Hypercapnia and ventilator-induced diaphragmatic dysfunction

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 eff ects 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 ventila tion [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-infl ammatory agents such as steroids may attenuate the process [5,6].
Hypercapnia and hypercapnic acidosis at mild to moderate levels have protective eff ects in many experimental models of organ injury. Hypercapnia increases cardiac output, and this eff ect appears to be due to inotropy rather than chronotropy, when tested using an arterial carbon dioxide pressure (PaCO 2 ) of up to 60 mmHg [7]. Hypercapnia also improves tissue oxygenation and perfusion [7][8][9][10]. Possibly, eff ects on oxygenation and perfusion are guided by elevating cardiac output and partially by peripheral vasodilatation eff ects as well as the rightward shifting of the oxyhemoglobin dissociation curve. In addition, hypercapnia has important eff ects on infl ammatory responses. Its eff ects on altering the proinfl ammatory response, preserving organ function during mechanical, mechano-chemical, and ischemia-reperfusion injury are a few examples of its potential benefi ts in the prevention of organ failure [11]. Laff ey and colleagues showed prophylactic and therapeutic roles of hypercapnia on oxygenation, infl ammation, and immunological outcomes [12]. Th ey concluded that hypercapnic acidosis was benefi cial 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 fl uid 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. Th ese important fi ndings 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-infl ammatory responses. Controlling lung injury, preventing diaphragmatic dysfunction, and altering exaggerated pro-infl ammatory responses may suggest an important potential role for mild to moderate hypercapnia and hypercapnic acidosis in acutely developing systemic infl am matory 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-specifi c benefi ts have been shown in animal studies. Th erefore,

Abstract
In the previous issue of Critical Care, Jung and colleagues report on the preventive eff ects of hypercapnia on ventilator-induced diaphragmatic dysfunction (VIDD) under controlled ventilation. Possibly, a combination of controlled hypercapnia and allowed spontaneous breathing eff orts may provide complementary protection for diaphragm and respiratory functionality during mechanical ventilation. However, further safety and effi cacy studies need to be performed in various diff erent animal models and patients before a universal application of hypercapnia in the critical care setting for the prevention of VIDD can be considered. most of these therapeutic eff ects need to be tested in relevant clinical settings under controlled environments and during critical illness. Second, the eff ects on infl ammatory 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 eff ects in the setting of pulmonary sepsis. Some of these are due to its eff ects in altering pro-infl ammatory responses during acute infection [13,14]. Hypercapnic acidosis appears to inhibit pulmonary epithelial wound healing by reducing cell migration via an NF-κBdependent mechanism. Th is mechanism may involve alterations in matrix metalloproteinase activity. Benefi cial eff ects of hypercapnia are mediated partially by inhibition of the host immune response, particularly the cytokine pathway, phagocyte function, and the adaptive immune response. Th ese immunosuppressive properties may prevent host defense systems from responding to pathogenic microorganisms suffi ciently [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 hyper capnia and allowed spontaneous breathing eff orts may provide complementary protection for diaphragm and respiratory functionality during mechanical ventilation. However, further safety, duration of therapy, and dose-fi nding studies need to be performed in various diff erent animal models and patients before a universal application of hypercapnia in the critical care setting for the prevention of VIDD can be considered.

Competing interests
The authors declare that they have no competing interests.