6.5.3) TREATMENT
A) MONITORING OF PATIENT 1) Monitor vital signs and mental status.
2) Monitor serum glucose and electrolytes (including magnesium).
3) In patients with severe withdrawal, monitor renal function, CBC, hepatic enzymes, bilirubin, and coagulation studies. Evaluate for infection.
4) Monitor creatinine phosphokinase and lactate levels in patients with prolonged agitation, seizures, or coma.
5) A head CT and/or lumbar puncture may be necessary, if the diagnosis is unclear.
B) REHYDRATION THERAPY 1) INDICATIONS a) In the early stage of alcohol withdrawal, patients may be overhydrated secondary to increases in antidiuretic hormone as alcohol levels fall; however, with the progression of symptoms, patients may have extensive fluid needs as result of diaphoresis, hyperthermia, tachypnea, and fever (Brewer & D'Onofrio, 1997).
b) Rehydration is extremely important because dehydration is a significant contributing factor to mortality in alcohol withdrawal syndrome, and aggressive hydration is generally required with severe withdrawal (Brewer & D'Onofrio, 1997).
c) Hypoglycemia and alcoholic ketoacidosis (AKA) may be present, requiring the use of dextrose solutions. Other conditions that may result in hypoglycemia are poor oral intake, thiamine deficiency, glycogen depletion, and decreased carbohydrate production (Kleinschmidt & Delaney, 1998). Monitor serum glucose and give dextrose and thiamine as required.
2) RECOMMENDATION a) HYPOVOLEMIA 1) Correct any fluid deficit with D5NS or D5LR at a rate of 200 to 1000 mL/hour until hypovolemia is corrected (as determined clinically by orthostatic pulse and pressure measurements, urine output and specific gravity, and, if necessary, central venous monitoring) (Brewer & D'Onofrio, 1997).
2) Maintenance fluid therapy with D5/0.2NS or D5/0.45NS can then be instituted at 100 to 150 mL/hour (Brewer & D'Onofrio, 1997).
C) DRUG THERAPY 1) BENZODIAZEPINES a) OVERVIEW 1) INDICATIONS: Without treatment alcohol-withdrawal symptoms generally peak about 72 hours after the last use of alcohol; however, symptoms can be reduced within hours with drug therapy (Kosten & O'Connor, 2003). The mainstay of therapy; reduces withdrawal severity (eg, decreases the incidence of delirium and seizures) (Holbrook et al, 1999; Mayo-Smith, 1997). 2) DRUGS OF CHOICE: Benzodiazepines are effective because of their sedative anxiolytic and anticonvulsive properties (Kleinschmidt & Delaney, 1998); diazepam offers the advantage of rapid onset of peak effect and active metabolites, leading to self-tapering. Dosage should be individualized based on withdrawal severity (Shaw, 1995; Hall & Zador, 1997; O'Connor & Schottenfeld, 1998a; Brewer & D'Onofrio, 1997; Mayo-Smith, 1997; Holbrook et al, 1999). 3) FIRST LINE OF THERAPY: Diazepam, lorazepam, and chlordiazepoxide are commonly used to treat alcohol withdrawal syndrome (Kleinschmidt & Delaney, 1998). 4) Other drugs, including clorazepate, oxazepam, halazepam, alprazolam, and clobazam have also been used, but offer no advantage over diazepam. 5) Benzodiazepines that undergo hepatic oxidation by cytochrome P450 (eg, clorazepate) may cause prolonged sedation in alcoholic patients (Guglielminotti et al, 1999). 6) ADVANTAGES a) Reduce anxiety, tremor, and agitation associated with alcohol withdrawal, but also reduces the risk of more serious complications (ie, seizures and delirium tremens) (Jaeger et al, 2001). A meta-analysis (n=1286) comparing benzodiazepines with placebo or an active control drug found a clinically significant reduction of symptoms within two days with benzodiazepines than with placebo (common odds ratio, 3.28; 95% confidence interval, 1.3 to 8.28) (Kosten & O'Connor, 2003). Six prospective trials also reported that benzodiazepines were more effective in reducing the incidence of seizures (risk reduction, 7.7 seizures per 100 patients treated; p=0.003) and delirium (risk reduction, 4.9 cases of delirium per 100 patients treated; p=0.04) (Kosten & O'Connor, 2003). 1) SYMPTOM-TRIGGERED THERAPY or LOADING has been supported in the literature and is based on the principle of administering benzodiazepine (with active metabolites such as diazepam) in an escalating bolus fashion. The symptoms can be quantified to allow symptom-triggered therapy. The patient only receives therapy when symptoms exceed a threshold based on careful and frequent monitoring using a valid withdrawal-symptoms scale (eg, the Clinical Institute Withdrawal Assessment for Alcohol) (Kosten & O'Connor, 2003). The initial doses can be quite high, but withdrawal is ultimately managed better with actually less benzodiazepine use and fewer symptoms. Initial, patient sedation can also provide a safer environment in which the patient is less likely to be violent or agitated (Hamilton, 1998; Kleinschmidt & Delaney, 1998). While this therapy has been most often studied in patients with mild withdrawal; it has widely been used in many populations with good results. (Kleinschmidt & Delaney, 1998). Drug therapy is usually not required after 7 days of therapy unless delirium is present (Kosten & O'Connor, 2003).
2) TYPICAL DOSING WITH THIS METHOD: 20 mg of diazepam is given orally every 1 to 2 hours until the patient experiences less symptoms or sedation. In this approach, patients receive on average four doses over 12 hours and required no further medication. Based on the long half-life of this drug and its active metabolite, therapeutic levels may persist beyond 72 hours (Kleinschmidt & Delaney, 1998). Oral therapy should never be used for anything greater than mild withdrawal symptoms, although a symptom-triggered approach should still be used with parenteral therapy. Any patient with abnormal vital signs, gastrointestinal symptoms, with an IV access, or any patient requiring hospitalization should be treated with parenteral therapy.
3) In a study of medical inpatients with alcohol withdrawal syndrome, symptom-triggered therapy (i.e., the dosage of benzodiazepine was determined by medical personnel based on a withdrawal assessment score and response to previous doses) was associated with a decreased occurrence of delirium tremens as compared to standard treatment. This method attempted to eliminate the under- or overmedication of some alcohol withdrawal patients by using objective data for treatment and evaluation of benzodiazepine therapy (Jaeger et al, 2001).
b) A meta-analysis of controlled trials comparing sedative-hypnotic use (diazepam, chlordiazepoxide, pentobarbital, paraldehyde, and barbital) and neuroleptic drugs (promazine, chlorpromazine, and perphenazine) in reducing mortality with alcohol withdrawal delirium (AWD) showed that sedative-hypnotic use was more effective than neuroleptic use. The summary relative risk of mortality with neuroleptic treatment compared with sedative-hypnotic treatment was 6.6 (95% confidence interval, 1.2 to 34.7). The duration of delirium was also more effectively reduced with sedative-hypnotic treatment compared with neuroleptic treatment (Mayo-Smith et al, 2004). c) DISADVANTAGES 1) There is a greater potential for abuse with agents that have a rapid onset (eg, diazepam, alprazolam, and lorazepam) than with agents such as chlordiazepoxide, oxazepam, and halazepam (Kosten & O'Connor, 2003).
2) DIAZEPAM a) INDICATIONS: One of the most commonly used benzodiazepines for treatment of alcohol withdrawal syndrome-related adrenergic hyperactivity (O'Connor & Schottenfeld, 1998; Brewer & D'Onofrio, 1997). Long half-life (20 to 70 hours; average 33 hours) (Kleinschmidt & Delaney, 1998). b) RECOMMENDATIONS (Brewer & D'Onofrio, 1997): 1) MILD ALCOHOL WITHDRAWAL SYNDROME a) ORAL INTAKE INTACT: ADULTS: 10 to 20 mg orally every one to two hours until symptoms resolve (maximum, 60 mg).
b) INADEQUATE ORAL INTAKE: ADULTS: 5 to 10 mg intravenously every one to two hours as needed until sedated or treat as moderate-to-severe withdrawal, if needed.
2) MODERATE TO SEVERE ALCOHOL WITHDRAWAL SYNDROME a) ADULTS: 5 to 10 mg intravenously every 5 to 10 minutes (maximum total dose, 100 mg/hour or 250 mg/8 hours).
3) SYMPTOM TRIGGERED THERAPY OR LOADING a) Goal of this therapy is to initially give high doses to minimize symptoms or sedate the patient which results in less medication and fewer withdrawal symptoms (Hamilton, 1998; Kleinschmidt & Delaney, 1998). Oral therapy should never be used for anything greater than mild withdrawal symptoms, although a symptom-triggered approach should still be used with parenteral therapy. Any patient with abnormal vital signs, gastrointestinal symptoms, with an IV access, or any patient requiring hospitalization should be treated with parenteral therapy.
b) TYPICAL DOSING WITH THIS METHOD: 20 mg of diazepam is given orally every 1 to 2 hours until the patient experiences less symptoms or sedation (Hamilton, 1998; Kleinschmidt & Delaney, 1998).
3) LORAZEPAM a) INDICATIONS: A drug of choice for treatment alcohol withdrawal syndrome-related adrenergic hyperactivity; may be preferred for patients unable to take oral medications, the elderly, and those with prolonged INR secondary to hepatic dysfunction (Brewer & D'Onofrio, 1997). Intermediate half-life (5 to 25 hours; average 15 hours) (Kleinschmidt & Delaney, 1998). Lorazepam is reliably absorbed intramuscularly, and may be preferred until IV access is established; however, it lacks active metabolites and peak effect is not seen until 15 minutes after administration, making it more difficult to titrate and less useful than diazepam overall once IV access has been established. b) RECOMMENDATION (Brewer & D'Onofrio, 1997): 1) ORAL INTAKE INTACT (Alternative): ADULTS: 2 mg orally every 2 hours until symptoms resolve. Oral therapy should never be used for anything greater than mild withdrawal symptoms, although a symptom-triggered approach should still be used with parenteral therapy. Any patient with abnormal vital signs, gastrointestinal symptoms, with an IV access, or any patient requiring hospitalization should be treated with parenteral therapy.
2) INADEQUATE ORAL INTAKE: ADULTS: 1 to 2 mg intravenously or intramuscularly every 1 to 2 hours as needed until sedated.
3) SEVERE ALCOHOL WITHDRAWAL SYNDROME: ADULTS: 1 to 2 mg intravenously every 10 to 15 minutes (maximum total dose, 20 mg/hour or 50 mg/eight hours).
4) AVAILABLE FORMS: Ativan(R)
4) CHLORDIAZEPOXIDE a) INDICATIONS: Commonly used long-acting benzodiazepine in alcohol withdrawal syndrome (Shaw, 1995). It appears to be beneficial in preventing the progression of withdrawal; long half-life (6 to 30 hours; average 10 hours) and it has active metabolites (Kleinschmidt & Delaney, 1998). b) RECOMMENDATION (Cydulka et al, 1995): 1) MILD ALCOHOL WITHDRAWAL SYNDROME: ADULTS: 25 to 100 mg orally every 2 to 6 hours.
2) MODERATE-TO-SEVERE ALCOHOL WITHDRAWAL SYNDROME: ADULTS: 25 mg intravenously every 2 to 4 hours until calm.
3) AVAILABLE FORMS: Librium(R) (capsules; injection) and generic products
5) CLORAZEPATE a) INDICATIONS: Clorazepate has the longest half-life (up to 96 hours) and is useful in monitored setting of alcohol detoxification. CAUTION: Benzodiazepines that undergo hepatic oxidation by cytochrome P450 (eg, clorazepate) may cause prolonged sedation in alcoholic patients (Guglielminotti et al, 1999). 1) RECOMMENDATION: ADULTS: 15 to 30 mg orally every 8 to 12 hours.
2) AVAILABLE FORMS: Tranxene(R) (capsules; sustained-release tablets); Azene(R) (capsules).
3) PRECAUTIONS: Contraindicated in acute alcohol intoxication in presence of depressed vital signs, depressive neurosis or psychosis when anxiety is not present; caution in elderly, in hepatic disease, and in pregnancy; tolerance and psychological/physical dependence occurs with prolonged use; withdrawal reactions, including seizures, can occur upon abrupt withdrawal after prolonged use; cimetidine prolongs duration of action.
6) OTHER a) PHENOBARBITAL AND OTHER BARBITURATES 1) These agents have a synergistic effect with benzodiazepines and should be considered in resistant alcohol withdrawal syndrome. Protect the airway, mechanical ventilatory support often necessary. 2) MECHANISM: Barbiturates act on the gamma-aminobutyric acid (alpha) receptor at a site distinct from the benzodiazepine receptor, directly opening the chloride channel. 3) DOSING: Phenobarbital may be given as a 130 to 260 mg IV load over 20 minutes. Repeated doses of 130 mg may be given up to every 30 minutes. Patients may require doses of up to 8.5 mg/kg. Phenobarbital levels are unnecessary, as the clinical endpoint of light sedation is used to titrate the dose (Martin et al, 1979) 4) PRECAUTIONS: Respiratory depression is significant and commonly requires mechanical ventilatory support. Hypotension may also occur. An intravenous fluid bolus is usually the only therapy required to treat hypotension in this setting. 5) A meta-analysis of controlled trials comparing sedative-hypnotic use (diazepam, chlordiazepoxide, pentobarbital, paraldehyde, and barbital) and neuroleptic drugs (promazine, chlorpromazine, and perphenazine) in reducing mortality with alcohol withdrawal delirium (AWD) showed that sedative-hypnotic use was more effective than neuroleptic use. The summary relative risk of mortality with neuroleptic treatment compared with sedative-hypnotic treatment was 6.6 (95% confidence interval, 1.2 to 34.7). The duration of delirium was also more effectively reduced with sedative-hypnotic treatment compared with neuroleptic treatment (Mayo-Smith et al, 2004). 6) PROPOFOL a) Successful use of propofol in delirium tremens refractory to benzodiazepines has been reported. It may be considered as an alternative agent when conventional therapy fails because of its rapid onset of hypnosis and anticonvulsant properties (Coomes & Smith, 1997).
b) In a small case series (n=4), patients with chronic alcohol abuse and severe delirium tremens refractory to high doses of benzodiazepines (one adult received greater than 3600 mg of lorazepam over a 72-hour period for profound agitation), propofol infusions appeared to be successful in controlling delirium tremens. The dosing and length of treatment were variable. Two patients required infusions of 80 to 90 mcg/kg/min for severe agitation for up to 11 days; the other two patients required doses of 40 to 45 mcg/kg/min for up to 10 days. Therapy was titrated based on individual response and level of agitation. Recovery was complete in each patient (McCowan & Marik, 2000).
c) MECHANISM: Propofol is thought to act similarly to alcohol on the central nervous system by acting on both the gamma-aminobutyric acid (GABA)-A and glutamate receptors (benzodiazepines are only active on GABA receptors). It directly activates the GABA-A-receptor-chloride ionophore complex and increases chloride conductance, as well as, inhibiting the N-methyl-D-aspartic acid subtype of glutamate receptor (McCowan & Marik, 2000).
d) BENEFITS: Propofol is easily titrated, provides predictable effects, and has a short duration of action even with prolonged use (McCowan & Marik, 2000).
e) PRECAUTIONS: Hyperlipidemia may occur following prolonged infusions; monitor lipid profile if infusion is required for greater than 72 hours (McCowan & Marik, 2000). Respiratory depression is common, and mechanical ventilation may be required.
b) BETA ADRENERGIC BLOCKERS 1) Not recommended as a monotherapy; can reduce some selected signs and symptoms of withdrawal, but does NOT reduce delirium or seizures. May be considered for use in conjunction with benzodiazepines in patients with coexisting coronary artery disease (Mayo-Smith, 1997).
c) DEXMEDETOMIDINE 1) SUMMARY: Dexmedetomidine has been used, on a limited basis, in the treatment of alcohol withdrawal syndrome (AWS) as adjunctive therapy to benzodiazepines in the intensive care setting. It is suggested that dexmedetomidine, as a highly selective alpha2-adrenoreceptor agonist without activity at GABA and opioid receptors, can produce sedation without the need for mechanical ventilation and decrease the need for high doses of benzodiazepines in the setting of AWS, thereby reducing the risk of GABA-ergic benzodiazepine-related adverse effects, including delirium, respiratory depression, and over sedation (Muzyk et al, 2013).
2) CASE REPORT: A 30-year-old man, with a history of chronic alcohol abuse, presented with agitation and altered mental status approximately 24 hours after his last intake of alcohol. He was initially treated with phenytoin and oxazepam; however, on hospital day 2, his agitation worsened, becoming disoriented and combative, with development of severe tremors and tachycardia. He was treated with IV midazolam infusion, resulting in a decrease in tremors and intermittent episodes of severe agitation. Approximately 31 hours after presentation, IV dexmedetomidine infusion was started with an initial dose of 0.2 mcg/kg/hour and titrated to 0.7 mcg/kg/hour, resulting in significant improvement in tremors and confusion, with fewer episodes of agitation. Midazolam infusion was gradually tapered, with the patient showing continual clinical improvement. Following cessation of midazolam, dexmedetomidine was slowly tapered and discontinued 24 hours later (total dexmedetomidine infusion time 39 hours, overlapping with midazolam the first 14 hours). The patient recovered and was discharged on hospital day 5 (Darrouj et al, 2008).
3) CASE REPORT: A 50-year-old man, with a history of severe alcohol dependence and several previous hospitalizations for alcohol-induced hallucinations and alcohol withdrawal delirium, presented with severe delirium and violent behavior. After alcohol abstinence of 3 days duration, the patient had a seizure with loss of consciousness of several minutes. He was tachycardic and became disoriented and confused with auditory and visual hallucinations. He was initially treated with oral diazepam and haloperidol, however, his agitation worsened. Dexmedetomidine was then initiated for sedation at a starting dose of 0.5 mcg/kg/hour for 10 minutes then decreased to 0.175 mcg/kg/hour over 90 minutes followed by 0.1 mcg/kg/hour for 6 hours, then 0.05 mcg/kg/hour for 8 hours. After the second hour of the dexmedetomidine infusion, the patient's tachycardia resolved and he became less combative. Following cessation of the infusion, he was mildly anxious, but fully oriented with no hallucinations. He was discharged 5 days after the infusion, with continued therapy of oral haloperidol and diazepam (Rovasalo et al, 2006).
4) CASE SERIES: A retrospective case series was conducted from 2006 to 2012, involving 33 patients admitted to an intensive care setting with a diagnosis of alcohol withdrawal syndrome. Indication for ICU admission included uncontrolled agitation, seizure, and respiratory insufficiency. Lorazepam was the primary benzodiazepine given, with a median of 110 mg as the total oral lorazepam equivalent requirement over the course of 7 days (from ICU admission to ICU discharge). Dexmedetomidine infusion was initiated at median of 11 hours from ICU admission, at an initial infusion rate of 0.15 to 1 mcg/kg/hour and titrated to a maximum of 0.2 to 2 mcg/kg/hour, depending on individual response. Most patients received 0.7 mcg/kg/hour or less (n=26). Approximately 12 hours after initiating dexmedetomidine therapy, benzodiazepine requirements significantly decreased with a median reduction of approximately 20 mg (p<0.001). There were also significant reductions in the mean arterial pressure (108 mmHg before dexmedetomidine initiation vs 94 mmHg after initiation, p=0.03) and in heart rate (116 beats/min before initiation vs 99 beats/min after initiation, p<0.001). Complications of dexmedetomidine therapy included hypotension (systolic less than 80 mmHg) in 4 patients and hypertension (systolic greater than 180 mmHg) in 6 patients. All patients recovered with supportive care. There were no episodes of bradycardia (Frazee et al, 2014).
5) A retrospective cohort study was conducted to evaluate efficacy and safety outcomes in 61 non-intubated patients with severe alcohol withdrawal syndrome (AWS) receiving a continuous benzodiazepine infusion (BZD; n=33) compared to those receiving a continuous dexmedetomidine infusion (DEX; n=28). All 61 patients also received intermittent benzodiazepines or antipsychotics as needed. The mean infusion rate of the BZD group was 3.5 +/- 3.5 mg/hour (mean total dose 157 +/- 146 mg; mean duration 55 +/- 45 hours). The mean infusion rate of the DEX group was 0.53 +/- 0.29 mcg/kg/hour (mean total dose 2512.3 +/- 2468 mcg; mean duration 60.4 +/- 37.5 hours). Although there was a lower median total dose of lorazepam equivalents in the DEX group as compared to the BZD group (3.5 mg vs 105 mg, respectively), this did not translate into a decreased need for intubation or a reduced hospital stay. There were no significant differences between the BZD group and the DEX group with respect to the occurrence of respiratory distress requiring intubation or alcohol withdrawal seizures. There was also no significant differences in the Richmond Agitation Sedation Scale (RASS) score. However, the incidences for bradycardia and hypotension were significantly higher in the DEX group compared to the BZD group (46.4% vs 15.2%, p<0.01, and 42.9% vs 12.1%, p<0.01, respectively). Based on the results of this study, although dexmedetomidine may exhibit a benzodiazepine-sparing effect, there was no proven benefit in using dexmedetomidine as primary therapy over benzodiazepine therapy, and should only be used as adjunctive therapy with benzodiazepines in the treatment of AWS (Crispo et al, 2014).
d) SODIUM OXYBATE 1) A phase IV, multicenter, randomized double-blind clinical trial was conducted to evaluate the efficacy of sodium oxybate compared to oxazepam in patients with uncomplicated (ie, no seizures or delirium) alcohol withdrawal syndrome (AWS). A total of 126 patients (ages ranging from 21 to 75 years) were randomized into two groups: sodium oxybate (SMO; n=61) 175 mg/mL oral suspension and oxazepam (n=65) 15 mg or 30 mg tablets. Dosage regimen for the SMO group was either 10 to 12 mL three times daily for days 1 through 5, 5 to 6 mL three times daily for days 6 and 7, and 2.5 to 3 mL three times daily for days 8 through 10. Dosage regimen for the oxazepam group was 60 mg twice daily and 90 mg once daily for days 1 through 5, 30 mg three times daily for days 6 and 7, and 15 mg three times daily for days 8 through 10. There was a significant difference in the mean total Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) scale scores of both groups when measured at baseline (day 1 of the study) to the end of the day (at day 10) (p<0.0001), however there were no significant differences in scores between the two treatments. There were also significant decreases in the sweating, tremors, and anxiety CIWA subscale scores of both groups from baseline to the end of the study (p<0.0001 for all scores); however, there were no significant differences between the two treatments with respect to the subscale scores. Both drugs were well-tolerated with no serious or fatal adverse effects reported. Based on the results of this study, sodium oxybate appears to be equally effective as oxazepam in the treatment of uncomplicated AWS, and may be considered a valid alternative to oxazepam in this setting (Caputo et al, 2014).
e) KETAMINE 1) A retrospective study was conducted to evaluate the safety and efficacy of using ketamine as adjunctive therapy to benzodiazepines for the management of patients with alcohol withdrawal syndrome (AWS). A total of 23 patients out of 235 patients screened were included in the study. Ketamine therapy was initiated, at a mean initial infusion dose of 0.21 mg/kg/hour, for either management of delirium tremens (n=10), for significant benzodiazepine requirements (n=3), or for another or unknown reason (n=10). The median infusion dose during therapy was 0.20 mg/kg/hour. The mean time to ketamine initiation from the first treatment of AWS was 33.6 hours and the mean total duration of therapy was 55.8 hours. Although there was no change in sedation or alcohol withdrawal scores 6 hours after beginning ketamine therapy, there was a decrease in benzodiazepine requirements, although not statistically significant, at 12 and 24 hours post-ketamine initiation (-40 mg and -13.3 mg, respectively). The mean time to AWS resolution was 5.6 days. Ketamine appeared to be well-tolerated, with oversedation, requiring a dose adjustment, reported in only one patient. Based on the results of this study, ketamine may be a possible adjunctive therapy to benzodiazepines for the management of AWS; however, further investigation is warranted (Wong et al, 2015).
f) MISCELLANEOUS AGENTS 1) Gamma-hydroxybutyric acid, nitrous oxide, phenobarbital, valproic acid, and other agents have been studied in alcohol withdrawal syndrome. None have been proven superior to benzodiazepines (Gillman & Lichtigfeld, 1990; Gallimberti et al, 1989; Hillbom et al, 1989; Cushman & Sowers, 1989; Ives et al, 1991; Stuppaeck et al, 1992). a) VALPROIC ACID 1) CLINICAL TRIAL: A double-blind placebo-controlled clinical trial was conducted with 36 inpatients in moderate alcohol withdrawal to evaluate the use of valproic sodium in the treatment of alcohol withdrawal syndrome. Each patient received a baseline dose of oxazepam (30 mg) and had additional oxazepam available as needed (based on standard, symptom-triggered detoxification protocol). Valproic acid, an anticonvulsant as well as an anti-kindling agent and gamma-aminobutyric acid enhancer, was given orally (500 mg three times daily) for 7 days. The valproic acid group used less oxazepam and had an overall decrease in the progression of withdrawal symptoms. Further study was recommended (Reoux et al, 2001).
b) Data gathered on 2500 patients, suggests that valproate can reduce symptoms of alcohol withdrawal. In these studies, patients receiving 1000 to 1200 mg of valproate for an average of 4 to 7 days had fewer seizures, less severe withdrawal symptoms, used less oxazepam than controls and were more likely to complete treatment than the controls that were treated with placebo or carbamazepine (Kosten & O'Connor, 2003). 2) ETHANOL has been used to prevent the progression of alcohol withdrawal syndrome; however, therapies such as benzodiazepines and beta-adrenergic blockers are generally preferred. g) CLONIDINE 1) Not recommended as a monotherapy; reduces selected signs and symptoms of withdrawal, but does not reduce delirium or seizures. May be considered for use in conjunction with benzodiazepines in patients with coexisting opiate withdrawal (Mayo-Smith, 1997).
h) CARBAMAZEPINE 1) Not recommended as a monotherapy; reduces selected signs and symptoms of withdrawal. In animal studies, carbamazepine has anticonvulsant activity and prevents alcohol-withdrawal seizures; human data is limited. It has been found to be superior to placebo and equal in efficacy to phenobarbital and oxazepam for patients experiencing mild-to-moderate withdrawal symptoms (Kosten & O'Connor, 2003). It has no potential for abuse. May be considered for use in conjunction with benzodiazepines in patients with coexisting benzodiazepine withdrawal (Mayo-Smith, 1997), but the data are somewhat limited (Kosten & O'Connor, 2003).
2) MECHANISM: Carbamazepine is thought to be effective (similar to benzodiazepines) because it has a cross-tolerance with ethanol at the type A gamma-aminobutyric acid receptor (Kosten & O'Connor, 2003).
i) BACLOFEN 1) EXPERIMENTAL THERAPY: In a small, uncontrolled study of 5 patients experiencing alcohol withdrawal, baclofen was found to be effective in suppressing most withdrawal symptoms. Upon admission, all patients scored 20 or higher on the Clinical Institute Withdrawal Assessment for Alcohol scale. Patients were initially treated with baclofen 10 mg orally and then every 8 hours for a total of 30 days. No other medications were given. Blood alcohol levels were 0.1 g/L or lower in all patients at the time of the initial dose of baclofen. Symptoms resolved within 3 hours of administration in all patients. Based on these limited data, further studies are required (Addolorato et al, 2002).
D) SEIZURE 1) OVERVIEW a) Seizures can occur at any level of alcohol withdrawal and are NOT dependent on the degree of withdrawal (Brewer & D'Onofrio, 1997). b) PROPHYLAXIS 1) Although standard therapy for recurrent seizures related to alcohol traditionally has been supportive care only, a prospective, randomized, double-blind trial found that patients with acute and chronic alcohol abuse who present with seizures may benefit from the use of lorazepam (D'Onofrio et al, 1999).
2) In a prospective, randomized, placebo-controlled, double-blind study of 55 patients who had seized from alcohol withdrawal, phenytoin was no more effective than placebo in preventing recurrence of alcohol withdrawal seizures (Chance, 1991).
3) Phenytoin does NOT protect against alcohol withdrawal seizures, and can NOT be recommended for use in alcohol-related seizures (Hamilton, 1998; Kleinschmidt & Delaney, 1998).
2) DRUG OF CHOICE: Lorazepam (Brewer & D'Onofrio, 1997): a) LORAZEPAM 1) INDICATIONS a) Treatment of alcohol-related seizures and recurrences; has longer duration of seizure control than diazepam (Brewer & D'Onofrio, 1997). b) LORAZEPAM 1) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
2) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
3) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
c) DIAZEPAM 1) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
2) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
3) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
d) NO INTRAVENOUS ACCESS 1) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
2) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
E) ANTIPSYCHOTIC 1) OVERVIEW a) INDICATIONS: NOT recommend as monotherapy; does not reduce delirium and does increase seizures. May be considered for use in conjunction with benzodiazepines for patients with marked agitation. b) Many authors feel that antipsychotic agents have NO role in the management of alcoholic withdrawal; and their use is only justified to treat an underlying medical problem that is unrelated to withdrawal (Hamilton, 1998; Kleinschmidt & Delaney, 1998). Others suggest a limited role when used in conjunction with high dose benzodiazepines in patients with severe agitation. 1) Serious DISADVANTAGES include lowering of seizure threshold and inducing dystonic reactions, and addition of potential anticholinergic toxicity, with hyperthermia to hyperadrenergic state. Dysrhythmias may also be seen, and electrolyte abnormalities common in alcohol-dependent patients (ie, hypomagnesemia, hypokalemia) may predispose patients to this complication.
c) A meta-analysis of controlled trials comparing sedative-hypnotic use (diazepam, chlordiazepoxide, pentobarbital, paraldehyde, and barbital) and neuroleptic drugs (promazine, chlorpromazine, and perphenazine) in reducing mortality with alcohol withdrawal delirium (AWD) showed that sedative-hypnotic use was more effective than neuroleptic use. The summary relative risk of mortality with neuroleptic treatment compared with sedative-hypnotic treatment was 6.6 (95% confidence interval, 1.2 to 34.7). The duration of delirium was also more effectively reduced with sedative-hypnotic treatment compared with neuroleptic treatment (Mayo-Smith et al, 2004). 2) HALOPERIDOL a) INDICATIONS 1) Haloperidol may be useful as an adjuvant therapy. It can reduce the signs and symptoms of withdrawal, but it is generally less effective than benzodiazepines in the prevention of delirium (a difference in risk 6.6 cases per 100 patients) and seizures (difference in risk, 12.4 seizures per 100 patients) (Kosten & O'Connor, 2003). It may be useful when benzodiazepines fail to relieve severe hallucinosis (McMicken, 1990). However, it should rarely be necessary when appropriate doses of diazepam are used.
2) If an antipsychotic agent is required, haloperidol is the agent of choice because of its relatively low degree of alpha-adrenergic blocking potential (McMicken, 1990).
b) DOSING: ADULTS: 2 to 10 mg intravenously or intramuscularly every 1 to 2 hours. 3) DROPERIDOL a) Droperidol may have some advantages over haloperidol, which can include a more rapid onset of action and shorter half-life (McMicken & Freedland, 1994). 1) CAUTION: DROPERIDOL: Based on cases of QT prolongation and/or torsades de pointes in patients receiving droperidol at doses at or below recommended dosing, it should be reserved for use in patients who fail to show an acceptable response to other agents (Anon , 2001).
2) A baseline ECG (repeat as indicated) and continuous cardiac monitoring for 3 hours are recommended for all patients receiving droperidol.
F) VITAMIN (CLASS) 1) MULTIVITAMINS a) INDICATIONS: Because alcohol abusers are subject to serious avitaminosis, including pellagra, scurvy, Wernicke-Korsakoff syndrome, and megaloblastic anemias, multivitamins should be administered daily.
b) RECOMMENDATION: ADULTS: One ampule in first liter of intravenous fluid; 1 mg folate should be added if it is not included in the multivitamin preparation (Brewer & D'Onofrio, 1997).
c) AVAILABLE FORMS: MVI(R) (injection); Solu B with Ascorbic Acid(R) (injection); Betalin Complex(R) (injection); Cernevit(R) (multivitamins for infusion).
d) MAJOR ADVERSE REACTIONS: Allergic reactions (due to thiamine) with IV use.
e) PRECAUTIONS: IV preparations: Must be diluted (undiluted injection may cause dizziness or fainting); MVI(R)-12 incompatible with cephalothin, cefazolin, and sodium bicarbonate (when administered in the same IV solution); do not mix with fat emulsion.
2) THIAMINE a) INDICATIONS: All patients with alcohol dependence at initial examination (Mayo-Smith, 1997). 1) ROUTE: Administer intravenously to the following patients: 1) Those suspected of alcohol withdrawal syndrome.
2) Chronic alcoholics, malnourished individuals, or those who have had protracted vomiting prior to giving carbohydrates (eg, dextrose)
3) Undiagnosed coma and altered mental status
4) Hypothermia of unknown cause
5) Orthostatic hypotension
6) Peripheral neuropathy
a) It is advisable to give 100 mg thiamine intramuscularly or intravenously to any patient at risk, even if parenteral or oral feeding is not begun.
b) RECOMMENDATION: ADULTS: 100 mg intramuscularly or intravenously (NOTE: Alcohol-dependent patients do not absorb oral thiamine well). Continue in doses of 50 to 100 mg/day until normal diet resumes for patients with Wernicke-Korsakoff syndrome, receiving parenteral nutrition only, or undergoing hemodialysis. (NOTE: Thiamine is a component of many multivitamin preparations and may not have to be given separately (eg, Multivits(R) contain 50 mg/ampule).). c) WERNICKE-KORSAKOFF: Patients with this syndrome may require doses of 100 mg IV per hour until ophthalmoplegia resolves. G) HYPOMAGNESEMIA 1) MAGNESIUM SULFATE a) Hypomagnesemia is a relatively common occurrence in alcohol withdrawal syndrome (Kleinschmidt & Delaney, 1998), particularly in patients with seizures or with minor reactions or hallucinations; mean levels range from 0.7 to 1.4 mEq/L (Mayo-Smith, 1997).
b) Routine parenteral administration is NOT recommended because existing data do not demonstrate improvement in alcohol withdrawal severity, delirium, or seizures. Although magnesium level decreases during the course of withdrawal, it spontaneously returns to normal as symptoms subside (Mayo-Smith, 1997). Monitor levels as indicated and supplement as needed if a magnesium deficiency is present (Hamilton, 1998). Possible indications for use have included cardiac dysrhythmias or seizures that may occur secondary to hypomagnesemia (Kleinschmidt & Delaney, 1998).
H) HYPOKALEMIA 1) POTASSIUM CHLORIDE a) INDICATIONS: Mild hypokalemia is noted often in alcohol withdrawal due to a low or absent intake of potassium. It also may occur in the alkalotic state. Hypomagnesemia may also be a contributing factor.
b) RECOMMENDATION: ADULTS: Replacement is based on serum potassium level and renal function.
I) SUPPORT 1) Nonpharmacologic approaches include reassurance, reality orientation, safety measures (risk for harming oneself increases during severe alcohol withdrawal syndrome), frequent monitoring of vital signs and laboratory parameters and potentially preparing the patient for long-term rehabilitation (Kleinschmidt & Delaney, 1998).
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