Using NAVA titration to determine optimal ventilatory support in neonates

The University of Toledo The University of Toledo Digital Repository Master s and Doctoral Projects Using NAVA titration to determine optimal ventilatory support in neonates Stacey Leigh Fisher The University of Toledo Follow this and additional works at: http://utdr.utoledo.edu/graduate-projects This Scholarly Project is brought to you for free and open access by The University of Toledo Digital Repository. It has been accepted for inclusion in Master s and Doctoral Projects by an authorized administrator of The University of Toledo Digital Repository. For more information, please see the repository's About page.

Using NAVA Titration to Determine Optimal Ventilatory Support in Neonates Stacey Leigh Fisher The University of Toledo 2012

ii Dedication This project is dedicated to everyone who has supported me throughout this incredible journey over the past 3 years. I could not have done it without the immense love and encouragement from my family and friends.

iii Acknowledgements First, I would like to thank my advisor Howard Stein, M.D. for his expertise, patience and enthusiasm throughout this project. I would also like to thank Donald White, Ph.D. and Samantha Meiers for their help with the statistical portion of this project. Finally, I would like to thank my friend and fellow student researcher Shanti Reddy for her continued support and guidance over the past year.

iv Table of Contents Introduction...1 Materials & Methods...4 Results...6 Discussion...8 Conclusion...11 References...12 Tables...13 Figures...14 Abstract...23

v List of Figures Figure 1 - Edi and peak pressure data demonstrating the Breakpoint...14 Figure 2 - Composite data of all patients on NAVA and NIV NAVA during the titration trial...15 Figure 3 - Composite data of all patients on NAVA during the titration trials...16 Figure 4 - Composite data of all patients on NIV NAVA during the titration trials...17 Figure 5 - Correlation between the calculated Breakpoint and the NAVA level...18 Figure 6 - Average Heart Rate and Mean Blood Pressure at each NAVA Level...19 Figure 7 - Average Oxygen Saturation, Respiratory Rate and Fraction of Inspired Oxygen at each NAVA level...20 Figure 8 - Average number of switches to backup ventilation...21 Figure 9 - Average percent of time spent in backup ventilation per minute...22

1 Introduction There are several modes of mechanical ventilation that serve to synchronize the patient s respiratory effort with mechanical ventilatory support. In conventional ventilation, the patient s inspiratory effort generates airway pressure to trigger a mechanical breath using a flow trigger. Pressure support ventilation (PSV) delivers a fixed peak pressure with variability in the tidal volume generated whereas volume ventilation delivers a fixed tidal volume with variability in the peak inspiratory pressure. These variations are not patient directed, but rather dependent upon breath-to-breath fluctuations in lung compliance (Sinderby, 2002). PSV is commonly used for adult ventilation, however, in the neonatal and pediatric ICU populations, it has been found to result in an increased peak inspiratory pressure (PIP) and result in less effective patient-ventilator synchrony when compared with other forms of ventilation (Breatnach, Conlon, Stack, Healy, & O'Hare, 2010) Neurally adjusted ventilator assist (NAVA) capitalizes on varying electrical activity of the diaphragm (Edi) to provide patient directed mechanical breath support. The central nervous system adjusts the strength of the electrical signal to generate breath-to-breath variations in tidal volume. A transesophageal electrode carefully positioned at the level of the crural diaphragm detects this fluctuating Edi. In conjunction with a healthcare provider-determined NAVA level, the Edi directs the ventilator to deliver varying airway pressures (Allo et al., 2006) and (Sinderby et al., 2007). This neural trigger is based on the patient s ventilatory need in contrast to the flow trigger which is based on the patient s respiratory effort. This improves patient-ventilator physiologic synchrony and prevents damage, such as over-inflation of the lungs due to delivery of excessive ventilator pressure or atelectasis due to delivery of inadequate airway pressure (Sinderby, 2002).

2 Determining the Appropriate NAVA Level Since the Edi in correlation with the NAVA level controls the NAVA ventilator support, the subject can control the delivered pressure through a neural feedback mechanism when the NAVA level is changed. As the NAVA level is increased the patient can either maintain the Edi, which translates to increased peak airway pressure (PP), or the patient can decrease Edi, which maintains the PP. Adult and animal studies demonstrate that systematically increasing the NAVA level initially increases peak pressure, PP, and tidal volume while maintaining a constant Edi. This is termed the first response, where respiratory muscles are inadequately unloaded. Ultimately, additional increases in NAVA level reduce respiratory drive, lowering the Edi, while the PP plateaus. This level is called the breakpoint (BP) or NAVA adequate level (Figure 1 (Stein & Firestone, 2012)). The BP is a unique value to each individual. In adults this systematic approach to setting the NAVA level offers a method to determine an appropriate assist level that results in sustained respiratory muscle unloading (Brander, Leong-Poi, Beck, Brunet, Hutchison, Slutsky, & Sinderby 2009) and (Spahija et al., 2010). NAVA level titration has previously been studied in rabbits with acute lung injury (Beck et al., 2007) and critically ill adult patients with hypoxemic respiratory failure (Brander et al., 2009). These studies conclude that by systematically increasing the NAVA level the adequate level, or breakpoint, of inspiratory muscle unloading can be determined. It is unknown if premature neonates are able to achieve this respiratory muscle unloading or if they exhibit a comparable BP to adults. There has been one reported observation of the BP occurring in premature neonates (Figure 1 (Stein & Firestone, 2012)) In neonates the NAVA level is currently determined clinically based on work of breathing and vital signs. This study is aimed to determine if premature neonates demonstrate respiratory muscle unloading and if they

3 show a BP. A secondary aim was to determine the correlation between the clinically determined NAVA level and the adequate NAVA level as determined by the BP.

4 Materials & Methods This was a prospective, one factoral, repeated measures, case series study conducted in the NICU at Toledo Children s Hospital and Akron Children s Hospital between February 2012 and June 2012. Both hospitals Institutional Review Boards approved the study and parental consent was obtained prior to performing the trials. The study population included neonates who were already stabilized and ventilated on NAVA or non-invasive (NIV)-NAVA. All neonates were ventilated with a Servo-I ventilator (MAQUET, Solna, Sweden). Before beginning each trial, information about the each of the patients characteristics was recorded including current NAVA level, FiO 2 level, birth weight and current weight, gestational age and current age, prenatal diagnosis, 1 minute and 5 minute Apgar score and reason for delivery. Also documented were the use of surfactant, use of maternal steroids and method and reason for delivery, as well as the patient s baseline heart rate, oxygen saturation, and mean blood pressure. Titration Protocol The NAVA level was initially reduced to 0.5 mcv/cmh 2 O for three minutes to inadequately unload the neonate s respiratory muscles. The NAVA level was then increased incrementally by 0.5 mcv/cmh 2 O every three minutes until reaching a maximum NAVA level of 4.0 mcv/cmh 2 O over 24 minutes. Heart rate and oxygen saturation were recorded every 30 seconds from the bedside monitor. Mean blood pressure (MBP) was measured at the end of each three-minute interval. After the titration was completed each neonate was returned to his or her prior NAVA level. Trial data was downloaded directly from the NAVA ventilator immediately after the conclusion of the trial and loaded into a Microsoft Excel program for analysis. Values recorded

5 on a breath by breath basis for the duration of the trial included the NAVA level (independent variable) and the dependent variables, PP, Edi peak, Edi minimum, respiratory rate (RR), the number of times per minute that the neonate switched to a backup ventilation mode and the percentage of each of minute that the neonate spent in the backup ventilation mode. Tidal volume (TV) was only measured for the intubated NAVA trials. The ventilator delivers a PP calculated from the Edi according to the formula PP (above PEEP) = NAVA level x (Edi Peak Min). This Edi Peak Min (abbreviated as Edi) was used for all statistical analysis. All variables were averaged over each three-minute interval. Statistical Analysis A non-linear regression with grid search was performed by Statistical Analysis System (SAS, Cary, NC). Prior to statistical analysis, constraints were placed on the slope of each line of the dependent variable so that the slope of the first phase ascent could not be greater than the slope of the second phase plateau. Each variable was averaged for each NAVA level, plotted on a graph, and then a line of best fit was added. The BP was determined by the intersection of the 2 lines. The data from the studies were then combined by averaging each variable at the BP and then for each change in NAVA level above and below the BP. Linear regression was done to look for differences in HR, MBP, Oxygen Saturation, the number of times per minute that the neonate switched to a backup ventilation mode and the percentage of each of minute that the neonate spent in the backup ventilation mode. The correlation coefficient between clinical NAVA level and BP was calculated by determining the best fit by the least squares method.

6 Results A total of 19 premature neonates were recruited for this study, totaling 26 trials. Eleven trials were completed on NAVA and 15 on NIV-NAVA. Seven neonates had trials on both NAVA and NIV-NAVA. Average birth weight was 1033 + 744 grams (range 380 grams to 3395 grams). The neonates weighed 1064 + 694 grams (range 490 grams and 3280 grams) at the time of the trial. Average gestational age was 27.6 + 3.5 weeks (range 24 weeks to 36 weeks) and their average age at the time of the trial was 13 + 11 days (range 1 to 39 days). Neonatal diagnoses are described in Table 1. Seventy nine percent were exposed to maternal steroids. Eighteen of the neonates were delivered by Cesarean section leaving only one being delivered by spontaneous vaginal delivery. Reasons for delivery can be found in Table 2. One minute Apgar score average was 3, with a range from 1 to 9, while the 5-minute Apgar average was approximately 7, ranging from 3 to 9. Thirteen of the neonates were given surfactant, 4 were given 2 doses and 2 patients did not receive any surfactant. NAVA and NIV-NAVA setting were comparable with a NAVA level that ranged from 1-3.5 mcv/cmh 2 O, PEEP 5 cm H 2 O, apnea time 3-5 sec, PP alarm 35 cmh 2 O, Edi Trigger 0.5 mcv and variable backup settings determined by the treating physician. All settings, except NAVA level and FiO2, were kept constant throughout the trial. Figure 2 shows the composite data from the neonates on NAVA and NIV-NAVA during the titration trial. All the data was normalized to the breakpoint (BP). At NAVA levels below the BP (BP-2 to BP-0.5), the PP and TV increased as NAVA level increased until the BP was reached. There were no further increases in PP with increases in NAVA level above the BP (BP+0.5 to BP+2). The Edi remained constant at NAVA levels below the BP until the BP was reached and then decreased with increases in the NAVA level above the BP. A similar response

7 was seen with neonates when divided into neonates on NAVA (Figure 3) and neonates on NIV- NAVA (Figure 4). Tidal volume measurements were not available for neonates on NIV-NAVA because of the inability to accurately measure tidal volumes non-invasively. Figure 5 shows the lack of correlation between clinical NAVA level and the optimal NAVA level as determined by the BP. Average heart rate and mean blood pressure for each NAVA level remained stable for the duration of the trial as shown in Figure 6. Oxygen saturation, RR and Fraction of Inspired Oxygen (FiO2) also remained stable throughout the trials (Figure 7). The average number of switches to backup per minute (Figure 8) was unchanged throughout the trial study. However, the percentage of time spent in backup per minute (Figure 9) was higher at the lower and higher NAVA levels compared to the middle of the titration trial but did not meet statistical significance (p = 0.06). No adverse patient events were noted during the studies.

8 Discussion This is the first study to show that premature neonates exhibit a response to increasing ventilatory support similar to that seen in adults. In all 26 of the trials, a BP was able to be determined, which demonstrated that as the NAVA level was systematically increased, the PP and TV increased until the respiratory muscles were adequately unloaded. At NAVA levels below the BP, the respiratory muscles were inadequately unloaded and the premature neonates needed to maintain a stronger respiratory drive reflected by a higher Edi. Increasing the NAVA level increased the amount of respiratory support and met the demands of this respiratory drive by providing higher PP and TV. At the BP, the neonate s respiratory demands were being met and any increases in NAVA level above the BP resulted in a decrease in respiratory drive (decrease in Edi) and no further increases in PP or TV. These findings are similar to others who showed that increasing the NAVA level could incrementally unload the diaphragm of rabbits with acute lung injuries and critically ill adults and simultaneously decrease the Edi (Ververidis, Van Gils, Passath, Takala, & Brander, 2011) and (Beck et al., 2007). There was no reliable way to measure TV in neonates on NIV-NAVA due to large leaks around the nasal interface. PP were also less reliable due to variable leaks and do not reflect transpulmonary pressures in the same way that PP would in intubated neonates. Despite these limitations, these findings were observed during both invasive and non-invasive ventilation. We anticipated that at NAVA levels below the BP, when the neonates were inadequately unloaded, we would see inadequate respiratory drive resulting in more switches to backup and more time in backup. We also anticipated an increase in RR and decreased Oxygen Saturation from lack of adequate respiratory support and an inability of the premature neonate to generate enough respiratory support themselves. Although there was small increase in time in backup

9 ventilation, all other variables remained stable. This was most likely due to the brief amount of time at low levels (3 minutes) and the anticipated changes may have become more evident if the neonates had remained at low levels of ventilatory support for longer periods. At high NAVA levels we anticipated a suppression of the respiratory drive and an increase in switches to backup and more time in backup ventilation. Although there was no increase in the switches to backup, there was an increase in the amount of time in backup that may reflect a decrease in sustained respiratory drive from over support. However, these results were most likely complicated by our premature patient population having baseline respiratory variability and apneas resulting in an increase in events even when adequately unloaded on NAVA. It may take a patient population with a more mature respiratory drive, such as older children or adults to show increases in number of switches to backup, and amount of time in backup with over or under ventilatory support. Heart Rate, RR, MBP and Oxygen Saturation remained stable throughout the trials even during the periods of inadequate and over ventilatory support. This was not surprising because the apnea time was set between short enough to not allow any of the neonates to experience respiratory pauses long enough to show any clinical deterioration with NAVA levels that were too low or too high. There was no correlation between the clinically set NAVA level and the calculated BP and this study does not give any insight as to which method is the most accurate to use clinically. All neonates enrolled in the study were clinically stable both prior to initiation and after completion of the titration trial. The clinician set the NAVA level to patient comfort prior to initiation of the titration trial. In other words, the neonate appeared comfortable without being fully unloaded (NAVA level set below the BP) or when being a little over assisted (NAVA level

10 set above the BP). It appears that there is a range of NAVA levels around the physiologic BP that result in acceptable clinical ventilatory assistance to the neonate. This was further reinforced by the stability in cardio-respiratory parameters like RR, FiO2, Oxygen Saturation, HR and MBP as NAVA level was changed. The primary limitation of the study was the inability to measure transpulmonary pressures to determine exactly what pressure was reaching the neonates lungs. This was especially true with NIV-NAVA where there was a large leak at the nasal interface. Other limitations include the inability to account for intrinsic respiratory variability seen in premature neonates and the inability to account for disease state or gestational age. NAVA level was changed every 3 minutes so certain variables that may take time to change (like RR or MBP) would not have had enough time to equilibrate.

11 Conclusion This study shows that in a population of preterm neonates ventilated on NAVA or NIV- NAVA, a distinct pattern of respiratory unloading can be seen as the NAVA level is incrementally increased. The ventilator provided more support as the NAVA level increased until the neonate s respiratory drive was met with adequate ventilatory pressure delivery. Further increases in the NAVA level resulted in stable pressure delivery and a decrease in the respiratory drive. There was no correlation between the clinically determined NAVA level and the calculated BP in addition to no changes in RR, FiO2, Oxygen Saturation, HR or MBP with changing NAVA level suggesting that the clinician has some leeway in choosing a NAVA level when titrating to patient comfort.

12 References Allo, J. C., Beck, J. C., Brander, L., Brunet, F., Slutsky, A. S., & Sinderby, C. A. (2006). Influence of neurally adjusted ventilatory assist and positive end-expiratory pressure on breathing pattern in rabbits with acute lung injury. Crit Care Med, 34(12), 2997-3004. Beck, J., Campoccia, F., Allo, J. C., Brander, L., Brunet, F., Slutsky, A. S., & Sinderby, C. (2007). Improved synchrony and respiratory unloading by neurally adjusted ventilatory assist (NAVA) in lung-injured rabbits. Pediatr Res, 61(3), 289-294. Brander, L., Leong-Poi, H., Beck, J., Brunet, F., Hutchison, S. J., Slutsky, A. S., & Sinderby, C. (2009). Titration and implementation of neurally adjusted ventilatory assist in critically ill patients. Chest, 135(3), 695-703. Breatnach, C., Conlon, N. P., Stack, M., Healy, M., & O'Hare, B. P. (2010). A prospective crossover comparison of neurally adjusted ventilatory assist and pressure-support ventilation in a pediatric and neonatal intensive care unit population. Pediatr Crit Care Med, 11(1), 7-11. Sinderby, C. (2002). Neurally adjusted ventilatory assist (NAVA). Minerva Anestesiol, 68(5), 378-380. Sinderby, C., Beck, J., Spahija, J., de Marchie, M., Lacroix, J., Navalesi, P., & Slutsky, A. S. (2007). Inspiratory muscle unloading by neurally adjusted ventilatory assist during maximal inspiratory efforts in healthy subjects. Chest, 131(3), 711-717. Spahija, J., De Marchie, M., Albert, M., Bellemare, P., Delisle, S., Beck, J., & Sinderby, C. (2010). Patient-ventilator interaction during pressure support ventilation and neurally adjusted ventilatory assist. Crit Care Med, 38, 518-526. Stein, H.M., & Firestone, K.S. (2012). Nava ventilation in neonates: Clinical guidelines and management strategies. Neonatology Today, 7(4), 1-8. Ververidis, D., Van Gils, M., Passath, C., Takala, J., & Brander, L.. (2011). Identification of adequate neurally adjusted ventilatory assist (NAVA) during systematic increases in the NAVA level. IEEE Trans Biomed Eng, 58(9), 2598-2606.

13 Tables Table 1. Neonatal Diagnosis Number of Patients Respiratory Distress Syndrome 9 Pulmonary Insufficiency of Prematurity 7 Pneumonia 2 PPHN 1 PPHN = Persistent Pulmonary Hypertension of the Newborn Table 2. Reason for Delivery Number of Patients Decelerations 5 Preterm Labor and Breech Positioning 4 Pregnancy Induced Hypertension 2 Chronic Hypertension 2 PPROM and Chorioamnionitis 2 Premature Rupture of Membranes 1 Abruption 1 Poor Fetal Heart Tones 1 Eclampsia 1 PPROM = Preterm Premature Rupture of Membranes

14 Figures Figure 1. Edi and peak pressure data from a 3 week old premature infant demonstrating the Breakpoint. (From Stein and Firestone, 2012, Neonatology Today. Reprinted with permission.)

Figure 2. Composite data of all patients on NAVA and NIV NAVA during the titration trial. BP breakpoint, BP+ - levels above the breakpoint, BP- - levels below the breakpoint. Peak pressure increased with increasing NAVA levels (mcv/cmh2o) until the breakpoint and then there were no further increases. Edi decreased after the breakpoint was reached. 15

Figure 3. Composite data of all patients on NAVA during the titration trials. BP breakpoint, BP+ - levels above the breakpoint, BP- - levels below the breakpoint. Both peak pressure and tidal volume increased with increasing NAVA levels (mcv/cmh2o) until the breakpoint and then there were no further increases. Edi decreased after the breakpoint was reached. 16

Figure 4. Composite data of all patients on NIV NAVA during the titration trials. BP breakpoint, BP+ - levels above the breakpoint, BP- - levels below the breakpoint. Peak pressure increased with increasing NAVA levels (mcv/cmh2o) until the breakpoint and then there were no further increases. 17

Figure 5. Scatter plot showing the lack of correlation between the calculated breakpoint (mcv/cmh2o) with the NAVA level (mcv/cmh2o) set clinically by the treating physician. The blue line represents a corrleation of 1. 18

Figure 6. Average Heart Rate (HR) and Mean Blood Pressure (MBP) at each NAVA Level. 19

Figure 7. Average Oxygen Saturation (O2 Sat), Respiratory Rate (RR) and Fraction of Inspired Oxygen (FiO2) at each NAVA level. 20

Figure 8. Average number of switches to backup. N-Clin designates the NAVA level determined by treating physician. N-0.5 is the NAVA level 0.5 below the clinically determined NAVA level, decreasing incrementally to N-2. N+0.5 is the NAVA level 0.5 above the clinically determined NAVA level, increasing incrementally to N+2. 21

Figure 9. Average percent of time spent in backup per minute. N-Clin designates the NAVA level determined by treating physician. N-0.5 is the NAVA level 0.5 below the clinically determined NAVA level, decreasing incrementally to N-2. N+0.5 is the NAVA level 0.5 above the clinically determined NAVA level, increasing incrementally to N+2. 22

23 Abstract Objective: To determine if a Breakpoint is able to be seen in a population of neonates on NAVA and NIV NAVA and whether the clinically determined NAVA level (CN) correlates with the calculated Breakpoint. Method: NAVA level was increased by 0.5 mcv/cmh 2 O each 3 minutes from a level of 0.5 to 4.0 mcv/cmh2o. Peak pressure (PP), Edi and Tidal Volume (TV) were analyzed. Mean blood pressure, heart rate, respiratory rate, oxygen saturation and FiO 2 were recorded. Results: Nineteen neonates were recruited, totaling 26 trials. 11 trials were on NIV NAVA and 15 on NAVA. PP and TV increased until the Breakpoint and then there were no further increases. Edi decreased after the Breakpoint was reached. All other measured variables were unchanged. There was no correlation between the CN and Breakpoint. Conclusion: Premature neonates exhibit a breakpoint correlating with adequate respiratory muscle unloading. The CN level did not correlate with the Breakpoint.