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



#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

3 – 4

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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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


27DeCarolis DD, et al. Pharmacotherapy. 2007


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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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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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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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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


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


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



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


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

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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


#FSHP2019Difference in Mean Total LorazepamEquivalent Dose


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?


#FSHP2019

47

Non-BZD Pharmacological Therapies Available For AWSPhenobarbital

Dexmedetomidine

Propofol

Baclofen

Ketamine

Carbamazepine and Valproic Acid

Enteral EthanolBZD: benzodiazepines; AWS: alcohol withdrawal syndrome


#FSHP2019SAS Symptom-DrivenDiazepam/Phenobarbital Protocol in ICU Patients

48


OutcomeGoal SAS

Treatment


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


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


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


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


Dexmedetomidine

Propofol

Baclofen

Ketamine




#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


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


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


Dexmedetomidine

Propofol

Baclofen

Ketamine




55 56

57 58

59 60

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11

#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


#FSHP2019

63


Dexmedetomidine

Propofol

Baclofen

Ketamine




#FSHP2019Baclofen Review for AWS

64


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


#FSHP2019

66


Dexmedetomidine

Propofol

Baclofen

Ketamine




61 62

63 64

65 66

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12

#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


#FSHP2019

69


Dexmedetomidine

Propofol

Baclofen

Ketamine




#FSHP2019Carbamazepine and Valproic Acid Review for AWS

70


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


Dexmedetomidine

Propofol

Baclofen

Ketamine




67 68

69 70

71 72

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#FSHP2019Enteral Ethanol

73


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

74

#FSHP2019

Mallory Fiorenza, PharmD, BCPS, BCCCPCritical Care Specialist

Lee Health, Fort Myers, FL

Management of Alcohol Withdrawal in Critically Ill Patients

73 74

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management of alcohol withdrawal in critically ill patients...7/10/2019 1 #fshp2019 mallory...

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