CALL FOR PAPERS Translational Research in Acute Lung Injury and Pulmonary

Fibrosis

Lung volume recruitment in a preterm pig model of lung immaturity

Esmond L. Arrindell, Jr.,1* Ramesh Krishnan,1* Marie van der Merwe,2 Frank Caminita,3

Scott C. Howard,2 Jie Zhang,4 and Randal K. Buddington2

1Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee; 2School of Health Studies, University ofMemphis, Memphis, Tennessee; 3Dräger Medical Inc., Telford, Pennsylvania; and 4Pathology, University of Tennessee HealthScience Center, Memphis, Tennessee

Submitted 20 August 2015; accepted in final form 17 September 2015

Arrindell EL Jr, Krishnan R, van der Merwe M, Caminita F,Howard SC, Zhang J, Buddington RK. Lung volume recruitment ina preterm pig model of lung immaturity. Am J Physiol Lung Cell MolPhysiol 309: L1088–L1092, 2015. First published September 25,2015; doi:10.1152/ajplung.00292.2015.—A translational preterm pigmodel analogous to infants born at 28 wk of gestation revealed thatcontinuous positive airway pressure results in limited lung recruitmentbut does not prevent respiratory distress syndrome, whereas assist-control� volume guarantee (AC�VG) ventilation improves recruitment but cancause injury, highlighting the need for improved ventilation strategies.We determined whether airway pressure release ventilation (APRV)can be used to recruit the immature lungs of preterm pigs withoutinjury. Spontaneously breathing pigs delivered at 89% of term (modelfor 28-wk infants) were randomized to 24 h of APRV (n � 9) vs.AC�VG with a tidal volume of 5 ml/kg (n � 10). Control pigs(n � 36) were provided with supplemental oxygen by an open mask.Nutrition and fluid support was provided throughout the 24-h period.All pigs supported with APRV and AC�VG survived 24 h, comparedwith 62% of control pigs. APRV resulted in improved lung volumerecruitment compared with AC�VG based on radiographs, lowerPCO2 levels (44 � 2.9 vs. 53 � 2.7 mmHg, P � 0.009) and lowerinspired oxygen fraction requirements (36 � 6 vs. 44 � 11%, P �0.001), and higher oxygenation index (5.1 � 1.5 vs. 2.9 � 1.1, P �0.001). There were no differences between APRV and AC�VG pigsfor heart rate, ratio of wet to dry lung mass, proinflammatory cyto-kines, or histopathological markers of lung injury. Lung protectiveventilation with APRV improved recruitment of alveoli of pretermlungs, enhanced development and maintenance of functional residualcapacity without injury, and improved clinical outcomes relative toAC�VG. Long-term consequences of lung volume recruitment byusing APRV should be evaluated.

prematurity; pulmonary; animal model; development

RESPIRATORY DISTRESS SYNDROME (RDS) remains the leadingcause of morbidity and mortality for preterm infants (16) andimproving neonatal resuscitation remains a priority (30). Rapidairway clearance and lung recruitment following preterm birthare crucial (10). Presently, preterm infants may be intubated foradministration of surfactant but because of concern of causingventilator-induced lung injury (VILI) are then extubated for theinitiation of noninvasive ventilation, generally with continuous

positive airway pressure (CPAP), despite concerns about itsefficacy, safety (3), and limited lung recruitment (2).

We hypothesized that lung-protective modes of mechanicalventilation (MV) can be adapted to recruit functional reservecapacity (FRC) immediately after birth without surfactant. Wecompared the commonly used assist-control � volume guar-antee (AC�VG) mode with airway pressure release ventilation(APRV), also known as biphasic positive airway pressure.APRV is a pressure-limited, time-cycled, time-triggered modeof ventilation (19) that recruits FRC using a defined peakpressure (Phigh) that is extended over a prolonged period(Thigh). Ventilation occurs when Phigh is reduced (Plow) for aperiod of time (Tlow) that allows for expiration but is shortenough to prevent alveolar collapse and derecruitment. Al-though APRV improves oxygenation, decreases physiologicaldead space ventilation, and reduces alveolar edema, surfactantinactivation, histopathological damage, and the incidence andseverity of RDS (17, 21), the use of APRV for pretermneonates has not been systematically studied, except for a fewcase studies after onset of RDS (8, 14). To determine theefficacy of proactive APRV initiated soon after delivery, weused a preterm pig model of lung immaturity and surfactantdeficiency, since it closely mimics respiratory issues in pretermhumans and therefore provides information that can readily betranslated to clinical care (2).

METHODS

Source of preterm pigs. The caesarian section, care, and samplingof preterm pigs followed our established protocol (2) and wereapproved by the Institutional Animal Care and Use Committees of theUniversity of Tennessee Health Science Center (location of caesariansection) and the University of Memphis (site of critical care). Pretermpigs were delivered from four specific pathogen-free, artificiallyinseminated sows of a defined genetic lineage without antenatalsteroids on gestation day 102 (89% of 115-day term), when lungdevelopment is similar to that of 28-wk preterm infants. After theairway was suctioned and cleared and spontaneous breathing wasestablished the pigs were transported to a facility established forchronic intensive care.

Processing and intensive care. Pigs with birth weight �600 g wereintubated with 2.5-French endotracheal tubes but were not providedsurfactant. Within each litter those of similar body weights wererandomized to either APRV (n � 9) or AC�VG (n � 10) usingDräger VN500 ventilators (Dräger Medical, Dräger, Telford, PA).Pigs with significant tracheal trauma (e.g., perforation) caused byplacement of the endotracheal tube were removed from the study

* E. L. Arrindell, Jr., and R. Krishnan are co-first authors.Address for reprint requests and other correspondence: R. K. Buddington,

School of Health Studies, 495 Zach Curlin Way, Univ. of Memphis, Memphis,TN 39152 (e-mail: rbddngtn@memphis.edu).

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(n � 7), regardless of the ventilator strategy to which they had beenassigned. Supplemental oxygen was provided to the remaining pigs ineach litter via an open mask.

The initial settings for APRV were a Phigh of 16 cmH2O, Plow of 0to minimize expiratory resistance, Thigh of 2 s, and Tlow set fortermination of expiration at 75% peak expiratory flow rate. The initialAC�VG settings of 40 breaths per minute, positive end expiratorypressure (PEEP) of 5 cmH2O, inhalation time of 0.35 s, tidal volumeof 5 ml/kg, and inspired oxygen fraction (FIO2) of 40% are consideredto be lung protective (18). All pigs were allowed to breathe sponta-neously. Caffeine or doxapram were not provided during the 24 h ofMV. Pigs were repositioned each hour to avoid dependent edema andlung atelectasis and sedated as needed (ketamine, Bioniche Teoranta,Galway, Ireland; 2 mg·kg�1·dose�1) via an umbilical catheter (3.5-FrArgyle, Covidien), which was also used for arterial blood sampling,parenteral nutrition, single prophylactic doses of maternal plasma(5 ml/kg) for passive immunity, antibiotic (cefazolin; 50mg·kg�1·dose�1), and supplemental lactated Ringer solution asneeded to maintain tissue perfusion (usually 3–4 ml·kg�1·h�1).

Heart rate and oxygen saturation were monitored continuously(Masimo Radical 7, Masimo). Arterial blood gas measurements(iSTAT and CG 4 cartridges; Abaxis, Union City, CA) were per-formed every 3 h or after adjustment of ventilator settings to maintaina pH of 7.25–7.35, PCO2 of 40–55 mmHg, and oxygen levels withina range of 90–95% saturation.

Radiography. A chest X-ray (CXR) was obtained after insertion ofthe endotracheal tube to confirm and if necessary adjust placementand as a baseline measure of lung volume recruitment (Duoview HighResolution Digital Radiography System, Revo2, Kennesaw, GA). Asecond CXR after 24 h was used to assess lung volume recruitment.

Necropsy. After 24 h of MV the pigs were euthanized (Euthasol;Virbac, Fort Worth, TX; 1 ml/kg iv); the lungs were removed en bloc,inflated by using the endotracheal tube and a NeoPuff (Fisher &Paykel Healthcare, Irvine, CA) to a pressure of 20 cmH2O; and thetrachea was clamped. The right lower lobe was tied off, excised, andsubmerged in formalin for histopathology. Bronchoalveolar lavagefluid (BALF) was collected from the right middle lobe for analysis ofcytokines. The weight of the left lung was recorded before and afterdrying (50°C for 48 h) to determine the ratio of dry weight relative towet weight as an indicator of pulmonary edema.

Histological analysis. The formalin-fixed tissues were processedinto paraffin, sectioned, and stained with hematoxylin and eosin. Apediatric pathologist, blinded to the study protocol, reviewed thesections for inflammation, hemorrhage, edema, necrosis, and atelec-tasis using a Likert scale that ranged from 0 (no injury), 1 (1–25%injury), 2 (26–50% injury), 3 (51–75% injury), to 4 (76–100%injury).

Cytokine analysis. Interleukin (IL)-1�, IL-1, IL-4, IL-6, IL-8,IFN-, and TNF-� were measured in the BALF by using MilliporeMilliplex Map Porcine Cytokine and Chemokine Magnetic BeadPanel (EMD, Millipore, Billerica, MA).

Statistical analysis. Data were analyzed by Student’s t-test andcategorical variables were compared by Fischer’s exact test. Theselected level of significance was a two-sided P � 0.05.

RESULTS

Preterm pigs are challenging to intubate and seven pigs wereexcluded because of substantial trauma or damage to thetrachea or a bronchus. The APRV and AC�VG pigs withineach litter had similar birth weights, with both larger thancontrols (Table 1). Litters 1 and 2 provided six pigs each thatwere large enough for successful intubation. Litters 3 and 4provided fewer pigs �600 g. All 19 of the successfully intu-bated pigs provided MV survived the 24 h period of mechanicalventilation, whereas 12/36 (33%) of the control pigs died sud-denly or required euthanasia prior to 24-h after developing symp-toms consistent with RDS. Risk of death for control pigs �600 gwas similar to pigs �600 g (P � 0.75).

Physiology. During the first 60 min of APRV, the Phigh (18.7 �0.2 cmH2O) exceeded the peak inspiratory pressure (PIP) requiredto achieve the targeted 5 ml/kg volume of the AC�VG protocol(13.7 � 1.1 ml/kg; P � 0.01) and yielded an average ventila-tion volume (VT) of 6.3 ml (�0.4). At 3 h the VT had increasedto 7.7 (�0.4; P � 0.008) despite gradually decreasing Phigh inresponse to blood gases and oxygenation (Fig. 1). Even thoughPhigh remained relatively stable after 3 h, lung recruitmentcontinued and the VT for the last hour of the study (9.1 � 0.4)was higher compared with 3 h (P � 0.02). As expected,adjusting Phigh changed ventilation volumes.

The PIP declined from 13.6 cmH2O (�0.4) for the first 60min to 11.6 cmH2O (�0.3) for the third hour of AC�VG (Fig.1; P � 0.002). During the last 2 h of ventilation the PIPincreased in 3 of the 10 AC�VG pigs and averaged �25cmH2O and FIO2

was increased to as high as 0.9 to maintaintargeted oxygen saturation. At necropsy, examination of thelungs revealed findings consistent with early RDS.

Pigs provided APRV required a lower FIO2(P � 0.001)

compared with pigs assigned to AC�VG (Table 2). PCO2 wasin the normal range for both groups but was higher amongAC�VG pigs. There were no differences for pH, PaO2

, andoxygen saturation, as expected since ventilator settings wereadjusted to maintain these values within the targeted range.The oxygenation index (FIO2

� mean airway pressure/PaO2)

was higher for the APRV pigs (P � 0.001), indicating im-proved gas exchange. The heart rate was similar for bothgroups of ventilated pigs.

Radiography and gross pathology. The lungs were consol-idated at the start of MV. After 24 h, lung expansion wassignificantly improved with APRV compared with AC�VG(Fig. 2). Inflation of the lungs to a pressure of 20 cmH2Orevealed the AC�VG pigs had extensive areas of atelecta-sis, patchy expansion, and focal sites of hemorrhage thatwere not evident in the APRV pigs (Fig. 2). As before (2),

Table 1. Birth weights of preterm pigs assigned for APRV, AC�VG, and as controls

Litter All (n, females, intubation failures) APRV (n, females) AC-VG (n, females) Control (n, females)

1 917 � 68(14,9,0) 1,076 � 33a (3,2) 1,177 � 49a (3,1) 760 � 77b (8,6)2 895 � 36(16,9,0) 1,029 � 18a (3,2) 1,038 � 20a (3,3) 813 � 38b (10,4)3 513 � 42(15,9,3) 644 � 190a(1,1) 655 � 83a (2,2) 422 � 40b (9,6)4 882 � 73(15,4,2) 991 � 25a (2,0) 1,093 � 101a(2,1) 780 � 112b(9,3)All 802 � 35(60,31,5) 1,019 � 27a (9,5) 1,005 � 78a (10,7) 695 � 42b (36,19)

Values are means � SE, in grams. Treatment groups with different superscripts are significantly different (P � 0.05). APRV, airway pressure releaseventilation; AC�VG, assist-control � volume guarantee.

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lung volume recruitment was limited among control pigsthat survived for 24 h.

The wet/dry lung ratio did not differ between the APRV andAC�VG groups (86.1 � 0.6 vs. 86.2 � 0.4% wet mass,respectively, P � 0.8).

Histopathology. There were no significant differences inhemorrhage, atelectasis, edema, necrosis, or inflammation,

with all scores averaging �1 for both groups (all P � 0.1). Thelungs of APRV pigs had regions with alveolar septal thinningwhereas the lungs of AC�VG pigs exhibited areas of micro-atelectasis (Fig. 2).

Inflammation. None of the proinflammatory cytokines IL-1�, IL-1, IL-6, and IL-8 measured in the lung lavage samplesdiffered between the groups of ventilated pigs. IL-10, IFN-,and TNF-� were below the limits of detection and IL-4 wasdetected at low levels in 1 of the 9 APRV and 1 of the 10AC�VG pigs.

DISCUSSION

Concern for VILI underlies the preference for noninvasiveventilation such as CPAP to provide the positive-pressure venti-lation support recommended to recruit FRC after preterm delivery(23). Using lung protective modes of MV proactively as analternative is novel and clinically relevant. The improved recruit-ment of FRC for the APRV pigs compared with AC�VG basedon CXR, gross pathology, lower FIO2

to meet targeted oxygensaturation, and higher oxygenation index are consistent with thelimited clinical data that suggest APRV as a rescue mode forpreterm infants with RDS results in improved gas exchangewithout causing excessive lung injury (8, 14).

The prolonged Thigh and short Tlow of APRV results in ahigher mean airway pressure without wide pressure swings thateffectively provides a continuous distending pressure that en-hances the replacement of fluid with air without allowingderecruitment (9, 21) and causes a progressive and evendistribution of lung recruitment in both the compliant andnoncompliant regions of the lung. The continuous but lowerpressure provided by CPAP results in minimal lung recruit-ment and lower survival (2) and is consistent with concerns ofefficacy for use with preterm infants �28 wk gestation (3).Conventional tidal ventilation such as AC�VG causes widerpressure fluctuations with fluid expulsion limited to the inspi-ration phase (12). Pressure during the expiration phase mustremain high enough to prevent the collapse of the distalairways and derecruitment (11, 25). Even though the 5 cmH2Opressure used for the PEEP is a common setting in clinicalpractice (18), the longer expiratory period of AC�VG resultsin a larger magnitude of pressure fluctuations and may increasethe risk of alveolar collapse and derecruitment of lung volume,contributing to regional variability in lung recruitment (1) andrequiring more time and a larger number of inflations to reacha full FRC. It is possible that a higher PEEP would enhance theefficacy of the AC�VG and decreased the risk of alveolarcollapse (11).

The similar wet-to-dry lung mass ratio for AC�VG andAPRV pigs is not surprising based on the limited differences inlung recruitment after 24 h. The proactive use of either modelof MV for 24 h did not result in VILI by histological criteria,even with the APRV protocol causing lung expansion to the11th rib, which is indicative of overdistension. However, theheterogeneous, patchy pattern of lung recruitment and hemor-rhage seen in the AC�VG pigs and the increasing PIP valuesrecorded during the final hours for 30% of the AC�VG pigsare suggestive of a decrease in lung compliance and derecruit-ment and coincided with increased FIO2

to maintain targetedoxygen saturation levels.

0 200 400 600 800 1000 1200 1400

V T

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igh

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A

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Fig. 1. Changes in PHigh (�) and ventilation volumes (�) during 24 h ofproviding airway pressure release ventilation (APRV) to preterm pigs (A) andpeak inspiratory pressure (PIP) while providing 24 h of assist-control �volume guarantee (AC�VG) to preterm pigs (B). Values are means andstandard errors calculated from the data collected by the Dräger VN500ventilators. Each data point for APRV is the mean of the 9 preterm pigs andfor AC�VG as the mean of 10 preterm pigs. Values for individual pigs wereaveraged from 4 recordings (total of 20 min). VT, ventilation volume; Phigh,peak pressure.

Table 2. Responses of preterm pigs to 24 h of APRV orAC�VG

APRV AC�VG P Value*

Survival 9 of 9 10 of 10 NSpH 7.4 (7.1–7.5) 7.3 (7.0–7.5) NSPCO2, mmHg 44 (31–74) 53 (30–79) 0.009PaO2, mmHg 105 (54–173) 100 (56–180) NSOxygenation index 5.1 (1.9–12.9) 2.9 (1.2–7.4) 0.001Fraction of inspired oxygen, % 36 (30–50) 44 (30–90) �0.001Dynamic compliance, ml/cmH2O 1.3 (1.1–1.5) 1.5 (0.9–1.7) NSOxygen saturation, % 97 (75–100) 96 (73–100) NSHeart rate, beats/min 160 (129–196) 167 (109–199) NSMean airway pressure, cmH2O 13 (9.4–18) 7.4 (4.4–20) �0.001

Values are means (ranges). *Result of Student’s t-test test for continuousvariables and Fishers exact test for categorical variables. NS, not significant.

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The APRV protocol is a gentler method than sustained lunginflation protocols that use high pressure or volume for neo-natal resuscitation and rapid lung recruitment (6, 19, 27).Rapid, large-scale lung distension can cause histopathologicaldamage, increase BALF protein concentrations, trigger rapid(�30 min) inflammatory responses (29), increase the expres-sion of inflammatory cytokines and acute phase proteins (10),and alter expression of genes associated with alveolar devel-opment and vascularization of newborn lungs (4, 15, 28).

One concern is the potential impact of APRV on cardiacfunction in neonates due to increased intrathoracic pressurethat could impede venous return. A small case series inchildren demonstrated that APRV does not decrease bloodpressure or urine output (13), but this needs to be investi-gated in preterm neonates. Though not specifically ad-

dressed in this study, there were no gross signs at necropsyof intracranial hemorrhage or compromised bowel. Thepossible increased translocation of bacteria from the lungsto the blood caused by the effectively higher PEEP of APRV(5) needs to be evaluated.

PERSPECTIVES

The present study is limited by the use of preterm pigs thatare relevant to 28-wk preterm infants that with surfactant oftendo well without intense ventilation support (2). The potentialbenefits and limitations of APRV need to be evaluated atearlier stages of preterm lung development, and the optimalinitial Phigh to effectively and safely recruit lung volume mustbe determined. Although the short-term benefits of proactive

C

A B

D

E F

Fig. 2. Representative chest X-rays, lungs, and histol-ogy (�10 magnification) after providing 24 h of ven-tilation support to preterm pigs by using APRV (A, C,E) or AC�VG (B, D, F). Expansion of the lungs withAPRV was to the 10th to 11th ribs and with AC�VGto the 8th to 9th ribs. The resected lungs were inflatedto a pressure of 20 cmH2O by using a Neopuff. Lungsfrom APRV pigs had uniform recruitment, minimal orno signs of hemorrhage, and a greater proportion ofexpanded alveoli and less microatelectasis than lungsof AC�VG pigs with patchy, heterogeneous recruit-ment, extensive areas of atelectasis, and focal points ofhemorrhage.

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APRV are evident, the longer-term pulmonary outcomes, in-cluding assessing the impact on survival, time to extubation,and subsequent lung development need to be evaluated.

ACKNOWLEDGMENTS

Our sincerest appreciation is extended to Drs. Bryanna Emr, MichaelaKollisch-Singule, and Nader Habashi and to Penny Andrews and GaryNeimann for assisting in conducting the studies. We acknowledge AshleyYacoubian for assistance in digitizing lung slides for quantitative scoring andElizabeth Tolley for assisting with statistical analysis. We are grateful forDräger Medical providing the ventilators, Dr. Karyl Buddington, Donny Ray,and the entire staff of the preterm pig NICU whose dedication to the care of thepreterm pigs made this study successful.

GRANTS

This study was supported in part by a grant from the LeBonheur Children’sHospital of Memphis, TN and by the University of Memphis.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).Although F. Caminita is an employee of Dräger Medical, the manufacturer ofthe ventilators used for this study, there is no conflict of interest. Ventilatorsfrom other suppliers include the same modes. Therefore the findings from thisstudy will also benefit competing companies.

AUTHOR CONTRIBUTIONS

E.L.A., M.v.d.M., F.C., and R.K.B. performed experiments; E.L.A.,M.v.d.M., F.C., S.C.H., J.Z., and R.K.B. analyzed data; E.L.A., R.K.,M.v.d.M., F.C., S.C.H., and R.K.B. interpreted results of experiments; E.L.A.,R.K., M.v.d.M., F.C., S.C.H., J.Z., and R.K.B. edited and revised manuscript;E.L.A., R.K., M.v.d.M., F.C., S.C.H., J.Z., and R.K.B. approved final versionof manuscript; R.K., F.C., and R.K.B. conception and design of research;R.K.B. prepared figures; R.K.B. drafted manuscript.

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Rapid Report

L1092 LUNG VOLUME RECRUITMENT AFTER PRETERM BIRTH

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