Ian J. Welsby

The use of a postoperative morbidity survey to evaluate patients with prolonged hospitalization after routine, moderate-risk, elective surgery

Vital healthcare resources are devoted to caring for patients with prolonged hospitalization after routine, moderate-risk surgery. Despite the significant cost,little is known about the overall incidence and pattern of complications in these patients. Four hundred thirty-eight patients undergoing a diverse group of routine, moderate-risk, elective surgical procedures were enrolled into a prospective, blinded, cohort study. Complications were assessed using a postoperative morbidity survey. The main outcome was postoperative complication, defined as either in-hospital death or prolonged postoperative hospitalization (>7 days). The mortality rate was 1.6%. Postoperative complications occurred in 118 patients (27% [95% CI 23-31]). Complications frequently observed in these patients included: gastrointestinal 51% (42-60), pulmonary 25% (17-33), renal 21% (14-28), and infectious 13% (7-19). Most complications were not directly related to the type/site of surgery. indices of tissue trauma (blood loss [P < 0.001], surgical duration [P = 0.001]) and tissue perfusion (arterial base deficit [P = 0.008], gastric pHi [P = 0.02]) were the strongest intraoperative predictors of complications. Despite a low mortality rate, we found that complications after routine, moderate-risk, elective surgery are common and involve multiple organ systems. Our 9-point survey can be used by healthcare providers and payers to characterize postoperative morbidity in their respective settings. Implications: Little is known about the overall incidence and pattern of complications in patients with prolonged hospitalization after routine, elective surgery. We prospectively assessed these complications using a novel postoperative morbidity survey. The postoperative morbidity survey can be used in future clinical outcome trials, as well as in routine hospital-based quality assurance.

The effect of aprotinin on outcome after coronary-artery bypass grafting.

BACKGROUND Aprotinin has recently been associated with adverse outcomes in patients undergoing cardiac surgery. We reviewed our experience with this agent in patients undergoing cardiac surgery at Duke University Medical Center. METHODS We retrieved data on 10,275 consecutive patients undergoing surgical coronary revascularization at Duke between January 1, 1996, and December 31, 2005. We fit data to a logistic-regression model predicting each patients likelihood of receiving aprotinin on the basis of preoperative characteristics and to models predicting long-term survival (up to 10 years) and decline in renal function, as measured by increases in serum creatinine levels. RESULTS A total of 1343 patients (13.2%) received aprotinin, 6776 patients (66.8%) received aminocaproic acid, and 2029 patients (20.0%) received no antifibrinolytic therapy. All patients underwent coronary-artery bypass grafting, and 1181 patients (11.5%) underwent combined coronary-artery bypass grafting and valve surgery. In the risk-adjusted model, survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% confidence interval [CI], 1.12 to 1.55) for the comparison with patients receiving no antifibrinolytic therapy (P=0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparison with patients receiving aminocaproic acid (P=0.004). As compared with the use of aminocaproic acid or no antifibrinolytic agent, aprotinin use was also associated with a larger risk-adjusted increase in the serum creatinine level (P<0.001) but not with a greater risk-adjusted incidence of dialysis (P=0.56). CONCLUSIONS Patients who received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than those who received aminocaproic acid or no antifibrinolytic agent.

Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy

Fibrinogen plays a critical role in achieving and maintaining hemostasis and is fundamental to effective clot formation. There is increasing awareness of the important role of fibrinogen as a key target for the treatment and prevention of acquired bleeding. Fibrinogen is the first coagulation factor to fall to critically low levels (<1.0 g/L) during major hemorrhage (normal plasma fibrinogen levels range from 2.0 to 4.5 g/L), and current guidelines recommend maintaining the plasma fibrinogen level above 1.5 g/L. Fibrinogen supplementation can be achieved using plasma or cryoprecipitate; however, there are a number of safety concerns associated with these allogeneic blood products and there is a lack of high‐quality evidence to support their use. Additionally, there is sometimes a long delay associated with the preparation of frozen products for infusion. Fibrinogen concentrate provides a promising alternative to allogeneic blood products and has a number of advantages: it allows a standardized dose of fibrinogen to be rapidly administered in a small volume, has a very good safety profile, and is virally inactivated as standard. Administration of fibrinogen concentrate, often guided by point‐of‐care viscoelastic testing to allow individualized dosing, has been successfully used as hemostatic therapy in a range of clinical settings, including cardiovascular surgery, postpartum hemorrhage, and trauma. Results show that fibrinogen concentrate is associated with a reduction or even total avoidance of allogeneic blood product transfusion. Fibrinogen concentrate represents an important option for the treatment of coagulopathic bleeding; further studies are needed to determine precise dosing strategies and thresholds for fibrinogen supplementation.

Inflammatory Gene Polymorphisms and Risk of Postoperative Myocardial Infarction After Cardiac Surgery

Background— The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. Methods and Results— We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level ≥10× upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P<0.05; false discovery rate <10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 −572G>C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G>T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). Conclusions— Functional genetic variants in cytokine and leukocyte–endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.

The association of complication type with mortality and prolonged stay after cardiac surgery with cardiopulmonary bypass.

Outcome after cardiac surgery varies depending on complication type. We therefore sought to determine the association between complication type, mortality, and length of stay in a large series of patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Multivariate logistic regression was used to test for differences between complication types in mortality and prolonged length of stay (>10 days) while controlling for preoperative and intraoperative risk factors. In 2609 consecutive cardiac surgical patients requiring CPB, the mortality rate was 3.6%; 36.5% had one or more complications, and 15.7% experienced an adverse outcome (death or prolonged length of stay). Multivariate logistic regression demonstrated that complication type was significantly associated with adverse outcome (P < 0.001) independent of Parsonnet score and CPB time (c-index = 0.80). The development of noncardiac complications only (Group NC) and cardiac complications with other organ involvement (Group B) significantly increased mortality and hospital and intensive care unit length of stay (P < 0.001) when compared with cardiac complications only (Group C). The incidences of adverse outcome in Groups C, NC, and B were 15%, 43%, and 67%, respectively; the mortality rates were 3%, 7%, and 20%, respectively. All these intergroup comparisons were significantly different (adjusted P < 0.05). Complications involving organs other than the heart appear to be more deleterious than cardiac complications alone, underscoring the need for strategies to reduce noncardiac complications.

Extracorporeal membrane oxygenation in the adult: a review of anticoagulation monitoring and transfusion.

Extracorporeal membrane oxygenation (ECMO) is a method of life support to maintain cardiopulmonary function. Its use as a medical application has increased since its inception to treat multiple conditions including acute respiratory distress syndrome, myocardial ischemia, cardiomyopathy, and septic shock. While complications including neurological and renal injury occur in patients on ECMO, bleeding and coagulopathy are most common. ECMO is associated with an inflammatory response promoting a hypercoagulable state, requiring anticoagulation to avoid thromboembolism originating in the nonendothelial surfaced circuit. However, excessive anticoagulation may result in bleeding complications including intracerebral hemorrhage. Monitoring anticoagulation for ECMO has its origins in cardiopulmonary bypass for cardiac surgery; however, there is no ideal level of anticoagulation, no standardized method to monitor anticoagulation, nor are all centers standardized on what is used for anticoagulation. Multiple blood products are used in an effort to decrease bleeding in the setting of anticoagulation, often in the setting of recent surgery, and this leads to significant increases in cost for patients on ECMO and transfusion-related complications. In this review article, we discuss the evolution of the various modalities of ECMO, indications, contraindications, and complications. Furthermore, we review the different strategies for anticoagulation and treatment of coagulopathy while on ECMO. Finally, we discuss the cost of ECMO and associated blood product transfusion.

Thromboelastography as a perioperative measure of anticoagulation resulting from low molecular weight heparin : a comparison with anti-Xa concentrations

Low molecular weight heparin (LMWH) is commonly used to prevent postoperative thromboembolism. Currently, there is no convenient test to measure the degree of anticoagulation from LMWH. This prospective study examines the relationship of thromboelastography and serum anti-Xa concentration in patients treated with enoxaparin. Twenty-four adult patients scheduled for orthopedic surgery using epidural anesthesia were enrolled. Epidural catheters were removed the morning after surgery before the commencement of subcutaneous enoxaparin 30 mg twice daily. Venous blood samples were obtained at 1) the induction of anesthesia (baseline), 2) immediately before the third dose of enoxaparin postoperatively (Day 2-trough), 3) 4 h after the third dose postoperatively (Day 2-peak), and 4) immediately before the fifth dose postoperatively (Day 3-trough). Whole blood samples were obtained for thromboelastography, activated clotting time, and anti-Xa level analyses at each of the four time intervals. At the four sample intervals, the r time (mean ± sem). (20 ± 1, 25 ± 2, 51 ± 6, 31 ± 3 mm) and the k time (9 ± 0.7, 12 ± 1, 27 ± 5, 14 ± 2 mm) of the thromboelastograph were significantly correlated with the expected peak and trough levels of LMWH and serum anti-Xa levels (P < 0.05). At the Day 3-trough, thromboelastograph r times exceeded the normal range in 6 of 25 patients (25%). Prolongation of r time and k time on postoperative Day 3 may indicate an exaggerated response to LMWH. Thromboelastography is a test that could potentially correlate with the degree of anticoagulation produced by low molecular weight heparin. Implications Thromboelastography is a test that could potentially correlate with the degree of anticoagulation produced by low molecular weight heparin. The r time from the thromboelastogram correlates with serum anti-Xa concentration.

Genetic factors contribute to bleeding after cardiac surgery

Summary.  Background: Postoperative bleeding remains a common, serious problem for cardiac surgery patients, with striking inter‐patient variability poorly explained by clinical, procedural, and biological markers. Objective: We tested the hypothesis that genetic polymorphisms of coagulation proteins and platelet glycoproteins are associated with bleeding after cardiac surgery. Patients/methods: Seven hundred and eighty patients undergoing aortocoronary surgery with cardiopulmonary bypass were studied. Clinical covariates previously associated with bleeding were recorded and DNA isolated from preoperative blood. Matrix Assisted Laser Desorption/Ionization, Time‐Of‐Flight (MALDI‐TOF) mass spectroscopy or polymerase chain reaction were used for genotype analysis. Multivariable linear regression modeling, including all genetic main effects and two‐way gene‐gene interactions, related clinical and genetic predictors to bleeding from the thorax and mediastinum. Results: Nineteen candidate polymorphisms were assessed; seven [GPIaIIa−52C>T and 807C>T, GPIbα 524C>T, tissue factor−603A>G, prothrombin 20210G>A, tissue factor pathway inhibitor−399C>T, and angiotensin converting enzyme (ACE) deletion/insertion] demonstrate significant association with bleeding (P < 0.01). Adding genetic to clinical predictors results improves the model, doubling overall ability to predict bleeding (P < 0.01). Conclusions: We identified seven genetic polymorphisms associated with bleeding after cardiac surgery. Genetic factors appear primarily independent of, and explain at least as much variation in bleeding as clinical covariates; combining genetic and clinical factors double our ability to predict bleeding after cardiac surgery. Accounting for genotype may be necessary when stratifying risk of bleeding after cardiac surgery.

Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) complicates the management of patients presenting for cardiac surgery, because high-dose heparin anticoagulation for cardiopulmonary bypass is contraindicated in these patients. Alternative anticoagulants are available, but there are concerns about dosing, efficacy, monitoring, thrombosis, and hemorrhage. METHODS: A retrospective chart review between November 2004 and March 2008 retrieved perioperative clinical and laboratory data for 11 adult cardiac surgical patients with a preoperative history of HIT and a current positive antiheparin/platelet factor 4 (anti-HPF4) antibody titer, who were managed with plasmapheresis and heparin anticoagulation. RESULTS: The median (interquartile range) preoperative anti-HPF4 antibody titer was 0.8 (0.7–2.2). Three of the 11 patients (27%) died of causes unrelated to HIT and 1 of these patients (9%) developed an ischemic foot, in the setting of cardiogenic shock, not thought to be HIT-related. A single plasmapheresis treatment reduced titers by 50%–84%, and 6 patients had negative titers after treatment; none of the 3 patients with reduced titers developed clinical HIT. CONCLUSIONS: This case series describes an alternative management strategy using intraoperative plasmapheresis for patients presenting for cardiac surgery with acute or subacute HIT. Reducing antibody load can potentially decrease the thrombotic risk associated with high anti-HPF4 titers and decrease the urgency to initiate postoperative anticoagulation in this patient group at high risk of postoperative bleeding.

Hemodynamic changes after protamine administration: Association with mortality after coronary artery bypass surgery

Background:Protamine sulfate is standard therapy to reverse heparin anticoagulation. Hemodynamic responses to protamine are common, ranging from minor perturbations to cardiovascular collapse. Although severe fatal reactions occur, the relation of less extreme responses with postoperative mortality is unknown. Therefore, the authors tested the hypothesis that hemodynamic “protamine reactions” (systemic hypotension and pulmonary hypertension) are associated with mortality after cardiac surgery. Methods:In a university hospital setting, the authors studied 6,921 coronary bypass patients using automated anesthesia record–keeping data and quality assurance databases. Degree/duration integrals of systemic hypotension (< 100 mmHg) and pulmonary hypertension (> 30 mmHg) for the 30-min after protamine administration were assessed for linear associations with mortality using multiple logistic regression models adjusting for risk factors. Results:Overall mortality was 2%; greater hemodynamic responses were associated with increased mortality by odds ratios of 1.28 (systemic hypotension: 95% confidence interval, 1.14–1.43; P < 0.001) and 1.27 (pulmonary hypertension: 95% confidence interval, 1.06–1.48; P < 0.001) per 150-mmHg · min increment. Proximity of the response to protamine administration strengthened the relation, which persisted after exclusion of major hemodynamic disturbances. Tests for linearity confirmed an association even at the lowest range of values for both pressure effects. Conclusions:Hemodynamic perturbations after protamine administration are independently related to in-hospital mortality after primary coronary artery bypass surgery; the relation is present even in the lowest observed range of values for both systemic hypotension and pulmonary hypertension. Although randomized trials are necessary to address causality, this evidence suggests that strategies that avoid or attenuate these reactions may improve patient care.