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Pathophysiology and treatment of chlorine gas-induced lung injury: an experimental study in pigs
Östergötlands Läns Landsting, Centre for Teaching and Research in Disaster Medicine and Traumatology, Centre for Teaching and Research in Disaster Medicine and Traumatology. Linköping University, Faculty of Health Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One of the most threatening scenarios in disaster medicine is the accidental release of toxic gases with the exposure of many people. In this respect, chlorine gas remains a significant threat due to its abundant use and transport through densely populated areas in modem society. Access to a simple and effective method of treatment that could be started early would be of great value. The main purpose of this study was to test a series of hypotheses related to chlorine gas lung injury and its treatment.

Anesthetized and mechanically ventilated pigs were exposed to chlorine gas (400 parts per million in air) using a closed system with a ventilator connected to gas cylinders. Plasma endothelin-1 (ET -1) and pro inflammatory cytokines were evaluated for 5 hours after injury while hemodynamics, gas exchange and lung mechanics were followed for 23 hours. Histopathology and lung water balance were assessed at the end of the experiment.

Chlorine gas exposure induced a rise in circulating ET-1 and circulating cytokines (TNF-α, and IL-1ß, IL-6). Pretreatment or treatment with tezosentan, a potent dual endothelin receptor antagonist, reduced the deterioration of pulmonary function induced by chlorine gas inhalation. Immediate prone positioning after chlorine gas injury not only inhibited deterioration of gas exchange but was also associated with improved pulmonary function and oxygen transport. Nebulized budesonide given within 30 minutes after chlorine gas lung injury was effective in preventing further progression of lung dysfunction but the effect of treatment given beyond 60 minutes was less efficient. The positive effects on pulmonary function and lung water were similar whether corticosteroids were given by aerosol or intravenously. Combined treatment with nebulized terbutaline and budesonide was associated with better recovery of lung function than either drug alone.

In conclusion, these studies outline the early pathophysiology of chlorine gas injury. They show that the endothelin system mediates the early pulmonary hypertensive and also to some extent the brochoconstrictive responses to inhaled chlorine gas. The work supports early administration of corticosteroids and ß2-agonists for individuals that are exposure to chlorine gas. In addition, early prone positioning of patients with severe chlorine gas lung injury may be useful.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2004. , 53 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 877
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24066Local ID: 3625ISBN: 91-7373-853-0 (print)OAI: oai:DiVA.org:liu-24066DiVA: diva2:244382
Public defence
2004-12-20, Aulan, Katastrofmedicinskt Centrum, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-26Bibliographically approved
List of papers
1. Effects of endothelin receptor antagonism on acute lung injury induced by chlorine gas
Open this publication in new window or tab >>Effects of endothelin receptor antagonism on acute lung injury induced by chlorine gas
Show others...
2006 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 34, no 6, 1731-1737 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To test the hypothesis that the endothelin system is involved in chlorine gas-induced lung injury.

DESIGN: Experimental study.

SETTING: Academic research laboratory.

SUBJECTS: Twenty-four domestic juvenile pigs.

INTERVENTIONS: Anesthetized, ventilated pigs were exposed to chlorine gas (400 parts per million in air) for 20 mins and then randomly allocated to four groups (n = 6 in each group). The tezosentan pretreatment group received the dual endothelin receptor antagonist tezosentan 20 mins before and hyperoxic gas (Fio2 0.6) after chlorine gas exposure. The tezosentan postinjury treatment group received hyperoxic gas after chlorine gas exposure and tezosentan 60 mins later. Animals in the oxygen group received hyperoxic gas after chlorine gas exposure. Pigs in the fourth group (air) were ventilated with room air (Fio2 0.21) throughout the experiment.

MEASUREMENTS AND MAIN RESULTS: Hemodynamics, gas exchange, lung mechanics, and plasma endothelin-1 were evaluated for 6 hrs. Chlorine gas exposure induced an increase in circulating endothelin-1 by 90% (p < .05). The acute chlorine gas-induced rise in pulmonary vascular resistance was partly blocked by tezosentan pretreatment (p < .001). Tezosentan postinjury treatment also decreased pulmonary vascular resistance to levels significantly lower than in the air and oxygen groups (p < .001). Recovery of peak airway pressure was better in the tezosentan-treated groups than in the air group. There were significant linear relationships between circulating endothelin-1 and pulmonary vascular resistance (r = .47, p < .001) and endothelin-1 and peak airway pressure (r = .41, p < .001). These relationships were modified by tezosentan.

CONCLUSIONS: Tezosentan modified chlorine gas-induced pulmonary dysfunction, indicating that the endothelin system is involved in this mode of acute lung injury.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37843 (URN)10.1097/01.CCM.0000218815.46611.63 (DOI)39627 (Local ID)39627 (Archive number)39627 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
2. Inhaled budesonide in experimental chlorine gas lung injury: influence of time interval between injury and treatment
Open this publication in new window or tab >>Inhaled budesonide in experimental chlorine gas lung injury: influence of time interval between injury and treatment
2002 (English)In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 28, no 3, 352-357 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To examine the time window between injury and treatment during which nebulized corticosteroid lessens lung injury induced by chlorine gas inhalation.

Design: An experimental laboratory study.

Setting: Academic research laboratory.

Subjects: Twenty-four juvenile female pigs.

Interventions: Twenty-four mechanically ventilated pigs were exposed to chlorine gas (400 PPM in air) for 20 min, then divided into four groups (six in each group). Nebulized budesonide (BUD) was given immediately (BUD 0 min), 30 min (BUD 30 min) or 60 min (BUD 60 min) after chlorine gas exposure. Six pigs receiving nebulized saline served as controls.

Measurements and main results: Hemodynamics, gas exchange and lung mechanics were evaluated for 5 h after chlorine gas exposure. All animals had an immediate increase in airway and pulmonary artery pressure and a sharp drop of arterial oxygenation. The mean arterial oxygen tension of BUD 0 min and BUD 30 min animals was significantly higher than in the control and the BUD 60 min groups (p<0.001). The recovery of lung compliance in the BUD 0 min and the BUD 30 min groups was significantly more rapid than in the control and the BUD 60 min groups (p<0.001). The pulmonary wet to dry weight ratio was greater in the control group than in the BUD-treated groups (p<0.05).

Conclusion: Treatment with inhaled budesonide immediately or 30 min after chlorine gas lung injury had similar positive effects on symptoms and signs of pulmonary injury, whereas treatment delayed for 60 min was less effective.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25446 (URN)10.1007/s00134-001-1175-4 (DOI)9892 (Local ID)9892 (Archive number)9892 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
3. Administration of aerosolized terbutaline and budesonide reduces chlorine gas-induced acute lung injury
Open this publication in new window or tab >>Administration of aerosolized terbutaline and budesonide reduces chlorine gas-induced acute lung injury
2004 (English)In: Journal of Trauma, ISSN 0022-5282, E-ISSN 1529-8809, Vol. 56, no 4, 850-862 p.Article in journal (Refereed) Published
Abstract [en]

Background: The pathophysiology and treatment of chlorine gas-induced acute lung injury is poorly characterized and based on anecdotal data. This study aimed to assess the effects of aerosolized beta-2 adrenergic agonist and corticosteroid therapy on chlorine gas-induced lung injury.

Methods: Anesthetized, ventilated pigs were exposed to chlorine gas (400 parts per million for 20 minutes), then assigned randomly 30 minutes later to receive aerosolized terbutaline, budesonide, terbutaline followed by budesonide or placebo (6 pigs in each group). Hemodynamics, gas exchange, and lung mechanics were evaluated for another 5 hours.

Results: All the animals demonstrated an immediate increase in airway and pulmonary artery pressure as well as sharp drops in arterial oxygen tension (PaO2) and lung compliance (C L). Recovery of PaO2 and CL was greatest in the terbutaline plus budesonide group, but therapy with terbutaline and budesonide alone also was associated with significant improvement in PaO2 and CL, as compared with placebo.

Conclusions. Treatment of acute chlorine gas lung injury with aerosolized terbutaline followed by aerosolized budesonide improved lung function. Combined treatment was more effective than treatment with either drug alone.

Keyword
acute lung injury, aerosol, chlorine gas, beta-2-adrenergic agonist, corticosteroid, experimental study, lung function
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-46235 (URN)10.1097/01.TA.0000078689.45384.8B (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
4. Effects of prone and supine posture on cardiopulmonary function after experimental chlorine gas lung injury
Open this publication in new window or tab >>Effects of prone and supine posture on cardiopulmonary function after experimental chlorine gas lung injury
2002 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 46, no 9, 1094-1102 p.Article in journal (Refereed) Published
Abstract [en]

Background: Chlorine gas may induce severe acute lung injury. Improvement of pulmonary gas exchange in patients and animals with acute lung injury nursed in the prone position was observed in recent years. The purpose of this study was to evaluate the effects of prone and supine positions on pulmonary and cardiovascular functions following experimental chlorine gas lung injury.

Methods: Twenty anesthetized and mechanically ventilated pigs were exposed to chlorine gas (400 p.p.m. in air) for 20 min in the supine position, then assigned randomly to ventilation in the supine or prone positions (n=10 in each group). Hemodynamics, gas exchange, lung mechanics and oxygen transport were evaluated for 5 h.

Results: All animals showed severe pulmonary dysfunction immediately after chlorine gassing with a threefold increase in pulmonary vascular resistance index, a drop in arterial oxygenation (12.3±1.3 kPa to 5.4±0.7 kPa) and a fall in lung-thorax compliance (22±1 ml cmH2O−1 to 8±2 ml cmH2O−1). Venous admixture (Qs/Qt) improved in animals in the prone position while there was no change in the supine position (prone 32±11% vs. supine 42±9% at 5 h,P<0.05). Lung-thorax compliance improved significantly with time in the prone group only (P<0.01). Oxygen delivery increased significantly in prone animals compared with animals nursed in the supine posture (P<0.001).

Conclusion: Immediate prone positioning after chlorine gas injury not only inhibited deterioration of gas exchange but was also associated with improved pulmonary function and oxygen transport.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24824 (URN)10.1034/j.1399-6576.2002.460907.x (DOI)9221 (Local ID)9221 (Archive number)9221 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
5. Inhaled and intravenous corticosteroids both attenuate chlorine gas-induced lung injury in pigs
Open this publication in new window or tab >>Inhaled and intravenous corticosteroids both attenuate chlorine gas-induced lung injury in pigs
2005 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 49, no 2, 183-190 p.Article in journal (Refereed) Published
Abstract [en]

Background:  The accidental release of chlorine gas is a constant threat in urban areas. The purpose of this randomized, blinded, controlled experiment was to examine the effects of post-injury administration of inhaled or intravenous corticosteroid in chlorine gas-injured pigs followed for 23 h.

Methods:  Anaesthetized, ventilated pigs (n = 24) in the prone position were exposed to chlorine gas (400 parts per million in air) (1160 mg/m3) for 15 min, then randomly allocated to receive inhaled budesonide (BUD) and intravenous placebo, intravenous betamethasone (BETA) and inhaled placebo or inhaled and intravenous placebo. Haemodynamics, gas exchange and lung mechanics were evaluated for 23 h after exposure to chlorine gas.

Results:  Airway and pulmonary artery pressures increased and arterial oxygenation fell sharply (from 13.5 ± 0.8 to 6.7 ± 0.9 kPa, P < 0.001) after chlorine gas exposure. These immediate changes were followed by a gradual improvement over 5–7 h to a stable level of dysfunction for the rest of the experiment in placebo animals. Arterial oxygen tension, pulmonary vascular resistance and airway pressure recovered faster and more completely in the budesonide and betamethasone groups than in the placebo group (P < 0.01). Lung wet weight to dry weight ratios were greater in the placebo group than in the budesonide and betamethasone groups (6.34 ± 0.59 vs. 5.56 ± 0.38 and 5.53 ± 0.54, respectively, P < 0.05). There was a trend towards lower histological injury scores compared with placebo in animals that received budesonide (P = 0.05) or betamethasone (P = 0.07).

Conclusion:  Treatment of chlorine gas lung injury with nebulized budesonide or intravenous betamethasone had similar positive effects on recovery of lung function.

Keyword
Acute lung injury, Chlorine gas, Experimental study, Intravenous corticosteroid, Nebulized corticosteroid, Randomized controlled study
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-45510 (URN)10.1111/j.1399-6576.2004.00563.x (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved

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