Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Intensive Care Medicine
Published in: Intensive Care Medicine 5/2010

01-05-2010 | Experimental

Hypercapnic acidosis in ventilator-induced lung injury

Authors: Vanya Peltekova, Doreen Engelberts, Gail Otulakowski, Satoko Uematsu, Martin Post, Brian P. Kavanagh

Published in: Intensive Care Medicine | Issue 5/2010

Login to get access

Abstract

Rationale

Permissive hypercapnia is established in lung injury management. Therapeutic hypercapnia causes benefit or harm, depending on the context. Ventilator-associated lung injury has a wide spectrum of candidate mechanisms, affording multiple opportunities for intervention such as hypercapnia to exert benefit or harm.

Objectives

To confirm (1) that hypercapnia attenuates in vivo ventilator-induced lung injury (VILI); (2) biological plausibility of such protection (e.g., dose-response, time series, inflammatory profile); and (3) that the associated biochemical events are consistently beneficial.

Methods

A mouse model of VILI was established in vivo. Injurious ventilation was established, hypercapnia applied and markers of inflammation measured.

Measurements

Lung injury was quantified by gas exchange, elastance, microvascular leak, histology and levels of cytokines and eicosanoids, cyclooxygenase and tissue nitrotyrosine.

Main results

Injurious ventilation caused significant lung injury (mechanics, microvascular leak, histology) and release of inflammatory cytokines, chemokines and eicosanoids. Hypercapnia attenuated these responses, with dose-response and time-dependent effects. No adverse effects of hypercapnia were observed in controls. Hypercapnia suppressed the transcription (mRNA) and translation (protein) of the major inducible prostanoid-generating enzyme (COX-2), but the effects on the downstream eicosanoids were modest. However, hypercapnia significantly increased lung tissue nitrotyrosine—at PaCO2 levels that were protective.

Conclusions

Hypercapnia provided consistent and biologically plausible in vivo protection against VILI, but elevated lung tissue levels of nitro-tyrosine as previously described in sepsis. Clinicians and those designing clinical trials need to be aware of the potential for detrimental effects when using hypercapnia in order to balance benefits versus harm with this approach.
Appendix
Available only for authorised users
Literature
1.
Hickling KG, Walsh J, Henderson S, Jackson R (1994) Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study. Crit Care Med 22:1568–1578CrossRefPubMed
2.
Hickling KG (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The acute respiratory distress syndrome network. N Engl J Med 342:1301–1308
3.
Kregenow DA, Swenson ER (2002) The lung and carbon dioxide: implications for permissive and therapeutic hypercapnia. Eur Respir J 20:6–11CrossRefPubMed
4.
Laffey JG, Kavanagh BP (2000) Biological effects of hypercapnia (Review). Intens Care Med 26:133–138CrossRef
5.
Kregenow DA, Rubenfeld GD, Hudson LD, Swenson ER (2006) Hypercapnic acidosis and mortality in acute lung injury. Crit Care Med 34:1–7CrossRefPubMed
6.
Laffey JG, Kavanagh BP (1999) Carbon dioxide and the critically ill—too little of a good thing? (Hypothesis Paper). Lancet 354:1283–1286CrossRefPubMed
7.
Shibata K, Cregg N, Engelberts D, Takeuchi A, Fedorko L, Kavanagh BP (1998) Hypercapnic acidosis may attenuate acute lung injury by inhibition of endogenous xanthine oxidase. Am J Resp Crit Care Med 158:1578–1584PubMed
8.
Halbertsma FJ, Vaneker M, Pickkers P, Snijdelaar DG, van Egmond J, Scheffer GJ, van der Hoeven HG (2008) Hypercapnic acidosis attenuates the pulmonary innate immune response in ventilated healthy mice. Crit Care Med 36:2403–2406CrossRefPubMed
9.
Sinclair SE, Kregenow DA, Lamm WJ, Starr IR, Chi EY, Hlastala MP (2002) Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med 166:403–408CrossRefPubMed
10.
Strand M, Ikegami M, Jobe AH (2003) Effects of high PCO2 on ventilated preterm lamb lungs. Pediatr Res 53:468–472CrossRefPubMed
11.
Broccard AF, Hotchkiss JR, Vannay C, Markert M, Sauty A, Feihl F, Schaller MD (2001) Protective effects of hypercapnic acidosis on ventilator-induced lung injury. Am J Respir Crit Care Med 164:802–806PubMed
12.
Laffey JG, Jankov RP, Engelberts D, Tanswell AK, Post M, Lindsay T, Mullen JB, Romaschin A, Stephens D, McKerlie C, Kavanagh BP (2003) Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injury. Am J Respir Crit Care Med 168:1383–1390CrossRefPubMed
13.
Laffey JG, Tanaka M, Engelberts D, Luo X, Yuan S, Keith Tanswell A, Post M, Lindsay T, Kavanagh BP (2000) Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir Crit Care Med 162:2287–2294PubMed
14.
Chonghaile MN, Higgins BD, Costello J, Laffey JG (2008) Hypercapnic acidosis attenuates lung injury induced by established bacterial pneumonia. Anesthesiology 109:837–848CrossRefPubMed
15.
Ni Chonghaile M, Higgins BD, Costello JF, Laffey JG (2008) Hypercapnic acidosis attenuates severe acute bacterial pneumonia-induced lung injury by a neutrophil-independent mechanism. Crit Care Med 36:3135–3144CrossRefPubMed
16.
Feihl F, Perret C (1994) Permissive hypercapnia. How permissive should we be? Am J Resp Crit Care Med 150:1722–1737PubMed
17.
Nunn JF (1987) Applied respiratory physiology. Butterworths, London, pp 235–283
18.
Zhu S, Basiouny KF, Crow JP, Matalon S (2000) Carbon dioxide enhances nitration of surfactant protein A by activated alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 278:L1025–L1031PubMed
19.
Lang JD Jr, Chumley P, Eiserich JP, Estevez A, Bamberg T, Adhami A, Crow J, Freeman BA (2000) Hypercapnia induces injury to alveolar epithelial cells via a nitric oxide-dependent pathway. Am J Physiol Lung Cell Mol Physiol 279:L994–L1002PubMed
20.
Lang JD, Figueroa M, Sanders KD, Aslan M, Liu Y, Chumley P, Freeman BA (2005) Hypercapnia via reduced rate and tidal volume contributes to lipopolysaccharide-induced lung injury. Am J Respir Crit Care Med 171:147–157CrossRefPubMed
21.
Doerr CH, Gajic O, Berrios JC, Caples S, Abdel M, Lymp JF, Hubmayr RD (2005) Hypercapnic acidosis impairs plasma membrane wound resealing in ventilator-injured lungs. Am J Respir Crit Care Med 171:1371–1377CrossRefPubMed
22.
Squadrito GL, Pryor WA (1998) Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med 25:392–403CrossRefPubMed
23.
Lymar SV, Hurst JK (1996) Carbon dioxide: physiological catalyst for peroxynitrite-mediated cellular damage or cellular protectant? Chem Res Toxicol 9:845–850CrossRefPubMed
24.
Lymar SV, Jiang Q, Hurst JK (1996) Mechanism of carbon dioxide-catalyzed oxidation of tyrosine by peroxynitrite. Biochemistry 35:7855–7861CrossRefPubMed
25.
Briva A, Vadasz I, Lecuona E, Welch LC, Chen J, Dada LA, Trejo HE, Dumasius V, Azzam ZS, Myrianthefs PM, Batlle D, Gruenbaum Y, Sznajder JI (2007) High CO2 levels impair alveolar epithelial function independently of pH. PLoS One 2:e1238CrossRefPubMed
26.
O’Croinin DF, Nichol AD, Hopkins N, Boylan J, O’Brien S, O’Connor C, Laffey JG, McLoughlin P (2008) Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury. Crit Care Med 36:2128–2135CrossRefPubMed
27.
D’Arcangelo D, Gaetano C, Capogrossi MC (2002) Acidification prevents endothelial cell apoptosis by Axl activation. Circ Res 91:e4–e12CrossRefPubMed
28.
Takeshita K, Suzuki Y, Nishio K, Takeuchi O, Toda K, Kudo H, Miyao N, Ishii M, Sato N, Naoki K, Aoki T, Suzuki K, Hiraoka R, Yamaguchi K (2003) Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation. Am J Respir Cell Mol Biol 29:124–132CrossRefPubMed
29.
Coakley RJ, Taggart C, Greene C, McElvaney NG, O’Neill SJ (2002) Ambient pCO2 modulates intracellular pH, intracellular oxidant generation, and interleukin-8 secretion in human neutrophils. J Leukoc Biol 71:603–610PubMed
30.
Wang X, Wu J, Li L, Chen F, Wang R, Jiang C (2003) Hypercapnic acidosis activates KATP channels in vascular smooth muscles. Circ Res 92:1225–1232CrossRefPubMed
31.
Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF, McLoughlin P (2004) Hypercapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit Care Med 169:46–56CrossRefPubMed
32.
Rai S, Engelberts D, Laffey JG, Frevert C, Kajikawa O, Martin TR, Post M, Kavanagh BP (2004) Therapeutic hypercapnia is not protective in the in vivo surfactant-depleted rabbit lung. Pediatr Res 55:42–49CrossRefPubMed
33.
Gomes RF, Shen X, Ramchandani R, Tepper RS, Bates JH (2000) Comparative respiratory system mechanics in rodents. J Appl Physiol 89:908–916PubMed
34.
Green TP, Johnson DE, Marchessault RP, Gatto CW (1988) Transvascular flux and tissue accrual of Evans blue: effects of endotoxin and histamine. J Lab Clin Med 111:173–183PubMed
35.
le Wang F, Patel M, Razavi HM, Weicker S, Joseph MG, McCormack DG, Mehta S (2002) Role of inducible nitric oxide synthase in pulmonary microvascular protein leak in murine sepsis. Am J Respir Crit Care Med 165:1634–1639CrossRef
36.
Espevik T, Nissen-Meyer J (1986) A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods 95:99–105CrossRefPubMed
37.
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefPubMed
38.
Copland IB, Reynaud D, Pace-Asciak C, Post M (2006) Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 291:L487–L495CrossRefPubMed
39.
Wilson MR, Choudhury S, Goddard ME, O’Dea KP, Nicholson AG, Takata M (2003) High tidal volume ventilation upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury. J Appl Physiol 95:1385–1393
40.
Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS (1997) Injurious ventilatory strategies increase cytokines and c-fos mRNA expression in an isolated rat lung model. J Clin Invest 99:944–952CrossRefPubMed
41.
von Bethmann AN, Brasch F, Nusing R, Vogt K, Volk HD, Muller KM, Wendel A, Uhlig S (1998) Hyperventilation induces release of cytokines from perfused mouse lung. Am J Respir Crit Care Med 157:263–272
42.
Ricard JD, Dreyfuss D, Saumon G (2001) Production of inflammatory cytokines in ventilator-induced lung injury: a reappraisal. Am J Respir Crit Care Med 163:1176–1180PubMed
43.
Bonnans C, Levy BD (2007) Lipid mediators as agonists for the resolution of acute lung inflammation and injury. Am J Respir Cell Mol Biol 36:201–205CrossRefPubMed
44.
Singer CA, Baker KJ, McCaffrey A, AuCoin DP, Dechert MA, Gerthoffer WT (2003) p38 MAPK and NF-kappaB mediate COX-2 expression in human airway myocytes. Am J Physiol Lung Cell Mol Physiol 285:L1087–L1098PubMed
45.
Catley MC, Chivers JE, Cambridge LM, Holden N, Slater DM, Staples KJ, Bergmann MW, Loser P, Barnes PJ, Newton R (2003) IL-1beta-dependent activation of NF-kappaB mediates PGE2 release via the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase. FEBS Lett 547:75–79CrossRefPubMed
46.
Mestre JR, Mackrell PJ, Rivadeneira DE, Stapleton PP, Tanabe T, Daly JM (2001) Redundancy in the signaling pathways and promoter elements regulating cyclooxygenase-2 gene expression in endotoxin-treated macrophage/monocytic cells. J Biol Chem 276:3977–3982CrossRefPubMed
47.
Held HD, Boettcher S, Hamann L, Uhlig S (2001) Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids. Am J Respir Crit Care Med 163:711–716PubMed
48.
Ricard JD, Dreyfuss D, Saumon G (2002) Ventilator-induced lung injury. Curr Opin Crit Care 8:12–20CrossRefPubMed
49.
50.
Minetti M, Mallozzi C, Di Stasi AM (2002) Peroxynitrite activates kinases of the src family and upregulates tyrosine phosphorylation signaling. Free Radic Biol Med 33:744–754CrossRefPubMed
51.
Mallozzi C, Di Stasi AM, Minetti M (2001) Nitrotyrosine mimics phosphotyrosine binding to the SH2 domain of the src family tyrosine kinase lyn. FEBS Lett 503:189–195CrossRefPubMed
52.
Liaudet L, Soriano FG, Szabo C (2000) Biology of nitric oxide signaling. Crit Care Med 28:N37–N52CrossRefPubMed
53.
Ishikawa TO, Jain NK, Taketo MM, Herschman HR (2006) Imaging cyclooxygenase-2 (Cox-2) gene expression in living animals with a luciferase knock-in reporter gene. Mol Imaging Biol 8:171–187CrossRefPubMed
Metadata
Title
Hypercapnic acidosis in ventilator-induced lung injury
Authors
Vanya Peltekova
Doreen Engelberts
Gail Otulakowski
Satoko Uematsu
Martin Post
Brian P. Kavanagh
Publication date
01-05-2010
Publisher
Springer-Verlag
Published in
Intensive Care Medicine / Issue 5/2010
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-010-1787-7

Other articles of this Issue 5/2010

Intensive Care Medicine 5/2010 Go to the issue

Original

A European care bundle for prevention of ventilator-associated pneumonia

Review

Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions

Brief Report

Effectiveness of acetazolamide for reversal of metabolic alkalosis in weaning COPD patients from mechanical ventilation

Original

Sildenafil attenuates pulmonary arterial pressure but does not improve oxygenation during ARDS

Brief Report

Daily skin cleansing with chlorhexidine did not reduce the rate of central-line associated bloodstream infection in a surgical intensive care unit

Original

Accuracy of C-reactive protein, procalcitonin, and mid-regional pro-atrial natriuretic peptide to guide site of care of community-acquired pneumonia