# Associations of intraoperative end-tidal carbon dioxide concentrations with postoperative outcomes: is mechanical power next?

Audrey de Jong, Samir Jaber

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## To cite this version:

Audrey de Jong, Samir Jaber. Associations of intraoperative end-tidal carbon dioxide concentrations with postoperative outcomes: is mechanical power next?. British Journal of Anaesthesia, 2025, 135 (6), pp.1591-1594. 10.1016/j.bja.2025.09.005. hal-05309504

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# Associations of intraoperative end-tidal carbon dioxide concentrations with postoperative outcomes: is mechanical power next?

Audrey De Jong<fnref n="1" />, Samir Jaber <fnref n="2" />

**Keywords:**

end-tidal carbon dioxide; mechanical power; positive end-expiratory pressure; postoperative pulmonary complications; respiratory rate; tidal volume; ventilation.

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<footnote n="1">¹ Anesthesiology and Intensive Care, Anesthesia and Critical Care Department B, Saint Eloi Teaching Hospital, Centre Hospitalier Universitaire Montpellier, Montpellier, France; PhyMedExp, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France. Electronic address: a-de_jong@chu-montpellier.fr.</footnote>

<footnote n="2">² Anesthesiology and Intensive Care, Anesthesia and Critical Care Department B, Saint Eloi Teaching Hospital, Centre Hospitalier Universitaire Montpellier, Montpellier, France; PhyMedExp, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France.</footnote>
Abstract

In an important patient-level analysis of two randomised controlled trials published in the British Journal of Anaesthesia, hypocapnia, as reflected by low end-tidal carbon dioxide (ETCO₂) during surgery was associated with worse outcomes than normocapnia, with higher rates of postoperative pulmonary complications (PPCs). The results can be used by anaesthesiologists in the operating theatre to reduce the occurrence of PPCs by carefully determining ventilatory settings to avoid overventilation in patients, and by considering cardiopulmonary interactions. This involves reducing tidal volume and respiratory rate as far as possible while aiming for a normal-to-high ETCO₂ (optimal cutoff to be determined). Previous trials assessing mechanical ventilation settings in the operating room have produced conflicting results. The answer might lie in the objective of ETCO₂ monitoring, as a surrogate of partial pressure of carbon dioxide (PaCO₂), which is strongly associated with mechanical power through ventilatory settings.
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In a patient-level analysis of two randomised controlled trials published recently in the British Journal of Anaesthesia, Nasa and colleagues 1 assessed the relationship between intraoperative end-tidal carbon dioxide (ETCO 2 ) concentrations and postoperative outcomes. They used individual data from two landmark randomised studies, PROVILHO 2 and PROBESE, 3 which included patients without 2 and with obesity 2 randomised to intraoperative ventilation with high or low positive end-expiratory pressure (PEEP) at a low tidal volume. --

To our knowledge, this is one of the first studies to identify patient characteristics associated with low ETCO 2 . Patients with low ETCO 2 were older, taller, and more often non-obese and had relatively higher respiratory system compliance than those without hypocapnia. 1 However, hypocapnia was associated with worse outcomes than normocapnia, with higher rates of postoperative pulmonary complications (PPCs). These findings of lower obesity levels and higher respiratory compliance in patients with hypocapnia, which itself is associated with poorer outcomes, clearly support the idea that ETCO 2 has an independent effect on outcomes, probably through the choice of respiratory settings. In line with this hypothesis, the authors found that patients with low ETCO 2 were ventilated with a higher tidal volume and a higher minute volume normalised to body weight. This is an alarming result, given that an inverse relationship was observed between mean ETCO 2 and PPCs, even at high ETCO 2 (>6 kPa or 45 mm Hg). The rate of hyperventilation is high inla large-scale studies, 2,3 and we can assume that it is much higher in daily practice. Two reasons might justify hyperventilation. First, some physicians want to compensate for the fact that insufflated CO 2 can enter the systemic circulation, even before it occurs. Second, some weak studies show that hyperventilation can be associated with less postoperative shoulder pain. 4-

Low intraoperative ETCO 2 concentrations are known to be associated with postoperative mortality, 5 and this association was further confirmed by Nasa and colleagues. 1 One possible explanation is the ventilatory settings, as observed by Nasa and colleagues. 1 An increase in tidal volume and respiratory rate could be associated with a higher incidence of PPCs, and consequently, increased mortality. 6 Another possible explanation is the presence of residual confounding factors when assessing the relationship between ETCO 2 and outcomes. Lower ETCO 2 might also be the consequence of an increase in the ETCO 2 —CO 2 gradient associated with pulmonary or cardiac comorbidities, and not determined by the ventilatory parameters established by the anaesthesiologist. For example, changes in ETCO 2 induced by the rapid infusion of 250 ml of 0.9% saline were associated with increased cardiac output, despite lacking the accuracy required to identify fluid responsiveness in patients with mechanical ventilation in the operating theatre. 7 When assessing ETCO 2 as a surrogate of partial pressure of carbon dioxide (PaCO 2 ), cardiac output is a likely confounder. As cardiac output increases, more CO 2 is returned to the lungs, increasing ETCO 2 . - -

In the OPTIMISE II trial, 8 an international, multicentre, pragmatic, randomised controlled trial, cardiac output-guided i. v. fluid therapy with low-dose inotrope infusion did not reduce the incidence of postoperative infections when compared with usual care in patients undergoing major gastrointestinal surgery. Moreover, it was associated with an increased incidence of acute cardiac events within 24 h. A systematic review and metaanalysis 9 showed that the treatment effect of perioperative goal-directed haemodynamic therapy on
pneumonia and surgical site infections in adults undergoing noncardiac surgery was inversely related to trial size. Beneficial effects were only observed in smaller trials. Interestingly, ETCO 2 was not included in the algorithms used in large trials assessing perioperative goal-directed haemodynamic therapy. - - - -

High tidal volume ventilation can decrease venous return through increased intrathoracic pressure, thereby decreasing cardiac output and ETCO 2. In these patients, an artificial increase in cardiac output using inotropes or vasopressors might not be beneficial, whereas a simple reduction in ventilation could have corrected cardiac output. Conversely, if ETCO 2 is low despite appropriate ventilation and fluid administration, it might be time to administer vasopressors or inotropes after a careful haemodynamic assessment. Considering these cardiopulmonary interactions, low ETCO 2 could also be useful for promptly diagnosing acute hypersensitivity reactions during anaesthesia in patients who are invasively mechanically ventilated. 10

The methodology used by Nasa and colleagues 1 was appropriate to consider as many confounding factors as possible. PPCs are common, affecting more >20% of patients after abdominal surgery. 11,12 Interestingly, a propensity matched analysis was performed to mitigate the confounding effect of known covariates on PPCs. The propensity matched cohort was matched based on age, body mass index (BMI), compliance, chronic obstructive pulmonary disease, and type of surgery. As presented in Figure 1 of their paper, 1 the results were similar before and after adjustment, showing an independent relationship between ETCO 2 and the occurrence of PPCs. The authors also used an elegant time-weighted analysis to ascertain the correlation between intraoperative ETCO 2 and PPCs. They determined the association between the time-weighted average of ETCO 2 and PPCs using a generalised mixed model, with locally estimated scatterplot smoothing (LOESS) regression to visualise the relationship between mean ETCO 2 as a continuous variable and PPCs (Fig. 2) 1. Two subgroup analyses were also performed to strengthen the results. Similar results were found in both the low PEEP (control) and high PEEP (intervention) groups, showing more PPCs in the low ETCO 2 group than in the normal/high ETCO 2 group. The second analysis showed more PPCs in open abdomen surgery when ETCO 2 was low, but not in laparoscopic surgery. To make the analysis and results even more reliable, the authors did three sensitivity analyses. One of these separated patients with a BMI >30 kg m² and patients with a BMI <30 kg m². Patients with low ETCO 2 were more likely to have PPCs, regardless of BMI. Other studies suggest comparable outcomes between patients with and without obesity, in the setting of weaning from invasive mechanical ventilation for instance. 13,14- - - - -

<table><caption>Table 1 Calculating mechanical power. Driving pressure = plateau pressure – PEEP. L/E, inspiratory:expiratory ratio; PEEP, positive end-expiratory pressure; Raw, airway resistance; RR, respiratory rate.</caption>
  <tr>
    <td>1. Reference formula<sup>17</sup></td>
    <td>• RR (tidal volume<sup>2</sup> *[0.5*elastance of the system +RR *(1+ 1/E)/(60*1/E)*Raw] +tidal volume *PEEP)</td>
  </tr>
  <tr>
    <td>2. Simplified formulae in volume-controlled ventilation</td>
    <td>• 0.098*tidal volume *RR *(peak pressure - ½*driving pressure)<sup>19</sup></td>
  </tr>
  <tr>
    <td></td>
    <td>• [tidal volume *RR *(peak pressure + PEEP + inspiratory flow/6)]/20<sup>18</sup></td>
  </tr>
  <tr>
    <td>3. Simplified formula in pressure-controlled ventilation</td>
    <td>• 0.098*RR *tidal volume *[PEEP + pressure above PEEP]<sup>18</sup></td>
  </tr>
</table>
One limitation, which the authors highlight, was the absence of arterial blood gases to assess the true PaCO2. In this post hoc analysis, 1 ETCO 2 was used as a surrogate for hypocapnia. However, without measuring both cardiac output and PaCO2, some patients could have had a substantial PaCO2—ETCO 2 gradient. It is possible that not all patients with low ETCO 2 were actually hypocapnic. The higher incidence of hypotension in the low ETCO 2 group might have affected the outcome. However, in daily clinical practice in the operating room, PaCO2 is monitored much less frequently than ETCO 2. This is a real-world study with clear findings that anaesthesiologists worldwide can apply. Another limitation is the possibility of residual confounding. 14 PPCs are still difficult to predict because of the uncertainty of prediction models, as suggested in a systematic review and meta-analysis. 15

Anaesthesiologists could apply the results of this study to reduce PPCs. This could involve titrating ventilatory settings to prevent overventilation while considering cardiopulmonary interactions and the impact of low cardiac output on ETCO 2. Decreasing tidal volume can decrease intrathoracic pressure, improve venous return, and increase cardiac output and ETCO 2. Reducing tidal volume and respiratory rate while aiming for normal ETCO 2 initiates a virtuous cycle that positively impacts respiratory and cardiac function. However, as it is the result of such a complex process involving cardiopulmonary interactions, the optimal ETCO 2 threshold remains a matter of discussion during surgery.

This important work 1 paves the way for other studies aiming to individualise titration of ventilatory parameters. Future trials involving PEEP titration, for example, should clearly state the role of ETCO 2 in their protocol. One promising parameter for titrating ventilation in the operating theatre is mechanical power, 16–18 which consistently comprises tidal volume, respiratory rate, and PEEP, among other variables. Table 1 shows the different ways of calculating mechanical power. In the future, we will need online monitoring of this calculated parameter in anaesthesia ventilators to further individualise ventilation management. 19 A higher respiratory rate and tidal volume result in higher mechanical power, which has been associated with higher rate of PPCs in several observational studies. 6,20 A recent study showed the need to normalise mechanical power to functional lung size. 21 If previous trials assessing mechanical ventilation settings in the operating room produced conflicting results, 2,3,6,22,23 the answer could lie in the objective of ETCO 2 monitoring as a surrogate of PaCO2, which is strongly associated with mechanical power through ventilatory settings. 24

What is the optimal ETCO 2 that we should aim for? The authors found an inverse relationship between ETCO 2 and PPCs, even for ETCO 2 >6 kPa. The next step could be to assess the optimal compromise between hypercapnic acidosis, cardiac output, tidal volume, and respiratory rate, and thereby determine the best ETCO 2 cutoff.
**Declarations of interest**

SJ has received consulting fees from Drager, Medtronic, Mindray, Fresenius, Baxter, and Fisher & Paykel. ADJ has received remuneration for presentations from Medtronic, Drager, and Fisher & Paykel.

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