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QUESTION 3
V Palanivel and M A Anjay Arch. Dis. Child. 2009;94;324-326 doi:10.1136/adc.2008.154450

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Archimedes
The benefits to the family of early identification (in terms of genetic counselling) may be marked in a condition such as fragile X where the clinical signs may only become apparent when the child is older. Up to 80% of children with fragile X have mild to severe learning difficulties. However, parents and educators should be aware from an early age that many children with fragile X achieve above the level that would have been predicted from measured IQ.9 Veronica B Kelly, Mary Sheridan Centre for Child Health, 5 Dugard Way off Renfrew Road, Kennington, London SE11 4TH, UK; vbkelly@ gmail.com A Salt, Great Ormond Street Hospital NHS Trust/ UCL Institute of Child Health, London, UK
Competing interests: None. Arch Dis Child 2009;94:323324. doi:10.1136/adc.2008.154443

consultant suggests that the child should be commenced on nasal continuous positive airway pressure (nCPAP). You wonder whether nCPAP in an infant with bronchiolitis would improve his clinical status and/or avoid intubation?

STRUCTURED CLINICAL QUESTION

In infants with worsening bronchiolitis [patient], does nasal continuous positive airway pressure [intervention], compared with the standard management of oxygen and supportive care [comparison], improve clinical status and/or avoid mechanical ventilation [outcome]?

SEARCH STRATEGY AND OUTCOME Primary sources

MEDLINE (1966 to date) and OLDMEDLINE (19501965) were searched via the PubMed interface on 25 July 2008. Bronchiolitis [MeSH] AND Continuous Positive Airway Pressure [MeSH] with no limits produced seven results. Searching again using free text words Bronchiolitis AND Continuous Positive Airway Pressure instead of MeSH keywords yielded 17 more results. These 24 studies were analysed. Fifteen were irrelevant to the question being discussed. Among the remaining nine, one article was in French, two were confounded by the concurrent use of heliox and one was purely anecdotal without any clearly defined outcomes. After excluding these papers, five were selected for final analysis.15 See table 3.

REFERENCES
1. Fombonne E, Du Mazaubrun C, Cans C, et al Autism and associated medical disorders in a French epidemiological survey. J Am Acad Child Adolesc Psychiatry 1997;36:15619. Kielinen M, Rantala H, Timonen E, et al. Associated medical disorders and disabilities in children with autistic disorder: a population-based study. Autism 2004;8:4960. Baird G, Simonoff E, Pickles A, et al. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 2006;368:21015. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004;113:e47286. Song FJ, Barton P, Sleightholme V, et al. Screening for fragile X syndrome: a literature review and modelling study. Health Technol Assess 2003;7(16). Hatton D, Sideris J, Skinner M, et al. Autistic behaviour in children with fragile X syndrome: prevalence, stability, and the impact of FMRP. Am J Med Gen A 2006;140A:180413. Cohen D, Prichard N, Tordjman S, et al. Specific genetic disorders and autism: clinical contribution towards their identification. J Autism Dev Disord 2005;35:10316. Fisch G. Is autism associated with the fragile X syndrome? Am J Med Gen 1992;43:4755. Feinstein C, Reiss A. Autism: the point of view from fragile X studies. J Autism Dev Disord 1998;28:393405. FitzPatrick DR, Pearson P, Halpin S, et al. A school based study of children with learning disability indicates poor levels of genetic investigation. J Med Genet 2002;39:e19.

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4. 5. 6.

Secondary sources
Cochrane Library, Best Evidence, Clinical Evidence: no relevant articles found.

7. 8. 9. 10.

COMMENTARY
Bronchiolitis is a common reason for admission to paediatric wards in the winter months and carries significant morbidity. Conventional management involves nursing care, oxygen and nasogastric feeds or intravenous fluids as necessary. In severe cases not responding to standard management, mechanical ventilation is the time

QUESTION 3
IS CONTINUOUS POSITIVE AIRWAY PRESSURE EFFECTIVE IN BRONCHIOLITIS? A 3-month-old boy is admitted to the paediatric ward with bronchiolitis. He is initially managed with oxygen, nursing care and intravenous fluids. However, his respiratory distress worsens a few hours after admission. The senior house officer measures a capillary blood gas which shows a PCO2 of 8.7 kPa. You, the on-call registrar, review the patient and discuss the situation with the consultant. The
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Clinical bottom line

c

There is no evidence that the use of nasal continuous positive airway pressure (nCPAP) in bronchiolitis can avoid mechanical ventilation. Weak evidence suggests that early use of nCPAP in moderate to severe bronchiolitis might lead to limited improvement in cardiorespiratory and ventilatory parameters. (Grade C)

honoured intervention. Many centres have tried nCPAP as a less invasive alternative to ventilation. However, evidence for the efficacy of this practice has not been comprehensively evaluated so far. The Scottish Intercollegiate Guidance Network guidelines for bronchiolitis in children did not identify any studies which provide evidence regarding the location and timing of ventilatory support (CPAP and negative pressure ventilation).6 CPAP was originally introduced for the treatment of respiratory distress syndrome in neonates by Gregory et al in 19717 and has since been extensively used for this as well as other indications. Beasley et al published their pioneering work demonstrating some utility in infants with bronchiolitis 10 years later.4 In subsequent years other researchers have tried to establish the same in various ways. An ideal study investigating this clinical question would be a randomised controlled trial with clearly defined outcomes including changes in ventilation parameters and avoidance of mechanical ventilation. The only randomised controlled trial on this subject was published recently by Thia et al.1 It showed that early use of CPAP improved clinical parameters and PCO2. However, the study had multiple methodological problems such as the use of a crossover design and the choice of a questionable surrogate endpoint (a 1 kPa decrease in PCO2). Extraction of the relevant data prior to crossover showed a mean drop in PCO2 of 1.35 in the CPAP group as compared to 0.53 in the standard treatment group. The clinical significance of this is not clear. A recent study by Cambonie et al not only demonstrated improvement in cardiorespiratory parameters and respiratory distress but also showed an objective improvement in several physiological parameters which measured respiratory effort.2 The majority of the other studies were observational and demonstrated some benefit in improving ventilation and several clinical parameters. However, these studies were severely hindered by very small sample sizes, the absence of control groups and lack of uniformity in inclusion criteria as well as poorly defined and measured outcomes. The nature of the intervention precluded blinding. The modality of CPAP varied between studies, with some using a bubble CPAP machine. The use of CPAP in neonates has been associated with adverse effects such as nasal trauma, gaseous distension and, rarely, air leak syndromes. No study has reported such adverse effects following its use in bronchiolitis, which might be a
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Archimedes
Table 3 Is continuous positive airway pressure effective in bronchiolitis?
Citation Thia et al, 2008 (UK)1 Study group 53 infants with bronchiolitis and PCO2 .6 kPa were recruited. 31 patients were included and randomised into two groups. 29 completed the study. Group 1: ST first 12 h, CPAP next 12 h Group 2: CPAP first 12 h, ST next 12 h 12 infants less than 3 months of age admitted to PICU with RSV bronchiolitis and severe respiratory distress, defined as PCO2 .50 mm Hg and mWCAS .5. Study type (level of evidence) Randomised controlled trial with crossover design (level 2b) Outcome Primary outcome: change in PCO2 at 12 and 24 h Secondary outcomes: change in capillary pH, respiratory rate, pulse rate and the need for invasive ventilatory support Key results Change in PCO2 (in kPa) for 012 and 1224 h, respectively group 1: 20.53, 20.41 group 2: 21.35, 0.5 Change after CPAP minus change after ST: group 1: 0.12 group 2: 21.85 (p,0.01) Comments Only randomised study to date Reasonable sample size Demonstrates reduction of PCO2 if CPAP initiated early Not fully blinded Crossover design questionable as all patients received CPAP. Washout effect impossible to exclude. Clinical severity of bronchiolitis not objectively assessed. 1 kPa change in PCO2 not powerful enough to demonstrate benefit. Specific outcomes discussed First study to demonstrate objective improvement in breathing pattern and decrease in respiratory effort Study hindered by small sample size and lack of controls

Cambonie et al, 2008 (France)2

Prospective case series (level 4)

Change in (a) respiratory distress (as measured by mWCAS, FiO2, pH, PCO2, HR, MABP) and (b) respiratory effort (Ti, Ti/Ttot, Pes swings, PTPesinsp/breath and PTPesinsp/min)

Soong et al, 1993 (Taiwan)3

10 infants admitted to PICU with impending respiratory failure from severe bronchiolitis

Prospective observational study (level 4)

Change in FiO2, PaO2/ FiO2 ratio, pH, PCO2, RR and HR 2 h after starting CPAP

Beasley et al, 1981 (UK)4

23 infants with bronchiolitis

Retrospective case series (level 4)

Change in PCO2, HR, respiratory rate

Cahill et al, 1983 (Ireland)5

7 infants admitted to ICU in a childrens hospital with bronchiolitis

Prospective case series (level 4)

Clinical improvement, change in PaO2 and PCO2

(a) Improvement in parameters indicating respiratory distress mean values before and after 1 h and 6 h CPAP for each outcome: m-WCAS 5.3 vs 3.1 vs 2.9 (p,0.05) FiO2 45 vs 27 vs 30 (p,0.05) pH 7.29 vs 7.35 vs 7.35 (NS) PCO2 64 vs 54 vs 49 (p,0.01) HR 159 vs 144 vs 142 (p,0.05) MABP 73 vs 56 vs 59 (p,0.05) (b) Significant improvement in parameters demonstrating respiratory effort (Ti, Ti/Ttot, Pes swings, PTPesinsp/breath and PTPesinsp/min) after 1 h of CPAP and did not change further after 6 h Mean values before and after CPAP for each outcome: FiO2 34.8 vs 34.5 (NS) RR 71 vs 54/min (p,0.01) HR 178 vs 153/min (p,0.01) pH 7.33 vs 7.37 (p,0.05) PCO2 48 vs 42.4 mm Hg (p,0.01) PaO2/FiO2 ratio 155 vs 175 (p,0.01) 14 managed with nCPAP alone. Data available for a total of 20 infants. Mean fall in PCO2 7.85 to 6.30 kPa (p,0.01) Mean HR dropped from 163 to 140/min (p,0.01). Mean RR fell from 69 to 53/ min (p,0.01). Clinical improvement noticed in 5 infants, Fluctuating PaO2 and PCO2 levels, but overall trend towards normal. 2 infants deteriorated but only 1 was intubated.

Very clearly defined outcomes Significant improvement in almost all clinical and laboratory parameters None required intubation Validity of conclusions limited by small sample size and lack of any randomisation or controls

Small sample size, no controls Greatest fall in PCO2 is noted in babies with PCO2 .8 kPa

Extremely small case series with poorly defined outcomes Used nasopharyngeal instead of nasal CPAP

CPAP, continuous positive airway pressure; HR, heart rate; ICU, intensive care unit; MABP, mean arterial blood pressure; m-WCAS, modified Woods Clinical Asthma Score; nCPAP, nasal continuous positive airway pressure; NS, not significant; Pes, oesophageal pressure; PICU, paediatric intensive care unit; PTPesinsp, inspiratory muscle pressure-time product; RR, respiratory rate; RSV, respiratory syncytial virus; ST, standard treatment; Ti, inspiratory time; Ttot, total respiratory cycle time.

reflection of the small sample sizes or could indicate possible publication bias. Various biological explanations for the mechanism of action of CPAP in bronchiolitis have been proposed. These include a pneumatic splinting effect expanding the
Arch Dis Child April 2009 Vol 94 No 4

airway diameter, improving airflow during exhalation in obstructive disease and decreasing the work of breathing in several ways.3 All the published studies have shown some evidence, although weak, demonstrating possible benefit for the use CPAP

in bronchiolitis. Anecdotally, it is being increasingly used in many centres throughout the world. Further well designed randomised multi-centre trials are required to provide more supporting information quantifying its utility. These
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Archimedes
studies should be large enough to demonstrate the effect of CPAP on clinically relevant outcomes such as the avoidance of mechanical ventilation and the duration of hospital stay as well as adverse events. In the meantime, clinicians managing a case of worsening bronchiolitis will have to make an individualised decision as to whether a judicious trial of CPAP is justified. M A Anjay, James Paget University Hospitals NHS Foundation Trust, Gorleston, Great Yarmouth, UK
Competing interests: None. Arch Dis Child 2009;94:324326. doi:10.1136/adc.2008.154450
severe acute viral bronchiolitis. Intensive Care Med 2008;34:186572. Soong WJ, Hwang B, Tang RB. Continuous positive airway pressure by nasal prongs in bronchiolitis. Pediatr Pulmonol 1993;16:1636. Beasley JM, Jones SEF. Continuous positive airway pressure in bronchiolitis. BMJ 1981;283:15069. Cahill J, Moore KP, Wren WS. Nasopharyngeal continuous positive airway pressure in the management of bronchiolitis. Ir Med J 1983;76:1912. Scottish Intercollegiate Guidelines Network (SIGN). Bronchiolitis in children. A national clinical guideline. SIGN publication no. 91. Edinburgh: SIGN, 2006. Gregory GA, Kitterman JA, Phibbs RH, et al. Treatment of the idiopathic respiratory distress syndrome with continuous positive airway pressure. N Engl J Med 1971;284:133340.

3. 4. 5. 6.

REFERENCES
1. Thia LP, McKenzie SA, Blyth TP, et al. Randomised controlled trial of nasal continuous positive airways pressure (CPAP) in bronchiolitis. Arch Dis Child 2008;93:457. Cambonie G, Mile si C, Jaber S, et al. Nasal continuous positive airway pressure decreases respiratory muscles overload in young infants with

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V Palanivel, Addenbrookes Hospital, Cambridge, CB2 0QQ, UK; vpalanivel@gmail.com

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