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Hypercapnia and ventilator-induced diaphragmatic dysfunction

Ozan Akca12* and Alexander Bautista1

Author Affiliations

1 Department of Anesthesiology and Perioperative Medicine, University of Louisville, 530 S. Jackson Street, Louisville, KY 40202, USA

2 Outcomes Research™ Consortium, Cleveland, OH 44195, USA

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Critical Care 2013, 17:129  doi:10.1186/cc12563

See related research by Jung et al.,

The electronic version of this article is the complete one and can be found online at:

Published:8 April 2013

© 2013 BioMed Central Ltd


In the previous issue of Critical Care, Jung and colleagues report on the preventive effects of hypercapnia on ventilator-induced diaphragmatic dysfunction (VIDD) under controlled ventilation. Possibly, a combination of controlled hypercapnia and allowed spontaneous breathing efforts may provide complementary protection for diaphragm and respiratory functionality during mechanical ventilation. However, further safety and efficacy studies need to be performed in various different animal models and patients before a universal application of hypercapnia in the critical care setting for the prevention of VIDD can be considered.


In the previous issue of Critical Care, Jung and colleagues [1] report on the effects of moderate hypercapnia on diaphragmatic function in mechanically ventilated piglets, in the absence of muscle relaxants. Ventilator-induced diaphragmatic dysfunction (VIDD) is a recently recognized complication of prolonged controlled ventilation, which may progress to diaphragmatic muscle atrophy and result in long-term dependence on mechanical ventilation [2]. Diaphragmatic muscle weakening is partially explained by proteolysis, apoptosis and oxidative stress [3], and appears to be directly proportional to duration of mechanical ventilation [4]; anti-oxidant and anti-inflammatory agents such as steroids may attenuate the process [5,6].

Hypercapnia and hypercapnic acidosis at mild to moderate levels have protective effects in many experimental models of organ injury. Hypercapnia increases cardiac output, and this effect appears to be due to inotropy rather than chronotropy, when tested using an arterial carbon dioxide pressure (PaCO2) of up to 60 mmHg [7]. Hypercapnia also improves tissue oxygenation and perfusion [7-10]. Possibly, effects on oxygenation and perfusion are guided by elevating cardiac output and partially by peripheral vasodilatation effects as well as the rightward shifting of the oxyhemoglobin dissociation curve. In addition, hypercapnia has important effects on inflammatory responses. Its effects on altering the proinflammatory response, preserving organ function during mechanical, mechano-chemical, and ischemia-reperfusion injury are a few examples of its potential benefits in the prevention of organ failure [11]. Laffey and colleagues showed prophylactic and therapeutic roles of hypercapnia on oxygenation, inflammation, and immunological outcomes [12]. They concluded that hypercapnic acidosis was beneficial in lipopolysaccharide-induced lung injury both prophylactically and therapeutically. Hypercapnic acidosis provided better alveolar-arterial oxygen gradients, better static compliance, histological outcomes, and diminished neutrophil counts in the bronchoalveolar lavage fluid as shown in this landmark work.

Jung and colleagues reported that after 72 hours of controlled mechanical ventilation, diaphragm contractions to maximal stimulus were preserved in hypercapnic animals compared to a 25% decrease in the normocapnic ventilated animals. These important findings strengthen the potential role of hypercapnia in injury prevention. Although the authors did not design the study to assess potential mechanistic explanations for their promising results, diaphragmatic function was likely preserved due to improved tissue perfusion and decreased pro-inflammatory responses. Controlling lung injury, preventing diaphragmatic dysfunction, and altering exaggerated pro-inflammatory responses may suggest an important potential role for mild to moderate hypercapnia and hypercapnic acidosis in acutely developing systemic inflammatory processes.

However, there are various hurdles to overcome before therapeutic utilization of hypercapnia can be considered. First, it should be noted that most of the organ-specific benefits have been shown in animal studies. Therefore, most of these therapeutic effects need to be tested in relevant clinical settings under controlled environments and during critical illness. Second, the effects on inflammatory responses need to be further detailed before giving consideration to its use in acute disease processes. While hypercapnic acidosis is protective against lung injury, there are major concerns about its potential side effects in the setting of pulmonary sepsis. Some of these are due to its effects in altering pro-inflammatory responses during acute infection [13,14]. Hypercapnic acidosis appears to inhibit pulmonary epithelial wound healing by reducing cell migration via an NF-κB-dependent mechanism. This mechanism may involve alterations in matrix metalloproteinase activity. Beneficial effects of hypercapnia are mediated partially by inhibition of the host immune response, particularly the cytokine pathway, phagocyte function, and the adaptive immune response. These immunosuppressive properties may prevent host defense systems from responding to pathogenic microorganisms sufficiently [15].

In summary, we applaud Jung and colleagues for their promising work of using hypercapnia to prevent initiation of VIDD. Possibly, a combination of controlled hypercapnia and allowed spontaneous breathing efforts may provide complementary protection for diaphragm and respiratory functionality during mechanical ventilation. However, further safety, duration of therapy, and dose-finding studies need to be performed in various different animal models and patients before a universal application of hypercapnia in the critical care setting for the prevention of VIDD can be considered.


NF: nuclear factor; VIDD: ventilator-induced diaphragmatic dysfunction.

Competing interests

The authors declare that they have no competing interests.


We would like to thank Dr Brian Kavanagh for his critical reading and suggestions.


  1. Jung B, Sebbane M, Le Goff C, Rossel N, Chanques G, Futier E, Constantin JM, Matecki S, Jaber S: Moderate and prolonged hypercapnic acidosis may protect against ventilator-induced diaphragmatic dysfunction in healthy piglet: an in vivo study.

    Crit Care 2013, 17:R15. PubMed Abstract | BioMed Central Full Text OpenURL

  2. Jaber S, Jung B, Matecki S, Petrof BJ: Clinical review: ventilator-induced diaphragmatic dysfunction--human studies confirm animal model findings!

    Crit Care 2011, 15:206. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  3. Petrof BJ, Jaber S, Matecki S: Ventilator-induced diaphragmatic dysfunction.

    Curr Opin Crit Care 2010, 16:19-25. PubMed Abstract | Publisher Full Text OpenURL

  4. Sassoon CS: Ventilator-associated diaphragmatic dysfunction.

    Am J Respir Crit Care Med 2002, 166:1017-1018. PubMed Abstract | Publisher Full Text OpenURL

  5. McClung JM, Kavazis AN, Whidden MA, DeRuisseau KC, Falk DJ, Criswell DS, Powers SK: Antioxidant administration attenuates mechanical ventilation-induced rat diaphragm muscle atrophy independent of protein kinase B (PKB Akt) signalling.

    J Physiol 2007, 585:203-215. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  6. Maes K, Testelmans D, Cadot P, Deruisseau K, Powers SK, Decramer M, Gayan-Ramirez G: Effects of acute administration of corticosteroids during mechanical ventilation on rat diaphragm.

    Am J Respir Crit Care Med 2008, 178:1219-1226. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  7. Akça O, Doufas A, Morioka N, Iscoe S, Fisher J, Sessler D: Hypercapnia improves tissue oxygenation.

    Anesthesiology 2002, 97:801-806. PubMed Abstract | Publisher Full Text OpenURL

  8. Laffey J, Kavanagh B: Carbon dioxide and the critically ill- too little of a good thing?

    Lancet 1999, 354:1283-1286. PubMed Abstract | Publisher Full Text OpenURL

  9. Laffey J, Kavanagh B: Biological effects of hypercapnia.

    Intensive Care Med 2000, 26:133-138. PubMed Abstract | Publisher Full Text OpenURL

  10. Akca O, Sessler DI, Delong D, Keijner R, Ganzel B, Doufas AG: Tissue oxygenation response to mild hypercapnia during cardiopulmonary bypass with constant pump output.

    Br J Anaesth 2006, 96:708-714. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  11. Laffey JG, Tanaka M, Engelberts D, Luo X, Yuan S, Tanswell AK, Post M, Lindsay T, Kavanagh BP: Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion.

    Am J Respir Crit Care Med 2000, 162:2287-2294. PubMed Abstract OpenURL

  12. Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF, McLoughlin P: Hypercapnic acidosis attenuates endotoxin-induced acute lung injury.

    Am J Respir Crit Care Med 2004, 169:46-56. PubMed Abstract OpenURL

  13. Ni Chonghaile M, Higgins BD, Costello JF, Laffey JG: Hypercapnic acidosis attenuates severe acute bacterial pneumonia-induced lung injury by a neutrophil-independent mechanism.

    Crit Care Med 2008, 36:3135-3144. PubMed Abstract | Publisher Full Text OpenURL

  14. O'Croinin DF, Nichol AD, Hopkins N, Boylan J, O'Brien S, O'Connor C, Laffey JG, McLoughlin P: Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury.

    Crit Care Med 2008, 36:2128-2135. PubMed Abstract | Publisher Full Text OpenURL

  15. Curley G, Contreras MM, Nichol AD, Higgins BD, Laffey JG: Hypercapnia and acidosis in sepsis: a double-edged sword?

    Anesthesiology 2010, 112:462-472. PubMed Abstract | Publisher Full Text OpenURL