In the past years, different pump-driven low-blood-flow systems for “CO2 dialysis,” “low-flow extracorporeal membrane oxygenation (EMCO),” or “extracorporeal CO2 removal” (ECCO2R)1 have been introduced. Combined with a double-lumen venous catheter and blood flow rates between only 300 and 500 ml/hour, these systems exclusively allow decarboxination without significant improvement of systemic oxygenation in patients with respiratory failure. Potential indications may be the reduction of tidal volumes during mechanical ventilation in acute respiratory distress syndrome (ARDS)2 and avoidance of intubation in chronic obstructive pulmonary disease (COPD) exacerbation3,4 or bridging to lung transplant.5 Some ongoing trials will probably give some support to clearly indicate these systems. The clinical acceptance until now, however, is poor: in a French national survey from January 2010 till January 2015 in 239 intensive care units (ICUs), only 303 patients were found to be treated with ECCO2R.6
The first system for ECCO2R was described in 1978 for facilitating low-frequency positive-pressure ventilation in a lamb model.7 As in this trial, pumpless arteriovenous systems were subsequently assessed mainly in ARDS patients to either lower peak pressure or decrease tidal volume during mechanical ventilation.8,9 Besides this, venovenous systems have also been developed and evaluated.10 In contrast to circuits using the pressure gradient between artery and vein to generate blood flow through the membrane, venovenous systems11 are dependent on a mechanical pump.
Because the catheters used are relatively small and the blood flow with only about 500 ml/min is only one-tenth compared with ECMO, ECCO2R systems are embellished with attributes like “less invasive” and “safe”12; some authors even proclaim ECCO2R systems to be used in ICU not experienced with (high-flow) ECMO therapy.13
The main complication of (high-flow) ECMO, however, is clinical bleeding in at least every third patient.14 Besides systemic anticoagulation, various acquired coagulation disorders such as thrombocytopenia, thrombocytopathy, fibrinogen and factor XIII deficiency,15 and acquired von Willebrand syndrome (AVWS) with loss of high-molecular-weight (HMW) von Willebrand factor (VWF) multimers16 are typically found in ECMO patients and may be responsible for hemorrhagic diathesis. These disorders partly cannot be monitored using standard coagulation tests or may be masked by heparin therapy, i.e., clinicians observe bleeding symptoms in their patients despite unsuspicious values of International normalized ratio (INR) and activated Partial Thromboplastin Time (aPTT).17
This study was designed for the first time to assess the influence of ECCO2R on blood cells and the coagulation system to appraise whether low-flow systems are really “less invasive” with regard to blood injury. We hypothesized that coagulation disorders known from ECMO would also be identified during ECCO2R.
Materials and Methods
Patients with predominant hypercapnic respiratory failure were connected to the Hemolung respiratory assist system (RAS; ALung Technologies Inc, Pittsburg, PA) when indicated by two experienced intensivists between May 2013 and January 2015 in a German university ECMO center. Indications were avoiding endotracheal intubation or facilitating extubation in patients suitable for lung transplant, providing lung protective ventilation in acute respiratory distress syndrome (ARDS), and preventing right-sided heart failure in persistent hypercarbia. With approval by the local ethics committee (EK 26/2013), demographic and specific laboratory details of the patients prospectively were anonymously collected in a registry provided by the manufacturer. According to departmental standards for diagnosis and treatment of ECMO patients, comprehensive laboratory analyses and rotation thrombelastography were performed regularly. Intensive care unit staff prospectively monitored and documented clinical bleeding signs three times a day. The local ethics committee approved the analysis and publication of the data and confirmed that no specific patient’s consent was necessary because of the anonymous and observational design of the study (EK 557/15).
The Hemolung RAS has been specifically described earlier.18,19 It consists of one unit in which blood is accelerated as well as gas exchange takes place. Inside this unit, blood flows centrally into a rotating core and is radially pumped through a stationary annular fiber bundle. The rotor is magnetically connected to the motor and the control console. The system is connected to the patient with a dual-lumen 15.5 Fr catheter placed either jugular or femoral into the superior or inferior vena cava. The oxygenator surface area is 0.59 m2. CO2 is washed out by a sweep gas flow sucked along the hollow fibers generated by a vacuum pump within the console. Depending on the hematocrit, resulting blood flow is 300–600 ml/min with a maximum rotation speed of 1,400 rpm.
Blood and Coagulation Tests
Blood cell count, INR, and aPTT were determined daily. Patients received unfractionated heparin aiming for an aPTT of 40–50 seconds according to the manufacturer’s recommendation. Until the desired aPTT level was achieved, analyses were performed 8 hourly. Rotation thrombelastography was conducted at the time of implantation and at least on days 6 and 8 after implantation and—if possible—after discontinuation of the RAS. On Mondays and Wednesdays, additionally, factor XIII and VWF analyses were performed. Lactate dehydrogenase (LDH) and if available serum-free hemoglobin were determined.
Basic analysis was performed by measuring von Willebrand factor activity (VWF:A) and von Willebrand factor antigen (VWF:Ag) and calculating the VWF:A/VWF:Ag ratio.
The comprehensive analyses for diagnosis of AVWS including collagen-binding capacity and separation of HMW VWF multimers have been described earlier.16 An AVWS was diagnosed if HMW multimers were missing and the VWF collagen-binding capacity (VWF:CB)/VWF:Ag ratio was below the normal range.
Threshold for transfusion of red blood cells (RBCs) was plasma hemoglobin less than 7 g/dl.
Statistical data were collected in Microsoft Excel (Microsoft, Redmond, Washington, DC). Statistical analysis was performed using SigmaPlot for Windows Version 11 (Systat Software Inc., San Jose, CA). Data were analyzed for normal distribution with Shapiro–Wilk test. For the differences between platelet count and Rotem at different time points, a one-way repeated-measures analysis of variance test was applied. To isolate the time points that differ from each other, a pairwise multiple comparison procedure following the Student–Newman–Keuls method was executed. For the before–after analysis of LDH and haptoglobin levels, a paired t-test was applied. A p value of less than 0.05 was chosen as level of significance. Statistical dispersion is presented as interquartile range (IQR) between first and third quartiles.
Eight patients received the RAS. One was excluded because of death within the first 24 hours of treatment caused by unforeseen multiorgan failure. Overall, 52 days of therapy have been observed. Details can be found in Table 1.
In three patients, before potential lung transplant (two with pulmonary fibrosis and one with exacerbated COPD), RAS was implanted because of respiratory acidosis despite noninvasive ventilation. Intubation was prevented in these cases. Two patients had a prolonged weaning after coronary bypass surgery (one of them with COPD stadium gold IV), and RAS was implanted because of persistent respiratory acidosis during lung-protective ventilation. One patient had undergone lobectomy because of pulmonary cancer and had to be reintubated several days later because of muscular weakness despite noninvasive ventilation. Extracorporeal CO2 removal was initiated to lower the ventilation pressure because of bronchopleural fistula. In one patient, with postaspiration ARDS, RAS was applied to facilitate lung-protective ventilation during prone positioning. One patient was referred to our center with massive bronchial obstruction caused by influenza infection. With invasive ventilation, severe respiratory acidosis persisted and ECCO2R was consecutively initiated.
Hemolung RAS Data
Motor speed was always set to 1,400 rpm. A median blood flow of 496 ml/min (IQR 52) was generated within all days of therapy. The median sweep gas flow was 10 l/min (0.95). The median CO2 removal rate was 104 ml/min (IQR 19).
Clinical Bleeding Symptoms
In four of seven patients (57%), clinical bleeding was observed: three patients showed abnormal bloody bronchial secretion, two of them also presented with unexpected large hematoma after venous puncture, and one developed tamponade of the urinary bladder because of spontaneous macrohematuria.
Standard Coagulation Parameters and Platelet Count
Median INR and median aPTT of all patients during RAS therapy was 1.05 (IQR 0.16) and 45 (11) seconds, respectively. For anticoagulation, a median of 18.4 thousand IU unfractionated heparin/day (IQR 14.7 thousand) was necessary. Six patients had regular values for platelet count before implantation of the RAS. One already suffered from idiopathic thrombocytopenia. Heparin-induced thrombocytopenia had been ruled out in his case. See Table 2 for daily details. In all patients, platelets decreased continuously during therapy. This trend is demonstrated in Figure 1. Platelet count within all patients showed a normal distribution so means were used in the figure to better demonstrate the platelet drop. The difference of means between the time points days 2, 4, 6, and 8 was significant in each case compared with the mean value before implantation of RAS (p < 0.001). There also was a statistical significant difference of each mean value at every time point compared to the former time point calculated with the Student–Newman–Keuls method (p < 0.001).
Acquired von Willebrand Syndrome
In five patients, VWF:A and VWF:Ag were determined and VWF:A/VWF:Ag ratio was calculated. All of them developed pathologic values less than 0.73, hinting to AVWS during RAS therapy.
To confirm this, in three of them, additionally comprehensive diagnostics including VWF:CB and multimer analysis were performed before implantation, during, and after explantation of the RAS. They all had a normal VWF:CB/VWF:Ag ratio at the beginning of the extracorporeal therapy and dropped far below 0.7 during the therapy. In combination with a loss of HMW VWF multimers, AVWS was diagnosed. One patient died during the extracorporeal therapy from right-sided heart failure; the other two patients recovered from AVWS within the first day after discontinuation of the RAS. As an example, we demonstrate the course of VWF:CB/VWF:Ag ratio of patient no. 8 in Figure 2.
Factor XIII Deficiency
In six patients, factor XIII activity was determined. Median factor XIII activity at the start of the extracorporeal therapy was 66.5% (IQR 9). Four patients (67%) developed factor XIII activity values below 60%, two of them even below 50%. One patient was substituted with factor XIII concentrate (Fibrogammin, CSL Behring, Marburg, Germany) because of clinical bleeding.
Repeated Rotem analysis did not significantly show differences in clot formation between days 1, 5/6, and 8/9. In addition, no case of relevant fibrinogen deficiency or hyperfibrinolysis was detected. None of the patients received fibrinogen concentrate. Detailed parameters can be found in Table 3.
In five patients, haptoglobin serum levels have been determined. Median haptoglobin was 191 mg/dl (IQR 96) before implantation of the RAS. In all patients, haptoglobin dropped below the limit of detection (< 5 mg/dl) within the first 2 days of therapy.
Median LDH was 428 IU/l (IQR 162) on the first day of RAS therapy and 842 IU/l (IQR 575) before explanting the system. For the differences of haptoglobin (p = 0.06) and LDH (p = 0.133) levels before implantation compared with a time point just before explantation, no statistical significance could be demonstrated because of the small patient groups. In two patients, we repetitively measured free hemoglobin serum levels. One had 0.4 mg/dl (reference: < 5 mg/dl) before RAS and developed values up to 16 mg/dl during the therapy. In the other patient, baseline levels for hemoglobin serum levels were not measured before RAS; however, increased values were found (up to 65 mg/day) during the therapy. All these findings are hinting to hemolysis.
One of seven patients did not need transfusion of blood products. The other six patients received a total of 19 units of RBCs during 43 days of therapy (0.44 units/day). One patient with preexisting thrombocytopenia also received 2 units of platelet concentrates because of clinical bleeding during the therapy. No plasma or fibrinogen concentrate was transfused. For detailed amount of transfused blood products, please see Table 4.
This observational prospective study for the first time evaluates blood cell injury and acquired coagulation disorders during ECCO2R therapy.
The main findings are that ECCO2R leads to hemolysis, thrombocytopenia, and AVWS (including loss of HMW VWF multimers) as well as factor XIII deficiency. Clinical bleeding symptoms and transfusion are common during ECCO2R therapy.
Blood cell damage and acquired coagulation disorders have been described in high-flow venovenous ECMO therapy. It is well known that ECMO leads to thrombocytopenia and thrombocytopathia,20–22 fibrinogen and factor XIII deficiency,23 and AVWS with loss of HMW VWF multimers.16,23 Bleeding is still the main problem in (high-flow) ECMO patients and is associated with worse survival,14 and it can hardly be predicted using standard coagulation parameters. There is incomplete data for bleeding during ECCO2R. Braune et al.3 report 11 major and 10 minor bleeding events in 25 COPD patients treated with the ilA activve (Novalung, Heilbronn, Germany) with a mean blood flow of 1.3 l/min. Fanelli et al.2 in their 15 ARDS patients treated with the Hemolung RAS simply do not report bleeding but had a relevant stake of patients transfused with RBCs. In four of seven ECCO2R patients in this study (57%), relevant clinical bleeding was observed. We confirm that the same coagulation disorders known from ECMO appear in ECCO2R and may be responsible for the clinical bleeding.
This finding shows that the quantity of blood flow is not necessarily the main factor for blood injury. We stated earlier that rather contact to the artificial surface per se and negative pressure phenomena, shear stress, and turbulences caused by the design of the extracorporeal system lead to the abovementioned coagulation disorders.24
Blood Cell Injury
Negative pressure phenomena, nonlinear flow, and shear stress cause damage to erythrocytes and platelets. In this study, a decrease of platelet count as well as the development of low haptoglobin levels in conjunction with elevated LDH and plasma free hemoglobin levels was observed. This confirms that ECCO2R causes relevant hemolysis.
Acquired Coagulation Disorders
Acquired von Willebrand syndrome has been described to increase the risk of bleeding complications in patients with ventricular assist devices25 and venoarterial as well as venovenous ECMO.16,26,27 Acquired von Willebrand syndrome results from increased shear stress caused by turbulent flow within extracorporeal systems. Because of shear stress, VWF is unfolded and subsequently cleaved by the metalloprotease A disintegrin and metalloprotease with thrombospondin-1-like domains 13 (ADAMTS-13).25,28–30 This results in the loss of the HMW multimers and consecutively decreased binding of VWF to collagen.
As basic tests, VWF:A and VWF:Ag were measured in five of seven patients. Decreased VWF:A/VWF:Ag ratios were found in all of them within 1–3 days of RAS therapy. Comprehensive testing in three of them showed VWF:CB/VWF:Ag ratios between 0.1 and 0.3 and loss of HMW multimers, confirming the diagnosis of severe AVWS. Results were similar to those found in high-flow ECMO.16,31
Factor XIII deficiency can be responsible for severe bleeding events in the peri-interventional and perioperative setting, and this pathology cannot be detected by usual coagulation tests such as aPTT or INR.32,33
In this study, almost 70% of the patients developed factor XIII deficiency, 28% with factor XIII activity below 50%. In high-flow ECMO, values below 50% are found in 80–90% of patients. Fibrinogen deficiency is reported with an incidence of up to 40% in ECMO patients. In this study, thrombelastography revealed no case of relevant fibrinogen deficiency or fibrinogen clot destabilization. We assume that the relatively small membrane surface of the RAS with 0.59 m2 may be responsible for this finding: in high-flow ECMO, surface area is relevantly larger (e.g., 1.8 m2 in the Maquet Quadrox-i-Oxygenator, Maquet Holding, Rastatt, Germany, or 1.2 m2 in the Sorin-EOS-Oxygenator, Sorin Group, Mirandola, Italy). We did not observe a case of relevant hyperfibrinolysis. Neither standard coagulation tests like INR and aPTT nor rotation thrombelastography were helpful to determine hemorrhagic diathesis.
Only one of seven patients did not require a transfusion of RBCs during ECCO2R therapy. Six patients received a total of 19 units of RBCs during 43 days of therapy (0.44 units/day). There are different reasons why patients suffer from anemia during critical care treatment: alterations in hematopoiesis because of critical illness, hemolysis, blood sample collection for laboratory analyses, and bleeding. In one patient with macrohematuria, the blood loss might have been a relevant cofactor, and for the other patients, hemolysis may be responsible for the increased requirement of RBC transfusion.
Indications for ECCO2R and Setting
The idea of ECCO2R is interesting and technically it works. Nevertheless, this procedure is still missing its clear indication. Recently, ECCO2R was evaluated to facilitate ultraprotective ventilation in patients with moderate ARDS,2 but of 15 patients included, only 6 were still treated with ECCO2R at the third day of therapy. With a 28 day mortality rate of 48%, outcome in moderate ARDS was not better than in studies without extracorporeal treatment. Extracorporeal CO2 removal also was applied to avoid intubation in 25 patients with exacerbated COPD.11 Eleven of them needed intubation during ECCO2R, seven of them because of hypoxemia. Two more patients had to be intubated after explantation of the system.
Two patients developed relevant hypoxic failure during ECCO2R therapy in our study. One had chronic pulmonary disease and it turned out that he was not suitable for lung transplant. Therapy was deescalated and the patient died in due course. The other had to be switched to high-flow venovenous ECMO. Extracorporeal membrane oxygenation cannulation was complicated because the right jugular vein—our preferred location to implant a double-lumen ECMO cannula—was already obstructed by the Hemolung cannula.
The experience with ECCO2R is still poor. Only 10 of 239 French ICUs used venovenous systems for CO2 removal.6 In addition, eight ICUs practiced ECCO2R with two catheters instead of one double-lumen cannula. Some of them had only one patient treated so far.
This single-center study therefore is the largest consecutive observation of the influence of ECCO2R on coagulation with the Hemolung RAS in one of the most experienced ECMO centers in Germany. With only seven patients included, however, future studies including more patients with Hemolung support are needed to give more comprehensive insights on the development of acquired bleeding disorders during ECCO2R support. In our study, we regulated anticoagulation with heparin using the aPTT. It would have been better to monitor antifactor Xa levels as this is a more precise testing than aPTT.34
The idea of CO2 removal with low blood flow rate is interesting, although patient groups taking advantage of this therapy are still not clearly identified. The assumption that ECCO2R is “less invasive” cannot be supported by the findings of this study: even in the low-flow area of extracorporeal lung support, relevant injury to the blood is traceable. Thrombopenia, hemolysis, factor XIII deficiency, and AVWS with consecutive blood product transfusion are common. In future studies evaluating ECCO2R, these parameters should be taken into concern. From our point of view, it is too early to appraise these systems as “safe.” For now, ECCO2R should exclusively be applied in ICUs experiencing hemostaseologic disorders during ECMO therapy.
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