Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity

Lemyre B, Davis PG, De Paoli AG

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs

Cover sheet

Title

Reviewers

Lemyre B, Davis PG, De Paoli AG

Dates

Date edited: 24/08/2004
Date of last substantive update: 23/10/2001
Date of last minor update: 18/06/2004
Date next stage expected / /
Protocol first published: Issue 4, 1999
Review first published: Issue 3, 2000

Contact reviewer

Brigitte Lemyre
Division of Neonatology
Children's Hospital of Eastern Ontario
401 Smyth Road
Ottawa
Ontario CANADA
KlH 8L1
Telephone 1: 1 613 737 2415
Facsimile: 1 613 738 4847
E-mail: blemyre@ottawahospital.on.ca

Contribution of reviewers

Internal sources of support

Royal Women's Hospital, Melbourne, AUSTRALIA
McMaster University, Hamilton, CANADA

External sources of support

None

What's new

This review updates the existing review of "Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity" which was published in The Cochrane Library, Issue 3, 2003 (Lemyre 2003)

No substantive change in the review update was made in June 2004 as no new trials were identified after a thorough literature search.

Dates

Date review re-formatted: / /
Date new studies sought but none found: 18/06/2004
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Nasal intermittent positive pressure ventilation (NIPPV) is a potentially beneficial treatment for apnea in premature babies, but more research is needed to confirm effectiveness and safety.

Recurrent spells of apnea (pause in breathing greater than 20 seconds) are almost universal in babies born before 34 weeks gestation. Nasal continuous positive airway pressure (NCPAP), delivered via small prongs inserted in the baby's nose, offers breathing support and is a useful treatment for apnea, but not all babies respond. Some infants fail and require a breathing tube inserted into their trachea (windpipe), which has potential complications (infection, injuries to the vocal cords). This review of two small trials suggests that nasal intermittent positive pressure ventilation (NIPPV), also delivered via nasal prongs, may be more effective than NCPAP alone in preterm babies whose apneas are frequent or severe. Further research is needed to confirm effectiveness and safety, as few babies have been studied so far.

Abstract

Background

Apnea of prematurity is almost universal in infants who are born before 34 weeks gestation. Previous randomised trials and systematic reviews have found methylxanthines to be effective in preventing apnea of prematurity. However, recent concerns about potential long term side effects of methylxanthines on the neurodevelopment of low birth weight infants have led to an increased interest in alternate methods of treating apnea of prematurity. Nasal continuous positive airway pressure (NCPAP) is a useful method of respiratory support which reduces the incidence of obstructive or mixed apnea. However, apneic infants managed with NCPAP, with or without methylxanthines, sometimes require endotracheal intubation with its attendant morbidity and cost. Nasal intermittent positive pressure ventilation (NIPPV) is a simple, effective mode of respiratory support for older children and adults. It has been used to treat apnea in preterm infants but case reports of gastrointestinal perforations have limited its widespread use.

Objectives

In preterm infants with recurrent apnea, does treatment with NIPPV lead to a greater reduction in apnea and need for intubation and mechanical ventilation, as compared with treatment with NCPAP? Does NIPPV increase the incidence of gastrointestinal complications, i.e. gastric distension leading to cessation of feeds, or perforation?

Search strategy

MEDLINE was searched (1966-week 2, June 2004). Other sources included the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004) and CINAHL (1982-week 2, June 2004). Also used were expert informants, previous reviews including cross-references, and conference and symposia proceedings.

Selection criteria

All randomised and quasi-randomised trials were included.
Participants included unventilated preterm infants experiencing apnea of prematurity.
Interventions compared were intermittent positive pressure ventilation administered via the nasal route, either by short nasal prongs or nasopharyngeal tube, and nasal CPAP delivered by the same methods.

Types of outcome measures:
- failure of therapy as defined by apnea that is frequent or severe requiring additional ventilatory support
- rates of endotracheal intubation
- rates of apnea and bradycardia expressed as events per hour
- gastrointestinal complications i.e. abdominal distension requiring cessation of feeds, or GI perforation

Data collection & analysis

Data were extracted independently by the three reviewers. The trials were analysed using relative risk (RR), risk difference (RD) and number needed to treat (NNT) for dichotomous data; means and weighted mean difference (WMD) were used for continuous data.

Main results

Two trials, enrolling 54 infants in total, fulfilled the inclusion criteria. Both reported only the short term results (4 to 6 hours) of the interventions. Only one infant (randomised to NCPAP) required intubation during this period. Ryan (1989), in a cross over study of 20 infants, showed no significant difference in rates of apnea (events/hr) between the 2 interventions {WMD -0.10 (-0.53,0.33)}. Lin (1998) randomised 34 infants and demonstrated a greater reduction in frequency of apneas (events/hr) with NIPPV compared to NCPAP { WMD -1.19 (-2.31,-0.07)}. Meta-analysis of both trials showed no difference in pCO2 (mmHg) at the end of the 4-6 hour study period {WMD 0.95 (-3.05,4.94)}. No data were reported on gastrointestinal complications.

Reviewers' conclusions

Implications for practice: NIPPV may be a useful method of augmenting the beneficial effects of NCPAP in preterm infants with apnea that is frequent or severe. Its use appears to reduce the frequency of apneas more effectively than NCPAP. Additional safety and efficacy data are required before recommending NIPPV as standard therapy for apnea.

Implications for research: Future trials with sufficient power should assess the efficacy (reduction in failure of therapy) and safety (GI complications) of NIPPV. Outcomes should be assessed throughout the entire period during which the infant requires assisted ventilation. The recent ability to synchronise NIPPV with an infant's spontaneous respirations is a promising development requiring further assessment.

Background

The majority of preterm infants born before 34 weeks gestation experience apnea of prematurity in the first 10 days of life (Barrington 1991). Apnea in infants has been defined as a pause in breathing of greater than 20 seconds or an apneic event less than 20 seconds associated with bradycardia and/or cyanosis (Nelson 1978). Apnea may be classified as obstructive (10-20%), central (10-55%) or mixed (33-71%) (Miller 1985, Ruggins 1991). Methylxanthines are effective in treating apnea of prematurity (Henderson-Smart 1999). Recent concerns about potential long term neurological morbidity associated with use of methylxanthines in preterm infants (Schmidt 1999) have renewed interest in other modalities of treatment for apnea of prematurity. NCPAP has been reported to be an effective treatment for apneas of obstructive and mixed types (small non-randomised studies), presumably by improving airway patency (Andréasson 1988, Miller 1985), but no systematic review comparing NCPAP to no treatment for apnea of prematurity could be found. Some infants treated with both methylxanthines and NCPAP continue to experience troublesome apnea. NIPPV is a potentially useful therapy for such infants.

Adults and older children with acute or chronic ventilatory failure of various etiologies, including chronic obstructive pulmonary disease (Bott 1993), severe kyphoscoliosis (Ellis 1988) and pre-lung transplantation cystic fibrosis (Piper 1992) have been treated with intermittent positive pressure ventilation delivered via a nasal interface. Improvements in hypoventilation and oxygen saturation levels have been described.

Miller 1985 reported a case series of 10 very small newborn infants with intractable apnea of prematurity who were treated with IPPV administered via nasal prongs. A survival rate of 50% was found, but there was no comparison with a control group. A more recent case series reported that 5 of 7 infants failing NCPAP because of intractable apnea were managed without intubation and mechanical ventilation using nasal IPPV, with only minor side effects (Derleth 1992). NIPPV in various forms was reported to be used by 53% of Canadian tertiary care nurseries in the mid 1980s (Ryan 1989). NIPPV has been shown to reduce asynchronous thoracoabdominal motion perhaps as a result of reducing tube resistance and/or better stabilisation of the chest wall (Kiciman 1998). The technique has not been without problems in neonates. Garland 1985 reported an association between the use of ventilation via nasal prongs and increased risk of gastrointestinal perforation.

Until recently, NIPPV was not synchronized with the infant's breathing. It is possible that gastrointestinal side-effects might be reduced if ventilator breaths were delivered in synchrony with laryngeal opening.

Objectives

Two primary objectives were identified:

1. In preterm infants with recurrent apnea, does treatment with NIPPV reduce the rate of failure of therapy (frequent or severe apneas requiring additional ventilatory support or use of endotracheal intubation) as compared with treatment with NCPAP?
2. Does NIPPV lead to more GI complications i.e. gastric distension requiring cessation of feeds, or GI perforation, as compared to NCPAP?

Subgroup analyses were planned on the basis of:
- method of NIPPV delivery (nasal prongs or nasopharyngeal tube)
- methylxanthine usage
- characteristics of participants: birth weight and corrected age at time of intervention, eg with cut-offs at 1000g and 28 weeks

Criteria for considering studies for this review

Types of studies

All randomised and quasi-randomised trials were included

Types of participants

Unventilated preterm infants (ie those born before 37 completed weeks gestation) experiencing apnea of prematurity

Types of interventions

Intermittent positive pressure ventilation administered via the nasal route, either by short nasal prongs or nasopharyngeal tube, vs nasal CPAP delivered by the same method

Types of outcome measures

Primary outcome measures:
1. Failure of therapy: defined as apnea that is sufficiently frequent or severe as to require additional ventilatory support (including NIPPV for infants failing NCPAP)
2. Endotracheal intubation
3. Rate of gastrointestinal complications:
a) abdominal distension requiring cessation of feeds
b) GI perforation diagnosed radiologically or at operation

Secondary outcome measures:
1. a) Rates of apnea and bradycardia expressed as events per hour
b) Differences in rates of apnea (before-after treatment) expressed as events per hour
- this outcome was identified after examining the available trials
2. C02 levels (mm Hg) after 4 to 6h of treatment - this outcome was identified after examining the available trials

Search strategy for identification of studies

Cochrane Neonatal Review Group search strategy.
An updated search was performed on June 18, 2004.
MEDLINE was searched (1966-week 2, June 2004) using the MeSH terms: infant, newborn (exp) and positive-pressure respiration (exp). Other sources including the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), CINAHL (1982-week 2, June 2004) (search terms: infant, newborn and intermittent positive pressure ventilation), expert informants, previous reviews including cross-references and conference and symposia proceedings were used.

Methods of the review

Criteria and methods used to assess the methodological quality of the trials: standard method of the Cochrane Collaboration and its Neonatal Group were used.

The three reviewers independently assessed the quality of studies using the following criteria: blinding of randomisation, blinding of intervention, completeness of followup and blinding of outcome measurement. Data were extracted independently by the 3 reviewers, then compared and differences resolved. Categorical data (proportion requiring intubation) were analysed using relative risk, risk difference and number needed to treat. Continuous data (frequency of apneas, C02 levels) were analysed using means and weighted mean difference. Additional information was sought from the authors: Lin 1998 generously provided individual patient data from which it was possible to calculate differences in apnea rates, i.e. rate before intervention minus that after intervention. The mean and standard deviation of the difference in apnea rate was then calculated. The fixed effects model was used. The crossover trial of Ryan (Ryan 1989) was handled in accordance with the methods of the Cochrane Neonatal Review Group - ie the effect and variance estimators from analysis of both periods combined were used.

Subgroup analyses were planned, using the same methods, to determine whether responses differed according to methods of NIPPV delivery and whether or not methylxanthines were used concurrently. Subgroup analyses based on characteristics of participants were planned: birth weight (eg infants < 1000g) and corrected age at time of intervention (eg infants < 28 weeks).

Description of studies

Two trials meeting the inclusion criteria of the review were identified - Lin 1998 and Ryan 1989.
Lin 1998 performed a randomised controlled trial which enrolled 34 premature infants (25-32 weeks) experiencing > 2 apneas per hour for 4 hours. All had received aminophylline. 18 were randomised to NIPPV (non-synchronised) and 16 to NCPAP, both delivered via Hudson prongs. Ryan 1989 performed a randomised 2-period crossover study, which enrolled 20 infants < 32 weeks gestation, treated for apnea with NCPAP and aminophylline. They were considered stable. Infants were randomly assigned to either NIPPV (non-synchronised) or NCPAP for 6h, both delivered either via nasal prongs or nasopharyngeal tubes (not specified for individual infants). Infants then crossed over to the alternate therapy for a further 6 hours.

Methodological quality of included studies

Methodological quality was assessed using the criteria of the Neonatal Cochrane Review Group.

Blinding of randomisation: The two studies met this criterion.

Blinding of intervention: This was not attempted by either study.

Complete follow-up: Achieved in both trials.

Blinding of outcome measurement: This was attempted only by Lin 1998. In this study, the primary outcomes, rates of apnea and bradycardia, were determined from printouts of cardiorespiratory traces assessed by observers blinded to treatment allocation.

Results

The two trials identified examined the short term (4-6 hours) effects of NCPAP and NIPPV in treating apnea of prematurity. No attempt was made to assess longer term effects such as endotracheal intubation beyond the trial period, or gastrointestinal complications.

1. Failure of therapy: need for additional ventilatory support during the 4 to 6 hour period of the study
No infants were "rescued" by the alternative mode of treatment, ie any infant requiring additional support received endotracheal intubation. Both trials (n=74 observations) reported this outcome, but only 1 infant (randomised to NCPAP) needed intubation {RR 0.30 (0.01, 6.84), RD -0.029 (-0.120, 0.062)}.

2. Rates of apnea (events/hour):
Ryan (1989) (40 observations) reported no significant decrease in rate of apnea with NIPPV as compared to NCPAP: WMD -0.10 (-0.53, 0.33).

3. Change in rates of apnea (events/hour):
Lin (1998)(n=34) showed a statistically significantly greater reduction in the rate of apnea in the NIPPV group: WMD -1.19 (-2.31, -0.07).

4. pC02 (mmHg) at 4 to 6h:
The final pCO2 value reported in each trial was used, at 4 hours for Lin and 6 hours for Ryan. The meta-analysis showed no significant difference in pCO2 values {WMD 0.95 (-3.05, 4.94)}.
Planned subgroup analyses could not be performed. Both trials used NIPPV that was not synchronised and both used aminophylline in all patients. Ryan (1989) used both nasal prongs and nasopharyngeal tubes but did not report results based on mode of CPAP delivery. Lin's patients were all treated with Hudson prongs.

Discussion

The two trials identified in this review enrolled small numbers of infants but had no major methodological limitations. Because of the nature of the interventions, it has been impossible to blind caregivers and the possibility exists that bias could have arisen through uneven use of cointerventions. Potential confounders such as methylxanthine usage have been dealt with in both trials as all infants were loaded with aminophylline prior to the intervention.

NIPPV is a potentially useful way of augmenting NCPAP. The relatively recent ability to synchronise ventilator breaths with the infant's own respiratory cycle has led to renewed interest in this mode of ventilatory support. For many reasons including trauma to the airway, barotrauma and infection, it appears desirable to minimise the usage and duration of endotracheal intubation of preterm infants and the results of this review suggest that NIPPV may assist in achieving this aim.

The question of whether NIPPV should be used for infants experiencing troublesome apnea has considerable overlap with that relating to postextubation care, given that one of the most common causes of extubation failure is recurrent apnea. Recent RCTs (Barrington 1999, Friedlich 1999) have shown that NIPPV is superior to CPAP in preventing extubation failure without major side effects (GI perforation or significant feeding intolerance leading to cessation of feeds).

Reviewers' conclusions

Implications for practice

NIPPV may be a useful method of augmenting the beneficial effects of NCPAP in preterm infants with apnea that is frequent or severe. Its use appears to reduce the frequency of apneas more effectively than NCPAP. Additional safety and efficacy data are required before recommending NIPPV as standard therapy for apnea.

Implications for research

A systematic review of NCPAP compared to no treatment for apnea of prematurity is needed.
Randomised trials of NCPAP vs NIPPV with larger numbers of infants, observed over their entire hospital course, are necessary to answer questions of both efficacy and safety. Outcomes including total days of assisted ventilation, rates of endotracheal intubation and rates of gastrointestinal complications should be assessed. The effect of synchronising NIPPV and the use of different devices for delivery warrant further investigation.

Acknowledgements

The authors acknowledge the extra information provided by Dr Lin and thank Prof David Henderson-Smart for his help in the preparation of this review.

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Lin 1998	Blinding of randomisation: Yes - sealed envelope Blinding of intervention: no Complete followup: Yes Blinding of outcome assessment: No	Included: premature infants not receiving ventilatory support, having > 2 apneas per hour over preceding 4 hours and failing to respond to tactile stimulation and oxygen supplementation and aminophylline. Excluded: infants with apnea related to IVH, sepsis, electrolyte imbalance of congenital anomalies.	Experimental group (n=18): non-synchronised, NIPPV with PIP of 12-20 delivered via nasal prongs. Control group (n=16): 4-5 cm H20 CPAP via Hudson prongs. Both groups had orogastric tube in situ and were not fed during the study. Infants were kept in the supine position and the mandible held with a strap to prevent air leakage.	Primary outcome: frequencies of apneic and bradycardic episodes before and after the intervention. Printouts of cardiorespiratory monitoring were reviewed by a blinded observer. Secondary outcomes: blood gas analyses before and after intervention.		A
Ryan 1989	Blinding of randomisation: Yes - computer generated randomisation schedule. Blinding of intervention: No Complete followup: Yes Blind outcome assessment: Yes for bradycardia and apnea.	Included: Stable infants < 32 weeks being treated with nasal CPAP for apnea of prematurity and receiving aminophylline. Excluded: infants with known causes of apnea.	20 infants enrolled in the trial: 10 randomized to NIPPV (not synchronised) with PIP of 20, PEEP of 4 and rate of 20 delivered by nasal prongs or nasopharyngeal tubes; 10 randomised to NCPAP of 4. Each group crossed over to the other treatment after 6 hours.	Primary outcomes: rates of apnea (>15 sec with fall in transcutaneous p02 of >5 mm Hg and/or drop in heart rate of > 20%) and bradycardia (>20% drop in baseline geart rate). Both expressed as events per hour. Secondary: arterial blood gases taken at 0, 2 and 6 hours of each treatment.	Crossover study: randomised, 2-period crossover	A

References to studies

References to included studies

Lin 1998 {published data only}

Lin CH, Wang ST, Lin YJ, Yeh TF. Efficacy of nasal intermittent positive pressure ventilation in treating apnea of prematurity. Pediatric Pulmonology 1998;26:349-53.

Ryan 1989 {published data only}

Ryan CA, Finer NN, Peters KL. Nasal intermittent positive-pressure ventilation offers no advantages over nasal continuous positive airway pressure in apnea of prematurity. American Journal of Diseases of Children 1989;143:1196-8.

* indicates the primary reference for the study

Other references

Additional references

Andréasson 1988

Andréasson B, Lindroth M, Svenningsen NW, Jonson B.. Effects on respiration of CPAP immediately after extubation in the very preterm infant. Pediatric Pulmonology 1988;4:213-8.

Barrington 1991

Barrington KJ, Finer NN. The natural history of the appearance of apnea of prematurity. Pediatric Research 1991;29:372-5.

Barrington 1999

Barrington KJ, Bull D, Finer NN. Randomized controlled trial of nasal synchronized intermittent mandatory ventilation after extubation of very low birth weight infants. Pediatric Research 1999;45:184A.

Bott 1993

Bott J, Carroll MP, Conway JH, Keitly SE, Ward EM, Brown AM et al. Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease. Lancet 1993;341:1555-7.

Derleth 1992

Derleth DP. Clinical experience with low rate mechanical ventilation via nasal prongs for intractable apnea of prematurity. Pediatric Research 1992;32:200A.

Ellis 1988

Ellis ER, Grunstein RR, Chan S, Bye PT, Sullivan CE. Noninvasive ventilatory support during sleep improves respiratory failure in kyphoscoliosis. Chest 1988;94:811-5.

Friedlich 1999

Friedlich P, Lecart C, Posen R, Ramicone E, Chan L, Ramanathan R. A randomized trial of nasopharyngeal synchronized intermittent mandatory ventilation versus nasopharyngeal continuous positive airway pressure in very low birth weight infants after extubation. Journal of Perinatology 1999;19:413-8.

Garland 1985

Garland JS, Nelson DB, Rice T, Neu J. Increased risk of gastrointestinal perforations in neonates mechanically ventilated with either face mask or nasal prongs. Pediatrics 1985;76:406-10.

Henderson-Smart 1999

Henderson-Smart D, Steer P. Methylxanthine treatment for apnea in preterm infants (Cochrane Review). In: Cochrane Library, Issue 4, 1999. Oxford: Update Software.

Kiciman 1998

Kiciman NM, Andréasson B, Bernstein G, Mannino FL, Rich W, Henderson C, Heldt GP. Thoracoabdominal motion in newborns during ventilation delivered by endotracheal tube or nasal prongs. Pediatric Pulmonology 1998;25:175-81.

Miller 1985

Miller MJ, Carlo WA, Martin RJ. Continuous positive airway pressure selectively reduces obstructive apnea in preterm infants. Journal of Pediatrics 1985;106:91-4.

Moretti 1981

Moretti C, Marzetti G, Agostino R, Panero A, Picece BS, Mendicini M et al. Prolonged intermittent positive pressure ventilation by nasal prongs in intractable apnea of prematurity. Acta Paediatrica Scandinavica 1981;70:211-6.

Nelson 1978

Nelson NM. Members of the task force on prolonged apnea of the American Academy of Pediatrics. Pediatrics 1978;61:651-2.

Piper 1992

Piper AJ, Parker S, Torzillo PJ, Sullivan CA, Bye PT. Nocturnal nasal IPPV stabilizes patients with cystic fibrosis and hypercapnic respiratory failure. Chest 1992;102:846-50.

Ruggins 1991

Ruggins NR. Pathophysiology of apnea in preterm infants. Archives of Disease in Childhood 1991;66:70-3.

Schmidt 1999

Schmidt BK. Methylxanthine therapy in premature infants: Sound practice, disaster, or fruitless byway? Journal of Pediatrics 1999;135:526-8.

Other published versions of this review

Lemyre 2000

Lemyre B, Davis PG, De Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity (Cochrane Review). In: The Cochrane Library, Issue 3, 2000. Oxford: Update Software.

Lemyre 2002

Lemyre 2003

Comparisons and data

01 NIPPV vs NCPAP

01.01 Failure of therapy: intubation

01.02 Rate of apnea (events/hr)

01.03 Change in rate of apnea (events/hr)

01.04 pC02 at 4-6h (mmHg)

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 NIPPV vs NCPAP
01 Failure of therapy: intubation	1	74	RR (fixed), 95% CI	0.30 [0.01, 6.84]
02 Rate of apnea (events/hr)	1	40	WMD (fixed), 95% CI	-0.10 [-0.53, 0.33]
03 Change in rate of apnea (events/hr)	1	34	WMD (fixed), 95% CI	-1.19 [-2.31, -0.07]
04 pC02 at 4-6h (mmHg)	2	74	WMD (fixed), 95% CI	0.95 [-3.04, 4.94]

Notes

Published notes

Amended sections

Cover sheet
Abstract
Search strategy for identification of studies
References to studies
Other references

Contact details for co-reviewers

Dr Peter G Davis, MD, MBBS
Consultant Paediatrician
Division of Paediatrics
Royal Women's Hospital
132 Grattan St
Melbourne
Victoria AUSTRALIA
3053
Telephone 1: +61 3 93442000 extension: 2130
Facsimile: +61 3 93471761
E-mail: pgd@unimelb.edu.au

Antonio G De Paoli, Dr
Neonatal Fellow
Neonatal Unit
Royal Women's Hospital
132 Grattan St
Carlton, Melbourne
Victoria AUSTRALIA
3053
Telephone 1: +61 3 93442000 extension: 2472
E-mail: depaolitony@netscape.net

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2004 (see http://www.thecochranelibrary.com/ for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the Review.