Early veno arterial PCO 2 difference is associated with outcome in peripheral veno arterial extracorporeal membrane oxygenation

increasingly used for cardiogenic failure. However, hemodynamic targets for adequate resuscitation remain a challenge. The PCO 2 gap and the ratio between PCO 2 gap and the arteriovenous difference in oxygen (PCO 2 gap/Da–vO 2 ) are marker of peripheral hypoperfusion. We hypothesized that the PCO 2 gap and the PCO 2 gap/Da–vO 2 ratio might be useful parameters in VA ECMO patients. Methods: We conducted an observational prospective study between September 2015 and February 2017. All consecutive patients >18 years of age who had been treated with peripheral VA ECMO for cardiac failure were included. We compared 2 groups of patients: patients who died of any cause under VA ECMO or in the 72h following VA ECMO weaning (early death group) - and patients who survived VA ECMO weaning more than 72h (surviving group). Blood samples were drawn from arterial and venous VA ECMO cannulas at H0 and H6. The ability of PCO 2 gap and PCO 2 gap/Da–vO 2 to discriminate between early mortality and surviving was studied using ROC curves analysis. Results: We included 20 patients in surviving group and 29 in early death group. The PCO 2 gap was higher in the early death group at H6 (7.4 [5.7– 10.1] vs. 5.9 [3.8–9.2], p < 0.01). AUC for PCO 2 gap at H6 was 0.76 (0.61– 0.92), with a cut-off of 6.2 mmHg. The PCO 2 gap/Da–vO 2 was higher in the early death group at H0 (2.1 [1.5–2.6] vs. 1.2 [0.9–2.4], p < 0.01) and at H6 (2.1 [1.3–2.6] vs. 1.0 [0.8–1.7], p < 0.01). AUC for PCO 2 gap/Da–vO 2 at H0 and H6 Conclusions: The PCO 2 gap and the PCO 2 gap/Da–vO2 ratio are associated with early death in patients who undergo VA ECMO.


BACKGROUND
The use of veno arterial extracorporeal membrane oxygenation (VA ECMO) to manage cardiocirculatory failure is becoming more common.
The main indications of the process include cardiogenic shock, refractory cardiac arrest (RCA), post-cardiotomy cardiac failure, and post-cardiac arrest syndrome 1-4. However, VA ECMO is a complex technique, and hemodynamic monitoring with targets for adequate resuscitation remains a challenge in the absence of clear recommendations 5. Ensuring adequate oxygen (regulation of flow rate and oxygenation) and perfusion pressure to organs are usually the main goals; these parameters have to be personalized depending on the patient's need. However, systemic hemodynamic parameters and oxygen metabolism markers do not always reflect adequate resuscitation 6. The use of lactate as a marker of anaerobic metabolism has been widely described 7-8. Lactate is used to guide therapy; it is also a prognostic marker during shock states 9-10.
However, lactate does not always reflect anaerobic metabolism, and confounding conditions are frequent: high lactatemia might result from reduced clearance (during liver or renal failure) or from the activation of glycolysis when high doses of adrenaline are administered 11-12. The partial pressure gradient in CO 2 between the venous and arterial level or the PCO 2 gap has been used as a marker of peripheral hypoperfusion, particularly in septic and cardiogenic shock 13-15. Recently, the ratio of the PCO 2 gap to the arteriovenous difference in oxygen (PCO 2 gap/Da-vO 2 ) has been described as a marker of anaerobic metabolism. A PCO 2 6 gap/Da-vO 2 > 1 as a target was found to be more relevant than the use of the PCO 2 gap alone 16-17.
This study hypothesized that the PCO 2 gap and the PCO 2 gap/Da-vO 2 ratio might serve as parameters of adequate resuscitation in VA ECMO patients. Hence, the aim of the study was to evaluate the usability of the PCO 2 gap, the PCO 2 gap/Da-vO 2 ratio, and lactatemia as prognostic markers of mortality occurring during peripheral VA ECMO support or early after VA ECMO withdrawal, highlighting inadequate resuscitation or incomplete organ recovery.

Patients and VA ECMO protocol
All patients over 18 years of age who were treated using peripheral VA ECMO for refractory cardiogenic shock, refractory cardiac arrest (RCA), post-cardiotomy cardiac failure, and/or post-cardiac arrest syndrome were included in the study. Exclusion criteria included patients with a central or pulmonary artery VA ECMO, and patients who already benefited from VA ECMO prior to the present episode. In the study institution, peripheral VA ECMO support initiation is standardized and

Study protocol
Baseline (H0) was set when the desired VA ECMO flow rate was reached. Blood samples were drawn from arterial (after the oxygenator) and venous (before oxygenator) VA ECMO cannulas after purging 5 mL of 9 blood to perform blood gas analyses and to measure lactate concentration on the VA ECMO at H0, H6, and H24. Arterial blood samples were drawn form VA ECMO arterial line due to variation of arterial catheter position (radial or femoral). The syringes were pneumatically sent to the laboratory (ABL800, Radiometer, Copenhagen, Denmark). For each series of samples, pH, CO 2 partial pressure (PCO 2 ), oxygen partial pressure (PO 2 ), oxygen saturation (SaO 2 ), bicarbonates, and lactate concentration were collected.
The venous saturation of the VA ECMO was considered as the venous saturation (SvO 2 ) of the patient. The PCO 2 gap was calculated as the difference between the venous partial pressure in CO 2 (PvCO 2 ) and the arterial partial pressure in CO 2 (PaCO 2 ): The PCO 2 /Da-vO 2 ratio was calculated as follows:

Study endpoints
The primary endpoint was the ability to use the PCO 2 gap to determine early mortality. The secondary end-points were the PCO 2 gap/Da-vO 2 ratio, SvO 2 , the SOFA score, and the IGS II score. Overall mortality was also evaluated at 28 days.

Statistical analysis
The quantitative data are presented as medians and interquartile ranges; the qualitative data are presented as numbers and percentages.
Appropriate parametric or non-parametric tests were also performed.

Population
During the study period, 51 adults were admitted to the ICU for VA ECMO. Two patients with metformin intoxication were excluded due to the inability to interpret lactate concentration; therefore, data from 49 patients were analyzed (Fig. 1). The baseline characteristics are shown in Table 1.

PCO 2 gap
The PCO 2 gap was significantly higher in the early death group at H6  Table 2). Area under the ROC curve, used to discriminate between early death and survival, was 0.76 (0.61-0.92), with an optimal cut-off of 6.2 (Table 3). Using a 6 mmHg threshold, a higher PCO 2 gap at H0 and H6 was associated with early death (Fig. 2).

PCO 2 gap/Da-vO 2
The PCO 2 gap/Da-vO 2 was also higher in the early death group at (Additional file - Table 2). Using an ROC curve analysis to discriminate between early death and survival at H0 and H6, the area was respectively 0.79 and 0.73; the best cut-off value was 1.4 (Table 3). Using a 1.4 threshold, a higher PCO 2 gap/Da-vO 2 ratio at H0 and H6 was associated with early death (Fig. 2).

Other metabolic variables
Arterial lactatemia was higher in the early death group at H0, H6, and H24 (Table 2). Lactatemia was not associated with VA ECMO flow rate.
Using ROC curve analysis, the area for discrimination between early death and survival at H0 and H6 was 0.77 and 0.74, respectively (

DECLARATIONS:
Ethics approval and consent to participate: N/A

Consent for publication: N/A
Availability of data and material: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests: none to declare.
Funding: none to declare.

Authors' contributions:
Study design: OE