Escolar Documentos
Profissional Documentos
Cultura Documentos
4
April 2013
Background: Alcohol withdrawal syndrome (AWS) occurs in 16 to 31% of intensive care unit
(ICU) patients after cessation of sedation. There exist many preventive and therapeutic strategies, but
no systematic review (SR) has been published on this topic so far. We aimed to perform a synopsis of
all controlled trials of AWS prevention and therapy in ICU published between 1971 and 30 March
2011 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement.
Methods: We performed a MEDLINE search with the terms alcohol AND ICU as well as
alcohol withdrawal AND intensive care. All publications that matched our eligibility criteria were
analyzed according to our predened criteria.
Results: We identied 6 controlled trials about AWS prevention and 8 about AWS therapy in
ICUs. For AWS prevention, benzodiazepines (BZO), ethanol (EtOH), and clonidine were evaluated as
single agents, and BZO, clonidine, clomethiazol and haloperidol were studied in drug combinations.
All evaluated single agents and combinations were found to be eective for AWS prevention. Clo-
methiazol was found to be associated with a higher tracheobronchitis rate and thus disadvised for criti-
cally ill patients. For AWS therapy, BZO, gamma-hydroxybutyric acid (GHB), and clomethiazol were
evaluated in randomized controlled trials as single agents and phenobarbital, clonidine, and haloperidol
as adjuncts. All evaluated regimens were found to be eective for AWS therapy. Overall, in the ICU,
BZO were found to be superior to GHB and clomethiazol regarding safety and ecacy. Furthermore, 4
cohort trials with historical control groups evaluated the eect of the implementation of a standardized
protocol of BZO therapy for AWS in ICUs. All of these 4 studies found better outcome for the inter-
vention groups.
Conclusions: Based on the evidence of this SR, EtOH or BZO can be advised for AWS prevention
on ICU patients with alcohol dependence, but EtOH is not allowed for therapy of AWS. AWS therapy
should be standardized and based on symptom-triggered BZO administration. Alpha2-agonists and
haloperidol should be added for autonomic and productive psychotic symptoms.
Key Words: Alcohol, EtOH, Alcohol Withdrawal, Intensive Care, Delirium.
then excluded all publications that not clearly dealt with patients care proceeded on the 30th of March 2011 revealed 545
in ICUs or failed to specify the prophylactic or therapeutic articles.
agents administered for AWS.
2. Of all 545 articles matching with the search terms above,
4. The remaining articles were divided into the groups PREVEN-
TION and THERAPY of AWS. 80 were found to deal with alcohol withdrawal (see Data
5. All remaining articles were individually graded according to S1 for complete reference list).
the Oxford Centre for Evidence-based Medicine. Thus, preli- 3. We excluded 18 of the 80 publications because they did
minary levels of evidence (LoE) were attributed to each article: not clearly deal with ICU patients or failed to specify the
1a (SRs of RCTs, 1a- in case of worrisome heterogeneity),
prophylactic or therapeutic agents administered for AWS
1b (individual RCTs, 1b- in case of wide condence inter-
val), 2a (SRs of cohort studies), 2b (individual cohort stud- (see Data S1 for list of excluded articles).
ies including low-quality RCTs), 3 (casecontrol studies), 4 4. As 10 of the 62 articles tted into both PREVENTION
(case series or case reports), or 5 (expert opinion). Again, and THERAPY groups, we counted 19 AWS prevention
this grading was performed by each of our 2 working groups and 53 AWS therapy publications.
separately to minimize conrmation or expectation bias. The
5. Our 2 working groups graded most of the articles equally.
preliminary LoE results were then discussed in a consensus
meeting. Four AWS prevention and 4 AWS therapy articles were
6. References of all graded articles were screened for additional graded dierently, which was not relevant for the selection
controlled trials possibly missed in the MEDLINE search. of our synopsis articles: The dissents were between LoE 1a-
7. All articles classied as LoE 1b, 1b-, or 2b and thus describing and 2a (review articles) in 1 case, between LoE 1b- (RCT
controlled trials were analyzed, and their main ndings were put
with wide condence interval) and 2b (cohort trial or
together in an SR.
low-quality RCT) in 1 case, and between LoE 4 (case
reports/case series) and 5 (expert opinion) in 6 cases.
RESULTS 6. The screening of the references of the 62 graded articles
revealed no additional controlled trials evaluating AWS
1. Our MEDLINE search with the terms alcohol AND
prevention or therapy in ICUs.
ICU as well as alcohol withdrawal AND intensive
REVIEW: ALCOHOL WITHDRAWAL ON ICU 677
7. Among all articles classied as LoE 1b, 1b-, or 2b, 6 were measurable inuence on AWS incidence, major complica-
about AWS prevention (Table 1) and 8 about AWS ther- tions, and ICU LOS. Only the clomethiazol-containing ther-
apy (Table 2). apy was associated with a higher tracheobronchitis rate,
probably due to bronchial hypersecretion.
AWS Prevention
EtOH. A 2-armed RCT (Weinberg et al., 2008) found
Six publications were classied as LoE 1b, 1b-, or 2b and no advantage of EtOH over diazepam regarding ecacy
thus included in the AWS prevention part of this review (see or adverse events. A 3-armed RCT (Huber et al., 1990)
Table 1 for details). Investigated drugs were benzodiazepines compared 3 monotherapeutic regimens (EtOH i.v., midazo-
(BZO), intravenous (i.v.) ethanol (EtOH), clonidine, clo- lam, and clonidine) and found slight outcome advantages in
methiazol, and haloperidol. Even if none of the trials was the midazolam group. In a 4-armed RCT (Spies et al., 1995),
placebo-controlled, all these drugs were concluded to be the authors found that EtOH was equally eective and safe
eective in AWS prevention. as 3 other double-drug combinations except clomethiazol
being associated with more respiratory complications. See
Benzodiazepines. Three studies compared dierent BZO benzodiazepine chapter above for these 3 studies and Table 1
with other agents for AWS prophylaxis and found a ten- for study details.
dency to slight advantages over EtOH and clonidine (Huber A study with a historical control group (Dissanaike et al.,
et al., 1990; Weinberg et al., 2008) and a safety advantage 2006) described benets of surgical ICU patients treated with
over clomethiazol (Spies et al., 1995). a standardized protocol of i.v. EtOH regarding treatment
A 2-armed RCT (Weinberg et al., 2008) compared EtOH duration and failure rate. Despite some methodological
with diazepam regarding ecacy and adverse events in 50 weaknesses (poor cohort description, lack of a validated
trauma patients with long-term alcohol abuse history. quantitative AWS score), it can be concluded that a stan-
During the rst hours of treatment, the diazepam-receiving dardized EtOH prophylaxis can be more eective in avoiding
patients were less agitated. After 48 hours, patients in both a long-lasting AWS in ICUs and ensuring a better care of
study arms had the same high success rates (88% calm and these patients than a nonstandardized EtOH administration.
cooperative). A concern is that we suspect a dosage bias: 19 Moreover, the sample size of this trial is large (160 patients),
of the 26 patients in the EtOH group had undetectable blood and the outcome dierences are clinically important (mean
alcohol concentration (BAC) levels at all times, and only 2 treatment duration 3 vs. 7 days, failure rate 7 vs. 20%).
had a higher BAC than 0.1 mg/ml at any time during the A small RCT with patients who reported regular EtOH
EtOH infusion. Furthermore, the authors only included consumption and underwent neck dissection (Heil et al.,
patients able to give their informed consent and thus not 1990) showed that in 10 patients treated with prophylactic
severely injured patients. The exclusion of strongly injured EtOH (2 to 4 g per hour), none developed AWS. In the non-
patients might weaken the power of this trial and thus prophylactically treated control group, 6 of 9 patients devel-
impede the comparability of the 2 patient groups as all oped AWS and had thus to be treated symptomatically with
included subjects had a good outcome and no severe compli- clomethiazol and haloperidol. The authors also mentioned
cations. However, the lack of any severe adverse event and that among the 31 not included patients that were at low
the high treatment success rate after 48 hours show that dependency risk following the Munich Alcoholism Test
AWS prophylaxis might have a favorable eectiveness and (MALT) (Feuerlein et al., 1979), none received EtOH
that both regimens are feasible and safe. prophylaxis and none developed AWS symptoms: 12 of these
A 3-armed RCT with 52 patients (Huber et al., 1990) patients were previously classied as dry alcoholics (absti-
compared 3 monotherapeutic regimens (EtOH i.v., midazo- nent at least since several weeks), 10 without abuse risk,
lam, and clonidine) and found a slight advantage of mi- and 9 with abuse risk but not dependent according to the
dazolam in symptom control, ICU length of stay (LOS), number of positive MALT questionnaire items. Despite the
time spent on mechanical ventilation, and mortality. How- low number of included patients, this trial suggests that
ever, the given dierences were small. The authors failed to EtOH is highly eective in preventing AWS in surgical ICU
report important additional information about the study patients and that the number needed to treat to see a benet
design like the number of patients per study arm, their in AWS prevention is amazingly low if adequate screening is
AWS denition, or administered additional sedative drugs. performed.
Also, the results might be biased by the dosage protocols
used in the dierent study arms. Thus, a critical evaluation Alpha2-Agonists. In a 3-armed RCT (Huber et al.,
and a statistical verication of the ndings cannot be per- 1990), the authors concluded clonidine to be equal to EtOH
formed properly. but slightly inferior to midazolam regarding outcome and
A 4-armed RCT of dierent prevention regimes (prophy- ecacy. A combination of clonidine + unitrazepam was
lactic EtOH i.v./unitrazepam + clonidine/clomethiazol + compared with clomethiazol + haloperidol, unitrazepam +
haloperidol/unitrazepam + haloperidol) (Spies et al., 1995) haloperidol, and EtOH in a 4-armed RCT (Spies et al.,
found that the choice of administered agents has no 1995). This trial found no dierences in eciency and
678
Reason Definition/
Intervention and for scoring of Additional Study Limitations/
Ref # Study design n Inclusion criteria ICU AWS AWS drugs outcome Main findings weaknesses
1 Two-armed Continuous At least 5 alcohol Non-CNS Riker narcotics Achievement -EtOH group: initially more -Many exclusion criteria
RCT EtOH (n = 26) beverage trauma Sedation (only given of a Riker deviations from a -No blinding
infusion vs. equivalents per day Agitation in morphine score of 4 Riker = 4 score (mostly -Agitation as only scored
scheduled during last Scale (1 equivalents, (calm and due to agitation) AWS symptom
bolus dosed 6 months, ability to to 7 not cooperative) -After 48 h: both groups -Rigid protocol (not
diazepam give consent points) precised) had a Riker = 4 symptom triggered, not
(n = 24) percentage of 88% body weight adjusted)
-In all patients the 48-hour-
weaning procedure was
successful (started 48 to
96 hours after treatment
initiation)
2 Controlled Protocol -Intervention group: Not DSM-IV Not reported -Duration of -Protocol group: earlier -No validated quantitative
nonrandomized implementation: history of AWS, specified definition treatment initiation and shorter AWS score
study i.v. EtOH alcohol abuse or -Incidence of duration of treatment (3 vs. -Poor description of patient
(n = 68) vs. alcohol-related AWS 7 days), lower failure rate cohort
historical CG conditions symptoms (7 vs. 20%) and higher -6 pat. secondary excluded
(i.v. EtOH -CG: i.v. EtOH -Referral to referral to substance due to protocol violation
without treatment and specialized abuse clinic (20 vs. 8%) -5 + 2 patients already had
protocol (n = 92) history of AWS/ abuse clinic -Only AE: asymptomatic AWS when EtOH infusion
alcohol abuse -AE hyponatremia (1 pat.) was started, blending of
therapy and prophylaxis
3 Controlled -Clonidine on Elective Esophag- RAMSAY Not reported Nitrogen -Less protein catabolism in -No randomization
nonrandomized POD 1 to 6 abdomino- ectomy sedation balance as clonidine group -No blinding/no placebo
study (n = 13) thoracic score surrogate for (cumulated values of POD -Low number of patients
-CG (n = 11): no esophageal protein 1 to 6): 1.5 vs. 17.6 g -CG not adequate for AWS
clonidine, cancer catabolism mean nitrogen loss (=36 evidence (pat. without no
pat. without resection vs. 422 g muscle mass alcohol history)
alcohol abuse equivalent) -No validated AWS score
history (!) -Similar Ramsay scores in
both groups
4 Four-armed Flunitrazepam + Alcohol Tumor CIWA-Ar Only in -ICU LOS -Higher tracheobronchitis -Cardiac/pulmonary risk
partially blinded clonidine dependence surgery (assessment secondary -AWS rate in clomethiazol + patients excluded due to
RTC (n = 52) vs. (DSM-III), by blinded excluded prevention haloperidol group safety concerns
clomethiazol + daily EtOH investigators), pat. -Major -No difference in AWS -No double-blinding
haloperidol intake of 60 g AWS confirmed complications incidence or severity, ICU -23 pat. secondary
(n = 49) vs. by a neurologist LOS, other major excluded (from which 10
flunitrazepam + complications or mortality due to AE; 5 to 8 due to
haloperidol additional AWS therapy)
(n = 50) vs.
EtOH i.v.
(n = 50)
Continued.
UNGUR ET AL.
REVIEW: ALCOHOL WITHDRAWAL ON ICU 679
intravenous; vs., versus; pat., patient(s); CNS, central nervous system; AE, adverse event(s); POD, postoperative day; BZO, benzodiazepines; DSM, Diagnostic and Statistical Manual of Mental Dis-
Ref # = reference number: 1. Weinberg and colleagues (2008); 2. Dissanaike and colleagues (2006); 3. Mertes and colleagues (1996); 4. Spies and colleagues (1995); 5. Huber and colleagues
(1990); 6. Heil and colleagues (1990); RCT, randomized controlled trial; n, number of patients; AWS, alcohol withdrawal syndrome; ICU, intensive care unit; CG, control group; EtOH, ethanol; i.v.,
important items not given
day) dosage
A small trial (Mertes et al., 1996) found much less protein
prophylaxis
-No blinding
catabolism in patients treated with clonidine than in non-
treated controls. In this study, patients with alcohol abuse
history were compared to patients without alcohol abuse
history; thus, no comparison of AWS prevention success can
additional sedation needed
-Midazolam group: weakest
-Clomethiazol + haloperidol
be made. Nevertheless, this trial suggests that one of the
ventilation and ICU LOS,
(significance unclear, no
-Respiratory
incidence
Study
-ICU LOS
-Seizures
duration
-Mortality
delirium
-AWS
sedation
additional
(no more
given)
Not reported
ICUs (Spies et al., 1995), see sections above and Table 1 for
details.
Esophag-
AWS Therapy
Reason
surgery
ectomy
ICU
for
Neck
symptomatic
haloperidol;
EtOH i.v. vs.
division not
Prophylactic
subgroup
reported)
EtOH i.v.
clonidine
therapy in ICUs.
n
therapy
(n = 52,
n = 9)
6
680
Continued.
UNGUR ET AL.
Table 2. (Continued)
Ref # = reference number: 1. Elsing and colleagues (2009); 2. Lansford and colleagues (2008); 3. Gold and colleagues (2007); 4. DeCarolis and colleagues (2007); 5. Spies and colleagues
(2003); 6. Lenzenhuber and colleagues (1999); 7. Spies and colleagues (1996a); 8. Hoey and colleagues (1994); RCT, randomized controlled trial; n, number of patients; AWS, alcohol withdrawal
syndrome; LOS, length of stay; ICU, intensive care unit; GHB, gamma-hydroxybutyric acid; CG, control group; CA, carcinoma; EtOH, ethanol; i.v., intravenous; vs., versus; BZO, benzodiazepines;
pat., patient(s); CIWA-Ar, Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised; DSM IV, Diagnostic and Statistic Manual of Mental Disorders, 4th edition; AE, adverse event.
681
682 UNGUR ET AL.
uber et al., 1999), both arms allowing adjunctive haloperidol Clomethiazol. A larger 3-armed RCT of double-drug
for hallucinations and clonidine for vegetative symptoms. combinations (Spies et al., 1996a) compared clomethiazol +
The authors concluded that GHB is stronger for the treat- haloperidol with benzodiazepine-based regimes (unitraze-
ment of vegetative symptoms but weaker against psychotic pam + haloperidol and unitrazepam + clonidine) for trauma
symptoms. More metabolic adverse events were seen in the ICU patients. Clomethiazol-treated patients were found to
GHB arm. All other outcome parameters (AWS severity and have a higher pneumonia rate and a longer time spent
duration, ICU LOS, severe complications, mortality) were on mechanical ventilation. Thus, the authors disadvised
equal in both arms. clomethiazol for critically ill patients.
The only double-blinded RCT for AWS therapy (Spies A small RCT (Elsing et al., 2009) compared GHB with
et al., 2003) compared bolus administration of unitrazepam clomethiazol. Despite the methodological weaknesses of this
with continuous infusion and found much lower intubation trial mentioned in the GHB chapter above, it has to be high-
rates for the bolus group and thus less ventilator associated lighted that clomethiazol was less ecient while it had no
pneumonia and a shorter ICU LOS. advantages compared to the GHB arm.
The eect of a standardized benzodiazepine protocol
implementation on dierent outcomes was analyzed in 4 Haloperidol. The authors of a 3-armed RCT of double-
studies (DeCarolis et al., 2007; Gold et al., 2007; Hoey et al., drug combinations described in the paragraphs above and in
1994; Lansford et al., 2008). Despite some methodological Table 2 (Spies et al., 1996a) advise the combination of unit-
weaknessesall 4 studies had historical control groups and razepam + haloperidol especially for patients with cardiac
were thus highly susceptible for experimenters biasit has risk because of reported cardiac adverse events in the cloni-
to be summarized that all 4 trials found clear outcome dine-containing arm and the higher pneumonia rate in the
advantages for the intervention groups (better and faster clomethiazol-based arm.
symptom control, partly less complications, and a shorter In the other analyzed AWS therapy trials, haloperidol was
ICU LOS). The ndings about the total drug doses were con- not tested against other agents but used as adjunct for psy-
tradictory, possibly due to dierent agents used in the con- chotic AWS symptoms within the study protocol (Lansford
trol and protocol groups. Other weaknesses of these 4 studies et al., 2008; Spies et al., 2003) or reported as part of addi-
were the partially small control group samples of 14 tional AWS therapy in case of insucient ecacy of the pro-
(Lansford et al., 2008) and 16 (DeCarolis et al., 2007) tocol agents (Elsing et al., 2009; Gold et al., 2007; Hoey
patients, too many outcome items, poor reporting of addi- et al., 1994; Lenzenhuber et al., 1999).
tional AWS medication, and poor control group descrip-
tions. Alpha2-Agonists. In the 3-armed RCT of double-drug
combinations described previously (Spies et al., 1996a),
Gamma-Hydroxybutyric Acid. A 2-armed RCT with 26 clonidine was combined with unitrazepam and found to be
patients classied as alcohol addicted and being admitted as ecient as unitrazepam + haloperidol or clomethiazol +
in ICUs because of AWS or other internal medicine disease haloperidol. However, the authors did not recommend this
(Elsing et al., 2009) compared GHB with clomethiazol while combination for cardiac risk patients due to more cardiac
clonidine was permitted as adjunct at any time and BZO and complications seen in the clonidine arm.
haloperidol after the seventh hour. As more than 60% of the In the other analyzed AWS therapy trials, clonidine was
patients in both study arms received additional AWS medi- not tested against other agents but used as adjunct for vege-
cation and the sample of patients in this trial was quite small, tative AWS symptoms within the study protocol (Lansford
it is dicult to draw conclusions of the outcome results. et al., 2008; Spies et al., 2003) or reported as part of addi-
Another weakness of this trial is the relatively small dosage tional o-protocol AWS therapy (Elsing et al., 2009; Len-
of oral clomethiazol (250 mg every 4 hours, not body weight zenhuber et al., 1999).
adjusted) compared with high-dose i.v. GHB (initially
30 mg/kg, then 15 mg/kg). However, apart from less AWS
symptoms during the rst 7 hours in the GHB group, possi- DISCUSSION
bly explained by the dosage bias, the authors described no
AWS Prevention
signicant dierences between the 2 cohorts.
Another RCT already described in the BZO chapter above There is sucient evidence proving that BZO are eec-
compared GHB with unitrazepam (Lenzenhuber et al., tive for AWS prevention in single administration (Huber
1999), both arms allowing adjunctive haloperidol and cloni- et al., 1990; Weinberg et al., 2008) and in combination with
dine. The authors concluded that GHB is stronger for the haloperidol or clonidine (Huber et al., 1990; Spies et al.,
treatment of vegetative symptoms but weaker against psy- 1995). Despite the diculty to dierentiate paradox eects
chotic symptoms and associated with more metabolic of BZO from AWS symptoms, clinicians should be aware
adverse events. All other outcome parameters (AWS severity of this potential risk. However, this adverse eect has not
and duration, ICU LOS, severe complications, mortality) been reported in any of our analyzed articles.
were equal in both arms.
REVIEW: ALCOHOL WITHDRAWAL ON ICU 683
The alpha2-agonist clonidine as single agent might be infe- on ambulant patients trials, but, however, this has not yet
rior compared to EtOH or midazolam, but this has only been been studied in ICU patients.
investigated in 1 trial with insuciently reported details on
statistics and patient samples (Huber et al., 1990).
AWS Therapy
Combinations containing clomethiazol should not be
preferred in critically ill patients because of bronchial Clomethiazol, for many years a common and widely
hypersecretion (Spies et al., 1995). However, this trial failed recommended agent against AWS (Batel and Lariviere,
to show statistical signicant dierences in ICU LOS or mor- 2000; Croissant and Mann, 2000; Dittmar, 1991, 1994;
tality. On the other hand, as 1 other trial showed longer ven- Engelhardt, 1996; Horstmann et al., 1989; Naber et al.,
tilation times and higher pneumonia rates in critically ill 1991; Spies and Rommelspacher, 1999; Tiecks and Einhaupl,
patients receiving clomethiazol for AWS therapy (Spies 1994; Vagts et al., 2003), was shown to be inferior to regi-
et al., 1996a), further investigation of this drug in ICUs mens based on BZO especially due to adverse events related
appears ethically questionable. to bronchial hypersecretion (Spies et al., 1996a) and inferior
Moderately dosed i.v. EtOH (2 to 4 g/h) seems to be safe to GHB regarding initial symptom control (Elsing et al.,
and as eective as the drugs above in preventing AWS 2009). Despite many case reports showing the ecacy of clo-
(Dissanaike et al., 2006; Heil et al., 1990; Spies et al., 1995). methiazol against AWS, it should be used with caution in
This stands in contrast to the critical appraisal of some other critically ill patients if they are in danger of needing mechani-
authors regarding i.v. EtOH administration (Sar and Gold, cal ventilation.
2010; Vagts et al., 2003). This critical standpoint might be GHB was inferior to a benzodiazepine regimen regard-
explained by blending of prophylaxis and therapy in litera- ing ecacy in hallucination control and metabolic side
ture assessment. Furthermore, Sar bases his skepticism on eects (Lenzenhuber et al., 1999) but still more potent
a trial with 32 treated patients (Eggers et al., 2002) without a than low-dosed clomethiazol following Elsings small RCT
control group. In this trial, patients received a quite high- (Elsing et al., 2009). Even if some experts see it as an eec-
loading dose of EtOH reaching a BAC of 0.7 mg/ml after tive agent for AWS treatment in ICUs (Kleinschmidt and
45 min. Then, they received a continuous EtOH infusion Mertzlut, 1995; Meyer et al., 2005; Vagts et al., 2003)
dosed upon their individual anamnestic drinking habit and our analyzed studies showed a sucient eect espe-
reports that lead to a BAC of around 0.1 mg/ml at day 2. cially for vegetative AWS symptoms, it has to be seen criti-
The AWS-enduring patients (40%, called failure group) cally because of its toxicity (Lenzenhuber et al., 1999) and
had a BAC of closely 0.0 mg/ml in contrast to 0.15 to its hallucinatory side eect. Another important concern
0.3 mg/ml in the success group. This suggests a bias due to about GHB is its strong dependence potential, a reason
inadequate dosing and supports the need of a standardized why it is declared as a controlled substance in some coun-
body weightadjusted EtOH infusion protocol. By imple- tries, and it is not approved at all in some other countries.
menting such a protocol (Dissanaike et al., 2006), the failure This might also be a concern about a general recommen-
rate was dropped from 20% to 8%, and the mean treatment dation for this drug. On the other hand, GHB is approved
was shortened from 7 to 3 days in 160 patients comprising in a few European countries to treat alcohol withdrawal
trial. Numerous previous publications see i.v. EtOH as an and dependence.
acceptable agent for AWS prophylaxis (Engelhardt, 1996; The only larger RCT investigating AWS therapy (n = 159;
Kork et al., 2010; Sander et al., 2006; Spies and Rommelsp- Spies et al., 1996a) prefers a combination of a benzodiaze-
acher, 1999; Vagts and Noldge-Schomburg, 2002). More pine (unitrazepam) and haloperidol for trauma or surgical
powerful multicenter trials are required to answer the ques- ICU patients because of worse outcome in clomethiazol-trea-
tion if any of the above-discussed agents or combinations is ted patients and cardiac complications associated with cloni-
superior to the others. dine. As shown in another double-blinded trial (Spies et al.,
There are many other potential substances or methods to 2003), BZO should be administered symptom driven instead
prevent AWS: some authors stress the importance of detect- of continuously. This was shown to be more eective, safer,
ing patients at risk by screening tools as well as general and less expensive. Clear outcome advantages of a standard-
measures like nutrition, volume resuscitation, and preopera- ized protocol for benzodiazepine administration against
tive abstinence (Kork et al., 2010; Sar and Gold, 2010). AWS in ICUs have been shown in all of our 4 analyzed
Two general review articles conclude that GHB can also be cohort trials (DeCarolis et al., 2007; Gold et al., 2007; Hoey
eective to prevent AWS in ICUs (Kleinschmidt and et al., 1994; Lansford et al., 2008). This conforms with
Mertzlut, 1995; Meyer et al., 2005), but there are no numerous recent review articles, case reports, and experts
published controlled trials that investigated GHB for AWS recommendations where BZO are seen as standard treatment
prevention. BZO seem to represent the rst choice substance for AWS in ICUs (Al-Sanouri et al., 2005; Bard et al., 2006;
class to prevent AWS following previous literature recom- Batel and Lariviere, 2000; Croissant and Mann, 2000; Dar-
mendations (Spies and Rommelspacher, 1999). Anticonvul- rouj et al., 2008; Hayner et al., 2009; van Klei et al., 2000;
sants in contrary are not ecient in AWS prevention, McCowan and Marik, 2000; Petignat, 2005; Phillips et al.,
following a review of Al-Sanouri and colleagues (2005) based 2006; Powell, 1999; Remennik et al., 2005; Sander et al.,
684 UNGUR ET AL.
2006; Sar and Gold, 2010; Skrobik, 2007, 2009; Spies and Clomethiazol should not be used in critically ill patients
Rommelspacher, 1999; Verstraete et al., 2008; de Wit et al., due to its risk of tracheobronchitis and pneumonia through
2007). higher bronchial secretion.
Clonidine and haloperidol were used as adjuncts for auto- EtOH is eective in AWS prevention but not recom-
nomic respectively productive-psychotic symptoms, and its mended for AWS therapy.
need was seen as surrogate markers for the potency or weak- GHB was found to be eective for AWS therapy but is not
ness of the backbone AWS drug in some studies (Elsing recommended as rst-choice agent because of safety con-
et al., 2009; Gold et al., 2007; Hoey et al., 1994; Lansford cerns, insucient potency against hallucinations, and legal
et al., 2008; Lenzenhuber et al., 1999; Spies et al., 1996a, concerns. It is also not available in all countries.
2003). No controlled trial investigated these substances as Safety concerns are seen in clonidine (cardio circulatory
single agents for AWS therapy in ICUs. Even if none of our side eects) and haloperidol (QT prolongation), but both
analyzed studies reported haloperidol-induced seizures as drugs are well established and have a proven ecacy as
adverse events, clinicians should be aware of the potential adjunctive substances for specic AWS autonomic (cloni-
epileptogenic side eect. dine) or psychotic (haloperidol) symptom control. As
Publications discussing EtOH, phenobarbital, propofol, clonidine is not available in all countries, a more potent
anticonvulsants, beta-blockers, opioids, thiamine, physo- alpha2-agonist, dexmedetomidine might also be used (LoE
stigmine, or dexmedetomidine for AWS therapy in ICUs 4; Tang et al., 2011).
are based on case report or expert opinion evidence and For all other possibly helpful agents, the riskbenet
see these agents mostly as second-line therapy or adjuncts ratios compared to the substances above remain to be eval-
for specic symptoms or comorbidities. (Al-Sanouri et al., uated in controlled trials. Useful further study designs
2005; Darrouj et al., 2008; Dittmar, 1991, 1994; Engel- could be placebo-controlled AWS prevention trials to evalu-
hardt, 1996; Eyer et al., 2011; Hayner et al., 2009; van ate a general benet of screening and prevention of AWS
Klei et al., 2000; Krumholz, 1996; McCowan and Marik, risk. To optimize AWS therapy, a next step could be to
2000; Muhl, 2006; Powell, 1999; Remennik et al., 2005; compare longer with shorter acting BZO in double-blinded
Sar and Gold, 2010; Spies and Rommelspacher, 1999; trials or to evaluate other adjuncts in placebo-controlled
Vagts and Noldge-Schomburg, 2002; de Wit et al., 2007; trials.
Zielmann et al., 2003).
DECLARATION OF INTEREST
Limitation Three analyzed trials have been performed by the authors
One important limitation of this review might consist department. The authors report no further conicts of inter-
in the overall thin evidence base: some of the available est. The authors alone are responsible for content and writ-
controlled trials had small patient samples (DeCarolis et al., ing of this article.
2007; Elsing et al., 2009; Heil et al., 1990; Lansford
et al., 2008; Mertes et al., 1996) and inadequate (Mertes ACKNOWLEDGMENTS
et al., 1996) or too numerous outcome items to allow strong
The authors thank Dr. Yoanna Skrobik for an interesting,
and concrete AWS prevention or therapy recommendations.
fruitful discussion. This systematic review has been funded
Furthermore, SRs are always potentially subject to publica-
by institutional resources of the Department of Anesthesiol-
tion bias, as we do not know if studies with negative or unfa-
ogy and Operative Intensive Care Medicine at the Charite
vorable results have remained unpublished. The authors
Universitatsmedizin Berlin.
neutrality might be aected by the fact that 3 of the analyzed
studies as well as some of other cited publications originate
from their own department. On the other hand, it can be seen REFERENCES
as strength that the authors used the PRISMA criteria and
Al-Sanouri I, Dikin M, Soubani AO (2005) Critical care aspects of alcohol
only highlighted recommendations based on evidence of abuse. South Med J 98:372381.
higher level. Bard MR, Goettler CE, Toschlog EA, Sagraves SG, Schenarts PJ, Newell
MA, Fugate M, Rotondo MF (2006) Alcohol withdrawal syndrome:
turning minor injuries into a major problem. J Trauma 61:14411445; dis-
CONCLUSIONS cussion 14451446.
Batel P, Lariviere P (2000) Late-onset alcohol withdrawal syndrome. Ann
BZO can be regarded as the standard of care for AWS pre- Med Interne (Paris) 151:B27B29.
vention and treatment. Symptom-triggered bolus administra- Croissant B, Mann K (2000) Alcohol withdrawal syndrome and its treat-
tion is more benecial than continuous infusion for AWS ment. Ther Umsch 57:257260.
therapy. Delirium monitoring with a validated score is obli- Darrouj J, Puri N, Prince E, Lomonaco A, Spevetz A, Gerber DR (2008)
gatory. Dierences in dosage and optimal adjunct substances Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for
acute alcohol withdrawal. Ann Pharmacother 42:17031705.
are still to be found in further studies.
REVIEW: ALCOHOL WITHDRAWAL ON ICU 685
DeCarolis DD, Rice KL, Ho L, Willenbring ML, Cassaro S (2007) Symp- sive care patients. A comparison between with two symptom-oriented
tom-driven lorazepam protocol for treatment of severe alcohol withdrawal therapeutic concepts. Anaesthesist 48:8996.
delirium in the intensive care unit. Pharmacotherapy 27:510518. McCowan C, Marik P (2000) Refractory delirium tremens treated with prop-
Dissanaike S, Halldorsson A, Frezza EE, Griswold J (2006) An ethanol proto- ofol: a case series. Crit Care Med 28:17811784.
col to prevent alcohol withdrawal syndrome. J Am Coll Surg 203:186191. Mertes N, Goeters C, Kuhmann M, Zander JF (1996) Postoperative alpha
Dittmar G (1991) Alcohol deliriumpathogenesis and therapy. Med Klin 2-adrenergic stimulation attenuates protein catabolism. Anesth Analg
(Munich) 86:607612. 82:258263.
Dittmar G (1994) Alcoholic deliriuma potentially life-threatening condi- Meyer S, Kleinschmidt S, Gottschling S, Gortner L, Strittmatter M (2005)
tion. Fortschr Med 112:274276. Gamma-hydroxy butyric acid: neurotransmitter, sedative and party drug.
Eggers V, Tio J, Neumann T, Pragst F, Muller C, Schmidt LG, Kox WJ, Wien Med Wochenschr 155:315322.
Spies CD (2002) Blood alcohol concentration for monitoring ethanol Muhl E (2006) Delirium and intensive care unit syndrome. Chirurg 77:
treatment to prevent alcohol withdrawal in the intensive care unit. Inten- 463471; quiz 472.
sive Care Med 28:14751482. Naber M, Franz W, Overbeck W (1991) Characteristics of alcohol with-
Elsing C, Stremmel W, Grenda U, Herrmann T (2009) Gamma-hydroxybu- drawal delirium in surgical patients and recommendations for treatment.
tyric acid versus clomethiazole for the treatment of alcohol withdrawal Chirurg 62:133137.
syndrome in a medical intensive care unit: an open, single-center random- Petignat PA (2005) The management of the alcohol withdrawal syndrome in
ized study. Am J Drug Alcohol Abuse 35:189192. the intensive care unit. Rev Med Suisse 1:29052911.
Engelhardt W (1996) Alcohol administration for prevention of withdrawal Phillips S, Haycock C, Boyle D (2006) Development of an alcohol with-
delirium in alcohol dependent surgical intensive care patients: pro. Anas- drawal protocol: CNS collaborative exemplar. Clin Nurse Spec 20:190
thesiol Intensivmed Notfallmed Schmerzther 31:183184. 198; quiz 199200.
Eyer F, Schreckenberg M, Hecht D, Adorjan K, Schuster T, Felgenhauer N, Powell AH (1999) Alcohol withdrawal in critical care. Dimens Crit Care
Pfab R, Strubel T, Zilker T (2011) Carbamazepine and valproate as Nurs 18:2428.
adjuncts in the treatment of alcohol withdrawal syndrome: a retrospective Remennik AG, Nepomnyashchikh LM, Remennik VI (2005) Progressive
cohort study. Alcohol Alcohol 46:177184. toxemia with acetaldehyde in a reactive form of alcohol withdrawal
Feuerlein W, Ringer C, Kufner H, Antons K (1979) Diagnosis of alcoholism: syndrome. Bull Exp Biol Med 139:732734.
the Munich Alcoholism Test (MALT). Curr Alcohol 7:137147. Sander M, Neumann T, von Dossow V, Schonfeld H, Lau A, Eggers V, Spies
Gold JA, Rimal B, Nolan A, Nelson LS (2007) A strategy of escalating C (2006) Alcohol use disorder: risks in anesthesia and intensive care medi-
doses of benzodiazepines and phenobarbital administration reduces the cine. Internist (Berl) 47:332, 334336, 338, passim.
need for mechanical ventilation in delirium tremens. Crit Care Med Sar M, Gold JA (2010) Alcohol withdrawal syndromes in the intensive care
35:724730. unit. Crit Care Med 38:S494S501.
Hayner CE, Wuestefeld NL, Bolton PJ (2009) Phenobarbital treatment in a Skrobik Y (2007) Protocols, practice, and patientsthe case of alcohol with-
patient with resistant alcohol withdrawal syndrome. Pharmacotherapy drawal. Crit Care Med 35:955.
29:875878. Skrobik Y (2009) Broadening our perspectives on ICU delirium risk factors.
Heil T, Martens D, Eyrich K (1990) Alcohol withdrawal syndrome in the Crit Care 13:160.
postoperative phasetherapy or prevention? Langenbecks Arch Chir Sup- Spies CD, Dubisz N, Funk W, Blum S, Muller C, Rommelspacher H,
pl II Verh Dtsch Ges Chir 1990:11371140. Brummer G, Specht M, Hannemann L, Striebel HW, Schaartzik W
Hoey LL, Nahum A, Vance-Bryan K (1994) A prospective evaluation of (1995) Prophylaxis of alcohol withdrawal syndrome in alcohol-dependent
benzodiazepine guidelines in the management of patients hospitalized for patients admitted to the intensive care unit after tumour resection. Br J
alcohol withdrawal. Pharmacotherapy 14:579585. Anaesth 75:734739.
Horstmann E, Conrad E, Daweke H (1989) Severe course of delirium tre- Spies CD, Dubisz N, Neumann T, Blum S, Muller C, Rommelspacher H,
mens. Results of treatment and late prognosis. Med Klin (Munich) 84: Brummer G, Specht M, Sanft C, Hannemann L, Striebel HW, Schaartzik
569573. W (1996a) Therapy of alcohol withdrawal syndrome in intensive care unit
Huber FT, Bartels H, Siewert JR (1990) Treatment of postoperative alcohol patients following trauma: results of a prospective, randomized trial. Crit
withdrawal syndrome after esophageal resection. Langenbecks Arch Chir Care Med 24:414422.
Suppl II Verh Dtsch Ges Chir 1990:11411143. Spies CD, Neuner B, Neumann T, Blum S, Muller C, Rommelspacher H,
van Klei WA, Havenaar JM, Klijn FA, van Dijk A (2000) Ethanol for Rieger A, Sanft C, Specht M, Hannemann L, Striebel HW, Schaartzik
treatment of delirium in alcohol dependent patients on intensive care W (1996b) Intercurrent complications in chronic alcoholic men admitted
units in the Netherlands: ecacy not proven. Ned Tijdschr Geneeskd to the intensive care unit following trauma. Intensive Care Med 22:
144:710713. 286293.
Kleinschmidt S, Mertzlut F (1995) Gamma-hydroxybutyric acidsigni- Spies CD, Otter HE, Huske B, Sinha P, Neumann T, Rettig J, Lenzenhuber
cance for anesthesia and intensive care medicine? Anasthesiol Intensivmed E, Kox WJ, Sellers EM (2003) Alcohol withdrawal severity is decreased by
Notfallmed Schmerzther 30:393402. symptom-orientated adjusted bolus therapy in the ICU. Intensive Care
Kork F, Neumann T, Spies C (2010) Perioperative management of patients Med 29:22302238.
with alcohol, tobacco and drug dependency. Curr Opin Anaesthesiol Spies CD, Rommelspacher H (1999) Alcohol withdrawal in the surgical
23:384390. patient: prevention and treatment. Anesth Analg 88:946954.
Krumholz W (1996) Alcohol as therapeutic drug in alcohol dependent inten- Tang JF, Chen PL, Tang EJ, May TA, Stiver SI (2011) Dexmedetomidine
sive care patients: contra. Anasthesiol Intensivmed Notfallmed Schmerz- controls agitation and facilitates reliable, serial neurological examinations
ther 31:181182. in a non-intubated patient with traumatic brain injury. Neurocrit Care
Lansford CD, Guerriero CH, Kocan MJ, Turley R, Groves MW, Bahl V, 15:175181.
Abrahamse P, Bradford CR, Chepeha DB, Moyer J, Prince ME, Wolf Tiecks FP, Einhaupl KM (1994) Treatment alternatives of alcohol with-
GT, Aebersold ML, Teknos TN (2008) Improved outcomes in patients drawal delirium. Nervenarzt 65:213219.
with head and neck cancer using a standardized care protocol for post- Vagts DA, Iber T, Noldge-Schomburg GF (2003) Alcohola perioperative
operative alcohol withdrawal. Arch Otolaryngol Head Neck Surg 134: problem of anaesthesia and intensive care medicine. Anasthesiol Intensiv-
865872. med Notfallmed Schmerzther 38:747761.
Lenzenhuber E, Muller C, Rommelspacher H, Spies C (1999) Gamma- Vagts DA, Noldge-Schomburg GF (2002) Managing anesthesia in the
hydroxybutyrate for treatment of alcohol withdrawal syndrome in inten- alcoholic patient. Anaesthesiol Reanim 27:160167.
686 UNGUR ET AL.
Verstraete L, Joosten E, Milisen K (2008) Opinions of physicians and nurses Zielmann S, Petrow H, Walther P, Henze T (2003) Intensive care of delirium
regarding the prevention, diagnosis and management of delirium. Tijdschr syndromes. Anaesthesiol Reanim 28:812.
Gerontol Geriatr 39:2634.
Weinberg JA, Magnotti LJ, Fischer PE, Edwards NM, Schroeppel T, Fabian
TC, Croce MA (2008) Comparison of intravenous ethanol versus diaze- SUPPORTING INFORMATION
pam for alcohol withdrawal prophylaxis in the trauma ICU: results of a
randomized trial. J Trauma 64:99104. Additional Supporting Information may be found in the
de Wit M, Wan SY, Gill S, Jenvey WI, Best AM, Tomlinson J, Weaver MF
(2007) Prevalence and impact of alcohol and other drug use disorders on
online version of this article:
sedation and mechanical ventilation: a retrospective study. BMC Anesthe- Data S1. Addendum.
siol 7:3.