Helium administration is more effective during piston-driven high-frequency oscillatory ventilation than conventional mechanical ventilation in a rabbit model

doi:10.21203/rs.3.rs-2243975/v1

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Helium administration is more effective during piston-driven high-frequency oscillatory ventilation than conventional mechanical ventilation in a rabbit model

https://doi.org/10.21203/rs.3.rs-2243975/v1

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published 26 Dec, 2023

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Background

Low-molecular-weight gases such as helium are more likely to form laminar flows. Using helium-oxygen mixtures instead of nitrogen-oxygen mixtures during mechanical ventilation has been shown to accelerate carbon dioxide (CO₂) excretion. Helium-oxygen mixtures have been used with mechanical ventilator settings such as high-frequency oscillatory ventilation (HFOV) and conventional mechanical ventilation (CMV). However, to the best of our knowledge, studies have not been conducted to determine the optimal ventilator setting for the promotion of CO₂ excretion when helium is administered. This study aimed to compare the efficacy of using helium-oxygen gas mixtures between pressure-controlled CMV and piston-driven HFOV in rabbit models. CO₂ transition was evaluated using blood gas analysis performed during and after helium administration. Experimental data were analyzed using parametric statistical methods. A repeated measures analysis of variance was used to compare CO₂ excretion between HFOV and CMV.

Results

There was no statistically significant difference in the partial pressure of CO₂ (PaCO₂) or oxygen (PaO₂) values before or after helium administration. Compared with pre-helium administration, PaCO₂ values during helium administration were decreased under both CMV and piston-driven HFOV. Moreover, the PaCO₂ transition during helium administration while using piston-driven HFOV was shown to be statistically significantly different (P < 0.001).

Conclusions

This study demonstrated that helium enhances CO₂ elimination more significantly during piston-driven HFOV compared with that in CMV in rabbit models with normal lungs. With further study and clinical trials, these results imply that the use of HFOV while using a helium-oxygen mixture may improve CO₂ excretion.

helium-oxygen mixtures

pressure-controlled ventilation

intermittent mandatory ventilation

high-frequency ventilation

high-frequency oscillatory ventilation

carbon dioxide excretion

rabbit models

Low-molecular-weight gases are more likely to create laminar flow and reduce airway resistance in turbulent flow(1). Subsequently, they are able to reach the alveoli more easily, diffuse more effectively, and may facilitate carbon dioxide (CO₂) elimination more rapidly(2–5). Helium is a unique gas in that it has a very small molecular weight (4 g/mol) and density (0.156 g/L [37°C, 1 atmosphere]). Unlike air (nitrogen-oxygen gas mixtures), helium-oxygen gas mixtures have a smaller weight and density.

Helium-oxygen gas mixtures have been used in several clinical scenarios, such as bronchiolitis and other forms of distal airway obstruction, as it is known to significantly decreasing airway resistance and ease breathing(6). In addition, a recent retrospective cohort study showed that a helium-oxygen gas mixture improved CO₂ washout in conventional mechanical ventilation (CMV) and decreased settings of ventilator in neonates with congenital diaphragmatic hernias(7).

The combination of high-frequency oscillatory ventilation (HFOV) and helium-oxygen gas mixtures has been researched in animal models(2–4, 8–10) and in clinical settings(11). These animal studies used different HFOV types. Some studies using membrane-driven HFOV (i.e., HFOVs in which the oscillation source is a membrane) showed that helium-oxygen mixtures were associated with a larger tidal volume delivery and did not improve CO₂ excretion(2–4). Other studies which used piston-driven HFOV (i.e., HFOVs in which the oscillation source is a piston) demonstrated that helium-oxygen mixture improved CO₂ excretion and enabled lower ventilatory settings in respiratory management(8, 9). However, the best of our knowledge, no studies have compared the use of piston-driven HFOV and CMV when using helium-oxygen gas mixtures. Therefore, the aim of this study was to compare the efficacy of using helium-oxygen gas mixtures between CMV and piston-driven HFOV in rabbit models.

Arterial blood gas samples were collected to determine the partial pressure of CO₂ (PaCO₂) and oxygen (PaO₂) values prior to helium administration (pre-He; helium concentration 0%), during helium administration (He; helium concentration 79%), and after helium discontinuation (post-He; helium concentration 0%) and compared under CMV and HFOV modes. The ventilator settings after initial adjustments are shown in Table 1.

Table 1

Used ventilator setting after initial adjustment
CMV	Mean (SD)
Peak inspiratory pressure (cmH₂O)	16.2 (2.4)
Ventilation rate (breaths/min)	15.5 (1.2)
Inspiratory time (s)	0.6 (0.0)
Positive end-expiratory pressure (cmH₂O)	5.0 (0.0)
HFOV
Mean airway pressure (cmH₂O)	10.3 (0.8)
Amplitude (cmH₂O)	22.2 (1.8)
Stroke volume (mL)	11.0 (1.1)
Frequency (Hz)	15 (0.0)
CMV: conventional mechanical ventilation; HFOV: high-frequency oscillatory ventilation; SD: standard deviation

There was no statistical difference in PaCO₂ or PaO₂ values (Table 2) between pre-He and post-He. PaCO₂ values during helium administration (He) decreased under both CMV and HFOV compared with those before helium administration (pre-He). Moreover, the PaCO₂ elimination with helium administration during HFOV was shown to be statistically significantly different (P < 0.001) from that with helium administration while using CMV (Fig. 1).

Table 2

Comparison of PaCO2 and PaO2 values before and after helium administration
Group	HFOV	CMV	P-value
PaCO₂; pre-He (mmHg)	50.8 (10.4)	54.4 (8.8)	0.534
PaCO₂; post-He (mmHg)	46.0 (14.9)	50.9 (3.2)	0.448
PaO₂; pre-He (mmHg)	417.2 (54.1)	457.8 (68.4)	0.28
PaO₂; post-He (mmHg)	391.5 (81.0)	409.0 (98.2)	0.743
Values are represented as means (standard deviation) PaCO₂: measured partial pressure of carbon dioxide in arterial blood; PaO₂: measured partial pressure of oxygen in arterial blood; HFOV: high-frequency oscillatory ventilation; CMV: conventional mechanical ventilation; pre-He: before helium administration; post-He: after helium administration

As far as we are aware, this is likely the first report to show the superior efficacy of helium-oxygen gas mixtures with HFOV compared with that of CMV. The effectiveness of helium administration in improving gas exchange during both HFOV and CMV in animal experiment models has been demonstrated(3, 4, 8, 9). These results varied depending on the type of HFOV used in each animal experiment.

Katz et al. used membrane-driven HFOV and initially reported that CO₂ excretion improved by replacing nitrogen-oxygen gas mixtures with helium-oxygen gas mixtures(3). However, they subsequently concluded that this finding was the direct result of the decreased airway resistance and increased tidal volume of HFOV. They also concluded that CO₂ excretion remains unchanged if the tidal volume of HFOV remained constant(4). In contrast, animal experiments using piston-driven HFOV showed that administration of helium-oxygen gas mixtures improved CO₂ excretion, which is consistent with our experimental results(8, 9). The presence or absence of improvement in CO₂ excretion depends on the difference between different models of HFOVs; that is, different models have different mechanisms for generating oscillations and whether expiration is actively performed (piston-driven) by the oscillator or not (passively: membrane-driven). These differences also result in different pressure waveforms generated by the oscillator and different inspiratory and expiratory ratios. Based on these differences, it is understandable that the effectiveness of helium administration in improving CO₂ excretion depends on the differences in HFOV machines(12–14).

Helium-oxygen gas mixtures have lower densities and viscosities than standard air (nitrogen-oxygen gas mixtures), and their use results in increased laminar flow and decreased turbulence(15). With a constant airway length and thickness, turbulent flow results in greater resistance than laminar flow. Furthermore, especially in pediatric and neonatal patients, mechanical ventilation through narrow tracheal tubes and airways further increase the Reynold’s number and leads to greater turbulence(6, 16). Due to its favorable properties, helium administration decreases the work of breathing during mechanical ventilation and during spontaneous ventilation (classical ventilation effect). Additionally, as helium has a higher diffusion coefficient, CO₂ diffuses 2.3–4 times faster in helium-oxygen gas mixtures than with standard air(5, 7) (diffusion effect).

Ventilation consists of several mechanisms including classical ventilation, dispersion (including Taylor’s dispersion and augmented dispersion), and diffusion(17). CMV mainly depends on classical ventilation, and HFOV mainly depends on dispersion and diffusion(18). The classical ventilation effect when using helium is dramatically shown in high resistance airway pathophysiologies, such as bronchial asthma, bronchiolitis, severe croup, or tracheal stenosis(6). However, this effect is minimal in normal airways, such as in the animal models used in this study. Conversely, the diffusion effect when using helium can be demonstrated even in a normal lung with normal airway resistance. We assume that this mechanism explains the greater efficacy of using helium-oxygen gas mixtures with HFOV compared with CMV.

Our comparative study is unique and suggests several future clinical applications. Originally, HFOV is a ventilatory method that uses a high lung expansion pressure and tidal volume below the anatomical dead space to maintain lung oxygenation (open lung approach) and to decrease ventilator-induced lung injury. Therefore, the main indications for HFOV would be diseases presenting with low lung compliance and hypoxia such as pneumonia, adult respiratory distress syndrome, and congenital diaphragmatic hernias(7). Contrastingly, diseases with increased airway resistance— such as bronchial asthma, bronchiolitis or tracheal stenosis— are more problematic since they result in significant hypercapnia compared with hypoxemia. Diseases with increased airway resistance are classically not good indications for the use of HFOV(11). In the clinical practice of pediatric respiratory management, children with bronchial asthma and infectious bronchiolitis sometimes require intubation and ventilation using a thin tracheal tube. Subsequently, ventilatory management may cause hypercapnia to develop, which is already difficult to manage despite CMV use(11, 16). These children occasionally require extracorporeal life support to manage hypercapnia. Our results suggest that a combination of helium-oxygen gas mixtures with piston-driven HFOV may be a new alternative for managing CO₂ excretion in patients with high airway resistance and hypercapnia that is difficult to manage with CMV.

This study had some limitations. Patients develop respiratory failure either due to low lung compliance, increased airway resistance, or both. However, our experimental model used the lungs of non-pathological rabbits, hence we could not replicate these conditions. Moreover, our experimental methods may have affected the results due to the non-crossover design, helium substitution using oxygen rather than nitrogen, and lack of measurements of tidal volume during CMV and/or HFOV.

Potential future research should include investigating the changes in CO₂ excretion rate for different helium concentrations while comparing different HFOV systems (source of oscillation, respiratory circuit, etc.), and varying the frequency of oscillation. In addition, studies of biochemical, genetic, and pathological investigations are warranted, in addition to physiological considerations.

This study demonstrated that helium enhances CO₂ elimination more significantly during HFOV than CMV in rabbit models with normal lungs. The results suggest that hypercapnia may be managed within the target range by administering helium-oxygen gas mixtures while using piston-driven HFOV in patients with hypercapnia due to conditions associated with high airway resistance, which are difficult to manage with CMV. In pediatric patients particularly, ventilatory management of bronchiolitis and bronchial asthma attacks can be challenging for the management of CO₂ excretion. If this method is found to be clinically useful, it is expected to make a great impact in the respiratory management of these cases.

Aim, design, and setting

The aim of this study was to compare the efficacy of CO₂ excretion using helium-oxygen gas mixtures between CMV and HFOV. A comparative animal study was completed at the experimental laboratory of Paediatrics, St. Marianna University School of Medicine.

Animal preparation

The study design, protocol, and procedures were approved by the Institutional Animal Care and Use Committee of St. Marianna University School of Medicine, Kanagawa, Japan. Six Japanese white rabbits (body weight, 2.94 ± 0.14 kg) were used for our study. Animals were premedicated by intramuscular administration of induction anesthesia with a cocktail of medetomidine hydrochloride (0.17 mg/kg/dose), midazolam (1 mg/kg/dose), and butorphanol tartrate (1.7 mg/kg/dose). Animals were placed in a supine position under an infant radiant warmer (V 3200®, Atom Medical Corporation, Tokyo, Japan), and an additional warmer (heater mat for small animals, Type III KN-475-3-40®, Natsume Seisakusho, Tokyo, Japan) was inserted between the body of the animal and the radiant warmer bed to maintain rectal temperature of 39–40 degrees Celsius throughout the entire study period. Electrocardiogram (ECG), percutaneous oxygen saturation (SpO₂), and rectal temperature (Trec) probes were applied/placed. The ear vein was cannulated using a 24 G peripheral intravenous catheter (Jelco®, Smiths Medical Japan Ltd, Tokyo, Japan) for intravenous fluid administration and continuous administration of intravenous anesthesia and analgesia. Topical anesthesia with 1% lidocaine (0.5 mL) was applied prior to performing the incision of the skin and tracheal wall for surgical tracheostomy. A non-cuffed endotracheal tube (internal diameter; 3.0 mm; Portex®, Smiths Medical Japan Ltd, Tokyo, Japan) was inserted to a depth of 3 cm from the lower edge of the cricoid cartilage and ligated and fixed to the muscle around the trachea with a silk suture. After initiating mechanical ventilation (Calliope α®; Metran Co., Ltd., Saitama, Japan) and maintenance fluid (Veen-D Inj.®; Fuso Pharmaceutical Industries, Ltd., Osaka, Japan), maintenance anesthesia with a cocktail of midazolam (0.1 mg/kg/h) and rocuronium bromide (1.6 mg/kg/h) were started. The femoral artery was cannulated surgically using a 24 G peripheral catheter (Jelco®) for arterial blood pressure (ABP) monitoring and intermittent arterial blood gas (ABG) sampling. Continuous monitoring of the ECG, SpO₂, Trec, and ABP were performed using a biometric information monitor (Intellivue MP30®ฏ; Philips, Amsterdam, Netherlands), and anesthesia and analgesia were adjusted accordingly. After all experiments were completed, animals were humanely euthanized using secobarbital sodium (100 mg/kg/dose).

Helium and ventilator preparation

Helium was prepared as helium-oxygen gas mixtures (Heliox®; Air Water Inc., Osaka, Japan) with a 750 L gas cylinder. A Heliox® (helium 79% and oxygen 21%) gas tube and 100% oxygen gas tube were connected to a helium blender (OA2015FVH; Sanyu Technology Co., Ltd., Tokyo, Japan). Helium concentration (0–79%) and gas flow (0–10 L/min) were determined by the helium blender. The helium blender gas outlet was connected to the Jackson-Rees system circuit inlet through a green tube, and gas flow was fixed at 4 L/min. The Jackson-Rees system bag was connected to the ventilator circuit. The Calliope α® ventilator (Metran Co. Ltd.), which is a composite mode ventilator capable of both CMV and HFOV, was used. An air compressor (MACS-50; Tokibo International Co., Ltd., Osaka, Japan) was used as a driving source for the ventilator and connected using a specially manufactured Y-shaped air piping connection. The schematic of the experimental system is shown in Fig. 2.

Interventions and measurements

Ventilation of the animals was initially stabilized under CMV time-cycled pressure-limited mode. The default initial settings were a peak inspiratory pressure (PIP) of 18 cmH₂O, positive end expiratory pressure (PEEP) of 5 cmH₂O, ventilatory rate (VR) of 15 breaths/min, inspiratory time (Ti) of 0.6 s, and helium concentration of 0% (F_IO₂ 1.0). CMV parameters were adjusted to control PaCO₂ between 40 and 69 mmHg before the intervention. ABG was sampled after 15 min after the ventilator settings were changed. After this initial adjustment, ABG (pre-He) was measured, and helium concentration was increased to 79% (F_IO₂ 0.21) using the helium blender. The same CMV settings were maintained for 15 minutes and the ABG (He) was measured. Then, helium concentration was decreased to 0% (F_IO₂ 1.0). Using the same CMV settings for 15 minutes, a repeat ABG (post-He) was measured. After the CMV intervention, the Calliope® CMV mode was switched to the HFOV mode. The default initial settings were a mean airway pressure (MAP) of 10 cmH₂O, stroke volume (SV) of 10 mL, and frequency (Fr) of 15 Hz. A sigh pressure of 20 cmH₂O and a sigh time of 6 s was used for each sigh. HFOV parameters were adjusted to maintain a PaCO₂ between 40 and 69 mmHg before the intervention. After this initial adjustment, ABG (pre-He) was measured, and helium concentration was increased to 79% (F_IO₂ 0.21) using the helium blender. The same HFOV settings were maintained for 15 minutes and the ABG (He) was measured. Then, the helium concentration was decreased to 0% (F_IO₂ 1.0). Once again, the same HFOV settings were maintained for 15 minutes, followed by ABG (post-He) measurement. A sigh was used after each HFOV setting change, including the helium concentration change. The ABG sample was taken from an arterial line using a heparin-coated syringe and measured/analyzed using the i-STAT 1 Analyzer® (Abbott, Chicago, Illinois, USA).

Statistical analysis

All data are presented as mean ± standard deviation. Experimental data were analyzed using parametric statistical methods including paired t-tests. For repeated measures, analysis of variance (ANOVA) was used for the comparison of the transition of CO₂ with helium administration between HFOV and CMV. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, the EZR is a modified version of R commander designed with additional statistical functions frequently used in biostatistics(19). Statistical significance was defined as P < 0.05.

CO₂, carbon dioxide; CMV, conventional mechanical ventilation; HFOV, high-frequency oscillatory ventilation; ECG, electrocardiogram; SpO₂, percutaneous oxygen saturation; Trec, rectal temperature; ABP, arterial blood pressure; ABG, arterial blood gas; PaCO₂, partial pressure measurement of carbon dioxide in arterial blood gas sampling; PaO₂, partial pressure measurement of oxygen in arterial blood gas sampling; PIP, peak inspiratory pressure; PEEP, positive end expiratory pressure; Ti, inspiratory time; VR, ventilatory rate; MAP, mean airway pressure; SV, stroke volume; Fr, frequency; ANOVA, analysis of variance; F_IO₂, fraction of inspiratory oxygen; SD, standard deviation

Ethics approval and consent to participate

All study protocols were approved by the Institutional Animal Care and Use Committee of St. Marianna University School of Medicine, Kanagawa, Japan.

Consent for publication

Not applicable

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no financial conflict of interest. A part of the experimental instrument (Calliope®; Metran) was rented from Metran Co., Ltd.

Funding

This animal experiment was funded by St. Marianna University Graduate School Research Support Fund.

Authors’ contributions

LA participated in the study design and performed the statistical analysis. MA participated in the study design and performed the experiments. TS supervised and advised this study from a statistical standpoint. NS conceived the study, participated in its design of, and performed statistical analysis. All authors have read and approved the final draft of the manuscript.

Acknowledgements

A part of the experiment instrument was donated by Tokyo Metropolitan Children’s Medical Centre. We would like to thank Drs Ichiro Watanabe, Takayuki Sueishi, and Osamu Saito, Department of Paediatric Emergency & Critical Care Medicine, Tokyo Metropolitan Children’s Medical Centre.

Papamoschou D. Theoretical validation of the respiratory benefits of helium-oxygen mixtures. Respir Physiol. 1995;99:183–90.
Jaeger MJ. High-frequency ventilation in dogs with three gases of different densities. J Appl Physiol (1985). 1991;70:2188-92.
Katz A, Gentile MA, Craig DM, Quick G, Meliones JN, Cheifetz IM. Heliox improves gas exchange during high-frequency ventilation in a pediatric model of acute lung injury. Am J Respir Crit Care Med. 2001;164:260–4.
Katz AL, Gentile MA, Craig DM, Quick G, Cheifetz IM. Heliox does not affect gas exchange during high-frequency oscillatory ventilation if tidal volume is held constant. Crit Care Med. 2003;31:2006–9.
Katz I, Caillibotte G, Martin AR, Arpentinier P. Property value estimation for inhaled therapeutic binary gas mixtures: He, Xe, N₂O, and N₂ with O₂. Med Gas Res. 2011; 1:28. doi: 10.1186/2045-9912-1-28
Gainnier M, Forel JM. Clinical review: use of helium-oxygen in critically ill patients. Crit Care. 2006;10:241. doi: 10.1186/cc5104
Wise AC, Boutin MA, Knodel EM, Proudfoot JA, Lane BP, Evans ML, et al. Heliox adjunct therapy for neonates with congenital diaphragmatic hernia. Respir Care. 2018;63:1147–53.
Zeynalov B, Hiroma T, Nakamura T. Effects of heliox as carrier gas on ventilation and oxygenation in an animal model of piston-type HFOV: a crossover experimental study. Biomed Eng Online. 2010; 9:71. doi: 10.1186/1475-925X-9-71
Baba A, Nakamura T, Aikawa T, Koike K. Extremely low flow tracheal gas insufflation of helium-oxygen mixture improves gas exchange in a rabbit model of piston-type high-frequency oscillatory ventilation. Biomed Eng Online. 2013; 12:29. doi: 10.1186/1475-925X-12-29
Mildner RJ, Frndova H, Cox PN. Effect of air and heliox as carrier gas on CO₂ transport in a model of high-frequency oscillation comparing two oscillators. Crit Care Med. 2003;31:1759–63.
Winters JW, Willing MA, Sanfilippo D. Heliox improves ventilation during high-frequency oscillatory ventilation in pediatric patients. Pediatr Crit Care Med. 2000;1:33–7.
Froese AB. High frequency ventilation: current status. Can Anaesth Soc J. 1984;31: S9-12.
Hatcher D, Watanabe H, Ashbury T, Vincent S, Fisher J, Froese A. Mechanical performance of clinically available, neonatal, high-frequency, oscillatory-type ventilators. Crit Care Med. 1998;26:1081–8.
Pillow JJ, Wilkinson MH, Neil HL, Ramsden CA. In vitro performance characteristics of high-frequency oscillatory ventilators. Am J Respir Crit Care Med. 2001;164:1019–24.
Katz IM, Martin AR, Muller PA, Terzibachi K, Feng CH, Caillibotte G, et al. The ventilation distribution of helium-oxygen mixtures and the role of inertial losses in the presence of heterogeneous airway obstructions. J Biomech. 2011;44:1137–43.
Orsini AJ, Stefano JL, Leef KH, Jasani M, Ginn A, Tice L, et al. Heliox improves pulmonary mechanics in a pediatric porcine model of induced severe bronchospasm and independent lung mechanical ventilation. Crit Care. 1999;3:65–70.
Fredberg JJ. Augmented diffusion in the airways can support pulmonary gas exchange. J Appl Physiol Respir Environ Exerc Physiol. 1980;49:232–8.
Chang HK. Mechanisms of gas transport during ventilation by high-frequency oscillation. J Appl Physiol Respir Environ Exerc Physiol. 1984;56:553–63.
Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

No competing interests reported.

Download PDF

Journal Publication

published 26 Dec, 2023

Read the published version in Journal of St. Marianna University →

Version 1

posted

You are reading this latest preprint version

Helium administration is more effective during piston-driven high-frequency oscillatory ventilation than conventional mechanical ventilation in a rabbit model

Status:

Journal Publication

Version 1

Abstract

Background

Results

Conclusions

Figures

Background

Results

Discussion

Conclusion

Methods

Aim, design, and setting

Animal preparation

Helium and ventilator preparation

Interventions and measurements

Statistical analysis

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1