Management of Alcohol Withdrawal in Critically Ill Patients...7/10/2019 1 #FSHP2019 Mallory...
Transcript of Management of Alcohol Withdrawal in Critically Ill Patients...7/10/2019 1 #FSHP2019 Mallory...
7/10/2019
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#FSHP2019
Mallory Fiorenza, PharmD, BCPS, BCCCPCritical Care Specialist
Lee Health, Fort Myers, FL
Management of Alcohol Withdrawal in Critically Ill Patients
#FSHP2019
• I do not have (nor does any immediate family member have):
– a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity
– any affiliation with an organization whose philosophy could potentially bias my presentation
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Disclosure
#FSHP2019Pharmacist Objectives
• Identify challenges and clinical tools for assessing alcohol withdrawal syndrome
• Discuss symptom-triggered versus fixed-schedule doses of benzodiazepines for alcohol withdrawal syndrome in critically ill patients
• Evaluate non-benzodiazepine pharmacological therapies utilized in alcohol withdrawal protocols and their effects on clinical outcomes
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#FSHP2019Epidemiology• Alcohol is the most abused drug in the United States
• ~17 million adults have an alcohol use disorder (AUD)
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Dixit D, et al. Pharmacotherapy. 2016Paupers M, et al. Neth J Crit Care. 2012Health Forum, LLC. AHA Hospital Statistics, (2017 survey data).
HospitalizedPatientswith AUD
25% will have AWS
~37 Million Hospital Admissions per Year in the United States
40%
ICUPatientswith AUD
16-31%
~6 Million Intensive Care Unit (ICU) Admissions per Year in the United States
10% will have AWS
AWS: Alcohol Withdrawal Syndrome
#FSHP2019How Much Alcohol Is Too Much?
• 60% of the United States population reports alcohol consumption• Moderate alcohol consumption
• ≥ 2 drinks daily in men • ≥ 1 drink daily in women
• Binge drinking within a period of two hours at least once a week• ≥ 5 drinks in men• ≥ 4 drinks in women
• Heavy alcohol use is defined by the Substance Abuse and Mental Health Services Administration (SAMHSA) as:
• Binge drinking on 5 or more days in the past month
5National Institute on Alcohol Abuse and Alcoholism
#FSHP2019Alcohol Withdrawal Timeline
6Stage Starts: Stage 1 Stage 2 Stage 3 If left untreated
Up to weeks6 – 24
hrs
7 – 48hrs
49 – 96 hrs
Time Since Last Drink
Stage Signs and Symptoms
1Tremor, autonomic activity, tachypnea, hyperventilation, headache, sweating, anorexia, nausea, vomiting
2Distractibility, tonic-clonic seizures, visual, tactile, or auditory hallucinations, autonomic instability, diarrhea
3Delirium tremens, severe autonomic instability, confusion, disorientation, extreme agitation
Dixit D, et al. Pharmacotherapy. 2016
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#FSHP2019Complications of AWS
7Dixit D, et al. Pharmacotherapy. 2016National Center for Chronic Disease Prevention and Health Promotion. 2018
Severe SymptomsCardiovascular and respiratory collapse
Arrhythmias
Dehydration
Electrolyte imbalances
Multi-organ dysfunction
Increased mortality 5 – 15% for untreated; 1 – 2% for treated
$ Healthcare$28 Billion
$Workplace
Productivity$179 Billion
Collisions$13 Billion$
CriminalJustice
$25 Billion$
$$
$ $$ $
$
Total United States Costs $249 Billion
#FSHP2019
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Risk Factors for Severe Alcohol WithdrawalPrior episodes of AWS including detoxification, seizures, or delirium tremens
Older age
Moderate to severe withdrawal symptoms at baseline (CIWA-Ar)
Concomitant medical or surgical illness (trauma, infections, sepsis, liver disease, etc.)
Higher blood or breath alcohol level on admission (i.e. >200 mg/dl)
Severity of alcohol dependence (quantity, frequency, duration of alcoholism)
Abnormal liver function (elevated AST)
Time since last drink
Prior benzodiazepine use
Male sexAST: aspartate aminotransferase, AWS: alcohol withdrawal syndrome, CIWA-Ar: Clinical Institute Withdrawal Assessment for Alcohol revised
Carlson RW, et al. Crit Care Clin. 2012 Saitz R, et al. Med Clin North Am. 1997
#FSHP2019Diagnosis of Alcohol Use Disorder (AUD)
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Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Criteria for AUDThe presence of at least 2 of these symptoms indicates an AUD1. Alcohol is often taken in larger amounts or over a longer period than was intended.2. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use.3. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects.4. Craving, or a strong desire or urge to use alcohol.5. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home.6. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol.7. Important social, occupational, or recreational activities are given up or reduced because of alcohol use.8. Recurrent alcohol use in situations in which it is physically hazardous.9. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that islikely to have been caused or exacerbated by alcohol.10. Tolerance, as defined by either of the following:a) A need for markedly increased amounts of alcohol to achieve intoxication or desired effect.b) A markedly diminished effect with continued use of the same amount of alcohol.
Withdrawal, as manifested by either of the following:a) The characteristic withdrawal syndrome for alcohol (refer to criteria A and B of the criteria set for alcohol withdrawal).b) Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms.
Diagnostic and Statistical Manual of Mental Disorders, 5th ed. © 2013. American Psychiatric Association.
#FSHP2019Diagnosis of Alcohol Withdrawal (AW)
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Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Criteria for AWA: Cessation of (or reduction in) alcohol use that has been heavy and prolonged.
B. Two (or more) of the following, developing within several hours to a few days after the cessation of(or reduction in) alcohol use described in Criterion A:(1) Autonomic hyperactivity (eg, sweating or pulse rate greater than 100)(2) Increased hand tremor(3) Insomnia(4) Nausea or vomiting(5) Transient visual, tactile, or auditory hallucinations or illusions(6) Psychomotor agitation(7) Anxiety(8) Grand mal seizures
C. The symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
D. The symptoms are not due to a general medical condition and are not better accounted.
Diagnostic and Statistical Manual of Mental Disorders, 5th ed. © 2013. American Psychiatric Association.
#FSHP2019Screening Tools Used to Detect AUD
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Tool Development Description
CAGE Ewing JA, et al (1984)
4-question tool for the detection of alcohol abuse: 1. Have you ever felt you should
Cut down on your drinking? 2. Have people Annoyed you by criticizing your drinking?
3. Have you ever felt bad or Guilty about your drinking? 4. Have you ever had a drink
first thing in the morning to steady your nerves or to get rid of a hangover (Eye opener)? Score of 2 or more indicates alcohol intake should be investigated further.
Michigan Alcohol
Screening Test (MAST)
Selzer M, et al (1971)25-question screening tool to identify drinking behavior, alcohol dependence, or adverse consequences of alcohol drinking. Shorter 13-question version developed for hospital use in 1975 (Short MAST).
Alcohol Use Disorders
Identification Test (AUDIT)
Babor TF, et al (1992)
10-question screening tool used to identify 3 aspects of an AUD: excessive drinking pattern, hazardous drinking, and harmful consumption of alcohol. Scores range from 0 to 40 (8 indicates potentially hazardous alcohol intake). Several shortened variants also developed (AUDIT C, AUDIT PC).
AUD: Alcohol Use Disorder; AUDIT C: Consumption; AUDIT PC: Piccinelli Consumption
Ewing JA, et al. JAMA. 1984 Selzer M, et al. Am J Psychiatry. 1971 Babor TF, et al. World Health Organization. 2001
Primary Care Setting
Primary Care Setting
Primary Care Setting
#FSHP2019Prediction Tool of Complicated AWS
• Systematic online literature search for clinical factors associated with the development of alcohol withdrawal syndromes (AWS)
• Total # of articles found; N = 5753• Duplicate articles were removed; N = 2802• Articles meeting inclusion criteria; N = 446• Unique articles describing predictive
factors of AWS; N = 233
• 10 items were identified that correlated with complicated AWS
12Maldonado JR, et al. Alcohol. 2014
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#FSHP2019Validation Study of the Predictionof Alcohol Withdrawal Severity Scale (PAWSS)
• Prospective study (12 month period)• Hospitalized to general medicine and surgical units (N = 403)• Compared PAWSS < 4 (low risk); N = 374 to PAWSS ≥ 4 (high risk); N = 29
13Maldonado JR, et al. Alcohol and Alcoholism. 2015
Threshold PAWSS ≥ 4
Sensitivity 93.5%
Specificity 99.5%
Positive Predictive Value 93.5%
Negative Predictive Value 99.5%
Not Studied in Critically Ill
Patients
#FSHP2019Symptoms Assessment Tool – Clinical Institute Withdrawal Assessment (CIWA-Ar)
CIWA-Ar Criterion Headache (0-7)* Anxiety (0-7)*
Tremor (0-7) Agitation (0-7)
Paroxysmal sweats (0-7)
Tactile disturbances (0-7)*
Auditory disturbances (0-7)*
Nausea/Vomiting (0-7) *
Visual disturbances (0-7)*
Orientation and clouding of sensorium (0-4)*
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• Severity of symptoms (max = 67):• < 8 = mild withdrawal• 8 – 15 = moderate withdrawal• > 20 severe withdrawal
• Treatment is recommended for scores > 8• Additional PRN medication is needed for
scores > 15 • Requires patient to be able to logically
respond to 7* of the 10 criterion
Not validated in the critically ill or in patients requiring mechanical ventilation
Sullivan JT, et al. Br J Addict.1989
#FSHP2019Additional Symptoms Assessment Tools
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Tool Development DescriptionAlcohol
Withdrawal Syndrome
(AWS) Scale
Used in patients presenting with severe withdrawal /
delirium as patient participation was not
required
This scale ranges from 0-38 and assesses somatic (ex. pulse rate, diastolic blood pressure, temperature, breathing rate, sweating, tremor) and mental symptoms (agitation, contact, orientation, hallucination, anxiety). Mild AWS is identified by a total score ≤5; moderate AWS scores 6–9; severe AWS results in a score ≥10.
Glasgow Modified Alcohol
Withdrawal (GMAWS) Scale
Identifies alcohol misuse and dependency in acute
hospital patients. Developed in the United Kingdom.
Five-variable (tremor, sweating, hallucination, orientation, agitation) scale that ranges from 0-10. Can’t use if patient is intoxicated it must be 8 hours from the last dose. Scoring levels are matched with symptom triggered diazepam dosing.
Minnesota Detoxification Scale (MINDS)
Does not require the patient to answer questions or respond to commands. Conducted in medical
intensive care unit patients.
Nine-variable scale (pulse, diastolic blood pressure, tremor, sweat, hallucinations, agitation, orientation, delusions, seizures) that ranges from 0-46. Mild AWS is identified by a score < 15; moderate AWS score 15-19; severe AWS results in a score > 19. Symptom triggered benzodiazepine dosing (midazolam and lorazepam) provided based on severity score.
Wetterling T, et al. Alcohol & Alcoholism. 1997 McPherson A, et al. Q J Med 2012 DeCarolis DD, et al. Pharmacotherapy. 2007
#FSHP2019Correlation Between mMINDS and CIWA-Ar Scoring Tools
• Modified Minnesota Detoxification Scale (mMINDS)• More detailed definitions for assessing tremor, delusions,
and hallucinations • The Richmond Agitation Sedation Scale (RASS) is used
to assess the level of agitation
• Littlefield AJ, et al (2018)• Single centered prospective correlation study• Total of 185 CIWA-Ar and mMINDS scores were collected
in 30 patients• Included adults admitted to a medical intensive care unit
or a medical step-down unit• Pearson correlation coefficient
• Strong correlation if coefficient was ≥ 0.80• Moderate correlation if coefficient was between 0.50
– 0.80• Weak correlation if coefficient was < 0.50
• Pearson correlation coefficient across all scores was 0.82 (strong correlation)
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CharacteristicPearson Correlation Coefficient (N = 185)
CIWA-Ar score ≤ 10 0.87
CIWA-Ar score > 10 0.52
Tremors 0.98
Agitation 0.84
Orientation 0.87
Tactile disturbance 0.07
Auditory disturbance -0.07
Visual disturbance 0.04
CIWA-Ar: Clinical Institute Withdrawal Assessment; mMINDS: modified Minnesota Detoxification Scale
Littlefield AJ, et al. AJCC. 2018
#FSHP2019Symptoms Assessment Tool for Intubated Patients
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Riker SedationAgitation Scale (SAS)Score State
7Dangerously
agitated
6 Very agitated
5 Agitated
4Calm and
cooperative
3 Sedated
2 Very Sedated
1 Unarousable
Richmond Agitation Sedation Scale (RASS)
Score State
+ 4 Combative
+ 3 Very agitated
+ 2 Agitated
+ 1 Restless
0 Alert and Calm
- 1 Drowsy
- 2 Light sedation
- 3 Moderate sedation
- 4 Deep sedation
- 5 UnarousableDixit D, et al. Pharmacotherapy. 2016
#FSHP2019Riker Sedation Agitation Scale (SAS)
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Study DescriptionPrimary
OutcomeGoal SAS
Results
Weinberg JA, et al. J Trauma.
2008
50 critically ill trauma patients with chronic daily alcohol use (≥ 5 drinks/day) were prospectively randomized to either IV ethanol EtOH or scheduled-dose diazepam (starting dose: 5 mg oral/IV every 6 hrs)
Prevention of AWS with particularemphasis on the sedative effects of each therapy
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EtOH group had a greater proportion of patients who deviated from a score of 4 during the course of tx (p = 0.020). One patient in the EtOH group failed tx. In both groups, the majority of deviation from a score of 4 reflected periods of undersedation.
Gold JA, et al. Crit
Care Med. 2007
Retrospective cohort that had 41 patients with SAS scores ≥ 5 who were admitted to the medical ICU solely for tx of severe AWS and were managed by titrating BZDs.
To determine if escalating doses of BZDs in combo with phenobarbital would improve outcomes
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Post-guideline (n = 41) there was an increase in the max individual dose of diazepam (32 mg vs. 86 mg; p = .001), total amount of diazepam (248 mg vs. 562 mg; p = .001), and phenobarbital use (17% vs. 58%; p = .01). This was associated with a reduction in the need for mechanical ventilation (47 vs. 22%; p = .008).
IV: intravenous; EtOH: ethanol infusion; BZDs: benzodiazipines; Tx: treatment; AWS: alcohol withdrawal syndrome
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#FSHP2019
Richmond Agitation Sedation Scale (RASS)
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Study DescriptionPrimary
OutcomeGoal RASS
Results
Duby JJ, et al. J Trauma
Acute Care Surg. 2014
Retrospective pre (N=60)-post (N=75) study of adults with AWS admitted to an ICU. Symptom-triggered doses of diazepam (max = 120 mg) every 15 – 30 minutes until target sedation level was achieved. Phenobarbital was given as an adjunct every 30 minutes (max = 240mg).
ICU LOS 0 to -2
POST group had decrease in mean ICU LOS from 9.6 ± 10.5 to 5.2 ± 6.4 days (p=0.0004), fewer ventilator days (5.6 ± 13.9 vs 1.31 ± 5.6 days, p<0.0001) and a decrease in BZD usage (319 mg ± 1084 mg vs 93 mg ± 171 mg, p=0.002).
AWS: alcohol withdrawal syndrome; ICU: intensive care unit; LOS: length of stay; BZD: benzodiazepines
#FSHP2019
• Survey questionnaire sent to hospitals with ≥ 100 beds located in the northeast region of the United States
• 90 hospitals in nine states were included
20Mo Y, et al. P T. 2018
61%22%
7%6%
4% Clinical Institute WithdrawalAssessment (CIWA-Ar)
Richmond Agitation SedationScale (RASS)
Riker Sedation AgitationScale (SAS)
Modified MinnesotaDetoxification Scale (MINDS)
Other
Most Common Clinical Tool for Assessing Severity of AWS
#FSHP2019Limitations of the Clinical Tools • Diagnosis of AUD/AWS: DSM-5 criteria
• Structured interview could be difficult, and it is conceptually unnecessary, because patients suffering from AWS usually show agitation and confusion
• Screening Tools to detect AUD: CAGE, MAST, AUDIT
• Developed in the primary care setting not in critically ill patients
• Prediction tool: PAWSS• Validated in medical inpatients only • Not studied in critically ill patients
• Symptom Assessment Tools• CIWA-Ar
• Majority of research was conducted in outpatient detoxification units
• Not validated in critically ill patients• Requires patient to be able to logically
respond to 7 of the 10 criterion • Cannot be used in up to 45% of
hospitalized patients due to lack of communication
• MINDS• Based on 1 single center study • Not validated
• SAS / RASS• Not validated
21Dixit D, et al. Pharmacotherapy. 2016 Sutton LJ, et al. Crit Care Nurse. 2016
#FSHP2019Which Clinical Tool?
• Guidelines• Support titrating medications to scores using clinical tools and judgment • Do not describe which tool maybe the best for critically ill or intubated
patients
• Based on Evidence• Using the CIWA-Ar or MINDS tool in patients capable of communicating
in combination with the SAS or RASS when patients could no longer communicate
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Stewart S, et al. Clin Med. 2012Mayo-Smith MF, et al. Arch Intern Med. 2004National Institute for Health and Clinical Excellence. London: NICE, 2010.
#FSHP2019Preferred First – Line Agent
• Benzodiazepines (BZDs) are the most studied and preferred due to their efficacy and safety profile
• Better at controlling signs and symptoms and are superior to placebo in stopping the progression to delirium tremens (DTs)
• BZDs approved by the Food and Drug Administration for the treatment of AWS are:
• Chlordiazepoxide• Diazepam
23Dixit D, et al. Pharmacotherapy. 2016 Sutton LJ, et al. Crit Care Nurse. 2016
#FSHP2019
DrugHalf-life
Active Metabolites Metabolism Excretion ~Equiv
Dose, mg DiazepamOral: 1 – 2 hIV: 1 – 5 min
33 – 45 h
Desmethyldiazepam (40-120h)Temazepam (8 – 15h)Oxazepam (5 – 15h)
N-demethylated by CYP3A4 and 2C19
Hepatic –urinary(metabolites)
10
ChlordiazepoxideOral: 2 h 24 – 48 h
Desmethylchlordiazepoxide (18h)Demoxepam (14 – 85h)
Desmethyldiazepam (40 – 120h)Oxazepam (5 – 15h)
DemethyldiazepamHepatic –
urinary(metabolites)25
LorazepamOral: 30 – 60 minIM: 20 – 30 minIV: 5 – 20 min
12 – 14 h None Glucuronide Hepatic 1
OxazepamOral: 1 – 3 h
~8 h (6 – 11)
None Glucuronide Hepatic 20
MidazolamIM:10 –15 minIV: 1 – 2 min
3 h (1.8 – 6.8)
Alph-ahydroxymidazolam CYP3A4 Hepatic 5
24Foertsch MJ, et al. Crit Care Nurs Q. 2019
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#FSHP2019Controversies of Benzodiazepine Treatment for AWS
• Who should receive treatment (low or high risk patients)?
• Which benzodiazepine is better?
• What dose should be used?
• How should benzodiazepines be administered?• Symptom triggered or fixed doses
25Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019MINDS Symptom-Driven LorazepamProtocol in ICU Patients
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Study Description Primary Outcome Goal Treatment
DeCarolis DD, et al. Pharmacotherapy. 2007
Retrospective observational study included 36 adult medical ICU patients with severe AWD at VA medical center.
• Time till MINDS score < 20• Total dose of BZD• Time on continuous BZD infusion• ICU and hospital LOS• Complications of treatment• Use of multiple BZD
MINDS < 15
Non-protocol midazolam continuous infusion
(standard local practice)
vs.
Symptom-driven lorazepamprotocol (see next slide)
AWD: alcohol withdrawal delirium; ICU: intensive care unit; LOS: length of stay; BZD: benzodiazepine; VA: Veterans Affairs; MINDS: Minnesota Detoxification Scale
#FSHP2019MINDS Symptom-Driven LorazepamProtocol in ICU Patients
27DeCarolis DD, et al. Pharmacotherapy. 2007
#FSHP2019MINDS Symptom-Driven LorazepamProtocol in ICU Patients
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Study Description Goal Results
DeCarolis DD, et al. Pharmacotherapy. 2007
Retrospective observational study included 36 adult medical ICU patients with severe AWD at VA medical center
MINDS < 15
Outcome
Symptom-Driven
LorazepamN = 15
Non-Protocol Continuous Midazolam
N = 21
pvalue
Time till the MINDS score was < 20 (hrs)
7.7 ± 4.9 19.4 ± 9.7 0.002
Cumulative BZD dose (mg)a 1044 ± 534 1677 ± 937 0.014
Time on continuous-infusion BZD (hrs)
52.0 ± 35.1 122.1 ± 64.4 0.001
ICU LOS (days) 5.6 ± 1.7 7.7 ± 6.3 0.207
Hospital LOS (days) 11.2 ± 3.4 15.3 ± 8.9 0.43
Values expressed as mean ± SD unless otherwise noted; AWD: alcohol withdrawal delirium; ICU: intensive care unit; LOS: length of stay; BZD: benzodiazepine; VA: Veterans Affairs; a: lorazepam equivalents; MINDS: Minnesota Detoxification Scale
#FSHP2019
CIWA-Ar Symptom-Driven Lorazepam Protocol
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Study DescriptionGoal
CIWA-ArPrimary
OutcomesTreatment Results
Maldonado JR, et al. Gen Hosp
Psychiatry.2012
Two hospitals in the USA
Adult general medicine
inpatients with ETOH
withdrawal ordependence
N = 47
< 8
Rates of change of
the CIWA-Arscores
Diazepam fixed dose + prn
vs.
Lorazepam prn only(symptom-driven)
No significant differences found in the average rate
of change of CIWA-Arscores, total BZD use or absence of symptoms
within 72 h between the groups
Sz: seizure; BZD: benzodiazepines; CIWA-Ar: Clinical Institute Withdrawal Assessment
#FSHP2019CIWA-Ar Symptom-Driven Chlordiazepoxide Protocol
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Study DescriptionGoal
CIWA-ArPrimary
OutcomesTreatment Results
Murdoch J, et al. Br J
Nurs. 2014
PRE-POST case audit in adult inpatients being detoxified in a general hospital setting in the UK was conducted to standardize AWS practicesusing evidence-based regimens.
< 8
To evaluate a symptom triggered protocol (STP) with chlordiazepoxide
Chlordiazepoxidefixed dose + prn
vs.
Chlordiazepoxideprn only
(symptom-driven)
POST STP showed a decrease in the mean chlordiazepoxide by
396.1 mg (the equivalent of ~16 mg of lorazepam) p = 0.001and a decrease in the mean duration of tx
for AWS by 3.88 days (p=0.001)
Sz: seizure; BZD: benzodiazepines; CIWA-Ar: Clinical Institute Withdrawal Assessment; UK: United Kingdom; Tx: treatment
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#FSHP2019CIWA-Ar Symptom-Driven Lorazepam Protocol
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Study DescriptionPrimary
OutcomeGoal
CIWA-ArTreatment Results
SachdevaA, et al.
Alcohol and Alcoholism.
2014
Single inpatient
detox center in India. AD
and uncomplicated
withdrawal.
N=63
Total amount and duration of lorazepam
tx and the incidence of
adverse events or
complications
< 8
Lorazepam fixed dose + prn
vs.
Lorazepam prn only
STG had lower lorazepamdoses than in the FTDG (9.5 mg vs 19.9 mg, p < 0.001), shorter duration of time (47.8h vs 146 h, p < 0.001).
No differences in terms of seizures or delirium tremens.
Detox: detoxification; Tx: treatment; BZD: benzodiazepines; AD: alcohol disorder; STG: symptom triggered group; FTDG: fixed tapering dose group; CIWA-Ar: Clinical Institute Withdrawal Assessment
#FSHP2019Symptom-Driven Lorazepam Protocol in ICU Patients
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Study DescriptionPrimary
OutcomeGoal Treatment
Sen S, et al. Annals of
Pharmacotherapy. 2017
Retrospective pre (N = 135) post (N = 32) study in patients with AWS admitted to a medical ICU
Duration of AWS tx
SAS < 4
CIWA- AR < 8
Pre-intervention (PRE) group: see next slide
vs.
Post-intervention (POST) group: see next slide
AWS: alcohol withdrawal syndrome; ICU: intensive care unit; Tx: treatment; BZD: benzodiazepines; SAS: Sedation Agitation Scale; CIWA-Ar: Clinical Institute Withdrawal Assessment
#FSHP2019Symptom-Driven LorazepamProtocol in ICU Patients
33Sen S, et al. Annals of Pharmacotherapy. 2017
Pre-Intervention Group
CIWA ≤ 10
CIWA 11 – 14
CIWA ≥ 15
10 mg IV LZ within 1 hr and
CIWA ≥ 15
1 – 3 mg PO LZ q6hrs x 8
doses
2 mg IV LZ q10min PRN, max dose 10
mg/hr
4 mg IV LZ q10min PRN, max dose 10
mg/hr
LZ infusion
Post-Intervention Group
SAS < 4
CIWA < 8 or SAS 4
CIWA 8 – 15 or SAS 5
CIWA ≥ 15 or SAS > 5
Hold LZ and re-assess in
10 min
0.5 – 2 mg PO LZ q6hrs
x 4 doses
2 mg IV LZ q10min PRN,
no max
4 mg IV LZ q10min PRN,
no max
LZ infusion not included
LZ: lorazepam
#FSHP2019Symptom-Driven Lorazepam Protocol in ICU Patients
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Study Description Goal Results
Sen S, et al. Annals of
Pharmacotherapy. 2017
Retrospective pre (N = 135) post (N = 32)
study in patients with
AWS admitted to a medical
ICU.
SAS < 4
CIWA < 8
OutcomePRE
N = 32POST
N = 135p-
value
Duration of AWS tx(days)
8.0 [5.0 – 12.0] 5.0 [4.0 – 8.0] <0.01
Intubated, n (%) 77 (57.0) 10 (31.3) 0.01
Ventilator Days 8 [4 – 10] 5 [2 – 9] 0.12
ICU LOS (days) 7 [4 – 11] 4 [2 – 7] 0.02
Hospital LOS (days) 13 [9 – 18] 9 [6 – 13] 0.01
ICU Mortality, n (%) 3 (2.2) 1 (3.1) 0.58
Values expressed as median interquartile range [25 – 75%] unless otherwise noted. AWS: alcohol withdrawal syndrome; ICU: intensive care unit; Tx: treatment; BZD: benzodiazepines; SAS: Sedation Agitation Scale; CIWA-Ar: Clinical Institute Withdrawal Assessment; LOS: length of stay
#FSHP2019mMINDS Symptom-Driven BZD Protocol
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Study DescriptionPrimary
OutcomeGoal
mMINDSTreatment
Heavner JJ, et al. Pharmacotherapy.
2018
Retrospective Pre (N = 139) and Post (N = 94) protocol in medical ICU patients. Included if only one dose of BZD was received.
Need for mechanical ventilation
< 15
Pre-protocol: CIWA-Ar–based txprotocol was used and patients were treated at the discretion of the prescribing physician
Post-protocol: See next slide for the Yale Alcohol WithdrawalProtocol (YAWP) which included different tx protocols based on the BZD selected (midazolam, lorazepam, diazepam)
ICU: intensive care unit; BZDs: benzodiazepines; Tx: treatment; mMINDS: modified Minnesota Detoxification Scale; CIWA-Ar: Clinical Institute Withdrawal Assessment for Alcohol revised
#FSHP2019
mMINDS Symptom-Driven Lorazepam Protocol
36Heavner JJ, et al. Pharmacotherapy. 2018
Step 1: RN Calculates Initial modified Minnesota Detoxification Scale (mMINDS) Score
Score ≥ 20
Midazolam 10 mg IVP and notify provider to assess
Proceed to Step 2 in 15 min
Lorazepam 4 mg IVPProceed to Step 2 in 30 min
Lorazepam 2 mg IVPProceed to Step 2 in 30 min
No BZDProceed to Step 2 in
60 min
Score 15 – 19 Score 5 – 14 Score < 5
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#FSHP2019
mMINDS Symptom-Driven Lorazepam Protocol
37Heavner JJ, et al. Pharmacotherapy. 2018
Step 2: RN Recalculates modified Minnesota Detoxification Scale (mMINDS) Score
Score ≥ 20
Midazolam 10 mg IVP and notify provider to assess
Proceed to Step 2 in 15 min
Lorazepam 4 mg IVPProceed to Step 2 in 30 min
Lorazepam 2 mg IVPProceed to Step 2 in 30 min
No BZDProceed to Step 2 in
60 min
Score 15 – 19 Score 5 – 14 Score < 5
If score remains > 20, provider to assess additional reasons
and consider adjunctive therapy (Phenobarbital 65 mg IVP). For score < 20 remain in step 2. For
score >20 go to step 3.
Consider adjunctive therapiesScore < 5 x 3, RN
reassesses score q8h for 48h and discuss with
provider about protocol discontinuation
#FSHP2019mMINDS Symptom-Driven Lorazepam Protocol
38Heavner JJ, et al. Pharmacotherapy. 2018
Step 3: Initiate Lorazepam Infusion
Score ≥ 20
Notify provider. Lorazepam 4 mg IVPAND
Increase lorazepam infusion by 4 mg/hrup to max of 20 mg/hr
RN to reassess score in 30 minCont in Step 3
No change in infusion rateRN reassesses score in 60 min
Cont in Step 3
Score 15 – 19 Score < 15
Consider adjunctive therapiesPhenobarbital 130 mg (1hr after 65 mg IVP dose)
If mMINDS score remains ≥ 20, consider dexmedetomidine infusion
Decrease rate by 2 mg/hruntil titrated off
RN reassesses score in 2hrOnce lorazepam infusion
stopped, go back to Step 2 with reassessment score
Lorazepam 4 mg IVP AND initiate lorazepam infusion at 4 mg/hrRN reassesses score in 30 min
If patient is obtunded, infusion may be stopped after provider assessment, and resumed at
Step 2 when patient is arousable
< 3% of patients received doses of Phenobarbital
and no patients received Dexmedetomidine
#FSHP2019
39
mMINDS Symptom-Driven BZD ProtocolStudy Description
Goal mMINDS
Results
Heavner JJ, et al. Pharmacotherapy.
2018
Retrospective Pre (N = 139) and Post (N = 94) protocol in medical ICU patients.
< 15
Outcomes in ICUPRE
(N = 139)POST
(N = 94)p-
value
Intubation, n (%) 36 (25.9) 8 (8.5) <0.001
Pneumonia, n (%) 30 (21.6) 10 (10.6) 0.03
ICU LOS (days) 3 [2 – 5] 3 [2 – 5] 0.2
Total lorazepamequivalents (mg)
18 [8 – 83.2] 30.3 [8 – 108] 0.5
BZD infusions, n (%) 48 (34.5) 38 (40.4) 0.4
Duration BZD infusion (hr)
42.5 [12.0 – 96.3] 28 [12.3 – 42.8] 0.7
Values expressed as median interquartile range [25 – 75%] unless otherwise noted. ICU: intensive care unit; BZD: benzodiazepines; mMINDS: modified Minnesota Detoxification Scale; LOS: length of stay
#FSHP2019Symptom Triggered vs. Fixed Dose: Meta-analysis
40Holleck JL, et al. J Gen Intern Med. 2019
Study N Setting Population Interventions Criteria Outcomes
Saitz1994
101Single inpatient detox center in the USA VA
47 years99% male
Chlordiazepoxide fixed + prn vs prn only
ETOH abuse ordependence
Deaths, delirium,
sz, duration, total
BZD dose
Daeppen2002
117Two inpatient
detox centers in Switz46.6 years
76.9% maleOxazepam fixed + prn vs
prn onlyInpatient ETOH
program
Weaver2006
183General medical service in single
hospital in the USA
48.9 years80.9% male
Lorazepam fixed dose + prn vs lorazepam prn
AD; abstinence < 72 h Deaths, sz, duration, total
BZD doseElhom2011
165Outpatient Tx
Center in Denmark49 years
83.7% maleChlordiazepoxide fixed
dose vs prn onlyICD-10 AD and AWS
and abstinence < 72 h
Maldonado2012
47Two hospitals in the
USA (general medical service)
51.7 years97.9% male
Diazepam fixed dose + prn vs lorazepam prn only
Adult inpatients with ETOH withdrawal or
dependence
Deaths, delirium,
sz, duration, total
BZD doseSachdeva
201463
Single inpatient detox center in India
38.6 years100% male
Lorazepam fixed dose + prn vs lorazepam prn only
AD and uncomplicated withdrawal
Detox: detoxification; Switz: Switzerland; Tx: treatment; VA: veterans affair; sz: seizure; BZD: benzodiazepines; AD: alcohol disorder
#FSHP2019Difference in Duration of Treatment Hours
41Holleck JL, et al. J Gen Intern Med. 2019
#FSHP2019Difference in Mean Total LorazepamEquivalent Dose
42Holleck JL, et al. J Gen Intern Med. 2019
37 38
39 40
41 42
7/10/2019
8
#FSHP2019
• Limitations• Inpatient studies were mostly specialized detoxification centers not medical/surgical
hospital floor patients • Large proportion of low risk patients• Smaller sample sizes
• Results• Overall symptom triggered therapy had less lorazepam equivalent doses and shorter
duration of therapy
• Conclusions• Value of symptom triggered therapy on major outcomes (mortality, delirium, and
seizure) couldn’t be determined due to lack of evidence • Moderate evidence supported symptom triggered therapy improved duration and total
benzodiazepine dose in detoxification centers of low-risk patients• Results can’t be extrapolated to the inpatient hospital setting
43
Symptom Triggered vs. Fixed Dose Meta-analysis
Holleck JL, et al. J Gen Intern Med. 2019
#FSHP2019
Inpatient Pharmacological Management Strategies
• Web-based survey was distributed to Society for Acute Medicine (SAM) members
• 104 acute hospital sites participated across the UK
• 40% used the CIWA-Ar scale • 80% used chlordiazepoxide
and 20% used diazepam
44
73%
27%
Benzodiazepine Dosing
Fixed Dosing
Symptom-Triggered
Ward D, et al. Q J Med. 2009
#FSHP2019Symptom Triggered or Fixed Dosing? • Guidelines/Reviews
• Recommend dosing based on measured symptom-triggered therapy (STT) rather than fixed-dose regimens
• STT is as effective as fixed-dose therapy but requires significantly less medication and leads to a more rapid detoxification
• Superior to fixed dosing in special patient populations (low-risk)
• Based on Evidence for STT • Protocols were inconsistent amongst the literature • Limited data to support one benzodiazepine (BZD) over others or specific
dosing regimens• Efficacy to support continuous BZD infusions are limited• Still need additional studies to assess outcomes and dosing strategies in
critically ill patients at high risk for withdrawal• Optimal BZD selection should be based on the severity of withdrawal and
concomitant diseases of the patient (ex. elderly or end-stage-liver-disease)• Consider lorazepam for STT as it was the most commonly evaluated
45Kosen TR, et al. NEJM. 2014 Holleck JL, et al. J Gen Intern Med. 2019 Dixit D, et al. Pharmacotherapy. 2016
No Universally Accepted Guidelines for AWS
#FSHP2019Additional Controversies of Benzodiazepine Treatment for AWS
• Are benzodiazepines (BZD) superior to other non-BZD for the treatment of alcohol withdrawal syndrome (AWS)?
• Which agents should be used to treat BZD-resistant patients?
• What other non-BZD pharmacological therapies are available to treat AWS and what are their effects on clinical outcomes?
46Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019
47
Non-BZD Pharmacological Therapies Available For AWSPhenobarbital
Dexmedetomidine
Propofol
Baclofen
Ketamine
Carbamazepine and Valproic Acid
Enteral EthanolBZD: benzodiazepines; AWS: alcohol withdrawal syndrome
Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019SAS Symptom-DrivenDiazepam/Phenobarbital Protocol in ICU Patients
48
Study DescriptionPrimary
OutcomeGoal SAS
Treatment
Gold JA, et al. Crit
Care Med. 2007
Retrospective cohort that had 54 patients pre-guideline and 41 patients post-guideline with SAS scores ≥ 5 who were admitted to the medical ICU solely for tx of severe AWS and were managed by titrating BZDs.
ICU admission criteria: 200 mg of diazepam in 4 hrs or an individual dose of > 40 mg of IV diazepam for control of agitation
To determine if escalating doses of BZDs in combination with phenobarbital would improve outcomes
3 – 4
Pre-guideline: Treated in a symptom-triggered fashion with no established guidelines for dose escalation. BZDs were initiated if the patient’s SAS score was ≥5.
Post-guidelines: see next slide
IV: intravenous; EtOH: ethanol infusion; BZDs: benzodiazepines; Tx: treatment; SAS: Sedation Agitation Scale
43 44
45 46
47 48
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9
#FSHP2019
49
SAS Symptom-Driven Diazepam/Phenobarbital Protocol in ICU Patients
Gold JA, et al. Crit Care Med. 2007
#FSHP2019SAS Symptom-DrivenDiazepam/Phenobarbital Protocol in ICU Patients
50
Study DescriptionGoal SAS
Results
Gold JA, et al. Crit
Care Med. 2007
Retrospective cohort that had 54 patientspre-guideline and 41 patients post-guideline with SAS scores ≥ 5 who were admitted to the medical ICU solely for tx of severe AWS and were managed by titrating BZDs.
3 – 4
OutcomePre
(N = 54)Post
(N = 41)p-
value
Max individual dose of diazepam
32 mg 86 mg 0.001
Total amount of diazepam
248 mg 562 mg 0.001
Phenobarbital use 17% 58% 0.01
Mechanically intubated 47% 22% 0.008
Phenobarbital given in the 1st 24 hrs (mg)
260 [87.5 – 650] 390 [130 – 1430] 0.1
Values expressed as median interquartile range [25 – 75%] unless otherwise noted. IV: intravenous; EtOH: ethanol infusion; BZDs: benzodiazepines; Tx: treatment; SAS: Sedation Agitation Scale
#FSHP2019CIWA Symptom-Driven LorazepamCompared to Phenobarbital in ED Patients
51
Study DescriptionPrimary
OutcomeGoal
CIWA-ArTreatment Results
HendeyGW, et al.
Am J Emerg
Med. 2011
Prospective randomized study that
include adults with AW in the
ED
Compare phenobarbital (N=25) to lorazepam(N=19) in the tx of AW in the ED and at 48 hours
< 8
Lorazepam 2 mg IV
vs.
Phenobarbital 260 mg initial dose or 130 mg for
subsequent doses IV
No differences between phenobarbital and lorazepamin baseline CIWA scores (p = 0.3), discharge scores (p = 0.4), ED LOS (267 mins vs256 mins, p = 0.8), or 48-hour follow-up CIWA scores (5.8 vs7.2, p = 0.6)
Tx: treatment; CIWA-Ar: Clinical Institute Withdrawal Assessment; AW: alcohol withdrawal; ED: emergency department; IV: intravenous; LOS: length of stay
#FSHP2019RASS Symptom-DrivenDiazepam/Phenobarbital Protocol in ICU Patients
52
Study DescriptionPrimary
OutcomeGoal RASS
Treatment
Duby JJ, et al. J Trauma
Acute Care Surg. 2014
Retrospective pre (N = 60 episodes) - post (N = 75 episodes) study of 132 adults with AWS admitted to an ICU.
ICU LOS 0 to -2
Pre-intervention (PRE) group were treated with BZD in a non-protocolized
fashion (continuous infusions or scheduled doses)
vs.
Post-intervention (POST) group: see next slide
AWS: alcohol withdrawal syndrome; ICU: intensive care unit; LOS: length of stay; BZD: benzodiazepines; RASS: Richmond Agitation Sedation Scale
#FSHP2019RASS Symptom-Driven Diazepam/Phenobarbital Protocol in ICU Patients
53Duby JJ, et al. J Trauma Acute Care Surg. 2014
Moderate to Severe RiskCIWA 8 – 20
Symptom-Triggered Escalating Load (ICU status)
Inadequate SedationRASS ≥ 1
Determine effective dose MD at bedside
Diazepam IV (mg)
Esc
alat
e
Repeat (x2)
10 10
20 20
30 30
40 40
50 50
80 80
Max: 120 mg
Max diazepam dose and RASS ≥ 1
Phenobarbital60 120 240 mg(repeat or escalate)
Re-assess 15 minafter each dose
Re-assess 30 minafter each dose
Optimal SedationRASS 0 to -2
suggests effective dose
OversedationRASS ≤ -3
Increase monitoring and hold sedatives
#FSHP2019RASS Symptom-DrivenDiazepam/Phenobarbital Protocol in ICU Patients
54
Study DescriptionGoal RASS
Results
Duby JJ, et al. J Trauma Acute Care Surg. 2014
Retrospective pre (N = 60 episodes) - post (N = 75 episodes) study of 132 adults with AWS admitted to an ICU.
0 to -2
Outcome PRE
N = 60POST
(N = 75)p-
value
ICU LOS (days) 9.6 ± 10.5 5.2 ± 6.4 <0.001
Ventilator days 5.6 ± 13.9 1.3 ± 5.6 <0.001
BZD use (mg) 319 ± 1084 93 ± 171 0.002
Intubated due to AWS; n (%) 13 (22) 4 (5) <0.001
Need for cont sedation; n (%) 33 (55) 18 (24) <0.001
Sedation days 10.8 ± 8.9 3.5 ± 3.5 <0.001
Values expressed as mean ± SD unless otherwise noted. AWS: alcohol withdrawal syndrome; ICU: intensive care unit; LOS: length of stay; BZD: benzodiazepines; RASS: Richmond Agitation Sedation Scale; Cont: continuous
49 50
51 52
53 54
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10
#FSHP2019Phenobarbital• Benefit
• Low addiction potential given long half-life (~79 hours)
• Concerns• Over-sedation and respiratory depression
• Role in therapy • Initial dose prior to implementing BZD therapy• Second line option for patients who are BZD-resistant
• No advantage over BZDs as an alternative55Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019
56
Non-BZD Pharmacological Therapies Available For AWSPhenobarbital
Dexmedetomidine
Propofol
Baclofen
Ketamine
Carbamazepine and Valproic Acid
Enteral EthanolBZD: benzodiazepines; AWS: alcohol withdrawal syndrome
Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019Retrospective Review of DEX for AW
57
Study N Design Criteria Treatment Primary Outcome/ResultsRayner2012
20 RCSMedical-surgical ICU pts
w/ AW diagnosed by ICD-9Compared 24hrs before
DEX and 24 hrs after DEX 24 hrs after initiation, there was less BZD use (52.7 mg vs20.3 mg), lower AxS, and lower systolic blood pressure and HR
Lizotte2014
41 RCSICU (medical/surgical
/cardic) pts w/ AWPts received DEX (n=34)
or PROP (n=7)24 hr pre-post LZ needs decreased from 20.9 mg to 4.4 mg in the DEX group and from 17.4 mg to 3.9 mg in the PROP group
Vander Weide2014
42 RCSICU pts w/ AW diagnosed by ICD-9 w/ CIWA >8 and
received > 8 mg of LZ
DEX (n=20) or Matched Controls (based on BZD
dose; n=22)
DEX group had reduced mean 12 hr pre-post BZD needs (−20 mg vs −8.3 mg; p=0.046) compared with the control group. No diff were found in ICU or hospital LOS or need for Intubation
Frazee2014
33Retrospective case series
ICU pts w/ AW diagnosed by ICD-9
Compared 12 hrs before DEX and 12 hrs after
12 hrs after DEX initiation BZD needs were reduced (30 mg vs8 mg; p<0.001) compared to the 12 hrs before. Improvements in
hypertension and tachycardia were also noted
Crispo2014
61 RCSICU pts w/ AW diagnosed
by ICD-9 DEX (n=28) or cont inf
BZD (n=33)No diff between groups in the composite endpoint of intubation
or AW sz (3 pts in the BZD group vs 2 pts in the DEX group)
Ludtke2015
32 RCSICU pts w/ AW diagnosed
by ICD-9 DEX (n=15) or cont inf
PROP and/or LZ (n=17)DEX had lower intubation rates than PROP and/or LZ to require
(2 pts vs 10 pts; p=0.006), no diff in ventilation days
Beg2016
77 RCSICU pts w/ AW diagnosed
by ICD-9 Compared 24hrs before
DEX and 24 hrs after
DEX decreased 24 hr CIWA scores (14.5 vs 8.5; p < 0.01), BZD doses at 24 hrs (21 mg vs 11 mg; p = 0.10) but ICU LOS was longer (1.4 days vs 2.9 days; p <0.01).
DEX: Dexmedetomidine; Tx: treatment; CIWA-Ar: Clinical Institute Withdrawal Assessment; AW: alcohol withdrawal; RCS: retrospective cohort study; LZ: lorazepam; w/: with; AxS: alcohol withdrawal scores; SZ: seizure; BZD: benzodiazepine; cont: continuous; PROP: propofol; HR: heart rate
Linn DD, et al. Ann Pharmacother. 2015 Beg M, et al. Perm J 2016
#FSHP2019Prospective Review of DEX for AW
58
Study N Design Criteria Treatment Primary Outcome/ResultsTolonen
201318 PCS
ICU pts w/ AWD diagnosed by CAM-ICU
DEX and pts also received BZD
DEX was used on average at a dose of 1.5 μg/kg/h for 23.9 hours; time to resolution of AWD was 3.8 days
Muller2014
24Prospective randomized
DB, PC
Medical ICU pts w/ CIWA ≥ 15 despite 16 mg of LZ
over 4 hrs
High (1.2 μg/kg/hr; n=8) or low dose (0.4
μg/kg/hr; n=8) DEX or placebo (n=8)
24-hr pre-post LZ requirements were −8 mg in the placebo group, −62.1 mg in the low-dose and −45 mg in the high dose DEX groups (p = 0.037; DEX vs placebo)
DEX: Dexmedetomidine; AWD: alcohol withdrawal delirium; CIWA-Ar: Clinical Institute Withdrawal Assessment; PCS: prospective cohort study; LZ: lorazepam; DB: double-blind; PC: placebo controlled; w/: with
Linn DD, et al. Ann Pharmacother. 2015
#FSHP2019Dexmedetomidine• Benefit
• Light sedation without respiratory depression• Anxiolytic/sympatholytic properties that reduce autonomic hyperactivity
which support its use in AWS
• Concerns• Bradycardia and hypotension (especially with loading dose) • Not able to prevent alcohol withdrawal seizures• Cost
• Role in therapy • Adjunctive to BZD and consideration for fixed-dose DEX (Mueller, et al.)
• Inconclusive data to suggest that DEX would reduce the need for intubation or affect ICU or hospital LOS
59Linn DD, et al. Ann Pharmacother. 2015
#FSHP2019
60
Non-BZD Pharmacological Therapies Available For AWSPhenobarbital
Dexmedetomidine
Propofol
Baclofen
Ketamine
Carbamazepine and Valproic Acid
Enteral EthanolBZD: benzodiazepines; AWS: alcohol withdrawal syndrome
Dixit D, et al. Pharmacotherapy. 2016
55 56
57 58
59 60
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#FSHP2019Retrospective Review of Propofol for AW
61
Study N Design Criteria Treatment Primary Outcome/Results
Lorentzen K, et al, Dan Med J.
201415 RCS
Intubated ICU pts w/ AWDrequiring up to 2000 mg of
BZD without effect and diagnosed DT
Propofol infusion was titrated to RASS of -4 to -5 for 48 h
Mean propofol infusion rate was 4.2 mg/kg/hour. 12 (80%) pts were symptom free after awakening from sedation; however, 13 pts (86.7%) had prolonged sedation, with an average time to awakening of 3.4 days after stopping propofol
Sohraby R, et al. Ann
Pharmacother.2014
64 RCSICU patients with AWS
diagnosed by ICD-9 requiring intubation
Propofol infusion regimen (n=46; 38 pts also received BZD
infusions) compared to BZD infusion monotherapy (n=18)
Time to resolution of AWS symptoms was similar in both groups (8 days vs 7 days; p=0.34). ICU and hospital LOS, and ventilation days were also similar
Wong A, et al. Drug and Alcohol
Dependence. 2015
66 RCS
ICU patients with AW diagnosed by ICD-9 that had
BZD resistant AW (requirement of ≥40 mg of diazepam administered
within 1h)
BZD dose-escalation only (n=33) or BZD plus propofol (n=33)
Propofol required longer time until resolution of AWS symptoms (5 days vs 7 days; p=0.025), required more days on the ventilator (2.5 days vs 7 days; p=0.017), longer ICU (4 days vs 10 days; p<0.001) and hospital LOS (6.7 days vs 16.2 days; p<0.001), higher total diazepam equivalent dose in the 7-day (576.7 mg vs 743.3 mg; (p=0.378) compared to the BZD only group
AWD: alcohol withdrawal delirium; RCS: retrospective cohort study; DT: delirium tremens: RASS: Richmond Agitation Sedation Scale
#FSHP2019Propofol• Benefit
• GABA-agonist activity at an alternative site to BZDs and antagonizes NMDA receptors
• Quick onset, short duration – allows for rapid titration
• Concerns• Bradycardia and hypotension• Greater degree of sedation could affect ventilator day and LOS
• Role in therapy • Second line option for patients who are BZD-resistant
• No advantage over BZDs as an alternative
62Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019
63
Non-BZD Pharmacological Therapies Available For AWSPhenobarbital
Dexmedetomidine
Propofol
Baclofen
Ketamine
Carbamazepine and Valproic Acid
Enteral EthanolBZD: benzodiazepines; AWS: alcohol withdrawal syndrome
Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019Baclofen Review for AWS
64
Study N Design Criteria Treatment Primary Outcome/Results
Addolorato G, et al. Am J Med. 2006
37 RCT
Adults admitted to the alcohol tx unit for
withdrawal diagnosed by DSM-IV criteria and had
more than 80 g alcohol/day during the
previous 24 hrs
Baclofen orally (30 mg/day for 10 days; n=18) vs Diazepam (0.5-0.75 mg/kg/day for 6 days, tapering the dose by 25% daily from day 7 to
day 10; n=19)
Both groups significantly decreased CIWA-Arscore, without significant differences between the 2 txs. Both txs decreased the agitation score, although diazepam was slightly more rapid than baclofen
Lyon JE, et al. J Hosp Med.
201179
Randomized double blind
placebo-controlled
Inpatient adults identified by clinical staff as being at risk for AWS with a CIWA-Ar score ≥ 11
ST BZD tx using LZ by standard protocol, and were randomized to
receive oral baclofen 10 mg or placebo three times per day
31 pts completed the 72 hr assessment. High doses of BZD (20 mg or more ofLZ over 72 hrs) to control AWS was less likely in the baclofen group (1 of 18) than in the placebo group (7 of 13) (p=0.004)
Girish K, et al. Biomed J.
201660
Randomized open-label, standard
controlled, parallel group
Adults with AWS diagnosed by DSM-IV criteria and last alcohol intake within 24 - 48 h
Baclofen (30 mg) or Chlordiazepoxide (75 mg) in
decremented fixed doseregimen for 9 days and either group
had prn LZ
Both showed reduction in the totalCIWA-Ar scores. Chlordiazepoxide showed a faster and a more effective control of anxiety and agitation requiring lesser LZ supplementation, and also showed a better subject satisfaction compared to baclofen
RCT: randomized control trial; LZ: lorazepam; DSM-IV: diagnostic and statistical manual of mental disorders; ST: symptom triggered; CIWA-Ar: Clinical Institute Withdrawal Assessment; AWS: alcohol withdrawal syndrome; tx: treatment
#FSHP2019Baclofen• Benefit
• GABAreceptor agonist has demonstrated the ability to rapidly control the manifestations of AWS without producing significant side effects
• Associated with reduced alcohol craving in the long-term management of alcohol dependence
• Concerns• Only studied orally (not ideal for ICU patients)
• Role in therapy • Adjunctive to BZD in outpatients• Further studies need to be conducted in ICU patients
65Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019
66
Non-BZD Pharmacological Therapies Available For AWSPhenobarbital
Dexmedetomidine
Propofol
Baclofen
Ketamine
Carbamazepine and Valproic Acid
Enteral EthanolBZD: benzodiazepines; AWS: alcohol withdrawal syndrome
Dixit D, et al. Pharmacotherapy. 2016
61 62
63 64
65 66
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#FSHP2019Retrospective Review of Ketamine for AW
67
Study N Design Criteria Treatment Primary Outcome/ResultsWong A,
et al, Ann Pharmacother
2015
23 RCSICU admissionsdirectly related
to AWS
Adjunctive ketamine infusions, in addition to hourly BZD as standard care
Median infusion dose was 0.20 mg/kg/hr (0.12–0.23). A nonsignificant decrease in diazepam equivalents used was seen at 12 hrs (40.0 mg, p=0.110) and 24 hrs (13.3 mg, p=0.330) after ketamine initiation
Shah P, et al. J Med Toxicol.
2018 30 RCS
Medical ICU patients with a CIWA-Ar ≥ 20 requiring LZ
infusion
Ketamine was initiated after a LZ infusion was inadequate in controlling
symptoms and was typically weaned off (starting dose of 0.5 mg/kg/h; max dose
of 4.5 mg/kg/h)
Ketamine was initiated ~41 hrs after a LZ infusion was started and the average LZ infusion rate was 14 mg/h at ketamine initiation. 73% of pts were intubated, with an average duration of 5.4 days. Within the first hour of initiation, LZ infusions were decreased at 24 hrs (− 4 mg/h; p = 0.01)
Pizon AF, et al. Crit Care Med.
201863 RCS
ICU ptsdiagnosed with DT by DSM-IV
criteria
PRE: ST BZD and/or phenobarbital POST: ST BZD and/or phenobarbital and
ketamine infusion (0.15-0.3 mg/kg/hr) was initiated as adjunct therapy until DT
resolved
Median ketamine duration was 47 hrs (mean infusion of 0.19 mg/kg/hr). Ketamine was associated with a significant reduction in ICU LOS (11.2 vs. 5.7 days, p<0.001) and intubation rates (22 vs. 10, p<0.001). Ketamine pts received fewer BZDs and propofol
RCS: retrospective cohort study; LZ: lorazepam; DSM-IV: diagnostic and statistical manual of mental disorders; ST: symptom triggered; CIWA-Ar: Clinical Institute Withdrawal Assessment; AWS: alcohol withdrawal syndrome; BZD: benzodiazepine; LOS: length of stay
#FSHP2019Ketamine• Benefit
• Mimics the effects of ethanol on the NMDA receptor provides an alternative mechanism
• Concerns• Dissociated state at high doses• Cost
• Role in therapy • Does not appear to have any clinically significant impact on the treatment
of AWS
• Still no consensus on the appropriate dose, timing of initiation, and the risk of adverse events or affect on ICU or hospital LOS
68Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019
69
Non-BZD Pharmacological Therapies Available For AWSPhenobarbital
Dexmedetomidine
Propofol
Baclofen
Ketamine
Carbamazepine and Valproic Acid
Enteral EthanolBZD: benzodiazepines; AWS: alcohol withdrawal syndrome
Dixit D, et al. Pharmacotherapy. 2016
#FSHP2019Carbamazepine and Valproic Acid Review for AWS
70
Study N Design Criteria Treatment Primary Outcome/Results
Eyer F, et al. Alcohol and Alcoholism.
2011
827RCS of 2 cohorts
Admitted for alcohol
intoxication, withdrawal
syndrome, or alcoholic DT
identified by ICD-10 codes
Comparing oral CBZ (n=374) and VPA (n=453) as adjunct
therapy with symptom-triggered clomethiazole and
clonidine
CBZ group had significantly higher median duration of pharmacological tx (91 hrs vs 76 hrs; p< 0.001), LOS (8 days vs 6 days; p < 0.001) and need for ICU admission (7 % vs2%; p=0.001). No significant difference in DT occurrence (p=0.52). CBZ was associated with more adverse events (p<0.001), especially CNS disturbances (p<0.001).
RCS: retrospective cohort study; DT: delirium tremens; LOS: length of stay; CBZ: carbamazepine; VPA: valproic acid; tx: treatment; LOS: length of stay; ICU: intensive care unit; CNS: central nervous system
#FSHP2019Carbamazepine and Valproic Acid• Benefit
• VPA has fewer side effects
• Concerns• CBZ associated with more adverse events (CNS disturbances)
• Role in therapy • VPA may be more effective adjunct than CBZ• More prospective studies need to be conducted that assess VPA or CBZ
as adjunct therapy to BZDs for AWS
• Cochrane review on anticonvulsants for alcohol dependence does not recommend anticonvulsants for AWS
71Dixit D, et al. Pharmacotherapy. 2016 Pani PP, et al. Cochrane Database Syst Rev. 2014
#FSHP2019
72
Non-BZD Pharmacological Therapies Available For AWSPhenobarbital
Dexmedetomidine
Propofol
Baclofen
Ketamine
Carbamazepine and Valproic Acid
Enteral EthanolBZD: benzodiazepines; AWS: alcohol withdrawal syndrome
Dixit D, et al. Pharmacotherapy. 2016
67 68
69 70
71 72
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#FSHP2019Enteral Ethanol
73
Study N Design Criteria Treatment Primary Outcome/Results
Fullwood JE, et al. AJCC.
201357
Prospective, randomized,
controlled pilot
Unstable angina or AMI who were admitted to the CCU and were identified as being at high risk for AW using the CAGE questionnaire
LZ
or
Ethanol and LZ
Safety-associated complication rates (self-extubation, delirium tremens, reinfarction) did not differ between groups (24% LZ vs 18% ethanol; p=0.56). Days spent in the CCU (7% LZ vs 2% ethanol; p= 0.32) and overall hospital stay (6% LZ vs 6% ethanol; p= 0.72) did not differ between the groups.
AMI: acute myocardial infarction; CCU: cardiac critical care unit; AW: alcohol withdrawal; LOS: length of stay; LZ: lorazepam
This small population, restriction to the CCU, and absence of cumulative dose data make it difficult to extrapolate this information to other ICU populations.
#FSHP2019Summary
• Clinical Tool• Using the CIWA-Ar or MINDS tool in patients capable of communicating in combination
with the SAS or RASS when patients could no longer communicate
• Symptom Triggered or Fixed Dosing • Recommend dosing based on measured symptom-triggered therapy (STT) rather than
fixed-dose regimens• Optimal BZD selection should be based on the severity of withdrawal and concomitant
diseases of the patient (ex. elderly or end-stage-liver-disease)• Consider lorazepam for STT as it was the most commonly evaluated
• Non-Benzodiazepine pharmacological therapies for alcohol withdrawal syndrome (AWS)• Data regarding non-benzodiazepines is limited (AWS)• Phenobarbital has the best available data for BZD-resistant or adjunctive BZD therapy
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#FSHP2019
Mallory Fiorenza, PharmD, BCPS, BCCCPCritical Care Specialist
Lee Health, Fort Myers, FL
Management of Alcohol Withdrawal in Critically Ill Patients
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