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Continuous positive airway pressure versus theophylline for apnea in preterm infants

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Authors

Henderson-Smart DJ, Subramaniam P, Davis PG

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


Dates

Date edited: 25/05/2005
Date of last substantive update: 22/07/2001
Date of last minor update: 25/04/2005
Date next stage expected / /
Protocol first published: Issue 2, 1998
Review first published: Issue 2, 1998

Contact reviewer

Prof David J Henderson-Smart

Director
NSW Centre for Perinatal Health Services Research
Queen Elizabeth II Research Institute
Building DO2
University of Sydney
Sydney
NSW AUSTRALIA
2006
Telephone 1: +61 2 93517318
Telephone 2: +61 2 93517728
Facsimile: +61 2 93517742

E-mail: dhs@perinatal.usyd.edu.au

Contribution of reviewers

Each reviewer independently evaluated the trials for quality and extracted the data. Henderson-Smart entered the data and wrote the text with input from the other two authors.

Sources of Support

Internal sources of support

NSW Centre for Perinatal Health Services Research, Sydney, AUSTRALIA
Royal Prince Alfred Hospital, Sydney, AUSTRALIA
Royal Women's Hospital, Melbourne, AUSTRALIA
University of Melbourne, AUSTRALIA
Department of Paediatrics, Ipoh Hospital, Ipoh, MALAYSIA
Murdoch Children's Research Institute, Melbourne, AUSTRALIA

External sources of support

  • None noted.

What's new

This is an update of the existing review "Continuous positive airway pressure versus theophylline for apnea in preterm infants" originally published in The Cochrane Library, Disk 2, 1998 (Henderson-Smart d) and updated in Disk 4, 2001 (Henderson-Smart e).

The search has been updated to March 2005. No new trials have been found.

Dates

Date review re-formatted: 07/09/1999
Date new studies sought but none found: 01/04/2005
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: / /

Synopsis

Theophylline may be more helpful in preventing problems for preterm babies with apnea than CPAP (blowing air) through a mask

Apnea is common in preterm babies (born before 37 weeks). It is a pause in breathing of more than 20 seconds, or less than 20 seconds but with a reduced heart rate and cyanosis (a blue tinge to the skin colour indicating not enough oxygen). Resuscitation may be needed. Drugs such as theophylline can be used to stimulate breathing or continuous positive airway pressure (CPAP) which helps breathing by blowing air into the baby through a mask or tube. The review of trials found theophylline is more effective than mask CPAP for preterm infants with apnea. More research is needed.

Abstract

Background

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Theophylline and continuous positive airways pressure (CPAP) are two treatments that have been used to prevent apnea and its consequences.

Objectives

The main objective was to determine in preterm infants with recurrent apnea, if treatment with CPAP compared with treatment with theophylline leads to a clinically important reduction in apnea or use of mechanical ventilation, without clinically important side effects.

Search strategy

Searches were made of the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1 2005), MEDLINE (1966 - March 2005), EMBASE (1980 - March 2005), and CINAHL (1982 - March 2005). Previous reviews including cross references were also examined. Expert informants were also questioned. Abstracts of the Society for Pediatric Research from 1996 - 2004 inclusive were searched.

Selection criteria

All trials using random or quasi-random allocation to CPAP or theophylline in preterm infants with clinical recurrent apnea/bradycardia were eligible.

Data collection & analysis

Data were extracted using standard methods of the Cochrane Collaboration and its Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk.

Main results

Only one eligible trial was found. The use of mask CPAP is associated with a higher treatment failure rate as measured by less than a 50% reduction in apnea or use of an alternative treatment [RR 2.89 (95% CI 1.12, 7.47); RD 0.42 (95% CI 0.11, 0.74)]. For every 2.4 infants (95% CI 1.4, 9.5) treated with mask CPAP rather than theophylline, there results one treatment failure. In the mask CPAP group there is more use of IPPV [RR 3.09 (1.42, 6.70); RD 0.58 (95% CI 0.30, 0.86). For every 1.7 infants (95% CI 1.2, 3.3) treated with mask CPAP rather than theophylline, one infant is intubated for IPPV.

In the mask CPAP group, there are trends towards more deaths in the first year, and in death or major disability in survivors at follow up, which do not reach significance. There are no differences in rates of necrotizing enterocolitis or major disability in survivors at follow up.

Reviewers' conclusions

Theophylline is more effective than mask CPAP for preterm infants with apnea. Since CPAP is no longer administered by mask, the results of this review have limited importance for current clinical practice. Further evaluation of the benefits and harms of CPAP vs theophylline for preterm infants with apnea requires further trials in which CPAP is administered by current methods.

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Background

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 (AAP 2003). Recurrent episodes of apnea are common in preterm infants and the incidence and severity increases at lower gestational ages. Although it can occur spontaneously and be attributed to prematurity alone, it can also be provoked or made more severe if there is some additional insult such as infection, hypoxemia or intracranial pathology (Samuels 1992; Henderson-Smart 1995).

If prolonged, apnea can lead to hypoxemia and reflex bradycardia which may require active resuscitative efforts to reverse. There are clinical concerns that these episodes might be harmful to the developing brain or cause dysfunction to the gut or developing organs. Frequent episodes may be accompanied by respiratory failure of sufficient severity as to lead to intubation and the use of intermittent positive pressure ventilation (IPPV).

Central apnea is defined as the absence of breathing efforts. The most common type of prolonged apnea is mixed apnea in which a central pause in breathing is followed by airway obstruction. Continuous positive airway pressure (CPAP) has been shown to reduce the obstructive component of mixed apnea (Miller 1985) and this would shorten the apnea and prevent worsening hypoxemia.

Various treatments for apnea in preterm infants have been used, including physical stimulation by nursing staff, pharmacological stimulation (methylxanthines and doxapram) and assisted ventilation using CPAP (see other Cochrane reviews by Henderson-Smart a; Henderson-Smart b; Steer 2005). Non-randomized observations (Kattwinkel 1975; Speidel 1976) suggest that CPAP reduces the rate of apnea. There are no published randomized controlled trials of CPAP vs control for apnea of prematurity. CPAP has been shown to be better than control for the facilitation of extubation after IPPV in preterm infants and part of this effect is thought to be due to the reduction of apnea (Davis 2005).

Objectives

Primary objective: in preterm infants with recurrent apnea, how does treatment with CPAP compare with treatment with theophylline in leading to a clinically important reduction in apnea and use of mechanical ventilation, without clinically important side effects?

Secondary objective: does the response differ if CPAP is administered by different methods (mask, nasal prongs, nasopharyngeal tubes); at different pressures; or in infants of different gestational ages?

Criteria for considering studies for this review

Types of studies

All trials using random or quasi-random patient allocation were eligible.

Types of participants

Preterm infants with clinical recurrent apnea/bradycardia as defined in background above. There must have been an effort to exclude specific causes of apnea.

Types of interventions

CPAP compared with methylxanthine (theophylline) for the treatment of apnea.

Types of outcome measures

Measures of the response to treatment must be consistent with an evaluation of 'clinical apnea', as defined by the American Academy of Pediatrics (see above).

Outcomes:
  1. failure of treatment as indicated by persisting episodes of apnea +\- bradycardia (less than 50% reduction) or use of an alternative treatment
  2. use of IPPV
  3. mean rates of apnea/bradycardia
  4. hypoxemic episodes associated with apnea
  5. side effects (nasal injury, tachycardia, feed intolerance)
  6. death
  7. rate of intraventricular hemorrhage and periventricular leukomalacia
  8. neurodevelopmental status at follow up

Search strategy for identification of studies

Searches were made of the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 1, 2005), MEDLINE (1966 - March 2005), EMBASE (1980 - March 2005), CINAHL (1982 - March 2005), using text words 'theophylline', 'caffeine', 'CPAP', 'CDAP', 'positive pressure', 'apnea or apnoea' and Mesh term 'infant, premature'. Previous reviews including cross references were also examined. Expert informants were also questioned. Abstracts of the Society for Pediatric Research from 1996 - 2004 inclusive were searched.

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Methods of the review

Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed by the second and third authors blinded to trial authors and institution(s). Each author extracted the data separately, then data were compared and differences resolved. The standard methods of the Neonatal Review Group to synthesise data using relative risk and risk difference were used.

Description of studies

Only one trial was found and this compared mask CPAP with theophylline. Details are given in the table of included studies. Mask CPAP was administered at 2 to 3 centimetres of water, increasing to 4 to 6 if there was no response. Standard doses of aminophylline IV or theophylline orally were used.

Methodological quality of included studies

This is detailed in the table of included studies. Concealment at randomization was attempted (sealed envelopes); treatment was not blinded; follow up was virtually complete (only one subject lost); outcome was not assessed blind to treatment group. The imbalance in numbers in the two groups probably arises because the trial was stopped when it was seven infants short of the intended sample size, with an equivalent number of unopened sealed envelopes remaining.

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Results

The use of mask CPAP is associated with a higher treatment failure rate as measured by less than a 50% reduction in apnea or use of the alternative treatment [RR 2.89 (95% CI 1.12, 7.47; RD 0.42 (95% CI 0.11, 0.74)]. For every 2.4 infants (95% CI 1.4, 9.5) treated with mask CPAP rather than theophylline, there results one treatment failure. Mean rates of apnea/bradycardia from polygraph recordings were only available on a small subgroup of infants (4 of CPAP group and 7 of theophylline group) and are not reported here. Hypoxic episodes were not separately reported.

In the mask CPAP group there was more use of IPPV [RR 3.09 (95% CI 1.42, 6.70); RD 0.58 (95% CI 0.30, 0.86)]. Thus, for every 1.7 infants (95% CI 1.2, 3.3) treated with mask CPAP rather than theophylline, one infant is intubated for IPPV.

In the mask CPAP group, there are trends towards more deaths in the first year, and in 'death or major disability' at follow up, which do not reach significance. There are no differences in rates of necrotizing enterocolitis or major disability in survivors at follow up.

Rates of intraventricular hemorrhage and periventricular leukomalacia could not be evaluated.

It was not possible to examine the secondary objectives relating to differences in ways of administering CPAP or the responses in infants born at different gestational ages.

Discussion

The results of this single trial with a small number of subjects are difficult to interpret in terms of current clinical practice. The main outcome here was failure of treatment as judged by continuing apnea/bradycardia from nursing records or the use of the alternate treatment. Nursing records have been shown to underestimate apnea/bradycardia detected by polygraphic recordings (reviewed in Samuels 1992). Nevertheless, in current clinical practice it is nursing records which determine management decisions.

The method used to apply CPAP was by mask as described by Allen 1975. This is no longer in general clinical use as most clinicians use CPAP via nasal prongs or a nasopharyngeal tube. The method used to strap the mask to the infant could possibly cause airway obstruction due to pressure displacing the jaw backwards. Alternatively, the increased ventilatory dead space may have compromised respiratory function. The pressures used initially were low by current standards. The use of low pressure CPAP has not been found to be effective when used for extubation (Davis 2005). Furthermore, responses might differ by type of apnea (central, obstructive or mixed) and in infants at different gestational ages, but these issues were not examined in this study.

Reviewers' conclusions

Implications for practice

Theophylline is more effective than mask CPAP for preterm infants with apnea. Since CPAP is no longer administered by mask, the results of this review have limited importance for current clinical practice.

Implications for research

Evaluation of the benefits and harms of CPAP vs theophylline for preterm infants with apnea requires further trials in which CPAP is administered by current methods. Trials should address the possibility that the effects of CPAP or theophylline might vary at different gestational ages and in infants with different types of apnea.

Acknowledgements

Dr Rosamond Jones kindly supplied additional information from her MD Thesis.

Potential conflict of interest

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Jones 1982 Concealment at randomization - yes (sealed envelopes); blinding of treatment - no; completeness of followup - yes (only one lost); blinding of outcome assessment - no. Thirty two preterm infants born at less than 33 weeks gestation who were less than 4 weeks of age and had apnea of more than 9 sec. with bradycardia (< 100 bpm) - 2 or more events in 6 hrs or 3 or more in 24 hrs. Infants with 10 or more apneas of > 19 sec without bradycardia were also eligible. Infants were not eligible if there was a 'cause' for the apnea such as infection, cardiac failure, convulsions or severe intraventricular hemorrhage. Mask CPAP (2 - 5 cms water) vs theophylline (6.2 mg/kg loading dose, then 4.4 mg/kg/day IV, then 1.5 mg/kg/6 hrs orally). Failed treatment (continuing apnea/bradycardia or use of other treatment), use of IPPV, death before discharge, necrotising enterocolitis, tachycardia, major disabilities at 12 - 24 month followup, death after discharge. Mask and attachment method according to Allen et al 1975. Additional information was obtained from the trial authors MD Thesis (Jones 1981). Trial was terminated with 7 envelopes unopened, due to slow recruitment. A

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References to studies

Included studies

Jones 1982

{published and unpublished data}

* Jones RAK. Apnoea of prematurity. 1. A controlled trial of theophylline and face mask continuous positive airways pressure. Archives of Disease in Childhood 1982;57:761-5.

Jones RAK. The management of recurrent apnoea in the preterm infant (MD thesis). London: University of London, 1981.

* indicates the primary reference for the study

Other references

Additional references

AAP 2003

American Academy of Pediatrics. Policy statement. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics 2003;111:914-17.

Allen 1975

Allen LP, Blake AM, Durbin GM, Ingram D, Reynolds EOR, Wimberley PD. Continuous positive airway pressure and mechanical ventilation by face mask in newborn infants. British Medical Journal 1975;iv:137-9.

Davis 2005

Davis PG, Henderson-Smart DJ. Prophylactic post-extubation nasal CPAP in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.

Henderson-Smart 1995

Henderson-Smart DJ. Recurrent apnoea. In: Yu VYH, editor(s). Bailliere's Clinical Paediatrics. Vol. 3. No. 1 Pulmonary Problems in the Perinatal Period and their Sequelae. London: Bailliere Tindall, 1995:203-22.

Henderson-Smart a

Henderson-Smart DJ, Steer PA. Methylxanthine treatment for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.

Henderson-Smart b

Henderson-Smart DJ, Steer PA. Doxapram treatment for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.

Henderson-Smart c

Henderson-Smart DJ, Steer PA. Doxapram versus methylxanthine for apnea in preterm infants. In: The Cochrane Database of Systemtatic Reviews, Issue 1, 2005.

Kattwinkel 1975

Kattwinkel J, Nearman HS, Fanaroff AA, Katona PG, Klaus MH. Apnea of prematurity. Comparative therapeutic effects of cutaneous stimulation and nasal continuous positive airway pressure. Journal of Pediatrics 1975;86:588-92.

Miller 1985

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

Samuels 1992

Samuels MP, Southall DP. Recurrent Apnea. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:385-97.

Speidel 1976

Speidel BD, Dunn PM. Use of nasal continuous positive airways pressure to treat severe recurrent apnoea in very preterm infants. Lancet 1976;ii:658-60.

Steer 2005

Steer PA, Henderson-Smart DJ. Caffeine versus theophylline for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.

Other published versions of this review

Henderson-Smart d

Henderson-Smart DJ, Subramaniam P, Davis PG. Continuous positive airway pressure versus theophylline for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 1998.

Henderson-Smart e

Henderson-Smart DJ, Subramaniam P, Davis PG. Continuous positive airway pressure versus theophylline for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 4, 2001.

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Data and analyses

01 Mask CPAP vs theophylline

Comparison or outcome Studies Participants Statistical method Effect size
01.01 Failed treatment 1 32 RR (fixed), 95% CI 2.89 [1.12, 7.47]
01.02 Use of IPPV 1 32 RR (fixed), 95% CI 3.09 [1.42, 6.70]
01.03 Death in the first year 1 32 RR (fixed), 95% CI 2.57 [0.97, 6.82]
01.04 Necrotizing enterocolitis 1 32 RR (fixed), 95% CI 0.64 [0.06, 6.39]
01.05 Major disability in survivors at 12 - 24 months 1 20 RR (fixed), 95% CI 0.78 [0.10, 6.05]
01.06 Death or major disability at 12 - 24 months 1 32 RR (fixed), 95% CI 1.65 [0.82, 3.32]

Additional tables

  • None noted.

Amended sections

Cover sheet
Abstract
Background
Criteria for considering studies for this review
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

Dr Prema Subramaniam

Consultant Paediatrician
Dept Paediatrics
Hospital Ipoh
Ipoh
MALAYSIA
30990
Telephone 1: +60 5 2533333 extension: 2441
Telephone 2: +60 5 2533333 extension: 2442
Facsimile: +60 5 2531541

E-mail: premasivapalan@hotmail.com

Secondary address:
Ipoh


The review is published as a Cochrane review in The Cochrane Library, Issue 3, 2005 (see http://www.thecochranelibrary.com External Web Site Policy 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 recent version of the review.