Relationship between early postoperative C-reactive protein elevation and long-term postoperative major adverse cardiovascular and cerebral events in patients undergoing off-pump coronary artery bypass graft surgery: a retrospective study.

BACKGROUND: Inflammation plays a key role in the pathogenesis of vascular occlusive diseases, such as myocardial infarction and stroke. Additionally, these conditions are predicted by C-reactive protein (CRP), a general inflammation marker. We hypothesized that the inflammation induced by surgery itself augments vascular occlusive disease. We retrospectively evaluated the relationship between postoperative CRP elevation and postoperative major adverse cardiovascular and cerebral events (MACCE) in patients undergoing off-pump coronary artery bypass surgery (OPCAB). METHODS: The electronic medical records of 1046 patients who underwent OPCAB were reviewed retrospectively. The relationship between postoperative serum CRP and long-term postoperative MACCE (median follow-up 28 months) was investigated. RESULTS: Patients were divided into quartiles according to maximum postoperative CRP levels (<18, 18-22, 22-27, ≥27 mg dl(-1)). The adjusted hazard ratios (HRs) were 2.15, 2.45, and 2.81, respectively (P=0.004), compared with the lowest quartile (<18 mg dl(-1)). In the multivariate analysis, the postoperative CRP quartile (HR 2.81; P=0.004), postoperative non-use of statins (HR 1.86; P=0.003), and postoperative maximum troponin I (HR 1.02; P<0.001) independently predicted postoperative MACCE, while preoperative CRP did not (P=0.203). Several parameters were correlated with postoperative maximum CRP level: body temperature (P=0.001) and heart rate (P<0.001) at the end of surgery; intraoperative last lactate (P<0.001) and base excess (P<0.001); and red blood cell transfusion (P=0.019). CONCLUSIONS: Postoperative CRP elevation was associated with long-term postoperative MACCE in OPCAB patients. This was mitigated by postoperative statin medication. Furthermore, postoperative CRP elevation was associated with intraoperative parameters reflecting hypoperfusion and inflammation.

Near-infrared spectroscopy as an index of brain and tissue oxygenation.

Continuous real-time monitoring of the adequacy of cerebral perfusion can provide important therapeutic information in a variety of clinical settings. The current clinical availability of several non-invasive near-infrared spectroscopy (NIRS)-based cerebral oximetry devices represents a potentially important development for the detection of cerebral ischaemia. In addition, a number of preliminary studies have reported on the application of cerebral oximetry sensors to other tissue beds including splanchnic, renal, and spinal cord. This review provides a synopsis of the mode of operation, current limitations and confounders, clinical applications, and potential future uses of such NIRS devices.

A randomized study of the influence of perfusion technique and pH management strategy in 316 patients undergoing coronary artery bypass surgery. I. Mortality and cardiovascular morbidity.

UNLABELLED: The impact of perfusion technique and mode of pH management during cardiopulmonary bypass has not been well characterized with respect to postoperative cardiovascular outcome. METHODS: This double-blind, randomized study comparing outcomes after alpha-stat or pH-stat management and pulsatile or nonpulsatile perfusion during moderate hypothermic cardiopulmonary bypass was undertaken in 316 patients undergoing coronary artery bypass operations. RESULTS: Cardiovascular morbidity and mortality were not affected by pH management, and the incidence of stroke (2.5%) did not differ between groups. Overall in-hospital mortality was 2.8%, eight of the nine deaths occurring in the nonpulsatile group (5.1% versus 0.6%; p = 0.018). The incidence of myocardial infarction was 5.7% in the nonpulsatile group and 0.6% in the pulsatile group (p = 0.010), and use of intraaortic balloon pulsation was significantly more common in the nonpulsatile group (7.0% versus 1.9%; p = 0.029). The overall percentage of patients having major complications was also significantly higher in the nonpulsatile group (15.2% versus 5.7%; p = 0.006). Duration of cardiopulmonary bypass, age, and use of nonpulsatile perfusion all correlated significantly with adverse outcome. CONCLUSIONS: Use of pulsatile perfusion during cardiopulmonary bypass was associated with decreased incidences of myocardial infarction, death, and major complications.

A randomized study of the influence of perfusion technique and pH management strategy in 316 patients undergoing coronary artery bypass surgery. II. Neurologic and cognitive outcomes.

UNLABELLED: This double-blind, randomized comparison of pulsatile or nonpulsatile perfusion and alpha-stat or pH-stat management during cardiopulmonary bypass was designed to assess postoperative central nervous system outcomes. METHODS: Neurologic and cognitive testing was conducted before the operation and 7 days and 2 months after the operation in 316 patients having coronary artery bypass and in a reference cohort of 40 patients having major vascular and thoracic operations. RESULTS: As detailed in part I of this study, mortality in patients having coronary bypass was 2.8%. The incidence of stroke was 2.5% and did not differ among bypass groups. Mortality was 2.5% for the major surgery cohort. The incidence of cognitive (p = 0.003) and either neurologic or cognitive dysfunction (p = 0.0002) was higher at 7 days for the coronary bypass group than for the major surgery cohort. The incidence of neurologic dysfunction remained higher (p = 0.050) at 2 months in the coronary bypass group. Cognitive dysfunction at 2 months was less prevalent after 90 minutes of cardiopulmonary bypass in patients managed with alpha-stat than with pH-stat strategy (27% versus 44%, p = 0.047). CONCLUSIONS: Postoperative central nervous system dysfunction is more prevalent in patients having coronary bypass than in those having major operations. Pulsatility has no effect on central nervous system outcomes, but alpha-stat management is associated with a decreased incidence of cognitive dysfunction in patients undergoing prolonged cardiopulmonary bypass.

Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations.

BACKGROUND: Patients with heart disease are frequently maintained on a regimen of aspirin because of its ability to decrease thrombotic complications and reduce the prevalence of unstable angina and myocardial infarction. Aspirin-induced platelet acetylation also increases bleeding caused by impairment of platelet function during cardiac surgery. METHODS: Between October 1990 and November 1991 this double-blind, randomized, placebo-controlled, parallel group interventional study examined the efficacy of high-dose aprotinin administration (up to 7 million KIU) to decrease blood loss and transfusion requirements in patients receiving aspirin within 48 hours of undergoing coronary bypass or valvular heart operations. Primary outcome measures in this study were total volume of blood loss (intraoperative blood loss plus postoperative chest tube drainage) and volume of transfusion during hospitalization. RESULTS: Patients treated with aprotinin (n = 29) had significantly lower total blood loss (1409 +/- 232 ml versus 2765 +/- 248 ml; p = 0.0002), intraoperative blood loss (503 +/- 53 ml versus 1055 +/- 199 ml; p = 0.0001), postoperative blood loss (906 +/- 204 ml versus 1710 +/- 202 ml; p = 0.0074), and prevalence of transfusion (59% versus 88% of patients; p = 0.016) than the placebo group (n = 25). The prevalence of complications including myocardial infarction was similar in the two groups. CONCLUSIONS: High-dose aprotinin significantly reduces blood loss and red blood cell transfusions in patients receiving aspirin who undergo cardiac operations.

The effect of temperature management during cardiopulmonary bypass on neurologic and neuropsychologic outcomes in patients undergoing coronary revascularization.

Several studies suggest that normothermic ("warm") bypass techniques may improve myocardial outcomes for patients undergoing cardiac operations. Normothermic temperatures during cardiopulmonary bypass may, however, decrease the brain's tolerance to the ischemic insults that accompany all cardiac procedures. To assess the effect of bypass temperature management strategy on central nervous system outcomes in patients undergoing coronary revascularization, 138 patients were randomly assigned to two treatment groups: (1) hypothermia (n = 70), patients cooled to a temperature less than 28 degrees C during cardiopulmonary bypass, or (2) normothermia (n = 68), patients actively warmed to a temperature of at least 35 degrees C. Patients underwent detailed neurologic examination before the operation, on postoperative days 1 to 3 and 7 to 10, and at approximately 1 month after operation. In addition, a battery of five neuropsychologic tests was administered before operation, on postoperative days 7 to 10, and at the 4- to 6-week follow-up visit. Patients in the normothermic treatment group were older (65 +/- 10 vs 61 +/- 11 years in the hypothermic group), had statistically less likelihood of preexisting cerebrovascular disease, and had higher bypass blood glucose values (276 +/- 100 mg/% vs. 152 +/- 66 mg/% in the hypothermic group). All other patient characteristics and intraoperative variables were similar in the two treatment groups. Seven of 68 patients in the normothermic group were found to have a central neurologic deficit, compared with none of the patients cooled to 28 degrees C (p = 0.006). Performance on at least one neuropsychologic test deteriorated in the immediate postoperative period in more than one half of all patients in both treatment groups but returned to preoperative levels approximately 1 month after the operation in most (85%). This pattern was not related to bypass temperature management strategy. We conclude that active warming during cardiopulmonary bypass to maintain systemic temperatures > or = 35 degrees C increases the risk of perioperative neurologic deficit in patients undergoing elective coronary revascularization.

A risk-benefit assessment of aprotinin in cardiac surgical procedures.

Aprotinin, a naturally occurring serine protease inhibitor, has found widespread application during cardiac surgical procedures as a consequence of its ability to decrease blood loss and transfusion requirements. While its efficacy in a variety of clinical situations associated with increased risk of blood loss has been well established, at the same time, various complications including anaphylaxis, renal insufficiency, graft closure and arterial thromboses have been reported in association with aprotinin administration. In order to more fully evaluate the risks and benefits associated with aprotinin usage, this review first of all examines the hazards associated with transfusion of blood and blood products. Consideration is then given to various alternatives to allogeneic transfusion, including autologous predonation, acute normovolemic hemodilution, perioperative cell salvage and intraoperative plasma sequestration. A critique of other available pharmacological therapies, specifically desmopressin, aminocaproic acid and tranexamic acid, reviewing their modes of action, efficacy and associated complications, is then made. The role of aprotinin in cardiac surgery is then discussed and its pharmacology, including consideration of its antifibrinolytic, platelet preserving and anti-inflammatory effects is reviewed. Finally, an analysis of potential complications associated with aprotinin administration is undertaken. Issues involving its influence on specific measures of anticoagulation, namely partial thromboplastin time and activated clotting time, and issues relating to graft patency, hypothermic circulatory arrest, renal function, and allergic reactions are analysed and interpreted. In summary, this review concludes that most of the risks associated with aprotinin administration primarily involve inadequate anticoagulation and those of developing an allergic reaction, particularly upon aproptinin re-exposure. The benefits of aproptinin to decrease blood loss and transfusion requirements are confirmed, and there is evidence pointing to the intriguing possibility of a potential salutary effect on perioperative central nervous system complications.

The role of CPB management in neurobehavioral outcomes after cardiac surgery.

Recent developments in techniques for managing cardiopulmonary bypass are outlined with a view toward interventions aimed at decreasing the incidence of perioperative central nervous system dysfunction and overt stroke. Recent reports assessing central nervous system dysfunction after hypothermic and normothermic cardiopulmonary bypass are reviewed and critiqued along with data assessing techniques for cerebral protection during hypothermic circulatory arrest. Controversy surrounding optimal pH management is explored along with a proposal that pH-stat may be most satisfactory to ensure better brain cooling where circulatory arrest is anticipated, whereas alpha-stat may avoid cerebral hyperemia and thus decrease the cerebral embolic load during moderate hypothermic cardiopulmonary bypass. Newer developments in cerebral monitoring techniques are also reviewed.

Attenuation of neurologic injury during cardiac surgery.

Neurologic injury after cardiac surgery can be divided into type I, including clinically apparent stroke, seizures stupor, or coma, and much more occurring type II injury, including intellectual deterioration, memory deficit, or seizures. Cerebral embolization is demonstrably etiologic in many such cases, and several new aortic cannulas are being introduced that are aimed at capturing or diverting potential cerebral emboli. No outcome data are yet available. Several potentially cerebroprotective pharmacologic therapies including thiopental, propofol, and nimodipine, have been assessed clinically but, generally, the results have been poor. Meta-analysis of the large North American aprotinin database of prospective, randomized, placebo-controlled clinical trials is suggestive of a cerebroprotective potential associated with high-dose aprotinin administration.

Anesthesia, the brain, and cardiopulmonary bypass.

The etiology and incidence of neurologic injury occurring after cardiac operations employing cardiopulmonary bypass is reviewed. Results of studies demonstrating the role of microemboli generated by pump oxygenators, and evidence for the efficacy of arterial line filtration to decrease delivery of emboli into the cerebral circulation and to decrease postoperative neuropsychological dysfunction, are similarly reviewed. The impact of different strategies for management of pH during moderate hypothermic cardiopulmonary bypass on cerebral blood flow and coupling of cerebral flow and metabolism, as well as their impact on the incidence of postoperative cognitive dysfunction, are also discussed, along with the results of studies examining the efficacy of various agents including thiopental, nimodipine, and nafamostat to decrease cognitive dysfunction subsequent to bypass.

Beating heart surgery: why expect less central nervous system morbidity?

BACKGROUND: The incidence and etiology of brain dysfunction after conventional coronary artery bypass surgery using cardiopulmonary bypass (CPB) are reviewed. METHODS: Stroke rates and incidences of cognitive dysfunction from various studies are considered. Mechanisms of injury including cerebral embolization as detected by transcranial Doppler and retinal angiography, and imaging-based evidence for postoperative cerebral edema, are discussed. Preliminary results from a prospective clinical trial assessing cognitive dysfunction after beating heart versus conventional coronary artery bypass with CPB are discussed. RESULTS: Initial evidence for lower overall postoperative morbidity, and for a lower incidence of cognitive dysfunction specifically, after nonpump coronary revascularization is presented. CONCLUSIONS: Beating heart surgery results in less potential for generation of cerebral emboli and appears to produce a lower incidence of cognitive dysfunction in both short- and intermediate-term postoperative follow-up periods as compared with conventional coronary artery bypass surgery using CPB.

Aprotinin decreases exposure to allogeneic blood during primary unilateral total hip replacement.

BACKGROUND: Aprotinin, a hemostatic agent, regulates fibrinolysis, modulates the intrinsic coagulation pathway, stabilizes platelet function, and exhibits anti-inflammatory properties through inhibition of serine proteases, such as trypsin, plasmin, and kallikrein. Aprotinin has been used successfully for many years in cardiac operations, and there have been preliminary investigations of its use in hip replacement operations. The objectives of this multicenter, randomized, placebo-controlled, double-blind trial were to evaluate the efficacy and safety of aprotinin as a blood-sparing agent in patients undergoing an elective primary unilateral total hip replacement and to examine its effect on the prevalence of deep-vein thrombosis in this population. METHODS: Seventy-three patients received a placebo; seventy-six patients, a low dose of aprotinin (a load of 500,000 kallikrein inhibitor units [KIU]); seventy-five, a medium dose of aprotinin (a load of 1,000,000 KIU, with infusion of 250,000 KIU per hour); and seventy-seven patients, a high dose of aprotinin (a load of 2,000,000 KIU, with infusion of 500,000 KIU per hour). The end points for the determination of efficacy were transfusion requirements and blood loss. Patients received standard prophylaxis against deep-vein thrombosis and underwent compression ultrasonography with color Doppler imaging of the proximal and distal venous systems of both legs to evaluate for the presence of deep-vein thrombosis. RESULTS: Aprotinin reduced the percentages of patients who required any form of blood transfusion (47 percent of the patients managed with a placebo needed a transfusion compared with 28 percent of those managed with low-dose aprotinin [p = 0.02],27 percent of those managed with high-dose aprotinin [p = 0.008], and 40 percent of those managed with medium-dose aprotinin [p = 0.5]). Only 6 percent (twelve) of the 212 patients treated with aprotinin required allogeneic blood compared with 15 percent (ten) of the sixty-eight patients treated with the placebo (p = 0.03). Aprotinin decreased the estimated intraoperative blood loss (p = 0.02 for the low-dose group, p = 0.04 for the medium-dose group, and p = 0.1 for the high-dose group), the measured postoperative drainage volume (p = 0.4 for the low-dose group, p = 0.006 for the medium-dose group, and p = 0.000 for the high-dose group), and the mean reduction in the hemoglobin level on the second postoperative day (thirty-four grams per liter for the placebo group, twenty-eight grams per liter for the low-dose group [p = 0.000], twenty-six grams per liter for the medium-dose group [p = 0.000], and twenty-three grams per liter for the high-dose group [p = 0.0001). The rate of deep-vein thrombosis was similar for all groups. CONCLUSIONS: We concluded that aprotinin is safe and effective for use as a hemostatic agent in primary unilateral total hip replacements. In patients who are at high risk of receiving allogeneic blood, use of aprotinin may be of particular clinical and economic benefit.

Beating heart surgery or conventional CABG: are neurologic outcomes different?

Although there has been much debate about the causes of neurologic complications associated with coronary artery bypass grafting (CABG), there is good evidence linking such complications with some of the pathophysiologic changes associated with use of conventional cardiopulmonary bypass (CPB). Several studies indicate that it is possible to significantly lower risk of stroke and other central nervous system (CNS) morbidity in patients undergoing CPB for CABG by application of selected techniques and equipment modifications. The resurgence of interest in coronary revascularization by using beating heart surgery (BHS) offers a unique opportunity to evaluate neurologic outcome independent of CPB. Currently, BHS would appear to significantly reduce morbidity in the elderly and to decrease the costs and resource use in coronary revascularization patients. It is hoped that by understanding the mechanisms of CNS injury associated with CABG, techniques can be developed to decrease the risk of neurologic injury associated with coronary revascularization, whether or not CPB is used. Definitive conclusions regarding outcomes after best practice CPB or BHS await large-scale, risk-stratisfied multicenter trials.

In vivo and in vitro evaluation of the heparin management test versus the activated coagulation time for monitoring anticoagulation level in aprotinin-treated patients during cardiac surgery.

INTRODUCTION: Monitoring whole blood anticoagulation therapy with the activated coagulation time (kaolin ACT) and the heparin management test (HMT) were correlated in vivo with the plasma anti-activated factor X (anti-Xa) heparin concentration in patients who received variable doses of aprotinin and in vitro in the presence of increasing concentrations of aprotinin. METHODS: In 38 elective cardiac surgical patients who received an average heparin dose of 400 IU/kg and an average total aprotinin dose of 3.6 10(6) kallikrein-inhibiting units (KIU), ACT and HMT were measured in duplicate 6 times intraoperatively at predetermined intervals. Blood samples at each interval were also assayed for the anti-Xa plasma heparin concentration with the IL Test heparin chromogenic assay. The influence of increasing concentrations of aprotinin on HMT and ACT was also measured in vitro by using blood samples containing 6 IU/mL heparin from 6 additional patients after adding specific aliquots of aprotinin to achieve concentrations of 50, 100, 200, and 300 KIU/mL aprotinin. Linear regression analysis was used to compare HMT and ACT against anti-Xa. A P level <.05 was required for statistical significance. RESULTS: Duplicate measurements were taken at all intervals, and HMT and ACT values were significantly correlated, both with each other (r = 0.86; P < .01) and with anti-Xa activity (HMT, r = 0.81 [P < .01]; ACT, r = 0.71 [P < .01]). Aprotinin prolonged both the kaolin ACT and the HMT time in a dose-dependent manner (P < .05), and its influence was significantly less in vivo on the HMT time than on the kaolin ACT (P < .001). CONCLUSIONS: The abilities of the HMT and the kaolin ACT to measure anticoagulation effects were not significantly different. Aprotinin prolonged both the kaolin ACT and the HMT time in a dose-dependent manner, but the HMT was significantly less affected by aprotinin in vivo. The HMT is a reliable alternative to measuring the ACT in cardiac operations and may offer greater accuracy in aprotinin-treated patients.