Anesthesia can be local, regional, or general (Table 46-1). Local anesthesia is accomplished using a local anesthetic drug that can be injected intradermally and is used for the removal of small lesions or to repair traumatic injuries. Local anesthesia is the most frequent anesthetic administered by surgeons and may be accompanied by IV sedation to improve patient comfort.
Table 46-1Anesthetic agents, their actions, and their clinical uses ||Download (.pdf) Table 46-1 Anesthetic agents, their actions, and their clinical uses
General anesthesia describes a triad of three major and separate effects: unconsciousness (and amnesia), analgesia, and muscle relaxation (see Table 46-1). IV drugs usually produce a single, discrete effect, while most inhaled anesthetics produce elements of all three. General anesthesia is achieved with a combination of IV and inhaled drugs, each used to its maximum benefit. The science and art of anesthesia are dynamic processes. As the amount of stimulus to the patient changes during surgery, the patient’s vital signs are used as a guide and the quantity of drugs is adjusted, maintaining an equilibrium between stimulus and dose. General anesthesia is what patients commonly think of when they are to be “put under” and can be a cause of considerable preoperative anxiety.13
Unconsciousness and Amnesia
The IV agents that produce unconsciousness and amnesia are frequently used for the induction of general anesthesia. They include barbiturates, benzodiazepines, propofol, etomidate, and ketamine. Except for ketamine, the following agents have no analgesic properties and do not cause paralysis or muscle relaxation.
The most common barbiturates are thiopental, thiamylal, and methohexital. The mechanism of action is at the γ-aminobutyric acid (GABA) receptor, where they inhibit excitatory synaptic transmission. They produce a rapid, smooth induction within 60 seconds, and wear off in about 5 minutes. In higher doses and in patients with intravascular depletion, they cause hypotension and myocardial depression. The barbiturates are anticonvulsants and protect the brain during neurosurgery by reducing cerebral metabolism.
Propofol is an alkylated phenol that inhibits synaptic transmission through its effects at the GABA receptor. With a short duration, rapid recovery, and low incidence of nausea and vomiting, it has emerged as the agent of choice for ambulatory and minor general surgery. Additionally, propofol has bronchodilatory properties that make its use attractive in asthmatic patients and smokers. Propofol may cause hypotension and should be used cautiously in patients with suspected hypovolemia and/or coronary artery disease (CAD), the latter of which may not tolerate a sudden drop in blood pressure. It can be used as a continuous infusion for sedation in the intensive care unit setting. Propofol is an irritant and frequently causes pain on injection.
The most important uses of the benzodiazepines are for reduction of anxiety and to produce amnesia. Frequently used IV benzodiazepines are diazepam, lorazepam, and midazolam. They all inhibit synaptic transmission at the GABA receptor but have differing durations of action. The benzodiazepines can produce peripheral vasodilatation and hypotension but have minimal effects on respiration when used alone. They must be used with caution when given with opioids; a synergistic reaction causing respiratory depression is common. The benzodiazepines are excellent anticonvulsants and only rarely cause allergic reactions.
Etomidate is an imidazole derivative used for IV induction. Its rapid and almost complete hydrolysis to inactive metabolites results in rapid awakening. Like the above IV agents, etomidate acts on the GABA receptor. It has little effect on cardiac output and heart rate, and induction doses usually produce less reduction in blood pressure than that seen with thiopental or propofol. Etomidate is associated with pain on injection and more nausea and vomiting than thiopental or propofol.
Ketamine differs from the above IV agents in that it produces analgesia as well as amnesia. Its principal action is on the N-methyl-d-aspartate receptor; it has no action on the GABA receptor. It is a dissociative anesthetic, producing a cataleptic gaze with nystagmus. Patients may associate this with delirium and hallucinations while regaining consciousness. The addition of benzodiazepines has been shown to prevent these side effects. Ketamine can increase heart rate and blood pressure, which may cause myocardial ischemia in patients with CAD. Ketamine is useful in acutely hypovolemic patients to maintain blood pressure via sympathetic stimulation but is a direct myocardial depressant in patients who are catecholamine depleted. Ketamine is a bronchodilator, making it useful for asthmatic patients, and rarely is associated with allergic reactions.
The IV analgesics most frequently used in anesthesia today have little effect on consciousness, amnesia, or muscle relaxation. The most important class is the opioids, so called because they were first isolated from opium, with morphine, codeine, meperidine, hydromorphone, and the fentanyl family being the most common. The most important nonopioid analgesics are ketamine (discussed earlier in the Ketamine section) and ketorolac, an IV nonsteroidal anti-inflammatory drug (NSAID).
The commonly used opioids—morphine, codeine, oxymorphone, meperidine, and the fentanyl-based compounds—act centrally on μ-receptors in the brain and spinal cord. The main side effects of opioids are euphoria, sedation, constipation, and respiratory depression, which also are mediated by the same μ-receptors in a dose-dependent fashion. Although opioids have differing potencies required for effective analgesia, equianalgesic doses of opioids result in equal degrees of respiratory depression. Thus, there is no completely safe opioid analgesic. The synthetic opioid fentanyl and its analogues sufentanil, alfentanil, and remifentanil are commonly used in the operating room. They differ pharmacokinetically in their lipid solubility, tissue binding, and elimination profiles and thus have differing potencies and durations of action. Remifentanil is remarkable in that it undergoes rapid hydrolysis that is unaffected by sex, age, weight, or renal or hepatic function, even after prolonged infusion. Recovery is within minutes, but there is little residual postoperative analgesia.
Naloxone and the longer-acting naltrexone are pure opioid antagonists. They can be used to reverse the side effects of opioid overdose (e.g., respiratory depression), but the analgesic effects of the opioid also will be reversed.
Ketamine, an N-methyl-d-aspartate receptor antagonist, is a potent analgesic, but is one of the few IV agents that also causes significant sedation and amnesia. Unlike the μ-receptor agonists, ketamine supports respiration. It can be used in combination with opioids, but the dysphoric effects must be masked with the simultaneous use of sedatives, usually a benzodiazepine like midazolam.
Ketorolac is a parenteral NSAID that produces analgesia by reducing prostaglandin formation via inhibition of the enzyme cyclooxygenase (COX). Intraoperative use of ketorolac reduces postoperative need for opioids. Two forms of COX have been identified: COX-1 is responsible for the synthesis of several prostaglandins as well as prostacyclin, which protects gastric mucosa, and thromboxane, which supports platelet function. COX-2 is induced by inflammatory reactions to produce more prostaglandins. Ketorolac (as well as many oral NSAIDs, aspirin, and indomethacin) inhibits both COX-1 and COX-2, which causes the major side effects of gastric bleeding, platelet dysfunction, and hepatic and renal damage. Parecoxib is a parenteral, predominantly COX-2 NSAID that presumably produces analgesia and reduces inflammation without causing gastrointestinal bleeding or platelet dysfunction.
Dexmedetomidine is an IV α2-adrenergic agonist, administered as a continuous infusion, and has sedative and analgesic properties. It is useful for sedation in an intensive care unit setting and as an adjunct to general anesthesia. Side effects are hypotension and bradycardia.
IV acetaminophen is an analgesic drug and antipyretic of moderate potency; its site of action is in the central nervous system (CNS), not peripherally. It does not have anti-inflammatory properties and is not considered an NSAID.14 When used as part of postoperative analgesic therapy, it will reduce the amount of opioids required, reducing side effects (e.g., constipation, sedation, respiratory depression).
Neuromuscular Blocking Agents
Neuromuscular blocking agents have no amnestic, hypnotic, or analgesic properties; patients must be properly anesthetized before and in addition to the administration of these agents. A paralyzed but unsedated patient will be aware, conscious, and in pain, yet be unable to communicate their predicament. Inappropriate administration of a neuromuscular blocking agent to an awake patient is one of the most traumatic experiences imaginable. Neuromuscular blockade is not a substitute for adequate anesthesia, but is rather an adjunct to the anesthetic. Depth of neuromuscular blockade is best monitored with a nerve stimulator to ensure patient immobility intraoperatively and to confirm a lack of residual paralysis postoperatively.15
Unlike the local anesthetics, which affect the ability of nerves to conduct impulses, the neuromuscular blockers have no effect on either nerves or muscles, but act primarily on the neuromuscular junction.
There is one commonly used depolarizing neuromuscular blocker—succinylcholine. This agent binds to acetylcholine receptors on the postjunctional membrane in the neuromuscular junction and causes depolarization of muscle fibers.
Although the rapid onset (<60 seconds) and rapid offset (5–8 minutes) make succinylcholine ideal for management of the airway in certain situations, total body muscle fasciculations can cause postoperative aches and pains, an elevation in serum potassium levels, and an increase in intraocular and intragastric pressure. Its use in patients with burns or traumatic tissue injuries may result in a high enough rise in serum potassium levels to produce arrhythmias and cardiac arrest. Unlike other neuromuscular blocking agents, the effects of succinylcholine cannot be reversed. Succinylcholine is rapidly hydrolyzed by plasma cholinesterase, also referred to as pseudocholinesterase. There are many reasons for a patient to have low pseudocholinesterase levels, such as liver disease, concomitant use of other drugs, pregnancy, and cancer. These factors are usually not clinically problematic, delaying return of motor function only by several minutes. Some patients have a genetic disorder manifesting as atypical plasma cholinesterase; the atypical enzyme has less-than-normal activity, and/or the patient has extremely low levels of the enzyme. The incidence of the homozygous form is approximately 1 in 3000; the effects of a single dose of succinylcholine may last several hours instead of several minutes. Treatment is to keep the patient sedated and unaware he or she is paralyzed, continue mechanical ventilation, test the return of motor function with a peripheral nerve stimulator, and extubate the patient only after he or she has fully regained motor strength. Two separate blood tests must be drawn: pseudocholinesterase level to determine the amount of enzyme present, and dibucaine number, which indicates the quality of the enzyme. Patients with laboratory-confirmed abnormal pseudocholinesterase levels and/or dibucaine numbers should be counseled to avoid succinylcholine as well as mivacurium, which is also hydrolyzed by pseudocholinesterase. First-degree family members should also be tested. Succinylcholine is the only IV triggering agent of malignant hyperthermia (discussed later in the Malignant Hyperthermia section).
There are several competitive nondepolarizing agents available for clinical use. The longest acting is pancuronium, which is excreted almost completely unchanged by the kidney. Intermediate-duration neuromuscular blockers include vecuronium and rocuronium, which are metabolized by both the kidneys and liver, and atracurium and cisatracurium, which undergo breakdown in plasma known as Hofmann elimination. The agent with shortest duration is mivacurium, the only nondepolarizer that is metabolized by plasma cholinesterase, and like succinylcholine, is subject to the same prolonged blockade in patients with plasma cholinesterase deficiency. All nondepolarizers reversibly bind to the postsynaptic terminal in the neuromuscular junction and prevent acetylcholine from depolarizing the muscle. Muscle blockade occurs without fasciculation and without the subsequent side effects seen with succinylcholine. The most commonly used agents of this type and their advantages and disadvantages are listed in Table 46-2.
Table 46-2Advantages and disadvantages to common nondepolarizing neuromuscular blocking agents ||Download (.pdf) Table 46-2 Advantages and disadvantages to common nondepolarizing neuromuscular blocking agents
|AGENT ||DURATION (H) ||ADVANTAGES ||DISADVANTAGES |
|Pancuronium ||>1 ||No histamine release ||Tachycardia; slow onset; long duration |
|Vecuronium ||<1 ||No cardiovascular effects ||Intermediate onset |
|Rocuronium ||<1 ||Fast onset; no cardiovascular effects ||— |
|Mivacurium ||<1 ||Fast onset; short duration & histamine release ||— |
The reversal of neuromuscular blockade is not a true reversal of the drug (as with protamine reversal of heparin) but a reversal of the effect of the neuromuscular blockade. Neuromuscular blocking reversal agents, usually neostigmine, edrophonium, or pyridostigmine, increase acetylcholine levels by inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine. The subsequently increased circulating levels of acetylcholine prevail in the competition for the postsynaptic receptor, and motor function returns. Use of the peripheral nerve stimulator is required to follow depth and reversal of motor blockade, but it is essential to correlate data from the nerve stimulator with clinical signs that indicate return of motor function, including tidal volume, vital capacity, hand grip, and 5-second sustained head lift.
Unlike the IV agents, the inhalational agents provide all three characteristics of general anesthesia: unconsciousness, analgesia, and muscle relaxation. However, it would be impractical to use an inhalation-only technique in larger surgical procedures, because the doses required would cause unacceptable side effects, so IV adjuncts such as opioid analgesics and neuromuscular blockers are added to optimize the anesthetic. All inhaled anesthetics display a dose-dependent reduction in mean arterial blood pressure except for nitrous oxide, which maintains or slightly raises the blood pressure. Nitrous oxide, although not potent enough to use alone, provides partial anesthesia and allows a second agent to be used in smaller doses, reducing side effects.
Minimum alveolar concentration (MAC) is a measure of anesthetic potency. It is the ED50 of an inhaled agent (i.e., the dose required to block a response to a painful stimulus in 50% of subjects). The higher the MAC, the less potent an agent is. The potency and speed of induction of inhaled agents correlate with their lipid solubility, and this is known as the Meyer-Overton rule. Nitrous oxide has a low solubility and is a weak anesthetic agent, but has the most rapid onset and offset. The “potent” gases (e.g., desflurane, sevoflurane, enflurane, and halothane) are more soluble in blood than nitrous oxide and can be given in lower concentrations, but have longer induction and emergence characteristics.
Sevoflurane and desflurane are the two most recently introduced inhalational agents in common use. Because of their relatively lower tissue and blood solubility, induction and recovery are more rapid than with isoflurane or enflurane.
All of the potent inhalational agents (e.g., halothane, isoflurane, enflurane, sevoflurane, and desflurane), as well as the depolarizing agent succinylcholine, are triggering agents for malignant hyperthermia. Table 46-3 lists the advantages and disadvantages of each agent.
Table 46-3Advantages and disadvantages of common inhalational agents ||Download (.pdf) Table 46-3 Advantages and disadvantages of common inhalational agents
|AGENT ||MAC (%) ||ADVANTAGES ||DISADVANTAGES |
|Nitrous oxide ||105 ||Analgesia; minimal cardiac and respiratory depression ||Sympathetic stimulation; expansion of closed air space |
|Halothane ||0.75 ||Effective in low concentrations; minimal airway irritability; inexpensive ||Cardiac depression and arrhythmia hepatic necrosis; slow elimination |
|Enflurane ||1.68 ||Muscle relaxation ||Strong smell; seizures |
| || ||No effect on cardiac rate or rhythm || |
|Isoflurane ||1.15 ||Muscle relaxation; no effect on cardiac rate or rhythm ||Strong smell |
|Desflurane ||6 ||Rapid induction and emergence ||Coughing; high cost |
|Sevoflurane ||1.71 ||Rapid induction and emergence; pleasant smell; ideal for mask induction ||High cost; metabolized by liver |
Local anesthetics are divided into two groups based on their chemical structure: the amides and the esters. In general, the amides are metabolized in the liver, and the esters are metabolized by plasma cholinesterases, which yield metabolites with slightly higher allergic potential than the amides (Table 46-4).
Table 46-4Biologic properties of commonly used local anesthetics ||Download (.pdf) Table 46-4 Biologic properties of commonly used local anesthetics
Lidocaine, bupivacaine, mepivacaine, prilocaine, and ropivacaine have in common an amide linkage between a benzene ring and a hydrocarbon chain that, in turn, is attached to a tertiary amine. The benzene ring confers lipid solubility for penetration of nerve membranes, and the tertiary amine attached to the hydrocarbon chain makes these local anesthetics water soluble. Lidocaine has a more rapid onset and is shorter acting than bupivacaine; however, both are widely used for tissue infiltration, regional nerve blocks, and spinal and epidural anesthesia. Ropivacaine is the most recently introduced local anesthetic. It is clinically similar to bupivacaine in that it has a slow onset and a long duration, but is less cardiotoxic. All amides are 95% metabolized in the liver, with 5% excreted unchanged by the kidneys.
Cocaine, procaine, chloroprocaine, tetracaine, and benzocaine have an ester linkage in place of the amide linkage mentioned earlier in the Amides section. Unique among local anesthetics, cocaine occurs in nature, was the first used clinically, produces vasoconstriction (making it useful for topical application, e.g., for intranasal surgery), releases norepinephrine from nerve terminals resulting in hypertension, and is highly addictive. Cocaine is a Schedule II drug. Procaine, synthesized in 1905 as a nontoxic substitute for cocaine, has a short duration and is used for infiltration. Tetracaine has a long duration and is useful as a spinal anesthetic for lengthy operations. Benzocaine is for topical use only. The esters are hydrolyzed in the blood by pseudocholinesterase. Some of the metabolites have a greater allergic potential than the metabolites of the amide anesthetics, but true allergies to local anesthetics are rare.
The common characteristic of all local anesthetics is a reversible block of the transmission of neural impulses when placed on or near a nerve membrane. Local anesthetics block nerve conduction by stabilizing sodium channels in their closed state, preventing action potentials from propagating along the nerve. The individual local anesthetic agents have different recovery times based on lipid solubility and tissue binding, but return of neural function is spontaneous as the drug is metabolized or removed from the nerve by the vascular system.
Toxicity of local anesthetics results from absorption into the bloodstream or from inadvertent direct intravascular injection. Toxicity manifests first in the more sensitive CNS and then the cardiovascular system.
Central Nervous System Toxicity
As plasma concentration of local anesthetic rises, symptoms progress from restlessness to complaints of tinnitus. Slurred speech, seizures, and unconsciousness follow. Cessation of the seizure via administration of a benzodiazepine or thiopental and maintenance of the airway are the immediate treatment. If the seizure persists, the trachea must be intubated with a cuffed endotracheal tube to guard against pulmonary aspiration of stomach contents.
Cardiovascular System Toxicity
With increasingly elevated plasma levels of local anesthetics, progression to hypotension, increased P-R intervals, bradycardia, and cardiac arrest may occur. Bupivacaine is more cardiotoxic than other local anesthetics. It has a direct effect on ventricular muscle, and because it is more lipid soluble than lidocaine, it binds tightly to sodium channels (it is called the fast-in, slow-out local anesthetic). Patients who have received an inadvertent intravascular injection of bupivacaine have experienced profound hypotension, ventricular tachycardia and fibrillation, and complete atrioventricular heart block that is extremely refractory to treatment. The toxic dose of lidocaine is approximately 5 mg/kg; that of bupivacaine is approximately 3 mg/kg.
Calculation of the toxic dose before injection is imperative. It is helpful to remember that for any drug or solution, 1% = 10 mg/mL. For a 50-kg person, the toxic dose of bupivacaine would be approximately 3 mg/kg, or 3 × 50 = 150 mg. A 0.5% solution of bupivacaine is 5 mg/mL, so 150 mL/5 mg/mL = 30 mL as the upper limit for infiltration. For lidocaine in the same patient, the calculation is 50 kg × 5 mg/mL = 250 mg toxic dose. If a 1% solution is used, the allowed amount would be 250 mg/10 mg/mL = 25 mL.
Additives to Local Anesthetics
Epinephrine has one physiologic and several clinical effects when added to local anesthetics. Epinephrine is a vasoconstrictor, and by reducing local bleeding, molecules of the local anesthetic remain in proximity to the nerve for a longer time period. Onset of the nerve block is faster, the quality of the block is improved, the duration is longer, and less local anesthetic will be absorbed into the bloodstream, thereby reducing toxicity. Although epinephrine 1:200,000 (5 g/mL) added to a local anesthetic for infiltration will greatly lengthen the time of analgesia, epinephrine-containing solutions should not be injected into body parts with end-arteries, such as toes or fingers, as vasoconstriction may lead to ischemia or loss of a digit. When added to the local anesthetic, sodium bicarbonate will raise the pH, favoring the nonionized uncharged form of the molecule. This speeds the onset of the block, especially in local anesthetics that are mixed with epinephrine. The pH of such solutions is around 4.5; therefore, the addition of sodium bicarbonate results in a relatively large increase in pH.16
Regional Anesthesia: Peripheral vs. Central
Local anesthetic can be injected peripherally, near a large nerve or plexus, to provide anesthesia to a larger region of the body. Examples include the brachial plexus for surgery of the arm or hand, blockade of the femoral and sciatic nerves for surgery of the lower extremity, ankle block for surgery of the foot or toes, intercostal block for analgesia of the thorax postoperatively, or blockade of the cervical plexus, which is ideal for carotid endarterectomy. Risks of peripheral regional nerve blocks are dependent on their location. For example, nerve blocks injected into the neck risk puncture of the carotid or vertebral arteries, intercostal nerves are in close proximity to the vascular bundle and have a high rate of absorption of local anesthetic, and nerve blocks of the thorax run the risk of causing pneumothorax. All peripheral nerve blocks may be supplemented intraoperatively with IV sedation and/or analgesics.
Central Nerve Blocks: Spinal and Epidural
Local anesthetic injected centrally near the spinal cord—spinal or epidural anesthesia—provides anesthesia for the lower half of the body. This is especially useful for genitourinary, gynecologic, inguinal hernia, or lower extremity procedures. Spinal and epidural anesthesia block the spinal nerves as they exit the spinal cord. Spinal nerves are mixed nerves; they contain motor, sensory, and sympathetic components. The subsequent block will cause sensory anesthesia, loss of motor function, and blockade of the sympathetic nerves from the level of the anesthetic distally to the lower extremities. Subsequent vasodilation of the vasculature from sympathetic block may result in hypotension, which is treatable with IV fluids and/or pressors.
Local anesthetic is injected directly into the dural sac surrounding the spinal cord. The level of injection is usually below L1 to L2, where the spinal cord ends in most adults. Because the local anesthetic is injected directly into the cerebrospinal fluid surrounding the spinal cord, only a small dose is needed, the onset of anesthesia is rapid, and the blockade is thorough. Lidocaine, bupivacaine, and tetracaine are commonly used agents of differing durations; the block wears off naturally via drug uptake by the cerebrospinal fluid, bloodstream, or diffusion into fat. Epinephrine as an additive to the local anesthetic will significantly prolong the blockade.
Possible complications include hypotension, especially if the patient is not adequately prehydrated; high spinal block requires immediate airway management; and postdural puncture headache sometimes occurs. Spinal headache is related to the diameter and configuration of the spinal needle and can be reduced to approximately 1% with the use of a small 25- or 27-gauge needle.
Cauda equina syndrome is injury to the nerves emanating distal to the spinal cord resulting in bowel and bladder dysfunction and lower extremity sensory and motor loss. It has mainly been seen in cases in which indwelling spinal microcatheters and high (5%) concentrations of lidocaine were used. Indwelling spinal catheters are no longer used.
Epidural anesthesia could also be called extradural anesthesia, because local anesthetics are injected into the epidural space surrounding the dural sac of the spinal cord. Much greater volumes of anesthetic are required than with spinal anesthesia, and the onset of the block is longer—10 to 15 minutes. As in spinal anesthesia, local anesthetic bathes the spinal nerves as they exit the dura; the patient achieves analgesia from the sensory block, muscle relaxation from blockade of the motor nerves, and hypotension from blockade of the sympathetic nerves as they exit the spinal cord. Note that regional anesthesia, whether peripheral or central, provides only two of the three major components of anesthesia—analgesia and muscle relaxation. Anxiolysis, amnesia, or sedation must be attained by supplemental IV administration of other drugs (e.g., the benzodiazepines or propofol infusion).
Complications are similar to those of spinal anesthesia. Inadvertent injection of local anesthetic into a dural tear will result in a high block, manifesting as unconsciousness, severe hypotension, and respiratory paralysis requiring immediate aggressive hemodynamic management and control of the airway. Indwelling catheters are often placed through introducers into the epidural space, allowing an intermittent or continuous technique, as opposed to the single-shot method of spinal anesthesia. By necessity, the epidural-introducing needles are of a much larger diameter (17- or 18-gauge) than spinal needles, and accidental dural puncture more often results in a severe headache that may last up to 10 days if left untreated.