Effectiveness and safety of nitrous oxide as sedation regimen in children – an HTA
Health technology assessment
|Published
The objective for the present report, is to systematically summarize published results on effectiveness using nitrous oxide in a paediatric setting for small, but painful hospital procedures. Safety issues for both the patients and health personnel exposed to nitrous oxide will also be reviewed.
Key message
Nitrous oxide, N2O, has a sedative and analgesic effect by inhalation. N2O is used at maternity wards and at dental offices in Norway. Additionally, a few hospitals use N2O for sedation of children for minor hospital procedures.
The objective for the present report, is to systematically summarize published results on effectiveness using nitrous oxide in a paediatric setting for small, but painful hospital procedures. Safety issues for both the patients and health personnel exposed to nitrous oxide will also be reviewed.
The most important findings in this HTA is:
- N2O can be used for sedation of children without serious adverse events
- The most prominent advantage with N2O may be the short recovery time compared to other active drugs
- Health personnel (midwives and dental assistants) exposed to N2O compared to no exposure did not increase the risk of spontaneous abortion
- Health personnel did not show reduced fertility at low exposure, but at high exposure
- The risk of congenital malfunctions in children was higher in N2O exposed mothers than mothers with no exposure
- No conclusions can be drawn on the effect of N2O on damage to DNA or other cellular mechanisms
- We did not find any studies on negative health effects in health personnel using N2O as sedation of children for small hospital procedures
The evidence for safety for health personnel had very low certainty due to the study design (retrospective cohorts) and that information about exposure levels were scarce. For health personnel working with N2O sedation of children we expect a significantly lower exposure than what was suggested in the cohorts because of present ventilation and scavenging systems of waste gas and since each procedure will be short (maximum 30 minutes) and the number of procedures per week will be minor (personal communication).
Background
Children (up to 18 years of age) who undergo painful procedures at hospitals are offered different kinds of pain relief (analgesics), often in combination with drugs for relaxation (sedatives). For successful procedures, as well as effective use of time and personnel, efforts are made to choose an efficient combination of analgesics and sedatives.
Nitrous oxide is an inorganic agent, administered by inhalation, colourless, odourless to sweet-smelling, and non-irritating to the tissues. It is an effective analgesic/anxiolytic/sedative agent causing central nervous system depression and euphoria with little effect on the respiratory system. Nitrous oxide has a rapid uptake, as it is being absorbed quickly from the alveoli, and is excreted quickly from the lungs. As nitrous oxide is 34 times more soluble than nitrogen in blood, diffusion hypoxia may occur.
Several guidelines include nitrous oxide in their lists of alternative sedation methods in children. A systematic review by Pedersen et al. summarize literature on nitrous oxide as a sedation method for minor paediatric procedures, suggesting it to be a safe and efficient sedation method which may ease the procedures.
Nitrous oxide has been considered safe for a patient who is exposed for a short time or only few times. However, adverse effects on health personnel is a greater concern. N2O is a suspected reproductive toxicants that may affect fertility, the rate of spontaneous abortion and congenital abnormalities. In addition, the risk of neurological effects and headache, fatigue and irritability, has limited the use of the gas in many settings. Also, damaging effects to DNA or to important metabolites in cellular or body function, as for example B12, has been studied with contradictory result.
Objective
The objective for the present report, is to systematically summarize published results on effectiveness using nitrous oxide in a paediatric setting for small, but painful hospital procedures. Safety issues for both the patients and health personnel exposed to nitrous oxide will also be reviewed.
Method
We performed a Health Technology Assessment on effectiveness and safety of nitrous oxide for sedation in children in accordance with the handbook "Slik oppsummerer vi forskning", by Norwegian Institute of Public Health.
We found literature from both hospital and dental settings. As our commissioner represents a hospital settings, we decided to narrow our report to only include efficiency assessment of literature covering a hospital setting. However, in the assessment of safety for health personnel, we included results also from dental setting.
Results
Literature search
We included 22 randomized controlled trials for the analyses of effect and safety of children. We also included 15 non-randomized controlled trials (19 articles) to document safety concerns of health personnel exposed to waste nitrous oxide. For the records only, we made a table of another 58 non-randomized controlled trials reporting results on safety of anaesthetic gases to health personnel, where nitrous oxide most likely is a part of the gas.
Effectiveness of nitrous oxide
We have shown that health personnel or patients had a higher satisfaction level, lower distress or anxiety, and higher success rate when N2O was used compared to the placebo group. However, when other sedatives were used, N2O showed no benefit. Further, the pain level was lower using N2O compared to midazolam and/or ketamine, but not to EMLA or placebo.
The certainty of evidence were from low to moderate, mostly due to lack of blinding and imprecision of the results.
Most evident results was the reduced recovery time using N2O over other active drugs, not surprisingly as N2O has a very rapid onset and offset time.
The certainty of evidence were high due to the pronounced differences in time and the objectivity in the outcome.
Safety of nitrous oxide
Fifteen studies (19 articles) reported data on adverse events. Of 525 patients sedated with N2O, independent of hospital procedure or control group, none of the adverse events reported met the U.S. Food and Drug Administration’s definition of a serious adverse events. In particular, none of the study participants experienced serious cardiac or respiratory events (including oxygen below saturation level). Nausea, vomiting, restlessness, and euphoria were the most common adverse events observed in the N2O group.
Health personnel exposed to waste N2O only, did not have an increased odds ratio for spontaneous abortion for none of the levels of N2O exposure (low exposure (OR=0.89; 95%CI=0.67, 1.19), high exposure (OR=1.18; 95%CI=0.84, 1.66) and unknown exposure (OR=1.30; 95%CI=0.43, 3.88)).
However, there were a dose dependent increase in the odds ratio for reduced fertility in N2O exposed health care personnel (low exposure: OR=0.79; 95%CI=0.48, 1.30; high exposure: OR=3.48; 95%CI=1.99, 6.08). Further, the adjusted rate of congenital abnormalities in children was higher in N2O exposed women than in the control group (5.5±0.95, N=579 vs 3.6±0.34, N=2882). The certainty of the effect estimate was very low for all results.
Sister chromatid exchange, micronuclei formation, DNA breaks and reactive oxygen species were methods to study the genotoxic effect of N2O exposure. The four included studies did not report evidence to reveal a potential genotoxic effect of N2O in the given settings (both dental offices and operating rooms). This was also true for the three included studies of neurological toxicity of N2O and for the four included studies of the effect of N2O on B12 metabolism.
Discussion
We included 19 randomized controlled trials in the analyses for effectiveness and safety for children. However, the studies used different effect estimates and the data were presented differently. It was not possible to obtain high certainty of evidence for the outcomes analysed due to poor presentation of data as well as wide confidence intervals. However, the findings support that N2O works similarly or better than existing sedation methods and that it also show an analgesic effect. Further, there were no serious adverse events reordered in any of the included studies.
Safety of health personnel exposed to N2O has for long time been a greater concern. Numerous studies have been performed on safety issues for health personnel in dental setting or working in operating theatres, analysing the effect of anaesthetic gases in general rather than N2O only. All studies on safety for health personnel included in this review are taken from either dental settings, operating theatres or maternity wards, suggesting an everyday, continuous exposure to N2O. The expected levels in a paediatric setting, as the background for this commission, using modern masks, effective scavenging and ventilation systems, and without an everyday exposure, will most probably be lower than in the studies showing adverse toxic effects. Although not documented, the time-weighted average (TWA) for the subjects experiencing the adverse effects were probably exposed to levels far above the Norwegian TWA threshold of 50 ppm. Further, none of the adverse effects are correlated to peak values, but rather to long term exposure at high levels.
Conclusion
The results show that nitrous oxide can be used for sedation of children without serious adverse events. The most noticeable advantage by using N2O is the short restitution compared to other sedation methods which shortens the whole procedure and may streamline hospital procedures in children.
The present technology assessment shows that midwives and dental personnel exposed to N2O compared to no exposure, did not increase the risk of spontaneous abortion or, at low exposure, reduced fertility. High exposure showed reduced fertility. The risk for congenital abnormalities born by exposed mothers (concentration or exposure degree not known) was higher than in non-exposed mothers. It is important to understand that these results are generated from data based on self-reporting questionnaires. Also, information about level of exposure were inadequate.
No sufficient evidence were shown to draw conclusions of the toxic effect of N2O on DNA or cellular mechanisms.
There were no studies on negative effects on reproductive health for health personnel in a setting where N2O were used for sedation of children for small hospital procedures. The personnel included in the present studies, were expected to have a more or less continuous exposure to N2O during their work hours. For personnel working with N2O sedation of children for small hospital procedures the exposure is expected to be significantly lower than the health care workers in the studies where toxic effects were reported, justified by two reasons. First, the concentration of N2O is expected to be lower because the access to better scavenging and ventilation systems; and second, the net exposure time would be lower as the procedure time (maximum 30 minutes per procedure) and the number for the hospital procedures per health worker per week would be relatively few (personal communication).
