PEDIATRICS Vol. 121 No. 5 May 2008, pp. e1190-e1195 (doi:10.1542/peds.2007-1840)
ARTICLE |
Nasal Continuous Positive Airway Pressure With Heliox Versus Air Oxygen in Infants With Acute Bronchiolitis: A Crossover Study
Pediatric Emergency and Critical Care Division, Department of Pediatrics, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain; Department of Pediatrics, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. The purpose of this work was to evaluate the effects of administering either heliox or air oxygen in combination with nasal continuous positive airway pressure in infants with refractory bronchiolitis.
PATIENT AND METHODS. We conducted a prospective, interventional, single-center, crossover study in a teaching hospital including infants 1 month to 2 years of age, consecutively admitted to the PICU from February 2004 to February 2005 for treatment of severe acute bronchiolitis unresponsive to therapy. Patients with a clinical score (Modified Wood's Clinical Asthma Score) of >5, arterial oxygen saturation of <92%, or transcutaneous CO2 pressure of >50 mmHg despite supportive therapy, nebulized L-epinephrine, and heliox therapy through a nonrebreathing reservoir face mask were eligible. During the study period, 40 infants with bronchiolitis were admitted to the PICU; 12 fulfilled inclusion criteria. A predetermined balanced sequential allocation to either 30 minutes of treatment with nasal continuous positive airway pressure with heliox or to air-oxygen nasal continuous positive airway pressure was performed. Measurements were taken at baseline and after 30 minutes of each treatment.
RESULTS. Baseline mean values were as follows: nasal continuous positive airway pressure of 7.2 cmH2O; clinical score of 7.7 points; transcutaneous CO2 pressure of 61.6 mmHg; and arterial oxygen saturation of 88.6%, with the fraction of inspired oxygen at 35.4%. Clinical score, transcutaneous CO2 pressure, and arterial oxygen saturation improved during the study time with both heliox-nasal continuous positive airway pressure and air-oxygen-nasal continuous positive airway pressure: after 1 hour, the clinical score fell 1.7 points, transcutaneous CO2 pressure decreased 8.2 mmHg, and arterial oxygen saturation increased by 7.7%. Improvement in clinical score was double with heliox-nasal continuous positive airway pressure compared with the air-oxygen-nasal continuous positive airway pressure (2.12 vs 1.08 points), and the fall in the transcutaneous CO2 pressure was greater with heliox-nasal continuous positive airway pressure compared with air-oxygen-nasal continuous positive airway pressure (9.7 vs 5.4 mm Hg). There was no difference in arterial oxygen saturation between groups. No patients required endotracheal intubation. No adverse effects attributable to either of the study interventions were detected.
CONCLUSIONS. Nasal continuous positive airway pressure improves the clinical score and the CO2 elimination of infants with refractory bronchiolitis. These positive effects are significantly enhanced when nasal continuous positive airway pressure is combined with heliox instead of air oxygen. Both techniques are noninvasive, seem safe, and may reduce the need for endotracheal intubation.
Key Words: helium-oxygen mixture • bronchiolitis • continuous positive airway pressure • noninvasive ventilation • respiratory therapy • pediatrics
Abbreviations: nCPAP—nasal continuous positive airway pressure • AO—air oxygen • RSV—respiratory syncytial virus • M-WCAS—Modified Wood's Clinical Asthma Score • satO2—arterial oxygen saturation • tcPCO2—transcutaneous CO2 pressure • FIO2—fraction of inspired oxygen
Bronchiolitis is the main reason for hospitalization for respiratory tract illness in infants.1 It can also cause respiratory insufficiency in approximately half the patients admitted to the PICU with this diagnosis.1,2 Although pathophysiology has been well described, and several therapeutic interventions have been assessed, no proven successful treatment has been demonstrated.2–4
Heliox therapy may be useful in the treatment of infants with acute viral bronchiolitis.5–7 It has also been shown that noninvasive ventilation and, specifically, nasal continuous positive airway pressure (nCPAP) may improve the respiratory status of children with hypoxemic respiratory failure.8–11 Taking existing data for adult patients,12,13 together with their theoretical bases,5–11 the combination of heliox and noninvasive ventilation could be synergistic and useful in pediatric patients.
We have reported previously in a preliminary uncontrolled study that the combination of heliox and nCPAP as a rescue treatment in infants with refractory bronchiolitis could improve the clinical score, and enhance the CO2 elimination in a safe and noninvasive manner. However, the study design did not allow us to determine precisely the separate effects of heliox or nCPAP.14 The aim of the present study was to assess the effects on ventilation and clinical score of administering either heliox with nCPAP or air oxygen with nCPAP, as a rescue treatment in infants with refractory acute severe bronchiolitis.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients and Participants
Eligible patients were infants 1 month to 2 years old, admitted to the PICU from February 2004 to February 2005, with respiratory syncytial virus (RSV) bronchiolitis and Modified Wood's Clinical Asthma Score (M-WCAS)
5,6 arterial oxygen saturation (satO2) <92%, or transcutaneous CO2 pressure (tcPCO2) >50 mmHg despite optimized supportive therapy, nebulized L-epinephrine, and heliox therapy at 10 to 15 L/min through a nonrebreathing reservoir face mask for 1 hour. Patients with underlying chronic lung disease were excluded.
Diagnostic criteria of bronchiolitis included tachypnea, cough, prolonged expiratory time, wheezing, rales, chest retraction, and hyperinflation of the lungs on chest radiograph.6 RSV infection was confirmed by enzyme-linked immunoadsorbent assay of nasal secretions. Moderate-to-severe respiratory distress was defined as an M-WCAS of 5.6
During the study period, 40 infants with acute bronchiolitis were admitted to our PICU. Twelve of them (7 boys and 5 girls), fulfilled the inclusion criteria and were enrolled in the study. The patients had a mean age of 4.7 months (2.5 months) and a median age of 4 months (range: 2–8 months). Two patients had underlying heart disease, 2 patients had been preterm births without chronic lung disease, and 1 patient had suffered from bronchiolitis in the preceding 2 months.
All of the patients received 1 dose of nebulized L-epinephrine at the start of the study; it was then administered at 2- to 6-hour intervals at the discretion of 1 of the 3 physicians responsible for the study. No patient received any nebulized medication other than epinephrine or systemic corticosteroids, either before enrollment or during the study. No patient required sedation to tolerate heliox and nCPAP. Nasal and pharyngeal secretions were deliberately removed before treatment in all of the patients.
Definitions
Nebulized L-epinephrine was 3 mg per dose every 2 to 6 hours. Heliox therapy6,15 included a mixture of helium at 70% and oxygen at 30%, warmed and humidified, administered at 10 to 15 L/min through a nonrebreathing reservoir face mask. A central wall supply of dry heliox with a fixed concentration (70% helium and 30% oxygen) was used (Air Liquide Medicinal, Madrid, Spain).
Study Design
We conducted a prospective, clinical, interventional, observational, single-center study using a crossover design with predetermined balanced sequential allocation. All of the patients fulfilling inclusion criteria received 30 minutes of treatment with each of heliox and AO via nCPAP. Patients were allocated sequentially to begin their treatment alternately with either heliox and nCPAP or AO-nCPAP. Measurements were taken at baseline and after 30 minutes of each treatment.
Initial optimal nCPAP was what could maintain satO2 >94% using the lowest fraction of inspired oxygen (FIO2). To achieve this, nCPAP was increased at 1 cmH2O increments to a maximum of 12 cmH2O while the FIO2 needed was above 0.4 by varying the flow of either AO or heliox. Minimum permitted levels were for nCPAP 5 cmH2O and for FIO2 0.3. After determining these values, the settings for nCPAP and FIO2 were maintained throughout the crossover phase of the study.
Having completed the crossover phase, patients were either maintained on or established on heliox and nCPAP using our usual protocols depending on patient needs.14 The study was approved by the school of medicine ethical committee, and written informed parental consent was obtained in all of the cases before enrollment.
Intervention: Heliox-nCPAP and AO-nCPAP Logistics
Gas Supply
A central wall supply of dry heliox with a fixed concentration (70% helium and 30% oxygen) was used (Air Liquide Medicinal). The heliox mixture was delivered to the patient, warmed, and humidified by means of a standard device (MR730 Humidification system, Fisher & Paykel Healthcare Spain, Madrid, Spain).
Noninvasive Ventilation Equipment
The noninvasive ventilation equipment used in this study was the Infant Flow Advance (Electro Medical Equipment Ltd, Brighton, United Kingdom), in continuous positive airway pressure mode.
Human Interface
Nasal equipment specific to the ventilator and generator were used (Infant Flow Generator, Electro Medical Equipment Ltd). Either nasal prongs or a nasal mask were selected for heliox and nCPAP delivery, determined by comfort, the size of the patient, and at the discretion of the physician.
Measurement Levels and Removal From the Study
During the crossover phase of the study, treatment with heliox-nCPAP or AO-nCPAP was considered to fail when satO2 fell below 92% with nCPAP >10 cmH2O and FIO2 >0.6, tcPCO2 persistently >60 mmHg, if the patient could not tolerate the procedure, or if the patient's clinical condition deteriorated acutely at any time during the study. In these circumstances, patients were to be returned to conventional therapy, reevaluated, and considered for endotracheal intubation and invasive mechanical ventilation.
After the experimental crossover study phase, patients either continued with or were started on heliox-nCPAP. To deliver the highest amount of helium to the patient, FIO2 was kept as low as possible while maintaining satO2 >94%. To do this, nCPAP and FIO2 were adjusted. When the FIO2 needed was >0.4, nCPAP was increased in 1 cmH2O increments. When FIO2 
0.3, tcPCO2 <50 mmHg and M-WCAS <5 were maintained for 6 hours, nCPAP was gradually decreased to 5 cmH2O, and then heliox-nCPAP was stopped. In this phase of the study, the same criteria for therapeutic failure were used as in the experimental phase. If needed, patients would receive conventional therapy, be reevaluated, and by considered for endotracheal intubation and invasive mechanical ventilation.
Measurements and Outcomes
M-WCAS, tcPCO2, satO2, and respiratory rate values were recorded at baseline, after 30 minutes of treatment with heliox-nCPAP or AO-nCPAP, and afterward at hourly intervals for 6 hours and then at 8 hour intervals until heliox-nCPAP was discontinued. Data obtained during the first 48 hours were analyzed. Demographic data, duration of heliox therapy, need for endotracheal intubation, time elapsed since admission to PICU until study inclusion, and administration of concurrent therapies were collected for each patient.
The main outcome measures were the changes in M-WCAS and tcPCO2. The sample size of 12 patients using 95% confidence levels allows >95% power in detecting a difference of 1 point on the M-WCAS scale and >70% power to detect a difference of 5 mmHg in tcPCO2.
In clinical scoring, we followed a previously applied methodology.6 The tcPCO2 was continuously monitored by means of an earlobe transcutaneous technique (Tosca, Linde Medical Sensors, Basel, Switzerland). The satO2 was continuously monitored using pulse oximetry (Radical Masimo SET pulse oximeter [Masimo Corporation, Irvine, CA]). Vital signs (ECG, respiratory rate, and noninvasive blood pressure) were also monitored in all of the patients. Any adverse event potentially related to the treatment with either heliox-nCPAP or AO-nCPAP was recorded. Patient tolerance of the technique was assessed primarily by the investigator and also by the nurse in attendance. Any need for sedation was also recorded. All of the patients were followed up for 6 months after discharge.
Statistical Analysis
The distribution of trial variables was assessed using the Shapiro-Wilk test. Differences between each treatment were analyzed using the paired t test. Group (sequential) differences were analyzed using the t test for independent variables. Data obtained after the crossover phase were analyzed by the Friedman test. The level of statistical significance was P < .05. The data are expressed as means (SDs). Charts show means and SEMs. All of the statistical analyses were performed by using SPSS 12.0 (SPSS Inc, Chicago, IL).
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Baseline characteristics of our patients were M-WCAS 7.7(1), tcPCO2 61.6 (10.5 mmHg), and satO2 88.6% (3.3%). nCPAP was set initially at 7.2 cmH2O (1.2 cmH2O) to maintain satO2
94% with FIO2 of 35% (6.2%). All of the values improved from baseline after treatment with both heliox-nCPAP and AO-nCPAP. M-WCAS fell 1.7 points (0.7 points) (P < .001), tcPCO2 fell 8.2 mmHg (4.2 mmHg) (P < .001), and satO2 increased by 7.7% (3.8%) (P < .001) after administration of both treatments. After treatment, M-WCAS was better with heliox-nCPAP than with AO-nCPAP: 5.58 points (0.9 points) vs 6.62 points (1.0 points), respectively (P < .001; Fig 1), with falls from baseline almost double with heliox-nCPAP than with AO-nCPAP, at 2.12 points (0.6 points) vs 1.08 points (0.4 points), respectively (P < .001).
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After treatment, tcPCO2 levels were better with heliox-nCPAP than with AO-nCPAP, at 51.9 mmHg (8.7 mmHg) vs 56.2 mmHg (10.2 mmHg), respectively (P < .001; Fig 2), with falls from baseline 80% greater with heliox-nCPAP than with AO-nCPAP, at 9.7 mmHg (3.3 mmHg) vs 5.4 mmHg (1.6 mmHg), respectively. There was no statistically significant difference in satO2 after treatment between heliox-nCPAP and AO-nCPAP, at 96.5% (1.9%) vs 95.5% (1.7%), respectively (P = .179).
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Analysis of study subjects in 2 groups, depending on the order in which they received heliox-nCPAP and AO-nCPAP, shows that the baseline measurements were similar (Table 1). However, final changes from baseline at the end of both treatments showed greater improvement when heliox and nCPAP was the second treatment, reaching statistical significance in M-WCAS and tcPCO2. The effects of heliox-nCPAP or of AO-nCPAP were similar, regardless of whether they were given first or second (Table 2).
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After the crossover phase, patients were treated with heliox-nCPAP, and M-WCAS, tcPCO2, and satO2 all continued to improve (P < .001; Fig 3) with changes from baseline at 48 hours of 3.41 points (1.2 points), 23.4 mmHg (6.7 mmHg), and 9% (3.7%), respectively.
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Total duration of heliox-nCPAP treatment was between 3 and 14 days, with a mean of 5.9 days (3.3 days). There were no treatment-related adverse events. All of the patients enrolled at baseline completed the crossover study phase. No patient required endotracheal intubation or mechanical ventilation. All of the patients recovered fully without sequelae continuing to develop normally over the follow-up period of 6 to 16 months. No patient required readmission to the PICU in the 3 months after discharge.
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This is the first crossover study to evaluate 2 different gases (heliox and AO) given with noninvasive positive pressure to infants with unresponsive severe acute bronchiolitis. Our results suggest that nCPAP with either gas is a safe and effective treatment as measured clinically (M-WCAS) or by tcPCO2 and by satO2 values. Furthermore, nCPAP with heliox in place of an AO mixture (AO-nCPAP) is clearly more efficacious, as shown by approximately twice the level of improvement in clinical scores and tcPCO2 levels after 30 minutes of therapy.
There are recent references in the literature to the utility of heliox or noninvasive ventilation in the management of infants with bronchiolitis.5–7,11,16 However, there is very little published on the combination of the two.14 Our work suggests that nCPAP is efficacious not only in patients unresponsive to conventional treatment but also in those not responding sufficiently to treatment with heliox through a nonrebreathing reservoir face mask. Furthermore, when nCPAP is used with heliox, it is significantly more efficacious than with AO. The degree of clinical improvement with heliox and nCPAP after the crossover phase was similar to our previous findings.14
Changes in oxygen saturation were much smaller than those in the clinical score or in alveolar ventilation. This is consistent with the theory of how heliox works, being less significant and less certain than on the elimination of carbon dioxide and on the clinical respiratory state. Improved oxygenation is most likely to be through nCPAP rather than a differential effect of heliox or AO. The study protocol also sought both to maintain the minimum FIO2 to maximize the proportion of heliox reaching patients' airways and to ensure that oxygen saturation was >94%.
The response to heliox is seen rapidly within the first hour and is maintained during treatment, consistent with its mechanism of action. This first hour is important because, given the safety of heliox, we can widen the pool of patients treated, yet quickly detect nonresponders, thereby minimizing ineffective treatment with prompt switching to other treatments.
Helium, a naturally inert gas with a low molecular weight, when mixed with 21% oxygen (the same concentration as in atmospheric air), produces a mixed gas one third as dense as air.6,15 Its use in illness where obstruction in the airways is important is through reduced resistance to gaseous flow and, thus, in respiratory effort.9–11 Furthermore, heliox can improve gaseous exchange, improve alveolar ventilation, and also, through its high diffusion coefficient, increase the elimination of carbon dioxide.6,15
There are no data in the literature on the specific use, in infants with acute bronchiolitis, of heliox and noninvasive ventilation in combination. Given what is understood of each of these treatments, the existing data in adults,12,13 and our initial experience in pediatric patients, we suggest that heliox-nCPAP is of clear additional benefit, with even synergy between the heliox and nCPAP. The nCPAP may contribute to decreased inspiratory muscle workload, prevent or relieve atelectasis, avoid airway collapse, and promote heliox distribution within the obstructed airways. Heliox can also reduce respiratory work, enhance carbon dioxide elimination, and increase expiratory flow at the same airway pressures compared with AO. This last effect may help to improve passive expiratory pulmonary mechanics, reducing the risk of barotrauma from gas trapping and, thus, limiting the potential detrimental effects of nCPAP. Use of nCPAP may also reduce the needed FIO2 in these children, further augmenting the actual helium concentration able to be delivered to the patient. On the other hand, it has been reported that heliox might cause hypoxia secondary to the development of atelectasis15,17; this potential adverse effect, not seen in our patients, may be easily prevented with the concomitant use of nCPAP.
As shown in the baseline data, all of the patients in this study fit the usual criteria for endotracheal intubation and for initiation of assisted ventilation.18,19 However, the use of nCPAP with heliox or AO enabled intubation to be avoided in all of our patients. A literature review suggests that 25% to 60% of infants with bronchiolitis admitted to a PICU may need intubation and ventilatory support.1,20–25 Although there may be influencing factors other than heliox and nCPAP treatment, such as PICU admission criteria, differences in RSV status, or disease stage or in intubation practices, none of the 40 patients admitted to our unit in the 12 months of this study required mechanical ventilation. This is remarkable and is consistent with our previous findings, suggesting that heliox, alone or with nCPAP, can avoid the need for intubation and mechanical ventilation.14 Between 1999 and 2006, only 1 (0.4%) of 231 patients admitted to our unit with acute bronchiolitis and managed according to our protocol has needed intubation and mechanical ventilation (95% exact CI: 0.07%–2.40%).
In none of our patients, regardless of the treatments administered, were there any adverse effects related to either heliox or to nCPAP. The techniques used were tolerated well in all of the patients. The inert nature of helium is responsible for the few secondary effects not only in our patients but also in general clinical practice.15
There are some limitations of this study. The number of study subjects was low. However, in completing the study, this did allow for the detection of significant changes in key metrics, validating initial estimates of the sample size needed to have the power to detect the differences in metrics required. Changes in the pitch of the voice or of crying because of heliox, together with the obvious changes in ventilator noise (because of the expiratory branch of the flow generator), removed study blinding. On the other hand, beyond their known limitations, clinical scores are often used as a research tool, and this particular scoring system has been validated previously and could have reasonably counteracted observer bias.6 The level of FIO2 and the pressure of nCPAP were deliberately kept constant during the crossover phase of the study to control for their possible effects in otherwise confusing the interpretation of the primary variables of interest: the clinical score and the elimination of carbon dioxide. Importantly, no rebound effect of heliox withdrawal was detected. This possibility has not been yet described in the literature or observed by us in previous studies.6,14 The design of our study and the conservative analysis of the data, together with the immediate switch from Heliox therapy to either AO-nCPAP or heliox-nCPAP during the crossover, should have prevented the influence of this theoretical effect on our results.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our data show an outstanding beneficial effect of heliox and nCPAP in infants with severe bronchiolitis, improving the clinical condition and blood gas status of these patients in a safe and noninvasive manner. Moreover, heliox and nCPAP may provide time for other therapeutic agents to work or for the disease to resolve naturally and might help to avoid more aggressive intervention, such as endotracheal intubation and invasive mechanical ventilation. Clearly, more studies are needed to further assess this and other issues, such as the optimal timing of intervention, the ideal initial and maintenance parameters to use, the duration of treatment, and the detection of nonresponders. Meanwhile heliox alone, or in combination with nCPAP, is probably a safe and effective tool for the management of infants with severe acute bronchiolitis.
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ACKNOWLEDGMENTS |
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We express our gratitude to John Rodriguez for his valuable input and thoughtful grammar/ style review of the manuscript.
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FOOTNOTES |
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Accepted Oct 1, 2007.
Address correspondence to Federico Martinón-Torres, MD, PhD, Unidad de Cuidados Intensivos Pediátricos, Departmento de Pediatria, Hospital Clínico Universitario de Santiago de Compostela, A choupana s.n. 15705 Santiago de Compostela, Spain. E-mail: federico.martinon.torres{at}sergas.es
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Very little is known, including only some positive but uncontrolled experience published previously by our group. The potential for its use comes from theory and adult data.
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| What This Study Adds This study adds objective support for the use of the combination of heliox and nCPAP in the management of infants with severe bronchiolitis refractory to usual therapies and a starting point for future research on this topic.
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REFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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