Blame it on the Alcohol: Comparison of Propofol vs Dexmedetomidine for Refractory Alcohol Withdrawal

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1 Blame it on the Alcohol: Comparison of Propofol vs Dexmedetomidine for Refractory Alcohol Withdrawal Kristi Hargrove, PharmD PGY1 Pharmacy Resident Department of Pharmacotherapy and Pharmacy Services, University Health System Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, UT Health San Antonio January 12, 2018 Learning Objectives: 1. Describe mechanisms of alcohol withdrawal and potential drug targets for treatment 2. Identify signs and symptoms of withdrawal, appropriate assessment of, and risk factors for complications associated with alcohol withdrawal 3. Summarize evidence for use of propofol and dexmedetomidine as adjunct agents in refractory alcohol withdrawal 4. Apply evidence to a patient case to provide appropriate recommendations based on clinical presentation and characteristics Hargrove 1

2 Assessment Questions 1. T/F: After cessation of chronic alcohol use, there is an increased excitatory signal due to an increase of NMDA receptors. a. True b. False 2. All the following are common symptoms of alcohol withdrawal except: a. Tremors b. Palpitations c. Reduced body temperature d. Hypertension 3. What is the first line treatment for alcohol withdrawal symptoms? a. Ketamine b. Benzodiazepines c. Metronidazole 4. T/F: Dexmedetomidine can be used alone as alcohol withdrawal treatment because it provides both sympatholytic and anticonvulsant properties. a. True b. False ***To obtain CE credit for attending this program please sign in. Attendees will be ed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an within 72 hours, please contact the CE Administrator at ana.francomartinez@uhs-sa.com *** Faculty (Speaker) Disclosure: Kristi L. Hargrove has indicated she has no relevant financial relationships to disclose relative to the content of her presentation Hargrove 2

3 Alcohol Withdrawal Syndrome I. Background and epidemiology 1-4 a. Approximately 20% of men and 10% of women will experience alcohol use disorder i. 50% of these will experience withdrawal symptoms following cessation or decreased consumption b. Morbidity and mortality i. Excessive alcohol consumption can lead to development of acute complications and chronic diseases including: 1. Cirrhosis 2. Cardiovascular disease including hypertension, heart disease, and stroke 3. Cancer including hepatocellular, colon, breast, mouth, and esophageal 4. Memory and learning difficulties including Wernicke s encephalopathy and dementia 5. Depression and anxiety 6. Alcohol dependence ii. As reported by the National Institute of Health (NIH), alcohol related mortality is the third leading cause of preventable death in the United States accounting for approximately 88,000 deaths annually 1. Deaths are attributed to both acute and chronic causes 2. Acute causes include motor vehicle crashes, poisoning, suicide secondary to alcohol use, fall injuries, homicide and fire injuries 3. Majority of chronic causes are attributed to abuse/dependence, liver disease/cirrhosis, and hemorrhagic stroke c. Economic and societal consequences i. In 2010, alcohol misuse cost $249 billion in the United States 1. 75% of this cost related to binge drinking ii. Excessive consumption can lead to loss of productivity/unemployment, family strain, and social stigma II. Definitions a. Alcohol use disorder 5 i. Chronic, relapsing disease characterized by compulsive alcohol use, lack of control over alcohol intake, and negative emotional state when not using alcohol ii. Classified as mild, moderate, or severe based on Diagnostic and Statistical Manual of Mental Disorders, 5 th edition (DSM-5) criteria iii. See Appendix A for criteria b. Alcohol withdrawal 1,2,5-7 i. Per DSM-5 must meet the following two criteria to be considered alcohol withdrawal: 1. Cessation or reduction in alcohol use that has been heavy and prolonged 2. Two or more of the following symptoms developed within several hours to a few days after alcohol cessation Table 1. Additional Diagnostic Criteria Autonomic hyperactivity Increased hand tremor Insomnia Nausea or vomiting Psychomotor agitation Anxiety Transient visual/auditory/tactile hallucination Generalized tonic-clonic seizures Hargrove 3

4 c. Refractory alcohol withdrawal 1,2,8,9 i. Current literature lacks a standardized definition ii. Defined as failure to control symptoms with high doses of benzodiazepines 1. Doses > 40 mg of diazepam (or equivalent benzodiazepine) in one hour 2. Doses > 50 mg diazepam or 10 mg lorazepam within first hour 3. Doses > 200 mg diazepam or 40 mg lorazepam within three hours iii. Associated with longer intensive care unit (ICU) stay, increased incidence of mechanical ventilation and increased risk of nosocomial pneumonia d. Clinical Institute Withdrawal Assessment for Alcohol Scale revised (CIWA-Ar) 8,9 i. Tool used for the assessment of severity of alcohol withdrawal and risk for seizures ii. Includes 10 common signs and symptoms 1. Patient must be able to verbalize and endorse signs and symptoms 2. Use in ICU is limited iii. Score Assessment: 1. Mild: CIWA-Ar = Moderate: CIWA-Ar = Severe: CIWA-Ar > 20 iv. See Appendix B for assessment scale III. Pathophysiology 2,6,7,12,13 a. Alcohol causes central nervous system depression via stimulation of Gamma-Aminobutyric Acid (GABA) receptors and antagonism of N-methyl-D-aspartate (NMDA) receptors b. Chronic alcohol consumption causes an imbalance in which the body tries to restore homeostasis by altering the number of GABA and NMDA receptors c. Cessation of alcohol returns to an unbalanced state secondary to these changes in receptors Chronic Alcohol Use Increased inhibitory tone Reduced excitatory tone Downregulation GABA receptor Upregulation NMDA receptor Reduced inhibitory signal Increased excitatory signal Figure 1. Progression of neurologic changes in alcohol use Figure 2. Homeostasis in chronic alcohol use 6 IV. Clinical manifestations 1,2,7,10,14-17 a. Alcohol undergoes saturable metabolism by the liver via alcohol dehydrogenase and CYP2E1 i. As the body metabolizes alcohol there is a reduction in blood alcohol level leading to withdrawal ii. Chronic alcohol use may lead to accelerated metabolism iii. Symptoms start within 6-8 hours, peak at 72 hours, and generally reduce by day 7 Hargrove 4

5 b. Initial phase: 6-12 hours Table 2. Symptoms of early alcohol withdrawal Tremors Diaphoresis Anxiety/insomnia Tachycardia Nausea/vomiting Hypertension Diarrhea Headache Palpitations Increase body temperature c. Late phase: hours i. Hallucinations ii. Seizures d. Delirium tremens (DT) > 3 days i. Definition: The most serious manifestation of alcohol withdrawal presenting with autonomic instability plus hyperactive delirium ii. Occurs in about 3-5% of patients hospitalized for alcohol withdrawal and has a mortality of up to 4-8% iii. Symptoms Table 3. Symptoms of DT Early Changes in level of consciousness Inattention/cognitive deficits Hallucinations Confusion Hypertension Progression Malignant arrhythmias Severe electrolyte abnormalities Dehydration Prolonged seizures Multiorgan dysfunction Death iv. DT risk factors 1. History of previous DT 6. Last alcohol intake > 2 days 2. Recent untreated withdrawal seizures 7. Age > 30 years 3. Systolic blood pressure > 150 mmhg or heart rate > 100 beats/minute 4. History of sustained drinking 9. Concurrent medical illness 5. CIWA-Ar ³15 8. Recent misuse of other depressants such as benzodiazepines Hargrove 5

6 Current Management I. Supportive therapy 1,2,6,18 a. Fluid repletion in patients who appear hypovolemic i. Alcohol leads to impaired salt and water absorption along with a diuretic effect (inhibition of antidiuretic hormone release) leading to a reduction in total water volume ii. Patients may not have baseline adequate fluid intake iii. Insensible losses through vomiting, diarrhea, fever and sweating b. Vitamin and electrolyte repletion i. Patients with chronic alcohol use are often malnourished 1. Poor nutrient intake 2. Increased metabolic rate ii. Increased gut motility and mucosal permeability leads to reduced absorption compounded by nutrient leakage iii. Decreased vitamin absorption due to changes in active transport 1. Macrocytic anemia (folate) 2. Risk of Wernicke s encephalopathy (thiamine) iv. Intake of solute free fluid and inability to handle fluid appropriately leads to relative sodium deficiency v. Structural changes in the kidney, including thickened membranes and altered cell structure, along with impaired regulation results in electrolyte disturbances 1. Loss of potassium can lead to deadly arrhythmias vi. Replete the following: 1. Thiamine 2. Folate 3. Multivitamin 4. Electrolytes as indicated: potassium, sodium, phosphate, and magnesium II. Benzodiazepine therapy 2,6,19,20 a. First studied in 1969, leading to the establishment of benzodiazepine therapy as first line treatment b. Follow institution specific guidelines for preferred benzodiazepine and dosing Fixed Dose Daily dose calculated according to average daily alcohol intake One standard drink = ~ 5 mg diazepam Total dose divided every 6 hours Daily maximum not to exceed diazepam 60 mg Benzodiazepine tapered after approximately 2-3 days of stabilization More reasonable for outpatient use if inpatient admission not an option Symptom Directed Standard of care as first line alcohol withdrawal treatment CIWA-Ar used to assess withdrawal and administer pre-specified doses of benzodiazepine Compared to fixed dose, overall reduction in benzodiazepine use and less unwanted sedation observed in symptom directed Caution in patients with a history of alcohol withdrawal seizures as seizures may precipitate even when CIWA-Ar appears controlled Figure 3. Strategies for benzodiazepine use Hargrove 6

7 III. Benzodiazepine refractory alcohol withdrawal 1,8,13,21,22 a. Benzodiazepine monotherapy is not always sufficient to control symptoms and escalating doses may lead to adverse effects i. Benzodiazepines may saturate binding site therefore targeting second GABA binding site may improve efficacy of therapy ii. Glutaminergic activity is fundamental to alcohol withdrawal symptoms and is not targeted by benzodiazepine therapy iii. Benzodiazepines may lead to over sedation due to sequestration in tissue following high dose regimens iv. High cumulative doses can lead to adverse outcomes including respiratory depression, increased aspiration/intubation risk, increased delirium risk and increased hospital length of stay b. Adjunct agents i. Various adjunctive agents have been employed for use in patients without adequate symptom control from initial benzodiazepines ii. Ideal management of benzodiazepine refractory alcohol withdrawal remains unclear Phenobarbital Propofol Dexmedetomidine Ketamine Binds GABA A receptor at separate site from GABA to enhance binding and potentiate inhibitory tone Block NMDA receptors to reduce excitatory tone Central acting a2 adrenergic agonist à reduction in norepinephrine release and sympathetic outflow NMDA receptor antagonist Synergistic effects with benzodiazepines in patients considered refractory Binds GABA, glycine, nicotinic and M 1 muscarinic receptors to reduce overal neural transmission NOTE: Does NOT provide anticonvulsant properties Oppose overexpressed excitatory signal leading to reduced benzodiazepine requirement Provides sedative, anxiolytic, anticonvulsant, amnestic and antiemetic properties Provides anxiolytic, sedative, analgesic and sympatholytic properties Adverse effects: hypotension and respiratory depression Adverse effects: bradycardia and hypotension Figure 4. Mechanism of action and pharmacologic properties of adjunct agents Hargrove 7

8 Literature Focus: Use of Propofol or Dexmedetomidine Propofol 7,9 I. Data to support use a. Case reports have described successful use of propofol in patients with refractory DT b. Use in patients with refractory alcohol withdrawal or requiring mechanical ventilation has been studied retrospectively Table 4. Studies evaluating the use of propofol in benzodiazepine refractory alcohol withdrawal Study design Patient population Intervention BZD doses Results Sohraby et al. (2014) 7 Retrospective n = 64 cohort analysis Admitted with alcohol withdrawal based on DSM IV criteria requiring MV and receiving BZD or PROP containing regimens PROP +/- BZD vs BZD infusion monotherapy Median BZD dose prior to intubation: - PROP = 56 mg LOR equivalents - BZD = 15 mg LOR equivalents p = 0.03 Median BZD dose after intervention: - PROP = 10 mg LOR equivalents - BZD = 36 mg LOR equivalents p = PROP patients had similar time to resolution (PROP 8 days vs BZD 7 days) despite higher BZD requirements prior to intubation and PROP initiation - Adverse event rates similar between groups and included hypotension and bradycardia in both groups; pancreatitis and AKI also observed in the PROP group (single episode of each) - PROP provides alternative treatment in patients with alcohol withdrawal uncontrolled by BZD requiring MV Retrospective cohort review Patients meeting refractory alcohol withdrawal criteria: Use of ³ 40 mg diazepam (or equivalent) within 1 hour Wong et al. (2015) 9 BZD + PROP vs BZD alone - Patients excluded if other adjunct agents were used Median BZD for refractory designation: - BZD + PROP = 54 mg DIA equivalents - BZD only = 50 mg DIA equivalents Total BZD requirement in 7- day period after refractory designation: - BZD + PROP = 743 mg DIA equivalents - BZD only = 576 mg DIA equivalents n = 66 - Longer time to resolution of symptoms in PROP containing group (PROP 7 days vs BZD 5 days) - The addition of PROP to BZD for refractory alcohol withdrawal was associated with more clinical care including longer ICU/hospital length of stay, increased nosocomial pneumonia and higher alcohol withdrawal related complications such as hallucination and DTs Abbreviations: AKI = Acute Kidney Injury, BZD = benzodiazepine, DIA = diazepam, DSM IV = Diagnostic and Statistical Manual of Mental Disorders, DT = delirium tremens, LOR = lorazepam, MV = mechanical ventilation, PROP = propofol Hargrove 8

9 Dexmedetomidine I. Data to support use a. Multiple retrospective case series and studies have investigated use of dexmedetomidine Table 5. Studies evaluating the use of dexmedetomidine in benzodiazepine refractory alcohol withdrawal Study design Patient population Intervention BZD dose Results Rayner et al. (2012) 23 Single center retrospective observational Retrospective case series Multicenter, retrospective cohort study Patients admitted to medical, surgical, neuroscience ICU - Predominately male subjects with average age 44.9 years - Excluded for severe comorbid disease including CNS trauma and CVA Critically ill adults with ICU admission diagnosis of alcohol withdrawal treated with DEX - Predominantly white male patients in the medical ICU Non-intubated adults age with alcohol withdrawal who received continuous infusion BZD Baseline Characteristics: DEX group included significantly older (p = 0.03), white (p < 0.01) males BZD group included younger, Hispanic males - Greater olanzapine and pre-study BZD use p < 0.01 Addition of DEX for documented management of alcohol withdrawal symptoms Average BZD dose prior to DEX: mg/24 hours Average BZD in first 24 hours after DEX initiation: mg/24 hours p < Frazee et al. (2014) 24 Provider driven addition of DEX to institutional standard symptom driven BZD protocol DEX infusion vs BZD infusion (lorazepam or midazolam) Cumulative median BZD dose - Prior to DEX: 30 mg - After DEX: 8 mg Crispo et al. (2014) 25 Cumulative mean BZD prior to study drug: - DEX = 8.4 mg LOR equivalents -BZD = 19.6 LOR equivalents Cumulative mean BZD dose during study - DEX = 10.8 mg LOR equivalents - BZD = mg LOR equivalents a n = 20 - DEX therapy associated with reduced BZD dosing and blunted hyperadrenergic response defined as a reduction in HR and SBP - One patient required discontinuation due to brief asystolic pauses. - Bradycardia and hypotension were not significantly different n = 33 - Reduction in BZD dose, SBP and HR after initiation of DEX - Early introduction of DEX for severe alcohol withdrawal decreased BZD requirements and autonomic hyper reactivity - Three patients experienced seizure secondary to withdrawal - Multimodal management may improve control of withdrawal in critically ill patients n = 61 - No difference in composite efficacy endpoint of respiratory distress or seizure - One patient in the DEX group developed a seizure after not receiving any BZD - Bradycardia (46.5% vs 15.2%) and hypotension (42.9% vs 12.1%) were both significantly higher in DEX group over BZD group (p < 0.01) - DEX demonstrated a BZD sparing effect - Protective effect to prevent intubation could not be proven Hargrove 9

10 Study design Patient population Intervention BZD dose Results VanderWeide et al. (2016) 26 Retrospective controlled cohort study DEX infusion vs matched control n = 20 Patients admitted to ICU with primary diagnosis of alcohol withdrawal receiving > 8 mg LOR within 6-hour window and CIWA- Ar > 8 included - Predominantly middle age (45-50 year old) white males - No significant differences at baseline 12 hour pre/post difference: - DEX = mg - Control = 8.3 mg - p = hour pre/post difference: - DEX = mg - Control = - 11 mg - p = Median 12 hour BZD requirement significantly decreased - No significant difference in BZD requirement at 24 hours - Patients receiving DEX experienced significantly more bradycardia (1 patient HR < 40) but not hypotension reinforcing safety concern with DEX use Abbreviations: BZD = benzodiazepine, CIWA-Ar = Clinical Institute Withdrawal Assessment Scale revised, CNS = central nervous system, CVA = cerebrovascular accident, DEX = dexmedetomidine, HR = heart rate, ICU = intensive care unit, LOR = lorazepam, SBP = systolic blood pressure a Included continuous infusion BZD in total dose Table 6. Mueller SW et al. A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal (2014) 27 Objective Evaluate the efficacy of DEX as adjunctive therapy to a symptom triggered alcohol withdrawal protocol Methods Single center, double blind, placebo controlled study Patient population Inclusion Adults admitted to medical ICU with severe alcohol withdrawal Receiving standard, symptom-driven therapy Severe alcohol withdrawal: CIWA-Ar ³ 15 and LOR use ³ 16mg in a 4-hour period Exclusion Age < 18 years old or > 85 years old Administration of BZD for other indications Current use of DEX Not admitted to ICU Comatose due to metabolic/neurologic cause Active MI/Heart block Child-Pugh class C liver disease Pregnancy Moribund state with planned withdrawal of life support Known history of adverse reaction to DEX Non-English speaking Abuse of multiple substances Intervention DEX low dose (LD) (0.4 mcg/kg/hr) vs DEX high dose (HD) (1.2 mcg/kg/hr) vs placebo Standard therapy included symptom-driven protocol with nurse-managed, sliding scale BZD according to withdrawal severity measured by CIWA score at minimum every 4 hours and after intervention Lorazepam 2-4 mg IV administered every 30 minutes for CIWA scores > 15 Provider notified if ³ 8mg LOR, then LOR infusion or adjunctive medications were initiated Patients received additional agents including opiates, antipsychotics and phenobarbital at the discretion of the provider Hargrove 10

11 Primary D LOR requirements over 24 hours Cumulative LOR requirement over 7 days Outcomes reported as LD, HD and combined treatment group (LD + HD) Outcomes Secondary Post-randomization and total daily LOR requirements Intubation Seizure after starting study drug Severity of severe alcohol withdrawal Safety outcomes: bradycardia (HR < 50) and hypotension (MAP < 65 or SBP < 90) and adjustment of infusion due to hemodynamic effects Statistics Outcomes were reported as median + IQR or proportions based on nature of the endpoint Goal enrollment 24 patients (2:1 randomization in combined DEX group to placebo) to achieve 80% power and 5% significance level based on a desired mean difference of 80 mg of LOR over the first 7 days p < 0.05 considered significant Baseline characteristics Predominantly middle aged (47-51 yo) males Baseline median APACHE III score significantly higher in the LD group as compared with placebo but not HD (p = 0.01 and p = respectively) Intubation at study entry: Placebo 3 (37.5%) vs LD 5 (62.5%) vs HD 3 (37.5%) Trend towards higher pre-study 24-hour requirement of lorazepam in the LD and HD group vs placebo though p values non-significant o Placebo = 39 mg vs LD = 94 mg vs HD = 75 mg (combined = 82 mg) Trend towards longer time study drug administration in LD group though no significant difference Results Duration of infusion: Placebo = hr vs LD = hr vs HD = 78 hr Placebo n = 8 LD n = 8 HD n = 8 LD + HD n = 16 Primary D LOR requirements over 24 hours -8mg mg p = mg p = mg p = Cumulative LOR requirement (7 days) mg mg p = mg p = mg p = 0.58 Secondary 24 hour LOR use 77.1 mg 28.5 mg p= mg p = mg p = 0.33 Total post study drug LOR requirements mg 58.5 mg p = mg p = mg p = 0.23 ICU length of stay 4 days 5.5 days p = days p = days p = 0.42 Hospital length of stay 7.4 days 10.9 days p = days p = days p = 0.71 No patients required intubation or experienced seizure after study initiation Safety: # of patients (%) Placebo LD HD LD + HD Bradycardia a 0 (0%) 1 (12.5%) p = 1 3 (37.5%) p = (25%) p = 0.26 Decrease HR by > 20 bpm 2 (25%) 3 (37.5%) p = 1 7 (87.5%) p = (62.5%) p = 0.19 Hypotension 0 (0%) 1 (12.5%) p = 1 2 (25%) p = (18.75%) p = 0.52 Intervention for 2 (25%) 3 (37.5%) p = 1 1 (12.5%) p = 1 4 (25%) p = 1 hypertension Temporary d/c or change in rate of study drug 0 (0%) 4 (50%) p = (50%) p = (50%) p = One patient required, discontinuation of therapy, fluid bolus for hypotension and then able to resume infusion. Hargrove 11

12 Conclusion Adjunctive use of DEX lead to short term (first 24 hour) but not 7-day benzodiazepine sparing effect Bradycardia necessitates need for monitoring however in this study DEX dose adjustment lead to resolution of side effect Reviewer s critique First prospective, placebo controlled study à new outlook on the use of dexmedetomidine for adjunct treatment Long term benzodiazepine reduction was not seen limiting value for overall reduction in benzodiazepine use o Possibly due to short infusion duration (maximum 3-4 days) which may not have an extended benefit Inclusion of more clinically significant outcomes, such as duration of alcohol withdrawal symptoms, could help tease out benefit of dexmedetomidine Strengths Limitations Prospective and placebo controlled Small sample size Provided clinically significant safety outcomes Sample size met power calculation however results Compared efficacy and safety at different DEX doses did not meet expected difference Described ICU alcohol withdrawal protocol Higher than expected baseline intubation rate reducing optimal assessment of alcohol withdrawal Variability in baseline characteristics Abbreviations: APACHE III = Acute Physiology and Chronic Health Evaluation, BZD = benzodiazepine, CIWA-Ar = Clinical Institute Withdrawal Assessment Scale revised, DEX = dexmedetomidine, HD = high dose, HR = heart rate, ICU = intensive care unit, IQR = interquartile range, LD = low dose, LOR = lorazepam, LOS = length of stay, MAP = mean arterial pressure, MI = myocardial infarction, SBP = systolic blood pressure Table 7. Bielka K et al. Addition of dexmedetomidine to benzodiazepines for patients with alcohol withdrawal syndrome in the intensive care unit: a randomized controlled study (2015) 28 Objective Evaluate if the addition of DEX to BZD therapy is effective to reduce BZD use for alcohol withdrawal syndrome patients in the ICU Methods Single center, randomized, controlled study in mixed ICU setting Patient population Inclusion Exclusion Age years old History of other substance abuse Diagnosis of alcohol withdrawal syndrome by DSM IV Use of general anesthesia in prior 24 hours Neurological disorder including TBI/stroke/dementia Co-morbid conditions: heart failure, MI, HR < 50, GFR < 30 ml/min, liver failure (Child-Pugh class C), acute respiratory failure Intervention DEX mcg/kg/hr titrated to target sedation and CIWA-Ar (Group D) vs control (Group C) Target RASS 0 to -2 Target CIWA-Ar < 15 BZD protocol: DIA 10mg every 30 minutes for RASS > +2 or CIWA-Ar > 15 Haloperidol 5mg IM permitted as rescue for severe agitation or hallucinations Outcomes Primary Efficacy 24-hour use of DIA Cumulative use of DIA in the ICU Secondary ICU LOS Rate of intubation Time spent at target RASS Necessity for rescue sedation Sedation stops Haloperidol requirements Safety Hypotension (SBP < 90) or hypertension (SBP > 160) Bradycardia (HR < 50) or tachycardia (HR > 110) Desaturation < 90% Hypoglycemia (< 70 mg/dl) or hyperglycemia (> 180 mg/dl) Hargrove 12

13 Statistics Categorical data presented as proportions Continuous data presented as medians with IQR p < 0.05 was considered significant Baseline characteristics Predominantly middle-aged (46 yo) males DIA dose: no difference Group D vs Group C (30 mg vs 30 mg) Median CIWA-Ar at ICU admission DEX vs placebo 25 vs 26 (p = 1) Median RASS at ICU admission +2 for both groups Results Duration of DEX infusion: 36 hours Median dose: 0.5 mcg/kg/hr Group D (n = 35) Group C (n = 32) p value Primary 24 hour DIA 20 mg 40 mg p < Cumulative use of DIA 60 mg 90 mg p < Secondary ICU LOS 50 hr 70 hr p = Sedation: Time target RASS 90% 64.5% p < Rescue sedation (#) p = Sedation stops (#/24h) 0 2 p = Haloperidol requirement 6% 31% p = 0.02 Haloperidol cumulative dose 50 mg 60 mg p = 0.2 Safety Group D Group C p value Tachycardia 0/35 (0%) 5/32 (16%) p = 0.02 Bradycardia 10/35 (31%) 2/32 (6%) p= 0.03 Hypertension 0/35 (0%) 4/32 (16%) p = 0.05 Rates of hypotension, desaturation, hypoglycemia and hyperglycemia were similar between groups Conclusions DEX significantly reduced DIA consumption of symptom triggered protocol as well as improved time in target sedation Use of DEX reduced hyperadrenergic symptoms including hypertension and tachycardia Patients receiving DEX should be monitored for bradycardia Addition of DEX to BZD therapy is safe and effective for patients with alcohol withdrawal syndrome in the ICU Reviewer s critique Additional measure of target sedation with RASS goal -2 to 0 was an adequate target to keep patient lightly sedated and able to arouse o Frequent monitoring for over sedation and airway protection required since not all patients were not intubated Bradycardia is a known safety concern with the use of dexmedetomidine which requires patients to be closely monitored and expected that this would occur more frequently Since alcohol withdrawal can present with tachycardia and hypertension, the adverse effects observed in this study in the placebo group could be due to inadequate control of alcohol withdrawal indicating additional management strategies could be appropriate Hargrove 13

14 Strengths Prospective Similar baseline characteristics Clinically significant outcomes measured and wide variety of safety end points Abbreviations: BZD = benzodiazepine, CIWA-Ar = Clinical Institute Withdrawal Assessment Scale revised, DEX = Dexmedetomidine, DIA = diazepam, DSM IV = Diagnostic and Statistical Manual of Mental Disorders, GFR = glomerular filtration rate, HR = heart rate, ICU = intensive care unit, IM = intramuscular, LOS = length of stay, MI = myocardial infarction, RASS = Richmond Agitation-Sedation Scale, SBP = systolic blood pressure, TBI = traumatic brain injury Clinical Question: Which sedative agent improves control of refractory alcohol withdrawal while maintaining safety outcomes? Table 8. Ludtke KA et al. Retrospective review of critically ill patients experiencing alcohol withdrawal: dexmedetomidine versus propofol and/or lorazepam continuous infusions (2015) 29 Objective Evaluate the incidence and duration of mechanical ventilation and ICU length of stay in alcohol withdrawal patients treated with DEX vs PROP and/or LOR continuous infusions Methods Single center retrospective chart review study of patients diagnosed with treated for alcohol withdrawal during their ICU admission Patient Population Inclusion Adult critical care patients Diagnosis of alcohol withdrawal Treated with continuous infusion of targeted agents Limitations No placebo comparator Small sample size Additional adjunct medication used Exclusion Treatment with continuous infusion of DEX + either PROP or LOR Intervention DEX continuous infusion vs PROP/LOR infusions representing standard of care Low dose intermittent BZD available as scheduled or as needed rescue medication due to lack of anticonvulsant effect of DEX Outcomes Primary Mechanical ventilation (MV) Length of MV ICU/hospital LOS Statistics Continuous variables used t test and Mann-Whitney-U test Categorical data were analyzed with Fisher s exact test Linear regression to determine predictors of ICU LOS and hospital LOS p < 0.05 considered significant Baseline Characteristics No significant differences in age and sex ICU admit mean CIWA significantly higher in patients treated with DEX (23.1 DEX vs 15 PROP/LOR p = 0.039) Results Primary: DEX (n = 15) vs PROP/LOR (n = 17) MV (days): 2 vs 10 (p = 0.006) Mean length of intubation (days): 0.95 vs 4.1 (p = 0.264) Mean ICU LOS (days): 2.2 vs 4.8 (p = 0.016) Mean hospital LOS (days): 5.7 vs 10 (p = 0.008) Conclusion Due to reduced intubation and shorter LOS, DEX is an attractive alternative to PROP and BZD infusions in the management of alcohol withdrawal syndrome Hargrove 14

15 Reviewer s Critique Compared DEX to the standard of care at the time including LOR and/or PROP infusion in severe alcohol withdrawal LOS and MV were statistically greater in the PROP/LOR group vs DEX o There was no breakdown of the 17 patients in the PROP/LOR group making it difficult to draw conclusions of DEX vs PROP as adjunct agents Further subgroup analysis would help distinguish benefits of DEX and PROP separately though authors commented that the goal was to compare standard of care to DEX Additionally, the study did not comment on observed adverse effects which are clinically important with use of these medications Strengths Direct comparison of study drugs Assessed appropriate clinical outcomes that may show benefit for use of one agent over the other based on patient characteristics and risk for complication Limitations: Retrospective leading to potential for missing data Baseline differences in study groups and no control for co-morbidities that may affect intubation or length of stay No subgroup analysis of PROP and LOR group separately Abbreviations: CIWA-Ar = Clinical Institute Withdrawal Assessment Scale, DEX = dexmedetomidine, ICU = intensive care unit, LOR = lorazepam, LOS = length of stay, MV = mechanical ventilation, PROP = propofol Table 9. Lizotte RJ et al. Evaluating the effects of dexmedetomidine compared to propofol as adjunctive therapy in patients with alcohol withdrawal (2014) 230 Objective Compare effects of DEX vs PROP on BZD and haloperidol requirements in patients with alcohol withdrawal Methods Single center, retrospective study of patients admitted to the medical, cardiac, surgical or transitional ICU with the alcohol withdrawal order set plus either DEX or PROP for sedation from November 2010 to October 2013 Patient population Inclusion Age > 18 years old Diagnosis of alcohol withdrawal Received sedation with DEX or PROP Actively receiving the institution s alcohol withdrawal order set Exclusion Alcohol withdrawal orders discontinued before start of sedation Scheduled BZD or antipsychotic from home Concomitant administration CI BZD Contraindications to BZD or antipsychotic use Received sedation within 4 hours of admission Combination DEX + PROP Intervention DEX vs PROP added to alcohol withdrawal protocol based on provider preference Alcohol Withdrawal Assessment Scale (AWAS): measures tremor, tachycardia, blood pressure, diaphoresis, fever, nausea/vomiting, agitation/confusion, sleeplessness and hallucinations for max score = 29 Lorazepam given based on current AWAS score > 11 assessed every 30 minutes Haloperidol permitted every 30 minutes for severe agitation Alcohol withdrawal protocol includes IV fluids, thiamine, vitamins, haloperidol and lorazepam Primary BZD and haloperidol utilization before and after addition of DEX or propofol Outcomes Secondary ICU LOS Rate and time of intubation Analgesic use AWAS score/rass/cam-icu Adverse effects: bradycardia (HR < 60) and hypotension (SBP < 90 mmhg) Hargrove 15

16 Statistics Primary outcome reported as a mean and analyzed using two-tailed Wilcoxon signed- rank tests Secondary outcomes reported as means and percentages and analyzed using two tailed Mann-Whitney U tests p < 0.05 considered significant Baseline Characteristics Baseline AWAS score prior to initiation: DEX = 11.4 (n = 24) PROP = 12.8 (n = 2) AWAS scores were not available for 15 patients CAM-ICU: 6 patients assessed at baseline and positive for CAM-ICU Results Baseline RASS: DEX = 0.11 PROP = 0.87 RASS not collected on 12 patients DEX (n = 34) PROP (n = 7) p value Primary BZD use before and after 20.9 mg vs 4.4 mg 17.4 mg vs 3.9 mg p = intervention p p = Haloperidol use before and 8.5 mg vs 0.9 mg p 8.7 mg vs 0.7 mg p = after intervention p = Secondary ICU length of stay (hrs) p = Intubation rate 5 (14.7%) 7 (100%) Duration of intubation (hrs) p = Analgesic use No difference reported Mean AWAS n = Not collected Mean RASS n = Safety Bradycardia 6 (17.6%) 0 Hypotension 6 (17.6%) 2 (28.5%) Conclusions This analysis supports the use of adjunctive therapy in severe alcohol withdrawal DEX and PROP significantly reduce alcohol withdrawal related symptoms and BZD/haloperidol requirements Reviewer s Critique Both agents significantly reduced benzodiazepine and haloperidol use with no difference between the two agents Patient specific characteristics and other drug considerations can be drawn from this study Rate and duration of intubation were longer in the propofol group accompanied by deeper sedation (mean RASS - 2.5) which may lead to ventilation and ICU related complications including infection and delirium o Not all patients in the dexmedetomidine group were intubated. However, those that were had shorter time to extubation o Including non-intubated patients reinforces advantage of dexmedetomidine use in sparing need for intubation As expected, higher rates of bradycardia and hypotension were seen with dexmedetomidine Opposing safety outcomes add to the lack of distinction between a clearly favorable choice Strengths First direct comparison of drugs previously studied vs placebo Assessed clinically appropriate adverse effects Compared differences within the drug as well as between the two drugs Limitations Did not define baseline characteristics or comment on potential differences Used institutional AWAS score rather than CIWA-Ar for assessment of withdrawal symptoms reducing outside applicability Incomplete data due to retrospective study Small sample size with mismatched number of patients in each group Abbreviations: AWAS = Acute withdrawal assessment scale, BZD = benzodiazepine, CAM-ICU = confusion assessment method in the ICU, CI = continuous infusion, CIWA-Ar = Clinical Institute Withdrawal Assessment Scale Revised, DEX = dexmedetomidine, HR = heart rate ICU = intensive care unit, LOS = length of stay, PROP = propofol, RASS = Richmond Agitation-Sedation Scale, SBP = systolic blood pressure Hargrove 16

17 Conclusion I. Overall a. Alcohol withdrawal is a serious complication of alcohol abuse which can lead to seizures, arrhythmias, delirium, organ failure and even death b. Initial treatment with a symptom directed benzodiazepine protocol is the standard of care for alcohol withdrawal c. Patients who require escalating doses of benzodiazepine without additional benefit or symptom improvement are considered refractory to first line treatment d. Dexmedetomidine and propofol are alternative adjunct agents used in refractory alcohol withdrawal e. Dexmedetomidine provides a viable additional option for sedation in benzodiazepine refractory alcohol withdrawal and does not require intubation. i. ICU level care is still required for monitoring of dose-related bradycardia and hypotension. f. Adjunct dexmedetomidine and propofol have been seen to reduce symptom triggered benzodiazepine requirement and shorten ICU length of stay reducing risk of delirium with favorable safety profile II. III. Future Directions a. Prospective head to head evaluation of dexmedetomidine vs propofol b. Study influence of time to initiation of sedative agent (earlier vs later addition) c. Further exploration of ketamine use and addition to dexmedetomidine (current study in progress) Treatment Recommendations a. Non-intubated patients: Recommend dexmedetomidine i. Reduce benzodiazepine requirements and hyperadrenergic related symptoms ii. Does not routinely require patient be intubated for initiation b. In intubated patients: Recommend dexmedetomidine i. Facilitate shorter intubation time ii. Potential reduction in intubation related complication c. Would not recommend dexmedetomidine in the following patient populations i. Patients with cardiac history (such as heart block) in which bradycardia could be harmful ii. Patients with active alcohol withdrawal seizures or recent history of alcohol withdrawal related seizure Hargrove 17

18 References 1. Long D, Long B, Koyfman A. The emergency medicine management of severe alcohol withdrawal. Am J Emerg Med. 2017;35: Schmidt KJ, Doshi MR, Holzhausen JM, et al. Treatment of severe alcohol withdrawal. Ann Pharmacother. 2016;50(5): National Institute on Alcohol Abuse and Alcoholism. Alcohol facts and statistics. Accessed November 10, Centers for Disease Control. Fact Sheets Alcohol use and your health. Accessed November 10, National Institute on Alcohol Abuse and Alcoholism. Alcohol use disorder. Accessed November 10, Kattimani S, Bharadwaj B. Clinical management of alcohol withdrawal: a systematic review. Ind Psychiatry J. 2013;22(2): Sohraby R, Attridge RL, Hughes DW. Use of propofol-containing versus benzodiazepine regimens for alcohol withdrawal requiring mechanical ventilation. Ann Pharmacother. 2014;48(4) Hack JB, Hoffman RS, Nelson LS. Resistant alcohol withdrawal: Does an unexpectedly large sedative requirement identify these patients early? J Med Toxicol. 2006;2(2): Wong A, Benedict NJ, Lohr BR, et al. Management of benzodiazepine-resistant alcohol withdrawal across a healthcare system: benzodiazepine doseescalation with or without propofol. Drug Alcohol Depend. 2015;154: Schuckit MA. Recognition and management of withdrawal delirium (delirium tremens). N Engl J Med. 2014;371(22): Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. 1989;84: Lorentzen K, Lauritsen AO, Bendtsen AO. Use of propofol infusion in alcohol withdrawal-induced refractory delirium tremens. Dan Med J. 2014;61(5): Wong A, Benedict NJ, Kane-Gill SL. Multicenter evaluation of pharmacologic management and outcomes associated with severe resistant alcohol withdrawal. J Crit Care. 2015;30(2): Jawa RS, Stothert JC, Shostrom VK, et al. Alcohol withdrawal syndrome in admitted trauma patients. Am J Surg. 2014;208(5): Makic MBF. Alcohol withdrawal syndrome. J Perianesth Nurs. 2017;32(2): Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. Arch Intern Med. 2004;164(13): Cederbaum AI. Alcohol metabolism. Clin Liver Dis. 2012;16(4): Epstein M. Alcohol s impact on kidney function. Alcohol Health Res World. 1997;21(1): Wong A, Smithburger PL, Kane-Gill SL. Review of adjunctive dexmedetomidine in the management of severe acute alcohol withdrawal syndrome. Am J Drug Alcohol Abuse. 2015;41(5): World Health Organization. Management of alcohol withdrawal. Accessed November 10, Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1): Wong A, Benedict NJ, Armahizer MJ, et al. Evaluation of adjunctive ketamine to benzodiazepine for management of alcohol withdrawal syndrome. Ann Pharmacother. 2015;49(1): Rayner SG, Weinert CR, Peng H, et al. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care. 2012;2(12) Frazee EN, Personett HA, Leung JG, et al. Influence of dexmedetomidine therapy on the management of severe alcohol withdrawal syndrome in critically ill patients. J Crit Care. 2014;29(2): Crispo AL, Daley MJ, Pepin JL, et al. Comparison of clinical outcomes in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: dexmedetomidine versus benzodiazepines. Pharmacotherapy. 2014;34(9): VanderWeide LA, Foster CJ, MacLaren R, et al. Evaluation of early dexmedetomidine addition to the standard of care for severe alcohol withdrawal in the ICU: A retrospective controlled cohort study. J Intensive Care Med. 2016;31(3): Mueller SW, Preslaski CR, Kiser TH, et al. A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Crit Care Med. 2014;42: Bielka K, Kuchyn I, Glumcher F. Addition of dexmedetomidine to benzodiazepines for patients with alcohol withdrawal syndrome in the intensive care unit: a randomized controlled study. Ann Intensive Care. 2015;5(33): Ludtke KA, Stanley KS, Yount NL, et al. Retrospective review of critically ill patients experiencing alcohol withdrawal: dexmedetomidine versus propofol and/or lorazepam continuous infusions. Hosp Pharm. 2015;50: Lizotte RJ, Kappes JA, Bartel BJ, et al. Evaluating the effects of dexmedetomidine compared to propofol as adjunctive therapy in patients with alcohol withdrawal. Clin Pharmacol. 2014;6: National Institute on Alcohol Abuse and Alcoholism. Alcohol use disorder: A comparison between DSM-IV and DSM-5. Accessed November 10, University Health System. STICU non weight based analgesia & sedation protocol for the mechanically intubated patient % pdf. Accessed January 10, Hargrove 18

19 Appendices I. Appendix A. DSM-5 criteria for alcohol use disorder 31 Hargrove 19

20 II. Appendix B. Clinical Institute Withdrawal Assessment for alcohol scale (CIWA-Ar) 10 III. Appendix C. Richmond Agitation-Sedation Scale (RASS) 32 Hargrove 20