Cardiopulmonary bypass (CPB) induces hemostatic derangements that may contribute to bleeding and the need for transfusions during and after pediatric and adult cardiac surgery.1–3 Blood transfusions have been associated with serious side effects including sternal wound infections, transfusion-related acute lung injury, immunomodulation, and in adult cardiac surgery increased mortality.4–8 In pediatric cardiac surgery, intraoperative and postoperative transfusions of blood and blood products are common and a prevalence of >80% has been reported.1,9
Early detection of hemostatic abnormalities increases the possibility of initiating countermeasures to minimize perioperative blood loss and the need for transfusions. Preoperative hemostatic screening tests have no or limited ability to identify patients with an increased bleeding risk10,11 and the use of routine coagulation assays is time consuming and may not be appropriate for intraoperative assessment during CPB, because of heparinization and hemodilution.12,13 Thromboelastometry (TEM) and thromboelastography (TEG®) are point-of-care methods for instant analysis of whole blood coagulation, measuring the viscoelastic properties of the developing blood clot in vitro.14 Intraoperative TEG® and TEM have been related to bleeding volume in pediatric cardiac surgery patients,10,15,16 and the use of intraoperative TEG®/TEM has been shown to reduce transfusion requirements and costs in adult cardiac surgery,17–20 but to the best of our knowledge, no study has investigated whether routine use of TEG®/TEM influences transfusion patterns in pediatric cardiac surgery. We hypothesized that routine use of intraoperative TEM as a decision support would reduce perioperative transfusions and influence transfusion patterns in pediatric cardiac surgery.
Patients and Procedures
The study was approved by the Regional Medical Research Ethics Committee. Written informed consent was signed by all parents in the study group. Informed parental consent for the control group was waived by the Ethics Committee.
Fifty patients were prospectively included in the study group. The study group underwent surgery between June 2007 and December 2008. The study group was compared with a procedure- and age-matched control group consisting of patients operated on between January 2006 and May 2007. If an identical control patient was lacking, a procedure with similar extracorporeal circulation time and aortic clamp time was chosen. In 3 patients, a matched patient was unavailable during this period and therefore 3 control subjects were selected from 2003. Procedure and age were used as the matching criteria based on previous studies in pediatric cardiac surgery patients that demonstrated that these 2 factors are main determinants of perioperative bleeding.3,10 Patients with a known coagulation defect or severe renal or hepatic disorder were excluded. There were 11 resternotomies in the study group and 12 in the control group. All patients in both the study group and the control group were operated on by a group of 4 surgeons and all cases were handled by the same 4 senior anesthesiologists. Patient characteristics and surgical procedures are given in Tables 1 and 2.
Intravenous midazolam and ketamine were used for induction of anesthesia. Maintenance of anesthesia included inhaled isoflurane before and during CPB, IV fentanyl (25–75 μg · kg−1), IV midazolam (0.1–0.3 mg · kg−1), IV pancuronium (0.1–0.3 mg · kg−1), supplemented with IV propofol in patients older than 1 year and weighing >10 kg, and we aimed for early tracheal extubation. The anesthetic procedure was unchanged during the study period and identical to that used for the matched controls.
Anticoagulation and Reversal
An initial IV bolus of unfractionated heparin (Leo Pharma A/S, Ballerup, Denmark) 400 U · kg−1 body weight was administered before cannulation. The level of anticoagulation was repeatedly controlled during bypass with activated clotting time (ACT) (Hemocron Jr. II ACT+; ITC, Edison, NJ) with kaolin as initiator. Reversal of heparinization was achieved by protamine (Leo Pharma A/S) 1 mg per 100 U of the heparin dose (excluding heparin in the prime and additional heparin given during CPB). Additional doses of protamine were administered to patients with continuing bleeding and ACT >130 seconds.
The CPB procedure was unchanged during the study period and identical for the study group and matched controls. CPB was conducted with a hard-shell reservoir and a patient size–adapted membrane oxygenator (Terumo, Tokyo, Japan). For patients weighing <10 kg or with a bypass flow <1.5 L · min−1, the oxygenator RX 05 was used and for patients weighing 10 to 40 kg or with a bypass flow of 1.5 to 4 L · min−1, RX 15 was used. Target rectal temperature (28°C–36°C) was decided by the surgeon depending on the type of surgery. The total pump prime volume ranged from 350 to 700 mL depending on the tubing and the oxygenator. The prime consisted of crystalloid fluid and allogenic packed red blood cells (PRBCs), mannitol 5 mL · kg−1, heparin (one-third to half of the initial IV prebypass heparin dose depending on the relationship between the patient's blood volume and the prime volume), and 100 mL Tribonat® (Fresenius Kabi AB, Uppsala, Sweden). Tribonat is a buffer agent; 100 mL binds 50 mmol H+. During bypass, heparin was administered at an ACT <480 seconds. PRBCs were added to the prime aiming at a target hematocrit (Hct) of 27% to 30% during CPB.
Myocardial protection was achieved with cold intermittent blood cardioplegia (30 mL · kg−1), which was prepared during CPB by adding buffered Plegisol® (Hospira, Inc., Lake Forest, IL) in the ratio 1:4 to whole blood obtained from the arterial line. The cardioplegia solution was kept at 2°C to 4°C before infusion.
Modified ultrafiltration was performed after weaning from CPB with cannulas in place aiming at a Hct of 40%. In children weighing <3 kg, or children planned for complex surgical procedures or elective reoperations, tranexamic acid was administered before initiation of CPB (50 mg · kg−1) and after CPB (30 mg · kg−1) (Table 1). Aprotinin was not used in any of the patients.
In all patients, routine blood samples for hemoglobin (Hb), Hct, prothrombin time, and platelet count were collected preoperatively. Repeated samples for Hb and Hct were analyzed during CPB, after modified ultrafiltration, and during wound closure. Hb, Hct, and platelet count were also analyzed on the first postoperative morning. All intraoperative samples were arterial, and an accredited university hospital laboratory performed all analyses. The only difference in perioperative laboratory analyses between the study group and the control group was the TEM analysis performed during CPB (see below).
Total postoperative bleeding was defined in both groups as the total drain loss until 06:00 on the first postoperative morning. Transfusion volumes of PRBCs, fresh frozen plasma (FFP), platelets, and fibrinogen concentrates (Haemocomplettan®; CSL Behring GmbH, Marburg, Germany) intraoperatively and in the intensive care unit (ICU) until 06:00 on the first postoperative morning were registered. All transfused PRBCs were <14 days old. Platelets were not volume reduced and 1 U consisted of platelets from 4 donors. The initial dose of PRBCs, platelets, and plasma was 10 mL · kg−1. The dose of fibrinogen was 0.25 g to children weighing <5 kg, and 0.5 g to children weighing >5 kg. Having PRBCs in the pump priming was not considered a transfusion. Transfusions in the ICU were not guided by TEM. Hb <110 g · L−1 was used as the transfusion threshold for PRBCs. In patients with a single ventricle, mixed venous saturation also guided PRBC transfusions. Donor exposure was defined as the number of donors that contributed to the products given to individual patients: for PRBCs and plasma, 1 donor contributed to each unit, whereas for platelets, there were 4 donors to each unit.
Modified Rotational TEM
Whole blood coagulation was analyzed by modified rotational TEM (ROTEM®; Pentapharm GmbH, Munich, Germany).11,14 Technical details and evaluation of the method have been reported.13,16,21 Nine hundred microliters of whole blood was obtained from the nonheparinized arterial line and collected in a citrate-containing tube (Minicollect; Greiner Bio-One GmbH, Kremsmünster, Austria). Samples of 300 μL each were analyzed at 37°C using in-TEM (contact pathway activation), hep-TEM (heparinase added for heparin-insensitive analysis), and fib-TEM (cytochalasin D added to discern fibrin polymerization from the platelet effects). A heparin-inhibiting agent is also included in the fib-TEM. Clotting time (CT), clot formation time (CFT), and maximum clot firmness (MCF) were measured in the in-TEM and hep-TEM channels. The specific importance of the fibrin polymerization for the MCF was evaluated in the fib-TEM analysis.
TEM as Decision Support for Transfusions
After rewarming, but before ultrafiltration and protamine administration, hep-TEM CT, hep-TEM CFT, hep-TEM MCF, and fib-TEM MCF were analyzed for a primary evaluation of coagulopathy. Abnormal TEM was defined as a hep-TEM CT >240 seconds, hep-TEM CFT >110 seconds, hep-TEM MCF <50 mm, and fib-TEM MCF <9 mm, according to the manufacturer's reference values for adults. Blood gases were simultaneously analyzed to adjust pH and ionized calcium.
After weaning from bypass and protamine administration, bleeding was clinically evaluated by observation of the operating field for presence of oozing without visible clots. In addition, hemodynamic derangements and repeated analyses of Hb and Hct were evaluated.
Four main scenarios based on clinical observation and TEM results were possible:
- Insignificant bleeding—normal TEM ⇒ no transfusions
- Insignificant bleeding—abnormal TEM ⇒ no transfusions
- Significant bleeding—normal TEM ⇒ surgical reevaluation
- Significant bleeding—abnormal TEM ⇒ transfusion of blood products as indicated by:
- hep-TEM MCF <50 mm ⇒ platelets
- fib-TEM MCF <9 mm ⇒ fibrinogen concentrate
- hep-TEM CT >240 seconds ⇒ FFP
- hep-TEM CFT >110 seconds ⇒ fibrinogen and/or platelets depending on MCF
If clinically indicated (continuing bleeding) or to verify the treatment effect and control heparin reversal, a second set of in-TEM, hep-TEM, and fib-TEM analyses were also performed during wound closure.10,22,23 ACT was tested in all patients to control for heparin reversal. If patients had both a pathological ACT and TEM, protamine was administered first.
The number of patients and the number and type of transfusions in the respective subgroup are given in the Results section.
The primary outcome variable was the proportion of patients receiving any perioperative transfusion (intraoperatively and in the ICU) in the study group and in the control group. The other analyses have mainly a descriptive purpose. No power calculation was performed. The results are presented as mean and SD if not otherwise indicated. For continuous variables, Student t test or Mann-Whitney U test was used as appropriate. The χ2 test was used for categorical variables. No corrections for multiplicity were made. A P value <0.05 was considered statistically significant. Statistical analysis was performed with SPSS 13.0 for Windows (SPSS Inc., Chicago, IL).
All children completed the study protocol. There were no perioperative deaths. For 1 patient in the study group, extracorporeal membrane oxygenation support was used because of postoperative heart failure. The patient was placed on extracorporeal membrane oxygenation after the data collection period ended.
There were no significant differences between the study group and the control group regarding age, gender, weight, or preoperative laboratory analyses (Table 1).
There were no significant differences between the study group and the control group in total CPB time or aortic cross-clamp time (Table 1).
A detailed description of the number and percentage of patients receiving transfusions intraoperatively and in the ICU, and transfusion volumes are presented in Figure 1 and Tables 3 and 4.
The proportion of patients receiving any transfusion of PRBCs, FFP, platelets, or fibrinogen concentrates intraoperatively was significantly lower in the study group than in the control group (50% vs 88%, P < 0.001). The proportion of patients receiving intraoperative PRBCs (34% vs 68%, P < 0.001) and FFP (8% vs 66%, P < 0.001) was significantly lower in the study group, whereas the proportion of patients receiving platelets (38% vs 10%, P < 0.001) and fibrinogen (16% vs 2%, P = 0.015) was larger.
The proportion of patients receiving any transfusion of PRBCs, FFP, platelets, or fibrinogen concentrates postoperatively was significantly lower in the study group than in the control group (44% vs 80%, P < 0.001). The proportion of patients receiving postoperative PRBCs did not differ significantly (36% vs 50%, P = 0.16). The proportion of patients receiving postoperative FFP transfusions was reduced (10% vs 54%, P < 0.001), whereas 1 patient in each group received platelets and no patient received fibrinogen postoperatively.
Intraoperative and Postoperative Transfusions
The proportion of patients receiving any intraoperative or postoperative transfusion of PRBCs, FFP, platelets, or fibrinogen concentrates was significantly lower in the study group than in the control group (32 of 50 [64%] vs 46 of 50 [92%], respectively; P < 0.001). Significantly fewer patients in the study group received transfusions of PRBCs (58% vs 78%, P = 0.032) and plasma (14% vs 78%, P < 0.001), whereas more patients in the study group received transfusions of platelets (38% vs 12%, P = 0.002) and fibrinogen concentrates (16% vs 2%, P = 0.015).
Median donor exposure was 2.6 donors (range, 0–11 donors) in the study group and 2.9 donors (range, 0–8 donors) in the control group (P = 0.09).
Seventeen patients in the study group and 19 in the control group received extra protamine because of ongoing postoperative bleeding and ACT >130 seconds. Neither the postoperative blood loss nor the postoperative Hb levels differed significantly between the study group and the control group (Table 5).
In the intraoperative TEM, analyzed during CPB, 29 of 50 patients (58%) had a hep-TEM CT value of >240 seconds, 43 of 50 (86%) had a hep-TEM CFT of >110 seconds, 37 of 50 (74%) had a hep-TEM MCF of <50 mm, and 45 of 50 (90%) had a fib-TEM MCF <9 mm.
Three patients in the study group had insignificant bleeding and normal TEM. None of these patients received any intraoperative or postoperative transfusions. Twenty patients had insignificant bleeding and abnormal TEM. None of these received intraoperative transfusions, whereas 7 received PRBCs in the ICU but not plasma or platelets. One patient had significant bleeding and normal TEM and underwent surgical reevaluation before the sternotomy was closed and did not receive any transfusions, neither intraoperatively nor in the ICU. Twenty-six patients had significant bleeding and abnormal TEM. Seventeen of these patients received PRBCs intraoperatively and 11 in the ICU. Four received plasma intraoperatively and 5 in the ICU. Nineteen patients in this subgroup received platelets intraoperatively and 1 in the ICU. Eight patients in this subgroup received fibrinogen intraoperatively. Seven patients received both fibrinogen and platelets whereas 19 received platelets only and 2 received fibrinogen only. In 6 patients, a second set of TEM analyses was performed.
In the neonate subgroup (<1 month old, n = 34), 10% of the children in the study group did not receive any transfusion compared with none in the control group (P = 0.22). There was a significant reduction in the proportion of patients receiving plasma transfusions in the neonate study group (25% vs 93%, P < 0.001) and a significant increase in platelet transfusions (75% vs 14%, P < 0.001). There were no significant differences in PRBC (75% vs 79%, P = 0.81) or fibrinogen (30% vs 7%, P = 0.10) transfusions. Bleeding volume and postoperative Hb levels did not differ significantly between the 2 groups.
In the study group, a larger proportion of neonates did receive PRBCs (75% vs 47%, P = 0.047), plasma (25% vs 7%, P = 0.07), platelets (75% vs 13%, P < 0.001), and fibrinogen (30% vs 7%, P = 0.028) compared with children >1 month old in the study group.
The main finding of the present study is that the routine use of intraoperative TEM to guide transfusions markedly reduced the overall transfusion prevalence in pediatric cardiac surgery patients. More specifically, red blood cell and plasma transfusion rates were decreased when intraoperative transfusion decisions were guided by TEM whereas the transfusion rate of platelets and fibrinogen concentrates increased (Fig. 1). The reduced intraoperative transfusion rate of plasma and red blood cells did not result in increased transfusion rates in the ICU, increased postoperative bleeding, or lower postoperative Hb levels (Tables 3–5). The results are thus in agreement with trials in adult cardiac surgery patients in whom the use of TEG®/TEM-guided transfusion algorithms resulted in fewer transfusions.18–20
TEG®/TEM has been evaluated in studies in pediatric cardiac surgery patients. The differences and similarities between TEG® and TEM have been described.14 Both methods measure the viscoelastic properties of the fibrin clot but with somewhat different technology and different terminology. TEG® is used to describe the assay performed using Haemoscope instrumentation (Haemonetics Corp., Braintree, MA) and TEM the alternative ROTEM instrumentation (Pentapharm GmbH). Osthaus et al.21 studied 51 infants and found that patients with congenital heart disease had an impaired clot formation that is most pronounced in children with cyanotic heart disease. Similar results have been presented by Haizinger et al.24 Straub et al.13 investigated 10 children undergoing cardiac surgery with deep hypothermic arrest and compared TEM with standard coagulation tests and flow cytometry. The authors concluded that TEM was faster than standard tests and that TEM may thus guide intraoperative transfusions as also identified by Martin et al.15 Miller et al.10,25 assessed the association between TEG® variables and bleeding in a series of investigations and found that postprotamine TEG® α and maximum amplitude correlates to 24-hour blood loss in children weighing >8 kg. Williams et al.16 confirmed the association between maximum amplitude and blood loss. The results were most recently also confirmed by Moganasundram et al.,12 who concluded that TEG® might be a useful tool to predict and guide treatment of bleeding in pediatric cardiac surgery. Taken together, the results suggest that TEG®/TEM may have a role in intraoperative monitoring of coagulation in pediatric cardiac surgery; however, the impact of routine intraoperative TEG®/TEM on bleeding and transfusions has not been determined.
Previous studies in pediatric cardiac surgery patients have indicated that procedure and age are 2 main determinants of postoperative blood loss and that neonates bleed more and receive more transfusions than older children.1,10 Furthermore, children undergoing cardiac surgery have a low plasma concentration of fibrinogen and low platelet count after CPB.26 In accordance, deranged TEG®/TEM variables reflecting reduced platelet count and low fibrinogen concentration have been reported to be common after CPB in pediatric cardiac surgery.10,12,13 These results were confirmed in the present study because bleeding and transfusions were more common in the neonate group and >90% of the children had a deranged TEM during CPB.
This study did not define explicit TEM cutoff values as the sole trigger for transfusions. Instead, TEM values were combined with clinical observations to guide transfusions in the immediate post-CPB period. Clinical observation of post-CPB bleeding was thus a prerequisite for transfusion and the TEM results were additional factors for deciding the appropriate therapy. In this study, the study group patients were divided in 4 groups based on clinical observations (significant or insignificant bleeding) and TEM variables (normal or abnormal TEM). The results of the study indicate 3 groups that are straightforward: patients with insignificant bleeding and normal TEM do not need transfusion and in patients with significant bleeding and normal TEM, a surgical cause of the bleeding is plausible. None of these patients received intraoperative transfusions in the present study. The patients with insignificant bleeding and abnormal TEM were not transfused intraoperatively in the present study because continuing bleeding was a prerequisite for transfusion. Finally, there was a group with significant bleeding and abnormal TEM. All patients in the study group who were transfused intraoperatively belonged to this subgroup. In these patients, TEM readings guided the decisions for transfusions, resulting in a tailored individualized treatment.
The definition of abnormal TEM in the present study was based on cutoff levels from adult values.27 This is a limitation because children with congenital cardiac defects have a larger age-dependent variability in their hemostatic system, as has been previously demonstrated.21,24 Future studies are necessary to define cutoff levels in the pediatric population. More refined cutoff levels have the potential to further optimize transfusions in pediatric cardiac surgery.
A notable difference between the groups in this study was the lower prevalence of plasma transfusions in the TEM group (14% vs 78%). This is of particular interest because recent data suggest that plasma transfusion is associated with acute lung injury, both in adult and pediatric patients.5,10,28,29 Platelet transfusions increased significantly in the study group, a finding likely caused by low platelet transfusions in the control group.9 This result may be attributable to concerns in our institution that platelet transfusion may compromise extra-anatomical shunts. The decisions to transfuse with platelets and/or fibrinogen in this study were based on low intraoperative hep-TEM and fib-TEM MCF values, indicating low clot firmness. Low clot firmness has been reported to be a common TEM/TEG® change after CPB in pediatric surgery patients and low clot firmness after CPB also correlates to postoperative blood loss.10,11,16
Hornykewycz et al.26 reported that the primary coagulation defect present in infants and small children after CPB is thrombocytopenia and hypofibrinogenemia. In that study, the authors measured platelet count and fibrinogen plasma levels with conventional laboratory analyses. In the present study, platelet count and fibrinogen levels were never measured but intraoperative TEM analysis led to treatment of the appropriate deficiencies.
The increased incidence of platelet transfusions in the study group also resulted in a nonsignificant difference in donor exposure between the groups (median, 2.6 in the study group vs 2.9 in the control group, P = 0.09) despite the large reduction in the number of transfused patients in the study group. Each platelet unit consisted of platelets from 4 donors, which has a large impact on the donor exposure calculations. If instead a single donor had been used for each platelet unit, the difference in donor exposure would have been significant (median, 1.4 vs 2.6, P < 0.001).
Another interesting finding was that not only intraoperative transfusions but also postoperative transfusions were reduced in the study group (Tables 3 and 4), despite that TEM was used only to guide intraoperative transfusions. There are 2 potential explanations for this finding. First, the children in the study group may have arrived to the ICU less coagulopathic, making further transfusions unnecessary. Alternatively, the transfusion policy in the ICU may be biased by the intraoperative use of TEM resulting in a more restrictive transfusion policy.
In this study, no preoperative analyses were performed. This decision was based on reports demonstrating that preoperative routine coagulation samples and preoperative TEM/TEG® variables do not correlate with intra- and postoperative bleeding.10,11 TEM was thus analyzed after rewarming, but before weaning off CPB, which allowed for the early specific evaluation of the most probable post-CPB coagulopathy.13,25
This study has important limitations. The results suggest that routine intraoperative TEM as decision support is associated with reduced transfusions in pediatric cardiac surgery. However, the present study design is not sufficient to prove a direct causality. The reduced transfusion rate may instead be caused by an increased vigilance on transfusions resulting in a changed transfusion policy.30 To prove causality, a randomized controlled trial is needed. Our design was a prospective study group and a matched historical control group. Irrespective of the reduction in transfusion prevalence being a direct effect of intraoperative TEM or that the reduction is biased by changes of transfusion policies, the study demonstrates that intraoperative PRBC and plasma transfusion in pediatric cardiac surgery can be reduced without increasing postoperative bleeding and ICU transfusions or reducing postoperative Hb levels. Furthermore, our data suggest that the study populations were reasonably well matched, and the CPB times suggest that the study group was potentially more complicated than the control group. Also, postoperative bleeding was defined as the total drainage loss until 06:00 the first postoperative morning, and the same definition was used both in the study group and in the matched control group. Multicenter randomized studies are needed to confirm our findings.
In conclusion, the results suggest that the routine use of intraoperative TEM to guide transfusions in pediatric cardiac surgery reduces the overall proportion of patients receiving transfusions of blood products. Furthermore, the results suggest that the routine use of intraoperative TEM as decision support alters the transfusion pattern in pediatric cardiac surgery resulting in fewer children receiving PRBCs and FFP and perhaps more children receiving platelets and fibrinogen concentrates.
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Study design: BSR, AJ, KN; conduct of data: BSR, HW, MS; data collection: BSR, HB, FB; data analysis: BSR, AJ, MS, FB; and manuscript preparation: BSR, AJ, KN, HW.