ResearchNicotine withdrawal and agitation in ventilated critically ill patients

Introduction: Smoking is highly addictive, and nicotine abstinence is associated with withdrawal syndrome in hospitalized patients. In this study, we aimed to evaluate the impact of sudden nicotine abstinence on the development of agitation and delirium, and on morbidities and outcomes in critically ill patients who required respiratory support, either noninvasive ventilation or intubation, and mechanical ventilation. Methods: We conducted a prospective, observational study in two intensive care units (ICUs). The 144 consecutive patients admitted to ICUs and requiring mechanical ventilation for >48 hours were included. Smoking status was assessed at ICU admission by using the Fagerström Test of Nicotine Dependence (FTND). Agitation, with the SedationAgitation Scale (SAS), and delirium, with the Intensive Care Delirium Screening Checklist (ICDSC), were tested twice daily during the ICU stay. Agitation and delirium were defined by SAS >4 and ICDSC >4, respectively. Nosocomial complications and outcomes were evaluated. Results: Smokers (n = 44) were younger and more frequently male and were more likely to have a history of alcoholism and to have septic shock as the reason for ICU admission than were nonsmokers. The incidence of agitation, but not delirium, increased significantly in the smoker group (64% versus 32%; P = 0.0005). Nicotine abstinence was associated with higher incidences of self-removal of tubes and catheters, and with more interventions, including the need for supplemental sedatives, analgesics, neuroleptics, and physical restraints. Sedation-free days, ventilator-free days, length of stay, and mortality in ICUs did not differ between groups. Multivariate analysis identified active smoking (OR, 3.13; 95% CI, 1.45-6.74; P = 0.003) as an independent risk factor for agitation. Based on a subgroup of 56 patients, analysis of 28 pairs of patients (smokers and nonsmokers in a 1:1 ratio) matched for age, gender, and alcoholism status found similar results regarding the role of nicotine withdrawal in increasing the risk of agitation during an ICU stay. Conclusions: Nicotine withdrawal was associated with agitation and higher morbidities in critically ill patients. These results suggest the need to look specifically at those patients with tobacco dependency by using the FTND in ICU settings. Identifying patients at risk of behavioral disorders may lead to earlier interventions in routine clinical practice. Introduction Cigarette smoking is the main addiction in the world [1]. Tobacco use is associated with a high prevalence of alcohol and drug dependence, depression, and anxiety disorders [2,3]. Because the body develops a homeostatic response to nicotine, smokers have withdrawal symptoms on abstinence from the drug [1]. These symptoms peak during the first week of abstinence but sometimes are persistent for several weeks or months, and then gradually decrease to baseline levels [4,5]. In hospitalized patients, studies have reported several manifestations related to sudden nicotine abstinence, such as bradycardia, irritability, anxiety and agitation, confusion, or hallucinations, but intensive care unit (ICU) patients are usually excluded from published studies [6]. Behavioral disorders such as delirium and agitation in the critically ill occur with a high frequency, ranging from 15% to 80% of patients, and have been associated with increased morbidity and risk of mortality [7-13]. Many risk factors, such as history of hypertension and alcoholism, higher severity of acute disease, and clinical effects of sedative and * Correspondence: ducheyron-d@chu-caen.fr 2 Service de Réanimation Médicale, CHU de Caen, 14033 Caen Cedex, France Full list of author information is available at the end of the article © 2010 du Cheyron et al.; licensee Biomed Central, Ltd. This is an open access article distributed under the terms of the Creative Commons attribution license (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lucidarme et al. Critical Care 2010, 14:R58 http://ccforum.com/content/14/2/R58 Page 2 of 10 analgesic agents, have been identified in the literature [12]. Few data exist in the literature regarding the behavioral impact of sudden nicotine abstinence in the ICU setting, except for one study, which identified smoking history as a risk factor for delirium in critically ill patients [8]. Moreover, nicotine-replacement therapy (NRT) remains a controversial topic in the ICU, and a retrospective study found an association between NRT and mortality [14]. Thus, we aimed to evaluate the nicotine-withdrawal syndrome in critically ill patients. We hypothesized that dependent smokers may have increased risk for agitation and delirium, and then increased morbidity, such as infections and accidental self-removal of tubes and catheters, related to these behavioral disorders. Materials and methods Patients This prospective observational study was conducted over a period running from June 2007 to April 2008 in two adult ICUs (a 22-bed medical ICU in the University Hospital of Caen, Center 1, and an eight-bed medicosurgical ICU in the tertiary Memorial Hospital of Saint-Lô, Center 2, Normandy, France). All patients admitted to the ICUs and mechanically ventilated with either noninvasive ventilation or intubation for respiratory support for longer than 48 hours were considered eligible for the investigation. Patients were excluded if they were younger than 18 years or were determined to have a history of chronic dementia and psychosis, or acute neurologic diseases on admission, such as severe traumatic brain injury, ischemic stroke, or cerebral hemorrhage. NRT was forbidden during the study period. The study was approved by the local ethics committee. Patients were included after informed consent of the patient or next-of-kin was obtained. Data collection The following demographic and clinical data were collected at ICU admission: age, gender, medical or surgical origin referring to the primary admission diagnosis, history of hypertension, chronic alcoholism and psychotropic therapy, smoking status, and primary diagnosis on admission to the ICUs. Alcohol consumption was considered chronic if it persisted for the whole year before admission, as defined by the National Institute on Alcohol Abuse and Alcoholism criteria for unhealthy alcohol use in the United States [15,16]. To assess the severity of the acute illness, the Simplified Acute Physiology Score II (SAPS II) [17] and the initial Sequential Organ Failure Assessment (SOFA) score [18] were determined within 24 hours after ICU admission. During the ICU stay, the duration of mechanical ventilation (either invasive or noninvasive ventilation), the cumulative dose and duration of drug exposure for sedation-analgesia, and the number of days per patient with heavy sedation, defined as a score ≥4 in the Ramsay sedation scale [19], were recorded. Finally, ICU length of stay and mortality were registered. Definitions Tabagism was evaluated according to the tobacco load, which is quantified in pack-years, and the nicotine dependence, as assessed by the Fagerström Test of Nicotine dependence (FTND) [20] (Additional data file 1), obtained from patients or their closest relatives. Patient dependency was dichotomized in weak and strong by using a threshold value of 4 in this smoking scale. Patients were divided into two distinct groups: (1) smoker group, including patients with active smoking status; and (2) nonsmoker group, including patients with nonsmoking history or tobacco discontinuation for >6 months. Agitation was assessed twice daily by nurses or physicians until ICU discharge, by using the modified SedationAgitation Scale (SAS) [21] (additional data file 2). SAS lists three levels of agitation. Patients were classified as "sedated" (SAS 1 to 3), "calm" (SAS 4), and "agitated" (SAS 5 to 7). Similarly, delirium was assessed for each patient twice daily by nurses or physicians until ICU discharge by using the Intensive Care Delirium Screening Checklist (ICDSC) score [22] (Additional data file 3). It includes eight items based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria [23] and features delirium, including inattention, disorientation, hallucination-delusion psychosis, psychomotor agitation or retardation, inappropriate speech or mood, sleep/wakecycle disturbances, and symptom fluctuation. For each abnormal item, a score of 1 was given. Patients with an ICDSC score >4 were considered to be delirious. Sedated patients with altered level of consciousness of A or B on the ICDSC scale were not considered to have delirium. All degrees of agitation and delirium were then confirmed by an independent physician by using chart assessment. Nosocomial infections were defined as follows: (1) ventilator-acquired pneumonia: clinical suspicion of pneumonia (that is, clinical and radiographic criteria), and at least one organism isolated by protective specimen brush at a concentration ≥103 colony-forming units (CFUs)/ml; (2) colonization of central venous catheters: at least one organism at a concentration ≥103 CFUs/ml identified by culture of the catheter tip with the Brun-Buisson technique [24]; (3) urinary catheter-related infection: the association of a leukocyturia at a concentration of ≥104/ml with the presence of an organism at a concentration of 105 CFU/ml; (4) bacteremia: a positive hemoculture with the isolation of an organism or at least two positive hemocultures for a coagulase-negative Staphylococcus, according to the usual definitions [25]. End points Primary end points were either one or more agitation or delirium events during the ICU stay. Secondary end points Lucidarme et al. Critical Care 2010, 14:R58 http://ccforum.com/content/14/2/R58 Page 3 of 10 were ventilator-free days (days alive and free from mechanical ventilation