Critical Care Medicine:
Creating and Implementing the 2013 ICU Pain, Agitation, and Delirium Guidelines for Adult Icu Patients
Alcohol, Nicotine, and Iatrogenic Withdrawals in the ICU
Awissi, Don-Kelena MSc Pharm, BCPS1; Lebrun, Genevieve MSc Pharm1; Fagnan, Mylene MSc Pharm1; Skrobik, Yoanna MD, FRCP2; for the Regroupement de Soins Critiques, Réseau de Soins Respiratoires, Québec
1Pharmacy Department, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.
2Département de médicine, Université de Montréal, Montréal, QC, Canada.
The authors have disclosed that they do not have any potential conflicts of interest.
For information regarding this article, E-mail: firstname.lastname@example.org
Objectives: The neurophysiology, risk factors, and screening tools associated with alcohol withdrawal syndrome in the ICU are reviewed. Alcohol withdrawal syndrome assessment and its treatment options are discussed. Description of nicotine withdrawal and related publications specific to the critically ill are also reviewed. A brief comment as to sedative and opiate withdrawal follows.
Data and Summary: The role of currently published alcohol withdrawal syndrome pharmacologic strategies (benzodiazepines, ethanol, clomethiazole, antipsychotics, barbiturates, propofol, and dexmedetomidine) is detailed. Studies on nicotine withdrawal management in the ICU focus mainly on the safety (mortality) of nicotine replacement therapy. Study characteristics and methodological limitations are presented.
Conclusion: We recommend a pharmacologic regimen titrated to withdrawal symptoms in ICU patients with alcohol withdrawal syndrome. Benzodiazepines are a reasonable option; phenobarbital appears to confer some advantages in combination with benzodiazepines. Propofol and dexmedetomidine have not been rigorously tested in comparative studies of drug withdrawal treatment; their use as additional or alternative strategies for managing withdrawal syndromes in ICU patients should therefore be individualized to each patient. Insufficient data preclude recommendations as to nicotine replacement therapy and management of iatrogenic drug withdrawal in ICU patients.
Substance and ethanol abuse-related admissions are reported to be as high as 28% in medical and surgical ICU (1) and are associated with poor long-term outcomes (2). In randomly selected mechanically ventilated medical ICU patients, the prevalence of alcohol and other drug use disorders was 39%, well above the U.S. population data (3). In 2011, 6.2% of Americans over the age of 12 years self-reported five or more simultaneously consumed drinks on at least five of the previous 30 days and 8.7% were current illicit drug users (4).
Cessation of alcohol, tobacco, or illicit drug consumption can lead to withdrawal symptoms and, in severe cases, require ICU monitoring. Medical, surgical, or trauma patients can develop agitation, hallucinations, tachycardia, hypertension, or fever related to the abrupt substance abuse cessation. Clinicians should be aware of the risk factors, symptoms, prevention, and treatment measures related to drug withdrawal. This article reviews the management of alcohol and nicotine withdrawal syndromes in critically ill patients.
Alcohosl Withdrawal Syndrome
Alcohol-dependent patients are more likely to require ICU admission for alcohol withdrawal syndrome (AWS) (5) and delirium tremens (DT) or for alcohol-related problems, such as complications of cirrhosis or gastrointestinal bleeding (6–8). These patients have longer durations of mechanical ventilation, longer ICU stays, more frequent infectious complications, and a higher mortality rate than those admitted without alcohol-related medical issues (9–12).
In surgical ICUs, the incidence of AWS in patients dependent on or abusive in their consumption of alcohol varies from 8% to 40%, despite pharmacologic prophylaxis (13–16). Patients with AWS are more likely to develop complications, mainly of infectious nature (12, 15, 17–19). The transfer rate to ICU in hospitalized AWS patients treated for withdrawal was 7% in a cohort of 827 patients (20), 8–25% (depending on the treatment strategy) in treated emergency department AWS patients (21), and 4% with the use of a pharmacologic AWS protocol compared with 29% without the symptom-triggered protocol in a head and neck surgery population (22).
Ethanol affects a large number of neurotransmitter receptors and signaling pathways. Its principal action on the CNS is mediated by neurotransmission of glutamate and γ-aminobutyric acid (GABA), the main excitatory and inhibitory neurotransmitters in CNS. Acute exposure to ethanol increases GABA’s activation at GABAA receptors, resulting in CNS depression. Ethanol also inhibits glutamate’s capacity to activate N-methyl-D-aspartate (NMDA) receptors by preventing the opening of the receptor’s cation channel. Many aspects of cognitive function, including learning and memory, are mediated by NMDA receptors and are therefore depressed by ethanol (23). Sympathetic stimulation also occurs during AWS and evolves over time, usually several days. Its mechanism is a decrease in the inhibitory activity of presynaptic α2-adrenoreceptors, leading to increased catecholamine levels (24).
Chronic high-dose ethanol consumption produces tolerance, as well as physical and psychological dependence. Tolerance of ethanol’s toxic effects is complex and poorly understood; they are thought to result from the NMDA subtype of glutamate receptor up-regulation in response to chronic ethanol exposure. Down-regulation of GABAA-mediated responses with continuous ethanol exposure can contribute to tolerance and dependence (23, 25). Many others neurotransmitters and pathways are involved in ethanol’s effect on the CNS, with dopamine, serotonin, nicotinic, and cannabinoid receptors among them (25, 26).
Definition of AWS.
AWS is a continuum of symptoms. According to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV), AWS is defined as the presence of at least two of the following findings, not due to a general condition and not attributed to another mental disorder, within hours to a few days following the cessation or reduction of alcohol use that has been heavy and prolonged (27): autonomic hyperactivity; increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; and grand mal seizures. Without treatment, the increase in autonomic activity leads to minor symptoms, such as tremors, diaphoresis, nausea, vomiting, and tachycardia, and may evolve to a more severe form of withdrawal. Historically, four stages of alcohol withdrawal have been described relative to the time of the reduction or cessation of alcohol intake (i.e., 6-8 hr and up to 5 d): 1) autonomic hyperactivity, 2) hallucinations, 3) seizures, and 4) DT. In practice, these stages are less distinct and may overlap (28–30). In studies of AWS in ICU patients, 30–40% of patients in AWS will have an episode of seizures prior to or at admission to the ICU (10, 31–35). Patients hospitalized with DT had an ICU admission rate varying from 15% to 50% (31, 34). Transfers to ICU were driven by the need for higher benzodiazepine doses, refractory or severe AWS, the need for physical restraints, or concern about life-threatening complications.
DT is considered to be the most severe form of alcohol withdrawal. The four diagnostic criteria for DT as defined in the DSM-IV (27) include: 1) a disturbance of consciousness (i.e., reduced clarity of awareness of the environment), with reduced ability to focus, sustain, or shift attention; 2) a change in cognition (such as memory deficit, disorientation, or language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia; 3) the disturbance develops over a short time period (usually hours to days) and tends to fluctuate during the day; and 4) there is evidence from the history, physical examination, or laboratory findings that the symptoms in criteria 1 and 2 developed during or shortly after the occurrence of an episode of AWS.
AWS develops in alcohol-dependent patients admitted in the ICU for postoperative care within 36–48 hours (range, 1–9 d) (13, 14, 17). The onset of symptoms may be delayed with exposure to anesthetic agents or sedative use in the ICU. In patients admitted to the ICU with a primary diagnosis of AWS, the delay between their arrival and last reported alcohol intake was usually less than 24 hours (33, 36) but has been reported up to 6 days (33, 36), with the delay from the alcohol-free period to full blown withdrawal around 50–60 hours (31, 37).
AWS Risk Factors.
No studies have prospectively evaluated what risk factors, other than alcohol consumption, predispose patients to develop AWS in the ICU. The epidemiologic challenge of population heterogeneity among the critically ill contributes to the difficulties in identifying generally applicable or population-specific AWS risk factors. Prior episodes of alcohol withdrawal or seizures are probably the most powerful predictors of withdrawal occurring in these patients (34, 38). Whether alcohol dependency reliably predicts withdrawal is not clear, as comparative studies in similar populations are lacking (38). Carbohydrate-deficient transferrin elevation has been described as a sensitive and specific marker to detect chronic alcohol consumption—that is, a daily alcohol intake of 50–80 g for over a week (39–41)—and this test is not readily available. The presence of structural brain lesions, comorbid (especially infectious) medical conditions, genetic predisposition, and delays in identification of withdrawal symptoms were also described as risk factors for DT in non-ICU-populations (20, 34, 35, 42). Blood alcohol levels at admission are not associated with AWS in the ICU (34, 38).
AWS Screening Tools.
Patients’ risk for developing AWS is underestimated (43). It seems reasonable to recommend routine self-report or surrogate alcohol-related questionnaires, such as the CAGE tool to detect patients with alcoholism when feasible (38). The CAGE screening tool asks patients to answer four questions: 1) Have you ever felt you needed to Cut down on your drinking? 2) Have people Annoyed you by criticizing your drinking? 3) Have you ever felt Guilty about drinking? 4) Have you ever felt you needed a drink first thing in the morning (Eye-opener) to steady your nerves or to get rid of a hangover? This questionnaire has been proven to be a validated screening tool to identify people with a high suspicion of alcoholism in the noncritically ill (medical and surgical inpatients, psychiatric inpatients, and ambulatory medical patients) (44, 45). A cutoff of 2 or more affirmative answers to these four questions is recommended to detect alcohol abuse or dependence and to provide the best combination of sensitivity, specificity, and positive predictive value (45). In the ICU, some authors suggest that a score of 1 or more should be considered positive and prompt further investigation (17, 22). Prior episodes of withdrawal, the most predictive factor for AWS, should also be noted (46).
Evaluating withdrawal symptoms using a scale to grade clinical symptoms improves pharmacologic intervention significantly. The revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar), which was neither developed nor validated for critically ill patients (Appendix 1), has been described the most in ICU symptom severity ratings (13, 14, 16, 47, 135). Most studies excluded mechanically ventilated patients, which is not surprising as patient cooperation is essential to calculate the CIWA score. A CIWA score of 10 or more is considered to be positive and a trigger for preventive measures; a CIWA score of 20 reflects full-blown AWS (13, 14, 16, 47). The frequency with which reassessments of CIWA should be performed is not well defined across studies. When dealing with severe AWS (i.e., CIWA score ≥ 20 or Sedation-Agitation Scale [SAS] ≥ 5), an evaluation within the hour of the most recent administered drug dose should be performed (every 15–60 min) and repeated as long as the patient remains agitated. When the agitation is controlled, the assessment frequency can be reduced to 1–4 hours. The SAS and the Richmond Agitation-Sedation Scale (RASS) have also been used to titrate pharmacologic intervention for patients with severe AWS, including mechanically ventilated patients (48–50). In uncooperative patients, the use of a sedation scale with a goal of a SAS score of 3–4 or a RASS score of 0 to –1 appears reasonable.
AWS Treatment Strategies.
There are a few studies addressing AWS prophylaxis and treatment in ICU patients. Most are either retrospective, randomized but open-label, or predesign and postdesign studies. Different drug classes are proposed, either alone or as a combination. Studies describing combinations of drug classes include benzodiazepines (14, 16, 22, 33, 36, 37, 47, 49, 50), clomethiazole (15, 16, 47), antipsychotics (specifically, haloperidol) (14, 16, 20, 22, 33, 36, 47), clonidine (14, 15, 20, 37, 51, 52), phenobarbital (50), propofol (16, 50, 53), and dexmedetomidine (48, 54–56).
Aggressive symptom-triggered titration is most commonly described in critically ill patients (38) and, in keeping with what has been shown in other populations (57), appears to be the approach associated with the most effective results. The use of standardized protocols for AWS management reduces benzodiazepine requirements (37), and aggressive titration of benzodiazepines and phenobarbital has been shown to reduce the need for mechanical ventilation by 50% (p = 0.008) in patients admitted to the ICU for AWS alone (50). ICU length of stay is also reduced by implementing AWS symptom-driven medication administration (33). Symptom-triggered bolus drug administration reduces the average drug doses needed, the duration of ICU treatment and mechanical ventilation, the prevalence of pneumonia, and the severity and duration of AWS when compared with continuous sedative infusions without AWS symptom-driven boluses (16).
Benzodiazepines, GABAA receptor agonists, are considered the cornerstone of therapy for prevention and treatment of AWS (58), despite uncertainty as to their effectiveness and safety. Various drugs of this class have been studied for the treatment of AWS in ICU patients: lorazepam (22, 33, 36, 37, 59), midazolam (33, 36), diazepam (33, 49, 50), flunitrazepam (14–16), and chlordiazepoxide (33, 36). Specific pharmacokinetic properties and administrative routes described for routine sedation may help guide clinicians in these choices (60). The IV route is preferred in ICU patients because of rapid onset and bioavailability considerations. Diazepam has a faster onset of action than lorazepam, midazolam, or chlordiazepoxide. Midazolam, diazepam, and chlordiazepoxide all undergo hepatic metabolism to active metabolites. Diazepam and chlordiazepoxide have the longest half-lives. In cirrhotic patients or in patients with alcoholic hepatitis, both dosing and timing of administration of these agents should therefore be cautiously readjusted or lowered once desired therapeutic effect has been achieved. In contrast, lorazepam is metabolized in the liver into inactive lorazepam-glucuronide (61) and may thus be preferable for patients with liver dysfunction. When comparing benzodiazepines for AWS management, no evidence supports a particular benzodiazepine (58) over another; no recommendation is provided for this reason.
Ethanol infusions have been evaluated for prevention of AWS in postoperative and trauma ICU patients (13, 14, 49, 62). Dose and administration vary widely (38) and the ethanol elimination rate is inconsistent in chronic alcoholic patients (62), making ethanol more challenging to administer and to titrate. Patients in whom AWS develops while receiving ethanol prophylaxis have similar blood alcohol concentrations than those who do not (13). Two studies compared the efficacy of ethanol infusion for AWS prophylaxis with benzodiazepines (49) or other treatments (i.e., benzodiazepine or clomethiazole, with either clonidine or haloperidol) (14). Similar rates of withdrawal prevention were observed. Ethanol administration presents some risks, however, including extravasation injury, and hepatic, gastrointestinal tract, hematologic, and neurological side effects (24, 57). As other treatment options with a lower risk profile are available, ethanol infusions are not recommended for the prevention or treatment of AWS (63).
This sedative-hypnotic drug, available in Europe, has been evaluated for prophylaxis (14) and treatment of AWS in ICU patients (16, 47, 64). The mechanism of action of this drug is similar to that of benzodiazepines. Clomethiazole also exerts unique anticonvulsant properties because it potentiates glycine (65), an amino acid with anticonvulsant effects in inborn metabolic disorders (66). In comparative studies, the prevalence of AWS and the ICU length of stay did not differ between patients receiving a clomethiazole-haloperidol regimen compared with benzodiazepine-based regimen (47). In this study, the clomethiazole group had a significantly increased prevalence of tracheobronchitis (p = 0.0023), probably secondary to an increase in bronchial secretions precipitated by clomethiazole administration (40).
Haloperidol, an antipsychotic with dominantly dopaminergic blocking activity (67), has been studied as a bolus or as a continuous infusion in ICU patients, in combination with other drugs, to manage hallucinations occurring in AWS (15, 16, 20, 22, 33, 47, 64, 68, 69). Little evidence can be found on use of atypical antipsychotics, with only one retrospective case series reporting the use of atypical antipsychotics in the treatment of AWS (69). Concerns about this drug class in alpha-amino-3-hydroxy-5-methyl-4-. isoxazole-propionic acid management include QT interval prolongation, lowering of the seizure threshold, thermoregulation abnormalities, and the increase in seizures associated with alcohol withdrawal in animal models (70). No study has compared benzodiazepines with haloperidol for AWS in the ICU. However, despite the absence of evidence as to any benefit in delirium among the critically ill (71), these agents may serve as adjunct pharmacotherapy in agitated and hallucinating patients during AWS, after optimization of benzodiazepine use.
Clonidine is a α2-adrenergic brainstem agonist receptor (α2A subtype); its pharmacologic effect results in a reduction of CNS sympathetic outflow (72), an effect associated with improvement in autonomic AWS symptoms. The addition of clonidine to benzodiazepines does not appear beneficial in AWS prophylaxis in ICU patients and has no impact on length of stay (14). Despite reports of its use, its benefits are not clearly established in prospective AWS management controlled trials (15, 16, 20, 22, 37, 47, 52, 64). The only two randomized controlled studies reporting its use assessed combinations of therapeutic approaches (16, 47). The first study investigated a combination of flunitrazepam-clonidine versus chlomethiazole-haloperidol and flunitrazepam-haloperidol titrated to AWS symptoms. The flunitrazepam-clonidine regimen was associated with significantly less pneumonia and more cardiac complications; four patients required additional medication (haloperidol) to control hallucinations and were withdrawn from the study. Clonidine infusion requires titration, weaning, and electrocardiogram monitoring, which may predict the unchanged length of stay in comparison with other treatment arms (47).
Barbiturates resemble benzodiazepines in their GABA receptor pharmacologic effect. In addition, barbiturates seem to increase the duration of the chloride channel opening associated with GABA receptor agonism. Barbiturates also directly activate GABA receptors at high concentrations, reduce excitatory neurotransmitter (glutamate) activity through AMPA receptor binding and possess nonsynaptic membrane effects (73), and have a half-life of 80–120 hours.
In a pre-post study describing two patient cohorts admitted to the ICU because of severe diazepam-resistant AWS and DT, a symptom-triggered protocol where phenobarbital administration followed escalating doses of diazepam was associated with several benefits: a significant reduction of the use of mechanical ventilation, less agitation, and a trend toward a reduction in the ICU length of stay (50). These benefits were observed despite the symptom-triggered protocol group using larger amounts of and much broader dose ranges of both benzodiazepines and phenobarbital. Another study addresses ICU transfer rates in AWS emergency department patients associated a single dose of IV phenobarbital (combined with a symptom-driven lorazepam-based AWS protocol) with a decreased ICU admission rate (8% vs 25%) and a reduction in continuous lorazepam infusion rates compared with the group who did not receive the phenobarbital bolus (21). Barbiturates as an adjunctive therapeutic agent are likely to be beneficial if early symptom-driven pharmacologic intervention with benzodiazepines is not effective within 4–6 hours.
Propofol is a sedative-hypnotic agent mediated by the activation of the GABAA receptor and inhibition of the NMDA subtype of glutamate receptor (53). Propofol use is described as rescue medication when other therapies, such as high doses of lorazepam or diazepam and phenobarbital, fail to control severe AWS (50, 53). When flunitrazepam, clonidine, and haloperidol boluses were compared with infusions, at least one third of patients required propofol as rescue medication (47).
Dexmedetomidine is an eight times more specific α2-agonist than clonidine (74) and has a shorter half-life and a greater titratability. In the CNS, dexmedetomidine acts on postsynaptic α2-adrenoreceptors to inhibit sympathetic activity, thereby decreasing blood pressure, heart rate, and anxiety (75). In the spinal cord, this mechanism produces analgesia (75). Calm wakefulness characterizes dexmedetomidine sedation and respiratory drive remains unaffected (74, 75). Because of its mechanism of actions, lack of respiratory depression, and GABA-independent action, the interest in dexmedetomidine use for AWS is on the rise.
Case reports (56, 68) and case series (48, 55, 69) describe dexmedetomidine administration in severe AWS in critically ill patients who failed benzodiazepine treatment. In all 30 identified cases, dexmedetomidine was used as add-on therapy to benzodiazepines, in some because of ongoing agitation, and in some because large amounts of benzodiazepine were not tolerated. In three cases, dexmedetomidine was the only administered treatment once the infusion started. Most patients in these reports received a dose ranging from 0.2 to 1.5 µg/kg/hr; boluses were not consistently given. Three patients had symptoms that were not adequately managed and dexmedetomidine infusion was discontinued; benzodiazepine and propofol infusions were substituted, and all three required mechanical ventilation. Response to therapy was not described consistently across case reports. One author used the RASS and the Confusion Assessment Method for ICU (CAM-ICU) to titrate medications (48). A reduction in benzodiazepine requirements was observed by some (56, 68). In an observational analysis of 20 patients who received dexmedetomidine as adjunct treatment for severe AWS in the ICU, a 61% reduction in benzodiazepine dosage and a 21% reduction in alcohol withdrawal severity score were observed in the first 24 hours of drug initiation (p < 0.05) (54). Adrenergic symptoms were reduced as well. The benefit of dexmedetomidine occurred within 4 hours of the drug initiation (only five patients received a bolus dose) and a dose of less than 0.7 µg/kg/hr was sufficient for most (54). Because of the lack of trials comparing the effectiveness of dexmedetomidine to standard agents, its use in AWS cannot be recommended at this time.
Two anticonvulsants, carbamazepine and valproate, were compared in AWS in an alcohol detoxification setting; the carbamazepine group had a higher transfer rate to ICU (20). Whether the anticonvulsants were continued in the ICU is unclear. The benefit of β-blocking agents has been proposed to counteract AWS’s autonomic symptoms (57). Limited or no evidence is available as to the efficacy and tolerability of β-blockers in ICU patients experiencing AWS.
Reports on magnesium deficiency in alcoholic patients suffering from AWS have been published since 1934 (57, 76). As glutamate-mediated pathways are very stimulated in AWS, magnesium has been proposed as potentially alleviating alcohol withdrawal symptoms by competing with glutamate’s NMDA receptor binding site and antagonizing this system’s activity (77), in addition to stimulating the GABAergic system (77, 78). Hypomagnesemia is the most common electrolyte abnormality among ethanol consumers (79, 80) through several mechanisms, including increased urinary magnesium excretion (81). Since magnesium is a cofactor for thiamine conversion (82), severe magnesium deficiency can lead to refractory unresponsiveness to thiamine (82), seizures, and cardiac arrhythmias (83). Despite these biologically plausible mechanisms, the only placebo-controlled study performed in hypomagnesemic alcohol consumers found no benefit to four 2-g doses of intramuscular magnesium administration on alcohol withdrawal severity (84), mitigating any recommendation for routine magnesium administration (57, 85). However, plasma magnesium levels should routinely monitored and repleted.
Supportive Care: Thiamine and Multivitamins.
Wernicke encephalopathy (WE) is an acute neuropsychiatric condition caused by thiamine (vitamin B1) deficiency (82). Its association with significant morbidity and mortality, bariatric surgery, hematologic and other malignancies and their treatment, and how frequently its diagnosis is missed have been described (82). Although 19% of patients have no specific symptoms, common symptoms include peripheral neuropathy, cerebellar ataxia, and myopathy (82). If WE is unrecognized or not treated early and adequately, patients are at risk developing a potentially irreversible alcohol-induced amnestic disorder: Korsakoff syndrome (KS). KS causes severe short-term memory loss and impaired capacity to integrate new information (86). Patients can initially present with confusion, ataxia, eye-movement abnormalities (gaze palsies, nystagmus), and other neurological signs (87, 88). These manifestations progressively subside but major memory impairment remains (89). To our knowledge, no study has evaluated the efficacy of thiamine and multivitamins and optimal dosage in prevention or treatment of WE in the critically ill. Evidence on prevention and treatment of WE and KS is studied in other patient populations (88) and extrapolated to ICU patients.
Thiamine repletion is influenced by transport mechanisms across the blood-brain barrier; thiamine transport is both active and passive. With low or depleted cerebral thiamine levels, in the setting of normal thiamine plasma concentrations, transport across the blood-brain barrier is almost exclusively active. When high-dose IV thiamine administered, serum levels rise rapidly, quick passive diffusion occurs, and the brain thiamine levels normalize rapidly. Oral thiamine repletion is limited by its intestinal absorption rate (82, 90), as an oral dose of 30 mg will permit absorption of about 4.5 mg. In chronic malnourished alcoholics, intestinal absorption of thiamine can be reduced by about 70% (91). In one third of malnourished patients, ethanol can decrease thiamine absorption by 50%. Furthermore, here is evidence that patients experiencing DT present impaired thiamine absorption (90). Thiamine repletion in the critically ill should unequivocally be managed with parenteral thiamine.
A Cochrane review states that there is not enough evidence based on randomized clinical trials to recommend dose, route of administration, and frequency of thiamine in the prevention and treatment of WE in patients consuming alcohol (92). Studies indicate several different regimens (82). Generally, a dose of 500 mg IV tid for 3–5 days is recommended based on clinical practice (82, 86). If response to therapy is observed, 250 mg parenterally for the subsequent 3–5 days should be prescribed (82). In alcoholic or alcohol-dependent patient without WE, at least 200 mg parenterally is necessary to prevent neurological symptoms (82, 93). Prophylactic parenteral administration of 250 mg of thiamine is recommended in patients suffering for severe AWS for 3–5 days, in poorly nourished or malnourished patients (82, 86). Multivitamins administered as an IV infusion are frequently prescribed even though no studies support this practice. Multivitamins are inexpensive and without significant adverse effects.
A pharmacologic regimen titrated to withdrawal symptoms should be the first approach to the ICU patients with AWS; no prophylaxis regimen can be unequivocally recommended. Benzodiazepines as first-line treatment are a reasonable option, although early phenobarbital administration appears to confer some advantages in combination with benzodiazepines. Propofol and dexmedetomidine are not rigorously tested in comparative studies; their use as additional or alternative choices should be guided by the clinician’s assessment of individual patient parameters.
Smoking tobacco is the most common addiction in the world. Nicotine inhalation increases the risk of cardiorespiratory diseases, a common cause of ICU admission. About 20–46% ICU patients are estimated to be smokers (94). Smokers are more likely to require postoperative ICU care (95). Nicotine withdrawal has been identified as one of the risk factors for agitation and delirium (96–98). A prospective observational cohort study that compared smokers with nonsmokers demonstrated that current smoking history is associated with an increased frequency of agitation and related adverse events, such as accidental removal of tubes and catheters, need for supplemental doses of sedatives, analgesics and neuroleptics, and requirement for physical restraints to prevent self-inflicted injuries (99). Nicotine withdrawal in ICU is not well characterized. Abstinence, independent of pack-year or recent smoking history, is associated with the development of agitation and of potentially life-threatening problems (99).
Nicotine addiction is attributed to neuroadaptative mechanisms. Nicotine-induced desensitization causes up-regulation of nicotinic acetylcholine receptors (nAchRs), and nAchRs modulate many major neurotransmitters, dopamine, and acetylcholine among them (100). The complex effects of chronic nicotine inhalation result from an alteration in neurotransmission that leads to sustained tobacco use. When smokers no longer inhale nicotine, the previous equilibrium is disrupted and withdrawal manifestations appear (100, 101).
Symptomatology of nicotine withdrawal is described mostly in outpatients. Several symptoms and their time of course have been identified. Some of them are validated and included in DSM-IV Text Revision, diagnostic criteria of tobacco withdrawal syndrome: anger, irritability, frustration, anxiety, dysphoria, concentration difficulties, impatience, sleep fragmentation, insomnia, restlessness, weight gain, and bradycardia. In general, withdrawal syndrome begins after 1–2 days of abstinence, will have its peaks within the first week, and can subside within the next 2–4 weeks after or persist longer (102–105).
Nicotine dependency is readily admitted by patients. Diverse screening tools have been elaborated and primarily used in epidemiologic and clinical studies. Biomarkers, such as serum, saliva, and urinary cotinine levels, a metabolite of nicotine, can be used to discriminate smokers from nonsmokers (106, 107). Acute smoking can also be assessed with carbon monoxide-hemoglobin and exhaled carbon monoxide (108–110). The Fagerström Test of Nicotine dependence allows the evaluation of degrees of tobacco dependency (111). None of these have been evaluated in the ICU.
Prevention and Treatment.
Efficacy of nicotine replacement therapy (NRT) to attenuate withdrawal signs and symptoms and facilitate smoking abandon has been recognized (112, 113). Safety of NRT is well established in the outpatient setting and hospitalized patients, even in populations with stable coronary artery disease. Thus far, clinical trials did not show any increased risk of angina, myocardial infarction, stroke, arrhythmia, or death with NRT (114–116). However, limited data are available for its safety in ICU patients. A few case reports have been published describing the potential benefit of NRT in delirious ICU patients with a smoking history (117–119). In agitated and delirious patients unresponsive to anxiolytics, symptoms resolved within a few hours of transdermal nicotine patch application. Most studies published on NRT in the ICU are single-center retrospective studies. Their main purpose is to determine if NRT is associated with an increased mortality rate in the ICU. No data on the timing of nicotine withdrawal, withdrawal descriptors, or risk factors other than being a current smoker can be extracted from those studies.
The first ICU NRT publication is a retrospective case-control study of 180 smokers admitted to a single-center medical ICU (120). The most common ICU admission diagnosis was drug overdose, with a median ICU length of stay of 2 days. Of 6,735 admissions, 115 patients had NRT prescriptions. Twenty-two percent of smokers who received NRT were excluded for a variety of reasons. The population was separated in two groups (those receiving NRT vs those without NRT); the decision to prescribe NRT was left to the physician’s discretion. The primary finding was a significant association between hospital mortality within the NRT group. The level of cigarette consumption and duration of tobacco use were not reported (120).
A study comparing the mortality rate between smokers (receiving or not given NRT) and nonsmokers undergoing coronary bypass graft surgery reported nonsignificant increases in hospital mortality between groups (smokers receiving NRT, smokers not receiving NRT, and nonsmokers) (121). When adjusted for age and presence of atrial fibrillation, which were higher in the nonsmoker group and no-NRT group, a significant increase in mortality was seen in the NRT versus non-NRT groups and in the NRT versus nonsmoker groups (121). Paciullo et al (121) highlighted the low power of their study but concluded nevertheless that critically ill cardiovascular patients should not receive NRT during their ICU stay, but that intervention should be considered after discharge from hospital.
The only prospective observational cohort study published to date was performed in a medical ICU on 330 active tobacco consumers: 174 received NRT at a median dose of 21 mg and 156 refused treatment (122). In this study, a nurse-managed tobacco assessment routinely screened all hospitalized patients for tobacco use, and current smokers or their next-of-kin were offered NRT, which was adjusted for daily cigarette consumption. Patients were included in the study if they were smoking during the last 30 days and were excluded if they had already received NRT for more than 24 hours. Low-risk patients admitted to ICU only for monitoring, and those who received non-NRT treatment for nicotine addiction, were also excluded. The group exposed to NRT was more likely not to be white, to have a higher smoking exposure (cigarettes per day and pack-years), to be mechanically ventilated, and to have less coronary artery disease. No significant difference was observed for hospital and ICU mortality, hospital length of stay, 28-day mechanical ventilator and ICU-free days, and Sequential Organ Failure Assessment score. Secondary analyses showed more days with positive CAM-ICU score for the NRT group (23% vs 13.1%, p < 0.001) and a greater need for physical restraints with NRT (38% vs 19.5%, p < 0.001) (122). On the other hand, the NRT group had lower median RASS scores, received higher cumulative doses of opioids and benzodiazepines, and required less dexmedetomidine and haloperidol. Cartin-Ceba et al (122) concluded that further studies are required to make any recommendations.
The latest study took place in a mixed medical and surgical ICU (123). Four hundred and twenty-three smokers were included in this retrospective cohort study. The study aimed to evaluate the ICU and hospital mortality risk. Transdermal NRT was applied to 73 patients at a median dose of 20 mg/d with a median delay of 2.3 days after ICU admission and for a median duration of 6 days; they were compared with 350 smokers without NRT. Alcohol intake greater than 21 U/wk was recorded as a possible confounder as the NRT group had a higher prevalence of alcohol abuse. Agitation or delirium was defined as a new prescription of two or more antiagitation drugs (benzodiazepines, haloperidol, or clonidine) and verified by a chart review confirming the presence of an acute confusional state. NRT-treated patients were significantly more likely to have received more than two sedative agents (25.7% vs 7.1%, p < 0.0010) (123). Thus, an agitation or delirious status may have created a propensity to prescribe NRT. Furthermore, the NRT group had an unadjusted survivor length of ICU stay almost double that of the non-NRT group. Behavioral disorders such as agitation and delirium are known to prolong ICU stays (124), perhaps explaining this difference. When adjusted for all covariates, hazard ratios for NRT administration were not significantly altered for both primary outcomes, ICU and in-hospital mortality. Gillies et al (123) concluded that a randomized blinded placebo-controlled trial is necessary to assess the safety and benefit of NRT in the ICU.
Discussion: Nicotine Withdrawal.
Nicotine withdrawal has been described in outpatients but very limited data exist in the ICU population. Nicotine withdrawal symptoms are challenging to assess in the critically ill, and the use of nicotine transdermal patches in this population has been controversial for many years. Studies enhance the fact that physicians seem to prescribe NRT as an alternative or additional pharmacologic intervention when agitation or delirium did not respond to regular anxiolytic or antipsychotic treatment. In addition, the outcome most described is mortality, and not treatment effectiveness, related to NRT. In order to reassure healthcare providers as to the safety and efficacy of NRT, further randomized controlled trials are essential, with stratification by different ICU populations (such as trauma, neurosurgery, and cardiovascular patients). Neither bupropion nor varenicline, agents believed to modulate nicotine withdrawal symptoms and used to enhance the effectiveness of smoking cessation (125), have been studied in an ICU context. Others avenues are promising, such as the α2-adrenergic receptor agonists, dexmedetomidine and clonidine, have benefits in attenuating stress-induced nicotine craving in animal and human models (126–128) but clinical studies as to their effectiveness and safety are currently lacking.
Withdrawal Symptoms of Opiates and Sedatives in the ICU
Prolonged or high-dose administration of analgesic or sedative agents appears to be associated with an increased risk of withdrawal syndromes in pediatric and adult critically ill patients (129, 130). Challenges in the recognition of withdrawal syndromes include confounding diagnoses such as delirium, other forms of withdrawal (e.g., ethanol), and the fact that patients are often exposed to multiple agents with the potential to cause withdrawal (131), in addition to pharmacodynamics considerations that vary according to individual pathophysiology and coadministered drugs (132, 133). Withdrawal prevalence ranges are reported in 17–57% of pediatric and 13–33% of adult critically ill patients. Opiates, benzodiazepines, and dexmedetomidine infusions are also associated with withdrawal symptoms (131). Withdrawal occurred following discontinuation of dexmedetomidine of 4.9%, versus 8.2% with midazolam, in a randomized controlled study comparing both agents (p = 0.25) (134). Most studies addressing iatrogenic withdrawal are retrospective and include patients receiving more than one sedative and/or analgesic agent. Specific prevalence and risk factors for drug withdrawal in ICU patients are thus challenging to describe. Furthermore, opioid and benzodiazepine withdrawal leads to nonspecific disturbances (e.g., agitation, anxiety, irritability, restlessness, sleep disturbances, hallucinations; vomiting and diarrhea; and tachycardia, tachypnea, sweating, and fever) (129). Although specific recommendations cannot be made for the prophylaxis or treatment of opioid or sedative withdrawal in ICU patients, the current pain, anxiety, and delirium management guidelines recommend that opioids and/or sedatives administered for prolonged periods (i.e., days) should be weaned over several days in order to reduce the risk of drug withdrawal (60).
Despite the high prevalence of alcohol, nicotine, and iatrogenic withdrawal syndromes in the critically ill, limited data exist to guide the clinician in determining best practice. Patients should be routinely screened on ICU admission for alcohol consumption and dependency, history of alcohol withdrawal, and nicotine consumption; assessments if the patient becomes agitated should include a differential diagnosis of withdrawal to either or both substances. AWS should be treated promptly and aggressively in a symptom-triggered manner. Furthermore, the administration of continuous sedatives and opiates, as well as their cumulative in-ICU doses, should be tallied daily and considered in their tapering with surveillance for withdrawal symptoms. Future studies should incorporate rigorous methods to better guide the practicing clinician in his or her therapeutic choices.
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APPENDIX 1. Revised Clinical Institute Withdrawal Assessment for Alcohol Scale (135)
alcohol; alcohol withdrawal syndrome; critical care; delirium tremens; intensive care; nicotine; nicotine withdrawal
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