Substance Use Disorders in Adult Critically Ill Patients

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Chapter 1
Epidemiology and Impact of Substance
Use Disorders on the Intensive Care Unit

Jon E. Grant

 revalence of Substance Use Disorders

P
in the General Population

Both alcohol and drug use disorders are common and associated with significant
morbidity and mortality [1–3]. In fact, the current prevalence rates of alcohol use
disorder and drug use disorders in the general population of the United States are
approximately 13.9% and 3.9%, respectively, based on the National Epidemiologic
Survey on Alcohol and Related Conditions [4, 5]. The lifetime prevalence rates of
alcohol use disorder and drug use disorders in the general population of the United
States are approximately 29.1% and 9.9%, respectively [4, 5]. This roughly trans-
lates to one out of every ten adults in America having a current substance use disor-
der and one out of every three people having a substance use disorder in their
lifetime. Past-year rates of nicotine dependence are found in 14.0% of the adult US
population as well [6].

Diagnosing a Substance Use Disorder

Clinically, we make the diagnosis of a substance use disorder based on the follow-
ing criteria set forth by the American Psychiatric Association’s Diagnostic and
Statistical Manual of Mental Disorders (DSM-5). To meet the criteria for substance
use disorder, the person must meet at least two criteria within the same 12-month
period [7]. The DSM-5 further allows clinicians to specify how severe or how much

J. E. Grant (*)
Department of Psychiatry and Behavioral Neurosciences, University of Chicago,
Chicago, IL, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 1

Switzerland AG 2024
K. Karamchandani, J. E. Grant (eds.), Substance Use Disorders in Adult
Critically Ill Patients, https://doi.org/10.1007/978-3-031-67069-5_1
2 J. E. Grant

of a problem the substance use disorder is, depending on how many symptoms are
identified. Two or three symptoms indicate a mild substance use disorder, four or
five symptoms indicate a moderate substance use disorder, and six or more symp-
toms indicate a severe substance use disorder.

Substance Use Disorder Criteria (Adapted from the DSM-5) [7]

The clinician using these criteria should first make sure a specific time period is
being referenced. That is, does the patient endorse these symptoms within the past
12 months (i.e., a current problem) or ever during their lifetime? These criteria
should be used separately for each substance that the person reports using. For
example, all 11 symptoms should be examined for alcohol and then separately for
cocaine, etc. The result of this assessment is that a person could have several sub-
stance use disorders, such as alcohol use disorder, cocaine use disorder, etc. As each
substance necessitates different interventions, it is important to diagnose which sub-
stance use disorders the person has.
1. The person takes the substance in larger amounts or for longer than intended.
2. They try unsuccessfully to cut down on or stop using the substance.
3. They spend a lot of time trying to acquire, use, or recover from the substance.
4. The person reports cravings and urges to use the substance.
5. They fail to fulfill obligations at work, home, or school because of substance use.
6. Even when substance use results in relationship problems, they continue
to use it.
7. They abandon important social, occupational, or recreational activities because
of substance use.
8. They use the substance even when it puts them in danger.
9. Even when you know you have a physical or psychological problem that could
have been caused or made worse by the substance, they continue to use it.
10. The amount of the substance increases over time to get the desired effect.
11. They experience withdrawal symptoms.
The DSM-5 criteria for substance use disorders is the gold standard, but many
research reports and clinical settings may prefer to screen for alcohol and drug use
disorders with shorter measures and then have mental health professionals do a
follow-up assessment for any patient with a positive substance use disorder screen.

Prevalence of Substance Use Disorders in Medical Settings

As common as these problems are in the general population, data show that the rates
of substance use disorders are even more frequently found in medical populations.
In primary care settings, 20–30% of patients can be expected to have some current
1 Epidemiology and Impact of Substance Use Disorders on the Intensive Care Unit 3

level of problem use of alcohol, and approximately 5–10% of patients have a current
substance use disorder [8–10]. In hospital settings, the problems with substances are
generally higher, with rates of current alcohol use disorder ranging as high as
19–50% and rates of current drug use disorders ranging from 12% to 15% [11–14].

Screening for Substance Use Disorders in Medical Settings

Because rates of substance use disorders are higher in medical settings compared to
the overall population, screening for use problems should be considered in all hos-
pital settings, including the emergency department and the intensive care units.
Emergency room screening is recommended by the American College of Emergency
Physicians, and as this may be the point of contact before the patient is admitted to
an intensive care unit (ICU), the screening in the emergency department may assist
with more appropriate treatment planning in the ICU. Ideally, a positive screen
should be followed by a more detailed diagnostic assessment by trained mental
health staff.
On a practical level, there are several measures that could be used in hospital
settings, including the ICU, to screen for substance use problems. A couple of the
most commonly reported instruments that are easy to use in an ICU to screen for
alcohol and drug use in adults are the AUDIT and the DSAT-10. The Alcohol Use
Disorders Identification Test (AUDIT) [15] is perhaps the most widely used screen-
ing tool for alcohol use. Instead of only screening for a formal alcohol use disorder,
the measure screens for unhealthy use and provides a level of risk that the person
meets (a score of ≥8 also suggests an alcohol use disorder). The most-used version
has ten items and takes a couple of minutes to administer. In terms of screening for
unhealthy drug use (or a substance use disorder), the most widely used measure is
the Drug Abuse Screening Test (DSAT-10) [16]. It also consists of ten questions and
takes only a few minutes to administer (a score of ≥3 also suggests a substance use
disorder).
Screening in a hospital setting, such as an emergency department or ICU, is
likely to result in a higher proportion of patients who screen positive, identify more
severe substance use, and be associated with complex psychiatric and medical
comorbidities compared to outpatient settings. Of course, screens are not the same
as diagnostic measures, and they are intended to over-identify problems. Clinicians
need to be aware of the limitations of these instruments and follow-up positive
screens with more detailed assessments.
The goals of screening in the ICU, for example, will also differ from those in
outpatient settings. At minimum, ICUs should screen to identify patients at high risk
for acute withdrawal or for procedural complications related to their substance use.
Screening in the ICU can also identify patients with substance use disorders who
need medications or ongoing treatment post-discharge. When substance use disor-
ders are identified by screening, ICUs may also afford themselves, where available,
of addiction consult services, which typically involve a team-based approach to
4 J. E. Grant

managing patients in the hospital and engaging them in post-discharge treatment

and harm reduction services. Controlling the substance use disorder post-discharge
is more likely to ensure the patient will also follow up with post-discharge medical
care for whatever complex health problem was the reason for the ICU admission.
This in turn should reduce readmission for the same problem or for complications.

Substance Use Disorders in the Intensive Care Unit

The epidemiology of substance use disorders in ICUs is largely unknown. As emer-

gency departments tend to have higher rates of substance use disorders than in the
general population, we might expect rates to be higher in ICUs as well, and some
data support this heuristic. Using 2016–2017 emergency department data from the
National Hospital Ambulatory Medical Care Survey, Zhang and colleagues exam-
ined adults with and without a substance use disorder and found that people seen in
emergency departments who had substance use disorders were more likely to be
hospitalized and admitted to the ICU (they were also more likely to experience
homelessness, suffer from mental illness, and require ambulance services) [17].
One study reported that approximately 16–31% of patients in ICUs have an alcohol
use disorder [18], which is higher than the current rate of 13.9% in the general popu-
lation [4]. Estimates from one community hospital, however, reported that 14% of
ICU admissions were non-tobacco substance-related [19], a rate similar to the gen-
eral population [4]. Another study found that 19% of ICU admissions in New York
City were due to alcohol and drug intoxication [20]. This study did not report rates
of substance use disorders but instead examined any level of unhealthy alcohol or
drug use. Another study found that of their mechanically ventilated patients in the
ICU, 39% had a substance use disorder [21].
Based on the available research, ICUs constitute a setting where clinicians will
have to be aware of and willing to manage a range of problems associated with
substance use disorders as well as misuse of alcohol and drugs (i.e., use that may not
be at the level of a substance use disorder but necessitates medical attention due to
the health consequences of the substance use).

Not All Substance Use Is a Substance Use Disorder

Of course, not all alcohol and drug use meets the diagnostic criteria for a substance
use disorder, and yet it can still impact patient care and outcomes. In fact, the screens
mentioned above were created to also examine levels of use that might be below the
severity of a substance use disorder but may still necessitate interventions as this
can cause some problems for the person. Thus, there are gradients of use from no
use to non-harmful recreational use, to misuse of drugs or alcohol (this might mean
meeting a single criterion for a substance use disorder such as in the case of
1 Epidemiology and Impact of Substance Use Disorders on the Intensive Care Unit 5

hazardous alcohol use), and finally to meeting DSM-5 diagnostic criteria for a sub-
stance use disorder (see above). In an ICU setting, this lower level of substance
misuse will often result in the same acute interventions. The difference between
misuse and a substance use disorder is generally more important for post-discharge
treatment planning.
Even at lower levels of use (often referred to as misuse or hazardous use), how-
ever, alcohol and drugs can lead to ICU admissions and resultant health problems.
Research suggests that prevalence rates of alcohol and drug misuse are actually
higher than the rates of substance use disorders, but oftentimes only come to the
attention of medical professionals when severe health problems occur [22–24]. For
example, hazardous drinking is common among college students in the United
States, with studies documenting prevalence estimates ranging from 33% to 57%
[25]. A Finnish study of 2045 patients admitted to the ICU found that 21% screened
positive for hazardous alcohol use [26]. Similarly, a trend worldwide has seen an
increase in opiate misuse among people who in turn need ICU admissions [27],
often leading to high mortality rates (up to 10%) [28].

 edical Problems Associated with Substance Use

M
in the Intensive Care Unit

Beyond the range of long-term health issues associated with substance use disorders
[29, 30], doctor and nurses in the ICU will often be called upon to manage substance
intoxication and potential withdrawal in many people, even those who do not meet
criteria for a use disorder. Additionally, as each substance results in different clinical
manifestations of intoxication and withdrawal, staff in an ICU need to understand
the clinical presentation of intoxication and withdrawal across a range of substances
(the various chapters of this volume will present the unique issues related to each
substance and management strategies).
One study suggested that approximately 16–31% of patients in an ICU are at risk
for developing alcohol withdrawal syndrome, and this is likely the most common
substance seen in ICU admissions [18]. Patients admitted to the ICU with alcohol
withdrawal tend to have longer ICU stays, a longer duration of mechanical ventila-
tion, higher costs, and increased mortality compared with those admitted who do
not go through alcohol withdrawal [18].
Medical management of substance use disorders is not confined to the intoxica-
tion or withdrawal from the misused substance. There are substantial health comor-
bidities related to chronic drug and alcohol misuse that often need to be managed in
the ICU, such as gastrointestinal bleeding due to alcohol misuse. Available data
demonstrate that substance use problems are major risk factors associated with poor
ICU outcomes. Patients in the ICU are more likely to experience delirium, which in
turn complicates the management of comorbid health conditions [31]. In a large
(n = 11,651) study of adult admissions to two urban ICUs, the researchers found
that 12.2% had a diagnosis consistent with alcohol dependence, and those patients
6 J. E. Grant

had higher rates of sepsis, organ failure, septic shock, and hospital mortality (a two-­
fold increased risk) [32].

 ental Health Problems Associated with Substance Use

M
in the Intensive Care Unit

Because substance use disorders are highly comorbid with multiple psychiatric dis-
orders [33], medical management of the substance problem in the ICU will further
require the management of an array of mental health problems as well.
Rates of depression, anxiety, personality disorders, suicidality, psychosis, and
bipolar disorder are all elevated in people who struggle with substance use disorder
compared to the general community [34, 35] and may present unique challenges to
the staff in the ICU. Although a detailed assessment and treatment plan for these
comorbid psychiatric disorders will be presented in a later chapter, suffice it to say
that consultation with mental health providers is often necessary during the ICU stay.

Costs of Substance Problems in the Intensive Care Unit

Substance problems in the ICU are costly to the healthcare system, but determining
how costly is not always clear or easily done. An early 1993 study reported that 28%
of ICU admissions over a 15-week period at Johns Hopkins Hospital were related to
substance abuse and accrued 39% of the hospital costs for that period [36]. A more
recent study of 611 ICU admissions over a 6-month period found that 25.7% of
admissions were related to substance abuse and accrued 23.1% of total hospital
charges, and more specifically, illicit drug-related admissions accounted for 13.1%
of admissions associated with 11.1% of total hospital charges, while alcohol
accounted for 9.7% of admissions and represented 7.8% of total charges [37]. In
2006, the estimated hospital costs for treatment of alcohol-related issues exceeded
$5 billion, but the total estimated economic cost of excessive drinking exceeded
$220 billion [38]. Another study found that in a 6-month period, alcohol and drug
abuse patients accrued over 7 million US dollars, largely in ICU admissions, and
that over 50% of this cohort were either admitted to Medicaid/managed care or
obtained emergency Medicaid in hospital [20].
Even patients who do not have a substance use disorder but simply misuse alco-
hol or drugs still seem to increase healthcare costs. In a study examining several
thousand patients in a national quality registry database for ICUs, the authors found
that intoxicated patients admitted to the ICU had in the year before and after ICU
admission much higher median healthcare costs per day compared to other ICU
patients and a general population control group [39]. Several studies from hospitals
1 Epidemiology and Impact of Substance Use Disorders on the Intensive Care Unit 7

around the world have found that the annual costs of drug and alcohol intoxication
cost, on average, several million dollars per year per hospital [40–42].

Treatment in the ICU

Hospital-based addiction treatment can dramatically improve the health outcomes

of hospitalized patients with substance use disorders and should begin in the
ICU. Treatment for the various substance problems will be the focus of chapters
within this volume. The vast majority of individuals with substance use disorders
do not feel that they need treatment, with only 12.5% of people with substance use
disorders perceiving a need for treatment [43]. In trauma patients, a formal dis-
cussion with their medical providers about their alcohol use, screening for alcohol
problems, and a discussion of how their alcohol use contributed to their injury has
been shown to significantly decrease recidivism in these patients for traumatic
injuries associated with alcohol use. The acuity and direct correlation of the two
problems (alcohol use and their injury) have been hypothesized to be a “teachable
moment” with a greater chance of initiating change. Substance misuse that leads
to an ICU admission is therefore an opportunity for medical providers to use the
life-­threatening medical problem to help patients with substance problems recog-
nize the issue, which may be an impetus for seeking treatment or behavioral change.

Treatment After the ICU

Although chapters in this book will discuss post-discharge planning, it is important to

note that discharge planning protocols, including medication-assisted treatment, for
patients admitted with substance problems may reduce subsequent emergency room
visits and 30-day rehospitalization. The addition of pharmacotherapy to psychosocial
treatment in patients with alcohol problems has been shown to improve outcomes.
Similarly, in patients admitted with opioid misuse, in-patient initiation of opioid ago-
nist therapy and early discharge planning may reduce rates of AMA discharge and
increase the likelihood of transfer to long-term out-patient addiction treatment.
Acknowledgment of Assistance None.

Previous Presentation None.

Relevant Financial Relationships Dr. Grant has received research grant support
from NIDA, Biohaven, and Janssen Pharmaceuticals. He receives yearly compensa-
tion from Springer Publishing for acting as Editor-in-Chief of the Journal of
Gambling Studies and has received royalties from Oxford University Press,
American Psychiatric Publishing, Inc., Norton Press, and McGraw Hill.
8 J. E. Grant

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Chapter 2
Alcohol Abuse Disorder: Alcohol
Withdrawal Syndrome

Deepali Dixit, Marissa Grillo, Jessica Hu, and Maria Cardinale-King

Introduction

Alcohol use disorder is a prevalent issue, affecting around 28.6 million adults, and
is especially common among those who are hospitalized [1, 2]. Patients with alco-
hol use disorder are at risk for alcohol withdrawal syndrome (AWS), which may
require admission to the intensive care unit (ICU) [3]. AWS poses significant chal-
lenges in the ICU due to its potential for severe complications. Patients admitted to
the ICU with AWS have a higher mortality rate, longer ICU stays, a longer duration
of ventilator support, and higher costs compared with patients without AWS [4, 5].
A substantial proportion of ICU admissions are related to alcohol abuse. The inci-
dence of AWS in the ICU varies, but estimates range from 20% to 30% of patients
with alcohol dependence [2, 3]. AWS encompasses a spectrum of symptoms that
develop after either sudden cessation or abrupt reduction of alcohol intake in long-­
term alcohol users [6]. Symptoms can range from mild, such as anxiety and tremors,
to severe or fatal, including delirium tremens (DTs) and seizures, which occur in
approximately 20% of patients admitted to the hospital with AWS [7, 8]. AWS is
associated with up to 10% of annual Medical ICU (MICU) admissions [9], and the
burden associated with this diagnosis exceeds 250 billion US dollars annually [10].
One of the goals of AWS treatment is to prevent the occurrence of the most
severe symptoms in high-risk patients. Early identification and treatment are vital in
reducing the risk of progressing to severe AWS [11]. Unfortunately, this history can
be difficult to obtain for critically ill patients who may not be able to communicate

D. Dixit (*) · J. Hu · M. Cardinale-King

Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey,
Piscataway, NJ, USA
e-mail: [email protected]
M. Grillo
Hackensack University Medical Center, Hackensack, NJ, USA

© The Author(s), under exclusive license to Springer Nature 11

Switzerland AG 2024
K. Karamchandani, J. E. Grant (eds.), Substance Use Disorders in Adult
Critically Ill Patients, https://doi.org/10.1007/978-3-031-67069-5_2
12 D. Dixit et al.

and who may not have a proxy to provide the information. Patients with a history of
prior withdrawal, seizures, or DTs, or those consuming alcohol while being treated
for alcohol use disorder, are at a greater risk for withdrawal [3].
With advancements in medical care and pharmacotherapy options, most patients
survive AWS acutely [12]. However, many patients remain at risk after the acute
AWS episode has subsided because of alcohol use after discharge. Approximately
44% of ICU patients who survive AWS are rehospitalized at least once or experi-
ence death within a year [13].

Pathophysiology of AWS

The pathophysiology of AWS involves several interconnected mechanisms, and

some of the key aspects are described here. Ethanol’s primary action on the central
nervous system (CNS) is mediated by the disruption of two major neurotransmitter
pathways: the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and
the excitatory neurotransmitter glutamate, which binds to the N-methyl-D-aspartate
(NMDA) receptor [5, 14].
1. Neuroadaptation: Chronic alcohol use leads to neuroadaptation, where the brain
adjusts its functioning to compensate for the presence of alcohol. The brain
becomes more excitable, and the GABA receptors are upregulated to counteract
alcohol’s sedating effects.
2. GABAergic and Glutamatergic Systems: With the sudden cessation of alcohol,
the upregulated GABA system continues to function, causing an imbalance
between inhibitory and excitatory neurotransmitters. The chronic suppression of
the excitatory neurotransmitter glutamate due to alcohol’s inhibitory effects is
suddenly unopposed, leading to hyperexcitability.
3. Excitatory Hyperactivity: The unopposed glutamate activity triggers excit-
atory hyperactivity, resulting in symptoms such as anxiety, restlessness, trem-
ors, and seizures. This hyperactivity can also contribute to increased
sympathetic nervous system activity, leading to elevated heart rate, blood pres-
sure, and diaphoresis.
4. Withdrawal Seizures: Alcohol withdrawal seizures are thought to result
from hyperexcitability in the brain, primarily involving the limbic system
and the kindling effect. Kindling refers to the phenomenon where repeated
alcohol withdrawals lead to an increased risk and severity of subsequent
seizures.
5. Alcohol Withdrawal Delirium (Delirium Tremens): In severe cases, AWS can
progress to delirium tremens (DTs). The exact mechanisms behind DTs are not
fully understood, but they involve complex interactions between neurotransmit-
ters, neuroinflammation, and imbalances in the brain’s reward system. DTs are
characterized by severe confusion, hallucinations, and cardiovascular instability
and can be life-threatening.
2 Alcohol Abuse Disorder: Alcohol Withdrawal Syndrome 13

Table 2.1 Stages of alcohol withdrawal symptoms [3, 15, 16]

Time since the last alcoholic
Stage drink Signs and symptoms
1 6–24 hours Tremor
Autonomic activity
Insomnia/agitation
Tachypnea/hyperventilation
Headache
Sweating
Anorexia/nausea/vomiting
2 7–48 hours Distractibility, tonic-clonic seizures (10% of patients)
Visual, tactile, or auditory hallucinations (30% of
patients)
Autonomic instability
Diarrhea
3 49–96 hours Intense tremor ➔ delirium tremens (5% of patients [25%
mortality].)
Severe autonomic instability
Confusion/disorientation/extreme agitation

Clinical Presentation

AWS represents a continuous spectrum of symptoms, ranging from mild symptoms

to DTs. The clinical presentation of AWS is individualized and influenced by the
patient’s intake pattern, comorbidities, and genetics [11]. While some patients may
not exhibit any symptoms, others may experience mild ones like insomnia, and
some may even develop severe AWS, which can include DTs [11]. The signs and
symptoms of AWS are well-defined. It is believed that they occur in stages, although
not every patient experiences a symptom in each stage. (Table 2.1) [15]. DTs are the
longest-lasting symptom of AWS and may occur as long as ten days after the onset
of AWS and may last for up to five days [15]. They are more likely to occur in
patients with a history of DTs and those who have low albumin levels, are hypoten-
sive, are tachycardic, have a high blood urea nitrogen level, or have a coexisting
medical illness [15]. DTs are a rare, serious complication of AWS associated with
disorientation and profound autonomic symptoms such as tachycardia, severe agita-
tion, fever, and hypertension [15].

Screening Tools

Symptom-triggered benzodiazepine protocols are the standard of care for the treat-
ment of AWS [16] because they have been shown to reduce benzodiazepine use and
total treatment time compared to fixed-dose protocols [17, 18]. The Clinical Institute
of Withdrawal Assessment for Alcohol, revised (CIWA-Ar), is the most common
symptom-triggered assessment tool [19]. However, the CIWA-Ar is a ten-item
14 D. Dixit et al.

instrument and relies on many subjective symptoms (e.g., anxiety, headache, nau-
sea); therefore, shorter and more objective scales may be helpful. Nine of the ten
CIWA-Ar items are scored using a broad 0–7 scale, raising concern for interrater
variability. Moreover, because of the subjective items, CIWA-Ar cannot be used on
patients who are delirious or cannot communicate. Once AWS occurs, early and
frequent assessment of symptoms is necessary to avoid potential complications
such as seizures. Several withdrawal and objective sedation-agitation scales have
been used to rate the severity of symptoms in patients experiencing AWS. The
revised CIWA-Ar and the Riker Sedation-Agitation Scale (SAS) are the most fre-
quently used tools for this purpose. Based on the available evidence, combining the
use of the CIWA-Ar tool in patients capable of communication and SAS to titrate
benzodiazepines for agitation symptoms in ICU patients that are unable to commu-
nicate may be the best approach to match medication dosing with symptom severity
to improve outcomes. The Richmond Agitation-Sedation Scale (RASS) has also
been used to titrate benzodiazepines and other agents in patients with severe AWS,
including those requiring mechanical ventilation [20].

Supportive Care

Clinicians must be aware of the complications that can develop in a patient during
withdrawal to provide appropriate management. The goals of care are to alleviate
AWS symptoms, prevent symptom progression, and treat underlying comorbidities.
Adequate fluid resuscitation is particularly vital, as individuals with a history of
alcoholism frequently experience intravascular depletion [5, 14]. Electrolyte defi-
ciencies are common in this population and require vigilant monitoring and replace-
ment [5, 14, 15]. Correcting these abnormalities may take several days of
supplementation, depending on the patient’s intracellular depletion. Electrolyte lev-
els should be monitored at least every day, although patients with more severe defi-
ciencies may require multiple checks within the day. Patients may be anemic due to
folate and/or vitamin B12 deficiencies secondary to inadequate nutritional intake
and require administration with one or both supplements. Decreased nutritional
intake also leads to thiamine deficiencies. Although the acuity of mild folate defi-
ciency is modest, thiamine deficiency can lead to Wernicke encephalopathy.
Wernicke encephalopathy is a neurological disorder caused by thiamine deficiency
[5, 14]. It can lead to various neurological symptoms and is usually associated with
chronic alcoholism [5, 14]. In most alcoholic patients, oral absorption of thiamine
is erratic. Initially, parenteral administration of thiamine 500 mg every hour is rec-
ommended [14]. A standard multivitamin and folate of 1 mg is also usually admin-
istered concurrently in a liter of normal saline daily for ~3 days.
Complications related to AWS also affect other areas of critical care manage-
ment. Patients may have or develop gastritis, gastrointestinal bleeding, or pancreati-
tis that could decrease the absorption of oral medications. The management of
pancreatitis generally would prevent the acute use of oral therapy [15]. AWS-related
2 Alcohol Abuse Disorder: Alcohol Withdrawal Syndrome 15

organ dysfunctions, such as liver dysfunction or cardiomyopathy, influence drug

selection and dosing. Finally, because alcoholics are at greater risk for aspiration,
elevation of the head of the bed to prevent aspiration and pneumonia is
recommended.

Management of Alcohol Withdrawal Syndrome

Benzodiazepines

Benzodiazepines first gained their recognition for the treatment of alcohol withdrawal
in a landmark study where chlordiazepoxide was determined to be the most effica-
cious in preventing seizures against three other drugs: chlorpromazine, hydroxyzine,
and thiamine [21]. Since then, benzodiazepines have traditionally been the mainstay
of treatment for alcohol withdrawal syndrome [22]. Benzodiazepines exert their
effects by enhancing GABA receptor function, promoting the receptor to stay open,
and allowing the influx of chloride ions into the neuron. This inhibitory effect reduces
the severity of withdrawal, preventing delirium and seizures. They are effective,
cheap, and conveniently can be dosed according to a fixed schedule, where the benzo-
diazepine is given at specific times throughout the day and additional as needed doses
are available, or a symptom-triggered schedule, where the benzodiazepine is given
according to the results of alcohol withdrawal scales performed. There is limited lit-
erature on whether a fixed or symptom-­triggered dosing schedule is preferable for
treating patients with alcohol withdrawal syndrome in an intensive care unit [23]. As
benzodiazepines have exhibited treatment success for this disease state, they do not
come without risks. Benzodiazepines have the potential for addiction, and depen-
dence can result from their use. High-­dose benzodiazepine therapy can lead to overse-
dation, respiratory depression, and even delirium [24].
There are many different medications in the class of benzodiazepines that can be
utilized for alcohol withdrawal syndrome. The first benzodiazepine discovered, chlor-
diazepoxide, continues to be a popular choice for treating alcohol withdrawal syn-
drome due to its long half-life of up to 48 hours, along with diazepam, another
long-acting benzodiazepine. Shorter-acting benzodiazepines such as lorazepam,
oxazepam, and midazolam have also been used to manage alcohol withdrawal syn-
drome; however, the longer-acting benzodiazepines may provide a smoother with-
drawal with their self-tapering effect. Despite that observation, there is insufficient
data to prove that one benzodiazepine is superior to the other [25, 14]. Other attributes
can then aid in determining which benzodiazepine to choose for specific patients, such
as liver function, as well as half-life, onset of action, and cost of the drug [26]. In a
2022 meta-analysis on the different pharmacotherapies used in treating alcohol with-
drawal syndrome, fixed-schedule lorazepam, diazepam, and chlordiazepoxide were
superior to placebo at reducing seizure complications from alcohol withdrawal. Fixed-
schedule diazepam was shown to reduce the incidence of delirium tremens, and fixed-
schedule oxazepam improved endpoint CIWA scores over placebo [27].
16 D. Dixit et al.

The optimal dosing protocol for benzodiazepines to treat alcohol withdrawal syn-
drome in an intensive care unit has not yet been established. In a retrospective observa-
tional study conducted in the intensive care unit, intermittent lorazepam injections
versus the institutional standard of continuous infusion midazolam resulted in decreased
time to symptom control, a decreased amount of sedative agent required, and decreased
time spent using a benzodiazepine [25]. When comparing fixed versus symptom-trig-
gered dosing strategies in an intensive care unit, a before-and-after study showed that a
symptom-triggered benzodiazepine dosing strategy was shown to result in a reduced
duration of alcohol withdrawal symptoms, need for mechanical ventilation, and ICU
and hospital length of stay [23]. In a non-­randomized controlled trial, symptom-trig-
gered benzodiazepine dosing also reduced alcohol-dependence relapse and cost [28].
Benzodiazepines still prove to be an efficacious treatment for alcohol withdrawal
syndrome in critically ill patients. There are many options that providers can utilize
while taking patient-specific characteristics into account due to the number of medi-
cations in the class as well as the different regimens that have been proven to be
successful for inpatient treatment. However, reports of benzodiazepine-refractory
alcohol withdrawal syndrome continue to arise, warranting the need for other treat-
ment options for alcohol withdrawal syndrome to be studied.

Phenobarbital

Phenobarbital, a medication in the class of barbiturates, is gaining interest in patients

with severe AWS that is refractory to first-line benzodiazepine treatment [29].As there
is limited literature on the dose of benzodiazepine that determines refractory-­AWS, or
benzodiazepine failure, a cohort of 19 patients points to an excess of 50 mg of diaze-
pam or 10 mg of lorazepam in the first hour, or an excess of 200 mg diazepam or
40 mg of lorazepam within four hours of treatment initiation, as possible thresholds
[30]. Another retrospective cohort study of 54 patients considered refractory AWS to
be an excess of 40 mg of diazepam needed in one hour, up to 150 mg per dose [31].
Phenobarbital acts on GABA receptors, binding to an allosteric site that allows for
inhibition of the receptor without the presence of the GABA neurotransmitter. This
increases the duration that the GABA chloride channel is opened for. Along with phe-
nobarbital’s long half-life and additional inhibitory effect on glutamate receptors, it
can offer advantages over traditional benzodiazepine therapy, especially with the
increasing need to escalate doses [32]. However, it is important to note that phenobar-
bital should not be used in patients with hepatic encephalopathy, liver failure, or con-
comitant drugs that are metabolized by cytochrome P450 3A4.
Phenobarbital presents itself as an attractive choice for monotherapy in treating
AWS. It produces no active metabolites and has a half-life of a mean average of
80 hours, eliminating the need to slowly taper the regimen [33]. As serum levels can
be measured, therapy with phenobarbital can be tightly controlled and adjusted as
needed. Phenobarbital can be given intravenously, intramuscularly, or orally, and its
low cost attributes to its popularity in treating AWS. In a retrospective observational