Make The Diagnosis - Severe Alcohol Withdrawal Syndrome

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The Rational Clinical Examination: EvidenceBased Clinical Diagnosis
Severe Alcohol Withdrawal Syndrome
David L. Simel
Make the Diagnosis: Severe Alcohol Withdrawal Syndrome

David L. Simel
Prior Probability of Severe Alcohol Withdrawal Syndrome
The incidence of alcohol withdrawal syndromes in hospitalized patients varies widely as a function of the patient population, care setting, and the reason for hospital admission.
About onehalf of patients who are longterm, heavy alcohol users will develop at least mild withdrawal symptoms when they stop drinking. The more significant symptoms of
hallucinations occur in 2% to 8% of patients, with 10% of those symptomatic patients affected by seizures. Among patients admitted specifically for alcohol withdrawal, the
incidence of severe alcohol withdrawal is 23% (95% CI, 20%27%).
For those admitted to general medical units who are at risk for alcohol withdrawal (defined as an Alcohol Use Disorders Identification TestConsumption [AUDITC] score > 8), the
incidence of any alcohol withdrawal syndrome is 1.9% (95% CI, 1.2%3.1%), though patients admitted with a blood alcohol level > 200 mg/dL, or a history of any drinking in the
prior 30 days, have an incidence of 6.7% (4.6%9.6%). Patients admitted after trauma are a particular concern because an accurate alcohol history may not be obtainable, but the
overall incidence of severe alcohol withdrawal syndrome among consecutive trauma patients is only 0.40% (95% CI, 0.33%0.48%).
Population of Hospitalized Patients Among Whom Alcohol Withdrawal Syndrome Should Be Considered
All hospitalized patients should be screened for atrisk or heavy drinking so that measures can be taken to lower the risk of severe alcohol withdrawal syndrome. A definition of at
risk or heavy alcohol use would be consumption of 4 drinks on any day or 14 drinks/week for men, or more than 3 drinks on any day or 7 drinks/week for women.1 When atrisk
patients are identified, the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) is used to measure the severity of withdrawal symptoms, and protocol that includes the
administration of benzodiazepine prophylaxis has been associated with a reduced incidence of delirium tremens (–4.9 cases per 100 patients) and seizures (–7.7 seizures per 100
patients).2
Assessing the Likelihood of Alcohol Withdrawal Syndrome
A prior history of delirium tremens is the finding that is both studied best (3 studies) and that is associated with increased likelihood of delirium tremens (likelihood ratio [LR], 2.9;
95% CI, 1.75.2; see Table 1051). A history of substance use disorders other than alcohol have been associated with increased risk of severe alcohol withdrawal syndrome (LR, 6.4;
95% CI, 1.234), but this risk factor was reported in only 1 highquality study. The presence of a blood alcohol level > 200 mg/dL (LR, 3.5; 95% CI, 3.04.0) is associated with increased
likelihood of any symptoms of alcohol withdrawal syndrome.
Table 1051.
Useful Findings for Assessing the Likelihood of Alcohol Withdrawal Syndrome
LR+ (95% CI) LR– (95% CI)
Single Findings
Substance use disorder, other than alcohol (1 study; for predicting severe alcohol withdrawal) 6.4 (1.234) 0.94 (0.851.0)
Blood alcohol level > 200 mg/dL (1 study; for alcohol withdrawal symptoms) 3.5 (3.04.0) 0.61 (0.550.67)
Prior delirium tremens (3 studies; for predicting delirium tremens) 2.9 (1.75.2) 0.78 (0.670.91)
Combination Finding
Prediction of Alcohol Withdrawal Severity Scale score ≥ 4 (1 study; for predicting severe alcohol withdrawal) 174 (43696) 0.07 (0.020.26)
Because individual findings do not reliably distinguish the patients who will have alcohol withdrawal syndrome from those who will not, combinations of findings are often used
after patients are assessed as being atrisk or heavy alcohol users. The Prediction of Alcohol Withdrawal Severity Scale (PAWSS; see Table 1051 and Box 1051) has been reported
in only 1 highquality study. In that study, the LR for a PAWSS score of ≥ 4 is very high (LR, 174; 95% CI, 43696), but the confidence intervals around this LR are wide and there may
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the presence of autonomic symptoms is part of the score. Nonetheless, a PAWSS score ≥ 4 could be useful for identifying patients who
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because these patients are at high risk for severe alcohol withdrawal syndrome. Those with a PAWSS score < 4 (LR, 0.07; 95% CI,Page
L. Simel 1 / 41
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alcohol withdrawal.
Box 1051.
Prediction of Alcohol Withdrawal Severity Scale score ≥ 4 (1 study; for predicting severe alcohol withdrawal) Pontificia 174
Universidade
(43696) Catolica de Campinas
0.07 (0.020.26)
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Because individual findings do not reliably distinguish the patients who will have alcohol withdrawal syndrome from those who will not, combinations of findings are often used
after patients are assessed as being atrisk or heavy alcohol users. The Prediction of Alcohol Withdrawal Severity Scale (PAWSS; see Table 1051 and Box 1051) has been reported
in only 1 highquality study. In that study, the LR for a PAWSS score of ≥ 4 is very high (LR, 174; 95% CI, 43696), but the confidence intervals around this LR are wide and there may
be incorporation bias in this LR because the presence of autonomic symptoms is part of the score. Nonetheless, a PAWSS score ≥ 4 could be useful for identifying patients who
should be placed on a CIWA protocol because these patients are at high risk for severe alcohol withdrawal syndrome. Those with a PAWSS score < 4 (LR, 0.07; 95% CI, 0.020.26) are
much less likely to develop severe alcohol withdrawal.
Box 1051.
Prediction of Alcohol Withdrawal Severity Scale4, a
Part A: Threshold criteria (yes or no; if "yes," proceed with questions)

Has the patient consumed any amount of alcohol (ie, been drinking) within the last 30 days?
OR, did the patient have a positive blood alcohol level upon admission?
Part B: Based on patient interview (positive findings get 1 point each)
1. Has the patient ever experienced previous episodes of alcohol withdrawal?
2. Has the patient ever experienced alcohol withdrawal seizures?
3. Has the patient ever experienced delirium tremens?
4. Has the patient ever undergone alcohol rehabilitation treatment?
5. Has the patient ever experienced blackouts?
6. Has the patient combined alcohol with "downers" like benzodiazepines or barbiturates during the last 90 days?
7. Has the patient combined alcohol with "downers" like benzodiazepines or barbiturates during the last 90 days?
Part C: Based on clinical evidence (positive findings get 1 point each)

8. Blood alcohol level on presentation > 200?
9. Increased autonomic activity (eg, heart rate greater than 120 bpm, tremor, sweating, agitation, nausea)?
aAdapted and published with permission from Oxford University Press.
Reference Standard Tests
The diagnostic criteria for alcohol withdrawal are defined by the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM5).3 All 4 findings must be present.
A. Cessation of alcohol use that has been heavy and prolonged
B. Two or more of the following, developing within several hours to a few days after cessation of (or reduction in) alcohol use described in criterion A
1. Autonomic hyperactivity
2. Increased hand tremor
3. Insomnia
4. Nausea or vomiting
5. Hallucinations
6. Psychomotor agitation
7. Anxiety
8. Generalized tonicclonic seizures
C. The symptoms in criterion B cause clinically significant distress
D. Symptoms or signs not better explained by another condition
References
1. National Institute on Alcohol Abuse and Alcoholism. Rethinking drinking: alcohol and your health. Bethesda, MD: National Institutes of Health; 2016. NIH publication 153770.
https://pubsniaaanih.ez128.periodicos.capes.gov.br/publications/rethinkingdrinking/rethinking_drinking.pdf. Published 2010. Revised May 2016. Accessed February 2, 2018.
2. MayoSmith MF; American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. Pharmacological management of alcohol
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withdrawal: a metaanalysis and evidencebased practice guideline. JAMA . 1997;278(2):144–151. Medline:9214531 [PubMed: 9214531]
Severe Alcohol Withdrawal Syndrome, David L. Simel Page 2 / 41
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3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM5TM . 5th ed. Arlington, VA: American Psychiatric Publishing Inc; 2013.
4. Maldonado JR, Sher Y, Das S, et al. Prospective validation study of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) in medically ill inpatients: a new scale for the
References Pontificia Universidade Catolica de Campinas
Access Provided by:
1. National Institute on Alcohol Abuse and Alcoholism. Rethinking drinking: alcohol and your health. Bethesda, MD: National Institutes of Health; 2016. NIH publication 153770.
withdrawal: a metaanalysis and evidencebased practice guideline. JAMA . 1997;278(2):144–151. Medline:9214531 [PubMed: 9214531]
prediction of complicated alcohol withdrawal syndrome. Alcohol Alcohol . 2015;50(5):509–518. Medline:25999438 [PubMed: 25999438]
Original Article: Will This Hospitalized Patient Develop Severe Alcohol Withdrawal Syndrome?
Evan Wood, Loai Albarqouni, Stacey Tkachuk, Carolyn J. Green, Keith Ahamad, Seonaid Nolan, Mark McLean, Jan Klimas
Clinical Scenario
Case
A 67yearold woman was admitted to the emergency department for a minor head laceration that occurred after a fall resulting from alcohol intoxication. She was alert, oriented,
looked well, and had a heart rate of 120/min. Her blood alcohol concentration (BAC) was 210 mg/dL (45.6 mmol/L). She reported drinking 8 beers daily for the past 5 years. She was
previously admitted to residential addiction treatment programs but never saw an addiction medicine physician. She became mildly tremulous during some, but not all, of her
prior attempts at alcohol cessation. She did not have a history of blackouts, withdrawal seizures, delirium tremens, or polysubstance use, including benzodiazepines. Eight hours
after her last drink, she looked well, was no longer intoxicated, and her heart rate was unchanged at 120/min. She was otherwise stable and asked about outpatient addiction
treatment. Although she appeared well, her physicians were concerned about her risk of developing delirium tremens or alcohol withdrawal seizures when she was discharged
home and stopped drinking alcohol. Can risk factors, symptoms, or signs be used to predict the probability of severe alcohol withdrawal syndrome (SAWS)?
Why This Question Is Important
Globally, harmful use of alcohol is responsible for approximately 33 deaths per 100 000 people and 85 million disabilityadjusted lifeyears annually.1 The prevalence of atrisk or
heavy alcohol use tends to be higher among adults actively seeking health care than estimated prevalence rates in the general population.24
One serious consequence of chronic alcohol use is the potential for SAWS when its use is reduced or stopped. SAWS is characterized by intense autonomic and psychological
symptoms and withdrawal seizures, delirium tremens, or both. SAWS can result in substantial morbidity, including aspiration pneumonia, arrhythmia, and myocardial infarction,5
and historically was associated with a mortality rate as high as 15%.6,7 Recently published data suggest that, with more aggressive prevention and management, SAWS is now
associated with mortality rates on the order of a few percent.8 The National Institute on Alcohol Abuse and Alcoholism and the American Psychiatric Association have developed
standardized criteria for atrisk drinking and alcohol withdrawal, respectively (Box 1052).9,11
Box 1052.
Definitions of AtRisk Drinking and Alcohol Withdrawal
AtRisk or Heavy Alcohol Usea
Alcohol consumption that exceeds more than 4 drinks on any day or 14 drinks per week for men, or more than 3 drinks on any day or 7 drinks per week for women
Alcohol Withdrawalb , c
These are the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM5) diagnostic criteria for alcohol withdrawal. All 4 must be present to diagnose alcohol
withdrawal.9
Cessation of (or reduction in) alcohol use that has been heavy and prolonged
Two (or more) of the following, developing within several hours to a few days after cessation of (or reduction in) alcohol use described in Criterion A:
1. Autonomic hyperactivity (eg, sweating or pulse rate greater than 100 bpm)
3. Insomnia
5. Transient visual, tactile, or auditory hallucinations or illusions
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The signs and symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
symptoms and withdrawal seizures, delirium tremens, or both. SAWS can result in substantial morbidity, including aspiration pneumonia, arrhythmia, and myocardial infarction,5
and historically was associated with a mortality rate as high as 15%.6,7 Recently published data suggest that, with more aggressive prevention and management, SAWS is now
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associated with mortality rates on the order of a few percent.8 The National Institute on Alcohol Abuse and Alcoholism and the American Psychiatric Association have developed
standardized criteria for atrisk drinking and alcohol withdrawal, respectively (Box 1052).9,11
Box 1052.
Definitions of AtRisk Drinking and Alcohol Withdrawal
AtRisk or Heavy Alcohol Usea
Alcohol consumption that exceeds more than 4 drinks on any day or 14 drinks per week for men, or more than 3 drinks on any day or 7 drinks per week for women
Alcohol Withdrawalb , c
These are the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM5) diagnostic criteria for alcohol withdrawal. All 4 must be present to diagnose alcohol
withdrawal.9
Cessation of (or reduction in) alcohol use that has been heavy and prolonged
Two (or more) of the following, developing within several hours to a few days after cessation of (or reduction in) alcohol use described in Criterion A:
1. Autonomic hyperactivity (eg, sweating or pulse rate greater than 100 bpm)
3. Insomnia
5. Transient visual, tactile, or auditory hallucinations or illusions
7. Anxiety
8. Generalized tonicclonic seizures
The signs and symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal
from another substance
Delirium
These are the DSM5 diagnostic criteria for delirium. All 5 must be present to diagnose delirium. The criteria for both alcohol withdrawal and delirium must be met to diagnose
alcohol withdrawal delirium, or delirium tremens.
A. A disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment)
B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in
severity during the course of a day
C. An additional disturbance in cognition (eg, memory deficit, disorientation, language, visuospatial ability, or perception)
D. The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of
severely reduced level of arousal, such as coma
E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition,
substance intoxication or withdrawal (ie, due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies
Alcohol Withdrawal Seizure
Typically the generalized tonicclonic type, characterized by rhythmic, yet jerking movement, especially of the limbs10
a US National Institute on Alcohol Abuse and Alcoholism definition.11
bNote that severe alcohol withdrawal is a clinical diagnosis for which a number of definitions were used in the studies reviewed in this article (Supplemental Table 1).
cReprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,9 (Copyright ©2013). American Psychiatric Association. All Rights
Reserved.
To prevent SAWS, various pharmacotherapeutic and programmatic strategies such as inpatient withdrawal management have been developed. Appropriate identification,
prophylaxis, and treatment of withdrawal is essential in reducing morbidity and mortality associated with this disorder. Although SAWS is relatively uncommon and its treatment
costly and risky, the prevalence of atrisk or heavy alcohol use is high, so tools are needed to accurately identify patients at risk of developing SAWS.
Physiologic Basis for Alcohol Withdrawal
The pathophysiology of alcohol withdrawal is incompletely understood. Alcohol is believed to affect the central nervous system (CNS) primarily by facilitating the actions of γ
cReprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,9 (Copyright ©2013). American Psychiatric Association. All Rights
Reserved.
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To prevent SAWS, various pharmacotherapeutic and programmatic strategies such as inpatient withdrawal management have been developed. Appropriate identification,
prophylaxis, and treatment of withdrawal is essential in reducing morbidity and mortality associated with this disorder. Although SAWS is relatively uncommon and its treatment
costly and risky, the prevalence of atrisk or heavy alcohol use is high, so tools are needed to accurately identify patients at risk of developing SAWS.
Physiologic Basis for Alcohol Withdrawal
The pathophysiology of alcohol withdrawal is incompletely understood. Alcohol is believed to affect the central nervous system (CNS) primarily by facilitating the actions of γ
aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. Alcohol increases the inhibitory effects of the GABAA receptor, while also suppressing the brain's
major excitatory neurotransmitter, glutamate, at the NmethylDaspartate (NMDA) receptor.5 Chronic, heavy alcohol use results in adaptive changes of the GABA and glutamate
neurotransmitter systems to compensate for the effects of alcohol on neural pathways and to restore neurochemical equilibrium.12 Sudden cessation of or a significant reduction
in alcohol consumption triggers an acute neurotransmitter imbalance with a rapid decline in inhibitory GABA activity and increased excitatory glutamate and NMDA receptor
activity, resulting in overall CNS hyperactivity and a lower threshold for seizures.12
Symptoms and Signs Predictive for SAWS
Up to 50% of individuals with a history of longterm, heavy alcohol consumption will experience some degree of mild withdrawal when alcohol use is stopped.1315 Symptoms
usually appear during the first 24 hours of abstinence, with autonomic hyperactivity manifesting in tremulousness, racing heart, sweating, nausea, and vomiting. These may be
accompanied by psychological symptoms such as anxiety, restlessness, sleep disturbance, or insomnia. Signs of alcohol withdrawal include diaphoresis, tremor, tachycardia,
hypertension, hyperthermia, and disorientation. Transient visual, auditory, or tactile hallucinations occur in about 2% to 8% of individuals.16,17 While alcohol withdrawal is usually
limited to these signs and symptoms, approximately 10% of symptomatic individuals experience withdrawalrelated generalized tonicclonic seizures.18,19 If left untreated, about
onethird of patients with withdrawal seizures will progress to delirium tremens.20 Delirium tremens is the most serious manifestation of alcohol withdrawal and is characterized
by severe confusion, disorientation, or hallucinations accompanied by severe autonomic hyperactivity.21 Delirium tremens occurs in 3% to 5% of patients who are hospitalized for
the management of alcohol withdrawal.22,23
Universal screening for atrisk or heavy drinking of all patients presenting in acute care settings can identify patients who are at increased risk of alcoholrelated harms, including
SAWS (Box 1052).24,25 Because patients may underreport the amount and frequency of alcohol use, accurately quantifying alcohol intake is important (Supplemental Box 1).
Family members may validate or refute patient reports. Patients meeting criteria for atrisk or heavy drinking should be asked when they last drank. They should be asked about
past alcohol cessation attempts and previous withdrawal symptoms. Given the high prevalence of polysubstance use, patients should be asked about use of other substances.
Complete blood count, electrolytes, liver function tests, and BAC should be obtained when assessing a patient for alcohol withdrawal. The likelihood of progression to more
severe symptoms, seizures, or delirium tremens should be assessed in all patients with alcohol use disorders, even those who are not experiencing withdrawal or whose
symptoms are mild.
This Rational Clinical Examination systematically reviewed the diagnostic accuracy of a range of clinical findings used to predict the risk of severe alcohol withdrawal symptoms,
seizures, and delirium tremens.
Methods
Search Strategy and Quality Review
Eligible studies compared alcohol use history, symptoms of alcohol withdrawal, laboratory findings, and physical examination findings between patients who did or did not
subsequently develop SAWS (Supplemental Table 1). To identify relevant articles, MEDLINE and EMBASE were searched from 1946 to January 2018, using search terms withdrawal,
alcohol drinking, the MESH term substance withdrawal syndrome, and terms previously found to be useful for retrieving diagnostic studies (Supplemental Appendix).26 Additional
studies were identified by searching reference lists of original and review articles. Studies that evaluated patients' past experiences with alcohol, past symptoms of alcohol
withdrawal, and physical examination and laboratory findings were included. Studies were excluded if they only described clinical examination findings for patients with severe
withdrawal. Review papers not reporting original data were also excluded.
Two authors (C.J.G., and S.T. or L.A.) independently reviewed abstracts for inclusion in this analysis and assessed study quality using the levels of evidence from The Rational
Clinical Examination handbook.27 Level 1 indicated the highest quality of evidence and was assigned to studies that used an independent blinded comparison of the symptoms or
signs with a valid criterion standard for more than 150 consecutive patients.27 Level 2 studies were similar to level 1 studies but enrolled fewer than 150 patients. Level 3 studies
enrolled nonconsecutive patients. Level 4 studies used nonindependent comparisons among a convenience sample of patients at risk of having the condition in question. Sources
of bias were also evaluated with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) Tool (Supplemental Table 2).2729
Statistical Methods
The population incidence of severe alcohol withdrawal after alcohol cessation was estimated from reports of the US National Institute on Alcohol Abuse and Alcoholism and the
World Health Organization.14,30,31 The incidence of individual alcohol withdrawal symptoms was estimated from the 14 studies included in this review. The summary incidence was
calculated as a randomeffects estimate from the included studies.
To evaluate the sensitivity, specificity, and likelihood ratios (LRs), 2 × 2 contingency tables were constructed for each symptom and sign. The reliability of symptoms and signs was
quantified with the κ statistic. Data were entered into Microsoft Excel spreadsheets predesigned to calculate the sensitivity, specificity, LRs, and their 95% CIs.32 To create summary
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the standards of level 1, 2, or 3 of The Rational Clinical Examination criteria were included.27
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and measures usedAssociation.
to define SAWSAll Rights
have Reserved.
traditionally involvedTerms
a rangeof
of Use • Privacy
criteria Policy
(Box 1052), • Notice
but the has not been consistent in the literature.33 For the
• Accessibility
definition
purpose of this review, we identified cases of SAWS as determined by individual study authors (Supplemental Table 1). Although delirium tremens and seizures may occur as an
initial presentation, we considered the manifestations of withdrawal along a continuum from mild to severe withdrawal symptoms that may progress to seizures and delirium
Pontificia
The population incidence of severe alcohol withdrawal after alcohol cessation was estimated from reports of the US National InstituteUniversidade
on Alcohol AbuseCatolica de Campinas
and Alcoholism and the
World Health Organization.14,30,31 The incidence of individual alcohol withdrawal symptoms was estimated from the 14 studies
Accessincluded in this review. The summary incidence was
Provided by:
calculated as a randomeffects estimate from the included studies.
To evaluate the sensitivity, specificity, and likelihood ratios (LRs), 2 × 2 contingency tables were constructed for each symptom and sign. The reliability of symptoms and signs was
quantified with the κ statistic. Data were entered into Microsoft Excel spreadsheets predesigned to calculate the sensitivity, specificity, LRs, and their 95% CIs.32 To create summary
measures and limit potential bias, only studies that met the standards of level 1, 2, or 3 of The Rational Clinical Examination criteria were included.27
Rating scales and measures used to define SAWS have traditionally involved a range of criteria (Box 1052), but the definition has not been consistent in the literature.33 For the
purpose of this review, we identified cases of SAWS as determined by individual study authors (Supplemental Table 1). Although delirium tremens and seizures may occur as an
initial presentation, we considered the manifestations of withdrawal along a continuum from mild to severe withdrawal symptoms that may progress to seizures and delirium
tremens. Therefore, if a study reported all 3 outcomes (SAWS, delirium tremens, and seizures), the study result was considered as reporting only an outcome of SAWS to avoid
double counting of events within patients. Similarly, if a study reported SAWS and delirium tremens, only SAWS was counted. Finally, if a study reported both delirium tremens
and seizure, only delirium tremens was counted.
When a symptom or sign was assessed in only 1 highquality study, the LRs and 95% CIs were reported for dichotomous variables or the standardized mean difference (SMD) for
continuous variables. When a symptom or sign was assessed in 2 studies, the range for the LR or SMD was reported.34 When considered in 3 studies, LR data were pooled using a
separate univariate randomeffects metaanalysis,35 and the I2 statistic was reported to supplement the information from the CI about the dispersion of results.36,37
Continuous variables were reported by calculating the SMDs, which reported the differences between patients who developed SAWS and those who did not. The SMD was
calculated by dividing the mean difference between groups by the standard deviation of the measurement.38 Standardized mean differences are unitless, reporting information as
multiples of the standard deviation, facilitating comparisons between groups irrespective of the measurement scale. The greater the absolute value of the SMD, the better the
differentiation between those who will be affected and those who will not. A general suggestion for interpreting the magnitude of the SMD is to recognize that the SMD is an effect
size for which values of approximately 0.2 represent small differences between groups, 0.5 represent moderate differences, and 0.8 or greater indicate potentially large
recognizable differences.39
Results
Search Results
The systematic search identified 530 studies for review, with 50 articles eligible for qualitative synthesis (Supplemental Figure 1). These 50 studies included patients with a
reasonable index of suspicion of alcohol withdrawal risk, ranged in size from 19 to 36, 331 patients, and included research and clinical studies of individuals presenting to alcohol
withdrawal management units and hospitals, both for alcohol withdrawal and for other reasons (Supplemental Table 1). Of these 50 studies, 14 met the study quality criteria for
levels 1 through 3 with bias addressed adequately on most items of the QUADAS tool (Supplemental Tables 1 to 3).28,29 Details of study site characteristics are reported in
Supplemental Table 1. These 14 higherquality studies included a total of 71, 295 patients and 1355 relevant cases of SAWS (1051 cases), seizure (53 cases), or delirium tremens
(251 cases) (Supplemental Table 1).
Incidence of Alcohol Withdrawal Syndrome
The incidence of SAWS was higher in studies designed to assess diagnostic accuracy of risk factors, symptoms, and signs than in populationbased surveys, which reported that
less than 1% of the general population experienced severe alcohol withdrawal symptoms in the year prior to being surveyed.31 The incidence also depended on the patient
population, care setting, and reason for admission (ie, inpatient withdrawal management vs general hospital admission). Across 3 studies of patients admitted to withdrawal
management facilities, the incidence of SAWS was 23% (95% CI, 20%27%; I2, 0%).4042 The incidence of alcohol withdrawal syndrome of any severity was much lower among atrisk
patients admitted to general medical units: 1.9% (95% CI, 1.23.1%) among patients with a score greater than 8 on the Alcohol Use Disorders Identification Test (AUDIT)43 and 6.7%
(95% CI, 4.6%9.6%) among patients with a BAC of more than 200 mg/dL or a history of any drinking in the prior 30 days.2
The incidence of SAWS among general hospitalized patients was low. In consecutive trauma patients, the incidence of SAWS was 0.40% (95% CI, 0.33%0.48%).8 In general medical
surgical patients, the incidence of alcohol withdrawal syndrome of any severity was 0.67% (95% CI, 0.58%0.75%).44 Among adults with available BAC admitted to a single,
academic, tertiary level I trauma center following motor vehicle crashes, 10% (95% CI, 9.3%–11%) developed an alcohol withdrawal syndrome.45
Reliability of the Clinical Diagnosis of Alcohol Withdrawal Syndrome
In a survey of 173 patients recruited from inpatient and outpatient substance abuse treatment facilities in the United States, the interrater reliability using the Diagnostic and
Statistical Manual of Mental Disorders (Fifth Edition)9 criteria for the diagnosis of alcohol withdrawal was excellent (κ, 0.80 [range, 0.71–0.89]).46 Maldonado et al2 evaluated the
interrater reliability in a random sample of 49 patients and found moderate to substantial agreement in the assessment of risk factors for alcohol withdrawal syndrome (AWS). In a
study of a random sample of 103 patients hospitalized with a diagnosis of AWS, interrater reliability between 2 blinded physicians for making the diagnosis was excellent (κ, 0.75
[95% CI, 0.660.84]).44 In a survey of 400 randomly selected patients from 8 regional facilities in the United States, testretest reliability of the diagnosis of AWS was good to
excellent with an interclass correlation coefficient of 0.82 (95% CI, 0.780.84).47 Sullivan et al48 showed an excellent interrater reliability using the revised Clinical Institute
Withdrawal Assessment for Alcohol (CIWAAr) scale for the diagnosis of AWS among a random sample of 100 patients (r > 0.8). When the same patient was evaluated twice by the
same interviewer, testretest reliability was also consistent.49
Risk Factors, Symptoms, and Signs
Risk Factors
ASevere
history of deliriumWithdrawal
Alcohol tremens was Syndrome,
the most frequently
Davidstudied finding (3 articles) and increased the likelihood that a patient would subsequently develop SAWS afterPage
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cessation (summary LR,
©2022 American 2.9 [95%Association.
Medical CI, 1.75.2]) (Table 1052, Supplemental
All Rights Reserved.Table 4). Some
Terms patients
of Use experienced
• Privacy Policyseizures during
• Notice a current alcohol cessation attempt prior to
• Accessibility
presenting for medical care. Patients who had 3 or more seizures (LR, 2.8 [95% CI, 1.45.9]) or 1 or 2 seizures (LR, 1.6 [95% CI, 1.42.2]) during their current alcohol cessation
attempt had an increased risk of progressing to delirium tremens. A history of withdrawal seizures (LR range, 0.471.7) during prior alcohol cessation episodes appeared to be less
excellent with an interclass correlation coefficient of 0.82 (95% CI, 0.780.84).47 Sullivan et al48 showed an excellent interrater reliability using the revised Clinical Institute
Pontificia
Withdrawal Assessment for Alcohol (CIWAAr) scale for the diagnosis of AWS among a random sample of 100 patients (r > 0.8). Universidade
When the Catolica
same patient was detwice
evaluated Campinas
by the
same interviewer, testretest reliability was also consistent.49 Access Provided by:
Risk Factors, Symptoms, and Signs
Risk Factors
A history of delirium tremens was the most frequently studied finding (3 articles) and increased the likelihood that a patient would subsequently develop SAWS after alcohol
cessation (summary LR, 2.9 [95% CI, 1.75.2]) (Table 1052, Supplemental Table 4). Some patients experienced seizures during a current alcohol cessation attempt prior to
presenting for medical care. Patients who had 3 or more seizures (LR, 2.8 [95% CI, 1.45.9]) or 1 or 2 seizures (LR, 1.6 [95% CI, 1.42.2]) during their current alcohol cessation
attempt had an increased risk of progressing to delirium tremens. A history of withdrawal seizures (LR range, 0.471.7) during prior alcohol cessation episodes appeared to be less
useful in predicting risk of SAWS than a history of delirium tremens.
Table 1052.
Summary Measures for Categorical Findings That Predict Seizure, Delirium Tremens, and Severe Alcohol Withdrawal Syndromea
Likelihood Ratio (95% CI)

Finding No. of Studies Sensitivity (95% CI) Specificity (95% CI) Conditions Studied
Positive Negative
Risk Factors
Demographics
Men 58,44,5052 0.79 (0.680.87) 0.39 (0.270.51) 1.3 (1.01.7) 0.58 (0.400.84) Seizure, DT, AWS, SAWS
I2, %b 95 71
White race/ethnicity (white) 38,44,50 0.69 (0.550.80) 0.34 (0.210.51) 1.1 (1.01.2) 0.84 (0.710.99) SAWS
I2, %b 0 0
Psychiatric history
Substance use disorder, other than alcohol 12 0.07 (0.020.22) 0.99 (0.971.0_) 6.4 (1.234) 0.94 (0.851.0) SAWS
Any psychiatric disorder 12 0.76 (0.580.88) 0.77 (0.720.81) 3.3 (2.54.4) 0.31 (0.160.60) SAWS
Mood disorders 12 0.48 (0.310.65) 0.84 (0.800.87) 3.0 (1.94.7) 0.62 (0.430.88) SAWS
Anxiety disorders 12 0.07 (0.020.22) 0.97 (0.950.98) 2.6 (0.6011) 0.96 (0.871.1) SAWS
Alcohol withdrawal history
History of delirium tremens 350,53,54 0.33 (0.230.46) 0.88 (0.770.94) 2.9 (1.75.2) 0.78 (0.670.91) DT
I2, %b 42 0
No. of epileptic seizures at diagnosis of minor AWS 152 DT
≥ 3 seizures 2.8 (1.45.9) DT
12 seizures 1.6 (1.42.2) DT
0 seizures 0.63 (0.500.78) DT
History of SAWS/AWS 250,52 0.240.78 0.730.91 1.52.0 0.640.91 DT
History of seizuresc 250,54 0.000.38 0.800.91 0.471.7 0.831.1 DT, seizure
Signs
Systolic blood pressure ≥ 140 mm Hgd 350,52,53 0.42 (0.330.51) 0.73 (0.590.84) 1.7 (1.32.3) 0.78 (0.690.89)
I 2, % 28 0
Laboratory
©2022 Americanfindings
Medical Association. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
BAC ≥ 200 mg/dL 145 0.48 (0.430.53) 0.86 (0.850.87) 3.5 (3.04.0) 0.61 (0.550.67)
History of seizuresc 250,54 0.000.38 0.800.91 0.471.7 0.831.1 DT, seizure
Signs Access Provided by:
Systolic blood pressure ≥ 140 mm Hgd 350,52,53 0.42 (0.330.51) 0.73 (0.590.84) 1.7 (1.32.3) 0.78 (0.690.89)
I 2, % 28 0
Laboratory findings
BAC ≥ 200 mg/dL 145 0.48 (0.430.53) 0.86 (0.850.87) 3.5 (3.04.0) 0.61 (0.550.67)
BUN > 26 mg/dL at admission 153 0.28 (0.150.46) 0.92 (0.860.96) 3.3 (1.47.6) 0.79 (0.631.0)
Thrombocytopenia (< 150 × 103/μL) 154 0.70 (0.400.89) 0.69 (0.640.74) 2.2 (1.43.4) 0.44 (0.171.1)
Composite measures
PAWSS ≥ 4e 12 0.93 (0.770.99) 0.99 (0.980.99) 174 (43696) 0.07 (0.020.26)
Independent clinical correlates ≥ 5f 142 0.13 (0.070.23) 1.0 (0.981.0) 27 (3.5209) 0.88 (0.800.96)
LARS10 ≥ 9g 140 0.95 (0.770.99) 0.93 (0.880.94) 12 (5.827) 0.05 (0.00.37)
AWS scale ≥ 10h 141 0.78 (0.590.90) 0.90 (0.850.93) 7.4 (4.811) 0.25 (0.120.50)
Independent clinical correlates = 4d 142 0.25 (0.160.36) 0.96 (0.920.98) 6.8 (3.115) 0.78 (0.680.89)
History of SAWS and ≥ 1 adverse clinical feature 150 0.40 (0.200.64) 0.91 (0.790.96) 4.5 (1.514) 0.66 (0.431.0)
Abnormal vital signi 140 0.37 (0.280.47) 0.82 (0.820.83) 2.1 (1.72.7) 0.76 (0.660.88)
Abbreviations: AWS, alcohol withdrawal syndrome; BAC, blood alcohol concentration; BUN, blood urea nitrogen; DT, delirium tremens; LARS, Luebeck Alcohol Risk Scale; PAWSS, Prediction of
Alcohol Withdrawal Severity Scale; SAWS, severe alcohol withdrawal syndrome.
SI conversion factor: To convert BUN to mmol/L, multiply by 0.357.
aSee Supplemental Table 4 and Supplemental Table 6 for results from individual studies.
b Heterogeneity was explored using I2, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance (I2 value of 25% categorized as low; 50%,
moderate; and 75%, high).
cIf a study reported both delirium tremens and seizure, only data for delirium tremens were pooled.
dPooled from 3 studies with thresholds of 140 mm Hg or more,53 145 mm Hg,50 and 150 mm Hg.52
eSee Box 1053.
f The 6 independent correlates were use of a morning eyeopener; initial CIWAAr score 10 or more; AST 80 or more U/L (to convert to μkat/L, multiply by 0.0167); past benzodiazepine use; history of
delirium tremens; and 2 or more prior alcohol treatments. Categories were low risk (02 correlates), moderate risk (3), and high risk (46).
gLARS10 is a 10item rating scale to predict the severity of AWS. Score range, 0 to 14; for which 9 or higher is considered SAWS.
h Rating scale for assessment of AWS (AWS scale) is an 11item rating scale. Each item is scored from 0 to 3 for somatic symptoms or 0 to 4 for mental symptoms. Score range, 0 to 38, for which 5 or
less is considered mild AWS, 6 to 9 is considered moderate AWS, and 10 or higher is considered severe AWS.
iAdmission systolic blood pressure is less than 80 mm Hg; respiratory rate, less than 10/min or more than 29/min; or heart rate more than 120/min.
Men were no more likely than women to have SAWS (summary LR for men, 1.3 [95% CI, 1.01.7]). White patients were no more likely than nonwhite patients to have SAWS
(summary LR for white patients, 1.1 [95% CI, 1.01.2]). Among continuous variables (Table 1053, Supplemental Table 5), patients who developed SAWS were younger than patients
who did not, although the effect size was small (summary SMD, –0.27 [95% CI, –0.49 to –0.05; P = .02]).
Table 1053.
Summary Measures for Continuous Findings of Seizure, Delirium Tremens, and Alcohol Withdrawal Syndromea
Finding No. of Studies No. of Participants SMD (95% CI) or Range Conditions Studied

Risk factor
Age 440,44,51,52 1250 –0.27 (–0.49 to –0.05) Seizure, DT, SAWS
Signs
iAdmission systolic blood pressure is less than 80 mm Hg; respiratory rate, less than 10/min or more than 29/min; or heart rate more than 120/min.
Men were no more likely than women to have SAWS (summary LR for men, 1.3 [95% CI, 1.01.7]). White patients were no more likely
Access than by:
Provided nonwhite patients to have SAWS
(summary LR for white patients, 1.1 [95% CI, 1.01.2]). Among continuous variables (Table 1053, Supplemental Table 5), patients who developed SAWS were younger than patients
who did not, although the effect size was small (summary SMD, –0.27 [95% CI, –0.49 to –0.05; P = .02]).
Table 1053.
Summary Measures for Continuous Findings of Seizure, Delirium Tremens, and Alcohol Withdrawal Syndromea
Finding No. of Studies No. of Participants SMD (95% CI) or Range Conditions Studied
Risk factor
Age 440,44,51,52 1250 –0.27 (–0.49 to –0.05) Seizure, DT, SAWS
Signs
Systolic BPb 252,54 697 –0.70 to 0.38c DT
Diastolic BP 252,54 637 –0.47 to 0.32c DT
Heart rateb 252,54 697 0.01 to 0.06c
Laboratory findings
GGT 252,54 637 0.03 to 1.41c DT
AST 252,54 637 0.07 to 0.88 DT
Potassium 252,54 637 –0.73 to –0.20c DT
ALT 252,54 637 0.04 to 0.18 DT
Platelet count 252,54 637 –0.59 to –0.35c DT
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; DT, delirium tremens; GGT, γglutamyl transferase; SAWS, severe alcohol withdrawal syndrome;
SMD, standardized mean difference.
aSee Supplemental Table 5 for results from individual studies.
b One study did not report standard deviations50; therefore, the SMD was calculated for 2 studies only.52,54
cRange of means for participants with the condition.
Individual studies have reported that patients with a concurrent substance use disorder or mental health condition (eg, mood or anxiety disorder) have an increased risk of SAWS
(Table 1052, Supplemental Table 6). Based on 3 studies, the absence of a history of delirium tremens had a small effect on identifying patients less likely to develop SAWS (LR, 0.78
[95% CI, 0.670.91]). There were no risk factors with a likelihood ratio smaller than 0.5 that would predict the likelihood of not developing SAWS.
Symptoms and Signs
No studies that met our inclusion criteria identified individual symptoms that were useful predictors of SAWS. A systolic blood pressure of 140 mm Hg or higher at admission was
associated with increased likelihood of severe alcohol withdrawal (summary LR, 1.7 [95% CI, 1.32.3]).
A normal systolic blood pressure was associated with patients less likely to develop SAWS (LR, 0.78 [95% CI, 0.690.89]). However, when evaluated as a continuous measure, those
who developed SAWS could not be distinguished by either the systolic blood pressure (range SMD, –0.70 to 0.38) or the diastolic blood pressure (range SMD, –0.47 to 0.32).
Although tachycardia is a hallmark of autonomic excitability, the heart rate had a very small effect size for identifying groups of patients more likely to have SAWS (range SMD, 0.01
0.06).
Laboratory Findings
One study suggested that a BAC of more than 200 mg/dL (LR, 3.5 [95% CI, 3.04.0]) was associated with increased likelihood of developing alcohol withdrawal.45 A blood urea
nitrogen of more than 26 mg/dL (to convert to millimoles per liter, multiply by 0.357) at admission (LR, 3.3 [95% CI, 1.47.6]) was associated with an increased likelihood of
developing delirium tremens in another study.53 A third study suggested an association between thrombocytopenia (platelets, < 150 × 103/μL) and an increased risk of delirium
tremens (LR, 2.2 [95% CI, 1.43.4]).54
When evaluated as continuous variables (Table 1053), 2 criteria had SMD effect sizes larger than 0.8. Groups of patients with a higher serum γglutamyl transferase (GGT; range
SMD, 0.031.4 U/L) or a higher serum aspartate aminotransferase (AST; range SMD, 0.070.88 U/L) had higher incidences of SAWS. The effect size and narrow range of the SMD for
serum alanine aminotransferase (ALT) approached 0 (range SMD, 0.040.18 U/L), suggesting that ALT may be less
©2022 American Medical Association. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility useful than AST. Lower serum potassium levels (range SMD, –
0.73 to –0.20 mEq/L) or lower platelet counts (range SMD, –0.59 to –0.35 x 103/μL) were associated with patients at risk for SAWS.
Combinations of Symptoms and Signs

One study suggested that a BAC of more than 200 mg/dL (LR, 3.5 [95% CI, 3.04.0]) was associated with increased likelihoodPontificia
of developing alcohol withdrawal.45 A blood urea
Universidade Catolica de Campinas
nitrogen of more than 26 mg/dL (to convert to millimoles per liter, multiply by 0.357) at admission (LR, 3.3 [95% CI, 1.47.6]) was associated with an increased likelihood of
Access Provided by:
developing delirium tremens in another study.53 A third study suggested an association between thrombocytopenia (platelets, < 150 × 103/μL) and an increased risk of delirium
tremens (LR, 2.2 [95% CI, 1.43.4]).54
When evaluated as continuous variables (Table 1053), 2 criteria had SMD effect sizes larger than 0.8. Groups of patients with a higher serum γglutamyl transferase (GGT; range
SMD, 0.031.4 U/L) or a higher serum aspartate aminotransferase (AST; range SMD, 0.070.88 U/L) had higher incidences of SAWS. The effect size and narrow range of the SMD for
serum alanine aminotransferase (ALT) approached 0 (range SMD, 0.040.18 U/L), suggesting that ALT may be less useful than AST. Lower serum potassium levels (range SMD, –
0.73 to –0.20 mEq/L) or lower platelet counts (range SMD, –0.59 to –0.35 x 103/μL) were associated with patients at risk for SAWS.
Combinations of Symptoms and Signs
Because individual findings had relatively low positive LRs and high negative LRs and effect sizes for continuous variables did not clearly identify patients most likely to have or not
have SAWS, several different composite measures were evaluated (Table 1052).
In 6 studies, 9 composite measures were used to identify patients at risk of developing SAWS.2,8,4042,50 No composite measures were validated after their initial report. The
Prediction of Alcohol Withdrawal Severity Scale (PAWSS) (Box 1053), which was developed for medically ill inpatients, had the best positive LR and the best negative LR.2 PAWSS
requires recording the presence or absence of 9 risk factors and 1 sign indicating increased autonomic activity (Box 1053). Among the PAWSS validation sample, having 4 or more
signs or risk factors made SAWS much more likely (LR, 174 [95% CI, 43696]), whereas having fewer than 4 signs or risk factors was associated with an LR of 0.07 (95% CI, 0.020.26).
PAWSS sensitivity was 0.93 (95% CI, 0.770.99) and specificity was 0.99 (95% CI, 0.980.99). Given the baseline incidence rate of approximately 5% among individuals hospitalized for
alcohol withdrawal,23 the positive predictive value (PAWSS, ≥ 4) would be 93% and the negative predictive value (PAWSS, < 4) would be 99% if the PAWSS was validated in new
populations.
Box 1053.
The Prediction of Alcohol Withdrawal Severity Scale (PAWSS)a
Part A: Threshold criteria (yes or no, no point):
1. Have you consumed any amount of alcohol (ie, been drinking) within the last 30 days? OR did the patient have a "+" BAL upon admission? IF the answer to either is YES,
proceed with test:
Part B: Based on patient interview (1 point each):
2. Have you ever experienced previous episodes of alcohol withdrawal?
3. Have you ever experienced alcohol withdrawal seizures?
4. Have you ever experienced delirium tremens or DTs?
5. Have you ever undergone alcohol rehabilitation treatment (ie, inpatient or outpatient treatment programs or AA attendance)?
6. Have you ever experienced blackouts?
7. Have you combined alcohol with other "downers" like benzodiazepines or barbiturates during the last 90 days?
8. Have you combined alcohol with any other substance of abuse during the last 90 days?
Part C: Based on clinical evidence (1 point each):
9. Was the patient's blood alcohol level (BAL) on presentation > 200?
10. Is there evidence of increased autonomic activity (eg, HR > 120/min, tremor, sweating, agitation, nausea)?
Notes: Maximum score = 10. This instrument is intended as a SCREENING TOOL. The greater the number of positive findings, the higher the risk for the development of AWS.
A score of ≥ 4 suggests HIGH RISK for moderate to severe (complicated) AWS; prophylaxis and/or treatment may be indicated.2
Abbreviation: AWS, alcohol withdrawal syndrome.
a Published with permission from Oxford University Press.
Prior research has investigated why these instruments seem to have such an effective diagnostic test performance.55 For PAWSS, incorporation bias is likely because it includes
increased autonomic activity in its score. One point on the 10point PAWSS scale is given when any one of the following is present: heart rate higher than 120/min, tremor,
sweating, agitation, or nausea. Of the remaining 9 points, 8 are questions about patients' past experience. Because all questions are weighted equally, further signs of increased
autonomic activity would not disproportionately increase the total PAWSS score and would not necessarily be required to obtain a positive score of 4 or higher. Nevertheless,
because increased autonomic activity is included in the criteria for diagnosing SAWS, its inclusion in PAWSS likely accounts for PAWSS' high sensitivity and specificity.
The Luebeck Alcohol Withdrawal Scale (LARS)40 relies on a patient's clinical history, physical examination, and laboratory results (Supplemental Table 7). The LARS10 total score
is calculated from 10 findings, yielding a score between 0 and 14. A point is added when any of the following are present: frequent sleep disturbance in the past week, nightmares
during the last week,
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present: Alcohol Withdrawal
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and heart David
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or higher. Three points are added when there is a history of 3 or more episodes of delirium tremens or 3 or more Page 10 / 41
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©2022 American
withdrawal Medical
seizures, for Association.
a possible All Rights
6 additional points. Reserved.
A score Terms
of 9 or more is of Use
associated with• aPrivacy Policy • of
greater likelihood Notice
severe•withdrawal
Accessibility
(LR, 12 [95% CI, 5.827]), whereas having a
score of less than 9 is associated with an LR of 0.05 (95% CI, 0.020.37). The sensitivity of LARS10 as a test for predicting SAWS is 0.95 (95% CI, 0.770.99) and specificity is 0.93 (95%
CI, 0.880.94). The items considered in a 20item and an 11item version of LARS are shown in Supplemental Table 7.
increased autonomic activity in its score. One point on the 10point PAWSS scale is given when any one of the following is present: heart rate higher than 120/min, tremor,
Pontificia
sweating, agitation, or nausea. Of the remaining 9 points, 8 are questions about patients' past experience. Because all questions Universidade
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autonomic activity would not disproportionately increase the total PAWSS score and would not necessarily be required to Access
obtainProvided
a positive
by: score of 4 or higher. Nevertheless,
because increased autonomic activity is included in the criteria for diagnosing SAWS, its inclusion in PAWSS likely accounts for PAWSS' high sensitivity and specificity.
The Luebeck Alcohol Withdrawal Scale (LARS)40 relies on a patient's clinical history, physical examination, and laboratory results (Supplemental Table 7). The LARS10 total score
is calculated from 10 findings, yielding a score between 0 and 14. A point is added when any of the following are present: frequent sleep disturbance in the past week, nightmares
during the last week, polyneuropathy, ataxia, or BAC of 100 mg/dL or higher. When the BAC is more than 100 mg/dL, an additional point is added for each of the following if
present: tremor, sweating, and heart rate of 100/min or higher. Three points are added when there is a history of 3 or more episodes of delirium tremens or 3 or more episodes of
withdrawal seizures, for a possible 6 additional points. A score of 9 or more is associated with a greater likelihood of severe withdrawal (LR, 12 [95% CI, 5.827]), whereas having a
score of less than 9 is associated with an LR of 0.05 (95% CI, 0.020.37). The sensitivity of LARS10 as a test for predicting SAWS is 0.95 (95% CI, 0.770.99) and specificity is 0.93 (95%
CI, 0.880.94). The items considered in a 20item and an 11item version of LARS are shown in Supplemental Table 7.
Limitations
This review has several limitations. First, although the literature search yielded 50 original studies reporting information about risk factors for SAWS, only 14 highquality articles
were identified. The 14 articles included more than 70 000 patients and 1300 cases of SAWS, seizure, or delirium tremens. Observational studies examining disease prognosis have
potential for bias related to study quality; both The Rational Clinical Examination criteria and the QUADAS tool to assess study quality were used in this review. The quality
assessment resulted in the exclusion of 12 of the 17 studies used in an earlier metaanalysis on this topic.14 Although some biases likely persist, some studies, including the
development of PAWSS, involved a range of protections against bias, including a separation between staff assessing study participant PAWSS scores and those diagnosing and
treating SAWS.
Second, the current evidence base was developed during an era when treatments that can change the natural history of alcohol withdrawal and prevent SAWS were available.56
Although not appropriate for all circumstances (eg, the assessment of nonverbal patients),57 the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) is often used to
measure the severity of withdrawal symptoms (ie, not to predict risk of developing future withdrawal) and used to guide administration of benzodiazepine prophylaxis to prevent
clinical deterioration. The CIWA can reduce incidence of delirium tremens (–4.9 cases per 100 patients) and seizures (–7.7 seizures per 100 patients).58 In the present review, use of
the CIWA scale was reported in 7 of the 14 higherquality studies, while the remaining studies used other approaches (Supplemental Table 3).48 Too much variation between the
studies in the CIWA threshold values used to establish a diagnosis of SAWS made a metaanalysis inappropriate (range: ≥ 8 to ≥ 15) (Supplemental Table 1). A baseline CIWA score
appeared useful in a single study8 and was included among the six independent correlates that constituted a composite measure assessed in Kraemer et al.42 Although CIWA and
other tools affect the natural history of alcohol withdrawal, assessing the accuracy of signs and symptoms is best undertaken in the context of current best practices that include
the use of these measures.
Third, the criterion standard for establishing a diagnosis of SAWS was not consistent across studies assessed in this review (Supplemental Table 1). Some studies only assessed
components of SAWS rather than the full syndrome. In this review, SAWS was assessed rather than individual symptoms or signs associated with the syndrome.
Scenario Resolution
Case
The patient presented to the emergency department with a known history of alcohol use disorder. Establishing a pretest probability for the incidence of SAWS required clinical
judgment and awareness of the variability in outcomes based on the setting and the planned treatment to lower the risk of withdrawal. Since she had a known alcohol use disorder
and presented without prolonged sobriety, her risk of developing SAWS in an acute care setting was approximately 5%.23 If she was admitted to a withdrawal management
specialty hospital, it would have been 20%.4042 Using the results from Table 1052, none of this patient's individual symptoms or signs were helpful for determining the likelihood
of subsequent severe withdrawal with the exception of the BAC of more than 200 mg/dL (LR, 3.5 [95% CI, 3.04.0]) (Table 1052). However, her PAWSS score was higher than 4,
based on her intoxication, alcohol treatment history, previous withdrawal symptoms, and BAC. When her PAWSS score of more than 4 (LR, 174 [95% CI, 43696]) (Table 1052) is
applied to the pretest probability of 5%, her likelihood of developing SAWS increased to approximately 90%. Based on the findings of this review, she required admission,
supportive care, and a therapeutic strategy (eg, benzodiazepine prophylaxis) to prevent the development of SAWS, regardless of the environment considered for assessing pretest
risk.59,60
Clinical Bottom Line
Patients admitted to a general medical hospital who have a history of heavy alcohol use have an approximately 2% to 7% chance of developing SAWS. If they are admitted to a
specialized treatment center, the likelihood increases to approximately 20%. Individual symptoms or signs do not effectively predict or exclude SAWS. Of the individual findings
that can be obtained from a clinical examination, a history of delirium tremens is the most effective finding (summary LR, 2.9 [95% CI, 1.75.2]) for predicting SAWS.
Younger patients tended to have more severe withdrawal. PAWSS performed best for predicting the development of SAWS (positive LR, 174; negative LR, 0.07).
Acknowledgment
The following disclosures were reported at the time this original article was first published in JAMA.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
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Interest and noneCatolica
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de Campinas
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Supplementary Online Content

Supplemental Appendix. Search Strategy
Alcohol Withdrawal Searches January 3, 2018
EMBASE 1980 to January 2018
1 physical examination.mp. or exp physical examination/ 234013
2 anamnesis/ 116129
3 exp professional competence/ 29293

Severe
4 Alcohol Withdrawal
(sensitivity Syndrome,
or specificity).mp. David
[mp=title, L. Simel
abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, Page 14 / 41
1565988
©2022 American
keyword]Medical Association. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
5 reproducibility of results.mp. or exp reproducibility/ 187103

Supplemental Appendix. Search Strategy Pontificia Universidade Catolica de Campinas
Access Provided by:
Alcohol Withdrawal Searches January 3, 2018
EMBASE 1980 to January 2018
2 anamnesis/ 116129
4 (sensitivity or specificity).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, 1565988
keyword]
6 exp diagnosis/or exp observer variation/ 5937781
7 diagnostic tests.mp. or exp diagnostic test/ 865628
8 exp decision support system/ 19577
9 exp pathology/or exp histology/or exp biochemistry/or exp methodology/or bayes theorum.mp. 7099673
10 alcohol withdrawal.mp. or exp alcohol withdrawal/ 8342
11 limit 10 to (human and english language) 5338
12 1 or 2 or 3 352025
13 11 and 12 179
14 4 and 11 242
15 5 or 6 or 7 or 8 or 9 11213981
16 11 and 15 2359
17 13 or 14 or 16 2518
Medline 1946 – January 2018
1 physical examination.mp. or exp Physical Examination/ 1406596
2 exp Medical History Taking/ 21228
3 exp Professional Competence/ 109821
4 (sensitivity and specificity).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary 478415
concept word, rare disease supplementary concept word, unique identifier]
5 exp "Reproducibility of Results"/ 387618
6 exp Observer Variation/ 43216
7 exp Diagnostic Tests, Routine/ 10638
8 exp Decision Support Techniques/ 77616
9 exp Bayes Theorem/ 30532
10 alcohol withdrawal.mp. 4756
11 limit 10 to (english language and humans) 2991
Downloaded
12 12022125
or 2 or 3 7:30 A Your IP is 200.130.40.29 1526192
©2022
13 American
11 and Medical
12 Association. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility 228
14 4 and 11 44
16 11 and 15 2359

17 13 or 14 or 16 2518
Access Provided by:
Medline 1946 – January 2018
4 (sensitivity and specificity).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary 478415
concept word, rare disease supplementary concept word, unique identifier]
11 limit 10 to (english language and humans) 2991
12 1 or 2 or 3 1526192
13 11 and 12 228
14 4 and 11 44
15 5 or 6 or 7 or 8 or 9 514431
16 11 and 15 35
17 13 or 14 or 16 291
18 remove duplicates from 17 278
19 alcohol withdrawal syndrome.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol 810
supplementary concept word, rare disease supplementary concept word, unique identifier]
20 substance withdrawal syndrome.mp. or exp Substance Withdrawal Syndrome/ 23986
21 alcohol drinking.mp. or exp Alcohol Drinking/ 68861
22 Substance Withdrawal Syndrome/ 22141
23 withdrawal.mp. or exp Substance Withdrawal Syndrome/ 96054
24 21 and 22 679
25 21 and 23 1431
26 20 and 21 820
27 24 or 25 or 26 1431
28 18 or 19 or 27 2364
29 limit 28 to (English language and humans) 1515
Combined Medline/EMBASE Search

©2022
1 Americanphysical
Medical Association.
examination.mp. Allphysical
or exp Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
examination/ 1501913
2 anamnesis/ 114985
28 18 or 19 or 27 Pontificia Universidade Catolica de2364
Campinas
Access Provided by:
Combined Medline/EMBASE Search
2 anamnesis/ 114985
4 (sensitivity or specificity).mp. [mp=ti, ab, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, ui] 3011862
6 exp diagnosis/or exp observer variation/ 13472443
7 diagnostic tests.mp. or exp diagnostic test/ 863305
8 exp decision support system/ 18490
9 exp pathology/or exp histology/or exp biochemistry/or exp methodology/or bayes theorum.mp. 7233019
10 alcohol withdrawal.mp. or exp alcohol withdrawal/ 12626
11 1 or 2 or 3 1717525
12 10 and 11 495
13 4 and 10 708
14 5 or 6 or 7 or 8 or 9 18756980
15 10 and 14 4055
16 12 and 13 and 15 33
17 12 or 13 or 15 4597
18 limit 17 to (human and English language) 3331
19 exp alcohol withdrawal/di, ep, et, si [Diagnosis, Epidemiology, Etiology, Side Effect] 14
20 18 and 19 7
24 (sensitivity and specificity).mp. [mp=ti, ab, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, ui] 833663
Downloaded
31 2022125 7:30 Alanguage
limit 30 to (English Your IP
andis 200.130.40.29
humans) 7964
©2022
32 American21Medical
or 22 or 23Association. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility 1806497
33 31 and 32 468
Access Provided by:
32 21 or 22 or 23 1806497
33 31 and 32 468
34 24 and 31 112
35 25 or 26 or 27 or 28 or 29 1506208
36 31 and 35 280
37 33 or 34 or 36 786
38 remove duplicates from 37 720
39 alcohol withdrawal syndrome.mp. [mp=ti, ab, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, ui] 1995
40 38 and 39 121
41 from 40 keep 195 121
42 *"alcohol withdrawal"/di [Diagnosis] 115
43 limit 42 to English language 90
44 limit 43 to human 82
45 41 or 44 254
Supplemental Box 1.
Approximate drinking equivalentsa when taking an alcohol use history
Beverage type Regular Beer Wineb Distilled spiritsc
Amount 12oz (355 ml) 5ozb (140 ml) 1.5ozc (40 ml)
Approximate alcohol content 5% alcohola 12% alcohol 40% alcohol
a The alcohol content varies by the exact beverage.
b Alcohol content varies greatly depending on the type of wine glass.
c The larger side of a typical drink measure used for distilled spirits.
Source: US National Institute on Alcohol Abuse and Alcoholism
Supplemental Figure 1:
Flowchart of studies

Supplemental Figure 1: Access Provided by:
Flowchart of studies
Supplemental Table 1.
Features of included studies
No.
Quality Study Study Signs, Symptoms, Scales, and/or
Study Sample size withdrawal AW outcomes
assessment design population Risk Factors
events (%)
Studies included in metaanalysis
Berggren et al, I 334 Retrospective Inpatient Thrombocytopenia, past history DT, past 10/317 (3%) DT or seizures
2009 cohort study admitted for history of seizures DTs, 8/333
detoxification (2%) seizure,
none both
Brathen et al, 2000 I 158 Prospective Inpatients Sex, Selfreported alcohol misuse, history 53/158 (34%) Seizures related to AW
cohort study with seizures of illegal drug misuse, identified by AUDIT positive
(score ≥8)
Dolman et al, 2005 I 874 Prospective Acute medical AUDIT as screen for AWS plus number of 17/874 (1.9%) CIWAAr (score >11)
cohort study admissions blood tests
Kapur et al, 2010 I 3729 Retrospective Inpatients Blood Alcohol Concentration (BAC) AW: No ETOH: AW: If patient required
cohort study admitted to 46/2210 (5%), treatment for signs or
trauma unit BAC < 100: symptoms of withdrawal or
following 47/338(29%), had an alcohol withdrawal
motor vehicle BAC 100–199: treatment sheet in their
accidents 104/538 (40%), chart
BAC ≥ 200:
181/643 (55%)
Kraemer et al, I 284 Retrospective Inpatient Age 20/284 (7%) CIWA Ar (score ≥8) + (1)
1997 cohort study admitted for delirium symptom severity, (2)
detoxification benzodiazepine
requirement, and (3)
complications delirium
using DSM III
Severe Alcohol
Kraemer et al, Withdrawal
I Syndrome,
284 David L. Retrospective
Simel Inpatients Use of a morning eye opener, an initial 71/284 (25%) Page
CIWAAr (score ≥10), DT, 19 / 41
©2022 American Medical Association. All Rightscohort
2003 Reserved.
study Terms for
admitted of UseCIWAAr
• Privacy Policy
score ≥10, • Notice
serum aspartate• Accessibility
severe diagnosed based on DSMIV
detoxification aminotransferase ≥80 U/L, past withdrawal, criteria, Severe AW =
benzodiazepine use, selfreported history 3/284 (1%) DT "Alcohol withdrawal
Kraemer et al, I 284 Retrospective Inpatient Age 20/284
Pontificia (7%) CIWA
Universidade Ar (score ≥8)
Catolica de+ (1)
Campinas
1997 cohort study admitted for delirium symptom severity, (2)
Access Provided by:
detoxification benzodiazepine
requirement, and (3)
complications delirium
using DSM III
Kraemer et al, I 284 Retrospective Inpatients Use of a morning eye opener, an initial 71/284 (25%) CIWAAr (score ≥10), DT,
2003 cohort study admitted for CIWAAr score ≥10, serum aspartate severe diagnosed based on DSMIV
detoxification aminotransferase ≥80 U/L, past withdrawal, criteria, Severe AW =
benzodiazepine use, selfreported history 3/284 (1%) DT "Alcohol withdrawal
of DT, prior participation in ≥2 alcohol symptoms and signs of
treatment programs, history of black sufficient severity to require
outs, history of withdrawal seizure, ≥2 close inpatient
prior inpatient detoxification, past heroin management" or "600mg of
use, past cocaine use, past benzo required"
benzodiazepine use, initial platelet count
<140 x 109/L, initial serum creatinine <70
umol/L, chloride <100 mmol/L.
Lee et al, 2005 I 178 cases in 147 Retrospective Inpatients Previous DT, Admission SBP >140, 59/178 (33%) DSMIV criteria for AW
patients cohort study under Admission PR >100 bpm, Admission BUN cases of DT delirium
internal >26 md/dL, Admission albumin <3.5 g/dL,
medicine with Admission sodium <135 mmol/L,
alcohol Admission potassium <3.5mmol/L,
dependence admission chloride <106 mmol/L
Maldonado et al, I 403 Prospective Inpatient, Ethnicity, gender, psychiatric 27/403 (7%) AW Scale (Wetterling 1997)
2015 cohort study medically ill comorbidities, Moderate or severe
patients withdrawal symptoms as
admitted to indicated by CIWAAr (score
general and ≥15)
surgery units
Monte et al, 2009 I 303 Retrospective Inpatients Sex, AW cause of admission, reasons for 156/303 (51%) DT and AWS DSMIVTR
cohort study with AWS stopping consumption, liver disease, criteria
prior AWS admission, Tremor, seats,
hallucinations, epileptic seizures, number
of seizures, psychomotor agitation, Temp
>38 degrees (OR), BP systolic >150
Pecoraro et al, I 36331 Retrospective Inpatients Sex, ethnicity, AUDITPC score (sensitivity, 414/36331 AWS (alcohol withdrawal
2014 case control nonICU specificity, PPV) (1%) and/or delirium tremens)
study identified by ICD9 codes
(AW or DT
treatment/diagnosis
dependent on CIWAAr
score ≥8)
Wetterling et al, I Phase I: 132 Prospective Inpatients AW score <10 or ≥ 10 Mild AW: New AWS scale validated
1997 Phase II: 256 cohort study admitted for 126/256 (49%) with CIWAA (mild AWS:
(development detoxification Mod AW: score ≤5, moderate AWS
of AW scale 72/256 (28%) score 6–9, severe AWS score
and Severe AW: ≥10)
assessment of 58/256 (23%)
feasibility see
notes)
Salottolo et al, I 28101 Retrospective Emergency Blinded prospective data collected by 86/28101 Degree of AW using CIWAAr
2017 cohort study department registrars: (0.3%) (minimal AWS score <10,
patients with Age (< 55 vs ≥ 55 yr), gender (male vs CIWAAr ≥20 mod. AWS score 1020, sev.
traumatic female), race (white vs not white), Injury points AWS score ≥20)
injury Severity Score (ISS, < 16 vs ≥ 16), injury
mechanism (motor vehicle accident [MVA]
vs other causes), presence of severe head
Downloaded 2022125 7:30 A Your IP is 200.130.40.29 injury (head Abbreviated Injury Scale [AIS]
score, ≥ 3 vs < 3), and an abnormal vital
sign (admission systolic blood pressure of
< 80 mm Hg, respiratory rate < 10 and > 29
breaths/min, or heart rate > 120
Salottolo et al, I 28101 Retrospective Emergency Blinded prospective data collected by 86/28101 Degree of AW using CIWAAr
2017 cohort study department registrars: (0.3%)
Pontificia (minimal
Universidade AWS score
Catolica de<10,
Campinas
patients with Age (< 55 vs ≥ 55 yr), gender (male vs CIWAAr ≥20 mod. AWS score 1020, sev.
Access Provided by:
traumatic female), race (white vs not white), Injury points AWS score ≥20)
injury Severity Score (ISS, < 16 vs ≥ 16), injury
mechanism (motor vehicle accident [MVA]
vs other causes), presence of severe head
injury (head Abbreviated Injury Scale [AIS]
score, ≥ 3 vs < 3), and an abnormal vital
sign (admission systolic blood pressure of
< 80 mm Hg, respiratory rate < 10 and > 29
breaths/min, or heart rate > 120
beats/min).
Blinded clinical outcomes: Hospital
length of stay, ICU length of stay, and AW
complications
Unblinded retrospective data abstracted
by coordinators from EMR:
Abnormal laboratory findings
(hypomagnesemia, < 1.7 mg/dL;
hypokalemia, < 3.5 mmol/L;
hypophosphatemia, < 2.5 mg/dL);
established withdrawal risk factors (any
of the following: binge drinking, drug
abuse, alcoholic liver disease or alcoholic
neuropathy, WernickeKorsakoff
syndrome, history of AWS, withdrawal
seizures, and medical seizures); admission
blood alcohol concentration (BAC,
dichotomized based on the median BAC
in the AWS population as > 200 vs ≤ 200
mg/dL), The highest baseline CIWAAr
score.
Wetterling et al, II 100 Cohort study inpatients Baseline: Age, smoking history, abuse of 20/100 (20%) AW Scale (Wetterling 1997)
2006 admitted for other substances, duration of Severe AW (Mild ≤6; Mod. = 6–9; Sev ≥9)
detox dependence, number of previous detox,
history of withdrawal delirium, duration
of last drinking period, quantity of
alcohol per day, BAC, LARS scale
AW scale: Rating Scale for the Assessment
of Alcohol Withdrawal Syndrome12
LARS scale: Prev. detox/delirium/seizures,
use of hypnotics, recent drinking, sleep
disturbances, malnutrition, vomiting,
BAC, tremor, sweating, HR,
polyneuropathy, ataxia, Na, K, Ca, Cl
Fiellin et al, 2002 III 60 Case control Inpatient Prior complicated withdrawal, systolic 15/15 (100%) DSMIV for DT (alcohol
study admitted for blood pressure, comorbidity all cases with withdrawal delirium)
detoxification DTs, when
controls are
included in
the
denominator
15/60 (25%)
Studies not included in metaanalysis
Ballenger et al, V 200 Cohort study Inpatients Years of alcohol abuse 43 (21.5%) 5point scale: none, mild
1978 with admitted for tremor, "shakes" automatic
retrospective detoxification hyperactivity, seizures
chart review confusion, DTs
Barrio et al, 2004 V 256 Cohort study Inpatients, Sex, irregular drinkers, spirits drinkers, 150 (58.6%) SAWS: delirium tremens,
heavy liver histopathology (table 2) By liver SAW disordered perceptions,
drinkers lesion: steatosis, alcoholic hepatitis, seizures associated with 21
Severe Alcohol Withdrawal Syndrome, David L. Simel Page / 41
©2022 American Medical Association. All Rights Reserved. Terms of Usecirrhosis plus hepatitis,
• Privacy Policy cirrhosis
• Noticealone• Accessibility alcohol abstinence
(table 3)
Bartolomei et al, V 60 Case control Inpatients, Seizure type, neurological signs, duration 14 of 60 (23%) AWS: patients in whom
Ballenger et al, V 200 Cohort study Inpatients Years of alcohol abuse 43 (21.5%) 5point scale: none, mild
1978 with admitted for Pontificia Universidade Catolica
tremor, "shakes"de Campinas
automatic
retrospective detoxification Access Provided by: hyperactivity, seizures
chart review confusion, DTs
Barrio et al, 2004 V 256 Cohort study Inpatients, Sex, irregular drinkers, spirits drinkers, 150 (58.6%) SAWS: delirium tremens,
heavy liver histopathology (table 2) By liver SAW disordered perceptions,
drinkers lesion: steatosis, alcoholic hepatitis, seizures associated with
cirrhosis plus hepatitis, cirrhosis alone alcohol abstinence
(table 3)
Bartolomei et al, V 60 Case control Inpatients, Seizure type, neurological signs, duration 14 of 60 (23%) AWS: patients in whom
1997 study neurological of intoxication, CT scan, EEG, with seizures occurred after an
unit proportion episode AW defined as a
fixed by period of abstinence (or
selection of severe alcohol deprivation)
control group lasting from 48 hours to 7
size days in most cases
associated with withdrawal
symptoms (tremor,
confusion, delirium)
Bleich et al, 2006 V 88 Prospective Inpatient Homocysteine 18/88 (21%) CIWAAr

cohort study admitted for first onset
detoxification seizure
Brower et al, 1994 V 84 Retrospective Inpatient List of withdrawal symptoms used as 75/84 (89%) Withdrawal symptoms
cohort study admitted for variables (disorientation or confusion), with shakes or
detoxification depressed mood, diaphoresis, tremors, 4/84
hallucinations, headache, insomnia, (5%)
daytime sleepiness, irritability, nausea or hallucinations
vomiting, psychomotor agitation,
seizures, tremors, weakness, high blood
pressure (systolic > 140 mm Hg or
diastolic > 90 mm Hg), pulse > 100, and
temperature > 99.6"F
Brown et al, 1988 V 50 Retrospective Inpatients Repeated alcohol withdrawal 50% seizures Withdrawal seizures
case control admitted to by study
study detoxification, design
psychiatry or
medical
surgical units
Buljan et al, 1996 V 78 Case control Not reported Age, ethnicity, amount of alcohol Not reported DSMIV criteria, ICD10
study consumer per day, tolerance to alcohol,
neurotransmitters
Burapakajornpong V 19 Prospective Inpatient Physician illness, psychiatric illness, Of 10/19 (53%) CIWAAr score
et al, 2011 cohort study admitted for history of epileptic seizures, with AWS
detoxification
Donovan et al, V 1335 Prospective Outpatients Tolerance, withdrawal symptoms, Zone 2: 3 zones of AUDIT total score
2006 cohort study alcohol physiological dependence, severity of 60/1335 (4%) compared; 8–15, 16–19, 20–
dependent dependence (mild, mod, severe), early Zone 3: 40
individuals onset (<25 years), prior treatment, 141/1335(11%)
entering out normal GGT, CDT normal, endorsing Zone 4:
patient abstinence goals 1134/1335
treatment (85%)
Essardas et al, V 72 Prospective Inpatients Seizures on admission, seizures as first Seizures: 33/72 DT= Freixa AWS score 1836
1994 cohort study admitted for manifestation of AW, history of DT (46%) Mild AW: Freixa AWS score
AWS DT: 36/72 <18
(50%)
Eyer et al, 2011 V 827 from 2691 Retrospective Inpatient Withdrawal severity post admission, 21/827 (2.5%) CIWAAr
Downloaded 2022125 7:30 A Your IPreviewed
charts is 200.130.40.29
cohort study admitted for withdrawal seizures as the cause of seizures, 9/827
Severe Alcohol Withdrawal Syndrome, David L. Simel detoxification admittance, serum potassium, platelet (1%) Page 22 / 41
©2022 American Medical Association. All Rights Reserved. Terms of Usecount, • Privacy Policy
structural • Notice • Accessibility
brain lesions
Ferguson et al, V 200 Retrospective Inpatients Days since last drink, concurrent acute 48/200 (24%) Severest form of alcohol
Essardas et al, V 72 Prospective Inpatients Pontificia
Seizures on admission, seizures as first Universidade
Seizures: 33/72 Catolica
DT= Freixa de Campinas
AWS score 1836
1994 cohort study admitted for manifestation of AW, history of DT (46%) Mild AW: Freixa AWS score
Access Provided by:
AWS DT: 36/72 <18
(50%)
Eyer et al, 2011 V 827 from 2691 Retrospective Inpatient Withdrawal severity post admission, 21/827 (2.5%) CIWAAr
charts reviewed cohort study admitted for withdrawal seizures as the cause of seizures, 9/827
detoxification admittance, serum potassium, platelet (1%)
count, structural brain lesions
Ferguson et al, V 200 Retrospective Inpatients Days since last drink, concurrent acute 48/200 (24%) Severest form of alcohol
1996 cohort study treated for medical illness delirium withdrawal using an AW
AWS or tremens; assessment instrument
detoxification 4/200 (2%) derived from DSM 3
death
Foy et al, 1988 V 2046 Prospective Inpatients Sex, withdrawal assessment scale 162/2046 (8%) Clinical criteria for risk of
cohort study admitted to at least one withdrawal: Current
general ward criterion for admission with an alcohol
risk of related diagnosis; past
withdrawal history of withdrawal; a
blood alcohol level of 0.2 %
without impairment of
consciousness; and
consumption of > 100 g
alcohol/day. Clinically
significant withdrawal: An
episode of hyperexcitability
yielding a withdrawal score
of ≥ 10 occurring in a patient
who had one or more of the
clinical criteria. Complicated
AW: AW complicated by
seizures, hallucinations,
delirium or a combination.
Foy et al, 1995 V 1353 Prospective Inpatients Sex, age 193/1353 CAST tool score ≥10,
cohort study admitted to (14%) complicated AW =
general withdrawal complicated by
surgical or seizures, hallucinations,
medical delirium.
wards with an
alcohol
related
diagnosis
JarqueLopez et V 247 Cohort study Inpatients Sex 87/247 (35%) Not specified
al, 2001 admitted to DTs
medical ward
Jochum et al, V 40 Case Control Inpatient Primary education (≤10 years of school), 20/40 (50%) AWS scale (Wetterling 1997,
2010. (Cerebral study males Secondary education (>10 years at 2006)
Autoregulation) admitted for school)
detoxification
Jochum et al, V 90 Case Control Inpatient Hypertension, chronic gastritis, peptic 30/90 (33%) AW Banger score,
2010. (Pain study males ulcers, brain injury with unconsciousness Wetterling AW scale
Sensitivity) admitted for in the past, chronic pain, alcoholrealted
detoxification medical disorders requiring current
treatment,
Kim et al, 2015 V 97 Retrospective Inpatients Sex, History of seizures, presence of 34/97 (35%) DT DSMIV criteria
cohort study with seizures structural lesion, Platelet (OR, sens,
related to AW specificity), Homocysteine (OR, sens,
specificity)
Severe
LasoAlcohol
et al, 1990Withdrawal
V Syndrome,
28 David L. Prospective
Simel Inpatient Hypokalemia (K <3.5 mmol/L) 13/28 (46%) AW scores based Page 23
on system / 41
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Reserved.
study Terms of Use • Privacy Policy • Notice • Accessibility
alcoholics presented in study. DT
diagnosed if score >27
detoxification medical disorders requiring current
treatment, Pontificia Universidade Catolica de Campinas
Access Provided by:
Kim et al, 2015 V 97 Retrospective Inpatients Sex, History of seizures, presence of 34/97 (35%) DT DSMIV criteria
cohort study with seizures structural lesion, Platelet (OR, sens,
related to AW specificity), Homocysteine (OR, sens,
specificity)
Laso et al, 1990 V 28 Prospective Inpatient Hypokalemia (K <3.5 mmol/L) 13/28 (46%) AW scores based on system
cohort study alcoholics presented in study. DT
diagnosed if score >27
Lechtenberg et al, V 500 Prospective Inpatients Number of illicit drugs used 55/500 (11%) No definition of AW or AW
1992 cohort study admitted for had AW seizure
detoxification seizures
Lukan et al, 2002 V 104 Retrospective Inpatients Sex, white race, Age >40, BAC ≥43.4 104/1856 (6%) DT (Diagnostic coding from
case control who mmol/L, type of insurance, mechanism of registry)
study developed DT injury, injury severity score ≥ 14, GCS
during score ≤ 7, ICU admission, Hospital
hospital stay disposition
or who
presented
with a
positive
blood alcohol
concentration
Maxson et al, 1999 V 321 Prospective Postop Alcoholic 9/321(3%) No definition of AW

cohort study inpatients
admitted to
ICU
MayoSmith et al, V 1044 Prospective Inpatients History of AW seizures, no prior 11/1044 (1%) Grand Mal Seizures
1995 case control with seizures detoxifications, 3 or more prior
study admitted for detoxifications, history of DTs,
detoxification
Metcalfe et al, V 142 Prospective Inpatients Sex, drinking alone 11/142 (8%) Complicated AW if
1995 cohort study admitted for convulsions, visual
detoxification hallucinations or
disorientation occurred,
used WCAWAS and SADQ
scores
Newsom et al, V 1231 Prospective Inpatients Recent psychotropic medication used, 20/1231 (2%) AW seizure (no definition
1979 cohort study admitted for seizure history provided)
detoxification
Pach et al, 2014 V 88 Cohort study Inpatient Hypoglycemia, normal glucose, impaired 37/88 (42%) Degree of AW using CIWAAr
men treated glucose tolerance and diabetes CIWAAr ≥25 ≤24 points and ≥25 points
for AW points
Rathlev et al, 2000 V 105 Retrospective Emergency Gender, History of alcohol related 31/105 (30%) Recurrent alcohol related
case control department seizure, history of nonalcohol related seizure (if had seizure during
study patients with seizure, ethanol intake ≤ 757 mL, ethanol 6hour emergency
seizure in intake > 757 mL, duration of ethanol department observation)
setting of abuse, ethanol level
alcohol abuse
Reoux et al, 2002 V 118 Prospective Inpatients Past occurrence of DT, Morning drinking 55/118 (47%) Clinically significant AWS
cohort study admitted for daily/almost daily, defined as CIWAAr score >9
detoxification
Schuckit et al, V 1648 Retrospective Alcoholics Sex, race, marital status, psychiatric 211/1648 History of DT or severe
1995 cohort study from illness diagnosis, alcohol dependence, (13%) withdrawal (selfreported
treatment antisocial personality disorder, other using SSAGA instrument
Severe Alcohol Withdrawal Syndrome, David L. Simel facilities, substance dependence, major depressive standardized instrument)
Page 24 / 41
©2022 American Medical Association. All Rights Reserved. Terms of Usedisorder,
alcoholic substances
• Privacy Policy used
• Notice • Accessibility
relatives and (amphetamines, cannabinols, cocaine,
controls later opiates, sedatives/hypnotics, IV drug use),
Reoux et al, 2002 V 118 Prospective Inpatients Past occurrence of DT, Morning drinking 55/118 (47%) Clinically significant AWS
cohort study admitted for daily/almost daily, Pontificia Universidade Catolica
defined descore
as CIWAAr Campinas
>9
detoxification Access Provided by:
Schuckit et al, V 1648 Retrospective Alcoholics Sex, race, marital status, psychiatric 211/1648 History of DT or severe
1995 cohort study from illness diagnosis, alcohol dependence, (13%) withdrawal (selfreported
treatment antisocial personality disorder, other using SSAGA instrument
facilities, substance dependence, major depressive standardized instrument)
alcoholic disorder, substances used
relatives and (amphetamines, cannabinols, cocaine,
controls later opiates, sedatives/hypnotics, IV drug use),
discovered to medical conditions (fair or poor general
be alcoholics health, head injury, liver disease, gastritis,
pancreatitis, cardiomyopathy, peripheral
neuropathy), psychiatric symptoms from
alcohol use (memory problems, feelings
of depression, feelings of anxiety, feelings
of paranoia)
Thaller et al, 1999 V 78 Case Control Inpatients, Duration of continuous drinking, 39/78 (50%) AWS DSMIV, ICD 10
Study males tolerance to alcohol, MCVE (Increased,
admitted for decrease normal), Increased GGT,
detoxification Increased SGOT, Increased SGPT, HDLC
(decreased, normal, increased), Feritine
(decreased, normal, increased), Increased
CDT, simultaneous increase of GGT and
MCVE, simultaneous increased in GGt,
SGOT and MCVE
Victor et al, 1967 V 180 Prospective Alcoholic Abnormal EEG 130/180 (72%) Alcoholic epilepsy (no
case control inpatients definition)
study (controls
were patients
with
idiopathic
epilepsy)
Wetterling et al, V 159 Prospective Inpatients Sex, history of head trauma, liver disease, Mild AW AW severity (scale not
1994 cohort study admitted for pancreatitis, delirium, seizure before AWS, 91/161 (57%) reported)
detoxification polyneuropathy, ataxia, chloride <96, Mod AW
to psychiatric Sodium <136, calcium <2.2, potassium 42/161 (26%)
ward <3.6, ALT >50, GGT >100 Delirium
19/161 (12%)
Wetterling et al, V 161 Prospective Inpatients Sex Mild AW AW severity (using AWS
1998 cohort study admitted for 43/161 (27%) scale)
detoxification Mod AW
46/161 (29%)
Severe AW
39/161 (24%)
Wetterling et al, V 723 Prospective Inpatients Age No/Mild AW: AWS scale and DT
2001 cohort study admitted for 298/723 (41%) (Wetterling 1997)
detoxification Mod AW:
264/723(37%)
Severe AW:
100/723 (14%)
DT: 61/723
(8%)
Wojnar et al, 1999 V 1179 patients Retrospective Inpatients History of head injury, neurological 52/2186 (2%) AW seizures
Kindling with 2186 cohort study diagnosed disorders, alcohol liver disease;
hospitalizations with AW or concomitant alcohol liver disease,
AW delirium neurological disorders, pneumonia, ALT
>25,

Wojnar et al, 2001 V 1213 Retrospective Inpatients Age DT: 293/1213 AW seizures and fully
cohort study diagnosed (24%) developed DT
with AW or AW seizure:
AW delirium 47/1213 (4%)
Wojnar et al, 1999 V 1179 patients Retrospective Inpatients History of head injury, neurological Pontificia
52/2186 (2%) AW seizures
Universidade Catolica de Campinas
Kindling with 2186 cohort study diagnosed disorders, alcohol liver disease;
Access Provided by:
hospitalizations with AW or concomitant alcohol liver disease,
AW delirium neurological disorders, pneumonia, ALT
>25,
Wojnar et al, 2001 V 1213 Retrospective Inpatients Age DT: 293/1213 AW seizures and fully
cohort study diagnosed (24%) developed DT
with AW or AW seizure:
AW delirium 47/1213 (4%)
Wright et al, 2006 V 56 Retrospective Inpatients Age, ethnicity, employment status, family 28/56 (50%) DT (ICD9 codes)
case control with AW history of alcoholism, history of DT
study delirium
(Cases) or AW
(controls)
Abbreviations: AUDIT = Alcohol Use Disorders Identification Test, ETOH = ethyl alcohol, DT = Delirium Tremens, AW = Alcohol Withdrawal, DSM = Diagnostic Statistical Manual, AWS = Alcohol
Withdrawal Syndrome, BP = blood pressure, ICD = International Statistical Classification of Diseases and Related Health Problems, ICU = Intensive care unit, EMR = electronic medical records, HR =
rapid heart rate, SAW = severe alcohol withdrawal, EEG = electroencephalography, GGT = gammaglutamyl transferase, CDT = carbohydratedeficient transferrin, OR = odds ratio, GCS = Glasgow
Coma Scale, WCAWAS = Windsor Clinic Alcohol Withdrawal Assessment Scale, SADQ = Severity of Alcohol Dependence Questionnaire, SSAGA = SemiStructured Assessment for the Genetics of
Alcoholism, MCVE = Mean corpuscular volume blood test, SGOT = Serum glutamic oxaloacetic transaminase, SGPT = Serum glutamic pyruvic transaminase, HDLC = Highdensity lipoprotein
cholesterol (blood test), CIWAAr = Clinical Institute Withdrawal Assessment for Alcohol, in all but 3 of the 14 included studies via the use of either a) CIWAAr (cutoff range: ≥6 to ≥20; see eTable 1),
b) DSM (III or IV), or c) ICD9 code for including severe withdrawal syndrome (1051 cases), alcohol withdrawal seizure(s) (53 cases), and delirium tremens (251 cases). The three exceptions applied
the following measures: Wetterling et al. (2006)14 used the AW Scale from Wetterling et al. (1997)13; Brathen et al. (2000)2 used AUDIT (score≥8) along with laboratory markers and clinician ratings
for likelihood of having a seizure However, "AUDIT was applied as the gold standard to which sensitivity and specificity of the various markers were related;" Kapur et al. (2010)40 used a patient
database to determine if patient required treatment for signs or symptoms of withdrawal or had an alcohol withdrawal treatment sheet in their chart.
QUADAS Assessment of Included articles applied to Alcohol withdrawal
1. Was the spectrum of patients representative of the patients who will receive the test in practice? Patients at risk of withdrawal (condition) = yes. If no risk of AW = no.
2. Were selection criteria clearly described? If reproducible = yes.
3. Is the reference standard likely to correctly classify the early AW disease? If standard laboratory techniques used to diagnose AW = yes. If ambiguous = no.
4. Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests? If AW testing and
assessment done as part of the same consultation or research study site visit = yes. If reported duration between assessment and AW testing more than 2 days = no.
5. Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis? Yes or no.
6. Did patients receive the same reference standard regardless of the index test result? Yes or no.
7. Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)? Yes or no.
8. Was the execution of the index test described in sufficient detail to permit replication of the test? If description adequately described to allow for replication, including a symptom
definition, = yes.
9. Was the execution of the reference standard described in sufficient detail to permit its replication? If laboratory approach to diagnosing AW described then = yes.
10. Were the index test results interpreted without knowledge of the results of the reference standard?
11. Were the reference standard results interpreted without knowledge of the results of the index test?
12. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? When the test executer had as much info as in clinical
practice = yes.
13. Were uninterpretable/intermediate test results reported? Not reported, numbers are correct = yes
14. Were withdrawals from the study explained? Not reported, numbers are correct = yes
a1. Did the study provide a clear definition of what was considered to be a 'positive' result?**
a2. Was treatment withheld until both the index test and reference standard were performed?**
a3. Was Clinical Institute Withdrawal Assessment for Alcohol (CIWA) performed?**
*all items are scored yes, no or unclear
**additional QUADAS tool item
QUADAS tool results (see eTable 2 for QUADAS tool items)
QUADAS tool items
Author, year
Downloaded 2022125
1 7:30 2A Your3 IP is 200.130.40.29
4 5 6 7 8 9 10 11 12 13 14 a1 a2 a3
published
Berggren et al, + U U + + U U U U U U U U U U U
20091
QUADAS tool results (see eTable 2 for QUADAS tool items)
Access Provided by:
QUADAS tool items
Author, year
1 2 3 4 5 6 7 8 9 10 11 12 13 14 a1 a2 a3
published
Berggren et al, + U U + + U U U U U U U U U U U
20091
Brathen et al, + + + U U U U + + U U U U U U U d
20002
Dolman et al, + + U + + U U U U U U U U U U +
20053
Fiellin et al, 20024 + + U U U U U + +
Kapur et al, 20105 + + + U + + + U + + U
Kraemer et al, + + U + + + + + U +
19976
Kraemer et al, + + + U + U + + + + +
20037
Lee et al, 20058 + + + + + + + + + U
Maldonado et al, + + + + + + + + + + + + + + + U +
20159
Monte et al, + + + + + U U U + U + U
200910
Pecoraro et al, + U U U U + + U U + U U + U +
201411
Salottolo et al, N + + U + + U U U U U + + + U +
201712
Wetterling et al, + U U U U U U U U U U U U U U U +
199713
Wetterling et al, + + + + + + + + + + + + e
20061 4
Studies not included in metaanalysis
Ballenger et al, + U + + + U U + + U
19781 5
Barrio et al, + + U U U U U U U U U U
20041 6
Bartolomei et al, U + U U U U U U U U U U U U U U
19971 7
Bleich et al, + + + U + U U U U U U U U U U +
20061 8
Brower et al, + + U U U U U U U U U U U U U U
19941 9

Severe Alcohol
Brown et al, Withdrawal
+ Syndrome,
+ U David U L. Simel
U U U U U U U U U U Page
U 27 / 41
©2022 American
198820 Medical Association. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Buljan et al, U U U U U U U U U U U U U U U U
19971 7

Bleich et al, + + + U + U U U U U U U U U U +
Access Provided by:
20061 8
Brower et al, + + U U U U U U U U U U U U U U
19941 9
Brown et al, + + U U U U U U U U U U U U U
19882 0
Buljan et al, U U U U U U U U U U U U U U U U
19962 1
Burapakajornpong + + + U U U U U U U U U U U U U +
et al, 20112 2
Donovan et al, + + U U U U U U U U U U U U U U +a
20062 3
Essardas et al, + U U U + U U U U U U U U U U U
19942 4
Eyer et al, 20112 5 + U U U U U U U U U U U U U U +
Ferguson et al, + U U + U U U U U U U U U U U +
19962 6
Foy et al, 19882 7 U + + U + U + + U +b
Foy et al, 19952 8 + + + + + + U + + + + U
JarqueLopez et + + + + U U + + + U
al, 20012 9
Jochum et al, 2010 U + + + + + U + + + U U

(Cerebral
Autoregulation)3 0
Jochum et al, 2010 U + + + + U + + U +

(Pain Sensitivity)3 1
Kim et al, 20153 2 + + + U + + U + + +
Laso et al, 19903 3 + + + + + + + + + +
Lechtenberg et al, + + U + + + + + + + + U
19923 4
Lukan et al, U U U + U U U + U + U U U U
20023 5
Maxson et al, + + U U U + + + + + + U
19993 6
MayoSmith et al, + + + + U + +
19953 7
Metcalfe et al, + U U U U U U U + + U c
19953 8
Newsom et al, + U U U U U U U U U U U
197939
Downloaded 2022125
Pach et al, 201440 7:30 +A YourUIP is 200.130.40.29
U U U U U U U U U U U U U +
©2022 American
Rathlev et al, Medical
+ Association.
+ U All Rights
U Reserved.
U U Terms
of Use
U • Privacy
U Policy
U • Notice
U • Accessibility
+ U U U U
20004 1
Metcalfe et al, + U U U U U U U + + U c
19953 8 Pontificia Universidade Catolica de Campinas
Access Provided by:
Newsom et al, + U U U U U U U U U U U
197939
Pach et al, 20144 0 + U U U U U U U U U U U U U U +
Rathlev et al, + + U U U U U U U U + U U U U
20004 1
Reoux et al, + + U U U U U U U U U U +
20024 2
Schuckit et al, + + U + U U U U + U U U U
19954 3
Thaller et al, + + + U U U U U U U + U U U U
19994 4
Victor et al, 19674 5 U U U U U U U U U U U U U U U U
Wetterling et al, + U + U + U U U U U + U U U
19944 6
Wetterling et al, + U + U U + + U U U U U U
19984 7
Wetterling et al, + U U U U U U U U U U U U U U
20014 8
Wojnar et al, 1999 + U U U U U U U U U U U U U U U

(Kindling)4 9
Wojnar et al, + + U U U U U U U U U U U U U +
20015 0
Abbreviations: +, Bias assessment adequately addressed; –, Bias assessment inadequately addressed; U, unknown; aCIWAAr used but as inclusion criteria but not for follow up; bModified version
of the CIWA; cUsed a modified version of CIWAAr: WCAWAS; The Revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWAAR) is a 10item scoring system used to determine the
severity of alcohol withdrawal symptoms; dCIWA not mentioned, but used antiepileptic drugs such as Carbamazepine or Valproate. eAssessment based on unpublished information from authors.
Results from individual studies – categorical variables
Reference No. with condition/sample Sensitivity (95% Specificity (95% LR+ (95%
Finding LR (95% CI)
# size (%) CI) CI) CI)
Symptoms and features of patient history
Condition under study: DT
Gender (male) 10 147/303 (48.5%) 0.87 (0.810.92) 0.11 (0.070.17) 0.98 (0.90 1.2 (0.642.2)
1.1)
Condition under study: seizure
Gender (male) 2 53/158 (33.5%) 0.66 (0.530.77) 0.54 (0.440.63) 1.5 (1.11.9) 0.63 (0.41
0.95)
Condition under study: AWS
Gender (male) 11 160/375 (42.7%) 0.92 (0.870.95) 0.82 (0.760.87) 5.20 (3.96.9) 0.10 (0.06
0.17)

Condition under study: SAWS
Gender (male)12 12 96/28070 (0.003%) 0.85 (0.770.91) 0.42 (0.420.43) 1.5 (1.41.6) 0.36 (0.23
0.56)
0.95)
Condition under study: AWS Access Provided by:
Gender (male) 11 160/375 (42.7%) 0.92 (0.870.95) 0.82 (0.760.87) 5.20 (3.96.9) 0.10 (0.06
0.17)
Gender (male)12 12 96/28070 (0.003%) 0.85 (0.770.91) 0.42 (0.420.43) 1.5 (1.41.6) 0.36 (0.23
0.56)
Raceethnicity (white) 4 12/60 (20%) 0.80 (0.520.96) 0.20 (0.100.35) 1.0 (0.75 1.0 (0.313.22)
1.34)
Raceethnicity (white)12 12 66/28070 (24%) 0.58 (0.490.68) 0.50 (0.500.51) 1.8 (1.11.3) 0.82 (0.71
0.95)
Raceethnicity (white)1 1 11 164/689 (23.8%) 0.74 (0.670.79) 0.32 (0.270.36) 1.1 (0.971.2) 0.84 (0.651.1)
History of DT 1 10/316 (3.2%) 0.40 (0.170.69) 0.93 (0.900.95) 5.6 (2.413) 0.65 (0.391.1)
History of DT 4 15/60 (25%) 0.47 (0.250.70) 0.76 (0.620.86) 1.9 (0.914.0) 0.71 (0.431.2)
History of DT 8 59/178 (33.1%) 0.27 (0.170.39) 0.90 (0.830.94) 2.7 (1.45.3) 0.81 (0.69
0.96)
History of severe alcohol withdrawal 4 15/60 (25%) 0.53 (0.300.75) 0.73 (0.590.84) 2.0 (1.03.9) 0.64 (0.361.1)
syndrome
History of severe alcohol withdrawal 10 147/303 (48.5%) 0.24 (0.180.32) 0.84 (0.770.89) 1.5 (0.942.4) 0.91 (0.811.0)
syndrome
History of seizures 4 15/60 (25%) 0.33 (0.150.58) 0.8 (0.660.89) 1.7 (0.664.2) 0.83 (0.571.2)
History of seizures 1 10/334 (3%) 0.0 (0.00.28) 0.90 (0.860.93) 0.47 (0.03 1.1 (0.931.2)
7.2)
Number of seizure: 0 10 147/303 (48.5%) 0.43 (0.350.51) 0.31 (0.240.39) 0.60 (0.50 1.8 (1.42.4)
0.78)
Number of seizure: 1 2 10 147/303 (48.5%) 0.41 (0.330.49) 0.74 (0.670.80) 1.6 (1.42.1) 0.79 (0.68
0.94)
Number of seizure: >=3 10 147/303 (48.5%) 0.16 (0.110.23) 0.94 (0.890.97) 2.8 (1.45.9) 0.89 (0.82
0.96)
History of alcohol misuse 2 53/158 (33.5%) 0.57 (0.440.69) 0.99 (0.951) 59 (8.3424) 0.44 (0.32
0.60)
Illegal drug use 2 53/158 (33.5%) 0.28 (0.180.41) 0.97 (0.920.99) 9.9 (3.033) 0.74 (0.62
0.88)
Signs and physical examination findings
Systolic blood pressure ≥145mmHg 4 15/60 (25%) 0.60 (0.360.80) 0.73 (0.590.84) 2.3 (1.24.3) 0.55 (0.291.0)
Systolic blood pressure ≥150mmHg 10 127/281 (45.2%) 0.37 (0.29 – 0.46) 0.81 (0.74 – 0.87) 1.7 (1.32.3) 0.78 (0.69
Downloaded 2022125 7:30 A Your IP is 200.130.40.29 0.89)
©2022 American Medical Association. All Rights
Systolic blood pressure ≥140mmHg 8
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59/178 (33.1%)
• Notice • Accessibility
0.42 (0.300.55) 0.68 (0.590.76) 1.3 (0.891.9) 0.85 (0.661.1)

Condition under study: DT Access Provided by:
Systolic blood pressure ≥145mmHg 4 15/60 (25%) 0.60 (0.360.80) 0.73 (0.590.84) 2.3 (1.24.3) 0.55 (0.291.0)
Systolic blood pressure ≥150mmHg 10 127/281 (45.2%) 0.37 (0.29 – 0.46) 0.81 (0.74 – 0.87) 1.7 (1.32.3) 0.78 (0.69
0.89)
Systolic blood pressure ≥140mmHg 8 59/178 (33.1%) 0.42 (0.300.55) 0.68 (0.590.76) 1.3 (0.891.9) 0.85 (0.661.1)
Blood Alcohol Concentration ≥ 2 0 0 5 380/3729 (10.2%) 0.48 (0.430.53) 0.86 (0.850.87) 3.5 0.61 (0.55
(3.04.0) 0.67)
Composite measure
Prediction of Alcohol Withdrawal Severity 9 29/403 (7.2%) 0.93 (0.77 – 0.99) 0.99 (0.98 – 0.99) 174 (43696) 0.069 (0.02
Scalea ≥4 0.26)
LARS10b > 914 14 19/100 (19%) 0.95 (0.770.99) 0.93 (0.880.94) 12 (5.827) 0.05 (0.00.37)
Abnormal vital sign 12 42/28070 0.37 (0.280.47) 0.82 (0.820.83) 2.10 (1.72.7) 0.76 (0.66
(0.001%) 0.88)
Abbreviations: LR = Likelihood Ratio; CI = Confidence Interval. LR calculated directly from 2x2 tables and then rounded. LARS = Luebeck Alcohol Risk Scale
aPAWWS is a 10item scale (possible score range: 0–10) for predicting risk of Alcohol Withdrawal Syndrome in hospitalized medically ill patients. A score of 4 or greater is considered to identify those
at high risk.
b LARS10 is a 10item rating scale (possible score range: 0–14) to predict the severity of alcohol withdrawal syndrome. A score 9 or greater is considered to identify patients with severe AWS.
Results from individual studies – continuous variables
Finding Reference # Mean+ SD+ n+ Mean SD n N
Age 10 45.3 12.1 147 46.3 12.9 156 303
Condition under study: seizures
Age 2 39.8 13.5 53 47.6 17.6 105 158
Age 11 54.7 14.2 223 61.7 18.4 466 689
A g e1 4 14 47.6 10.2 20 47.6 9.9 80 100
Heart rate 1 88 15 10 87 18 324 334
Heart rate 4 92 15 91 45 60
Heart rate 10 95 17.5 147 94.8 12.3 156 303

Severe
SBPAlcohol Withdrawal Syndrome,
1 David L. Simel 120 22 10 136 23 324 334
Page 31 / 41
SBP 4 146 15 137 45 60
Heart rate 1 88 15 10 87 18 by:
Access Provided 324 334
Heart rate 4 92 15 91 45 60
Heart rate 10 95 17.5 147 94.8 12.3 156 303
SBP 1 120 22 10 136 23 324 334
SBP 4 146 15 137 45 60
SBP 10 140 19.1 147 133 18.2 156 303
DBP 1 77 12 10 84 15 324 334
DBP 10 80.6 13.5 147 76.4 12.9 156 303
Laboratory findings
ALT (IU/L) 10 67.4 61.4 147 65.1 47.5 156 303
ALT (IU/L) 1 135.3 105.9 10 88.2 258.8 324 334
AST (IU/L) 10 124.7 205.1 147 112.8 111.7 156 303
AST (IU/L) 1 188.2 176.5 10 88.2 111.8 324 334
GGT (u/L) 10 457.9 497.1 147 446.2 249 156 303
GGT (u/L) 1 863.8 1679.7 10 216 371.9 324 334
Platelet (×109/L) 10 144.85 70.53 147 170.71 78.13 156 303
Platelet (×109/L) 1 149 100 10 201 88 324 334
Potassium (mmol/L) 10 3.7 0.5 147 3.8 0.5 156 303
Potassium (mmol/L) 1 3.6 0.7 10 3.9 0.4 324 334
Abbreviations: Mean+ = mean of the finding for patients with the condition; SD+ = standard deviation of the finding for patients with the condition; n+ = number of patients with the condition;
Mean = mean of finding for patients without the condition; SD = standard deviation of the finding for patients without the condition; n = number of patients without the condition;
Results from individual studies – categorical variables reported only in 1 highquality study
Reference No. with condition/sample Sensitivity Specificity LR+ (95% LR (95%
Finding
# size (%) (95% CI) (95% CI) CI) CI)
History of a SAWS and at least 1 adverse clinical feature 4 15/60 (25%) 0.40 (0.200.64) 0.91 (0.790.96) 4.5 (1.514) 0.66 (0.43
1.0)
History of seizures 1 8/333 (2%) 0.38 (0.140.70) 0.91 (0.870.94) 4.4 (1.711) 0.68 (0.40
1.2)
Substance use disorder, other than alcohol 9 29/403 (7%) 0.07 (0.020.22) 0.99 (0.971.0) 6.4 (1.234) 0.94 (0.85
1.0)
Any substance or alcohol use disorder 9 29/403 (7%) 0.14 (0.060.31) 0.98 (0.960.99) 5.7 (1.918) 0.88 (0.76
Downloaded 2022125 7:30 A Your IP is 200.130.40.29 1.0)
©2022
AnyAmerican
psychiatricMedical
disorder Association. All Rights Reserved.
9 Terms 29/403
of Use • Privacy Policy • Notice
(7%) • Accessibility
0.76 (0.580.88) 0.77 (0.720.81) 3.3 (2.5 0.31 (0.16
4.4) 0.6)
Condition under study: SAWS Pontificia Universidade Catolica de Campinas
Access Provided by:
Substance use disorder, other than alcohol 9 29/403 (7%) 0.07 (0.020.22) 0.99 (0.971.0) 6.4 (1.234) 0.94 (0.85
1.0)
Any substance or alcohol use disorder 9 29/403 (7%) 0.14 (0.060.31) 0.98 (0.960.99) 5.7 (1.918) 0.88 (0.76
1.0)
Any psychiatric disorder 9 29/403 (7%) 0.76 (0.580.88) 0.77 (0.720.81) 3.3 (2.5 0.31 (0.16
4.4) 0.6)
Mood disorders 9 29/403 (7%) 0.48 (0.310.65) 0.84 (0.80.87) 3.0 (1.9 0.62 (0.43
4.7) 0.88)
Anxiety disorders 9 29/403 (7%) 0.07 (0.020.22) 0.97 (0.950.98) 2.6 (0.60 0.96 (0.87
11) 1.1)
Laboratory findings
Blood Alcohol Concentration ≥ 2 0 0 5 380/3729 (10%) 0.48 (0.430.53) 0.86 (0.850.87) 3.5 (3.0 0.61 (0.55
4.0) 0.67)
Blood urea nitrogen (BUN at Admission) 8 29/148 (20%) 0.28 (0.150.46) 0.92 (0.860.96) 3.3 (1.4 0.79 (0.63
7.6) 1.0)
Thrombocytopenia (<150 * 109 / L ) 1 10/334 (3%) 0.70 (0.400.89) 0.69 (0.640.74) 2.2 (1.4 0.44 (0.17
3.4) 1.1)
Condition under study: Seizure
Thrombocytopenia (<150 * 109 / L ) 1 8/333 (2%) 0.75 (0.410.93) 0.69 (0.640.74) 2.4 (1.6 0.36 (0.11
3.7) 1.2)
Composite measures
Independent clinical correlates ≥ 6 7 71/284 (25%) 0.13 (0.070.23) 1.0 (0.981.0) 27 (3.5 0.88 (0.80
209) 0.96)
Rating scale for the assessment of the alcoholwithdrawal 12 27/256 (11%) 0.78 (0.590.90) 0.9 (0.850.93) 7.4 (4.811) 0.25 (0.12
s y n d r o m ea ≥1 0 0.50)
Independent clinical correlates = 4 7 71/284 (25%) 0.25 (0.160.36) 0.96 (0.920.98) 6.8 (3.115) 0.78 (0.68
0.89)
Total LARSb ≥1 6 14 20/100 (20%) 1.0 (0.831.0) 0.88 (0.830.88) 7.5 (4.313) 0.03 (0.0
0.42)
LARS10b ≥ 914 14 19/100 (19%) 0.95 (0.770.99) 0.93 (0.880.94) 12 (5.827) 0.05 (0.0
0.37)
LARS11b ≥ 1 0 14 19/100 (19%) 0.95 (0.770.99) 0.89 (0.840.9) 8.4 (4.516) 0.06 (0.0
0.38)
Abnormal vital sign12 12 42/28070 0.37 (0.280.47) 0.82 (0.820.83) 2.1 (1.7 0.76 (0.66
(0.001%) 2.7) 0.88)
Downloaded
NB. Only signs or2022125 7:30
symptoms with A Your
a LR+>2 IP is are
or an LR<0.5 200.130.40.29
reported.
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of the All Rights
alcoholwithdrawal syndromeReserved. Terms
(AWS Scale) is an ofrating
11item Usescale,
• Privacy
in whichPolicy • isNotice
each item • Accessibility
scored from 0 –3 for somatic symptoms or 0–4 for mental symptoms
(total possible score range: 0–38). A score of 5 or less is considered to identify patients with mild AWS; a score of 6–9 is considered to identify patients with moderate AWS; and a score of 10 or
greater is considered to identify patients with severe AWS.
Abnormal vital sign12 12 42/28070 Pontificia0.82
0.37 (0.280.47) Universidade
(0.820.83) Catolica
2.1 (1.7 de
0.76Campinas
(0.66
(0.001%) 2.7) 0.88)
Access Provided by:
NB. Only signs or symptoms with a LR+>2 or an LR<0.5 are reported.
a: Rating scale for assessment of the alcoholwithdrawal syndrome (AWS Scale) is an 11item rating scale, in which each item is scored from 0 –3 for somatic symptoms or 0–4 for mental symptoms
(total possible score range: 0–38). A score of 5 or less is considered to identify patients with mild AWS; a score of 6–9 is considered to identify patients with moderate AWS; and a score of 10 or
greater is considered to identify patients with severe AWS.
b: LARS is a rating scale to predict the severity of alcohol withdrawal syndrome. Different versions of the scale contain 1022 items. On LARS10, a score 9 or greater (possible score range: 014) is
considered to identify patients with severe AWS.
Items of Composite Measures for Alcohol Withdrawal Risk
LARS101 4 PAWSS9 Alcohol Withdrawal Rating Scale1 3
1. Previous withdrawal delirium Part A: Threshold Criteria: Scored 1–3:

(≥3 = 3) 1. Have you consumed any amount of alcohol (i.e., been drinking) within the last 30 days 1. Pulse rate (per min)
2. Previous withdrawal seizures OR did the patient have a +BAL upon admission? <100 =0, 101110 =1, 111120 =2, >120 =3
(≥3 = 3) Part B: Based on patient interview: 2. Diastolic blood pressure (mmHg)
3. Frequent sleep disturbances 2. Have you ever experienced previous episodes of alcohol withdrawal? <95=0, 96100=1, 101105=2, >105=3
during the last week 3. Have you ever experienced alcohol withdrawal seizures? 3. Temperature (°C)
4. Nightmares during the last 4. Have you ever experienced delirium tremens or DT? <37=0, 3737.5=1, 37.638=2, >38=3
week 5. Have you ever undergone alcohol rehabilitation treatment? (i.e., inpatient or out 4. Breathing rate (per min)
5. BAC 1 g/l patient treatment programs or AA attendance) <20=0, 2024=1, >24=2
6. Tremor (despite BAC≥1 g/l) 6. Have you ever experienced blackouts? 5. Sweating
7. Sweating (despite BAC≥1 g/l) 7. Have you combined alcohol with "downers" like benzodiazepines or barbiturates none=0, mild=1, moderate=2, severe=3
8. Pulse rate ≥100/min (despite during the last 90 days 6. Tremor
BAC≥1 g/l) 8. Have you combined alcohol with any other substance of abuse during the last 90 none=0, mild =1, moderate=2, severe=3
9. Polyneuropathy days? Scored 1–4:
10. Ataxia Part C: Based on clinical evidence: 7. Agitation
9. Was the patient's blood alcohol level (BAL) on presentation > 200? None=0, fastening=1, rolling in bed=2, try to leave bed=3,
10. Is there evidence of increased autonomic activity (e.g., HR > 120 bpm, tremor, in rage=4
sweating, agitation, nausea) 8. Contact
short talk possible=0, easily distractible=1, drifting
contact=2, dialogue impossible=3
9. Orientiation (time, place, person, situation)
fully aware=0, one kind=1, two kinds=2, totally
confused=3
10. Hallucinations (optical, acoustic, and tactile)
none=0, suggestive=1, one kind=2, two kinds=3, all
kinds=4
11. Anxiety
none=0, mild=1, severe=2
BAC= blood alcohol concentration; BAL= blood alcohol level; mmHg= millimeters of mercury; g= gram; l= liter; C= Celsius; bpm= beats per minute'
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The Rational Clinical Examination: Evidence­Based Clinical Diagnosis

Severe Alcohol Withdrawal Syndrome

Make the Diagnosis: Severe Alcohol Withdrawal Syndrome

Prior Probability of Severe Alcohol Withdrawal Syndrome

Assessing the Likelihood of Alcohol Withdrawal Syndrome

LR+ (95% CI) LR– (95% CI)

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Part A: Threshold criteria (yes or no; if "yes," proceed with questions)

Part C: Based on clinical evidence (positive findings get 1 point each)

aAdapted and published with permission from Oxford University Press.

Reference Standard Tests

A. Cessation of alcohol use that has been heavy and prolonged

2. Increased hand tremor

8. Generalized tonic­clonic seizures

C. The symptoms in criterion B cause clinically significant distress

D. Symptoms or signs not better explained by another condition

Why This Question Is Important

At­Risk or Heavy Alcohol Usea

2. Increased hand tremor

5. Transient visual, tactile, or auditory hallucinations or illusions

At­Risk or Heavy Alcohol Usea

2. Increased hand tremor

5. Transient visual, tactile, or auditory hallucinations or illusions

8. Generalized tonic­clonic seizures

Alcohol Withdrawal Seizure

a US National Institute on Alcohol Abuse and Alcoholism definition.11

Physiologic Basis for Alcohol Withdrawal

Symptoms and Signs Predictive for SAWS

Search Strategy and Quality Review

Incidence of Alcohol Withdrawal Syndrome

Reliability of the Clinical Diagnosis of Alcohol Withdrawal Syndrome

Risk Factors, Symptoms, and Signs

Risk Factors, Symptoms, and Signs

Likelihood Ratio (95% CI)

Alcohol withdrawal history

No. of epileptic seizures at diagnosis of minor AWS 152 DT

≥ 3 seizures 2.8 (1.4­5.9) DT

1­2 seizures 1.6 (1.4­2.2) DT

0 seizures 0.63 (0.50­0.78) DT

History of SAWS/AWS 250,52 0.24­0.78 0.73­0.91 1.5­2.0 0.64­0.91 DT

History of seizuresc 250,54 0.00­0.38 0.80­0.91 0.47­1.7 0.83­1.1 DT, seizure

PAWSS ≥ 4e 12 0.93 (0.77­0.99) 0.99 (0.98­0.99) 174 (43­696) 0.07 (0.02­0.26)

LARS­10 ≥ 9g 140 0.95 (0.77­0.99) 0.93 (0.88­0.94) 12 (5.8­27) 0.05 (0.0­0.37)

SI conversion factor: To convert BUN to mmol/L, multiply by 0.357.

moderate; and 75%, high).

eSee Box 105­3.

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Age 440,44,51,52 1250 –0.27 (–0.49 to –0.05) Seizure, DT, SAWS

Systolic BPb 252,54 697 –0.70 to 0.38c DT

Diastolic BP 252,54 637 –0.47 to 0.32c DT

Heart rateb 252,54 697 0.01 to 0.06c

GGT 252,54 637 0.03 to 1.41c DT

AST 252,54 637 0.07 to 0.88 DT

Potassium 252,54 637 –0.73 to –0.20c DT

ALT 252,54 637 0.04 to 0.18 DT

Platelet count 252,54 637 –0.59 to –0.35c DT

aSee Supplemental Table 5 for results from individual studies.

cRange of means for participants with the condition.

Symptoms and Signs

Combinations of Symptoms and Signs

The Rational Clinical Examination: EvidenceBased Clinical Diagnosis

8. Generalized tonicclonic seizures

AtRisk or Heavy Alcohol Usea

AtRisk or Heavy Alcohol Usea

8. Generalized tonicclonic seizures

≥ 3 seizures 2.8 (1.45.9) DT

12 seizures 1.6 (1.42.2) DT

0 seizures 0.63 (0.500.78) DT

History of SAWS/AWS 250,52 0.240.78 0.730.91 1.52.0 0.640.91 DT

History of seizuresc 250,54 0.000.38 0.800.91 0.471.7 0.831.1 DT, seizure

PAWSS ≥ 4e 12 0.93 (0.770.99) 0.99 (0.980.99) 174 (43696) 0.07 (0.020.26)

LARS10 ≥ 9g 140 0.95 (0.770.99) 0.93 (0.880.94) 12 (5.827) 0.05 (0.00.37)

eSee Box 1053.

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35. Comprehensive Metaanalysis. Version 2.0. Englewood, NJ: Biostat; 2005.