentanil +++ + + + - - Fig. 3. Chemical structure of ketamine. - - - Naltrexone - - ++ DPDPE ++ OH DADLE + +++ +? NorBNI - - (CH3)2HC~/~'~./CH(CH3) 2 DSLET + ++

Naltrindole - -

Source: Modified from Goodman and Gilman's (2001) The PharmacologicalBasis of Therapeutics, 10th Ed. (Hardman, J.G. and Limbird, L.E., eds.), McGraw-Hill, New York, NY. Fig. 4. Chemical structure of propofol. DPDPE, [D-Pen-~,S]-enkephalin;DADLE, [D-AIaz, D-LeuS]- enkephalin; NorBNI, nor-binaltorphimine; DSLET, [D-Ser2, Leu 5, Thr6]-enkephalin 0, no change; +, increased; ++, more increased; +++, most increased; -, decreased; --, more decreased; ---, most decreased. It should be noted that pulmonary artery pressure may also become increased after the administration of ketamine. Another important side effect attributed to ketamine administration is bronchodilation; thus, patients with, or at risk for, broncho- 4.4. Ketamine spasm may benefit from ketamine induction. In contrast, in Ketamine is a derivative (Fig. 3) that causes patients with depleted catecholamine stores, ketamine may intense analgesia and anesthesia. Patients who cause a serious depression of myocardial function (42); thus, its receive ketamine can obtain a cataleptic state with open eyes use may be contraindicated in patients with coronary artery or ocular nystagmus. The typical routes for ketamine admin- disease, subaortic stenosis, or increased intracranial pressures. istration include intravenous (1-2 mg/kg), intramuscular (3-6 mg/kg), or oral (5-6 mg/kg). In general, the effects of 4.5. Propofol ketamine on the central nervous system are considered caused Propofol (1% solution) is a 2,6-diisopropylphenol (Fig. 4) by interactions with multiple receptors, including N-methyl- that is typically administered intravenously for sedation or in- D-asparate, , opioid, or muscarinic receptors. duction of anesthesia. Importantly, intravenous injections of Potential side effects of ketamine include the stimulation of propofol (1.5-2 mg/kg) are associated with rapid (30-60 s) loss the central sympathetic nervous system and thus an increase in of ; hence, this has obvious clinical advantages. circulating epinephrine and norepinephrine. In patients for A maintenance infusion of propofol is typically achieved with whom maintenance of myocardial contractility and systemic 100-200 ~tg/kg/min iv. Additional advantages of propofol in- vascular resistance is vital (i.e., because of hypovolemia, clude clear awakening, small cumulative effects, and decreased trauma, and shock), ketamine may better stimulate the cardio- incidence of nausea and vomiting. vascular system to maintain cardiac output and blood pressure; Propofol is considered also to interact with GABA receptors ketamine acts to cause an increase in heart rate, blood pressure, and activate them in a similar fashion as barbiturates. Likewise, cardiac output, and myocardial oxygen consumption. activation of GABA receptors by propofol increases the con- CHAPTER 13 /ANESTHESIAAND CARDIOVASCULAREFFECTS 177

Table 7 Nondepolarizing Muscle Relaxants Histamine release Vagal blockade Atracurium + 0 Cisatracurium 0 0 HCCH 3 Mivacurium + 0 I N Pancuronium 0 ++ Rocuronium 0 0/+ Vecuronium 0 0 Tubocurarine +++ 0 Succinylcholine 0 - 0, no change; +,increased; ++,more increased; +++,most Fig. 5. Chemical structure of etomidate. increased; -, decreased; - -, more decreased; - - -, most decreased.

ductance of chloride channels, resulting in inhibition of postsyn- 4.7. Nondepolarizing Muscle Relaxants aptic . Of clinical significance, the administration of propofol com- The majority of nondepolarizing muscle relaxants have monly causes a decrease in both systemic vascular resistance minimal effects on cardiovascular and hemodynamic stability. and cardiac contractility, hence resulting in decreased cardiac When induced, nondepolarizing muscle relaxants are believed output. This reduction in systemic vascular resistance (and to elicit their cardiovascular effects by stimulating the release vasodilation) is considered caused by decreased sympathetic of histamine and affecting muscarinic and nicotinic receptors vasoconstrictor activation of vascular smooth muscle (43). The (Table 7). For example, pancuronium may cause vagal block- inhibition of sympathetic tone by propofol is reported to be ade (antimuscarinic effect) at the sinoatrial node, resulting in greater than inhibition of parasympathetic activity; this may elevation of heart rate. The administration of pancuronium is result in significant bradycardia and even asystole (44--46). The also associated with activation of the sympathetic nervous induced decrease in cardiac contractility is likely because of system (51,52). Likewise, large doses of atracurium and decreases in calcium uptake into the sarcoplasmic reticulum. mivacurium are associated with histamine release, which may Decreased reuptake of calcium results in less calcium available result in tachycardia and hypotension; such patients may dis- for the next activation sequence (47). play facial flushing as a result of histamine release. Interest- Again it should be noted that, in patients with decreased left ingly, cisatracurium (a stereoisomer of atracurium) is not ventricular function (e.g., the elderly and patients with hypov- associated with histamine release. Finally, vecuronium and olemia), the administration of propofol may result in severe rocuronium are agents that are considered totally devoid of hypotension. Therefore, the careful titration of propofol and significant cardiovascular effects. adequate intravascular hydration are important for these types 4.8. Depolarizing Muscle Relaxant of patients. Succinylcholine is a depolarizing muscle relaxant; it has a 4.6. Etomidate structure similar to acetylcholine and mimics it by binding to Etomidate (Fig. 5) is an compound that is water nicotinic cholinergic receptors. The duration of action of succi- soluble at lower pH and lipid soluble at physiologic pH. Rapid nylcholine is short (minutes) and is broken down by the abun- loss of consciousness is accomplished after intravenous injec- dant pseudocholinesterase enzyme. Importantly, the adminis- tion of etomidate (0.2-0.4 mg/kg). It is important to recognize tration of succinylcholine may be associated with cardiac that etomidate lacks analgesic properties and does not blunt dysrhythmias (i.e.,junctional rhythm and sinus bradycardia) by sympathetic responses to direct laryngoscopy and endotracheal its muscarinic activity at the sinoatrial node. Administration of intubation. succinylcholine may also be associated with hyperkalemia in Generally, etomidate provides cardiovascular and pulmo- susceptible patients, such as those with malignant hyperther- nary stability; typical induction doses of etomidate result in mia, muscular dystrophy, spinal cord injury, and burn injury. minimal changes in heart rate and cardiac output. Myocardial More specifically, in boys with Duchenne muscular dystrophy, contractility is well maintained at doses needed to induce gen- the administration of succinylcholine has been linked to epi- eral anesthesia (23) and is considered to produce less myocar- sodes of sudden cardiac death. dial depression compared to thiopental (48). Etomidate does 5. PHYSIOLOGIC EFFECTS OF ACUPUNCTURE not induce significant histamine release, but it does depress adrenocortical function by inhibiting the conversion of choles- Acupuncture involves stimulation of specific anatomical terol to cortisol (49). Specifically, a single induction dose of locations on the to alter energy flow patterns throughout etomidate can cause adrenal suppression for 5-8 h (50), and a the body. The skin can be stimulated by manual or electrical continuous infusion of etomidate will cause further adrenocor- stimulation or the more typical placement of small metallic tical suppression. needles. Acupuncture has been used in China for thousands of 178 PART Ill: PHYSIOLOGYAND ASSESSMENT/ LOUSHIN

years; there has been a surge of interest in these nontraditional agents. This includes myocardial preconditioning with vola- methodologies in the United States. tile anesthetics such as desflurane (59), isoflurane (60,61), Acupuncture has been utilized for treatment and prevention and sevoflurane (62) and intravenous opioid agonists (63,64). of multiple health conditions, such as chronic , nausea and Pharmacological preconditioning is not limited to cardiac tis- vomiting, obesity, substance abuse, and asthma. Stress response sue only; other tissues, such as lungs, brain, and skeletal and cardiovascular effects of pain have reportedly been attenu- muscle (65), may benefit from preconditioning. In summary, ated by nonpharmacological techniques such as acupuncture; preconditioning with anesthetics may offer life-extending it modulates the body's pain system, increases the release of benefits in cardiac vascular and organ transplantation surgical endogenous opioids (53), and/or decreases postoperative pain patients. (For more details on this topic, see Chapter 12.) (54). In a feline cardiovascular model, the utilization of electro- 8. HEART TRANSPLANT acupuncture induced improvements in regional cardiac wall motion activity during myocardial ischemia (55). Furthermore, With the increasing numbers of successful heart transplants, acupressure applied to females undergoing elective cesarean anesthetic management of the patient after a heart transplant section with spinal anesthesia displayed a reduction in nausea procedure requires special considerations. A transplanted heart and vomiting (56). is totally denervated and usually has a higher basal heart rate The potential advantages of acupuncture for the treatment of (90-110 beats/min); direct autonomic nervous system effects medical conditions continue to be investigated. With initial are mostly absent. Thus, agents such as and glycopy- studies indicating numerous promising benefits of acupuncture rrolate will not cause an increase in heart rate. Vagal stimula- for treatment of multiple medical conditions, the National Insti- tion maneuvers such as carotid massage and oculocardiac reflex tutes of Health Consensus Conference has recommended that are also minimized. However, acetylcholinesterase inhibitors acupuncture be included in comprehensive management and such as have been associated with severe brady- may be useful as an adjunct treatment or an acceptable alterna- cardia. If bradycardia develops, administration of direct-acting tive (57). Finally, limitations in the validation of acupuncture cardiac agents such as isoproterenol or epinephrine may be may stem from difficulty creating randomized, blinded, pla- required. The transplanted heart continues to respond to circu- cebo-controlled clinical studies. lating catecholamines, and thus maintenance of cardiac output is aided by increased stroke volume (Frank-Starling relation- 6. ANESTHESIA AND TEMPERATURE ship); maintaining adequate preload is considered essential in REGULATION patients post-heart transplant. (See Chapter 10 for additional General and regional anesthesia are often associated with information.) disregulation of body temperature and thus decreases in core 9. SUMMARY body temperature. Most of the body heat lost during anesthesia is via convection and radiation, with some losses caused by With the aging population and an increase in health prob- conduction and evaporation. Principally, anesthetics cause the lems such as obesity, diabetes, and coronary artery diseases, core body heat to redistribute to the periphery, resulting in a perioperative management and anesthetic technique and medi- drop in core body temperature (58). Under anesthesia, patients cations that promote cardiovascular stability continue to offer become poikilotherms (have minimal ability to thermoregu- challenges and new developments in the field of anesthesiol- late). Therefore, multiple modalities to maintain normothermia ogy. These include new anesthesia medications, medical during surgery have been developed, including forced-air equipment and surgical technology, and anesthetic and surgi- warming devices, fluid warmers, ventilator humidifiers, water cal techniques. With further understanding of inhalational and mattresses and vests, radiant lamps, and warm blankets. Other intravenous anesthetics, maintaining stable, physiological car- modalities for warming patients include altering ambient room diovascular function may be possible. temperatures or the temperatures of irrigation solutions. Importantly, postoperative hypothermia may be associated COMPANION CD MATERIAL with ( 1) delayed awakening from general anesthesia, (2) slowed JPEG 1. drug , (3) coagulopathy, (4) vasoconstriction and An anesthesiologist administering intrave- poor tissue perfusion, (5) increases in blood viscosity, and/or nous medications to a patient for induction (6) induced shivering. Importantly, postoperative shiver may of general anesthesia. be detrimental in patients with coronary artery disease because JPEG 2. shivering causes increases in oxygen consumption and tachy- An anesthesia machine and ventilator. cardia. Currently, meperidine is clinically approved for treat- JPEG 3. ment of excessive shivering in postoperative situations. An anesthesiologist titrating the dose of an to maintain anesthesia 7. MYOCARDIAL PRECONDITIONING and cardiovascular stability. WITH INHALATIONAL AND INTRAVENOUS ANESTHETICS REFERENCES Since the initial report by Murray et al. (29) on ischemic 1. American Society of Anesthesiologists (October 2003) ASA Stan- preconditioning of dog myocardium, there has been great dards. Guidelines and Statements. American Society of Anesthesi- interest in myocardial preconditioning with pharmacological ologists, Park Ridge, IL. CHAPTER 13 / ANESTHESIA AND CARDIOVASCULAR EFFECTS 179

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