Nicotine Replacement Therapy in the Intensive Care Unit

A Randomized Controlled Pilot Study

Report Research Clerkship

Anne Schuppers

University of Groningen

S2016575

Faculty and daily supervisor: Second supervisor:

H. van den Oever, MD B. de Jong, MD

Deventer Hospital Gelderse Vallei Hospital Ede

Department of Intensive care Department of Intensive care

Presently Radboudumc Nijmegen

Co-investigators: Department of Intensive care

M. Arbouw, PhD

Deventer Hospital Co-investigator:

Department of Clinical Pharmacy A. R. H. van Zanten, MD, PhD

A. Kruisdijk-Gerritsen, ICU nurse Gelderse Vallei Hospital Ede

Deventer Hospital Department of Intensive care

Department of Intensive care

2

Table of contents

Table of contents......................................................................................................................2

Abstract (English)....................................................................................................................3

Abstract (Nederlands).............................................................................................................4

List of abbreviations................................................................................................................5

Introduction.............................................................................................................................6 Delirium and nicotine withdrawal

Nicotine replacement therapy (NRT)

Metabolism of nicotine

Previous studies in critically ill patients

Aim of the study.......................................................................................................................8

Materials and methods............................................................................................................9

Trial design

Participants

Randomisation

Blinding

Data collection

Data analysis

Statistical methods

Ethics approval

Results......................................................................................................................................13

Study progress

Baseline characteristics

Primary outcome parameter

Secondary outcome parameters

Safety evaluation

Outcome parameters defined post hoc

Discussion.................................................................................................................................20

Summary of main findings

Strengths and weaknesses

Conclusion................................................................................................................................22

Recommendations

Acknowledgements..................................................................................................................23

References................................................................................................................................24

Appendix..................................................................................................................................27

1 AUDIT test om alcoholafhankelijkheid te meten

2 Test van Fagerström om nicotineafhankelijkheid te meten

3 Charlson Comorbidity index

4 SOFA SCORE, The APACHE II score and The APACHE IV score

5 Sample size calculations

Supplementary figures............................................................................................................33

3

Abstract (English)

Nicotine Replacement Therapy in the Intensive Care Unit; a Randomized Controlled

Pilot Study

Introduction:

Delirium and agitation are common in mechanically ventilated patients admitted to the

intensive care unit (ICU). Retrospective data have shown that smoking, or the acute

abstinence of smoking, is an additional risk factor for agitation. A safe and effective method

to treat nicotine withdrawal symptoms in outpatient and hospitalized smoking adults is

transdermal nicotine replacement therapy (NRT). Previous studies on the use of transdermal

NRT in critically ill smokers admitted to the ICU have produced conflicting results.

The aim of this study was to assess the safety and efficacy of transdermal NRT in

mechanically ventilated smokers admitted to the ICU.

Methods:

In this two-centre, randomized, controlled pilot study, mechanically ventilated smokers

admitted to the ICU were included. Subjects received either a nicotine patch (14 or 21

mg/day) or a placebo patch daily until ICU discharge or for a maximum of 30 days. The

primary outcome was 30-day mortality. Secondary outcomes included 90-day mortality,

length of stay, duration of ventilation, delirium, RASS score, SOFA score, hours of physical

restraint, incidence of new nosocomial infections, number of self-removed devices and

number of (serious) adverse events. We performed a post hoc analysis and defined the

outcome parameter as time spent in a favourable condition (alive without sedation and

delirium in the ICU) during the first 30 days.

Results:

Due to recruitment failure the study was stopped after the inclusion of 47 patients. The two

groups were comparable with respect to baseline characteristics. No differences were found in

30-day mortality and 90-day mortality between NRT and the control group (2/21 vs. 2/26;

p=0.843 and 3/21 vs. 5/26; p=0.665). During the first 10 days the NRT group had spent more

time in a ‘favourable’ condition (160 hours (96-216) vs. 88 hours (20-210) (p=0.043)) and

during the first 20 days (400 hours (316-448) vs. 304 hours (110-432) (p=0.033)).There was

no difference in the number of adverse and serious adverse events between NRT and control

patients (102 vs. 177 (p=0.096) and 5 vs. 11 (p=0.251)).

Conclusion:

The results of this pilot study showed that with some modifications of the trial design, a

randomized controlled study to assess the safety and efficacy of transdermal NRT in

mechanically ventilated smokers admitted to the ICU is feasible. Transdermal NRT in

mechanically ventilated smokers had no effect on 30- and 90-day mortality, although our

study was underpowered to establish such differences. Furthermore, the number of (serious)

adverse events between the two groups were comparable. Finally, patients with NRT spent

more time in a ‘favourable’ condition during the first 20 days of admission to the ICU. We

suggest that future trials should focus on a possible effect of NRT on predefined delirium and

agitation endpoints, particularly in the second and third week of ICU stay.

4

Abstract (Nederlands)

Nicotine vervangende therapie op de intensive care; een gerandomiseerde,

gecontroleerde pilotstudie

Introductie:

Delirium en agitatie zijn veelvoorkomend bij beademende intensive care (IC) patiënten.

Retrospectieve studies hebben aangetoond dat roken, of het acuut abstineren van roken, een

extra risicofactor is voor agitatie. Nicotine vervangende therapie is een veilige en effectieve

manier om nicotine ontwenningsverschijnselen te behandelen bij volwassen rokers binnen en

buiten het ziekenhuis. Eerdere studies naar het gebruik van transdermale nicotinevervangende

therapie bij ernstig zieke rokers opgenomen op de IC hebben tegenstrijdige resultaten laten

zien.

Het doel van onze studie was om de veiligheid en werkzaamheid van transdermale nicotine

vervangende therapie bij beademende IC patiënten te beoordelen.

Methoden:

Beademende rokers die opgenomen lagen op de IC werden geïncludeerd in deze

gerandomiseerde, gecontroleerde pilotstudie uitgevoerd in twee centra. Proefpersonen kregen

dagelijks een nicotinepleister (14 of 21 mg/dag) of een placebo pleister gedurende hun IC

opname of voor een maximale duur van 30 dagen. De primaire uitkomstmaat was 30-dagen

mortaliteit. Secondaire uitkomstmaten waren 90-dagen mortaliteit, opnameduur,

beademingsduur, delirium, RASS score, SOFA score, aantal uren fixatie, incidentie van

nieuwe nosocomiale infecties, aantal zelfverwijderde tubes en lijnen en aantal (ernstig)

ongewenste medische voorvallen. Een gecombineerde post-hoc uitkomstmaat werd

gedefinieerd als tijd levend doorgebracht zonder sedatie of delirium op de IC gedurende de

eerste 30 dagen.

Resultaten:

Na 47 patiënten is de studie gestopt als gevolg van moeizame inclusie. De twee groepen

waren vergelijkbaar met betrekking tot basiskarakteristieken. Er werd geen verschil gevonden

in 30-dagen en 90-dagen mortaliteit tussen de behandelde groep en de controle groep (2/21

vs. 2/26; p=0.843 and 3/21 vs. 5/26; p=0.665). Gedurende de eerste 10 dagen had de

behandelde groep meer tijd levend doorgebracht zonder sedatie of delirium (160 uren (96-

216) vs. 88 uren (20-210) (p=0.043)) en in de eerste 20 dagen (400 uren (316-448) vs. 304

uren (110-432) (p=0.033)). Er was geen verschil met betrekking tot het aantal ongewenste en

ernstige, ongewenste medische voorvallen tussen de behandelde groep en de controle groep

(102 vs. 177 (p=0.096) and 5 vs. 11 (p=0.251)).

Conclusie:

Op basis van de resultaten van deze pilotstudie is een gerandomiseerde, gecontroleerde studie

om de veiligheid en werkzaamheid van transdermale nicotine vervangende therapie bij

beademende IC patiënten te beoordelen haalbaar. Transdermale nicotine vervangende therapie

had geen effect op 30-dagen en 90-dagen mortaliteit bij beademde rokers, hoewel onze studie

onvoldoende power had om dergelijke verschillen vast te stellen. Het aantal (ernstig)

ongewenste medische voorvallen was vergelijkbaar tussen de twee groepen. Gedurende de

eerste 20 dagen brachten patiënten in de behandelde groep meer tijd door zonder delirium of

sedatie. Het is aan te raden om in toekomstige studies de focus te leggen op een mogelijk

effect van nicotinevervangende therapie op vooraf gedefinieerde delirium en agitatie

uitkomstmaten en dan voornamelijk gedurende de tweede en derde week van een IC opname.

5

List of abbreviations

AE Adverse Event

APACHE Acute Physiology and Chronic Health Evaluation

AUDIT Alcohol Use Disorders Identification Test (1)

BMI Body Mass Index

CAM-ICU Confusion Assessment Method for the Intensive Care Unit

CI Confidence Interval

DOS Delirium Observation Screening

DH Deventer Hospital

FTND Fagerström Test for Nicotine Dependence

ICU Intensive Care Unit

IQR Interquartile range

ITT Intention-to-treat

NPPV Non-invasive Positive Pressure Ventilation

NRT Nicotine Replacement Therapy

OR Odds Ratio

RASS Richmond Agitation-Sedation Scale

SAE Serious Adverse Event

SD Standard Deviation

SOFA Sequential Organ Failure Assessment

GVH Gelderse Vallei Hospital

6

Introduction

Delirium and nicotine withdrawal

Delirium is a disturbance in attention, awareness and cognition which develops over a short

period and fluctuates over time (2). Two types of delirium are recognized, a hypoactive and

hyperactive form (3). Many factors can contribute to the emergence of delirium, including

alcohol abstinence, acute illness or changes in medication (4). An association between

enforced nicotine abstinence, agitation, and (hyperactive) delirium has been suggested by

several authors (5-7). However, it remains unclear whether this should be seen as

(hyperactive) delirium provoked by enforced nicotine abstinence, or nicotine withdrawal with

a similar symptomatology (confusion, restlessness and irritability) not sufficient to meet the

criteria of delirium (8). The incidence of delirium in the general ICU population is

approximately 32 percent (9) and may rise as high as 89 percent when mechanically

ventilated patients are considered (10,11). Delirium has been associated with increased

mortality (9,10,12), greater need for sedatives (13), physical restraints (13), extended duration

of mechanical ventilation and in-hospital/ICU stay (9,10,12) and therefore prevention is

considered important. Patients smoking ≥ 10 cigarettes per day have a significantly increased

risk of developing delirium (14). The prevalence of smoking in ICU patients is estimated at

20-57 percent (15-19). It is generally believed that nicotine abstinence can lead to withdrawal

symptoms, including difficulty concentrating, insomnia, agitation and physical complains (20-

22). These symptoms generally peak within the first week and continue for 2 to 4 weeks (23).

Although the symptoms of nicotine abstinence are non-life threatening in outpatient and

hospitalized adults, their role in the mental processes of mechanically ventilated patients is

not well understood (24).

Nicotine replacement therapy (NRT)

NRT is a safe and effective method to treat nicotine withdrawal symptoms in smoking healthy

and hospitalized adults (25-27). It might be plausible to assume that nicotine withdrawal

symptoms also play a role when actively smoking patients are mechanically ventilated, and

that these patients therefore would benefit from NRT. A reduction of symptoms of nicotine

withdrawal could prevent self-removal of tubes and catheters, need for supplemental

medication and physical restraints (6). On the other hand, nicotine is a potentially harmful

drug and if replacement does not prevent withdrawal symptoms and/or delirium, its side

effects might actually cause harm. In order to prevent or ease nicotine withdrawal symptoms

transdermal NRT is a potential option because it provides relatively constant withdrawal relief

over 24 hours (28). It has been used in hospitalized smokers in whom it immediately

alleviated or remedied withdrawal symptoms (29). Common side effects related to NRT

products reported in the general population include local irritation, headache, vertigo,

insomnia and gastrointestinal symptoms (21,22,30).

Metabolism of nicotine

Approximately 80 to 90 percent of nicotine is metabolized by lung, liver and kidney (31) and

17 percent of nicotine is excreted unchanged in the urine (32). Cotinine is a metabolite of

nicotine and is used as a biomarker of nicotine exposure. The plasma concentration of

cotinine is 10 times higher than nicotine. The half-life of cotinine is 15 to 20 hours (31).

7

Previous studies in critically ill patients

Some authors have reported beneficial effects of NRT in patients admitted to the ICU. One of

the success stories was a case series describing 5 smokers admitted to the neuro-ICU, who

developed an agitated delirium 2 to 10 days after smoking cessation and showed improvement

after placement of a 21 mg nicotine patch (7). It was recognized that the risk of selection bias

was considerable. Soon, several retrospective cohort studies, evaluating NRT in ICU patients,

appeared in the literature. In general, these were not supportive of NRT. In a cohort of

neurosurgical ICU patients, Panos et al. showed that smokers receiving NRT had longer ICU

stay and hospital stay than smokers who did not receive NRT or nonsmokers (33).

Prevalences of delirium or agitation were not reported in that study. The issue of agitation was

addressed in two other studies. The group of Kerr et al. (34) did a case-control study,

comparing smokers who received NRT to smokers who did not. They found that NRT treated

patients were intubated longer, and required more antipsychotic medication and physical

restraints. These results seemed to match well with the observations described by Seder et al.,

who found more delirium and more seizures in a neuro-ICU cohort of smokers who had

received NRT, compared to an untreated cohort (35). These latter two studies also looked at

mortality. There was no mortality difference in the Kerr study and, quite remarkably, in the

Seder study, despite the higher incidence of delirium, NRT was associated with a survival

benefit through multivariate analysis (34,35). In contrast with the Seder study, Lee and Afessa

showed data from a case-control study in their medical ICU, which quite convincingly

demonstrated increased mortality in active smokers treated with NRT (36). A trend towards

increased mortality was also found in the intervention group in actively smoking coronary

artery bypass graft surgery patients admitted to an ICU (37). A retrospective cohort study in a

mixed ICU, done by Gillies et al., showed that in terms of mortality, smokers receiving NRT

fared neither worse, nor better, than smokers without NRT (38). A prospective observational

study by Cartin-Ceba, looking at smokers admitted to a medical ICU with and without NRT,

also showed similar mortality rates (39).

These nonrandomized studies, whether focussing on delirium and agitation, or on mortality,

all suffer from the same potential bias: it is not known why some smokers were prescribed

NRT and others not. It might be that some received NRT because they were already agitated

or because it was recognized that they were more prone to delirium. Perhaps a higher risk of

mortality was appreciated early on, which may have influenced the decision to pre-emptively

treat against nicotine withdrawal symptoms. However, this respectable body of retrospective

research cleared the way for randomized studies.

One single-centre, randomized double-blind pilot study has been published today. The results

showed a trend towards decrease in ICU stay and duration of mechanical ventilation in the

NRT group, although this was not statistically significant. However, this was a pilot study

with a small sample size (40 subjects) (40).

Two systematic reviews in 2014 and 2016 concluded that there is no consensus on whether

NRT is a safe and effective method to prevent or treat nicotine withdrawal symptoms in

critically ill smokers. They suggested that powered randomized controlled trials are needed

with regards to the use of NRT to prevent, ease, or treat delirium and agitation in patients

admitted to the ICU (41,42).

8

Aim of the study

Previous studies on the use of transdermal NRT in critically ill smokers admitted to the ICU

have produced conflicting results and have been mainly retrospective which made them

vulnerable to selection bias and confounding. There is a need for randomized, controlled

research.

We set out to conduct a two-centre pilot study to investigate whether a randomized controlled

trial would be feasible.

The objective of this study was to assess the safety and efficacy of transdermal nicotine

replacement therapy in mechanically ventilated smokers admitted to the ICU.

The following hypothesis was tested:

H0: the effect of transdermal nicotine replacement therapy is equal to the effect of the control

product with respect to 30-day mortality in mechanically ventilated smokers admitted to the

ICU.

9

Materials and methods

Trial design

A two-centre, randomized, controlled, double-blind, parallel-group, pilot study was

conducted.

Participants

Mechanically ventilated smokers admitted to the ICU in two centres (Deventer Hospital (DH)

and Gelderse Vallei Hospital (GVH), the Netherlands) were included in this study. Table 1

shows the inclusion and exclusion criteria. Eligible patients or their legal representatives were

informed about the study and gave written consent. When surrogate consent was obtained, the

patient was requested to confirm the consent in writing when approachable and accountable.

The number of patients screened for inclusion was not recorded, although every mechanically

ventilated smoker admitted to the ICU had been screened.

Table 1. Inclusion and exclusion criteria. Inclusion criteria Exclusion criteria

- ≥ 18 years

- Understanding Dutch

- Critically ill smokers

- Being mechanically ventilated

- Start of study product application within 48

hours after ICU admission

- Mechanical ventilation was expected to be

continued for > 48 hours from the start of the

study onwards

- Written informed consent must be obtained

from each subject or legal representative

- Cardiovascular diseases*

- Chronic dementia or psychosis

- (Acute) neurologic disease

- Hearing deficiency

- Moribund

- Pregnant or breastfeeding woman

- Last cigarette smoked > 72 hours before

admission

- NRT within two weeks before admission

- Skin diseases interfering with NRT

absorption

- Hyper sensibility to nicotine or components

of the transdermal therapeutic system

- Participating in another study

* Acute myocardial infarction, severe cardiac arrhythmia, unstable/deteriorating angina pectoris.

Randomisation Participants were randomly allocated to receive either the test product or the control product

in a 1:1 ratio by block randomisation in groups of four, stratified to patient type (medical vs.

surgical), study site (GVH vs. DH) and nicotine dosage (14 vs. 21 mg/day). A randomisation

list, developed by using a computer random number generator, was kept at the hospital

pharmacy. Randomisation codes were unknown to the investigator and site staff. Details of

the product codes were contained in a set of opaque sealed code envelopes.

Blinding

Participants received either a transdermal nicotine patch (Nicotinell, Novartis Consumer

Health) or a nontransparent plaster similar in size, shape, and colour until ICU discharge or

with a maximum of 30 days. The dosage of the test product was aligned with the amount of

cigarettes smoked on a daily bases as indicated by the participant or next of kin. Participants

smoking ≤ 20 cigarettes per day were given 14 mg nicotine per 24 hours and participants

smoking ≥ 21 cigarettes per day were given 21 mg nicotine per 24 hours. Subsequently, a non

transparent plaster was used to cover the transdermal nicotine patch. The plasters were

exchanged by nurses not involved in the daily care of the participants. In GVH nurses from

the lung department exchanged the plasters. In DH, this was done by registered nurses from

the ICU, who were solely devoted to management tasks during the week and by nurses from

the coronary care unit (CCU) on weekends.

10

Start of study product application occurred within 48 hours after ICU admission.

There were no restrictions in any other treatment modalities except the use of nicotine

replacement therapy for both the test group and control group.

Data collection

Baseline

Patients characteristics were collected at baseline, including age, sex, and body height and

weight (in order to calculate Body Mass Index (BMI)). Next of kin were interviewed using

the Alcohol Use Disorders Identification Test (AUDIT) to assess alcohol consumption,

drinking behaviour, and alcohol-related problems (Appendix 1), and the Fagerström Test for

Nicotine Dependence to evaluate the quantity of cigarette consumption, the compulsion to

use, and dependence (Appendix 2). Admission diagnosis, patient type (medical vs. surgical)

and comorbidities according to the Charlson Comorbidity index were also recorded (Appendix

3). A pregnancy test was conducted for women with childbearing potential. Sequential Organ

Failure Assessment (SOFA) score on admission, Acute Physiology and Chronic Health

Evaluation (APACHE) II and APACHE IV scores were determined over the first 24 hours

after ICU admission (Appendix 4). In order to determinate serum cotinine concentrations,

blood samples were gathered before the start of the study product application.

Intervention period (day 0 - day 30)

The following assessments were performed daily: SOFA score, hours of physical restraints,

self-removed devices, duration of mechanical ventilation, serious adverse events and adverse

events, new nosocomial infections according to the CDC definitions (43,44), and total dosage

of antipsychotics. RASS score (agitation/sedation score), CAM-ICU score and DOS score

(delirium scores) were expressed as hours. Because sedation and delirium were measured

three times per day (once per nursing shift) numbers of hours resulted in multiples of eight.

Follow up (day 90)

Patient location and survival status was confirmed by telephone interviews with the patient or

their legal representative to document mortality, length of stay (ICU, in-hospital) and patient

location (ICU, in-hospital, care facility, home or death).

Data analysis

Outcome parameters predefined in the study protocol

The primary outcome parameter was 30-day mortality.

Secondary outcome parameters included 90-day mortality, ICU and in-hospital mortality,

length of stay and patient location at day 30 and 90, total maximum SOFA score (summing

the worst scores for each of the organ systems) (45), delta SOFA score (total maximum SOFA

score minus total SOFA score) at admission (46), RASS score (median, highest, lowest, and

number of hours scored outside the optimal range, defined as <-3 and/or >1, ventilation-free

hours starting 48 hours after extubation or stop non-invasive positive pressure ventilation

(NPPV), the number of hours with delirium assessed by CAM-ICU score or DOS score, hours

of physical restraint, number of self-extubations (tube and tracheal cannula), self-removed

catheters (urinary catheter, venflon, arterial catheter, central line, nasogastric tube), new

nosocomial infections, total dosage of antipsychotics and number of serious adverse events

and adverse events.

11

Outcome parameter defined after data analysis

A post hoc outcome parameter was created and defined as time (hours) spent in a ‘favourable’

condition (discharged from the ICU or alive without sedation and without delirium in the

ICU) or ‘unfavourable’ condition (sedated, delirious or death). These parameters were

measured during the first 30 days for each individual subject after admission to the ICU or till

discharge to the general ward. Delirium was recorded by using the CAM-ICU score or DOS

score and sedation based on the RASS score. A subgroup analysis dosage-effect relationship

was performed on this composite endpoint parameter.

Statistical methods

Sample size

The combined mortality among smokers and non-smokers on the ICU was estimated to be

about 13% (data GVH). Assuming a higher mortality in smokers than in non-smokers and a

decrease in mortality due to NRT, we calculated that 485 patients per group would be needed

to detect a reduction in mortality from 20% to 15% (using a significance level (α) of 0.05, and

a power of 80%). This would not be feasible within two years. The number of hours of

admission or mechanical ventilation could have been an outcome parameter, but would

require more than 250 or 450 patients. Overseeing these large sample sizes we concluded that

a randomized controlled trial would not be possible within the two ICUs involved. For this

reason we chose to conduct a pilot study with 70 subjects, 35 patients per study arm.

Statistical analysis

Descriptive statistics were used to compare the groups at baseline.

Data were presented as mean (±SD) or median (IQR) depending on their distribution.

Each parameter was tested for normality. Student’s t-test was used to analyse differences

between continuous data which were normally distributed and the Mann-Whitney U test was

used when data were not normally distributed. To analyse categorical data we used the

Fisher’s exact or the Chi-Square test. Survival analysis was assessed by using Kaplan-Meier

curves using the log-rank test. The primary outcome parameter was subjected to logistic

multivariate analysis, in which the stratification variables (patient type, nicotine dosage and

study site) were included (47). A p-value < 0.05 was considered significant.

Data were collected in a database using Microsoft Office Access 2007 and were analysed

using IBM SPSS Statistics 22 on an intention-to-treat (ITT) basis.

Ethics approval

The study was approved by the Medical Research Ethics Committee of the University

Medical Centre Utrecht.

12

Schematic diagram of trial design.

13

Results

Study progress

After enrolment of 48 patients from July 2012 to June 2016 the study was stopped due to

recruitment failure. One patient was excluded from the study at her own request and the data

were removed from the analysis, resulting in 47 patients remaining for analysis: 21(45%) in

the NRT group and 26 (55%) in the control group. GVH included 26 patients and DH 21

patients. Median time from ICU admission until the start of the study was 38 hours (IQR 22-

48). 3.2% of the delirium and agitation/sedation scores were missing, however by screening

the electronic record files and by clinical reasoning complete records were available for all

cases with regards to the outcome parameters. Protocol violation was recorded in one patient

in the control group refusing the patch since day two after the start of the study and in one

patient in the NRT group receiving a placebo patch instead of a nicotine patch for one day.

The number of patients screened and the reasons for exclusion were not formally recorded.

However, the perception was that because of the contraindication of cardiovascular diseases

(indistinctness regarding unstable angina pectoris or increased cardiac enzymes secondary to

critical illness), as well as language barrier and mental deficit, many patients were excluded.

Presumably, the absence of the principal investigator in GVH during the last phase of the

study period caused a significant decrease in the number of inclusions. Data on the number of

ventilated patients and number of enrolled patients per ICU per year are listed in Table 1.

Table 1. Number of ventilated patients and number of enrolled patients per location. DH, 12 ICU beds GVH, 17 ICU beds

Year Ventilated patients Inclusions Ventilated patients Inclusions

2012-2013 317 0* 516 15

2013-2014 297 8 461 8

2014-2015 292 6 464 2

2015-2016 211 7 474 1

*Inclusion in DH was started ± 1 year after GVH.

Baseline characteristics

The two groups were comparable with respect to baseline characteristics.

Baseline characteristics are presented in Table 2. Data on alcohol units per day were missing

for 3 patients. There were 5 missing scores on the AUDIT test and 2 on the Fagerström test.

14

Table 2. Differences in baseline characteristics of critically ill smokers treated with and

without nicotine replacement therapy. NRT group

n=21

Control group

n=26

Demographic variables

Age, years* 60.1 (± 10.55) 65. 2 (± 9.13)

Male** 12 (57%) 16 (62%)

BMI* 26.4 (± 6.75) 27.8 (± 5.95)

Charlson Comorbidity index*** 1 (0-1) 1(0-2.25)

Intoxications

Smoking, cigarettes/day*** 20 (12,5-27.5) 15 (14.5-25.0)

Fagerström test for nicotine dependence*** 5.5 (4-7.75) 5.0 (4-7)

Alcohol, units/day*** 2 (0-4) 2 (0-4)

AUDIT test for alcohol dependence*** 5.5 (0.75-12) 5.0 (1-10.75)

Severity of illness

Admission SOFA score* 6.5 (± 2.94) 6.9 (± 2.94)

APACHE II score* 19.0 (± 5.03) 21.1 (± 8.60)

APACHE IV score* 69.7 (±19.01) 75.9 (± 34.20)

Stratified variables

Location GVH** 12 (57%) 14 (54%)

Patient type medical** 16 (76%) 15 (58%)

Dosage 21 mg** 13 (62%) NA

* Mean (± SD).

** No. (%).

*** Median (IQR).

NA = not applicable.

Primary outcome parameter

30-day mortality

No difference was found in 30-day mortality between NRT group and control group (2/21

(9.5%) vs. 2/26 (7.7%); p=0.843 (Figure 1).

Figure 1. 30-day and 90-day patients survival. Kaplan-Meier Survival Curves, using the log-rank test to compare mortality rates.

15

Secondary outcome parameters

90-day mortality

No difference was found in 90-day mortality between NRT group and control group (3/21

(14.3%) vs. 5/26 (19.2%) p=0.665) (Figure 1). Four patients died during their ICU stay, one

(5%) in the NRT group and three (12%) in the control group (p=0.617).

Length of stay

The median ICU stay at 30 days was 186 hours in the NRT group (IQR 127-278) vs. 246

hours in the control group (IQR 88-694), which was not significantly different. The median

length of stay at day 90 was similar, and was not significantly different between the groups

(Figure 2A).

2A p=0.410 p=0.392

The median hospital stay at 30 days was 313 hours (IQR 226-528) in the NRT group vs. 408

hours (IQR 220-720) in the control group. The median hospital stay at day 90 was similar,

except for the IRQ of the control group (220-885) (Figure 2B).

2B p=0.356 p=0.369

Figure 2. Length of stay in the Intensive Care Unit (Figure 2A) and in the hospital (Figure

2B) at day 30 and day 90. Median (IQR), lowest value and highest value, using the Mann-Whitney U test to compare the medians.

Mechanical ventilation There was no significant difference in mechanical ventilation-free hours between the two

groups at day 30 (Table 3). 17 patients (81%) in the NRT received respiratory support for

more than 48 hours and 20 patients (77%) in the control group. In the NRT group two patients

(9.5%) and in the control group one patient (3.8%) received only non-invasive ventilation.

16

Sequential Organ Failure Assessment (SOFA) score

There was no significant difference in the total maximum SOFA score and the delta SOFA

score between the NRT group and the control group as presented in Table 3.

Table 3. Secondary outcome parameters. NRT group

n=21

Control group

n=26

p-value

(2-tailed)

Mechanical ventilation

Mechanical ventilation-free hours at day 30* 559 (494-605) 515 (135-606) 0.152

SOFA score

Total maximum SOFA score** 7.6 (3,0) 8.2 (3,0) 0.462

Delta SOFA score* 1.0 (0.0-2) 0.5 (0-2.25) 0.982

Delirium

Hours with delirium* 8 (0-44) 16 (0-86) 0.274

RASS score

Mean RASS score* -1.0 (-2.1/-0.2) -1.3 (-2.3/-0.7) 0.266

Highest RASS score* 1 (0-1) 1 (0/1) 0.615

Lowest RASS score* -4 (-5/-2.5) -5 (-5/-4) 0.132

Hours RASS score outside optimal range* 40 (0-64) 48 (14-122) 0.202

Physical restraints

Hours of physical restraints* 12.0 (0-85.5) 44.5 (0-123) 0.417

Number of self-removed devices

Self-extubations*** 1 4 0.245

Self-removed catheters*** 24 36 0.886

Number of new nosocomial infections*** 7 22 0.285

Total dosage of haloperidol (mg)* 9 (0-24.5) 19.5 (3.25-31) 0.185

* Median (IQR), the Mann-Whitney U test was used to compare the two groups.

** Mean (±SD), using the Student’s t-test to compare means.

*** Group differences were tested with the Mann-Witney U test.

SOFA score = Sequential Organ Failure Assessment.

RASS score = Richmond Agitation-Sedation Scale.

Delirium, agitation and sedation

Hours with delirium assessed by the CAM-ICU score and DOS score were not significantly

different between the NRT group and the control group (Table 3).

When comparing the Richmond Agitation-Sedation Scale (RASS) score between the two

groups there were no significant differences in mean, highest and lowest RASS score and

hours RASS score outside optimal range (< -3 and/or > +1) (Table 3).

There was no significant difference in the hours of physical restraints (Table 3).

Self-removed devices and new nosocomial infections

No significant differences were found between the two groups when comparing number of

self-extubations (tube and tracheal cannula), self-removed catheters (urinary catheter,

intravenous cannula, arterial catheter, central line, nasogastric tube) and new nosocomial

infections (Table 3).

17

Total dosage of antipsychotics

The median dosage of haloperidol was not significantly different between the two groups,

9.0 mg (IQR 0.0-24.5) in the NRT group and 19.5 mg (IQR 3.25-31.0) in the control group

(p=0.185) within the first 30 days (Table 3). In addition, one patient in the NRT group

received 120 mg of olanzapine and one patient in the control group 17.5 mg, none of the

patients received quetiapine.

Patient location on day 30 and day 90

At day 30, there was a significant difference in patient location between the two groups. In

the NRT group, more patients were in a care facility or at home as compared to the control

group (more patients still in the hospital or the ICU). This difference disappeared after 90

days, as shown in (Figure 3).

p=0.028 p=0.338

Figure 3. Patient location on day 30 and day 90. The Chi-Square test was used to compare the two groups.

NRT = Nicotine replacement therapy.

ICU = Intensive Care Unit.

Safety evaluation

Serious adverse events (SAE)

In total, 15 SAE were reported, 4 in the NRT group and 11 in the control group (p=0.129).

The causes of death in the NRT group (n=2) were respiratory failure and hypercapnic coma

after extubation with treatment limitations. The 2 other SAE in the NRT group were

hemothorax and respiratory insufficiency after extubation. The causes of death in the control

group (n=3) were respiratory failure, refractory pneumosepsis and acute persistent severe

hypoxemia following no reintubation at patients request. In the control group, there were 8

other SAE including hemorrhagic shock, respiratory insufficiency (2 times), stoma necrosis,

duodenal perforation, sigmoid ischemia, asystole and ischemic colitis with abdominal

compartment syndrome and multi-organ failure. None of the SAEs were attributed to the

treatment with, or abstinence from nicotine.

Adverse events

There was no significant difference between treatment groups in the occurrence of 279

adverse events (p=0.096) (Table 4). However, it was remarkable that the frequency of

cardiovascular adverse events, tended to occur more often in the control group than in the

NRT group.

18

Table 4. Serious adverse events and adverse events. Total NRT group

n=21

Control group

n=26

Serious adverse events 15 4 11

Adverse events

Electrolyte disturbances 85 36 49

Gastrointestinal 67 27 40

Cardiovascular 59 16 43

Arrhythmia 24 5 19

Hypotension/hypertension 28 10 18

Ischemia 6 1 5

Cardiac enzymes elevated 1 0 1

Pulmonary 13 5 8

Renal 7 1 6

Others* 48 17 31

Total adverse events 279 102 177

*Others: fever, fungal infection, sinusitis, allergic reaction, skin lesion, subcutaneous emphysema, hypercapnia,

thrombocytopenia, anaemia, pancytopenia, hypothermia/hyperthermia, hypothyroidism, bleeding other, critical

illness polyneuropathy, hemiplegic, anxiety/sleep disturbances/agitation.

NRT = nicotine replacement therapy.

Outcome parameters defined post hoc

Composite endpoint parameter

A post hoc outcome parameter was defined as time (hours) spent in a ‘favourable’ condition

(discharged from the ICU or alive without sedation and without delirium in the ICU),

represented as median. As can be seen in Figure 4, the NRT and control groups entered the

study with a similar percentage of patients in ‘favourable’ condition (24 and 23%). During the

first 10 and the first 20 days the NRT group spent significantly more time in a ‘favourable’

condition (160 hours (respectively (IQR 96-216) vs. 88 hours (IQR 20-210) (p=0.043) and

(400 hours (IQR 316-448) vs. 304 hours (IQR 110-432) (p=0.033)) The difference between

NRT and control group in the amount of time spent in a ‘favourable’ condition during the first

30 days (640 hours (IQR 548-680) vs. 554 hours (IQR 314-672)) tended to diminish

(p=0.077). At the end of the follow-up period (day 90), the percentage of patients in

‘favourable’ condition was similar again, between 85 and 90%.

Figure 4. Time spent in a ‘favourable’ condition (%) in the first 30 days. The Mann-Whitney U test was used to compare the two groups during the first 10, 20 and 30 days.

NRT = nicotine replacement therapy.

19

Subgroup analysis dosage-effect relationship of nicotine replacement therapy

After dividing the study population into dosage groups 14 mg/day (n=23) and 21 mg/day

(n=24), the difference in time spent in ‘favourable’ condition between NRT and control

groups remained consistent (no statistics performed) (Supplementary figure 1). A presumed

stronger effect in the higher treatment group was not observed (Table 5). A correlation

between the serum cotinine and the number of cigarettes per day has not been found

(Supplementary figure 2A). Between the serum cotinine and the Fägerstrom test for nicotine

dependence no correlation had been found either (Supplementary figure 2B).

Table 5. Dosage-effect relationship of nicotine replacement therapy.

Time (hours) spent in a ‘favourable’ condition. During the first 10 days During the first 20 days During the first 30 days

Control group total 88 304 554

14 mg 56 304 528

21 mg 96 320 560

NRT group total 160 400 640

14 mg 200 440 680

21 mg 144 376 616

NRT = nicotine replacement therapy.

Multivariate analyses on the primary outcome parameter using randomisation strata

The odds ratio (OR; 95% CI) for 30-day mortality in a logistic univariate analysis for the

NRT group was 1.263 (0.163-9.815) suggesting that the risk for 30-day mortality was similar

between the NRT group and the control group (Table 6). After introducing the three

randomisation strata (patient type, dosage nicotine, study site) into a multivariate model, the

OR was 0.956 (0.111-8.228) (Table 6). As the CIs overlapped, patient type, dosage nicotine

and study site were not considered confounders for the lack of association between NRT or

control group and 30 day mortality.

Table 6. Univariate and multivariate analysis for 30-day mortality for the nicotine

replacement therapy group. Odds ratio Confidence interval

Univariate analysis 1.263 0.163-9.815

Multivariate analysis* 0.956 0.111-8.228

*After introducing the three randomisation strata (patient type, dosage nicotine, study site).

20

Discussion

The aim of this project as a pilot study was to evaluate on the feasibility of a randomized

controlled trial, to predict sample sizes and to explore alternatives for improvement of the

study design. Our results showed that, with some modifications of the trial design (discussed

below under ‘Recommendations’), a randomized controlled study to assess the safety and

efficacy of transdermal NRT in mechanically ventilated smokers admitted to the ICU is

feasible.

The objective of this pilot study was to assess the safety and efficacy of transdermal NRT in

mechanically ventilated smokers admitted to the ICU. Based on our study results, the

hypothesis that ‘the effect of transdermal NRT was equal to the effect of the control product

with respect to 30-day mortality in mechanically ventilated smokers admitted to the ICU’

could not be rejected.

Summary of main findings

The NRT and control groups were comparable with respect to baseline characteristics.

The results indicated that transdermal NRT in mechanically ventilated smokers had no

significant effect on 30-day and 90-day mortality. Relevant for the interpretation of these data

is that our study had limited power to identify such an effect, even if it existed. Therefore, the

null hypothesis could also not be confirmed. Based on our results, a large effect of NRT on

mortality would be unlikely. In previous studies there were varying results with respect to

mortality, ranging from increased to reduced risk or no difference, but all of these studies

were retrospective and of limited sample size, and therefore prone to unrecognized

confounding (34-37). In order to detect a 20% mortality difference (from 8% to 10%, as in

our study), applying commonly used cut-off values for type I and II errors (α = 0.05 and

power 80 %), a total number of 6452 patients would need to be randomized (see Appendix 5

for calculations). We are inclined to regard that as not feasible.

The patient location on day 30 was significantly different between the two groups with a

higher number of patients at home or in a care facility in the NRT group and more patients

located in the ICU or the hospital in the control group. This difference was no longer visible

on day 90. At this point, it is not clear what this means, as the observed difference was not

supported by other outcomes such as a longer stay in the ICU or in the hospital. There was

also no significant difference in other outcome parameters such as mechanical ventilation free

hours, hours with delirium, sedation/agitation scores, antipsychotic use, or any of the other

predefined secondary outcome parameters, although most of these parameters were trending

towards benefit for the NRT group.

The reason for stopping this study before 70 patients had been included was a low inclusion

rate. Although we did not exactly monitor the reasons for exclusion, it was felt that

recruitment proceeded much slower than anticipated due to the protocolized exclusion of

comorbidities such as acute myocardial infarction, severe cardiac arrhythmia or unstable

angina pectoris. These comorbidities are prevalent among smokers. On the other hand, in

critically ill and mechanically ventilated ICU patients, transient increases in cardiac enzymes

are common and it is often difficult to establish whether these are due to cardiac ischemia or

for example secondary to sepsis or other critical illnesses. We suspect that an unknown

number of patients have been excluded for this reason, in the absence of true coronary artery

disease. Because the numbers of adverse events, serious adverse events, and specifically

cardiac events were comparable between the two groups and actually trended toward benefit

21

in the NRT group, we would advocate that the exclusion of patients with cardiovascular

diseases in future NRT trials would be applied less strictly.

To summarize these findings, our study showed no relevant differences in predefined outcome

parameters. However, in order to get a better understanding of the prevalence of delirium and

agitation, and the interaction with the need for sedation in our study patients over time, a

composite outcome parameter was created post hoc. It was recognized that sedation and

delirium can be competing events, because delirium can not be measured in sedated patients

and patients may be sedated longer when signs of (hyperactive) delirium are present.

Therefore, this parameter was defined as time (hours) spent in a ‘favourable’ condition

(discharged from the ICU or alive without sedation and without delirium on in the ICU). Both

groups had a similar percentage of patients in a ‘favourable’ condition at the start of the study.

During the first 10 and 20 days the NRT group had spent significantly more time alive and

free of delirium and sedation or discharged from the ICU than the control group. When

comparing the two groups in the last 10 days (day 20 till day 30), this difference seemed to

gradually stagnate. At the end of the 30 days of study period, the majority of patients were

unsedated and free of delirium in both groups. A small percentage of patients (8% in the NRT

group and 10% in controls) was no longer alive at day 30. The observed differences remained

unaltered after correction for the stratification parameters in multivariate logistic analysis.

Strengths and weaknesses

The strength of this study lies in the fact that this was a randomized controlled study, which

can prevent selection bias and the influence of the results by confounders. The randomisation

was stratified to nicotine dosage (14 vs. 21 mg/day), study site (GVH vs. DH) and patient type

(medical vs. surgical) to prevent possible unequal distribution of these prognostic factors. This

stratification was used in combination with block randomisation in order to distribute the

intervention evenly on both study arms. As a result, groups were balanced well on baseline

characteristics. The internal validity was ensured by random treatment allocation that was

done by an independent party and by blinding of the patient, the investigator, and the

attending staff. The number of protocol violations was low. Moreover, follow-up was

complete for all subjects and analysis was done on an intention-to-treat (ITT) basis. The ITT-

analysis avoids bias associated with non-random loss of participants, which increases the

credibility of this research. In addition, there were few missing values which ensured high

quality of data including a representative overview of our group and thereby reducing the

probability of selection bias.

The study findings are limited by low event rates and a small sample size. This study was

underpowered to establish significant differences in primary and secondary outcome

parameters between the NRT group and the control group. It is of concern that due to small

numbers, relatively small baseline differences might become relevant confounders. Despite

adequate randomization, unrecognized confounders, which may not have been accounted for

in multivariate analysis, may have influenced the outcomes. Analyses that were not

predefined in the study protocol are particularly vulnerable to that. Furthermore, it can be seen

as an omission that the number of screened patients has not been recorded, as this figure in

combination with power analysis could have helped to determine the size of a future trial.

Only two ICUs were involved in this trial, which limits the generalizability and therefore

external validity to broader ICU settings. We selected ICU patients who were mechanically

ventilated, thereby being at risk of emergence of delirium and agitation (and possible death).

However, because of the strict exclusion criteria, especially the patients with cardiovascular

diseases (which may be related to their smoking behaviour) were excluded because of the

22

precaution of using NRT in these patients, while one might expect that these patients in

particular could benefit from NRT. In addition, delirium and sedation were only recorded

during ICU admission and when patients were discharged from the ICU it was assumed that

they were not delirious or sedated, which may not always be true. It would have been more

accurate to continue recording delirium scores on the general wards. Finally, the delirium and

agitation outcome parameter was defined post hoc. This puts these conclusions at risk of

being data driven. However, as this was a pilot study, these results can be useful to improve

future study designs.

Conclusion Our results demonstrated that, with proper modifications of the trial design, a randomized

controlled study to assess the safety and efficacy of transdermal NRT in mechanically

ventilated smokers admitted to the ICU would be feasible. In our pilot of 47 randomized

patients transdermal NRT in mechanically ventilated smokers had no effect on 30-day and 90-

day mortality, although our study was underpowered to establish such differences.

Furthermore, the number of (serious) adverse events between the two groups was comparable.

Finally, patients with NRT spent more time being discharged from the ICU or alive and free

from delirium and sedation during the first 20 days after ICU admission.

Recommendations

Despite the fact that this was a two-centre pilot study with a small sample size, some positive-

trending results indicated the need for further randomized studies. Enrolling more subjects to

increase the power of the study would help to better define the effects of NRT in the ICU

setting. In a future study, we would suggest that limiting the cardiovascular exclusion criteria

could augment patient recruitment. This might be justified, because the potential of benefit of

NRT is the largest in heavy smokers, who by necessity bring along related comorbidities. Our

pilot showed no trend towards cardiovascular harm in the NRT group. Excluding too many

active smokers might limit not only the practical feasibility, but also the generalizability of a

future NRT trial. We would also suggest that future trials should not focus on mortality, but

rather on predefined delirium and agitation endpoints. The difficulty with quantifying

delirium is that patients may be sedated longer to attenuate the related restlessness, and also

that delirium itself might increase mortality. In this way, the prevalences of sedation and

death may actually compete with the prevalence of delirium. One way to manage competing

events would be, as we did in our post hoc analysis, to create a composite end-point of

delirium and agitation free days. This has been done in other delirium studies in the ICU

population (48). The separation on the composite delirium endpoint between the NRT and the

control groups was most pronounced between day 4 and day 21 of the study period. In order

to avoid unnecessary data collection we would recommend a study period of 2 to 3 weeks

after admission to the ICU. This is supported by the theory that nicotine withdrawal

symptoms also peak in the first 2 to 3 weeks (23). Furthermore, we advise that data should be

collected on delirium in the period after ICU discharge as well, to obtain reliable data for the

entire follow up period. In Appendix 5 an example of a power analysis is presented that would

provide 80% power and an α of 0.05 if one were to use the composite delirium and agitation

endpoint that we proposed in our post hoc analysis to design a future RCT. This power

analysis shows that to reveal a difference of 2 days on this composite endpoint (time

discharged from the ICU or spent alive on the ICU without sedation or delirium during the

first 20 days) 218 patients would be needed. A multicentre trial in this order of magnitude

would be feasible. Being a multifactorial disorder, an intervention study to diminish delirium

is particularly prone to confounding by imbalances at study entry. Therefore, a balanced

allocation design might deserve consideration, stratifying at baseline for factors that are

23

known to influence the delirium risk, such as alcohol or nicotine use, disease severity or age

(4). From the literature it is known that, infection, changes in medication, acute illness and

pre-existing delirium

might be relevant confounders to consider (4,11). Although the findings of our study are

valuable and warrant further investigation, based on the data published thus far, considerable

reserve is warranted with regards to the use of NRT in patients admitted to the ICU. Earlier

studies have pointed to potential harm and this study does not change that. Future studies

must reveal whether or not the transdermal NRT is safe and efficacy in smokers admitted to

the ICU.

Acknowledgments

Special thanks to my daily supervisor Huub van den Oever for his support and feedback

during the research clerckship and to my second supervisor Ben de Jong. I would like to thank

them for the opportunity to conduct this reseach clerkship with their supervision.

Gratitude is also expressed to Arriette Kruisdijk-Gerritsen, Maurits Arbouw, Arthur van

Zanten en Esther van ’t Riet for their help during the research clerkship.

24

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Appendix 1

AUDIT test om alcoholafhankelijkheid te meten 1. Hoe vaak drinkt u alcohol? □ 4 of meer keer per week 4 punten

□ 2 tot 3 keer per week 3 punten □ 2 tot 4 keer per maand 2 punten □ 1 keer per maand of minder 1 punt □ Nooit 0 punten 2. Op een dag waarop u alcohol drinkt, hoeveel glazen drinkt u dan gewoonlijk? □ 10 of meer 4 punten

□ 7 tot 9 3 punten □ 5 of 6 2 punten □ 3 of 4 1 punt □ 1 of 2 0 punten 3. Hoe vaak zijn er gelegenheden waarop u 6 of meer glazen alcohol drinkt? □ Dagelijks of bijna dagelijks 4 punten

□ Wekelijks 3 punten □ Maandelijks 2 punten □ Minder dan 1 keer per week 1 punt □ Nooit 0 punten 4. Hoe vaak heeft u het afgelopen jaar gemerkt dat u niet kon stoppen met drinken als u

eenmaal begonnen was? □ Dagelijks of bijna dagelijks 4 punten

□ Wekelijks 3 punten □ Maandelijks 2 punten □ Minder dan 1 keer per week 1 punt □ Nooit 0 punten 5. Hoe vaak was u in het afgelopen jaar vanwege drankgebruik niet in staat om de dingen te

doen die normaal van u verwacht worden? □ Dagelijks of bijna dagelijks 4 punten

□ Wekelijks 3 punten □ Maandelijks 2 punten □ Minder dan 1 keer per week 1 punt □ Nooit 0 punten 6. Hoe vaak heeft u het afgelopen jaar ’s ochtends alcohol nodig gehad om weer op gang te

komen nadat u veel had gedronken? □ Dagelijks of bijna dagelijks 4 punten

□ Wekelijks 3 punten □ Maandelijks 2 punten □ Minder dan 1 keer per week 1 punt □ Nooit 0 punten 7. Hoe vaak heeft u zich het afgelopen jaar schuldig gevoeld of spijt gehad nadat u

gedronken had? □ Dagelijks of bijna dagelijks 4 punten

□ Wekelijks 3 punten □ Maandelijks 2 punten □ Minder dan 1 keer per week 1 punt □ Nooit 0 punten

28

8. Hoe vaak kon u zich het afgelopen jaar niet herinneren wat de vorige avond gebeurd was

doordat u gedronken had? □ Dagelijks of bijna dagelijks 4 punten

□ Wekelijks 3 punten □ Maandelijks 2 punten □ Minder dan 1 keer per week 1 punt □ Nooit 0 punten 9. Bent uzelf, of is iemand anders ooit gewond geraakt doordat u gedronken had? □ Ja, in het afgelopen jaar 4 punten □ Ja, maar niet in het afgelopen jaar 2 punten □ Nee 0 punten 10. Heeft een familielid, vriend, dokter of andere hulpverlener zich ooit zorgen gemaakt over

uw drankgebruik of u aangeraden om minder te drinken? □ Ja, in het afgelopen jaar 4 punten □ Ja, maar niet in het afgelopen jaar 2 punten □ Nee 0 punten Totaal aantal punten:

29

Appendix 2

Test van Fagerström om nicotineafhankelijkheid te meten 1. Wanneer steekt u na het ontwaken uw eerste sigaret op? □ Binnen 5 minuten 3 punten □ Binnen 30 minuten 2 punten □ Binnen 60 minuten 1 punt □ Na meer dan 60 minuten 0 punten 2. Vindt u het moeilijk om niet te roken op plaatsen waar dit is verboden, bijvoorbeeld de

kerk, bibliotheek of bioscoop? □ Ja 1 punt □ Nee 0 punten 3. Welke sigaret kunt u het moeilijkste missen? □ De eerste sigaret ’s morgens 1 punt □ Alle andere sigaretten 0 punten 4. Hoeveel sigaretten rookt u per dag? □ 31 of meer 3 punten □ 21 – 30 2 punten □ 11 – 20 1 punt □ 10 of minder 0 punten 5. Rookt u meer tijdens de eerste uren na het ontwaken dan de rest van de dag? □ Ja 1 punt □ Nee 0 punten 6. Rookt u als u zo ziek bent dat u gedurende het grootste gedeelte van de dag in bed moet

blijven? □ Ja 1 punt □ Nee 0 punten Totaal aantal punten:

30

Appendix 3

31

Appendix 4

The SOFA score

The SOFA score describes the degree of organ dysfunction over time and evaluates morbidity

in ICU patients. The SOFA scoring scheme daily assigns 1 to 4 points to each of the

following six organ systems depending on the level of dysfunction: respiratory, circulatory,

renal, haematology, hepatic and central nervous system. The point score is calculated by

summing the worst scores for each organ system from admission until randomisation or until

maximally 24 hours after admission (for screening) or over the scheduled calendar days.

The APACHE II score

APACHE II score is an adult ICU severity of disease classification system. The point score is

calculated by summing the worst scores from 12 routine physiological measurements during

the first 24 hours after admission (temperature, mean arterial pressure, heart rate,

respiratory rate, oxygenation, arterial pH, serum sodium, potassium and creatinine,

hematocrit, white blood cell count, and Glascow Coma Scale), a history of chronic organ

insufficiency or immunosuppresion, age and the absence/presence of acute renal failure.

The APACHE IV score

APACHE IV score is an adult ICU severity of disease classification system. The point score

is calculated by summing the highest and/or lowest values from 19 physiological

measurements during the first 24 hours after admission (temperature, systolic and diastolic

blood pressure, heart rate, respiratory rate, FiO2, arterial pH, arterial PO2 and PCO2, serum

sodium, glucose, creatinine, albumin, bilirubin, blood urea nitrogen, urine output, white

blood cell count, hematocrit, Glascow Coma Scale), age, chronic health condition and ICU

admission information.

32

Appendix 5

Sample size calculations

In order to detect a 20% mortality difference (from 8 to 10%, as in our study), applying

commonly used cut-off values for type I and II errors (α = 0.05 and power 80 %), a total

number of 6452 patients would need to be randomized.

(z1-α/2 + z1-β)2 (σ1

2+σ2

2)

n1 = n2 = ----------------------------

(m1-m2)2

σ1 = standard deviation for the NRT group = 0.301

σ2 = standard deviation for the control group = 0.272

m1 = mean value of the NRT group = 0.10

m2 = mean value of the control group = 0.08

n1 = n2 = 3225,866 (rounded to 3226) per treatment arm

n x 2 = 6452

A power analysis that provides 80% power and an α of 0.05 if one were to use the composite

delirium and sedation endpoint that we proposed in our post hoc analysis to design a future

RCT. It shows that to reveal a difference of 2 days on this composite endpoint (time

discharged from the ICU, or spent alive on the ICU without sedation or delirium during the

first 20 days), 218 patients would be needed.

n2= 2 x ((s 12+ s 2

2)/2) (z1-α/2 + z1-β)

2

-----------------------------------

ν2

ν = difference = 2 days (2 days = 6 shifts of 8 hours)

s 1 = standard deviation for the NRT group = 10.505

s 2 =standard deviation for the control group = 19.717

n2 = 109

n x 2 = 218

33

Supplementary figures

Supplementary figure 1. Subgroup analysis dosage-effect relationship of nicotine

replacement therapy. Time spent in a ‘favourable’ condition (%) in the first 30 days.

1A

1B

After dividing the study population into dosage groups 14 mg/day (n=23) and 21 mg/day

(n=24), the difference in time spent in favourable condition between NRT and control groups

remained consistent (no statistics performed).

0%

20%

40%

60%

80%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

% F

avo

ura

ble

co

nd

itio

n

Days after inclusion

Control group 14 mg

NRT group 14 mg

0%

20%

40%

60%

80%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

% F

avo

ura

ble

co

nd

itio

n

Days after inclusion

Control group 21 mg

NRT group 21 mg

34

Supplementary figure 2A. Correlation between number of cigarettes per day reported by

relatives and the serum cotinine.

Supplementary figure 2B. Correlation between the Fägerstrom test for nicotine dependence

and the serum cotinine.

A correlation between the serum cotinine and the number of cigarettes per day has not been

found. Between the serum cotinine and the Fägerstrom test for nicotine dependence no

correlation had been found either.