Comparing peri-operative complications of paediatric and adult anaesthesia: A retrospective cohort study of 81 267 cases.

BACKGROUND: Comparisons of peri-operative complications associated with paediatric (≤16 years) and adult anaesthesia are poorly available, especially in which cardiac surgery, organ transplantation and neurosurgery are involved. OBJECTIVE: The aim of this study was to evaluate the nature and incidence of peri-operative complications that might be due to anaesthesia and to identify independent risk factors for complications in children and adults, including those undergoing cardiac surgery, organ transplantation and neurosurgery. DESIGN: Retrospective cohort study. SETTING: The study was performed at the University Medical Centre Groningen in the 4 years between 1 January 2010 and the 31 December 2013. MAIN OUTCOME MEASURES: Complications and their severity were graded according to the standard complication score (20 items) of the Dutch Society of Anaesthesia. Univariate and multivariate regression analysis was used to identify independent risk factors for the reported complications. RESULTS: A total of 81 267 anaesthetic cases were included. In the paediatric cohort, there were 410 (2.9%) complications and 1675 (2.5%) in the adults. In both cohorts age, American Society of Anaesthesiologists classification and emergency treatment were independent risk factors for complications. With respect to age, infants less than 1 year were at the highest risk, whereas in the adult cohort, increased age was related to a greater number of complications. The incidences of the specific complications were different between both cohorts. Upper airway obstruction was more frequently observed in paediatric patients (26%), whereas in the adults, complications with the highest incidence concerned conversion of regional-to-general anaesthesia (25%) and hypotension (17%). CONCLUSION: Risk factors for all peri-operative complications were similar for paediatric and adult anaesthesia. However, the incidence of specific complications differed between both age categories.

Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial.

BACKGROUND: In patients with cirrhosis, the synthesis of coagulation factors can fall short, reflected by a prolonged prothrombin time. Although anticoagulants factors are decreased as well, blood loss during orthotopic liver transplantation can still be excessive. Blood loss during orthotopic liver transplantation is currently managed by transfusion of red blood cell concentrates, platelet concentrates, fresh frozen plasma, and fibrinogen concentrate. Transfusion of these products may paradoxically result in an increased bleeding tendency due to aggravated portal hypertension. The hemostatic effect of these products may therefore be overshadowed by bleeding complications due to volume overload.In contrast to these transfusion products, prothrombin complex concentrate is a low-volume highly purified concentrate, containing the four vitamin K dependent coagulation factors. Previous studies have suggested that administration of prothrombin complex concentrate is an effective method to normalize a prolonged prothrombin time in patients with liver cirrhosis. We aim to investigate whether the pre-operative administration of prothrombin complex concentrate in patients undergoing liver transplantation for end-stage liver cirrhosis, is a safe and effective method to reduce perioperative blood loss and transfusion requirements. METHODS/DESIGN: This is a double blind, multicenter, placebo-controlled randomized trial.Cirrhotic patients with a prolonged INR (≥1.5) undergoing liver transplantation will be randomized between placebo or prothrombin complex concentrate administration prior to surgery. Demographic, surgical and transfusion data will be recorded. The primary outcome of this study is RBC transfusion requirements. DISCUSSION: Patients with advanced cirrhosis have reduced plasma levels of both pro- and anticoagulant coagulation proteins. Prothrombin complex concentrate is a low-volume plasma product that contains both procoagulant and anticoagulant proteins and transfusion will not affect the volume status prior to the surgical procedure. We hypothesize that administration of prothrombin complex concentrate will result in a reduction of perioperative blood loss and transfusion requirements. Theoretically, the administration of prothrombin complex concentrate may be associated with a higher risk of thromboembolic complications. Therefore, thromboembolic complications are an important secondary endpoint and the occurrence of this type of complication will be closely monitored during the study. TRIAL REGISTRATION: The trial is registered at http://www.trialregister.nl with number NTR3174. This registry is accepted by the ICMJE.

Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests.

BACKGROUND & AIMS: Patients with liver disease often show substantial changes in their hemostatic system, which may aggravate further during liver transplantation. Recently, thrombin generation in patients with stable disease was shown to be indistinguishable from controls provided thrombomodulin, the natural activator of the anticoagulant protein C system, was added to the plasma. These results indicated that the hemostatic balance is preserved in patients with liver disease, despite conventional coagulation tests suggest otherwise. METHODS: Here we examined thrombin generation profiles in serial plasma samples taken from ten consecutive patients undergoing liver transplantation. RESULTS: At all time points, the endogenous thrombin potential (ETP) was slightly lower compared to healthy volunteers, despite substantially prolonged PT and APTT values. However, when thrombin generation was tested in the presence of thrombomodulin, the ETP was equal to or even higher than that in healthy subjects. In fact, thrombin generation was hardly affected by thrombomodulin, while thrombin generation in healthy subjects decreased profoundly upon the addition of thrombomodulin. In patients undergoing liver transplantation, efficient thrombin generation in the presence of thrombomodulin may be explained by decreased levels of protein C, S, and antithrombin, and by elevated levels of FVIII. CONCLUSIONS: Thrombin generation in patients undergoing liver transplantation is equal or even superior to thrombin generation in healthy volunteers when tested in the presence of exogenous thrombomodulin. These results support the recently advocated restrictive use of plasma during liver transplantation and warrants further study of the prophylactic use of anticoagulants to reduce thromboembolic complications after transplantation.

An assessment of clinical interchangeability of TEG and RoTEM thromboelastographic variables in cardiac surgical patients.

BACKGROUND: Bedside thromboelastography is increasingly used, but an assessment of the clinical interchangeability of the 2 major systems, TEG (Hemoscope) and RoTEM (Pentapharm), has not been performed. METHODS: We measured blood samples from 46 cardiac surgical patients after induction of anesthesia with kaolin TEG(R) (kaoTEG), native TEG(R) (natTEG), intrinsic RoTEM (inTEM), and extrinsic RoTEM (exTEM). Each measurement consisted of reaction time (R), coagulation time (K), maximum amplitude (MA), and angle (alpha). Bland-Altman plots and mixed-model analysis were used. To assess repeatability, we made 7 replicated measurements in rapid succession in 2 volunteers. RESULTS: One hundred sixty-six measurements were available for analysis. The R time of the kaoTEG (345 + or - 102 seconds, mean + or - sd) was longer than that of the inTEM (179 + or - 74 seconds, P < 0.001) and the exTEM (55 + or - 28 seconds, P < 0.001). The K time of the kaoTEG (78 + or - 18s) was not different from that of the inTEM (75 + or - 52 seconds, P = 0.60) but was longer than the K time of the exTEM (61 + or - 24 seconds, P < 0.003). The MA of the kaoTEG (71 + or - 6.5 mm) was larger than the MA of the inTEM (67 + or - 5.2 mm, P < 0.02) and almost similar to that of the exTEM (69 + or - 6.3 mm). The alpha of the kaoTEG (72 degrees + or - 4.1 degrees ) was not significantly different from that of both the inTEM (76 degrees + or - 7 degrees ) and the exTEM (79 degrees + or - 4.5 degrees ). The variability for MA and alpha was <10%. The repeatability of the R and K times was poor in both devices, whereas the repeatability of the MA and alpha was sufficient for clinical purposes. CONCLUSIONS: The TEG and RoTEM measurements demonstrated a close correlation for the MA, but the alpha did not for the R and K variables. The kaoTEG had the best agreement with the exTEM measurement. Therefore TEG and RoTEM measurements are not completely interchangeable, and the clinical interpretation of thromboelastograhic data should be used with caution.

No evidence for systemic platelet activation during or after orthotopic liver transplantation.

Platelet function is thought to deteriorate during liver transplantation as a result of platelet activation and proteolysis of platelet receptors by plasmin following reperfusion. However, this hypothesis has never been formally tested. Twenty patients undergoing a first or second liver transplant were included in the study. Blood samples were taken at standardized time points during transplantation and up to 10 days after transplantation. Platelet activation was assessed by detection of the activation markers P-selectin and activated integrin alphaIIbbeta3 with flow cytometry. Proteolytic cleavage of platelet receptors was assessed by flow cytometry measurement of the constitutively expressed platelet receptors glycoprotein Ibalpha and integrin alphaIIbbeta3. In addition, using enzyme-linked immunosorbent assay techniques, we measured plasma levels of platelet activation products beta-thromboglobulin and platelet factor 4 and plasma levels of cleaved fragments of glycoproteins Ibalpha and V. Flow cytometry analyses provided no evidence of substantial platelet activation during transplantation. In fact, the expression of activated integrin alphaIIbbeta3 decreased postoperatively; this indicated that platelets were in a slightly activated state prior to surgery. Plasma levels of beta-thromboglobulin and platelet factor 4 also substantially decreased after transplantation. In addition, no changes were observed in the constitutively expressed platelet receptors or in the plasma levels of platelet receptor fragments, and this indicated a lack of substantial receptor proteolysis. In conclusion, no evidence was found for significant activation of circulating blood platelets or the proteolysis of key platelet receptors during liver transplantation. These findings suggest that the platelet functional capacity does not decrease during liver transplantation. Liver Transpl 15:956-962, 2009. (c) 2009 AASLD.

Platelet transfusion during liver transplantation is associated with increased postoperative mortality due to acute lung injury.

BACKGROUND: Platelet transfusions have been identified as an independent risk factor for survival after orthotopic liver transplantation (OLT). In this study, we analyzed the specific causes of mortality and graft loss in relation to platelet transfusions during OLT. METHODS: In a series of 449 consecutive adult patients undergoing a first OLT, the causes of patient death and graft failure were studied in patients who did or did not receive perioperative platelet transfusions. RESULTS: Patient and graft survival were significantly reduced in patients who received platelet transfusions, compared with those who did not (74% vs 92%, and 69% vs 85%, respectively at 1 yr; P < 0.001). Lower survival rates in patients who received platelets were attributed to a significantly higher rate of early mortality because of acute lung injury (4.4% vs 0.4%; P = 0.004). There were no significant differences in other causes of mortality between the two groups. The main cause of graft loss in patients receiving platelets was patient death with a functioning graft. CONCLUSIONS: These findings suggest that platelet transfusions are an important risk factor for mortality after OLT. The current study extends previous observations by identifying acute lung injury as the main determinant of increased mortality. The higher rate of graft loss in patients receiving platelets is related to the higher overall mortality rate and does not result from specific adverse effects of transfused platelets on the grafted liver.

The impact of intraoperative transfusion of platelets and red blood cells on survival after liver transplantation.

BACKGROUND: Intraoperative transfusion of red blood cells (RBC) is associated with adverse outcome after orthotopic liver transplantation (OLT). Although experimental studies have shown that platelets contribute to reperfusion injury of the liver, the influence of allogeneic platelet transfusion on outcome has not been studied in detail. In this study, we evaluate the impact of various blood products on outcome after OLT. METHODS: Twenty-nine variables, including blood product transfusions, were studied in relation to outcome in 433 adult patients undergoing a first OLT between 1989 and 2004. Data were analyzed using uni- and multivariate stepwise Cox's proportional hazards analyses, as well as propensity score-adjusted analyses for platelet transfusion to control for selection bias in the use of blood products. RESULTS: The proportion of patients receiving transfusion of any blood component decreased from 100% in the period 1989-1996 to 74% in the period 1997-2004. In uni- and multivariate analyses, the indication for transplantation, transfusion of platelets and RBC were highly dominant in predicting 1-yr patient survival. These risk factors were independent from well-accepted indices of disease, such as the Model for End-Stage Liver Disease score and Karnofsky score. The effect on 1-yr survival was dose-related with a hazard ratio of 1.377 per unit of platelets (P = 0.01) and 1.057 per unit of RBC (P = 0.001). The negative impact of platelet transfusion on survival was confirmed by propensity-adjusted analysis. CONCLUSION: This retrospective study indicates that, in addition to RBC, platelet transfusions are an independent risk factor for survival after OLT. These findings have important implications for transfusion practice in liver transplant recipients.

Recombinant factor VIIa in orthotopic liver transplantation: influence on parameters of coagulation and fibrinolysis.

The effect of recombinant factor VIIa (rFVIIa) on blood loss was evaluated in cirrhotic patients undergoing orthotopic liver transplantation. In the present study, we explored the effect of rFVIIa on coagulation and fibrinolysis during orthotopic liver transplantation. Coagulation factors, parameters of thrombin generation and parameters of fibrinolysis were measured in six patients who had received a single dose of 80 micro g/kg rFVIIa and in ten controls, during and after orthotopic liver transplantation. Baseline concentrations and course of coagulation factors were similar in patients and controls. Thrombin generation did not rise after the administration of rFVIIa, but showed a sharp increase after reperfusion in patients, as compared with controls. No difference in fibrinolysis was apparent between patients and controls. No evidence of diffuse intravascular coagulation was seen. We conclude that the use of rFVIIa in orthotopic liver transplantation seems to enhance thrombin generation in a localized and time-limited matter, without causing systemic coagulation.

Thromboelastography in patients with cerebral venous thrombosis.

INTRODUCTION: Cerebral venous thrombosis (CVT) is a rare presentation of venous thrombosis and has been associated with many conditions. In about 20% no risk factor is identified. The aim of this study was to assess the clot formation by thromboelastography (TEG) in patients with a history of CVT compared with healthy controls. MATERIALS AND METHODS: TEG analysis was performed on recalcified blood samples of 19 CVT patients from a single centre cohort and 1:1 sex/ age (+/-3 year) matched controls. Four TEG parameters were monitored: reaction time (r) to clot initiation, time to reach a 20 mm level of clot formation (K), slope angle alpha from r to K (alpha) and maximum vertical amplitude (MA). Patients were tested for thrombophilic defects, including deficiencies of antithrombin, protein C and protein S, factor V Leiden, prothrombin G20210A mutation, lupus anticoagulant, antiphospholipid antibodies, and high factor VIII levels. RESULTS: Thrombophilia testing identified a prothrombotic abnormality in 11 patients (58%). Sixteen patients (84%) had one or more transient risk factor. There were no significant differences in TEG parameters between CVT patients and controls, neither between the subgroup of patients with a thrombophilic defect and controls. Seven of all patients (37%), including 5 patients with abnormal thrombophilia testing, and 5 controls (26%) had one or more TEG hypercoagulable parameters. CONCLUSIONS: A persistent hypercoagulable state which could have predisposed to venous thrombosis in CVT patients and in the subgroup of patients with a thrombophilic defect could not be demonstrated by TEG.

Effects of acidosis, alkalosis, hyperthermia and hypothermia on haemostasis: results of point-of-care testing with the thromboelastography analyser.

In this study we assessed the effects of changes in pH, temperature, and their combination in whole blood on thromboelastographic variables. Blood was collected from six healthy volunteers. Thromboelastograph (TEG series 5000; Haemoscope Corporation, Illinois, USA) channels were set at temperatures of 32, 37, and 39 degrees C and each was filled with artificially acidified, alkalified, and neutral blood, respectively. Acidification (pH 6.95) significantly impairs thromboelastographic variables reaction time r (from 23.3 to 33.7 min; P = 0.0280), kinetic time k (from 8.7 to 16.1 min; P = 0.028), angle alpha (from 24.3 degrees to 13.8 degrees ; P = 0.028), prothrombin time (from 11.4 to 12.1 s; P = 0.044), and activated partial thromboplastin time (from 29.3 to 45.0 s; P = 0.028). A temperature drop from 37 to 32 degrees C in blood of neutral pH significantly impaired k (from 8.7 to 10.2 min; P = 0.028) and alpha (from 24.3 degrees to 21.0 degrees ; P = 0.027), whereas maximum amplitude ma significantly increased (from 46.5 to 52.5 mm; P = 0.027). A temperature rise from 37 to 39 degrees C at pH 7.37 did not affect any of the TEG variables. Artificial alkalization (pH 7.68) at a temperature of 37 degrees C had no effect on any of the measured variables. Acidosis causes a significant impairment of clot formation and clot strength. Hypothermia had the same effects, but to a lesser extent. These findings emphasize the need for correction of acidosis and hypothermia to normalize haemostasis.

Myth or reality: hematocrit and hemoglobin differ in trauma.

BACKGROUND: Estimating blood loss in trauma patients usually involves the determination of hematocrit (Ht) or hemoglobin (Hb). However, in trauma patients, a poorly substantiated habit exists to determine both Ht and Hb in assessing acute blood loss. This suggests that Ht and Hb provide different information. Moreover, a survey of the literature showed a significant association of the subject trauma with the use of Ht. We investigated whether Ht and Hb differ in trauma patients. METHODS: Trauma patients with an Injury Severity Score>15 admitted from 1996 to 2004 to the University Medical Center Groningen were analyzed. All blood samples obtained during the first 7 days postinjury in which both Ht and Hb were determined were studied. Ht and Hb were measured with a Coulter Counter. The relation between Ht and Hb was analyzed with linear regression. The potential effect of hemolysis was studied by analyzing lactate dehydrogenase levels. RESULTS: In 671 patients 2,461 paired Ht levels and Hb levels were obtained. The mean Ht was 30.9%+/-6.9% (interquartile range 25.8%-35.8%). The mean concentration of Hb was 10.4+/-2.3 g/dL (interquartile range 8.7-12.1 g/dL). Ht and Hb had a Pearson's R of 0.99 and the following relations applied: Ht (%)=2.953xHb (g/dL) or Hb (g/dL)=0.334xHt (%). Lactate dehydrogenase was not related with Ht and Hb, indicating hemolysis was not relevant. CONCLUSIONS: In a large series of trauma patients, Ht and Hb behaved as identical parameters. The idea that Ht is different from or even superior to Hb is a misconception. There is no reason for determining both Ht and Hb in trauma patients.

Minimizing blood loss in liver transplantation: progress through research and evolution of techniques.

Blood loss during liver transplantation has long been recognized as an important cause of morbidity and, especially in the early days, also mortality. It is well known that blood transfusions are associated with an increased risk of postoperative complications, such as infections, pulmonary complications, protracted recovery, and a higher rate of reoperations. Many studies have been performed during the past decades to elucidate the mechanisms of increased blood loss in liver transplantation. In the late 1980s, primary hyperfibrinolysis was identified as an important mechanism of bleeding during liver transplantation. This has provided the scientific basis for the use of antifibrinolytic drugs in liver transplant recipients. Several randomized, controlled studies have shown the efficacy of these compounds in reducing blood loss and transfusion requirements during liver transplantation. In addition, increasing experience and improvements in surgical technique, anesthesiological care and better graft preservation methods have contributed to a steady decrease in blood transfusion requirements in most liver transplant programs. Several centers are now reporting liver transplantation without any need for blood transfusion in up to 30% of their patients. Despite these improvements, most patients undergoing liver transplantation still require blood transfusions that have a negative impact on outcome, emphasizing the need for further attempts to control blood loss by surgeons and anesthesiologists. This paper provides an overview of the clinical and research developments, which have contributed to a reduction in blood loss and transfusion requirements, resulting in an important reduction in morbidity and mortality after liver transplantation during the last two decades.