Journal of Perinatology (2014) 34, 524–527 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Lung recruitment maneuver during proportional assist ventilation of preterm infants with acute respiratory distress syndrome R Wu1,4, S-B Li2,4, Z-F Tian3,4, N Li1, G-F Zheng1, Y-X Zhao1, H-L Zhu1, J-H Hu1, L Zha1, M-Y Dai1 and W-Y Xu1 OBJECTIVE: To investigate the effect of lung recruitment maneuver (LRM) with positive end-expiratory pressure (PEEP) on oxygenation and outcomes in preterm infants ventilated by proportional assist ventilation (PAV) for respiratory distress syndrome (RDS). STUDY DESIGN: Preterm infants on PAV for RDS after surfactant randomly received an LRM (group A, n = 12) or did not (group B, n = 12). LRM entailed increments of 0.2 cm H2O PEEP every 5 min, until fraction of inspired oxygen (FiO2) = 0.25. Then PEEP was reduced and the lung volume was set on the deflation limb of the pressure/volume curve. When saturation of peripheral oxygen fell and FiO2 rose, we reincremented PEEP until SpO2 became stable. RESULT: Group A and B infants were similar: gestational age 29.5 ± 1.0 vs 29.4 ± 0.9 weeks; body weight 1314 ± 96 vs 1296 ± 88 g; Silverman Anderson score for babies at start of ventilation 8.6 ± 0.8 vs 8.2 ± 0.7; initial FiO2 0.56 ± 0.16 vs 0.51 ± 0.14, respectively. The less doses of surfactant administered in group A than that in group B (P o 0.05). Groups A and B showed different max PEEP during the first 12 h of life (8.4 ± 0.5 vs 6.7 ± 0.6 cm H2O, P = 0.00), time to lowest FiO2 (101 ± 18 versus 342 ± 128 min; P = 0.000) and O2 dependency (7.83 ± 2.04 vs 9.92 ± 2.78 days; P = 0.04). FiO2 levels progressively decreased (F = 43.240, P = 0.000) and a/AO2 ratio gradually increased (F = 30.594, P = 0.000). No adverse events and no differences in the outcomes were observed. CONCLUSION: LRM led to the earlier lowest FiO2 of the first 12 h of life and a shorter O2 dependency. Journal of Perinatology (2014) 34, 524–527; doi:10.1038/jp.2014.53; published online 3 April 2014
INTRODUCTION Respiratory distress syndrome (RDS) is the most common condition of preterm infants in neonatal intensive care unit (NICU) with complications due to RDS constituting the most significant cause of mortality and long-term morbidity. Neonatal mechanical ventilator is considered a valuable tool to manage RDS in preterm infants. Several types of ventilation modes and strategies have been explored in clinical practice to optimize mechanical ventilation, so as to reduce the risk of ventilator-induced lung injury. There are several mechanisms that may underlie lung protection from lung recruitment maneuver (LRM). First, recruiting collapsed alveoli may temporarily improve gas exchange and thus reduce the FiO2. Second, with an open lung, a lower pressure can expand the lungs through the tidal range. Third, if applied with positive end-expiratory pressure (PEEP), an LRM may reduce repetitive opening and closing that causes shear stress that can damage terminal lung units.1 In summary, LRM that achieves an open lung may reduce the risk of oxygen toxicity, overdistention injury and shear-stress injury. Open-lung ventilation uses LRM to open alveoli and optimize lung volume and avoids excessive lung inflation. There is evidence that open-lung ventilation with LRM can also reduce ventilator-induced lung injury and may be an
important adjunct to limiting tidal volume (VT) and applying adequate PEEP.2,3 Proportional assist ventilation (PAV) is a mode in which the ventilator guarantees a percentage of work regardless of changes in pulmonary compliance and resistance. Consequently, the VT and pressure of the ventilator are varied based on the patient’s work of breathing and the amount it delivers is proportional to the percentage of assistance it is set to provide.4 In this pilot study, we prospectively collected data on ventilatory parameters—FiO2 requirements, gas exchange and respiratory outcomes—to investigate the effect of an LRM in preterm infants who received LRM plus PAV versus those who received PAV only during the acute phase of RDS, using saturation of peripheral oxygen (SpO2) to guide the maneuver. METHODS Patient population This study was performed at the NICU of Huaian Maternity and Child Healthcare Hospital, after the local ethical committee’s approval. We studied infants with gestational age (GA) 28–30 weeks and birth weigh (BW) 1000–1500 g who received at least one course of prenatal glucocorticoids and required tracheal intubation and mechanical ventilation in
1 Neonatal Medical Center, Huaian Maternity and Child Healthcare Hospital, Anhui Medical University, Huaian, China; 2Anhui Medical University, Hefei, China and 3Huaian First People's Hospital, Nanjing Medical University, Huaian, China. Correspondence: Professor R Wu, Neonatal Medical Center, Huaian Maternity and Child Healthcare Hospital, Anhui Medical University, No.104, South Renmin Road, Huaian, Jiangsu Province 223002, China. E-mail: [email protected] 4 These authors contributed equally to this work. Received 7 October 2013; revised 18 February 2014; accepted 18 February 2014; published online 3 April 2014
Lung recruitment maneuver R Wu et al
525 the first six hours of life due to severe RDS, with written parental consent. Exclusion criteria included lethal congenital anomalies, severe intraventricular hemorrhage (above grade II), no spontaneous breathing or spontaneous breathing weak and absence of parental consent. The sample size was determined by the number of early preterm infants admitted to our hospital in 1 year.
than grade 2 retinopathy of prematurity (ROP). BPD was defined as oxygen requirement at 36 weeks of postconceptional age.9 We calculated BPD rate in survivors. Follow-up for BPD definition was completed before discharge. Intraventricular hemorrhage was classified according to Papile et al.10 and ROP was graded according to the international classification of ROP.11
Data processing and statistical analysis Study design This study is a randomized trial. The enrolled infants were randomly assigned to receive an LRM in the second 2 h of life (group A) or not (group B), using sequentially numbered, sealed opaque envelopes. RDS diagnosis was based on the clinical presentation, such as early respiratory distress, which includes cyanosis, grunting, sternal and intercostal recession and tachypnoea. Clinical diagnosis was confirmed with chest X-ray changes that included a ‘ground glass’ appearance and air bronchograms.5 Severe RDS was defined as arterial-to-alveolar oxygen ratio o0.2. All neonates underwent the same management in the delivery room according to our NICU protocols and as recommended by European consensus guidelines.6 From the delivery room, all infants were transferred to the NICU in T-piece devices (set background continuous positive airways pressure (PEEP level = 5 cm H2O level) with a measured peak inspiratory pressure during occlusion of the T-piece). All the patients received the first dose of endotracheal porcine natural surfactant (200 mg/kg; Curosurf, Chiesi, Italy) immediately after tracheal intubation according to our standard protocol for infants of GA 28–30 weeks. During the first 6 h of life, intubated infants were supported with PAV (Stephanie infant ventilator, Gackenbach, Germany) with the following starting parameters: VT = 4–6 ml/kg, and an initial PEEP = 5 cm H2O. The elastic unloading and resistive unloading was set to maintain VT in 4–6 ml/kg. Backup conventional mechanical ventilation (SIMV mode) automatically initiated 10 s after cessation of spontaneous breathing. When spontaneous breath recurred, backup ventilation automatically suppressed and PAV resumed. During mechanical ventilation, the FiO2 level was chosen to maintain a preductal SpO2 of 85 to 93%,6 the range of the peak inspiratory pressure was 10–20 cm H2O, and PEEP was 5–9 cm H2O. After setting a starting PEEP level of 5 cm H2O, we applied repeated increments of 0.2 cm H2O of PEEP every 5 min, monitoring the FiO2 requirements and SpO2 levels. During the 5 min of monitoring, SpO2 level was the signal to proceed with the Fio2 requirements and the PEEP level. We adjusted infant's PEEP and Fio2 in accordance with SpO2. SpO2 rose gradually with increasing PEEP. As soon as SpO2 approached 93%, we began decreasing FiO2, which resulted in a slow drop in SpO2. When SpO2 approached 85%, we stop decreasing FiO2. When FiO2 reached 0.25, a slow stepwise PEEP reduction was started while monitoring the SpO2 levels. When oxygenation levels fell and FiO2 administration rose consequently, we reincreased the PEEP level until stable oxygenation was achieved and the FiO2 level reached levels prior to the fall in oxygenation. CO2 levels (monitored with N-85 handheld detecter, Pleasanton, CA; Non-dispersive infrared and Microstream capnography technology, Nellcor Puritan Bennett, US)7 and cardiovascular status (heart rate, systemic blood pressure) were monitored as well; the rise in CO2 levels and changes of the cardiovascular status were considered signals of stress and overdistention and we interrupted the maneuver if necessary. Mechanical ventilation was stopped when FiO2 was ⩽ 0.30, PEEP = 5 cm H2O, MAP was ⩽ 6 cm H2O, and partial pressure of oxygen in arterial blood and PaCO2 were ⩾ 50 mm Hg and o 65 mm Hg, respectively. The management after the extubation was balanced between the groups. In both groups, following NICU protocols, the extubation of mechanically ventilated infants was mandatory within 2 h after they reached extubation criteria. After extubation, the decision as to whether to begin nasal continuous positive airways pressure to prevent the need for reintubation, to offer oxygen supplementation only, or to put the patient directly into room air was completely up to the neonatologist on duty. Nasal continuous positive airways pressure was stopped when neonates with adequate spontaneous respiratory effort had FiO2 ⩽ 0.30, CDP ⩽ 5 cm H2O, PaO2 ⩾ 50 mm Hg and PaCO2 o65 mm Hg. Oxygen saturation-SpO2, arterial/alveolar oxygen ratio, FiO2 requirements and cardiovascular status were monitored during the procedure, after LRM, or within 12 h of life. All infants were evaluated before respiratory support by the Silverman Anderson score.8 The following data were also recorded for each infant: GA, BW, sex, need for additional surfactant, length of oxygen therapy, duration of mechanical ventilation and of ventilatory assistance (noninvasive plus mechanical ventilation), air leak/pneumothorax, extubation failure occurred, BPD, grade 3 or 4 intraventricular hemorrhage and greater © 2014 Nature America, Inc.
Clinical characteristics of infants in the two groups were described using mean values and s.d. or rate and percentage. The Student’s t-test was performed for parametric continuous variables and the Fisher’s exact test for categorical variables. Kolmogorov–Smirnov tests on population in total and on the two groups confirmed the normal distribution of the variables ‘duration of ventilation’ and ‘length of oxygen exposure’ and appropriateness of Student's t-test. The linear change of PEEP, FiO2 and a/AO2 ratio during the LRM application to infants of group A were analyzed by repeated measures analysis of variance. Po0.05 was considered statistically significant.
RESULTS Twenty four infants were included in the study. Clinical characteristics of infants in the two groups were similar (group A, n = 12, GA 29.5 ± 1.0 weeks, BW 1314 ± 96 g,Silverman Anderson score 8.6 ± 0.8, females 7/12; group B, n = 12, GA 29.4 ± 0.9 weeks; BW 1296 ± 88 g; Silverman Anderson score 8.2 ± 0.7, females 6/12). Group A received the LRM at 96 ± 25 min of age and the maneuver lasted for 70 ± 12 min. Ventilatory and gas analysis changes during the maneuver are described in Tables 1–3. There were no statistically significant differences between the two groups in FiO2, PEEP, a/AO2 ratio and PaO2 at the start of LRM and number of extubation failure (P>0.05). The maximum PEEP level at the end of the incremental increase was higher in group A (P o 0.05). The final PEEP level after decrementing PEEP and completing the entire process was lower (P o 0.05). Moreover, the a/AO2 ratio in the first 12 h of life was significantly higher (P o 0.05). A shorter need for mechanical ventilation (P o 0.05) and duration of oxygen therapy (Po 0.05) in the treated group was observed. The number of surfactant doses used in group A were significantly lower than that of group B (P o0.05). Group A and B showed differences in max PEEP during the first 12 h of life (8.4 ± 0.5 cm versus 6.7 ± 0.6 cm H2O, P = 0.000) and time to lowest FiO2 (101 ± 18 min versus 342 ± 128 min; P = 0.000). FiO2 levels progressively decreased (F = 43.240, P = 0.000) and a/AO2 ratio gradually increased (F = 30.594, P = 0.000) during the LRM application to infants of group A. No differences were observed in extubation failure, BPD, ROP and death between the two groups. In Figure 1, step-by-step changes in SpO2 and FiO2 related to PEEP levels during the LRM
Table 1.
Ventilatory and gas analysis changes during the LRM and in the first 12 h of life Group A (n = 12) FiO2 at the start fo LRM Lowest FiO2a Time to the lowest FiO2 (min) PEEP at the start of LRM (cm H2O) Max PEEP during LRM (cm H2O) Final PEEP at the end of LRM (cm H2O) a/AO2 ratio at the start of LRM a/AO2 ratio at the end of LRMa
Group B (n = 12)
P
0.55 ± 0.16 0.51 ± 0.14 0.744 0.27 ± 0.02 0.39 ± 0.06 0.000 101 ± 18 342 ± 128 0.000 6.6 ± 0.5 6.5 ± 0.5 0.698 8.4 ± 0.5 6.7 ± 0.6 0.000 6.4 ± 0.4 6.6 ± 0.4 0.293 0.24 ± 0.06 0.25 ± 0.06 0.817 0.45 ± 0.10 0.35 ± 0.08 0.013
Abbreviations: a/AO2, arterial/alveolar oxygen ratio; FiO2, fraction of inspired oxygen; LRM, lung recruitment maneuver; PaO2, partial pressure of oxygen in arterial blood; PEEP, positive end-expiratory pressure. a In the first 12 h of life.
Journal of Perinatology (2014), 524 – 527
Lung recruitment maneuver R Wu et al
526 105
Respiratory and clinical outcomes P
Surfactant doses (n) 1.1 ± 0.3 Extubation failure (n) 1 Length of respiratory support (d) 5.6 ± 1.4 Length of tracheal intubation (d) 4.8 ± 1.0 BPD (n) 0 PDA occurrence (n) 3/12 Sepsis (n) 2/12 ROP grade >2 (n) 0 Moderate or severe BPD (n) 0 Death (n) 0 7.83 ± 2.04 O2 dependency (d)
1.5 ± 0.5 1 6.1 ± 2.0 5.8 ± 1.0 1 3/12 2/12 0 0 0 9.92 ± 2.78
0.027 NS 0.026 0.026 NS NS NS NS NS NS 0.049
Abbreviations: BPD, bronchopulmonary dysplasia; NS, not significant; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity.
Table 3.
Changes of PEEP, FiO2 and a/AO2 ratio in the course of lung recruitment maneuver in the group A (n = 12) Different time point
PEEP (cm H2O)
FiO2
a/AO2 ratio
The start of LRM Max PEEP of LRM The end of LRM F P
6.6 ± 0.5 8.4 ± 0.5 6.4 ± 0.4a 257.552 0.000
0.55 ± 0.16 0.27 ± 0.02 0.29 ± 0.03a 43.240 0.000
0.24 ± 0.06 0.34 ± 0.06 0.45 ± 0.10a 30.594 0.000
Abbreviations: a/AO2 ratio, alveolar/Arterial oxygen ratio; FiO2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure. a Po 0.05 versus start level.
application in the group A are shown. FiO2 levels progressively decreased with the LRM for the growing SpO2 levels. When the PEEP level reached 5 cm H2O, a reduction of SpO2 was recorded and the PEEP level was reincreased to achieve prior SpO2 levels. During the LRM application, no adverse events occurred, circulatory parameters were stable, and the maneuver was well tolerated.
DISCUSSION LRM can be defined as a transient increase of transpulmonary pressure with the goal of opening or recovering alveolar units with high critical opening pressure, thus increasing end-expiratory lung volume.12 These effects may be temporary, but, over time, alveolar stability may be preserved with maintenance of an adequate PEEP after RM administration.13–15 In the NICU, LRM have been limited primarily to increasing mean airway pressure during high frequency ventilation. Once the ventilation mode is determined, the most important factor is selecting a ventilation strategy that optimizes lung volume. There is evidence that optimization of the lung volume is critical to lung protection, regardless of what ventilation mode is used.16–18 PEEP was used mainly as an adjunct to improve oxygenation and decrease work of breathing by shifting tidal breathing to a more compliant portion of the pressure–volume curve.19 PEEP is now considered a means to recruit the lung and minimize injury associated with repeated opening and closure of an atelectatic lung.20 There is potential to prevent recollapse of alveoli if PEEP is applied after recruitment.21 Clinical studies are required to determine whether setting the right level of PEEP should be Journal of Perinatology (2014), 524 – 527
0.8 0.7
100
0.6 95
0.5
90
0.4
FiO2
Group B (n = 12)
Group A (n = 12)
SpO2 (%)
Table 2.
0.3
85
0.2 80
SpO2 FiO2
75 5
6
7
8
7
6
5
0.1 0
6
PEEP (cm H2O)
Figure 1. Changes of fraction of inspired oxygen (FiO2) and saturation of peripheral oxygen (SpO2) related to positive endexpiratory pressure (PEEP) levels during lung recruitment maneuver in the group A.
performed according to inflation or deflation P–V curves; in other words, should PEEP be systematically implemented after a recruitment maneuver. An optimal PEEP may be defined as the level of continuous pressure that, after an LRM, prevents alveolar collapse and avoids overinflation with optimal lung volume.22 There is no evidence that starting the maneuver with a different level of PEEP changes the effects of the practice. The settings we chosen in this study are all according to the referenced literature.23 Castoldi F et al.23 found that the adequate PEEP, added to VG ventilation, can improve the effect of volumetargeted ventilation in acute neonatal RDS. Our results suggest that, in the LRM group, we more rapidly obtained an optimal lung volume (proved by a significantly reduced time to achieve a good oxygen saturation with minimal FiO2 and a better final a/AO2 ratio. Furthermore, the duration of mechanical ventilation and oxygen therapy in the LRM group was significantly reduced, which is consistent with the findings of Castoldi F et al.23 group. Surfactant is now often given shortly after birth as prophylaxis against RDS. In preterm lambs, surfactant spreads less homogeneously in a ventilated lung than when given before the first breath.24 In premature infants, whose clinical condition requires emergency intubation or in whom elective intubation has been chosen, it is good practice to administer exogenous surfactant as early as possible.25,26 If given later, the clinical effect of surfactant is so far insufficient for treating RDS. In our study, surfactant was given as soon as possible after tracheal intubation. Our study has several limitations. First, the sample size is small. Further, larger studies of the similar experiments are warranted. Second, we did not measure intrinsic PEEP. Many preterm infants with RDS can have intrinsic PEEP and it is possible that intrinsic PEEP may have affected both gas exchange and lung mechanics parameters of study. Third, this study only observed the shortterm effects on oxygenation and ventilator parameters. Long-term clinical effects need to be studied to adequately address the issue of safety. In conclusion, early LRM in preterm infants with RDS resulted in an earlier achievement of the lowest FiO2 for the first 12 h of life, which was significantly lower than the FiO2 previously necessary to obtain adequate arterial oxygenation, and a shorter O2 dependency. These results suggest that the LRM is a reasonable practice to improve the effect of premature RDS.
CONFLICT OF INTEREST The authors declare no conflict of interest.
© 2014 Nature America, Inc.
Lung recruitment maneuver R Wu et al
ACKNOWLEDGEMENTS We thank all the neonatal units and staff who responded to our survey. This research was funded by grants from Jiangsu Province Health Department (Project no: F201233).
REFERENCES 1 Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994; 149: 1327–1334. 2 Van Kaam AH, de Jaegere A, Haitsma JJ, Van Aalderen WM, Kok JH, Lachmann B. Positive pressure ventilation with the open lung concept optimizes gas exchange and reduces ventilator induced lung injury in newborn piglets. Pediatr Res 2003; 53: 245–253. 3 Rimensberger PC, Cox PN, Frndova H, Bryan AC. The open lung during small tidal volume ventilation: concepts of recruitment and ‘optimal’ positive end-expiratory pressure. Crit Care Med 1999; 27: 1946–1952. 4 Schulze A, Bancalari E. Proportional assist ventilation in infants. Clin Perinatol 2001; 28: 561–578. 5 Sabapathi S, David GS. Management of neonatal respiratory distress syndrome. Paediatr Child Health 2012; 22: 518–522. 6 Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants-2010 update. Neonatology 2010; 97: 402–417. 7 Colman Y, Krauss B. Microstream capnography technology: A new approach to an old problem. J Clin Monit 1999; 15: 403–409. 8 Silverman WC, Anderson DH. Controlled clinical trial on effects of water mist on obstructive respiratory signs, death rate and necropsy findings among premature infants. Pediatrics 1956; 17: 1–4. 9 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA et al. National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116: 1353–1360. 10 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: 529–534. 11 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005; 123: 991–999.
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527 12 Richard JC, Maggiore SM, Mercat A. Clinical review: bedside assessment of alveolar recruitment. Crit Care 2004; 8: 163–169. 13 Rouby JJ. Lung overinflation: the hidden face of alveolar recruitment. Anesthesiology 2003; 99: 2–4. 14 Muscedere JG, Mullen JBM, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994; 149: 1327–1334. 15 Halter JM, Steinberg JM, Schiller HJ, Da Silva M, Gatto LA, Landas S et al. Positive end-expiratory pressure after a recruitment maneuver prevents both alveolar collapse and recruitment/derecruitment. Am J Respir Crit Care Med 2003; 167: 1620–1626. 16 Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994; 149: 1327–1334. 17 Dreyfuss D, Saumon G. Barotrauma is volutrauma but which volume is the one responsible? Intensive Care Med 1992; 18: 139–141. 18 Ricard JD, Dreyfuss D, Saumon G. Ventilator-induced lung injury. Eur Respir J Suppl 2003; (42: 2S–9S. 19 Tobin MJ. Mechanical ventilation. N Engl J Med 1994; 330: 1056–1061. 20 Muscedere JG, Mullen BM, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994; 149: 1327–1334. 21 Tusman G, Bohm SH, Vazquez de Anda GF, do Campo JL, Lachmann B. ‘Alveolar recruitment strategy’ improves arterial oxygenation during general anaesthesia. Br J Anaesth 1999; 82: 8–13. 22 Maisch S, Reissmann H, Fuellekrug B, Weismann D, Rutkowski T, Tusman G et al. Compliance and dead space fraction indicate an optimal level of positive endexpiratory pressure after recruitment in anesthetized patients. Anesth Analg 2008; 106: 175–181. 23 Castoldi F, Daniele I, Fontana P, Cavigioli F, Lupo E, Lista G. Lung Recruitment Maneuver during Volume Guarantee Ventilation of Preterm Infants with Acute Respiratory Distress Syndrome. Am J Perinatol 2011; 28: 521–528. 24 Jobe A, Ikegami M, Jacobs H, Jones S. Surfactant and pulmonary blood flow distributions following treatment of premature lambs with natural surfactant. J Clin Invest 1984; 73: 848–856. 25 O ’Donnell CPF, Stenson BJ. Respiratory strategies for preterm infants at birth. Semin Fetal Neonatal Med 2008; 13: 401–409. 26 Moya FR, Sinha SK. Surfactant trials. Pediatrics 2006; 117: 245–247.
Journal of Perinatology (2014), 524 – 527
ORIGINAL ARTICLE
Lung recruitment maneuver during proportional assist ventilation of preterm infants with acute respiratory distress syndrome R Wu1,4, S-B Li2,4, Z-F Tian3,4, N Li1, G-F Zheng1, Y-X Zhao1, H-L Zhu1, J-H Hu1, L Zha1, M-Y Dai1 and W-Y Xu1 OBJECTIVE: To investigate the effect of lung recruitment maneuver (LRM) with positive end-expiratory pressure (PEEP) on oxygenation and outcomes in preterm infants ventilated by proportional assist ventilation (PAV) for respiratory distress syndrome (RDS). STUDY DESIGN: Preterm infants on PAV for RDS after surfactant randomly received an LRM (group A, n = 12) or did not (group B, n = 12). LRM entailed increments of 0.2 cm H2O PEEP every 5 min, until fraction of inspired oxygen (FiO2) = 0.25. Then PEEP was reduced and the lung volume was set on the deflation limb of the pressure/volume curve. When saturation of peripheral oxygen fell and FiO2 rose, we reincremented PEEP until SpO2 became stable. RESULT: Group A and B infants were similar: gestational age 29.5 ± 1.0 vs 29.4 ± 0.9 weeks; body weight 1314 ± 96 vs 1296 ± 88 g; Silverman Anderson score for babies at start of ventilation 8.6 ± 0.8 vs 8.2 ± 0.7; initial FiO2 0.56 ± 0.16 vs 0.51 ± 0.14, respectively. The less doses of surfactant administered in group A than that in group B (P o 0.05). Groups A and B showed different max PEEP during the first 12 h of life (8.4 ± 0.5 vs 6.7 ± 0.6 cm H2O, P = 0.00), time to lowest FiO2 (101 ± 18 versus 342 ± 128 min; P = 0.000) and O2 dependency (7.83 ± 2.04 vs 9.92 ± 2.78 days; P = 0.04). FiO2 levels progressively decreased (F = 43.240, P = 0.000) and a/AO2 ratio gradually increased (F = 30.594, P = 0.000). No adverse events and no differences in the outcomes were observed. CONCLUSION: LRM led to the earlier lowest FiO2 of the first 12 h of life and a shorter O2 dependency. Journal of Perinatology (2014) 34, 524–527; doi:10.1038/jp.2014.53; published online 3 April 2014
INTRODUCTION Respiratory distress syndrome (RDS) is the most common condition of preterm infants in neonatal intensive care unit (NICU) with complications due to RDS constituting the most significant cause of mortality and long-term morbidity. Neonatal mechanical ventilator is considered a valuable tool to manage RDS in preterm infants. Several types of ventilation modes and strategies have been explored in clinical practice to optimize mechanical ventilation, so as to reduce the risk of ventilator-induced lung injury. There are several mechanisms that may underlie lung protection from lung recruitment maneuver (LRM). First, recruiting collapsed alveoli may temporarily improve gas exchange and thus reduce the FiO2. Second, with an open lung, a lower pressure can expand the lungs through the tidal range. Third, if applied with positive end-expiratory pressure (PEEP), an LRM may reduce repetitive opening and closing that causes shear stress that can damage terminal lung units.1 In summary, LRM that achieves an open lung may reduce the risk of oxygen toxicity, overdistention injury and shear-stress injury. Open-lung ventilation uses LRM to open alveoli and optimize lung volume and avoids excessive lung inflation. There is evidence that open-lung ventilation with LRM can also reduce ventilator-induced lung injury and may be an
important adjunct to limiting tidal volume (VT) and applying adequate PEEP.2,3 Proportional assist ventilation (PAV) is a mode in which the ventilator guarantees a percentage of work regardless of changes in pulmonary compliance and resistance. Consequently, the VT and pressure of the ventilator are varied based on the patient’s work of breathing and the amount it delivers is proportional to the percentage of assistance it is set to provide.4 In this pilot study, we prospectively collected data on ventilatory parameters—FiO2 requirements, gas exchange and respiratory outcomes—to investigate the effect of an LRM in preterm infants who received LRM plus PAV versus those who received PAV only during the acute phase of RDS, using saturation of peripheral oxygen (SpO2) to guide the maneuver. METHODS Patient population This study was performed at the NICU of Huaian Maternity and Child Healthcare Hospital, after the local ethical committee’s approval. We studied infants with gestational age (GA) 28–30 weeks and birth weigh (BW) 1000–1500 g who received at least one course of prenatal glucocorticoids and required tracheal intubation and mechanical ventilation in
1 Neonatal Medical Center, Huaian Maternity and Child Healthcare Hospital, Anhui Medical University, Huaian, China; 2Anhui Medical University, Hefei, China and 3Huaian First People's Hospital, Nanjing Medical University, Huaian, China. Correspondence: Professor R Wu, Neonatal Medical Center, Huaian Maternity and Child Healthcare Hospital, Anhui Medical University, No.104, South Renmin Road, Huaian, Jiangsu Province 223002, China. E-mail: [email protected] 4 These authors contributed equally to this work. Received 7 October 2013; revised 18 February 2014; accepted 18 February 2014; published online 3 April 2014
Lung recruitment maneuver R Wu et al
525 the first six hours of life due to severe RDS, with written parental consent. Exclusion criteria included lethal congenital anomalies, severe intraventricular hemorrhage (above grade II), no spontaneous breathing or spontaneous breathing weak and absence of parental consent. The sample size was determined by the number of early preterm infants admitted to our hospital in 1 year.
than grade 2 retinopathy of prematurity (ROP). BPD was defined as oxygen requirement at 36 weeks of postconceptional age.9 We calculated BPD rate in survivors. Follow-up for BPD definition was completed before discharge. Intraventricular hemorrhage was classified according to Papile et al.10 and ROP was graded according to the international classification of ROP.11
Data processing and statistical analysis Study design This study is a randomized trial. The enrolled infants were randomly assigned to receive an LRM in the second 2 h of life (group A) or not (group B), using sequentially numbered, sealed opaque envelopes. RDS diagnosis was based on the clinical presentation, such as early respiratory distress, which includes cyanosis, grunting, sternal and intercostal recession and tachypnoea. Clinical diagnosis was confirmed with chest X-ray changes that included a ‘ground glass’ appearance and air bronchograms.5 Severe RDS was defined as arterial-to-alveolar oxygen ratio o0.2. All neonates underwent the same management in the delivery room according to our NICU protocols and as recommended by European consensus guidelines.6 From the delivery room, all infants were transferred to the NICU in T-piece devices (set background continuous positive airways pressure (PEEP level = 5 cm H2O level) with a measured peak inspiratory pressure during occlusion of the T-piece). All the patients received the first dose of endotracheal porcine natural surfactant (200 mg/kg; Curosurf, Chiesi, Italy) immediately after tracheal intubation according to our standard protocol for infants of GA 28–30 weeks. During the first 6 h of life, intubated infants were supported with PAV (Stephanie infant ventilator, Gackenbach, Germany) with the following starting parameters: VT = 4–6 ml/kg, and an initial PEEP = 5 cm H2O. The elastic unloading and resistive unloading was set to maintain VT in 4–6 ml/kg. Backup conventional mechanical ventilation (SIMV mode) automatically initiated 10 s after cessation of spontaneous breathing. When spontaneous breath recurred, backup ventilation automatically suppressed and PAV resumed. During mechanical ventilation, the FiO2 level was chosen to maintain a preductal SpO2 of 85 to 93%,6 the range of the peak inspiratory pressure was 10–20 cm H2O, and PEEP was 5–9 cm H2O. After setting a starting PEEP level of 5 cm H2O, we applied repeated increments of 0.2 cm H2O of PEEP every 5 min, monitoring the FiO2 requirements and SpO2 levels. During the 5 min of monitoring, SpO2 level was the signal to proceed with the Fio2 requirements and the PEEP level. We adjusted infant's PEEP and Fio2 in accordance with SpO2. SpO2 rose gradually with increasing PEEP. As soon as SpO2 approached 93%, we began decreasing FiO2, which resulted in a slow drop in SpO2. When SpO2 approached 85%, we stop decreasing FiO2. When FiO2 reached 0.25, a slow stepwise PEEP reduction was started while monitoring the SpO2 levels. When oxygenation levels fell and FiO2 administration rose consequently, we reincreased the PEEP level until stable oxygenation was achieved and the FiO2 level reached levels prior to the fall in oxygenation. CO2 levels (monitored with N-85 handheld detecter, Pleasanton, CA; Non-dispersive infrared and Microstream capnography technology, Nellcor Puritan Bennett, US)7 and cardiovascular status (heart rate, systemic blood pressure) were monitored as well; the rise in CO2 levels and changes of the cardiovascular status were considered signals of stress and overdistention and we interrupted the maneuver if necessary. Mechanical ventilation was stopped when FiO2 was ⩽ 0.30, PEEP = 5 cm H2O, MAP was ⩽ 6 cm H2O, and partial pressure of oxygen in arterial blood and PaCO2 were ⩾ 50 mm Hg and o 65 mm Hg, respectively. The management after the extubation was balanced between the groups. In both groups, following NICU protocols, the extubation of mechanically ventilated infants was mandatory within 2 h after they reached extubation criteria. After extubation, the decision as to whether to begin nasal continuous positive airways pressure to prevent the need for reintubation, to offer oxygen supplementation only, or to put the patient directly into room air was completely up to the neonatologist on duty. Nasal continuous positive airways pressure was stopped when neonates with adequate spontaneous respiratory effort had FiO2 ⩽ 0.30, CDP ⩽ 5 cm H2O, PaO2 ⩾ 50 mm Hg and PaCO2 o65 mm Hg. Oxygen saturation-SpO2, arterial/alveolar oxygen ratio, FiO2 requirements and cardiovascular status were monitored during the procedure, after LRM, or within 12 h of life. All infants were evaluated before respiratory support by the Silverman Anderson score.8 The following data were also recorded for each infant: GA, BW, sex, need for additional surfactant, length of oxygen therapy, duration of mechanical ventilation and of ventilatory assistance (noninvasive plus mechanical ventilation), air leak/pneumothorax, extubation failure occurred, BPD, grade 3 or 4 intraventricular hemorrhage and greater © 2014 Nature America, Inc.
Clinical characteristics of infants in the two groups were described using mean values and s.d. or rate and percentage. The Student’s t-test was performed for parametric continuous variables and the Fisher’s exact test for categorical variables. Kolmogorov–Smirnov tests on population in total and on the two groups confirmed the normal distribution of the variables ‘duration of ventilation’ and ‘length of oxygen exposure’ and appropriateness of Student's t-test. The linear change of PEEP, FiO2 and a/AO2 ratio during the LRM application to infants of group A were analyzed by repeated measures analysis of variance. Po0.05 was considered statistically significant.
RESULTS Twenty four infants were included in the study. Clinical characteristics of infants in the two groups were similar (group A, n = 12, GA 29.5 ± 1.0 weeks, BW 1314 ± 96 g,Silverman Anderson score 8.6 ± 0.8, females 7/12; group B, n = 12, GA 29.4 ± 0.9 weeks; BW 1296 ± 88 g; Silverman Anderson score 8.2 ± 0.7, females 6/12). Group A received the LRM at 96 ± 25 min of age and the maneuver lasted for 70 ± 12 min. Ventilatory and gas analysis changes during the maneuver are described in Tables 1–3. There were no statistically significant differences between the two groups in FiO2, PEEP, a/AO2 ratio and PaO2 at the start of LRM and number of extubation failure (P>0.05). The maximum PEEP level at the end of the incremental increase was higher in group A (P o 0.05). The final PEEP level after decrementing PEEP and completing the entire process was lower (P o 0.05). Moreover, the a/AO2 ratio in the first 12 h of life was significantly higher (P o 0.05). A shorter need for mechanical ventilation (P o 0.05) and duration of oxygen therapy (Po 0.05) in the treated group was observed. The number of surfactant doses used in group A were significantly lower than that of group B (P o0.05). Group A and B showed differences in max PEEP during the first 12 h of life (8.4 ± 0.5 cm versus 6.7 ± 0.6 cm H2O, P = 0.000) and time to lowest FiO2 (101 ± 18 min versus 342 ± 128 min; P = 0.000). FiO2 levels progressively decreased (F = 43.240, P = 0.000) and a/AO2 ratio gradually increased (F = 30.594, P = 0.000) during the LRM application to infants of group A. No differences were observed in extubation failure, BPD, ROP and death between the two groups. In Figure 1, step-by-step changes in SpO2 and FiO2 related to PEEP levels during the LRM
Table 1.
Ventilatory and gas analysis changes during the LRM and in the first 12 h of life Group A (n = 12) FiO2 at the start fo LRM Lowest FiO2a Time to the lowest FiO2 (min) PEEP at the start of LRM (cm H2O) Max PEEP during LRM (cm H2O) Final PEEP at the end of LRM (cm H2O) a/AO2 ratio at the start of LRM a/AO2 ratio at the end of LRMa
Group B (n = 12)
P
0.55 ± 0.16 0.51 ± 0.14 0.744 0.27 ± 0.02 0.39 ± 0.06 0.000 101 ± 18 342 ± 128 0.000 6.6 ± 0.5 6.5 ± 0.5 0.698 8.4 ± 0.5 6.7 ± 0.6 0.000 6.4 ± 0.4 6.6 ± 0.4 0.293 0.24 ± 0.06 0.25 ± 0.06 0.817 0.45 ± 0.10 0.35 ± 0.08 0.013
Abbreviations: a/AO2, arterial/alveolar oxygen ratio; FiO2, fraction of inspired oxygen; LRM, lung recruitment maneuver; PaO2, partial pressure of oxygen in arterial blood; PEEP, positive end-expiratory pressure. a In the first 12 h of life.
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526 105
Respiratory and clinical outcomes P
Surfactant doses (n) 1.1 ± 0.3 Extubation failure (n) 1 Length of respiratory support (d) 5.6 ± 1.4 Length of tracheal intubation (d) 4.8 ± 1.0 BPD (n) 0 PDA occurrence (n) 3/12 Sepsis (n) 2/12 ROP grade >2 (n) 0 Moderate or severe BPD (n) 0 Death (n) 0 7.83 ± 2.04 O2 dependency (d)
1.5 ± 0.5 1 6.1 ± 2.0 5.8 ± 1.0 1 3/12 2/12 0 0 0 9.92 ± 2.78
0.027 NS 0.026 0.026 NS NS NS NS NS NS 0.049
Abbreviations: BPD, bronchopulmonary dysplasia; NS, not significant; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity.
Table 3.
Changes of PEEP, FiO2 and a/AO2 ratio in the course of lung recruitment maneuver in the group A (n = 12) Different time point
PEEP (cm H2O)
FiO2
a/AO2 ratio
The start of LRM Max PEEP of LRM The end of LRM F P
6.6 ± 0.5 8.4 ± 0.5 6.4 ± 0.4a 257.552 0.000
0.55 ± 0.16 0.27 ± 0.02 0.29 ± 0.03a 43.240 0.000
0.24 ± 0.06 0.34 ± 0.06 0.45 ± 0.10a 30.594 0.000
Abbreviations: a/AO2 ratio, alveolar/Arterial oxygen ratio; FiO2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure. a Po 0.05 versus start level.
application in the group A are shown. FiO2 levels progressively decreased with the LRM for the growing SpO2 levels. When the PEEP level reached 5 cm H2O, a reduction of SpO2 was recorded and the PEEP level was reincreased to achieve prior SpO2 levels. During the LRM application, no adverse events occurred, circulatory parameters were stable, and the maneuver was well tolerated.
DISCUSSION LRM can be defined as a transient increase of transpulmonary pressure with the goal of opening or recovering alveolar units with high critical opening pressure, thus increasing end-expiratory lung volume.12 These effects may be temporary, but, over time, alveolar stability may be preserved with maintenance of an adequate PEEP after RM administration.13–15 In the NICU, LRM have been limited primarily to increasing mean airway pressure during high frequency ventilation. Once the ventilation mode is determined, the most important factor is selecting a ventilation strategy that optimizes lung volume. There is evidence that optimization of the lung volume is critical to lung protection, regardless of what ventilation mode is used.16–18 PEEP was used mainly as an adjunct to improve oxygenation and decrease work of breathing by shifting tidal breathing to a more compliant portion of the pressure–volume curve.19 PEEP is now considered a means to recruit the lung and minimize injury associated with repeated opening and closure of an atelectatic lung.20 There is potential to prevent recollapse of alveoli if PEEP is applied after recruitment.21 Clinical studies are required to determine whether setting the right level of PEEP should be Journal of Perinatology (2014), 524 – 527
0.8 0.7
100
0.6 95
0.5
90
0.4
FiO2
Group B (n = 12)
Group A (n = 12)
SpO2 (%)
Table 2.
0.3
85
0.2 80
SpO2 FiO2
75 5
6
7
8
7
6
5
0.1 0
6
PEEP (cm H2O)
Figure 1. Changes of fraction of inspired oxygen (FiO2) and saturation of peripheral oxygen (SpO2) related to positive endexpiratory pressure (PEEP) levels during lung recruitment maneuver in the group A.
performed according to inflation or deflation P–V curves; in other words, should PEEP be systematically implemented after a recruitment maneuver. An optimal PEEP may be defined as the level of continuous pressure that, after an LRM, prevents alveolar collapse and avoids overinflation with optimal lung volume.22 There is no evidence that starting the maneuver with a different level of PEEP changes the effects of the practice. The settings we chosen in this study are all according to the referenced literature.23 Castoldi F et al.23 found that the adequate PEEP, added to VG ventilation, can improve the effect of volumetargeted ventilation in acute neonatal RDS. Our results suggest that, in the LRM group, we more rapidly obtained an optimal lung volume (proved by a significantly reduced time to achieve a good oxygen saturation with minimal FiO2 and a better final a/AO2 ratio. Furthermore, the duration of mechanical ventilation and oxygen therapy in the LRM group was significantly reduced, which is consistent with the findings of Castoldi F et al.23 group. Surfactant is now often given shortly after birth as prophylaxis against RDS. In preterm lambs, surfactant spreads less homogeneously in a ventilated lung than when given before the first breath.24 In premature infants, whose clinical condition requires emergency intubation or in whom elective intubation has been chosen, it is good practice to administer exogenous surfactant as early as possible.25,26 If given later, the clinical effect of surfactant is so far insufficient for treating RDS. In our study, surfactant was given as soon as possible after tracheal intubation. Our study has several limitations. First, the sample size is small. Further, larger studies of the similar experiments are warranted. Second, we did not measure intrinsic PEEP. Many preterm infants with RDS can have intrinsic PEEP and it is possible that intrinsic PEEP may have affected both gas exchange and lung mechanics parameters of study. Third, this study only observed the shortterm effects on oxygenation and ventilator parameters. Long-term clinical effects need to be studied to adequately address the issue of safety. In conclusion, early LRM in preterm infants with RDS resulted in an earlier achievement of the lowest FiO2 for the first 12 h of life, which was significantly lower than the FiO2 previously necessary to obtain adequate arterial oxygenation, and a shorter O2 dependency. These results suggest that the LRM is a reasonable practice to improve the effect of premature RDS.
CONFLICT OF INTEREST The authors declare no conflict of interest.
© 2014 Nature America, Inc.
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ACKNOWLEDGEMENTS We thank all the neonatal units and staff who responded to our survey. This research was funded by grants from Jiangsu Province Health Department (Project no: F201233).
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