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Three Part Question

In [children requiring lumbar puncture] is [nitrous oxide] effective at reducing the [level of pain and distress experienced]?

Clinical Scenario

Whilst working as a registrar in the paediatric emergency department a 9 year old boy presents with a headache, low grade fever, photophobia and neck stiffness. He requires a diagnostic lumbar puncture to look for meningitis. You wonder if nitrous oxide might be an effective method of reducing the pain and distress associated with this procedure.

Search Strategy

Medline 1950-July 2010 week 3 via the OVID interface.
EMBase 1980-July 2010 week 3 via the OVID interface.
[(lumbar puncture.mp OR exp. spinal puncture) AND (nitrous oxide.mp OR exp. nitrous oxide)] LIMIT to human and english language.

mp=title, original title, abstract, name of substance word, subject heading word, unique identifier

Search Outcome

Using MEDLINE 9 papers were identified of which 3 were relevant.
Using EMBase 45 papers were identified of which 11 were relevant. 6 were review articles and were excluded (3 papers were duplicates from the MEDLINE search).
The remaining 5 relevant papers are listed in the table below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kanagasundaram SA et al. 2000 Australia	90 children with medical, surgical or oncological conditions requiring repeated painful procedures (lumbar puncture, bone marrow aspirate, venous cannulation, or dressing changes). Patients given inhaled nitrous oxide at a variable concentration of 50-70%. Procedures performed in ward treatment rooms. 45 (50%) of children underwent lumbar puncture.	Poor quality prospective, cohort study with no control group. Level 4.	Observational Scale of Behavioural Distress-Revised (OSBD-R)	In the lumbar puncture group, highest distress scores were recorded in waiting period prior to procedure and positioning and skin cleaning. For all painful procedures together, nitrous oxide significantly more effective at reducing OSBD scores in older children > 6 years than younger children in both induction with nitrous oxide (p0.000), during the painful procedure (p=0.001) and immediately post procedure (p=0.000).	Relatively small sample size with no sample size estimate. No control group used so no baseline with which to compare behavioural distress scores. OSBD scores given for each procedure separately but not possible to determine the side-effects, level of sedation and recovery time specifically for the lumbar puncture group. Cognitive therapy including imagery, distraction and positive incentive also provided to some children. Parents may or may not have been present. No attempt made to adjust for these potential confounding variables. Children too young to be questioned regarding recollection of procedure not included in amnesia results. Author's conclusion that inhalation of nitrous oxide is effective in alleviating distress not justified in the absence of a control group with which to compare OSBD scores for an overall reduction with N20.
			Side-effects of vomiting, excitement, dysphoria or desaturation.	7.8% vomiting, 4.4% excitement, 2.0% dysphoria, 8.9% desaturation.
			Level of sedation	93.3% awake (conscious sedation), 5.6% drowsy, 1.1% asleep, rousable, 0% unrousable.
			Recovery time	3.08 (SD 1.37) mins
			Amnesia	Achieved in 65% (if old enough to be questioned).
Iannalfi A. et al 2005 Italy	31 children with cancer between 1 and 16 years, undergoing a total of 65 procedures (lumbar puncture and/or bone marrow aspirate) on a paediatric oncology ward over a 4 month period. Randomly assigned to receive either: 1. moderate sedation (MS) with premixed nitrous oxide (50%), oxygen (50%) AND/OR midazolam 0.05-0.1mg/kg iv or 2. general anaesthesia (GA) with nitrous oxide, 50% in O2 (50%), midazolam iv, fentanyl iv, ketamine iv, or sevoflurane 2-4% in O2. These agents were used either alone or in combination. EMLA universally applied to procedure site 90 minutes prior to procedure and 2% lidocaine carbonate instilled a few minutes prior to LP of BM needle insertion. 25 (38.5%) had LP, 26 (40.0%) had BMA and 14 (21.5%) had BMA + LP.	Prospective study with random allocation of patients to the two treatment arms. Level 2b.	Procedure Behaviour Check List (PBCL) administered by neutral observer.	No significant difference between MS and GA in terms of either anxiety or pain.	Very small sample size, no sample size estimate performed. Not fully blinded. Some children had more than one procedure. Results for each procedure type not considered separately. Results for each combination of sedation drugs used not considered separately so impossible to tell if one agent (or combination of agents) was more effective than another. Half of the patients in the moderate sedation group also received non-pharmacological techniques such as distraction/hypnosis, not fully adjusted for in the results.
			Perception evaluation questionnaire for child.	No significant difference between MS and GA groups.
			Perception evaluation questionnaire for parents.	No significant difference between MS and GA groups.
			Side effects: vomiting, coughing, late recovery or agitation.	No significant difference between MS and GA groups.
			Post-procedure recovery time.	Significantly shorter for MS group 43min (range 36-51min) than GA group 117min (range 97-137min). p<0.05.
			Number of inadequate sedations.	6.6% (2) with MS versus 0 in the GA group.
Brown SC et al. 2009 Canada	36 children aged 3-9 years requiring invasive procedures such as sutures, iv lines and lumbar punctures. Subjects randomised to receive either standard sedation or PediSedate®, which delivers 50% nitrous oxide in oxygen via a simple nosepiece, combined with an interactive video component to distract the child during drug delivery. Setting was suitably equipped treatment rooms in the emergency department. No patient underwent lumbar puncture in either group. Intravenous access and blood collection were the most frequent invasive procedures performed for subjects in both treatment groups.	Randomised clinical trial. Level 2b.	Observational Scale of Behavioural Distress (OBSD)	Mean OSBD score during procedure significantly lower for children who received PediSedate® (mean 1.8, SD 3.2) than for those who received standard care (mean 9.3, SD 5.6). P<0.0001.	Small study size with no sample size estimate. Not blinded. Various additional pain control methods such as topical local anaesthetic and comforting were used in both groups which may have introduced bias. No recognised validated scale was used to assess child acceptance or patient cooperation as assessed by nurses so measurements may not be reliable or reproducible. 18.2% (4/22) children withdrew from the PediSedate® arm as they refused to wear the helmet. Children could not refuse standard care, even if they stated that they wanted to stop treatment.
			Child acceptance.	Acceptance levels of PediSedate® significantly greater than for standard care. 72.2% vs 16.7%, p = 0.001.
			Cooperation-nurse rating.	Significantly more children were judged to be cooperative with PediSedate® than with standard care. 83.3% vs 5.6%. p = 0.000003.
			Child's self-report pain rating.	Significantly more children reported no or little pain with PediSedate® vs standard care. 83.3% vs 11.1%, p = 0.0001.
Annequin et al, 2000, France	1019 children aged 18 years or under receiving 50:50 Nitrous Oxide Oxygen mixture analgesia for a painful or invasive procedure. Procedures performed outside the operating theatre in 31 French centers over a 2-month period. The most commonly performed procedures were lumbar puncture 286 (28.1%), bone marrow aspiration 231 (22.7%) and laceration repair 215 (21.1%). A second drug was administered in 182 (17.9%) of procedures, most often midazolam (63%). EMLA cream was applied in 98.6% of lumbar punctures and 93.7% of bone marrow aspirations.	Prospective multicentre survey. Level 4.	Self-assessment of procedural pain by children 6 years or older (visual analog scale VAS 0 to 100).	Of 286 children undergoing LP, 194 were old enough to respond. Median VAS score 5 (interquartile [IQR] range 0-20). For all procedures, of 647 children able to respond, median VAS score 9 (IQR 0-30).	As survey participation was voluntary there may be selection bias; those centers with the best experience of using Nitrous Oxide may have been more likely to respond. Also, practitioners completing and returning the survey may be those most motivated to use this type of analgesia. No control group so no comparison can be made with procedures performed with no analgesia, or standard care. No comment can therefore be made on analgesia efficacy. Some missing data: not all patients had their procedural pain evaluated by nurses and even fewer had parental pain assessments performed. No recognized, validated scale used for behavioral and pain assessment so the measurements may not be entirely reliable or reproducible.
			Procedural pain evaluation by nurse and parents (0-10 numerical scale).	269 of 286 children undergoing LP had procedural pain assessed by nurses. Median pain assessment 0 (IQR 0-2). For all 1019 procedures, 975 had procedural pain assessed by nurses. Median pain assessment 1 (IQR 0-3). No separate LP figures quoted for parental evaluation.
			4-level team satisfaction regarding efficacy.	(975/1019 responses) 56.7% very satisfied, 31.3% satisfied, 8.6& not satisfied, and 3.3% very unsatisfied. Results for all procedures.
			Child agreement for future N2O administration.	93% of 647 children able to answer said they would accept N2O administration for future procedures
			Behavioural reactions	Seen to be age dependent (results for all procedures). Cry observed in 44.1% < 3years, 24.4% 4-6 years, 12.9% 7-10 years and 8.4% > 11years.
			Side effects	Minor side effects observed in 381 (37%) of all inhalations. Euphoria (20.1%, change in visual or auditory perception 7.0%, dreams 5.7%, nausea and vomiting 3.7%, deep sedation 2.1%. All side effects were transient and vanished within 5 minutes of removing the inhalation device. No serious side effects noted.
Zier J et al. 2010, USA	1858 administrations of N2O to 1585 patients younger than 18 years, requiring sedation for a painful or invasive procedure. Procedures performed at a single US centre, in various departments including emergency, radiology, haematology-oncology clinic and short-stay areas, over a 16-month period. Most administrations (91.3%) were N2O concentration >50%, all were administered via a dental nasal mask. Verbal distraction (e.g. storytelling and soothing discourse) was provided throughout the procedure. A small proportion of patients (<1%) received an additional potentially sedating medication such as midazolam prior to the administration of N2O. Lumbar punctures only accounted for 36 (1.9%) of the total procedures performed. The most commonly performed procedures were urinary catheterization (58.9%), intramuscular injection (9.4%) and vascular access (8.3%).	Retrospective chart review. Level 4.	Level of sedation score (Children’s Hospital of Wisconsin Sedation Scale) 6 = Inadequate, 5 = Minimal, 4 = Drowsy, 3 = Moderate-deep, 2 = Deep, 1= Deeper, 0 = anaesthesia.	Considering all procedures together (no separate LP data recorded): 1.3% scored 6 (anxious, agitated or in pain), 94.3% scored 5 (spontaneous awake without stimulus), 4.3% scored 4 (eyes open or closed, but easily arouses to consciousness with verbal stimulus). No patient reached a sedation score <4. No difference in number of patients reaching sedation level of 4 between those receiving N2O <50% and N2O >50% (p=0.234), duration of N2O administration (p=0.062) or median age of patient (p=0.639). 7.4% of younger patients <2years achieved a sedation level of 4 cf 4% > 2 years (p=0.044). Inadequately sedated patients (level 6) were significantly younger (median 3.2 years; range 0.8-16.8) than the remainder of the group (median 5.2 years; range 0.2-18.9) p=0.017.	No control group so no comparison can be made. Paediatric sedation scale used is unvalidated and can be subjective to administer. Very limited data available with respect to lumbar punctures alone. Actual sample size undergoing LP was very small (only 36 patients) and the only separately recorded outcome was successful completion, which gives no indication of the level of pain and distress experienced by the child. Significant proportion of missing completion outcomes for the LP group. No data on patient’s own level of distress or recall or acceptability of technique. Nasal hood delivery system is commonly used in dental practice, but results cannot be generalized to the full facemask system more commonly employed in hospital practice.
			Able to successfully complete procedure	For lumbar punctures alone: 29/36 (80.5%) successfully completed, 1/36 (2.8%) not able to be completed, 6/36 (16.7%) completion outcome unknown. Together with vascular access (79.2%) this was the lowest successful completion percentage of all conducted procedures (may be due to missing data). For all 1590 sedation events for which procedure completion data was available: 94.1% completed with the patient calm and still, 5.0% completed without the patient able to remain still or calm, 0.9% unable to be completed because of inadequate sedation or problems unrelated to sedation.
			Adverse effects	Data only available for 1762 N2O administrations. 3/155 patients (1.9%) in the < 50% N2O group and 56/1607 (3.5%) in the >50% N2O group experienced adverse events (p=0.343). The most common adverse events were vomiting and nausea, inadequate sedation and agitation.

Comment(s)

Nitrous oxide is an inhalational agent known for its sedative, anxiolytic, amnesiac and analgesic effects. It is technically classified as an anaesthetic agent, but due to its relatively weak potency in relation to other inhaled drugs, it is rarely used to provide general anaesthesia, except in combination with other agents. It has been extensively used over the past 50 years to provide analgesia in prehospital and hospital settings, as well as being a mainstay of current dental practice. More recently it has been used in the paediatric population in an attempt to reduce the pain and anxiety associated with painful or invasive procedures including venepuncture, lumbar puncture, bone marrow aspiration, fracture reduction, laceration repair and dressing changes.

At present there is very little literature specifically addressing the use of nitrous oxide for lumbar punctures in either paediatric or adult patients. Indeed, the search strategy employed here failed to identify any relevant adult studies. Of the 5 paediatric studies identified, none specifically looked at lumbar punctures in isolation, but considered N2O use for a variety of painful procedures including LP.

Only 2 studies (Kanagasundaram et al. and Annequin et al.) recorded pain and behavioral scores for LPs separately from other procedures, and these were both level 4 studies without control groups. Although both showed relatively low pain and distress scores associated with LP, in the absence of a comparable control group receiving standard therapy, it is impossible to comment upon the effectiveness of these interventions. Any conclusions drawn from the remaining 3 studies are merely extrapolations, as they do not relate to LPs alone. All 5 studies also only included very small sample sizes.

Of the two studies that involved an element of randomization, one (Brown et al.) did not include any patients undergoing LP, and hence the results must be discounted when considering the specific 3 part question. The other study (Iannalfi et al.) directly compared moderate sedation with 50:50 nitrous oxide:oxygen and/or midazolam against general anaesthesia and found them to be comparable at reducing both anxiety and pain. However, 80% (24/30) children receiving nitrous oxide also received iv midazolam as an additional sedative agent, so it is impossible to comment on the efficacy of nitrous oxide alone.

One study (Zier et al.) was primarily designed to look at the level of sedation associated with variable concentrations of nitrous oxide and did not specifically address either pain or anxiety as an outcome measure. Instead it primarily looked at whether the procedure could be successfully completed, and if additional physical restraint was required.

The three lowest quality (level 4 studies) all quoted age related results for painful procedures as a whole, although not specifically for LPs. Kanagasundaram et al. found that children less than 6 years had significantly higher levels of distress in the waiting period prior to the procedure/induction phases (p=0.000, p=0.000) as well as during the actual procedure (p=0.001) and immediately afterwards (p=0.000), in comparison with older children. Annequin et al. noted that nurse assessed pain scores were higher in children aged 3 years or younger than in those older than 3 years [median (range) 2(0-10) versus 1(0-10), p=<0.00001)]. Children younger than 3 were also much more likely to cry or need to be physically restrained. In the study by Zier et al., patients judged to be inadequately sedated were younger [median (range) 3.2(0.8-16.8) versus 5.2(0.2-18.9), p=0.017)].

Younger children are more likely to resist application of the facemask for nitrous oxide administration, leading to a greater need for physical restraint and higher distress scores. They are also less likely to respond to cognitive techniques such as distraction therapy. In addition, the minimum alveolar concentration of anaesthetic gases is known to be higher in this age group, giving a physiological reason for reduced efficacy (Mapleson W).

Four of the five studies recorded side effects experienced with nitrous oxide use. The quoted side effect incidence ranged from 1.9% with < 50%N2O (Zier et al) to 37% (Annequin et al). All of the side-effects were minor, most commonly vomiting/nausea (3 out of 4 studies), and euphoria. No serious adverse effects were reported. The mean recovery time post procedure (if recorded) ranged from 3 minutes with no premedication or additional sedative agent (Kanagasundaram et al.) to 43 mins (Iannalfi et al) when the majority of patients received nitrous oxide combined with intravenous midazolam. Short recovery times, minimal side effects and the ability to be administered by non-anaesthetists are commonly quoted reasons for the increasing popularity of nitrous oxide use in paediatric practice, particularly in the emergency department setting.

In order to reliably answer the 3-part question, further research is required, preferably in the form of randomized control trials evaluating the use of nitrous oxide alone against standard care in paediatric patients undergoing diagnostic lumbar puncture.

Clinical Bottom Line

Moderate sedation with nitrous oxide (when used in combination with midazolam) is as effective as general anaesthesia at reducing the level of pain and anxiety associated with lumbar puncture in children [grade C].

Nitrous oxide is significantly more effective in older than younger children at reducing the level of pain (children > 6 years), and distress (children > 3 years), associated with lumbar puncture [grade C].

References

1. Kanagasundaram SA, Lane LJ, Cavalletto, BP, Keneally JP and Cooper MG. Efficacy and safety of nitrous oxide in alleviating pain and anxiety during painful procedures. Arch Dis Child 2001;84:492-495.
2. Iannalfi A, Bernini G, Caprilli S, Lipi A, Tucci F and Messeri A. Painful Procedures in Children with Cancer: Comparison of Moderate Sedation and General Anaesthesia for Lumbar Puncture and Bone Marrow Aspiration. Pediatr Blood Cancer 2005;45:933-938.
3. Brown SC, Hart G, Chastain DP, Schneeweiss S and McGrath PA. Reducing distress for children during invasive procedures: randomised clinical trial of effectiveness of the PediSedate® Pediatric Anesthesia 2009;9:725-731.
4. Annequin D, Carbajal R, Chauvin P, Gall O, Tourniaire B and Murat I. Fixed 50% nitrous oxygen mixture for painful procedures: a French survey. Pediatrics 105(4):E47,2000.
5. Mapleson WW. Effect of age on MAC in humans: a meta-analysis. Br J Anaesth. 1996;76:179-185.
6. Zier JL, Tarrago R and Liu M. Level of sedation with nitrous oxide for pediatric medical procedures. Anesth Analg 110(5):1399-405, 2010.