Effects of body size on operative, intermediate, and long-term outcomes after coronary artery bypass operation.

BACKGROUND: To investigate the role of body size, if any, on operative and longer term outcomes following coronary artery surgery. METHODS: A total of 3,560 consecutive patients undergoing coronary artery bypass grafting from 1991 to 1997, including 2,401 (67%) males and a mean +/- SD age of 63 +/- 10 years were ranked based on their body mass index (BMI). The association in these patients of preoperative, long-term, and economic data with variations in BMI were studied using regression analyses. Long-term survival was studied using 5-year Kaplan-Meier survival analysis. RESULTS: Operative mortality, myocardial infarction, cerebrovascular accidents, blood transfusions, and length of hospital stay were all increased in the smallest patients (BMI < or = 24 kg/m2). Obesity did not increase adverse operative outcomes except for a greater rate of sternal wound infections occurring with increasing severity of obesity. Direct variable costs were lowest in patients clustered around normal BMI, with cost increasing similarly at low and high extremes. This effect was correlated with similar BMI effects on ventilatory and intensive care requirements. Excluding operative mortality, 5-year survival trends were similarly worse for the smallest (BMI < or = 24) and most severely obese (BMI > 34) patients. Mild obesity (BMI > or = 30 to BMI < 34) did not affect long-term survival. CONCLUSIONS: Among study patients, immediate operative outcomes were adversely affected by small body size, which reflected older age (66 +/- 10 years) and an exaggerated adverse impact of cardiopulmonary bypass. Younger age and smaller effects of cardiopulmonary bypass lead to better operative outcomes in the obese. Long-term outcomes were, however, suboptimal in severely obese patients although that group was the youngest (60 +/- 10 years). In addition to their large body habitus, other factors, including substantial prevalence of diabetes, insulin dependence and hypertension, probably played a significant role in the poor long-term outcome in the severely obese.

Predictors of gastrointestinal complications in cardiac surgery.

Gastrointestinal problems are infrequent but serious complications of cardiac surgery, with high rates of morbidity and mortality. Predictors of these complications are not well developed, and the role of fundamental variables remains controversial. In a retrospective review of our cardiac surgery experience from July 1991 through December 1997 we found that postoperative gastrointestinal complications were diagnosed in 86 of 4,463 consecutive patients (1.9%). We categorized these 86 patients into 2 groups--Surgical and Medical--according to the method of treatment used for their complications. In the Medical group, 9 of 52 patients (17%) died; in the Surgical group, 17 of 34 (50%) died. By logistic multivariate analysis, we identified 8 parameters that predicted gastrointestinal complications: age greater than 70 years, duration of cardiopulmonary bypass, need for blood transfusions, reoperation, triple-vessel disease, New York Heart Association functional class IV, peripheral vascular disease, and congestive heart failure. Postoperative re-exploration for bleeding was a predictor specific to the Surgical group. Use of an intraaortic balloon pump was markedly higher in the Gastrointestinal group than in the Control group (30% vs 10%, respectively), as was the use of inotropic support in the immediate postoperative period (27% vs 5.6%). Our results suggest that intra-abdominal ischemic injury is a likely contributing factor in most gastrointestinal complications. In turn, the ischemia is probably caused by hypoperfusion due to low cardiac output, hypotension due to blood loss, and intra-abdominal atheroemboli. The derived models are useful for identifying patients whose risk of gastrointestinal complications after cardiac surgery may be reduced by clinical measures designed to counter these mechanisms.

Resource utilization in coronary artery bypass operation: does surgical risk predict cost?

BACKGROUND: Current healthcare trends may render financial risk of cardiac operation a key component of clinical decision making. It has been suggested, based on large cohorts of patients stratified by clinical risk, that the cost of operation can be predicted from models of clinical risk since length of stay (LOS) is highly correlated to clinical risk, and LOS is correlated to hospital costs and charges. Direct correlation of actual surgical costs with surgical risk are lacking. METHODS: Variable direct costs, LOS, and The Society of Thoracic Surgeons predicted mortality risk [STS risk (%)] were collected and analyzed in 628 consecutive patients undergoing coronary artery bypass grafting (CABG) at our institution in 1997. RESULTS: Cost of CABG had a near-normal distribution, and cost in 21 outlier patients (cost > two standard deviations above the mean) was an average 5.3 times normal (median cost). For individual patients, cost was well correlated to LOS (R2 = 0.48) but not with STS risk (R2 = 0.12). LOS was also poorly predicted by STS risk (R2 = 0.09). However, despite its poor prediction of cost, STS risk was an unbiased estimator over the entire population. A result manifested, when patients were grouped into similar risk (<1%, 1-2%, 2+ -3%, 3+ -5%, 5+ -10%, and >10%) cohorts, by high correlation between cost and STS risk (R2 = 0.99), cost and LOS risk (R2 = 0.99), and LOS and STS risk (R2 = 0.97). CONCLUSIONS: Our data demonstrated that, in large CABG cohorts, surgical risk models can accurately predict cost of CABG. However, despite a trend for increasing cost with increasing STS risk, surgical risk models based on preoperative data are poor predictors of cost in individual patients. Use of these models should be limited to analysis of cost trends in cardiac operation, but not for predicting financial risk in individual patients during clinical decision making.

Prolongation of skin allografts by recombinant tumor necrosis factor and interleukin-1.

OBJECTIVE: The hypothesis is that systemic administration of recombinant tumor necrosis factor-alpha (TNF-alpha) and/or recombinant interleukin-1 alpha (IL-1 alpha) can decrease the rejection of a skin allograft. SUMMARY BACKGROUND DATA: Tumor necrosis factor and IL-1 are pluripotent cytokine hormones that are central to the host immunologic response to foreign substances. Cytokine effects and toxicity may be reduced by systemic administration of recombinant cytokines. The authors previously have demonstrated that pretreatment with cytokines such as IL-1 or TNF can reduce the lethality of endotoxin (lipopolysaccharide), gram-negative sepsis, cancer cachexia, and oxygen toxicity. METHODS: Skin grafts from the tails of Balb/c mice were placed on the backs of C57Bl/6 mice. Mice were treated with daily intraperitoneal saline, recombinant m-TNF (Genentech, South San Francisco, CA) or h-IL-1 (Hoffman LaRoche, Nutley, NJ) from postgraft day 1 to postgraft day 28. Tumor necrosis factor and IL-1 high doses were chosen because they protected mice from the lethality of lipopolysaccharide. Animals were examined daily for toxicity and graft rejection. Graft survival was plotted in a Kaplan-Meier plot and analyzed by the log-rank test. Comparison of proportions was done using the Fisher's exact test. RESULTS: Either TNF or IL-1 alone significantly prolonged skin graft survival compared with saline control. Furthermore, the combination of TNF and IL-1 prolonged skin graft survival longer than either cytokine alone. Mice on the highest dose TNF and IL-1 combination did not reject skin grafts during the 28-day treatment period. Significant toxicity was associated with cytokine treatment. Similar significant proportions of death occurred with IL-1 alone and the highest combination of TNF and IL-1. CONCLUSION: Both TNF and IL-1 can be effective as suppressors of skin allograft rejection in mice.

Humanized antibody directed to the IL-2 receptor beta-chain prolongs primate cardiac allograft survival.

IL-2Rs are expressed by T cells activated in response to foreign histocompatibility Ags but not by normal cells. This difference in IL-2R expression is exploited by blockade of IL-2Rs to achieve immunosuppression. High affinity IL-2Rs involve three subunits, IL-2R alpha, IL-2R beta, and IL-2R gamma. Murine Mik beta 1, a mAb that blocks IL-2 binding to IL-2R beta, was developed as an immunosuppressive agent. There was modest prolongation of cynomolgus cardiac allograft survival in animals treated with murine Mik beta 1 (mean survival 11.8 +/- 1.6 days compared with 8.2 +/- 0.4 days in untreated animals; p = 0.06). However, murine Mik beta 1 is ineffective in recruiting primate effector cells and is neutralized by monkey Abs directed toward the infused Ab. To circumvent these limitations, a humanized form of Mik beta 1, which is a largely human IgG1k Ab, except that murine hypervariable regions are retained, was developed. In vivo plasma survival of humanized Mik beta 1 was threefold longer than simultaneously administered murine Mik beta 1 (terminal t1/2, 104 +/- 10 h vs 37 +/- 2 h). Furthermore, humanized Mik beta 1 manifests Ab-dependent cellular cytotoxicity, an activity that is absent with the parental murine Mik beta 1. Graft survival was significantly prolonged by humanized Mik beta 1 treatment with survivals of 22, 22, 24, 27, 44, and > 300 days (p vs control < 0.01; p vs murine Mik beta 1 < 0.01). Survival was not prolonged further (p > 0.3) by the addition of humanized anti-Tac, which blocks interaction of IL-2 with IL-2R alpha subunits. There was no toxicity attributable to the use of Mik beta 1 Abs. Thus, humanized Mik beta 1 prolonged cardiac allograft survival in primates without toxicity and may be effective as an adjunct to standard immunosuppressive therapy.

Prolongation of graft survival in primate allograft transplantation by yttrium-90-labeled anti-Tac in conjunction with granulocyte colony-stimulating factor.

High-affinity IL-2 receptors are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac, a murine monoclonal antibody specific for the IL-2R alpha subunit, was used to inhibit organ allograft rejection. To enhance its effector function, anti-Tac was armed by chelation with yttrium-90, a pure beta-emitting radionuclide. Animals received no immunosuppression (n = 5, group I, controls), unmodified anti-Tac (n = 5, 1 mg/kg q.o.d., group II), or 90Y-anti-Tac (n = 5, 1.6 mCi/kg divided into four doses, group III). The animals in group IV (n = 4) were treated identically to those in group III with the exception that 5 micrograms/kg/dose of granulocyte colony-stimulating factor was administered intramuscularly on the days when the yttrium-90 was given and on postoperative days 12 through 35 in order to reduce hematopoietic toxicity. Mean graft survival +/- S.E.M. for the control group was 8.2 +/- 0.5 days as compared with 13.8 +/- 2.1 days (P < 0.05) for those monkeys treated with unmodified anti-Tac. Graft survival was further prolonged in animals of group III that received 90Y-anti-Tac, with a mean graft survival of 45.0 +/- 11.8 days; however, three of the five monkeys retained viable grafts within this group but died secondary to bone marrow suppression. In comparison, the monkeys in group IV that were treated with G-CSF in conjunction with 90Y-anti-Tac had a mean graft survival of 49.2 +/- 2.9 days. In contrast to group III there were no deaths in the group (IV) receiving G-CSF. Furthermore, animals in group IV had a reduced magnitude and shortened duration of irradiation-induced neutropenia when compared with that observed in group III animals that did not receive G-CSF. Thus, treatment with 90Y-anti-Tac in conjunction with G-CSF may have potential applications in organ transplantation and the treatment of IL-2 receptor-expressing neoplastic diseases.

Biochemical effects of ischemia on isolated, perfused rat heart tissues.

Isolated working rat hearts perfused with Krebs-Hensleit buffer were arrested and made ischemic. After 22 min, the hearts were reperfused with buffer, yielding restoration of function. Nucleotide levels rose and fell in the cardiac tissue as ischemia was imposed; the changes were consistent with the energy needs of the tissue. ATP concentrations in the tissues fell by 75% during ischemia, AMP levels were low initially and subsequently rose 5-fold, and ADP levels were essentially unchanged. Upon reperfusion ATP levels rebounded, although not to initial values, and AMP returned to initial values. During ischemia, there was a 10-fold or greater rise in inosine, hypoxanthine, and xanthine levels which fell to normally low levels upon reperfusion. Lactate dehydrogenase (LDH) activity rose during ischemia and returned to baseline upon reperfusion. Changes in LDH isozyme distribution suggest that, during ischemia, there is an increased proportion of liver-associated forms which returns to normally low levels upon reperfusion. Glutamate oxalacetate transaminase activity rose slightly at 5 min of ischemia, but, by 22 min of ischemia, it had fallen to 60% of initial values. Upon reperfusion, activity rose and, by 15 min, had reached 127% of initial values. On the other hand, there is no significant change in levels of extractable creatine kinase or isocitrate dehydrogenase activities as a result of the various conditions imposed on the hearts. As an index of protein oxidation, carbonyl levels in extractable protein rose during ischemia and were over four times the initial values at 5 min of reperfusion but, with continued reperfusion, declined to approximately 150% of initial values at 15 min.

Prevention of ischemia-reperfusion injury by the allergy drug lodoxamide tromethamine.

Lodoxamide tromethamine, an orphan antiallergy drug, inhibits degranulation of mast cells that reside in the myocardium and inhibits xanthine oxidase located in myocytes and predominantly in the vascular endothelium. The hypothesis evaluated was that lodoxamide tromethamine would attenuate oxygen free radical damage. Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing 0, 1, 10, 100, or 1,000 mumol/L lodoxamide tromethamine at 37 degrees and 24 degrees C with ischemic times of 22 and 93 minutes, respectively. These ischemic intervals yielded 50% survival and 50% return of function in untreated hearts. Lodoxamide treatment alone at the onset of reperfusion was also studied. Performance end points were aortic flow, pressure, and coronary flow. Biochemical analyses included serotonin collected from coronary effluent as a marker of mast cell degranulation, uric acid for xanthine oxidase inhibition, myocardial adenosine triphosphate, and carbonyl group concentrations. Performance data demonstrated that lodoxamide was beneficial in a log-linear dose response when given continuously at both temperatures. Percent of preischemic values for untreated and maximal responses at 1,000 mumol/L of lodoxamide were as follows: a mortality of 50% in nontreated hearts versus 0%; aortic flow, 47% to 94% (37 degrees C), 46% to 86% (24 degrees C); cardiac output, 60% to 98% (37 degrees C), 58% to 97% (24 degrees C); adenosine triphosphate, 59% to 90% (37 degrees C), 48% to 65% (24 degrees C). Serotonin was undetectable from any hearts. Uric acid concentrations and carbonyl group content did not change with increasing dose. Lodoxamide demonstrated no benefit when given only during reperfusion, suggesting injury occurred at times other than reperfusion.

Pretreatment with nicardipine preserves ventricular function after hypothermic ischemic arrest.

Calcium antagonists have a protective effect on postischemic myocardial function when included in normothermic cardioplegia solutions. This effect varies with the calcium antagonist, but is generally lost under hypothermic conditions. The hypothesis tested was that a calcium antagonist would increase postischemic myocardial performance if given before the onset of hypothermic arrest. Isolated working rat hearts were used with an oxygenated modified Krebs-Henseleit buffer solution as a perfusion media. Rats were pretreated with 1 of 9 doses of a nicardipine solution (0 to 100 micrograms/kg, intraperitoneally) 20 minutes before excision of the heart. Nicardipine is a light-stable, water-soluble calcium antagonist with minimal myocardial depressant effects. The hearts were arrested for 25 minutes at 37 degrees C or 93 minutes at 24 degrees C with 20 mL of cardioplegia solution containing 0.05 mmol/L CaCl2. Postischemic performance and adenosine triphosphate content were used as determinants of efficacy. Eighty-three percent of 101 treated hearts recovered in contrast to a mortality of 50% in the 24 nontreated hearts. Pretreatment with 25 micrograms/kg significantly increased (p less than 0.05) the percent recovery (compared with the nontreated group) of the following variables of cardiac function: systolic pressure, 74% to 96% (37 degrees C), 76% to 90% (24 degrees C); cardiac output, 61% to 90% (37 degrees C), 62% to 84% (24 degrees C); stroke work, 49% to 95% (37 degrees C), 50% to 92% (24 degrees C); and adenosine triphosphate, 76% to 87% (37 degrees C), 58% to 68% (24 degrees C). Progressive increases in postischemic function at 37 degrees and 24 degrees C were seen as the dose of nicardipine was increased from 0 to 25 micrograms/kg and decreased function was seen with a pretreatment dose greater than 25 micrograms/kg of nicardipine. Pretreatment with nicardipine significantly improved postischemic myocardial performance under hypothermic conditions and should be administered or at least not discontinued before cardiac operations.

Anti-Tac-H, a humanized antibody to the interleukin 2 receptor, prolongs primate cardiac allograft survival.

High-affinity interleukin 2 receptors (IL-2Rs) are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac-M, a murine monoclonal antibody specific for the IL-2R alpha chain, was used to inhibit organ allograft rejection. However, the use of murine anti-Tac as an immunosuppressive agent was limited by neutralization by human anti-murine antibodies and by weak recruitment of effector functions. To circumvent these difficulties, a humanized antibody to the IL-2R, anti-Tac-H, was prepared. This molecule is human with the exception of the hypervariable segments, which are retained from the mouse. In vivo survival of anti-Tac-H is 2.5-fold longer than simultaneously administered anti-Tac-M (terminal t1/2, 103 hr vs. 38 hr). In addition, anti-Tac-H is less immunogenic than anti-Tac-M when administered to cynomolgus monkeys undergoing heterotopic cardiac allografting. Specifically, all monkeys treated with anti-Tac-M developed measurable anti-anti-Tac-M levels by day 15 (mean onset, 11 days). In contrast, none of the animals receiving anti-Tac-H produced measurable antibodies to this monoclonal antibody before day 33. Finally, there was a prolongation of graft survival in the cynomolgus heterotopic cardiac allograft model in animals receiving anti-Tac. In animals that received anti-Tac-M, the allograft survival was prolonged compared to that of the control group (mean survival, 14 +/- 1.98 days compared to 9.2 +/- 0.48 days; P less than 0.025). Graft survival was further prolonged by anti-Tac-H with a mean survival of 20.0 +/- 0.55 days (compared to controls, P less than 0.001; compared to anti-Tac-M, P less than 0.02). There was no toxicity attributable to the administration of either form of anti-Tac. Thus, anti-Tac-H significantly prolonged allograft survival in primates, without toxic side effects, and may be of value as an adjunct to standard immunosuppressive therapy in humans.

Magnesium ion is beneficial in hypothermic crystalloid cardioplegia.

The role of magnesium ion and its relation to the calcium concentration of cardioplegic solutions was reexamined in this study. Isolated rat hearts were used with an oxygenated modified Krebs-Henseleit bicarbonate buffer as perfusion medium. The hearts were arrested for 20 minutes at 37 degrees C or 90 minutes at 24 degrees C. Treatment groups received one dose of nine possible cardioplegic solutions containing magnesium (0, 1.2, or 15 mmol/L) and calcium (0.05, 1.5, or 4.5 mmol/L). Ninety-six percent of the 75 magnesium-treated hearts recovered, regardless of the calcium concentration, in contrast to a 52% recovery rate in the 69 hearts that did not receive magnesium. The addition of 15 mmol/L Mg2+ to a cardioplegic solution containing no magnesium but 0.05 mmol/L Ca2+ significantly increased (p less than 0.01) the percent recovery of the following parameters of cardiac function: systolic pressure, 74% to 93% (37 degrees C), 64% to 98% (24 degrees C); cardiac output, 76% to 101% (37 degrees C), 71% to 102% (24 degrees C); stroke work, 64% to 104% (37 degrees C), 52% to 99% (24 degrees C); and adenosine triphosphate level, 75% to 83% (37 degrees C), 58% to 90% (24 degrees C). There were significant reductions (p less than 0.03) in percent recovery (37 degrees C and 24 degrees C) of cardiac output, stroke work, and adenosine triphosphate level in the groups that contained 0 or 15 mmol/L Mg2+ as the calcium concentration was increased from 0.05 to 4.5 mmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)