ORIGINAL ARTICLE. DD Woodhead, DK Lambert, JM Clark and RD Christensen. Intermountain Healthcare, McKay-Dee Hospital, Ogden, UT, USA

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1 ORIGINAL ARTICLE Comparing two methods of delivering high-flow gas therapy by nasal cannula following endotracheal extubation: a prospective, randomized, masked, crossover trial DD Woodhead, DK Lambert, JM Clark and RD Christensen Intermountain Healthcare, McKay-Dee Hospital, Ogden, UT, USA (2006) 26, r 2006 Nature Publishing Group All rights reserved /06 $30 Objective: We compared two methods of delivering high-flow gas therapy by nasal cannula, applied immediately after planned endotracheal extubations of NICU patients. Study design and methods: Thirty NICU patients who were about to be extubated from mechanical ventilation were randomized into two groups; Group 1 received Vapotherm s for the first 24 h after extubation, then standard high-flow nasal cannula for the next 24 h, and received standard high-flow therapy for the first 24 h, then Vapotherm s for the next 24 h. At 24 h after extubation and again 48 h after extubation, a neonatologist who was not aware which modality the patient had been receiving examined the nasal mucosa and applied a scoring system. A research nurse who was unaware of the modality abstracted respiratory rates and respiratory effort scores from a specific study-bedside record. The experimental design was such that a patient could fail extubation either by reintubation for mechanical ventilation, or by rescue to the opposite modality before completing the 24-h test period. Results: Fifteen patients were randomized to Group 1 and 15 to. No differences were apparent between the groups in birth weight, gestational age, age at study entry, gender or underlying pulmonary disorder. Respiratory rates were similar while on Vapotherm s (52±13 breaths/min, mean±s.d.) and high-flow (54±14/min). At 24 h after starting the modality, those on Vapotherm s had more normal examinations of the nasal mucosa (2.7±1.2 vs 7.8±1.7, P<0.0005) and lower respiratory effort scores (1.2±0.6 vs 2.0±0.9, P<0.05) than did those on high-flow. No patients failed while on Vapotherm s, but seven failed while on high-flow (two reintubations and five rescue switches to Vapotherm s, P<0.005). Conclusions: Among NICU patients immediately following extubation, Vapotherm s performed better than a standard high-flow nasal cannula in maintaining a normal appearing nasal mucosa, a lower respiratory effort score, and averting reintubation. Correspondence: Dr RD Christensen, Intermountain Healthcare, McKay-Dee Hospital, 4403 Harrison Blvd, Ogden, UT 84403, USA. rdchris4@ihc.com Received 6 February 2006; revised 3 April 2006; accepted 5 April 2006; published online 25 May 2006 (2006) 26, doi: /sj.jp ; published online 25 May 2006 Keywords: high-flow nasal cannula; endotracheal extubation; reintubation; Vapotherm s Introduction One potential use of a high-flow nasal cannula in the NICU is to reduce the need for reintubation following extubation from mechanical ventilation. 1,2 The high-flow nasal cannula system has been reported to be less invasive than nasal CPAP. 1,2 However, the high-flow cannula can dry the nasal mucosa, particularly when gas flows exceed 1 or 2 l/min. 2,3 Mucosal dryness and thick nasal secretions sometimes occur when neonates are treated with highflow nasal cannula gas delivery. Vapotherm s was devised as a method, in the opinion of the company, for humidifying and warming inhaled gas to prevent dryness of the nasal mucosa. 4 6 However, to date no prospective, randomized studies have been published directly comparing Vapotherm s with a standard highflow nasal cannula on recently extubated neonates. To obtain this comparison, we devised a randomized, prospective, masked, crossover trial. Methods Patients were deemed eligible to participate in the study if they were in the NICU with an endotracheal tube in place for mechanical ventilation, and had a physician s order to extubate to a highflow (X1 l/min) nasal cannula. They were only eligible if the attending neonatologist predicted that they were likely to need a high-flow nasal cannula for at least the next 48 h, and if the parent or responsible guardian signed the informed consent document. Patients were ineligible for study participation if they had what the attending neonatologist judged to be a lethal congenital abnormality or if they were judged by the attending neonatologist as likely to be transferred to another hospital before the study (48 h) had ended.

2 482 Vapotherm s vs high-flow nasal cannula after extubation Eligible patients were randomized before extubation, using a list constructed by a random number table, to either Group 1 or Group 2. Group 1 patients received Vapotherm s for the first 24 h after extubation and were then crossed over to a standard high-flow nasal cannula for the next 24 h. patients received standard high-flow nasal cannula treatment for the first 24 h after extubation and then were crossed over to Vapotherm s for the next 24 h. To avoid maldistribution, by chance, with a preponderance of smaller subjects in one study group, the randomization was blocked on birth weight, using three categories; <1000, and >1500 g. Thirty patients, 15 per group, were planned for this pilot study, as a convenience sample, based on the projection that about one patient per week could be studied and the desire to conduct the study within a 6-month period. Guidelines of the American Association of Respiratory Care were used to assess when a patient should be extubated from mechanical ventilation. 7,8 Specific factors considered included; acceptable blood gasses on weaning ventilator settings, adequate breath sounds, an improving chest X-ray, and anticipated stamina sufficient to not need mechanical ventilation any longer. Immediately following extubation, a nasal cannula was put in place. Depending on the size of the patient either the premature (model MA1100A), the neonate (model MN1100B), or the infant (model MI1300) cannula was used (manufactured by Vapotherm Inc., Stevensville, MD, USA). The cannula tubing was then attached to either Vapotherm s or a standard high-flow system. In each individual, the same cannula was used for the entire 48 h of study. Adjustments in the FiO 2 and gas flow were made by the respiratory therapist and/or nurse bedside in consultation with the neonatologist and in accordance with manufacture s recommendations order to provide what they interpreted as optimal individual support to that patient. At 24 h after extubation the nasal cannula was briefly and temporarily discontinued while a neonatologist who was unaware of whether the patient had been receiving high-flow or Vapotherm s performed an examination of the nasal mucosa using a speculum and otoscope. The scoring system is shown in Table 1. Before each examination of the nasal mucosa, the nasal prongs were slid out of the nares so that the nasal mucosa could be seen. When the examining neonatologist left the bedside, the respiratory therapist set up the opposite modality for delivering nasal gas flow for the next 24-h period. A second nasal examination was performed, using the same procedure, after a 24-h period on the second modality. To help keep the examining neonatologist unaware of which modality was being used, a Vapotherm s unit was always set up at the bedside of study patients (whether they were actually receiving Vapotherm s or high-flow). In this way, it was not obvious to the examiner whether the patient had been receiving Vapotherm s or high-flow. A research nurse (DKL) who was unaware of the randomization, recorded each respiratory rate and respiratory effort score from a study-specific bedside chart, on which the bedside nurse or Table 1 Scoring the nasal examinations Right nare Left nare 1 1 Completely normal 2 2 Erythematous mucosa 3 3 Erythematous and edematous mucosa 4 4 Erythema or edema and thick mucous 5 5 Occluded with thick mucous and edema and/or hemorrhagic A neonatologist that was unaware of whether the patient had been on Vapotherm s or standard high-flow for the past 24 h examined the nasal mucosa. Two such examinations were performed on each patient, one after each 24-h study period. The findings of each examination were recorded on a score sheet by circling the appropriate numbers (below). The scores were the sum of the numbers recorded for each nare, therefore, the values ranged from 2 (minimum) to 10 (maximum). respiratory therapist periodically recorded respiratory rates and a description of retractions during the two 24 h study periods. The research nurse recorded the data in an office, where she could not see which treatment devise the patient was receiving. The respiratory effort score was listed as; 0 (no retractions), 1 (mild retractions), 2 (moderate retractions) or 3 (severe retractions). Five categories of retractions were listed: supraclavicular, suprasternal, intercostal, substernal and subcostal. In that way respiratory effort scores could range from a low of 0 (no retractions in any of the five categories) to a high of 15 (three in each of the five categories). Reintubation of a study patient, for return to mechanical ventilation, occurred under the direction of the clinical care team (neonatologist, neonatal nurse practitioner, respiratory therapist and bedside nurse). The team members were aware of whether the patient was receiving Vapotherm s or standard high-flow nasal cannula. No set criteria were used for determining when a patient required reintubation for mechanical ventilation. However, considerations included a consistently rising FiO 2, deteriorating blood gases, increased respiratory effort, and increased apnea and bradycardia requiring repeated bag/mask breaths. In a similar fashion, a patient receiving one modality could be switched to the opposite modality if the clinical care team judged the patient was failing that modality, but not to the point where reintubation was needed immediately. If patients were reintubated a tracheal aspirate was obtained for Gram stain and culture. Descriptive statistics were calculated using SPSS (v 13.0) for Windows. Between group means were tested using independent samples t-tests when parametric assumptions were met, with Wilcoxon Rank-Sum tests used for non-parametric comparisons. Proportions were compared between groups using w 2 tests or, when expected counts were small, Fisher s exact test. For all tests, 2-tailed tests were used, and a was set at The study protocol was approved by the Intermountain Healthcare Institutional Review

3 483 Board, and parents of the study subjects signed informed consent documents. Results During the months of July 2005 through November 2005, the families of 35 NICU patients who were receiving mechanical ventilation were contacted to inquire whether they were interested in learning about the extubation study. Thirty-four of the 35 families gave written consent for their neonate to participate in the study, and of these, 30 were enrolled in the study. Three of the consented patients were not enrolled because at the time of endotracheal extubation the attending neonatologist decided that the patient would not be extubated to a high-flow nasal cannula, but rather to a low-flow (<0.5 l/min) nasal cannula. One of the consented patients was not enrolled because he was transferred to another hospital before endotracheal extubation. No patients were excluded from the study on the basis that they were deemed to have a lethal congenital abnormality or on the basis that they were likely to be transferred to another hospital before the study had ended. Table 2 Characteristics of the study subjects Group 1 (received Vapotherm s first) n ¼ 15 (received highflow first) n ¼ 15 Birth weight (grams, mean±s.d.) 1630± ±880 Gestational age at delivery (weeks days; 31.0± ±3.1 mean±s.d.) Age at study entry (days; median, range) 3 (1 19) 5 (1 16) Gender (% male) Initial primary lung disorder: HMD treated with surfactant 60% 73% HMD not treated with surfactant 33% 27% Pneumonia/sepsis 7% F Meconium aspiration F F TTN F F Other F F Race/ethnicity White 80% 87% Hispanic 20% 13% Black F F American Indian F F Pacific Islander F F Other F F F ¼ zero percent. Thirty patients were enrolled, randomized, and begun on one modality or the other for delivering high-flow nasal gas therapy. The characteristics of the 30 are given in Table 2. No significant differences were observed in the characteristics of the 15 randomized to Group 1 and the 15 randomized to. Immediately following extubation the subjects were treated with either Vapotherm s (Group 1) or high-flow (), but during the first 24 h of study, seven were weaned to a low-flow (<0.5 l/ min) nasal cannula. Three of these were in Group 1 and four were in (Table 3). These seven continued to wean from supplemental O 2, none required reintubation and none were discharged home on supplemental O 2. Of the remaining 23 patients, 14 finished the 48-h study, but seven failed. None failed while receiving Vapotherm s ; all seven failures were while receiving high-flow (Table 3). Two failed during the first 24 h after extubation due to reintubation because of increasing PCO 2 and FiO 2 and increasing atelectasis on chest X-ray, all of which were unresponsive to increasing cannula gas flow (from 1 to 2 l/min). Tracheal aspirates of these two following reintubation grew no organisms. Five failed during the second 24 h because they were switched from high-flow back to Vapotherm s before the 24-h study period on high-flow ended. These five were switched after 9.5 h (median; range, 1.5 to 20 h) on high-flow. Two of the five were switched on the basis of increasing episodes of apnea and bradycardia that subsided when switched back to Vapotherm s ; two others were switched because of increasing PCO 2 and respiratory rate, which improved when moved back to Vapotherm s, and the fifth was switched because of increasing FiO 2 with diminished breath sounds, which improved when moved back to Vapotherm s. Results of the Vapotherm s and standard high-flow nasal cannula treatment on respiratory rate, examinations of the nasal mucosa, and respiratory effort scores, are shown in Table 4. All 30 patients had a test period on high-flow, but only 28 had a test period on Vapotherm s. This is because two (both in ) failed high-flow within the first 24 h and were reintubated without ever receiving a trial of Vapotherm s. No differences were observed in respiratory rates during the period on Vapotherm s vs the period Table 3 Short-term outcomes of patients randomized to Group 1 and Group 1 (n ¼ 15) (n ¼ 15) Weaned to low-flow in first 24 h Failed in first 24 h Crossed to opposite modality at 24 h Failed in second 24 h Group 1 Vapotherm for first 24 h, then high-flow for second 24 h. High-flow for first 24 h, then Vapotherm for second 24 h.

4 484 Table 4 Respiratory rates, nasal mucosa examination scores, and respiratory effort scores while on Vapotherm s vs while on the standard high-flow cannula Respiratory rate a during the test period Nasal exam score b at the end of the test period Respiratory effort score c at the end of the test period Vapotherm s 52±13 (24) 2.7±1.2 (20) 1.2±0.6 (21) High-flow 54±14 (27) 7.8±1.7 (16) 2.0±0.9 (16) P-value NS < <0.05 a All respiratory rates (breaths per minute) charted during the test period. b Nasal examination scores could range from a low of 2 (normal) to a high of 10 (bilaterally occluded or hemorrhagic nares see Table 1). c Respiratory effort scores tabulated retractions, and could range from a low of 0 (no retractions) to a high of 15 (severe supraclavicular, suprasternal, intercostal, substernal, and subcostal retractions). (n) ¼ number of patients available to be included in this score. (Patients not available to be included had either no nasal exam score or no respiratory effort score at the end of the study period, because they had failed and were either intubated or rescued to Vapotherm. One nasal exam was inadvertently missed on one Vapotherm patient). NS ¼ not significant (P>0.05). on high-flow. One nasal examination was inadvertently missed in one subject after the period on Vapotherm s. At the conclusion of 24 h on Vapotherm s, nares were significantly more normal appearing (score of 2.7±1.2), than at the conclusion of 24 h on high-flow cannula treatment (score of 7.8±1.7, P<0.0005). At the conclusion of 24 h on Vapotherm s, respiratory effort scores were slightly lower (less retractions) than were those on high-flow (1.2±0.6 vs 2.0±0.9, P<0.05). When respiratory effort scores were compared before vs at the end of the 24-h period, no subjects had an increase in score during the period on Vapotherm s.in contrast, six subjects had an increase in respiratory effort score during the 24-h period on high-flow (P<0.05). The nasal gas flow used during the period on Vapotherm s was 3.1±0.6 l/min, compared with 1.8±0.4 l/min during the period on standard high-flow (P<0.01). The FiO 2 used during the period on Vapotherm s was 0.31±0.04, compared with 0.32±0.04 during the period on standard high-flow. Caffeine was administered to all of the eight extubated subjects <1000 g birth weight, to five of the 12 who were g birth weight (two in Group 1 and three in ), and to none of the 10 who were >1500 g birth weight. The subjects on caffeine treatment all received doses while on Vapotherm and while on high-flow. Three of the 30 patients had a documented infection during the hospitalization. None were in proximity to the study. One was early-onset Escherichia coli sepsis (12 days before the study). One developed clinical sepsis with Enterobacter cloacae grown from a tracheal aspirate through a newly placed endotracheal tube (but not grown from blood or spinal fluid). This occurred 10 days after completing the study. For the 8 days preceding the onset of symptoms that patient was on a low-flow (0.3 l/min) nasal cannula (not Vapotherm s ). The third infection was a coagulase negative Staphylococcus grown from one of two blood cultures eight days following completion of the study, when the patient was receiving low-flow (0.3 l/min) nasal cannula (not Vapotherm s ). Three of the 30 patients had a documented occurrence of extraventilatory air during the hospitalization. None were in proximity to the study. Two had a pneumothorax and one had a pneumomediastinum. These all occurred two to three days before extubation and thus before study-onset. No cases of pneumothorax or pulmonary interstitital emphysemia occurred after study-onset. Discussion Vapotherm s was developed, in the opinion of the company, to deliver molecular water vapor through a nasal cannula with nearly 100% relative humidity at body temperature. 4 6 The device was designed to deliver gasses in the range of 5 to 40 l/min, but for use in neonates a low-flow vapor transfer cartridge was developed that allows flows, according to manufacture instructions, of 1 to 8 l/ min. 4,5 Vapotherm s has been used recently in many NICU s for a variety of indications, including as a substitute for nasal CPAP among neonates recently extubated. 9 Despite its apparent popularity, we could find no published, peer-reviewed, randomized trials testing Vapotherm s in a NICU population. 9 For the present study, we focused on the problems following extubation from mechanical ventilation, and we postulated that Vapotherm s would perform better than a standard high-flow nasal cannula, among recently extubated neonates. The specific performance measures we selected were; (1) appearance of the nasal mucosa, respiratory rate, respiratory effort score, and failure of extubation. We used a crossover design so each study patient would be treated with both modalities. We randomized patients regarding which of the two test treatments would be administered first, in case the first treatment biased or conditioned the patient regarding the response to the second treatment. We observed that following extubation, patients placed on standard high-flow cannula treatment were more likely to experience an increase in retractions than were those on Vapotherm s. Furthermore, while on Vapotherm s, the patients were more likely to have a normal appearance of their nasal mucosa and fewer extubation failures. We speculate that the better respiratory effort scores were, at least in part, due to the higher gas flow during the Vapotherm s period. However, despite the higher flows, the nasal mucosa during Vapotherm s appeared more normal. We speculate that this was the result of the higher humidity and body temperature of the gas. During the course of our study, the Centers for Disease Control and Prevention began an investigation of Ralstonia in association with Vapotherm s use. 10 This issue had not been widely recognized as a concern during the time our study was being designed, and

5 485 consequently no cultures of the nasal mucosa, equipment, or trachea were included in the study protocol. However, we obtained tracheal aspirates in the two patients who were reintubated, and both were sterile. These two had been on high-flow and not Vapotherm s at the time of the reintubation. In no case was Ralstonia 10 or Pseudomonas recovered from any culture of any of the 30 study patients at any time during their hospitalization. Another concern regarding Vapotherm s is the unmeasured end-expiratory distending pressures generated, and the attendant fear that, under some circumstances, very high continuous positive end-expiratory pressures (CPAP) can inadvertently be administered. 9,11,12 As commented on recently by Finer, 12 efforts are needed to quantify and monitor unregulated CPAP, when using high-flow rates through a nasal cannula. We observed no cases of pneumothorax or pulmonary interstitial emphysemia on any study patient between study entry and discharge home, although this was not specifically sought as part of the study design. We recognize various shortcomings of our study. First, although the neonatologist conducting the nasal examinations and the research nurse abstracting the charts were effectively blinded to the study arm, we had no way of similarly blinding the bedside nurse, bedside respiratory therapist, and attending neonatologist. We realize that this could introduce a source of bias. Second, we knew that the convenience sample of only 30 subjects would be too small to evaluate relatively rare adverse events due to one modality or the other. Indeed, the lack of infections and pneumothoracies among our 30 subjects during the study does not exclude these as real risks of Vapotherm s. Third, the method by which retractions are scored (absent, mild, moderate or severe) on our bedside charts is subjective, thus minimizing the importance of the observed better respiratory effort scores while on Vapotherm s. In conclusion, among 30 NICU patients in a cross-over study immediately following endotracheal extubation, it appears that Vapotherm s performed better than a standard high-flow nasal cannula in maintaining normal appearing nasal mucosa, a lower respiratory effort, and averting reintubation, with no recognized complications. Acknowledgments The authors thank the nurses and respiratory therapists at the McKay-Dee Hospital NICU for their valuable assistance with the study. We also thank Gorgi Rigby, RRT, LDS Hospital NICU, Salt Lake City, UT for helpful discussions about the research project. References 1 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: Myers TR. AARC clinical practice guideline. Selection of an oxygen delivery devise for neonatal and pediatric patients. Respir Care 2002; 47: Kopelman A, Holbert D. Use of oxygen cannulas in extremely low birth weight infants is associated with mucosal trauma and bleeding, and possibly with coagulase-negative staphylococcal sepsis. J Perinatol 2003; 23: In-house literature. Vapotherm Inc. 198 Log Canoe Circle: Stevensville, MD. 6 Waugh JB, Granger WM. An evaluation of 2 new devices for nasal high-flow gas therapy. Respir Care 2004; 49: A Collective Task Force Facilitated by the American College of Chest Physicians, the American Association for Respiratory Care, and the American College of Critical Care Medicine. Evidence-based guidelines for weaning and discontinuing ventilatory support. Respir Care 2002; 47: Durbin Jr CG, Campbell RS, Bransone RD. AARC clinical practice guideline. Removal of the endotracheal tube. Respir Care 1999; 44: deklerk A. Humidified high flow nasal cannulae. Hot Topics Neonatol 2005; 4 6: Centers for Disease Control and Prevention. Ralstonia associated with Vapotherm oxygen delivery device United States, Morb Mortal Wkly Rep 2005; 54: Locke RG, Wolfson MR, Shaffer TH, Rubinstein SD, Greenspan JS. Inadvertent administration of positive-end-distending pressure during nasal cannula flow. Pediatrics 1993; 91: Finer NN. Nasal cannula use in the preterm infant: oxygen or pressure? Pediatrics 2005; 116: