Name: halogenated agent delivery in porcine model of acute respiratory distress syndrome via an intensive care unit type device
Uploaded: 2020-09-24T13:30:00
Description: Watch this Scientific Journal Video about Halogenated Agent Delivery in Porcine Model of Acute Respiratory Distress Syndrome via an Intensive Care Unit Type Device at JoVE.com

The authors would like to thank the staff from the GreD, the Universit&#233; Clermont Auvergne, and the Centre International de Chirurgie Endoscopique (all in Clermont-Ferrand, France).

The study protocol was approved by the Animal Ethics Committee of the French Minist&#232;re de l&#8217;Education Nationale, de l&#8217;Enseignement Sup&#233;rieur et de la Recherche (approval number 01505.03) before being registered at preclinicaltrials.eu (Pre-clinical registry identifier PCTE0000129). All procedures were performed in the Centre International de Chirurgie Endoscopique, Universit&#233; Clermont Auvergne, Clermont-Ferrand, France, in accordance with the Animal Research: Reportin...

This article describes a reproducible experimental model of ARDS induced by the intratracheal instillation of HCl in piglets to investigate the lung-protective effects of halogenated volatiles, such as sevoflurane or isoflurane, delivered using an anesthetic conserving device.
The primary goal of this study was to develop an experimental model of ARDS in which volatile agents could be delivered by an anesthetic conserving device, such as those used in ICU patients. Although some effects of hal...

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure and death in critically ill patients1. It is characterized by both diffuse alveolar epithelial and endothelial injuries, leading to increased permeability and pulmonary edema, altered alveolar fluid clearance (AFC), and worsened respiratory distress2. The resorption of alveolar edema and recovery from ARDS require epithelial fluid transport through the alveoli to remain intact, which suggests that a therapy improving AFC could be useful3,4. Although lung-protective ventilation and a restrictive strategy for intravenous fluid therapy have proven beneficial in improving outcomes2,5, they are still associated with high mortality and morbidity6. Therefore, there is an urgent need to develop effective therapies for the syndrome and to better understand the precise mechanisms through which such therapies might work.
Halogenated anesthetics, such as isoflurane or sevoflurane, have been widely used for general anesthesia in the operating room. Sevoflurane is associated with decreased inflammation in the lungs of patients undergoing thoracic surgery and with a decrease in postoperative pulmonary complications, such as ARDS7. Similar results have been found in a meta-analysis of patients after cardiac surgery8. Halogenated volatiles also have a bronchodilatory effect9,10 and perhaps some properties that protect several organs, such as the heart8,11 and the kidneys12,13,14. Recently, there has been growing interest in the clinical use of inhaled anesthetics as sedatives in the intensive care unit (ICU). Both animal and human studies support the protective effects of pretreatment with halogenated agents before prolonged ischemia of the liver15, the brain16, or the heart11. Halogenated agents also have potential pharmacokinetic and pharmacodynamic advantages over other intravenous agents for the sedation of critically ill patients, including a rapid onset of action and fast offset due to little accumulation in tissues. Inhaled halogenated agents decrease intubation times in comparison with intravenous sedation in patients undergoing cardiac surgery17. Several studies support the safety and efficacy of halogenated agents in the sedation of ICU patients18,19,20. In experimental models of ARDS, inhaled sevoflurane improves gas exchange21,22, reduces alveolar edema21,22, and attenuates both pulmonary and systemic inflammation23. Isoflurane also ameliorates lung repair after injury by maintaining the integrity of the alveolar-capillary barrier, possibly by modulating the expression of a key tight junction protein24,25,26. In addition, mouse macrophages that were cultured and treated with isoflurane had better phagocytic effects on neutrophils than macrophages that were not treated with isoflurane27.
However, the precise biological pathways and mechanisms accounting for the lung-protective properties of volatile anesthetics remain largely unknown to date, requiring further investigation18. Additional studies are also warranted to investigate the precise effects of sevoflurane on lung injury and to verify whether experimental evidence can be translated to patients. The first randomized control trial from our team found that the administration of inhaled sevoflurane in patients with ARDS was associated with oxygenation improvement and decreased levels of both pro-inflammatory cytokines and lung epithelial injury markers, as assessed by plasma and alveolar soluble receptors for advanced glycation end products (sRAGE)28. As sRAGE is now considered as a marker of alveolar type 1 cell injury and a key mediator of alveolar inflammation, these results could suggest some beneficial effects of sevoflurane on the lung alveolar epithelial injury21,29,30.
The use of halogenated agents for inhaled ICU sedation has long required operating room anesthesia ventilators and gas vaporizers to be deployed in the ICU. Since then, anesthetic reflectors suitable for the use with modern critical care ventilators have been developed for specific use in the ICU31. These devices feature modified heat and moisture exchanging filters inserted between the Y-piece of the respiratory circuit and the endotracheal tube. They allow the administration of halogenated agents, with isoflurane and sevoflurane being the most frequently used, and they consist of a porous polypropylene evaporator rod, into which a liquid agent, delivered by a specific syringe pump, is released. The halogenated agent is absorbed during expiration by a reflecting medium contained in the device and it is released during the next inspiration, allowing recirculation of approximately 90% of the expired halogenated agent31,32. Recently, a miniaturized version of the device was developed with an instrumental dead space of 50 mL, making it even more suitable for use during ultra-protective ventilation in ARDS patients, with tidal volumes that could be as low as 200 mL31. Such a miniaturized device has never been studied in an experimental piglet model of ARDS.
Because previous research supports the promising roles of halogenated volatiles in lung alveolar inflammation and injury during ARDS, we designed an experimental animal model to achieve a translational understanding of the mechanisms of the effects of halogenated agents on lung injury and repair33,34,35. In this study, we developed a model of hydrochloric acid (HCl)-induced ARDS in piglets in whom inhaled sedation can be delivered using the miniaturized version of the anesthetic conserving device, an ICU-type device. This large animal model of ARDS could be used to further our understanding of the potential lung-protective effects of inhaled halogenated agents.

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			<td>Tracheal intubation</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Endotracheal tube 6-mm</td>
			<td>Covidien</td>
			<td>18860</td>
			<td></td>
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			<td></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Animal preparation</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Central venous catheter 3-lumens catheter (7 French - 16 cm)</td>
			<td>Arrow</td>
			<td>CV-12703</td>
			<td></td>
		</tr>
		<tr>
			<td>Pulse contour cardiac output monitor PiCCO catheter (3-5 French - 20 cm)</td>
			<td>Getinge Pulsion Medical System</td>
			<td>catheter</td>
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		</tr>
		<tr>
			<td>Warm blankets WarmTouch5300</td>
			<td>MedTronic</td>
			<td>5300</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td></td>
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		<tr>
			<td>Monitoring</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>External monitor IntelliVue MP40</td>
			<td>Phillips</td>
			<td>MNT 142</td>
			<td></td>
		</tr>
		<tr>
			<td>Point-of-care blood gas analyzer Epoc&#174; Blood Analysis System</td>
			<td>Siemens</td>
			<td>20093</td>
			<td></td>
		</tr>
		<tr>
			<td>Pulse contour cardiac output monitor PiCCO Device PulsioFlex Monitor</td>
			<td>Getinge Pulsion Medical System</td>
			<td>PulsioFlex</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
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			<td>Mechanical ventilation</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Ventilator Engstr&#246;m Carestation</td>
			<td>General Electrics</td>
			<td>Engstr&#246;m</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
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			<td>Halogenated anesthetics</td>
			<td></td>
			<td></td>
			<td></td>
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		<tr>
			<td>Anaconda Syringe</td>
			<td>SedanaMedical</td>
			<td>26022</td>
			<td></td>
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			<td>Anesthetic conserving device AnaConDa-S</td>
			<td>SedanaMedical</td>
			<td>26050</td>
			<td></td>
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			<td>Charcoal filter FlurAbsorb</td>
			<td>SedanaMedical</td>
			<td>26096</td>
			<td></td>
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			<td>Filling Adaptaters</td>
			<td>SedanaMedical</td>
			<td>26042</td>
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		</tr>
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			<td>Ionomer membrane dryer line Nafion</td>
			<td>SedanaMedical</td>
			<td>26053</td>
			<td></td>
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		<tr>
			<td></td>
			<td></td>
			<td></td>
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		</tr>
		<tr>
			<td>Products</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Propofol</td>
			<td>Mylan</td>
			<td>66617123</td>
			<td></td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>Virbac</td>
			<td>QN01AB06</td>
			<td></td>
		</tr>
		<tr>
			<td>Pentobarbital</td>
			<td>PanPharma</td>
			<td>68942457</td>
			<td></td>
		</tr>
		<tr>
			<td>Sevoflurane</td>
			<td>Abbvie</td>
			<td>N01AB08</td>
			<td></td>
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			<td>Sufentanil</td>
			<td>Mylan</td>
			<td>62404996</td>
			<td></td>
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</table>

halogenated agent delivery in porcine model of acute respiratory distress syndrome via an intensive care unit type device

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure and death in critically ill patients, and there is an urgent need to find effective therapies. Preclinical studies have shown that inhaled halogenated agents may have beneficial effects in animal models of ARDS. The development of new devices to administer halogenated agents using modern intensive care unit (ICU) ventilators has significantly simplified the dispensing of halogenated agents to ICU patients. Because previous experimental and clinical research suggested potential benefits of halogenated volatiles, such as sevoflurane or isoflurane, for lung alveolar epithelial injury and inflammation, two pathophysiologic landmarks of diffuse alveolar damage during ARDS, we designed an animal model to understand the mechanisms of the effects of halogenated agents on lung injury and repair. After general anesthesia, tracheal intubation, and the initiation of mechanical ventilation, ARDS was induced in piglets via the intratracheal instillation of hydrochloric acid. Then, the piglets were sedated with inhaled sevoflurane or isoflurane using an ICU-type device, and the animals were ventilated with lung-protective mechanical ventilation during a 4 h period. During the study period, blood and alveolar samples were collected to evaluate arterial oxygenation, the permeability of the alveolar-capillary membrane, alveolar fluid clearance, and lung inflammation. Mechanical ventilation parameters were also collected throughout the experiment. Although this model induced a marked decrease in arterial oxygenation with altered alveolar-capillary permeability, it is reproducible and is characterized by a rapid onset, good stability over time, and no fatal complications.
We have developed a piglet model of acid aspiration that reproduces most of the physiological, biological, and pathological features of clinical ARDS, and it will be helpful to further our understanding of the potential lung-protective effects of halogenated agents delivered through devices used for inhaled ICU sedation.

For this experiment, 25 piglets were anesthetized and divided in two groups: 12 piglets in the untreated group (SHAM group) and 13 piglets in the acid-injured group (HCl group). No piglet died before the end of the experiment. A two-way repeated-measures analysis of variance (RM-ANOVA) indicated a significant time by group interaction (P &#60; 10&#8722;4) with a detrimental effect of HCl-induced ARDS on PaO2/FiO2, compared to sham animals without ARDS (Figure 3</stron...

Watch this Scientific Journal Video about Halogenated Agent Delivery in Porcine Model of Acute Respiratory Distress Syndrome via an Intensive Care Unit Type Device at JoVE.com

Halogenated Agent Delivery in Porcine Model of Acute Respiratory Distress Syndrome via an Intensive Care Unit Type Device

We describe a model of hydrochloric acid-induced acute respiratory distress syndrome (ARDS) in piglets receiving sedation with halogenated agents, isoflurane and sevoflurane, through a device used for inhaled intensive care sedation. This model can be used to investigate the biological mechanisms of halogenated agents on lung injury and repair.

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure and death in critically ill patients, and there is an urgent ...

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