A repeat literature search showed no new trials eligible for inclusion and there have been no substantive changes to the review.
No evidence that time on endotracheal CPAP (continuous low pressure rather than intermittent breaths from the ventilator) before taking preterm babies off a ventilator helps them adjust to breathing on their own.
Babies in neonatal intensive care often need help to breathe, sometimes via an endotracheal tube (through the windpipe) connected to a ventilator (machine). It has been thought that it might help a baby adjust to breathing after ventilation if there was a period of CPAP (continuous positive airways pressure) before extubation (coming off the ventilator). However, there have also been concerns that this may be too much hard work for the baby, and may cause harm. The review of trials found that a trial of CPAP first before extubation does not improve the baby's ability to breathe on their own.
Failure of extubation and subsequent reintubation may result in additional stress and trauma to the premature infant. Testing infants about to be extubated with a period of endotracheal CPAP has been suggested as a method of demonstrating readiness for extubation. However, this process has been criticized as increasing the neonate's work of breathing and perhaps increasing the likelihood of extubation failure.
In premature infants having their endotracheal tube removed, is direct extubation from low rate intermittent positive pressure ventilation (IPPV) more successful than that following a period of endotracheal continuous positive airway pressure (CPAP)?
The standard search strategy of the Cochrane Neonatal Review Group as outlined Tn the Cochrane Library was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, previous reviews including cross references, abstracts, conferences, symposia proceedings, expert informants and journal hand searching mainly in the English language. These searches were updated in March 2003.
All trials using random or quasi-random allocation of premature infants to endotracheal CPAP or direct extubation following a period of IPPV were included.
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.
Direct extubation from low rate ventilation is associated with a trend to increased chance of successful extubation when compared to extubation after a period of endotracheal CPAP, RR 0.45 (0.19,1.07), RD -0.103 (-0.200,-0.006), NNT 10 (5,167). When only truly randomized trials are considered, this result becomes both statistically significant and clinically important, RR 0.10 (0.01,0.78), RD -0.201 (-0.319,-0.083), NNT 5 (3,12). Similar differences are seen for the secondary outcome, apnea.
Preterm infants no longer requiring endotracheal intubation and IPPV should be directly extubated without a trial of ETT CPAP.
Endotracheal intubation and intermittent positive pressure ventilation (IPPV) of infants with respiratory failure provides life-saving support until the underlying pulmonary pathology has resolved spontaneously or been successfully treated. Weaning of ventilatory support occurs during the resolution phase and when an infant is able to generate sufficient respiratory effort, the endotracheal tube (ETT) is removed.
Minimising the duration of endotracheal intubation is thought to reduce the risks of chronic lung disease, sepsis and upper airway trauma. A trial of endotracheal continuous positive airway pressure (ETT CPAP) prior to extubation has been advocated by Nugent and others (Nugent 1988) to demonstrate the readiness of an infant to breath without IPPV. However, the same authors go on to suggest that in small infants, the added dead space and resistance to gas flow imposed by the ETT may increase the work of breathing (Nugent 1988). Le Souef and others (LeSouef 1984) demonstrated a substantial decrease in resistance of the respiratory system following extubation. They also showed that diaphragmatic activity was greater when an infant was on ETT CPAP and concluded that the presence of the ETT increased the work of breathing. Lopes 1981 suggested that diaphragmatic fatigue might precede the development of apnea in some infants.
Failure of extubation and subsequent reintubation may result in additional stress and physical trauma to the infant. Maximising the likelihood of successful extubation is therefore an important goal. Failure of extubation may be indicated by increasing rates of apnea and bradycardia, increasing oxygen requirements or respiratory acidosis.
Previous reviews suggest that factors such as the use of postextubation nasal CPAP (Davis 1997), the administration of methylxanthines (Henderson-Smart 1997) and in some cases dexamethasone (Davis P 1997), improve the likelihood of successful extubation. The use of these therapies has implications for this comparison of extubation from low rate vs ETT CPAP.
In premature infants having their endotracheal tube removed, is direct extubation from low rate ventilation more successful than extubation following a period of endotracheal CPAP? Success was defined as avoidance of endotracheal reintubation for treatment of apnea/bradycardia, increasing oxygen requirements and respiratory acidosis.
Subgroup analyses were planned to determine whether there were any differences between the group as a whole and subgroups of very low birth weight (VLBW) infants, ie those < 1500g, and extremely low birth weight (ELBW) infants, ie those < 1000g. Analysis according to level of CPAP used (less than 5 cm water vs 5 cm or greater) was also to be undertaken if differences between studies existed.
Sensitivity analysis was planned to investigate the role of potential confounding variables such as the use of postextubation NCPAP, methylxanthines and dexamethasone. Sensitivity analysis according to quality of trial was to be performed if differences existed.
All trials using random or quasi-random patient allocation were included.
Premature infants who received IPPV and were about to have their endotracheal tube removed.
The use of endotracheal CPAP for at least 6 hours prior to extubation.
The primary outcome of interest was the need for reintubation of the trachea.
Secondary outcomes thought worthy of assessment included: rates of chronic lung disease, growth, long term neurological development, rates of intraventricular haemorrhage and radiological outcomes such as post-extubation atelectasis or collapse. Incidence of apneic events was added as a post hoc assessment using the definition of greater than 0.5 events per hour as indicating significant apnea.
See: Cochrane Neonatal Review Group search strategy
The standard search strategy of the Cochrane Neonatal Review Group as
outlined in The Cochrane Library was used. This included searches of the
Oxford Database of Perinatal Trials, The Cochrane Central Register of Controlled
Trials (CENTRAL, The Cochrane Library, Issue 1, 2003): text words - extubation
and neonatal}, MEDLINE {PubMed - 1966 to March 2003: Infant, Newborn (explode)
[MeSH heading] and Positive Pressure Respiration (explode) [MeSH heading]
and extubation [text word]}, previous reviews including cross references,
abstracts, conferences, symposia proceedings, expert informants and journal
hand searching mainly in the English language.
Criteria and methods used to assess the methodological quality of the
included trials:
The standard method of the Cochrane Collaboration and its Neonatal Review
Group was used. The methodological quality of each trial was reviewed by
the second author blinded to trial authors and institutions.
Methods used to collect data from the included trials:
Each author extracted data separately before comparison and resolution
of differences.
Methods used to synthesise data:
Standard method of the Neonatal Review Group with the use of relative
risk (RR) and risk difference (RD). The number needed to treat (NNT) was
calculated as the inverse of the RD.
Subgroup analysis was planned to determine whether there was a difference in response between the group of premature infants as a whole and VLBW and ELBW infants. Sensitivity analysis was planned to investigate the role of potential confounding variables such as the use of nasal CPAP post-extubation, methylxanthines and dexamethasone. Analysis on the basis of trial quality, ie randomized or quasi-randomized, was performed on a post hoc basis.
Using the search strategy described above, three clinical trials were identified which addressed the issue of whether extubation of infants directly from IPPV was more successful than extubation following a short period of endotracheal CPAP. In two of the studies (Kim 1989 and Kim 1987) the ETT CPAP group was designated as the control group. This convention is followed throughout this review. A full description of each study is included in the Table, Characteristics of Included Studies. No trials were excluded from the review and no ongoing trials were identified.
Kim 1987 and Tapia 1995 recruited infants less than 1250g and 1500g respectively. Kim 1989 excluded infants with size 2.5 ETTs and therefore enrolled a population that was both heavier (mean birthweight 1.93kg) and more mature (mean gestational age 33 weeks). Almost all infants studied were treated prophylactically with aminophylline and all were weaned to minimal levels of IPPV before study commencement. Surfactant usage was confined to a small subgroup of babies recruited in the latter stages of the trial of Tapia. All three studies excluded infants with conditions which might make successful extubation less likely, eg neuromuscular disorders, patent ductus arteriosus, CNS depressant medication.
Following removal of their endotracheal tube, infants in the trials of Kim 1989 and Kim 1987 were placed in headbox oxygen. The trial of Tapia 1995 allocated infants to either headbox oxygen or nasal CPAP following direct extubation and to headbox only following ETT CPAP. The use of dexamethasone, either as a short course to facilitate extubation or as a longer course as treatment for chronic lung disease, is not recorded in any of the trials.
All three trials used low levels of ETT CPAP, ranging from as low as 2
cm water in the trial of Kim and Boutwell, to a maximum of 4 cm in the
trial of Tapia.
The criteria for reintubation were similar across the studies. These
included frequent apnea (greater than 2/hour for Kim
1989 and Kim 1987 and greater than 3/hour
for Tapia) or apnea requiring positive pressure ventilation and respiratory
acidosis. Tapia had the additional indication for reintubation of the need
for greater than 60% inspired oxygen concentration.
It was possible to derive the proportion of infants having clinically
important apneic events, ie more frequently than 0.5/hour, in the trials
of Kim 1989 and Kim 1987.
This was not possible in the trial of Tapia 1995
in which only the presence or absence of apnea was noted.
No trials reported rates of IVH, CLD, growth or Xray changes determined throughout the in-hospital stay or long term neurodevelopmental follow-up.
Full details are provided in the Table, Characteristics of Included Studies.
Method of subject allocation:
The trials of Kim 1989 and Kim 1987 were randomized controlled trials although
only the former specified the use of sequentially numbered sealed envelopes.
The trial of Tapia 1995 used a method of allocation
in which subjects were sequentially allocated to each of 3 groups (communication
with author).
Masking of caregivers:
The nature of the intervention meant that caregivers were aware of the
group of assignment.
Completeness of outcome assessment:
This was greater than 90% in all trials.
Masking of outcome assessors:
This was not performed.
There was no disagreement between reviewers with respect to quality assessment done independently.
The use of a period of ETT CPAP prior to removal of the endotracheal tube confers no advantage over direct extubation. Using the summary statistic, relative risk (RR), there is a trend favouring direct extubation which does not reach statistical significance 0.45 (0.19, 1.07); however, the risk difference (RD) shows a significant difference of -0.103 (-0.200,-0.006) giving a number needed to treat (NNT) of 10 (5,167). When the quasi-randomized trial of Tapia is excluded a statistically significant benefit of direct extubation is observed: summary RR 0.10 (0.01,0.78), RD -0.201 (-0.319,-0.083) and NNT 5 (3,12).
Sub-analysis on the basis of care received after removal of the endotracheal tube shows that the benefits of direct extubation are sustained when extubation is to headbox oxygen - RR 0.21 (0.06.0.72), RD -0.151 (-0.246,-0.057), NNT 7 (4,18). There were no trials in which both groups were managed with NCPAP after removal of the endotracheal tube. There is no difference between direct extubation and ETT CPAP groups when the direct extubation group only is managed with NCPAP. This result should be interpreted with caution given that the same trial of Tapia was the "outlier" in the meta-analysis of trials evaluating the usefulness of post-extubation NCPAP (Davis and Henderson-Smart) which concluded that NCPAP was more effective than headbox oxygen.
The use of ETT CPAP is associated with a trend towards increased frequency of apnea when all three trials are considered. Exclusion of the trial by Tapia on the basis of quality again leads to this result achieving statistical significance: RR 0.15 (0.03,0.77), RD -0.202 (-0.337,-0.067), NNT 5 (3,15).
Planned subgroup analysis on the basis of the level of ETT CPAP applied (high or low) was not performed because all trials used a pressure less than 5 cm water.
The use of a trial of ETT CPAP, at pressures of 2 to 4 cm water, as the
final stage of weaning ventilator rate prior to extubation is not supported
by this meta-analysis. Successful extubation is more likely if infants
are extubated directly from a low rate of IPPV. Physiological reasons for
this result have been mentioned previously - when small infants breathe
through endotracheal tubes with narrow diameters, airway resistance and
therefore work of breathing increase to a point where spontaneous respirations
are unable to be sustained. It is possible that higher levels of CPAP might
be more effective but there are no data available to evaluate this.
The potential confounding variables, use of methylxanthines and post-natal
steroids, were not able to be assessed because of the almost universal
usage of the former and lack of usage of the latter. Nasal CPAP has been
shown in a previous review to be effective in facilitating extubation. Its
impact on the question posed in the current review is not able to be determined.
The two trials that were truly randomized did not use NCPAP for post-extubation
care and the quasi-randomized trial of Tapia used this method of treatment
only for infants directly extubated from IPPV.
Direct subgroup analysis on the basis of birthweight is not possible using the published data from these trials. However inferences may be drawn on the basis of the trials of Kim 1989 and Kim 1987. The former trial enrolled only infants with a size 2.5 mm endotracheal tube and the latter excluded these infants and enrolled only infants having 3.0 and 3.5 mm diameter tubes. Since choice of size of endotracheal tube is influenced mainly by weight these trials provide information relevant to the question of whether the effect of ETT CPAP differs according to weight of the neonate. It appears that ETT CPAP is more strongly associated with adverse outcomes in smaller infants (with smaller endotracheal tubes) than it is in larger infants.
Premature infants no longer requiring endotracheal intubation and IPPV should be directly extubated without a trial of ETT CPAP.
Future trials may address the issue of whether higher levels of ETT CPAP are useful in this situation.
The reviewers wish to acknowledge the additional information kindly provided by Dr. Tapia in regard to his 1995 trial.
None
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Kim 1987 | 1) Blinding of randomization - yes: method not specified 2) Blinding of intervention - no 3) Complete followup - yes 4) Blinding of outcome measurement - no |
Included: infants <1250g, ventilated more than 12 hours
but less than 28 days via 2.5mm endotracheal tube. Almost all (23/27)
treated with aminophylline. Reached minimal levels of ventilation - rate
6 to 10, PIP < 16, PEEP = 3 (>1kg) or 2 (<1kg). Excluded: infants with neuromuscular disorders or on CNS depressant medication. |
Direct extubation from a ventilator rate of between 6 and 10 or extubation following a 6 hour trial on endotracheal CPAP (at a level = PEEP before randomization) | Failure = need to resume IPPV because either 1) 2 or more episodes of apnea or bradycardia requiring vigorous stimulation within 30 minutes, 2) any use of IPPV for profound apnea or bradycardia or 3) respiratory acidosis with pH < 7.3 (CO2 not specified) | Length of time after extubation during which an infant could fail is not specified. Obligatory crossover after failure. | B |
| Kim 1989 | 1) Blinding of randomization - yes: sequentially numbered sealed
envelopes 2) Blinding of intervention - no 3) Complete followup - yes 4) Blinding of outcome measurement - no |
Included: all newborn infants intubated with a size 3.0 or
3.5 ETT and ventilated > 12 hours. All infants < 37 weeks gestation
received theophylline. Excluded: infants with neuromuscular disorders, apnea and bradycardia in 24 hours pre-extubation, CNS depressant medication. |
Direct extubation from IPPV or extubation following 6 hours of ETT CPAP (3 cm water). Both groups extubated to headbox oxygen. | Resumption of IPPV for either : 1) 2 episodes of severe apnea/bradycardia requiring vigorous stimulation within 30 minutes 2) apnea/bradycardia requiring IPPV 3) Respiratory acidosis with pH < 7.30 Assessed for the 6 hour period following randomization. |
Infants stratified according to diameter of ETT ie 3.0 or 3.5
mm. After failure, infants were crossed over to the alternate strategy. |
A |
| Tapia 1995 | 1) Blinding of randomization - no: sequential assignment of
infants to each of 3 groups 2) Blinding of intervention - no 3) Complete follow-up - yes (3/90 lost after randomization because accidental extubation) 4) Blinding of outcome measurement - no |
Included: preterm infants < 1500g admitted to either of
2 participating centres, ventilated for > 48 hours and weaned to minimal,
defined levels of ventilatory support Excluded: infants with sepsis, necrotizing enterocolitis, symptomatic patent ductus arteriosus, major congenital malformations, neuromuscular disorders, grade 3 or 4 intraventricular hemorrhage or other severe neurological damage. |
Direct extubation from IPPV to either headbox or NCPAP or extubation to headbox following 12 -24 hours of ETT CPAP (3-4 cm water). | Failure of extubation indicated by the need for the reventilation
within 72 hours for 1) apnea - frequent or severe, 2) respiratory acidosis (pH < 7.25 and pCO2 > 60, or 3) need for inspired oxygen concentration > 60%. |
Quasi-randomized design. Allocation by "systematic sampling" was in fact sequential assignment to 3 groups in rotation (information from author). Surfactant usage was confined to one of two centres involved and for less than one third of the trial's recruitment time. | C |
Kim EH, Boutwell WC. Successful direct extubation of very low birth weight infants from low intermittent mandatory ventilation rate. Pediatrics 1987;80:409-414.
Kim 1989 {published data only}
Kim EH. Successful extubation of newborn infants without preextubation trial of continuous positive airway pressure. J Perinatol 1989;9:72-76.
Tapia 1995 {published data only}
Tapia J, Bancalari A, Gonzalez A, Mercado M. Does continuous positive airways pressure (CPAP) during weaning from intermittent mandatory ventilation in very low birthweight infants have risks or benefits? A controlled trial. Ped Pulmonol 1995;19:269-279.
* indicates the primary reference for the study
Davis PG, Henderson-Smart DJ. Prophylactic post-extubation nasal CPAP in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 1997. Oxford: Update Software.
Davis PG, Henderson-Smart DJ. Intravenous dexamethasone in neonates being extubated (Cochrane Review). In: The Cochrane Library, Issue 4, 1997. Oxford: Update Software.
Henderson-Smart DJ, Davis PG. Prophylactic methylxanthine for extubation in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 1997. Oxford: Update Software.
LeSouef PN, England SJ, Bryan AC. Total resistance of the respiratory system in preterm infants with and without an endotracheal tube. J Pediatr 1984;104:108-111.
Lopes JM, Muller NL, Bryan MH, Bryan AC. Synergistic behaviour of inspiratory muscles after diaphragmatic fatigue in the newborn. J Appl Physiol 1981;51:547-551.
Nugent J, Matthews BJ, Goldsmith JP. Pulmonary care. In: Goldsmith and Karotkin, editor(s). Assisted ventilation of the neonate. Philadelphia: WB Saunders, 1988:103-4.
Davis PG, Henderson-Smart DJ. Extubation from low-rate intermittent positive airway pressure versus extubation after a trial of endotracheal continuous positive airway pressure in intubated preterm infants (Cochrane Review). In: The Cochrane Library, Issue 3, 1998. Oxford: Update Software.
Davis PG, Henderson-Smart DJ. Extubation from low-rate intermittent positive airways pressure versus extubation after a trial of endotracheal continuous positive airways pressure in intubated preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software.
01.01 Extubation failure
01.02 Extubation failure (extubated to headbox)
01.03 Extubation failure (extubated to NCPAP)
01.04 Extubation failure (true RCTs only)
01.05 Apnea
01.06 Apnea (true RCTs only)
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Extubation from IPPV vs ETT CPAP | ||||
| 01 Extubation failure | 3 | 174 | RR (fixed), 95% CI | 0.45 [0.19, 1.07] |
| 02 Extubation failure (extubated to headbox) | 3 | 145 | RR (fixed), 95% CI | 0.21 [0.06, 0.72] |
| 03 Extubation failure (extubated to NCPAP) | 1 | 57 | RR (fixed), 95% CI | 1.69 [0.55, 5.14] |
| 04 Extubation failure (true RCTs only) | 2 | 87 | RR (fixed), 95% CI | 0.10 [0.01, 0.78] |
| 05 Apnea | 3 | 174 | RR (fixed), 95% CI | 0.66 [0.35, 1.25] |
| 06 Apnea (true RCTs only) | 2 | 87 | RR (fixed), 95% CI | 0.15 [0.03, 0.77] |
| This review is published as a Cochrane review
in The Cochrane Library 2003, Issue 3, 2003 (see www.CochraneLibrary.net
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. |
