Evaluation of Lung Volumes and Gas Exchange in Surfactant-Deficient Rabbits Between Variable and Fixed Servo Pressures During High-Frequency Jet Ventilation

doi:10.21203/rs.3.rs-3214580/v1

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Evaluation of Lung Volumes and Gas Exchange in Surfactant-Deficient Rabbits Between Variable and Fixed Servo Pressures During High-Frequency Jet Ventilation

https://doi.org/10.21203/rs.3.rs-3214580/v1

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Journal Publication

published 25 Nov, 2023

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Objective

To investigate a novel servo pressure (SP) setting during high-frequency jet ventilation (HFJV) for a lung protective strategy in a neonatal model of acute respiratory distress.

Study design:

Comparison of efficacy between variable (standard) and fixed SP settings in a randomized animal study using rabbits (n = 10, mean weight = 1.80 kg) with surfactant-deficiency by repeated lung lavages.

Results

Rabbits in fixed SP group had greater peak inspiratory pressure, SP, minute volume, pH, and PaO₂, and lower PaCO₂ after lung lavage than the variable SP group. Lung volume monitoring with electrical impedance tomography showed that fixed SP reduced the decline of the global lung tidal variation at 30 minutes after lung lavage (-17.4% from baseline before lavage) compared to variable SP (-44.9%).

Conclusion

HFJV with fixed SP significantly improved gas exchange and lung volumes compared to variable SP. Applying a fixed SP may have important clinical implications for patients receiving HFJV.

High-Frequency Ventilation

High-Frequency Jet Ventilation

RDS

Infant mechanical ventilation

High-frequency jet ventilation (HFJV) is a lung-protective strategy used in critically ill neonates with severe lung disease as a rescue modality or as first-line treatment in extremely low birth weight infants at high risk of lung injury. HFJV provides more efficient gas exchange at lower airway pressures than other forms of high-frequency ventilation [1]. The approach with HFJV is to recruit, stabilize and maintain open lungs and facilitate gas exchange with intermittent recruitment breaths and positive end-expiratory pressure (PEEP) generated by the conventional ventilator [2]. In HFJV, the very short inspiratory times combined with the peak inspiratory pressure (PIP) setting generate very small tidal volumes (V_T) [3]. The jet ventilator is designed to function as a pressure-controlled ventilator. The servo pressure (SP) is the driving pressure that regulates the gas flow from the ventilator needed to maintain the set PIP. The SP and flow output decrease in patients with worsening lung mechanics (compliance and resistance) because a smaller volume of gas is needed to maintain the set PIP, similar to pressure control ventilation, which can lead to hypoventilation and worsening oxygenation.

In contrast, the SP and gas flow will increase with improving lung mechanics, which leads to overventilation and potential overexpansion of the lungs, unless the changes in lung mechanics signaled by the increasing SP are recognized and the set PIP manually adjusted accordingly. Because CO₂ elimination is proportional to approximately VT², even small changes in lung mechanics could result in fluctuations in the inspiratory V_T and alveolar minute ventilation that could have important implications for lung protection and arterial CO₂ levels. Reduced V_T can result in the repeated collapse of unstable airways and lung units, resulting in atelectotrauma and hypercapnia. Excessive V_T delivery may cause volutrauma in surfactant-deficient lungs. Both forms of ventilator-induced lung injury expose neonatal lungs to injury, inflammation, and the development of bronchopulmonary dysplasia (BPD). Reduced alveolar ventilation and hypercapnia can cause cerebral vasodilation and increased cerebral blood flow; conversely, excessive ventilation and hypocapnia can lead to vasoconstriction and decreased cerebral blood flow [4], increasing the risk of neonatal brain injury [5]. A Cochrane meta-analysis showed ventilators that target a constant V_T (i.e., volume-targeted and volume-controlled) reduced death or BPD, mean duration on ventilation, air leaks, hypocarbia, severe intraventricular hemorrhage and periventricular leukomalacia than did pressure-controlled (i.e., pressure control, variable inspiratory flow) ventilation in preterm infants [6]. These improved pulmonary and neurodevelopmental outcomes make lung protective strategies that apply volume-focused algorithms with high-frequency ventilation appear promising [7].

In theory, HFJV with a locked or “Fixed” SP may minimize fluctuations in flow, V_T, minute ventilation and gas exchange with changes in lung mechanics, similar to volume-targeted conventional ventilation. This strategy could attenuate lung injury/inflammation and reduce fluctuations in arterial CO₂, thus minimizing the risk of developing BPD and neurological sequelae. A preliminary bench study using an excised rat lung in a miniature body plethysmograph demonstrated that the change in minute ventilation across a five-fold range of compliances was much smaller when the fixed SP approach was used, compared to the standard SP function targeting a fixed PIP (unpublished data). The following preclinical study in vivo evaluated the short-term physiologic effects of a novel prototype of HFJV (Bunnell Life Pulse HFV204 Ventilator, Salt Lake City, Utah) that applies a fixed SP to maintain a constant flow output. This initial proof of concept pre-clinical study was conducted in surfactant-deficient rabbits with progressive pulmonary compliance deterioration using an established surfactant deficiency and respiratory distress syndrome (RDS) model [8]. The null hypothesis was that there would be no differences in pulmonary gas exchange, lung volumes, and disease severity between variable (standard) and fixed SP settings during HFJV.

Animal Study Surgical Preparation/Instrumentation

Under an institutionally approved animal study protocol, juvenile female New Zealand White rabbits (Western Oregon Rabbit Company, Philomath, OR, n = 10, mean weight = 1.80 kg) were tranquilized with 1 mg/kg acepromazine and anesthetized with 33 mg/kg ketamine, 6.6 mg/kg xylazine. The SpO₂ was monitored (Rad 7, Massimo, Italy) with a tail probe and body temperature was monitored continuously with a rectal temperature probe and maintained normothermic (38–39 ^˚C) using a warming pad. The neck and upper chest were shaved, and subcutaneous lidocaine was administered around the trachea, for local anesthesia, before blunt dissection to isolate and visualize the trachea and allow proper placement of the endotracheal tube. Animals were orally intubated with a 2.5 mm endotracheal tube. A strand of umbilical tape was tied around the trachea and endotracheal tube to prevent displacement, gas leakage, and saline leakage during lung lavage. Auscultation of bilateral breath sounds and the presence of end-tidal CO₂ confirmed proper tube placement. Animals were ventilated in the assist/control volume-guarantee mode on the VN500 ventilator (Draeger, Lubeck, Germany) at 40 breaths/min, 0.30-sec inspiratory time, and an initial positive end-expiratory pressure (PEEP) of 5 cmH₂O with V_T targeted to 6 mL/kg. Gases were conditioned to 37–40 ˚C with a heated humidifier (MR 850, Fisher Paykel Healthcare, Auckland, New Zealand). The ventilator rates were adjusted to maintain pH 7.35–7.45. A 20-gauge angiocatheter was placed in the left jugular vein to administer fluids and drugs. Sedation and analgesia were maintained to minimize pain using a continuous intravenous (IV) infusion of ketamine and xylazine (3 and 0.18 ml × kg-1 × hr^− 1, respectively) and titrated based on blood pressure, heart rate, and maintenance of an anesthetic plane. Maintenance IV fluids were provided with a continuous infusion at 3 ml × kg-1 × hr^− 1 of 0.9% saline containing 5% dextrose. A 22-gauge angiocatheter was placed in the right carotid artery for heart rate, blood pressure monitoring and sampling for arterial blood-gas analyses (ABGs). ABGs (pH, PaCO₂, PaO₂) were measured using a Radiometer ABL 800 (Radiometer America, Brea, CA). A maintenance IV flush solution using 0.9% saline was administered at 1 ml·kg^− 1 to maintain arterial catheter patency.

Electrical Impedance Tomography (EIT) was measured with sixteen electrodes placed on the circumference of the thorax and connected to an EIT device (Pulmovista 500, Draeger Medical, Lubeck, Germany). EIT monitoring was used to estimate the effect of SP interventions on cross-sectional regional lung volume loss and recovery during inhalation and exhalation [9, 10]. A unidirectional flow sensor (AliCat M-20SLPM-D/5M, manufacturer) was placed into the HFJV gas outlet to continuously record the minute volume delivered to the circuit. Rocuronium Bromide (10 mg/mL) was used to induce chemical paralysis and eliminate intrinsic breathing efforts during HFJV. Subjects were initially placed onto HFJV with the conventional variable SP setting with FiO₂ of 1.0, Rate of 420, I-time of 0.02s, PIP of 20 cmH₂O, and PEEP of 5 cmH₂O in conjunction with the Draeger VN500 (Medical, Lubeck, Germany) conventional ventilator. As part of the initial stabilization on HFJV, PIP was adjusted to maintain pH between 7.35–7.45. Following a 30-minute stabilization on HFJV, a baseline pre-lavage measurement (ABGs, EIT, etc.) was obtained and monitored HFJV values (PIP, SP, and minute volume) were recorded.

Animals were randomized to HFJV, with half of the animals being supported by conventional variable SP (n = 5) and the other half being supported by experimental fixed SP (n = 5). Animals remained within the assigned SP groups for the remainder of the experiment (see Fig. 1).

Induction of Surfactant Deficiency, Lung Injury, and HFJV Support

The FiO₂ was increased to 1.0; the subjects were disconnected from the ventilator, and the lungs were depleted of surfactant by repeated lavage with 25 mL/kg of warmed (39^oC) normal saline (0.9%) using a glass syringe, with 5-minute recoveries between lavages. A total of 10 lavages were used to induce acute respiratory illness/injury and deterioration in gas exchange and lung mechanics. This method has been previously shown to reduce dynamic compliance by ~ 50% of the non-lavage value (0.50–0.60 mL/cmH₂O) [8]. Following every other lavage and a 5-minute recovery period, ABGs, vital signs, ventilator pressures, minute volume, and EIT measurements were acquired to evaluate the effects of the different SP strategies on lung recruitment and gas exchange for a total of five runs. Following the final (10th ) lavage, the subjects were supported on HFJV for 30 minutes, and a last set of measurements were obtained. Animals were euthanized with 100 mg/kg Euthasol.

Data Analysis

The disease severity was calculated based on the ventilator parameters and ABG values at baseline and each lavage interval as Oxygenation Index (OI) and ventilation efficiency index (VEI) [11–13].

The pixel waveforms' tidal peak-to-trough impedance changes (ΔZ, tidal variation) were used to assess regional differences in the local inspiratory V_T. End-expiratory lung impedance (EELI) estimates the end-expiratory lung volume (EELV) and serves as a surrogate measure of functional residual capacity (FRC) in the lungs [9, 10, 14]. Tidal variation and EELV changes were calculated based on % change between the pre-lavage baseline and at each post-lavage condition.

Statistical analysis

Data were calculated as mean ± standard error (SE) or median (interquartile range), for all continuous physiologic outcome variables for pre-lavage baseline, after 2nd, 4th, 6th, 8th, and 10th lavage, and 30 min post-lavage. Pre-lavage baseline data between the two groups were compared using non-parametric analyses (Mann–Whitney test). Evaluation of maneuvers effects of group and time and their interaction was exanimated by two-way repeated measure analysis of variance (ANOVA), followed by Sidak's and Dunnett's multiple comparison tests. All statistical analyses were performed in PRISM 9 (Graph Pad Software Inc.). Results were considered statistically significant at p < 0.05 for all comparisons.

Animal Descriptions

The two groups had no differences in body weight, gas exchange and disease severity at the pre-lavage baseline HFJV condition (Table 1). During the experiment, there were no differences in heart rate (P = 0.15) or blood pressure (P = 0.9) between the Fixed and Variable SP groups. The HFJV PIP and SP measurements on the HFJV were higher with fixed SP than variable SP following lung lavage, and the minute volume measurements were greater with fixed SP than variable SP following the 6th lavage (Fig. 2). By the end of lavage and 30 min later, the minute ventilation was 6.8% lower with variable SP and 12.7% lower with fixed SP, compared to pre-lavage baseline.

Table 1

Pre-lavage baseline data.
	Fixed Servo Pressure (n = 5)	Variable Servo Pressure (n = 5)	P-value
BW (kg)	1.80 (0.43)	1.80 (0.23)	0.63
pH	7.39 (0.02)	7.42 (0.06)	0.37
PaCO₂ (mmHg)	42.0 (10.5)	41.0 (22.0)	0.51
PaO₂ (mmHg)	378 (30)	352 (77)	0.55
OI	1.60 (0.78)	1.70 (1.01)	0.87
VEI (mL/kg/mmHg)	0.098 (0.012)	0.097 (0.069)	> 0.99
A-aDO₂ (mmHg)	282.5 (43.1)	308.8 (95.0)	0.55
BW, body weight; OI, oxygenation index; VEI, ventilation efficiency index; A-aDO2, alveolar to arterial oxygenation difference. Values are shown as median (interquartile range).

Gas Exchange

The pH and PaO₂ were greater with Fixed SP than Variable SP at the 30 min post-lavage measurement (Fig. 3). The PaCO₂ was lower in the Fixed SP group than the Variable SP group following the 8th lung lavage (Fig. 3). The mean PaCO₂ increased to 90 torr (132% from baseline) with variable SP and 60 torr (46% from baseline) with fixed SP at the end of lavage and 30 min later.

Indices of Disease Severity

The VEI and OI were not different between the fixed and variable SP groups. There was a non-significant trend toward lower OI with fixed SP than variable SP (Fig. 3, p = 0.09)

Lung Volume Recruitment

Both SP interventions showed a reduced tidal variation and EELV from baseline following the repeated lavages. The % change in global tidal variation (Fig. 4A, p = 0.0003) and EELV (Fig. 4B, p = 0.02) was lower with fixed SP than with variable SP. Figure 4C shows the progression of EELV following lung lavage in a subject supported with Fixed SP (Top) and a subject supported with variable SP (Bottom).

This study is the first in vivo proof-of-concept study to compare differences in short-term physiologic outcomes in animals with progressively worsening lung mechanics and deterioration in gas exchange using a fixed SP algorithm on a prototype HFJV device. The significant findings from this study showed that HFJV with fixed SP resulted in higher PIP and minute volume output of the HFJV and stabilization in the minute ventilation, corresponding to improvements in alveolar recruitment, ventilation, and pulmonary gas exchange. With a fixed SP, the volume of gas injected into the endotracheal tube remains relatively constant, making the jet ventilator function more as a volume-controlled ventilator. This is because the SP value is an order of magnitude higher (measured in pounds per square inch) than the intratracheal pressure and therefore the pressure gradient across the fixed resistance of the jet injector that drives volume delivery changes only modestly when compliance deteriorates and airway pressure increases, explaining the observed effect on airway pressures, minute ventilation and PaCO₂.

The relative improvement in alveolar recruitment and lung volume recovery observed with EIT following lung lavage with fixed SP resulted from the fixed SP or 'driving pressure,' prompting higher PIPs that helped maintain alveolar recruitment during HFJV. This approach that mimics volume-targeted ventilation may be clinically meaningful for maintaining consistent gas exchange and lung volumes, translating to improved neurological and lung protection. However, unlike patients who remain on HFJV, animals in the current study were repeatedly removed from HFJV for lung lavage, resulting in rapid lung volume reduction and pulmonary atelectasis with each disconnection. Thus, the pulmonary response to the different SP strategies was likely delayed due to insufficient time for alveolar recruitment. To evaluate the effectiveness of the different SP approaches, supporting subjects on the baseline HFJV settings was necessary without any further adjustment in the PIP, PEEP, or frequency settings following lung lavage, explaining why we did not see any significant differences in the lung disease severity based on the OI and VEI in these experiments. Thus, we postulate that in the clinical setting, where patients are more likely to experience subtle changes in lung mechanics over time and adjustments in the PIP, PEEP and frequency are made, there is expected to be a more significant benefit with HFJV with fixed SP. We could not directly measure the minute volume or V_T proximal to the subjects. Thus, based on the EIT and gas exchange, we can only speculate that maintenance of the inspiratory V_T, FRC, and alveolar ventilation led to improved outcomes in animals supported with a fixed SP.

Limitations

This experiment was conducted using an established animal model of RDS [15, 16]. We could not apply other models of neonatal respiratory failure, thus limiting the findings to a particular disease state [17]. While juvenile rabbits' lungs lack some of the structural and developmental (i.e., alveolar simplification) phenotypes associated with preterm humans' lungs, the lungs have not completed alveolarization (< 5 weeks) and, thus, still serve as an excellent preclinical model to evaluate neonatal response to different forms of ventilation [18]. Our experimental model of whole lung lavage in rabbits closely mimics lung pathophysiology involving surfactant deficiency, inflammation, and injury response in neonates with severe RDS [16]. Using mechanical ventilation and high FiO₂ following lung lavage maintains injury, inflammation, and stability in disease severity. However, this model may have lungs that are generally more recruitable than human infants with RDS. One limitation of this study was that animals were repeatedly disconnected from HFJV during the repeated lavage sequences, representing a worst-case scenario and starting point to reinflate the lungs from low FRC, which was the goal of these experiments. As such, the 30-minute measurement following the tenth and final lung lavage may not have provided enough time for the lung volumes to reach a steady state to assess the longer-term effects of these settings on lung recruitment, overdistention, and gas exchange.

Nonetheless, we could still show important benefits of Fixed SP, which had a more demonstrable effect over an extended period (> 30 mins) of uninterrupted HFJV. Also, we did not measure mediators of lung inflammation/injury to determine the impact of SP settings on lung protection. Future animal studies are needed to support subjects over a more extended period and assess pulmonary inflammation and injury response between these approaches.

Our preclinical studies showed improved alveolar recruitment, oxygenation, and ventilation with a novel prototype employing a fixed SP with HFJV in animals that developed progressively worsening lung disease and gas exchange. These combined effects may contribute to greater lung protection and stabilization of gas exchange with HFJV in the clinical setting. HFJV in its current variable SP mode has many proven benefits and has served the neonatal community well for almost 40 years. The variable SP algorithm was an ingenious way to convert the jet ventilator to a pressure-controlled device, an understandable goal at a time when pressure-controlled ventilation was the only approach in newborn infants. With the advent of volume-targeted conventional and oscillatory ventilation modes in neonatology, allowing the user to elect to use the device in either pressure-controlled (i.e., variable SP) or volume targeted mode (i.e., fixed, manually adjusted SP mode) would be desirable and theoretically possible. Further preclinical and clinical studies would be needed to validate this concept.

Conflict of Interest: As noted in the manuscript, Robert DiBlasi has received funding from Bunnell, Inc to conduct this preclinical research. He has also received research funding or served on the speaker’s bureau for Medtronic, Draeger Medical, and ABRMC Medical. Jeff Orth is the Chief Technology Officer, and Evan Richards is Bunnell's Advanced Practice Clinical Consultant. Martin Keszler has disclosed relationships with Bunnell Inc. and Draeger Medical.

Ethawi YH, Abou Mehrem A, Minski J, Ruth CA, Davis PG. High frequency jet ventilation versus high frequency oscillatory ventilation for pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev 2016, 2016(5): CD010548.
Musk GC, Polglase GR, Bunnell JB, McLean CJ, Nitsos I, Song Y, et al. High positive end-expiratory pressure during high-frequency jet ventilation improves oxygenation and ventilation in preterm lambs. Pediatr Res 2011, 69(4): 319-324.
Musk GC, Polglase GR, Song Y, Pillow JJ. Impact of conventional breath inspiratory time during high-frequency jet ventilation in preterm lambs. Neonatology 2012, 101(4): 267-273.
Brown MK, Poeltler DM, Hassen KO, Lazarus DV, Brown VK, Stout JJ, et al. Incidence of Hypocapnia, Hypercapnia, and Acidosis and the Associated Risk of Adverse Events in Preterm Neonates. Respir Care 2018, 63(8): 943-949.
Zhou W, Liu W. Hypercapnia and hypocapnia in neonates. World J Pediatr 2008, 4(3): 192-196.
Klingenberg C, Wheeler KI, McCallion N, Morley CJ, Davis PG. Volume-targeted versus pressure-limited ventilation in neonates. Cochrane Database Syst Rev 2017, 10(10): CD003666.
Enomoto M, Keszler M, Sakuma M, Kikuchi S, Katayama Y, Takei A, et al. Effect of Volume Guarantee in Preterm Infants on High-Frequency Oscillatory Ventilation: A Pilot Study. Am J Perinatol 2017, 34(1): 26-30.
DiBlasi RM, Kearney CN, Hotz JC, Salyer JW, Poli JA, Crotwell DN, et al. Physiologic Effects of 3 Different Neonatal Volume-Targeted Ventilation Modes in Surfactant-Deficient Juvenile Rabbits. Respir Care 2019, 64(4): 361-371.
van Genderingen HR, van Vught AJ, Jansen JR. Estimation of regional lung volume changes by electrical impedance pressures tomography during a pressure-volume maneuver. Intensive Care Med 2003, 29(2): 233-240.
Hinz J, Hahn G, Neumann P, Sydow M, Mohrenweiser P, Hellige G, et al. End-expiratory lung impedance change enables bedside monitoring of end-expiratory lung volume change. Intensive Care Med 2003, 29(1): 37-43.
Katalan S, Falach R, Rosner A, Goldvaser M, Brosh-Nissimov T, Dvir A, et al. A novel swine model of ricin-induced acute respiratory distress syndrome. Dis Model Mech 2017, 10(2): 173-183.
Kopincova J, Mikolka P, Kolomaznik M, Kosutova P, Calkovska A, Mokra D. Selective inhibition of NF-kappaB and surfactant therapy in experimental meconium-induced lung injury. Physiol Res 2017, 66(Suppl 2): S227-S236.
Notter RH, Egan EA, Kwong MS, Holm BA, Shapiro DL. Lung surfactant replacement in premature lambs with extracted lipids from bovine lung lavage: effects of dose, dispersion technique, and gestational age. Pediatr Res 1985, 19(6): 569-577.
Riedel T, Kyburz M, Latzin P, Thamrin C, Frey U. Regional and overall ventilation inhomogeneities in preterm and term-born infants. Intensive Care Med 2009, 35(1): 144-151.
Ballard-Croft C, Wang D, Sumpter LR, Zhou X, Zwischenberger JB. Large-animal models of acute respiratory distress syndrome. Ann Thorac Surg 2012, 93(4): 1331-1339.
DiBlasi RM, Micheletti KJ, Zimmerman JD, Poli JA, Fink JB, Kajimoto M. Physiologic Effects of Instilled and Aerosolized Surfactant Using a Breath-Synchronized Nebulizer on Surfactant-Deficient Rabbits. Pharmaceutics 2021, 13(10).
Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2008, 295(3): L379-399.
Kamaruzaman NA, Kardia E, Kamaldin N, Latahir AZ, Yahaya BH. The rabbit as a model for studying lung disease and stem cell therapy. Biomed Res Int 2013, 2013: 691830.

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You are reading this latest preprint version

Evaluation of Lung Volumes and Gas Exchange in Surfactant-Deficient Rabbits Between Variable and Fixed Servo Pressures During High-Frequency Jet Ventilation

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Materials and Methods

Animal Study Surgical Preparation/Instrumentation

Induction of Surfactant Deficiency, Lung Injury, and HFJV Support

Data Analysis

Statistical analysis

Results

Animal Descriptions

Gas Exchange

Indices of Disease Severity

Lung Volume Recruitment

Discussion/Conclusion

Conclusions

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1