Alcohol withdrawal and delirium in the intensive care unit

Copyright 2012, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received April 2011; accepted February 2012 Review Alcohol withdrawal and delirium in the intensive care unit 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 alcohol 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 delirium tremens. Keywords - ICU, withdrawal, alcohol, delirium, alcohol withdrawal syndrome (AWS) Introduction Besides nicotine, alcohol is the most abused drug worldwide [1-4]. About one-fifth of the patients seen in clinical practice present with an alcohol use disorder (AUD) [2,5]. The prevalence of AUD, i.e. alcohol abuse or harmful use and alcohol dependence among patients undergoing surgical or diagnostic procedures is seen in approximately 20% of cases and nearly half of the surgical patients with AUD have alcohol dependence [6]. Alcoholdependent patients usually present alcohol withdrawal after surgery [7]. In ICU patients, delirium triggered by alcohol withdrawal is a frequent complication and seen in approximately 10% of all ICU patients. The incidence of postoperative delirium (POD) in patients with AUD can reach 50% if not prevented. Effective prevention halves the incidence of POD in patients and - if not prevented - reduces its severity [8-10]. Delirium independent of different etiologies is seen in up to 82% of ICU patients and is associated with poor outcome [11]. Its presence in ICU patients is an independent predictor of an increased duration of mechanical ventilation, length of ICU and hospital stay [11-14] and overall elevated hospital costs [11,15]. Moreover, duration of delirium is associated with an increased risk of one-year mortality and in cases of survival, cognitive dysfunction [16,17]. Therefore, it is crucial for the clinician to prevent and detect this serious complication early on in order to avoid consequences that lead to elevated morbidity and mortality [11]. Evidence suggests that in those patients for whom appropriate care and immediate treatment is provided, mortality can be reduced [7]. Correspondence CD Spies E-Mail: claudia.spies@charite.de This article gives an overview on how to reduce and treat this potentially life-threatening complication [18] in critically ill patients with an underlying AUD. Alcohol use disorders Alcohol use disorders (AUD) include a wide range of drinking behaviours from hazardous use of alcohol to alcohol abuse, harmful consumption, and alcohol dependence. Hazardous use means exceeding a daily alcohol intake of 60g per day (g alcohol equals ml of drunken alcohol times % of alcohol included in beverage x 0.8). 60g/d of ethanol means three to four bottles of beer and ¾ of a bottle of wine, respectively. This is associated with a higher rate of complications and a poor outcome [8,19,20]. This cut-off is not related to dependency but it determines the complication threshold for patients undergoing surgical or interventional procedures. Alcohol abuse is included in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM IV-TR) [21] and harmful use is included in the International Classification of Diseases (ICD-10) criteria [22], not fulfilling the dependence criteria. Alcohol dependence Approximately 10% of all hospitalized patients can be diagnosed as alcohol-dependent [6,23]. Patients with alcohol dependence show the highest risk of all patients with AUD for severe complications such as delirium, infection, sepsis, septic shock, postoperative haemorrhage and long-term cognitive dysfunction [8,16,24-28]. 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 present together at some time during the last 12 months. DSM-IV- TR requires at least three out of seven symptoms occurring at any time in the last 12 months for the diagnosis of alcohol dependence. 84

Alcohol withdrawal and delirium in the intensive care unit Identification of AUD patients Screening patients for AUD is the precondition to taking preventive measures and improving outcome as well as reducing the length of hospital stay (LOS). Prevention should be started as early as possible to shorten or even avoid ICU treatment [6]. Alcoholrelated 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]. eight or more points reveals hazardous or harmful alcohol use (ICD-10) [33]. Neumann et al. showed a lower cut-off for women (men eight points and women five points) of the AUDIT in an interactive computerized lifestyle assessment including the AUDIT [33]. 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 preoperative assessment by anaesthesiologists [2]. The use of self-report questionnaires such as AUDIT with high sensitivity is recommended for AUD screening [31]. Martin et al. described an increase of the detection rate of AUD in clinical routine if patients are visited more than once - from 16% after one visit to 34% after a third visit [32]. Alcohol-related questionnaires Alcohol-related questionnaires are the basic tools for identifying patients with AUD. The most commonly used is the Alcohol Use Disorder Identification Test (AUDIT). AUDIT The Alcohol Use Disorder Identification Test (AUDIT) developed by the World Health Organization (WHO) consists of ten questions with a score ranging from zero to 40 points. An overall score of Table 1. Criteria for diagnosis of alcohol dependence Diagnostic and Statistical Manual (DSM-IV-TR) Tolerance to alcohol Withdrawal syndrome Continued alcohol use despite physical or psychological problems Neglect of important social, occupational, or recreational activities because of alcohol use Persistent desire to use alcohol or unsuccessful efforts to cut down or control alcohol use alcohol is used in larger amounts or over a longer period than intended Large proportion of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects International Classification of Diseases (ICD10) Tolerance to alcohol Withdrawal syndrome Continued alcohol use despite clear evidence of harmful consequences Neglect of pleasures or interests, increased amount of time necessary to obtain or take the substance or to recover from its effects Strong desire or compulsion to use alcohol Inability to control alcohol use (Diagnosis of alcohol dependence: ICD-10: 3 symptoms of dependence present together at some time during the last 12 months; DSM-IV-TR: 3 symptoms of dependence occurring at any time in the last 12 months) Modified from references [21,22,29]. AUDIT-Test: Alcohol-Use Disorder Identification Test How often do you have a drink containing alcohol? How many drinks containing alcohol do you have on a typical day when you are drinking? How often do you have six or more drinks on a occasion? How often during the last year have you found that you were not able to stop drinking once you had started? How often have you failed to do what was normally expected from you because of drinking? How often have you needed a first drink in the morning to get yourself going after a heavy drinking session? How often during the last year have you had a feeling of guilt or remorse after drinking? How often during the last year have you been unable to remember what happened the night before because you have been drinking? Have you or someone else been injured as a result of your drinking? Has a relative or friend, or a doctor or other health worker been concerned about your drinking or suggested you to cut down? (1) once per month or less (2) 2-4 times per month (3) 2-3 times per week (4) 4 times or more per week (0) 1-2 (1) 3-4 (2) 5-6 (3) 7-9 (4) 10 or more (0) no (2) yes, before last year (4) yes, in the last year (0) no (2) yes, before last year (4) yes, in the last year An overall AUDIT score 8 reveals any AUD (hazardous or harmful alcohol use or dependence). (AUD: 8; No AUD: <8) Adapted from references [30] and [37]. 85

M Paupers, A Schiemann, CD Spies Table 3. CIWA-Ar scale Bush et al. published a short version of the AUDIT (AUDIT C) as a brief screening tool to detect heavy drinking, active alcohol abuse or dependence [34]. In a meta-analysis the accuracy differed non significantly between the ten-item AUDIT and the AUDIT C with three items. But also worth mentioning is the fact that the results of the evaluated studies were heterogeneous and they used different reference standards [35]. The ten-item AUDIT can also be easily used in web-based settings [2]. In a previous study, in which the full ten-item AUDIT and the short three-item AUDIT-C were compared a clinically relevant disagreement was revealed. More than 10% of the patients (male and female) were either AUDIT-C and AUDIT negative or vice versa. Sensitivity and specificity were not evaluated, because no gold standard measure exists. The AUDIT-C seems to be an attractive and easy to handle alternative to the ten-item AUDIT when time is lacking in the clinical setting [36]. The most important fact for performing any AUD test is granted anonymity of the patient in case the patient does not want to have the diagnosis included in the routine chart [2]. Biomarkers Biomarkers frequently used in clinical practice for screening alcohol abuse are surrogate markers like mean corpuscular volume of the red blood cell (MCV), gamma-glutamyl transpeptidase (GGT) and carbohydrate deficient transferrin (CDT) because they only reflect the status of organ dysfunction of an ongoing disease [5]. Although no single marker has sufficient sensitivity and specificity alone, a combination and pattern of blood samples can help to identify AUD patients when questionnaires cannot be applied. If the implementation of questionnaires is possible the biomarkers are not beneficial because they do not contribute to improvement in screening results [31]. Sensitivity (MCV 34%-89%, GGT 34%- 85%, CDT 39%-94%) and specificity (MCV 26%-91%, GGT 11%-85%, CDT 82%-100%) of these biomarkers varies widely depending on the study population. It is important to mention that blood samples of these biomarkers have to be drawn at the beginning of the hospital stay otherwise the sensitivity will decrease due to interventions, volume therapy, loss of blood, etc. [37]. Direct metabolites of alcohol cannot differ between social alcohol consumption and abuses. Short markers like blood alcohol concentration of ethyl glucoronide of fatty acid derivatives only have a short half-life in blood, substances like ethyl glucoronide can also be determined in the hair showing a continuous input of ethanol over several months. A more stable metabolite is phosphatidyl ethanol that remains detectable for up to 14 days [38]. However, all these ethanol metabolites usually do not mean that the individual has an AUD, it only shows that the person drank alcohol. In ICU settings, determining biomarkers for alcohol consumption can be a good option for detecting alcohol consumption (metabolites) or possibly alcohol-related organ dysfunction although they cannot distinguish between social or hazardous or alcohol abuse / harmful use or alcohol dependence [5]; they may, however, be a trigger for further evaluation asking the patient or Revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) Nausea and vomiting Tremor Paroxysmal sweats Anxiety Agitation Tactile disturbances Auditory disturbances Visual disturbances Headache/ fullness in head Orientation/ clouding of sensorium (0) no nausea, no vomiting (1) mild nausea without vomiting (4) intermittent nausea with dry heaves (7) constant nausea, frequent dry heaves, and vomiting (0) no tremor (1) not visible, but can be felt fingertip to fingertip (4) moderate, with patient s arms extended (7 ) severe, even with arms not extended (0) no sweat visible (1) barely perceptible sweating, palms moist (4) beads of sweat obvious on forehead (7) drenching sweat (0) no anxiety, at ease (1) mildly anxious (4) moderately anxious or guarded, so that anxiety is inferred (7) equivalent to acute panic states seen in severe delirium or acute schizophrenic reactions (0) normal activity (1) somewhat more than normal activity (4) moderately fidgety and restless (7) paces back and forth during most of the interview or thrashes about constantly (0) none (1) very mild itching, pins and needles, burning, or numbness (2) mild itching pins and needles, burning, or numbness (3) moderate itching, pins and needles, burning, or numbness (4) moderately severe hallucinations (5) severe hallucinations (6) extremely severe hallucinations (7) continuous hallucinations (0) not present (1 ) very mild harshness or ability to frighten (2 ) mild harshness or ability to frighten (3) moderate harshness or ability to frighten (4) moderately severe hallucinations (5) severe hallucinations (6) extremely severe hallucinations (7) continuous hallucinations (0) not present (1) very mild sensitivity (2 ) mild sensitivity (3) moderate sensitivity (4) moderately severe hallucinations (5) severe hallucinations (6) extremely severe hallucinations (7) continuous hallucinations (0) not present (1) very mild (2 ) mild (3) moderate (4) moderately severe (5) severe (6) very severe (7) extremely severe (0) oriented and can do serial additions (1) cannot do serial additions or is uncertain about date (2) disoriented as to date by 2 calendar days (3) disoriented as to date by >2 calendar days (4) disoriented as to place and/ or person CIWA-Ar Score should be taken every 2 hours also at night and if CIWA-Ar >10: patient should be pharmacologically treated; CIWA-Ar Score>20: patient should be considered to be transferred to ICU because side effects due to pharmacological treatment may become vitally threatening Modified from references [40] and [39]. 86

Alcohol withdrawal and delirium in the intensive care unit relatives before alcohol withdrawal related delirium occurs. In addition, metabolites are very useful for abstinence screening such as prior to liver transplant. Delirium tremens and alcohol withdrawal syndrome (AWS) in ICU CIWA-Ar and AWS 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 evaluate the severity of alcohol withdrawal. It is based on ten frequently seen withdrawal symptoms including nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache, fullness in head, orientation and clouding of sensorium. If the score exceeds 10 points, pharmacological therapy should be started immediately, if it exceeds 20 points, monitoring in Figure 1. Screening and Prevention of Alcohol Withdrawal Table 4. Delirium Detection Score (DDS) Screening AUD before elective surgery with AUDIT or CAGE Delirium Detection score (DDS) Orientation Hallucinations Agitation Anxiety Myoclonus/ Convulsions Paroxysmal Sweating Altered Sleep- Waking Cycle Tremor (0) Orientated to time, place and personal identity, able to concentrate (1) Not sure about time and/ or place, not able to concentrate (4) Not orientated to time and/ or place (7) Not orientated to time, place, and personal identity (0) None (1) Mild hallucinations at times (4) Permanent mild-to-moderate hallucinations (7 ) Permanent severe hallucinations (0) Normal activity (1) Slightly higher activity (4) Moderate restlessness (7) Severe restlessness (0) No anxiety when resting (1) Slight anxiety (4) Moderate anxiety at times (7) Acute panic attacks (0) None (1) Myoclonus (7) Convulsions (0) No sweating (1) Almost not detectable, only palms (4) Beads of perspiration on the forehead (7) Heavy sweating (0) None (1 ) Mild, patient complaints about problems to sleep (4) Patient sleeps only with high medication (7) Patient does not sleep despite medication at night, tired at day time (0) None (1) Not visible, but can be felt (4) Moderate tremor (arms stretched out) (7) Severe tremor (without stretching arms) DDS: The cut-off relevant to ICU delirium was >3 in all ICU patients with delirium [44] and was increased in patients with alcohol withdrawal [43]. The advantage to use 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 helps to consider the adequate treatment required in these patients. Adapted from references [43] and [44]. (Delirium: 4; No Delirium: < 4) AUDIT CAGE FRAMES DDx: Before diagnosing AWS further causes for delirium must be excluded I WATCH DEATH AWS CIWA-Ar Nu-DESC ICU DDS ICDSC CAM-ICU DDx Tx I WATCH DEATH Intervene according to FRAMES criteria Abstinence in a 4-week period and /or brief intervention Prevention of AWS and Delirium Delirium Screening every 8 hour with: Ward: CIWA-Ar Alternatively: Nu-DESC (recovery room / ward) ICU: DDS Alternatively: ICDSC, CAM-ICU (ICU) Tx: Symptom orientated treatment Reevaluation [2,11,30,39,43,44,46-48,56,57,65] Alcohol Use Disorder Identification Test Cut down, Annoyance, Guilt, Eye opener questionnaire Feedback, Responsibility, Advice, Menu of Options, Empathy, Self-efficacy Alcohol Withdrawal Syndrome The revised Clinical Institute Withdrawal Assessment Scale Nursing Delirium Screening Scale Intensive Care Unit Delirium Detection Score Intensive Care Delirium Screening Checklist Confusion Assessment Method for the Intensive Care Unit Differential Diagnosis early Treatment Infections, Acute Metabolic, Trauma, Central nervous system pathology, Hypoxia, Deficiencies, Endocrinopathies, Acute vascular, Toxins/drugs, Heavy metals 87

M Paupers, A Schiemann, CD Spies the ICU is necessary [37]. The CIWA-Ar can be applied in the ward and also in the ICU setting, presupposed the patient is not sedated and able to communicate. Alcohol withdrawal appears in 25% of ICU patients after reduction of sedation and analgesics. Without treatment 15% will die which can be significantly reduced to 2% with treatment [37,40]. Delirium tremens Delirium triggered by alcohol withdrawal is an often seen phenomenon in ICU patients. Patients admitted to the ICU are often not identified as AUD patients. This means that withdrawal prophylaxis is not administered [41]. The differential diagnosis of an alcohol withdrawal syndrome (AWS) in sedated, ventilated, and intubated ICU patients is extremely difficult. The CIWA- Ar often cannot be completed in ICU environments because treatment requires intubation and therefore productive-psychotic signs are difficult to obtain [41]. Before diagnosing AWS, further causes of delirium must be excluded. A useful scheme to perform differential diagnosis is the acronym I WATCH DEATH infections, withdrawal, acute metabolic, trauma, central nervous Table 5. Perioperative preventive treatment for AUD Prevention of AWS and Delirium 1 Brief intervention, can be performed by any trained staff (nurses or physicians or otherwise trained) if alcohol dependence is present: consider detoxification for dependence before or after surgery; requires psychiatric consultation 2 Stress prevention: morphine 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 3 Perioperative and intraoperative prevention of delirium: (a) Premedication if indicated - long-acting benzodiazepine the evening before surgery (e.g. lorazepam) - short-acting benzodiazepine the morning of surgery (e.g. midazolam) (b) Before induction of anaesthesia if not adequately premedicated - midazolam (0.5 5 mg i.v. titrated) (c) Initiated with induction of anaesthesia - ketamine 0.5 mg/kg (d) Initiated after induction of anaesthesia - clonidine (0.5 microg/kg/h) (e) Initiated after induction of anaesthesia in case of early delirium - haloperidol (up to 3.5 mg per day) 4 Prevention of Wernicke s encepaholpathy: - thiamine 200mg parenterally for at least 3 5 days. 5 Non-pharmacological Measures: Avoid volume depletion and starving Facilitate re-orientation (hearing aids, glasses, watches) Avoid noise Maintain a sleep pattern (day-night-shift) Support mobilization Modified from references [6,56,57] system pathology, hypoxia, deficiencies, endocrinopathies, acute vascular, toxins/drugs, heavy metals [37,40]. The current American Psychiatrists Association practice guidelines refer to DSM-IV and state that fewer than 5% of individuals with alcohol withdrawal develop severe symptoms [18], however, this is difficult to estimate because the diagnosis of AUD is often missed [2]. In spite of the above, the interaction of precipitating and predisposing factors may result in delirium, however, the risk of severe delirium caused by alcohol withdrawal is definitely many times higher [42]. For the diagnosis of ICU delirium a validated score should be applied. Delirium Detection Score (DDS) The Delirium Detection Score (DDS) is the result of an ICU adaptation of the CIWA-Ar score to the requirements of diagnosing delirium and validated for ICU settings by Otter et al. for alcohol withdrawal [43] and Lütz et al. for delirium per se [44]. It includes items which are usually seen in alcohol withdrawal related delirium (e.g., tremor, sweating) [45]. The cut-off relevant to ICU delirium was >3 in all ICU patients with delirium [44] and 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 also helps to consider the effective treatment required in these patients. Table 6. Symptom-orientated therapy according to the prevalent symptoms titrated to the needs of the patient Symptom-orientated therapy according to the prevalent symptoms titrated to the needs of the patient Agitation: 1. Benzodiazepines prefer long-acting benzodiazepine (e.g. Lorazepam, Diazepam) 2. Barbiturates phenobarbital 3. Anticonvulsants (also possible as adjunctive therapy to benzodiazepines) e.g. carbamazepine, levetiracetame Autonomic Symptoms clonidine or dexmedetomidine or as an adjunct to benzodiazepines, barbiturates or anticonvulsants Psychotic Symptoms haloperidol* (or others such as quetiapine; so far no advantage over haloperidol proven) To avoid *Torsade de pointes arrhythmias (as a side effect of neuroleptic agents) give magnesium sulphate Maintenance of day-night rhythm propofol (however: non-rem sleep) Prevention of Wernicke s encephalopathy thiamine 200mg parenterally for at least 3 5 days. Modified version [6,7,9,40,56] 88

Alcohol withdrawal and delirium in the intensive care unit Other Delirium Scores The CAM-ICU Score [46] and the Intensive Care Delirium Screening Checklist (ICDSC) [47] are also validated for ICU delirium screening. In addition, the Nursing Delirium Screening Scale (Nu-DESC) can be used for ICU, recovery room and peripheral ward monitoring [48]. Importantly, any delirium screening at all helps to start treatment early. Prevention of AWS and Delirium A previous study found that postoperative complications and ICU length of stay increased in AUD patients when prophylaxis was not applied [40]. AWS occurs in 50% of AUD patients when preoperative diagnosis is missed. It can be reduced by 50% in these patients if preventive measures are taken [24,40]. Therefore, the prevention of alcohol withdrawal syndrome (AWS) and delirium tremens should start before elective surgery to reduce health risks [6]. Considering the high perioperative risk for patients with AUD, possibilities such as abstinence in a four-week period prior to elective surgery and medication-based prevention of alcohol withdrawal might be implemented. However, to date there has been only one small study considering these options for reducing risks for AUD patients [49]. A so-called brief intervention as a short non-confronting conversation based on the FRAMES criteria (Feedback, Responsibility, Advice, Menu of Options, Empathy) [50] for example, on the patient s pathologic liver enzymes can help to trigger reflection on attitude and drinking behaviour. It has been shown to result in a statistically better outcome and a reduction of risk drinking which can lead to a potential reduction of withdrawal and delirium in further treatment [19,37,51,52]. The risk of severe delirium escalating into delirium tremens caused by alcohol withdrawal is well-known [42,53]. Especially in AUD patients the preventive administration of medication to reduce the incidence or severity of AWS is auxiliary. In a randomised controlled trial, benzodiazepines, alpha-2-agonists (clonidine or dexmedetomidine) and also neuroleptic agents (haloperidol), as well as ethanol - especially in patients having no wish for abstinence (requires documentation) - were equally efficient for pharmacological prophylaxis of AWS in ICU patients [54]. In addition, stress prevention can reduce hypothalamicpituitary-adrenal axis (HPA) stimulation in all AUD patients [27]. A prophylaxis with morphine (15 microg/kg/h) or in cases where the patient consented and had no wish for abstinence, ethanol (0.5 g/kg/d) in low doses were found to be suitable for clinical routine and also prevented pneumonia and decreased ICU length of stay [27]. Delirium and infection monitoring should be closely implemented since patients with AUD often develop infections that are not treated in time due to a misleading diagnosis of AWS [6,24,27]. Wernicke s encephalopathy, induced by a lack of thiamine is a frequently seen complication in patients with AUD and AWS. Patients with alcohol dependence should be given supplements of parenteral B complex vitamins including thiamine (B1), riboflavin (B2), pyridoxine (B6), nicotinamide and also ascorbic acid [6,7,40,55]. It is important that the patient receives thiamine before IV glucose or other glucose-containing fluids, because administration of glucose may trigger acute thiamine deficiency [7]. Because of a lack of sufficient evidence from clinical randomized trials for the prevention and treatment of Wernicke s encephalopathy, a definitive recommendation in the dose and route of thiamine hydrochloride is not possible [56]. In several articles there was mention of a recommended initial dose of 500mg thiamine hydrochloride continued 2-3 days and Sechi et al. suggested further dosage with 250mg per day for days 3-5 when initial treatment showed an effective response [40, 56-58]. Non-pharmacological treatment of delirium of any cause whatsoever includes prevention of sleep deprivation and support of mobilization, re-orientation, vision and hearing aids as well as volume repletion and maintenance of circadian rhythm [42, 44, 59-64]. Treatment of AWS-related delirium ICU patients requiring sedation and mechanical ventilation per se have an increased risk of delirium and long-term cognitive deficit [26,59,66-69]. Furthermore, a prolongation of sedation increases the incidence of delirium and long-time cognitive impairment [16]. Therefore, in ICU patients, sedation, pain, and delirium management should be protocol based with continuous reevaluation [44,60-63]. The default protocol-driven management of sedation, analgesia and delirium in ICU patients is associated with extended time requiring sedation and intensive care [44,60-63,70]. Daily interruption of sedation with a spontaneous breathing trial (SBT) and a spontaneous awaking trial (SAT) reduces ICU length of stay and 1-year mortality [68, 71]. Pisani et al. showed that prolongation of delirium in critically ill patients is associated with an increased one-year-mortality [17]. Delayed therapy of delirium worsens the outcome of patients, i.e. elevates the rate of nosocomial infections, prolongs mechanical ventilation and increases the risk of death [11]. Therefore, first and foremost the occurrence of delirious states should be prevented. If delirium has already occurred, it is essential to shorten the duration of delirious states as far as possible in order to avoid further deterioration. It is a vicious circle in the sense that delirious patients have a high risk of developing severe complications and of prolonged ICU stay. AWS and delirium tremens are life-threatening states [6] that require special management compared to other forms of ICU delirium. The severity of AWS reaches from mild withdrawal symptoms to delirium tremens. The pharmacological treatment of AWS delirium in the ICU should be a symptom-orientated and bolus-titrated therapy. In a randomized controlled double-blinded ICU trial, Spies et al. showed that symptom-orientated treatment decreased severity and duration of AWS, reduced pneumonia rate and shortened ventilator treatment as well as ICU LOS [9]. The following pharmacological options described are used in clinical practice: 89

M Paupers, A Schiemann, CD Spies Benzodiazepines showed a protective benefit against alcohol withdrawal symptoms, in particular seizures [72]. They should be given to treat agitation, anxiety and seizures. Long-acting benzodiazepines (e.g. lorazepam, diazepam) are preferred for the treatment of delirium caused by alcohol withdrawal [9,41,72,73] despite the fact they potentially trigger delirium in other settings [69]. No significant differences were found when benzodiazepines were evaluated and compared among themselves in safety and the treatment of alcohol withdrawal [72]. Hendey GW et al. found no significant differences in the effectiveness of benzodiazepines compared with the barbiturate phenobarbital to treat moderate alcohol withdrawal in an emergency department [74]. Statistically significant differences among various benzodiazepines and barbiturates were not found [7]. Patients with cirrhosis or reduced liver function should receive benzodiazepines without active metabolites like lorazepam [75]. Clomethiazole is indicated in AWS but contraindicated in ICU settings because of an increased pneumonia rate due to hypersalivation [41]. In a systematic review of the Cochrane Database, Minozzi S et al. found no advantage of anticonvulsants compared to benzodiazepines for treatment of AWS as adjunctive agent to benzodiazepines in the treatment of AWS [76]. A Metaanalysis by Mayo-Smith et al. of nine prospective controlled trials demonstrated that sedative-hypnotic agents are more effective than neuroleptic agents in reducing duration of delirium and mortality, with a relative risk of death when using neuroleptic agents in patients outside ICUs [7]. The typical neuroleptic haloperidol is a potential antipsychotic agent to treat symptoms like hallucinations. Side effects are usually not expected if the dosage does not exceed 3.5 mg/d. If the dosage is increased prolongation of QT-interval, malignant arrhythmias and neurological symptoms like dyskinesia have been reported. In ICU settings high-dose neuroleptics are sometimes required to treat productive-psychotic symptoms and then frequently haloperidol with a total average dose of 30 to 150 mg per day is used without having reports on major side effects [9,41]. An ECG monitoring is a cornerstone of any ICU treatment. In cases where QT prolongation is observed on routine monitoring, ECG documentation and magnesium treatment should be considered to avoid Torsade de pointes arrhythmias [69,77]. Should Torsade de pointes arrhythmias occur then intravenous magnesium sulphate (2 g bolus followed by an infusion of 2-4 mg/ minute) is the initial therapy of choice regardless of serum level. If sustained, haemodynamically unstable polymorphic ventricular tachycardia or VF develops, immediate non-synchronized defibrillation is indicated. Serum potassium should be maintained in the high-normal range (4.5-5 mmol/l). QT prolonging medications and drugs interfering with their metabolism must be promptly discontinued [78]. The alpha-2-agonists clonidine and dexmedetomidine are useful agents for the treatment of autonomic signs and should be given either as a preventive measure [54] or in order to supplement the treatment with benzodiazepines [9]. If autonomic and productive signs are present then alpha-2-agonists should be given [40]. ECG monitoring usually reveals bradycardia. If this is observed it requires ECG documentation. In alcohol withdrawal treatment, haloperidol-induced QTc prolongation can be more severe if clonidine is given, therefore, daily QTc documentation is necessary if both drugs are being given, and magnesium treatment should be considered. Treatment after ICU stay Patients with alcohol dependence need ongoing outpatient care with psychosocial intervention and potentially medical pharmacological treatment. Naltrexone, acamprosate, disulfiram, and topiramate are used for this purpose [6,79-85]. However, without combined behavioural intervention these treatments should not be administered. Naltrexone seems to be an agent with the effect of inhibiting craving and it reduces the risk of relapse [6,85,86]. Medical management with naltrexone, combined behavioural intervention (CBI) or both presented a better drinking outcome [84]. Johnson et al. demonstrated in two randomized controlled trials the efficacy of topiramate, an agent which inhibits the dopamine release, to treat alcohol dependence. They showed improved course in alcohol dependence concerning increased days of abstinence, reduced drinking days and drinks per day, respectively [79-81]. Conclusion Delirium due to AWS and progressed to delirium tremens is a potentially life-threatening complication in ICU settings which may result in extended ICU length of stay and worsen patients outcome significantly. There are options for prevention, pharmacological and non-pharmacological treatment available leading to significant improvements in outcome. As well as the need for implementation of protocol-based prevention and therapy, further research is necessary to improve screening, prevention and treatment strategies. Early screening to recognize AUD patients using validated questionnaires can reduce delay in diagnosing AWS which is the precondition for an early treatment to avoid further deterioration of ICU patients and worsen their outcome. A prolonged delirium and ICU length of stay often leads to substantial health impairment for the patient. Acknowledgement The authors had no conflict of interest to declare in relation to this article. 90

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