Prospective Interventional Cohort Study using AIIMS Simplified POC Algorithm for Restricted Blood Transfusion in Cyanotic Children

INTRODUCTION

Congenital heart diseases (CHDs) are developmental anomalies of the heart during intrauterine life. CHD may be acyanotic (ACHD) or cyanotic (CCHD).

CCHD patients are at high risk of peri- operative bleeding because of- reduced production of coagulation factors in view of hypoxic liver injury, deposition of platelets and coagulation factor in the sluggish vascular bed and also reduced platelet production due to erythrocytosis, relatively friable tissue, increased vascularity due to collaterals and release of nitric oxide (NO) from endothelium, hypothermia and also from effects of CPB. Peri-operative bleeding causes hypotension, metabolic acidosis and infection which further cause multi-organ damage.^[1-4] CCHD have also been associated with abnormal coagulation, including low levels of fibrinogen, low platelet count and also platelet dysfunction,^[5-7] making them susceptible to thrombosis and organ infarction.

Blood loss and coagulopathy is treated according to lab tests, like platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), plasma fibrinogen concentration, with packed red blood cells (PRBC), fresh frozen plasma (FFP), platelet concentrate (PC), cryoprecipitate (CRYO) and hemostatic agents (like tranexamic acid, epsilon aminocaproic acid). However, due to relatively long reporting time and poor ability to predict exact cause of bleeding, there is high susceptibility of massive transfusion.

Blood transfusion is associated with various life-threatening complications, also, like transfusion related acute lung injury (TRALI), anaphylactic reaction, hemolytic and non-hemolytic reactions, transfusion related infections etc., resulting in increased morbidity, prolonged ventilator support, prolonged ICU stay and overall expenses. Judicious use of blood and blood components in cardiac surgery is hence very important.

Pediatric patients are not miniature adults because, the absolute circulating blood volume in them is much less than adults, thereby, even minor blood losses, which are insignificant in adults may be life threatening in pediatric age group.^[8]

Reduction in the use of blood during cardiac surgery has started from the beginning of CPB yet to be achieved. As per recent study at least 30-70% of open-heart surgeries required blood transfusions.^[9]

This study will guide us to formulate blood conservation strategies on the basis of our simplified point of care test algorithm to reduce the requirement of blood and blood products and their rational utilization. The development of this algorithm in easy-to-perform steps was the main aim of this research.

MATERIAL AND METHODS

Study design

This prospective randomized controlled trial with alternate allocation was conducted after Institutional Ethics Committee approval. Patients were enrolled after obtaining informed and written consent. None of them were on pre- operative anticoagulation therapy. Study was conducted as the following Consort Flow Diagram [Flowchart 1].

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Flowchart 1:

Consort Flow Diagram.

POC: Point of Care, ROTEM: Rotational Thromboelastometry, CTVS: Cardio Thoracic and Vascular Surgery.

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Strategy in the presence of point of care POC testing

In case of diffuse bleeding intraoperative (post-protamine) or significant bleeding (drain output (>2 mL/kg b.w./h) →first check and optimize body (core) temperature, blood pH, and ionized calcium level in ABG→Check ACT → if more than 150 s/or >20% of baseline ACT value and 20-50 for normal ROTEM parameters, chiefly/CTINTEM > 240; L130 (94 – 100%); FIBTEM MCF (9 - 25mm) and ML (<15%). If CTHEPTEM:CTINTEM<0.9 give additional protamine (0.5-0.8 mg/kg, never exceeding more than 1 mg/kg of protamine reversal) if act is less than baseline → go for other ROTEM^® testing results to know the cause of bleeding.

In ROTEM^® results, if CTEXTEM >100 s then → transfuse prothrombin complex concentrate (PCC) 10–15 iu/kg/(or) fresh frozen plasma (FFP) (10–15 mL/kg) (if PCC is not available) → If ML_INTEM/EXTEM >7% of MCF (within 30 min)/>15% of MCF in 60 min → give tranexamic acid 15–25 mg/kg as bolus iv (in addition to local protocol) → if still bleeding not controlled and A10EXTEM ≤40 mm and A10FIBTEM <10 mm → transfuse CRYO (25 mL/unit) 1 unit/10 kg (or) fibrinogen concentrate with a target of A10FIBTEM >10–23 mm → but if A10EXTEM <40 mm and A10FIBTEM >9 mm then→patient needs platelet concentrate (PC) transfusion (50 mL/unit) of 1 unit/10 kg → If bleeding if still not controlled and still CTINTEM and CTHEPTEM >280 s (consider protamine overdose re-check CT after 10 min)→ consider additional FFP (10 mL/kg)→ if bleeding still continues surgical bleeding is most likely and surgical re-exploration and hemostasis. is needed. A5 FIBTEM has shorter turnaround time and similar diagnostic performance to A10 and can be used instead. New cyanotic POC All India Institute of Medical Sciences algorithm to implement blood conservation strategy is shown in Figure 1.

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Figure 1:

New cyanotic POC All India Institute of Medical Sciences algorithm to implement blood conservation strategy. OT: Operation theater, ACT: Activated clotting time, CT: Clotting time, PCC: Prothrombin complex concentrate, FFP: Fresh frozen plasma, POC: Point of care, DDAVP: Desmopressin acetate.

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RESULTS

After analysis, we found mean aortic cross-clamp time in the POC group (group A) was 100.75 min and 90.20 min in the non-POC group (group B) (P = 0.351). The mean CPB time in group A was 158.10 min, and in group B, it was 131.03 min (P = 0.016). The mean total drain output (from surgery to removal) was 525.78 and 536.54 mL in group A and group B, respectively (P = 0.002). The mean duration of ventilator support was 37.86 and 71.60 h in group A and group B, respectively (P = 0.312), whereas the mean duration of ICU stay was 7.29 and 9.19 days in group A and group B, respectively (P = 0.003). Group A had a mean hospital stay of 13.78 days, whereas Group B had 14.41 days with P = 0.776. Postoperative complication rate in group A was 48.6% (34/70) and in group B 57.5% (46/80) (p value:0.275). Overall mortality rate in group A was 6.25% (5/80) and in group B was 14.29% (10/70) (p value:0.102) [see Tables 3, 8, and 9].

Regarding transfusion requirement, group A required an average of 3.05 units of PRBC, 0.86 units of FFP, 1.66 units of PC, and 0.76 units of CRYO transfusion, whereas group B required 6.16 units of PRBC, 3.43 units of FFP, 4.96 units of PC, and 1.03 units of CRYO transfusion. Except for CRYO (P < 0.065), all other components transfusion was significantly lower in group A (P < 0.001) in our study [Table 4].

There was no statistically significant difference between the two groups with respect to diagnosis [Table 5].

There was a statistically significant difference between the two groups with respect to PT and APTT [Table 6 and Figure 2].

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Figure 2:

Pre-operative laboratory parameters (T1) difference between two groups. APTT: Activated partial thromboplastin time, ACT: Activated clotting time, PT: Prothrombin time, INR: International normalized ratio, Hb: Hemoglobin, HCT: hematocrit, TLC: Total lymphocyte count,POC: Point of Care.

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There was a statistically significant difference between the two groups with respect to PRBC requested, PRBC transfused, FFP requested, FFP transfused, PC requested, and PC transfused [Table 7].

DISCUSSION

Congenital heart disease (CHD) prevalence is about 8–9/1000 live births, with approximately 25% are cyanotic congenital heart diseases. Among them, tetralogy of Fallot accounts for 5%, and transposition of great arteries accounts for 2% of cases and presents in the first week of life.^[11]

In a hospital, the majority of blood transfusions are for cardiac surgical patients. Leukocyte-related target organ damage (2–5%), febrile non-hemolytic transfusion reaction (1%), transfusion-related lung injury (0.05%), and bacterial infection/sepsis (0.05%) are the most common complications of blood transfusion.^[12] Risk of cardiac complications such as – low cardiac output syndrome, increased inotropic usage, acute kidney injury, duration of mechanical ventilation, longer intensive care unit (ICU) and hospital stay, and overall, increased treatment cost, morbidity, and mortality are also increased with more transfusion of blood and blood products.^[13-18]

The number of complex congenital heart surgeries is increasing nowadays. In children, the average amount of perioperative blood loss and blood transfusion are up to 15–110 mL/kg and 155 mL/kg, respectively.^[19,20] Chambers et al., in 1996, showed that 98% of children undergoing on-pump cardiac surgery required blood transfusion,^[21] while recent reports tell us that 38–74% of children undergoing cardiac surgery required blood and blood products transfusion.^[22]

Children are at high risk of hemodilution and coagulopathies from CPB priming solutions, intravenous fluids, inability to maintain the cardiac output on demand and operative bleeding.^[23]

Minimized circuit volume, ultrafiltration, anti-fibrinolytics use, and proper treatment of coagulopathy can limit the transfusion requirements. Various factors such as patient age and weight, surgical complexity, duration of surgery, degree of cyanosis, and CPB-induced coagulopathies can influence anemia tolerance, risk of bleeding, and transfusion requirement.^[17,23-25]

According to a study of 2006 on “morbidity and mortality risk associated with red blood cell (RBC) and blood-component transfusion,” they found that, following cardiac surgery without and with PRBCs transfusion, renal morbid events were 0% and 1. 81%; prolonged ventilator support, 0.44% and 9.14%; serious post-operative infection, 0.24% and 5.03%; cardiac morbidity, 0.05% and 3.03%; neurologic morbidity, 0.37% and 2.41%; and overall post-operative morbidity, 0.96% and 12.33%, respectively, and overall mortality for patients without transfusion was 0. 05%, while, in PRBC transfusion group, it was 3.07%.^[25,26]

This was more helpful in predicting the need for haemostatic interventions after heparin reversal by protamine. The second blood sample (T2) taken at 10-15 min after protamine in bleeding patients? Late blood sampling in bleeding patients results in a delay in treatment particularly with interventions that are not immediately available such as cryoprecipitate and further blood loss.

Late blood sampling in bleeding patients result in a delay in treatment interventions particularly with which are not immediately available such as cryoprecipitate and further blood loss.

Since PRBC transfusion may be the primary endpoint of this study (unfortunately not specified in the method section), the transfusion trigger and target for PRBC transfusion is very important. Secondary endpoints are mortality. complication rate, patient outcome and length of ICU stay.

According to the combined results of two National Institute of Health-supported trials in 2008, the goal HCT of 30 or 35% could be achieved during CPB without transfusion. These authors also concluded that an HCT >24% during CPB has better psychomotor development at 1 year of age.^[26]

Red blood cells (RBC) transfusion improves oxygen delivery, so the main rationale for RBC transfusion in pediatric cardiac surgery patients is to treat anemia.

Multidisciplinary approach including use of low-prime volume circuits with or without vacuum-assisted venous drainage, ultra-filtration (pre-bypass, conventional, and modified), and “cell-saver” for all pediatric patients.^[28-30]

Restrictive transfusion strategy has a similar outcome in comparison to a liberal transfusion strategy for adult cardiac patients in terms of all-cause mortality, myocardial infarction, stroke, or new-onset renal failure with dialysis on 28 days to 6 months after surgery.^[31]

Common causes of mortality in patients of post-CCHD surgery are – age at the time of operation, complexity of surgery, massive transfusion, and prolonged bypass time.^[14,15] It is now well-accepted that perioperative blood transfusion is a modifiable risk factor causing mortality and morbidity in children undergoing congenital cardiac surgery^[15,16]

ROTEM-guided patient blood management (PBM) has been shown to be effective in reducing bleeding, transfusion requirements, complication rates, and healthcare costs.^[32]

Recent PBM strategy published by European Association for Cardio Thoracic Surgery (EACTS) and European Association of Cardiothoracic anesthesia (EACTA) provides practical recommendations for adult cardiac surgeries^[33] but specific guidelines for pediatric cardiac surgery are still lacking. Use of POC tests will help in transfusing right blood components to reduce post-operative bleeding in cyanotic children also^[34] which in turn restricts the exposure to blood and blood components and was associated with reduced ICU and hospital stay in pediatric congenital cyanotic surgical patients.^[35-44]

In our study also, in spite of relatively higher CPB and cross-clamp time in group A patients, we found statistically significant lower drain output, a reduced incidence of postoperative complications and a shorter duration of the ICU stay [Tables 1,3,8,9]. The reduction of in-hospital mortality from 14.29 to 6.25% (RR = 0.4375; P = 0.1138) did not reach statistical significance; however, the study was not powered for a difference in mortality. All the blood component transfusion requirements were significantly lower in group A (where we followed POC algorithm), too, except for cryoprecipitate [Table 2].

In summary, despite a longer CPB time in group A – which is a known good predictor for bleeding, transfusion and bad outcome – we found a significant lower total drain output, transfusion requirements, post op complication rate, and ICU length of stay in the POC-guided group A [Tables 3,4,8, and 9]. However, the reduction in mortality did not reach statistical significance (Risk ratio [95% Confidence Interval]; = 0.4375 [0.1571 to 1.2187]; p = 0.1138) but the study was not powered for a difference in mortality. Furthermore, all blood components transfusion requirements were significantly lower in group A (POC-guided group), except for cryoprecipitate which did not change significantly [Table 4].

Despite satisfactory results, our study has some limitations such as being a single center, single surgeon study with limited patient number. This algorithm may not be cost effective in a developing country like ours. Relatively high infection rate and sepsis being the major cause of complication and mortality, coagulation profile may also be deranged in such cases. There was no long-term follow-up data taken into consideration in this study.

CONCLUSION

Our ROTEM^® based POC algorithm is a good guide for rational and restricted blood components utilization and may helps to avoid transfusion related complications too. Risk awareness and our easily interpretable algorithm will be helpful in the intra and post-operative care of pediatric cyanotic congenital cardiac surgical patients.