Influence of High-Dose Heparin on CT EXTEM of ROTEM Sigma and ROTEM Delta During Cardiopulmonary Bypass

Transfusion management during cardiac surgery is commonly guided by algorithms using viscoelastic tests such as Rotational Thromboelastometry (ROTEM). Recently, the ROTEM Sigma, a new device developed as a fully automated successor to the ROTEM Delta (which required multiple pipetting steps), was approved by the Food and Drug Administration (FDA).1 At our institution, we transitioned from the ROTEM Delta to the ROTEM Sigma and assessed the interchangeability of these 2 devices in the context of a postprotamine reversal transfusion algorithm, where the cutoff value for CT EXTEM is set at 80 seconds.2,3 However, other algorithms use ROTEM measurements during the “rewarming phase,” when the patient is heparinized, and apply higher cutoff values for CT EXTEM of 100 seconds, such as recommended by the Society of Cardiovascular Anesthesiologists.4 Previous studies have shown that CT EXTEM may be sensitive to heparin both in vitro5 and potentially in vivo.6,7 During our analysis, we noted differences in CT EXTEM values between the Delta and Sigma devices during cardiac surgery, particularly in the presence of heparin, which are potentially clinically relevant. These findings are reported here. The objective of this subanalysis was to assess whether CT EXTEM values from ROTEM Sigma are more influenced by heparin than those from ROTEM Delta during cardiopulmonary bypass. METHODS In the original study in patients undergoing elective thoracic aortic surgery, ROTEM measurements were performed at 3 timepoints per patient.2 The first measurement was taken before heparinization (baseline, timepoint 1), the second after declamping of the aorta (heparinized, timepoint 2), and the third at the end of surgery after protamine reversal (postprotamine, timepoint 3). Patients received an initial heparin bolus of 300 IU/kg, and ACT values were kept >450 seconds while on bypass. At each timepoint, 2 blood tubes were taken and simultaneously run in the ROTEM Sigma and the ROTEM Delta device. The original study was submitted to the Ethics Committee on March 29, 2021, and the Ethics Committee confirmed that the Medical Research Involving Human Subjects Act (WMO) did not apply to this study (W21_186 # 21.201). The primary objective of this subanalysis was to establish if there was a different trend from baseline to heparinized CT EXTEM in Sigma compared to Delta; thus, only timepoint 1 and 2 were analyzed. A linear mixed-effects model was used to analyze the effect of timepoint and device on CT EXTEM, accounting for repeated measures from participants. The model was specified as: CT EXTEM ∼ timepoint x device + (timepoint | patient ID). This approach allowed for the assessment of both fixed effects (timepoint, device, and their interaction) and random effects associated with individual participants (random intercept and random slope). To compare the trends between the 2 devices, the interaction effect from the linear mixed model was analyzed. RESULTS A total of 111 patients with at least 1 matched ROTEM measurement were originally included. Of those, 86 patients had both a CT EXTEMbaseline and CT EXTEMheparinized measurement and were included in the current analysis. The Delta device showed a significant increase in CT EXTEM from timepoint 1 to timepoint 2, with a mean increase of 17 seconds (95% confidence interval [CI], 11–24). The Sigma device exhibited a greater increase in CT EXTEM, with a mean increase of 24 seconds (95% CI, 18–31). CT EXTEM measured by Sigma increased 7 seconds more than Delta (95% CI, 1–13, P = .026, Figure). While the cutoff value for CT EXTEM in some transfusion algorithms during heparinization is 100 seconds, we report that the mean CT EXTEM of Sigma at timepoint 2 exceeded this threshold (mean: 101 seconds, standard deviation [SD]: 33) and was observed in 33 of 86 patients (38%). In comparison, the CT EXTEM of Delta had a mean of 96 seconds (SD 28) and a value exceeding 100 seconds was observed in 26 patients (30%, P = .195, Table). Although not the primary focus of our analysis, we also observed differences in MCF EXTEM and MCF FIBTEM values between the devices. MCF EXTEM decreased more in the Delta device than Sigma when heparinized, while MCF FIBTEM values were consistently lower in Sigma compared to Delta, both before and after heparinization, most likely due to the addition of tirofiban to cytochalasin as a platelet inactivator in ROTEM Sigma in contrast to cytochalasin only in Delta. Table. - Overview of CT EXTEM Values and the Proportion of CT EXTEM >100 s Per Timepoint Timepoint 1 Timepoint 2 Delta Sigma Difference* P value* Delta Sigma Difference* P value* CT EXTEM in s (mean (SD)) 79 (23) 76 (33) -3 (−6 to 2) 0.210 96 (28) 101 (33) 4 (0–8) .060 Proportion CT EXTEM >100 s (n, %) 6 (7) 7 (8) 1 (−8 to 1) 0.687 26 (30) 33 (38) 8 (−5 to 20) .195 *Difference = for means, the estimated mean difference with 95% confidence intervals (bootstrap method) and paired t test for P values. For proportions, the paired difference in proportion with 95% CI (Newcombe’s exact method) and McNemar’s test for P values. Figure.: The difference in trend between CT EXTEM Delta and CT EXTEM Sigma Timepoint 1 = baseline measurement, before heparin administration. Timepoint 2 = heparinized measurement, after declamping of the aorta. Model = measurement ∼ timepoint x device + (timepoint | patient ID). The model contains 86 patients and 344 observations. Interaction Estimate = the difference in increase between timepoint 1 and 2 when comparing Delta and Sigma. 95% CI = the confidence intervals around the interaction estimate. Correlation with intercept: = the correlation between the increase and the starting point at timepoint 1 (eg the higher the starting point at timepoint 1, the smaller the increase).DISCUSSION In this substudy, CT EXTEM in heparinized samples appears to be higher with the Sigma device compared to the Delta device. In contrast, in the parent study, we observed the opposite in postprotamine samples: after heparin reversal, CT EXTEM is lower for Sigma than for Delta.2 This suggests that Sigma may be more sensitive to heparin. Since both devices analyzed the same patient sample at the same time, the difference likely stems from how the reagents in each device interact with the patient’s blood. Gronchi et al. (2014) hypothesized that the prolongation of CT EXTEM in the presence of high-dose heparin could be attributed either to a direct effect of heparin on ROTEM test reagents or to an actual hemostatic alteration.7 Given that their study was conducted using the ROTEM Delta device, our comparison with the Sigma device offers additional insight. If the observed prolongation was purely due to a hemostatic alteration, it should be equally evident in both devices. While CT EXTEM does increase with the Delta device, the more pronounced increase in Sigma suggests that differences in reagents play a role. These results indicate that CT EXTEM of the Sigma device prolongs more than CT EXTEM of the Delta device during cardiopulmonary bypass in the presence of high-dose heparin. This is especially relevant for ROTEM-guided transfusion algorithms that anticipate transfusion and coagulation factor administration based on measurements during the rewarming phase with a cutoff value of 100 seconds,4 as using the same cutoff value that was based on the Delta device could result in more transfusion of plasma or prothrombin complex concentrate when using Sigma. Local calibration of this parameter, as recommended by the manufacturer, should be considered. Alternatively, viscoelastic testing may be delayed until after heparin reversal with protamine, as is standard in many protocols. However, based on the findings of the original study,2 calibration of the CT EXTEM value for ROTEM Sigma would still be required in this setting and should be followed with updates to institutional transfusion algorithms as appropriate. DISCLOSURES Conflicts of Interest: H. Hermanns and S. Eberl received an unrestricted grant from Octapharma Benelux. Octapharma had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. A. P. J. Vlaar received an unrestricted grant and consulting fee from C.S.L. Behring, paid to the institution. No other authors declared Conflicts of Interest. Funding: None. This manuscript was handled by: Roman M. Sniecinski, MD, MSc.