The search has been updated to March 2005. No new trials have been found.
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.
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.
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.
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.
All trials using random or quasi-random allocation to CPAP or theophylline in preterm infants with clinical recurrent apnea/bradycardia were eligible.
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.
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.
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.
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).
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?
All trials using random or quasi-random patient allocation were eligible.
Preterm infants with clinical recurrent apnea/bradycardia as defined in background above. There must have been an effort to exclude specific causes of apnea.
CPAP compared with methylxanthine (theophylline) for the treatment of apnea.
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
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.
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.
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.
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.
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.
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.
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.
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.
Dr Rosamond Jones kindly supplied additional information from her MD Thesis.
None.
| 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 |
* 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
American Academy of Pediatrics. Policy statement. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics 2003;111:914-17.
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 PG, Henderson-Smart DJ. Prophylactic post-extubation nasal CPAP in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.
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 DJ, Steer PA. Methylxanthine treatment for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.
Henderson-Smart DJ, Steer PA. Doxapram treatment for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.
Henderson-Smart DJ, Steer PA. Doxapram versus methylxanthine for apnea in preterm infants. In: The Cochrane Database of Systemtatic Reviews, Issue 1, 2005.
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 MJ, Carlo WA, Martin RJ. Continuous positive pressure selectively reduces obstructive apnea in preterm infants. Journal of Pediatrics 1985;106:91-4.
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 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 PA, Henderson-Smart DJ. Caffeine versus theophylline for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.
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 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.
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Mask CPAP vs theophylline | ||||
| 01 Failed treatment | 1 | 32 | RR (fixed), 95% CI | 2.89 [1.12, 7.47] |
| 02 Use of IPPV | 1 | 32 | RR (fixed), 95% CI | 3.09 [1.42, 6.70] |
| 03 Death in the first year | 1 | 32 | RR (fixed), 95% CI | 2.57 [0.97, 6.82] |
| 04 Necrotizing enterocolitis | 1 | 32 | RR (fixed), 95% CI | 0.64 [0.06, 6.39] |
| 05 Major disability in survivors at 12 - 24 months | 1 | 20 | RR (fixed), 95% CI | 0.78 [0.10, 6.05] |
| 06 Death or major disability at 12 - 24 months | 1 | 32 | RR (fixed), 95% CI | 1.65 [0.82, 3.32] |
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 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. |