Hospital Pharmacy - October 2017 - 609

Hammond et al
therapies for treatment of AWS, and patient outcomes, if
available. Two reviewers independently used quality assessment tools from the National Heart, Lung, and Blood Institute
to assess study quality.39 Discrepancies were resolved
through discussion with all study investigators.

Analyzed Outcomes
Outcomes that were analyzed included frequency of ICU
admission, first intubation for mechanical ventilation, continuous infusion BZD, and breakthrough BZD or PHB use. In
addition, differences in the duration of ICU, hospital, and ED
stay and mechanical ventilation were evaluated. Differences
in cumulative amounts and maximum doses of BZD and PHB
as well as serum concentrations of PHB were calculated.
Changes in AWS symptoms and development of adverse
effects with PHB were determined.

Results
Our literature search identified 294 studies from which 21
studies were reviewed and 9 were included in the systematic
review17-25 (Table 1). Four of these studies included patients
who received concomitant BZD therapy in the PHB group,17-20
and 5 studies included patients who received PHB as monotherapy.21-25 The comparator groups included BZD therapy
(n = 6),17-21,23 carbamazepine (n = 1),23 gabapentin (n = 1),25
propofol (n = 1),19 PHB (n = 3),18,19,25 and no comparator
group (n = 2).21,24 Three studies included more than 1 agent in
a comparator group.18,19,24 Three of the studies included
patients with severe AWS (33%-100%) as designated by the
study authors or because patients received care in the ICU,17-19
and 6 included patients with mild-to-moderate AWS (40100%) as designated by the study authors.20-25 When evaluated
according to quality of study, 2 were good quality,17,21 4 were
fair quality,18-20,22 and 3 were poor quality.23-25 Four trials were
excluded because they either used barbital or did not include
enough patients or describe PHB use with enough detail to
identify exposure with outcomes.26-29 Two case reports were
excluded30,31 (Figure 1).

PHB With Concomitant BZD Therapy
Severe AWS. Rosenson and colleagues performed a randomized, double-blind, controlled trial in which they evaluated
the effectiveness of single-dose PHB (10 mg/kg) compared
with placebo (n = 51 in each group) in nonintubated patients
with AWS at ED admission.17 A modified CIWA score was
used for evaluation of AWS. The primary outcome was the
initial level of hospital admission from the ED. The study
found a decreased ICU admission rate with PHB treatment
compared with placebo (8.0% vs 25.0%, no P value provided). Patients in the PHB group required less total lorazepam (26.0 mg vs 49.0 mg, no P value provided) and fewer
requirements for lorazepam infusions (4.0% vs 31.0%, no P

609
value provided). There were no differences in ICU or hospital LOS or adverse outcomes (eg, intubation) between the 2
groups. There were 48 patients who met inclusion criteria
who were not included in the study based on ED provider
judgment, which may have affected results. In addition, 8
(15.7%) patients in the placebo group still received PHB.
The use of PHB appeared to decrease BZD requirements and
need for ICU admission in this study.
Duby and colleagues performed a pre-post intervention
study at a single-center ICU in patients with a diagnosis of
AWS.18 Patients in the preintervention phase were treated per
provider discretion. The intervention was the inclusion of a
protocol that used escalating BZD doses and PHB though
routes were not provided. Diazepam doses were initiated at
10 mg escalated in 10 to 20 mg increments every 15 to 30
minutes to a target sedation level: Richmond Agitation
Sedation Scale score of 0 to −2. Once diazepam doses
reached 120 mg, PHB was administered as an adjunct every
30 minutes to a maximum dose of 240 mg. Routes of administration for diazepam and PHB were not provided. The primary outcome was the ICU LOS. A total of 135 patients
(preintervention: n = 60; postintervention: n = 75) were
included in the analysis. There was a significant decrease in
the mean ICU LOS in the postintervention group (5.2 days vs
9.6 days, P = .0004), compared with the preintervention
group. There were also significant decreases in mean duration of mechanical ventilation (1.3 days vs 5.6 days, P <
.001) and need for continuous sedation in the postintervention group (24.0% vs 55.0%, P < .001). There was a substantial decrease in mean BZD requirements in the
postintervention group (P = .0002), although PHB was still
rarely used even in the postintervention group. This study
largely compared nonprotocolized care versus protocolized
care. The benefits of PHB treatment are difficult to extrapolate, given its limited use in this study.
Gold and colleagues performed a pre-post intervention
study at a single-center medical ICU in patients with an
admission diagnosis of AWS.19 Requirement for ICU admission was >200 mg of diazepam within 4 hours or an individual dose of >40 mg of diazepam for management of AWS.
All subjects were treated using a symptom-triggered
approach, which depended on the presence of a Riker
Sedation-Agitation Scale score ≥5 given a goal of 3 to 4. The
authors believe the preguideline dosing strategy was leading
to underdosing of patients; therefore, the postguideline intervention was an escalating BZD dosing protocol for patients
who did not have control of agitation from a dose of BZD for
≥1 hour. Doses of diazepam were escalated until agitation
was controlled for ≥1 hour, and intravenous PHB was added
in a similar fashion (65 mg with doses doubled up to a 260
mg maximum dose) to patients who required diazepam doses
of >100 mg. This study was conducted to describe the outcomes of patients with severe AWS and whether dose escalation of BZDs in combination with PHB improves those
outcomes. A total of 95 patients were included in the analysis

Table of Contents for the Digital Edition of Hospital Pharmacy - October 2017