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The Journal of Maternal-Fetal & Neonatal Medicine

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High frequency jet ventilation in preterm infants:experience from Western Australia

Ajay P. Anvekar, Piyush S. Shah, Elizabeth A. Nathan, Dorota A. Doherty,Sanjay K. Patole & Karen N. Simmer

To cite this article: Ajay P. Anvekar, Piyush S. Shah, Elizabeth A. Nathan, Dorota A. Doherty,Sanjay K. Patole & Karen N. Simmer (2018): High frequency jet ventilation in preterm infants:experience from Western Australia, The Journal of Maternal-Fetal & Neonatal Medicine, DOI:10.1080/14767058.2018.1449827

To link to this article: https://doi.org/10.1080/14767058.2018.1449827

Published online: 20 Mar 2018.

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ORIGINAL ARTICLE

High frequency jet ventilation in preterm infants: experience fromWestern Australia

Ajay P. Anvekara, Piyush S. Shaha, Elizabeth A. Nathanb,c, Dorota A. Dohertyb,c, Sanjay K. Patolea,d andKaren N. Simmera,d

aDepartment of Neonatal Paediatrics, King Edward Memorial Hospital for Women, Perth, Australia; bWomen and Infants ResearchFoundation, KEM Hospital for Women, Perth, Australia; cDivision of Obstetrics and Gynaecology, University of Western Australia,Perth, Australia; dCentre for Neonatal Research and Education, University of Western Australia, Perth, Australia

ABSTRACTObjective: To assess if high frequency jet ventilation (HFJV) is associated with reduced odds ofdeath or discharge home on oxygen in preterm infants.Methods: A case control study (1 February 2010 – 1 June 2014) comparing the primary outcomeas “death or discharge home on oxygen” in preterm infants who needed HFJV (Cases) versusthose who did not (Controls). Controls were matched to cases (1:1) on gestation, birthweight,gender, place of birth, growth status, antenatal glucocorticoids, and dexamethasone astreatment for severe bronchopulmonary dysplasia (BPD). Logistic regression analysis was used tocontrol for confounders.Results: Data on all preterm infants who needed HFJV (Cases: n¼ 50) and 50 controls duringthe study period were analysed. Primary outcome was more frequent in cases versus controls,but not significant after adjusting for mean airway pressure and adjuvant therapy (e.g. diuretics)[aOR: 1.46 (0.23–9.14), p¼ .687]. Death before discharge [odds ratios (OR): 6.00 (1.34–55.2),p¼ .013] was more frequent in cases; discharge on home oxygen [OR: 0.88 (0.27–2.76),p¼ 1.000] was comparable between groups. Duration of oxygen [adjusted hazard ratios (aHR):1.23 (0.69–2.17), p¼ .475] and incidence of treatment warranting retinopathy of prematurity[aOR: 0.10 (0.01–1.96), p¼ .127] was not significant between cases versus controls.Conclusions: HFJV was not associated with reduced odds of death or discharge home onoxygen in preterm infants in our study. Adequately powered randomized trials are required toassess the efficacy and safety of HFJV in preterm infants.

ARTICLE HISTORYReceived 27 December 2017Accepted 5 March 2018

KEYWORDSInfants; high frequency; jetventilation; preterm;bronchopulmonarydysplasia

Introduction

Bronchopulmonary dysplasia (BPD) is a significantissue in preterm infants with gestation <32 weeks.BPD affects �25% of preterm very low birth weight(VLBW:< 1500 g) infants and 68% of those bornbetween 22 and 26 weeks’ gestation [1,2]. It is charac-terised by heterogeneous aeration with poorly sup-ported, floppy airways, pulmonary inflammation,interstitial oedema, and air trapping [1]. BPD isassociated with significant mortality and morbidityincluding long-term neurodevelopmental delay [1,2].Conventional strategies such as antenatal glucocorti-coids [3], early surfactant therapy [4], early extubation,and support with continuous positive airway pressure(CPAP) [5] have had limited success in preventing BPD.Avoiding mechanical ventilation or adopting gentleventilation strategies to minimise ventilator-induced

lung injury, and optimising nutrition are important forpreventing BPD.

High frequency jet ventilation (HFJV) is a uniquestrategy for management of preterm neonates withrespiratory distress, who are at high risk for developingBPD. The principles of HFJV relate to the observationthat panting animals breathe effectively using smalltidal volumes because of transitional airflow pattern[6]. The nozzle of the HFJV produces very brief, highvelocity transitional inspiratory breaths allowing thefresh gas to go close to the alveoli; penetrating thedead space gas and making smaller tidal volumeseffective using low pressures [7]. Optimal positive endexpiratory pressure (PEEP) during HFJV prevents alveolifrom collapsing or over distention for gas exchange[8]. Passive exhalation, mucociliary clearance, and abil-ity to reach injured lung parenchyma are advantagesof HFJV over high frequency oscillatory ventilation

CONTACT Ajay Anvekar ajayanvekar@yahoo.co.in Department of Neonatal Paediatrics, KEM Hospital for Women, 374 Bagot Road, Subiaco,Western Australia� 2018 Informa UK Limited, trading as Taylor & Francis Group

THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE, 2018https://doi.org/10.1080/14767058.2018.1449827

(HFOV) [7]. The first randomised controlled trial (RCT)comparing HFJV versus conventional mechanical venti-lation (CMV) was reported by Carlo et al. in 1987 [9].Life pulse HFJV was approved by the US Food andDrug Administration for clinical use since 1988 [7].HFJV, compared with CMV or HFOV, improves gasexchange and facilitates weaning from ventilation inpreterm infants with evolving BPD [10]. It is importantto note that despite its potential benefits; currentlythere is no evidence of superiority of HFJV or HFOVfor long-term outcomes in preterm infants withrespiratory distress.

Our unit annually admits �500 preterm infantsborn <32 weeks, including 100–110 born <28 weeks,who are at high risk for severe lung disease progress-ing to BPD. HFJV was introduced in our neonatal unitin 2010 as a rescue therapy for preterm infants withsevere lung disease indicating evolving BPD. Extensiveeducation sessions were conducted for the staff priorto its introduction. Based on its potential benefits, weaimed to assess if HFJV was associated with reducedodds of death or discharge home on oxygen (a markerof severe BPD) in preterm infants.

Materials and methods

Design and setting

A case control study in a tertiary level neonatal inten-sive care unit (NICU).

Participants

All preterm infants admitted between February 2010and June 2014, were eligible for participation. Casesand controls were defined as preterm infants who didversus who did not need HFJV (exposure of interest),respectively, during the study period. For each case, acontrol was selected matching for gestation, birth-weight, gender, place of birth, growth status, antenatalglucocorticoid exposure, and postnatal dexamethasoneas treatment for severe BPD. Postnatal dexamethasonewas used to match severity of the lung disease incases versus controls. Exclusion criteria included pres-ence of congenital anomalies or critical car-diac conditions.

Outcomes

The primary outcome was the composite of “deathbefore discharge or discharge on home oxygen”.Secondary outcomes included death before discharge,discharge on home oxygen, duration of mechanical

ventilation, CPAP, and oxygen requirement, andretinopathy of prematurity (ROP) needing treatment.All outcomes were recorded from admission till deathor discharge home from the unit.

Ethics approval

Approval from the institutional ethics committee(GEKO7426) was obtained before commencingthe study.

Data collection

Data were collected from the medical notes using astandardised, prepiloted data collection form.Demographic data included antenatal risk factors,antenatal glucocorticoids, place of birth, gestation,birth weight, gender, growth status, mode of delivery,Apgar scores, and resuscitation at birth. Outcome dataincluded ventilatory support during the NICU stay,adjuvant therapies for BPD (e.g. postnatal dexametha-sone, diuretics, pentoxifylline), treatment for patentductus arteriosus, inhaled nitric oxide (INO) for pul-monary hypertension, and findings such as intraven-tricular haemorrhage (IVH) on head scans. Severity oflung disease was assessed by the hourly recorded dataon mean airway pressure (MAP) for 7 days before theinfant went on HFJV. Recording only the peak MAPvalue over the 1-week period before commencingHFJV was considered unreliable in reflecting the trueseverity of the underlying lung condition. For eachcase, the matched control had their MAP recorded for7 days before the postnatal age when the case wenton to need HFJV. Diuretics and pentoxifylline wereconsidered as adjuvant therapy and used in adjustingfor severity of lung disease.

Guidelines for management of respiratory distress

Respiratory distress syndrome (RDS) was managedusing bubble CPAP (Infant Prongs, Hudson RCITM, CA);Bubble Flow, Fisher & Paykel Healthcare, NZ) and/ormechanical ventilation in preterm infants. CPAP failurewas defined as the need for CPAP of �6 cmH20 andoxygen >30% to maintain target saturation of 92–95%and/or persistence of arterial blood pH <7.2with arterial partial pressure of carbon dioxide(PaCO2)> 60mmHg, or worsening respiratory acidosis.CPAP failure was treated with mechanical ventilationand surfactant (100mg/kg/dose, maximum 2 doses).Caffeine was administered routinely to all preterminfants with gestation <32 weeks. All infants withrespiratory distress were managed using arterial or

2 A. P. ANVEKAR ET AL.

capillary blood gases. Permissive hypercapnia(PCO2> 55mm of Hg) was accepted if pH is >7.2. INOwas used to improve oxygenation in cases with severerespiratory failure with pulmonary hypertension diag-nosed by echocardiography. Inhaled pentoxifylline, sys-temic dexamethasone, and diuretics were used asadjuvant therapies for BPD as per the unit guidelines.Inhaled pentoxifylline is used when oxygen needs are>30% after the first week of life in infants whoneeded mechanical ventilation and surfactant therapyfor respiratory distress after birth. Dexamethasone anddiuretics were used when oxygen needs are >70%after 4 weeks of life.

Conventional ventilatory support

The Drager Babylog 8000þ ventilator (Dr€ager,Lu€abeck, Germany) was used for CMV. The primaryCMV modality was synchronised intermittently positivepressure ventilation (SIPPV) with volume guarantee(VG) of 4–6mL/kg/breath.

Approach to HFJV

This mode of ventilation was offered as an early rescueusing the Life Pulse High Frequency Jet Ventilator,Bunnell Incorporated, Salt Lake City, UT). HFJV was ini-tiated for severe lung disease indicated by the

presence of air leaks (pulmonary interstitial emphy-sema (PIE)/pneumothorax) and/or failure to respond toCMV or HFOV with (1) Oxygenation failure: MAP�10 cm H2O despite surfactant therapy and oxygen>30% and/or (2) Ventilation failure: worsening respira-tory acidosis with PaCO2> 45 and pH <7.2 at tidal vol-ume 4–6mL/kg/breath. The general approach to HFJVin the presence of homogeneous or nonhomogeneouslung disease or air-leaks was based on the unit proto-col (Figure 1). Briefly, HFJV was commenced initially ata rate of 240 breaths/min, inspiratory time0.02 seconds, PEEP, and peak inspiratory pressures(PIP) to achieve an adequate tidal volume and main-tain MAP at least at the setting before change fromCMV to HFJV. High volume strategy was used for lungrecruitment during HFJV.

Statistical approach

Continuous data were summarised with medians andinterquartile ranges (IQR), and categorical data as fre-quency distributions. Comparisons of continuous databetween matched case-control pairs were made usingthe Wilcoxon signed-rank test and categorical compari-sons were made using the McNemar test. Time toevent data, including duration of ventilation, CPAPand oxygen requirement were summarised univariatelyusing Kaplan–Meier survival estimates and the log

Figure 1. HFJV unit protocol. Adapted from http://www.bunl.com/index.html. HFJV: High frequency jet ventilation; CV:conventional; PEEP: positive end expiratory pressure; PIP: peak inspiratory pressure; FiO2: fractional inspired oxygen; IT: inspiratorytime; MAP: mean airway pressure.

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rank test, with deaths before discharge censored foranalysis. Conditional logistic regression analysis wasused to assess the effects of exposure to HFJV on thea priori composite outcome of home oxygen or deathbefore discharge, and categorical secondary outcomesincluding treatment for ROP. Exact estimation methodswere used on outcomes with rare events such asdeath and ROP treatment. Cox proportional hazardregression incorporating a random effect for matchedpairs was used to assess the impact of exposure toHFJV on duration of ventilation, oxygen, and CPAP.Adjustment for MAP and adjuvant therapy (diureticsand/or pentoxifylline) as indicators of severity of lungdisease was made in multivariable modelling.Univariate and adjusted effects were summarised asodds ratios (OR), adjusted OR (aOR), hazard ratios (HR)and adjusted hazard ratios (aHR), and 95% confidenceintervals (CI). IBM SPSS 20.0 statistical software (IBMCorp, Armonk, NY) and Stata 12 statistical software(Stata Corp, College Station, TX) were used for dataanalysis. p values <.05 were considered as statisticallysignificant.

Results

All 50 cases managed over the study period, werecompared to 50 controls matched for gestation, birth-weight, gender, place of birth, growth status, antenatalglucocorticoid exposure, and postnatal dexamethasoneas treatment for BPD.

Cases were less likely to have adjuvant therapy(62% cases versus 80% controls, p¼ .035) and ROPrequiring treatment (8 versus 26%, p¼ .035), and were

more likely to have a higher MAP (Medians: 10 versus7.6, p< .001) and oxygen (Medians: 42.5 versus 29.8%,p< .001). Other demographic and clinical characteris-tics were comparable between cases and controls(Table 1).

Univariately, deaths before discharge were higheramong cases (24 versus 4%, OR: 6.00, 95%CI:1.34–55.2, p¼ .013), proportion of infants dischargedhome on oxygen was similar (34% cases versus 36%controls, OR: 0.88, 95%CI: 0.27–2.76, p¼ 1.000), andthe composite outcome of death or home oxygen wasmarginally higher among cases (58 versus 40%, OR:3.25, 95%CI: 1.00–13.68, p¼ .049) (Table 2). Afteradjustment for MAP and adjuvant therapy, the com-posite outcome was not significantly different betweencases and controls (aOR: 1.46, 95%CI: 0.23–9.14,p¼ .687) (Table 3).

Of the secondary outcomes assessed, cases were athigher risk of longer ventilation times both univariately(Medians: 776 versus 493 hours, HR: 2.04, 95%CI:1.28–3.33, p¼ .003) and after adjustment for MAP andadjuvant therapy (aHR: 1.82, 95%CI: 1.04–3.13,p¼ .037). The duration of CPAP was shorter amongcases in the adjusted analysis (938 versus 1269 hours,aHR: 0.56, 95%CI: 0.30–1.04, p¼ .065); but not statistic-ally significant. Duration of oxygen did not differbetween cases and controls. While cases had a lowerincidence of ROP needing treatment on univariate ana-lysis (8 versus 26%, OR: 0.25, 95%CI: 0.07–0.89,p¼ .032), there was no difference after adjustment forduration and level of oxygen (%) need (aOR: 0.10,95%CI: 0.01–1.96, p¼ .127) (Table 3).

Table 1. Demographic and clinical characteristics.Cases N¼ 50 Controls N¼ 50 p value

Gestational age (w) 25.9 (24.9–28.4) 25.5 (24.2–28.2) .899Birthweight (g) 795 (635–1190) 765 (640–1106) .220Male gender 30 (60%) 28 (56%) .839Any antenatal glucocorticoida 46 (92%) 43 (92%) 1.000Complete antenatal glucocorticoida 39 (78%) 32 (64%) .180Inborn 48 (96%) 47 (94%) 1.000Intrauterine growth restriction 11 (22%) 10 (20%) 1.000Caesarean delivery 32 (64%) 35 (70%) .629Apgar <7 at 5 mins 17 (34%) 14 (28%) .678Patent ductus arteriosus treated 36 (72%) 35 (70%) 1.000Postnatal dexamethasone 28 (56%) 29 (58%) 1.000Diuretics 15 (30%) 40 (80%) <.001Pentoxifylline 24 (48%) – <.001Adjuvant therapyb 31 (62%) 40 (80%) .035IVH (any grade) 14 (28%) 12 (24%) .791IVH (grade 3 and 4) 3 (6%) 3 (6%) 1.000Mean airway pressurec 10 (8.5–12.0) 7.6 (6.2–9.1) <.001Oxygen level (%)c 42.5 (33.0–58.3) 29.8 (23.5–37.5) <.001aThree missing in control group, p value based on 47 pairs.bAdjuvant therapy is diuretics and/or pentoxifylline.cHourly recording over 7 days.IVH: Intraventricular haemorrhage.Data represent median, interquartile range, and percentage.

4 A. P. ANVEKAR ET AL.

Discussion

Our results indicate that HFJV as a rescue treatmentwas not associated with significant reduction in thecomposite outcome of death/discharge on home oxy-gen in predominantly (43/50) preterm infants <30weeks’ gestation. The higher MAP and oxygen needs,higher frequency of ROP needing treatment and lon-ger duration of mechanical ventilation in cases prob-ably reflects their severity of lung disease comparedwith controls.

Caution is needed in interpreting our results consid-ering the risk of bias due to small sample size, retro-spective design, and inability to control for all knownand importantly unknown confounders. The influenceof selection bias cannot be ruled out despite our effortsto match cases with controls, by matching for demo-graphic variables. We matched controls with cases byneed for dexamethasone for BPD as a marker for sever-ity of lung condition. We could not obtain data onother markers such as oxygenation index. This was dueto lack of arterial lines in most of the participants at apostnatal age in question. Our study also includes fewrelatively mature infants (7/50)� 30 weeks’ gestation.It is important to note that the previous studies ofHFJV are from an era when aggressive noninvasive ven-tilation was not a common practice, and the overallstandard of care was also different. A direct comparisonof our data with these studies is hence inappropriate.Our HFJV protocol involved staring with a lower (240

bpm) rate. We are unable to comment on whether ourresults may have been different if a higher starting rate(�400 bpm) was used for HFJV.

Keszler et al. reported the first RCT of rescue HFJV ininfants with PIE [11]. HFJV had higher success definedas resolution of PIE �24hours, substantial radiographicimprovement of PIE and reduction in MAP to 40% lessthan baseline value before the study (61 versus 37%;p< .01), and higher survival (64.9 versus 47.1%; p< .05)than CMV. However, there was no significant differencein CLD. They concluded that HFJV is safe and moreeffective in the treatment of preterm infants with PIE[11]. Compared to Keszler et al. [11], mortality washigher in HFJV group and the composite outcome ofdeath/discharge on home oxygen was comparablebetween the HFJV and CMV group in our study, prob-ably due to more severe lung disease in the infants.The Cochrane systematic review of rescue HFJV thatincluded the only RCT by Keszler et al. showed no stat-istically significant difference in mortality betweenHFJV and CMV group infants [RR: 1.07, (95%CI: 0.67,1.72)] [12]. However, on secondary analysis, rescue withHFJV until the time of cross-over was associated withlower mortality; RR: 0.66 (95%CI: 0.45, 0.97) [12].

Plavka et al. have reported a case series (n¼ 10) ofextremely preterm infants where rescue HFJV was usedwith high PEEP as optimal lung volume strategy (OLVS)[10]. The median (IQR) gestation and birth weight was23.6 (22.3–26.3) weeks and 645 (390–1020) grams,

Table 2. Primary and secondary outcomes.Cases N¼ 50 Controls N¼ 50 p value

Death before discharge 12 (24%) 2 (4%) .013Home oxygen 17 (34%) 18 (36%) 1.000Home on oxygen among survivorsa 17/38 (45%) 18/48 (38%) .424Home oxygen/death 29 (58%) 20 (40%) .049ROP treated 4 (8%) 13 (26%) .032Median (IQR) duration of:Ventilation (h) 776 (352–1204) 493 (84–1005) .009CPAP (h) 938 (487–1431) 1269 (766–1560) .444Oxygen (h) 2733 (1609–3301) 2000 (655–3108) .229ap value represents comparison of 36 case-control pairs.IQR: Interquartile range; ROP: retinopathy of prematurity; CPAP: continuous positive airway pressure.

Table 3. Unadjusted and adjusted results for primary and secondary outcomes.Unadjusted OR p value Adjusted OR p value

Home oxygen/deatha 3.25 (1.00–13.68) .049 1.46 (0.23–9.14) .687Death before discharge 6.00 (1.34–55.2) .013 –Home oxygen 0.88 (0.27–2.76) 1.000 –ROP treatedb 0.25 (0.07–0.89) .032 0.10 (0.01–1.96) .127Duration of:a

Ventilation (h) HR: 2.04 (1.28–3.33) 0.003 aHR: 1.82 (1.04–3.13) .037CPAP (h) HR: 0.71 (0.43–1.16) 0.170 aHR: 0.56 (0.30–1.04) .065Oxygen (h) HR: 1.59 (0.97–2.63) 0.064 aHR: 1.23 (0.69–2.17) .475aAdjusted for MAP and adjuvant therapy.bAdjusted for oxygen level (%) and duration.ROP: retinopathy of prematurity; CPAP: continuous positive airway pressure; MAP: mean airway pressure.Hazard ratios are reported such that a higher hazard ratio indicates an increased risk of longer duration.

THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5

respectively. HFJV was initiated when OI was >10 oran exhaled tidal volume (VT,E) of 7mL/kg was requiredto maintain PaCO2< 60mmHg. Inspiratory time andrespiratory rate were set initially at 0.02 seconds and310–420 breaths/min, respectively. Pressure amplitudewas adjusted to keep PaCO2 between 45 and 55mmHg. All patients were successfully extubated to nasalCPAP with a median HFJV duration of 15.5 days. Of thenine survivors, all required oxygen at 36 weeks PMA[10]. Compared to Plavka et al. [10], the infants in ourstudy were more mature [Median (IQR) gestation: 25.8(25–28.3) weeks], and our starting PEEP on HFJV was1–2 cm higher than that on CMV. The median postnatalage at changeover from CMV to HFJV was earlier (11versus 19 days) in our cohort, indicating that ourinfants were sick early in the course of their lungdisease. This is supported by the fact that there were6/12 deaths whilst the infants were on HFJV.

The safety of HFJV (high or low volume strategy)with regards to IVH and cystic periventricular leukoma-lacia (PVL) needs to be discussed. In a systematicreview of elective HFJV versus CMV [13], there was nosignificant difference in IVH (any grade or grade 3 or4) between the two modes of ventilation. However,there was a trend towards increased risk of IVH (allgrades and grade 3/4) when low volume HFJV wasused [13]. Keszler et al. did not find an increased inci-dence of IVH in infants with PIE who were treatedwith rescue HFJV or CMV [11]. In our study, there wasno difference in any grade IVH [14 (28%) versus 12(24%), p¼ .791] and severe IVH (grade 3 and 4) [3 (6%)versus 3 (6%), p¼ 1.000] between the HFJV (high vol-ume strategy) and non-HFJV group infants.

In summary, HFJV was not associated with reducedodds of death or discharge home on oxygen in pre-term infants in our study. Adequately poweredrandomised trials are required to assess the efficacyand safety (e.g. IVH, PVL) of HFJV in reducing therisk of death or discharge home on oxygen inthis population.

Disclosure statement

The authors report no conflict of interest

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