British Journal of Anaesthesia 1996; 76: 186–193
Omitting nitrous oxide in general anaesthesia: meta-analysis of
intraoperative awareness and postoperative emesis in randomized
controlled trials
M. TRAMÈR, A. MOORE AND H. MCQUAY
Summary
We have reviewed randomized controlled trials to
assess the effectiveness and safety of anaesthetics
which omitted nitrous oxide (N2O) to prevent
postoperative nausea and vomiting (PONV). Early
and late PONV (6 and 48 h after operation,
respectively), and adverse effects were evaluated
using the numbers-needed-to-treat (NNT) method.
In 24 reports with information on 2478 patients, the
mean incidence of early and late vomiting with N2O
(control) was 17 % and 30 %, respectively. Omitting
N2O significantly reduced vomiting compared with
a N2O regimen; the combined NNT to prevent both
early and late vomiting with a N2O-free regimen
was about 13 (95 % confidence intervals (CI) 9,
30). The magnitude of the effect depended on the
incidence of vomiting in controls. In studies with a
baseline risk higher than the mean of all reports, the
NNT to prevent both early and late vomiting with a
N2O-free anaesthetic was 5 (95 % CI 4, 10). When
the baseline risk was lower than the mean, omitting
N2O did not improve outcome. Omitting N2O had
no effect on complete control of emesis or nausea.
The NNT for intraoperative awareness with a N2Ofree anaesthetic was 46 compared with anaesthetics
where N2O was used. This clinically important risk
of major harm reduces the usefulness of omitting
N2O to prevent postoperative emesis. (Br. J.
Anaesth. 1996; 76: 186–193)
Key words
Anaesthetics gases, nitrous oxide. Vomiting, nausea. Memory.
Vomiting, nausea, anaesthetic factors. Anaesthesia, audit. Anaesthesia, depth.
Theoretically, nitrous oxide (N2O) is an emetic and
it is generally believed to be associated with
postoperative nausea and vomiting (PONV). N2O
penetrates easily into closed spaces such as the bowel
[1, 2] or middle ear [3–5], activates the medullary
dopaminergic system [6] and increases cerebrospinal
opioid peptides [7]. In humans, N2O analgesia was
shown to be reversible by naloxone [8]. These data
suggest that N2O could induce PONV through at
least three mechanisms and experimental studies
with N2O reported nausea and vomiting in healthy
volunteers [9–11].
The effect of N2O on the incidence of PONV is
controversial [12]. Palazzo and Strunin classified
N2O as an agent known to cause PONV, claiming
that the most likely mechanism was gastrointestinal
distension by manual ventilation and N2O transfer to
the gastrointestinal tract [13]. Others questioned a
decrease in the incidence of PONV when N2O was
omitted in halogenated inhalation anaesthetics, but
suggested that omitting N2O in propofol anaesthesia
may be beneficial [14].
This meta-analysis of randomized controlled trials
(RCT) tested the evidence that general anaesthetics
which omit N2O are associated with a decreased
incidence of PONV. Statistical and clinical significance of the effect of N2O-free anaesthetics on
PONV compared with regimens including N2O, and
anaesthesia-related complications were evaluated
using odds ratio and number-needed-to-treat
(NNT) methods.
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 TRAMÈR, 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.
PONV, awareness and nitrous oxide
mentioned specifically in the reports (number of
patients without any emetic symptoms, for instance).
The incidence of nausea and vomiting was analysed
separately when reported. Retching, when reported
as a separate outcome, was added to the incidence of
vomiting. No weighting was used for different grades
of nausea, number of vomiting episodes, time to first
vomiting episode, number of patients needing antiemetic rescue therapy or delay until discharge. The
incidence of intraoperative awareness was recorded
as indicated in the reports.
Odds ratios (OR) with 95 % confidence intervals
(95 % CI) were calculated using a fixed effects model.
NNT and 95 % CI were calculated [17]. This was
done for effectiveness and adverse effects, both for
individual reports and by combining single treatment
or control arms. A statistically significant improvement in a N2O-free regimen compared with control
was assumed when the lower limit of the 95 % CI of
the OR was 91. In the text, NNT for effectiveness
and adverse effects are reported with 95 % CI only
when the OR indicated a statistically significant
improvement in the treatment compared with control. Point estimates of the NNT without 95 % CI
are reported when the OR was not statistically
significant. An infinite value for NNT indicates a
negative value. Calculations were performed using
Excel v 4.0 on a Macintosh IIci.
Results
REPORTS
We identified 32 publications. Our search strategy
detected 17 reports from Medline. Eight trials were
excluded; one was not randomized [18], five had an
inadequate randomization method (alternate allocation [19]; patient’s date of birth [16, 20, 21];
patient’s registration number [22]), and in two the
emetic outcome was not reported as dichotomous
data [23, 24]. One RCT without dichotomous PONV
data was included in the awareness analysis because
recall was an outcome [25].
The 24 analysed reports contained data on 2478
patients. N2O and PONV interactions were evaluated
with isoflurane (eight trials), enflurane (three),
halothane (three), desflurane (five) and propofol
(six). In the three largest RCT, more than 680
patients had a N2O-free anaesthetic with either
isoflurane [26, 27], enflurane [26] or halothane [28].
In three studies, about 50 treated patients were
analysed in each treatment arm [29–31]. In each of
the remaining 18 studies, N2O and PONV interactions were investigated in no more than 35 patients
who had a N2O-free anaesthetic [1, 25, 32–47].
Tables containing information extracted from all
trials are available from the authors.
OUTCOMES
Complete control of emesis with no emetic symptoms
in the postoperative period was reported in four
studies. In two studies, this was the only emetic
outcome [36, 45]. For both early and late complete
emetic control, there was no significant improvement
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
All three large studies reported vomiting as a separate
outcome [26–28]. In two the incidence of vomiting in
controls was less than 10 % for early and only
13.3–28.7 % for late vomiting [26, 28]. NNT point
estimates were 29 and 105 to prevent early vomiting
and 30 and 305 to prevent late vomiting. The third
reported a high baseline risk for late vomiting in
controls (46 %) and the NNT point estimate to
prevent vomiting with a N2O-free regimen was 8.5
[27].
When all trials reporting vomiting as an outcome
were analysed baseline risks of vomiting and corresponding NNT to prevent vomiting by omitting
N2O showed an inverse relationship (figs 1, 2).
Combined analysis of trials with a baseline risk lower
than the mean of all trials showed no improvement in
the N2O-free groups over controls (tables 2, 3). In
this subgroup, the mean baseline risk was very low;
7 % (range 0–13 %) for early and 20 % (0–29 %) for
late vomiting. Combined analysis of trials with a
baseline risk higher than the mean showed statistically significant improvement of the N2O-free
regimens over control (tables 2, 3). In this subgroup,
the mean baseline risk was high; 35 % (21–50 %) for
early and 51 % (43–71 %) for late vomiting, and the
NNT to prevent early and late vomiting with a N2Ofree technique were 4.8 (95 % CI 3.6, 7.3) and 5.6
(3.9, 10.1), respectively. Anaesthetic techniques and
types of surgery were similar in the subgroups
(tables 2, 3).
Subgroups were different from each other in terms
of risk reductions and NNT to prevent vomiting
with a N2O-free technique (tables 2, 3). For early
vomiting the risk reduction was twice, and for late
vomiting it was three times higher in studies with a
high baseline risk of vomiting compared with those
with a low risk (tables 2, 3). The corresponding
NNT to prevent vomiting with a N2O-free technique
were 8–12-fold different.
When the three large studies [26–28] were excluded from the subgroup analysis the inverse
relationship between incidence of vomiting in controls and corresponding NNT to prevent vomiting
188
British Journal of Anaesthesia
Table 1 Odds ratio and numbers-needed-to-treat (NNT) to prevent early and late postoperative emesis by omitting nitrous oxide.
∞ Infinite value
Early complete emetic control
Late complete emetic control
Prevention of early nausea
Prevention of late nausea
Prevention of early vomiting
Prevention of late vomiting
Absence
of emesis
on air–O2
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
1.1 (0.7, 1.6)
1.1 (0.8, 1.5)
1.3 (0.9, 1.8)
1.1 (0.9, 1.5)
2.4 (1.7, 3.3)
1.5 (1.2, 1.8)
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, 30–32, 34, 35, 37, 38, 40–43, 46, 47]
[26–30, 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.)
with a N2O-free anaesthetic was maintained (tables
2, 3).
PROPOFOL
The incidence of vomiting was analysed separately in
five studies investigating N2O and propofol interactions [29, 34, 35, 42, 46]. For both early and late
vomiting, a total i.v. anaesthetic (TIVA) with
propofol led to a statistically significant improvement
compared with a propofol–N2O regimen (lower 95 %
CI of the OR 1.1 for early and 1.4 for late vomiting,
respectively). The NNT to prevent early vomiting
with a propofol-based TIVA was 10.4 (5.4, 149) in
four studies with 94 treated patients [34, 35, 42, 46].
The NNT to prevent late vomiting was 7.4 (4.5, 22)
in four studies with 134 treated patients
[29, 35, 42, 46]. Only one study reported statistically
significant improvement in the N2O-free propofol
anaesthetic compared with control for both early and
late vomiting [46]. Another study reported statistically significant improvement in the N2O-free
regimen for late but not for early vomiting [42]. In
both reports the incidence of vomiting in controls
was high; 47 % for early and 44–60 % for late
vomiting [42, 46].
Surgery
Mode of
ventilation
Studies with low baseline risk ( :17 %)
[32]
Extra-abd
Isoflurane
Intubation
[32]
Extra-abd
Isoflurane
Intubation
[34]
Gyn major
Propofol
Intubation
[35]
Gyn minor
Propofol
Mask
[26]
Adults diff
Enflurane
Intubation
[26]
Adults diff
Isoflurane
Intubation
[42]
Paed strab
Propofol
Intubation
Combined data
Combined data without large trials ([26–28])
Studies with high baseline risk ( 917 %)
Ortho minor
Desflurane
Intubation
[37]
Gyn laps
Enflurane
Intubation
[30]
Paed tons
Halothane
Intubation
[38]
Abd major
Isoflurane
Intubation
[40]
Ortho minor
Desflurane
Intubation
[41]
Laps
Enflurane
Intubation
[43]
Paed strab
Propofol
Intubation
[46]
Paed ENT
Halothane
Mask
[31]
Ortho minor
Desflurane
Intubation
[47]
Combined data
Combined data without large trials ([26–28])
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
930 min (an)
930 min (an)
30–68 min
5–10 min
80 min (an)
80 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
air–O2
(active)
75 %
85 %
20 %
52 %
32 %
61 %
64 %
80 %
100 %
60 %
50 %
113 %
0%
0%
15 %
43 %
0%
27 %
Risk
reduction
(%)
5.6 (1.2, 2.6)
6.2 (2, 19.4)
1.5 (0.5, 4.1)
2.5 (0.7, 8.7)
1.7 (0.5, 6.0)
3.1 (0.97, 9.7)
3.9 (1.3, 11.5)
4.6 (1.4, 15.5)
8.9 (1.1, 71.2)
3.1 (2.1, 4.6)
3.1 (2.1, 4.6)
2.0 (0.2, 21.2)
0.5 (0.04, 4.7)
0
0
1.2 (0.5, 2.7)
1.8 (0.8, 4.1)
1.0 (0.1, 16.5)
1.4 (0.8, 2.4)
1.0 (0.2, 4.1)
Odds ratio
(95 % CI)
2.7 (1.5, 14.9)
4.0 (2.5, 10.2)
10 (2.9, ∞)
5.6 (2.4, ∞)
9.4 (2.8, ∞)
4.9 (2.5, ∞)
3.3 (1.9, 13)
5.8 (3.3, 24.3)
3.5 (1.9, 20.4)
4.8 (3.6, 7.3)
4.8 (3.6, 7.3)
∞
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
PONV, awareness and nitrous oxide
189
Surgery
Mode of
ventilation
Studies with high baseline risk (930 %)
Adults diff
[27]
Isoflurane
Intubation
Gyn laps
[33]
Desflurane
Intubation
Gyn laps
[30]
Enflurane
Intubation
Paed tons
[38]
Halothane
Intubation
Gyn major
[39]
Isoflurane
Intubation
Paed strab
[42]
Propofol
Intubation
Paed strab
[46]
Propofol
Intubation
Combined data
Combined data without large trials ([26–28])
Studies with low baseline risk (:30 %)
Gyn + Uro
[29]
Propofol
Mask
Gyn minor
[35]
Propofol
Mask
Adults diff
[26]
Enflurane
Intubation
Adults diff
[26]
Isoflurane
Intubation
Paed ENT
[28]
Halothane
Mask
Combined data
Combined data without large trials ([26–28])
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
178 min (an)
25 min (an)
40 min (an)
37 min
99 min
29 min
54 min
12 min (an)
5–10 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
air–O2
(active)
25 %
7%
64 %
10 %
40 %
36 %
61 %
35 %
100 %
0%
9%
14 %
2%
12 %
Risk
reduction
(%)
1.6 (1, 2.7)
1.1 (0.3, 4.8)
4.1 (1.7, 10.2)
1.3 (0.5, 3.8)
3.1 (0.8, 11.3)
2 (0.6, 6.2)
4.4 (1.6, 12.2)
2.1 (1.5, 2.9)
2.7 (1.7, 4.3)
7.7 (0.8, 75.8)
0
1.1 (0.7, 1.8)
1.2 (0.7, 2)
1 (0.5, 2)
1.2 (0.9, 1.6)
7.7 (0.8, 75.8)
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
PONV, awareness and nitrous oxide
INTRAOPERATIVE AWARENESS
One RCT reported intraoperative awareness in six of
134 patients in the N2O-free group and in one of 126
in the control group [27]. Patients in this study were
premedicated with triazolam. In one study without
premedication, one incidence of recall was reported
in 31 patients in the N2O-free group [43]. Five
studies reported explicitly the absence of intraoperative awareness in the N2O-free groups
[25, 30, 34, 36, 47]. The NNT for one patient experiencing intraoperative awareness with a N2O-free
anaesthetic compared with a regimen with N2O was
46.2 (24.1, 581); the odds ratio was 4.5 (1.1, 18).
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 12–14 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.
References
1. Scheinin B, Lindgren L, Scheinin TM. Peroperative nitrous
oxide delays bowel function after colonic surgery. British
Journal of Anaesthesia 1990; 64: 154–158.
2. Giuffre M, Gross JB. The effects of nitrous oxide on
postoperative bowel motility. Anesthesiology 1986; 65: 699–
700.
3. Blackstock D, Gettes MA. Negative pressure in the middle
ear in children after nitrous oxide anaesthesia. Canadian
Anaesthetists Society Journal 1986; 33: 32–35.
4. Davies I, Moore JRM, Lahiri SK. Nitrous oxide and the
middle ear. Anaesthesia 1979; 34: 147–151.
5. Montgomery CJ, Vaghadia H, Blackstock D. Negative middle
ear pressure and postoperative vomiting in pediatric outpatients. Anesthesiology 1988; 68: 288–291.
6. Murakawa M, Adachi T, Nakao S, Seo N, Shingu K, Mori
K. Activation of the cortical and medullary dopaminergic
systems by nitrous oxide in rats: a possible neurochemical
basis for psychotropic effects and postanesthetic nausea and
vomiting. Anesthesia and Analgesia 1994; 78: 376–381.
7. Finck DA, Samaniego E, Ngai SH. Nitrous oxide selectively
releases met5-enkephalin and met5-enkephalin-arg6-phe7 into
canine third ventricular cerebrospinal fluid. Anesthesia and
Analgesia 1995; 80: 664–670.
British Journal of Anaesthesia
8. Yang JC, Clark WC, Ngai SH. Antagonism of nitrous oxide
analgesia by naloxone in man. Anesthesiology 1980; 52:
414–417.
9. Brandt L, Pohar H, Gehl A, Neugebauer I. La phase
postanaesthésique après inhalation d’halothane, d’enflurane,
d’isoflurane et de protoxyde d’azote. Cahiers d’Anesthésiologie
1985; 33: 161–163.
10. Russel GB, Snider MT, Richard RB, Loomis JL. Hyperbaric
nitrous oxide as a sole anesthetic agent in humans. Anesthesia
and Analgesia 1990; 70: 289–295.
11. Hornbein TF, Eger EI II, Winter PM, Smith G, Wetstone D,
Smith KH. The minimum alveolar concentration of nitrous
oxide in man. Anesthesia and Analgesia 1982; 61: 553–556.
12. Rabey PG, Smith G. Anaesthetic factors contributing to
postoperative nausea and vomiting. British Journal of Anaesthesia 1992; 69 (Suppl. 1): 40S–45S.
13. Palazzo MGA, Strunin L. Anaesthesia and emesis II:
prevention and management. Canadian Anaesthetists Society
Journal 1984; 31: 407–415.
14. Watcha MF, White PF. Postoperative nausea and vomiting.
Its etiology, treatment, and prevention. Anesthesiology 1992;
77: 162–184.
15. Jadad AR. Meta-analysis of Randomised Clinical trials in Pain
Relief, thesis. Oxford: Balliol College, 1994; appendix 3.1.
16. Korttila K, Hovorka J, Erkola O. Nitrous oxide does not
increase the incidence of nausea and vomiting after isoflurane
anesthesia. Anesthesia and Analgesia 1987; 66: 761–765.
17. Cook RJ, Sackett DL. The number needed to treat: a
clinically useful measure of treatment effect. British Medical
Journal 1995; 310: 452–454.
18. Smiley BAS, Paradise NF. Does the duration of N2O
administration affect postoperative nausea and vomiting?
Nurse Anesthesia 1991; 2: 13–18.
19. Lind B, Roland P. Kurznarkosen mit Propanidid. Wie hoch
sind die Brechreizfrequenzen? Der Anaesthesist 1969; 18:
82–85.
20. Hovorka J, Korttila K, Erkola O. Nitrous oxide does not
increase nausea and vomiting following gynaecological laparoscopy. Canadian Journal of Anaesthesia 1989; 36: 145–148.
21. Melnick BM, Johnson LS. Effects of eliminating nitrous
oxide in outpatient anesthesia. Anesthesiology 1987; 67:
982–984.
22. Felts JA, Poler SM, Spitznagel EL. Nitrous oxide, nausea,
and vomiting after outpatient gynecologic surgery. Journal of
Clinical Anesthesia 1990; 2: 168–171.
23. Lindekaer A, Skielboe M, Guldager H, Jensen EW. The
influence of nitrous oxide on propofol dosage and recovery
after total intravenous anaesthesia for day-case surgery.
Anaesthesia 1995; 50: 397–399.
24. Taylor E, Feinstein R, White PF, Soper N. Anesthesia for
laparoscopic cholecystectomy. Is nitrous oxide contraindicated? Anesthesiology 1992; 76: 541–543.
25. Girardi G, Rossi R, Cellai MP, Pieraccioli E, Novelli GP.
Anestesia con isoflurano in aria e con isoflurano e protossido
di azoto. Minerva Anestesiologica 1994; 60: 321–328.
26. Muir JJ, Warner MA, Offord KP, Buck CF, Harper JV,
Kunkel SE. Role of nitrous oxide and other factors in
postoperative nausea and vomiting: a randomized and blinded
prospective study. Anesthesiology 1987; 66: 513–518.
27. Eger EI II, Lampe GH, Wauk LZ, Whitendale P, Cahalan
MK, Donegan JH. Clinical pharmacology of nitrous oxide:
an argument for its continued use. Anesthesia and Analgesia
1990; 71: 575–585.
28. Splinter WM, Roberts DJ, Rhine EJ, MacNeill HB, Komocar
L. Nitrous oxide does not increase vomiting in children after
myringotomy. Canadian Journal of Anaesthesia 1995; 42:
274–276.
29. Akhtar TM, Kerr WJ, Kenny GNC. Effect of nitrous oxide
on post-operative nausea and vomiting during propofol
anaesthesia for short surgical operations. European Journal of
Anaesthesiology 1993; 10: 337–341.
30. Lonie DS, Harper NJN. Nitrous oxide anaesthesia and
vomiting. The effect of nitrous oxide anaesthesia on the
incidence of vomiting following gynaecological laparoscopy.
Anaesthesia 1986; 41: 703–707.
31. Wilson IG, Fell D. Nitrous oxide and postoperative vomiting
in children undergoing myringotomy as a day case. Paediatric
Anaesthesia 1993; 3: 283–285.
32. Bloomfield E, Hilberman M, Brown P, Noe H, Gaydos J,
PONV, awareness and nitrous oxide
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
Miller G, Sherrill D, Williams G. Postoperative nausea and
vomiting. A comparison of sufentanil, nitrous oxide, and
isoflurane. Cleveland Clinical Journal of Medicine 1988; 55:
549–552.
Graham SG, Aitkenhead AR. A comparison between propofol and desflurane anaesthesia for minor gynaecological
laparoscopic surgery. Anaesthesia 1993; 48: 471–475.
Gregory MA, Gin T, Yau G, Leung RKW, Chan K, Oh TE.
Propofol infusion anaesthesia for Caesarean section. Canadian
Journal of Anaesthesia 1990; 37: 514–520.
Gunawardene RD, White DC. Propofol and emesis. Anaesthesia 1988; 43 (Suppl.): 65–67.
Lampe GH, Wauk LZ, Donegan JH, Pitts LH, Jackler RK,
Litt LL, Rampil IJ, Eger EI II. Effect on outcome of
prolonged exposure of patients to nitrous oxide. Anesthesia
and Analgesia 1990; 71: 586–590.
Lebenbom-Mansour MH, Pandit SK, Kothary SP, Randel
GI, Levy L. Desflurane versus propofol anesthesia: a
comparative analysis in outpatients. Anesthesia and Analgesia
1993; 76: 936–941.
Pandit UA, Malviya S, Lewis IH. Vomiting after outpatient
tonsillectomy and adenoidectomy in children: the role of
nitrous oxide. Anesthesia and Analgesia 1995; 80: 230–233.
Pedersen FM, Wilken-Jensen C, Knudsen F, Lindekaer AL,
Svare EI. The influence of nitrous oxide on recovery of bowel
function after abdominal hysterectomy. Acta Anaesthesiologica Scandinavica 1993; 37: 692–696.
Ranta P, Nuutinen L, Laitinen J. The role of nitrous oxide in
postoperative nausea and recovery in patients undergoing
upper abdominal surgery. Acta Anaesthesiologica Scandinavica 1991; 35: 339–341.
Rapp SE, Conahan TJ, Pavlin DJ, Levy WJ, Hautman B,
Lecky J, Luke J, Nessly ML. Comparison of desflurane with
propofol in outpatients undergoing peripheral orthopedic
surgery. Anesthesia and Analgesia 1992; 75: 572–579.
Reimer EJ, Montgomery CJ, Bevan JC, Merrick PM,
Blackstock D, Popovic V. Propofol anaesthesia reduces early
postoperative emesis after paediatric strabismus surgery.
Canadian Journal of Anaesthesia 1993; 40: 927–933.
Sengupta P, Plantevin OM. Nitrous oxide and day-case
laparoscopy: effects on nausea, vomiting and return to normal
activity. British Journal of Anaesthesia 1988; 60: 570–573.
193
44. Sukhani R, Lurie J, Jabamoni R. Propofol for ambulatory
gynecologic laparoscopy: does omission of nitrous oxide alter
postoperative emetic sequelae and recovery? Anesthesia and
Analgesia 1994; 78: 831–835.
45. Van Hemelrijck J, Smith I, White PF. Use of desflurane for
outpatient anesthesia. Anesthesiology 1991; 75: 197–203.
46. Watcha MF, Simeon RM, White PF, Stevens JL. Effect of
propofol on the incidence of postoperative vomiting after
strabismus surgery in pediatric outpatients. Anesthesiology
1991; 75: 204–209.
47. Wrigley SR, Fairfield JE, Jones RM, Black AE. Induction
and recovery characteristics of desflurane in day case patients:
A comparison with propofol. Anaesthesia 1991; 46: 615–622.
48. Hartung J. Nitrous oxide—it’s enough to make you vomit
(letter). Anesthesiology 1993; 78: 403–405.
49. Watcha MF, White PF. In reply to Hartung J. 1993.
Anesthesiology 1993; 78: 405–406.
50. Tramèr M, Moore A, McQuay H. Prevention of vomiting
after paediatric strabismus surgery: a systematic review using
the numbers-needed-to-treat method. British Journal of
Anaesthesia 1995; 75: 556–561.
51. Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical
Epidemiology: A Basic Science for Clinical Medicine, 2nd Edn.
Boston/Toronto/London: Little, Brown and Company,
1991.
52. Oxman AD, Guyatt AH. A consumer’s guide to subgroup
analyses. Annals of Internal Medicine 1992; 116: 78–84.
53. Moseley H, Kumar AY, Bhavani Shankar K, Rao PS, Homi
J. Should air–oxygen replace nitrous oxide–oxygen in general
anaesthesia? Anaesthesia 1985; 42: 609–612.
54. Hanley JA, Lippman-Hand A. If nothing goes wrong, is
everything all right? Interpreting zero numerators. Journal of
the American Medical Association 1983; 249: 1743–1745.
55. Bergström H, Bernstein K. Psychic reactions after analgesia
without nitrous oxide for caesarean section. Lancet 1968; ii:
541–542.
56. Blacher RS. On awakening paralyzed during surgery. A
syndrome of traumatic neurosis. Journal of the American
Medical Association 1975; 234: 67–68.
57. Cormack RS. Conscious levels during anaesthesia. British
Journal of Anaesthesia 1993; 71: 469–471.