Effect of bivalirudin on coagulation in neonatal (cord) and adult human blood in vitro.

INTRODUCTION: Bivalirudin is recommended as an alternative to heparin in cardiac surgery with cardiopulmonary bypass. Although it has been used in infants and children for this indication, there is a paucity of data on the pharmacologic effects of bivalirudin in neonates. Given the immaturity of the hemostatic system in neonates, we hypothesized that coagulation responses to bivalirudin in this population would be different than in adults. METHODS: Blood samples were drawn from placenta-cord units and from healthy adult donors. The study was carried out in two steps. First, bivalirudin was added to cord and adult blood samples at concentrations of 0, 5, 10, 15, and 20 µg/mL. Activated clotting time and thromboelastographic variables were recorded. Next, we used a Chandler loop system to assess the efficacy of bivalirudin in a simple model of cardiopulmonary bypass. The loops were primed with cord or adult blood and were run until thrombus was detected. Plasma bivalirudin concentrations were measured at 1, 15, 30, 45, 60, and 75 min after initiating rotation of the loops using liquid chromatography/mass spectrometry. RESULTS: Bivalirudin elicited a dose-dependent prolongation inhibition of coagulation in both cord and adult blood samples with greater potency in cord blood in comparison to adult blood (activated clotting time: 627 ± 50 vs. 452 ± 22 s at 15 µg/mL bivalirudin, p < .0001). This relative potency was also demonstrated in the Chandler loop system, but interestingly, cord blood appeared to inactivate bivalirudin more rapidly than adult blood with earlier clotting in loops containing cord blood. CONCLUSIONS: This study demonstrates that bivalirudin has greater potency in cord blood in vitro than in adult blood. Plasma degradation appears to proceed more rapidly in cord blood than in adults. Both of these findings should be considered when planning dosing regimens in neonatal patients.

Measuring Childbirth Outcomes Using Administrative and Birth Certificate Data.

BACKGROUND: The number of pregnancy-related deaths and severe maternal complications continues to rise in the United States, and the quality of obstetrical care across U.S. hospitals is uneven. Providing hospitals with performance feedback may help reduce the rates of severe complications in mothers and their newborns. The aim of this study was to develop a risk-adjusted composite measure of severe maternal morbidity and severe newborn morbidity based on administrative and birth certificate data. METHODS: This study was conducted using linked administrative data and birth certificate data from California. Hierarchical logistic regression prediction models for severe maternal morbidity and severe newborn morbidity were developed using 2011 data and validated using 2012 data. The composite metric was calculated using the geometric mean of the risk-standardized rates of severe maternal morbidity and severe newborn morbidity. RESULTS: The study was based on 883,121 obstetric deliveries in 2011 and 2012. The rates of severe maternal morbidity and severe newborn morbidity were 1.53% and 3.67%, respectively. Both the severe maternal morbidity model and the severe newborn models exhibited acceptable levels of discrimination and calibration. Hospital risk-adjusted rates of severe maternal morbidity were poorly correlated with hospital rates of severe newborn morbidity (intraclass correlation coefficient, 0.016). Hospital rankings based on the composite measure exhibited moderate levels of agreement with hospital rankings based either on the maternal measure or the newborn measure (κ statistic 0.49 and 0.60, respectively.) However, 10% of hospitals classified as average using the composite measure had below-average maternal outcomes, and 20% of hospitals classified as average using the composite measure had below-average newborn outcomes. CONCLUSIONS: Maternal and newborn outcomes should be jointly reported because hospital rates of maternal morbidity and newborn morbidity are poorly correlated. This can be done using a childbirth composite measure alongside separate measures of maternal and newborn outcomes.

Rates of major obstetrical complications vary almost fivefold among US hospitals.

Of the approximately four million women who give birth each year in the United States, nearly 13 percent experience one or more major complications. But the extent to which the rates of major obstetrical complications vary across hospitals in the United States is unknown. We used multivariable logistic regression models to examine the variation in obstetrical complication outcomes across US hospitals among a large, nationally representative sample of more than 750,000 obstetrical deliveries in 2010. We found that 22.55 percent of patients delivering vaginally at low-performing hospitals experienced major complications, compared to 10.42 percent of similar patients delivering vaginally at high-performing hospitals. Hospitals were classified as having low, average, or high performance based on a calculation of the relative risk that a patient would experience a major complication. Patients undergoing a cesarean delivery at low-performing hospitals had nearly five times the rate of major complications that patients undergoing a cesarean delivery at high-performing hospitals had (20.93 percent compared to 4.37 percent). Our finding that the rate of major obstetrical complications varies markedly across US hospitals should prompt clinicians and policy makers to develop comprehensive quality metrics for obstetrical care and focus on improving obstetrical outcomes.

Racial disparities in the use of blood transfusion in major surgery.

BACKGROUND: Racial disparities in healthcare in the United States are widespread and have been well documented. However, it is unknown whether racial disparities exist in the use of blood transfusion for patients undergoing major surgery. METHODS: We used the University HealthSystem Consortium database (2009-2011) to examine racial disparities in perioperative red blood cells (RBCs) transfusion in patients undergoing coronary artery bypass surgery (CABG), total hip replacement (THR), and colectomy. We estimated multivariable logistic regressions to examine whether black patients are more likely than white patients to receive perioperative RBC transfusion, and to investigate potential sources of racial disparities. RESULTS: After adjusting for patient-level factors, black patients were more likely to receive RBC transfusions for CABG (AOR = 1.41, 95% CI: [1.13, 1.76], p = 0.002) and THR (AOR = 1.39, 95% CI: [1.20, 1.62], p < 0.001), but not for colectomy (AOR = 1.08, 95% CI: [0.90, 1.30], p = 0.40). Black-white disparities in blood transfusion persisted after controlling for patient insurance and hospital effects (CABG: AOR = 1.42, 95% CI: [1.30, 1.56], p < 0.001; THR: AOR = 1.43, 95% CI: [1.29, 1.58], p < 0.001). CONCLUSIONS: We detected racial disparities in the use of blood transfusion for CABG and THR (black patients tended to receive more transfusions compared with whites), but not for colectomy. Reporting racial disparities in contemporary transfusion practices may help reduce potentially unnecessary blood transfusions in minority patients.

Preoperative thrombocytopenia and postoperative outcomes after noncardiac surgery.

BACKGROUND: Most studies examining the prognostic value of preoperative coagulation testing are too small to examine the predictive value of routine preoperative coagulation testing in patients having noncardiac surgery. METHODS: Using data from the American College of Surgeons National Surgical Quality Improvement database, the authors performed a retrospective observational study on 316,644 patients having noncardiac surgery who did not have clinical indications for preoperative coagulation testing. The authors used multivariable logistic regression analysis to explore the association between platelet count abnormalities and red cell transfusion, mortality, and major complications. RESULTS: Thrombocytopenia or thrombocytosis occurred in 1 in 14 patients without clinical indications for preoperative platelet testing. Patients with mild thrombocytopenia (101,000-150,000 µl), moderate-to-severe thrombocytopenia (<100,000 µl), and thrombocytosis (≥450,000 µl) were significantly more likely to be transfused (7.3%, 11.8%, 8.9%, 3.1%) and had significantly higher 30-day mortality rates (1.5%, 2.6%, 0.9%, 0.5%) compared with patients with a normal platelet count. In the multivariable analyses, mild thrombocytopenia (adjusted odds ratio [AOR], 1.28; 95% CI, 1.18-1.39) and moderate-to-severe thrombocytopenia (AOR, 1.76; 95% CI, 1.49-2.08), and thrombocytosis (AOR, 1.44; 95% CI, 1.30-1.60) were associated with increased risk of blood transfusion. Mild thrombocytopenia (AOR, 1.31; 95% CI, 1.11-1.56) and moderate-to-severe thrombocytopenia (AOR, 1.93; 95% CI, 1.43-2.61) were also associated with increased risk of 30-day mortality, whereas thrombocytosis was not (AOR, 0.94; 95% CI, 0.72-1.22). CONCLUSION: Platelet count abnormalities found in the course of routine preoperative screening are associated with a higher risk of blood transfusion and death.

The effective concentration of tranexamic acid for inhibition of fibrinolysis in neonatal plasma in vitro.

BACKGROUND: Neonates are at high risk for bleeding complications after cardiovascular surgery. Activation of intravascular fibrinolysis is one of the principal effects of cardiopulmonary bypass that causes poor postoperative hemostasis. Antifibrinolytic medications such as tranexamic acid are often used as prophylaxis against fibrinolysis, but concentration/effect data to guide dosing are sparse for adults and have not been published for neonates. Higher concentrations of tranexamic acid than those necessary for inhibition of fibrinolysis may have adverse effects. Therefore, we investigated the concentration of tranexamic acid necessary to inhibit activated fibrinolysis in neonatal plasma. METHODS: We conducted an in vitro study using neonatal plasma derived from the placenta/cord units from 20 term, elective cesarean deliveries. Graded concentrations of tranexamic acid were added to aliquots of the pooled plasma before maximally activating fibrinolysis with high-dose tissue-type plasminogen activator. Thromboelastography was then performed with the primary outcome variable being lysis at 30 minutes. These procedures were repeated on pooled adult normal plasma and dilutions of neonatal plasma. RESULTS: The minimum concentrations of tranexamic acid to completely prevent fibrinolysis were 6.54 µg/mL (95% confidence interval, 5.19-7.91) for neonatal plasma and 17.5 µg/mL (95% confidence interval, 14.59-20.41) for adult plasma. Neonatal plasma requires a significantly lower concentration than adult plasma (P < 0.0001, 2-sided Wald test). CONCLUSIONS: Our data establish the minimal effective concentration of tranexamic acid necessary to completely prevent fibrinolysis in neonatal plasma in vitro. These data may be useful in designing a dosing scheme for tranexamic acid appropriate for neonates.

Labor epidural anesthesia, obstetric factors and breastfeeding cessation.

Breastfeeding benefits both infant and maternal health. Use of epidural anesthesia during labor is increasingly common and may interfere with breastfeeding. Studies analyzing epidural anesthesia's association with breastfeeding outcomes show mixed results; many have methodological flaws. We analyzed potential associations between epidural anesthesia and overall breast-feeding cessation within 30 days postpartum while adjusting for standard and novel covariates and uniquely accounting for labor induction. A pooled analysis using Kaplan-Meier curves and modified Cox Proportional Hazard models included 772 breastfeeding mothers from upstate New York who had vaginal term births of healthy singleton infants. Subjects were drawn from two cohort studies (recruited postpartum between 2005 and 2008) and included maternal self-report and maternal and infant medical record data. Analyses of potential associations between epidural anesthesia and overall breastfeeding cessation within 1 month included additional covariates and uniquely accounted for labor induction. After adjusting for standard demographics and intrapartum factors, epidural anesthesia significantly predicted breastfeeding cessation (hazard ratio 1.26 [95% confidence interval 1.10, 1.44], p < 0.01) as did hospital type, maternal age, income, education, planned breastfeeding goal, and breastfeeding confidence. In post hoc analyses stratified by Baby Friendly Hospital (BFH) status, epidural anesthesia significantly predicted breastfeeding cessation (BFH: 1.19 [1.01, 1.41], p < 0.04; non-BFH: 1.65 [1.31, 2.08], p < 0.01). A relationship between epidural anesthesia and breastfeeding was found but is complex and involves institutional, clinical, maternal and infant factors. These findings have implications for clinical care and hospital policies and point to the need for prospective studies.

Variation of blood transfusion in patients undergoing major noncardiac surgery.

OBJECTIVE: To examine the hospital variability in use of red blood cells (RBCs), fresh-frozen plasma (FFP), and platelet transfusions in patients undergoing major noncardiac surgery. BACKGROUND: Blood transfusion is commonly used in surgical procedures in the United States. Little is known about the hospital variability in perioperative transfusion rates for noncardiac surgery. METHODS: We used the University HealthSystem Consortium database (2006-2010) to examine hospital variability in use of allogeneic RBC, FFP, and platelet transfusions in patients undergoing major noncardiac surgery. We used regression-based techniques to quantify the variability in hospital transfusion practices and to study the association between hospital characteristics and the likelihood of transfusion. RESULTS: After adjusting for patient risk factors, hospital transfusion rates varied widely for patients undergoing total hip replacement (THR), colectomy, and pancreaticoduodenectomy. Compared with patients undergoing THR in average-transfusion hospitals, patients treated in high-transfusion hospitals have a greater than twofold higher odds of being transfused with RBCs [adjusted odds ratio (AOR) = 2.41; 95% confidence interval (CI), 1.89-3.09], FFP (AOR = 2.81; 95% CI, 2.02-3.91), and platelets (AOR = 2.52; 95% CI, 1.95-3.25), whereas patients in low-transfusion hospitals have an approximately 50% lower odds of receiving RBCs (AOR = 0.45; 95% CI, 0.35-0.57), FFP (AOR = 0.37; 95% CI, 0.27-0.51), and platelets (AOR = 0.42; 95% CI, 0.29-0.62). Similar results were obtained for colectomy and pancreaticoduodenectomy. CONCLUSIONS: There was dramatic hospital variability in perioperative transfusion rates among patients undergoing major noncardiac surgery at academic medical centers. In light of the potential complications of transfusion therapy, reducing this variability in hospital transfusion practices may result in improved surgical outcomes.

Association between Leapfrog safe practices score and hospital mortality in major surgery.

BACKGROUND: The Leapfrog Group reports on hospitals' adoption of the National Quality Forum Patient Safety Practices. However, it is unknown whether hospital compliance with these safe practices is associated with improved outcomes in patients undergoing major surgery. METHODS: We analyzed the association between hospital mortality and Leapfrog Safe Practices among patients undergoing coronary artery bypass graft surgery (n=18,565), abdominal aortic aneurysm repair (n=2777), and hip replacement (n=25,067) in hospitals participating in the 2007 Leapfrog Hospital Survey using logistic regression. RESULTS: After adjusting for patient and hospital factors, we found that the total safety score (adjusted odds ratio: 1.000, 95% confidence interval: 0.999-1.001) was not associated with hospital mortality. Computerized physician order entry and ICU physician staffing were also not associated with hospital mortality. CONCLUSIONS: We did not find evidence that patients undergoing major surgery at hospitals which scored higher on the Leapfrog Safe Practices Survey had lower mortality rates. The Leapfrog safe practices score as a standalone quality measure may have limited power to distinguish between high-quality and low-quality hospitals.

Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery.

BACKGROUND: The impact of intraoperative erythrocyte transfusion on outcomes of anemic patients undergoing noncardiac surgery has not been well characterized. The objective of this study was to examine the association between blood transfusion and mortality and morbidity in patients with severe anemia (hematocrit less than 30%) who are exposed to one or two units of erythrocytes intraoperatively. METHODS: This was a retrospective analysis of the association of blood transfusion and 30-day mortality and 30-day morbidity in 10,100 patients undergoing general, vascular, or orthopedic surgery. We estimated separate multivariate logistic regression models for 30-day mortality and for 30-day complications. RESULTS: Intraoperative blood transfusion was associated with an increased risk of death (odds ratio [OR], 1.29; 95% CI, 1.03-1.62). Patients receiving an intraoperative transfusion were more likely to have pulmonary, septic, wound, or thromboembolic complications, compared with patients not receiving an intraoperative transfusion. Compared with patients who were not transfused, patients receiving one or two units of erythrocytes were more likely to have pulmonary complications (OR, 1.76; 95% CI, 1.48-2.09), sepsis (OR, 1.43; 95% CI, 1.21-1.68), thromboembolic complications (OR, 1.77; 95% CI, 1.32-2.38), and wound complications (OR, 1.87; 95% CI, 1.47-2.37). CONCLUSIONS: Intraoperative blood transfusion is associated with a higher risk of mortality and morbidity in surgical patients with severe anemia. It is unknown whether this association is due to the adverse effects of blood transfusion or is, instead, the result of increased blood loss in the patients receiving blood.

Perioperative outcomes among patients with the modified metabolic syndrome who are undergoing noncardiac surgery.

BACKGROUND: Previous studies have demonstrated that obesity is paradoxically associated with a lower risk of mortality after noncardiac surgery. This study will determine the impact of the modified metabolic syndrome (defined as the presence of obesity, hypertension, and diabetes) on perioperative outcomes. METHODS: This study is based on data from 310,208 patients in the American College of Surgeons National Surgical Quality Improvement Program database. We estimated separate multivariate logistic regression models for 30-day mortality and for 30-day complications. RESULTS: Patients with the modified metabolic syndrome who are super obese had a 2-fold increased risk of death (adjusted odds ratio [AOR] 1.99; 95% CI 1.41-2.80). As stratified by body mass index, patients with the modified metabolic syndrome had a 2- to 2.5-fold higher risk of cardiac adverse events (CAE) compared with normal-weight patients: obese (AOR 1.70; 95% CI 1.40-2.07), morbidly obese (AOR 2.01; 95% CI 1.48-2.73), and super obese (AOR 2.66; 95% CI 1.68-4.19). In addition, the risk of acute kidney injury (AKI) was 3- to 7-fold higher in these patients: obese (AOR 3.30; 95% CI 2.75-3.94), morbidly obese (AOR 5.01; 95% CI 3.87-6.49), and super obese (AOR 7.29; 95% CI 5.27-10.1). CONCLUSION: Patients with the modified metabolic syndrome undergoing noncardiac surgery are at substantially higher risk of complications compared with patients of normal weight.

The effective concentration of epsilon-aminocaproic Acid for inhibition of fibrinolysis in neonatal plasma in vitro.

INTRODUCTION: Pediatric patients, particularly neonates, are at high risk for bleeding complications after cardiovascular surgery because of their immature hemostatic system, small size, and the complex operations they require. Activation of intravascular fibrinolysis is one of the principle effects of cardiopulmonary bypass that causes poor postoperative hemostasis. This complication has long been recognized and treated with antifibrinolytic medications, including the lysine analog epsilon aminocaproic acid (EACA). The therapeutic plasma concentration of EACA has been scientifically determined for the adult population, but the current recommended dosage for neonates has been empirically derived from adult studies. Therefore, we investigated the appropriate concentration of EACA for neonates undergoing bypass. METHODS: We conducted an in vitro study using neonatal plasma derived from the placenta/cord units from 20 term, elective cesarean deliveries. Graded concentrations of EACA were added to aliquots of the plasma pool before activating fibrinolysis with tissue-type plasminogen activator. Standard kaolin-activated thromboelastograms were then run with the primary outcome variable being estimated percent lysis. These procedures were repeated on samples of commercially available pooled adult normal plasma for comparison. RESULTS: We found that neonatal plasma required significantly lower concentrations of EACA to completely prevent fibrinolysis than did adult plasma (44.2 microg/mL and 47.8 microg/mL for neonatal plasma and 94.4 and 131.4 microg/mL in adult plasma for 400 and 1000 U/mL of plasminogen activator, respectively, P < 0.001). CONCLUSIONS: Our data establish the minimal effective concentration of EACA necessary to completely prevent fibrinolysis in neonatal blood in vitro. This concentration is significantly less than that targeted by current dosing schemes, indicating that neonates are possibly being exposed to greater levels of EACA than is clinically necessary.

Epidural multiorifice catheters function as single-orifice catheters: an in vitro study.

In an in vitro study, we determined the flow rates required to use selective orifices of multiorifice catheters. Saline was infused at rates between 1 and 360 mL/h through Portex and Braun 20-gauge multiorifice catheters using Baxter, Abbott Laboratories, and Alaris infusion pumps. The numbers of orifices used via infusion and manual injection, and the pressure within the catheter during continuous infusion, were recorded. Infusion rates <80 mL/h used one orifice, between 100 and 280 mL/h used two orifices, and >300 mL/h used three orifices. Catheter pressures with Braun catheters were 40% greater than with Portex catheters. Manual injections by all 12 residents used all three orifices. Twenty-gauge multiorifice catheters function as single-orifice catheters at clinically relevant infusion rates, but function as multiorifice catheters during manual boluses.

A randomized, double-masked, multicenter comparison of the safety of continuous intrathecal labor analgesia using a 28-gauge catheter versus continuous epidural labor analgesia.

BACKGROUND: Continuous intrathecal labor analgesia produces rapid analgesia or anesthesia and allows substantial flexibility in medication choice. The US Food and Drug Administration, in 1992, removed intrathecal microcatheters (27-32 gauge) from clinical use after reports of neurologic injury in nonobstetric patients. This study examined the safety and efficacy of a 28-gauge intrathecal catheter for labor analgesia in a prospective, randomized, multicenter trial. METHODS: Laboring patients were randomly assigned to continuous intrathecal analgesia with a 28-gauge catheter (n = 329) or continuous epidural analgesia with a 20-gauge catheter (n = 100), using bupivacaine and sufentanil. The primary outcome was the incidence of neurologic complications, as determined by masked neurologic examinations at 24 and 48 h postpartum, plus telephone follow-up at 7-10 and 30 days after delivery. The secondary outcomes included adequacy of labor analgesia, maternal satisfaction, and neonatal status. RESULTS: No patient had a permanent neurologic change. The continuous intrathecal analgesia patients had better early analgesia, less motor blockade, more pruritus, and higher maternal satisfaction with pain relief at 24 h postpartum. The intrathecal catheter was significantly more difficult to remove. There were no significant differences between the two groups in neonatal status, post-dural puncture headache, hemodynamic stability, or obstetric outcomes. CONCLUSIONS: Providing intrathecal labor analgesia with sufentanil and bupivacaine via a 28-gauge catheter has an incidence of neurologic complication less than 1%, and produces better initial pain relief and higher maternal satisfaction, but is associated with more technical difficulties and catheter failures compared with epidural analgesia.

Racial differences in the use of epidural analgesia for labor.

BACKGROUND: There is strong evidence that pain is undertreated in black and Hispanic patients. The association between race and ethnicity and the use of epidural analgesia for labor is not well described. METHODS: Using the New York State Perinatal Database, the authors examined whether race and ethnicity were associated with the likelihood of receiving epidural analgesia for labor after adjusting for clinical characteristics, demographics, insurance coverage, and provider effect. This retrospective cohort study was based on 81,883 women admitted for childbirth between 1998 and 2003. RESULTS: Overall, 38.3% of the patients received epidural analgesia for labor. After adjusting for clinical risk factors, socioeconomic status, and provider fixed effects, Hispanic and black patients were less likely than non-Hispanic white patients to receive epidural analgesia: The adjusted odds ratio was 0.85 (95% CI, 0.78-0.93) for white/Hispanic and 0.78 (0.74-0.83) for blacks compared with non-Hispanic whites. Compared with patients with private insurance, patients without insurance were least likely to receive epidural analgesia (adjusted odds ratio, 0.76; 95% CI, 0.64-0.89). Black patients with private insurance had similar rates of epidural use to white/non-Hispanic patients without insurance coverage: The adjusted odds ratio was 0.66 (95% CI, 0.53-0.82) for white/non-Hispanic patients without insurance versus 0.69 (0.57-0.85) for black patients with private insurance. CONCLUSION: Black and Hispanic women in labor are less likely than non-Hispanic white women to receive epidural analgesia. These differences remain after accounting for differences in insurance coverage, provider practice, and clinical characteristics.