CO₂ and O₂ removal during continuous veno-venous hemofiltration: a pilot study

Red blood cells and plasma harbour carbon dioxide (CO₂) in the form of dissolved CO₂, bicarbonate, and carbamino compounds which are in equilibrium with each other [1]. The sum of all components is expressed as total CO₂ (tCO₂).

CO₂ accumulation causes hypercarbia which may be a challenge in intensive care unit (ICU) patients. It has propagated a more extensive use of extracorporeal techniques to enable ultra-protective ventilation in acute respiratory distress syndrome or to avoid intubation in patients with severe exacerbation of chronic obstructive lung disease [2]. Although renal replacement therapy (RRT) is advocated to generate small amounts of CO₂ due to the red blood cell passing through the filter [3], the net effect is a removal of CO₂ in an intermittent hemodialysis (IHD) model with acetate [3, 4] This CO₂ extraction of 41 ml/min seemed to correlate with a deficit of 46 ml/min in expired CO₂ [5]. Different methods have been explored to increase the removal of CO₂ in effluent by increasing pH with THAM or NaOH but it seemed too complex and too dangerous to be used in humans. [6] Extraction reached up to 120 ml/min in an in vitro model of IHD [7]. “CO₂ loss” induced by RRT may become clinically relevant as mean expired CO₂ in ICU patients is 180 ml/min [8]. Continuous RRT (CRRT) is progressively supplanting intermittent dialysis in the ICU. CRRT is hemodynamically well-tolerated, may provide easier control of metabolic alterations and fluid overload, and is associated with less chronic kidney disease in the post-ICU phase [9‐11]. The impact of CRRT on CO₂ metabolism is remarkably poorly documented. In addition, trisodium citrate - the preferred anticoagulant for CRRT- acts as a weak acid [12]. This will alter the Henderson-Hasselbalch equation, disrupt the balance between the different CO₂ forms, and thus potentially influence CO₂ extraction during CRRT.

We designed a study to better understand CO₂ and O₂ extraction during CRRT. Based on obtained data, formulas were constructed to assess CRRT-related CO₂ clearance at the bedside.

A prospective study was performed in critically ill patients undergoing continuous veno-venous hemofiltration (CVVH). The study was approved by the Ethical Committee of the University Hospital Brussels (reference BUN 143201731636) and registered at https://​clinicaltrials.​gov (reference NCT03314363). Informed consent was obtained from the patient or a legal representative.

CVVH was performed with the Prismaflex®(Lund, Sweden) Baxter® device equipped with a Prismaflex® Baxter®, AN69 surface treated (ST) filter of 1.5 square meter (Meyzieu, France). Prismocitrate®18/0 (Sondalo, Italy) Baxter® was used as predilution and Prismocal® B22 (Sondalo, Italy) Baxter® or NaCl 0.9% as postdilution fluid. Dosing and postdilution fluid use were initiated and adapted according to an implemented standard CVVH protocol.

Inclusion and exclusion criteria are listed in Additional file 1. Blood samples were taken at 5 different sample points (SP) (Fig. 1). SP were located at the distal end of the arterial dialysis catheter lumen (SP1); between citrate predilution infusion port and filter (SP2); directly after the filter (SP3); at the effluent conduit (SP4); proximal to the venous dialysis catheter lumen (SP5). At every SP, pH, HCO₃-, tCO₂, pCO₂, pO₂, hemoglobin (Hb) and Hb saturation were measured using a blood gas analyzer [ABL90 Flex®, Radiometer(Bronshoj, Denmark)]. Subsequently, citrate predilution was stopped and replaced for at least 20 min by NaCl 0.9% at similar flow. Blood gas analysis was repeated according to the same protocol.

O₂ content (tO₂) was calculated as Hb x Hb saturation × 1.35 [1]. CO₂ (V̇CO₂) and O₂ flow (V̇O₂) at the specific SP were calculated by multiplying the set fluid flow (Q) on CVVH with respectively tCO₂ and tO₂. Results were adjusted from mmol to ml by using Boyle’s gas law: pV = nRT (p: pressure of the gas, V: volume of gas, n: amount of substance of gas, R: gas constant, T absolute temperature of the gas). The average air pressure recorded by the Belgian national weather institute was applied and ambient temperature was measured. “Transmembrane” (i.e before and after the filter) V̇CO₂ was calculated by subtracting V̇CO₂ at SP3 from V̇CO₂ at SP2. “Transmembrane tCO₂” was calculated in the same way.

tCO₂ of bicarbonate fluid was 22 mmol/l, converted by gas law to ml/l depending on ambient conditions, and calculated in ml/min based on the flow set on CVVH. When bicarbonate was used, the “expected V̇CO₂ at SP5” was calculated by adding the calculated V̇CO₂ of the postdilution fluid to the V̇CO₂ at SP3.

Relevant parameters such as CRRT settings were collected tobe used in a predictive equation.

Summary of patient characteristics are depicted in Table 1. CVVH settings of patients are provided in Additional file 2. Predilution citrate was not replaced by NaCl 0.9% in 2 patients because pre-existing hypercoagulability could compromise filter function.

We present the first study that prospectively evaluated CO₂ and O₂ behavior in patients undergoing CVVH. The main finding was that a substantial amount of 26.0 ml/min CO₂ was removed in the effluent. This represents approximately 14% of the average expired V̇CO₂ measured in ICU patients [8] and thus could be clinically relevant. Furthermore, CO₂ removal during CVVH was found to be 80% lower than previously observed in an in vitro hemodialysis model. This is explained by the almost threefold higher blood flow rate used in this model as compared to our CVVH setting [7]. V̇CO₂ before and after predilution (Δ V̇CO₂ between SP1 and SP2) was statistically different, probably because the set CVVH fluid flow at these SP did not correspond with real fluid flow [9]. Blood analysis also depended on “snapshot” sampling which might not exactly reflect average flow. However, this difference did not seem clinically relevant compared with average expired V̇CO₂ (< 1%). CO₂ flow was then divided between the effluent and the blood running to the de-aeration chamber (SP3 and SP4). The CO₂ flow in the effluent correlated with V̇CO₂ loss in the blood after passing the filter [\( \dot{\mathrm{V}}{\mathrm{CO}}_{2\left(\mathrm{SP}2\right)}-\dot{\mathrm{V}}{\mathrm{CO}}_{2\left(\mathrm{SP}3\right)}=\dot{\mathrm{V}}{\mathrm{CO}}_{2\left(\mathrm{SP}4\right)} \)].

In patients receiving postdilution NaCl 0.9%, 1.3 ml/min of CO₂ was removed in the de-aeration chamber. This is a very small quantity compared to the average V̇CO₂ in ICU patients [8]. Thus, CO₂ removal was almost entirely determined by transmembrane filtering and measurable in the effluent. However, when postdilution bicarbonate was used, the expected V̇CO₂ did not correspond with the calculated V̇CO₂ in the blood before it re-entered the body. Several assumptions may explain this observation. First, measurements may be incorrect when CO₂ fails to enter red blood cells after being infused in the postdilution fluid into the extracorporeal circuit. Second, tCO₂ was calculated and not measured. Formulas for these calculations may not be applicable in a non-physiological state of bicarbonate-induced blood alkalinization. Studies measuring blood tCO₂ are needed to elucidate this problem.

As suggested by in vitro hemodialysis, CO₂ is removed in the effluent in gas form and as HCO₃- [7]. The CO₂ concentration or tCO₂ is the driving force for this removal as it remains constant in effluent and in the blood passing through the filter [tCO_2(SP2) = tCO_2(SP3) = tCO_2(SP4)]. By adding predilution fluid, tCO₂ decreased between SP1 and SP2.

Citrate anticoagulation did not influence tCO₂ extraction. Only the short term effect of citrate upon CO₂ removal was evaluated as an influencer of acid-base homeostasis. Over a longer time period, citrate could possibly affect CO₂ clearance because it preserves membrane porosity better than heparin. tCO₂ in blood passing through the CVVH circuit decreased as it was diluted by bicarbonate-free solutions. CVVH had no impact on V̇O₂ because values remained constant at the different SP.

Based on previous findings, different formulas were constructed to calculate CO₂ removal by CVVH in a clinical setting with the use of only one blood gas analysis in the extracorporeal circuit at a preexisting sample point. As these are the first data that were acquired in a CVVH setting, formulas could not be compared to data from other articles [7]. Further studies need to confirm our findings.

Several limitations of our study must be emphasized. First, despite the high number of analyses per patient, the sample size remains small and future studies in more patients are needed to confirm our results. Second, assumptions were made based on “snapshot” blood gas analysis. Continuous monitoring would be more precise. Third, fluid flows as set on CVVH may not correlate with real flow [13]. In-circuit flow measurements may be a better option. Finally, it remains to be determined whether the removed CO₂ influences expired CO₂.

A significant amount of CO₂, both as gas and bicarbonate and measurable in the effluent, is removed during CVVH under citrate anticoagulation. Pre-filter tCO₂ is the major determinant for CO₂ removal. Citrate does not influence CO₂ elimination. To a certain extent, bicarbonate fluids influence blood gases but data are too limited to permit relevant conclusions. Oxygen flow is not influenced by CVVH. CO₂ removal by CVVH in bicarbonate-free conditions can be calculated by multiplying effluent or blood flow with CO2 content at a preexisting sample point. Their clinical relevance requires confirmation.