Perioperative Considerations for Patients Exposed to Psychostimulants

Trent D. Emerick, MD, MBA; Thomas J. Martin, PhD; Douglas G. Ririe, MD, PhD

Anesth Analg. 2023;137(3):474-487.

Abstract and Introduction

Abstract

Concerns regarding the perioperative management of acute psychostimulant intoxication have been recognized for decades, but novel and diverse substances in this class continue to be developed. Despite the similarities in mechanisms of action among psychostimulants, each subclass within this broad category has unique receptor specificity and different mechanisms that play a role in patient clinical presentation. These issues present challenges to anesthesia providers when caring for patients with either acute or chronic exposure to psychostimulants during the perioperative period. Challenges result from both physiological and psychological effects that influence the action of the primary anesthetic agent, adjuvant anesthetics, and analgesics used for perioperative management of pain. The epidemiology, pharmacology, and perioperative implications of psychostimulant use are presented for amphetamines and similar acting nonamphetamines, cocaine, and, finally, the mixed-action drugs known as entactogens that share stimulant and psychedelic properties. This information is then used as the foundation for safe and effective perioperative management of patients exposed to psychostimulants.

Introduction

The use of psychostimulants is widespread, with an estimated lifetime prevalence of 7%,^[1,2] and psychostimulant-related mortality continues to rise (Figure 1).^[3] The well-known stimulants methamphetamine and cocaine remain readily accessible as new substances are synthesized. Escalating legal use of prescription psychostimulants, particularly treatment of attention deficit hyperactivity disorder (ADHD) and even narcolepsy, has contributed to increased nonmedical use.^[4] Psychostimulants may play a role in the management of chronic noncancer pain as well, especially pain of neuropathic origin.^[5]

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Figure 1.

Increase in psychostimulant use. Overdose deaths with cocaine and psychostimulants in the United States from 1999 to 2020. Over the time period, deaths have increased, with a rapid escalation over the past 5 years. From 2019 to 2020, the rate of drug overdose deaths involving cocaine increased 22%, while overdose deaths involving psychostimulants with abuse potential increased 50%. Cocaine is the blue line, and psychostimulants with abuse potential are the orange line. Psychostimulants with abuse potential include such drugs as methamphetamine, amphetamine, and methylphenidate. Deaths may involve more than 1 drug. The percentage of drug overdose deaths that identified the specific drugs involved varied by year, ranging from 75% early to 94% in 2020. Adapted from Hedegaard et al.³

Many psychostimulants used recreationally act by increasing catecholamine levels, generally by increasing release or blocking reuptake, while others are more varied in their neurotransmitter activity. Some compounds display both psychostimulant and hallucinogenic activity through a combination of pharmacological activities.

Considering the ubiquity of psychostimulants, anesthesia providers should be familiar with the clinical features of acute intoxication and chronic use. Patients exposed to these substances present for both elective and emergent surgeries. Appreciation of the perioperative implications is essential to effectively manage patients in the safest manner. Herein, we review the pharmacology of these drugs and the considerations of exposure in patients presenting for anesthetic care, particularly focusing on substances with known perioperative implications.

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Table 1. Classification of Psychostimulants and Entactogens With Summary of Action and Side Effects
Categories	Example	Principle mechanism of action	Other actions	Desired effects	Specific adverse effects	Shared common adverse effects	Abuse	Physical dependence
Amphetamines and similar-acting nonamphetamine stimulants	Amphetamine and methylphenidate	Increased norepinephrine and dopamine; release of dopamine and norepinephrine and inhibition of transporters	Release of epinephrine, serotonin, and histamine; also inhibits MAO	Increased energy, wakefulness, excitement/euphoria, improved cognition, enhanced physical performance, and decreased appetite		Tachycardia, tachypnea, hypertension, diaphoresis, agitation, confusion, delirium, psychosis, hyperthermia, and hypovolemia	Yes	Yes
Amphetamines and similar-acting nonamphetamine stimulants	Amphetamine derivatives: methamphetamine	Release of dopamine and serotonin; reverse transport of dopamine	Release of norepinephrine, epinephrine; and inactivates reuptake		Dopaminergic toxicity and resulting Parkinsonism; short- and long-term paranoia and psychosis		Yes	Yes
Local anesthetic–based stimulant	Cocaine	Increase dopamine and norepinephrine by inhibiting reuptake; also blocks sodium channels	Also increase serotonin and epinephrine	Increased energy, sense of well-being, euphoria/invincibility, confidence, elevated mood, and increased libido	Peripheral vasoconstrictive effects on heart and vasculature; chest pain, arrhythmias, and myocardial ischemia		Yes	Yes
Entactogens: stimulants with psychedelic properties, including social and sensory effects	Synthetic amphetamine derivatives: MDMA/ecstasy	Release of serotonin	Release of dopamine	Increased energy, feeling of personal relatedness/connectedness, euphoria, perception of sociability and enhanced communication, ability to empathize, and sexual arousal	Serotonin syndrome		Yes	Yes
	Nonamphetamine synthetics	Release dopamine, norepinephrine and serotonin; and reverse transport	May interact directly with monoamine receptors; may block reuptake		Excited/agitated delirium; serotonin syndrome		Yes	Yes
	Khat derivatives: cathinones*				Excited/agitated delirium; serotonin syndrome		Yes	Yes

Abbreviations: MAO, monoamine oxidase; MDMA, 3,4-methylenedioxymethamphetamine.

Table 2. Therapy for Management of Acute Psychostimulant Intoxication
Indication	Medication class	Medications/therapies	Effects	Adverse effects
CNS excitement and agitation, tachycardia, and hypertension	Benzodiazepines	Midazolam and lorazepam	Sedation, blunt hyperadrenergic effect, reduced motor agitation, and reduced violence; reduced centrally mediated tachycardia and hypertension	Respiratory depression
CNS excitement and agitation, tachycardia, and hypertension	Alpha-2 agonists	Dexmedetomidine	Sedation, reduced blood pressure and heart rate	Transient increase in blood pressure
Psychotic features and benzodiazepine failure	Neuroleptics	Haloperidol	Sedation	Long QT, reduced heat dissipation, neuroleptic malignant syndrome, may lower seizure threshold
Hypertension, stroke, myocardial ischemia, and hemorrhage	Direct-acting vasodilators	Nitroprusside, nitroglycerin, and hydralazine	Reduced blood pressure and compensatory increase in heart rate	Toxicity of nitroprusside
Reduce blood pressure and/or heart rate control	Calcium channel blockers	Nicardipine, diltiazem, and clevidipine	Reduced blood pressure and decreased tachycardia	Cardiac conduction disturbances
Hypertension and tachycardia	Mixed alpha- and beta-antagonists	Labetalol	Reduced blood pressure and decreased tachycardia	Much more beta- than alpha-antagonist
Hypotensive vasoplegia	Monoamine oxidase inhibitors	Methylene blue	Inhibited vasorelaxation	Serotonin syndrome
Serotonin syndrome	Benzodiazepines and serotonin antagonists	Midazolam, lorazepam, cyproheptadine, fluid management, and supportive treatment	Sedation, reduced motor agitation, maintain normothermia, minimized hemodynamic and autonomic instability, minimized agitation, and reversed serotonin effects	Respiratory depression: benzodiazepines; antihistamine effects of cyproheptadine: urinary retention, dry mouth, and blurred vision
Rhabdomyolysis	Crystalloid	Normal saline fluid management, supportive treatment, monitor for compartment syndrome, and monitor serum electrolytes	Maintained appropriate urine output, avoided hypovolemia, and managed potassium	Fluid overload, acid-base, or electrolyte disturbance

Abbreviation: CNS, central nervous system.

Table 3. Anesthetic Implications of Psychostimulants.
Common issues with psychostimulants	Tachycardia, hypertension, arrhythmia, myocardial infarction, vasospasm, delayed emergence, emergence delirium, and agitation
Regional anesthesia	May be beneficial to monitor neurological status; general anesthesia may be of benefit to control CNS stimulation-related problems, reduce metabolic demands, manage cardiovascular issues, and to facilitate cooling
Adrenergic blockade	Beta-blockers are generally contraindicated, as with other stimulants such as cocaine, due to the unopposed alpha-adrenergic agonism; labetalol, with its dual mechanism of alpha and beta antagonism, is also less than ideal
Commonly used medications	Benzodiazepines, alpha-2 agonists, and propofol are often useful. Benzodiazepines and antidepressant medications can be used to treat withdrawal symptoms of amphetamines
Serotonin syndrome	Serotonin syndrome risk exists (especially MDMA)
Treatment of hypotension	Direct-acting vasopressors, phenylephrine, epinephrine, or norepinephrine should be used to treat hypotension; ephedrine should be avoided
Change in anesthetic requirements	Initial sympathomimetic state from amphetamines may initially raise the MAC; chronic use of amphetamines seems to lower MAC or have little effect
Pulmonary complications	Pulmonary complications are common from inhalational injury, noncardiogenic pulmonary edema, pulmonary hypertension, pneumonia, or aspiration pneumonia
Medications to avoid	Succinylcholine should be avoided (or dose reduced) due to possible rhabdomyolysis and hyperkalemia
Supportive care	Supportive treatment is critical (fluids, electrolyte, acid-base balance)
Thermoregulation	Antipyretics and active cooling mechanisms may be needed