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Home , Alcohol dependence, Delirium tremens

Netherlands Journal of Critical Care

Copyright © 2012, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received April 2011; accepted February 2012 Review

Alcohol withdrawal and in the

M Paupers*, A Schiemann*, CD Spies

* marco Paupers and Alexander Schiemann contributed equally to this article Universitätsklinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin, Charité -Universitätsmedizin Berlin, Berlin, Germany

Abstract - In intensive care patients, delirium triggered by withdrawal is underestimated despite the fact that it occurs in approximately 10% of all ICU patients. Alcohol withdrawal delirium is the most serious manifestation of alcohol withdrawal and it is associated with even more complications and poor outcome. Therefore, it should be prevented; if it does occur it should be treated as early as possible to avoid negative sequelae, in particular infections, cardiac complications and long-term cognitive dysfunction. In this article we summarize strategies to detect alcohol use disorders and alcohol withdrawal and those for treating alcoholic withdrawal and .

Keywords - ICU, withdrawal, alcohol, delirium, alcohol withdrawal syndrome (AWS)

Introduction This article gives an overview on how to reduce and treat this Besides , alcohol is the most abused drug worldwide [1- potentially life-threatening [18] in critically ill patients 4]. About one-fifth of the patients seen in clinical practice present with an underlying AUD. with an alcohol use disorder (AUD) [2,5]. The prevalence of AUD, i.e. or harmful use and Alcohol use disorders among patients undergoing surgical or diagnostic procedures Alcohol use disorders (AUD) include a wide range of drinking is seen in approximately 20% of cases and nearly half of the behaviours from hazardous use of alcohol to alcohol abuse, surgical patients with AUD have alcohol dependence [6]. Alcohol- harmful consumption, and alcohol dependence. dependent patients usually present alcohol withdrawal after Hazardous use means exceeding a daily alcohol intake of surgery [7]. 60g per day (g alcohol equals mL of drunken alcohol times % In ICU patients, delirium triggered by alcohol withdrawal is of alcohol included in beverage x 0.8). 60g/d of means a frequent complication and seen in approximately 10% of all three to four bottles of and ¾ of a bottle of , respectively. ICU patients. The incidence of postoperative delirium (POD) in This is associated with a higher rate of complications and a poor patients with AUD can reach 50% if not prevented. Effective outcome [8,19,20]. This cut-off is not related to dependency but prevention halves the incidence of POD in patients and - if not it determines the complication threshold for patients undergoing prevented - reduces its severity [8-10]. surgical or interventional procedures. Delirium independent of different etiologies is seen in up to Alcohol abuse is included in the Diagnostic and Statistical 82% of ICU patients and is associated with poor outcome [11]. Manual of Mental Disorders, 4th edition, Text Revision (DSM IV-TR) Its presence in ICU patients is an independent predictor of an [21] and harmful use is included in the International Classification increased duration of mechanical ventilation, length of ICU and of Diseases (ICD-10) criteria [22], not fulfilling the dependence hospital stay [11-14] and overall elevated hospital costs [11,15]. criteria. Moreover, duration of delirium is associated with an increased risk of one-year mortality and in cases of survival, cognitive Alcohol dependence dysfunction [16,17]. Therefore, it is crucial for the clinician to Approximately 10% of all hospitalized patients can be diagnosed as prevent and detect this serious complication early on in order alcohol-dependent [6,23]. Patients with alcohol dependence show to avoid consequences that lead to elevated morbidity and the highest risk of all patients with AUD for severe complications mortality [11]. Evidence suggests that in those patients for whom such as delirium, infection, sepsis, septic shock, postoperative appropriate care and immediate treatment is provided, mortality haemorrhage and long-term cognitive dysfunction [8,16,24-28]. can be reduced [7]. Alcohol dependence have similar DSM IV-TR [21] and ICD- 10 criteria [22]. The ICD-10 diagnosis of alcohol dependence is given if at least three out of six dependence criteria have been Correspondence present together at some time during the last 12 months. DSM-IV- TR requires at least three out of seven symptoms occurring at any CD Spies time in the last 12 months for the diagnosis of alcohol dependence. E-Mail: [email protected]

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Identification of AUD patients eight or more points reveals hazardous or harmful alcohol use Screening patients for AUD is the precondition to taking preventive (ICD-10) [33]. measures and improving outcome as well as reducing the length Neumann et al. showed a lower cut-off for women (men eight of hospital stay (LOS). Prevention should be started as early as points and women five points) of the AUDIT in an interactive possible to shorten or even avoid ICU treatment [6]. Alcohol- computerized lifestyle assessment including the AUDIT [33]. related questionnaires enable validated scores to be obtained for screening. These scores can either be used as paper-pencil as well as computerized self-evaluation [2]. Table 2. AUDIT-Test: Alcohol-Use Disorder Identification Test

The computer-based AUDIT [30] self-assessment showed in a study significantly higher AUD detection rates than the AUDIT-Test: Alcohol-Use Disorder Identification Test preoperative assessment by anaesthesiologists [2]. The use of How often do you have a drink (0) never self-report questionnaires such as AUDIT with high sensitivity is containing alcohol? (1) once per month or less recommended for AUD screening [31]. Martin et al. described an (2) 2-4 times per month (3) 2-3 times per week increase of the detection rate of AUD in clinical routine if patients (4) 4 times or more per week are visited more than once - from 16% after one visit to 34% after How many drinks containing alcohol (0) 1-2 a third visit [32]. do you have on a typical day when you (1) 3-4 are drinking? (2) 5-6 (3) 7-9 Alcohol-related questionnaires (4) 10 or more Alcohol-related questionnaires are the basic tools for identifying How often do you have six or more (0) never patients with AUD. The most commonly used is the Alcohol Use drinks on a occasion? (1) less than monthly Disorder Identification Test (AUDIT). (2) monthly (3) weekly (4) daily or almost daily AUDIT How often during the last year have (0) never The Alcohol Use Disorder Identification Test (AUDIT) developed you found that you were not able to (1) less than monthly by the World Health Organization (WHO) consists of ten questions stop drinking once you had started? (2) monthly with a score ranging from zero to 40 points. An overall score of (3) weekly (4) daily or almost daily How often have you failed to do what (0) never Criteria for diagnosis of alcohol dependence Table 1. was normally expected from you (1) less than monthly because of drinking? (2) monthly (3) weekly (4) daily or almost daily Diagnostic and Statistical International Classification How often have you needed a first (0) never Manual (DSM-IV-TR) of Diseases (ICD10) drink in the morning to get yourself (1) less than monthly Tolerance to to alcohol going after a heavy drinking session? (2) monthly (3) weekly Withdrawal syndrome Withdrawal syndrome (4) daily or almost daily Continued alcohol use despite Continued alcohol use despite How often during the last year have (0) never physical or psychological clear evidence of harmful you had a feeling of guilt or remorse (1) less than monthly problems consequences after drinking? (2) monthly Neglect of important social, Neglect of pleasures or interests, (3) weekly occupational, or recreational increased amount of time (4) daily or almost daily activities because of alcohol use necessary to obtain or take the How often during the last year have (0) never substance or to recover from its you been unable to remember what (1) less than monthly effects happened the night before because (2) monthly Persistent desire to use alcohol or Strong desire or compulsion to you have been drinking? (3) weekly unsuccessful efforts to cut down use alcohol (4) daily or almost daily or control alcohol use Have you or someone else been (0) no alcohol is used in larger amounts Inability to control alcohol use injured as a result of your drinking? (2) yes, before last year or over a longer period than (4) yes, in the last year intended Large proportion of time is spent Has a relative or friend, or a doctor or (0) no in activities necessary to obtain other health worker been concerned (2) yes, before last year alcohol, use alcohol, or recover about your drinking or suggested you (4) yes, in the last year from its effects to cut down?

(Diagnosis of alcohol dependence: ICD-10: ≥3 symptoms of dependence An overall AUDIT score ≥ 8 reveals any AUD (hazardous or harmful alcohol present together at some time during the last 12 months; DSM-IV-TR: ≥3 use or dependence). symptoms of dependence occurring at any time in the last 12 months) (AUD: ≥8; No AUD: <8) Modified from references [21,22,29]. Adapted from references [30] and [37].

NETH J CRIT CARE - VOLUME 16 - NO 3 - JUNE 2012 85 Netherlands Journal of Critical Care M Paupers, A Schiemann, CD Spies Table 3. CIWA-Ar scale

Bush et al. published a short version of the AUDIT (AUDIT C) Revised Clinical Institute Withdrawal Assessment for Alcohol as a brief screening tool to detect heavy drinking, active alcohol Scale (CIWA-Ar) abuse or dependence [34]. In a meta-analysis the accuracy and (0) no nausea, no differed non significantly between the ten-item AUDIT andthe vomiting (1) mild nausea without vomiting AUDIT C with three items. But also worth mentioning is the fact (4) intermittent nausea with dry heaves (7) constant nausea, frequent dry heaves, and vomiting that the results of the evaluated studies were heterogeneous and (0) no tremor they used different reference standards [35]. The ten-item AUDIT (1) not visible, but can be felt fingertip to fingertip can also be easily used in web-based settings [2]. (4) moderate, with patient’s arms extended In a previous study, in which the full ten-item AUDIT and the (7 ) severe, even with arms not extended short three-item AUDIT-C were compared a clinically relevant Paroxysmal (0) no sweat visible disagreement was revealed. More than 10% of the patients sweats (1) barely perceptible sweating, palms moist (4) beads of sweat obvious on forehead (male and female) were either AUDIT-C and AUDIT negative (7) drenching sweat or vice versa. Sensitivity and specificity were not evaluated, (0) no anxiety, at ease because no gold standard measure exists. The AUDIT-C seems (1) mildly anxious to be an attractive and easy to handle alternative to the ten-item (4) moderately anxious or guarded, so that anxiety is inferred (7) equivalent to acute panic states seen in severe delirium AUDIT when time is lacking in the clinical setting [36]. The most or acute schizophrenic reactions important fact for performing any AUD test is granted anonymity Agitation (0) normal activity of the patient in case the patient does not want to have the (1) somewhat more than normal activity diagnosis included in the routine chart [2]. (4) moderately fidgety and restless (7) paces back and forth during most of the interview or thrashes about constantly Biomarkers Tactile (0) none Biomarkers frequently used in clinical practice for screening alcohol disturbances (1) very mild itching, pins and needles, burning, or numbness abuse are surrogate markers like mean corpuscular volume of (2) mild itching pins and needles, burning, or numbness the red blood cell (MCV), gamma-glutamyl transpeptidase (GGT) (3) moderate itching, pins and needles, burning, or numbness (4) moderately severe and carbohydrate deficient transferrin (CDT) because they only (5) severe hallucinations reflect the status of organ dysfunction of an ongoing disease [5]. (6) extremely severe hallucinations Although no single marker has sufficient sensitivity and specificity (7) continuous hallucinations alone, a combination and pattern of blood samples can help to Auditory (0) not present disturbances (1 ) very mild harshness or ability to frighten identify AUD patients when questionnaires cannot be applied. If (2 ) mild harshness or ability to frighten the implementation of questionnaires is possible the biomarkers (3) moderate harshness or ability to frighten are not beneficial because they do not contribute to improvement (4) moderately severe hallucinations (5) severe hallucinations in screening results [31]. Sensitivity (MCV 34%-89%, GGT 34%- (6) extremely severe hallucinations 85%, CDT 39%-94%) and specificity (MCV 26%-91%, GGT (7) continuous hallucinations 11%-85%, CDT 82%-100%) of these biomarkers varies widely Visual (0) not present depending on the study population. It is important to mention disturbances (1) very mild sensitivity (2 ) mild sensitivity that blood samples of these biomarkers have to be drawn at (3) moderate sensitivity the beginning of the hospital stay otherwise the sensitivity will (4) moderately severe hallucinations decrease due to interventions, volume therapy, loss of blood, etc. (5) severe hallucinations (6) extremely severe hallucinations [37]. (7) continuous hallucinations Direct metabolites of alcohol cannot differ between social Headache/ (0) not present alcohol consumption and abuses. Short markers like blood fullness in (1) very mild alcohol concentration of ethyl glucoronide of fatty acid head (2 ) mild (3) moderate derivatives only have a short half-life in blood, substances like (4) moderately severe ethyl glucoronide can also be determined in the hair showing a (5) severe continuous input of ethanol over several months. A more stable (6) very severe (7) extremely severe metabolite is phosphatidyl ethanol that remains detectable for up to 14 days [38]. However, all these ethanol metabolites usually do Orientation/ (0) oriented and can do serial additions clouding of (1) cannot do serial additions or is uncertain about date not mean that the individual has an AUD, it only shows that the sensorium (2) disoriented as to date by ≤2 calendar days person drank alcohol. (3) disoriented as to date by >2 calendar days In ICU settings, determining biomarkers for alcohol consump­ (4) disoriented as to place and/ or person tion can be a good option for detecting alcohol consumption CIWA-Ar Score should be taken every 2 hours also at night and if CIWA-Ar >10: patient (metabolites) or possibly alcohol-related organ dysfunction should be pharmacologically treated; CIWA-Ar Score>20: patient should be consid- although they cannot distinguish between social or hazardous or ered to be transferred to ICU because side effects due to pharmacological treatment alcohol abuse / harmful use or alcohol dependence [5]; they may, may become vitally threatening however, be a trigger for further evaluation asking the patient or Modified from references [40] and [39].

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relatives before alcohol withdrawal related delirium occurs. In evaluate the severity of alcohol withdrawal. It is based on ten addition, metabolites are very useful for abstinence screening frequently seen withdrawal symptoms including nausea and such as prior to liver transplant. vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, Delirium tremens and alcohol withdrawal syndrome headache, fullness in head, orientation and clouding of sensorium. (AWS) in ICU If the score exceeds 10 points, pharmacological therapy should CIWA-Ar and AWS be started immediately, if it exceeds 20 points, monitoring in The revised Clinical Institute withdrawal assessment scale (CIWA-Ar) is a commonly used validated tool to diagnose alcohol withdrawal. The CIWA-Ar [39] scores from zero to 67 points to Figure 1. Screening and Prevention of Alcohol Withdrawal

Table 4. Delirium Detection Score (DDS) Screening AUD before elective surgery with AUDIT or CAGE

Intervene according to FRAMES criteria Delirium Detection score (DDS)

Orientation (0) Orientated to time, place and personal identity, able to concentrate Abstinence in a 4-week period and /or brief (1) Not sure about time and/ or place, not able to intervention concentrate (4) Not orientated to time and/ or place (7) Not orientated to time, place, and personal Prevention identity of AWS and Delirium Hallucinations (0) None (1) Mild hallucinations at times (4) Permanent mild-to-moderate hallucinations (7 ) Permanent severe hallucinations Delirium Screening every 8 hour with: Agitation (0) Normal activity Ward: CIWA-Ar Alternatively: Nu-DESC (recovery room / ward) (1) Slightly higher activity (4) Moderate restlessness ICU: DDS (7) Severe restlessness Alternatively: ICDSC, CAM-ICU (ICU) Anxiety (0) No anxiety when resting (1) Slight anxiety (4) Moderate anxiety at times (7) Acute panic attacks DDx: Before diagnosing AWS Tx: Symptom orientated treatment further causes for delirium must be Myoclonus/ (0) None excluded Convulsions (1) Myoclonus “I WATCH DEATH” (7) Convulsions Paroxysmal (0) No sweating Sweating (1) Almost not detectable, only palms Reevaluation (4) Beads of on the forehead (7) Heavy sweating

Altered Sleep- (0) None [2,11,30,39,43,44,46-48,56,57,65] Waking Cycle (1 ) Mild, patient complaints about problems to AUDIT Alcohol Use Disorder IdentificationT est sleep (4) Patient sleeps only with high medication CAGE ”Cut down”, “Annoyance”, “Guilt”, “Eye opener” questionnaire (7) Patient does not sleep despite medication at FRAMES Feedback, Responsibility, Advice, Menu of Options, Empathy, night, tired at day time Self-efficacy Tremor (0) None AWS Alcohol Withdrawal Syndrome (1) Not visible, but can be felt CIWA-Ar The revised Clinical Institute Withdrawal Assessment Scale (4) Moderate tremor (arms stretched out) Nu-DESC Nursing Delirium Screening Scale (7) Severe tremor (without stretching arms) ICU Intensive Care Unit DDS: The cut-off relevant to ICU delirium was >3 in all ICU patients with de- DDS Delirium Detection Score lirium [44] and was increased in patients with alcohol withdrawal [43]. The ICDSC Intensive Care Delirium Screening Checklist advantage to use this validated score for AWS related delirium rather than CAM-ICU Confusion Assessment Method for the Intensive Care Unit the other scores is that a symptom-orientated scoring including agitation, DDx DifferentialD iagnosis productive-psychotic and autonomic signs helps to consider the adequate Tx early Treatment treatment required in these patients. I WATCH DEATH Infections, Acute Metabolic, Trauma, Central nervous system Adapted from references [43] and [44]. pathology, Hypoxia, Deficiencies,E ndocrinopathies, Acute (Delirium: ≥ 4; No Delirium: < 4) vascular, Toxins/drugs, Heavy metals

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the ICU is necessary [37]. The CIWA-Ar can be applied in the system pathology, hypoxia, deficiencies, endocrinopathies, ward and also in the ICU setting, presupposed the patient is not acute vascular, toxins/drugs, heavy metals [37,40]. The current sedated and able to communicate. American Psychiatrists Association practice guidelines refer Alcohol withdrawal appears in 25% of ICU patients after to DSM-IV and state that fewer than 5% of individuals with reduction of sedation and analgesics. Without treatment 15% alcohol withdrawal develop severe symptoms [18], however, this will die which can be significantly reduced to 2% with treatment is difficult to estimate because the diagnosis of AUD is often [37,40]. missed [2]. In spite of the above, the interaction of precipitating and Delirium tremens predisposing factors may result in delirium, however, the risk of Delirium triggered by alcohol withdrawal is an often seen severe delirium caused by alcohol withdrawal is definitely many phenomenon in ICU patients. Patients admitted to the ICU are times higher [42]. For the diagnosis of ICU delirium a validated often not identified as AUD patients. This means that withdrawal score should be applied. prophylaxis is not administered [41]. The differential diagnosis of an alcohol withdrawal syndrome (AWS) in sedated, ventilated, Delirium Detection Score (DDS) and intubated ICU patients is extremely difficult. The CIWA- The Delirium Detection Score (DDS) is the result of an ICU Ar often cannot be completed in ICU environments because adaptation of the CIWA-Ar score to the requirements of treatment requires intubation and therefore productive-psychotic diagnosing delirium and validated for ICU settings by Otter et al. signs are difficult to obtain [41] . Before diagnosing AWS, further for alcohol withdrawal [43] and Lütz et al. for delirium per se [44]. causes of delirium must be excluded. A useful scheme to It includes items which are usually seen in alcohol withdrawal perform differential diagnosis is the acronym “I WATCH DEATH” related delirium (e.g., tremor, sweating) [45]. The cut-off relevant infections, withdrawal, acute metabolic, trauma, central nervous to ICU delirium was >3 in all ICU patients with delirium [44] and Table 5. Perioperative preventive treatment for AUD was increased in patients with alcohol withdrawal [45]. The advantage of using this validated score for AWS-related delirium rather than the other scores is that a symptom-orientated scoring including agitation, productive-psychotic and autonomic signs Prevention of AWS and Delirium also helps to consider the effective treatment required in these

1 , can be performed by any trained staff (nurses patients. or physicians or otherwise trained) if alcohol dependence is present: consider detoxification Table 6. Symptom-orientated therapy according to the prevalent for dependence before or after surgery; requires psychiatric consultation symptoms – titrated to the needs of the patient 2 Stress prevention: 15 microg/kg/h initiated before induction of anaesthesia and maintained until day 3 after surgery or alternatively, if the patient agrees, postoperatively 0.5 g/kg/d ethanol instead of morphine Symptom-orientated therapy according to the 3 Perioperative and intraoperative prevention of delirium: (a) Premedication if indicated prevalent symptoms – titrated to the needs of - long-acting the evening before surgery the patient (e.g. ) - short-acting benzodiazepine the morning of surgery Agitation: (e.g. midazolam) 1. (b) Before induction of anaesthesia if not adequately prefer long-acting benzodiazepine (e.g. Lorazepam, ) premedicated 2. - midazolam (0.5–5 mg i.v. titrated) (c) Initiated with induction of anaesthesia 3. Anticonvulsants (also possible as adjunctive therapy to - ketamine 0.5 mg/kg benzodiazepines) (d) Initiated after induction of anaesthesia e.g. carbamazepine, levetiracetame - (0.5 microg/kg/h) Autonomic Symptoms (e) Initiated after induction of anaesthesia in case of early clonidine or dexmedetomidine or as an adjunct to benzodiazepines, delirium barbiturates or anticonvulsants - (up to 3.5 mg per day) Psychotic Symptoms 4 Prevention of Wernicke’s encepaholpathy: haloperidol* (or others such as quetiapine; so far no advantage over - thiamine 200mg parenterally for at least 3–5 days. haloperidol proven) 5 Non-pharmacological Measures: To avoid *Torsade de pointes” arrhythmias (as a side effect of Avoid volume depletion and starving neuroleptic agents) give magnesium sulphate Facilitate re-orientation (hearing aids, glasses, watches) Maintenance of day-night rhythm Avoid noise propofol (however: non-REM sleep) Maintain a sleep pattern (day-night-shift) Prevention of Wernicke’s encephalopathy Support mobilization thiamine 200mg parenterally for at least 3–5 days. Modified from references [6,56,57] Modified version [6,7,9,40,56]

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Other Delirium Scores ments of parenteral B complex vitamins including thiamine (B1), The CAM-ICU Score [46] and the Intensive Care Delirium riboflavin (B2), pyridoxine (B6), nicotinamide and also ascorbic Screening Checklist (ICDSC) [47] are also validated for ICU acid [6,7,40,55]. It is important that the patient receives thiamine delirium screening. In addition, the Nursing Delirium Screening before IV glucose or other glucose-containing fluids, because Scale (Nu-DESC) can be used for ICU, recovery room and administration of glucose may trigger acute peripheral ward monitoring [48]. Importantly, any delirium [7]. Because of a lack of sufficient evidence from clinical ran- screening at all helps to start treatment early. domized trials for the prevention and treatment of Wernicke’s encephalopathy, a definitive recommendation in the dose and Prevention of AWS and Delirium route of thiamine hydrochloride is not possible [56]. In several A previous study found that postoperative complications and articles there was mention of a recommended initial dose of ICU length of stay increased in AUD patients when prophylaxis 500mg thiamine hydrochloride continued 2-3 days and Sechi et was not applied [40]. AWS occurs in 50% of AUD patients al. suggested further dosage with 250mg per day for days 3-5 when preoperative diagnosis is missed. It can be reduced by when initial treatment showed an effective response [40, 56-58]. 50% in these patients if preventive measures are taken [24,40]. Non-pharmacological treatment of delirium of any cause Therefore, the prevention of alcohol withdrawal syndrome (AWS) whatsoever includes prevention of sleep deprivation and support and delirium tremens should start before elective surgery to of mobilization, re-orientation, vision and hearing aids as well as reduce health risks [6]. Considering the high perioperative risk for volume repletion and maintenance of circadian rhythm [42, 44, patients with AUD, possibilities such as abstinence in a four-week 59-64]. period prior to elective surgery and medication-based prevention of alcohol withdrawal might be implemented. However, to date Treatment of AWS-related delirium there has been only one small study considering these options ICU patients requiring sedation and mechanical ventilation per se for reducing risks for AUD patients [49]. have an increased risk of delirium and long-term cognitive deficit A so-called “brief intervention” as a short non-confronting [26,59,66-69]. Furthermore, a prolongation of sedation increases conversation based on the FRAMES criteria (Feedback, the incidence of delirium and long-time cognitive impairment Responsibility, Advice, Menu of Options, Empathy) [50] for [16]. Therefore, in ICU patients, sedation, pain, and delirium example, on the patient’s pathologic liver enzymes can help to management should be protocol based with continuous re- trigger reflection on attitude and drinking behaviour. It has been evaluation [44,60-63]. The default protocol-driven management shown to result in a statistically better outcome and a reduction of of sedation, analgesia and delirium in ICU patients is associated risk drinking which can lead to a potential reduction of withdrawal with extended time requiring sedation and intensive care and delirium in further treatment [19,37,51,52]. [44,60-63,70]. Daily interruption of sedation with a spontaneous The risk of severe delirium escalating into delirium tremens breathing trial (SBT) and a spontaneous awaking trial (SAT) caused by alcohol withdrawal is well-known [42,53]. Especially reduces ICU length of stay and 1-year mortality [68, 71]. in AUD patients the preventive administration of medication Pisani et al. showed that prolongation of delirium in critically ill to reduce the incidence or severity of AWS is auxiliary. In a patients is associated with an increased one-year-mortality [17]. randomised controlled trial, benzodiazepines, alpha-2-agonists Delayed therapy of delirium worsens the outcome of patients, i.e. (clonidine or dexmedetomidine) and also neuroleptic agents elevates the rate of nosocomial infections, prolongs mechanical (haloperidol), as well as ethanol - especially in patients having ventilation and increases the risk of death [11]. Therefore, first and no wish for abstinence (requires documentation) - were equally foremost the occurrence of delirious states should be prevented. efficient for pharmacological prophylaxis of AWS in ICU patients If delirium has already occurred, it is essential to shorten the [54]. duration of delirious states as far as possible in order to avoid In addition, stress prevention can reduce hypothalamic- further deterioration. It is a vicious circle in the sense that delirious pituitary-adrenal axis (HPA) stimulation in all AUD patients [27]. A patients have a high risk of developing severe complications and prophylaxis with morphine (15 microg/kg/h) or in cases where the of prolonged ICU stay. patient consented and had no wish for abstinence, ethanol (0.5 AWS and delirium tremens are life-threatening states [6] that g/kg/d) in low doses were found to be suitable for clinical routine require special management compared to other forms of ICU and also prevented pneumonia and decreased ICU length of stay delirium. The severity of AWS reaches from mild withdrawal [27]. symptoms to delirium tremens. The pharmacological treatment Delirium and infection monitoring should be closely of AWS delirium in the ICU should be a symptom-orientated and implemented since patients with AUD often develop infections bolus-titrated therapy. In a randomized controlled double-blinded that are not treated in time due to a misleading diagnosis of AWS ICU trial, Spies et al. showed that symptom-orientated treatment [6,24,27]. decreased severity and duration of AWS, reduced pneumonia rate and shortened ventilator treatment as well as ICU LOS [9]. Wernicke’s encephalopathy, induced by a lack of thiamine is The following pharmacological options described are used in a frequently seen complication in patients with AUD and AWS. clinical practice: Patients with alcohol dependence should be given supple-

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Benzodiazepines showed a protective benefit against alcohol The alpha-2-agonists clonidine and dexmedetomidine are useful withdrawal symptoms, in particular [72]. They should agents for the treatment of autonomic signs and should be given be given to treat agitation, anxiety and seizures. Long-acting either as a preventive measure [54] or in order to supplement benzodiazepines (e.g. lorazepam, diazepam) are preferred for the the treatment with benzodiazepines [9]. If autonomic and treatment of delirium caused by alcohol withdrawal [9,41,72,73] productive signs are present then alpha-2-agonists should be despite the fact they potentially trigger delirium in other settings given [40]. ECG monitoring usually reveals bradycardia. If this is [69]. No significant differences were found when benzodiazepines observed it requires ECG documentation. In alcohol withdrawal were evaluated and compared among themselves in safety and treatment, haloperidol-induced QTc prolongation can be more the treatment of alcohol withdrawal [72]. severe if clonidine is given, therefore, daily QTc documentation Hendey GW et al. found no significant differences in the is necessary if both drugs are being given, and magnesium effectiveness of benzodiazepines compared with the treatment should be considered. phenobarbital to treat moderate alcohol withdrawal in an emergency department [74]. Statistically significant differences Treatment after ICU stay among various benzodiazepines and barbiturates were not found Patients with alcohol dependence need ongoing outpatient [7]. Patients with cirrhosis or reduced liver function should receive care with psychosocial intervention and potentially medical benzodiazepines without active metabolites like lorazepam pharmacological treatment. , , , [75]. is indicated in AWS but contraindicated in and are used for this purpose [6,79-85]. However, ICU settings because of an increased pneumonia rate due to without combined behavioural intervention these treatments hypersalivation [41]. should not be administered. Naltrexone seems to be an agent with In a systematic review of the Cochrane Database, Minozzi the effect of inhibiting craving and it reduces the risk of relapse S et al. found no advantage of anticonvulsants compared to [6,85,86]. Medical management with naltrexone, combined benzodiazepines for treatment of AWS as adjunctive agent behavioural intervention (CBI) or both presented a better drinking to benzodiazepines in the treatment of AWS [76]. A Meta- outcome [84]. Johnson et al. demonstrated in two randomized analysis by Mayo-Smith et al. of nine prospective controlled controlled trials the efficacy of topiramate, an agent which inhibits trials demonstrated that - agents are more the dopamine release, to treat alcohol dependence. They showed effective than neuroleptic agents in reducing duration of improved course in alcohol dependence concerning increased delirium and mortality, with a relative risk of death when using days of abstinence, reduced drinking days and drinks per day, neuroleptic agents in patients outside ICUs [7]. The typical respectively [79-81]. neuroleptic haloperidol is a potential agent to treat symptoms like hallucinations. Side effects are usually not Conclusion expected if the dosage does not exceed 3.5 mg/d. If the dosage Delirium due to AWS and progressed to delirium tremens is increased prolongation of QT-interval, malignant arrhythmias is a potentially life-threatening complication in ICU settings and neurological symptoms like dyskinesia have been reported. which may result in extended ICU length of stay and worsen In ICU settings high-dose neuroleptics are sometimes required patients’ outcome significantly. There are options for prevention, to treat productive-psychotic symptoms and then frequently pharmacological and non-pharmacological treatment available haloperidol with a total average dose of 30 to 150 mg per day leading to significant improvements in outcome. As well as is used without having reports on major side effects [9,41]. An the need for implementation of protocol-based prevention and ECG monitoring is a cornerstone of any ICU treatment. In cases therapy, further research is necessary to improve screening, where QT prolongation is observed on routine monitoring, ECG prevention and treatment strategies. documentation and magnesium treatment should be considered Early screening to recognize AUD patients using validated to avoid Torsade de pointes arrhythmias [69,77]. questionnaires can reduce delay in diagnosing AWS which is the should Torsade de pointes arrhythmias occur then intravenous precondition for an early treatment to avoid further deterioration magnesium sulphate (2 g bolus followed by an infusion of 2-4 mg/ of ICU patients and worsen their outcome. A prolonged delirium minute) is the initial therapy of choice regardless of serum level. and ICU length of stay often leads to substantial health impairment If sustained, haemodynamically unstable polymorphic ventricular for the patient. or VF develops, immediate non-synchronized defibrillation is indicated. Serum potassium should be maintained Acknowledgement in the high-normal range (4.5-5 mmol/L). QT prolonging The authors had no conflict of interest to declare in relation to medications and drugs interfering with their metabolism must be this article. promptly discontinued [78].

90 NETH J CRIT CARE - VOLUME 16 - NO 3 - JUNE 2012 Netherlands Journal of Critical Care Alcohol withdrawal and delirium in the intensive care unit

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