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Delirium tremens
- 1. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg DELIRIUM TREMENS Background: Delirium tremens (DT) is a potentially fatal form of ethanol (alcohol) withdrawal. Symptoms of ethanol withdrawal and DT have been recognized for hundreds of years, but the debate over their etiology continued into the 1950s. The work of Victor and Adams as well as Isbell finally demonstrated the symptoms related to ethanol abstinence. Symptoms may begin a few hours after the cessation of ethanol, but may not peak until 48-72 hours. Emergency physicians must recognize that the presenting symptoms may not be severe and identify those at risk for developing DT. For patients in DT, early recognition and therapy are necessary to prevent significant morbidity and death. Delirium tremens (DTs) is a severe manifestation of alcohol withdrawal. Pearson first described it in 1813 as an acute psychosis following abstinence from alcohol. Although it only occurs in a relatively small number of patients who undergo alcohol withdrawal, it can be fatal. DTs is a medical emergency that requires prompt recognition and treatment. Pathophysiology: Chronic intake of alcohol affects several of the neurotransmitter systems in the brain. These effects include increased release of endogenous opiates; activation of the gamma-aminobutyric acid-A (GABA-A) receptor and a decrease in GABA-A receptor function, with resultant influx of chloride ions; inhibition of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, which mediates the postsynaptic excitatory effects of glutamate, with up-regulation of this receptor; and interactions with serotonin and dopamine receptors. During withdrawal from alcohol, the loss of GABA-A receptor stimulation causes a reduction in chloride flux and is associated with tremors, diaphoresis, tachycardia, anxiety, and seizures. In addition, the lack of inhibition of the NMDA receptors may lead to seizures and delirium. Excessive nervous system excitability during periods of abstinence from alcohol is related to the effect of alcohol on the number and function of brain receptors. . Frequency: ● In the US: Only 5% of patients with ethanol withdrawal progress to DT. Mortality/Morbidity: Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 2. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg ● Mortality rate may be as high as 35% if untreated but is less than 5% with early recognition and treatment. ● Patients at greatest risk for death are those with extreme fever, fluid and electrolyte imbalance, or intercurrent illness such as pneumonia, hepatitis, or pancreatitis. Sex: Approximately 10% of males and 3-5% of females are alcoholic; 5% of each group experiences DT. Age: Adolescence to late adulthood is typical. History: Alcohol withdrawal syndrome is the clinical syndrome that occurs when people who are physically dependent upon alcohol stop drinking or reduce their alcohol consumption. Alcohol withdrawal syndrome is divided into 4 categories. ● Minor withdrawal (withdrawal tremulousness) occurs within 6-24 hours following the last drink and is characterized by tremor, anxiety, nausea, vomiting, and insomnia. ● Major withdrawal (hallucinations) occurs 10-72 hours after the last drink. The signs and symptoms include visual and auditory hallucinations, whole body tremor, vomiting, diaphoresis, and hypertension. ● Withdrawal seizures (rum fits) occur within 6-48 hours of alcohol cessation and are characterized by major motor seizures that occur during withdrawal in patients who normally have no seizures and have normal EEGs. In 60% of patients, the seizures are multiple, but only 3% of patients go on to develop status epilepticus. About 30-40% of patients with alcohol withdrawal seizures progress to DTs. ● DTs is the most severe manifestation of alcohol withdrawal. It occurs 3-10 days following the last drink. Clinical manifestations include agitation, global confusion, disorientation, hallucinations, fever, and autonomic hyperactivity (tachycardia and hypertension). DT is more common in patients with a long history of ethanol use and a prior history of significant withdrawal. Manifestations of ethanol withdrawal may start several hours to days after cessation or diminution of ethanol intake. Ethanol withdrawal seizures typically occur 6-48 hours after the last drink. DT usually begins 24-72 hours after cessation or reduction of ethanol use. Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 3. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg ● Diagnosis is made when the course progresses beyond the usual symptoms of withdrawal to include altered mental status (eg, confusion, hallucinations, severe agitation) or generalized seizures. Symptoms may include the following: o Tremors o Irritability o Insomnia o Nausea/vomiting (frequently secondary to gastritis or pancreatitis) o Hallucinations (auditory, visual, or olfactory) o Confusion o Delusions o Severe agitation o Seizures - Begin 6-48 hours after the last drink. (Status epilepticus is uncommon in patients with ethanol withdrawal, but ethanol withdrawal is still one of more common causes of status epilepticus.) Physical: ● Examination findings may be nonspecific. Clinicians should look for stigmata of habitual ethanol use, other potential causes for altered mental status (eg, CNS trauma/infection), and any associated medical problems (eg, hepatitis, pancreatitis, pneumonia). o Tachycardia o Hyperthermia o Hypertension o Tachypnea o Diaphoresis o Tremor Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 4. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg o Mydriasis o Diaphoresis o Ataxia o Altered mental status o o Hallucination o Cardiovascular collapse Causes: ● Risk factors for developing DT o Ethanol withdrawal seizures o Prior history of DT o Higher-than-usual quantity and frequency of ethanol consumption (So much individual variability exists that the actual answer may not be clinically relevant.) ● Associated infections or medical problems (eg, pneumonia, hepatitis, pancreatitis) Alcoholic Ketoacidosis Anxiety Epidural and Subdural Infections Herpes Simplex Herpes Simplex Encephalitis Hypocalcemia Hypoglycemia Hypomagnesemia Meningitis Neoplasms, Brain Neuroleptic Malignant Syndrome Status Epilepticus Toxicity, Amphetamine Toxicity, Cocaine Toxicity, Hallucinogen Toxicity, Monoamine Oxidase Inhibitor Toxicity, Phencyclidine Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 5. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg Toxicity, Sympathomimetic Toxicity, Thyroid Hormone Wernicke Encephalopathy Withdrawal Syndromes Lab Studies: ● DT is a clinical diagnosis. Laboratory studies exclude associated medical problems or other diseases. ● Glucose - Low levels due to chronic ethanol ingestion causing glycogen depletion ● Complete blood count (CBC) - Leukocytosis, anemia, elevated mean cell volume, low platelets ● Liver function tests (LFTs) - Elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamyltransferase (GGT), and bilirubin ● PT and aPTT - Elevated PT due to vitamin K deficiency and liver disease ● Arterial blood gases (ABG) - If alcoholic ketoacidosis, diabetic ketoacidosis, or a significant metabolic acidosis is suspected ● Creatine phosphokinase (CPK) - If myocardial infarction is suspected or the patient was unconscious for a long period of time (rhabdomyolysis) ● Ethanol ● BUN/creatinine ● Electrolytes ● Amylase/lipase ● Blood cultures if infection is suspected Imaging Studies: ● Chest x-ray (CXR): Concomitant pneumonia is common in patients with DT. Routinely obtain CXR, particularly in patients with hypoxia, tachypnea, fever, cough, or respiratory distress. Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 6. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg ● CT scan of the head: Indications include focal seizures, status epilepticus, prolonged postictal period, recent head injury. ● Electrocardiogram o Atrial fibrillation is the most common presenting cardiac complaint in the alcoholic patient. o Other findings include atrial flutter, premature atrial contractions, supraventricular tachycardia, and premature ventricular beats. ● The most objective and best validated tool to assess the severity of alcohol withdrawal is the Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar). o This survey consists of 10 items and can be administered rapidly at the bedside. The 10 items include nausea and vomiting, anxiety, tremor, sweating, auditory disturbances, visual disturbances, tactile disturbances, headache, agitation, and clouding of sensorium. Zero to 7 points are assigned for each item except for the last item, which is assigned 0-4 points, with a total possible score of 67. o This scale has been demonstrated to have high reliability, reproducibility, and validity based on comparisons with ratings by experienced clinicians and has been shown to be usable in detoxication units, psychiatry units, and hospital medical/surgical wards. o A score of greater than 15 is seen in patients with moderate-to-severe alcohol withdrawal. Patients with a score greater than 15 or those who have a history of alcohol withdrawal seizures should be treated with medication upon presentation. These patients need to be monitored carefully for the development of DTs. Patients with a score of 8-15, who have mild alcohol withdrawal, should probably also receive drug treatment. Careful and frequent monitoring with the CIWA-Ar is particularly helpful in patients receiving treatment with symptom-triggered drug therapy Procedures: Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 7. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg ● Lumbar puncture: Consider for patients with DT since CNS infections (eg, meningitis, encephalitis) may also present with altered mental status, seizures, and fever. Emergency Department Care: ● Morbidity and mortality from DT are secondary to a hyperadrenergic state and other associated medical problems (eg, infections, fluid and electrolyte abnormalities). The goal is to blunt the hyperadrenergic state and treat associated medical problems. o Large-bore intravenous (IV) line, isotonic saline o Cardiac monitor o Oxygen, 2-4 liters per nasal cannula o Immediate bedside glucose testing or D50 administration o Thiamine administration (100 mg IV) o Sedation with benzodiazepines A large number of pharmacologic agents have been used to treat DT; however, benzodiazepines are the medication of choice because they have a high therapeutic index and interact with ethanol on the benzodiazepine-GABAa-chloride receptor complex. Benzodiazepines such as diazepam have an ideal pharmacologic profile because of their rapid onset of action and prolonged duration of effects. Benzodiazepine dose required may be highly variable and should be titrated until the patient is calm and peaceful. For some patients, several hundred milligrams of a diazepam equivalent may be required over the first few hours. Barbiturates such as phenobarbital and pentobarbital also are useful to treat DT despite their lower therapeutic indexes. Barbiturates may be required (rarely) for patients refractory to benzodiazepine treatment. Do not use phenothiazines, because they lower the seizure threshold and do not affect the benzodiazepine-GABAa-chloride receptor complex. Ethanol is effective in blunting withdrawal symptoms, but it is no longer indicated because of associated electrolyte abnormalities, potential worsening of gastritis, hepatitis, and pancreatitis. Ethanol use may promote continued ethanol usage. Phenytoin is probably not helpful in most patients with DT and seizures. Benzodiazepines or barbiturates treat seizures and manifestations of DT. Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 8. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg Drug Category: Benzodiazepines -- These agents bind to benzodiazepine receptors in the benzodiazepine-GABAa-chloride receptor complex to enhance the binding of GABA, causing enhanced chloride flux, hyperpolarization of the membrane, and neural inhibitory effects. Drug Name Diazepam (Valium) -- Because of rapid onset, prolonged duration of effects, and high therapeutic index, diazepam is drug of choice. Volumes of literature exist regarding usage of diazepam for ethanol withdrawal. Onset of action is within a couple of min after IV administration. Has active metabolite (desmethyl-diazepam) that has longer duration of action than diazepam. Adult Dose 5-10 mg IV bolus q5-15min until sedated Large cumulative doses may be required to treat DT Pediatric Dose 0.05-0.3 mg/kg/dose IV over 2-3 min q15-30min until sedated; not to exceed 5 mg/dose Contraindications Documented hypersensitivity; narrow-angle glaucoma Interactions Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, or MAOIs Pregnancy D - Unsafe in pregnancy Precautions Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity) Drug Name Lorazepam (Ativan) -- Sedative hypnotic in benzodiazepine class that has short onset of effect and relatively long half-life. Monitor patient's BP after administering dose and adjust as necessary. Adult Dose 1-2 mg IV bolus q5-15min until sedated Pediatric Dose 0.1 mg/kg IV slowly over 2-5 min; repeat prn in 10-15 min at a dose of 0.05 mg/kg IV administered slowly until sedated; not to exceed 4 mg/dose Contraindications Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma Interactions Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, or MAOIs Pregnancy D - Unsafe in pregnancy Precautions Because of delayed peak onset of action, sedation may not peak for 20-30 min; cumulative effects of repeated bolus may cause sudden onset of oversedation or respiratory Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 9. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg depression Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease Drug Name Chlordiazepoxide (Librium) -- Depresses all levels of CNS including limbic and reticular formation, possibly by increasing GABA activity. Parenteral form usually used initially. Adult Dose 50-100 mg IV q5-15min until sedated Pediatric Dose Not established Contraindications Documented hypersensitivity; narrow-angle glaucoma Interactions Coadministration with alcohols, phenothiazines, barbiturates, or MAOIs increases CNS toxicity; cisapride can increase levels significantly Pregnancy D - Unsafe in pregnancy Precautions Cumulative effects of repeated bolus may cause sudden onset of oversedation or respiratory depression Caution in low albumin levels or hepatic failure, as diazepam toxicity may increase Drug Category: Barbiturates -- These agents have direct effects on benzodiazepine-GABAa-chloride receptor complex in enhancing chloride flux. Barbiturates may be useful in patients refractory to benzodiazepines. Respiratory depression may be common at large doses. Ventilatory support may be required in most patients receiving high-dose barbiturates. Because of their lower therapeutic index, benzodiazepines should be considered the DOC. Drug Name Phenobarbital (Luminal, Barbita) -- Have direct effects on benzodiazepine-GABAa-chloride receptor complex in enhancing chloride flux. May be useful in patients refractory to benzodiazepines. Exhibits anticonvulsant properties in anesthetic doses. Since a barbiturate-induced depression may occur, especially after previous benzodiazepine therapy, early mechanical ventilation should be considered. Adult Dose 130 mg IV over 1-2 min q5-15min until sedated Pediatric Dose Not established Contraindications Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis Interactions Coadministration with alcohol may produce additive CNS effects and death; may decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 10. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may also occur) Pregnancy D - Unsafe in pregnancy Precautions In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia since adverse reactions can occur; caution in myasthenia gravis and myxedema Drug Name Pentobarbital (Nembutal) -- Short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties and can produce all levels of CNS mood alteration. Adult Dose 100 mg IV over 1-2 min q5-15min until sedated Pediatric Dose Not established Contraindications Documented hypersensitivity; liver failure Interactions Concomitant use with alcohol may produce additive CNS effects and death; chloramphenicol may inhibit metabolism; may enhance chloramphenicol metabolism; MAOIs may enhance sedative effects; valproic acid appears to decrease metabolism, increasing toxicity; can decrease effects of anticoagulants (patients may require dosage adjustments if barbiturates added to or withdrawn from regimen); may decrease oral contraceptive effect by induction of microsomal enzymes (alternate form of birth control suggested); may decrease corticosteroid and digitoxin effects through induction of hepatic microsomal enzymes, which increase metabolism; decreases theophylline levels, and may decrease effects; may decrease verapamil bioavailability Pregnancy D - Unsafe in pregnancy Precautions Patient may become tolerant to hypnotic effects; caution in hypovolemic shock, respiratory dysfunction, renal dysfunction, previous addiction to sedative hypnotics, and CHF Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 11. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg Drug Category: Vitamins and Nutrients -- These agents are used to treat the hypoglycemia and nutrient deficiencies associated with DT. Alcoholics usually are deficient in thiamine, which functions as a cofactor for a number of important enzymes, such as pyruvate dehydrogenase, transketolase, and alpha-ketoglutarate dehydrogenase. Deficiency leads to Wernicke encephalopathy, peripheral neuropathy, cardiomyopathy, and metabolic acidosis. Alcoholics usually are magnesium deficient due to a poor nutritional status and malabsorption from ethanol. Magnesium stabilizes membranes, helps in the maintenance of potassium and calcium homeostasis, and may protect against seizures and arrhythmias. Drug Name Dextrose 50% (D-Glucose) -- Monosaccharide absorbed from intestine and distributed, stored, and used by tissues. Parenterally injected dextrose used in patients unable to obtain adequate oral intake. Direct oral absorption results in rapid increase of blood glucose concentrations. Effective in small doses; no evidence of toxicity. Concentrated dextrose infusions provide higher amounts of glucose and increased caloric intake, with minimal fluid volume. Use 1 ampule of 50 mL of a 50% glucose solution (25 g). Adult Dose 0.5-1 mg/kg IV bolus Pediatric Dose <12 years: Not established >12 years: Administer as in adults Contraindications Do not administer to a patient in diabetic coma if blood sugar levels are extremely high, and avoid in severely dehydrated patients Do not administer concentrated solution if intraspinal or intracranial hemorrhage is present; avoid in dehydrated patients with DT, hepatic coma, or glucose-galactose malabsorption syndrome Interactions Caution when administering parenteral fluids to patients receiving corticosteroids or corticotropin, especially if solution contains sodium ions Pregnancy A - Safe in pregnancy Precautions Extravasation may cause significant tissue necrosis when used IV; Isolated reports of nausea, which may also occur with hypoglycemia, have been recorded; Dextrose solutions administered IV can result in dilution of serum electrolyte concentrations and overhydration when there is fluid overload; caution in congested states or pulmonary edema Drug Name Thiamine (Vitamin B-1) -- Used to treat thiamine deficiency, including Wernicke encephalopathy syndrome. Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 12. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg Adult Dose 100 mg IV Pediatric Dose 50 mg IV initially, followed by 10-25 mg/d IV/IM Contraindications Documented hypersensitivity Interactions None reported Pregnancy A - Safe in pregnancy Precautions Sensitivity reactions can occur (intradermal test-dose recommended in suspected sensitivity); deaths have resulted from IV use; sudden onset or worsening of Wernicke encephalopathy, following glucose, may occur in thiamine-deficient patients; administer before or together with dextrose-containing fluids in suspected thiamine deficiency Drug Name Folic acid (Folate) -- Dietary deficiency of folic acid common in alcoholics. Folic acid important cofactor for enzymes used in production of RBCs. Adult Dose 1 mg PO/IV Pediatric Dose Administer as in adults Contraindications Documented hypersensitivity Interactions Increase in seizure frequency and decrease in subtherapeutic levels of phenytoin reported when used concurrently Pregnancy A - Safe in pregnancy Precautions Benzyl alcohol may be contained in some products as a preservative (associated with a fatal gasping syndrome in premature infants); resistance to treatment may occur in patients with alcoholism and deficiencies of other vitamins Drug Name Magnesium sulfate -- Used to treat and prevent seizures. Decreases amount of acetylcholine liberated at endplate by motor nerve impulse. Blocks neuromuscular transmission associated with seizure activity. Magnesium also has CNS depressant effect. Monitor carefully; may cause respiratory depression, hyporeflexia, and bradycardia. Infusion should be discontinued if reflexes are absent or if magnesium levels exceed 6-8 mEq/L. Calcium chloride, 10 mL IV of a 10% solution, can be given as antidote for clinically significant hypermagnesemia. Adult Dose 2 g in 50 mL of D5W over 20 min IV Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 13. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg Pediatric Dose 25-50 mg/kg/dose; maximum single dose of 2 g may also be administered and repeated if hypomagnesemia persists Contraindications Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis Interactions Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade seen with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, or succinylcholine; may increase CNS effects and toxicity of CNS depressants or betamethasone; may increase cardiotoxicity of ritodrine Pregnancy A - Safe in pregnancy Precautions Magnesium may alter cardiac conduction, leading to heart block in digitalized patients; respiratory rate, deep tendon reflexes, and renal function should be monitored when electrolyte is administered parenterally; caution when administering, since may produce significant hypertension or asystole; in overdose, calcium gluconate, 10-20 mL IV of 10% solution, can be given as antidote for clinically significant hypermagnesemia Further Inpatient Care: ● Admit all patients with DT to the ICU. ● Continue sedation as necessary to keep to patients calm. Sedation dosing may be tapered over the next 5-7 days. Due to the long duration of action of diazepam or phenobarbital, patients who are adequately sedated initially may require prolonged monitoring and treatment. Further Outpatient Care: ● Do not discharge from the ED patients with DT or thought to be developing DT. ● Refer patients discharged after hospitalization for continued rehabilitation. Medical/Legal Pitfalls: ● Failure to diagnose such conditions as hypoglycemia, CNS trauma, and CNS infections Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava
- 14. “It is not only in medicine that persons in authority will resist any investigation that might reduce their authority.” ― Steven Weinberg ● Failure to use adequate chemical sedation with use of physical restraints Special Concerns: ● Do not use neuroleptics in the treatment of withdrawal. ● Administer adequate sedation to blunt agitation to and prevent the exacerbation of hyperthermia, acidosis, and rhabdomyolysis. ● Because of the kindling phenomenon associated with ethanol withdrawal and DT, inadequate sedation initially leads to escalating drug requirement for the treatment of withdrawal. ● Anticonvulsant therapy is not indicated for ethanol withdrawal seizures; however, it is indicated for patients with underlying seizure disorders. ● Phenytoin is ineffective in preventing ethanol withdrawal seizures. Non nobis solum nati sumus (Not for ourselves alone are we born) -Dr. Eashan Srivastava