Blood compatibility of cetyl alcohol/polysorbate-based nanoparticles.

PURPOSE: Pegylated and nonpegylated cetyl alcohol/polysorbate nanoparticles (E78 NPs) are being tested as drug carriers for specific tumor and brain targeting. Because these nanoparticle formulations are designed for systemic administration, it is important to test the compatibility of these lipid-based NPs with blood and blood cells. METHODS: The hemocompatibility of E78 NPs was evaluated with a particular focus on hemolytic activity, platelet function, and blood coagulation. Human red blood cell lysis was determined by measuring hemoglobin release. Activation and aggregation of human platelets were determined using flow cytometry and aggregometry, respectively. Finally, the whole blood clotting time was measured using human blood. RESULTS: E78 NPs did not cause in vitro red blood cell lysis at concentrations up to 1 mg/mL. In addition, under conditions tested, E78 and polyethylene glycol (PEG)-coated E78 NPs (PEG-E78 NPs) did not activate platelets. In fact, both NP formulations very rapidly inhibited agonist-induced platelet activation and aggregation in a dose-dependent manner. Additionally, E78 NPs significantly prolonged in vitro whole blood clotting time at a concentration of 500 microg/mL or greater. CONCLUSIONS: It was concluded that PEG-coated and nonpegylated E78 NPs have potential blood compatibility at clinically relevant doses. Based on the calculated nanoparticle-to-platelet ratio, the concentration at which E78 NPs could potentially affect platelet function in vivo was approximately 1 mg/mL.

Risk factors for early hospital readmission after cardiac operations.

OBJECTIVE: Early hospital readmissions after cardiac procedures are both costly and harmful to patients. We investigated the factors that predispose to readmission to develop strategies to minimize this problem. METHODS: As part of a prospective data collection, patients having cardiac procedures at our institution are routinely tracked for 30 days after their discharge from the hospital. We reviewed 2650 patients in our cardiac database who underwent operations over the past 5 years. We used univariate and multivariate statistical techniques to identify risks for readmission. RESULTS: Of 2574 discharged patients, 252 (9.8%) required readmission. The most common causes of readmission are cardiac (42%), pulmonary (19%), gastrointestinal (10%), extremity complications (6.7%; deep vein thrombophlebitis, peripheral arterial vascular disease, and saphenous vein harvest site problems), sternal wound problems (7.5%), and metabolic problems (4%). Of more than 70 variables studied, only 6 are significant multivariate predictors of readmission: female sex (P =.002); diabetes (P =.001); chronic lung problems (P =.011); increased distance between home and hospital (P >.001); preoperative atrial fibrillation (P =.002); and preoperative chronic renal insufficiency (P =.002). Type of operation, redo procedures, and other intraoperative and postoperative variables are not important multivariate predictors of readmission. Prolonged hospital length of stay for the initial procedure did not cause more frequent readmission. The costs of initial hospitalization (operating room costs combined with postoperative in-hospital costs) were not significantly increased in those patients who required readmission. CONCLUSIONS: The high-risk patient for readmission is a woman with diabetes, chronic lung disease, renal insufficiency, and preoperative atrial fibrillation who lives at a distance from the hospital. Readmission does not depend on periprocedural variables (eg, cardiopulmonary bypass time) or on postoperative complications. High procedural costs from the initial hospitalization do not predispose to readmission. These results suggest interventions that may reduce readmission.

Oropharyngeal dysphagia after cardiac operations.

BACKGROUND: As many as 15% of hospitalized patients have oropharyngeal dysphagia. The incidence and causes of postoperative oropharyngeal dysphagia (OD) in patients having cardiac operations are poorly documented and the best treatment is uncertain. We undertook a study to evaluate OD in patients having cardiac operations. METHODS: As part of a quality improvement project, all patients operated on in 1998 and 1999 were monitored for the signs or symptoms of OD. Patients with OD had diagnostic and therapeutic interventions to limit adverse outcomes. At the end of the 2-year evaluation period, patient risk factors, diagnoses, results of interventions, and outcomes were measured. RESULTS: Thirty-one out of 1,042, patients (3%) had OD. OD is more common in older patients (p < 0.0001) with diabetes (p = 0.02), renal insufficiency (p = 0.012), hyperlipidemia (p = 0.046), and preoperative congestive heart failure (p < 0.0001), and in those having noncoronary artery bypass procedures (p < 0.0001). One patient with OD died from respiratory arrest, presumably secondary to aspiration. Modified barium swallow (MBS) identified oral dysphagia in 2 patients, pharyngeal dysphagia in 7 patients, and both oral and pharyngeal dysphagia in 17 patients. One patient had a structural defect (cervical osteophyte) causing dysphagia and 4 patients had no identifiable cause of dysphagia on MBS. Postoperative neurologic complications are more common in patients with OD. Ten of 31 patients (32%) with OD had some new neurologic complication after operation compared with 36 of 1,011 (3.5%) who had a postoperative neurologic problem without OD. In 19 patients with OD no cause for swallowing difficulty was identified. Specifically, no metabolic, myopathic, or infectious abnormalities were identified in any patient with OD. Hospital charges were significantly increased in patients with OD ($69,320 versus $36,087, p < 0.0001). Therapy consisting of modification of eating behavior and swallowing technique and in some severe cases enteral or parenteral feeding was successful in all patients except 1, but 4 patients required more than 4 months of supportive care before return to oral feeding was possible. CONCLUSIONS: OD is associated with increased cost and morbidity. Older patients with diabetes, preoperative heart failure, and renal insufficiency are at increased risk for OD. Early recognition and intervention is likely to result in satisfactory outcome but may be associated with a protracted postoperative course.

Cost-effectiveness of minimally invasive cardiac operations.

BACKGROUND: Minimally invasive cardiac operations (MICOs) are reported to reduce procedural costs while at the same time decreasing operative morbidity and improving patient comfort. However, most of the cost data available for minimally invasive cardiac procedures is limited to short-term, peri-procedure, in-hospital costs. The scarcity of data to support claims for long-term cost-effectiveness prompted our interest in pursuing this research. METHODS: Cost-effectiveness analysis was used to estimate the monetary cost required to achieve a gain in health benefit. We reviewed the literature to accumulate all available relevant cost data regarding MICO in order to apply the principles of cost-effectiveness analysis to this relatively new procedure. For purposes of the analysis, two assumptions were made: (1) MICOs have a less favorable long-term survival outcome than does conventional coronary artery bypass grafting using cardiopulmonary bypass (CABG), and (2) the reintervention rates and long-term costs resulting from MICOs are similar to those of percutaneous transluminal coronary angioplasty with intracoronary stenting (PTCA/stenting). RESULTS: The average procedural costs from published literature were $13,782 for PTCA/stenting, $16,082 for MICO, and $23,938 for CABG. The cost-effectiveness of CABG and MICO were compared using PTCA/stenting as a standard of comparison. These estimations suggest that MICO is less cost-effective than CABG ($112,200 per year of life saved by MICO and $56,280 per year of life saved by CABG). CONCLUSIONS: Usable data to provide accurate cost-effectiveness estimates for MICO is scarce. Preliminary estimates based on available data suggest two means of improving the cost-effectiveness of MICO. First, technical advances that improve the quality of MICO (e.g., improved patency rates for mammary anastomoses and complete revascularization strategies) will decrease the reintervention rates and out-of-hospital costs. Second, application of MICO to a high-risk subset of patients who will experience improved survival compared to other alternatives will improve cost-effectiveness by prolonging life for those patients. Therefore, in order to be cost-effective, MICOs must obtain high quality results, including complete revascularization, and must be used primarily in high-risk patients.

Long-term angiographic results of coronary endarterectomy.

BACKGROUND: To evaluate the long-term patency of endarterectomized coronary vessels, we studied patients having recatheterization after coronary artery bypass grafting. METHODS: Forty-one clinical and angiographic variables were analyzed in 97 study patients who had coronary endarterectomy (CE) and in 154 control patients who did not have CE but who had repeat catheterization after coronary artery bypass grafting. RESULTS: Ninety-seven patients had 132 CEs. The right coronary artery was the most commonly endarterectomized vessel (73 of the 132 endarterectomized vessels). At a mean of 7.1 years of follow-up, significantly fewer bypass grafts to endarterectomized vessels were patent compared with nonendarterectomized vessels (40% of endarterectomized vessels compared with 58% of nonendarterectomized vessels in study patients and 65% in control patients, p = 0.0003). The only predictor of long-term CE graft patency is age-adjusted body surface area (p = 0.0068). Patency in grafts to nonendarterectomized vessels is diminished by hypertension (p = 0.046) and current cigarette use (p = 0.024) and improved by use of mammary artery grafting (p < 0.0001). CONCLUSIONS: These results show that long-term patency in bypass grafts to endarterectomized vessels is less common than in nonendarterectomized vessels and that this patency is related to larger body size. Patency in nonendarterectomized vessels is reduced by risks of arteriosclerosis. This suggests that CE should be used with caution in smaller patients and that aggressive control of risk factors for atherogenesis is particularly important in patients who have CE. On the basis of these results, we speculate that the extent of disease is advanced in patients who require CE.

Operative outcome and hospital cost.

INTRODUCTION: Because of concern about increasing health care costs, we undertook a study to find patient risk factors associated with increased hospital costs and to evaluate the relationship between increased cost and in-hospital mortality and serious morbidity. METHODS: More than 100 patient variables were screened in 1221 patients undergoing cardiac procedures. Simultaneously, patient hospital costs were computed from the cost-to-charge ratio. Univariate and multivariate statistics were used to explore the relationship between hospital cost and patient outcomes, including operative death, in-hospital morbidity, and length of stay. RESULTS: The greatest costs were for 31 patients who did not survive operation ($74,466, 95% confidence interval $27,102 to $198,025), greater than the costs for 120 patients who had serious, nonfatal morbidity ($60,335, 95% confidence interval $28,381 to $130,897, p = 0.02) and those for 1070 patients who survived operation without complication ($31,459, 95% confidence interval $21,944 to $49,849, p = 0.001). Breakdown of the components of hospital costs in fatalities and in cases with nonfatal complications revealed that the greatest contributions were in anesthesia and operating room costs. Significant (by stepwise linear regression analysis) independent risks for increased hospital cost were as follows (in order of decreasing importance): (1) preoperative congestive heart failure, (2) serum creatinine level greater than 2.5 mg/dl, (3) New York state predicted mortality risk, (4), type of operation (coronary artery bypass grafting, valve, valve plus coronary artery bypass grafting, or other), (5) preoperative hematocrit, (6) need for reoperative procedure, (7) operative priority, and (8) sex. These risks were different than those for in-hospitality death or increased length of stay. Hospital cost correlated with length of stay (r = 0.63, p < 0.001), but there were many outliers at the high end of the hospital cost spectrum. CONCLUSIONS: We conclude that operative death is the most costly outcome; length of stay is an unreliable indicator of hospital cost, especially at the high end of the cost spectrum; risks of increased hospital cost are different than those for perioperative mortality or increased length of stay; and ventricular dysfunction in elderly patients undergoing urgent operations for other than coronary disease is associated with increased cost. Certain patient factors, such as preoperative anemia and congestive heart failure, are amenable to preoperative intervention to reduce costs, and a high-risk patient profile can serve as a target for cost-reduction strategies.

The platelet thrombin receptor and postoperative bleeding.

BACKGROUND: We hypothesized that small amounts of thrombin desensitize the platelet thrombin receptor during cardiopulmonary bypass (CPB), resulting in postoperative platelet dysfunction and bleeding. METHODS: Seventy-nine patients were entered into a study designed to measure changes in platelet thrombin receptor function during CPB and to correlate them to postoperative bleeding. In addition to measurements of clinical blood loss, platelet function tests of aggregation, activation, and cell-cell adhesion were used. The thrombin receptor agonist peptide (TRAP) was used to activate the platelets. Flow cytometry was used to measure various platelet surface markers and platelet-white cell interactions during CPB. RESULTS: Compared with preoperative values, both aggregometry and flow cytometry measured a significant reduction of TRAP-induced activation immediately and up to 24 hours after CPB. The response of other activating agents returned to normal by 24 hours. Postoperatively, 8 of 79 patients required excessive blood transfusion (> or = 10 units of blood products) and had significantly decreased TRAP-induced aggregation response. CONCLUSIONS: Our results show that (1) platelet activation, aggregation, and adhesion to leukocytes induced by TRAP are reduced after CPB, (2) decreased thrombin receptor responsiveness is associated with excessive postoperative blood loss, and (3) because the aggregation and activation responses are different for TRAP and thrombin, there may be a second thrombin receptor on platelets that is protected from damage during CPB. These results imply that prevention of the CPB-induced effects on the thrombin receptor will lessen postoperative morbidity associated with blood transfusion.

Risk factors for postoperative morbidity.

OBJECTIVE: Analysis of outcomes after coronary artery bypass grafting has focused on risk factors for operative mortality. Nonfatal perioperative morbidity is far more costly and more common after operation. To identify the risk factors that lead to postoperative morbidity, we evaluated 938 patients undergoing coronary artery bypass grafting at Albany Medical Center Hospital during 1993. METHODS: Multivariate statistical analysis was performed on preoperative patient variables to identify risk factors for either serious postoperative morbidity or increased hospital length of stay. Variables were considered both individually and in combination. For example, age was considered individually or in combination with other variables, including parameters of blood volume (i.e., age divided by red blood cell volume or Age/RBCVOL). Similar multivariate analysis was performed to identify independent risk factors for hospital mortality. RESULTS: In order of decreasing importance, the following patient variables were significantly associated with increased length of stay by stepwise Cox regression analysis: Age/RBCVOL, history of congestive heart failure, hypertension, femoral-popliteal peripheral vascular disease, chronic obstructive lung disease, and renal dysfunction. The combination variable, Age/RBCVOL, was an important risk factor for both increased length of stay and serious postoperative morbidity. Variables that were significant independent predictors of increased mortality, such as preoperative shock, and redo operation, were not risk factors for either serious morbidity or increased length of stay. CONCLUSIONS: We conclude that risk factors for postoperative morbidity are different from those for postoperative mortality. These results suggest that older patients with preoperative anemia and low blood volume who also have other comorbidities (congestive heart failure, stroke, chronic obstructive pulmonary disease, or hypertension) are at increased risk for postoperative complications. This allows identification of a high-risk cohort of patients who are likely candidates for interventions to lessen postoperative morbidity.

Thrombin receptor-related hemostatic defect after cardiopulmonary bypass.

Platelet abnormalities have been blamed for the hemostatic defect that develops after cardiopulmonary bypass (CPB), but investigators have not been able to agree upon an intrinsic platelet abnormality responsible for the observed defect. To better define the blood components responsible for this post-operative hemostatic defect, we compared platelet function in whole blood (WB) to that in platelet-rich plasma (PRP) in 33 patients undergoing coronary artery bypass grafting. We measured platelet aggregation in response to various platelet agonists, including thrombin and TRAP-6 (a 6-amino acid peptide that activates the thrombin "tethered ligand" receptor site). In WB there was a lasting, diminished response to TRAP-6, but not to gamma-thrombin, after CPB. Control experiments showed that this diminished response to TRAP-6: (1) was not related to heparin or heparin-protamine complexes, (2) was not the result of hemodilution during CPB, (3) was not related to increased amounts of naturally occurring enzymes (aminopeptidases) that degrade TRAP, and (4) was not able to be reversed by the addition of as much as a 10-fold excess of the usual TRAP-6 aggregating dose to WB preparations. In contrast, no corresponding defect in platelet aggregation could be identified in PRP obtained from patients after CPB. These results show that, in post-operative blood samples, blood components present in WB and not in PRP (eg, red blood cells, activated white cells or platelets bound to white cells) diminish the ability of TRAP peptides to activate the thrombin receptor but do not decrease the ability of gamma-thrombin to induce platelet aggregation. This suggests that for circulating platelets after CPB: (1) interactions of platelets with other blood cell elements are the cause of altered postoperative platelet reactivity rather than any intrinsic CPB-induced platelet defect, (2) drugs, such as aprotinin, that limit activation of white cells and the fibrinolytic system may also have beneficial effects on platelet function after CPB, and (3) alternate mechanisms exist that allow thrombin, but not TRAP-6, to activate platelets normally after CPB (perhaps a second, as yet undefined, thrombin receptor).

Limiting excessive postoperative blood transfusion after cardiac procedures. A review.

Analysis of blood product use after cardiac operations reveals that a few patients (< or = 20%) consume the majority of blood products (> 80%). The risk factors that predispose a minority of patients to excessive blood use include patient-related factors, transfusion practices, drug-related causes, and procedure-related factors. Multivariate studies suggest that patient age and red blood cell volume are independent patient-related variables that predict excessive blood product transfusion after cardiac procedures. Other factors include preoperative aspirin ingestion, type of operation, over- or underutilization of heparin during cardiopulmonary bypass, failure to correct hypothermia after cardiopulmonary bypass, and physician overtransfusion. A survey of the currently available blood conservation techniques reveals 5 that stand out as reliable methods: 1) high-dose aprotinin therapy, 2) preoperative erythropoietin therapy when time permits adequate dosage before operation, 3) hemodilution by harvest of whole blood immediately before cardiopulmonary bypass, 4) autologous predonation of blood, and 5) salvage of oxygenator blood after cardiopulmonary bypass. Other methods, such as the use of epsilon-aminocaproic acid or desmopressin, cell saving devices, reinfusion of shed mediastinal blood, and hemofiltration have been reported to be less reliable and may even be harmful in some high-risk patients. Consideration of the available data allows formulation of a 4-pronged plan for limiting excessive blood transfusion after surgery: 1) recognize the causes of excessive transfusion, including the importance of red blood cell volume, type of procedure being performed, preoperative aspirin ingestion, etc.; 2) establish a quality management program, including a survey of transfusion practices that emphasizes physician education and availability of real-time laboratory testing to guide transfusion therapy; 3) adopt a multimodal approach using institution-proven techniques; and 4) continually reassess blood product use and analyze the cost-benefits of blood conservation interventions.

Simultaneous determination of inosine, hypoxanthine, xanthine, and uric acid and the effect of metal chelators.

We describe a sensitive, reproducible method for the simultaneous determination of the ATP catabolites inosine, hypoxanthine, xanthine, and uric acid in biological samples and organ perfusate using reverse-phase chromatography and multiwavelength detection at 254, 270, and 292 nm. Sample preparation includes precipitating proteins with perchloric acid, neutralizing the sample, passing the supernatant over a polyethyleneimine column, and analyzing the collected fractions by high-performance liquid chromatography. Addition of metal chelators to the perchloric acid resulted in increased values for xanthine, hypoxanthine, and uric acid. The method was sensitive (limit of detection, 0.08 nmol on column; S/N = 4) and linear over the range 0.5-30 microM. Precision and accuracy of the method were evaluated for lung tissue and lung perfusate. Coefficients of variation ranged from 2.8 to 6.1% for perfusate and from 1.7 to 12.6% for tissue. Recoveries for all compounds exceeded 90%. We applied this method to rat lung tissue, lung perfusate, and rat and human blood. Advantages of this method are simultaneous quantitation with excellent sensitivity of all compounds, simplified peak identification by using multiwavelength detection, and improved accuracy by preventing loss of compounds with metal chelators.

Predictors of postoperative ventricular dysrhythmias: a multivariate study.

Postoperative ventricular dysrhythmias were studied to document their incidence after coronary bypass grafting and to identify risk factors for their development with the hope of finding a subgroup of patients who might benefit from postoperative, prophylactic drug therapy. One-hundred-nine patients who were undergoing urgent or elective coronary bypass grafting were studied, prospectively. Twenty-five of 109 patients (23%) developed significant postoperative ventricular dysrhythmias that required counter-shock or drug intervention. Seven of eight instances of sustained ventricular tachycardia, the most serious dysrhythmia, occurred within 36 hours of operation. There was no postoperative mortality related to these dysrhythmias. Serious postoperative complications, such as stroke, hemorrhage, or myocardial infarction, were decreased in patients with ventricular dysrhythmias versus those without (8% versus 16%, p = 0.053 for the Fisher's exact test statistic). Univariate statistical analysis was performed using 15 patient variables and revealed that advanced age (p = 0.008 for the unpaired t test), failure to use an internal mammary artery conduit (p = 0.03 for the two-tailed Fisher's exact test), and development of postoperative atrial dysrhythmias (p = 0.02 for the two-tailed Fisher's exact test) were significantly more common in patients with postoperative ventricular dysrhythmias. Variables such as previous myocardial infarction, ejection fraction less than 50%, prolonged operative time, perioperative myocardial infarction, or fewer number of vessels bypassed were not significantly increased in patients with dysrhythmias (the statistical power for these "negative" results was greater than 0.8).(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative aspirin ingestion increases operative blood loss after coronary artery bypass grafting.

Thirty-four patients were entered into a non-blinded, randomized study to test the effect of preoperative aspirin ingestion on postoperative blood loss and transfusion requirements after coronary artery bypass grafting. Sixteen patients in the aspirin-treated group had significantly increased chest-tube blood loss 12 hours after operation (1,513 +/- 978 versus 916 +/- 482 ml; p = 0.038). In addition, aspirin users had significantly increased requirements for postoperative packed red blood cells (4.4 +/- 3.5 versus 1.8 +/- 1.3 units; p = 0.014), platelets (1.3 +/- 1.3 versus 0.2 +/- 0.4 six-donor units, p = 0.0049), and fresh-frozen plasma (3.6 +/- 5.0 versus 0.78 +/- 1.6 units; p = 0.042) transfusions. The only patients requiring reoperation for bleeding were in the aspirin-treated group (2 patients). Six patients were not entered into the randomized part of the study because of excessively prolonged post-aspirin bleeding times (greater than 10 minutes). This finding suggests that a subset of patients are particularly sensitive to aspirin and have significantly prolonged bleeding times after aspirin ingestion. We conclude that aspirin ingestion increases postoperative blood loss and transfusion requirements, and we recommend discontinuation of aspirin therapy before cardiac procedures.

Verapamil prophylaxis for postoperative atrial dysrhythmias: a prospective, randomized, double-blind study using drug level monitoring.

Orally administered verapamil hydrochloride (80 mg every 8 hours) or a placebo was given to 109 patients after coronary artery bypass grafting in a randomized, double-blind manner to test the efficacy of verapamil in preventing postoperative atrial dysrhythmias. The test drug was given through a nasogastric tube beginning 4 to 6 hours after operation until oral ingestion was possible. Serum levels of verapamil were measured at selected times after operation and when postoperative atrial dysrhythmias occurred. Postoperative atrial dysrhythmias occurred in 10 of the 53 verapamil-treated patients and in 20 of the 56 placebo-treated patients. Patients with verapamil drug levels higher than 150 ng/ml had fewer postoperative atrial dysrhythmias than those with lesser verapamil levels (p = .034) or than placebo-treated patients (p = .012). Only 2 of 31 patients with drug levels higher than 150 ng/ml experienced postoperative atrial dysrhythmias. Approximately 40% of verapamil-treated patients had drug levels lower than 150 ng/ml at 48 hours after operation. It is concluded that oral administration of verapamil prevents postoperative atrial dysrhythmias in a dose-dependent fashion.