No additional studies or data were obtained on the updated search to December 2004.
Some evidence that theophylline may be more effective for apnea in preterm babies than kinesthetic stimulation, but more research is needed.
Apnea is a pause in breathing of greater than 20 seconds. It may occur repeatedly in preterm babies (born before 34 weeks). Immaturity alone can cause apnea, but so can infections. Apnea may be harmful to the developing brain or organs if it continues. Various methods have been tried to reduce apnea in premature babies including drugs, physical stimulation by nurses and kinesthetic stimulation (using an oscillating mattress which moves from side to side). The review of trials found some evidence that the drug theophylline may be more effective than kinesthetic stimulation for apnea but more research is needed.
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). 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 (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, although there are no data to support this. 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).
Various treatments for apnea in preterm infants have been used, including physical stimulation by nursing staff, pharmacological stimulation including methylxanthines (HendersonSmart 2005a) and continuous positive airway pressure (CPAP) (HendersonSmart 2005b). Physical stimulation by nursing staff is commonly used to arouse the apneic infant and so stimulate breathing. This raises the question of whether frequent physical stimuli might reduce the number of apneic events. Furthermore, some believe that the preterm infant is deprived of the frequent stimuli that would be felt in utero and that substituting these with an oscillating mattress to provide kinesthetic stimulation might improve growth and development. Kinesthetic stimulation using various forms of oscillating mattress has been used in both prevention and treatment for apnea which are the subject of other Cochrane reviews (HendersonSmart 2005c; Osborn 2005). This review compares the effects of kinesthetic stimulation and methylxanthines for the treatment of preterm infants with apnea.
In preterm infants with apnea, to determine if kinesthetic stimulation is more effective than a methylxanthine in preventing clinically important apnea, the need for mechanical ventilation or continuous positive airways pressure support, and neurodevelopmental disability without clinically important side effects.
All trials using random or quasi-random patient allocation, in which kinesthetic stimulation was compared to methylxanthine therapy for apnea of prematurity, were eligible.
Preterm infants with recurrent clinical apnea with or without associated bradycardia, cyanosis or hypoxia.
Kinesthetic stimulation (various forms of oscillating mattresses or other repetitive stimulation involving moving the baby) compared with methylxanthine 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) Persisting apneas with or without bradycardia (>4 and > 10 episodes/day)
2) Greater than a 50% reduction in the daily rates of apnea with or without bradycardia
3) Hypoxemic episodes associated with apnea
4) Failure of treatment as indicated by use of additional measures such
as use of mechanical ventilation (IPPV), CPAP, or doxapram
5) Side effects (tachycardia, feed intolerance)
6) Death before hospital discharge
7) Rate of intraventricular haemorrhage
8) Neurodevelopmental status at follow up
The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2004), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching mainly in the English language. MEDLINE (1966-December 2004), EMBASE (1980-December 2004) and CINAHL (1982-December 2004) were searched. Abstracts of the Society for Pediatric Research were hand searched for the years 1996 to 2004 inclusive.
The Cochrane Controlled Trials Register was searched using search terms '(theophylline or methylxanthine) and (infant or preterm or neonate or newborn)', 'water bed', 'air bed', 'oscillating', '(apnea or apnoea) and (infant or preterm or neonate or newborn)', 'rocking', and 'vertical pulsating'.
MEDLINE was searched using Mesh headings 'apnea and infant-premature', 'theophylline and infant-premature', text words 'water bed', 'air bed', 'oscillating', '(apnea or apnoea) and (infant or premature or preterm or neonate or newborn)', '(theophylline) and (infant or preterm or neonate or newborn)' 'rocking', and 'vertical pulsating'.
The Oxford Database of Perinatal Trials was searched using search terms 'apnea' and 'methylxanthines'.
Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed by the second author blinded to trial authors and institution(s). Each author extracted the data separately, then compared and resolved differences. The standard method of the Neonatal Review Group to synthesise data was followed, using the fixed effects model to calculate relative risk (RR), risk difference (RD) and mean difference (MD) or weighted mean difference (WMD) where appropriate.
Details of the included study (Saigal 1986) have been entered into the Included Studies Table. This study randomized infants to either a regularly oscillating water bed (12-14 cycles/minute) or oral theophylline (or aminophylline) 6 mg/kg loading dose, 2 mg/kg 12 hourly maintenance dose (adjusted after 4 days to keep serum levels 6 - 12 micrograms/ml).
Preterm infants included in the study were of birth weight 750 - 1750 gms, age 1-21 days, and >5 apnea/bradycardia per 24 hrs. They were stratified by birth weight <1000 gms, 1000 - 1499 gms & 1500 - 1750 gms, and excluded if they had a major congenital abnormality, grade 3 or 4 IVH, IPPV >48 hrs, or had secondary apnea. Of 111 admissions in the weight range, 43 were eligible, two refused, 21 conflicted with other research protocols, and 20 were randomized.
Apnea and bradycardia events were recorded by nursing staff (monitor alarms due to apnea > 14 seconds or bradycardia < 100 bpm) and cyanosis, need for stimulation and ventilation recorded. Polygraphic recording was also assessed for apnea > 14 seconds by a blinded observer. Death, use of IPPV, sleep states, Albert Einstein Neurobehavioral Scales at term equivalent age, auditory/cardiac habituation test at three months corrected, and Bayley Scales of Infant Development at six and 12 months corrected were assessed.
A power calculation was performed and 50 infants were estimated to be required but the study was performed as a feasibility study of 20 infants.
Details of the methodological quality of the Saigal 1986 study are given in the Table of Included Studies.
Randomization was by use of random number table. Randomization was in three birth weight strata. Concealment of allocation was not specified.
Due to the nature of the treatment, blinding of intervention was not possible.
Follow up was complete for apnea, mortality, and use of CPAP and IPPV. Neurodevelopmental follow up of surviving infants was complete except for two deaths in the oscillating water bed group and one death in theophylline group.
The primary outcomes of nursing recorded apnea/bradycardia were not blindly assessed. Polygraphic assessment of apnea, assessment of sleep states, Albert Einstein Neurobehavioral Scales at term equivalent age, auditory/cardiac habituation test at three months corrected, and Bayley Scales of Infant Development at six and 12 months corrected were assessed blind to treatment allocation.
Saigal 1986 reported that infants in the theophylline group had slightly more respiratory distress syndrome at study entry than infants on the oscillating water bed (OWB). They also had different rates of baseline apnea (higher in the infants on the OWB). No significant differences were seen between the groups in demographic and other neonatal data.
Categorical data on apnea/bradycardic episodes could not be obtained as original data could not be located by the author. Data could not be extracted to determine: 1) persisting apneas with or without bradycardia (>4 and > 10 episodes /day) and 2) greater than a 50% reduction in the daily rates of apnea with or without bradycardia. Daily rates of clinically important apnea (nursing observation) were available for episodes of apnea (> 14 seconds) with bradycardia (< 100 bpm) and cyanosis OR receiving stimulation, as well as for episodes of apnea (> 14 seconds) with bradycardia (< 100 bpm) and cyanosis AND receiving stimulation.
Saigal 1986 reported no significant difference in apnea defined as daily episodes of apnea associated with bradycardia and cyanosis and receiving stimulation (MD 3.36, 95%B CI -0.07, 6.79). However, infants on an OWB compared to those receiving theophylline had a significant increase in daily episodes of apnea defined as apnea and bradycardia and cyanosis or receiving stimulation (MD 4.88, 95% CI 0.33, 9.43). Blinded polygraphic recordings also supported the finding of a significant benefit of theophylline as compared to the OWB in mean frequencies of apnea and bradycardia. Saigal also reported blinded polygraphic recordings of apnea >15s and bradycardia <80bpm. Saigal found baseline differences in rates of apnea between the two groups. Using analysis of co-variance to correct for these differences, Saigal reported a significantly lower incidence of both apnea >15s and bradycardia <80bpm in the theophylline group.
There was no significant difference in terms of sleep states, death, neurological abnormality, neurological abnormality or death, the Einstein Neurodevelopmental Scale at term corrected age, or the Bayley Mental Development Index at six or 12 months corrected age. A difference in psychomotor performance was found with infants on the OWB performing better at six months, but not 12 months corrected age.
The single trial in this review suggests that theophylline is significantly better than the oscillating water bed (OWB) at reducing clinically significant apnea without important adverse effects in terms of sleep states, neurological abnormality and abnormal neurodevelopment.
The limitations of this review are the availability of a single study, the small sample size of the study, and the lack of dichotomous data for rates of clinically significant apneas.
Although a previous review has suggested a lack of effect of prophylactic kinesthetic stimulation at preventing apnea of prematurity (HendersonSmart 2005c), this does not preclude a possible benefit of kinesthetic stimulation in the treatment of infants with established apnea of prematurity (Osborn 2005).
The results of this review should be treated with caution. Theophylline has been shown in one small study to be superior to kinesthetic stimulation at treating clinically important apnea of prematurity.
There are currently no clear research questions regarding the comparison of methylxanthines and kinesthetic stimulation to treat apnea of prematurity.
Professor Saroj Saigal for her kind attempt at locating the raw data.
None.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Saigal 1986 | Randomization: Random number table. Allocation concealment: Not specified. Blinding of intervention: No. Complete followup: Yes. Blinding of outcome measurement: No for nursing recorded apnea/bradycardia. Yes for polygraphic recorded apnea/bradycardia and long term follow up. Power unsatisfactory as 50 infants estimated to be needed. Done as feasibility study of 20 infants. | Preterm infants of birth weight 750 - 1750 gms, age 1-21 days, >5 apnea/bradycardia per 24 hrs. Stratified by birth weight <1000 gms, 1000 - 1499 gms & 1500 - 1750 gms. Excluded if; major congenital abnormality; grade 3 or 4 IVH; IPPV >48 hrs; secondary apnea. Of 43 admissions in weight range, 43 eligible, 2 refused, 21 conflicted with other research protocols, 20 randomized. | Oscillating water bed 12 - 14/min vs theophylline 6 mg/kg loading dose and 2 mg/kg 12 hrly (adjusted after 4 days to keep serum levels 6 - 12 micrograms/ml) (or equivalent dose of aminophylline if not tolerating feeds). | Clinical (nursing records) and polygraph recorded apnea/bradycardia; death; use of IPPV; sleep states; Albert Einstein Neurobehavioral Scales at term equivalent age; auditory/cardiac habituation test at 3 months corrected; Bayley Scales of Infant Development at 6 and 12 months corrected. | Original data requested from author but not available. | B |
Saigal S, Campell D, Watts J, Ferguson S, Duffy A. Immediate and longterm outcomes of the use of an oscillating water bed or theophylline in preterm infants with apnea: a randomized clinical trial. Journal of Perinatology 1986;6:33-8.
* indicates the primary reference for the study
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 P. Methylxanthine treatment for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 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, 2005.
Henderson-Smart DJ, Osborn DA. Kinesthetic stimulation for preventing apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 2005.
Nelson NM. Members of the Task Force on Prolonged Apnea of the American Academy of Pediatrics. Prolonged apnea. Pediatrics 1978;61:651-2.
Osborn DA, Henderson-Smart DJ. Kinesthetic stimulation for treating apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 2005.
Osborn DA, Henderson-Smart DJ. Kinesthetic stimulation versus theophylline for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 1998.
Osborn DA, Henderson-Smart DJ. Kinesthetic stimulation versus theophylline for apnea in preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 2, 2002.
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Oscillating water bed vs theophylline | ||||
| 01 Daily rate apnea/ bradycardia/ cyanosis and stimulation | 1 | 20 | WMD (fixed), 95% CI | 3.36 [-0.07, 6.79] |
| 02 Daily rate apnea/ bradycardia/ cyanosis or stimulation | 1 | 20 | WMD (fixed), 95% CI | 4.88 [0.33, 9.43] |
| 03 Death | 1 | 20 | RR (fixed), 95% CI | 2.44 [0.26, 22.80] |
| 04 Use of IPPV or CPAP | 1 | 20 | RR (fixed), 95% CI | 8.40 [0.49, 144.04] |
| 05 Neurological abnormality in survivors. | 1 | 17 | RR (fixed), 95% CI | 4.13 [0.19, 88.71] |
| 06 Neurological abnormality in survivors or death | 1 | 20 | RR (fixed), 95% CI | 3.67 [0.46, 29.49] |
| 07 Bayley MDI at 6 months | 1 | 17 | WMD (fixed), 95% CI | 6.00 [-7.00, 19.00] |
| 08 Bayley PDI at 6 months | 1 | 17 | WMD (fixed), 95% CI | 15.00 [3.10, 26.90] |
| 09 Bayley MDI at 12 months | 1 | 17 | WMD (fixed), 95% CI | 6.00 [-5.90, 17.90] |
| 10 Bayley PDI at 12 months | 1 | 17 | WMD (fixed), 95% CI | 7.00 [-5.17, 19.17] |
| The review is published as a Cochrane review in The
Cochrane Library, Issue 2, 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. |