0, no change; +, increased; ++, more increased; +++, most increased; -, decreased; —, more decreased;---, most decreased.

0, no change; +, increased; ++, more increased; +++, most increased; -, decreased; —, more decreased;---, most decreased.

Anesthetic uptake is determined by its blood solubility, cardiac output, and the difference between alveolar and venous partial pressure (2). The greater the uptake of anesthetic gas, the slower is the rate of induction. Inhalational anesthetics with lower blood:gas solubility (i.e., desflurane and sevoflurane) will cause faster induction and emergence from general anesthesia.

3.1. Blood Pressure and Systemic Vascular Resistance

All volatile anesthetics (e.g., isoflurane, desflurane, sevo-flurane, and halothane) cause dose-dependent effects on cardiovascular function. For example, these agents cause a dose-dependent decrease in mean arterial blood pressure (3-6). The relative decrease in mean arterial blood pressure is considered to be caused by decreases in systemic vascular resistance, myocardial contractility, sympathetic output, or a combination of these. In particular, isoflurane, desflurane, and sevoflurane cause greater decreases in systemic vascular resistance compared to halothane (Table 3). Further, increasing doses of hal-othane result in small changes in system vascular resistance (7), and decreases in mean arterial pressure. Yet, halothane administration is associated with decreases in cardiac output.

In general, volatile anesthetics decrease systemic vascular resistance by causing peripheral vasodilation, thus increasing blood flow to cutaneous and skeletal muscle tissues (3). It should be noted that nitrous oxide causes a minimal alteration of systemic vascular resistance when administered alone.

3.2. Cardiac Conduction System and Heart Rate

Baroreceptors located near the aortic root, carotid arteries, and other sites detect changes in arterial blood pressures which then influences cardiovascular function. A typical barorecep-tor reflex from the carotid artery includes the afferent (cranial nerve IX) and efferent (cranial nerve X) nerves. An increase in arterial blood pressure is detected by the baroreceptors, causing a reflex decrease in the heart rate. A decrease in arterial blood pressure causes a reflex tachycardia to maintain cardiac output and organ perfusion. Importantly, volatile anesthetics cause dose-dependent decreases in baroreceptor reflex activities (8); hence, hemodynamic compensatory responses are attenuated by volatile anesthetics (9,10). It is common that alterations in hemodynamics caused by volatile anesthetics may require administrations of other pressor medications to offset the attenuation of these normal physiological protective functions.

Volatile anesthetics may also cause specific cardiac dysrhythmias. Specifically, volatile anesthetics have been reported both to slow the rate of sinoatrial node discharge and to increase ventricular and His bundle conduction times (11), which may increase the development of nodal rhythms. Further, volatile anesthetics may increase ventricular automaticity by altering potassium and calcium ion channels (11).

It has been reported that halothane increases the incidence of ventricular dysrhythmias, especially when coadministered with epinephrine; in contrast, the coadministration of epinephrine with isoflurane, desflurane, or sevoflurane has minimal effects on increasing the incidence of ventricular dysrhythmias (1214). Furthermore, halothane may blunt the reflex increases in heart rates that typically accompany decreases in blood pressure; it may also slow conduction from the sinoatrial node, resulting in junctional ventricular rhythms.

Sevoflurane and desflurane are also known to blunt sympathetic baroreflex sensitivity partially. Importantly, isoflurane is well known to cause significant decreases in systemic vascular resistances and thus in blood pressure. Yet, the baro-receptor response remains partially intact, and cardiac output is maintained relatively stable with isoflurane via associated increases in heart rate.

3.3. Coronary Blood Flow

In general, volatile anesthetics cause a dose-dependent coronary vasodilation, with isoflurane having a greater effect than halothane (15,16). Increasing the concentration of isoflurane increases coronary blood flow and this has the potential to cause "coronary steal" syndrome (17,18). Coronary steal is caused by vasodilation of healthy coronary arteries and shunting of blood from myocardium at risk to areas not at risk; in coronary artery disease, areas at ischemic risk for myocardial ischemia have coronary arteries that are already maximally vasodilated. Desflurane and sevoflurane have not been associated with coronary steal syndrome (19,20). Nevertheless, the exact clinical significance of coronary steal in humans is generally considered somewhat unresolved.

3.4. Contractility and Cardiac Output

Volatile anesthetics depress myocardial contractility by inducing alterations of calcium ion flux (21). The mechanism of negative inotropic effects of volatile anesthetics include: decreased free Ca2+, decreased Ca2+ release from sarcoplasmic reticulum, and/or altered contractile protein response to Ca2+ (21,22). Halothane diminishes myocardial contractility more than isoflurane, desflurane, and nitrous oxide. Isoflurane and sevoflurane cause minimal change in contractility and thus allow for better maintained systemic cardiac output (22). Because of the better cardiovascular stability following either isoflurane or sevoflurane administration compared to halothane, the former agents are utilized frequently in patients with congenital heart defects or depressed myocardial function.

Because of the simultaneous stimulation of the sympathetic nervous system, the myocardial depressant effects of nitrous oxide are usually not evident in healthy individuals. Yet, in a compromised and failing myocardium, its depressant effects on contractility become much more evident. More specifically, nitrous oxide has been associated with sympathomimetic effects because it increases plasma catecholamines, mydriasis, and vasoconstriction of both systemic and pulmonary circulations (23). When nitrous oxide is administered with opioids such as fentanyl, the sympathomimetic effects are abolished. Therefore, the combined administration of nitrous oxide and opioids may result in a significant overall decrease in mean arterial pressure and cardiac output.

The abrupt increase in a patient's desflurane concentration has been associated with a significant increase in sympathetic output, resulting in increased heart rate and mean arterial pressure. A proposed mechanism for this sympathetic stimulation is that it is caused by airway and lung irritation with a high concentration of desflurane (24). A smaller increase in sympathetic output is commonly associated with isoflurane administration, whereas sevoflurane, because of lack of airway irritation with its administration, is not associated with any increase in sympathetic output, even with a very rapid increase in concentration. Because of the favorable airway properties of sevoflurane, it is used frequently for inhalation induction of anesthesia in children. Importantly, a high concentration of sevoflurane (4-8%) for rapid mask induction is well tolerated in children.

3.5. Pulmonary Blood Flow

Volatile anesthetics are potent bronchodilators; in some cases, they have been used for the treatment of status asthma-ticus. In general, it is considered that volatile anesthetics may cause a mild decrease in pulmonary vascular resistance, whereas with nitrous oxide, they can cause a significant increase in pulmonary vascular resistance. In patients with congenital heart defects (i.e., intracardiac shunts, single ventricle, transposition of great arteries, tetralogy of Fallot), the properties of select volatile anesthetics may be critical in offering better cardiovascular stability. Administration of nitrous oxide in patients with preexisting pulmonary artery hypertension may exacerbate the strain on the right heart by increasing pulmonary vascular resistance. The elevated pulmonary vascular resistance may also result in right-to-left intracardiac shunting in susceptible patients (i.e., those with ventriculoseptal defect). Volatile anesthetics may also diminish the degree of hypoxic pulmonary vasoconstriction, which may result in hypoxia.

3.6. Cardioprotection/Preconditioning

The potential for myocardial preconditioning with volatile anesthetics has been extensively studied. Importantly, halo-genated volatile anesthetics have been shown to provide car-

dioprotection against injury associated with ischemia and reperfusion (25-28). The mechanism of cardioprotection seems to be similar to ischemic preconditioning first described by Murray et al. (29) and thus likely involves the mitochondrial potassium (KATP) channel (30).

3.7. Future Inhalational Anesthetics

Xenon was first used as an anesthetic gas in humans by Cullen and Gross in 1951 (31). Xenon, an inert gas, has many properties that make it an ideal anesthetic gas. It has very low toxicity and is nonexplosive and nonflammable. The MAC of xenon is approx 70%. Its very low blood-to-gas solubility partition coefficient (0.115) provides for fast onset and emergence from anesthesia (32). Preliminary clinical studies with xenon have shown minimal adverse effects on the cardiovascular system and general hemodynamics parameters (32-34). More specifically, xenon has been shown to induce minimal effects on alterations in heart rates, coronary blood flows, left ventricular pressures, and/or atrioventricular conduction times (35). However, factors that may limit the use of xenon as an anesthetic gas are its cost and unique delivery system; xenon must be extracted from the atmosphere, and the process is expensive. Nevertheless, special breathing and delivery systems are in development.

All volatile anesthetics may trigger malignant hyperthermia in susceptible patients. Malignant hyperthermia is an inherited pharmacogenetic disorder that affects skeletal muscle and is characterized by a hypermetabolic response when exposed to a triggering agent such as volatile anesthetics and succinylcho-line. Disregulation of the ryanodine receptor, the calcium release channel of sarcoplasmic reticulum, is involved in the unregulated release of calcium from this storage site. Signs and symptoms of malignant hyperthermia include sympathetic hyperactivity, elevated carbon dioxide production, muscle rigidity, hyperthermia, metabolic acidosis, dysrhythmias, and hyperkalemia. Treatment of malignant hyperther-mia requires removal of the triggering agent, intravenous administration of dantrolene, and management of the associated symptoms.


In general, barbiturates cause central nervous system inhibition (depression) by enhancing the effects of y-aminobutyric acid (GABA) (36). Barbiturates bind to the GABA receptor complex, which increases chloride channel activity, causing subsequent inhibition of the central nervous system. The GABA receptor complex has binding affinities for GABA, barbiturates, benzodiazepines, propofol, and alcohol (23).

Thiopental (3-5 mg/kg) and methohexital (1.5-2 mg/kg) are common barbiturates used for induction of general anesthesia (Fig. 2). After intravenous injection of thiopental or methohexital, anesthesia is induced rapidly, within seconds. The duration of induced anesthesia after a single bolus dose of intravenous barbiturate is short (approx 5 min) because of rapid redistribution from the brain to other tissues, such as muscle and adipose. Importantly, intraarterial injection of thiopental can result in severe vasospasm, which may lead to thrombosis, tissue injury, or gangrene. If intraarterial injections do occur, counteractive

Fig. 2. Chemical structure of thiopental and methohexital.

measures such as sympathetic nerve blocks or administration of papaverine, phenoxybenzamine, or lidocaine may be initiated to decrease arterial vasospasm.

Administration of barbiturates is typically associated with decreases in mean arterial pressure, which result from both induced vasodilation and decreased myocardial contractility (Table 4). Barbiturates have been shown to cause dose-related myocardial depression, which is not as pronounced as that associated with volatile anesthetics. Barbiturates may cause a slight depression of carotid and aortic baroreceptors; therefore, a decrease in mean arterial pressure leads to reflex tachycardia. If intravenous barbiturates are administered slowly, relative hemodynamic stability can be maintained (37). In contrast, a rapid infusion of barbiturates, especially in hypovolemic patients, may result in significant hypotension. Subsequently, 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 sensitize the myocardium to the potential arrhythmic effects of administered catecholamines.

4.2. Benzodiazepines

Benzodiazepines are considered to produce central nervous system depression by binding to the GABA receptor complex and ultimately increasing chloride channel activity. Benzodiazepines, such as midazolam and diazepam, are often administered as adjuncts to anesthesia for sedation, amnesia, and anxiolysis. Benzodiazepines themselves do not have analgesic properties. However, they possess anticonvulsant properties and hence are utilized in acute management of seizures.

Interestingly, the acute administration of benzodiazepines is not associated with significant changes in hemodynamic parameters; blood pressure, heart rate, and systemic vascular resistance are fairly well maintained. However, systemic vascular resistance decreases in a dose-related fashion (38), but a typical dose required for sedation and anxiolysis in adults (1-2 mg iv) usually is not associated with any significant hemodynamic alteration.

More specifically, induction of anesthesia with midazolam (0.2-0.3 mg/kg iv) is associated with a decrease in systemic vascular resistance, but with a minimal effect on cardiac output; the baroreceptor reflex remains intact, and a decrease in mean arterial pressure results in a responsive increase in heart rate. It has been reported that diazepam elicits even fewer cardiovascular effects than midazolam. At most, diazepam may cause a

Table 4

Cardiovascular Effects of Intravenous Anesthetics

Table 4

Cardiovascular Effects of Intravenous Anesthetics

Essentials of Human Physiology

Essentials of Human Physiology

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