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What interventions facilitate weaning from the ventilator? A review of the evidence from systematic reviews
PAEDIATRIC RESPIRATORY REVIEWS (2004) 5(Suppl A), S347–S352
What interventions facilitate weaning from the ventilator? A review of the evidence from systematic reviews Henry L. Halliday° Department of Child Health, Queens, University of Belfast and Regional Neonatal Unit, Royal Maternity Hospital, Belfast, Northern Ireland
Summary Introduction: Mechanical ventilation is life saving for many very preterm babies but prolonged use can have adverse effects increasing the risk of subglottic injury and chronic lung disease (CLD). Shorter ventilation should reduce these risks and a number of interventions have been tested to facilitate earlier extubation. Methods: The Cochrane Library was searched for systematic reviews of randomised controlled trials of interventions to facilitate extubation and reduce post-extubation atelectasis. These interventions included nasal continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), chest physiotherapy, intravenous dexamethasone and methylxanthine treatment. Outcomes are given as numbers needed to treat (NNT) with 95% confidence intervals (CI). Results: Nasal CPAP reduces the incidence of adverse effects after extubation including failure (NNT 6; 95% CI 4–15) and CLD at 28 days (NNT 6; 95% CI 3–22). NIPPV is superior to nasal CPAP at preventing extubation failure (NNT 3; 95% CI 2–5). Chest physiotherapy after extubation does not reduce alveolar atelectasis but it decreases need for re-intubation (NNT 6; 95% CI 4–23). Chest physiotherapy needs to be given 1–2 hourly to obtain this effect. Intravenous dexamethasone reduces the need for re-intubation (NNT 6; 95% CI 3–250) but adverse effects preclude its routine use. Methylxanthines also improve the chances of successful extubation (NNT 4; 95% CI 2–7) and the effect is greatest in infants <1000 g birthweight and <7 days postnatal age (NNT 2; 95% CI 1–8). Conclusions: Nasal CPAP, NIPPV and methylxanthines are evidence-based treatments to facilitate weaning and extubation of preterm infants but only the first 2 can be recommended for routine use. Chest physiotherapy and dexamethasone may be effective but should not be used routinely because of serious adverse effects. © 2004 Elsevier Science Ltd.
INTRODUCTION The first randomised trials of mechanical ventilation for the newborn were conducted in the late 1960s1−3 but in only one was endotracheal intubation used.1 In the other trials intermittent negative pressure ventilation was used.2,3 These and other randomised * Tel.: +44-(2890)-894687; Fax: +44-2890-236203; E-mail: [email protected]; Correspondence address: Regional Neonatal Unit, Royal Maternity Hospital, Grosvenor Road, Belfast BT12 6BB 1526-0542/$ – see front matter
trials of mechanical ventilation demonstrated a significant reduction in neonatal mortality4 (estimated relative risk (ERR) 0.8; 95% confidence interval (CI) 0.68–0.93 and number needed to treat (NNT) 8; 95% CI 5–26). Mechanical ventilation of preterm and term newborns with respiratory failure is now accepted as a life-saving intervention.5 Surfactant treatment for respiratory distress syndrome (RDS) was introduced in the 1980s6 and its use further reduced neonatal mortality and pulmonary air © 2004 Elsevier Science Ltd. All rights reserved.
S348
H.L. HALLIDAY Table 1 Interventions to prevent extubation failure Intervention
Methylxanthines (all)
Number Trials
Babies
RR
95% CI
NNT
95% CI
4
134
0.44
0.27–0.72
4
<1000 g
2
50
0.60
0.30–1.21
–
–
<1000 g + <1 wk
1
32
0.40
0.16–0.95
2
1–8
1
25
0.39
0.19–0.81
2
1–4
Use of CPAP
2–7
Doxapram
1
29
0.80
0.22–2.97
–
–
Nasal CPAP (all)
7
479
0.62
0.49–0.79
2
4–11
>14 d
2
66
1.12
0.58–2.15
–
–
<14 d
5
296
0.57
0.42–0.77
5
3–9
5 cm H2 O
5
300
0.49
0.37–0.66
3
2–5
5 cm H2 O
2
179
1.09
0.69–1.73
–
–
<2000 g
6
461
0.65
0.51–0.84
6
4–14
NIPPV vs nasal CPAP
3
159
0.21
0.10–0.45
3
2–5
IPPV vs CPAP prior to
2
87
0.10
0.01–0.78
5
3–12
leaks.7 Endotracheal intubation is necessary to administer surfactant and to provide intermittent positive pressure ventilation (IPPV) before and afterwards. Prolonged intubation is associated with complications such as chronic lung disease (CLD), respiratory infections and subglottic stenosis.4 Early weaning from the ventilator to less invasive forms of assisted ventilation such as nasal continuous positive airway pressure (CPAP) is now a top priority for practising neonatologists.8 Failure to extubate may be due to alveolar or lobar atelectasis associated with retained secretions, and/or reduced respiratory drive, both problems that are associated with extreme prematurity. Several interventions have been studied to promote earlier extubation of preterm infants and the aim of this review is to report those that are evidence-based.9
MATERIALS AND METHODS The Cochrane Library (2001) was searched for systematic reviews of randomised controlled trials of interventions to facilitate extubation and reduce post-extubation atelectasis in preterm infants. Such interventions included nasal CPAP, respiratory stimulants, chest physiotherapy and dexamethasone. The outcomes assessed included post-extubation atelectasis, need for re-intubation, failure of extubation and need for supplemental oxygen at 28 days.9 Each systematic review reported a number of meta-analyses and the results were given as relative risks (RR) with 95% CI and NNT also with 95% CI.10 Ten systematic reviews dealt with various aspects of weaning from ventilation11−20 but one contained no
randomised controlled trials.19 Failure of extubation was defined as need for re-intubation within 5 days,21 7 days22 or at any time23 and cross over from headbox to nasal CPAP or vice versa.24−26 Postextubation atelectasis was defined as lobar in 3 trials27−29 and was not stated in 4 trials.30−33
RESULTS Extubation failure Methylxanthines, doxapram, nasal CPAP and NIPPV have been used to try to prevent extubation failure (Table 1). Many of the systematic reviews contained small numbers of trials and almost half had less than 100 babies in total. Nevertheless, many of these interventions appear to be successful at preventing extubation failure. Nasal CPAP after extubation was assessed in 7 trials comprising 479 babies. The NNT for prevention of extubation failure is 6 (95% CI 4–11). When subgroups are assessed it would appear that nasal CPAP is successful when used within 14 days of birth, with a pressure of 5 or more cm H2 O and in infants of <2000 g birth weight. Three trials showed that NIPPV is even more effective than nasal CPAP at preventing extubation failure (NNT 3; 95% CI 2–5). Methylxanthines are also effective at preventing extubation failure (NNT 4; 95% CI 2–7). Use of CPAP with methylxanthine treatment is even more effective (NNT 2; 95% CI 1–4). Success in babies of <1000 g birth weight is more likely if extubation occurs in the first week of life (NNT 2; 95% CI 1–8). Doxapram was studied in one small trial and found to be ineffective.
WEANING NEONATES FROM VENTILATION
S349
Table 2 Need for re-intubation Intervention
RR
Number Trials
95% CI
NNT
95% CI
Babies
Nasal CPAP (all)
7
279
0.84
0.64–1.10
–
–
NIPPV vs nasal CPAP
3
159
0.39
0.16–0.97
9
5–83
Chest physiotherapy (all)
3
138
0.24
0.08–0.75
6
4–23
1–2 hourly
3
108
0.14
0.03–0.63
5
3–12
4 hourly
2
61
0.80
0.21–2.99
–
Dexamethasone
3
160
0.18
0.04–0.97
12
Oral vs nasal tube prior to
2
160
0.61
0.28–1.33
–
Number
RR
95% CI
NNT
95% CI
– 6–100 –
Table 3 Post-extubation atelectasis Intervention
Trials
Babies
3
138
1.69
0.33–1.45
–
–
1–2 hourly
3
108
0.61
0.28–1.33
–
–
4 hourly
2
61
1.45
0.51–4.09
–
–
Dexamethasone
2
110
0.54
0.19–1.53
–
–
Oral vs nasal tube prior to
2
160
0.54
0.31–0.92
6
3–37
Chest physiotherapy (all)
In another 2 trials extubation after a period of endotracheal CPAP was compared to extubation from low rate IPPV. The latter was found to be more effective in preventing extubation failure (NNT 5; 95% CI 3–12).
atelectasis (Table 3). Perhaps surprisingly the use of an oral rather than a nasal endotracheal tube prior to extubation appears to reduce the risk of postextubation atelectasis (NNT 6; 95% CI 3–37). Other outcomes
Need for re-intubation This is not the same as extubation failure (see Methods). Perhaps surprisingly nasal CPAP was not found to be effective at preventing the need for reintubation (Table 2). NIPPV is more effective than nasal CPAP (NNT 9; 95% CI 5–83). Use of oral or nasal endotracheal tubes prior to extubation does not have a significant effect on this outcome. Chest physiotherapy reduces the need for reintubation (NNT 6; 95% CI 4–23) but apparently only if intensive, 1–2 hourly physiotherapy is performed (NNT 5; 95% CI 3–12). Four hourly chest physiotherapy is ineffective at preventing need for re-intubation. Intravenous dexamethasone just prior to extubation also reduces the need for re-intubation (NNT 12; 95% CI 6–100). Post-extubation atelectasis Chest physiotherapy and intravenous dexamethasone are ineffective at preventing post-extubation
No intervention significantly reduces the need for supplemental oxygen at either 28 days or 36 weeks corrected age (Table 4). However, further trials of NIPPV versus nasal CPAP might be warranted as there was a trend toward a benefit with the former. Post-extubation stridor is reduced by intravenous dexamethasone just prior to extubation (NNT 6; 95% CI 3–37). Other interventions to reduce time on the ventilator Bronchodilator drugs34 and racemic epinephrine19 have no effect on age of weaning or need to re-intubate. Dexamethasone does reduce time on ventilation.35,36 and diuretics may have a similar effect but only one study has been performed.37 Patient triggered ventilation may also be helpful38 but other trials are needed. Prophylactic or early surfactant treatment can often be followed by extubation to nasal CPAP.8 This shortens the time on the ventilator but does not decrease the risk of CLD.
S350
H.L. HALLIDAY Table 4 Other outcomes RR
95% CI
NNT
95% CI
109
0.39
0.16–0.93
6
3–37
4
283
0.86
0.67–1.10
–
–
1
29
3.20
0.14–72.6
–
–
2
118
0.73
0.49–1.07
–
–
Outcome and intervention
Number Trials
Babies
2
Nasal CPAP Doxapram
Post-extubation stridor Dexamethasone Oxygen at 28 days
Oxygen at 36 weeks NIPPV vs nasal CPAP
DISCUSSION Early weaning of preterm babies from ventilation is clearly desirable to reduce the risk of CLD and other complications associated with prolonged mechanical ventilation. Both immaturity and the severity of initial respiratory distress will be limiting factors preventing routine early extubation of all preterm babies. Preventing immaturity is difficult and often this problem is unavoidable. However, there are some evidence-based interventions to reduce the severity of respiratory distress syndrome. These are prenatal corticosteroids39 and early or prophylactic surfactant.7 Indeed, early use of surfactant in very preterm babies frequently allows immediate extubation to nasal CPAP.8 Similarly surfactant and CPAP from birth might avoid the need for mechanical ventilation in infants of 26 weeks’ gestation and above. Often infants of 23−25 weeks’ gestation, despite prophylactic surfactant, need assisted ventilation because of their extreme immaturity. When mechanical ventilation cannot be avoided early weaning should be the aim. A number of interventions to facilitate early extubation have been studied.9 Of these methylxanthines (aminophylline, theophylline or caffeine),11 CPAP12 and NIPPV13 seem to be effective. Three of the 4 trials of methylxanthine treatment showed a reduction in the use of mechanical ventilation but one small trial of aminophylline showed no benefit.22 One study showed that theophylline was most effective in infants of <1000 g birth weight who were also <1 week old.23 However, the results of these trials do not allow firm recommendations for clinical practice as there are still concerns about potential adverse effects of methylxanthines on the developing central nervous system. These concerns are currently being addressed in the Caffeine for Apnea of Prematurity (CAP) Trial co-ordinated by Dr Barbara Schmidt at McMaster University in Canada. There may be a
role for limited use of methylxanthines in facilitating extubation in infants who are anticipated to have reduced respiratory drive, but these infants, the most immature ones, are those most likely to be affected by any adverse neurological effects of these drugs. Nasal CPAP after extubation reduces apnoea, respiratory acidosis and need for increased supplemental oxygen.12 There is also a trend towards a reduction in the risk of CLD at 28 days. The data support a recommendation to give nasal CPAP following extubation but further studies are needed to define the gestational age and birth-weight groups most likely to benefit. The synchronised form of NIPPV has a clinically important effect in preventing extubation failure and it appears to be superior to nasal CPAP.13 There have been no reports of gastro-intestinal perforation with its use but larger trials will be needed to provide complete reassurance. NIPPV showed a trend towards reducing the risk of CLD at 36 weeks and its use can be recommended after extubation for infants in whom nasal CPAP alone is less likely to be successful. Other interventions such as chest physiotherapy,14 intravenous dexamethasone,15 doxapram16 and nebulised racemic epinephrine19 are either ineffective or associated with unacceptable adverse effects. Vigorous chest physiotherapy after extubation is not associated with a reduction in post-extubation lobar collapse but it does reduce the need for re-intubation if given 1–2 hourly.14 However, there is not enough information on adverse effects, either short or longterm, in very immature infants to recommend routine chest physiotherapy. Intravenous dexamethasone also reduces the need for re-intubation in both a high-risk group of babies and the total population being extubated.15 The high-risk group were those who had traumatic or multiple intubations or were intubated for >14 days. The incidence of extubation failure in the low-
WEANING NEONATES FROM VENTILATION risk group was zero and adverse effects of hyperglycaemia and glycosuria were reported. Any recommendation to use intravenous dexamethasone in a high-risk group for airway edema must be tempered with the reported long-term adverse neurological effects of this drug.35 Two trials of doxapram demonstrated no effect on failed extubation, duration of IPPV or respiratory failure.16 There were also trends towards increased side effects of hypertension and irritability. There is no evidence to support routine use of doxapram to assist extubation. Two systematic reviews addressed the effects of ventilation settings prior to extubation on outcome.17,18 There was a trend towards an increased chance of successful extubation from low rate IPPV compared with endotracheal CPAP.17 This was a significant benefit when only truly randomised trials were considered and this is also true for a reduction in post-extubation apnoea. Therefore, it is safe to extubate from low rate IPPV and it is not necessary to try endotracheal CPAP first. Of the 2 trials comparing nasal and oral endotracheal intubation one found that postextubation atelectasis occurred more frequently in the nasal group who weighed <1500 g.32 However, there was no difference in the need for re-intubation. There is no convincing evidence to recommend either route of endotracheal intubation and larger trials would be needed to assess any worthwhile clinical differences in outcome.18 In conclusion, although nasal CPAP, NIPPV and methylxanthines are evidence-based treatments to facilitate weaning and extubation of preterm infants, only the first 2 can be recommended for routine use.
S351
8.
9. 10.
11.
12.
13.
14.
15.
16.
17.
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In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD000511. Verder H, Albertsen P, Ebbesen F, et al. Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 week’s gestation. Pediatrics 1999; 103: e24. Halliday HL. Towards earlier neonatal extubation. Lancet 2000; 355: 2091−2092. The Cochrane Library incorporating the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effectiveness, the Cochrane Controlled Trials Register and the Cochrane Review Methodology Database. Summertown Pavilion, Issue 4, 2001. Oxford: Update Software. Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 0000139. Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 0000143. Davis PC, Lemyre B, De Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 003212. Flenady VJ, Gray PH. Chest physiotherapy for preventing morbidity in babies being extubated from mechanical ventilation (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 000283. Davis PG, Henderson-Smart DJ. Intravenous dexamethasone for extubation of newborn infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 000308. Henderson-Smart DJ, Davis PG. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 001966. 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, CD 001078. Spence K, Barr P. Nasal versus oral intubation for mechanical ventilation of newborn infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 000948. Davis MW, Davis PG. Nebulized racemic epinephrine for extubation of newborn infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 000506. Markovitz BP, Randolph AG. Corticosteroids for the prevention and treatment of post-extubation stridor in neonates, children and adults (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 001000. Viscardi M, Faix RG, Nicks JJ, Grasela TH. Efficacy of theophylline for prevention of post-extubation respiratory failure in very low birthweight infants. J Pediatr 1985; 107: 469−472. Barrington KJ, Finer NN. A randomized controlled trial of aminophylline in ventilatory weaning of premature infants. Crit Care Med 1993; 21: 846−850. Durand DJ, Goodman A, Ray P, Ballard RA, Clyman R. Theophylline treatment in the extubation of infants weighing
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less than 1250 grams: a controlled trial. Pediatrics 1987; 80: 684−688. Higgins RD, Richter SE, Davis JM. Nasal continuous positive pressure facilitates extubation of very low birthweight neonates. Pediatrics 1991; 88: 999−1003. Engelke SC, Roloff DW, Kuhns LR. Post extubation nasal continuous positive airway pressure. Am J Dis Child 1982; 136: 359−361. Davis P, Jankov R, Doyle L, Henschke P. Randomized, controlled trial of nasal continuous positive airway pressure in the extubation of infants weighing 600–1250 g. Arch Dis Child Fetal Neonatal Ed 1998; 79: F54−F57. Finer NN, Boyd DPT. Chest physiotherapy in the neonate: a controlled study. Pediatrics 1978; 61: 282−285. Finer N, Moriartey R, Boyd J, Phillips H, Stewart A, Ulan O. Post-extubation atelectasis: a retrospective review and a prospective controlled study. J Pediatr 1979; 94: 110−113. Al-Alaiyan S, Dyer D, Khan B. Chest physiotherapy and postextubation atelectasis in infants. Pediatr Pulmonol 1996; 21: 227−230. Ferrara TB, Georgieff MIC, Ebert J, Figher JB. Routine use of dexamethasone for prevention of post-extubation respiratory distress. J Perinatol 1989; 9: 287−290. Courtney SE, Weber KR, Siervogel RM, et al. Effects of dexamethasone on pulmonary function following extubation. J Perinatol 1992; 12: 246−251. Spitzer AR, Fox WW. Post extubation atelectasis – the role of oral versus nasal endotracheal tubes. J Pediatr 1982; 100: 806−810.
H.L. HALLIDAY 33. McMillan DD, Rademaker AW, Buchan KA, Reid A, Machin G, Sauve RS. Benefits of orotracheal and nasotracheal intubation in neonates requiring ventilatory assistance. Pediatrics 1986; 77: 39−44. 34. Ng GYT, de Silva O, Ohlsson A. Bronchodilators for the prevention of chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 003214. 35. Halliday HL, Ehrenkranz RA. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 001146. 36. Halliday HL, Ehrenkranz RA. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 001144. 37. Brion LP, Soll RF. Diuretics for respiratory distress syndrome in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 001454. 38. Greenough A, Milner AD, Dimitriou G. Synchronized mechanical ventilation for respiratory support in newborn infants. (Cochrane Review) In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 000456. 39. Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software, CD 000065.
What interventions facilitate weaning from the ventilator? A review of the evidence from systematic reviews Henry L. Halliday° Department of Child Health, Queens, University of Belfast and Regional Neonatal Unit, Royal Maternity Hospital, Belfast, Northern Ireland
Summary Introduction: Mechanical ventilation is life saving for many very preterm babies but prolonged use can have adverse effects increasing the risk of subglottic injury and chronic lung disease (CLD). Shorter ventilation should reduce these risks and a number of interventions have been tested to facilitate earlier extubation. Methods: The Cochrane Library was searched for systematic reviews of randomised controlled trials of interventions to facilitate extubation and reduce post-extubation atelectasis. These interventions included nasal continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), chest physiotherapy, intravenous dexamethasone and methylxanthine treatment. Outcomes are given as numbers needed to treat (NNT) with 95% confidence intervals (CI). Results: Nasal CPAP reduces the incidence of adverse effects after extubation including failure (NNT 6; 95% CI 4–15) and CLD at 28 days (NNT 6; 95% CI 3–22). NIPPV is superior to nasal CPAP at preventing extubation failure (NNT 3; 95% CI 2–5). Chest physiotherapy after extubation does not reduce alveolar atelectasis but it decreases need for re-intubation (NNT 6; 95% CI 4–23). Chest physiotherapy needs to be given 1–2 hourly to obtain this effect. Intravenous dexamethasone reduces the need for re-intubation (NNT 6; 95% CI 3–250) but adverse effects preclude its routine use. Methylxanthines also improve the chances of successful extubation (NNT 4; 95% CI 2–7) and the effect is greatest in infants <1000 g birthweight and <7 days postnatal age (NNT 2; 95% CI 1–8). Conclusions: Nasal CPAP, NIPPV and methylxanthines are evidence-based treatments to facilitate weaning and extubation of preterm infants but only the first 2 can be recommended for routine use. Chest physiotherapy and dexamethasone may be effective but should not be used routinely because of serious adverse effects. © 2004 Elsevier Science Ltd.
INTRODUCTION The first randomised trials of mechanical ventilation for the newborn were conducted in the late 1960s1−3 but in only one was endotracheal intubation used.1 In the other trials intermittent negative pressure ventilation was used.2,3 These and other randomised * Tel.: +44-(2890)-894687; Fax: +44-2890-236203; E-mail: [email protected]; Correspondence address: Regional Neonatal Unit, Royal Maternity Hospital, Grosvenor Road, Belfast BT12 6BB 1526-0542/$ – see front matter
trials of mechanical ventilation demonstrated a significant reduction in neonatal mortality4 (estimated relative risk (ERR) 0.8; 95% confidence interval (CI) 0.68–0.93 and number needed to treat (NNT) 8; 95% CI 5–26). Mechanical ventilation of preterm and term newborns with respiratory failure is now accepted as a life-saving intervention.5 Surfactant treatment for respiratory distress syndrome (RDS) was introduced in the 1980s6 and its use further reduced neonatal mortality and pulmonary air © 2004 Elsevier Science Ltd. All rights reserved.
S348
H.L. HALLIDAY Table 1 Interventions to prevent extubation failure Intervention
Methylxanthines (all)
Number Trials
Babies
RR
95% CI
NNT
95% CI
4
134
0.44
0.27–0.72
4
<1000 g
2
50
0.60
0.30–1.21
–
–
<1000 g + <1 wk
1
32
0.40
0.16–0.95
2
1–8
1
25
0.39
0.19–0.81
2
1–4
Use of CPAP
2–7
Doxapram
1
29
0.80
0.22–2.97
–
–
Nasal CPAP (all)
7
479
0.62
0.49–0.79
2
4–11
>14 d
2
66
1.12
0.58–2.15
–
–
<14 d
5
296
0.57
0.42–0.77
5
3–9
5 cm H2 O
5
300
0.49
0.37–0.66
3
2–5
5 cm H2 O
2
179
1.09
0.69–1.73
–
–
<2000 g
6
461
0.65
0.51–0.84
6
4–14
NIPPV vs nasal CPAP
3
159
0.21
0.10–0.45
3
2–5
IPPV vs CPAP prior to
2
87
0.10
0.01–0.78
5
3–12
leaks.7 Endotracheal intubation is necessary to administer surfactant and to provide intermittent positive pressure ventilation (IPPV) before and afterwards. Prolonged intubation is associated with complications such as chronic lung disease (CLD), respiratory infections and subglottic stenosis.4 Early weaning from the ventilator to less invasive forms of assisted ventilation such as nasal continuous positive airway pressure (CPAP) is now a top priority for practising neonatologists.8 Failure to extubate may be due to alveolar or lobar atelectasis associated with retained secretions, and/or reduced respiratory drive, both problems that are associated with extreme prematurity. Several interventions have been studied to promote earlier extubation of preterm infants and the aim of this review is to report those that are evidence-based.9
MATERIALS AND METHODS The Cochrane Library (2001) was searched for systematic reviews of randomised controlled trials of interventions to facilitate extubation and reduce post-extubation atelectasis in preterm infants. Such interventions included nasal CPAP, respiratory stimulants, chest physiotherapy and dexamethasone. The outcomes assessed included post-extubation atelectasis, need for re-intubation, failure of extubation and need for supplemental oxygen at 28 days.9 Each systematic review reported a number of meta-analyses and the results were given as relative risks (RR) with 95% CI and NNT also with 95% CI.10 Ten systematic reviews dealt with various aspects of weaning from ventilation11−20 but one contained no
randomised controlled trials.19 Failure of extubation was defined as need for re-intubation within 5 days,21 7 days22 or at any time23 and cross over from headbox to nasal CPAP or vice versa.24−26 Postextubation atelectasis was defined as lobar in 3 trials27−29 and was not stated in 4 trials.30−33
RESULTS Extubation failure Methylxanthines, doxapram, nasal CPAP and NIPPV have been used to try to prevent extubation failure (Table 1). Many of the systematic reviews contained small numbers of trials and almost half had less than 100 babies in total. Nevertheless, many of these interventions appear to be successful at preventing extubation failure. Nasal CPAP after extubation was assessed in 7 trials comprising 479 babies. The NNT for prevention of extubation failure is 6 (95% CI 4–11). When subgroups are assessed it would appear that nasal CPAP is successful when used within 14 days of birth, with a pressure of 5 or more cm H2 O and in infants of <2000 g birth weight. Three trials showed that NIPPV is even more effective than nasal CPAP at preventing extubation failure (NNT 3; 95% CI 2–5). Methylxanthines are also effective at preventing extubation failure (NNT 4; 95% CI 2–7). Use of CPAP with methylxanthine treatment is even more effective (NNT 2; 95% CI 1–4). Success in babies of <1000 g birth weight is more likely if extubation occurs in the first week of life (NNT 2; 95% CI 1–8). Doxapram was studied in one small trial and found to be ineffective.
WEANING NEONATES FROM VENTILATION
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Table 2 Need for re-intubation Intervention
RR
Number Trials
95% CI
NNT
95% CI
Babies
Nasal CPAP (all)
7
279
0.84
0.64–1.10
–
–
NIPPV vs nasal CPAP
3
159
0.39
0.16–0.97
9
5–83
Chest physiotherapy (all)
3
138
0.24
0.08–0.75
6
4–23
1–2 hourly
3
108
0.14
0.03–0.63
5
3–12
4 hourly
2
61
0.80
0.21–2.99
–
Dexamethasone
3
160
0.18
0.04–0.97
12
Oral vs nasal tube prior to
2
160
0.61
0.28–1.33
–
Number
RR
95% CI
NNT
95% CI
– 6–100 –
Table 3 Post-extubation atelectasis Intervention
Trials
Babies
3
138
1.69
0.33–1.45
–
–
1–2 hourly
3
108
0.61
0.28–1.33
–
–
4 hourly
2
61
1.45
0.51–4.09
–
–
Dexamethasone
2
110
0.54
0.19–1.53
–
–
Oral vs nasal tube prior to
2
160
0.54
0.31–0.92
6
3–37
Chest physiotherapy (all)
In another 2 trials extubation after a period of endotracheal CPAP was compared to extubation from low rate IPPV. The latter was found to be more effective in preventing extubation failure (NNT 5; 95% CI 3–12).
atelectasis (Table 3). Perhaps surprisingly the use of an oral rather than a nasal endotracheal tube prior to extubation appears to reduce the risk of postextubation atelectasis (NNT 6; 95% CI 3–37). Other outcomes
Need for re-intubation This is not the same as extubation failure (see Methods). Perhaps surprisingly nasal CPAP was not found to be effective at preventing the need for reintubation (Table 2). NIPPV is more effective than nasal CPAP (NNT 9; 95% CI 5–83). Use of oral or nasal endotracheal tubes prior to extubation does not have a significant effect on this outcome. Chest physiotherapy reduces the need for reintubation (NNT 6; 95% CI 4–23) but apparently only if intensive, 1–2 hourly physiotherapy is performed (NNT 5; 95% CI 3–12). Four hourly chest physiotherapy is ineffective at preventing need for re-intubation. Intravenous dexamethasone just prior to extubation also reduces the need for re-intubation (NNT 12; 95% CI 6–100). Post-extubation atelectasis Chest physiotherapy and intravenous dexamethasone are ineffective at preventing post-extubation
No intervention significantly reduces the need for supplemental oxygen at either 28 days or 36 weeks corrected age (Table 4). However, further trials of NIPPV versus nasal CPAP might be warranted as there was a trend toward a benefit with the former. Post-extubation stridor is reduced by intravenous dexamethasone just prior to extubation (NNT 6; 95% CI 3–37). Other interventions to reduce time on the ventilator Bronchodilator drugs34 and racemic epinephrine19 have no effect on age of weaning or need to re-intubate. Dexamethasone does reduce time on ventilation.35,36 and diuretics may have a similar effect but only one study has been performed.37 Patient triggered ventilation may also be helpful38 but other trials are needed. Prophylactic or early surfactant treatment can often be followed by extubation to nasal CPAP.8 This shortens the time on the ventilator but does not decrease the risk of CLD.
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H.L. HALLIDAY Table 4 Other outcomes RR
95% CI
NNT
95% CI
109
0.39
0.16–0.93
6
3–37
4
283
0.86
0.67–1.10
–
–
1
29
3.20
0.14–72.6
–
–
2
118
0.73
0.49–1.07
–
–
Outcome and intervention
Number Trials
Babies
2
Nasal CPAP Doxapram
Post-extubation stridor Dexamethasone Oxygen at 28 days
Oxygen at 36 weeks NIPPV vs nasal CPAP
DISCUSSION Early weaning of preterm babies from ventilation is clearly desirable to reduce the risk of CLD and other complications associated with prolonged mechanical ventilation. Both immaturity and the severity of initial respiratory distress will be limiting factors preventing routine early extubation of all preterm babies. Preventing immaturity is difficult and often this problem is unavoidable. However, there are some evidence-based interventions to reduce the severity of respiratory distress syndrome. These are prenatal corticosteroids39 and early or prophylactic surfactant.7 Indeed, early use of surfactant in very preterm babies frequently allows immediate extubation to nasal CPAP.8 Similarly surfactant and CPAP from birth might avoid the need for mechanical ventilation in infants of 26 weeks’ gestation and above. Often infants of 23−25 weeks’ gestation, despite prophylactic surfactant, need assisted ventilation because of their extreme immaturity. When mechanical ventilation cannot be avoided early weaning should be the aim. A number of interventions to facilitate early extubation have been studied.9 Of these methylxanthines (aminophylline, theophylline or caffeine),11 CPAP12 and NIPPV13 seem to be effective. Three of the 4 trials of methylxanthine treatment showed a reduction in the use of mechanical ventilation but one small trial of aminophylline showed no benefit.22 One study showed that theophylline was most effective in infants of <1000 g birth weight who were also <1 week old.23 However, the results of these trials do not allow firm recommendations for clinical practice as there are still concerns about potential adverse effects of methylxanthines on the developing central nervous system. These concerns are currently being addressed in the Caffeine for Apnea of Prematurity (CAP) Trial co-ordinated by Dr Barbara Schmidt at McMaster University in Canada. There may be a
role for limited use of methylxanthines in facilitating extubation in infants who are anticipated to have reduced respiratory drive, but these infants, the most immature ones, are those most likely to be affected by any adverse neurological effects of these drugs. Nasal CPAP after extubation reduces apnoea, respiratory acidosis and need for increased supplemental oxygen.12 There is also a trend towards a reduction in the risk of CLD at 28 days. The data support a recommendation to give nasal CPAP following extubation but further studies are needed to define the gestational age and birth-weight groups most likely to benefit. The synchronised form of NIPPV has a clinically important effect in preventing extubation failure and it appears to be superior to nasal CPAP.13 There have been no reports of gastro-intestinal perforation with its use but larger trials will be needed to provide complete reassurance. NIPPV showed a trend towards reducing the risk of CLD at 36 weeks and its use can be recommended after extubation for infants in whom nasal CPAP alone is less likely to be successful. Other interventions such as chest physiotherapy,14 intravenous dexamethasone,15 doxapram16 and nebulised racemic epinephrine19 are either ineffective or associated with unacceptable adverse effects. Vigorous chest physiotherapy after extubation is not associated with a reduction in post-extubation lobar collapse but it does reduce the need for re-intubation if given 1–2 hourly.14 However, there is not enough information on adverse effects, either short or longterm, in very immature infants to recommend routine chest physiotherapy. Intravenous dexamethasone also reduces the need for re-intubation in both a high-risk group of babies and the total population being extubated.15 The high-risk group were those who had traumatic or multiple intubations or were intubated for >14 days. The incidence of extubation failure in the low-
WEANING NEONATES FROM VENTILATION risk group was zero and adverse effects of hyperglycaemia and glycosuria were reported. Any recommendation to use intravenous dexamethasone in a high-risk group for airway edema must be tempered with the reported long-term adverse neurological effects of this drug.35 Two trials of doxapram demonstrated no effect on failed extubation, duration of IPPV or respiratory failure.16 There were also trends towards increased side effects of hypertension and irritability. There is no evidence to support routine use of doxapram to assist extubation. Two systematic reviews addressed the effects of ventilation settings prior to extubation on outcome.17,18 There was a trend towards an increased chance of successful extubation from low rate IPPV compared with endotracheal CPAP.17 This was a significant benefit when only truly randomised trials were considered and this is also true for a reduction in post-extubation apnoea. Therefore, it is safe to extubate from low rate IPPV and it is not necessary to try endotracheal CPAP first. Of the 2 trials comparing nasal and oral endotracheal intubation one found that postextubation atelectasis occurred more frequently in the nasal group who weighed <1500 g.32 However, there was no difference in the need for re-intubation. There is no convincing evidence to recommend either route of endotracheal intubation and larger trials would be needed to assess any worthwhile clinical differences in outcome.18 In conclusion, although nasal CPAP, NIPPV and methylxanthines are evidence-based treatments to facilitate weaning and extubation of preterm infants, only the first 2 can be recommended for routine use.
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9. 10.
11.
12.
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14.
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16.
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