Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal Syndrome

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1 Journal of Pharmacy and Pharmacology (014) 1-7 D DAVID PUBLISHING Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal Cristina Roman, Sibusisiwe Gumbo and Kevin Okuni Department of Inpatient Pharmacy, Mercy San Juan Medical Center, Carmichael 908, California, United States Abstract: Severe AWS (alcohol withdrawal syndrome) and AWD (alcohol withdrawal associated delirium) are common indications for intensive care unit admissions. Approximately % of patients with severe alcohol withdrawal require prolonged critical care hospital courses, often complicated by respiratory failure, need for mechanical ventilation due to administration of sedative continuous infusions and development of nosocomial infections. Although benzodiazepines are the mainstay of therapy for alcohol withdrawal, some patients exhibit benzodiazepine-refractory alcohol withdrawal. The use of phenobarbital as adjunct to benzodiazepines has been shown in studies to be effective in enhancing therapeutic responsiveness to benzodiazepines and reducing the need for mechanical ventilation. The objective of this study is to evaluate whether severe alcohol withdrawal treatment based on combining symptom-triggered benzodiazepine therapy with adjunctive phenobarbital will result in decreased mechanical ventilation rates, decreased use of continuous sedative infusions, decreased time to withdrawal symptom resolution and decreased length of stay in the intensive care unit. Chart reviews were utilized to determine total amount of benzodiazepine and phenobarbital use, need for mechanical ventilation, requirement of continuous lorazepam, dexmedetomidine or propofol infusions, average intensive care unit length of stay and incidence of adverse effects. Key words: Clinical institute withdrawal assessment of alcohol scale, alcohol withdrawal syndrome, dexmedetomidine, intensive care, phenobarbital, lorazepam. 1. Introduction Abrupt reduction or total cessation of long term alcohol consumption produces a cluster of symptoms called alcohol withdrawal. Classic symptoms of AWS include adrenergic activation, psychiatric agitation including seizures, metabolic and respiratory dysfunction. These clinical manifestations occur due to a combination of effects on the GABA (gamma-aminobutyric acid) and glutamate receptors. Severe alcohol withdrawal syndrome and alcohol withdrawal associated delirium are common indications for patient admission to the ICU (intensive care unit). Majority of patients with severe AWS are currently managed with benzodiazepines and typically require ICU level of care for - days. However, approximately % of patients with severe AWS have Corresponding author: Cristina Roman, Pharm.D., research field: severe alcohol withdrawal syndrome in the Intensive Care Unit. cristina.roman@dignityhealth.org. prolonged critical care courses, often complicated by respiratory failure, excessive sedation, need for mechanical ventilation and risk for complications such as VAP (ventilator-associated pneumonia) [1]. Mechanical ventilation is associated with significantly higher daily costs for patients receiving treatment in the ICU compared to no mechanical ventilation. The average daily ICU cost for patients who are mechanically ventilated is about $10,794 while the average daily ICU cost for patients that are not mechanically ventilated is about $,7 dollars []. Interventions that result in reduced intensive care unit length of stay and/or duration of mechanical ventilation could lead to substantial reductions in total inpatient cost. Many patients with severe alcohol withdrawal require the use of benzodiazepine continuous infusions, which have been shown by several investigators to result in excessive and prolonged sedation. These infusions may also increase the risk of propylene glycol

2 Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal toxicity (manifested as a hyperosmolar state with a metabolic acidosis) []. Benzodiazepine continuous infusion association with excessive respiratory depression and metabolic acidosis increases the likelihood of respiratory failure, need for mechanical ventilation and increase in the risk of complications such as ventilator-associated pneumonia. The requirement for mechanical ventilation additionally prolongs the course of treatment for AWS because of the need for prolonged sedation. Strategies to control AWS that control symptoms but avoid adverse effects of excessive respiratory depression are needed to improve patient outcomes and reduce costs.. Methods.1 Study Design The current study was conducted using retrospective chart reviews of all subjects admitted to the Mercy San Juan Medical Center ICUs from June 1, 011 to January 1, 01 (pre guideline) and February 1, 011 to April 0, 01 (post guideline) with a primary or secondary admission diagnosis of severe alcohol withdrawal syndrome.. Intervention Initially, patients were evaluated for the presence of alcohol withdrawal symptoms using the CIWA-Ar (Clinical Institute Withdrawal Assessment for Alcohol Scale) (Fig. 1), which is a 10 item scale consisting of the following signs and symptoms: nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache, and orientation. This scale was provided to nursing staff in paper form for the initial trial. The benzodiazepine of choice for the management of AWS (Alcohol Withdrawal ) at Mercy San Juan Medical Center is lorazepam. All patients admitted to the ICU with a primary or secondary admission diagnosis of alcohol withdrawal received increasing bolus doses of lorazepam and adjunct bolus doses of phenobarbital titrated based on the SAS (Sedation Agitation Scale) (Figs. -), a scale that is built into the electronic medical record system at Mercy San Juan Medical Center.. Operational Definition of Study Variables Inclusion criteria: subjects fulfilling the following criteria were eligible to participate: (1) age > 18; () admission to the intensive care unit with a primary or secondary admission diagnosis of alcohol withdrawal. Exclusion criteria: subjects were not eligible if any of the following criteria were met: (1) documented allergy to phenobarbital or lorazepam; () age < 18; () use of benzodiazepines for reasons other than AWS..4 Outcome Measures Primary outcomes investigated were use of mechanical ventilation, intensive care unit length of stay and time to symptom resolution. Secondary outcomes investigated were total lorazepam amount required per patient, total phenobarbital amount required per patient, use of lorazepam, dexmedetomidine or propofol continuous infusions, incidence of adverse events (respiratory depression (RR < 1), hypotension (BP < 90/0)) and alcohol withdrawal seizure incidence.. Data Collection Date collection was performed for the following variables: use of mechanical ventilation, intensive care unit length of stay, time to symptom resolution, use of lorazepam, propofol or dexmedetomidine continuous infusions, total lorazepam amount (mg) used per hospital admission, total phenobarbital amount (mg) used per hospital admission, blood alcohol level on admission, seizure development, respiratory depression (RR < 1), hypotension (BP < 90/0), psychiatric evaluation.. Statistical Analysis Descriptive statistics were used to analyze age, ethanol level and adverse events (seizure development,

3 Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal Nausea/Vomiting-Rate on scale none 1 mild nausea with no vomiting 4 intermittent nausea 7 constant nausea and frequent dry heaves and vomiting Tremors-have patient extend arms and spread fingers. Rate on scale no tremor 1 not visible, but can be felt fingertip to fingertip 4 moderate, with patient s arms extended 7 severe, even w/arms not extended Anxiety-Rate on scale 0-7 Agitation-Rate on scale no anxiety, patient at ease 0 normal activity 1 mildly anxious 1 somewhat normal activity 4 moderately anxious or guarded, so anxiety is inferred 7 equivalent to acute panic states seen in severe delirium or acute schizophrenic reactions. 4 moderately fidgety and restless 7 paces back and forth, or constantly thrashes about Paroxysmal Sweats-Rate on Scale no sweats Orientation and clouding of sensorium-ask, What day is this? Where are you? Who am I? Rate scale barely perceptible sweating, palms moist 0-oriented 1 cannot do serial additions or is uncertain about date 4 beads of sweat obvious on forehead disoriented to date by no more than calendar days disoriented to date by more than calendar days 7 drenching sweats 4 disoriented to place and/or person Tactile disturbances-ask, Have you experienced any itching, pins & needles sensation, burning or numbness, or a feeling of bugs crawling on or under your skin? 0 none 1 very mild itching, pins & needles, burning, or numbness mild itching, pins & needles, burning, or numbness moderate itching, pins & needles, burning, or numbness Auditory disturbances-ask, Are you more aware of sounds around you? Are they harsh? Do they startle you? Do you hear anything that disturbs you or that you know isn t there? 0 not present 1 very mild harshness or ability to startle mild harshness or ability to startle moderate harshness or ability to startle 4 moderate hallucinations 4 moderate hallucinations severe hallucinations severe hallucinations extremely severe hallucinations extremely severe hallucinations 7 continuous hallucinations 7 continuous hallucinations Visual disturbances-ask, Does the light appear to be too bright? Is its color different than normal? Does it hurt your eyes? Are you seeing anything that disturbs you or that you know isn t there? 0 not present 1 very mild sensitivity Fig. 1 CIWA-Ar (Clinical Institute Withdrawal Assessment of Alcohol Scale). Headache-Ask, Does your head feel different than usual? Does it feel like there is a band around your head? Do not rate dizziness or lightheadedness. 0 not present 1 very mild mild sensitivity mild moderate sensitivity moderate 4 moderate hallucinations 4 moderately severe severe hallucinations severe extremely severe hallucinations very severe 7 continuous hallucinations 7 extremely severe

4 4 Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal SEDATION AGITATION SCALE Score Term Description 0 Unarousable Unresponsive/comatose, no response to noxious stimuli 1 Very sedated Arouses to noxious stimuli, does not follow commands, may move spontaneously Sedated Responds appropriately to verbal/physical stimuli, follows simple commands, may move spontaneously Awakens easily/spontaneously to verbal/physical stimuli, follows complex commands, Calm and cooperative purposeful movement 4 Agitated Restless, anxious, cooperative to verbal commands, purposeful movement Very agitated Very restless, not consistently cooperative to verbal commands, movement may be inappropriate, may require physical restraints Dangerously agitated Uncooperative, attempting to pull at lines and tubes, striking at staff, thrashing side to side, attempting to climb out of bed, requires physical restraints Fig. The SAS (Sedation Agitation Scale) used to score level of agitation. SAS Score LORAZEPAM DOSING SYMPTOM TRIGGERED DOSING ESCALATION 0 to No dose necessary, hold sedating agents No dose necessary (Optimal Sedation) If SAS = for 1 h, proceed to Fig. 4 Start mg IV -> Reassess SAS after 1 min-> If SAS 4, give another mg IV -> Reassess SAS after 1 min If SAS 4, give 4 mg IV ->Reassess SAS after 1 min-> If SAS 4, give another 4 mg IV-> Reassess after 1min If SAS 4, give mg IV ->Reassess SAS after 1 min-> If SAS 4, give another mg IV -> Reassess after 1 mins 4 If SAS 4, give 8 mg IV -> Reassess SAS after 1 min -> If SAS 4, give another 8 mg IV-> Reassess after 1 mins-> If SAS 4 Consider Phenobarbital (Maximum lorazepam dose: 8 mg IV/dose) CONSIDER PHENOBARBITAL Give mg IV ->Reassess SAS after 0 min If SAS 4 give mg IV ->Reassess SAS after 0 min If SAS 4 give another mg IV ->Reassess SAS after 0 min 8 mg IV per If SAS 4 give 10 mg IV -> Reassess SAS after 0 min lorazepam dose If SAS 4 give 10 mg IV -> Reassess SAS after 0 min required If SAS 4 give 0 mg IV ->Reassess SAS after 0 min If SAS 4 give 0 mg IV ->Reassess SAS after 0 min Continue lorazepam at maximum dose for SAS 4 while on phenobarbital If SAS = for 1 h : Go back to maximum effective lorazepam dose and proceed to Fig. 4 Fig. Symptom triggered dosing escalation used during the lorazepam/phenobarbital dosing protocol. Effective dose = dose required to control withdrawal symptoms 1 h. MAINTENANCE LORAZEPAM DOSING OPTIMAL SEDATION (SAS ) SAS Score Suggests effective dose Re-Assess SAS SAS = every 1 min : YES -> decrease monitoring frequency to every 0 min NO-> effective dose PRN SAS 4 SAS = every 0 min : YES -> decrease monitoring frequency to every 1- h NO-> effective dose PRN SAS 4 SAS = every 1 h : YES -> proceed to Fig. NO-> effective dose PRN SAS 4 Fig. 4 Symptom triggered maintenance dosing used during the lorazepam/phenobarbital dosing protocol. Effective dose = dose required to control withdrawal symptoms 1 h.

5 Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal SYMPTOM TRIGGERED DE-ESCALATION SAS Score Assess SAS (target ) every 1- h and 1 min after sedative dose Lorazepam Effective dose IV 4 0% effective dose I No dose necessary(optimal sedation) 0 to No dose necessary, hold sedating agents Same lorazepam dose 4h Decrease effective dose by 0% at a time No lorazepam given 4 h Stop lorazepam Fig. Symptom triggered dosing de-escalation used during the lorazepam/phenobarbital dosing protocol. Effective dose = dose required to control withdrawal symptoms 1 h. respiratory depression RR < 1 and hypotension BP < 90/0). Once patients were enrolled and adequate data was gathered, chi-square test was used to analyze outcome proportion differences between groups (pre and post intervention (X/n, y%)) (mechanical ventilation, use of lorazepam, propofol and dexmedetomidine continuous infusions). Unpaired t test was used to analyze differences between continuous variables pre and post intervention (ICU length of stay, time to symptom resolution, amount of lorazepam/phenobarbital required per patient per admission). P-values (P) of < 0.0 were considered statistically significant.. Results During the pre guideline period, thirty patients were identified to have severe enough alcohol withdrawal and were managed in the intensive care unit. Demographics and clinical characteristics for the pre guideline period can be found in Table 1. Forty seven percent of subjects required mechanical ventilation and the average intensive care unit length of stay was.9 days, these rates being consistent with previous reports [4] looking at similar protocols. Twenty three percent of the subjects received lorazepam continuous infusions, thirty percent of the patients received propofol continuous infusions and 4% of the patients received dexmedetomidine continuous infusions. Approximately 0% of the subjects experienced some degree of hypotension, while 7% of the subjects experienced respiratory depression. Following institution of the new dosing guideline, we identified three patients that qualified to use the lorazepam-phenobarbital dosing protocol. The demographics and clinical characteristics for the post guideline period can be found in Table. None of the three subjects required mechanical ventilation and none of the subjects required propofol or dexmedetomidine continuous infusions as seen in Table 4. One patient was started on a lorazepam continuous infusion, however, the subject did not require mechanical ventilation. Two of the subjects had a three day intensive care unit length of stay, while the third patient had a four day intensive care unit length of stay. Overall, there was a significant shorter intensive care unit length of stay post guideline as opposed to pre guideline. None of the post guideline subjects experienced adverse effects or alcohol withdrawal seizures. 4. Discussion Our study adds to existing literature on the successful use of phenobarbital as adjunct to benzodiazepines in the management of severe alcohol withdrawal syndrome []. Several studies suggest that administration of benzodiazepines in a symptom-triggered fashion reduces the total amount of benzodiazepines administered, reduces mechanical ventilation rates and shortens the duration of therapy Table 1 Clinical characteristics for pre guideline period. Pre guideline (n = 0) Male, n (%) 7 (90) Age, years 48.4 ± 9.8 ETOH level on admission (g/dl) 10.8 ± 14.1

6 Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal Table Clinical outcomes for pre guideline period. Pre guideline (n = 0) Mechanical ventilation, n (%) 14 (4.7) Lorazepam continuous infusion, n (%) 7 (.) Propofol continuous infusion, n (%) 9 (0) Dexmedetomidine continuous infusion, n (%) 1 (4.) Average ICU length of stay, days.9 ±.1 Average time to symptom resolution, days. ± 4.1 Average amount of lorazepam required per patient per admission (mg) 114. ± 18. Hypotension, n (%) (0) Respiratory depression, n (%) 8 (.7) Alcohol withdrawal seizures, n (%) 4 (1.) Table Clinical characteristics for post guideline period. Post guideline Patient #1 Patient # Patient # Age, years 1 ETOH level on admission (g/dl) Table 4 Clinical outcomes for post guideline period. Post guideline P Patient #1 Patient # Patient # Mechanical ventilation No No No Lorazepam continuous infusion No Yes No Propofol continuous infusion No No No Dexmedetomidine continuous infusion No No No ICU length of stay, days 4 Time to symptom resolution, days 4 Amount of lorazepam used per admission, mg 18 Amount of phenobarbital used per admission, mg Hypotension No No No Respiratory depression No No No Alcohol withdrawal seizures No No No [4, -9]. However, AWS is difficult to manage using solely benzodiazepines because many patients are resistant to standard benzodiazepine doses. These patients may have low endogenous levels of GABA or conformational changes in their GABA receptor subunits preventing effective signaling and thus diminishing efficacy of benzodiazepines [10]. However, these changes do not impair activation of the GABA receptor by barbiturates, therefore the use of barbiturates such as phenobarbital, can be effectively used as adjuncts to benzodiazepines. The combined effect of benzodiazepines, which increase the frequency of the GABA chloride channel opening, and phenobarbital, which increases the duration of the chloride channel opening may enhance therapeutic responsiveness to treatment. In addition, phenobarbital also binds the AMPA site of glutamate receptors further blocking the glutamate excitotoxicity observed in AWS [11-1]. There were several limitations to our study. This study was not randomized and decisions such as need for intensive care unit admission or need for endotracheal intubations were left up to the individual practitioner. There was also lack of objective categorization with the use of CIWA and SAS assessment tools. Another limitation was the time

7 Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal 7 component of the project; the complexity of implementing a new protocol while staying within time constraints impeded us from gathering enough data points for the post guideline period.. Conclusion The lorazepam and phenobarbital dosing protocol for the management of severe alcohol withdrawal syndrome was implemented in January 01 and proved to be successful at our facility. None of the patients using the new lorazepam-phenobarbital dosing protocol required mechanical ventilation or the use of dexmedetomidine or propofol continuous infusions which proved what we initially expected. The overall intensive care unit length of stay was shorter after the guideline implementation as opposed to the pre guideline study period. References [1] De Wit, M., Jones, D. G., Sessler, C. N., Zilberberg, M. D., and Weaver, M. F Alcohol Use Disorders in the Critically Ill Patient. Chest 18 (4): [] Dasta, J. F., McLaughlin, T. P., Mody, S. H., and Piech, C. T. 00. Daily Cost of an Intensive Care Unit Day: The Contribution of Mechanical Ventilation. Critical Care Medicine (): [] Horinek, E., Kiser, T., Fish, D., and MacLaren, R Propylene Glycol Accumulation in Critically Ill Patients Receiving Continuous Intravenous Lorazepam Infusions. Annals of Pharmacotherapy 4 (1): [4] Gold, J., Binaya, R., Nolan, A., and Nelson L. S A Strategy of Escalating Doses of Benzodiazepines and Phenobarbital Administration Reduces the Need for Mechanical Ventilation in Delirium Tremens. Critical Care Medicine : [] Hayner, C. E., Wuestefeld, N. L., and Bolton, P. J Phenobarbital Treatment in a Patient with Resistant Alcohol Withdrawal. Pharmacotherapy 9 (7): [] Daeppen, J. B. 00. Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal: A Randomized Treatment Trial. Archives of Internal Medicine 1: [7] Saitz, R Individualized Treatment for Alcohol Withdrawal. A Randomized Double-Blind Controlled Trial. Jama 7: 19-. [8] Spies, C. D. 00. Alcohol Withdrawal Severity is Decreased by Symptom-Oriented Adjusted Bolus Therapy in the ICU. Intensive Care Medicine 9: 0-8. [9] DeCarolis, D., Rice, K., Ho, L., Willenbring, M., and Cassaro, S Symptom-Driven Lorazepam Protocol for Treatment of Severe Alcohol Withdrawal Delirium in an Intensive Care Unit. Pharmacotherapy 7 (4): [10] Cagetti, E., Liang, J., Spigelman, I., and Olsen, R. W. 00. Withdrawal from Chronic Intermittent Ethanol Treatment Changes Subunit Composition, Reduces Synaptic Function, and Decreases Behavioral Responses to Positive Allosteric Modulators of GABAA Receptors. Molecular Pharmacology : -4. [11] Ives, T. J., Mooney, A. J., and Gwyther, R. E Pharmacokinetic Dosing of Phenobarbital in the Treatment of Alcohol Withdrawal. Southern Medical Journal 84 (1): [1] Richards, R Phenobarbital for Alcohol Withdrawal: Rapid Patient Disposition. California Journal of Emergency Medicine 1: -4. [1] Kramp, P., and Rafaelsen, O. J Delirium Tremens: A Double Blind Comparison of Diazepam and Barbital Treatment. Acta Psychiatrica Scandinavica 8: