ORIGINAL ARTICLE Nasal continuous positive airway pressure from high flow cannula versus Infant Flow for preterm infants DM Campbell 1,2 , PS Shah 1 , V Shah 1 and EN Kelly 1 1 Department of Paediatrics, Mt Sinai Hospital, University of Toronto, Toronto, ON, Canada and 2 Department of Paediatrics, St Michael’s Hospital, University of Toronto, Toronto, ON, Canada Objective: To compare the feasibility of continuous positive airway pressure (CPAP) support generated by high flow nasal cannula with conventional CPAP for prevention of reintubation among preterm infants with a birth weight of p1250 g. Study Design: Preterm infants were randomized to CPAP generated via high flow cannula or the Infant Flow Nasal CPAP System (VIASYS, Conshohocken, PA, USA) at extubation. Primary outcome was incidence of reintubation within 7 days. Secondary outcomes included change in oxygen use and frequency of apnea and bradycardias postextubation. Results: Forty neonates were randomized. Twelve of 20 infants randomized to high flow cannula CPAP were reintubated compared to three of 20 using Infant Flow (P ¼ 0.003). The high flow cannula group had increased oxygen use and more apneas and bradycardias postextubation. Conclusions: CPAP delivered by high flow nasal cannula failed to maintain extubation status among preterm infants p1250 g as effectively as Infant Flow CPAP. Journal of Perinatology (2006) 26, 546–549. doi:10.1038/sj.jp.7211561; published online 13 July 2006 Keywords: infant; premature; extubation; randomized trial Introduction Continuous positive airway pressure (CPAP) facilitates extubation by preventing atelectasis, maximizing the functional residual capacity of the lung, and recruiting collapsed alveoli.1 In preterm infants CPAP decreases the incidence and severity of apneas, reduces the degree of asynchronous breathing, and prevents reintubation following initial extubation.2,3 One of the most common forms of CPAP currently used is the Infant Flow system (VIASYS) (IF-CPAP). With this device, gas flowing through nasal prongs is facilitated during exhalation via a fluidic-flip design.4,5 IF-CPAP has been shown to decrease oxygen requirement, improve respiratory effort6–9 and prevent extubation failure in preterm infants when compared to traditional nasal prong systems and bubble CPAP.9,10 However, nasal prong CPAP devices have been shown to damage the nares of infants, causing discomfort and rarely, long-term disfigurement.11,12 Simple nasal cannula has recently been shown to generate positive end-expiratory pressure (PEEP) in preterm infants if air or oxygen is delivered at a high flow rate (i.e. 1–2 l/min).13,14 The amount of distending pressure generated by such cannula depends on the size of the cannula, flow rate and size of the infant.13 In a recent study, investigators were able to generate a positive distending pressure of 4.5 cm H2O via simple nasal cannula using a calculated flow rate based on infant’s weight. This method of CPAP (high flow CPAP (HF-CPAP)) generated comparable pressure to that delivered by Hudson nasal prong CPAP set to deliver a pressure of 6 cm H2O. 14 HF-CPAP was also shown to be equally effective compared to the Hudson prong nasal CPAP in the management of apnea of prematurity over a 6 h period.14 This type of HF-CPAP has the advantage of being easy to administer at a lower cost. The purpose of this study was to evaluate the feasibility of HF-CPAP in preventing extubation failure of preterm infants with birth weight p1250 g, compared to IF-CPAP. Materials and methods Eligibility Intubated preterm infants with a birth weight p1250 g admitted to the Level III neonatal intensive care unit at Mt. Sinai Hospital, Toronto, Canada were eligible for inclusion in this study. Patients were excluded if there were signs and symptoms of upper airway obstruction, or congenital anomalies of the airway. Randomization and allocation This study was approved by the Mt Sinai Hospital Research Ethics Board. Informed written consent was obtained from parents before the neonate’s first extubation. In our unit, infants are usually extubated to nasal prong CPAP (IF-CPAP) at the time of first Received 22 February 2006; revised 18 May 2006; accepted 7 June 2006; published online 13 July 2006 Correspondence: Dr DM Campbell, Department of Paediatrics, St Michael’s Hospital, 30 Bond Street, Rm 15-014, Toronto, ON, Canada M5B 1W8. E-mail: campbelld@smh.toronto.on.ca Journal of Perinatology (2006) 26, 546–549 r 2006 Nature Publishing Group All rights reserved. 0743-8346/06 $30 www.nature.com/jp extubation. Time of extubation, ventilatory settings at extubation, and use of caffeine was determined by the medical team. Randomization cards were generated using random number tables and stratified in groups of 10. The randomization cards were sealed in sequentially marked opaque envelopes and opened immediately before extubation. The infants were randomly allocated to either HF-CPAP or IF-CPAP just before extubation. Procedure The IF-CPAP circuit used was the Infant Flow system (VIASYS r, Conshohocken, PA, USA). Six mm long nasal prongs were available in three sizes (4, 4.5 and 5 mm). The largest prongs that fit easily into the nares were used for each infant. Flow of air/oxygen was adjusted in order to deliver between 5 and 6 cm H2O of pressure. The HF-CPAP system consisted of a gas source, air-oxygen blender and a nonheated bubble humidifier delivering air/oxygen via standard nasal cannula (Infant size, Salter Labs, Arvin, CA, USA). HF-CPAP air/oxygen flow through the cannula was adjusted using the following formula as reported by Sreenan et al. 14 Flow ðl=minÞ ¼ 0:92 þ 0:68x ðx ¼ weight in kgÞ Nasal cannula flow delivered at this rate in very low birth weight preterm infants has been estimated to deliver distending pressure of 4.5 cm H2O, comparable to that of Hudson nasal CPAP prongs set at 6 cm H20. 14 In the post-extubation period CPAP was not weaned. Infants were maintained in a proper position to maintain a good seal. Oxygen saturation guidelines for all infants during the study period were identical. The decision to reintubate an infant was made by the team based on one or more of the following criteria: an uncompensated respiratory acidosis with a pH of <7.25, an oxygen requirement of >60% to maintain a transcutaneous saturation of >90%, severe apnea (defined as apnea and bradycardia requiring bag and mask ventilation or reintubation for recovery) or frequent apnea (defined as three or more, apneas of any severity in one hour). Outcome The primary outcome was success of extubation, defined as remaining extubated for at least 7 days. Secondary outcomes included: change in the amount of oxygen between pre- and postextubation and frequency of apnea and bradycardia events. The definition of apnea was a pause in breathing for >20 s. The definition of bradycardia was heart rate less than 80 beats per minute for 10 s. Nurses’ notes were used to record these parameters. Change in oxygen use post-extubation was calculated as the difference between the daily percent FiO2 post-extubation (over 7 days) and the percent FiO2 pre-extubation (up to 12 h pre- extubation). Daily percent FiO2 was estimated by calculating the mean from hourly percent FiO2 recorded in the chart. Nasal damage was qualitatively assessed by digital photography at 1, 7 and 30 days post-extubation using the following scale: (0) no appreciable damage, (1) mild (erythema of nares), (2) moderate (bleeding of nasal mucosa or nares), (3) severe (deformation of nares, perforation of nasal mucosa). Data regarding: number of days required to come off any form of CPAP, time to reach full feeds, rate of weight gain, frequency of chronic lung disease (need for supplemental oxygen at 36 weeks post- conceptional age), necrotizing enterocolitis, intraventricular hemorrhage, sepsis and retinopathy of prematurity were also collected. Sample size and statistical analysis A historical successful extubation rate for preterm infants p1250 g, observed over 12 months preceding the start of the study, was 70%. In order to demonstrate a difference of 15% in extubation rates between the two strategies, in excess of 400 infants would be required (a of 0.05 and a power of 0.80). A pilot study was therefore undertaken, with 20 patients randomized to each group. Student’s t-tests were performed for continuous variables and w2-test for categorical data. Wilcoxon rank sum tests were used to compare data sets for groups of patients with unequal numbers. Fisher’s least significant difference test was used for post hoc analysis. Results The baseline characteristics were similar for both groups of patients (Table 1). The majority of infants were extubated within 5 days of age in each group (n ¼ 16, 80%). Most were extubated from synchronized intermittent mandatory ventilation (HF-CPAP n ¼ 16, IF-CPAP n ¼ 14) at similar ventilatory settings (Table 1). Other forms of ventilation used before extubation included: pressure support (HF-CPAP n ¼ 3, IF-CPAP 2), assist control ventilation (HF-CPAP n ¼ 0, IF-CPAP n ¼ 2), or high frequency ventilation (HF-CPAP 1, IF-CPAP 2). Mean flow rate used in the HF-CPAP group was 1.6 l/min (range 1.4 to 1.7 l/min). Flow rates used to generate IF-CPAP were not recorded but generally involved flow rates from 6 to 8 l/min. All infants who received caffeine had it administered before extubation. Twelve of 20 infants, 12 randomized to HF-CPAP required reintubation within 7 days compared to three of 20 infants in the IF-CPAP group (relative risk 2.1, 95% confidence interval 1.3–3.0, P ¼ 0.003). Of the 12 infants in the HF-CPAP group who failed extubation, seven were reintubated within 48 h. All infants were reintubated due to severe apnea or increased frequency of apneas. Secondary outcomes for all infants are reported in Table 2. There were no statistically significant differences noted in the incidence of necrotizing enterocolitis, intraventricular hemorrhage, chronic lung disease, sepsis and retinopathy of prematurity between groups. Eight of 20 infants extubated to HF-CPAP remained extubated on this form of distending pressure for more than 7 days. This High flow nasal cannula in preterm infants DM Campbell et al 547 Journal of Perinatology subgroup of infants also had higher oxygen use post-extubation compared to those who remained extubated on IF-CPAP (2.0±1.9 versus 0.4±1.6, P ¼ 0.04). Differences in secondary outcomes were not observed in infants who remained extubated, including time to reach full feeds and weight gain at 7, 14 and 30 days of age. Nasal damage as assessed by digital photography of stages 1, 2 or 3 was not observed among any infants. Discussion Previous studies have demonstrated that high flow nasal cannula can deliver positive distending pressure equivalent to conventional forms of nasal CPAP. 13,14 HF-CPAP has also been shown to be as effective as conventional CPAP in managing apnea of prematurity.14 As a result of this study the use of high flow nasal cannula as an ‘equivalent’ form of CPAP has increased. Anecdotal nursing reports also affirmed the early use of HF-CPAP, since it was felt to ‘spare’ the preterm infants from nasal damage, which was occasionally seen in infants managed with nasal prong CPAP. However, recent reports have demonstrated side effects of high air flow through simple nasal cannula including drying and bleeding of the nasal mucosa as well as airway obstruction. 15,16 Our findings suggest that HF-CPAP probably should not be used as an equivalent form of CPAP in preterm infants. Compared to IF-CPAP, HF-CPAP was associated with an increase in the number of extubation failures, higher oxygen use, and more apneas and bradycardias. This occurred despite the fact that there was a trend for more infants randomized to the HF-CPAP arm to be on caffeine before extubation. We were unable to detect any nasal damage from either form of CPAP, although this may have been due to ‘study effect’ in which respiratory therapists and nurses were more careful in monitoring the nares of the infants. Sreenan et al. 14 reported that HF-CPAP was effective in the management of apneas and bradycardias over a 6 h period. The infants studied by Sreenan et al.14 were of higher gestational age compared to this study (30.3 weeks versus 27.5) and also had a higher number of apneas (1–2/6 h) and bradycardias (2–3/6 h). Most of their patients were already established on CPAP, and had therapeutic levels of theophylline. Our findings differ from their report. The reason for this difference may be the outcome studied. Table 1 Baseline characteristics of study population Variables HF-CPAP (n ¼ 20) IF-CPAP (n ¼ 20) P-value Male:female 11:9 10:10 0.75 Gestational age in weeks 27.4±1.6 27.6±1.9 0.56 Birth weight in grams 1008±157 925±188 0.12 Age at extubation in hours (median and range) 39 (7.5–792) 24 (18–1224) 0.98 Mean airway pressure at time of extubation (cm H20) 7.7±0.9 7.8±1.3 0.51 Administration of surfactant (n) 19 18 1.00 Administration of antenatal steroids (n) 18 15 0.41 Administration of caffeine (n) 14 9 0.11 % Oxygen use at the time of extubation 21.4±1.1 23.5±5.5 0.13 Abbreviations: IF-CPAP, Infant Flow system (VIASYS) continuous positive airway pressure; HF-CPAP, high flow CPAP. Values expressed as mean±s.d. unless otherwise stated. Table 2 Primary and secondary outcomes among all randomized infants Variables HF-CPAP (n ¼ 20) IF-CPAP (n ¼ 20) P-value Remained extubated at 7 days (n) 8 17 0.003* Change in oxygen use postextubation (%) 4.7±6.4 1.0±2.1 0.025* Episodes of apnea and bradycardia/day 6±8 2±3 0.045* Days to reach full feeds 14±6 16±10 0.530 Weight gain postextubation in grams 7 days �28±82 �25±64 0.85 14 days 102±125 102±98 0.89 30 days 492±189 521±217 0.57 Abbreviations: IF-CPAP, Infant Flow system (VIASYS) continuous positive airway pressure; HF-CPAP, high flow CPAP. *P<0.05; values expressed as mean±s.d. unless otherwise stated. High flow nasal cannula in preterm infants DM Campbell et al 548 Journal of Perinatology Successful extubation at 7 days was felt to be more clinically relevant outcome and a better overall reflection of CPAP efficacy. Since we were not monitoring pressure delivered by the HF-CPAP device it is possible that we were unable to generate sustained distending pressure for extended periods of time despite replicating Sreenan et al’s. technique. We performed this pilot study to assess the feasibility of this intervention in order to form a basis for a large randomized controlled trial. Perceived advantages of alternate forms of CPAP using simple nasal cannula include ease of administration, possible reduction in nasal damage and increased ability for parents to hold and bond with their infants. We failed to show any benefits with this method of CPAP, and demonstrated that it may be harmful. A post hoc power calculation using the observed sample sizes and failure rates, and a type 1 error rate of 5% demonstrates that our study has a statistical power of 87% that the difference in reintubation rates was not due to chance alone. Limitations of our study include an inability to mask the intervention, small sample size and not monitoring the actual distending pressure generated. In conclusion, CPAP delivered by high flow nasal cannula failed to maintain extubation status among preterm infants p1250 g. This form of continuous positive airway pressure is not an effective alternative to conventional nasal continuous positive airway pressure. Its use in other patients, such as older preterm infants, remains to be determined. Acknowledgments We would like to thank Ms Shafah Fallagh, PhD for her role as a statistical consultant on this paper. Financial support provided by Physician Services Incorporated Foundation Toronto, Canada (02-29R). References 1 da Silva WJ, Abbasi S, Pereira G, Bhutani VK. Role of positive end-expiratory changes on functional residual capacity in surfactant treated preterm infants. Pediatr Pulmonol 1994; 18: 89–92. 2 Locke R, Greenspan JS, Schaffer TH, Rubenstein SD, Wolfson MR. Effect of nasal CPAP on thoracoabdominal motion in neonates with respiratory insufficiency. Pediatr Pulmonol 1991; 11: 259–264. 3 Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants. Cochrane Database Syst Rev 2003; 2: CD000143. 4 Moa G, Nilsson K, Zetterstrom H, Jonsson LO. A new device for administration of nasal continuous positive airways pressure in the newborn: an experimental study. Crit Care Med 1988; 16: 1238–1242. 5 Moa G, Nilsson K. Nasal continuous positive airways pressure: experiences with a new technical approach. Acta Pediatr 1993; 82: 210–211. 6 Klausner JF, Lee AY, Hutchison AA. Decreased imposed work with a new nasal continuous positive airway pressure device. Pediatr Pulmonol 1996; 22: 188–194. 7 Courtney SE, Pyon KH, Saslow JG, Arnold GK, Pandit PB, Habib RH. Lung recruitment and breathing pattern during variable versus continuous flow nasal continuous positive airway pressure in preterm infants: an evaluation of three devices. Pediatrics 2001; 107: 304–308. 8 Pandit PB, Courtney SE, Pyon KH, Saslow JG, Habib RH. Work of breathing during constant- and variable-flow nasal continuous positive airway pressure in preterm neonates. Pediatrics 2001; 108: 682–685. 9 Lipsten E, Aghai ZH, Pyon KH, Saslow JG, Nakhla T, Long J et al. Work of Breathing during nasal continuous positive airway pressure in preterm infants: a comparison of bubble vs variable-flow devices. J Perinatol 2005; 25: 453–458. 10 Mazzella M, Bellini C, Calevo MG, Campone F, Massocco D, Mezzano P et al. A randomised control study comparing the Infant Flow driver with nasal continuous positive airway pressure in preterm infants. Arch Dis Child Fetal Neonatal Ed 2001; 85: F86–F90. 11 Robertson NJ, McCarthy LS, Hamilton PA, Moss AL. Nasal deformities resulting from flow driver continuous positive airway pressure. Arch Dis Child Fetal Neonatal Ed 1996; 75: F209–F212. 12 Loftus BC, Ahn J, Haddad Jr J. Neonatal nasal deformities secondary to nasal continuous positive airway pressure. Laryngoscope 1994; 104: 1019–1022. 13 Locke RG, Wolfson MR, Shaffer TH, Rubenstein SD, Greenspan JS. Inadvertent administration of positive end-distending pressure during nasal cannula flow. Pediatrics 1993; 91: 135–138. 14 Sreenan C, Lemke RP, Hudson-Mason A, Osiovich H. High-flow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure. Pediatrics 2001; 107: 1081–1083. 15 Kopleman AE, Holbert D. Use of oxygen cannulas in extremely low birthweight infants is associated with mucosal trauma and bleeding, and possibly with coagulase-negative staphylococcal sepsis. J Perinatol 2003; 23(2): 94–97. 16 Kopelman AE. Airway obstruction in the extremely low birthweight infant treated with oxygen cannula. J Perinatol 2003; 23(2): 164–165. High flow nasal cannula in preterm infants DM Campbell et al 549 Journal of Perinatology Nasal continuous positive airway pressure from high flow cannula versus Infant Flow for preterm infants Introduction Materials and methods Eligibility Randomization and allocation Procedure Outcome Sample size and statistical analysis Results Discussion Acknowledgements References