Hypercapnia during ARDS ventilation: testing the limits of permissibility

From the 1990s, lung-protective ventilation using low tidal volumes and limitation of plateau pressures emerged as a pivotal strategy in patients with acute respiratory failure, especially with acute respiratory distress syndrome (ARDS), who undergo mechanical ventilation (1). Amato et al., in a landmark study, titrated positive end-expiratory pressures (PEEP) levels to higher than the lower inflection point of the pressure-volume curve, with tidal volumes of less than 6 ml/kg and driving pressures of less than 20 cm of H2O in patients with ARDS. On the pressure-controlled mode of ventilator support, they allowed permissive hypercapnia as part of a lung-protective strategy. This strategy resulted in higher PCO2 values compared to the control arm that used a tidal volume of 12 ml/kg (55 vs. 38 mm Hg). However, the lung-protective strategy led to a significantly lower 28-day mortality, less barotrauma, and a higher rate of successful weaning from mechanical ventilation (2). The use of a low tidal volume strategy was further bolstered by the ARMA trial and widely accepted as the optimal approach to ventilation in patients with ARDS (3). 

Is hypercapnia protective? 

Clearly, a lung-protective ventilation strategy using low tidal volumes often results in hypercapnia among patients with ARDS. However, the effect of hypercapnia and respiratory acidosis remains unclear. Hypercapnia and respiratory acidosis have even been postulated to offer possible beneficial effects in ARDS through down-regulation of pro-inflammatory mediators in experimental studies. In experimental animal models, hypercapnia has been shown to reduce the severity of ventilator-induced lung injury (4,5). Kregenow et al. evaluated the effect of hypercapnic respiratory acidosis by performing a secondary analysis of data from the ARDS Network trial that compared tidal volumes of 6 vs.12 ml/kg. They observed a reduction in mortality among patients with hypercapnic respiratory acidosis who were randomized to receive a tidal volume of 12 ml/kg of predicted body weight. The investigators suggested that hypercapnic respiratory acidosis may ameliorate the injurious effects of high tidal volume ventilation in patients with ARDS (6). 

Adverse effects of hypercapnia 

The putative beneficial effects of hypercapnia have not been substantiated in clinical studies. Hypercapnic acidosis has been shown to inhibit adaptive immune responses through suppression of neutrophil and macrophage migration and impaired phagocytosis (7). Acute hypercapnia may also trigger a rise in pulmonary artery pressures and right ventricular dysfunction, leading to acute cor pulmonale (8). Besides, hypercapnia may result in increased tissue susceptibility to infection. In-hospital mortality was significantly higher among hypercapnic patients with community-acquired pneumonia in an observational study (9). Furthermore, high carbon dioxide levels may impair left ventricular contractility due to intracellular acidosis (10). 

Evidence of harm from hypercapnia 

Nin et al. analyzed data from 18,302 patients with ARDS from three international observational studies who underwent invasive mechanical ventilation for more than 24 hours or developed ARDS after 24 hours of mechanical ventilation. On multivariate analysis, they observed a significantly higher mortality among patients with a maximum PaCOlevel of more than 50 mm Hg (defined as “severe” hypercapnia) during the first 48 hours of ventilation compared to those with a maximum PaCOlevel of less than 50 mm Hg. After adjusting for baseline characteristics, an independent association was observed between severe hypercapnia and ICU mortality. Furthermore, the incidence of complications and organ dysfunction, including barotrauma, renal and cardiovascular dysfunction, were more common among hypercapnic patients. ICU mortality was also significantly higher among patients who received a tidal volume of more than 8 ml/kg (11).  

Tiruvoipati et al. collated data from the Australian and New Zealand Intensive Care Society (ANZICS) database in patients who were mechanically ventilated over a 14-year period. Adult patients who received mechanical ventilation during the first 24 hours of ICU stay were included.  Patients were divided into three groups – with normal pH and PCO2, compensated hypercapnia, and hypercapnic acidosis. The study comprised of 252,812 patients including 110,104 with normal pH and normal PCO2, 20,643 with compensated hypercapnia, and 122,245 with hypercapnic acidosis (12). 

On multivariate analysis, a significantly higher mortality was observed among patients with compensated hypercapnia and hypercapnic acidosis compared to patients with normocapnia and normal pH levels. The mortality difference was unrelated to the P/F ratio. Among patients with compensated hypercapnia, the mortality increased with increasing PCO2 levels up to 65 mm Hg; a further rise in PCOrevealed a trend towards lower mortality. However, in patients with hypercapnic acidosis, the mortality plateaued after a peak PCOlevel of  65 mm Hg. The authors hypothesized that the variable influence of hypercapnia on the arteriolar myogenic tone and consequent modulation of the microcirculation might contribute to this plateau effect (12). 

Is extracorporeal COremoval the future of ARDS ventilation? 

The SUPERNOVA study assessed the feasibility of extracorporeal carbon dioxide removal (ECCO2R) combined with ultra-low tidal volume (4 ml/kg) ventilation among patients with moderate ARDS. Among the 95 patients who were enrolled, ultra-protective settings were achieved in 82% by 24 hours; the PCO2 levels rose by less than 20% of baseline levels, and the arterial pH remained > 7.30 (13). A randomized controlled trial is currently in progress to evaluate the benefit of ECCO2R combined with tidal volumes equal to or less than 3 ml/kg, compared to standard care, using tidal volumes of 6 ml/kg (14). 

The bottom line 

  • The concept of permissive hypercapnia evolved with the use of low tidal volume ventilation strategies.
  • High COlevels were considered to be harmless or even protective; however, clinical evidence suggests worse clinical outcomes among hypercapnic patients with ARDS.
  • It may be appropriate to aim for PCO2 levels of less than 50 mm Hg in patients with ARDS who are mechanically ventilated (12,15).
  • A strategy of “ultra” low tidal volume ventilation combined with extracorporeal carbon dioxide removal is currently being evaluated in a randomized controlled trial.


1.         Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med. 1990;16(6):372–7. 

2.         Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998 Feb 5;338(6):347–54. 

3.         Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 04;342(18):1301–8. 

4.         Sinclair SE, Kregenow DA, Lamm WJE, Starr IR, Chi EY, Hlastala MP. Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med. 2002 Aug 1;166(3):403–8. 

5.         Broccard AF, Hotchkiss JR, Vannay C, Markert M, Sauty A, Feihl F, et al. Protective effects of hypercapnic acidosis on ventilator-induced lung injury. Am J Respir Crit Care Med. 2001 Sep 1;164(5):802–6. 

6.         Kregenow DA, Rubenfeld GD, Hudson LD, Swenson ER. Hypercapnic acidosis and mortality in acute lung injury*: Crit Care Med. 2006 Jan;34(1):1–7. 

7.         Coakley RJ, Taggart C, Greene C, McElvaney NG, O’Neill SJ. Ambient pCO2 modulates intracellular pH, intracellular oxidant generation, and interleukin-8 secretion in human neutrophils. J Leukoc Biol. 2002 Apr;71(4):603–10. 

8.         Jardin F, Dubourg O, Bourdarias JP. Echocardiographic pattern of acute cor pulmonale. Chest. 1997 Jan;111(1):209–17. 

9.         Sin DD, Man SFP, Marrie TJ. Arterial carbon dioxide tension on admission as a marker of in-hospital mortality in community-acquired pneumonia. Am J Med. 2005 Feb;118(2):145–50. 

10.       Jerusalem E, Starling EH. On the significance of carbon dioxide for the heart beat. J Physiol. 1910 May 13;40(4):279–94. 

11.       for the VENTILA Group, Nin N, Muriel A, Peñuelas O, Brochard L, Lorente JA, et al. Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome. Intensive Care Med. 2017 Feb;43(2):200–8. 

12.       Tiruvoipati R, Pilcher D, Buscher H, Botha J, Bailey M. Effects of Hypercapnia and Hypercapnic Acidosis on Hospital Mortality in Mechanically Ventilated Patients*: Crit Care Med. 2017 Jul;45(7):e649–56. 

13.       Combes A, Fanelli V, Pham T, Ranieri VM, European Society of Intensive Care Medicine Trials Group and the “Strategy of Ultra-Protective lung ventilation with Extracorporeal CO2 Removal for New-Onset moderate to severe ARDS” (SUPERNOVA) investigators. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study. Intensive Care Med. 2019;45(5):592–600. 

14.       McNamee JJ, Gillies MA, Barrett NA, Agus AM, Beale R, Bentley A, et al. pRotective vEntilation with veno-venouS lung assisT in respiratory failure: A protocol for a multicentre randomised controlled trial of extracorporeal carbon dioxide removal in patients with acute hypoxaemic respiratory failure. J Intensive Care Soc. 2017 May;18(2):159–69. 

15.       Repessé X, Vieillard-Baron A. Hypercapnia during acute respiratory distress syndrome: the tree that hides the forest! J Thorac Dis. 2017 Jun 13;9(6):1420-1425–1425. 

4 thoughts on “Hypercapnia during ARDS ventilation: testing the limits of permissibility”

  1. Dr Chacko
    Well explained, thanks as always.

    Shall we then strategize the decision of putting patients of severe ARDS on ECMO to oxygenation as well as Hypercapnia both, or there should be two arms that is patients with severe Refractory hypoxia should proceed to V-V ECMO and those patients with CO2 levels building up dangerously should go for Extracorporial CO2 removal hoping that it will help in oxygenation also.

Leave a Reply