Etiology and pathogenesis
|
• Several drugs can cause coma (both alone and in combination with other drugs). |
|
• 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.
Table 1. Etiological Classification of Coma due to Drug Intoxication
|
• Alcohol: combination with sedative-hypnotics • Anesthetics: eg, propofol • Direct effect from prolonged use or overdose of following drugs: |
|
- Anticholinergic drugs - Antipsychotics - Barbiturates - Benzodiazepines in combination with other CNS depressants - Cephalosporins - Cholinergic drugs - Lithium overdose - Metronidazole - Opioids - Sympatholytic drugs - Tricyclic antidepressants - Valproic acid - Vigabatrin |
• Secondary effect of other drug-induced adverse effects |
|
- Drug-induced hypoglycemia, eg, insulin - Drugs-induced serotonin syndrome - Drug-induced diabetes insipidus with hyperosmolar coma - Drug-induced hyperosmolar non-ketotic diabetic coma: eg, prednisone - Drug-induced hepatic encephalopathy, eg, 5-fluorouracil - Drug-induced cerebrovascular disorders: cerebral vasculitis, cerebral hemorrhage - Drug-induced cardiovascular disorders - Drug-induced hyponatremia - Drug-induced renal disorders: uremic encephalopathy - Neuroleptic malignant syndrome |
• Poisons: eg, cyanide, carbon monoxide • Recreational drugs and drug abuse |
|
- MDMA (Ecstasy) - Gamma-hydroxybutyric acid - Methaqualone - Psychedelics, eg, LSD - Synthetic cannabinoids |
Updated from: (10). |
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 (20). |
|
• 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, 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 (19).
Benzodiazepines. Enhancement of GABA activity at specific cerebral 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 (15).
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 (13).
Cocaine. Cocaine is a psychostimulant and local anesthetic, which is sniffed, injected, or smoked. The latter alkaloidal form is known as “crack” and increasingly common also in European cities. Cocaine is associated with dyskinesias, paranoia, and hallucinatory psychosis. Overdose may lead to hypertensive crisis, malignant hyperthermia, cardiac arrhythmia, myoclonus, seizures, and myoglobinuria, ultimately leading to coma and death. Cerebral vasoconstriction syndrome may lead to infarctions (see also clinical vignette).
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 (18). 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 (09). 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 hypertriglyceridemia, 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 (16). 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.