Acute respiratory infections remain a leading cause of mortality in children throughout the world, with 2 million deaths

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1 A Randomized Clinical Trial Evaluating Nasal Continuous Positive Airway Pressure for Acute Respiratory Distress in a Developing Country Patrick T. Wilson, MD, MPH 1, Marilyn C. Morris, MD, MPH 1, Katherine V. Biagas, MD 1, Easmon Otupiri, PhD, DVM, MSc, MPH 2, and Rachel T. Moresky, MD, MPH 3 Objective Invasive mechanical ventilation is often not an option for children with acute respiratory infections in developing countries. An alternative is continuous positive airway pressure (CPAP). The authors evaluated the effectiveness of CPAP in children presenting with acute respiratory distress in a developing country. Study design A randomized, controlled trial was conducted in 4 rural hospitals in Ghana. Children, 3 months to 5 years of age, presenting with tachypnea and intercostal or subcostal retractions or nasal flaring were randomly assigned to receive CPAP immediately or 1 hour after presentation. CPAP was applied by locally trained nurses. The primary outcome measure was change in respiratory rate at 1 hour. Results The study was stopped after the enrollment of 70 subjects because of a predetermined stop value of P <.001. Mean respiratory rate of children who received immediate CPAP fell by 16 breaths/min (95% CI 10-21) in the first hour compared with no change in children who had CPAP delayed by 1 hour (95% CI 2 to +5). Thirty-five of the patients had a positive malaria blood smear. There were 3 deaths as a result of severe malaria. No major complications of CPAP use were noted. Conclusions CPAP decreases respiratory rate in children with respiratory distress compared with children not receiving CPAP. The technology was successfully used by local nurses. No complications were associated with its use. CPAP is a relatively low-cost, low-technology that is a safe method to decrease respiratory rate in children with nonspecific respiratory distress. (J Pediatr 2012;-:---). See editorial, p Acute respiratory infections remain a leading cause of mortality in children throughout the world, with 2 million deaths per year in the under-5 age group. 1 In developing countries with limited resources, the use of invasive mechanical ventilation for respiratory distress or insufficiency is often not an option. One alternative to support children with reversible conditions during their acute respiratory distress stage is nasal continuous positive airway pressure (CPAP). The use of CPAP may increase lung volume and improve ventilation-perfusion matching and pulmonary compliance, resulting in improved oxygenation and decreased work of breathing. 2-4 Several randomized controlled trials in developed countries support the use of CPAP in adults with acute pulmonary edema, 4-6 and others have shown significant early improvements in oxygenation and respiratory rate with CPAP in adult patients with acute respiratory insufficiency. 7,8 In developing countries, CPAP has been used in neonates with respiratory distress syndrome. These studies show the technology is much less expensive, has lower complication rates, and requires less technical skill than mechanical ventilation, making it an attractive option in resource-limited countries We conducted a randomized controlled trial to determine whether CPAP, applied by locally trained nurses, decreases respiratory rate in children presenting with undifferentiated respiratory insufficiency in 4 Ghanaian district hospital emergency wards. Methods The study was approved by the Columbia University Institutional Review Board and the Committee on Human Research Publication and Ethics at the Kwame Nkrumah University of Science and Technology in Kumasi, Ghana. Nasal bubble CPAP was introduced to local nurses through an intensive 4-hour didactic and hands-on training session led by 2 experienced neonatal intensive care unit nurses and a pediatric critical care physician from Columbia University, New York, NY. Emergency ward nurses received CPAP training: 4 in Kintampo, 4 CPAP SaO 2 Continuous positive airway pressure Arterial oxygen saturation From the 1 Division of Pediatric Critical Care Medicine, Columbia University Medical Center, New York, NY; 2 Department of Community Health, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana; and 3 Mailman School of Public Health, Columbia University, New York, NY Funded by the GE Foundation to the Mailman School of Public Health. The authors declare no conflicts of interest. Portions of this article were published as a poster at the Society of Critical Care Medicine Conference, Houston, TX, February 4-8, /$ - see front matter. Copyright ª 2012 Mosby Inc. All rights reserved. 1

2 THE JOURNAL OF PEDIATRICS Vol. -, No.- in Mampong, 4 in Nkoranza, and 5 in Wenchi. Two of the nurses had been exposed to CPAP during their training in Ghana before the start of this study. In the following month, the physician spent 1 day a week at each site providing the nurses with in-service training and reviewing how to properly apply CPAP, obtain vital signs according to the standard method, and accurately complete datasheets. All nurses were observed successfully placing CPAP on at least 1 pediatric patient before the start of the study. One nurse at each site was selected as the site coordinator and received additional in-depth training on informed consent, study protocol, CPAP trouble-shooting, adverse events, and data entry. A randomized controlled parallel-study design was used to test the hypothesis that CPAP reduces respiratory rate in children 3 months to 5 years of age presenting with tachypnea and retractions or nasal flaring. A computer-generated randomization scheme was used, with blocks of 24. Study assignments were kept at each site, in sequentially numbered, sealed opaque envelopes. Eligible subjects were children 3 months to 5 years of age presenting to the participating emergency wards with tachypnea (respiratory rate >50 breaths/min in children 3 months to 1 year of age or >40 breaths/min in children 1-5 years of age) with the presence of at least one of the following: subcostal, intercostal, or supraclavicular retractions or nasal flaring. Children were excluded if they had skin breakdown around the nose or mouth, facial trauma, inability to protect their airway, uncontrollable emesis, poor respiratory effort requiring positive pressure ventilation or the need for invasive mechanical ventilation for respiratory failure, known or suspected cardiac disease, or known or suspected pneumothorax. All children had vital signs measured on study entry and every 20 minutes for a period of 2 hours. Children who were assigned to immediate CPAP had CPAP initiated after baseline vital signs were measured. Those assigned to delayed CPAP were managed according to Ghana Health Service protocols for the first hour of the study. After the 1-hour vital signs were obtained, CPAP was initiated (Figure 1). The primary outcome measure was change in respiratory rate from the start of the study to the 1-hour time point. Both groups received supplemental oxygen if the arterial oxygen saturation (SaO 2 ) was <92% and were treated according to the Ghana Health Service s standards of care. After 2 hours, CPAP was continued at the discretion of the treating health care provider. Baseline demographics (sex and date of birth) and physical examination (weight and vital signs) were obtained. All laboratory results requested by the Ghanaian health care provider were recorded. Respiratory rate was counted for 60 seconds, either continuously or in two 30-second blocks using a stopwatch or the second hand of a timepiece. GE Dinamap V100 (Fairfield, Connecticut) machines were used to measure Sao 2, heart rate, and temperature. Respiratory rate, heart rate, and SaO 2 were obtained every 20 minutes for a total of 2 hours. Dispositions of patients were categorized as death, intubation, transfer to other facility, admission to pediatric ward, or discharge home. The device used in the study was the Hudson RCI CPAP nasal cannula (Durham, North Carolina). A DeVilbiss IntelliPAP CPAP machine (Somerset, Pennsylvania) was used to deliver a pressure of 5 cm H 2 O in the inspiratory limb of the system, while the expiratory limb was placed 5 cm below the level of a % acetate solution in water. Adequacy of seal was monitored by observing air bubbles in the water/acetate solution during expiration. Oxygen was administered as needed for SaO 2 levels <92%, via a nonrebreather face mask or through the CPAP circuit. All equipment provided for the study was left with the hospitals for clinical use after the study. Statistical Analyses The anticipated sample size was calculated to be 48 subjects per group, assuming a difference of 7 breaths/min (SD, 12 breaths/min) between the groups, with a 2-sided a of 0.05 and a power of 80%. A Data and Safety Monitoring Board composed of a Ghanaian physician, a Ghanaian biostatician, and a US physician performed planned interim analyses at 25% and 50% of anticipated enrollment for safety monitoring, and a predetermined stop value of P <.001 was used (Haybittle-Peto rule). 12 Normally distributed continuous variables were compared using the Student t test, nonnormally distributed data using the Mann-Whitney test, and categorical variables using c 2 or Fisher exact tests. Results Between June 27 and November 22, 2011, the parents of 70 eligible children were approached for consent to participate in the study; all 70 provided written documentation of consent. Consent was sought by local investigators in the local language if the parents did not speak English. Thirty-one children were randomized to the immediate CPAP group, and 39 were randomized to the delayed CPAP group. Respiratory rates were not recorded at any time point for one subject in the delayed group, so that subject was not included in the analysis. That subject improved and was admitted to the pediatric ward. Baseline characteristics of the 2 groups are summarized in the Table. CPAP was successfully initiated in all children assigned to the immediate CPAP group. In children assigned to immediate CPAP, the mean respiratory rate fell by 16 breaths/min (66-50, 24% decrease) over the first hour of the study (95% CI 10-21) compared with little change (61-60, 2% decrease) in the delayed CPAP group (95% CI 2 to +5) (P <.001 for a difference in magnitude of drop in respiratory rate; Figure 2). All subjects assigned to delayed CPAP had CPAP initiated at 1 hour. The mean respiratory rate of children in the delayed CPAP group decreased by 13 breaths/min (95% CI 8-19, P <.01) over the second hour of the study (Figure 2). Heart rates did not differ between the 2 groups. Thirty-five of the patients had positive blood smears for malaria on light microscopy. There were 3 deaths as a result of severe malaria reported in the immediate CPAP group (P =.09); 1 patient was transferred to a higher-level facility 2 Wilson et al

3 ORIGINAL ARTICLES Inclusion Criteria 3 months-5 years Tachypnea for age Retractions or nasal flaring Immediate Group (n=31) (Nasal CPAP O 2 if SaO 2 < 92%) Block randomization at 4 study sites Delayed Group (n=38) (Face mask O 2 if SaO 2 <92%) Baseline Vitals Vitals 20 min CPAP Applied Baseline Vitals Vitals 20 min Vitals 40 min Vitals 40 min Vitals 1 hour Vitals 1 hour CPAP Applied Vitals 80 min Vitals 80 min Vitals 100 min Vitals 100 min Vitals 2 hours CPAP continued at the discretion of treating health care provider Vitals 2 hours Figure 1. Participants were block randomized into 2 groups: immediate CPAP or delayed CPAP. CPAP commenced after obtaining baseline vital signs in the immediate group and 1 hour after vital signs in the delayed group. Vital signs were recorded every 20 minutes in each group and oxygen was administered if SaO 2 was <92%. After 2 hours, CPAP was continued at the discretion of the treating health care provider. for worsening respiratory status. The remainder were admitted to the pediatric ward or discharged home. Two of the children with positive malaria blood smears died without having received antimalaria therapy, and the third patient with malaria and severe anemia died without receiving a blood transfusion secondary to delays in the hospital laboratory. All 3 deaths were reviewed by local health care providers and the Data Safety and Monitoring Board and found to be unrelated to the use of CPAP. Discussion This study demonstrates that nurses in developing countries can successfully and safely apply CPAP after receiving appropriate training. Because there are few physicians or mid-level providers in many parts of the developing world, nurses are the first-line providers of life-sustaining interventions and should be empowered with the knowledge and ability to manage acute respiratory distress. Much of the success of the study was secondary to identifying qualified and committed nurses who were interested in learning a new technology and conducting clinical research. We found that CPAP decreases respiratory rate in children presenting with respiratory distress in rural Ghana. In our study, CPAP was well tolerated and without complications. The patients included in the study represent a heterogeneous group of diagnoses: pneumonia, sepsis, malaria, and severe anemia. The effectiveness of CPAP in this heterogeneous group is particularly significant as many health facilities in resource-poor areas lack the ability to perform adequate diagnostic tests. The broader significance of our findings depends on the extent to which the use of CPAP may improve the outcomes in children with respiratory insufficiency and on the ability to sustainably and cost-effectively provide CPAP in resourcelimited settings. The CPAP setup used in this study is Table. Baseline characteristics of study participants Delayed (n = 38) Immediate (n = 31) P Female, No. 15 (39%) 10 (32%).62 Age, mo 14 (9-21) 13 (7-24).54 Weight, kg 8.3 (7.5-11) 9 (7.2-10).86 Respiratory rate, breaths/min Heart rate, beats/min SaO 2, % 98 (93-100) 99 (95-100).76 Temperature, C Malaria-positive blood smears, No. 19 (50%) 16 (52%) 1.00 Hemoglobin, g/dl Normally distributed continuous variables expressed as mean SD, t test. Skewed continuous variables expressed as median (IQR), Mann-Whitney. Categorical variables expressed as number and (percentage of total), c 2 or Fisher exact test. A Randomized Clinical Trial Evaluating Nasal Continuous Positive Airway Pressure for Acute Respiratory Distress in a Developing Country 3

4 THE JOURNAL OF PEDIATRICS Vol. -, No.- Breaths per minute Immediate versus Delayed CPAP * CPAP initiated Minutes Immediate Delayed *P <.001 **P <.01 Figure 2. Mean respiratory rates in each group every 20 minutes for 2 hours. A decrease in respiratory rate is seen in the immediate group with CPAP compared with the delayed group, who did not receive CPAP for the first hour. A decrease in respiratory rate in the delayed group is seen after the initiation of CPAP at 1 hour. inexpensive compared with mechanical ventilators ($400 compared with several thousand dollars for a typical, basic mechanical ventilator) and has the additional advantage of being easy to use and safe. Nevertheless, the CPAP machines used in the study do require electricity and contain parts that may not be available in low-income regions of the world. As it is possible for CPAP machines to run off of battery power or compressed air, several research groups are actively developing low-cost CPAP machines with minimal parts that will allow the technology to be sustainable in resource-poor areas of the world. Further, even the cost of patient interfaces (nasal prongs $32) may be prohibitive in many cases. If CPAP is found to improve outcomes, efforts to develop low-cost alternatives to current CPAP machines and interfaces will become all the more critical. There were 3 deaths in the immediate CPAP group and none in the delayed CPAP group. Although this difference was not statistically significant it requires close attention. The study was not powered to detect a difference between malaria-positive and malaria-negative patients, but a similar trend of decreased respiratory rates was observed in those malaria-positive subjects who received CPAP. Because malaria contributes significantly to the mortality of children <5 years old in sub-saharan Africa, it will be important to specifically determine whether CPAP is as effective in patients with severe malaria as in those with a primary respiratory diagnosis. There are several limitations to the study. The study was designed to evaluate the impact of CPAP on respiratory rate but not to evaluate clinically meaningful outcomes such as survival. The impact of CPAP on outcome will be evaluated in an upcoming study. Although the primary outcome measure was objective, the study was not blinded, leaving investigators susceptible to bias. Diagnostic testing was limited, so we cannot determine whether certain subgroups benefited more or less than others. ** The 100% consent rate of parents approached for participation in this study raises the question of whether parents may have felt coerced to participate. Parents were given a small gift for the child (a diaper for infants or pencil and notepad for older children), in accordance with local research practices, but the gifts were not mentioned to parents before consent was obtained. We recognize that the opportunity for truly informed consent may be impeded by parental eagerness to access a medical device that would otherwise not be available. Conducting research in low-resource areas requires extra attention to avoid coercion and ensure full understanding of the research. We conducted this randomized controlled trial of CPAP in children 3 months to 5 years of age with acute respiratory distress in a developing country to demonstrate the feasibility of nurses applying the technology. We have shown that it is a safe and effective method to decrease respiratory rates in children presenting with nonspecific respiratory distress. The next step will be to determine whether the use of CPAP results in improved outcomes. We plan a multicenter controlled trial to determine whether the use of CPAP decreases mortality in our cohort of children and to define the epidemiology of their respiratory distress. n The authors thank all the participating children and families in Ghana and recognize Peter Fair and Harriet White for providing the CPAP training and NanaAma Adom-Boakye and Beth Rubenstein for their administrative and logistical support. The study would not have been possible without the hard work and dedication of the nurses at Mampong District Hospital Yunnus Suleman, Joyce Pobi, Emmanuel Kpimetone Gelyi, Wisdom Amedior, Victor Owusu Opoku Samuel, and George Osei-Tutu; Kintampo District Hospital Brian Fosu, Ernest Oppong, and Anthony Agamba; Nkoranza District Hospital Esther Maajuugh and Enock Owusu Afriyie; and Wenchi District Hospital George Addai. The authors also recognize the support of the medical superintendents and administrators at each district hospital and at Ghana Health Services. Submitted for publication Jun 22, 2012; last revision received Aug 27, 2012; accepted Oct 8, Reprint requests: Patrick T. Wilson, MD, MPH, 3959 Broadway, CHN 10-24, New York, NY ptw2107@columbia.edu References 1. Bryce J, Boschi-Pinto C, Shibuya K, Black RE, the WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet 2005;365: Brett A, Sinclair DG. Use of continuous positive airway pressure in the management of community acquired pneumonia. Thorax 1993;48: Lindner KH, Lotz P, Ahnefeld FW. Continuous positive airway pressure effect on functional residual capacity, vital capacity and its subdivisions. Chest 1987;92: Rasanen J, Heikkila J, Downs J, Nikki P, Vaisanen I, Viitanen A. Continuous positive airway pressure by face mask in acute cardiogenic pulmonary edema. Am J Cardiol 1985;55: Bersten AD, Holt AW, Vedig AE, Skowronski GA, Baggoley CJ. 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