Physiologic Effect of High-Flow Nasal Cannula in Infants With Bronchiolitis Judith L. Hough, PhD1,2,3; Trang M. T. Pham, BEng1; Andreas Schibler, MD, FCICM1
Objective: To assess the effect of delivering high-flow nasal cannula flow on end-expiratory lung volume, continuous distending pressure, and regional ventilation distribution in infants less than 12 months old with bronchiolitis. Design: Prospective observational clinical study. Setting: Nineteen bed medical and surgical PICU. Patients: Thirteen infants with bronchiolitis on high-flow nasal therapy. Interventions: The study infants were measured on a flow rate applied at 2 and 8 L/min through the high-flow nasal cannula system. Measurements and Results: Ventilation distribution was measured with regional electrical impedance amplitudes and end-expiratory lung volume using electrical impedance tomography. Changes in continuous distending pressure were measured from the esophagus via the nasogastric tube. Physiological variables were also recorded. High-flow nasal cannula delivered at 8 L/min resulted in significant increases in global and anterior end-expiratory lung volume (p < 0.01) and improvements in the physiological variables of respiratory rate, Spo2, and Fio2 when compared with flows of 2 L/min. Conclusion: In infants with bronchiolitis, high-flow nasal cannula oxygen/air delivered at 8 L/min resulted in increases in end-expiratory lung volume and improved respiratory rate, Fio2, and Spo2. (Pediatr Crit Care Med 2014; 15:e214–e219) Key Words: continuous positive airways pressure; electrical impedance tomography; high-flow nasal cannula; oxygen delivery; ventilation distribution
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ronchiolitis is the leading cause of pediatric hospitalization in Australia and New Zealand and accounts for approximately 8,000 admissions annually (1). Respiratory support is fundamental to the treatment of severe Paediatric Critical Care Research Group, Paediatric Intensive Care Unit, Mater Children’s Hospital, South Brisbane, QLD, Australia. 2 School of Physiotherapy, Australian Catholic University, Banyo, QLD, Australia. 3 Critical Care of the Newborn Program, Mater Research, South Brisbane, QLD, Australia. Dr. Schibler’s institution received grant support from Fisher & Paykel Healthcare. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000112 1
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bronchiolitis, and various forms of noninvasive respiratory therapy have been used in its treatment (2). Continuous positive airways pressure (CPAP) has been used to decrease the work of breathing, improve functional residual capacity, and reduce regional atelectasis associated with this disease (3, 4). CPAP can be delivered via nasopharyngeal tube or face mask and generated by a water column (bubble CPAP) or a dedicated CPAP driver (5). Despite the acknowledged clinical usefulness of nasal CPAP, uncertainties regarding aspects of its application remain. Furthermore, defining the optimal nasal CPAP system is complicated by the multiplicity of nasal CPAP devices and techniques available to the clinician (6). Recently high-flow nasal cannula (HFNC) therapy has been introduced to provide respiratory support in infants (7–9). HFNC is considered to be the delivery of gas flow rates exceeding 2 L/min. HFNC therapy has many possible advantages over other forms of oxygen therapy: the inspired gas mixture can be heated and humidified to reduce damage to the upper airway mucosa; the inspired oxygen concentration can be titrated to the patients need; anecdotally, it is better tolerated by the patient; and potentially, CPAP can be delivered (10–13). Studies in neonates have shown that the amount of CPAP delivered by HFNC depends on the flow (relative to the size of the patient) and on the leak around the nasal cannula (14). Most studies of HFNC therapy have been performed in neonates, and little clinical experience is reported in older children (7). A number of studies have investigated the effect of HFNC in treating apnoea of prematurity (15), on the CPAP effect in neonates (14, 16), pharyngeal pressure (12), and its role in the postextubation period (8, 17, 18). Despite its acceptance, the use of HFNC is still controversial and not recommended by some outside of a research protocol (19–22). Of primary concern is the paucity of available evidence on the effect of HFNC on CPAP and end-expiratory lung volume (EELV). The purpose of this study was to investigate the effect of HFNC flow on CPAP, EELV, regional ventilation distribution, and other respiratory physiological variables in infants with bronchiolitis.
METHODS Study Design In a prospective interventional study, infants with bronchiolitis were measured on and off HFNC. June 2014 • Volume 15 • Number 5
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Subjects Infants with the diagnosis of bronchiolitis were recruited from the PICU at the Mater Children’s Hospital, South Brisbane, Australia. Criteria for admission to PICU were an oxygen requirement of more than 2 L/min to maintain Spo2 more than 94% and the need for respiratory support due to increased work of breathing. Inclusion criteria for the study were infants less than 12 months old who were placed on HFNC respiratory support for respiratory distress due to a viral bronchiolitis (confirmed with a positive polymerase chain reaction test for viral infection in the nasopharyngeal aspirate) and who had a nasogastric (NG) feeding tube in place. Exclusion criteria were an oxygen requirement of more than 60%, structural upper airway obstruction, or craniofacial malformation. The study protocol was approved by the Human Research Ethics Committee of the Mater Health Services, South Brisbane, Queensland. Informed written consent was obtained from the parents. HFNC System The Fisher & Paykel humidified high-flow system was used with a low resistance pediatric binasal cannula (BC3780 and RT329; Fisher & Paykel Healthcare, Auckland, New Zealand). Inspired oxygen concentration was titrated to achieve pulse oximeter oxygen saturations (Spo2) between 94% and 98%. The flow rate used was set at 8 L/min (equipment limitation) at the beginning of the HFNC treatment. The study infants were measured on a flow rate applied at 2 or 8 L/min through the HFNC system with the order of the applied flow rate randomized. A period of at least 5 minutes was allowed to stabilize before taking measurements over a 3-minute period. At the conclusion of the study, infants were placed back on their prestudy flow rate of 8 L/min for ongoing treatment. All infants were nursed in the supine position throughout the study. Measurements Electrical impedance tomography (EIT) data allow measurement of change in end-expiratory level (or lung volume, EELV) and changes in regional ventilation distribution or regional tidal volume changes in spontaneously breathing subjects without interfering with normal breathing. The principle of EIT is based on the rapid cyclic acquisition of potential differences on the surface of the chest produced by repetitive injections of a small electrical current. Both the voltages and current are measured between pairs of 16 conventional electrodes (Kendall, Kittycat 1050NPSM; Tyco Healthcare group, Mansfield, MA) placed circumferentially around the chest at nipple level. EIT scans are generated from the collected potential differences and the known excitation currents using weighted back-projection in a 32 × 32 pixel matrix (23). Each pixel represents the instantaneous relative local impedance change relative to baseline. The majority of the measured impedance change is caused by local air volume change, and hence, the measured impedance change of each pixel correlates closely to local (tidal) volume change (24). In summary, EIT allows measuring change of lung volume (comparable to functional residual capacity measurements) and measuring regional tidal breathing. Pediatric Critical Care Medicine
A Gottingen GoeMF II tomograph (VIASYS Healthcare, Houten, The Netherlands) was used. Three-minute measurements were taken at 2 and 8 L/min flow rates. Software provided with the equipment was used for data acquisition and reconstruction of functional relative EIT images (25). Data were further analyzed off-line using Matlab 7.7 (R2008b; The MathWorks, Natick, MA). Data Processing and Analysis EIT data were band-pass filtered to include the first and second harmonic of the respiratory rate (26). A cutoff mask of 20% of the peak impedance signal was applied (27) to reduce cardiac interference (28). Regular sections of data were selected for analysis. The following criteria were used to select these periods (29). 1 . Length of 3–5 breaths 2. Regular breathing rate 3. Stable tidal volume and EELV 4. Rejection of the first breath if a respiratory pause preceded the tidal breathing period Measurement of End-Expiratory Level and Regional Ventilation Distribution Changes in EELV at 2 L/min were compared with 8 L/min flow rates for the global, the dependent (posterior), and nondependent (anterior) lung. An example of global EELV change with a switch from “off HFNC” to “on HFNC” is shown in F igure 1. Regional impedance amplitudes were used to describe the magnitude of the regional tidal volume change within an individual over time. Impedance amplitudes for the global, the dependent (posterior), and nondependent (anterior) lung were calculated by averaging the impedance differences in each pixel of the measurement period between the end-expiratory and end-inspiratory periods. To account for the unequal number of pixels analyzed in each region of interest (ROI), the average amplitude for each ROI was reported. A global inhomogeneity (GI) index was also calculated for the entire lung region using a tidal EIT image of the endexpiration to end-inspiration differences of the EIT impedance signal of each image pixel. The GI index is used as an indicator of inhomogeneous ventilation by describing variations in the pixel values of the tidal EIT image (30). The higher the GI value the more ventilation inhomogeneity exists. Measurement of Esophageal Pressure Esophageal pressure (Poe) measurements were taken as an indication of CPAP. To achieve this measurement, the NG tube was connected to a pressure transducer and the in situ NG feeding tube was pulled back to the distal third of the esophagus where it was positioned to achieve a waveform in the range of –5 to 5 kPa that was free from cardiac artifact (31). Feeds were discontinued for the length of the study. To maintain patency of the NG tube, it was flushed with normal saline at a rate of 1 mL/hr. Mouth closure was required for measurements, either spontaneously or with a pacifier. The pressure signal was connected into the EIT equipment to synchronize the signals. Poe was measured at 2 and 8 L/min and measures taken at end inspiration and end expiration. Additionally, we calculated the pressure rate product www.pccmjournal.org
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any equipment adjustment disturbed the breathing pattern of the subject and the quality of the signals. The successfully measured infants had a mean (± sd) age of 3.17 months (± 2.06 mo) and a mean study weight of 4.76 kg (± 1.39 kg), and the study group consisted of six female and seven male infants. HFNC was delivered at an average rate of 1.7 L/kg/min (± 0.26 L/kg/min), whereas standard oxygen delivery at 2 L/min was equivalent to 0.4 L/kg/min. Changes in EELV and Regional Ventilation Distribution Changes in EELV at 2 L/min (off HFNC) were compared with 8 L/min (on HFNC). An example of global EELV change Figure 1. Illustration of the change in end-expiratory level (EEL) measured with electrical impedance tomography on and off high-flow nasal cannula (HFNC). with a switch from off HFNC to on HFNC is shown in Figure 1. The EELV increased significantly on HFNC for the ante(PRP), which was calculated by multiplying the expiratory presrior (nondependent) lung (p = 0.017), and there was a trend sure amplitude with the respiratory rate. A decrease in the PRP toward increased EELV in the posterior and for the global lung, indicates a decrease in the work of breathing. but the change did not reach a significant level (Fig. 2). Similarly to the EELV, the global and regional impedance ampliMeasurement of Physiologic Variables Inspired oxygen (Fio2), respiratory rate (RR), heart rate (HR), tudes were higher on HFNC compared with low-flow nasal and Spo2 were monitored using the Dräger infinity SC800 mon- cannula, but the differences did not reach significance. The GI itoring system (Dräger Medical AG & Co. KG, Lübeck, Ger- index decreased on HFNC compared with off HFNC indicating improved ventilation distribution, but the differences did many) throughout the study. These were manually recorded at the time of each EIT recording. From the collected data, the not reach statistical significance (p = 0.053). Spo2/Fio2 ratio was calculated (32). Statistics Results are described using mean and ses. After testing for normality (Levene’s test), a paired t test was used to compare results. A p value of less than 0.05 was considered significant. All statistical analyses were performed using SPSS (v15.0; Lead Technologies, Chicago, IL). It was the original intention to enroll 20 infants based on pilot trials which showed that 1 L/min air flow causes an increase of continuous distending pressure (CDP) of 2.8 cm H2O (sd, 2.7; n = 9). Using a power of 90% and a p value of less than 0.05, we needed to enroll at least 12 infants. However, due to a change in the circuit available and the unit policy for HFNC use, the study was forced to discontinue after 13 infants were recruited.
RESULTS Patient Characteristics We enrolled 13 patients into the study but could only obtain meaningful EIT and pressure signal readings in 11 infants, as e216
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Measurement of Poe Poe at end expiration increased significantly from –0.2 ± 7.6 cm H2O to 6.9 ± 2.1 cm H2O (p = 0.045). Poe at end inspiration increased only moderately from –1.9 ± 4.8 cm H2O to –0.2 ± 4.8 cm H2O (p = not significant). The PRP decreased from 1,003 ± 214 to 956 ± 138 (p = 0.14) (Fig. 3). Changes in Physiologic Variables RR dropped significantly (p = 0.045) when on HFNC, but there were no other significant differences in the physiological variables such as HR, Fio2, Sao2, and Sao2/Fio2 on and off HFNC. There was a tendency for all of these variables to improve with HFNC (Table 1). Adverse Events There were no adverse events recorded during the study period.
DISCUSSION The main finding of this physiological study was that there were increased end-expiratory Poe associated at HFNC of 8 L/min June 2014 • Volume 15 • Number 5
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Figure 3. Change in esophageal pressure (Poe) (upper panel) and pressure rate product (PRP) (lower panel) on and off high-flow nasal cannula (HFNC). # denotes significant difference for Poe at end expiration (p < 0.05). Figure 2. Change of end-expiratory level (EEL) (upper panel) and global and regional impedance amplitudes (lower panel) measured with electrical impedance tomography on and off high-flow nasal cannula (HFNC). # denotes significant difference for the anterior lung (p < 0.05).
compared with standard flow 2 L/min with a corresponding increase in EELV in the anterior lung and a decrease in respiratory rate. This is the first report documenting a change in EELV in infants with bronchiolitis treated with HFNC. One of the main difficulties in obtaining accurate lung function data on patients on HFNC therapy is that most techniques cannot be used while high flow is delivered. Although there are some data on lung function in ventilated infants with bronchiolitis, little Table 1. Effect of the Flow Rates of 2 and 8 L/min on Physiological Characteristics of the Infants: Mean (se) of Each Intervention Intervention 2 L/min (n = 13)
Outcome
8 L/min (n = 13)
Heart rate (beats/min)
139.9 ± 5.9
134.8 ± 4.5
Respiratory rate (breaths/min)
68.5 ± 6.0
56.9 ± 3.2a
Spo2 (%)
95.6 ± 0.9
97.3 ± 0.6
Fio2
0.42 ± 0.04
0.34 ± 0.02
Spo2/Fio2
251.6 ± 25.9 280.0 ± 20.3
a
Respiratory rate decreased significantly on high-flow nasal cannula of 8 L/min (p = 0.045).
a
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information is currently available for spontaneously breathing infants on HFNC. Despite presenting only a small dataset, our findings are consistent with previous reports on the physiological effect of high flow. Effect of HFNC on Esophagus Pressure We showed that at flow rates of 1.7 L/kg/min, the end-expiratory Poe was significantly higher compared with low-flow oxygen delivery (0.4 L/kg/min). Of particular interest was that the Poe difference between the end-expiratory and end-inspiratory phase of the respiratory cycle was much greater on HFNC than off HFNC (Fig. 3). This effect is best explained with the observation that during the expiratory phase, the unidirectional high flow toward the larynx streams against the expiratory flow of the patient, creating some resistance and positive pressure. During the inspiratory phase, however, the unidirectional flow of the HFNC is in the same direction as the inspiratory flow of the patient, and hence, the observed pressure drops. Although HFNC increases the expiratory pressure, it differs from CPAP during the inspiratory phase. Such differences between inspiratory and expiratory Poe observed during HFNC are not consistent with the definition of CPAP (continuous positive airway pressure) but better described as a positive expiratory pressure. A positive end-inspiratory pressure can only be achieved if the flow of the HFNC is greater than the maximal inspiratory flow of the patient. In our study, we achieved on average 1.7 L/kg/ min high flow and an average inspiratory Poe of approximately zero. Hence, to achieve some positive pressure during the inspiratory phase, even greater flows than 1.7 L/kg/min may need to www.pccmjournal.org
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be delivered. We estimate that 2 L/kg/min may be an adequate flow rate, a flow rate that normally has been used in the past to titrate the circuit flow in a continuous bypass neonatal ventilator. The PRP was only moderately reduced on HFNC, which is not surprising as the PRP is a composite of pressure amplitude and respiratory rate. The pressure amplitude as per Figure 3 increased due to the positive end-expiratory pressure effect of HFNC but the respiratory rate dropped. We may speculate that the flow rate used in our study was not sufficient to decrease the work of breathing significantly. This argument may be supported by the fact that in premature infants, flow rates between 5 and 8 L/min are used to reduce the work of breathing in babies with a body weight of 1,000 g, which is equivalent to 5–8 L/kg/min. Our results are consistent with measurements that have recently been published in infants with bronchiolitis using pharyngeal pressure (33). Another explanation could be that the higher end-expiratory pressure might be splinting the airways open, helping to decrease expiratory airflow limitation. There have been a number of studies investigating the effect of change in airway pressure with increasing flow rates and results have varied markedly with no consensus reached and concerns still related to uncontrolled airway pressure (11, 12, 14, 34–36), which includes air escaping when the mouth is open. An increase in airway pressure is only one of the mechanisms thought to responsible for the positive effects of HFNC. The variation in results in the literature could be because there are alternative mechanisms involved. Other proposed mechanisms include washout of nasopharyngeal dead space, reduction of inspiratory airflow resistance, improved lung mechanics, reduced metabolic work required for gas warming, and humidification (10, 36–38). In situations in which the flow delivered by the oxygen delivery method is lower than the maximal inspiratory flow of the patient, then an air leak around the nasal cannula is needed to entrain air. Similarly during the expiratory phase, an air leak, either via mouth or around the nasal cannula, is mandatory. These leak conditions are absolutely mandatory to be present for the safe use of HFNC. Effect of HFNC on EELV To our knowledge, this is the first study describing changes in EELV in infants with bronchiolitis and on HFNC. The change in EELV in our study was moderate but consistent for all patients. Interestingly, the anterior (nondependent) lung showed the greatest increase. Bronchiolitis per se is associated with hyperinflation and air trapping due to small airway disease. Hence, any further increase of EELV seems surprising. First, any positive airway pressure may recruit previously collapsed alveoli; microatelectasis is one of the main features of bronchiolitis. The CDP then will splint airway passages helping to mitigate the effect of expiratory airflow limitation. These findings mirror those found in a cohort of 20 adults who also demonstrated an increase in global and ventral end-expiratory lung impedance variation when placed on HFNC (39). The global and regional amplitudes were higher on HFNC compared with e218
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low-flow nasal cannula. The GI index as a measure of ventilation inhomogeneity improved; however, the differences did not reach significance (p = 0.053). Limitations The study represents a relatively small number of patients. This was due to difficulties encountered with data collection, particularly with relation to noisy signals obtained from the esophageal monitoring and the EIT. Despite that we have selected measurement techniques which do not interfere with the patients breathing, the investigated infants were disturbed when the esophagus probe was adjusted or the electrodes applied. Since the use of HFNC is becoming more popular in many pediatric hospitals, the understanding of the physiological mechanisms is important. Not all changes that we observed were significant, but they certainly were physiologically plausible. One further limitation of the high-flow use is that the variation of the applied positive airway pressure is greatly affected by air leaks that occur around the nasal cannula and through the mouth. Although EIT measurements in infants are technically challenging with electrode placement difficulties increasing recorded noise, the midthoracic placement of electrodes has been confirmed by MRI to produce impedance values reflective of the entire lung (40). How Can High Flow Be Defined? Based on our findings, adequate flow rates are achieved when increased positive expiratory Poe were observed and potentially even positive airway pressures during the inspiratory phase. The measurement of Poe for the titration of high flow is clinically too cumbersome, similarly to the routine use of EIT. Based on our and other recent studies, flow rates of greater than 1.7 L/min/kg, probably for ease of use 2 L/kg/min, should be discussed. These flow rates, however, should be tested in larger studies and investigated whether any benefit can be observed. We cannot yet provide any suggestions to the upper limits of flow rates, but based on our own experience and a just recently finished pilot study (41), flow rates of 2 L/kg/min for infants with bronchiolitis are well tolerated. Artificial limitations of the flow delivery systems have in the past limited the investigation of higher flow rates.
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Objective: To assess the effect of delivering high-flow nasal cannula flow on end-expiratory lung volume, continuous distending pressure, and regional ventilation distribution in infants less than 12 months old with bronchiolitis. Design: Prospective observational clinical study. Setting: Nineteen bed medical and surgical PICU. Patients: Thirteen infants with bronchiolitis on high-flow nasal therapy. Interventions: The study infants were measured on a flow rate applied at 2 and 8 L/min through the high-flow nasal cannula system. Measurements and Results: Ventilation distribution was measured with regional electrical impedance amplitudes and end-expiratory lung volume using electrical impedance tomography. Changes in continuous distending pressure were measured from the esophagus via the nasogastric tube. Physiological variables were also recorded. High-flow nasal cannula delivered at 8 L/min resulted in significant increases in global and anterior end-expiratory lung volume (p < 0.01) and improvements in the physiological variables of respiratory rate, Spo2, and Fio2 when compared with flows of 2 L/min. Conclusion: In infants with bronchiolitis, high-flow nasal cannula oxygen/air delivered at 8 L/min resulted in increases in end-expiratory lung volume and improved respiratory rate, Fio2, and Spo2. (Pediatr Crit Care Med 2014; 15:e214–e219) Key Words: continuous positive airways pressure; electrical impedance tomography; high-flow nasal cannula; oxygen delivery; ventilation distribution
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ronchiolitis is the leading cause of pediatric hospitalization in Australia and New Zealand and accounts for approximately 8,000 admissions annually (1). Respiratory support is fundamental to the treatment of severe Paediatric Critical Care Research Group, Paediatric Intensive Care Unit, Mater Children’s Hospital, South Brisbane, QLD, Australia. 2 School of Physiotherapy, Australian Catholic University, Banyo, QLD, Australia. 3 Critical Care of the Newborn Program, Mater Research, South Brisbane, QLD, Australia. Dr. Schibler’s institution received grant support from Fisher & Paykel Healthcare. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000112 1
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bronchiolitis, and various forms of noninvasive respiratory therapy have been used in its treatment (2). Continuous positive airways pressure (CPAP) has been used to decrease the work of breathing, improve functional residual capacity, and reduce regional atelectasis associated with this disease (3, 4). CPAP can be delivered via nasopharyngeal tube or face mask and generated by a water column (bubble CPAP) or a dedicated CPAP driver (5). Despite the acknowledged clinical usefulness of nasal CPAP, uncertainties regarding aspects of its application remain. Furthermore, defining the optimal nasal CPAP system is complicated by the multiplicity of nasal CPAP devices and techniques available to the clinician (6). Recently high-flow nasal cannula (HFNC) therapy has been introduced to provide respiratory support in infants (7–9). HFNC is considered to be the delivery of gas flow rates exceeding 2 L/min. HFNC therapy has many possible advantages over other forms of oxygen therapy: the inspired gas mixture can be heated and humidified to reduce damage to the upper airway mucosa; the inspired oxygen concentration can be titrated to the patients need; anecdotally, it is better tolerated by the patient; and potentially, CPAP can be delivered (10–13). Studies in neonates have shown that the amount of CPAP delivered by HFNC depends on the flow (relative to the size of the patient) and on the leak around the nasal cannula (14). Most studies of HFNC therapy have been performed in neonates, and little clinical experience is reported in older children (7). A number of studies have investigated the effect of HFNC in treating apnoea of prematurity (15), on the CPAP effect in neonates (14, 16), pharyngeal pressure (12), and its role in the postextubation period (8, 17, 18). Despite its acceptance, the use of HFNC is still controversial and not recommended by some outside of a research protocol (19–22). Of primary concern is the paucity of available evidence on the effect of HFNC on CPAP and end-expiratory lung volume (EELV). The purpose of this study was to investigate the effect of HFNC flow on CPAP, EELV, regional ventilation distribution, and other respiratory physiological variables in infants with bronchiolitis.
METHODS Study Design In a prospective interventional study, infants with bronchiolitis were measured on and off HFNC. June 2014 • Volume 15 • Number 5
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Subjects Infants with the diagnosis of bronchiolitis were recruited from the PICU at the Mater Children’s Hospital, South Brisbane, Australia. Criteria for admission to PICU were an oxygen requirement of more than 2 L/min to maintain Spo2 more than 94% and the need for respiratory support due to increased work of breathing. Inclusion criteria for the study were infants less than 12 months old who were placed on HFNC respiratory support for respiratory distress due to a viral bronchiolitis (confirmed with a positive polymerase chain reaction test for viral infection in the nasopharyngeal aspirate) and who had a nasogastric (NG) feeding tube in place. Exclusion criteria were an oxygen requirement of more than 60%, structural upper airway obstruction, or craniofacial malformation. The study protocol was approved by the Human Research Ethics Committee of the Mater Health Services, South Brisbane, Queensland. Informed written consent was obtained from the parents. HFNC System The Fisher & Paykel humidified high-flow system was used with a low resistance pediatric binasal cannula (BC3780 and RT329; Fisher & Paykel Healthcare, Auckland, New Zealand). Inspired oxygen concentration was titrated to achieve pulse oximeter oxygen saturations (Spo2) between 94% and 98%. The flow rate used was set at 8 L/min (equipment limitation) at the beginning of the HFNC treatment. The study infants were measured on a flow rate applied at 2 or 8 L/min through the HFNC system with the order of the applied flow rate randomized. A period of at least 5 minutes was allowed to stabilize before taking measurements over a 3-minute period. At the conclusion of the study, infants were placed back on their prestudy flow rate of 8 L/min for ongoing treatment. All infants were nursed in the supine position throughout the study. Measurements Electrical impedance tomography (EIT) data allow measurement of change in end-expiratory level (or lung volume, EELV) and changes in regional ventilation distribution or regional tidal volume changes in spontaneously breathing subjects without interfering with normal breathing. The principle of EIT is based on the rapid cyclic acquisition of potential differences on the surface of the chest produced by repetitive injections of a small electrical current. Both the voltages and current are measured between pairs of 16 conventional electrodes (Kendall, Kittycat 1050NPSM; Tyco Healthcare group, Mansfield, MA) placed circumferentially around the chest at nipple level. EIT scans are generated from the collected potential differences and the known excitation currents using weighted back-projection in a 32 × 32 pixel matrix (23). Each pixel represents the instantaneous relative local impedance change relative to baseline. The majority of the measured impedance change is caused by local air volume change, and hence, the measured impedance change of each pixel correlates closely to local (tidal) volume change (24). In summary, EIT allows measuring change of lung volume (comparable to functional residual capacity measurements) and measuring regional tidal breathing. Pediatric Critical Care Medicine
A Gottingen GoeMF II tomograph (VIASYS Healthcare, Houten, The Netherlands) was used. Three-minute measurements were taken at 2 and 8 L/min flow rates. Software provided with the equipment was used for data acquisition and reconstruction of functional relative EIT images (25). Data were further analyzed off-line using Matlab 7.7 (R2008b; The MathWorks, Natick, MA). Data Processing and Analysis EIT data were band-pass filtered to include the first and second harmonic of the respiratory rate (26). A cutoff mask of 20% of the peak impedance signal was applied (27) to reduce cardiac interference (28). Regular sections of data were selected for analysis. The following criteria were used to select these periods (29). 1 . Length of 3–5 breaths 2. Regular breathing rate 3. Stable tidal volume and EELV 4. Rejection of the first breath if a respiratory pause preceded the tidal breathing period Measurement of End-Expiratory Level and Regional Ventilation Distribution Changes in EELV at 2 L/min were compared with 8 L/min flow rates for the global, the dependent (posterior), and nondependent (anterior) lung. An example of global EELV change with a switch from “off HFNC” to “on HFNC” is shown in F igure 1. Regional impedance amplitudes were used to describe the magnitude of the regional tidal volume change within an individual over time. Impedance amplitudes for the global, the dependent (posterior), and nondependent (anterior) lung were calculated by averaging the impedance differences in each pixel of the measurement period between the end-expiratory and end-inspiratory periods. To account for the unequal number of pixels analyzed in each region of interest (ROI), the average amplitude for each ROI was reported. A global inhomogeneity (GI) index was also calculated for the entire lung region using a tidal EIT image of the endexpiration to end-inspiration differences of the EIT impedance signal of each image pixel. The GI index is used as an indicator of inhomogeneous ventilation by describing variations in the pixel values of the tidal EIT image (30). The higher the GI value the more ventilation inhomogeneity exists. Measurement of Esophageal Pressure Esophageal pressure (Poe) measurements were taken as an indication of CPAP. To achieve this measurement, the NG tube was connected to a pressure transducer and the in situ NG feeding tube was pulled back to the distal third of the esophagus where it was positioned to achieve a waveform in the range of –5 to 5 kPa that was free from cardiac artifact (31). Feeds were discontinued for the length of the study. To maintain patency of the NG tube, it was flushed with normal saline at a rate of 1 mL/hr. Mouth closure was required for measurements, either spontaneously or with a pacifier. The pressure signal was connected into the EIT equipment to synchronize the signals. Poe was measured at 2 and 8 L/min and measures taken at end inspiration and end expiration. Additionally, we calculated the pressure rate product www.pccmjournal.org
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any equipment adjustment disturbed the breathing pattern of the subject and the quality of the signals. The successfully measured infants had a mean (± sd) age of 3.17 months (± 2.06 mo) and a mean study weight of 4.76 kg (± 1.39 kg), and the study group consisted of six female and seven male infants. HFNC was delivered at an average rate of 1.7 L/kg/min (± 0.26 L/kg/min), whereas standard oxygen delivery at 2 L/min was equivalent to 0.4 L/kg/min. Changes in EELV and Regional Ventilation Distribution Changes in EELV at 2 L/min (off HFNC) were compared with 8 L/min (on HFNC). An example of global EELV change Figure 1. Illustration of the change in end-expiratory level (EEL) measured with electrical impedance tomography on and off high-flow nasal cannula (HFNC). with a switch from off HFNC to on HFNC is shown in Figure 1. The EELV increased significantly on HFNC for the ante(PRP), which was calculated by multiplying the expiratory presrior (nondependent) lung (p = 0.017), and there was a trend sure amplitude with the respiratory rate. A decrease in the PRP toward increased EELV in the posterior and for the global lung, indicates a decrease in the work of breathing. but the change did not reach a significant level (Fig. 2). Similarly to the EELV, the global and regional impedance ampliMeasurement of Physiologic Variables Inspired oxygen (Fio2), respiratory rate (RR), heart rate (HR), tudes were higher on HFNC compared with low-flow nasal and Spo2 were monitored using the Dräger infinity SC800 mon- cannula, but the differences did not reach significance. The GI itoring system (Dräger Medical AG & Co. KG, Lübeck, Ger- index decreased on HFNC compared with off HFNC indicating improved ventilation distribution, but the differences did many) throughout the study. These were manually recorded at the time of each EIT recording. From the collected data, the not reach statistical significance (p = 0.053). Spo2/Fio2 ratio was calculated (32). Statistics Results are described using mean and ses. After testing for normality (Levene’s test), a paired t test was used to compare results. A p value of less than 0.05 was considered significant. All statistical analyses were performed using SPSS (v15.0; Lead Technologies, Chicago, IL). It was the original intention to enroll 20 infants based on pilot trials which showed that 1 L/min air flow causes an increase of continuous distending pressure (CDP) of 2.8 cm H2O (sd, 2.7; n = 9). Using a power of 90% and a p value of less than 0.05, we needed to enroll at least 12 infants. However, due to a change in the circuit available and the unit policy for HFNC use, the study was forced to discontinue after 13 infants were recruited.
RESULTS Patient Characteristics We enrolled 13 patients into the study but could only obtain meaningful EIT and pressure signal readings in 11 infants, as e216
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Measurement of Poe Poe at end expiration increased significantly from –0.2 ± 7.6 cm H2O to 6.9 ± 2.1 cm H2O (p = 0.045). Poe at end inspiration increased only moderately from –1.9 ± 4.8 cm H2O to –0.2 ± 4.8 cm H2O (p = not significant). The PRP decreased from 1,003 ± 214 to 956 ± 138 (p = 0.14) (Fig. 3). Changes in Physiologic Variables RR dropped significantly (p = 0.045) when on HFNC, but there were no other significant differences in the physiological variables such as HR, Fio2, Sao2, and Sao2/Fio2 on and off HFNC. There was a tendency for all of these variables to improve with HFNC (Table 1). Adverse Events There were no adverse events recorded during the study period.
DISCUSSION The main finding of this physiological study was that there were increased end-expiratory Poe associated at HFNC of 8 L/min June 2014 • Volume 15 • Number 5
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Figure 3. Change in esophageal pressure (Poe) (upper panel) and pressure rate product (PRP) (lower panel) on and off high-flow nasal cannula (HFNC). # denotes significant difference for Poe at end expiration (p < 0.05). Figure 2. Change of end-expiratory level (EEL) (upper panel) and global and regional impedance amplitudes (lower panel) measured with electrical impedance tomography on and off high-flow nasal cannula (HFNC). # denotes significant difference for the anterior lung (p < 0.05).
compared with standard flow 2 L/min with a corresponding increase in EELV in the anterior lung and a decrease in respiratory rate. This is the first report documenting a change in EELV in infants with bronchiolitis treated with HFNC. One of the main difficulties in obtaining accurate lung function data on patients on HFNC therapy is that most techniques cannot be used while high flow is delivered. Although there are some data on lung function in ventilated infants with bronchiolitis, little Table 1. Effect of the Flow Rates of 2 and 8 L/min on Physiological Characteristics of the Infants: Mean (se) of Each Intervention Intervention 2 L/min (n = 13)
Outcome
8 L/min (n = 13)
Heart rate (beats/min)
139.9 ± 5.9
134.8 ± 4.5
Respiratory rate (breaths/min)
68.5 ± 6.0
56.9 ± 3.2a
Spo2 (%)
95.6 ± 0.9
97.3 ± 0.6
Fio2
0.42 ± 0.04
0.34 ± 0.02
Spo2/Fio2
251.6 ± 25.9 280.0 ± 20.3
a
Respiratory rate decreased significantly on high-flow nasal cannula of 8 L/min (p = 0.045).
a
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information is currently available for spontaneously breathing infants on HFNC. Despite presenting only a small dataset, our findings are consistent with previous reports on the physiological effect of high flow. Effect of HFNC on Esophagus Pressure We showed that at flow rates of 1.7 L/kg/min, the end-expiratory Poe was significantly higher compared with low-flow oxygen delivery (0.4 L/kg/min). Of particular interest was that the Poe difference between the end-expiratory and end-inspiratory phase of the respiratory cycle was much greater on HFNC than off HFNC (Fig. 3). This effect is best explained with the observation that during the expiratory phase, the unidirectional high flow toward the larynx streams against the expiratory flow of the patient, creating some resistance and positive pressure. During the inspiratory phase, however, the unidirectional flow of the HFNC is in the same direction as the inspiratory flow of the patient, and hence, the observed pressure drops. Although HFNC increases the expiratory pressure, it differs from CPAP during the inspiratory phase. Such differences between inspiratory and expiratory Poe observed during HFNC are not consistent with the definition of CPAP (continuous positive airway pressure) but better described as a positive expiratory pressure. A positive end-inspiratory pressure can only be achieved if the flow of the HFNC is greater than the maximal inspiratory flow of the patient. In our study, we achieved on average 1.7 L/kg/ min high flow and an average inspiratory Poe of approximately zero. Hence, to achieve some positive pressure during the inspiratory phase, even greater flows than 1.7 L/kg/min may need to www.pccmjournal.org
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be delivered. We estimate that 2 L/kg/min may be an adequate flow rate, a flow rate that normally has been used in the past to titrate the circuit flow in a continuous bypass neonatal ventilator. The PRP was only moderately reduced on HFNC, which is not surprising as the PRP is a composite of pressure amplitude and respiratory rate. The pressure amplitude as per Figure 3 increased due to the positive end-expiratory pressure effect of HFNC but the respiratory rate dropped. We may speculate that the flow rate used in our study was not sufficient to decrease the work of breathing significantly. This argument may be supported by the fact that in premature infants, flow rates between 5 and 8 L/min are used to reduce the work of breathing in babies with a body weight of 1,000 g, which is equivalent to 5–8 L/kg/min. Our results are consistent with measurements that have recently been published in infants with bronchiolitis using pharyngeal pressure (33). Another explanation could be that the higher end-expiratory pressure might be splinting the airways open, helping to decrease expiratory airflow limitation. There have been a number of studies investigating the effect of change in airway pressure with increasing flow rates and results have varied markedly with no consensus reached and concerns still related to uncontrolled airway pressure (11, 12, 14, 34–36), which includes air escaping when the mouth is open. An increase in airway pressure is only one of the mechanisms thought to responsible for the positive effects of HFNC. The variation in results in the literature could be because there are alternative mechanisms involved. Other proposed mechanisms include washout of nasopharyngeal dead space, reduction of inspiratory airflow resistance, improved lung mechanics, reduced metabolic work required for gas warming, and humidification (10, 36–38). In situations in which the flow delivered by the oxygen delivery method is lower than the maximal inspiratory flow of the patient, then an air leak around the nasal cannula is needed to entrain air. Similarly during the expiratory phase, an air leak, either via mouth or around the nasal cannula, is mandatory. These leak conditions are absolutely mandatory to be present for the safe use of HFNC. Effect of HFNC on EELV To our knowledge, this is the first study describing changes in EELV in infants with bronchiolitis and on HFNC. The change in EELV in our study was moderate but consistent for all patients. Interestingly, the anterior (nondependent) lung showed the greatest increase. Bronchiolitis per se is associated with hyperinflation and air trapping due to small airway disease. Hence, any further increase of EELV seems surprising. First, any positive airway pressure may recruit previously collapsed alveoli; microatelectasis is one of the main features of bronchiolitis. The CDP then will splint airway passages helping to mitigate the effect of expiratory airflow limitation. These findings mirror those found in a cohort of 20 adults who also demonstrated an increase in global and ventral end-expiratory lung impedance variation when placed on HFNC (39). The global and regional amplitudes were higher on HFNC compared with e218
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low-flow nasal cannula. The GI index as a measure of ventilation inhomogeneity improved; however, the differences did not reach significance (p = 0.053). Limitations The study represents a relatively small number of patients. This was due to difficulties encountered with data collection, particularly with relation to noisy signals obtained from the esophageal monitoring and the EIT. Despite that we have selected measurement techniques which do not interfere with the patients breathing, the investigated infants were disturbed when the esophagus probe was adjusted or the electrodes applied. Since the use of HFNC is becoming more popular in many pediatric hospitals, the understanding of the physiological mechanisms is important. Not all changes that we observed were significant, but they certainly were physiologically plausible. One further limitation of the high-flow use is that the variation of the applied positive airway pressure is greatly affected by air leaks that occur around the nasal cannula and through the mouth. Although EIT measurements in infants are technically challenging with electrode placement difficulties increasing recorded noise, the midthoracic placement of electrodes has been confirmed by MRI to produce impedance values reflective of the entire lung (40). How Can High Flow Be Defined? Based on our findings, adequate flow rates are achieved when increased positive expiratory Poe were observed and potentially even positive airway pressures during the inspiratory phase. The measurement of Poe for the titration of high flow is clinically too cumbersome, similarly to the routine use of EIT. Based on our and other recent studies, flow rates of greater than 1.7 L/min/kg, probably for ease of use 2 L/kg/min, should be discussed. These flow rates, however, should be tested in larger studies and investigated whether any benefit can be observed. We cannot yet provide any suggestions to the upper limits of flow rates, but based on our own experience and a just recently finished pilot study (41), flow rates of 2 L/kg/min for infants with bronchiolitis are well tolerated. Artificial limitations of the flow delivery systems have in the past limited the investigation of higher flow rates.
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