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Methods
Medline was searched (1966 to May 1995) without
language restriction for RCT which evaluated the
effect on PONV of a N2O-free anaesthetic (treatment) compared with the same anaesthetic but
including N2O (control). Key words used were
nitrous oxide and vomiting or nausea.
Additional reports were identified from the reference
lists of retrieved trials and from review articles of
PONV. Unpublished studies were not sought. Each
published report which could possibly be described
as an RCT was read independently by each of the
authors, who scored the reports for quality using a
three item scale [15] and then met to agree consensus
scores. All RCT reporting emetic outcome as
dichotomous data were included. Studies without
randomization and abstracts were not considered.
Information on patient characteristics, surgery,
anaesthetics, definition of emesis and adverse effects
was obtained from each report. Dichotomous data of
the incidence of early PONV (up to 6 h after
operation) and late PONV (up to 48 h after operation) were extracted. When several incidences of
PONV were reported at different times (time
intervals, for instance [16]) the two cumulative values
nearest to 6 h and 48 h after operation were analysed.
Effectiveness was defined as absence of emesis.
Complete control of emesis was analysed when
MARTIN TRAMR, MD, ANDREW MOORE, DPHIL, HENRY MCQUAY,
DM, Pain Research, Nuffield Department of Anaesthetics,
Churchill Hospital, Headington, Oxford OX3 7LJ. Accepted for
publication: September 19, 1995;
Correspondence to M. T.
Results
REPORTS
187
in N2O-free techniques compared with control (table
1).
Nausea as a separate outcome was reported in 14
studies. In one study this was the only emetic
outcome [1]. Omitting N2O had no impact on early
or late postoperative nausea (table 1).
The incidence of vomiting, with or without
retching, was reported in 19 studies. In four studies
this was the only emetic outcome [27, 28, 37, 46].
For early and late times, the mean incidence of
vomiting in controls was 17 % and 30 %, respectively. For early vomiting, anaesthetics which omitted
N2O produced statistically significant improvement
over control and the combined NNT to prevent
early vomiting was 11.8 (8.5, 19.4) (table 1). For late
vomiting, N2O-free regimens also produced a statistically significant improvement over control, and
the combined NNT to prevent late vomiting was
13.8 (8.8, 31.6) (table 1).
EFFECT OF BASELINE RISK ON OUTCOME
188
Table 1 Odds ratio and numbers-needed-to-treat (NNT) to prevent early and late postoperative emesis by omitting nitrous oxide.
Infinite value
Absence
of emesis
on airO2
Absence
of emesis
on N2O
Odds ratio
(95% CI)
NNT
(95% CI)
Reference
363/417
269/416
524/610
359/526
689/749
700/907
352/409
247/398
502/608
329/502
619/741
609/871
101 (17.7, )
38.4 (10.8, )
30 (13.5, )
36.9 (11.8, )
11.8 (8.5, 19.4)
13.8 (8.8, 31.6)
[26, 45]
[26, 36, 44]
[1, 26, 32, 34, 35, 40, 41, 43, 44, 47]
[26, 29, 30, 33, 35, 39]
[26, 3032, 34, 35, 37, 38, 4043, 46, 47]
[2630, 33, 35, 38, 39, 42, 46]
Figure 1 Incidence of early vomiting in controls (baseline risk) and corresponding numbers-needed-to-treat
(NNT) to prevent early vomiting by omiting nitrous oxide. [Numbers in square brackets are reference numbers.]
(Numbers in parentheses indicate the number of patients in the nitrous oxide-free group.) Infinite value.
Figure 2 Incidence of late vomiting in controls (baseline risk) and corresponding numbers-needed-to-treat
(NNT) to prevent late vomiting by omitting nitrous oxide. [Numbers in square brackets are reference numbers.]
(Numbers in parentheses indicate the number of patients in the nitrous oxide-free groups.)
Surgery
Mode of
ventilation
Ref.
Main
anaesthetic
Yes
Yes
No
No
No
No
No
No
No
Yes
Yes
No
No
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Gastric
suction
No
Yes
Yes
No
Yes
Yes
Yes
Opioid
use
94 min (an)
40 min (an)
37 min
121 min (an)
57 min
15 min
54 min
10 min (an)
29 min
Duration of
intervention
(mean)
an anaesthetic
V
V
RV
RV
V
V
V
RV
V
V
V
V
V
RV
RV
RV
Def. of
PONV
50 %
29 %
50 %
35 %
33 %
33 %
47 %
21 %
29 %
35 %
13 %
6%
0%
0%
7%
8%
4%
7%
%PONV
N2O
(control)
13 %
4%
40 %
17 %
23 %
13 %
17 %
4%
0%
14 %
6%
13 %
0%
0%
6%
5%
4%
5%
%PONV
airO2
(active)
75 %
85 %
20 %
52 %
32 %
61 %
64 %
80 %
100 %
60 %
50 %
113 %
0%
0%
15 %
43 %
0%
27 %
Risk
reduction
(%)
Odds ratio
(95 % CI)
0
0
104.9 (17.6, )
29.1 (12.1, )
0 (9.2, )
57.8 (21.4, )
16 (3.8, )
NNT
(95 % CI)
Table 2 Baseline risk, risk reduction, and numbers-needed-to-treat (NNT) to prevent early vomiting by omitting nitrous oxide. Infinite value. Def. Definition ; PONV
postoperative nausea and vomiting; V vomiting; R retching; N2O nitrous oxide; Extra-abd extra-abdominal; Abd abdominal; Gyn gynaecological; Uro urological; Laps
laparoscopy; diff different operations; Paed strab paediatric strabismus surgery; Paed tons paediatric tonsillectomies; Ortho orthopaedic operations; ENT ear, nose and throat
Surgery
Mode of
ventilation
Ref.
Main
anaesthetic
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
Opioid
use
No
No
No
Yes
No
No
Yes
No
No
No
No
No
Gastric
suction
12 min (an)
510 min
80 min
80 min
12 min (an)
Duration of
intervention
(mean)
an anaesthetic
V
V
V
RV
V
RV
V
V
V
RV
RV
V
Def. of
PONV
46 %
43 %
49 %
67 %
71 %
44 %
60 %
51 %
6%
0%
29 %
24 %
13 %
20 %
% PONV
N2O
(control)
34 %
40 %
17 %
60 %
42 %
28 %
23 %
33 %
0%
0%
26 %
21 %
13 %
18 %
% PONV
airO2
(active)
25 %
7%
64 %
10 %
40 %
36 %
61 %
35 %
100 %
0%
9%
14 %
2%
12 %
Risk
reduction
(%)
Odds ratio
(95 % CI)
Table 3 Baseline risk, risk reduction, and numbers-needed-to-treat (NNT) to prevent late vomiting by omitting nitrous oxide. Infinite value. (Abbreviations as in table 2)
8.5 (4.3, )
35 (2.6, )
3.2 (2, 8)
15 (3.3, )
3.5 (1.7, )
6.3 (2.4, )
2.7 (1.7, 7.4)
5.6 (3.9, 10.1)
4.1 (2.8, 7.4)
16.7 (8, )
0
37.3 (8.4, )
30.2 (8.4, )
304.7 (13, )
43.5 (14.9, )
26.3 (12.5, )
NNT
(95 % CI)
190
British Journal of Anaesthesia
Discussion
The controversy on the effect of N2O on PONV
[48, 49] may result from three problems. First, most
data from N2O and PONV interactions are based on
small studies and some showed statistically significant improvement with N2O-free regimens
[30, 31, 37, 46, 47] whereas large studies involving
hundreds of patients did not show any difference
[22, 26, 28]. Second, pharmacological antiemetic effectiveness can be reported as absence of nausea, of
vomiting with or without retching, or of any emetic
event (i.e. complete emetic control). Some studies
reported only one of these outcomes. However, the
effect of N2O on these emetic outcomes was shown to
be different. Finally, the confusion about N2O and
PONV interactions may simply reflect general
difficulty in interpreting the clinical significance of
the effectiveness of a N2O-free regimen in preventing
PONV.
This meta-analysis overcame these problems by
combining results from all relevant reports, by
recording each emetic outcome separately and by
analysing both the statistical and clinical significance
of the effect of a N2O-free anaesthetic on PONV.
Omitting N2O in general anaesthesia had no effect on
the incidence of nausea or on complete emetic
control; however, it was followed by a statistically
significant reduction in early and late vomiting and
the NNT indicated that patients at high risk of
vomiting were the most likely to profit from omitting
N2O.
The baseline risk of vomiting is of multifactorial
origin. Types of surgery, anaesthetic techniques, sex
and age of patients were comparable in subgroups
with a low or high baseline risk of vomiting. Even in
paediatric strabismus surgery, a well defined subgroup with a recognized high baseline risk of
postoperative vomiting, an extraordinarily wide
range of vomiting incidence has been reported [50].
This suggests that the baseline risk of vomiting is not
simply dependent on a particular type of surgery,
anaesthetic or patient but is rather defined by the
whole clinical setting.
Interestingly, the risk reduction was not useful as
a predictor of the emesis-reducing effect of a N2Ofree anaesthetic. For early vomiting, the combined
risk reduction with a N2O-free anaesthetic was 27 %
in studies with a low baseline incidence of vomiting.
However, the NNT method indicated that almost 60
191
patients would need to be treated with a N2O-free
anaesthetic in this setting for one to profit. For late
vomiting the risk reduction with a N2O-free anaesthetic in studies with a high baseline risk of
vomiting was only slightly higher (35 %) but this
time only six patients needed to undergo a N2O-free
anaesthetic for one to profit. This proves that the
NNT is a useful measure of clinical significance
because it takes into account the risk both with and
without treatment. This also confirms that the NNT
method is helpful in identifying a high-response
subgroup of patients who have the most to gain from
the treatment [51].
Subgroup analysis can be informative but it is also
potentially misleading [52]. To omit such pitfalls, we
first described a difference in the magnitude of the
emesis-preventing effect of a N2O-free anaesthetic
that is clinically important. Second, if a hypothesis is
confirmed in a meta-analysis that excludes data from
the study that originally suggested a particular
interaction, the inference is stronger. Analysis of the
largest trials suggested an inverse relationship between baseline risk of vomiting and NNT to prevent
vomiting with a N2O-free anaesthetic. Exclusion of
these studies from the combined analysis confirmed
or even accentuated the results of the subgroup
analysis. Third, the larger the difference between the
effect in a particular subgroup and the overall effect,
the more plausible it is that the effect is real.
Compared with the combined outcome of all RCT
(NNT 1214 to prevent vomiting) the prevention of
vomiting efficiency of a N2O-free regimen was
increased almost three-fold when only the subgroup
with a high baseline risk was analysed. When only
trials with a low baseline risk were analysed, the
overall efficiency of a N2O-free regimen in decreasing
vomiting became three times weaker. Finally, this
overview of the relevant literature found an interaction between baseline risk of vomiting and N2O
which was present consistently. It has been suggested that such consistency is the best single index
as to whether or not the results of a subgroup
analysis should be believed [52].
It has been suggested that omitting N2O in
propofol anaesthesia would be followed by a more
pronounced decrease in PONV than omitting N2O in
halogenated anaesthetics [49]. A TIVA with propofol was followed by a statistically significant
decrease in vomiting compared with control and the
combined NNT to prevent early and late vomiting
were lower than the combined data of all RCT.
However, the two propofol studies reporting statistically significant improvement in the N2O-free
anaesthetic also reported a high incidence of vomiting in controls, supporting the results of the baseline
risk subgroup analysis. Moreover, for early vomiting, the confidence interval of the combined NNT
was very wide, indicating that this result has to be
interpreted cautiously.
The benefit of a particular intervention has to be
balanced against its potential for harm. In the most
advantageous clinical situation (i.e. a setting with a
high risk of PONV), 20 % of treated patients may
profit from the emesis-reducing effect of a N2O-free
anaesthetic. Based on data from this meta-analysis
192
the risk of intraoperative awareness is 10 times lower
in the same setting. In the least advantageous
situation (i.e. a setting with a low risk of PONV), for
every patient profiting from a N2O-free anaesthetic
one other would experience intraoperative awareness. The question is then if the result of the metaanalysis is representative, as only seven of 24 RCT
reported recall as an outcome. The confidence
interval of the NNT indicated that we can be 95 %
confident that intraoperative awareness does occur
between in as many as 4 % or in as few as 0.17 % of
patients undergoing a N2O-free anaesthetic. In a
series of 180 consecutive patients undergoing general
anaesthesia without N2O, none reported recall [53].
In this situation we would be 95 % confident that the
chance of intraoperative awareness with a N2O-free
anaesthetic is at most 1.7 % [54]. The result of
Moseley and colleagues [53] is in agreement with the
result of our meta-analysis and we have to assume
that the NNT point estimate from our calculation
(NNT 46) lies close to the true value. Conscious
awareness with recall produced by a particular
anaesthetic technique is major harm and indeed is of
major concern both to patients and anaesthetists. It
can lead to serious psychological sequelae [55, 56].
Premedication with benzodiazepines does not guarantee absence of recall [27], but even in the presence
of N2O, intraoperative awareness may occur [57].
In conclusion, omitting N2O from general anaesthetics decreases postoperative vomiting significantly
but only if the baseline risk of vomiting is high.
Omitting N2O does not affect nausea or complete
control of emesis. There is no evidence that omitting
N2O is more effective in propofol than in halogenated
anaesthetics. The clinically important risk of intraoperative awareness with a N2O-free anaesthetic
reduces the usefulness of this method of preventing
postoperative vomiting.
Acknowledgements
Salary and support for M. T. were provided by the Swiss National
Science Foundation and the Swiss Anaesthetic Society. The
review was funded by Pain Research Funds.
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