Clinical Drug Investigation August 2007, Volume 27, Issue 8, 8, pp 559-564 Nicotine Patch for the Prevention of Postoperative Nausea and Vomiting A Prospective Randomised Trial
Dr Daniela Ionescu,
Cristina Badescu,
Iurie Acalovschi Abstract Background and objective: It has been demonstrated dem onstrated that smoking significantly reduces
postoperative nausea and vomiting (PONV). However, there are approximately 4000 substances in cigarette smoke that can be responsible for this effect. To demonstrate whether nicotine is the substance with antiemetic effects we applied a nicotine patch in patients undergoing laparoscopic cholecystectomy under general anaesthesia. Seventy-five five patients classified as ASA (American Society of Anesthesiologists’ Methods: Seventyclassification) I/II were divided in three groups: group 1 (n = 25), which w hich comprised nonnon smokers; group 2 (n = 25), which comprised patients who had given up smoking for the last 5 years and received perioperatively a nicotine patch that contained 16.6mg nicotine/patch; and group 3 (n = 25), which comprised actual smokers. Postoperatively, the incidence of PONV and the need for antiemetic rescue medication were monitored every 6 hours. Results: We found a significant reduction in the incidence of PONV in group 2 (5/ 25 [20%], p
= 0.0001 vs group 1) and group 3 (8/25 [32%], p = 0.002 vs group 1) compared with group 1 (18/25 [76%]). The difference in incidence of PONV between group 2 and group 3 was not significant (p > 0.05). Conclusions: Nicotine significantly reduced the incidence of PONV after laparoscopic
cholecystectomy.
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Latar belakang dan tujuan: Telah menunjukkan bahwa merokok secara signifikan mengurangi mual dan muntah pasca operasi (PONV). Namun, ada sekitar 4000 zat dalam asap rokok yang dapat bertanggung jawab untuk efek ini. Untuk menunjukkan apakah nikotin adalah zat dengan efek antiemetik kami menerapkan patch nikotin pada pasien yang menjalani kolesistektomi laparoskopi dengan anestesi umum. Metode: Tujuh puluh lima pasien diklasifikasikan sebagai ASA (American Society of anestesi klasifikasi ') I / II dibagi dalam tiga kelompok: kelompok 1 (n = 25), yang terdiri dari non perokok, kelompok 2 (n = 25), yang terdiri pasien yang telah berhenti merokok selama 5 tahun terakhir dan diterima perioperatif patch nikotin yang terkandung nikotin 16.6mg / patch, dan kelompok 3 (n = 25), yang terdiri dari perokok yang sebenarnya. Pasca operasi, kejadian PONV dan kebutuhan untuk obat penyelamatan antiemetik dipantau setiap 6 jam. Hasil: Kami menemukan penurunan yang signifikan dalam kejadian PONV pada kelompok 2 (5/25 [20%], p = 0.0001 vs kelompok 1) dan kelompok 3 (8/25 [32%], p = 0,002 vs kelompok 1) dibandingkan dengan kelompok 1 (18/25 [76%]). Perbedaan kejadian PONV antara kelompok 2 dan kelompok 3 tidak signifikan (p> 0,05). Kesimpulan: Nikotin secara signifikan mengurangi kejadian PONV setelah laparoskopi kolesistektomi.
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Abstract WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• There is empirical evidence that smokers are less likely to suffer from postoperative nausea and vomiting (PONV). • Tobacco smoke is known to induce enzymes, for instance, cytochrome P450, and this may partially explain the PONV-protecting effect of smoking. • Chronic exposure to nicotine that is contained in the tobacco may lead to a desensitization of central nicotine receptors, and, subsequently, to an increased tolerance to the emetogenic effects of surgery and anaesthesia. WHAT THIS STUDY ADDS
• In non-smokers undergoing surgery under general anaesthesia, pre-operatively administered transcutaneous nicotine did not decrease the incidence of PONV within 24 h. • Patients receiving nicotine had a tendency to develop PONV symptoms earlier than controls. • Exposure to transcutaneous nicotine significantly increased the risk of insomnia during the first postoperative night. AIMS There is empirical evidence that smokers are less likely to suffer from postoperative
nausea and vomiting (PONV). We sought to investigate whether transcutaneus nicotine prevents PONV. METHODS Non-smokers receiving general anaesthesia for surgery were randomly allocated to 2
Nicotinell® Patch 10 cm (TTS 10), containing 17.5 mg of nicotine (average delivery rate, −1
7 mg 24 h ) or matching placebo patch. Patches were applied 1 h before surgery and were left in situ until 24 h after surgery (or until the first PONV symptoms occurred). RESULTS We randomized 90 patients (45 nicotine, 45 placebo). In the post-anaesthetic care
unit, the incidence of nausea was 22.2% with nicotine and 24.4% with placebo (P = 0.80), and the incidence of vomiting was 20.0% with nicotine and 17.8% with placebo ( P = 0.78). Cumulative 24 h incidence of nausea was 42.2% with nicotine and 40.0% with placebo ( P = 0.83), and of vomiting was 31.1% with nicotine and 28.9% with placebo ( P = 0.81). PONV episodes tended to occur earlier in the nicotine group. Postoperative headache occurred in 17.8% of patients treated with nicotine and in 15.6% with placebo ( P = 0.49). More patients receiving nicotine reported a low quality of sleep during the first postoperative night (26.7% vs. 6.8% with placebo; P = 0.01).
3
CONCLUSIONS Non-smokers receiving a prophylactic nicotine patch had a similar incidence
of PONV during the first 24 h and tended to develop PONV symptoms earlier compared with controls. They had a significantly increased risk of insomnia during the first postoperative night. Introduction
Postoperative nausea and vomiting (PONV) is a disorder that has been frequently underestimated because of its self-limiting character, and since it never becomes chronic and almost never kills. However, serious complications related to vomiting have been described [1]. In 1998, 10% of the French population underwent general anaesthesia [2]. Since there is evidence that 20% to 30% of surgical patients are suffering from PONV symptoms despite the use of modern anaesthetics [3], it may be inferred that PONV remains a major healthcare burden. Today, several groups of drugs are recognized as truly useful, alone or in combination, for the control of PONV. Among those are corticosteroids, serotonin (5-HT3) receptor antagonists, and dopamine (D2) receptor antagonists [4]. However, none of these is universally effective; each has advantages and disadvantages, and none can be regarded as a gold-standard. Thus, there is a need for alternative molecules that may further improve the control of PONV. One strategy to decrease the incidence of PONV is to identify patients at high-risk of developing PONV symptoms and subsequently to target pharmacologic prophylaxis [5]. Identification of predictive factors for PONV has been the subject of many studies [6 – 8]. They mainly confirmed what clinicians have felt for a long time, namely that female gender, opioid use or a positive history of PONV or motion sickness increased the likelihood of PONV. However, new knowledge was that smokers were less likely to suffer from PONV than non-smokers. At first view this was an unexpected finding since it was well known that adverse effects related to first exposure to low nicotine concentrations or on exposure to very high nicotine concentrations included nausea and vomiting. However, tobacco smoke is known to induce enzymes, for instance, cytochrome P450 [9], and this may partially explain the PONV-protecting effect of smoking. An alternative explanation would be that chronic exposure to nicotine that is contained in the tobacco would lead to a desensitization of central nicotine receptors, and, subsequently, to an increased tolerance to the emetogenic effects of surgery and anaesthesia. This begs the question as to whether in nicotine-naïve patients a short pre-operative exposure to nicotine may decrease the likelihood of PONV. We set out to test this hypothesis in a clinical trial.
4
Methods Pati ent selection , study dru g admini str ati on and anaestheti c management
This randomized, placebo-controlled trial was approved by the institutional Ethics Committee and the Swiss agency for therapeutic products (Swissmedic), and was registered at clinicaltrials.gov (identifier: NCT00553709). Written informed consent was obtained from all patients. We recruited non-smokers (or ex-smokers who had not been smoking for more than 2 years), ASA physical status I or II, aged 18 to 80 years, scheduled for elective inpatient surgery (ear, nose and throat, lumber disc, abdominal) under general anaesthesia. Patients receiving nicotine replacement therapy, needing prolonged postoperative intubation or nasogastric tube, having hypersensitivity of the skin to nicotine or one of the components of the patch, with systemic cutaneous disease, unstable angina pectoris, recent myocardial infarction, severe arrhythmia, recent cerebral vascular accident, parkinsonism, renal or hepatic failure, diabetes, uncontrolled arterial hypertension, hyperthyroidism, or gastroduodenal ulcer, and pregnant and breastfeeding women were not included in the study. Patients and investigators were blinded to the study drug. Study medications were randomized in blocks of ten (five nicotine and five placebo) using a computer program by the pharmacy of Geneva University Hospitals and were kept concealed in a neutral opaque cover. Patients were allocated to one of two groups. In the nicotine group, patients received a Nicotinell® Patch 2
10 cm ,
containing
17.5 mg
of
nicotine,
with
an
average
delivery
rate
of
7 mg
−1
nicotine 24 h (= TTS 10). This is the smallest dose of transdermal nicotine patch available on the Swiss market. We expected the nicotine load of this patch size to be of low and acceptable toxicity in non-smoking adults. Controls received a matching placebo patch. Patches were applied on to the thorax or the upper arm and secured with adhesive tape (Mefix®, Mölnlycke Health Care US, Norcross) at the time of premedication with oral midazolam 7.5 mg 1 h prior to induction of anaesthesia. Patches were left in situ until 24 h after surgery, or until the first PONV episode occurred. −1
−1
General anaesthesia was induced with thiopental 3 to 5 mg kg or propofol 1.5 to 2.5 mg kg . −1
−1
Tracheal intubation was facilitated with rocuronium 0.6 mg kg or atracurium 0.5 mg kg . Anaesthesia was maintained with isoflurane (0.5 to 2.5%) or sevoflurane (2 to 4%). Propofol for maintenance was not permitted. The choice of nitrous oxide was left to the discretion of the 5
anaesthetist who was in charge of the patient. Intra-operative analgesia was with sufentanil 0.2 to −1
−1
0.4 µg kg or fentanyl 1 to 2 µg kg . Neuromuscular blockade was reversed with neostigmine −1
−1
50 µg kg and glycopyrrolate 10 µg kg if deemed necessary by the anaesthetist who was in charge of the patient. Prophylactic anti-emetics (D2-receptor antagonists, steroids, 5HT3 receptor antagonists) were not allowed before, during or after surgery. After surgery, patients stayed in the postoperative anaesthesia care unit (PACU) for about 2 h and were then transferred to the ward. Postoperative analgesia was with morphine, paracetamol, and ketorolac or ibuprofen. M easur ements
The primary endpoint of the study was the cumulative incidence of PONV (i.e. any nausea and/or vomiting symptom) within 24 h. Nausea was defined as an unpleasant feeling of sickness in the stomach, often associated with an urge to vomit. Any symptom and sign of nausea (independent of intensity) was considered as nausea. Vomiting was defined as the act of regurgitation of stomach contents. Retching was regarded as vomiting. Nausea, retching and vomiting were evaluated through direct questioning of the patient by a research nurse blinded to treatment allocation. At 24 h, ward charts were reviewed for additional information on nausea, vomiting and anti-emetic rescue treatment. Patients who were vomiting or nauseous were considered as prevention failures and were analysed as such. Patients with PONV symptoms received anti-emetic rescue treatment (intravenous ondansetron 4 mg or intravenous droperidol 0.5 to 1 mg), and their patch was removed immediately. Secondary endpoints were any adverse effects that were possibly related to the nicotine exposure, such as headache or cardiovascular adverse effects (arterial hypertension, defined as a ≥20% increase in systolic blood pressure compared with pre-operative values, tachycardia, defined as a ≥20% increase in heart rate compared with pre-operative values, arrhythmia, angina). Quality of sleep was measured after the first postoperative night using a 0 to 10 cm visual analogue scale (0 = not sleeping at all, 10 = excellent sleep). Scores below 4 were regarded as inappropriate sleep quality and the scale was subsequently dichotomized into insomnia (≤4) and appropriate quality of sleep (>4). Analyses
All patients randomized to receive nicotine patch or placebo were included in the intention-totreat analysis. Baseline demographic characteristics and outcomes were described as frequencies, 6
proportions or means with standard deviation (SD). Baseline categorical and numerical variables were compared with Chi-square, Fisher's exact test and the unpaired Student's t -test. Analysis of the primary endpoints (incidence of PONV, nausea or vomiting within 24 h) and secondary endpoints (headache, cardiovascular adverse effects, insomnia) was done with Chi-square and Fisher's exact test for expected values <5. Results were expressed as proportions, odds ratios (OR) with 95% confidence intervals (CI) and P values. Time to first symptoms of nausea and vomiting were described graphically using Kaplan-Meier survival curves, summarized by median times to event with inter-quartile ranges, and compared by the log-rank (Kaplan-Meier) and Mann-Whitney (medians) test. A two-tailed P value < 0.05 was considered statistically significant. Sample size was calculated on a cumulative expected incidence of PONV within 24 h in controls of 30%. A decrease of that incidence to 10% with transdermal nicotine (i.e. an absolute risk reduction of 20%) was regarded as a clinically relevant improvement in this context [3]. For a 80% power and a 0.05 significance level (Chi-Square test), 90 patients were needed in both active and control groups to test this hypothesis. We intended to include 100 patients in each group to allow for dropouts and study withdrawals. Analyses were performed with Software PASS (PASS/NCSS 2000, NCSS Corp., Kaysville, UT). Results
During a 24 month period, 260 eligible patients were invited to take part in this trial but only 90 (34.6%) eventually agreed. The recruitment rate was unexpectedly low. Some patients refused to participate spontaneously since they feared adverse effects due to the nicotine and others worried about becoming addicted to nicotine. The low recruitment rate and expiring patches motivated us to terminate the study prematurely after having included 90 patients. When recruitment was stopped, the cumulative 24 h PONV incidence in controls was 53%, and thus almost twice as high as expected. A post hoc power analysis revealed that the final study cohort of 90 randomized patients still had an 80% power at a 0.05 significance level to detect a 30% difference between the two groups in the 24 h incidence of PONV. The 90 included patients were randomized into two equal groups of 45 each; all received the assigned study treatment (Figure 1). There were two dropouts in the placebo group; one patient refused the patch application and one received intrathecal anaesthesia. Figure 1. Flow chart. GA, general anaesthesia 7
There were no differences between the groups with respect to gender, age, weight, ex-smoker status, PONV risk factors, type of surgery, induction agent or the use of nitrous oxide or neostigmine (Table 1). All patients received opioids postoperatively. Placebo n =
Nicotine n =
Odds
ratio
45
45
difference
(95%
CI)
for
group
val P ue
* Data are means (SD). PONV, postoperative nausea and vomiting. Patients Age (years)
46.8 (15.1)
41.8 (13.6)
–
0.12
Weight (kg)
73.3 (15.0)
74.1 (15.2)
–
0.80
Female gender
17 (37.8%)
20 (44.4%)
1.31 (0.56, 3.05)
0.52
Non-smoker
38 (84.4%)
37 (82.2%)
0.85 (0.28, 2.58)
0.77
Ex-smoker
7 (15.6%)
8 (17.8%)
1.17 (0.38, 3.56)
0.70
PONV history
15 (33.3%)
12 (26.7%)
0.72 (0.29, 1.79)
0.49
Motion sickness
13 (28.9%)
14 (31.1%)
1.11 (0.45, 2.74)
0.81
Migraine
14 (31.1%)
17 (37.8%)
1.34 (0.56, 3.21)
0.50
Ear, nose and throat
23 (51.1%)
26 (57.8%)
1.30 (0.57, 3.01)
0.52
Lumbar disc
4 (8.9%)
1 (2.2%)
0.23 (0.02, 2.17)
0.16
Abdominal
16 (35.6%)
18 (40.0%)
1.20 (0.51, 2.83)
0.66
1 (2.2%)
1 (2.2%)
1.00 (0.06, 16.49)
1.00
PONV risk factors
Surgery
Anaesthesia Thiopentone
8
Placebo n =
Nicotine n =
Odds
ratio
(95%
CI)
for
group
P val
45
45
difference
ue
Propofol
42 (93.3%)
44 (97.8%)
3.14 (0.31, 31.42)
0.30
Nitrous oxide
18 (40.0%)
18 (40.0%)
1.00 (0.43, 2.32)
1.00
Neostigmine
9 (20.0%)
15 (33.3%)
2.00 (0.76, 5.21)
0.15
Table 1. Baseline comparative patient characteristics and procedures
Neither in the PACU nor within 24 h was there any significant difference in nausea or vomiting rates between patients treated with nicotine or controls (Table 2, Figure 2). Cumulative 24 h incidence of PONV was 68.9% with nicotine and was 53.3% with placebo (OR 1.93, 95% CI 0.81, 4.58, P = 0.13). The 24 h vomiting incidence was 31.1% with nicotine and 28.9% with placebo (OR 1.11, 95% CI 0.45, 2.74, P = 0.81). The 24 h incidence of nausea was 42.2% with nicotine and 40.0% with placebo (OR 1.09, 95% CI 0.47, 2.53, P = 0.83) (Table 2).
1.
Placebo n =
Nicotine n =
Odds ratio (95% CI) for group
45
45
difference
value P
PACU, post-anaesthesia care unit; PONV, postoperative nausea and/or vo miting (including retching)
Nausea in PACU
10 (22.0%)
11 (24.4%)
1.13 (0.42, 3.01)
0.80
Vomiting in PACU
8 (17.8%)
9 (20.0%)
1.15 (0.40, 3.32)
0.78
Nausea within first 24 h
18 (40.0%)
19 (42.2%)
1.09 (0.47, 2.53)
0.83
Vomiting within first 24 h
13 (28.9%)
14 (31.1%)
1.11 (0.45, 2.74)
0.81
PONV within first 24 h
24 (53.3%)
31 (68.9%)
1.93 (0.81, 4.58)
0.13
23 (51.5%)
26 (57.8%)
1.30 (0.57, 3.00)
0.52
Anti-emetic medication
rescue
Table 2. Postoperative nausea and vomiting (PONV) outcomes Figure 2. Cumulative probability of postoperative nausea and vomiting (PONV) with nicotine
and placebo. Difference between groups: P = 0.17 following log-rank test
9
Nicotine treated patients tended to have their first episodes of nausea and vomiting earlier than controls, but differences did not reach statistical significance (Table 3). No patient had a first episode of nausea or vomiting after 24 h. Placebo n = 45
1.
Nicotine n = 45
value* P
Data are medians (inter-quartile range). * P value following Mann-Whitney.
Time to first nausea episode (min)
120.0 (53.5 – 293.0)
119.0 (55.0 – 160.0)
0.65
Time to first vomiting episode (min)
99.0 (52.5 – 324.5)
62.5 (12.0 – 209.2)
0.19
Table 3. Time to first episodes of nausea and vomiting
In the placebo group, seven of 45 (15.6%) patients were ex-smokers and of those, four (57.1%) developed PONV symptoms. In the nicotine group, eight of 45 (17.8%) patients were exsmokers and of those, seven (87.5%) developed PONV symptoms ( P = 0.28). There was no difference between groups in the incidence of cardiovascular adverse effects or postoperative headache (Table 4). More patients receiving nicotine reported a low quality of sleep (visual analogue scale ≤4/10) during the first postoperative night (26.7% with nicotine vs. 6.8% with placebo, P = 0.01). Placebo n = 45
Nicotine n = 45
Odds ratio (95% CI) for group difference
P valu
* Visual analogue scale <4/10. † †Arterial hypertension, tachycardia, arrhythmia, angina. ‡ ‡Composite endpoint. Headache
8 (17.8%)
7 (15.6%)
0.72 (0.29, 1.79)
0.49
Insomnia
3 (6.8%)
12 (26.7%)
5.09 (1.32, 19.5)
0.01
Cardiovascular
5 (11.1%)
1 (2.2%)
0.18 (0.02, 1.62)
0.09
Any
16 (35.6%)
14 (31.1%)
0.81 (0.34, 1.96)
0.65
Table 4. Adverse effects 10
Discussion
In non-smokers undergoing surgery under general anaesthesia, a low dose of pre-operatively administered transcutaneous nicotine did not decrease the incidence of PONV within 24 h. Patients receiving nicotine had a tendency to develop PONV symptoms even earlier and they had a lower quality of sleep during the first postoperative night. No other drug-related adverse effects were observed. Basic mechanisms underlying nicotine action may help to understand the relationship between nicotine and emesis. Nicotine is a small alkaloid that can mimic the effects of the endogenous neurotransmitter acetylcholine. When nicotine binds on acetylcholine receptors in the central nervous system it perturbs the functioning of the neuronal network. Nicotine exerts both adverse and beneficial effects. Adverse effects include nausea and vomiting and are observed on first exposure to low nicotine concentrations or on exposure to very high nicotine concentrations. The acute emetic effects of nicotine have been well documented. Extreme cases are represented by tobacco field workers who develop the so-called ‘green tobacco sickness’[10]. Increased tolerance to the adverse effects of nicotine can, however, be observed during prolonged exposure to this alkaloid. This may explain why smokers experience no repulsion when exposed to tobacco fumes. The effect of tobacco, and more specifically nicotine, on outcome after surgery has been studied before. Studies investigating risk factors for PONV have consistently reported that non-smokers were at higher risk of developing nausea and vomiting after surgery compared with smokers [6 – 8]. A recently published observational study reported on a 50% reduction in the risk of PONV in patients who were chronically smoking and in patients who were snuffing tobacco. This reduction in risk was independent of gender [11]. These observations indicate that substances in the tobacco that are administered by both the inhalational (smoking) and the non-inhalational (snuffing) route might be responsible for the anti-emetic effect of tobacco after surgery. This decreases the likelihood of carbon monoxide or other inhaled substances as being responsible for the reduction of PONV in smokers. A possible explanation for the lower incidence of PONV in smokers may be that smokers are more resistant to emetogenic stimulations in general, and therefore may support the emetogenic effect of nicotine better than non-smokers. Consequently, they may be more prone to develop an 11
addiction to tobacco and, subsequently, to become chronic smokers. Nicotine absorption might therefore not act as an anti-emetic but rather represent a marker for natural resistance to emetogenic substances and to PONV in general. One may therefore hypothesize that the nonsmokers included in the present study were all at a similar risk for developing PONV and those who were exposed to a low dose of the emetogenic nicotine expressed a tendency towards more PONV symptoms, or at least towards earlier PONV. However, the analysis of the subpopulation of ex-smokers in our study did not support this h ypothesis. Others have reported on the effect of nicotine administration on PONV before. In an observational study Ionescu et al . compared non-smokers, ex-smokers who received a nicotine patch containing 16.6 mg nicotine 1 h before surgery and active smokers undergoing laparoscopic cholecystectomy [12]. The incidence of PONV was lower in the group of exsmokers who had received the nicotine patch (20%) and the active smokers (32%) compared with the non-smokers who had not received nicotine (76%). These data suggested that both chronic tobacco consumption and nicotine administration in non-smokers reduced the incidence of PONV. However, these results need to be interpreted carefully, since due to the observational design of that study, selection and observer bias cannot be ruled out. Two previously published randomized trials studied the potential analgesic efficacy of transdermal nicotine in non-smokers undergoing surgery [13, 14]. Both studies reported on PONV symptoms as secondary outcomes. Habib et al . randomized 90 non-smokers undergoing radical prostatectomy under general anaesthesia to receive a similar patch of nicotine as in our study (releasing 7 mg of nicotine per 24 h) or placebo. In the nicotine group, cumulative morphine consumption at 24 h was significantly reduced but there was no difference in pain intensity. There was no difference between groups in the incidence of PONV or the need for rescue anti-emetics despite the decreased morphine consumption in the nicotine group. Maximum nausea verbal rating scale scores were even higher in the nicotine group. There were no significant differences between the groups in postoperative heart rate, arterial blood pressure, respiratory rate or oxygen saturation, and there were also no significant differences between the two groups in the quality of sleep [13]. Hong et al . randomized 40 patients undergoing general surgery to a transdermal patch that delivered 5, 10 or 15 mg nicotine per 16 h or placebo [14]. Patches were applied immediately before surgery. Patients treated with nicotine reported lower pain scores when compared with 12
those treated with placebo for 5 days after surgery. There was no increased benefit of nicotine with doses larger than 5 mg. There was a trend suggesting an increase in the incidence of nausea with nicotine. Finally, there were no differences in heart rate or arterial blood pressure between the two groups during the first hour after surgery, or in the degree of sedation [14]. Our study has limitations. Firstly, we did not measure plasma concentrations of nicotine or its main metabolite, cotinine. These could be regarded as convincing evidence of successful absorption, and thus as a basis for a biological effect, in patients who received transdermal nicotine. There are, however, several arguments in favour of an appropriate nicotine absorption in our study despite lacking plasma concentrations. For instance, we used a patch that has been commercially available for the prevention of withdrawal symptoms for many years. The pharmacokinetics of transdermal nicotine have been studied extensively [15]. Also, Habib et al . who studied the effect of transdermal nicotine on postoperative pain, were using a similar nicotine patch to ours and they were able to quantify nicotine concentrations in the plasma [13]. Finally, in our double-blind study, nicotine-treated patients reported on impaired quality of sleep during the first postoperative night. Insomnia is a well-known adverse effect of transcutaneous nicotine application in nicotine-naïve volunteer s[16]. In non-smoking volunteers performing boring tasks under experimental conditions, transdermal nicotine was show n to act as a stimulant and to prevent an increase in fatigue [17]. Thus, this centrally mediated adverse effect that was observed in our study suggests strongly that the nicotine must have been well absorbed in those patients who had received nicotine transdermally. Premature termination must be regarded as a further limitation of our study. Recruitment appeared to be much more difficult than expected and this may have reflected the reluctance of nicotine-naïve patients to accept nicotine as a treatment for PONV. Stopping a trial early has the potential to exaggerate the magnitude of benefit [18]. We do not know how this translates into an equivalence study. We were unable to show any benefit with nicotine despite a much higher baseline risk than expected. We may assume that, in view of the high baseline risk, it is unlikely that the results of our study would have been in favour of the nicotine treatment had we randomized more patients. Finally, a potential limitation of our study related to the choice of timing and dosing of the nicotine administration. Our rationale was to choose the minimal effective dose that would not provoke unacceptable adverse effects in nicotine-naïve patients but would have a beneficial effect on PONV. Consequently we chose the lowest dose patch that was commercially available. We 13
applied the patches shortly before start of surgery; based on the well-studied pharmacokinetics of transdermal nicotine administration [15], we expected plasma concentrations to build up during the surgical procedure while the patients were still under general anaesthesia and to be maintained at steady state for several hours postoperatively. However, it cannot be excluded that the chosen dose was too low. None of the patients reported on nicotine-related adverse effects before induction of anaesthesia. This suggests that nicotine-naïve patients may be exposed to higher doses of transdermal nicotine. We do not know whether a higher dose of nicotine or an earlier time point of patch administration before surgery (with subsequently a longer exposure to nicotine), would have changed our results. Our findings have implications for future research. In non-smokers, a single short administration of a small dose of transdermal nicotine does not seem to have a PONV-preventing effect. Also, previous studies have suggested that not only smokers but also individuals who are snuffing tobacco are protected against PONV [11]. These findings suggest that it may not be the smoking status per se that should be regarded as a predictive factor for PONV [7]. It may also be inferred that within tobacco, it is not the nicotine that has a relevant protective effect against emesis after surgery. There is some evidence that regular alcohol consumers are less likely to develop PONV symptoms after surgery [19]. This may simply indicate that regular exposure to multiple exogeneous toxins, such as alcohol or tobacco, protects to some extent from the detrimental metabolic and pharmacologic impact of surgery and anaesthesia. Further research should elucidate what substances within the tobacco have a protective effect against PONV. It cannot be excluded either that in our study, exposure time was too short. It may be that in order to desensitize nicotine receptors to a relevant degree in nicotine-naïve subjects, the nicotine patch would have to be applied days and perhaps even weeks before surgery. This, however, is not feasible in daily clinical practice. Also, there is a risk, albeit small, that longer-term administration of nicotine in nicotine-naïve subjects may induce nicotine dependence. In summary, in non-smokers undergoing surgery under general anaesthesia, a low dose of transcutaneous nicotine, administered shortly before surgery, did not decrease the incidence of nausea and vomiting within the first 24 h postoperatively. Patients receiving transcutaneous nicotine tended to have nausea and vomiting symptoms even earlier and they suffered more often from insomnia during the first postoperative night. Transcutaneous nicotine cannot be recommended as an anti-emetic prophylaxis in surgical patients. 14
Competing interests
There are no competing interests to declare. We are grateful to Ms Béatrice Gil-Wey, Division of Anaesthesiology, University Hospitals of Geneva, for her role as a research assistant. The study was funded by institutional funds. The nicotine and placebo patches were kindly provided by LTS Lohmann Therapie-Systeme AG, Andernach, Germany.
Introduction
Pengantar Mual dan muntah pasca operasi (PONV) adalah gangguan yang telah sering diremehkan karena sifatnya membatasi diri, dan karena itu tidak pernah menjadi kronis dan hampir tidak pernah membunuh. Namun, komplikasi serius yang berhubungan dengan muntah telah dijelaskan [1]. Pada tahun 1998, 10% penduduk Perancis menjalani anestesi umum [2]. Karena ada bukti bahwa 20% sampai 30% dari pasien bedah menderita gejala PONV meskipun penggunaan anestesi yang modern [3], dapat disimpulkan bahwa PONV tetap menjadi beban kesehatan utama. Hari ini, beberapa kelompok obat diakui sebagai benar-benar berguna, sendiri atau dalam kombinasi, untuk kontrol PONV. Di antara mereka adalah kortikosteroid, serotonin (5-HT3) antagonis reseptor, dan dopamin (D2) antagonis reseptor [4]. Namun, tidak satupun dari secara universal efektif, masing-masing memiliki kelebihan dan kekurangan, dan tidak dapat dianggap sebagai standar emas. Dengan demikian, ada kebutuhan untuk molekul alternatif yang lebih lanjut dapat meningkatkan pengendalian PONV. Salah satu strategi untuk mengurangi kejadian PONV adalah untuk mengidentifikasi pasien yang berisiko tinggi mengembangkan gejala PONV dan selanjutnya untuk menargetkan farmakologis profilaksis [5]. Identifikasi faktor prediktif untuk PONV telah menjadi subyek dari banyak penelitian [6-8]. Mereka terutama dikonfirmasi apa yang dokter merasa untuk waktu yang lama, yaitu bahwa jenis kelamin perempuan, penggunaan opioid atau riwayat positif PONV atau mabuk meningkatkan kemungkinan PONV. Namun, pengetahuan baru adalah bahwa perokok cenderung menderita PONV dibandingkan non-perokok. Pada pandangan pertama ini adalah temuan tak terduga karena sudah diketahui bahwa efek samping yang berkaitan dengan paparan pertama konsentrasi rendah nikotin atau paparan konsentrasi nikotin yang sangat tinggi termasuk 15
mual dan muntah. Namun, asap tembakau dikenal untuk menginduksi enzim, misalnya, sitokrom P450 [9], dan ini sebagian dapat menjelaskan efek PONV-melindungi merokok. Penjelasan alternatif akan bahwa paparan kronis nikotin yang terkandung dalam tembakau akan mengakibatkan desensitisasi reseptor nikotin pusat, dan, kemudian, dengan peningkatan toleransi terhadap efek emetogenik dari operasi dan anestesi. Ini menimbulkan pertanyaan, apakah pada pasien nikotin naif pendek paparan pra-operasi terhadap nikotin dapat menurunkan kemungkinan dari PONV. Kami berangkat untuk menguji hipotesis ini dalam percobaan klinis. Metode Pemilihan pasien, obat administrasi penelitian dan manajemen an estesi Acak percobaan ini, plasebo-terkontrol telah disetujui oleh Komite Etika kelembagaan dan lembaga Swiss untuk produk terapi (Swissmedic), dan telah didaftarkan di clinicaltrials.gov (identifier: NCT00553709). Informed consent tertulis diperoleh dari semua pasien. Kami merekrut non-perokok (atau mantan perokok yang tidak pernah merokok selama lebih dari 2 tahun), status fisik ASA I atau II, berusia 18 hingga 80 tahun, dijadwalkan untuk operasi elektif rawat inap (telinga, hidung dan tenggorokan, disc kayu, ) perut bawah anestesi umum. Pasien yang menerima terapi penggantian nikotin, membutuhkan intubasi pasca operasi lama atau selang nasogastrik, memiliki hipersensitivitas kulit terhadap nikotin atau salah satu komponen patch, dengan penyakit sistemik kulit, angina pektoris tidak stabil, infark miokard, aritmia berat, kecelakaan pembuluh darah otak baru-baru ini , parkinson, ginjal atau gagal hati, diabetes, hipertensi yang tidak terkontrol arteri, hipertiroidisme, atau ulkus lambung, dan wanita hamil dan menyusui tidak dimasukkan dalam penelitian ini. Pasien dan peneliti buta dengan obat studi. Obat penelitian secara acak di blok sepuluh (lima nikotin dan lima plasebo) menggunakan program komputer oleh farmasi dari Universitas Jenewa Rumah Sakit dan tetap tersembunyi di sampul buram netral. Pasien yang dialokasikan untuk salah satu dari dua kelompok. Pada kelompok nikotin, pasien menerima Nicotinell ® patch 10 cm2, mengandung 17,5 mg nikotin, dengan tingkat pengiriman rata-rata 7 mg nikotin 24 h-1 (= TTS 10). Ini adalah dosis terkecil patch nikotin transdermal tersedia di pasar Swiss. Kita diharapkan beban nikotin ini ukuran patch untuk menjadi toksisitas rendah dan dapat diterima pada orang dewasa non-merokok. Kontrol menerima patch plasebo. Patch diaplikasikan pada ke dada atau lengan atas dan dijamin dengan pita perekat (Mefix ®, Mölnlycke Kesehatan AS, Norcross) pada saat premedikasi dengan midazolam oral 7,5 mg 1 jam sebelum induksi anestesi. 16
Patch yang tersisa in situ sampai 24 jam setelah operasi, atau sampai pertama PONV episode terjadi.
Anestesi umum diinduksi dengan thiopental 3 sampai 5 mg kg-1 atau propofol 1,5 sampai 2,5 mg kg-1. Intubasi trakea difasilitasi dengan rocuronium 0,6 mg kg-1 atau atrakurium 0,5 mg kg1. Anestesi dipertahankan dengan isoflurane (0,5 sampai 2,5%) atau sevoflurane (2 sampai 4%). Propofol untuk pemeliharaan tidak diizinkan. Pilihan nitrous oxide yang diserahkan kepada kebijaksanaan dari anestesi yang bertanggung jawab atas pasien. Analgesia intra-operasi itu dengan sufentanil 0,2-0,4 mg kg-1 atau fentanil 1 sampai 2 mg kg-1. Blokade neuromuskular terbalik dengan neostigmin 50 mg kg-1 dan glycopyrrolate 10 mg kg-1 jika dianggap perlu oleh dokter anestesi yang bertanggung jawab atas pasien. Profilaksis antiemetik (antagonis reseptor D2-, steroid, 5-HT3 antagonis reseptor) tidak diperbolehkan sebelum, selama atau setelah operasi. Setelah operasi, pasien tinggal di unit perawatan pasca operasi anestesi (PACU) selama sekitar 2 jam dan kemudian dipindahkan ke bangsal. Analgesia pascaoperasi adalah dengan morfin, parasetamol, dan ketorolac atau ibuprofen. Pengukuran Titik akhir primer dari penelitian ini adalah kejadian kumulatif dari PONV (yaitu mual apapun dan / atau gejala muntah) dalam waktu 24 jam. Mual didefinisikan sebagai perasaan yang tidak menyenangkan penyakit dalam perut, sering dikaitkan dengan keinginan untuk muntah. Setiap gejala dan tanda-tanda mual (independen intensitas) dianggap sebagai mual. Muntah didefinisikan sebagai tindakan regurgitasi isi lambung. Muntah dianggap sebagai muntah. Mual, muntah dan muntah dievaluasi melalui tanya jawab langsung dari pasien oleh perawat penelitian buta untuk alokasi pengobatan. Pada 24 jam, grafik lingkungan ditinjau untuk informasi tambahan mengenai mual, muntah dan pengobatan penyelamatan anti-muntah. Pasien yang muntah atau mual dianggap sebagai kegagalan pencegahan dan dianalisis seperti itu. Pasien dengan gejala PONV menerima pengobatan penyelamatan anti-emetik (intravena ondansetron 4 mg atau intravena droperidol 0,5-1 mg), dan patch mereka telah dihapus segera. Tujuan sekunder adalah efek samping yang mungkin berhubungan dengan paparan nikotin, seperti sakit kepala atau efek samping kardiovaskular (hipertensi arteri, didefinisikan sebagai peningkatan ≥ 20% tekanan darah sistolik dibandingkan dengan nilai pra-operasi, takikardia, yang didefinisikan sebagai ≥ a meningkat 20% denyut jantung dibandingkan dengan nilai pra17
operasi, aritmia, angina). Kualitas tidur diukur setelah malam pertama pasca operasi menggunakan 0 sampai 10 cm skala analog visual (0 = tidak tidur sama sekali, 10 = sangat baik tidur). Nilai di bawah 4 dianggap sebagai kualitas tidur yang tidak pantas dan skala itu kemudian dibagi ke Insomnia (≤ 4) dan kualitas yang tepat tidur (> 4). Analisis Semua pasien secara acak untuk menerima nikotin atau plasebo dimasukkan dalam niat-to-treat. Karakteristik demografi awal dan hasil yang digamb arkan sebagai frekuensi, proporsi atau sarana dengan standar deviasi (SD). Dasar variabel kategori dan numerik dibandingkan dengan Chisquare, uji Fisher dan t-tes berpasangan Mahasiswa. Analisis akhir primer (kejadian PONV, mual atau muntah dalam waktu 24 jam) dan titik akhir sekunder (sakit kepala, efek samping kardiovaskular, insomnia) dilakukan dengan Chi-square dan uji eksak Fisher untuk nilai-nilai yang diharapkan <5. Hasil dinyatakan sebagai proporsi, odds ratio (OR) dengan interval kepercayaan 95% (CI) dan nilai-nilai P. Waktu untuk gejala pertama mual dan muntah digambarkan secara grafis dengan menggunakan kurva survival Kaplan-Meier, diringkas dengan waktu median untuk acara dengan rentang antar-kuartil, dan dibandingkan dengan log-rank (Kaplan-Meier) dan Mann-Whitney (median) uji . Sebuah dua sisi nilai P <0,05 dianggap signifikan secara statistik. Ukuran sampel dihitung pada kejadian yang diharapkan kumulatif PONV dalam waktu 24 jam dalam kontrol dari 30%. Penurunan kejadian yang sampai 10% dengan nikotin transdermal (yaitu pengurangan risiko absolut dari 20%) dianggap sebagai perbaikan klinis yang relevan dalam konteks ini [3]. Untuk kekuatan 80% dan tingkat signifikansi 0,05 (uji Chi-Square), 90 pasien yang diperlukan dalam kelompok baik aktif dan kontrol untuk menguji hipotesis ini. Kami dimaksudkan untuk mencakup 100 pasien dalam setiap kelompok untuk memungkinkan putus sekolah dan penarikan studi. Analisis dilakukan dengan Software LULUS (LULUS / NCSS 2000, NCSS Corp, Kaysville, UT). Hasil
Selama periode 24 bulan, 260 pasien yang memenuhi syarat diundang untuk mengambil bagian dalam percobaan ini tetapi hanya 90 (34,6%) akhirnya setuju. Tingkat perekrutan adalah tiba-tiba rendah. Beberapa pasien menolak untuk berpartisipasi secara spontan karena mereka takut efek samping karena nikotin dan lain-lain khawatir tentang menjadi kecanduan nikotin. Tingkat rekrutmen rendah dan patch berakhir memotivasi kami untuk mengakhiri studi prematur setelah 18
termasuk 90 pasien. Ketika perekrutan dihentikan, kumulatif 24 h PONV kejadian di kontrol adalah 53%, dan dengan demikian hampir dua kali lebih tinggi seperti yang diharapkan. Sebuah post hoc analisis kekuatan mengungkapkan bahwa studi kohort akhir 90 pasien secara acak masih memiliki kekuatan 80% pada tingkat signifikansi 0,05 untuk mendeteksi perbedaan 30% antara kedua kelompok dalam 24 jam kejadian PONV. 90 pasien yang dimasukkan secara acak menjadi dua kelompok yang sama dari 45 masingmasing, semua menerima pengobatan tugas belajar (Gambar 1). Ada dua putus pada kelompok plasebo, satu pasien menolak aplikasi tambalan dan satu menerima intratekal anestesi. Diskusi
Dalam non-perokok yang menjalani pembedahan dengan anestesi umum, dosis rendah diberikan pra-bedah nikotin transkutan tidak menurunkan kejadian PONV dalam 24 jam. Pasien yang menerima nikotin memiliki kecenderungan untuk mengembangkan gejala PONV lebih awal dan mereka memiliki kualitas yang lebih rendah dari tidur pada malam pertama pasca operasi. Tidak ada efek samping obat-terkait lainnya yang diamati. Mekanisme dasar yang mendasari tindakan nikotin dapat membantu untuk memahami hubungan antara nikotin dan emesis. Nikotin adalah alkaloid kecil yang bisa meniru efek dari neurotransmitter asetilkolin endogen. Ketika nikotin mengikat pada reseptor asetilkolin pada sistem saraf pusat itu perturbs fungsi dari jaringan saraf. Nikotin menggunakan efek samping baik dan bermanfaat. Efek samping termasuk mual dan muntah dan diamati pada paparan pertama konsentrasi rendah nikotin atau paparan konsentrasi nikotin yang sangat tinggi. Efek muntah akut nikotin telah didokumentasikan dengan baik. Kasus-kasus ekstrim diwakili oleh pekerja lapangan tembakau yang mengembangkan apa yang disebut 'penyakit tembakau hijau' [10]. Peningkatan toleransi terhadap efek merugikan dari nikotin bisa, bagaimanapun, akan diamati selama paparan alkaloid ini. Hal ini mungkin menjelaskan mengapa perokok tidak mengalami tolakan bila terkena asap tembakau. Pengaruh tembakau, dan lebih khusus lagi nikotin, pada hasil setelah operasi telah dipelajari sebelumnya. Studi menyelidiki faktor risiko PONV secara konsisten melaporkan bahwa non perokok beresiko lebih tinggi mengalami mual dan muntah setelah operasi dibandingkan dengan perokok [6-8]. Sebuah studi observasional baru diterbitkan melaporkan penurunan 50% dalam risiko PONV pada pasien yang merokok dan kronis pada pasien yang snuffing tembakau. Penurunan risiko adalah independen gender [11]. Pengamatan ini menunjukkan bahwa zat dalam 19
tembakau yang dikelola oleh kedua inhalasi (merokok) dan non-inhalasi (snuffing) rute mungkin bertanggung jawab untuk efek anti-muntah tembakau setelah operasi. Hal ini mengurangi kemungkinan karbon monoksida atau inhalasi zat lain sebagai bertanggung jawab untuk pengurangan PONV pada perokok. Sebuah penjelasan yang mungkin untuk lebih rendah insiden PONV pada perokok mungkin bahwa perokok lebih tahan terhadap rangsangan emetogenik pada umumnya, dan karena itu dapat mendukung efek emetogenik nikotin lebih baik daripada non-perokok. Akibatnya, mereka mungkin lebih rentan untuk mengembangkan kecanduan tembakau dan, kemudian, untuk menjadi perokok kronis. Penyerapan nikotin mungkin karena itu tidak bertindak sebagai antiemetik melainkan merupakan penanda untuk kekebalan alami terhadap zat emetogenik dan PONV pada umumnya. Seseorang mungkin karena itu berhipotesis bahwa non-perokok yang termasuk dalam penelitian ini adalah semua pada risiko yang sama untuk mengembangkan PONV dan mereka yang terkena dosis rendah nikotin emetogenik mengungkapkan kecenderungan gejala yang lebih PONV, atau setidaknya menuju PONV sebelumnya . Namun, analisis subpopulasi mantan perokok dalam penelitian kami tidak mendukung hipotesis ini. Orang lain telah dilaporkan pada efek pemberian nikotin pada PONV sebelumnya. Dalam sebuah studi observasional Ionescu dkk. dibandingkan non-perokok, mantan perokok yang menerima patch nikotin yang mengandung 16,6 mg nikotin 1 jam sebelum operasi dan perokok aktif menjalani laparoskopi kolesistektomi [12]. Kejadian PONV lebih rendah pada kelompok mantan perokok yang telah menerima patch nikotin (20%) dan perokok aktif (32%) dibandingkan dengan non-perokok yang tidak menerima nikotin (76%). Data ini menyarankan bahwa kedua konsumsi tembakau kronis dan administrasi nikotin dalam non-perokok mengurangi insiden PONV. Namun, hasil ini harus ditafsirkan dengan hati-hati, karena karena desain pengamatan bahwa penelitian, seleksi dan pengamat Bias tidak dapat dikesampingkan. Dua diterbitkan sebelumnya percobaan acak mempelajari kemanjuran analgesik potensi nikotin transdermal pada non-perokok yang menjalani operasi [13, 14]. Kedua studi melaporkan gejala PONV sebagai hasil sekunder. Habib et al. acak 90 non-perokok yang menjalani prostatektomi radikal di bawah anestesi umum untuk menerima patch nikotin yang sama seperti dalam penelitian kami (melepaskan 7 mg nikotin per 24 jam) atau plasebo. Pada kelompok nikotin, konsumsi morfin kumulatif pada 24 jam berkurang secara signifikan tetapi tidak ada perbedaan dalam intensitas nyeri. Tidak ada perbedaan antara kelompok dalam kejadian PONV atau 20
kebutuhan untuk penyelamatan antiemetik meskipun konsumsi morfin menurun pada kelompok nikotin. Maksimum mual skor skala penilaian lisan bahkan lebih tinggi pada kelompok nikotin. Tidak ada perbedaan yang signifikan antara kelompok dalam denyut jantung pasca operasi, tekanan darah arteri, tingkat pernapasan atau saturasi oksigen, dan ada juga tidak ada perbedaan yang signifikan antara kedua kelompok dalam kualitas tidur [13]. Hong et al. acak 40 pasien yang menjalani operasi umum untuk patch transdermal yang disampaikan 5, 10 atau 15 mg nikotin per 16 jam atau plasebo [14]. Patch yang diterapkan segera sebelum operasi. Pasien yang diobati dengan nikotin melaporkan skor nyeri yang lebih rendah bila dibandingkan dengan mereka yang diobati dengan plasebo selama 5 hari setelah operasi. Tidak ada manfaat meningkat nikotin dengan dosis yang lebih besar dari 5 mg. Ada kecenderungan yang menunjukkan peningkatan kejadian mual dengan nikotin. Akhirnya, tidak ada perbedaan denyut jantung atau tekanan darah arteri antara kedua kelompok selama satu jam pertama setelah operasi, atau tingkat sedasi [14]. Penelitian kami memiliki keterbatasan. Pertama, kita tidak mengukur konsentrasi plasma nikotin atau metabolit utama, cotinine nya. Ini dapat dianggap sebagai bukti yang meyakinkan penyerapan sukses, dan dengan demikian sebagai dasar untuk efek biologis, pada pasien yang menerima nikotin transdermal. Namun demikian, beberapa argumen yang mendukung penyerapan nikotin yang tepat dalam penelitian kami meskipun kurang konsentrasi plasma. Misalnya, kami menggunakan patch yang telah tersedia secara komersial untuk pencegahan gejala penarikan selama bertahun-tahun. Farmakokinetik nikotin transdermal telah dipelajari secara ekstensif [15]. Juga, Habib et al. yang mempelajari pengaruh nikotin transdermal pada nyeri pasca operasi, yang menggunakan patch nikotin mirip dengan kita dan mereka mampu mengukur konsentrasi nikotin dalam plasma [13]. Akhirnya, dalam studi double-blind kami, pasien yang diobati nikotin melaporkan gangguan kualitas tidur pada malam pertama pasca operasi. Insomnia adalah efek samping terkenal aplikasi nikotin transkutan pada sukarelawan nikotin naif [16]. Dalam relawan non-merokok melakukan tugas membosankan di bawah kondisi percobaan, nikotin transdermal ditunjukkan untuk bertindak sebagai stimulan dan untuk mencegah peningkatan kelelahan [17]. Dengan demikian, efek samping tersebut terpusat dimediasi yang diamati dalam penelitian kami menunjukkan kuat bahwa nikotin harus telah diserap dengan baik pada pasien yang telah menerima nikotin transdermal. Penghentian prematur harus dianggap sebagai pembatasan lebih lanjut dari penelitian kami. Rekrutmen tampaknya jauh 21
lebih sulit dari yang diharapkan dan ini mungkin mencerminkan keengganan pasien nikotin naif untuk menerima nikotin sebagai pengobatan untuk PONV. Menghentikan percobaan awal memiliki potensi untuk membesar-besarkan besarnya manfaat [18]. Kami tidak tahu bagaimana ini diterjemahkan menjadi studi kesetaraan. Kami tidak dapat menunjukkan manfaat dengan nikotin meskipun risiko dasar yang jauh lebih tinggi dari yang diharapkan. Kita mungkin menganggap bahwa, dalam pandangan dari risiko awal yang tinggi, tidak mungkin bahwa hasil penelitian kami akan mendukung pengobatan nikotin telah kami acak lebih banyak pasien. Akhirnya, keterbatasan potensi penelitian kami terkait dengan pilihan waktu dan dosis administrasi nikotin. Alasan kami adalah untuk memilih dosis minimal yang efektif yang tidak akan memprovokasi efek samping yang tidak dapat diterima pada pasien nikotin naif tapi akan memiliki efek menguntungkan pada PONV. Akibatnya kami memilih patch dosis terendah yang tersedia secara komersial. Kami menerapkan patch lama sebelum dimulainya operasi, berdasarkan farmakokinetik dipelajari dengan baik administrasi nikotin transdermal [15], kita diharapkan konsentrasi plasma untuk membangun selama prosedur bedah sementara pasien masih di bawah anestesi umum dan dipertahankan pada stabil negara selama beberapa jam pasca operasi. Namun, tidak dapat dikesampingkan bahwa dosis yang dipilih terlalu rendah. Tak satu pun dari pasien yang melaporkan efek samping nikotin terkait sebelum induksi anestesi. Hal ini menunjukkan bahwa pasien nikotin naif dapat terkena dosis tinggi nikotin transdermal. Kami tidak tahu apakah dosis yang lebih tinggi dari nikotin atau titik waktu sebelumnya administrasi Patch sebelum operasi (dengan kemudian lebih lama paparan nikotin), akan mengubah hasil kami. Temuan kami memiliki implikasi untuk penelitian masa depan. Dalam non-perokok, administrasi pendek tunggal dosis kecil nikotin transdermal tampaknya tidak memiliki efek-mencegah PONV. Juga, studi sebelumnya telah menyarankan bahwa tidak hanya perokok tapi juga individu yang snuffing tembakau dilindungi terhadap PONV [11]. Temuan ini menunjukkan bahwa hal itu mungkin bukan status merokok per se yang harus dianggap sebagai faktor prediktif untuk PONV [7]. Hal ini juga dapat disimpulkan bahwa dalam tembakau, itu bukan nikotin yang memiliki efek perlindungan yang relevan terhadap emesis setelah operasi. Ada beberapa bukti bahwa konsumen alkohol secara teratur lebih kecil kemungkinannya untuk mengembangkan gejala PONV setelah operasi [19]. Ini mungkin hanya menunjukkan bahwa eksposur rutin ke beberapa racun exogeneous, seperti alkohol atau tembakau, melindungi sampai batas tertentu 22
dari metabolisme merugikan dan dampak farmakologis operasi dan anestesi. Penelitian lebih lanjut harus menjelaskan apa zat dalam tembakau memiliki efek perlindungan terhadap PONV. Hal ini tidak dapat dikesampingkan baik bahwa dalam penelitian kami, waktu pemaparan terlalu singkat. Ini mungkin bahwa dalam rangka untuk menurunkan rasa mudah terpengaruh reseptor nikotin untuk gelar yang relevan dalam mata pelajaran nikotin naif, patch nikotin akan menjadi hari diterapkan dan mungkin bahkan berminggu-minggu sebelum operasi. Ini, bagaimanapun, tidak layak dalam praktek klinis sehari-hari. Juga, ada risiko, meskipun kecil, bahwa pemberian jangka panjang dari nikotin dalam mata pelajaran nikotin naif dapat menyebabkan ketergantungan nikotin. Singkatnya, pada non-perokok yang menjalani pembedahan dengan anestesi umum, dosis rendah nikotin transkutan, diberikan segera sebelum operasi, tidak menurunkan kejadian mual dan muntah dalam 24 jam pertama pasca operasi. Pasien yang menerima nikotin transkutan cenderung memiliki gejala mual dan muntah lebih awal dan mereka lebih sering menderita insomnia selama malam pertama pasca operasi. Nikotin transkutan tidak dapat direkomendasikan sebagai profilaksis anti-muntah pada pasien bedah.
23
