- Email: [email protected]
Myth: mechanical ventilation is a therapeutic relic
Seminars in Fetal & Neonatal Medicine 16 (2011) 275e278
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Myth: mechanical ventilation is a therapeutic relic Samir Gupta a, *, Sunil K. Sinha b, Steven M. Donn c a
Department of Neonatal Paediatrics, University Hospital of North Tees, Stockton, UK Department of Neonatal Paediatrics, The James Cook University Hospital, Middlesbrough, UK c Department of Pediatrics, Division of NeonatalePerinatal Medicine, C.S. Mott Children’s Hospital, University of Michigan Health System, Ann Arbor, Michigan, USA b
s u m m a r y Keywords: Continuous positive airway pressure Non-invasive support Respiratory distress syndrome Surfactant Ventilation
Non-invasive respiratory support techniques such as continuous positive airway pressure (CPAP) have been increasingly used for management of surfactant-deficient lung disease in preterm infants. The successful use of this approach depends upon the condition of the baby at birth and requires the establishment of spontaneous breathing at birth. The reported advantages of CPAP in observational studies demonstrating a reduction in chronic lung disease have not been substantiated in recently reported well-designed randomised trials. This approach is now more established in larger and more mature preterm infants, and proper patient selection with close observation should be exercised when used in extremely low gestational age infants. Ó 2011 Published by Elsevier Ltd.
1. Introduction
2. Historical perspective
Optimising respiratory support of preterm babies has remained a challenge for neonatologists. With the survival of extremely premature infants at the margin of viability, the incidence of chronic lung disease (CLD) has remained essentially unchanged. Many believe that there has been a change in the pathophysiology of the CLD, with diminished alveolarisation seen in these extreme premature infants.1 The challenge of minimising ventilator-induced lung injury2 to the underdeveloped lung, which is still in the canalicular stage, has been the subject of much clinical research in the last decade. This has led clinicians to evaluate the safety and efficacy of other forms of respiratory support techniques, such as continuous positive airway pressure (CPAP). Until recently, exogenous surfactant replacement therapy and mechanical ventilation (MV) has remained the gold standard of treatment. However, this requires endotracheal intubation, an invasive procedure associated with multiple potential complications. In some instances, there are inadequate numbers of clinicians who possess the skills required to intubate very small babies. Despite these limitations, newborn babies with inadequate respiratory effort, severe surfactant deficiency, and those depressed at birth by maternal drugs, especially magnesium sulphate, may still require mechanical ventilation at birth. In addition, babies with underlying airway anomalies, abdominal masses pressing upon the diaphragm and other organ system failure often require mechanical ventilation.
There are no doubt, some babies born prematurely but with adequate respiratory drive and only mild to moderate respiratory distress, who can be managed with non-invasive respiratory support. Until recently, most of these babies were routinely intubated at birth, given surfactant (when it became available), and managed with mechanical ventilation. In 1987 a landmark paper by Avery et al.3 compared the immediate respiratory practices of eight prestigious neonatal units in the USA. One of these eight units (Columbia University) managed babies with CPAP from birth and had significantly lower rates of CLD at comparative gestations. Because this study was performed in pre-surfactant era, Van Marter did another comparison in the surfactant era4 and confirmed that the use of mechanical ventilation on day 1 increased the odds of an infant developing CLD. These studies were observational, and the findings require confirmation from randomised controlled trials. In the last decade, three such trials were conducted.
* Corresponding author. Tel.: þ44 1642 624250. E-mail address: [email protected] (S. Gupta). 1744-165X/$ e see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.siny.2011.04.007
3. Non-invasive support with CPAP CPAP provides continuous distending pressure using an aireoxygen mixture and a device to generate continuous distending pressure. The application of CPAP keeps the upper airway open during both inspiration and expiration and improves the functional residual capacity. The nasal interface may be long or short, single or bi-nasal prongs. Current evidence supports the use of short bi-nasal prongs.5 The method of generation of nasal CPAP (nCPAP) also differs between devices and may be categorised by flow mechanics into two main types, ‘variable’ or ‘continuous’. The two commonly
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Table 1 Early CPAP vs ventilation trials in extremely low gestational age newborns e background. Trial
Primary outcome
Intervention
Mean GA (weeks)
Mean birth weight (g)
Antenatal steroid use
Male
COIN SUPPORT VON
Death/BPD at 36 weeks Death/BPD at 36 weeks Death/BPD at 36 weeks
CPAP 8 cmH2O; surfactant on intubation CPAP 5 cm; surfactant within 1 h CPAP (not specified); surfactant (not specified)
26.9 26.2 28.1
960 830 1050
94% 96% 99%
53% 54% 54%
CPAP, continuous positive airway pressure; GA, gestational age; BPD, bronchopulmonary dysplasia; SUPPORT, Surfactant Positive Pressure and Oxygen Randomised Trial; VON, Vermont Oxford Network.
used nCPAP devices are the variable flow infant flow driver (IFD), and continuous flow bubble CPAP. There are limited data comparing the use of nCPAP devices at birth; however, there are reported physiological and clinical advantages of individual CPAP devices.6,7 4. nCPAP at birth: the evidence Three large randomised controlled trials have been attempted; two were completed and one terminated early. All compared nCPAP with intubation and mechanical ventilation at birth in extremely low gestational age newborns (ELGANS) (Tables 1e3). 4.1. The COIN (CPAP Or nasal INtubation at birth) trial This was a large randomised controlled study that compared the use of CPAP versus early intubation in the delivery room; 610 preterm infants born at 25 weeks to 28 þ 6 weeks of gestation were recruited. Eligible infants had to be breathing spontaneously at 5 min of age but still in need of respiratory support, exhibiting increased respiratory effort, grunting, or cyanosis. There were no protocol requirements for the administration of surfactant to infants in either arm, and no specific extubation criteria. CPAP was set at 8 cmH2O and administered with single or bi-nasal prongs. Pressure was changed only after admission to the neonatal unit. The group assigned to CPAP underwent intubation if there was apnoea unresponsive to stimuli and methylxanthine treatment, uncompensated respiratory acidosis, or the need for FiO2 > 0.6. The primary outcome was death or bronchopulmonary dysplasia (BPD; CLD) at 36 weeks of gestational age. At 28 days, the unadjusted odds ratio for death or need for oxygen treatment was in favour of the CPAP group. However, at 36 weeks there was no difference in death or BPD between the two groups taken together or when analysed as subgroups stratified by gestational age. As expected, the CPAP group needed less surfactant (38% vs 77%; P < 0.001) and also had a significantly shorter duration of intubation and mechanical ventilation (3 vs 4 days; P < 0.001). Alarmingly, the CPAP group had a significantly higher incidence of pneumothorax (9.1% vs 3.0%; P < 0.001).8 The results of the COIN trial are difficult to interpret. The proponents of CPAP can argue that ELGANS who are breathing spontaneously by 5 min can be managed with early CPAP, although more than a third either died or required mechanical ventilation, but this difference was not statistically significant. The infants in the Table 2 Early CPAP vs ventilation trials in extremely low gestational age newborns e outcome data.
COIN SUPPORT VON
Death/BPD
IPPV
CPAP
Surfactant
CPAP
Surfactant
CPAP
Surfactant
34% 49% 30%
39% 54% 28%
46% 24.8 days 45%
100% 27.7 days 51%
38% 67% 46%
77% 99% 99%
CPAP group also required significantly less postnatal corticosteroid therapy for BPD (7.2% vs 13.2%; P < 0.001), and when a subset of babies underwent pulmonary function testing at 8 weeks’ post-term age, the CPAP group performed better.9 On the other hand, the threefold increase in pneumothorax is concerning. Moreover, only 77% of intubated babies received surfactant, and it is conceivable that the intubated group might have done even better if all the babies had received surfactant. Many have questioned the arbitrary use of 8 cmH2O selected for the trial as being possibly too high. Though there are encouraging observational data from Columbia University and the Scandinavian countries to favour early CPAP, the COIN trial might have been undermined by the limited experience of some participating investigators. Proponents of invasive ventilation argue against the evidence and indicate that the trial failed to show differences in the primary outcome measures, increase in air leaks, and that infants who failed CPAP received rescue surfactant treatment rather than prophylactic or early treatment, thus availing less benefit. 4.2. SUPPORT (Surfactant Positive Pressure and Oxygen Randomised Trial) This recently published study compared early CPAP to early surfactant therapy after intubation and mechanical ventilation according to the Neonatal Resuscitation Program guidelines10 among infants of 24 to 27 þ 6 weeks of gestation. The primary outcome for this study was death or BPD at 36 weeks of gestation age, the same as the COIN trial.11 However, this trial differed from the COIN trial in many respects. SUPPORT included more immature infants, randomisation was performed prior to delivery, and there was no selection criterion for spontaneous breathing. CPAP was initiated at 5 cmH2O with the option of using any CPAP device. There were well-defined criteria for both intubation and extubation. A room air challenge was performed at 36 weeks to rule out CLD if oxygen requirements were <30%. No difference was reported in the primary outcome of death or CLD: 47.8% with CPAP vs 51.0% with ventilation and surfactant (odds ratio: 0.95; 95% confidence interval (CI): 0.85e1.05)]. Significantly fewer babies required positive pressure ventilation at birth or received surfactant with primary CPAP treatment. There was no difference in air leaks, but in the CPAP group fewer babies required mechanical ventilation among survivors, fewer were alive without mechanical ventilation at 7 days, and survivors required less postnatal steroids treatment. Table 3 Early CPAP vs ventilation trials in extremely low gestational age newborns e complications. Trial
Surfactant
CPAP, continuous positive airway pressure; BPD, bronchopulmonary dysplasia; IPPV, intermittent positive pressure ventilation; SUPPORT, Surfactant Positive Pressure and Oxygen Randomised Trial; VON, Vermont Oxford Network.
COIN SUPPORT VON
Pneumothorax
Severe IVH
PVL
CPAP
Surfactant
CPAP
Surfactant
CPAP
Surfactant
9% 7% 5%
3% 7% 3%
9% 14% 3%
9% 11% 4%
3% e e
4% e e
CPAP, continuous positive airway pressure; IVH, intraventricular haemorrhage; PVL, periventricular leukomalacia; COIN, CPAP Or nasal INtubation at birth; SUPPORT, Surfactant Positive Pressure and Oxygen Randomised Trial; VON, Vermont Oxford Network.
S. Gupta et al. / Seminars in Fetal & Neonatal Medicine 16 (2011) 275e278
Interestingly, in the 24e25 week stratum, the CPAP group also had a significantly lower mortality, 23.9% vs 32.1%; relative risk: 0.74 (95% CI: 0.57e0.98). The results of the SUPPORT trial are somewhat more reassuring than the COIN trial, with a lower selection bias, and babies were randomised before birth irrespective of the condition at birth. The use of 5 cmH2O CPAP seems safer in this trial than the 8 cmH2O used in the COIN trial. Finally, the lack of surfactant in CPAP group did not affect the mortality, although the antenatal steroid exposure was very high (96e97%) in both groups. Nevertheless, these results lead to additional questions. It might be argued that infants in this trial represent a very select group of ELGANS, where mothers were hospitalised remote enough to delivery to allow formal discussion of the research protocol and securing informed consent. Is this going to be exportable to the real-world experience? This trial will also be evaluating ‘long term’ outcome at 2 years of age. Since there are no ostensible differences between early CPAP and intubation with surfactant, it would behove us to wait for the long term outcomes analysis before we accept this approach without question.
4.3. Vermont Oxford Network (VON) Trial This was another randomised controlled trial with three arms: (1) intubation þ prophylactic surfactant þ ventilation (PS group), (2) intubation þ prophylactic surfactant þ rapid extubation (ISX group), and (3) early nCPAP with selective intubation and surfactant (nCPAP group). It included infants born at 26 to 29 þ 6 weeks of gestation and randomised before birth. The sample size for this trial was calculated to be 876 infants to demonstrate a 30% reduction in CLD or death at 36 weeks. The primary outcome was similar to the other two trials, death or CLD at 36 weeks of gestational age. This trial recruited 648 infants from 27 centres but was terminated early because of poor recruitment. The exposure to antenatal steroids was nearly 100% in each arm. There were no differences in death or CLD at 36 weeks between the three groups. Almost half of the infants in the nCPAP or ISX groups required intubation in the first week (51.4% in ISX group vs 45.1% in nCPAP group). There were no differences in the rates of pneumothorax between the three groups.12 These results, although underpowered because of early termination, mirror the results from the COIN and SUPPORT trials. They are, however, contrary to the previously reported study by Dani et al.13 and the INSURE (INtubationeSURfactanteExtubation) approach suggested by Verder et al.,14 now a standard practice in Denmark.
4.4. IFDAS (Infant Flow Driver And Surfactant) Trial In another study, Thomson et al. randomised infants between 27 and 29 weeks of gestation to early nCPAP and prophylactic surfactant, early nCPAP and rescue surfactant, early intermittent positive pressure ventilation (IPPV) and prophylactic surfactant, and early IPPV and rescue surfactant (conventional management). They randomised 237 babies and the antenatal steroid exposure rate was 97% for all infants. The nCPAP support was provided using IFD CPAP and only CurosurfÒ was used. The requirement for mechanical ventilation in the first 120 h (5 days) was lowest in the group of babies managed with early nCPAP and prophylactic surfactant, and highest in the group with early IPPV and prophylactic surfactant. They did not find any differences in the rates of CLD at 36 weeks or other complications of prematurity between the study groups. These findings are only available in abstract form and have never been published. Thus, without a detailed evaluation of data and peer review it is unwise to draw any conclusions.15
277
5. CPAP with or without surfactant Some studies have examined the combined use of early surfactant and CPAP treatment. The DanisheSwedish multicentre group routinely uses nCPAP for management of respiratory distress syndrome (RDS) at birth. Verder et al. reported two trials14,16 in which preterm infants were randomised to receive early surfactant after intubation with a brief period of ventilation followed by extubation to nCPAP, and compared them to infants continuing CPAP with later administration of rescue surfactant and mechanical ventilation followed by extubation. Both studies were stopped after interim analysis showed a statistically significant reduction in the need for ventilation or death for the surfactant-treated infants within 7 days. In their study, they randomised preterm infants with RDS (n ¼ 60) to receive a single dose of Curosurf, either immediately after randomisation or when the arterial:alveolar oxygen ratio fell below 0.22. nCPAP was begun at a median age of 17 min after birth, and randomisation occurred at a median age of 4.3 h. The need for mechanical ventilation was reduced from 68% in the late-treated infants to 25% in the earlytreated infants, and among infants born to women receiving antenatal steroids the outcome was observed to be even better. This INSURE technique has gained some acceptance around the world.17 Two recently reported trials compared the use of surfactant with nCPAP in preterm babies. The trial by Sandri18 compared prophylactic surfactant followed by rapid extubation to nCPAP, with nCPAP and early selective surfactant if the oxygen requirement increased to >40%. A total of 208 ELGANS between 25 and 28 weeks of gestation were included in this study. There was no difference reported for the need for mechanical ventilation in the first 5 days of life, survival at 28 days of life and 36 weeks of postmenstrual age, or typical morbidities of prematurity. This study reassures clinicians that selective use of surfactant is still safe in babies managed with nCPAP as long as there is close monitoring and active intervention should the oxygen requirements increase. The difference from Verder et al.’s trials could arise from earlier intervention points with babies in Verder et al.’s trials left on CPAP for a longer time with intervention occurring in babies whose health had deteriorated. The recent comparison of prophylactic surfactant and CPAP with nCPAP alone in larger preterm babies (27e31 weeks of gestation) reported an advantage of the INSURE technique over nCPAP without surfactant.19 6. Conclusions There is evidence demonstrating the feasibility of managing some extremely preterm infants with non-invasive respiratory support. This approach has comparable short-term outcomes to intubation and mechanical ventilation with the administration of surfactant, an approach that has been practised for decades. The short-term outcome data provide evidence of no harm, but the long term outcome data must be evaluated before this becomes the standard approach to management. The question of whether or not to give surfactant with nCPAP seems to favour a combined approach with close monitoring and early intervention for infants with increasing respiratory distress who are not tolerating CPAP. The success of non-invasive support is significantly affected by the expertise and experience of the units adopting this strategy. Finally, patient selection may be the most important determinant of success. Did the mother receive antenatal steroid therapy? Are there comorbidities, such as chorioamnionitis, which should be considered in anticipatory management? Were pharmacological agents administered to the mother, such as morphine, magnesium sulphate, or caesarean section under general anaesthesia, which could depress the infant’s respiratory drive? Is the baby displaying any apnoea, hypotonia, or neurological depression? Any of these
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could be sufficient clinical grounds to wheel the ventilator from the storage room to the bedside.
Practice points A proportion of very preterm babies can be managed with CPAP. Babies requiring intubation and mechanical ventilation should be recognised early after birth and given surfactant. The short-term outcome data of early CPAP use provide evidence of no harm but the long term outcome data must be evaluated before this becomes the standard approach to management. Patient selection plays a crucial role.
Research directions Further define patients likely to respond to non-invasive treatment. Examine the role that non-invasive ventilation may play in augmenting nCPAP. Continue research into aerosolisation of surfactant and its delivery by CPAP, thus obviating the need for intubation.
Funding sources None. Conflict of interest statement None declared. References 1. Gupta S, Sinha SK, Donn SM. Ventilatory management and bronchopulmonary dysplasia in preterm infants. Semin Fetal Neonatal Med 2009;14:367e73. 2. Donn SM, Sinha SK. Minimising ventilator induced lung injury in preterm infants. Arch Dis Child Fetal Neonatal Ed 2006;91:F226e30.
3. Avery ME, Tooley WH, Keller JB, et al. Is chronic lung disease in low birth weight infants preventable? A survey of eight centers. Pediatrics 1987;79:26e30. 4. Van Marter LJ, Allred EN, Leviton A, Pagano M, Parad R, Moore M. Antenatal glucocorticoid treatment does not reduce chronic lung disease among surviving preterm infants. J Pediatr 2001;138:198e204. 5. De Paoli AG, Davis PG, Faber B, Morley CJ. Devices and pressure sources for administration of nasal continuous positive airway pressure (NCPAP) in preterm neonates. Cochrane Database Syst Rev 2002;(4):CD002977. 6. Gupta S, Sinha SK, Tin W, Donn SM. A randomized controlled trial of postextubation bubble continuous positive airway pressure versus infant flow driver continuous positive airway pressure in preterm infants with respiratory distress syndrome. J Pediatr 2009;154:645e50. 7. Pandit PB, Courtney SE, Pyon KH, Saslow JG, Habib RH. Work of breathing during constant- and variable-flow nasal continuous positive airway pressure in preterm neonates. Pediatrics 2001;108:682e5. 8. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008;358:700e8. 9. Roehr CC, Proquitte H, Hammer H, Wauer RR, Morley CJ, Schmalisch G. Positive effects of early continuous positive airway pressure on pulmonary function in extremely premature infants: results of a subgroup analysis of the COIN trial. Arch Dis Child Fetal Neonatal Ed; 2010 Jun 28 [Epub ahead of print]. 10. Niermeyer S, Kattwinkel J, Van Reempts P, et al. International guidelines for neonatal resuscitation: an excerpt from the guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: international consensus on science. Contributors and reviewers for the neonatal resuscitation guidelines. Pediatrics 2000;106:E29. 11. Finer NN, Carlo WA, Walsh MC, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362:1970e9. 12. Dunn MKJ, de Klerk A, de Klerk R, et al. Delivery room management of preterm infants at risk for respiratory distress syndrome (RDS). Vancouver: Pediatric Academic Society; 2010. 13. Dani C, Bertini G, Pezzati M, Cecchi A, Caviglioli C, Rubaltelli FF. Early extubation and nasal continuous positive airway pressure after surfactant treatment for respiratory distress syndrome among preterm infants <30 weeks’ gestation. Pediatrics 2004;113:e560e3. 14. Verder H, Robertson B, Greisen G, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. DanisheSwedish Multicenter Study Group. N Engl J Med 1994;331:1051e5. 15. Thomson M. Early nasal CPAP þ prophylactic surfactant for neonates at risk of RDS. The IFDAS trial. Pediatr Res 2001;50:304A. 16. 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 weeks’ gestation. Pediatrics 1999;103:E24. 17. Verder H. Nasal CPAP has become an indispensable part of the primary treatment of newborns with respiratory distress syndrome. Acta Paediatr 2007;96:482e4. 18. Sandri F, Plavka R, Ancora G, et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010;125:e1402e9. 19. Verder H, Bohlin K, Kamper J, Lindwall R, Jonsson B. Nasal CPAP and surfactant for treatment of respiratory distress syndrome and prevention of bronchopulmonary dysplasia. Acta Paediatr 2009;98:1400e8.
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Myth: mechanical ventilation is a therapeutic relic Samir Gupta a, *, Sunil K. Sinha b, Steven M. Donn c a
Department of Neonatal Paediatrics, University Hospital of North Tees, Stockton, UK Department of Neonatal Paediatrics, The James Cook University Hospital, Middlesbrough, UK c Department of Pediatrics, Division of NeonatalePerinatal Medicine, C.S. Mott Children’s Hospital, University of Michigan Health System, Ann Arbor, Michigan, USA b
s u m m a r y Keywords: Continuous positive airway pressure Non-invasive support Respiratory distress syndrome Surfactant Ventilation
Non-invasive respiratory support techniques such as continuous positive airway pressure (CPAP) have been increasingly used for management of surfactant-deficient lung disease in preterm infants. The successful use of this approach depends upon the condition of the baby at birth and requires the establishment of spontaneous breathing at birth. The reported advantages of CPAP in observational studies demonstrating a reduction in chronic lung disease have not been substantiated in recently reported well-designed randomised trials. This approach is now more established in larger and more mature preterm infants, and proper patient selection with close observation should be exercised when used in extremely low gestational age infants. Ó 2011 Published by Elsevier Ltd.
1. Introduction
2. Historical perspective
Optimising respiratory support of preterm babies has remained a challenge for neonatologists. With the survival of extremely premature infants at the margin of viability, the incidence of chronic lung disease (CLD) has remained essentially unchanged. Many believe that there has been a change in the pathophysiology of the CLD, with diminished alveolarisation seen in these extreme premature infants.1 The challenge of minimising ventilator-induced lung injury2 to the underdeveloped lung, which is still in the canalicular stage, has been the subject of much clinical research in the last decade. This has led clinicians to evaluate the safety and efficacy of other forms of respiratory support techniques, such as continuous positive airway pressure (CPAP). Until recently, exogenous surfactant replacement therapy and mechanical ventilation (MV) has remained the gold standard of treatment. However, this requires endotracheal intubation, an invasive procedure associated with multiple potential complications. In some instances, there are inadequate numbers of clinicians who possess the skills required to intubate very small babies. Despite these limitations, newborn babies with inadequate respiratory effort, severe surfactant deficiency, and those depressed at birth by maternal drugs, especially magnesium sulphate, may still require mechanical ventilation at birth. In addition, babies with underlying airway anomalies, abdominal masses pressing upon the diaphragm and other organ system failure often require mechanical ventilation.
There are no doubt, some babies born prematurely but with adequate respiratory drive and only mild to moderate respiratory distress, who can be managed with non-invasive respiratory support. Until recently, most of these babies were routinely intubated at birth, given surfactant (when it became available), and managed with mechanical ventilation. In 1987 a landmark paper by Avery et al.3 compared the immediate respiratory practices of eight prestigious neonatal units in the USA. One of these eight units (Columbia University) managed babies with CPAP from birth and had significantly lower rates of CLD at comparative gestations. Because this study was performed in pre-surfactant era, Van Marter did another comparison in the surfactant era4 and confirmed that the use of mechanical ventilation on day 1 increased the odds of an infant developing CLD. These studies were observational, and the findings require confirmation from randomised controlled trials. In the last decade, three such trials were conducted.
* Corresponding author. Tel.: þ44 1642 624250. E-mail address: [email protected] (S. Gupta). 1744-165X/$ e see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.siny.2011.04.007
3. Non-invasive support with CPAP CPAP provides continuous distending pressure using an aireoxygen mixture and a device to generate continuous distending pressure. The application of CPAP keeps the upper airway open during both inspiration and expiration and improves the functional residual capacity. The nasal interface may be long or short, single or bi-nasal prongs. Current evidence supports the use of short bi-nasal prongs.5 The method of generation of nasal CPAP (nCPAP) also differs between devices and may be categorised by flow mechanics into two main types, ‘variable’ or ‘continuous’. The two commonly
276
S. Gupta et al. / Seminars in Fetal & Neonatal Medicine 16 (2011) 275e278
Table 1 Early CPAP vs ventilation trials in extremely low gestational age newborns e background. Trial
Primary outcome
Intervention
Mean GA (weeks)
Mean birth weight (g)
Antenatal steroid use
Male
COIN SUPPORT VON
Death/BPD at 36 weeks Death/BPD at 36 weeks Death/BPD at 36 weeks
CPAP 8 cmH2O; surfactant on intubation CPAP 5 cm; surfactant within 1 h CPAP (not specified); surfactant (not specified)
26.9 26.2 28.1
960 830 1050
94% 96% 99%
53% 54% 54%
CPAP, continuous positive airway pressure; GA, gestational age; BPD, bronchopulmonary dysplasia; SUPPORT, Surfactant Positive Pressure and Oxygen Randomised Trial; VON, Vermont Oxford Network.
used nCPAP devices are the variable flow infant flow driver (IFD), and continuous flow bubble CPAP. There are limited data comparing the use of nCPAP devices at birth; however, there are reported physiological and clinical advantages of individual CPAP devices.6,7 4. nCPAP at birth: the evidence Three large randomised controlled trials have been attempted; two were completed and one terminated early. All compared nCPAP with intubation and mechanical ventilation at birth in extremely low gestational age newborns (ELGANS) (Tables 1e3). 4.1. The COIN (CPAP Or nasal INtubation at birth) trial This was a large randomised controlled study that compared the use of CPAP versus early intubation in the delivery room; 610 preterm infants born at 25 weeks to 28 þ 6 weeks of gestation were recruited. Eligible infants had to be breathing spontaneously at 5 min of age but still in need of respiratory support, exhibiting increased respiratory effort, grunting, or cyanosis. There were no protocol requirements for the administration of surfactant to infants in either arm, and no specific extubation criteria. CPAP was set at 8 cmH2O and administered with single or bi-nasal prongs. Pressure was changed only after admission to the neonatal unit. The group assigned to CPAP underwent intubation if there was apnoea unresponsive to stimuli and methylxanthine treatment, uncompensated respiratory acidosis, or the need for FiO2 > 0.6. The primary outcome was death or bronchopulmonary dysplasia (BPD; CLD) at 36 weeks of gestational age. At 28 days, the unadjusted odds ratio for death or need for oxygen treatment was in favour of the CPAP group. However, at 36 weeks there was no difference in death or BPD between the two groups taken together or when analysed as subgroups stratified by gestational age. As expected, the CPAP group needed less surfactant (38% vs 77%; P < 0.001) and also had a significantly shorter duration of intubation and mechanical ventilation (3 vs 4 days; P < 0.001). Alarmingly, the CPAP group had a significantly higher incidence of pneumothorax (9.1% vs 3.0%; P < 0.001).8 The results of the COIN trial are difficult to interpret. The proponents of CPAP can argue that ELGANS who are breathing spontaneously by 5 min can be managed with early CPAP, although more than a third either died or required mechanical ventilation, but this difference was not statistically significant. The infants in the Table 2 Early CPAP vs ventilation trials in extremely low gestational age newborns e outcome data.
COIN SUPPORT VON
Death/BPD
IPPV
CPAP
Surfactant
CPAP
Surfactant
CPAP
Surfactant
34% 49% 30%
39% 54% 28%
46% 24.8 days 45%
100% 27.7 days 51%
38% 67% 46%
77% 99% 99%
CPAP group also required significantly less postnatal corticosteroid therapy for BPD (7.2% vs 13.2%; P < 0.001), and when a subset of babies underwent pulmonary function testing at 8 weeks’ post-term age, the CPAP group performed better.9 On the other hand, the threefold increase in pneumothorax is concerning. Moreover, only 77% of intubated babies received surfactant, and it is conceivable that the intubated group might have done even better if all the babies had received surfactant. Many have questioned the arbitrary use of 8 cmH2O selected for the trial as being possibly too high. Though there are encouraging observational data from Columbia University and the Scandinavian countries to favour early CPAP, the COIN trial might have been undermined by the limited experience of some participating investigators. Proponents of invasive ventilation argue against the evidence and indicate that the trial failed to show differences in the primary outcome measures, increase in air leaks, and that infants who failed CPAP received rescue surfactant treatment rather than prophylactic or early treatment, thus availing less benefit. 4.2. SUPPORT (Surfactant Positive Pressure and Oxygen Randomised Trial) This recently published study compared early CPAP to early surfactant therapy after intubation and mechanical ventilation according to the Neonatal Resuscitation Program guidelines10 among infants of 24 to 27 þ 6 weeks of gestation. The primary outcome for this study was death or BPD at 36 weeks of gestation age, the same as the COIN trial.11 However, this trial differed from the COIN trial in many respects. SUPPORT included more immature infants, randomisation was performed prior to delivery, and there was no selection criterion for spontaneous breathing. CPAP was initiated at 5 cmH2O with the option of using any CPAP device. There were well-defined criteria for both intubation and extubation. A room air challenge was performed at 36 weeks to rule out CLD if oxygen requirements were <30%. No difference was reported in the primary outcome of death or CLD: 47.8% with CPAP vs 51.0% with ventilation and surfactant (odds ratio: 0.95; 95% confidence interval (CI): 0.85e1.05)]. Significantly fewer babies required positive pressure ventilation at birth or received surfactant with primary CPAP treatment. There was no difference in air leaks, but in the CPAP group fewer babies required mechanical ventilation among survivors, fewer were alive without mechanical ventilation at 7 days, and survivors required less postnatal steroids treatment. Table 3 Early CPAP vs ventilation trials in extremely low gestational age newborns e complications. Trial
Surfactant
CPAP, continuous positive airway pressure; BPD, bronchopulmonary dysplasia; IPPV, intermittent positive pressure ventilation; SUPPORT, Surfactant Positive Pressure and Oxygen Randomised Trial; VON, Vermont Oxford Network.
COIN SUPPORT VON
Pneumothorax
Severe IVH
PVL
CPAP
Surfactant
CPAP
Surfactant
CPAP
Surfactant
9% 7% 5%
3% 7% 3%
9% 14% 3%
9% 11% 4%
3% e e
4% e e
CPAP, continuous positive airway pressure; IVH, intraventricular haemorrhage; PVL, periventricular leukomalacia; COIN, CPAP Or nasal INtubation at birth; SUPPORT, Surfactant Positive Pressure and Oxygen Randomised Trial; VON, Vermont Oxford Network.
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Interestingly, in the 24e25 week stratum, the CPAP group also had a significantly lower mortality, 23.9% vs 32.1%; relative risk: 0.74 (95% CI: 0.57e0.98). The results of the SUPPORT trial are somewhat more reassuring than the COIN trial, with a lower selection bias, and babies were randomised before birth irrespective of the condition at birth. The use of 5 cmH2O CPAP seems safer in this trial than the 8 cmH2O used in the COIN trial. Finally, the lack of surfactant in CPAP group did not affect the mortality, although the antenatal steroid exposure was very high (96e97%) in both groups. Nevertheless, these results lead to additional questions. It might be argued that infants in this trial represent a very select group of ELGANS, where mothers were hospitalised remote enough to delivery to allow formal discussion of the research protocol and securing informed consent. Is this going to be exportable to the real-world experience? This trial will also be evaluating ‘long term’ outcome at 2 years of age. Since there are no ostensible differences between early CPAP and intubation with surfactant, it would behove us to wait for the long term outcomes analysis before we accept this approach without question.
4.3. Vermont Oxford Network (VON) Trial This was another randomised controlled trial with three arms: (1) intubation þ prophylactic surfactant þ ventilation (PS group), (2) intubation þ prophylactic surfactant þ rapid extubation (ISX group), and (3) early nCPAP with selective intubation and surfactant (nCPAP group). It included infants born at 26 to 29 þ 6 weeks of gestation and randomised before birth. The sample size for this trial was calculated to be 876 infants to demonstrate a 30% reduction in CLD or death at 36 weeks. The primary outcome was similar to the other two trials, death or CLD at 36 weeks of gestational age. This trial recruited 648 infants from 27 centres but was terminated early because of poor recruitment. The exposure to antenatal steroids was nearly 100% in each arm. There were no differences in death or CLD at 36 weeks between the three groups. Almost half of the infants in the nCPAP or ISX groups required intubation in the first week (51.4% in ISX group vs 45.1% in nCPAP group). There were no differences in the rates of pneumothorax between the three groups.12 These results, although underpowered because of early termination, mirror the results from the COIN and SUPPORT trials. They are, however, contrary to the previously reported study by Dani et al.13 and the INSURE (INtubationeSURfactanteExtubation) approach suggested by Verder et al.,14 now a standard practice in Denmark.
4.4. IFDAS (Infant Flow Driver And Surfactant) Trial In another study, Thomson et al. randomised infants between 27 and 29 weeks of gestation to early nCPAP and prophylactic surfactant, early nCPAP and rescue surfactant, early intermittent positive pressure ventilation (IPPV) and prophylactic surfactant, and early IPPV and rescue surfactant (conventional management). They randomised 237 babies and the antenatal steroid exposure rate was 97% for all infants. The nCPAP support was provided using IFD CPAP and only CurosurfÒ was used. The requirement for mechanical ventilation in the first 120 h (5 days) was lowest in the group of babies managed with early nCPAP and prophylactic surfactant, and highest in the group with early IPPV and prophylactic surfactant. They did not find any differences in the rates of CLD at 36 weeks or other complications of prematurity between the study groups. These findings are only available in abstract form and have never been published. Thus, without a detailed evaluation of data and peer review it is unwise to draw any conclusions.15
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5. CPAP with or without surfactant Some studies have examined the combined use of early surfactant and CPAP treatment. The DanisheSwedish multicentre group routinely uses nCPAP for management of respiratory distress syndrome (RDS) at birth. Verder et al. reported two trials14,16 in which preterm infants were randomised to receive early surfactant after intubation with a brief period of ventilation followed by extubation to nCPAP, and compared them to infants continuing CPAP with later administration of rescue surfactant and mechanical ventilation followed by extubation. Both studies were stopped after interim analysis showed a statistically significant reduction in the need for ventilation or death for the surfactant-treated infants within 7 days. In their study, they randomised preterm infants with RDS (n ¼ 60) to receive a single dose of Curosurf, either immediately after randomisation or when the arterial:alveolar oxygen ratio fell below 0.22. nCPAP was begun at a median age of 17 min after birth, and randomisation occurred at a median age of 4.3 h. The need for mechanical ventilation was reduced from 68% in the late-treated infants to 25% in the earlytreated infants, and among infants born to women receiving antenatal steroids the outcome was observed to be even better. This INSURE technique has gained some acceptance around the world.17 Two recently reported trials compared the use of surfactant with nCPAP in preterm babies. The trial by Sandri18 compared prophylactic surfactant followed by rapid extubation to nCPAP, with nCPAP and early selective surfactant if the oxygen requirement increased to >40%. A total of 208 ELGANS between 25 and 28 weeks of gestation were included in this study. There was no difference reported for the need for mechanical ventilation in the first 5 days of life, survival at 28 days of life and 36 weeks of postmenstrual age, or typical morbidities of prematurity. This study reassures clinicians that selective use of surfactant is still safe in babies managed with nCPAP as long as there is close monitoring and active intervention should the oxygen requirements increase. The difference from Verder et al.’s trials could arise from earlier intervention points with babies in Verder et al.’s trials left on CPAP for a longer time with intervention occurring in babies whose health had deteriorated. The recent comparison of prophylactic surfactant and CPAP with nCPAP alone in larger preterm babies (27e31 weeks of gestation) reported an advantage of the INSURE technique over nCPAP without surfactant.19 6. Conclusions There is evidence demonstrating the feasibility of managing some extremely preterm infants with non-invasive respiratory support. This approach has comparable short-term outcomes to intubation and mechanical ventilation with the administration of surfactant, an approach that has been practised for decades. The short-term outcome data provide evidence of no harm, but the long term outcome data must be evaluated before this becomes the standard approach to management. The question of whether or not to give surfactant with nCPAP seems to favour a combined approach with close monitoring and early intervention for infants with increasing respiratory distress who are not tolerating CPAP. The success of non-invasive support is significantly affected by the expertise and experience of the units adopting this strategy. Finally, patient selection may be the most important determinant of success. Did the mother receive antenatal steroid therapy? Are there comorbidities, such as chorioamnionitis, which should be considered in anticipatory management? Were pharmacological agents administered to the mother, such as morphine, magnesium sulphate, or caesarean section under general anaesthesia, which could depress the infant’s respiratory drive? Is the baby displaying any apnoea, hypotonia, or neurological depression? Any of these
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could be sufficient clinical grounds to wheel the ventilator from the storage room to the bedside.
Practice points A proportion of very preterm babies can be managed with CPAP. Babies requiring intubation and mechanical ventilation should be recognised early after birth and given surfactant. The short-term outcome data of early CPAP use provide evidence of no harm but the long term outcome data must be evaluated before this becomes the standard approach to management. Patient selection plays a crucial role.
Research directions Further define patients likely to respond to non-invasive treatment. Examine the role that non-invasive ventilation may play in augmenting nCPAP. Continue research into aerosolisation of surfactant and its delivery by CPAP, thus obviating the need for intubation.
Funding sources None. Conflict of interest statement None declared. References 1. Gupta S, Sinha SK, Donn SM. Ventilatory management and bronchopulmonary dysplasia in preterm infants. Semin Fetal Neonatal Med 2009;14:367e73. 2. Donn SM, Sinha SK. Minimising ventilator induced lung injury in preterm infants. Arch Dis Child Fetal Neonatal Ed 2006;91:F226e30.
3. Avery ME, Tooley WH, Keller JB, et al. Is chronic lung disease in low birth weight infants preventable? A survey of eight centers. Pediatrics 1987;79:26e30. 4. Van Marter LJ, Allred EN, Leviton A, Pagano M, Parad R, Moore M. Antenatal glucocorticoid treatment does not reduce chronic lung disease among surviving preterm infants. J Pediatr 2001;138:198e204. 5. De Paoli AG, Davis PG, Faber B, Morley CJ. Devices and pressure sources for administration of nasal continuous positive airway pressure (NCPAP) in preterm neonates. Cochrane Database Syst Rev 2002;(4):CD002977. 6. Gupta S, Sinha SK, Tin W, Donn SM. A randomized controlled trial of postextubation bubble continuous positive airway pressure versus infant flow driver continuous positive airway pressure in preterm infants with respiratory distress syndrome. J Pediatr 2009;154:645e50. 7. Pandit PB, Courtney SE, Pyon KH, Saslow JG, Habib RH. Work of breathing during constant- and variable-flow nasal continuous positive airway pressure in preterm neonates. Pediatrics 2001;108:682e5. 8. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008;358:700e8. 9. Roehr CC, Proquitte H, Hammer H, Wauer RR, Morley CJ, Schmalisch G. Positive effects of early continuous positive airway pressure on pulmonary function in extremely premature infants: results of a subgroup analysis of the COIN trial. Arch Dis Child Fetal Neonatal Ed; 2010 Jun 28 [Epub ahead of print]. 10. Niermeyer S, Kattwinkel J, Van Reempts P, et al. International guidelines for neonatal resuscitation: an excerpt from the guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: international consensus on science. Contributors and reviewers for the neonatal resuscitation guidelines. Pediatrics 2000;106:E29. 11. Finer NN, Carlo WA, Walsh MC, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362:1970e9. 12. Dunn MKJ, de Klerk A, de Klerk R, et al. Delivery room management of preterm infants at risk for respiratory distress syndrome (RDS). Vancouver: Pediatric Academic Society; 2010. 13. Dani C, Bertini G, Pezzati M, Cecchi A, Caviglioli C, Rubaltelli FF. Early extubation and nasal continuous positive airway pressure after surfactant treatment for respiratory distress syndrome among preterm infants <30 weeks’ gestation. Pediatrics 2004;113:e560e3. 14. Verder H, Robertson B, Greisen G, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. DanisheSwedish Multicenter Study Group. N Engl J Med 1994;331:1051e5. 15. Thomson M. Early nasal CPAP þ prophylactic surfactant for neonates at risk of RDS. The IFDAS trial. Pediatr Res 2001;50:304A. 16. 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 weeks’ gestation. Pediatrics 1999;103:E24. 17. Verder H. Nasal CPAP has become an indispensable part of the primary treatment of newborns with respiratory distress syndrome. Acta Paediatr 2007;96:482e4. 18. Sandri F, Plavka R, Ancora G, et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010;125:e1402e9. 19. Verder H, Bohlin K, Kamper J, Lindwall R, Jonsson B. Nasal CPAP and surfactant for treatment of respiratory distress syndrome and prevention of bronchopulmonary dysplasia. Acta Paediatr 2009;98:1400e8.