Edward D. Verrier

Postoperative myocardial ischemia. Therapeutic trials using intensive analgesia following surgery

Recent data suggest that postbypass and postoperative myocardial ischemia are related to adverse cardiac outcome following myocardial revascularization. Therapeutic trials to suppress postoperative ischemia are warranted. Because anesthetics can suppress a variety of physiologic responses to stress as well as myocardial ischemia intraoperatively, we examined whether use of intensive analgesia in the stressful postoperative period could decrease postoperative ischemia. In 106 patients undergoing elective myocardial revascularization, we standardized the anesthetic prior to bypass (sufentanil 5-10 micrograms/kg [induction] and 4.2-6.0 micrograms.kg-1.h-1 [infusion] supplemented with up to 0.5 mg/kg of diazepam). During bypass, patients were randomly assigned to receive either morphine sulfate (group M, n = 54, up to 2 mg/kg) or sufentanil (group S, n = 52, 1 microgram/kg and 1 microgram.kg-1.h-1). In the intensive care unit (ICU), group M received low-dose analgesia (morphine sulfate 1-10 mg intravenously every 30 min, average dose = 2.2 +/- 2.1 mg/h), while group S continued to receive intensive analgesia (infusion of sufentanil at 1 microgram.kg-1.h-1). Both groups received supplemental midazolam in the ICU (group M = 1.1 +/- 1.1 mg/h; group S = 0.6 +/- 0.6 mg/h; P = 0.01). All analgesic and sedative-hypnotic medications were discontinued at 18 hours following myocardial revascularization. Using continuous two-channel electrocardiographic (ECG) monitoring (CC5 and CM5), we documented and characterized ECG changes consistent with ischemia during the preoperative, intraoperative (pre- and postbypass), and postoperative (on- and off-treatment) periods. The total ECG monitoring time was 8,486 h, averaging 81 h per patient. During the prebypass (anesthetic control) period, groups M and S had a similar incidence, but group S episodes were more severe: maximum ST-segment change (median), S versus M: -1.8 mm versus -1.4 mm (P = 0.04). During the postbypass period, both groups had a similar incidence of ischemia, but episodes in group S were less severe: maximum ST-segment change, S versus M: -1.8 mm versus -2.7 mm (P = 0.0005). During the ICU-on-therapy period, the incidence of ischemic episodes was less in group S patients, and the severity was less: area-under-the-ST-time curve, S versus M: -21 mm.min versus -161 mm.min (P = 0.05). After discontinuation of the drug regimen in the ICU, the incidence and severity of ischemic episodes was similar. The incidence of hypotension, hypertension, and tachycardia was similar in both groups in both the intraoperative and ICU periods.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in transfusion therapy and reexploration rate after institution of a blood management program in cardiac surgical patients

A retrospective study was performed to determine the impact of a coagulation and transfusion management program on blood utilization in 1,079 sequential patients for myocardial revascularization and open ventricle or combined procedures. Four hundred and eighty-eight patients (group 1) before, and 591 patients (group 2) after institution of thromboelastography (TEG)-guided coagulation were studied and compared for transfusion requirements, donor exposure, and the incidence of reoperation for hemorrhage. Group 2 patients had a significantly lower incidence of overall transfusion (78.5% v 86.3%) during hospitalization and in total transfusion in the operating room (57.9% v 66.4%). The incidence of each transfusion subtype was also significantly lower in group 2 patients. Actual total median donor exposure was 8 in group 1 patients and 6 exposures in group 2 patients. Mediastinal reexploration for hemorrhage was 5.7% before institution of TEG-based coagulation monitoring and 1.5% in TEG-monitored patients. Use of TEG monitoring before reexploration has decreased the cost and potential risk for patients undergoing CABG surgery.

Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response.

Many of the components currently used to perform cardiovascular operations lead to systemic insults that result from cardiopulmonary bypass circuit-induced contact activation, circulatory shock, and resuscitation, and a syndrome similar to endotoxemia. Experimental observations have demonstrated that these events have profound effects on activating endothelial cells to recruit neutrophils from the circulation. Once adherent to the endothelium, neutrophils release cytotoxic proteases and oxygen-derived free radicals, which are responsible for much of the end-organ damage seen after cardiovascular operations. Recently the cellular and molecular mechanisms of endothelial cell activation have become increasingly understood. It is conceivable that once the molecular mechanisms of endothelial cell activation are better defined, therapies will be developed allowing the selective or collective inhibition of vascular endothelial activation during the perioperative period.

Endothelial Cell Injury in Cardiovascular Surgery

In the last decade the endothelium has been shown to play a major role in regulating membrane permeability, lipid transport, vasomotor tone, coagulation, inflammation, and vascular wall structure. These critical endothelial cell functions are extremely sensitive to injury in the form of hypoxia, exposure to cytokines, endotoxin, cholesterol, nicotine, surgical manipulation, or hemodynamic shear stress. In response to injury endothelial cells become activated, tipping the balance of endothelial-derived factors to disrupt barrier function, and enhance vasoconstriction, coagulation, leukocyte adhesion, and smooth muscle cell proliferation. Although these responses likely exist as protective mechanisms, if the stimuli are severe the responses may become excessive, resulting in damaged tissue, impaired organ function, and an abnormal fibroproliferative response. Recent discoveries in the field of vascular biology have led to an expanded understanding of many of the complications of cardiovascular operations. Because of the wide impact endothelial cell dysfunction has on patients with cardiovascular disease, issues pertaining to endothelial biology are in the forefront of research that will affect the current and future practice of cardiothoracic surgery.

Inhibition of Toll-like Receptor 4 With Eritoran Attenuates Myocardial Ischemia-Reperfusion Injury

Background— We previously reported that the functional mutation of Toll-like receptor 4 (TLR4) in C3H/HeJ mice subjected to myocardial ischemia-reperfusion (MI/R) injury resulted in an attenuation of myocardial infarction size. To investigate the ligand-activating TLR4 during MI/R injury, we evaluated the effect of eritoran, a specific TLR4 antagonist, on MI/R injury, with the goal of defining better therapeutic options for MI/R injury. Methods and Results— C57BL/6 mice received eritoran (5 mg/kg) intravenously 10 minutes before 30 minutes of in situ of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. Infarct size was measured using triphenyltetrazoliumchloride staining. A c-Jun NH2-terminal kinase (JNK) activation was determined by Western blotting, nuclear factor (NF)-&kgr;B activity was detected by gel-shift assay, and cytokine expression was measured by ribonuclease protection assay. Mice treated with eritoran developed significantly smaller infarcts when compared with mice treated with vehicle alone (21.0±6.4% versus 30.9±13.9%; P=0.041). Eritoran pretreatment resulted in a reduction in JNK phosphorylation (eritoran versus vehicle: 3.98±0.81 versus 7.01±2.21-fold increase; P=0.020), less nuclear NF-&kgr;B translocation (2.70±0.35 versus 7.75±0.60-fold increase; P=0.00007), and a decrease in cytokine expression (P<0.05). Conclusions— We conclude that inhibition of TLR4 with eritoran in an in situ murine model significantly reduces MI/R injury and markers of an inflammatory response.

Studies in fetal wound healing: I. A factor in fetal serum that stimulates deposition of hyaluronic acid

Fetal wound healing without scar formations, fibrosis, or contracture might be accompanied by major differences in the wound extracellular matrix. The matrix of fetal wounds is rich in hyaluronic acid, a glycosaminoglycan found in high concentrations whenever there is tissue proliferation, regeneration, and repair. Although hyaluronic acid is a critical molecule for both embryonic development and wound healing, no factor has yet been identified that modulates hyaluronic acid in a consistent manner. We describe here a substance present in fetal sheep serum that stimulates hyaluronic acid synthesis by cultured fibroblasts. This glycoprotein factor appears to be ubiquitous, present in fetal sheep and bovine serum, reaching a peak in each at 40% of the way through gestation. This factor is also present in amniotic fluid. It might control hyaluronic acid deposition. In turn, hyaluronic acid, by creating an extracellular environment permissive for cell motility and proliferation, might be critical for fetal development. We suggest that the same sequence of events underlie the unique properties observed in fetal wound healing.

Perioperative myocardial ischemia: importance of the preoperative ischemic pattern.

Previous studies investigating the incidence of myocardial ischemia in patients undergoing coronary-artery bypass grafting (CABG) surgery have not considered the potential significance of the preoperative myocardial ischemia and infarction. Accordingly, the authors compared the frequency and severity of pre-, intra-, and postoperative ischemic episodes (ST-segment depression ≥ mV or elevation ≥ 0.2 mV) in 50 men with severe coronary artery disease scheduled for elective CABG. All subjects were monitored by continuous electrocardiography (ECG) (Holter monitor) for 2 preoperative days, intraoperatively, and 2 postoperative days (total monitoring time = 4,363 h). Routine anti-anginal medications were continued until the morning of surgery, and the anesthetic management of the patient was not controlled. During the preoperative period, 42% of the patients had ECG ischemic episodes, 87% of which were clinically silent. Only 18% developed intraoperative ischemia. Postoperatively, the incidence increased to 40%. The number of ischemic episodes/hour (epis/h) of monitoring among the three monitoring periods was similar (0.09 ± 0.12 epis/h preoperatively, 0.11 ± 0.20 epis/h intraoperatively, and 0.05 ± 0.08 epis/h postoperatively; P = NS). The median duration of ischemic episodes was similar pre- and intraoperatively (16 vs. 18.5 min, P = NS), but greater postoperatively (41 min, P < 0.05). Seventy-six per cent of the perioperative ECG ischemia occurred without acute change (±20% of control) in blood pressure of heart rate. Intraoperative myocardial ischemia occurred in 33% of those patients with preopearative ischemia, but in only 7% of patients without preoperative ischemia (P < 0.05). However, neither pre- nor intraoperative ischemia predicted the development of postoperative ischemia, Major outcome (myocardial infarction and/or death) occured in seven patients. Although all seven major outcomes were preceded by ischemic episodes at some time during the study, perioperatiye ischemia was not a specific predictor of major outcome. The authors conclude that: 1) CABG patients have frequent preoperative episodes of myocardial ischemia, most of which are silent; 2) anesthesia and surgery do not worsen the prcoperative ischemic pattern; 3) ECG changes suggestive of myocardial ischemia fequently follow CABG surgery, although their pathogenesis and significance is as yet unknown; 4) the majority of perioperative ischemic ECG changes occur without acute hemodynamic changes prior to the onset of ischemia; and 5) because the prcoperative ischemic pattern appears to be recapitulated intraoperatively, it is relevant to examine the preoperative ischemic pattern to assess the impact of anesthesia and surgery in the development of intraoperative myocardial ischemia.

Inhibition of the Tissue Factor-Thrombin Pathway Limits Infarct Size after Myocardial Ischemia-Reperfusion Injury by Reducing Inflammation

Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.

Endothelial Cell Injury in Cardiovascular Surgery: Ischemia-Reperfusion

Myocardial ischemia and reperfusion is a common occurrence in cardiovascular surgery patients. Acute ischemia results in a spectrum of derangements, which range from transient reversible stunning of the myocardium to severe irreversible abnormalities such as infarction. Many of these abnormalities are accentuated upon reperfusion with oxygenated blood. Recently, the endothelium has been shown to play a key role in the injury suffered after ischemia and reperfusion. When rendered hypoxic and then reoxygenated, endothelial cells become activated to express proinflammatory properties that include the induction of leukocyte-adhesion molecules, procoagulant factors and vasoconstrictive agents that increase vasomotor tone. These changes may contribute to the no-reflow phenomenon by promoting endothelial edema, neutrophil and platelet plugging, microthrombosis, and enhanced vasomotor tone. An increased understanding of the role that hypoxic endothelial cell activation plays in myocardial dysfunction after ischemia/reperfusion may allow therapies to be designed to further attenuate this response.

Dependence of Gorlin formula and continuity equation valve areas on transvalvular volume flow rate in valvular aortic stenosis.

BackgroundValve areas derived by the Gorlin formula have been observed to vary with transvalvular volume flow rate. Continuity equation valve areas calculated from Doppler- echo data have become a widely used alternate index of stenosis severity, but it is unclear whether continuity equation valve areas also vary with volume flow rate. This study was designed to investigate the effects of changing transvalvular volume flow rate on aortic valve areas calculated using both the Gorlin formula and the continuity equation in a model of chronic valvular aortic stenosis. Methods and ResultsUsing a canine model of chronic valvular aortic stenosis in which anatomy and hemodynamics are similar to those of degenerative aortic stenosis, each subject (n=8) underwent three studies at 2-week intervals. In each study, transvalvular volume flow rates were altered with saline or dobutamine infusion (mean, 10.3±5.1 flow rates per study). Simultaneous measurements were made of hemodynamics using micromanometer-tipped catheters, of ascending aortic instantaneous volume flow rate using a transit-time flowmeter, and of left ventricular outflow and aortic jet velocity curves using Doppler echocardiography. Valve areas were calculated from the invasive data by the Gorlin equation and from the Doppler-echo data by the continuity equation. In the 24 studies, mean transit-time transvalvular volume flow rate ranged from 80±33 to 153±49 mL/min (P < .0001). Comparing minimum to maximum mean volume flow rates, the Gorlin valve area changed from 0.54±0.22 cm2 to 0.68±0.21 cm2 (P < .0001), and the continuity equation valve area changed from 0.57±0.18 cm2 to 0.70±0.20 cm2 (P < .0001). A strong linear relation was observed between Gorlin valve area and mean transit-time volume flow rate for each study (median, r = .88), but the slope of this relation varied between studies. The Doppler-echo continuity equation valve area had a weaker linear relation with transit-time volume flow rate for each study (median, r = .51). ConclusionsIn this model of chronic valvular aortic stenosis, both Gorlin and continuity equation valve areas were flow-dependent indices of stenosis severity and demonstrated linear relations with transvalvular volume flow rate. The changes in calculated valve area that occur with changes in transvalvular volume flow should be considered when measures of valve area are used to assess the hemodynamic severity of valvular aortic stenosis.