Since 2009, the publication year of the CESAR (Conventional Ventilatory Support Versus
Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure) trial (1),
the fascinating technique of extracorporeal support for the failing lung or for life-threatening
cardiac instability has celebrated a triumph that continues to this day (2). Without
doubt, the application of new technologies, such as extracorporeal membrane oxygenation
(ECMO), may save life in many cases. Yet, ECMO is a complex and risky measure, and
it may be accompanied by severe adverse events, such as bleeding or neurologic injuries
(3). The precise knowledge of ECMO management in critically ill patients is crucial
for survival and for ensuring the health-related quality of life after transfer from
the ICU. Interprofessional teamworking and a high level of expertise are required
in terms of mechanical ventilation during ECMO (4), anticoagulation, positioning of
the patients, and strategies of weaning. Incidentally, a position paper, among the
quality aspects, on the use of such an attractive device was published in 2018 (5).
In accordance with the mostly accepted indications for ECMO (6), such a technique
should be considered in severe hypoxemia or hypercapnia (venovenous ECMO), or in acute
cardiac failure (venoarterial ECMO). Although most intensivists report a rapid (and
perhaps lifesaving) increase in oxygenation after the initiation of ECMO, less attention
was paid to changes in the carbon dioxide (CO2) levels in the early phase of ECMO
treatment. Most ECMO users are happy with a relatively high sweep gas flow resulting
in a prompt oxygen increase in the blood, accompanied by a rapid decrease in PaCO2
and an increase in the pH value. In a recent international multicenter prospective
cohort study (7) on current practices in ECMO management, a sweep gas flow of around
5 L/min was preferred by most intensivists, resulting in a significant, and often
rapidly occurring, reduction in arterial CO2 levels because CO2 removal is predominantly
and very effectively regulated by the amount of the sweep gas flow. Remarkably, in
an experimental animal study in 1995, Liem and colleagues (8) observed adverse effects
of hypercapnia and hypocapnia in pigs on ECMO, and they recommended that “it is important
to keep arterial CO2 tension stable and in normal range during clinical ECMO.” Over
and above this, some small retrospective observational studies found deleterious effects
of a rapid reduction in CO2 levels in patients using ECMO after cannulation (9, 10).
In this issue of the Journal, Cavayas and colleagues (pp. 1525–1535) report on the
data of around 12,000 patients with ECMO derived from the registry of the Extracorporeal
Life Support Organization (11). They retrospectively recorded the relative changes
in arterial Pco
2 levels in the first 24 hours after initiation of ECMO, and they associated these
findings with neurologic complications. The results of this investigation are impressive
and deserve attention. Patients with an early relative decrease in Pco
2 of greater than 50% (19% of patients) had a higher incidence of neurologic adverse
events (9.8%) compared with the group of patients with a smaller relative decrease
in Pco
2 (6.4%; P < 0.001). Interestingly, a “U-shaped” association was observed: a marked
rapid decrease in PaCO2
and a significant relative CO2 increase were associated with high numbers of neurologic
complications, whereas patients on the ground of the “U” (lowest relative PaCO2
changes) had a low incidence of neurologic complications. Furthermore, after adjustment
for confounders and risk factors by multiple logistic regression analyses, a large
relative decrease in PaCO2
greater than 50% was still independently associated with adverse neurologic events
(odds ratio, 1.7; 95% confidence interval, 1.3–2.3; P < 0.001).
Registry-based clinical research is an important retrospective observational tool
in assessing healthcare interventions, whereas randomized trials assess efficacy for
a carefully selected patient group (12). The interpretation of registry data should
be handled with caution because the quality, completeness, and accuracy of the entered
data might be critical. The large database in the present study by Cavayas and colleagues
(11) combined with a convincing concept among the pathophysiologic essentials of adverse
effects due to rapid alterations in the CO2 homeostasis make the results conclusive.
A marked and rapid shift in PaCO2
was associated with seizure, cerebral hemorrhage, or brain death, but we do not know
the effect of the altered CO2 homeostasis on the general cognitive function or on
mental disorders in surviving patients. We may expect a similar impact on cognitive
capability in daily life activities. Such an important aspect has not been investigated
yet. In a multivariate adjusted dichotomized analysis of a recent German prospective
multicenter observational study (DACAPO) on health-related quality of life in survivors
of acute respiratory distress syndrome (13), low Vt ventilation (≤7 ml/kg) with hypercapnia
was associated with a significantly more impaired 3-month mental quality-of-life score
(SF-12) compared with the higher Vt group (>7 ml/kg) representing normocapnia. Although
“permissive,” pronounced hypercapnia may disturb the homeostasis of the CO2 system
as well as marked hypocapnia.
In light of the study by Cavayas and colleagues (11), the plea for a rapid (and sometimes
rigorous) correction of hypercapnia in patients with acute lung failure after the
insertion of ECMO must be reevaluated because a high price may be paid for the abrupt
alteration in the CO2 equilibrium. To facilitate a slow PaCO2
removal, the authors suggest frequent monitoring by blood gases to avoid rapid PaCO2
changes; furthermore, they postulate a moderate and “soft” level of sweep gas flow.
The latter one is useful and important, whereas, unfortunately, frequent blood gas
monitorings are time-consuming but have no alternative. Near-infrared spectroscopy
for the assessment of cerebral vasoconstriction (14) and transcutaneous continuous
CO2 monitoring (15) are currently not suitable or precise enough to guide the management
of CO2 removal by sweep gas flow.
The fascinating technique of ECMO is lifesaving but has some serious and inherent
shortcomings, requiring expertise to avoid them. The investigation of Cavayas and
colleagues (11) yields very important insights on how to improve the quality of care.
An ultima ratio strategy for critically ill patients needing the use of ECMO should
be a medical and ethical dictate. Addressing the issues of physiological PaCO2
and pH level in patients using ECMO may be beneficial; but, if so, be gentle and patient
with your patient using ECMO!