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Depression is a very common mood disorder characterized by sadness and pessimism. Its cause is multifactorial, but pharmacological treatment is based on the presumption that its manifestations are due to a brain deficiency of dopamine, norepinephrine, and serotonin or altered receptor activities. Up to 50% of patients with major depression hypersecrete cortisol and have abnormal circadian secretion. Current pharmacological therapy utilizes drugs that increase brain levels of these neurotransmitters: tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), MAO inhibitors, and atypical antidepressants. The mechanisms of action of these drugs result in some potentially serious anesthetic interactions. Electroconvulsive therapy (ECT) is increasingly used for refractory severe cases and may be continued prophylactically after the patient’s mood recovers. The use of general anesthesia for ECT is largely responsible for its safety and widespread acceptance.
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Selective Serotonin Reuptake Inhibitors
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SSRIs include fluoxetine, sertraline, and paroxetine, which some clinicians consider first-line agents of choice for depression. A surprisingly large fraction of patients undergoing elective surgery will be receiving one of these agents. These agents have little or no anticholinergic activity and do not generally affect cardiac conduction. Their principal side effects are headache, agitation, and insomnia. Other agents include the norepinephrine–dopamine reuptake inhibitors and the serotonin–norepinephrine reuptake inhibitors.
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Tricyclic Antidepressants
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Tricyclic antidepressants are used for the treatment of depression and chronic pain syndromes. All tricyclic antidepressants work at nerve synapses by blocking neuronal reuptake of catecholamines, serotonin, or both. Desipramine and nortriptyline are used because they are less sedating and tend to have fewer side effects. Other agents are generally more sedating and include amitriptyline, imipramine, protriptyline, amoxapine, doxepin, and trimipramine. Clomipramine is used in the treatment of obsessive–compulsive disorders. Most tricyclic antidepressants also have significant anticholinergic (antimuscarinic) actions: dry mouth, blurred vision, prolonged gastric emptying, and urinary retention. Quinidine-like cardiac effects include tachycardia, T-wave flattening or inversion, and prolongation of the PR, QRS, and QT intervals. Amitriptyline has the most marked anticholinergic effects, whereas doxepin has the fewest cardiac effects.
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St. John’s wort is being used with increased frequency as an over-the-counter therapy for depression. Because it induces hepatic enzymes, blood levels of other drugs may decrease, sometimes with serious complications. During the preoperative evaluation, the use of all over-the-counter medications should be reviewed.
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Perioperative Management
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Antidepressant drugs are generally continued perioperatively. Increased anesthetic requirements, presumably from enhanced brain catecholamine activity, have been reported with these agents. Potentiation of centrally acting anticholinergic agents (atropine and scopolamine) may increase the likelihood of postoperative sedation, confusion, delirium, blurred vision, and urinary retention.
The most important interaction between anesthetic agents and tricyclic antidepressants is an exaggerated response to both indirect-acting vasopressors and sympathetic stimulation. Chronic therapy with tricyclic antidepressants is reported to deplete cardiac catecholamines, theoretically potentiating the cardiac depressant effects of anesthetics. If hypotension occurs, small doses of a direct-acting vasopressor should be used instead of an indirect-acting agent. Amitriptyline’s anticholinergic action may occasionally contribute to postoperative delirium.
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Monoamine Oxidase Inhibitors
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MAO inhibitors were the first medications shown to be effective for depression. They are no longer considered first- or second-line agents due to their side effects. MAO inhibitors block the oxidative deamination of naturally occurring amines. At least two MAO isoenzymes (types A and B) with differential substrate selectivities have been identified. MAO-A is selective for serotonin, dopamine, and norepinephrine, whereas MAO-B is selective for dopamine and phenylethylamine. Nonselective MAO inhibitors include phenelzine, isocarboxazid, and tranylcypromine. Selective MAO-B inhibitors are useful in the treatment of PD. Additionally, unlike older nonreversible MAO inhibitors, reversible MAO-A inhibitors have been developed. Side effects include orthostatic hypotension, agitation, tremor, seizures, muscle spasms, urinary retention, paresthesias, and jaundice. The most serious sequela is a hypertensive crisis that occurs following ingestion of tyramine-containing foods (cheeses and red wines), because tyramine is used to generate norepinephrine.
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Phenelzine can decrease plasma cholinesterase activity and prolong the duration of succinylcholine. Opioids should generally be used with caution in patients receiving MAO inhibitors, as rare but serious reactions to opioids have been reported. Most serious reactions are associated with meperidine, resulting in hyperthermia, seizures, and coma. Meperidine should not be administered to patients receiving MAO inhibitors. As with tricyclic antidepressants, exaggerated responses to vasopressors and sympathetic stimulation should be expected. If a vasopressor is necessary, a direct-acting agent in small doses should be employed. MAO inhibitors are used today infrequently.
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Patients taking St. John’s wort are at increased risk of serotonin syndrome, as are those taking drugs with similar effects (eg, MAO inhibitors, meperidine). Serotonin syndrome manifestations include agitation, hypertension, hyperthermia, tremor, acidosis, and autonomic instability. Treatment is supportive, along with the administration of a 5-HT antagonist (eg, cyproheptadine).
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Mania is a mood disorder characterized by elation, hyperactivity, and flight of ideas. Manic episodes may alternate with depression in patients with a bipolar (formerly manic–depressive) disorder. Mania is thought to be related to excessive norepinephrine activity in the brain. The most common agents used for maintenance therapy for this condition are lithium, valproate, quetiapine, and lamotrigine. Aripiprazole, olanzapine, and risperidone are used if the first group fails.
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The mechanism of action of lithium is poorly understood. It has a narrow therapeutic range, with a desirable blood concentration between 0.8 and 1.0 mEq/L. Side effects include reversible T-wave changes, mild leukocytosis, and, on rare occasions, hypothyroidism or a vasopressin-resistant diabetes insipidus-like syndrome. Toxic blood concentrations produce confusion, sedation, muscle weakness, tremor, and slurred speech. Still higher concentrations result in widening of the QRS complex, atrioventricular block, hypotension, and seizures.
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Although lithium is reported to decrease minimum alveolar concentration and prolong the duration of some NMBs, clinically these effects seem to be minor. Blood levels should be checked perioperatively. Sodium depletion (secondary to loop or thiazide diuretics) decreases renal excretion of lithium and can lead to lithium toxicity. Fluid restriction and overdiuresis should be avoided. Lithium dilution cardiac output measurements are contraindicated in patients on lithium therapy.
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Patients with schizophrenia display delusions, hallucinations, disorganized or withdrawn behavior, disorganized speech, and severe emotional withdrawal. The diagnoses of schizoaffective disorder, bipolar disorder, and severe depression will need to be excluded. Schizophrenia is thought to result from an excess of dopaminergic activity in the brain.
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The most commonly used antipsychotics include phenothiazines, thioxanthenes, phenylbutylpiperidines, dihydroindolones, dibenzapines, benzisoxazoles, and butyrophenones. There are numerous trade names for these drugs. First-generation antipsychotic medications had strong dopamine antagonistic effects, leading to extrapyramidal side effects (eg, muscle rigidity and progression to tardive dyskinesia). Second-generation agents have less dopamine antagonism and reduced extrapyramidal effects. The antipsychotic effect of these agents seems to be due to dopamine antagonist activity. Most cause weight gain and sedation and are mildly anxiolytic. Mild α-adrenergic blockade and anticholinergic activity are also observed. Side effects include orthostatic hypotension, acute dystonic reactions, and parkinsonism-like manifestations. Risperidone and clozapine have little extrapyramidal activity, but the latter is associated with a significant incidence of granulocytopenia. T-wave flattening, ST segment depression, and prolongation of the PR and QT intervals may be seen, increasing the risk of les torsades des pointes.
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Continuing antipsychotic medication perioperatively is desirable. Reduced anesthetic requirements may be observed in some patients, and some patients may experience perioperative hypotension.
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NEUROLEPTIC MALIGNANT SYNDROME
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Neuroleptic malignant syndrome is a rare and life-threatening complication of antipsychotic therapy that may occur hours or weeks after drug administration. It has also accompanied abrupt withdrawal of medication for PD. Meperidine and metoclopramide can also precipitate the disorder. The mechanism is related to dopamine blockade in the basal ganglia and hypothalamus and impairment of thermoregulation. In its most severe form, the presentation is similar to that of malignant hyperthermia. Muscle rigidity, hyperthermia, rhabdomyolysis, autonomic instability, and altered consciousness are seen. Creatine kinase levels are often high. The mortality rate approaches 20% to 30%, with deaths occurring primarily as a result of kidney failure or arrhythmias. Treatment begins with stopping the offending agent and initiating supportive care. Dantrolene and bromocriptine have been used, but there is no strong evidence for consistent efficacy. Differential diagnoses include serotonin syndrome, malignant hyperthermia, malignant catatonia, and some other acute intoxications (eg, cocaine).
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Behavioral disorders from abuse of psychotropic (mind-altering) substances may involve a socially acceptable drug (alcohol), a medically prescribed drug (eg, an opioid or diazepam), or an illegal substance (eg, cocaine or “ecstasy”). With chronic abuse, patients develop tolerance to the drug and varying degrees of psychological and physical dependence. Physical dependence is most often seen with opioids, barbiturates, alcohol, and benzodiazepines. Life-threatening complications primarily due to sympathetic overactivity can develop during abstention.
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Knowledge of a patient’s substance abuse preoperatively may prevent adverse drug interactions, predict tolerance to anesthetic agents, and facilitate the recognition of drug withdrawal. The history of substance abuse may be volunteered by the patient (usually only on direct questioning) or deliberately hidden.
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Anesthetic requirements for substance abusers vary, depending on whether the drug exposure is acute or chronic (Table 28–4). Elective procedures should be postponed for acutely intoxicated patients and those with signs of withdrawal. When surgery is deemed necessary in patients with physical dependence, perioperative doses of the abused substance should be provided, or specific agents should be given to prevent withdrawal. In the case of opioid dependence, any opioid can be used, whereas for alcohol, a benzodiazepine is usually substituted due to the reluctance of hospital pharmacies to dispense alcohol-containing beverages to patients. Alcoholic patients should receive B vitamin/folate supplementation to prevent Korsakoff syndrome. Tolerance to most anesthetic agents is often seen but is not always predictable. For general anesthesia, a technique primarily relying on a volatile inhalation agent may be preferable so that anesthetic depth can be readily adjusted according to individual need. Awareness monitoring should be likewise considered. Opioids with mixed agonist–antagonist activity can precipitate acute withdrawal. Nevertheless, buprenorphine is often used to manage substance disorders. Clonidine is a useful adjuvant in the treatment of postoperative withdrawal syndromes.
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Patients routinely present acutely intoxicated for emergency surgery following trauma related to substance abuse. Patients may have consumed more than one intoxicating agent. Acute cocaine intoxication may produce hypertension secondary to the increase in central neurotransmitters, such as norepinephrine and dopamine. Hypertension and arrhythmias can occur perioperatively. Chronic abusers deplete their sympathomimetic neurotransmitters, potentially developing hypotension. Amphetamine abusers have similar anesthetic concerns, as amphetamines also affect the sympathetic nervous system.
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Patients on chronic, prescribed opioid therapy, or those taking medications illicitly, have substantially increased postoperative opioid requirements. We strongly advocate for multimodal approaches to pain control perioperatively. Whenever possible patients should remain on their maintenance methadone or buprenorphine.
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Consultation with pain management and addiction specialists is often indicated.
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CASE DISCUSSION Anesthesia for Electroconvulsive Therapy
A 64-year-old man with depression refractory to drug therapy is scheduled for electroconvulsive therapy (ECT).
How is ECT administered? The electroconvulsive shock is applied to one or both cerebral hemispheres to induce a seizure. Variables include stimulus pattern, amplitude, and duration. The goal is to produce a therapeutic generalized seizure 30 to 60 s in duration. Electrical stimuli are usually administered until a therapeutic seizure is induced. A good therapeutic effect is generally not achieved until a total of 400 to 700 seizure seconds have been induced. Because only one treatment is given per day, patients are usually scheduled for a series of treatments, generally two or three a week. Progressive memory loss often occurs with an increasing number of treatments, particularly when electrodes are applied bilaterally.
Why is anesthesia necessary? When the efficacy of ECT was discovered, enthusiasm was tempered in the medical community because drugs were not used to control the violent seizures caused by the procedure, thus engendering a relatively high incidence of musculoskeletal injuries. Moreover, when an NMB was used alone, patients sometimes recalled being paralyzed and awake just prior to the shock. The routine use of general anesthesia to ensure amnesia and neuromuscular blockade to prevent injuries has renewed interest in ECT. The current mortality rate for ECT is estimated to be one death per 10,000 treatments.
What are the physiological effects of ECT-induced seizures? Seizure activity is characteristically associated with an initial parasympathetic discharge followed by a more sustained sympathetic discharge. The initial phase is characterized by bradycardia and increased secretions. Marked bradycardia (<30 beats/min) including transient asystole, is occasionally seen. The hypertension and tachycardia that follow are typically sustained for several minutes. Transient autonomic imbalance can produce arrhythmias and T-wave abnormalities on the electrocardiogram. Cerebral blood flow and ICP, intragastric pressure, and intraocular pressure all transiently increase.
Are there any contraindications to ECT? Contraindications are a recent myocardial infarction (usually <3 months), a recent stroke (usually <1 month), an intracranial mass or aneurysm, or increased ICP from any cause. More relative contraindications include angina, poorly controlled heart failure, significant pulmonary disease, bone fractures, severe osteoporosis, pregnancy, glaucoma, and retinal detachment.
What are the important considerations in selecting anesthetic agents? Amnesia is required only for the brief period (1–5 min) from when the NMB is given to when a therapeutic seizure has been successfully induced. The seizure itself usually results in a brief period of anterograde amnesia, somnolence, and often confusion. Consequently, only a short-acting induction agent is necessary. Moreover, because most induction agents (barbiturates, etomidate, benzodiazepines, and propofol) have anticonvulsant properties, small doses must be used. Seizure threshold is increased and seizure duration is decreased by all of these agents.
Following adequate preoxygenation, methohexital (0.5–1 mg/kg) is most commonly employed. Propofol (1–1.5 mg/kg) may be used, but higher doses reduce seizure duration. Benzodiazepines raise the seizure threshold and decrease duration. Ketamine increases seizure duration but is generally not used because it also increases the incidence of delayed awakening, nausea, and ataxia and is also associated with hallucinations during emergence. Use of etomidate also prolongs recovery. Short-acting opioids, such as alfentanil, are not given alone because they do not consistently produce amnesia. However, alfentanil can be a useful adjunct when very small doses of methohexital (10–20 mg) are required in patients with a high seizure threshold. In very small doses, methohexital may actually enhance seizure activity. Increases in seizure threshold are often observed with each subsequent ECT.
Neuromuscular blockade is required from the time of electrical stimulation until the end of the seizure. A short-acting agent, such as succinylcholine (0.25–0.5 mg/kg), is most often selected. Controlled mask ventilation, using a self-inflating bag device or an anesthesia circle system, is required until spontaneous respirations resume.
Can seizure duration be increased without increasing the electrical stimulus? Hyperventilation can increase seizure duration and is routinely employed in some centers. Intravenous caffeine (125–250 mg), given slowly, has also been reported to increase seizure duration.
What monitors should be used during ECT? Monitoring should be similar to what is appropriate with the use of any other general anesthetic. Seizure activity is sometimes monitored by an unprocessed electroencephalogram. It can also be monitored in an isolated limb: a tourniquet is inflated around one arm prior to injection of succinylcholine, preventing entry of the NMB and allowing observation of convulsive motor activity in that arm.
How can the adverse hemodynamic effects of the seizure be controlled in patients with limited cardiovascular reserve? Exaggerated parasympathetic effects should be treated with atropine. In fact, premedication with glycopyrrolate is desirable both to prevent the profuse secretions associated with seizures and to attenuate bradycardia. Nitroglycerin, nifedipine, and α- and β-adrenergic blockers have all been employed successfully to control sympathetic manifestations. High doses of β-adrenergic blockers (esmolol, 200 mg), however, are reported to decrease seizure duration.
What if the patient has a pacemaker? Patients with pacemakers may safely undergo electroconvulsive treatments, but a magnet should be readily available to convert the pacemaker to a fixed mode, if necessary.