Martin Besser

The prevalence and association with transfusion, intensive care unit stay and mortality of pre-operative anaemia in a cohort of cardiac surgery patients.

Anaemia is increasingly prevalent in the United Kingdom. Despite recommendations to the contrary, many patients undergo cardiac surgery with undiagnosed and untreated anaemia. According to the World Health Organization definition, 1463/2688 (54.4%) patients undergoing cardiac surgery between 2008 and 2009 in our institution were anaemic. Compared with non‐anaemic patients, anaemia was significantly associated with transfusion (791 (54.1%) vs 275 (22.4%), p < 0.001, OR (95% CI) 3.4 (2.8–4.1)), death (45 (3.1%) vs 13 (1.1%), p = 0.0005, OR 2.4 (1.2–4.5)), and prolonged ICU stay (287 (19.6%) vs 168 (13.7%) p < 0.001, OR 1.3 (1.0–1.6)). The prevalence of anaemia in this cohort is much greater than that previously reported. The cause of this excess is not clear. Pre‐operative anaemia is a strong predictor of increased transfusion requirement, risk of ICU stay and death during cardiac surgery. The effect of increasing haemoglobin concentration therapeutically is not yet clear.

Haemostatic management of cardiac surgical haemorrhage

Almost 30 000 cardiopulmonary bypass operations are performed in the UK every year, consuming a considerable portion of the UK blood supply. Each year, in cardiac surgery, 90% of blood products are used by only 10% of patients, and over the past 25 years, much innovation and research has gone into improving peri‐operative diagnosis and therapy for these patients. Visco‐elastic tests performed at the bedside, with modifications to allow direct quantification of fibrinogen levels, are probably the biggest advancement. There is no clear advantage of thromboelastometry over thromboelastography, and the published literature remains scarce. Visco‐elastic testing has recently been coupled with the systematic replacement of clotting factors by means of factor concentrates, with objective improvement in terms of blood loss, red blood cell usage and surgical re‐exploration. The National Institute for Health and Care Excellence has reviewed the available evidence and recommended visco‐elastic tests as cost effective in cardiac surgery. Factor concentrates, however, carry significant risks, particularly unnecessary donor exposures, potential selective over‐correction of partial deficiencies and the possibility that the postoperative risk of venous thromboembolism is increased; as yet there are no data on risk–benefit analysis. There are a number of promising drugs used in topical haemostasis, but the requirement to apply these before major bleeding is manifest limits their use considerably. Hyperfibrinolysis is less important than in the past due to the wide spread adoption of antifibrinolytic agents and close intra‐operative monitoring of heparin effect.

An Exploratory Cohort Study Comparing Prothrombin Complex Concentrate and Fresh Frozen Plasma for the Treatment of Coagulopathy After Complex Cardiac Surgery

BACKGROUND:Administration of coagulation factor concentrates to treat bleeding after cardiac surgery with cardiopulmonary bypass might be a strategy for reducing allogeneic blood transfusions, particularly for patients treated with warfarin preoperatively. We performed an exploratory analysis on whether the use of prothrombin complex concentrate (PCC) is safe and effective compared with fresh frozen plasma (FFP) to treat coagulopathy after pulmonary endarterectomy surgery with deep hypothermic circulatory arrest. METHODS:Consecutive adult patients who underwent pulmonary endarterectomy surgery between January 2010 and September 2012 and received PCC or FFP to treat coagulopathy were studied. Blood loss during the first 12 hours of admission to the intensive care unit and patient outcomes were compared with propensity score adjustment. RESULTS:Three hundred fifty-one patients underwent pulmonary endarterectomy surgery, all of whom had warfarin discontinued for up to 5 days before surgery; bleeding complications requiring transfusion of blood products were observed in 108 (31%) patients. Of those, 55 received only FFP and 45 received only PCC, whereas 8 received both. Blood loss was significantly greater in the FFP group compared with the PCC group after 12 hours (median [interquartile range], 650 mL [325–1075] vs 277 mL [175–608], P = 0.008). However, there was no difference in the frequency of patients receiving a red blood cell transfusion (number [percent], 44 [80%] vs 34 [76%], P = 0.594) or in the number of units of red blood cells transfused (median [interquartile range], 2 [1–4] vs 3 [1–5] units, P = 0.181). The final propensity score included preoperative international normalized ratio, postoperative activated partial thromboplastin time, and postoperative platelet count. After inclusion of the propensity score in the regression analyses, there were no differences between patients receiving only PCC and patients receiving only FFP in the need for renal replacement therapy (odds ratio [OR] 2.39, 95% confidence interval [CI] 0.51–11.20, P = 0.27), 30-day-mortality (OR 0.32, 95% CI 0.03–3.36, P = 0.35), intracranial hemorrhage (OR 0.73, 95% CI 0.14–3.89, P = 0.71), hospital length of stay (hazard ratio 0.77, 95% CI 0.50–1.19, P = 0.24), or duration of intensive care stay (hazard ratio 0.91, 95% CI 0.59–1.40, P = 0.66). CONCLUSIONS:This retrospective analysis suggests that PCC may be an alternative to FFP in patients previously treated with warfarin who are coagulopathic after major cardiac surgery. Randomized controlled studies powered to evaluate efficacy and important postoperative outcomes for patients receiving PCC versus FFP for coagulopathic bleeding after cardiopulmonary bypass are warranted.

A prospective observational cohort study to identify the causes of anaemia and association with outcome in cardiac surgical patients

Objectives Preoperative anaemia is associated with increased morbidity and mortality. We sought to determine the relative frequencies of the different causes of anaemia including absolute and functional iron deficiency, and the association of different haematological parameters, including plasma hepcidin, a key protein responsible for iron regulation, with outcomes after cardiac surgery. Methods Prospective observational study between January 2012 and 2013; 200 anaemic cardiac surgical patients were recruited and 165 were studied. Detailed blood and bone marrow analysis was performed. Primary outcome was days alive and out of hospital. Results Mean (SD) haemoglobin (Hb) was 102 (8) g/L for women and 112 (11) g/L for men. Regarding outcomes, 137 (83%) patients were transfused at least one unit of red blood cells; 30-day mortality was 1.8% (three patients). Functional iron deficiency was diagnosed in 78 patients (47%). Plasma hepcidin concentration was the only haematological variable associated with outcome, with mean days alive and out of hospital 2.7 (95% CI 0.4 to 5.1) days less if hepcidin ≥20 ng/mL compared with <20 ng/mL (p=0.024). Multivariable analysis showed that the association between hepcidin and outcome was independent of risk (European System for Cardiac Operative Risk Evaluation), transfusion and Hb. Conclusions Functional iron deficiency was the most common cause of anaemia but was not associated with outcome. The only haematological parameter that was associated with outcome was hepcidin concentration, which is a novel finding and introduces further complexity into our understanding of the role of iron and its regulation by hepcidin. We propose that future research should target patients with elevated hepcidin.

The coagulopathy of cardiopulmonary bypass.

There have been numerous publications on the coagulopathy of cardiopulmonary bypass (CPB). This review provides an introduction to the history and main components of current CPB circuits and summarizes the current knowledge of pathogenesis, prevention, and treatment of the CPB coagulopathy. It encompasses an overview of intra- and postoperative monitoring of coagulation with special emphasis on the near-patient testing, its main complications, and the transfusion support, while taking into account the major changes in the technology used and supportive care provided since its inception.

Point-of-care assessment of hypothermia and protamine-induced platelet dysfunction with multiple electrode aggregometry (Multiplate®) in patients undergoing cardiopulmonary bypass.

BACKGROUND:Coagulopathy is common after cardiopulmonary bypass (CPB), and platelet dysfunction is frequently considered to be a major contributor to excessive bleeding. Exposure to hypothermia may exacerbate the platelet function defect. We assessed platelet function during and after deep hypothermia with multiple electrode aggregometry (Multiplate®; Verum Diagnostica GmbH, Munich, Germany). METHODS:Twenty adult patients undergoing pulmonary endarterectomy for chronic pulmonary hypertension were cooled on CPB to 20°C and deep hypothermic arrest was used to facilitate surgery. We analyzed platelet aggregation in whole blood samples at 12 measuring points during and after the procedure. Platelet aggregation was stimulated via the thrombin receptor (TRAPtest) at the patient’s actual body temperature (AUC-CT) and after rewarming the samples to 37°C (AUC-37). In addition, we tested samples at 2 time points after 2 minutes of in vitro incubation with 20 &mgr;g protamine (0.067 &mgr;g/&mgr;L). Results are expressed as area under the aggregation curve (AUC). RESULTS:Cooling resulted in a marked decrease of platelet aggregation to a minimum AUC-CT of 20.5 (95% confidence interval [CI] 8.9–32.1) at 20°C body temperature. AUC-CT was significantly different from baseline (92.8, 95% CI 82.5–103.1) for temperatures of ⩽28°C (P < 0.001), whereas the change in AUC-37 only became significant at the lowest body temperature (59.4, 95% CI 41.3–77.4). After rewarming to 36°C, AUC-CT and AUC-37 had recovered to 67.6 (95% CI 53.9–81.3) and 71.7 (95% CI 52.5–90.8), respectively. The mean AUC-CT was significantly lower than the mean AUC-37 from cooling at 28°C to warming at 24°C inclusive, and the relationship with temperature during cooling was significantly different between AUC-CT and AUC-37 (regression coefficients 4.7 [95% CI 4.2–5.2] vs 1.3 [95% CI 0.7–1.9]; P < 0.0001). After administration of protamine, mean aggregation decreased significantly for both measurements by 38.2 (95% CI −27.9 to −48.5; P < 0.001) and 44.5 (95% CI −58.5 to −30.5; P < 0.001), respectively. Similarly, adding protamine in vitro resulted in a decrease of mean aggregation by 35.1 (95% CI −71.0 to 0.8; P = 0.055) when measured after administration of heparin, and 56.5 (95% CI −94.5 to −18.5; P = 0.005) at the end of CPB. CONCLUSION:Platelet aggregation, assessed by multiple electrode aggregometry (Multiplate), was severely affected during deep, whole-body hypothermia. This effect was partially reversible after rewarming, and was distinct from a general decline of platelet aggregation during CPB. Protamine also caused a significant decrease in platelet aggregation in vivo and in vitro.

Pulmonary endarterectomy is effective and safe in patients with haemoglobinopathies and abnormal red blood cells: the Papworth experience†.

OBJECTIVES Patients with haemoglobinopathies and congenital haemolytic anaemia constitute a unique population more predisposed to developing chronic thromboembolic pulmonary hypertension (CTEPH). Although pulmonary endarterectomy (PEA) is accepted as the best treatment for CTEPH, PEA in these patients poses significant practical challenges. Apart from a few case reports, the results of PEA in this patient population have not been previously reported. The aim of this study was to review the outcome of PEA in this patient population. METHODS We performed a retrospective analysis, from our dedicated CTEPH database, of all patients who underwent PEA surgery and had abnormal haemoglobin or congenital haemolytic anaemia. We reviewed diagnosis, exchange transfusions on cardiopulmonary bypass, preoperative and postoperative pulmonary haemodynamic and functional data and outcomes for this group. Paired data analysis was performed by Students t-test; P < 0.05 was statistically significant. RESULTS Between the start of our PEA programme in 1997 and April 2015, we performed PEA in 19 patients with haemoglobinopathy or congenital haemolytic anaemia. The mean age was 52 ± 15 years. There were 9 patients with sickle cell trait, 2 with coexisting alpha+ thalassaemia trait, 2 patients with HbSC disease, 2 patients with beta-thalassaemia major, 3 patients with hereditary spherocytosis, 2 patients with stomatocytosis (one with the cryohydrocytosis subtype) and 1 patient with HbC trait. In the 9 HbAS patients, the mean HbS% was 31.9 ± 6%, and in the HbSC patients, the mean HbS% was 46.5 ± 1.3% preoperatively. To reduce this HbS to ≤20%, for safe PEA with deep hypothermic circulatory arrest, we used exchange blood transfusion. Immediately postoperatively, there was a significant improvement in pulmonary vascular resistance (938 ± 462 to 260 ± 167 dyne s cm(-5); P < 0.0001). One patient died 81 days following surgery; 18 patients are alive at a median follow-up of 3.4 ± 3 years. Six months postoperatively, the patients showed significant improvement in New York Heart Association status (P < 0.0001), and in 6-min walk distance from 251 ± 111 to 399 ± 69 m (P < 0.0001). CONCLUSIONS Results of PEA in this complex patient group were satisfactory. Expert haematological advice is important and exchange blood transfusions may be necessary. The presence of abnormal haemoglobin does not contra-indicate PEA surgery.

Coagulopathy associated with massive cell salvage transfusion following aortic surgery

Cell saver blood is used within the peri-operative setting of cardiothoracic surgery to reduce the need for transfusion of allogenic blood products. Several meta-analyses have proven a significant decrease in allogenic transfusion with the use of cell salvage techniques. Washing of red cells by the cell saver and subsequent transfusion of suspended red cells can occasionally cause coagulopathy, particularly when using high concentration heparin saline to wash the spilled blood. We present the case of a 74-year-old female who underwent complicated aortic surgery and was transfused large volumes of cell-saved blood due to post-operative bleeding, which subsequently led to coagulopathy.

Extracorporeal membrane oxygenation for the treatment of adult sickle cell acute chest syndrome

Sickle cell disease (SCD) is a hereditary haemoglobinopathy that results in polymerization of haemoglobin molecules and subsequent vaso-occlusion. A common cause of death in adults is acute chest syndrome (AChS) with resulting hypoxemic respiratory failure. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has been used successfully in acutely reversible respiratory failure when conventional mechanical ventilation has been unable to adequately oxygenate and ventilate in a lung-protective fashion. We present an adult SCD patient with severe respiratory failure due to AChS, successfully treated with VV-ECMO. We also discuss some of the technical challenges and considerations when using ECMO in the SCD patient.

Clinical use of low haemoglobin density, transferrin saturation, bone marrow morphology, Perl's stain and other plasma markers in the identification of treatable anaemia presenting for cardiac surgery in a prospective cohort study

Objectives The differential diagnosis between iron deficiency anaemia (IDA) and anaemia of chronic disease (ACD) with or without associated iron deficiency can be challenging. We assessed the use of different parameters, both classical like ferritin, transferrin saturation and stainable bone marrow iron stores, and novel markers such as low haemoglobin density (LHD) and hepcidin to help discriminate between the three entities. This would allow the detection of patients with ACD with associated iron deficiency, which could benefit from iron supplementation that would have otherwise remained undetected. Materials and methods Prospective and observational cohort study from 2012 to 2013 where 200 anaemic cardiac surgical patients were recruited and 165 were studied. Detailed blood and bone marrow analyses were performed to establish the aetiology of anaemia. Results Seventy-four patients (44.8%) had ACD and 29 (39%) of these had an elevated LHD indicating concomitant iron deficiency. Hepcidin was inappropriately normal or increased in the IDA and ACD group. Mean hepcidin was however lower in the group with IDA (4.8 ng/mL) than in the ACD group (15.0 ng/mL; p=0.002). Median hepcidin was lower in patients with ACD and iron restriction as indicated by LHD >4% (17.5 ng/mL) than on those with no iron restriction (25.9 ng/mL; p=0.045). In patients with ACD there was no concordance between Perls stain and LHD. Conclusions LHD was superior to hepcidin and bone marrow iron stores in identifying patients with ACD and associated iron deficiency, which would potentially benefit from parenteral iron therapy.