Nicotine Replacement Therapy in the Intensive Care Unit: a randomized, controlled pilot study.

Cigarette smoking remains the leading cause of preventable disease and
premature death worldwide. There are about 1.2 billion smokers in the world,
half of whom will die from diseases caused by smoking. Smoking causes 5 million
deaths per year, and if present trends continue, 10 million smokers per year
are projected to die by 2025.
Furthermore, abstinence from the highly addictive tobacco products can lead to
withdrawal symptoms. Although these symptoms are non-life threatening in
healthy and hospitalized adults they are not well described in the mechanically
ventilated active smoking patient.
An observational study found a higher incidence of agitation, self-removal of
tubes/catheters and the need for sedatives, analgesics, neuroleptics and
physical restraints in mechanically ventilated smoking patients . Mayer et al.
described in a case-report five smoking critically ill neurologic patients
developing a sustaining agitated delirium with a rapid and dramatic improvement
after placement of a 21-mg nicotine patch .
Whether nicotine replacement therapy is a safe and effective method for
treating nicotine withdrawal symptoms in the critically ill smoking patient
remains unclear. Lee and Afessa described in a retrospective study for the
first time a higher mortality in medical patients admitted to the ICU and
receiving nicotine replacement therapy . Another retrospective study found a
higher mortality in CABG surgery patients admitted to an ICU for cardiothoracic
surgery. However, other studies found no difference or a lower mortality in
critically ill patients receiving nicotine replacement therapy compared to
patients receiving no nicotine replacement.
Because of these conflicting results and the absence of a randomized controlled
trial studying the safety and efficacy of transdermal nicotine replacement
therapy in the critically ill smoking patient a clinical study should be
conducted.

To determine the safety and efficacy of transdermal nicotine replacement
therapy in mechanically ventilated and active smoking patients admitted to the
intensive care unit.

Study design
Single-country, multicentre, randomized, controlled, double-blind,
parallel-group, pilot study.

Study description
In this study mechanically ventilated, active smoking ICU patients will be
screened for in- and exclusion criteria. Before screening, informed consent
will be obtained from the patient or legal representative. At screening age,
sex, medical, trauma/surgical origin referring to primary admission diagnosis,
admission source, primary diagnosis, smoking behavior, alcohol and drugs
consumption, medical history, pre-existing conditions and medication use will
be recorded. The SOFA score (from admission to the ICU until 24 hours after
admission or until randomisation in case of randomisation before 24 hours after
admission) will be determined. Patients that meet all the inclusion criteria
and none of the exclusion criteria will be randomly allocated to either the
nicotine patch or the control patch. At baseline the Acute Physiology and
Chronic Health Evaluation (APACHE-II and APACHE-IV) score will be determined.
From start of the study product until discharge from the ICU
or day 30 SOFA score, RASS score, CAM-ICU score and DOS score will be assessed
daily. From start of the study product until discharge from the hospital or day
30 the number and type of infections according to the CDC definitions, adverse
events and medication use will be assessed daily.
A blood and urine sample will be drawn at baseline (just before start study
product administration) for determination of serum cotinine and urine NNAL
concentrations. Blood samples will be taken for storage that may be used after
conduct of the trial for determination of mechanistic parameters for
clarification of clinical outcome results.
In case of discharge from ICU or at day 30 mortality or discharge and duration
of mechanical ventilation will be documented.
A follow up will be performed 90 days after start study product to document
mortality, length of stay and patient location.

The test product is a nicotine patch applied to the skin, delivering 14 or 21
mg nicotine/24 hrs. All subjects will get a nontransparent plaster
('blindingplaster') which is applied over the nicotine patch for the
intervention group. This for the double-blind design. Within 48 hours after ICU
admission a nicotine patch and/or blindingplaster will be applied to the
undamaged skin. Every 24 hours the nicotine and blindings patch will be
renewed. Product regime will be finished on day 30 of ICU admission or after
ICU discharge.

Before the application of the study product a blood and urine sample will be
drawn from indwelling arterial and urinary catheters.
Furthermore, alcohol use will be assessed using the Alcohol Use Disorders
Identification Test as well as smoking behaviour and history using the
Fagerström Test of Nicotine Dependence. Legal representatives will be asked for
informed consent in case of patient's incapacity.
Part of routine ICU care is the daily assessment of various clinical scales,
such as the RASS score, CAM-ICU score, DOS score, Behavior Pain Scale and the
Numeric Rating Scale. Results of scoring will be documented in the
Investigators Site File.
In accordance with routine ICU care blood samples are drawn daily. To calculate
the SOFA score, the remaining blood will be analysed.
At day 90 the patient location and survival status will be confirmed by
telephone interviews with the patient or legal representative.

Among adverse events related to transdermal nicotine replacement therapy, skin
irritation, insomnia, coughing, heart palpitations, nausea, vomiting, headache,
hiccoughs and gastrointestinal complaints have been noted. Possible adverse
events related to the control product are skin irritation.
During the study period subjects will not receive other nicotine replacement
therapy, possibly leading to more agitation and delirium in the placebo group.

The study is considered to be of minimal burden to the patient with a low risk
of mild adverse events. Moreover, it is not possible to address the research
question without conducting this trial in critically ill incompetent patients.
Because of conflicting results of previous studies on this topic and the
absence of a randomized controlled trial studying the efficacy and safety of
transdermal nicotine replacement therapy in the critically ill smoking patient
a clinical study is highly relevant. This study could provide insight by either
protect future ICU patients for possible harmful effects of nicotine
replacement therapy or provide a safe and effective therapy for nicotine
withdrawal in the ICU.