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.

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.

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.

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.

Stress and inflammatory response after beating heart surgery versus conventional bypass surgery: the role of thoracic epidural anesthesia.

Cardiac surgery elicits a cascade of stress responses mediated by the release of various cytokines and stress hormones [Roth-Isigkeit 1998]. Apart from the stress induced by the surgical process, cardiopulmonary bypass (CPB) has been documented to play a major role in the perioperative stress response seen following cardiac surgery [Butler 1993, McBride 1995, Hall 1997]. The imbalance in pro- and anti-inflammatory responses may affect outcome in cardiac surgery patients [Casey 1993, McBride 1995, Menasch 1995]. Contact of blood with the CPB circuit, along with hypoperfusion of various organs prior to and during CPB, may aggravate this stress response and contribute to adverse outcomes in the perioperative period [Casey 1993, Menasch 1995, Tonnesen 1996]. Splanchnic hypoperfusion that occurs in cardiac surgery patients [Landow 1991] can result in increased permeability of the gut mucosal barrier, resulting in endotoxemia and release of proinflammatory cytokines. Lungs and kidneys play a role in sequestrating the proinflammatory cytokines and, in the presence of hypoperfusion, may be damaged by these cytokines [Gilliland 1999, Liebold 1999, Gormley 2000]. Avoiding CPB may reduce this stress response. Anesthetic techniques such as thoracic epidural analgesia (TEA) that improve splanchnic perfusion [Moore 1995, Kapral 1999, Ai 2001] may have a role in improving patient outcome. It is further known that ischemic myocardium can be a major source of proinflammatory cytokines [Wan 1999a]. The cardiac sympathetic block resulting from TEA has been shown to reduce ischemia reperfusion injury [Blomberg 1989, Blomberg 1990, Liem 1992a, Liem 1992b, Liem 1992c, Kirno 1994, Stenseth 1994]. Beating heart surgery done without the aid of CPB significantly attenuates cytokine and stress response [Brasil 1998, Fransen 1998, Gu 1998, Wan 1999b, Ganapathy 1999a, Ganapathy 2000a]. There is reduced renal dysfunction following beating heart surgery [Ascione 1999], which may be related to reduced proinflammatory cytokine surge. Thoracic epidural analgesia inhibits intraoperative cortisol as well as catecholamine surge but does not add further to the reduction in cytokine response [Ganapathy 1999b].

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.

Rate of change of cerebral blood flow velocity with hyperventilation during anesthesia in humans.

PURPOSE: Although it has been suggested that the rate at which the cerebral circulation responds to changes in PaCO2 is different with differing anesthetics, there have been no attempts to measure this. Transcranial Doppler allows the continuous measurement of cerebral blood flow velocity (CBFV) and any changes over time. Our aim was to compare the rate of change of CBFV when end-tidal CO2 (P(ET)CO2) was rapidly altered during halothane or isoflurane anesthesia. METHODS: Twenty-eight unpremedicated healthy patients were randomly assigned to receive air/O2 and either 1-1.5 MAC halothane or isoflurane as the primary anesthetic. After 15 min of steady state, P(ET)CO2 was rapidly reduced from 45 mm Hg to 30 mm Hg. CBFV and P(ET)CO2 were recorded every 30 sec for the next 10 min. RESULTS: The rate of change of normalized CBFV (delta CBFV vs. delta time) was more rapid in the isoflurane group (P <0.0001) especially in the initial few minutes. In all patients anesthetized with isoflurane, and in all but two patients anesthetized with halothane, the reduction in P(ET)CO2 produced a corresponding decrease in CBFV However, there were no differences in the magnitude of cerebrovascular CO2 reactivity (delta CBFV vs. delta P(ET)CO2) between the two groups. CONCLUSIONS: The rate of change of CBFV was faster in the isoflurane than in the halothane group especially in the initial few minutes. Indeed, for two patients in the halothane group Vmca did not change despite a change in P(ET)CO2. This may be of clinical importance when cerebrovascular tone needs to be changed rapidly.

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.

Etiology and incidence of brain dysfunction after cardiac surgery.

The frequency and severity of central nervous system complications in patients undergoing cardiopulmonary bypass (CPB) may be greater than previously thought, particularly in the older population. The risks of embolic neurologic complications and stroke in the population older than 70 years from a severely atherosclerotic ascending aorta are well documented. Moreover, while the majority of CPB patients do not experience perioperative stroke, a high incidence of more subtle central nervous system dysfunction has been demonstrated to persist for up to 1 year after surgery. This report reviews the incidence and severity of cerebral injury during CPB and the effects of both age and the severely atherosclerotic ascending aorta on adverse neurologic outcomes. It discusses perioperative diagnostic methods, including transesophageal echocardiography, periaortic echocardiography, transcranial Doppler, and retinal fluorescein angiography, and the benefit of pH management. Ischemic brain injury resulting from activation of injury-related enzymes as part of the systemic inflammatory response is briefly reviewed. Age has been shown to be the strongest predictor of neurologic sequelae in patients undergoing CPB. The risk of embolic complications in the brain also increases in proportion to the degree of atherosclerosis in the ascending aorta, which is age-related. Transesophageal echocardiography has been found to be only partly useful in diagnosing these lesions or in guiding surgical manipulations in comparison with epiaortic imaging, which is more discreet. Transcranial Doppler and retinal fluorescein angiography have provided further evidence of microemboli during surgical manipulations. In a 316-patient prospective study, we found no differences in outcome between pH-stat and alpha-stat strategies during moderate hypothermic CPB, except in patients who were on bypass for more than 90 minutes. Approximately 90% of these had a significant reduction in cognitive impairment with the alpha-stat method. Aprotinin, a serine protease inhibitor, has been found in two separate, randomized, placebo-controlled trials to significantly lower incidences of perioperative stroke. Further study to develop therapeutic and preemptive strategies for prevention of brain injury is required, especially in the elderly. Aprotinin and other modalities aimed at suppressing the inflammatory response to CPB may offer hope because they act to suppress injury-provoking enzymes and leukocyte activation that are, in part, responsible for organ system dysfunction following CPB.

Ineffectiveness of burst suppression therapy in mitigating perioperative cerebrovascular dysfunction. Multicenter Study of Perioperative Ischemia (McSPI) Research Group.

BACKGROUND: Cerebral injury is among the most common and disabling complications of open heart surgery. Attempts to provide neuroprotection have yielded conflicting results. We assessed the potential of propofol-induced burst suppression during open heart surgery to provide cerebral protection as determined by postoperative neuropsychologic function. METHODS: Two hundred twenty-five patients undergoing valve surgery were randomized to receive either sufentanil or sufentanil plus propofol titrated to electroencephalographic burst suppression. Blinded investigators performed neurologic and neuropsychologic testing at baseline, postoperative day (POD) 1 (neurologic testing only), PODs 5-7, and PODs 50-70. Neuropsychologic tests were compared with the results of 40 nonsurgical patients matched for age and education. RESULTS: Electroencephalographic burst suppression was successfully achieved in all 109 propofol patients. However, these patients sustained at least as many adverse neurologic outcomes as the 116 controls: POD 1, 40% versus 25%, P = 0.06; PODs 5-7, -18% versus 8%, P = 0.07; PODs 50-70, -6% versus 6%, P = 0.80. No differences in the incidence of neuropsychologic deficits were detected, with 91% of the propofol patients versus 92% of the control patients being impaired at PODs 5-7, decreasing to 52 and 47%, respectively, by PODs 50-70. No significant differences in the severity of neuropsychologic dysfunction, depression, or anxiety were noted. CONCLUSIONS: Electroencephalographic burst suppression surgery with propofol during cardiac valve replacement did not significantly reduce the incidence or severity of neurologic or neuropsychologic dysfunction. The authors' results suggest that neither cerebral metabolic suppression nor reduction in cerebral blood flow reliably provide neuroprotection during open heart surgery. Other therapeutic approaches must be evaluated to address this important medical problem.

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.