Outcome of Nicotine Replacement Therapy in Patients Admitted to ICU: A Randomized Controlled Double-Blind Prospective Pilot Study

Discussion

This study sought to preliminarily address the critical factors in an ICU setting (ie, need for sedative and analgesics, number of days on the ventilator, and ICU stay) by using nicotine replacement patches in the ICU setting with smokers. Nicotine replacement patches have been shown to be the most consistently effective NRT, when it is not coupled with adjuvant behavioral therapy, which is not feasible in the ICU. Importantly, NRT has been shown to be effective in hospitalized subjects in a meta-analysis of 17 double-blind, placebo-controlled studies.⁵ The nicotine patch delivers a constant rate of nicotine transdermally, which will not interfere with other ICU procedures (ie, sedation and/or ventilation procedures).

Though not statistically significant, our preliminary results demonstrate a trend toward decreased ICU stay with NRT. Although our data indicate that neither ventilator days nor days using analgesics, vasopressors, or sedation were significantly different between the NRT-treated and placebo groups, more subjects are needed to better evaluate whether the subjects' agitation levels contributed to their ICU stays.

In the general population, NRT is highly effective for smoking cessation, by limiting the side effects, including agitation, associated with smoking cessation. However, there are limited studies addressing its use in hospitalized subjects.^1,6–8 Mayer and colleagues⁹ reported 5 cases of agitated delirium in smokers hospitalized for brain injury. The delirium developed 2–10 days after smoking cessation, and either completely resolved or substantially improved following NRT. In another report, Tran-Van et al¹⁰ described a subject with restlessness and difficulty being weaned from mechanical ventilation, which was attributed to nicotine withdrawal. The patient's condition improved following NRT.

Although most studies assess NRT as having a positive correlation with death, the literature reveals that the more pertinent outcome to measure is the need for additional sedatives and/or analgesics, and then correlating this need to measured agitation and the occurrence of adverse events. According to Woods et al,¹¹ in a 2004 study, reducing ICU agitation not only benefits the patient by reducing the need for sedatives and decreasing the time on the ventilator, but also lowers treatment cost by minimizing the need for additional medications associated with minimizing patient agitation. Downstream consequences of these sedatives include lowered breathing frequency and increased chance of ICU-associated pneumonia.^11–13

Additionally, studies have shown that younger patients are more likely to become agitated in the ICU.¹¹ The median age in the present study was 57.4 y in the NRT group and 52.3 y in the no-NRT group. This age population is not noted for increased risk of agitation when in the ICU and on mechanical ventilation. Therefore, performing a focused study on NRT in a younger ICU population with the focus on preventing agitation and associated adverse events may reveal a greater benefit in the ICU.

Studies have demonstrated that the patients who sit up, ambulate, and interact with their support network have a lower mortality rate in the ICU.^12,13 NRT is potentially another means to facilitate this active behavior in the ICU and to lessen the need for agitation-induced sedation. Our results indicate a trend in reducing ICU stay and decreasing the duration of mechanical ventilation.

Lucidarme and colleagues² described the impact of nicotine abstinence on the clinical course of critically ill patients receiving mechanical ventilation for at least 48 hours. Their study included 144 subjects (44 smokers and 100 non-smokers) and showed active smoking to be an independent risk factor for agitation. However, a prospective randomized clinical trial of hospitalized smokers by Lewis and colleagues¹⁴ did not show any difference in mortality between the nicotine patch versus placebo. Because of the paucity of clinical trials demonstrating the benefit of NRT for smoking cessation in ICU patients, NRT is generally used exclusively by intensivists, to ease or prevent withdrawal symptoms.

Cartin-Ceba et al¹⁵ completed a prospective observational study of smokers admitted to the ICU, in which they sought to investigate the impact of NRT on critically ill subjects, including hospital mortality (primary outcome), delirium, and cumulative doses of sedation and analgesia (secondary outcomes). A total of 330 active smokers (older than 18 years of age) were evaluated, and 174 received NRT upon admission to the ICU. A total of 14 subjects from the group receiving NRT (7.8%) died, as did 10 subjects from the non-NRT group (6.3%): a difference that was not statistically significant (P = .60). However, the NRT group did experience significantly more delirium than the non-NRT group (average ICU days 169 d [23%] vs 75 d [13.1%], P ≤ .001). Their results showed that NRT was not associated with increased hospital mortality after adjustment for severity of disease, pack-years of smoking, and do-not-resuscitate status upon ICU admission (odds ratio 1.6, 95% CI 0.6–4.1, P = .35). They noted that a randomized controlled trial was needed to really evaluate these risks and benefits.

A double-blind, placebo-controlled clinical trial by Warner et al¹⁶ reported that routine NRT was not beneficial in the management of perioperative nicotine withdrawal in smokers who underwent elective surgery. Lee and Afessa¹⁷ conducted a retrospective case-control study in which they identified 90 cases (smokers who received nicotine replacement in the first 24 h of their medical ICU admission) and 90 controls (smokers who did not receive nicotine replacement), matched for APACHE III score and age. Unadjusted mortality was 20% in those who received nicotine replacement, and 7% in those who did not. When adjusted for severity of illness and mechanical ventilation, those who received NRT still had significantly higher mortality (odds ratio 24.6, CI 3.6–167.6). They concluded that NRT was associated with increased hospital mortality in critically ill subjects. Although their findings are striking, it was a single-center, retrospective study.

Paciullo et al¹⁸ studied the impact of NRT on in-hospital mortality following coronary artery bypass graft surgery. Sixty-seven subjects who received NRT were matched with 67 current smokers in terms of baseline demographics and surgical procedures. Mortality was nonsignificantly higher in the NRT group versus the non-NRT smoker group (4.5% vs 0%, P = .08). In a follow-up commentary to Lucidarme et al,² Afessa and Keegan¹⁹ affirmed that, due to the paucity of data describing nicotine withdrawal in the critically ill, prospective studies are needed to address the issues of mortality, as well as prevention and treatment options.

Although this was a pilot study with a small sample size, the positive-trending results indicate further studies should be performed on a larger scale at this and other institutions, to broaden the population of this study. Despite having a broad protocol in which patients from the emergency department or the general medical floor could be included in the study, the majority of subjects in this study were admitted to the ICU from the emergency room; the one subject who was not admitted through the emergency room spent ≤ 1 hour on the general medical floor. In future studies we aim to evaluate the patient population admitted from the general medical floor to the ICU to compare the results to our present study.