Extracorporeal membrane oxygenation (ECMO) is a form of life support for patients with respiratory, cardiac, or combined cardiorespiratory failure. ECMO provides a temporary bridge to recovery, transplant, or another form of mechanical circulatory support. Once the artificial components of the ECMO circuit contact blood, activation of hemostatic and inflammatory systems ensue.1,2 This activation ultimately prompts thrombin generation and clot formation that if left unchecked could be detrimental. Thrombotic or hemorrhagic complications while on ECMO support may be life threatening, especially when the central nervous system (CNS) is involved.3–5 Data from the Extracorporeal Life Support Organization Registry demonstrated that cerebrovascular complications during pediatric and adult ECMO support occur with an incidence of 5–13%. These complications dramatically increase in-hospital mortality.4,5 Anticoagulation is initiated as an effort to decrease these complications.3 An unbalanced state in which therapeutic anticoagulation is not reached increases the risk for thrombosis while excessive anticoagulation increases the risk of hemorrhagic events.
Achieving this perfect anticoagulation balance is arguably the most challenging problem in the management of ECMO patients.6 Use of variable anticoagulants such as antithrombin, bivalirudin, and argatroban has not demonstrated a significant impact on hemorrhagic complications.7 More recently the focus has shifted to using nontraditional coagulation studies to monitor the anticoagulant effect of unfractionated heparin. Monitoring has evolved with no clear identification of an ideal parameter.7,8 There are no consensus anticoagulation guidelines established by Extracorporeal Life Support Organization nor national standardized protocols to guide anticoagulation on ECMO.6 Therefore, monitoring varies among centers choosing between activated clotting time (ACT), partial thromboplastin time (PTT), antifactor Xa, thromboelastography (TEG), rotational thromboelastometry (ROTEM), or a combination of them.7,9,10 Given the frequent incidence of CNS complications on ECMO, despite close anticoagulation monitoring, we hypothesized that the traditional coagulation profile would not predict an intracranial hemorrhage or infarct in pediatric ECMO patients.
MATERIALS AND METHODS
The study was conducted in a tertiary level multidisciplinary pediatric intensive care unit. It was designed as a retrospective individually matched case–control study. Approval from the institutional review board was obtained, with waiver of informed consent and waiver of Health Insurance Portability and Accountability Act authorization.
From all the children (1 day to 18 years of age) supported on ECMO between January 2009 and December 2014, cases of intracranial hemorrhage and infarct were identified along with matched control subjects. Exclusion criteria included patients with a medical history of prior neurologic injury (including CNS hemorrhage or infarct), genetic syndrome, or chromosomal abnormalities associated with cerebrovascular complications, as well as patients with incomplete laboratory or imaging data.
Data Collection and Definitions
Eligible patients were identified through our institutional ECMO database. Medical records were reviewed retrospectively to obtain demographic, diagnosis, and ECMO data. Information regarding the presence of a cerebrovascular event, coagulation profile, unfractionated heparin use, the presence of pre-ECMO coagulopathy, and in-hospital mortality were also recorded. Demographic data including age, weight, gender, and race were collected. Primary diagnoses were categorized into 5 classes: neonatal lung disease, pediatric respiratory failure, nonsurgical cardiac, postoperative cardiac, and sepsis. ECMO data included ECMO type, indication, and duration of ECMO, ECMO time to event, cannulation site, and maximum ECMO flow. ECMO type was categorized as venovenous when there was no arterial cannulation during the ECMO run. All the others were defined as venoarterial ECMO. ECMO indications were classified into pulmonary, cardiac, and extracorporeal cardiopulmonary resuscitation based on the primary indication for ECMO. Extracorporeal cardiopulmonary resuscitation was defined as initiation of ECMO during cardiopulmonary resuscitation. ECMO duration was defined as the time from ECMO cannulation through decannulation. ECMO time to event was defined as duration in days from cannulation to cerebrovascular event.
Cerebrovascular events were identified by extensive review of the head ultrasound (US) or head computerized tomography performed during ECMO support and interpreted by the pediatric neuroradiology team. In our institution, routine head US is performed in neonates and infants with open fontanel, daily for the first 3 days then weekly and as needed while on ECMO support. Head computerized tomography is performed in children when clinical neurologic changes occur during ECMO support, or when the head US results are indeterminate or inconsistent with the patient’s neurologic symptoms. All cerebrovascular events were classified according to the initial insult identified by neuroimaging as intracranial hemorrhage or infarct. Intracranial hemorrhage was defined as a focal collection of blood within the brain parenchyma, subarachnoid, ventricular system, subdural, and/or epidural spaces.11 Grade I interventricular hemorrhages were excluded similarly to previous ECMO studies.4 Intracranial infarct was defined as an ischemic injury within the cranial vault.11 Ischemic changes with subsequent hemorrhagic conversion were classified as intracranial infarct based on the initial insult. Event day for each case was defined as the date when the cerebrovascular event was first identified by neuroimaging during the ECMO run. For the control subjects, this date was calculated as the number of days from cannulation to the corresponding event day for the matched case. This counting system assured equal ECMO time to event for every matched case–control pair and was designed to minimize bias due to ECMO duration.12
Pre-ECMO coagulopathy was defined as the presence of at least 2 abnormal data points during the 24 hour period before ECMO cannulation. To provide baseline data before initiating ECMO, pre-ECMO coagulation studies have been routinely collected in our institution. Following published definitions of coagulopathy,13 abnormal data points were defined based on reference (Ref) values used in our institution’s laboratory: platelet count <100,000/µL (Ref 150,000–550,000/µL), fibrinogen <100 mg/dL (Ref 150–400 mg/dL), prothrombin time (PT) > 18 seconds (Ref 12–15.3 seconds), PTT > 44 seconds (Ref 21.3–38.8 seconds), d-dimer > 0.5 µg/ml (Ref 0–0.5 µg/ml). Coagulation laboratory tests during ECMO were classified into 2 categories: 1) data that assisted with heparin anticoagulation monitoring including PTT, ACT, and antifactor Xa (IU/ml) and 2) data that assisted with blood product administration including platelet count, d-dimer, fibrinogen, and PT. Coagulation profile was defined as the median daily value for every laboratory test during the 24 and 72 hour period before the event. Total heparin dose (U/kg/day) was defined as the median daily dose of the unfractionated heparin infusion and bolus doses administered during the 72 hour period before the event. The median heparin infusion rate and a weighted average heparin dose (U/kg/hour) in addition to the number of heparin boluses were also collected.
Each case was individually matched with a control. Each control was validated as not having a cerebrovascular event by review of all neuroradiology imaging results during and after ECMO support. Matching occurred on the basis of age group, primary diagnosis, the presence of pre-ECMO coagulopathy, ECMO type, and cannulation site. Age group was categorized as neonates (1 day–30 days), infants (31 days–1 year old), 1–6 years old, and >6 years old based on previous literature describing age-related physiologic differences in the hemostatic system.14 Primary diagnosis and the presence of pre-ECMO coagulopathy were used as matching criteria to minimize bias due to residual heparinization or postoperative coagulopathy after cardiac surgery, hepatic failure complicating primary disease, or inflammatory states after cardiopulmonary bypass (CPB) or sepsis.7,15 Patients were also matched for ECMO type and cannulation site based on data suggesting increased risk of cerebrovascular events in patients undergoing venoarterial ECMO16 and in those with right carotid artery cannulation.17
Anticoagulation Management on Extracorporeal Membrane Oxygenation
The study patients received an unfractionated heparin bolus of 50–100 U/kg after skin incision just before cannula insertion. Unfractionated heparin infusion was started at 28 U/kg/hour for patients younger than 1 year and at 20 U/kg/hour for children greater than 1 year, and it was titrated based on conventional target therapeutic goals of ACT (160–195 seconds), PTT (60–80 seconds), and antifactor Xa (0.3–0.7 IU/ml) unless otherwise dictated by the patient status. Heparin boluses (10 U/kg) were administered when the therapeutic goals remained low necessitating infusion titration. Heparin infusions were titrated by 10% of the current dose. During routine heparin administration, ACT served as the primary marker of unfractionated heparin activity. ACT was assessed hourly and as needed. PTT was obtained every 12 hours with antifactor Xa obtained every 24 hours. All laboratory studies were obtained as needed when anticoagulation status was uncertain. When a patient’s clinical status did not correlate with the ACT data then PTT and antifactor Xa were relied on for anticoagulation management. Hematology consultation at the initiation of ECMO occurred for majority of the ECMO patients. Input from the hematology team balanced practitioner preferences toward certain laboratory tests. PT, fibrinogen, d-dimer, and platelet count were also monitored every 12–24 hours to assess need for blood product replacement. Transfusion parameters included platelets for platelet count <100,000/μL, fresh-frozen plasma for PT > 18 seconds and cryoprecipitate for fibrinogen < 125 mg/dl. Antithrombin activity, although not routinely monitored, was checked and lead to antithrombin replacement for patients with escalating heparin requirements at doses >35–40 U/kg/hour and laboratory evidence of antithrombin activity deficiency.
In our institution, blood samples of patients on ECMO support are obtained from the first-line postpump and preoxygenator, while unfractionated heparin infusion and boluses are given through the fourth-line postpump and preoxygenator. Blood samples are collected using BD Vacutainer tubes (Becton Dickinson, Plymouth, Devon, UK) with a blood to citrate concentration of 9:1. Coagulation tests are measured using the STA-R evolution coagulation analyzer (Stago Diagnostica, Vilvoorde, Belgium). Activated clotting time is calculated using the I-STAT kaolin ACT analyzer (Abbott Point of Care, Princeton, NJ). The automated blood cell analyzer Sysmex XN-2000 (Sysmex, Kobe, Japan) is used to quantify platelet count.
Demographic, clinical, ECMO, and laboratory characteristics for the overall sample of patients were described using the sample median and range for continuous variables and the frequency and percentage for categorical variables. Based on institutional values described before, coagulation data were categorized into normal and abnormal (see Table 1, Supplemental Digital Content 1, http://links.lww.com/ASAIO/A149), for each of the parameters and analyzed with 2 × 2 tables for paired observations using the McNemar test (see Table 2, Supplemental Digital Content 2, http://links.lww.com/ASAIO/A150). To address whether there were differences in baseline characteristics and coagulation profile between cases and controls, the nonparametric two-tailed paired Wilcoxon rank sum tests (for continuous variables) and the paired Fisher exact tests (for categorical variables) were utilized. One-sample one-tailed t-tests were utilized to analyze whether there were differences in heparin dosage between each cerebrovascular group and their respective control subjects. Two tailed t-tests were utilized to analyze whether there were differences in minimum and maximum heparin dosage between each cerebrovascular group and their respective control subjects. Statistical significance was defined as p < 0.05. All analyses were performed using R version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria, http://www.R-project.org/).
Patient and Extracorporeal Membrane Oxygenation Characteristics
Two hundred and forty-one neonates and children received ECMO support from January 2009 to December 2014. Intracranial hemorrhage was identified in 22 patients (9.2%), and infarct was identified in 19 patients (7.9%). Five patients were excluded from the study because of incomplete coagulation data (n = 2) and inability to identify appropriate matched control subjects (n = 3). A total of 36 cases (19 with intracranial hemorrhage and 17 with infarct) were included and matched 1:1 with 36 appropriate control subjects (Figure 1). No significant differences were observed between cases and controls in demographic characteristics, ECMO indication and duration, ECMO time to event, and maximum ECMO flow (Table 1). However, in-hospital mortality was significantly higher in cases compared with controls (75 vs. 22%, p < 0.01).
The median values of the laboratory data that assisted with heparin anticoagulation monitoring (ACT, PTT, and antifactor Xa) during the 24 and 72 hour period before the cerebrovascular event were not significantly different between the hemorrhage group and their control subjects or between the infarct group and their control subjects (Figure 2). Additionally, analysis of the average minimum and maximum values for PT, PTT, and antifactor Xa levels between the infarct and hemorrhage groups and their control subjects revealed the only difference being significantly lower maximum antifactor Xa values in the hemorrhage group compared with their control subjects. Though the antifactor Xa values were lower, they remained in the range targeted for patient management. The median values of the laboratory data that assisted with blood product administration (platelet count, PT, fibrinogen, and d-dimer) during the 24 and 72 hour period before the cerebrovascular event did not show any significant difference between the hemorrhage group and their control subjects nor between the infarct group and their control subjects (Figure 3).
No differences were observed in the median heparin infusion rate in either the hemorrhage or infarct groups compared with control subjects. There were no differences in the total number of heparin boluses between the hemorrhage group compared with their control subjects during the 24 or 72 hour period before the event. However, there was a significant difference in the number of heparin boluses received by the infarct group 72 hours before the event. This difference was not sustained at 24 hours before the event (Table 2). The hemorrhage group required significantly less heparin than their control subjects to achieve the goal coagulation parameters. This was seen with lower total heparin doses at both 24 and 72 hours before the event in addition to lower maximum heparin doses in the hemorrhage group (Table 3). The infarct group required significantly less heparin than their control subjects to achieve the goal coagulation parameters at 72 hours before the event; however, the difference was not sustained at 24 hours before the event (Table 2).
This study is the first to date to evaluate whether the traditional coagulation profile predicts an intracranial hemorrhage or infarct in pediatric ECMO patients using a matched case–control design. In our cohort, after matching individual cases with control subjects for infarct or hemorrhage, no differences were observed in coagulation parameters during the 24 and 72 hour period before a cerebrovascular complication. Our data suggest that the traditional coagulation profile does not predict cerebrovascular events in neonates and children on ECMO support.
Our findings conflict with previous adult and pediatric studies demonstrating an association between cerebrovascular complications and anticoagulation monitoring data18–21 as well as product replacement levels of platelets18,20,22,23 and fibrinogen.18 The differences between our results and previous literature may be attributable to study design disparity. First, some of the previous studies did not employ a matching design.19,21–23 Furthermore, in studies where matching was employed the strategy did not include ECMO mechanics, ECMO time to event, or coagulopathy before cannulation in their criteria.16–18,20 Second, the majority of the prior studies assessed subpopulations of infants with specific diagnostic categories unlike the diagnosis inclusiveness seen in our cohort.18,19,22 Third, in other studies, heparin titration was guided with ACT goals higher than those used in our cohort.18,19,22 Finally, variation between institutional laboratory technology, transfusion parameters as well as anticoagulation and ECMO management likely influenced individual study results.
Interestingly, in our study, we observed a trend toward lower fibrinogen levels in the infarct group compared with control subjects that did not reach statistical significance. This differs from the work done by Doymaz et al.18 that demonstrated an association between low fibrinogen levels and intracranial hemorrhage, which may be in part explained by their higher fibrinogen threshold for cryoprecipitate transfusion. Circuit cleavage of fibrinogen leading to fibrin deposition, development of vascular thrombosis, and subsequent CNS embolization may be a possible explanation for our finding.
Furthermore, our study suggests that no single laboratory coagulation test looking at individual aspects of coagulation can reliably predict the occurrence of cerebrovascular complications on ECMO. The traditional coagulation profile does not take into account pro- and antihemostatic pathways or the effects of platelet and endothelial contributions.24 We believe that the use of standard coagulation tests does not comprehensively assess anticoagulation on ECMO. Since cerebrovascular events persist despite directed anticoagulation management based on traditional coagulation studies, consideration for a more comprehensive assessment of clot dynamics should be entertained. Whole blood viscoelastic coagulation tests, such as TEG or ROTEM, evaluate heparin effect as well as underlying hypo- or hypercoagulable states after reversal with heparinase.7,8 In the pediatric population, studies have evaluated the use of TEG/ROTEM on ECMO to assist coagulation management in the context of excessive bleeding8,25,26 or platelet dysfunction.27 However, weak correlation has been observed between TEG values and the traditional anticoagulation markers, as well as TEG values and hemorrhage prediction during ECMO support.9,10 Larger prospective studies are necessary to evaluate the accuracy of TEG/ROTEM to safely monitor anticoagulation on ECMO.
Our findings also demonstrate that patients with both intracranial infarct and hemorrhage required less heparin to maintain the same anticoagulation parameters compared with their controls. It is unclear why patients with cerebrovascular events required less heparin to achieve the same anticoagulation as control subjects. This finding adds to previous ECMO studies reporting intracranial hemorrhage to be associated with heparin dosage.18,22 In fact, several factors may influence heparin dosage such as the presence of circulating heparin not completely antagonized by protamine in patients requiring ECMO after CPB,28 the release of heparin from the surface of the heparin-coated circuit,29 and the presence of endogenous substances with heparin-like effect.28,29 In our cohort, there were no differences between cases and controls in respect to requiring ECMO after CPB nor in exposure to heparin-coated circuits. Analysis of heparin released from the circuit or effects from endogenous substances were not assessed in our retrospective review, however, should receive consideration in future prospective studies.
Finally, our findings lead us to hypothesize that unbalanced anticoagulation is not the sole causal factor prompting cerebrovascular complications on ECMO. Underlying patient conditions previously described to increase the risk for cerebrovascular events on ECMO (such as sepsis, congenital diaphragmatic hernia, renal dysfunction, and hemostasis disorders)15,30–32 and physiologic changes (such as acidosis,20,32–34 hypoxia,35,36 hypertension,18,37 rapid changes in partial pressure of carbon dioxide,31 and inflammation38,39) should be considered when monitoring ECMO anticoagulation.
Interpretation of our findings must be cautioned because of the limitations of the methods. Our experience comes from a single center with a small sample. Absence of guidelines for management and monitoring anticoagulation could reflect differences in practitioner preferences, especially related to preferred tests for heparin titration. The variability in patient severity of illness may have also influenced the results. Finally, despite efforts to streamline ECMO management, our results could have been affected by equipment modifications during the study period.
The traditional coagulation profile did not predict acute cerebrovascular events in our cohort. A more comprehensive assessment of clot dynamics should be considered to better monitor anticoagulation on ECMO. Acknowledging other factors predisposing to cerebrovascular complications on ECMO should be considered and further elucidated in a prospective manner.
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extracorporeal membrane oxygenation; anticoagulation; unfractionated heparin; intracranial hemorrhage; infarct
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