To tube or not to tube babies with respiratory distress syndrome

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1 (2009) 29, S68 S72 r 2009 Nature Publishing Group All rights reserved /09 $32 REVIEW To tube or not to tube babies with respiratory distress syndrome Department of Pediatrics, Neonatal-Perinatal Medicine, Neonatal Intensive Care Unit, Infant Breathing Disorders Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA The use of mechanical ventilation in premature infants with respiratory distress syndrome (RDS) and respiratory failure often results in barotrauma, volutrauma and chronic lung disease (CLD). Research indicates that early surfactant therapy and initiation of nasal continuous positive airway pressure (CPAP) for these infants significantly reduces the need for mechanical ventilation and the incidence of CLD. Different CPAP delivery systems exist, each with some practical and clinical advantages and disadvantages. Clinical trials indicate that optimal management of neonatal RDS could be improved by early surfactant treatment followed immediately by extubation and stabilization on CPAP. Evidence suggests a synergistic effect between early surfactant administration (within 2 h of birth) and rapid extubation to nasal CPAP with a significant reduction in the need for mechanical ventilation and its associated morbidities. (2009) 29, S68 S72; doi: /jp Keywords: continuous positive airway pressure (CPAP); premature infant; respiratory distress syndrome; surfactant; bronchopulmonary dysplasia; chronic lung disease Introduction The treatment of surfactant-deficient respiratory distress syndrome (RDS) in low birth weight infants (LBW) involves surfactant administration, mechanical ventilation and nutritional support. 1 However, a more gentle ventilatory approach using early surfactant administration followed quickly by extubation and use of nasal continuous positive airway pressure (CPAP) instead of mechanical ventilation has been shown to be successful for many of these infants with less adverse sequelae. Advances in technology make it possible to provide mechanical ventilation either with a conventional ventilator or with a high-frequency ventilator. Modern conventional ventilators, which are microprocessor driven, have several modes with the capability of synchronizing infant breaths with mechanical breaths. High-frequency ventilators, jet ventilators or high-frequency oscillators generate tidal volumes that are less than the anatomical dead space at very high rates. Despite these significant Correspondence: Dr KC Sekar, University of Oklahoma Health Sciences Center, Children s Hospital, 1200 Everett Drive, 7th Floor North Pavilion, Oklahoma City, OK 73104, USA. kris-sekar@ouhsc.edu technological advances in mechanical ventilators, the incidence of chronic lung disease (CLD) in preterm infants has not decreased. Mechanical ventilation requires prolonged intubation, which is associated with morbidities ranging from mild physical trauma to severe complications such as vocal cord paralysis. 2,3 In addition, long-term ventilation can result in CLD/bronchopulmonary dysplasia (BPD) because of excess pressure (barotrauma) and/or high gas volume (volutrauma). 2 6 These ventilator-associated lung injuries also trigger a cascade of events because of the generation of inflammatory cytokines (biotrauma), which could potentially lead to multi-system organ failure. 4,5 Ventilator-associated lung injury in LBW infants leads to the development of BPD. 4,5 Although the development of BPD is dependent on several factors, excessive oxygen exposure and barotrauma are the most important triggering events in the onset of inflammation. 7 9 Research has shown that maintaining the pulse oxygen saturations between 85 and 93% in LBW infants requiring supplemental oxygen results in less CLD without compromising tissue oxygen delivery. 10 However, the incidence of BPD varies between institutions. For example, in a comparison of the incidence of BPD between two Boston hospitals and Children s Hospital of New York (CHONY, Columbia University), the incidence of BPD was significantly lower in CHONY in similar LBW babies. 4 Further multivariate analysis comparing specific measures of respiratory care during the first postnatal week in these institutions revealed that the only variable responsible for improvement in the incidence of morbidity at Columbia was the early initiation of CPAP compared with mechanical ventilation in the Boston Hospitals. 4 This article will focus on an overview of CPAP for RDS in tiny preterm infants and its clinical benefits based on key clinical studies. Continuous positive airway pressure In RDS, there is a deficiency of surfactant, which increases the surface tension at the air liquid interface leading to alveolar collapse at end expiration. 11 Therefore, in addition to surfactant therapy, these alveoli require support to prevent this collapse and maintain functional residual capacity at end expiration. This can

2 To tube or not to tube in RDS S69 be achieved by CPAP, avoiding intubation and its associated morbidities. 3,12 14 CPAP also enhances endogenous surfactant production 15 and reduces the incidence of morbidities associated with intermittent mandatory ventilation in the management of LBW infants. 2,14,16 CPAP systems have three basic parts: (1) a supply of heated and humidified air, (2) a patient interface such as a nasal cannula or a face mask and (3) an expiratory valve to provide positive airway pressure within the system. 2 There are different CPAP systems available for use in infants. The greatest variation among different CPAP systems is in the patient interface component. There are practical and clinical advantages and disadvantages with each delivery system. Binasal prongs are preferred to single nasal prongs. 17 In its simplest form, the bubble CPAP device uses continuous air flow with the depth of immersion of the expiratory air flow in a water bottle determining positive end expiratory pressure (Figure 1). 16 Bubble CPAP has been shown to provide oscillatory effects in the lungs. 18,19 Kahn et al. 18 have shown significant fluctuations in pressure in the bubble CPAP device compared with ventilator-delivered CPAP. Variable flow CPAP devices have been shown to decrease the work of breathing compared with constant flow devices. 20 Studies using CPAP in RDS There are essentially two approaches to CPAP therapy in RDS: (1) The INSURE approach (INtubation, SURfactant and Extubation), involving intubating babies only to administer the surfactant and quickly extubating them to nasal CPAP 21 and (2) the Columbia approach in which infants are started on CPAP in the delivery room and intubation is considered only if they meet the criteria for surfactant administration and mechanical ventilation later. Several studies have been published based on the INSURE approach all consistently producing similar results. Verder et al. 22 examined babies that were given Poractant-alfa with extubation to CPAP and compared them with babies undergoing conventional treatment (n ¼ 68). The need for mechanical ventilation was significantly reduced in the CPAP group (43 vs 85%) requiring the study to be terminated early. In a similar trial looking at early vs late surfactant with CPAP (n ¼ 60) the early group had a significant reduction in the need for mechanical ventilation (21 vs 63%) and this study was also terminated early. 23 Several other clinical trials have confirmed that the practice of surfactant therapy followed by extubation to nasal CPAP reduces the need for mechanical ventilation The key findings of these trials are shown in Table 1. The Texas Neonatal Research Group did not find a significant difference in the duration of mechanical ventilation when surfactant was electively administered to larger infants (>1250 g) compared with expectant management. 29 Similar to this study in larger infants, weeks gestational age (GA), Sandri et al. 30 did not find a significant difference in the need for mechanical ventilation when comparing prophylactic nasal CPAP vs rescue surfactant and CPAP when the oxygen requirement was >0.4. However, a Cochrane Review evaluating the use of surfactant and rapid extubation to nasal CPAP in six studies found that Figure 1 Nasal Prongs Bubble Water-seal CPAP Delivery System. Reprinted with permission from Aly, 16 p 760.

3 S70 To tube or not to tube in RDS infants with RDS treated with early surfactant replacement therapy and nasal CPAP were less likely to need mechanical ventilation and were at a lower risk for air leaks than infants treated with nasal CPAP and later surfactant therapy. 1 A more recent meta analysis showed relative risk for BPD of 0.51 (95% CI 0.26 to 0.99) when early surfactant treatment and nasal CPAP were compared with late selective surfactant treatment in preterm infants at risk for RDS. 31 A retrospective observational study showed that extremely preterm infants (<1000 g, GA <26 weeks) had a predictive probability of successful extubation to CPAP on day 1 of 66% (95% CI; 46 to 86%) and on day 2 of 80% (95% CI: 60 to 99%). 32 Columbia Hospital s approach and patient outcome data have been published. 19,33 The Columbia approach involves stabilization of infants in the delivery room with CPAP and continuation of CPAP post-resuscitation. These babies are intubated and surfactant considered only if they meet the following criteria: FiO 2 > , persistent severe hypercarbia (PaCO 2 >70 mm Hg), apnea, severe retractions on CPAP, intractable metabolic acidosis (BD>10 meq/l 1 ), cardiovascular collapse or neuromuscular disorder. The success rate of CPAP alone in their population was 37% in babies less than 750 g, 72.7% in babies 750 to 999 g and 91.3% in babies 1000 to 1250 g. This translates to 30.2% CPAP success in babies less than 26 weeks GA and 84.6% CPAP success in babies greater than 26 weeks GA. These remarkable results show that a significant number of very tiny babies could be successfully transitioned to nasal CPAP without the need for intubation in the delivery room. Their severe BPD incidence based on the newer NICHD definition 34 is 3.3% in babies less than 750 g and none in babies greater than 750 g. 19,33 Narendran et al. 35 introduced early bubble CPAP in the delivery room and compared their outcome before and after the introduction of early CPAP in LBW infants. There was a significant reduction in the rate of intubation before vs after CPAP (59.8 vs 31.6%), mean days on mechanical ventilation (28 vs 13) and an increase in the mean days on CPAP (4 vs 16). However, there was no significant reduction in BPD with the early introduction of bubble CPAP. Finer et al. 36 reported that it is feasible to start CPAP in the delivery room from a multicenter trial. 36 Aly et al. 37 reported in a retrospective trial that babies who remain on CPAP post-resuscitation in the delivery room had the shortest length of hospital stay and the least number of days requiring oxygen. The CPAP or Intubation (COIN) trial is the largest randomized trial involving CPAP and mechanical ventilation. This trial randomized babies at 5 min of age either to CPAP or to mechanical ventilation (n ¼ 610). 38 In the CPAP group surfactant and mechanical ventilation were initiated only if established criteria were met. Mechanical ventilation strategies were not specified in the ventilated group. The primary outcome was death or the requirement for oxygen at 36 weeks post-conceptional age. The results showed no difference in the primary outcomes of death or BPD between these groups. In the CPAP group the need for surfactant administration was significantly reduced (38 vs 77%, P<0.001). There was also a significantly higher incidence of pneumothorax in the CPAP group (9.1 vs 3%, P ¼ 0.001). As the babies were randomized at 5 min of age, sicker infants who required intubation earlier than 5 min were not included in the study. 38 There are several other trials involving surfactant and nasal CPAP currently underway. The results of these trials will further define the role of CPAP in LBW infants. Table 1 Summary of CPAP studies involving surfactants Investigator (year) Surfactant+CPAP Control Infant characteristics Age at surfactant treatment Key findings Reininger (2005) (surfactant + IMV) weeks GA 24 h Less day on IMV, Early study termination Haberman (2002) (surfactant ¼ IMV) g 12 h Less day on IMV, Early study termination Verder (1994) (poractant alfa) 33 (CPAP alone) weeks GA Decreased need for mechanical ventilation Verder (1999) (early poractant alfa + CPAP Soll (2003) (CPAP with later rescue 27 (Early poractant alfa + CPAP) < 30 weeks GA 5.2 vs 9.9 h Early Poractant alfa + CPAP: decreased need for MV, improved oxygenation + survival g 2 24 h Decreased days of MV surfactant + IMV Dani (2004) (poractant alfa) 14 (Poractant alfa + IMV) <30 weeks GA 2.7 vs 3/5 h Decreased days on MV, O 2, NICU length of stay & 2nd dose of Poractant alfa Tooley and Dyke (2003) (surfactant + CPAP in 1 h) 21 (surfactant + IMV) /7 weeks GA At birth 38% of CPAP babies did not require IMV No difference in BPD Abbreviations: IMV, Intermittent mandatory ventilation; MV, Mechanical ventilation; NICU, Neonatal Intensive Care Unit; O 2, oxygen. Adapted from Sekar. 40

4 To tube or not to tube in RDS S71 Conclusions The INSURE approach has consistently shown a reduction in the need for mechanical ventilation in the LBW infants. This may have an indirect effect on the incidence of BPD. This approach is feasible and should be started as soon as possible in the delivery room after stabilization. With this approach, intubation is used only as a means to administer the surfactant. The Columbia approach of using nasal CPAP starting in the delivery room on LBW has shown a significant reduction in BPD. These remarkable results have not been reproduced in other centers. The COIN trial did not show significant differences in the outcome in babies who were randomized at 5 min of age if they still remained extubated. The trial thus excluded sicker babies that required intubation earlier than 5 min. Thus the recommended approach for LBW infants with respiratory distress is to start CPAP in the delivery room immediately after stabilization, with intubation only for surfactant administration. In addition, adjusting supplemental oxygen intake to maintain pulse oximetry saturations between 85 93% for infants less than 32 weeks GA is recommended. Mechanical ventilation is utilized only if infants meet strict intubation criteria. This approach has been shown to reduce morbidity in LBW infants. In addition, assuring high amino acid intake within the first day of life to optimize nutritional intake must be considered for improved overall postnatal growth and outcome. 39 Disclosure KC Sekar is a member of the speaker s bureau and a consultant for Dey, LP. KE Corff has declared no conflict of interest. This paper was based on a talk presented at the Evidence vs Experience in Neonatal Practices Fifth Annual CME Conference that was supported by an unrestricted educational grant from Dey, LP. 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