Indian J Pediatr (May 2014) 81(5):481–488 DOI 10.1007/s12098-014-1405-8
REVIEW ARTICLE
Use of CPAP and Surfactant Therapy in Newborns with Respiratory Distress Syndrome Srinivas Murki & Ashok Deorari & Dharmapuri Vidyasagar
Received: 8 October 2013 / Accepted: 5 March 2014 / Published online: 12 April 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Respiratory distress syndrome (RDS) is a major disease burden in the developing countries. Current evidence supports early continuous positive airway pressure (CPAP) use and early selective surfactant administration as the most efficacious interventions in the management of RDS, both in developed and developing countries. In developing countries, it is recommended to increase institutional deliveries and increase the coverage of antenatal steroids in women in preterm labor as preventive measures. Establishing intervention of CPAP and surfactant therapies in the Level II special care newborn units (SCNUs) and Level III units requires focus on training nursing staff and pediatricians across the board. These approaches would pave the way in optimizing the care of the preterm infants with RDS and decrease their mortality and morbidity significantly. Keywords RDS . nCPAP . Surfactant . Developing country
Introduction Respiratory distress is one of the commonest morbidities in babies admitted in sick newborn care units (SCNUs). Respiratory distress syndrome (RDS) is the commonest cause
S. Murki Department of Pediatrics, Fernandez Hospital, Hyderabad, India A. Deorari (*) Department of Pediatrics, Division of Neonatology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India e-mail: [email protected] D. Vidyasagar Division of Neonatology, University of Illinois at Chicago, Chicago, IL, USA
of respiratory distress in preterm infants. Lower the gestation, higher is the incidence of RDS, accounting for nearly 80 % incidence in preterm infants with gestation less than 28 wk. Surfactant deficiency is the major underlying cause of RDS [1]. Surfactant deficiency results in lower functional residual capacity, increased work of breathing and respiratory failure. In 1967, Gregory et al. reported the value of application of continuous positive airway pressure in the management of RDS [2]. Successful surfactant replacement therapy in RDS was reported by Fujiwara et al. [3]. Continuous positive airway pressure (CPAP) coupled with surfactant replacement therapy appears to be the ideal choice for the management of respiratory distress in preterm infants with RDS in low and middle income countries [4]. In RDS, CPAP prevents alveolar collapse, improves the functional residual capacity (FRC), brings the FRC above the closing volume, reduces the protein leak and conserves surfactant. As per Laplace law, the collapsing alveoli pressure is proportional to surface tension at air liquid interface in the alveoli and inversely proportional to the radii of the alveoli. CPAP works by improving the alveoli radii and surfactant by decreasing the surface tension. Surfactant a complex lipoprotein forms a monolayer on the air fluid interface in the alveolar membrane and thereby decreases the surface tension. Both surfactant and CPAP together would improve the FRC and homogenize lung expansion [5, 6]. As stated earlier RDS is primarily associated with prematurity. It is well recognized that prematurity is a global issue, with large proportion of premature babies born in developing countries. In India, nearly 26 million infants are born every year. Assuming 10 % incidence of respiratory distress in newborn infants [7], nearly 2.6 million infants are at need of oxygen or CPAP for respiratory distress. Assuming 20 % of infants with oxygen need may require non invasive respiratory support (CPAP) for respiratory distress [8], nearly 5 lakhs (0.5 million) infants per annum require CPAP as a mode of respiratory support. As most of these infants either die or referred to
Neocosur [11]
N=256
CPAP Continuous positive airway pressure; CNP Continuous negative pressure; MV Mechanical ventilation; RDS Respiratory distress syndrome; BPD Bronchopulmonary dysplasia
• RDS diagnosed based on X-ray and clinical • ANS 88–90 % • Failure and ventilation criteria well defined • Developing countries
• Surfactant at FiO 35 % in 2 oxygen group
• Prophylactic CPAP
• Need for mechanical ventilation 29.8 % vs. 50.4 % (p=0.001) • Surfactant use 27.5 % vs. 46.4 % (p=0.002) • No difference in death or BPD at 36 wk • No difference in pneumothorax CPAP/INSURE
Oxygen/Surfactant/MV
• Need for mechanical ventilation • Death/BPD
• Less surfactant use Conducted in level II NICU, non tertiary care units in Australia 23 % vs. 40 % p=0.02 Need for up transfer or treatment failure Hood oxygen
> 31 wk > 1,200 g N=300 800–1,500 g Buckmaster et al., 2007 [8]
CPAP
• RR 2.64 (95 % CI 1.39, 5.04)
• RR 0.65 (95 % CI 0.52–0.81)
• Death/need for mechanical ventilation • Pneumothorax MV Six trials Cochrane 2002 [7]
Intervention Participants Study Title
The first successful use of CPAP in treating RDS was reported by Gregory et al. [2]. Since then many investigators have published randomized controlled studies evaluating the effectiveness of CPAP in RDS. Randomized controlled trials evaluating CPAP vs. Hood oxygen for RDS were conducted in early 1970’s on more mature infants and used a variety of devices. These studies were conducted before the widespread use of antenatal corticosteroids and surfactant. Pooled analysis of these trials showed that use of CPAP reduced the overall rate of mortality (RR 0.52: 0.32–0.87) and the rate of combined outcome, death and assisted ventilation (RR 0.65: 0.52– 0.81, NNT 5: 3–11). Use of CPAP was associated with an increased risk of pneumothorax (RR 2.64: 1.39–5.04) [7]. However, the course of respiratory illness, the method of CPAP application and the devices differ significantly from those reported nearly 4 decades ago, limiting the external validity of these studies. In a recent trial of early CPAP by the South American Neocosur Network, infants were randomized either to early CPAP or Hood oxygen. There was a reduction of the need for mechanical ventilation and BPD/ death rate in the early CPAP group [11]. Buckmaster et al. in a recent RCT compared CPAP with Hood oxygen for management of respiratory distress in non tertiary care neonatal units. The population included infants less than 24 h of age with respiratory distress who required oxygen beyond 30 min of age. Infants had to be > 31 wk gestation and > 1,200 g. The primary outcome measured was the rate of transfer to a NICU and/or treatment failure. Nasal continuous positive airway pressure (nCPAP) (at 6 cm H2O) was shown to significantly
Table 1 CPAP vs. Hood oxygen or ventilation
CPAP vs. Hood Oxygen (Table 1)
CPAP (including CNP), old generation interfaces
Main Results Outcomes Controls
Remarks
tertiary care facilities, CPAP would have a major role in preventing the neonatal deaths in preterm infants and also in decreasing the up-transfers. Because of the magnitude of burden of disease of prematurity and associated RDS related morbidity and mortality in developing countries including India there is great interest to prevent prematurity, RDS and also introduce appropriate treatment strategies. A review of global literature by Barros et al. found 11 evidence based interventions that were effective in improving survival of preterm infants [9]. Among these, antenatal steroid administration to mothers in premature labor, application of CPAP and/or surfactant therapy were found to be effective treatments in low middle income countries (LMICs). At the time of their review, there were few studies from LMICs. Recently one of the authors reviewed the state of surfactant replacement therapy in developing countries [10]. In the present article the authors’ review experience of using CPAP and surfactant in general and Indian experience in particular.
• More mature babies
Indian J Pediatr (May 2014) 81(5):481–488 • Less antenatal steroids 20–35 %
482
483
RR 0.83 (95 % CI 0.64–1.09), 29.6 % vs. 36.5 %. CPAP in DR and early surfactant or CPAP alone 26–29+6 N=648 VON DRM Dunn et al., 2011 [16]
DR Delivery room; MV Mechanical ventilation; CLD Chronic lung disease
CLD at 36 wk or mortality
CPAP in DR 24–27+6 N=1,316 SUPPORT Finer et al., 2010 [15]
MV and prophylactic surfactant
OR 0.95 (95 % CI 0.85–1.05) CLD at 36 wk or mortality
CPAP in DR at 5 min in spontaneously breathing infants with respiratory distress 25–28+6 wk N=610 COIN Morley et al., 2008 [14]
MV and surfactant
OR 0.80 (95 % CI 0.58–1.12) CLD at 36 wk or mortality
Outcomes Control Intervention Participants Study title
Table 2 CPAP vs. mechanical ventilation
Traditionally, the respiratory support for very premature infants with RDS had been intubation and mechanical ventilation. A retrospective analysis of eight different units by Avery and colleagues reported lower incidence of chronic lung disease in units with higher use of CPAP in comparison of mechanical ventilation [13]. Similarly in 2001, Van Marter and colleagues noted protective findings of nCPAP on chronic lung disease in comparison with stabilization with mechanical ventilation. In the COIN (CPAP or Intubation) trial, very preterm infants (25 to 28 wk gestation) with respiratory distress were randomized at 5 min of life to CPAP alone or intubation and ventilation [14]. Among the infants randomized to receive CPAP, single or binasal prongs delivered CPAP pressure of 8 cm of H2O. Infants randomized to the nCPAP group were intubated if they had severe apnea, hypoxia [fraction of inspired oxygen (FiO2) >0.6], or severe respiratory acidosis. The protocol did not specify that the infants randomized to intubation be given surfactant and there were no discrete extubation criteria. CPAP started this early was as effective as ventilation in reducing the rate or death or bronchopulmonary distress at 36 wk gestational age. However the CPAP group had higher incidence of pneumothorax but had fewer days of ventilation, fewer infants receiving surfactant (38 % vs. 77 %, p0.6 in CPAP alone group • MV avoided in 48 % infants • No difference in air leaks
Indian J Pediatr (May 2014) 81(5):481–488
484
not uniform between the two groups in either of the trials. In the Support trial, infants who were born between 24 wk 0 d and 27 wk 6 d of gestation were randomly assigned to CPAP treatment initiated in the delivery room or intubation and surfactant treatment (within 1 h after birth). A total of 1,316 infants were enroled in the study. The rates of the primary outcome (death or BPD at 36 wk) did not differ significantly between the CPAP group and the surfactant group [47.8 % and 51.0 %, respectively; relative risk with CPAP, 0.95; 95 % confidence interval (CI), 0.85 to 1.05] after adjustment for gestational age, center, and familial clustering. Infants who received CPAP treatment, as compared with infants who received MV and surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P0.30 and Verder et al. [18] a/A PaO2 0.4 • 51 % infants in control group did not require rescue surfactant CURPAP Sandri et al., 2010 [22]
MV Mechanical ventilation; CLD Chronic lung disease; BPD Bronchopulmonary dysplasia
RR 0.95 (0.64–1.41) Need for MV in first 5 d of life CPAP and selective surfactant
RR 0.41 (95 % CI 0.19–0.91) Need for MV CPAP
Early INSURE within 2 h of life CPAP and prophylactic surfactant/INSURE 28–33+6 wk N=153 25–28+6 wk N=208 Kandraju et al., 2012 [21]
Need for MV CPAP Early INSURE 27–31+6 wk N=279 Rojas et al., 2009 [20]
Need for MV Late INSURE 29–35 wk Reininger et al., 2005 [19]
CPAP
RR 0.69 (95 % CI 0.49–0.97)
• INSURE>2 h of life • Median time of randomization 12 h • No difference in CLD • Ventilator CPAP • Blinded study • Rescue CPAP • Insure group surfactant within 1 h • Trend towards less BPD in Insure group • Less pneumothorax in INSURE group • No difference in air leaks, CLD 43 % vs. 85 % p=0.003 Need for MV Late INSURE 25–35 wk N=73 Verder et al., 1994 [18]
Continued CPAP
50 % vs. 70 % p=0.04
Remarks Outcomes Controls Intervention Participants Study title
Table 3 CPAP with or without surfactant
485
Main results
Indian J Pediatr (May 2014) 81(5):481–488
(16.2 vs. 31.6 %; relative risk 0.41, 95 % confidence interval 0.19–0.91). The incidence of pneumothorax (1.9 vs. 2.3 %) and the need for supplemental O2 at 28 d (2.7 vs. 8.9 %) were similar in the two groups. These results affirm the advantages of using nCPAP as a primary strategy in resource limited countries. When CPAP was started immediately after birth even before of the onset of respiratory distress as in CURPAP [22] and DRM trials [16], CPAP alone was as effective as CPAP with prophylactic surfactant. High antenatal steroid use, early rescue surfactant in the nCPAP group and pre-intubation sedation for surfactant administration may be the reasons for success of nCPAP alone in these trials. In the CURPAP trial, 208 inborn infants who were born at 25 to 28 wks’ gestation and not intubated at birth were randomly assigned to prophylactic surfactant and nCPAP or nCPAP with selective surfactant within 30 min of birth. Outcomes were assessed within the first 5 d of life and until death or discharge of the infants from hospital. In the nCPAP group surfactant was given when the FiO2 requirement exceeded 0.40. Thirty-three (31.4 %) infants in the prophylactic surfactant group needed MV in the first 5 d of life compared with 34 (33.0 %) in the nCPAP group [risk ratio: 0.95 (95 % confidence interval: 0.64 –1.41); P=0.80]. Death and type of survival at 28 d of life and 36 wks’ postmenstrual age and incidence of main morbidities of prematurity (secondary outcomes) were similar in the two groups. A total of 78.1 % of infants in the prophylactic surfactant group and 78.6 % in the nCPAP group survived in room air at 36 wks’ postmenstrual age. In this trial nCPAP started in the delivery room was as effective as nCPAP with surfactant. In the DRM trial too, nCPAP started in the delivery room was as effective as prophylactic surfactant with nCPAP and prophylactic surfactant with mechanical ventilation.
Nasal Continuous Positive Airway Pressure (nCPAP) vs. Nasal Synchronized Intermittent Mandatory Ventilation (nSIMV) (Table 4)
The current evidence comparing nCPAP with nSIMV or nasal intermittent positive pressure ventilation (NIPPV) does not support superiority of nSIMV over CPAP as the primary mode of respiratory support in preterm infants with RDS. Bisceglia and colleagues randomized 88 preterm infants with RDS to either continued CPAP or NIPPV [23]. The investigators reported improved PCO2 levels and shorter duration of mechanical ventilation when it was indicated in the NIPPV group, but no difference was noted in the need for endotracheal ventilation. The investigators did not report mortality or CLD outcomes. A second study, reported by Kugelman and colleagues, randomized 84 infants born less than 35 wks’ gestation with clinical RDS to either NIPPV or CPAP. Infants from either arm were eligible for intubation, rescue surfactant
OR 1.05(0.80–1.39)
NIPPV Nasal intermittent positive pressure ventilation; PIP Peak inspiratory pressure; PEEP Positive end-expiratory pressure; CLD Chronic lung disease; BPD Bronchopulmonary dysplasia
Kripalani et al., 2013 [27]
CPAP NIPPV < 30 wk, < 1,000 g
Death or BPD at 36 wk
No difference
• No difference in air leaks, BPD • Increased abdominal girth • Randomized at any fist use of non-invasive support in first 28 dol • No difference in air leaks Sai Sunil Kishore et al., 2009 [26]
CPAP 5 NIPPV (rate 50/min, PIP 15–16, PEEP 5, Ti 0.3 28–34 wk, > 750 g, N=76
Need for intubation in first 72 h
CPAP vs. NIPPV 40 % vs. 17 % OR 3.6 (1.5–8.7) RR 0.38 (0.15–0.89) CPAP 5 cm H2O Ramanathan et al., 2012 [25]
NIPPV (PIP 10–15, PEEP 5, Ti 0.5, rate 30–40)
Need for ventilation at 7 dol
2 % vs.17 % p=0.03 CPAP (6–7 cm of H2O) NIPPV (rate 12–30, PIP 14–22, PEEP 6–7, Ti=0.3 s) Kugelman et al., 2007 [24]
24–34 wk N=84 < 30 wk N=110
CLD at 36 wk
No difference in intubation rates Bisceglia et al., 2007 [23]
CPAP 4–6 NIPPV (rate 40, PIP 14–20, PEEP 4–6) N=88
Intubation
Main results Outcomes Controls Intervention Participants Study title
Table 4 nCPAP vs. nSIMV
• Less apnea, shorter duration of respiratory support • Primary mode • Less intubation rates 25 % vs. 49 % • Primary mode • Incidence of BPD was more in group 39 % vs. 21 % OR 2.4 (1.02–5.6)
Indian J Pediatr (May 2014) 81(5):481–488
Remarks
486
administration, and mechanical ventilation using uniform criteria. In this trial, infants initially stabilized using NIPPV were less likely to be intubated (25 % vs. 49 %, P=0.04) and less likely to have CLD (2 % vs. 17 %, P=0 .03) [24]. In another RCT, Ramanathan and colleagues randomized 110 spontaneously breathing preterm infants born between 26 and 29 wks’ gestation to either nCPAP or NIPPV post INSURE [25]. Surfactant was administered to all the eligible infants within the first hour of life. Infants randomized to extubation with CPAP remained on CPAP until at least 72 h of life or until they no longer had an O2 requirement. Infants randomized to extubation on NIPPV were weaned according to a standard guideline; however, infants were maintained on NIPPV for at least 24 h following extubation. Both groups were reintubated for the same indications (severe apnea, FiO2 >0.6, pH < 7.25, PCO2 >65 mm Hg). Days spent on endotracheal mechanical ventilation were shorter in the group randomized to NIPPV compared with CPAP (median 1 vs. 7 d, p=0.006). CLD was observed in 39 % of the infants in the CPAP group compared with 21 % in the NIPPV group [OR 2.4 (95 % CI 1.02–5.6)]. No differences were observed in mortality rates or in the combined outcome of mortality and CLD. In a study from North India, 76 preterm infants with respiratory distress were randomized to either nasal IMV or CPAP [26]. The need for intubation in the first 72 h of life was significantly lesser in the nasal IMV group. In another recent multicenter RCT, 1,009 infants with a birth weight of less than 1,000 g and a gestational age of less than 30 wk were randomized to one of two forms of non-invasive respiratory support nasal intermittent positive-pressure ventilation (IPPV) or nasal continuous positive airway pressure (CPAP) at the time of the first use of non-invasive respiratory support during the first 28 d of life [27]. The primary outcome was death before 36 wk of postmenstrual age or survival with bronchopulmonary dysplasia. Of the 497 infants assigned to nasal IPPV for whom adequate data were available, 191 died or survived with bronchopulmonary dysplasia (38.4 %), as compared with 180 of 490 infants assigned to nasal CPAP (36.7 %) (adjusted odds ratio, 1.09; 95 % confidence interval, 0.83 to 1.43; P= 0.56). The frequencies of air leaks and necrotizing enterocolitis, the duration of respiratory support, and the time to full feedings did not differ significantly between treatment groups. This large RCT concludes CPAP as effective as nSIMV in the management of preterm infants with RDS both as a primary mode as well for post extubation management.
Surfactant vs. CPAP in Developing Countries There are limited data from developing countries regarding the use of CPAP and CPAP in conjunction with surfactant therapy. Barros et al. after reviewing the data on the interventions to improve survival of preterm infants strongly
Indian J Pediatr (May 2014) 81(5):481–488
recommend use of CPAP and Surfactant in the management of RDS especially in the LMICs [9]. In the studies from developing countries, the efficacy of CPAP alone was found to be highly effective in treating infants with RDS [10]. Further the cost of CPAP device was found to be only 15 % of surfactant therapy. Thus CPAP is a cost effective non-invasive support for infants with RDS in LMICs. In India and other developing countries starting nCPAP services in the special care newborns units with good level II care may be a better option than mechanical ventilation. This would improve the quality of care and also decrease the uptransfers to already over burdened level III NICUs in the medical colleges. Antenatal corticosteroids for women who deliver preterm babies, along with early use of CPAP and early use of surfactant in select cases would help in further reducing the need for mechanical ventilation especially in preterm infants with respiratory distress and incomplete steroid coverage, gestation 0.30), white out on the chest x-ray, where the risk of CPAP failure is very high [28, 29]. There is an urgent need to train specialist doctors and nurses working in SCNUs for effective use of CPAP. In this regard the WHO collaboration center for training & research in newborn care at AIIMS, New Delhi and PGIMER, Chandigarh along with other neonatologists have taken the lead in training nearly 3,000 pediatricians and nurses on the science and art of CPAP in different parts of India and South East Asia in the last 3 y [30].
Key Messages 1. Good antenatal care, early recognition of preterm labor, use of antenatal corticosteroid coverage and optimum delivery practices are critical to optimize the care of preterm infant. 2. Nasal CPAP started early in the course of RDS is effective in decreasing the need for mechanical ventilation, and the need for up-transfers to level III NICU. 3. Nasal CPAP immediately after birth with selective surfactant is as effective as mechanical ventilation with prophylactic surfactant. Starting nCPAP early would decrease the overall days on mechanical ventilation or need for oxygen at 28 d of life. 4. In preterm infants with RDS, combining nCPAP with surfactant is more effective than nCPAP alone in reducing the subsequent need for mechanical ventilation. 5. In very preterm infants (
REVIEW ARTICLE
Use of CPAP and Surfactant Therapy in Newborns with Respiratory Distress Syndrome Srinivas Murki & Ashok Deorari & Dharmapuri Vidyasagar
Received: 8 October 2013 / Accepted: 5 March 2014 / Published online: 12 April 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Respiratory distress syndrome (RDS) is a major disease burden in the developing countries. Current evidence supports early continuous positive airway pressure (CPAP) use and early selective surfactant administration as the most efficacious interventions in the management of RDS, both in developed and developing countries. In developing countries, it is recommended to increase institutional deliveries and increase the coverage of antenatal steroids in women in preterm labor as preventive measures. Establishing intervention of CPAP and surfactant therapies in the Level II special care newborn units (SCNUs) and Level III units requires focus on training nursing staff and pediatricians across the board. These approaches would pave the way in optimizing the care of the preterm infants with RDS and decrease their mortality and morbidity significantly. Keywords RDS . nCPAP . Surfactant . Developing country
Introduction Respiratory distress is one of the commonest morbidities in babies admitted in sick newborn care units (SCNUs). Respiratory distress syndrome (RDS) is the commonest cause
S. Murki Department of Pediatrics, Fernandez Hospital, Hyderabad, India A. Deorari (*) Department of Pediatrics, Division of Neonatology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India e-mail: [email protected] D. Vidyasagar Division of Neonatology, University of Illinois at Chicago, Chicago, IL, USA
of respiratory distress in preterm infants. Lower the gestation, higher is the incidence of RDS, accounting for nearly 80 % incidence in preterm infants with gestation less than 28 wk. Surfactant deficiency is the major underlying cause of RDS [1]. Surfactant deficiency results in lower functional residual capacity, increased work of breathing and respiratory failure. In 1967, Gregory et al. reported the value of application of continuous positive airway pressure in the management of RDS [2]. Successful surfactant replacement therapy in RDS was reported by Fujiwara et al. [3]. Continuous positive airway pressure (CPAP) coupled with surfactant replacement therapy appears to be the ideal choice for the management of respiratory distress in preterm infants with RDS in low and middle income countries [4]. In RDS, CPAP prevents alveolar collapse, improves the functional residual capacity (FRC), brings the FRC above the closing volume, reduces the protein leak and conserves surfactant. As per Laplace law, the collapsing alveoli pressure is proportional to surface tension at air liquid interface in the alveoli and inversely proportional to the radii of the alveoli. CPAP works by improving the alveoli radii and surfactant by decreasing the surface tension. Surfactant a complex lipoprotein forms a monolayer on the air fluid interface in the alveolar membrane and thereby decreases the surface tension. Both surfactant and CPAP together would improve the FRC and homogenize lung expansion [5, 6]. As stated earlier RDS is primarily associated with prematurity. It is well recognized that prematurity is a global issue, with large proportion of premature babies born in developing countries. In India, nearly 26 million infants are born every year. Assuming 10 % incidence of respiratory distress in newborn infants [7], nearly 2.6 million infants are at need of oxygen or CPAP for respiratory distress. Assuming 20 % of infants with oxygen need may require non invasive respiratory support (CPAP) for respiratory distress [8], nearly 5 lakhs (0.5 million) infants per annum require CPAP as a mode of respiratory support. As most of these infants either die or referred to
Neocosur [11]
N=256
CPAP Continuous positive airway pressure; CNP Continuous negative pressure; MV Mechanical ventilation; RDS Respiratory distress syndrome; BPD Bronchopulmonary dysplasia
• RDS diagnosed based on X-ray and clinical • ANS 88–90 % • Failure and ventilation criteria well defined • Developing countries
• Surfactant at FiO 35 % in 2 oxygen group
• Prophylactic CPAP
• Need for mechanical ventilation 29.8 % vs. 50.4 % (p=0.001) • Surfactant use 27.5 % vs. 46.4 % (p=0.002) • No difference in death or BPD at 36 wk • No difference in pneumothorax CPAP/INSURE
Oxygen/Surfactant/MV
• Need for mechanical ventilation • Death/BPD
• Less surfactant use Conducted in level II NICU, non tertiary care units in Australia 23 % vs. 40 % p=0.02 Need for up transfer or treatment failure Hood oxygen
> 31 wk > 1,200 g N=300 800–1,500 g Buckmaster et al., 2007 [8]
CPAP
• RR 2.64 (95 % CI 1.39, 5.04)
• RR 0.65 (95 % CI 0.52–0.81)
• Death/need for mechanical ventilation • Pneumothorax MV Six trials Cochrane 2002 [7]
Intervention Participants Study Title
The first successful use of CPAP in treating RDS was reported by Gregory et al. [2]. Since then many investigators have published randomized controlled studies evaluating the effectiveness of CPAP in RDS. Randomized controlled trials evaluating CPAP vs. Hood oxygen for RDS were conducted in early 1970’s on more mature infants and used a variety of devices. These studies were conducted before the widespread use of antenatal corticosteroids and surfactant. Pooled analysis of these trials showed that use of CPAP reduced the overall rate of mortality (RR 0.52: 0.32–0.87) and the rate of combined outcome, death and assisted ventilation (RR 0.65: 0.52– 0.81, NNT 5: 3–11). Use of CPAP was associated with an increased risk of pneumothorax (RR 2.64: 1.39–5.04) [7]. However, the course of respiratory illness, the method of CPAP application and the devices differ significantly from those reported nearly 4 decades ago, limiting the external validity of these studies. In a recent trial of early CPAP by the South American Neocosur Network, infants were randomized either to early CPAP or Hood oxygen. There was a reduction of the need for mechanical ventilation and BPD/ death rate in the early CPAP group [11]. Buckmaster et al. in a recent RCT compared CPAP with Hood oxygen for management of respiratory distress in non tertiary care neonatal units. The population included infants less than 24 h of age with respiratory distress who required oxygen beyond 30 min of age. Infants had to be > 31 wk gestation and > 1,200 g. The primary outcome measured was the rate of transfer to a NICU and/or treatment failure. Nasal continuous positive airway pressure (nCPAP) (at 6 cm H2O) was shown to significantly
Table 1 CPAP vs. Hood oxygen or ventilation
CPAP vs. Hood Oxygen (Table 1)
CPAP (including CNP), old generation interfaces
Main Results Outcomes Controls
Remarks
tertiary care facilities, CPAP would have a major role in preventing the neonatal deaths in preterm infants and also in decreasing the up-transfers. Because of the magnitude of burden of disease of prematurity and associated RDS related morbidity and mortality in developing countries including India there is great interest to prevent prematurity, RDS and also introduce appropriate treatment strategies. A review of global literature by Barros et al. found 11 evidence based interventions that were effective in improving survival of preterm infants [9]. Among these, antenatal steroid administration to mothers in premature labor, application of CPAP and/or surfactant therapy were found to be effective treatments in low middle income countries (LMICs). At the time of their review, there were few studies from LMICs. Recently one of the authors reviewed the state of surfactant replacement therapy in developing countries [10]. In the present article the authors’ review experience of using CPAP and surfactant in general and Indian experience in particular.
• More mature babies
Indian J Pediatr (May 2014) 81(5):481–488 • Less antenatal steroids 20–35 %
482
483
RR 0.83 (95 % CI 0.64–1.09), 29.6 % vs. 36.5 %. CPAP in DR and early surfactant or CPAP alone 26–29+6 N=648 VON DRM Dunn et al., 2011 [16]
DR Delivery room; MV Mechanical ventilation; CLD Chronic lung disease
CLD at 36 wk or mortality
CPAP in DR 24–27+6 N=1,316 SUPPORT Finer et al., 2010 [15]
MV and prophylactic surfactant
OR 0.95 (95 % CI 0.85–1.05) CLD at 36 wk or mortality
CPAP in DR at 5 min in spontaneously breathing infants with respiratory distress 25–28+6 wk N=610 COIN Morley et al., 2008 [14]
MV and surfactant
OR 0.80 (95 % CI 0.58–1.12) CLD at 36 wk or mortality
Outcomes Control Intervention Participants Study title
Table 2 CPAP vs. mechanical ventilation
Traditionally, the respiratory support for very premature infants with RDS had been intubation and mechanical ventilation. A retrospective analysis of eight different units by Avery and colleagues reported lower incidence of chronic lung disease in units with higher use of CPAP in comparison of mechanical ventilation [13]. Similarly in 2001, Van Marter and colleagues noted protective findings of nCPAP on chronic lung disease in comparison with stabilization with mechanical ventilation. In the COIN (CPAP or Intubation) trial, very preterm infants (25 to 28 wk gestation) with respiratory distress were randomized at 5 min of life to CPAP alone or intubation and ventilation [14]. Among the infants randomized to receive CPAP, single or binasal prongs delivered CPAP pressure of 8 cm of H2O. Infants randomized to the nCPAP group were intubated if they had severe apnea, hypoxia [fraction of inspired oxygen (FiO2) >0.6], or severe respiratory acidosis. The protocol did not specify that the infants randomized to intubation be given surfactant and there were no discrete extubation criteria. CPAP started this early was as effective as ventilation in reducing the rate or death or bronchopulmonary distress at 36 wk gestational age. However the CPAP group had higher incidence of pneumothorax but had fewer days of ventilation, fewer infants receiving surfactant (38 % vs. 77 %, p0.6 in CPAP alone group • MV avoided in 48 % infants • No difference in air leaks
Indian J Pediatr (May 2014) 81(5):481–488
484
not uniform between the two groups in either of the trials. In the Support trial, infants who were born between 24 wk 0 d and 27 wk 6 d of gestation were randomly assigned to CPAP treatment initiated in the delivery room or intubation and surfactant treatment (within 1 h after birth). A total of 1,316 infants were enroled in the study. The rates of the primary outcome (death or BPD at 36 wk) did not differ significantly between the CPAP group and the surfactant group [47.8 % and 51.0 %, respectively; relative risk with CPAP, 0.95; 95 % confidence interval (CI), 0.85 to 1.05] after adjustment for gestational age, center, and familial clustering. Infants who received CPAP treatment, as compared with infants who received MV and surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P0.30 and Verder et al. [18] a/A PaO2 0.4 • 51 % infants in control group did not require rescue surfactant CURPAP Sandri et al., 2010 [22]
MV Mechanical ventilation; CLD Chronic lung disease; BPD Bronchopulmonary dysplasia
RR 0.95 (0.64–1.41) Need for MV in first 5 d of life CPAP and selective surfactant
RR 0.41 (95 % CI 0.19–0.91) Need for MV CPAP
Early INSURE within 2 h of life CPAP and prophylactic surfactant/INSURE 28–33+6 wk N=153 25–28+6 wk N=208 Kandraju et al., 2012 [21]
Need for MV CPAP Early INSURE 27–31+6 wk N=279 Rojas et al., 2009 [20]
Need for MV Late INSURE 29–35 wk Reininger et al., 2005 [19]
CPAP
RR 0.69 (95 % CI 0.49–0.97)
• INSURE>2 h of life • Median time of randomization 12 h • No difference in CLD • Ventilator CPAP • Blinded study • Rescue CPAP • Insure group surfactant within 1 h • Trend towards less BPD in Insure group • Less pneumothorax in INSURE group • No difference in air leaks, CLD 43 % vs. 85 % p=0.003 Need for MV Late INSURE 25–35 wk N=73 Verder et al., 1994 [18]
Continued CPAP
50 % vs. 70 % p=0.04
Remarks Outcomes Controls Intervention Participants Study title
Table 3 CPAP with or without surfactant
485
Main results
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(16.2 vs. 31.6 %; relative risk 0.41, 95 % confidence interval 0.19–0.91). The incidence of pneumothorax (1.9 vs. 2.3 %) and the need for supplemental O2 at 28 d (2.7 vs. 8.9 %) were similar in the two groups. These results affirm the advantages of using nCPAP as a primary strategy in resource limited countries. When CPAP was started immediately after birth even before of the onset of respiratory distress as in CURPAP [22] and DRM trials [16], CPAP alone was as effective as CPAP with prophylactic surfactant. High antenatal steroid use, early rescue surfactant in the nCPAP group and pre-intubation sedation for surfactant administration may be the reasons for success of nCPAP alone in these trials. In the CURPAP trial, 208 inborn infants who were born at 25 to 28 wks’ gestation and not intubated at birth were randomly assigned to prophylactic surfactant and nCPAP or nCPAP with selective surfactant within 30 min of birth. Outcomes were assessed within the first 5 d of life and until death or discharge of the infants from hospital. In the nCPAP group surfactant was given when the FiO2 requirement exceeded 0.40. Thirty-three (31.4 %) infants in the prophylactic surfactant group needed MV in the first 5 d of life compared with 34 (33.0 %) in the nCPAP group [risk ratio: 0.95 (95 % confidence interval: 0.64 –1.41); P=0.80]. Death and type of survival at 28 d of life and 36 wks’ postmenstrual age and incidence of main morbidities of prematurity (secondary outcomes) were similar in the two groups. A total of 78.1 % of infants in the prophylactic surfactant group and 78.6 % in the nCPAP group survived in room air at 36 wks’ postmenstrual age. In this trial nCPAP started in the delivery room was as effective as nCPAP with surfactant. In the DRM trial too, nCPAP started in the delivery room was as effective as prophylactic surfactant with nCPAP and prophylactic surfactant with mechanical ventilation.
Nasal Continuous Positive Airway Pressure (nCPAP) vs. Nasal Synchronized Intermittent Mandatory Ventilation (nSIMV) (Table 4)
The current evidence comparing nCPAP with nSIMV or nasal intermittent positive pressure ventilation (NIPPV) does not support superiority of nSIMV over CPAP as the primary mode of respiratory support in preterm infants with RDS. Bisceglia and colleagues randomized 88 preterm infants with RDS to either continued CPAP or NIPPV [23]. The investigators reported improved PCO2 levels and shorter duration of mechanical ventilation when it was indicated in the NIPPV group, but no difference was noted in the need for endotracheal ventilation. The investigators did not report mortality or CLD outcomes. A second study, reported by Kugelman and colleagues, randomized 84 infants born less than 35 wks’ gestation with clinical RDS to either NIPPV or CPAP. Infants from either arm were eligible for intubation, rescue surfactant
OR 1.05(0.80–1.39)
NIPPV Nasal intermittent positive pressure ventilation; PIP Peak inspiratory pressure; PEEP Positive end-expiratory pressure; CLD Chronic lung disease; BPD Bronchopulmonary dysplasia
Kripalani et al., 2013 [27]
CPAP NIPPV < 30 wk, < 1,000 g
Death or BPD at 36 wk
No difference
• No difference in air leaks, BPD • Increased abdominal girth • Randomized at any fist use of non-invasive support in first 28 dol • No difference in air leaks Sai Sunil Kishore et al., 2009 [26]
CPAP 5 NIPPV (rate 50/min, PIP 15–16, PEEP 5, Ti 0.3 28–34 wk, > 750 g, N=76
Need for intubation in first 72 h
CPAP vs. NIPPV 40 % vs. 17 % OR 3.6 (1.5–8.7) RR 0.38 (0.15–0.89) CPAP 5 cm H2O Ramanathan et al., 2012 [25]
NIPPV (PIP 10–15, PEEP 5, Ti 0.5, rate 30–40)
Need for ventilation at 7 dol
2 % vs.17 % p=0.03 CPAP (6–7 cm of H2O) NIPPV (rate 12–30, PIP 14–22, PEEP 6–7, Ti=0.3 s) Kugelman et al., 2007 [24]
24–34 wk N=84 < 30 wk N=110
CLD at 36 wk
No difference in intubation rates Bisceglia et al., 2007 [23]
CPAP 4–6 NIPPV (rate 40, PIP 14–20, PEEP 4–6) N=88
Intubation
Main results Outcomes Controls Intervention Participants Study title
Table 4 nCPAP vs. nSIMV
• Less apnea, shorter duration of respiratory support • Primary mode • Less intubation rates 25 % vs. 49 % • Primary mode • Incidence of BPD was more in group 39 % vs. 21 % OR 2.4 (1.02–5.6)
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Remarks
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administration, and mechanical ventilation using uniform criteria. In this trial, infants initially stabilized using NIPPV were less likely to be intubated (25 % vs. 49 %, P=0.04) and less likely to have CLD (2 % vs. 17 %, P=0 .03) [24]. In another RCT, Ramanathan and colleagues randomized 110 spontaneously breathing preterm infants born between 26 and 29 wks’ gestation to either nCPAP or NIPPV post INSURE [25]. Surfactant was administered to all the eligible infants within the first hour of life. Infants randomized to extubation with CPAP remained on CPAP until at least 72 h of life or until they no longer had an O2 requirement. Infants randomized to extubation on NIPPV were weaned according to a standard guideline; however, infants were maintained on NIPPV for at least 24 h following extubation. Both groups were reintubated for the same indications (severe apnea, FiO2 >0.6, pH < 7.25, PCO2 >65 mm Hg). Days spent on endotracheal mechanical ventilation were shorter in the group randomized to NIPPV compared with CPAP (median 1 vs. 7 d, p=0.006). CLD was observed in 39 % of the infants in the CPAP group compared with 21 % in the NIPPV group [OR 2.4 (95 % CI 1.02–5.6)]. No differences were observed in mortality rates or in the combined outcome of mortality and CLD. In a study from North India, 76 preterm infants with respiratory distress were randomized to either nasal IMV or CPAP [26]. The need for intubation in the first 72 h of life was significantly lesser in the nasal IMV group. In another recent multicenter RCT, 1,009 infants with a birth weight of less than 1,000 g and a gestational age of less than 30 wk were randomized to one of two forms of non-invasive respiratory support nasal intermittent positive-pressure ventilation (IPPV) or nasal continuous positive airway pressure (CPAP) at the time of the first use of non-invasive respiratory support during the first 28 d of life [27]. The primary outcome was death before 36 wk of postmenstrual age or survival with bronchopulmonary dysplasia. Of the 497 infants assigned to nasal IPPV for whom adequate data were available, 191 died or survived with bronchopulmonary dysplasia (38.4 %), as compared with 180 of 490 infants assigned to nasal CPAP (36.7 %) (adjusted odds ratio, 1.09; 95 % confidence interval, 0.83 to 1.43; P= 0.56). The frequencies of air leaks and necrotizing enterocolitis, the duration of respiratory support, and the time to full feedings did not differ significantly between treatment groups. This large RCT concludes CPAP as effective as nSIMV in the management of preterm infants with RDS both as a primary mode as well for post extubation management.
Surfactant vs. CPAP in Developing Countries There are limited data from developing countries regarding the use of CPAP and CPAP in conjunction with surfactant therapy. Barros et al. after reviewing the data on the interventions to improve survival of preterm infants strongly
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recommend use of CPAP and Surfactant in the management of RDS especially in the LMICs [9]. In the studies from developing countries, the efficacy of CPAP alone was found to be highly effective in treating infants with RDS [10]. Further the cost of CPAP device was found to be only 15 % of surfactant therapy. Thus CPAP is a cost effective non-invasive support for infants with RDS in LMICs. In India and other developing countries starting nCPAP services in the special care newborns units with good level II care may be a better option than mechanical ventilation. This would improve the quality of care and also decrease the uptransfers to already over burdened level III NICUs in the medical colleges. Antenatal corticosteroids for women who deliver preterm babies, along with early use of CPAP and early use of surfactant in select cases would help in further reducing the need for mechanical ventilation especially in preterm infants with respiratory distress and incomplete steroid coverage, gestation 0.30), white out on the chest x-ray, where the risk of CPAP failure is very high [28, 29]. There is an urgent need to train specialist doctors and nurses working in SCNUs for effective use of CPAP. In this regard the WHO collaboration center for training & research in newborn care at AIIMS, New Delhi and PGIMER, Chandigarh along with other neonatologists have taken the lead in training nearly 3,000 pediatricians and nurses on the science and art of CPAP in different parts of India and South East Asia in the last 3 y [30].
Key Messages 1. Good antenatal care, early recognition of preterm labor, use of antenatal corticosteroid coverage and optimum delivery practices are critical to optimize the care of preterm infant. 2. Nasal CPAP started early in the course of RDS is effective in decreasing the need for mechanical ventilation, and the need for up-transfers to level III NICU. 3. Nasal CPAP immediately after birth with selective surfactant is as effective as mechanical ventilation with prophylactic surfactant. Starting nCPAP early would decrease the overall days on mechanical ventilation or need for oxygen at 28 d of life. 4. In preterm infants with RDS, combining nCPAP with surfactant is more effective than nCPAP alone in reducing the subsequent need for mechanical ventilation. 5. In very preterm infants (
