Posttraumatic sleep disturbance
Sep. 01, 2023
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This article describes coma due to drug intoxication, including recreational and illicit drugs as well as more commonly used medications such as antidepressant, antiepileptic, and psychotropic medications. Common clinical manifestations are discussed, as well as involvement of organs other than the brain, which may also contribute to the patient’s coma. Other syndromes such as serotonin syndrome, neuroleptic malignant syndrome, and propofol infusion syndrome that may be characterized by drug-induced coma are not discussed in detail.
• Several drugs, therapeutic as well as recreational, can produce a comatose state, either as a desired effect of their administration (eg, anesthetic medications) or due to inappropriate administration, overdose, toxic side effects, or idiopathic reaction.
• Coma may be due to direct toxic effect of drugs on the brain or indirect effect due to disturbances of other systems.
• Response to emergency therapy is helpful in the differential diagnosis, eg, response by recovery after intravenous glucose indicates hypoglycemic coma.
• Coma due to structural lesions usually progresses, whereas toxic or metabolic coma is usually stable or improves.
• In addition to basic care of a comatose patient, specific measures include drug clearance therapy, removal of the unabsorbed drug, and use of drug antagonists, which may be combined in some cases.
Disorders of consciousness include a spectrum of clinical states, with coma at the most severe end of the spectrum. Multiple stages of impairment of consciousness prior to reaching a comatose state include the following (in order of increasing severity): (1) delirium, a state of waxing and waning consciousness with prominent disorientation, fear, and hallucinations, as well as an altered sleep/wake cycle; (2) obtundation, which implies a mild-to-moderate reduction in alertness, with increasing time spent in the sleep state; (3) stupor, a state of deep sleep, from which the patient can be aroused only with repeated and vigorous stimulation; and (4) coma. The term coma, as defined in the classic work of Plum and Posner, is reserved for patients who are in a state of “unarousable psychologic unresponsiveness” (15). Comatose patients do not show any signs of awareness of themselves or of their environment; brainstem reflexes and posturing movements of the extremities are permissible, but eye opening should not occur in response to an external stimulus (even though this notion has been challenged) (13), and the patient should not move in a purposeful fashion.
Many drugs can cause a comatose state, either as an anticipated and desired effect of their administration (eg, anesthetic medications) or due to inappropriate administration, overdose, toxic side effects, or idiopathic reaction. Coma can result from therapeutic drugs as well as recreational drugs and drug abuse. The term “drug-induced coma” often refers to coma induced for therapeutic purposes, eg, barbiturate-induced coma as a neuroprotective measure against hypoxia/ischemia. Therefore, the term “coma due to drug intoxication” is preferred when it is due to drug overdose, inappropriate use, or as an adverse reaction.
The term “encephalopathy” refers to generalized dysfunction of the brain with manifestations varying according to the involvement of brain structures, and coma may occur in severe cases. The causes are varied and may be toxic, metabolic, degenerative, inflammatory, vascular, or posttraumatic. The term “drug-induced encephalopathy” is used when the cause is use or abuse of therapeutic drugs as well as illicit or recreational drugs, but it may be secondary to other drug-induced disorders, such as hepatic encephalopathy, hypertensive encephalopathy, uremic encephalopathy, hyponatremia, and hypoglycemia (11). Encephalopathy may be associated with other neurologic manifestations and does not necessarily lead to coma. Because the focus of this article is on coma due to drug intoxication and not lesser degrees of disturbances of consciousness, reference to encephalopathy will be given only where it is relevant.
• Drug intoxication should be suspected in any patient presenting with extreme drowsiness and coma-altered mental state without another overt etiology.
• History of background illness and drug ingestion is important.
• The neurologic examination may provide clues to drug intoxication.
• The prognosis with most drug intoxications may be good if the patient is carefully supported with adequate critical care.
Drug intoxication leading to coma should be suspected in any patient presenting in an altered mental state without another overt etiology for their clinical condition. A careful history, often obtained from the caregivers of the patient, may help to elucidate predisposing conditions, such as depression or a seizure disorder, drug abuse, as well as prescription medications taken by the individual. Any recent history of erratic or unusual behavior or overt depression should alert the clinician of the possibility of medication overdose. In the absence of ancillary history, a toxicology screen should be performed, including serum and urine. Toxicodynetics aims at defining the time-course of major clinical events in drug overdose.
The physical examination may also give clues to the possibility of drug use or intoxication. The presentation of patients with encephalopathy or coma from drug intoxication is most often acute and rapidly progressive, but in some situations, the patient may have a more subacute course, eg, in acetaminophen overdose leading to hepatic failure. Patients may have adequate treatment of the underlying intoxication but may have further clinical deterioration due to the systemic effects of the offending drug, eg, with lithium-induced renal failure, hypoglycemia due to antiglycemic drugs.
The general physical exam may point to drug abuse as the cause of coma. A careful skin exam may reveal signs of venipuncture, suggesting self-injection of drugs, including heroin. The skin may look jaundiced and the sclera icteric, suggesting hepatic insufficiency. There may be evidence of epistaxis, common with nasal ingestion of cocaine. External signs of trauma, particularly to the head (“battle sign,” “raccoon eyes”), should alert the physician to the possibility of concomitant head injury. The vital signs of the patient may also reflect drug intoxication. For example, benzodiazepines and opiates commonly cause respiratory suppression; amphetamines and cocaine cause hypertension, tachydysrhythmias, and myocardial infarction; and tricyclic antidepressants (TCA) may cause conduction block. Drugs that affect the autonomic nervous system can also cause temperature disturbances, vasoconstriction or vasodilation, and cardiac rhythm disturbances.
The neurologic examination likewise may provide clues to drug intoxication. The pupillary exam may be abnormal; for example, opiates often cause profound miosis, whereas sympathomimetics cause mydriasis. The muscle tone in the extremities may be increased with certain agents, such as psychotropic medications (antipsychotics, selective serotonin reuptake inhibitors), even leading to neuroleptic malignant syndrome. Any focal neurologic signs should alert the clinician to a structural lesion, such as a stroke, which can occur as a complication of drug intoxication (eg, cocaine-induced vasculitis, heroin injection associated with bacterial endocarditis).
The prognosis with most drug intoxications may be good, even for those causing coma, provided that the patient can be carefully supported during the time of intoxication with adequate critical care and management of medical complications. Most often, the effect of the offending medication is relatively short-lived, and a full recovery may be expected within several days. Exceptions include drugs with direct CNS toxic effects, such as cyanide or carbon monoxide, which impair the ability to adequately oxygenate the brain. Other variables affecting outcome include secondary injuries caused to the brain, such as cerebral infarction from a cocaine-induced vasculitis, global anoxic injury from prolonged impaired ventilation with hypotension as may be seen with opiate overdose, or hepatic encephalopathy with hyperammonemia seen in fulminant liver failure caused by acetaminophen overdose.
A 17-year-old male was brought into the emergency department by his friends after a seizure. He was at a party and had been in a back room with “other people” his friends did not know. When discovered by his friends, he was unresponsive, and appeared to have bitten his tongue and been incontinent of urine. He had multiple bruises on his arms and legs, but no overt signs of trauma to his head.
In the emergency department, the patient was stuporous and only briefly and minimally responsive to vigorous shaking and nail bed pressure. His vital signs were: blood pressure 180/100, heart rate 130, respiratory rate 32, temperature 38.5°C. His pupils were 1 mm and equal, but reaction to light was difficult to discern. His corneal and oculocephalic reflexes were intact. His tone was rigid throughout, perhaps more on the right side, and his deep tendon reflexes appeared brisker on the right side. A Babinski sign was present on the right. Initial laboratory evaluation revealed normal complete blood count, serum electrolytes, urinalysis, blood urea nitrogen, creatinine, and glucose.
He was given naloxone 1 mg intravenously, resulting in a temporary mild improvement in his level of arousal. However, with ongoing stupor and concerns for protection of his airway, he was intubated and taken for a head CT, which was normal. With the persistence of right-sided hyperreflexia, he was subsequently taken to MRI, which showed a region of restricted diffusion in the subcortical white matter in the left frontal lobe, consistent with an acute infarction. His serum toxicology screen was positive for opiates and the urine toxicology screen positive for opiates as well as cocaine. It was determined that he had a cocaine-induced vasoconstriction syndrome, and he was admitted to the intensive care unit for supportive management. His blood pressure normalized over the next 24 hours, and he was successfully extubated.
• Several drugs can cause coma.
• Coma may be due to direct toxic effect of drugs on the brain or indirect effect due to disturbances of other systems.
Several drugs can cause coma. An etiological classification of drug-induced coma is shown in Table 1.
• Alcohol: combination with sedative-hypnotics
- Anticholinergic drugs
• Secondary effect of other drug-induced adverse effects
- Drug-induced hypoglycemia, eg, insulin
• Poisons: eg, cyanide, carbon monoxide
- MDMA (Ecstasy)
Table 1 updated from: (11).
Pathomechanism. Coma may be due to direct toxic effect of drugs on the brain or indirect effect due to disturbances of other systems.
• Direct effect of drugs on the brain. This is usually due to drugs that act mainly on the nervous system such as sedative hypnotics. However, overdose of drugs not normally acting on the CNS (eg, propranolol) may also induce coma.
• Coma may be reversible or irreversible if there is significant structural damage to the brain such as in leukoencephalopathy.
• Indirect effect on the brain by drug-induced disorders of other systems. Examples of this are hepatic and renal failure and drug-induced hypoglycemia. A case has been reported of hepatic coma due to hepatotoxicity of abiraterone acetate, a drug used for the treatment of castration-resistant prostate cancer (19).
• Hyperammonemic encephalopathy may occur due to Krebs cycle inhibition or urea cycle deficiency following 5-fluorouracil infusion, but recovery of consciousness usually follows with proper management of hyperammonemia (03).
• Drug-induced respiratory or circulatory failure can also depress the reticular activating system, leading to coma.
Coma is associated with several drug-induced encephalopathies. Normal doses of some drugs may produce overdose effect in some circumstances, such as drug interactions and renal failure, impairing excretion of the drug.
Generally, older patients metabolize medications more slowly and, thus, the elderly population may be at risk of side effects from psychoactive medications, and the duration of effect may be more prolonged. Furthermore, the effect of medications is influenced by concomitant organ system disease, particularly those affecting clearance (hepatic, renal).
Opiates. Overdose of various opiates can cause coma, and this may occur in the hospital setting, such as with unintended overdose of morphine sulfate or with recreational drug use, such as with heroin use. Overdose of opioids causes the triad of coma, respiratory depression, and pinpoint pupils. Systemic manifestations of opiate overdose include hypothermia, hypoventilation, bradycardia, hypotension, and cool, clammy skin. Needle marks should be sought in suspected intravenous drug use, although heroin may also be sniffed, and even first-time users can present in severe states. Respiratory decompensation occurs either because of CNS suppression or secondary to pulmonary edema. The pupils are typically small but reactive and dilate widely in response to a narcotic antagonist (eg, naloxone). Methadone-induced hypoglycemia has been reported in patients with cancer receiving long-acting methadone for pain. The case of an infant who developed hypoketotic, hyperinsulinemic hypoglycemia after an acute, unintentional methadone exposure indicates that hypoglycemia is due to methadone-induced insulin secretion (18).
Benzodiazepines. Distribution of benzodiazepines in the brain and their enhancement of GABA activity at specific sites accounts for the clinical features of benzodiazepine-induced coma to a large extent. Toxicodynetic studies show that nordiazepam is not a cause of coma even in large overdose, whereas oxazepam causes coma only at a very high dose. Deep coma in overdose of nordiazepam and oxazepam involving therapeutic index of less than 20 results from an unrecognized drug-drug interaction (16).
Benzodiazepines can cause decrease in cerebral blood flow and cerebral metabolism, the distribution of which correlates with density of benzodiazepine binding sites. Endozepines, the ligands for benzodiazepine recognition sites on GABAA receptors in the CNS, are elevated. The major site of action of the benzodiazepines is the reticular activating system; however, in high doses generalized cortical depression may occur, which contributes to stupor. Benzodiazepines potentiate the effects of other CNS depressants. With concomitant ethanol ingestion, respiratory depression becomes much more dramatic, and patients may become comatose and require ventilatory support.
Barbiturates. At high concentrations barbiturates dissolve in lipid membranes and interfere with ionic transfer and calcium uptake by nerve cell membrane. They cause a dose-dependent decrease in cerebral blood flow and glucose utilization. Barbiturates act mainly at GABA synapses where they enhance inhibition and suppress excitation. Hypnotic and sedative effects of barbiturates may depress other brain structures in addition to the reticular activating system. Depression of the cerebral cortex can lead to confusion and intellectual impairment. A state of anesthesia supervenes as dosage increases above the hypnotic range. The clinical manifestations include hypotension, hypoventilation, hypothermia, and cool and dry skin. Patients are often hyporeflexive and, with larger doses, brainstem or cranial nerve dysfunction can occur. Pupillary responses, however, are still preserved, except in cases of extreme doses.
Review of literature shows that phenobarbital for the management of seizures in newborns and children might be associated with poisoning, particularly if therapeutic drug monitoring is not used (08).
Cephalosporins. Cephalosporins are an important cause of drug-induced adverse effects on the central nervous system. An analysis of reports of serious adverse reactions of cephalosporins in the French Pharmacovigilance database from 1987 to 2017 revealed that 30.3% of these were encephalopathies (14).
Methamphetamine overdose. This causes delirium, tachycardia, hypertensive crisis, malignant hyperthermia, cardiac arrhythmia, myoclonus, seizures, myoglobinuria, shock, coma, and death.
Methaqualone intoxication. This manifests like barbiturate overdose, but hallucinations and agitated delirium are more common, and with higher doses there may be seizures and coma.
Gamma-hydroxybutyrate (GHB). This is a popular euphoriant as are two of its precursors, gamma-butyrolactone and 1,4-butanediol. Combined with ethanol, these agents have been used as “date-rape” drugs. Overdose can cause sedation, respiratory depression, and coma. A study on patients presenting with drug-induced coma showed that emergency department physicians underestimate diagnoses of GHB intoxication based on clinical observations alone (17). Comparison of clinical diagnosis with the confirmation gas chromatography urine test for GHB intoxication showed sensitivity of 63% and specificity of 93%. Combination of clinical impression with a rapid reliable initial analytical GHB test would be valuable for reducing false negative diagnosis in the future.
Glutethimide toxicity. This resembles barbiturate coma, but pupils are often unequal and nonreactive.
Propofol. This is an agent that may be used to purposefully induce coma as a sedating agent or for control of status epilepticus. Anesthesia is a reversible drug-induced coma and not a state of deep sleep. The mechanisms underlying anesthesia-induced loss of consciousness are not clearly defined. Loss of consciousness is marked simultaneously by an increase in low-frequency EEG power (< 1 Hz), the loss of spatially coherent occipital alpha oscillations (8-12 Hz), and the appearance of spatially coherent frontal alpha oscillations, which reverse with recovery of consciousness (10). Propofol is attractive due to its short half-life, allowing for interruption of infusions to assess the neurologic state of the patient. Misuse of propofol outside the setting of anesthetist supervision, particularly in combination with other CNS depressants, may lead to coma of longer duration with systemic complications. Pop singer Michael Jackson died from a combination of propofol and lorazepam administered at home. Propofol infusion syndrome is a life-threatening syndrome, which includes cardiac failure, severe metabolic acidosis, renal failure, and rhabdomyolysis.
Lithium overdose. This causes drowsiness and sometimes leads to coma, often with seizures. Systemic complications include renal failure, hypothyroidism, and metabolic disturbances.
Metronidazole. Chronic use of metronidazole, an antimicrobial agent, can cause neurotoxic effects including encephalopathy with impairment of consciousness and brain lesions demonstrated on MRI. Some patients recover following discontinuation of the drug. A fatal outcome of metronidazole encephalopathy has been reported in a patient on fluorouracil anticancer therapy when metronidazole was added for treatment of an infection (07).
Valproic acid. Several cases of coma due to therapeutic use of valproic acid in epilepsy as well as to its overdose have been reported in literature. Various explanations have been given for valproic acid-induced coma, and some of these are:
• Overdose is more likely to occur in bipolar disorder where higher doses are used.
• Increased permeability of blood-brain barrier due to intracranial lesions such as glioblastoma multiforme may allow excessive amount of valproic acid to enter the brain.
• Polytherapy with antiepileptic drugs where coma may result from drug interaction after addition of valproic acid.
• Carnitine deficiency. Low serum carnitine levels may predispose patients to impairment of consciousness when treated with valproic acid.
• Hyperammonemia has been reported in valproic acid-induced coma.
Tricyclic antidepressant overdose. This is often seen in attempted suicide, but patients rarely present in coma; more commonly, they are confused, agitated, and lethargic.
Antipsychotic medications. These are commonly used to control agitation and psychosis, but significant side effects can occur with high doses. Hypotension and prolonged Q-T syndrome are the most common cardiovascular side effects, and these can be life threatening. Neuroleptic malignant syndrome manifests as high fever, severe muscle rigidity, and autonomic dysfunction. The presumed pathological mechanism underlying neuroleptic malignant syndrome is sudden and profound central dopamine blockade in the setting of receiving neuroleptic medications, particularly affecting the basal ganglia and hypothalamus. Young males appear to be particularly susceptible to developing neuroleptic malignant syndrome, and other predisposing factors include dehydration, preexisting cognitive dysfunction, and high doses of higher potency neuroleptics (eg, haloperidol), especially when given as an intramuscular injection. A similar syndrome can be seen with abrupt withdrawal of dopaminergic agents, such as levodopa or pramipexole, as well as atypical neuroleptics, such as clozapine and olanzapine.
Anticholinergic syndrome. Accidental ingestion of anticholinergic medications (eg, diphenhydramine) can lead to the anticholinergic syndrome, with blockade of parasympathetic receptors leading to unopposed sympathetic activity. These patients present with tachycardia, hypertension, fever (due to blocked exocrine secretions), dry skin, ileus, and urinary retention, but the presentation with these features can be variable. Patients are delirious, with dilated pupils that are sometimes unreactive. Severe hallucinations, seizures, and cardiac rhythm disturbances can occur. Rarely a comatose state may result. Other drugs that can cause this syndrome include atropine, certain agents used for treatment of Parkinson disease, muscle relaxants, neuroleptics, and tricyclic antidepressants.
Cholinergic syndrome. This can occur with overdose of cholinesterase inhibitors, such as pyridostigmine used by patients with myasthenia gravis, or in poisoning with insecticides, such as organophosphates. These compounds can have muscarinic and nicotinic effects. Manifestations of muscarinic stimulation include excessive salivation, sweating, lacrimation, urination and defecation, muscle fasciculation, miosis, bradycardia, and hypotension. The nicotinic effects include sympathetic stimulation with resulting tachycardia and hypertension.
Sympatholytic syndrome. This occurs with overdose of alpha2-sympathetic agonists, such as clonidine, but it may also occur with opiates and high doses of sedative or hypnotic agents. With the resulting interruption of the sympathetic outflow tract, miosis, bradycardia, hypotension, and hypoventilation occur. Patients develop a decreased level of consciousness and sometimes become comatose.
Salicylate intoxication. This can produce coma via its systemic effects, including fever, anion gap acidosis, pulmonary edema, and respiratory alkalosis. CNS effects include progressive delirium, seizures, and coma.
Cyanide poisoning. This can occur by inhalation or ingestion. Cyanide inhibits electron transfer in the mitochondrial cytochrome oxidase pathway by binding to iron, leading to anaerobic metabolism, lactic acidosis, and histotoxic hypoxia. Clinical manifestations are rapidly progressive delirium, seizures, and coma.
Carbon monoxide (CO) poisoning. Carbon monoxide poisoning typically occurs with exposure to fires, suicide attempts, or defective room ventilation. It is associated with disturbances of neuronal function, membrane metabolism, and anaerobic energy metabolism, respectively. Carbon monoxide, alone or in combination with smoke intoxication, is one of the major causes of poisoning injury and death worldwide; yet, CO intoxication is often overlooked because carbon monoxide is an odorless gas and induces various non-specific symptoms. The first of these to appear are often headache, fatigue, nausea, and concentration difficulties. Acute low-dose carbon monoxide exposure may result in substantial but reversible neuropsychological impairment. The brain and heart are particularly vulnerable to carbon monoxide and, consequently, high-dose exposure may lead to myocardial ischemia and arrhythmia and to neurologic disturbances, including coma, seizures, and focal signs. Carbon monoxide can also evoke chronic neurologic deficits despite normalized carboxyhemoglobin (COHb) levels at the time of hospital admission. Two syndromes occur after acute carbon monoxide poisoning: persistent neurologic sequelae and the interval form of CO poisoning. The latter may occur in 15% to 40% of survivors following acute carbon monoxide poisoning. In patients with the interval form of CO poisoning, neurologic impairment occurs days to weeks after a lucid period. In both syndromes, deficits usually include motor and neuropsychiatric symptoms.
Alcohol and related substances. Alcohol is a common agent of intoxication causing encephalopathy, affecting nearly all age groups and genders. Ethanol alcohol use is commonly complicated by combined overdose with other recreational drugs. Isopropyl alcohol ingestion, found in rubbing alcohol, may cause rapidly progressive coma, hemorrhagic gastritis, and circulatory collapse. Its removal can be aided by hemodialysis. Methanol (methyl alcohol or wood alcohol) when ingested orally is metabolized first to formaldehyde and then to formic acid and its salts, which are toxic to the central nervous system and can cause an anion gap metabolic acidosis. Clinical manifestations of methanol ingestion include optic neuropathy, abdominal pain, and impairment of consciousness, which may result in coma. Intoxication, due to ethylene glycol, commonly used as antifreeze, appears to progress in three discrete stages. The first stage consists of CNS effects: encephalopathy, coma, and seizures. The second stage manifests with cardiopulmonary effects: respiratory failure, pulmonary edema, and heart failure. The third stage involves progressive renal failure and death. The management of both methanol and ethylene glycol intoxication consists of administration of ethanol to block the metabolism of these drugs to their toxic derivatives, hemodialysis, and correction of the metabolic acidosis.
Coma due to acute intoxication with synthetic cannabinoids. Synthetic cannabinoids are designer drugs that bind to the same receptors to which cannabis plant extracts tetrahydrocannabinol (THC) and cannabidiol (CBD) attach. They are also referred to as “synthetic pot” or “spice,” but are not approved for human use. A review of the Toxicology Investigators Consortium Case Registry revealed that among adolescents presenting to an emergency department with acute intoxication due to cannabis or a combination with other drugs, those using only synthetic cannabinoids had three times the odds of having coma, seizures, and central nervous system depression (02).
Coma due to drug-induced cerebrovascular disorders. Drug-induced cerebral vasculitis, often associated with drug abuse, is an example of complications that may be associated with a comatose state. Vasculitis associated with drugs is usually hypersensitivity vasculitis, which can be considered an explanation of acute neurologic deficits resulting from the administration of drugs that normally do not affect the cerebral blood vessels.
Another example is coma with intracerebral hemorrhage due to use of anticoagulants. Drug-induced hypertensive crisis and cardiac arrhythmias are associated with neurologic complications including a comatose state. Drug-induced cardiovascular collapse with cardiac arrest may lead to coma due to cerebral ischemia/hypoxia if resuscitation is not carried out promptly. Drug-induced ischemic stroke involving the brain stem is likely to be associated with coma.
Drugs producing hypoglycemia. Glucose is the only nutrient that brain cells can utilize in sufficient quantity to meet their energy requirements. Fall of blood glucose level to 20 to 50 mg/dL range (normal 80 to 100 mg/dL) can produce convulsions and coma. The most likely cause of hypoglycemia is insulin overdose, but several other drugs can produce hypoglycemia in nondiabetic patients.
Drugs producing hyponatremia. Several drugs produce hyponatremia, which can lead to coma. One example is oxcarbazepine, which can produce hyponatremia (serum sodium level 115 mmol/L), leading to coma.
Miscellaneous drugs with case reports of coma. Rare instances of coma have been reported with selected drugs: cefepime, colloidal silver, lamotrigine, intranasal desmopressin with severe hyponatremia, chloroquine, baclofen, tramadol, acyclovir, primidone, bromide, and over-the-counter hypnotics.
• Elderly persons are more liable to suffer toxic effects of therapeutic drugs due to polypharmacy and overdose effects resulting from renal and hepatic impairment.
• Younger persons are more likely to suffer from toxic effects of drug abuse or suicidal attempts with drugs.
• Children are more susceptible to toxicity due to accidental ingestion of drugs.
There are no overall figures for incidence and prevalence of coma due to drug toxicity. Most of the available information is on coma due to individual drug toxicity. Coma with drug intoxication can affect any age group, and there is no gender predilection. The age group can, however, provide insight to the type of drug intoxication that may have occurred. Small children are susceptible to accidental ingestion, and a careful history of medications in the home may provide clues to the agent. Young adults are more likely to experiment with recreational drugs but are also at risk for suicide attempts, as are those in their middle ages. Elderly patients are more susceptible to the psychoactive effects of medications, and with a higher likelihood of hepatic or renal dysfunction, they are more likely to have ineffective clearance of medications. Elderly persons are the most likely group to be exposed to polypharmacy, and the interaction of different medications becomes even more important.
• The key to prevention of drug poisoning is education at multiple levels.
Parents need to be educated to the risks of prescription medications if accidentally ingested by a child, and childproof caps should be utilized. Education in schools, by public awareness campaigns, and by parents is instrumental in decreasing illicit drug use in teenagers and young adults. Patients should be educated to the potential side effects of prescription medications, and doctors, nurses, and other caregivers must also be aware of the potential for iatrogenic encephalopathy and coma when prescribing and administering drugs.
Drug-induced coma should be differentiated from coma due to structural lesions of the brain and metabolic encephalopathies. There are no hard and fast rules because drug-induced coma may resemble metabolic encephalopathy on one hand and may induce structural lesions in the brain. It is helpful to keep in mind a few rules of classical neurology while investigating a patient with possible drug-induced coma.
• Coma due to structural lesions usually progresses, whereas toxic or metabolic coma is usually stable or improves.
• Structural brain lesions have focal or localizing features, and the manifestations are asymmetrical. Toxic and metabolic lesions usually present with symmetrical neurologic signs but can also have asymmetrical features.
• Abnormal movements often accompany coma due to toxic-metabolic causes, whereas coma due to structural lesions is accompanied by abnormal posturing.
• Reflex eye movements are usually intact in toxic-metabolic coma except with overdose of some drugs such as phenytoin.
• Pupil reactivity is usually spared in toxic-metabolic coma with exception of drugs such as atropine, which dilate the pupils.
• Raised intracranial pressure and papilledema is more likely in intracranial space-occupying lesions. Occasionally these findings may be drug-induced.
• Response to emergency therapy is helpful in the differential diagnosis. Response by recovery after intravenous glucose indicates hypoglycemic coma, response to naloxone usually indicates opiate drug overdose, and response to flumazenil indicates benzodiazepine overdose.
Hypoglycemia should be ruled out immediately, and if there is delay in doing so, patients may be treated with glucose infusion preceded by IV thiamine prophylactically.
A cerebrovascular event must be considered early, as the treatment window is narrow. These may be ischemic, hemorrhagic (subarachnoid hemorrhage, primary intracerebral hemorrhage), cerebral vasoconstriction syndromes, or a reversible posterior leukoencephalopathy caused by hypertension. Clues to the presence of a vascular event include the timing, which is usually sudden or rapidly progressive, with focal neurologic signs on examination. Neuroimaging is instrumental in making the diagnosis, and if a brainstem stroke is suggested, MRI with diffusion-weighted imaging is particularly sensitive for detecting early infarction. Of course, a global anoxic event, such as a cardiac arrest, may often lead to coma as well.
A single seizure rarely produces coma, but status epilepticus can because repeated seizures can prevent the brain from recovering in between seizures. In a patient without overt seizures but continued unexplained unresponsiveness, nonconvulsive seizures should be considered. Severe hyper- or hypothermia can cause coma. Trauma, either specific to the head or to other parts of the body leading to hypotension or hypoxia, should be considered in patients found unconscious.
Multiple metabolic abnormalities can contribute to coma. Severe hyper- or hypoglycemia as well as hypoxia can significantly impair consciousness. Other parameters include imbalances of carbon dioxide, sodium, phosphorus, calcium, and magnesium. Uremia and hyperammonemia should be investigated, particularly if there is suspicion of hepatic encephalopathy. Infections, either systemic or primary to the CNS, need to be addressed rapidly; bacterial meningitis continues to have a significant morbidity and mortality rate associated with it, as do certain viral infections (eg, Herpes simplex virus, West Nile virus). Chronic meningitis may lead to coma due to impaired CSF absorption and elevated intracranial pressure with, or even without, hydrocephalus.
Effects of intoxicating substances, alcohol, or drugs may further impair the level of consciousness in a patient with traumatic brain injury. A study has reviewed initial Glasgow Coma Scale (GCS) score and toxicology screening in patients with blunt head trauma from a trauma database and found that changes in GCS score were significantly higher in the impaired group compared to those with negative drug screening (05). The authors recommended that intoxicating substances should be reversed or allowed to wear off before GCS score is reliably recorded as this can have effects on guiding patient care as well as prognosis.
Neoplasms and infectious mass lesions may cause alteration in mental status and even coma. This may occur secondary to herniation from mass effect, acute hydrocephalus with blockage of the ventricular system, or as an effect of a remote tumor, such as with a paraneoplastic syndrome. Endocrine disorders may alter the mental state, including hypothyroidism and hypocortisolemia. Some dietary deficiencies may cause encephalopathy, most commonly thiamine deficiency in alcoholics. Other considerations include vitamin B12 and niacin deficiency. Coma may be due to rare metabolic disorders such as porphyria and urea cycle defects. Finally, as a diagnosis by exclusion, patients may have psychogenic unresponsiveness.
• Toxicology screen should be performed on serum and urine.
• Complete blood count, blood chemistry, liver function studies, ammonia level, and an arterial blood gas.
• Lumbar puncture if there is suspicion of meningoencephalitis.
• Brain imaging to rule out a primary brain lesion.
The workup for a patient in coma with potential drug intoxication should be rapid, concentrating not only on the potential drug, but also on alternative causes that may require different modes of treatment. A phone call to a family member or housemate can sometimes be helpful, especially if it reveals available drugs, history of previous overdose or illicit drug use, and history of underlying relevant illness (ie, diabetes, metabolic disorder, depression, etc.). After an initial brief examination, stabilization of the patient, blood and urine sampling, administration of glucose, thiamine, and potentially naloxone, then rapid consideration should be given to neuroimaging to rule out a primary CNS event. CT is widely available and has the advantages of being rapid and relatively resistant to mild degrees of patient motion. Intravenous contrast is most often not required in the acute setting, as a CNS event severe enough to cause coma is most likely to be seen on a noncontrast imaging study. One notable exception would be an acute basilar thrombosis, and if this diagnosis is entertained, options to further evaluate this include CT angiography, MRI with diffusion-weighted imaging, and MRA. The most characteristic MRI findings in methanol intoxication with stupor or coma are bilateral putaminal necrosis with or without hemorrhage (04). An emergency EEG should be considered in cases with ongoing seizures with possible status epilepticus and in selected cases in which nonconvulsive status epilepticus is being considered.
A rapid laboratory evaluation is paramount, as this is often the earliest and best clue to potential drug intoxication. This should include a full chemistry profile (including extended electrolytes), complete blood count, blood urea nitrogen, creatinine, glucose, liver function studies, ammonia level, and an arterial blood gas, as well as a thyroid stimulating level and cortisol level in certain circumstances. A CSF evaluation should be considered in patients with signs and symptoms of meningoencephalitis or if the cause is not clear.
The key to establishing a drug as the offending cause of coma is a rapid and comprehensive toxicology screen, which should include both serum and urine. Acetaminophen level is often not included in standard toxicology screens, but if this drug is suspected based on the history, it should be specifically requested. Given the rapid metabolism of some drugs, the urine toxicology screen is important in some cases and should not be overlooked, as the offending agent may have cleared from the blood stream by the time of evaluation. In a retrospective study, use of rapid testing of urine for drugs and other relevant changes in the emergency department had an impact on management of patients with suspected overdose (06). An example of therapy guided by drug-specific urinary findings in this study was administration of bicarbonate for overdose with tricyclic antidepressants.
• Initial step in the care of a comatose patient is respiratory and cardiovascular stabilization.
• Acid-base disturbances should be corrected.
• Secondary cerebral injuries require therapy according to specific complication.
• Drug clearance, use of drug-antagonists, and removal of the unabsorbed drug.
The initial goals in the management of the comatose patient are directed toward respiratory and cardiovascular stabilization. A proper airway should be secured, and if the patients are unable to breathe adequately on their own, they should be intubated and mechanically ventilated. Significant hypotension or hypertension should be recognized early, and adequately treated with vasopressor or antihypertensive medications, respectively, to prevent secondary end-organ injury, including injury to the brain. Cardiac rhythm disturbances are common with certain medications, such as tricyclic antidepressants, and these patients may require temporary pacemaker placement, either by external pads or transvenous pacing wires.
Correction of acid-base disturbances. This is important because many drugs can cause an anion-gap metabolic acidosis (see Table 2), which can lead to further instability.
Anion gap = Na+ - (Cl- + HCO3-)
Normal = 12-15
In patients with suspected acetaminophen overdose, N-acetyl cysteine should be administered, but unfortunately some patients progress to fulminant liver failure and may require transplantation.
Management of secondary cerebral injuries. Patients who develop secondary cerebral injuries require therapy directed at the specific complication. Cerebral vasoconstriction syndromes caused by cocaine, amphetamines, or selective serotonin reuptake inhibitors are often managed with calcium channel blockers. If an intracerebral hemorrhage has developed, strict blood pressure control and correction of any underlying coagulopathy are imperative.
Discontinuation of the offending drug. With idiopathic or unexpected reactions to medications, the offending medication should be investigated and discontinued. In elderly patients, this may be a particularly confusing issue, given the propensity for polypharmacy, but looking for the most recently added agent(s) may provide clues.
Detoxification. This is possible in the acute setting of specific drugs. Acute opiate intoxication may be reversed with naloxone (0.4 to 2.0 mg intravenous, intramuscular, subcutaneous; repeat every 2 to 3 minutes as needed); the potential complications of naloxone include cardiac dysrhythmias (ventricular fibrillation), hypertension, hypotension, pulmonary edema, and hepatotoxicity. Flumazenil is a benzodiazepines antagonist and may be used in cases of benzodiazepines overdose (0.2 mg intravenous over 30 seconds; additional doses up to 0.5 mg may be repeated every minute, up to a cumulative dose of 3 mg; it may be repeated in 20 minutes, but the total dose should not exceed 3 mg in any given hour). Risks associated with flumazenil include seizures, especially in those receiving benzodiazepines as treatment for epilepsy, as well as cardiac dysrhythmias and death.
Drug clearance therapy. Various methods for clearing the responsible drug in cases of poisoning include plasmapheresis and hemodialysis, but elimination of the drug is dependent on the volume of distribution and the degree of protein binding, both of which can hinder the effectiveness of elimination. With lithium overdose, elimination can be enhanced by performing hemodialysis or continuous venovenous hemodialysis. Hemodialysis is not effective, however, for tricyclic antidepressant overdose, but serum alkalinization with intravenous boluses of sodium bicarbonate should be performed, which helps to reduce QRS widening. Intubation and hyperventilation may aid in this process. Flumazenil is contraindicated in patients with tricyclic antidepressant overdose, even with suspected concomitant benzodiazepines use, as this has been associated with an increased risk of seizures and ventricular dysrhythmias. Extracorporeal sorbent detoxification has been proposed as a means of treating severe tricyclic antidepressant overdose. Valproic acid overdose can be treated with L-carnitine therapy, which can enhance the excretion and help to prevent fatal liver failure.
Use of drug antagonists. Physostigmine is used for reversal of anticholinergic toxicity, but it should be reserved for refractory cases because of its adverse effects that include seizures and cardiac rhythm disturbances. Physostigmine has been reported to be successful in the rapid reversal of coma caused by gamma-hydroxybutyric acid, but its use is controversial. Atropine is used to reverse the effects of cholinergic excess. Organophosphate poisoning can be treated with pralidoxime, which releases the toxin bound to acetylcholinesterase. Carnitine supplementation may be useful for treating valproic acid-induced toxicity by limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation.
Removal of the unabsorbed drug. Most other drugs do not have specific antagonists, but deactivation and catharsis of the agent may be effective in decreasing the overall absorption of the medication if still present in the digestive tract. Induced emesis is contraindicated in a patient with a depressed level of consciousness, but gastric lavage may be performed if the patient has the airway secured with an endotracheal tube. A large bore nasogastric tube should be placed, and 5 to 10 ml/kg of normal saline instilled and subsequently aspirated. This should be repeated multiple times until the aspirate becomes clear. A cathartic, such as magnesium or sodium sulfate, may also be given.
Hyperbaric oxygen. Hyperbaric oxygen has been used in the management of coma due to carbon monoxide poisoning and to counteract hypoxia from other tissue poisons such as cyanide, hydrogen sulfide, and carbon tetrachloride (12).
Combination of various methods. Some cases of coma due to drug intoxication require simultaneous use of various approaches. Treatment of methamphetamine poisoning includes sedation with benzodiazepines, oxygen, bicarbonate for acidosis, anticonvulsants, cooling, blood pressure control (preferably with an alpha blocker or direct vasodilator), respiratory and blood pressure support, and cardiac monitoring (09). A comatose patient, who was admitted in respiratory failure and shock after the intentional ingestion of about 280 extended-release 200 mg carbamazepine tablets with a peak serum concentration of 138 µg/mL, developed seizures with an EEG pattern of stimulus-induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction (01). A combination of therapies was used in this case, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous venovenous hemodialysis, and endoscopic intestinal decontamination. Elevation of serum lactate level with high mixed venous saturation suggested possible mitochondrial dysfunction, prompting use of barbiturate-induced coma to reduce cerebral metabolic demand. The patient made a full recovery with normalization of laboratory values. This case illustrates that barbiturate-induced coma, usually used as a neuroprotective measure to prolong coma due to other insults to the brain such as traumatic brain injury, can also be useful in coma due to drug toxicity resulting in impairment of cerebral metabolism.
Most of the available treatments are safe and effective for managing patients with drug-induced coma but some neurologic sequelae may not be reversible.
In the pregnant patient with drug-induced coma, there is added concern of toxic effects of drugs that can cross the placenta, as well as the susceptibility of the fetus to medical complications, such as systemic hypotension or hypoxia.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Daniel Kondziella MD PhD
Dr. Kondziella of Copenhagen University Hospital has no financial relationships to disclose.See Profile
Peter J Koehler MD PhD
Dr. Koehler of Maastricht University has no relevant financial relationships to disclose.See Profile
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