Paul M. Walker

Risk factors for stroke in patients undergoing coronary artery bypass grafting

OBJECTIVEnTo determine predictors of stroke in patients undergoing first-time coronary bypass grafting, we prospectively collected data on 1631 consecutive patients.nnnMETHODSnPatients with a history of stroke and/or central nervous system symptoms (n = 134) and/or carotid bruits (n = 95) underwent carotid Doppler evaluation. Stenosis greater than 70% was considered significant. Patients with symptomatic disease or asymptomatic bilateral disease were referred for combined coronary bypass and carotid endarterectomy (n = 21). Patients with neurologic symptoms after the operation were assessed by a neurologist and underwent a computed tomographic scan. Events were classified as reversible transient ischemic attack, reversible ischemic neurologic deficit, or irreversible stroke.nnnRESULTSnThere were 19 strokes (1.2%) and 20 deaths (1.2%) in this series. In patients with carotid screening, risk of stroke increased with severity of carotid disease and ranged from 0% in patients without stenosis, to 3.2% (1/31) in those with greater than 70% stenosis, and to 27.3% (6/22) in those with carotid occlusion. By stepwise logistic regression analysis six variables were identified as risk factors for stroke. The most important predictor was carotid occlusion with or without contralateral stenosis (odds ratio = 28, 95% confidence interval (8,105). In this group, four of five strokes occurred on the occluded side. Other risk factors were presence of ascending aortic disease at the time of surgery (odds ratio = 12.8, confidence interval 3,48), perioperative myocardial infarction (odds ratio = 8.2, confidence interval 2,33), poor left ventricular function (odds ratio = 4.6, confidence interval 1,19), peripheral vascular disease (odds ratio = 3.2, confidence interval 1,9), and age > 60 years (odds ratio = 2.9, confidence interval 0.8,11).nnnCONCLUSIONnWe conclude that risk factors for perioperative stroke in patients undergoing coronary artery bypass grafting are multiple. Carotid scanning in patients with neurologic symptoms or carotid bruits can identify patients at increased risk. Patients with carotid occlusion are at high risk for stroke on the occluded side.

Mesenteric arterial bypass grafts: Early and late results and suggested surgical approach for chronic and acute mesenteric ischemia

BACKGROUNDnThe purposes of this study were to determine the early and late results of placement of arterial bypass grafts in the treatment of chronic and acute intestinal ischemia and to ascertain whether multiple grafts provide better late results than a single graft.nnnMETHODSnRecords of 34 patients who underwent mesenteric vascular graft placement were retrospectively reviewed.nnnRESULTSnAll 21 patients with chronic ischemia had a history of intestinal angina and weight loss. Food fear was reported by 33% of patients; also, diarrhea in 57%, constipation in 29%, acalculous cholecystitis in 19%, ischemic gastritis or peptic ulcer in 19%, and elevation of liver enzymes in 22% were reported. Angiogram showed more than 50% stenosis or occlusion of the superior mesenteric artery (SMA) in 100% of patients, celiac artery in 90%, and inferior mesenteric artery in 90%. Although not described previously, a reduction in collateral flow from the internal iliac arteries was caused by severe pelvic disease in 56% of patients. There were no in-hospital deaths. The rate of survival at 1 year was 100%; at 2 years it was 93% +/- 6%, at 3 years 86% +/- 9%, at 5 years 79% +/- 11%, and at 10 years 50% +/- 15%. During follow-up, graft thrombosis occurred in three patients. Of the patients who underwent only a single SMA or celiac bypass, two of five died of bowel infarction; only one of 16 patients who underwent both celiac and SMA bypass had to undergo a repeat surgical procedure because of graft occlusion. Three of 16 retrograde bypasses thrombosed, compared with zero of five prograde bypasses. In nine patients who underwent placement of mesenteric bypass grafts because of acute ischemia caused by acute mesenteric thrombosis, the early mortality rate was 22%; the two deaths were the result of bowel ischemia. The cumulative survival rate was 78% +/- 14% at 1 month, 65% +/- 17% at 1 year, and 52% +/- 16% at 5 years. One of the two late deaths was due to graft thrombosis and bowel infarction. Three of four patients who underwent concomitant mesenteric bypass at the time of aneurysm repair or aortobifemoral bypass survived the surgical procedure.nnnCONCLUSIONSnWhen chronic and acute mesenteric ischemia are diagnosed and treated with a bypass graft, the early and late results are good. Complete revascularization of the SMA and celiac artery or pelvis or both and prograde bypass may reduce the risk of late bowel ischemia.

A rapid assay of endotoxin in whole blood using autologous neutrophil dependent chemiluminescence.

A rapid (30 min) whole blood assay for the detection of lipopolysaccharide (LPS) is described. This chemiluminescent (CL) assay utilizes the CR1 and CR3 receptor-induced oxidant production of polymorphonuclear leucocytes as a detection platform. The differential priming of neutrophils in whole blood by LPS-antibody complexes allows the specificity of the assay to be achieved. Oxidant released in response to complement opsonized zymosan results in luminol oxidation and subsequent light emission. This is dependent on heat labile putative complement proteins in the plasma. The assay consists of a control which measures baseline whole blood neutrophil oxidant production. The test assay contains murine monoclonal IgM antibody against the Lipid A epitope of LPS and measures the enhanced chemiluminescent response of the neutrophils in the presence of LPS-antibody complexes. Maximal sensitivity of the CL assay is dependent upon optimal antigen-antibody equivalence and duration of pre-incubation with the whole blood sample. The quantification of LPS is possible by inclusion of a positive control containing a maximally reactive LPS dose (800 pg/ml Escherichia coli 055:B5 LPS at an antibody concentration of 0.8 microg/assay). The CL assay is insensitive to variations in patient neutrophil concentration over a minimum range of 0.5 to 20 x 10(9) cells/l. The CL assay is widely reactive with the LPS of many strains of gram negative bacteria but not with the cell wall products of gram positive bacteria or Candida and Aspergillus. In comparison to acid extraction chromogenic LAL, the CL assay demonstrates superior recovery precision and accuracy in in vitro studies. This was reproducible over a wide range of LPS concentrations (0.017-1.6 EU/ml or 20-2000 pg/ml). This assay may be a clinically useful tool for the diagnosis of infection or endotoxin in patients.

An isolated skeletal muscle model suitable for acute ischemia studies

A modified isolated canine gracilis model of acute complete muscle ischemia was developed and then tested metabolically and histologically in 25 animals to assess its validity. In each dog, both gracili were isolated on their major vascular pedicles. One muscle underwent ischemia and reperfusion by placing and removing microvascular clips on the artery and vein. The other gracilis muscle was used as a control. Total muscle blood flow measurements, blood samples, and muscle biopsies were taken every other hour for up to 11 hr after preparation. The fiber-type profile of the gracilis was determined bilaterally using a myosin ATPase stain (n = 10). The results verified these hypotheses: after surgical preparation, the right and left muscles in the same dog are equivalent metabolically, after a 2-hr stabilization period, gracilis blood flow, oxygen and glucose uptake, lactate release, and tissue glycogen, lactate, phosphocreatine, and ATP levels remain within normal limits and unchanged for the next 9 hr, the surgical isolation of the gracilis muscle on a single vascular pedicle does not result in significant metabolic changes, in this model, a 2-hr ischemia is reversible, but a 7-hr ischemia results in irreversible ischemic injury. As well, fiber-type profile, muscle blood flow, and metabolic parameters can very significantly among animals supporting the necessity of a contralateral control. Therefore, this modified gracilis muscle model with its contralateral muscle as a control is suitable for acute skeletal muscle ischemia experiments of at least 9-hr duration.

Current indications for axillounifemoral and axillobifemoral bypass grafts

Revascularization of the lower extremities may require an axillofemoral bypass when an aortobifemoral bypass is contraindicated. Thirty-one patients underwent axillounifemoral and 59 had an axillobifemoral bypass, with a mortality rate of 9%. The indication for operation was limb salvage in 67%, intra-abdominal sepsis in 21%, and disabling claudication in 12%. Cumulative survival, patency, and limb salvage rates were determined by life-table analysis. The cumulative patency and limb salvage rates (with standard errors) at 3 years were 68% +/- 8% and 78% +/- 9%, respectively. When stratified for type of operation, axillobifemoral bypass had a superior patency rate compared with axillounifemoral bypass (log rank = 3.882, p less than 0.05). There was no significant difference when patients were stratified for diabetes (log rank = 2.213, p = no significance [NS]), operative indication (disabling claudication vs. limb salvage) (log rank = 0.0005, p = NS), or outflow (no profundaplasty vs. profundaplasty) (log rank = 2.011, p = NS). We conclude that axillofemoral bypass is a reasonable alternative for revascularization in high-risk patients or in those patients in whom a transabdominal approach is contraindicated. We recommend aggressive use of the profunda femoris artery when the superficial femoral artery is occluded to achieve optimal results.

Cardiac dysfunction during abdominal aortic operation: The limitations of pulmonary wedge pressures

The mortality rate for elective abdominal aortic operations remains between 3% and 8% despite careful hemodynamic monitoring, and half of these deaths are cardiac in origin. An extensive evaluation of ventricular function was performed during abdominal aortic operation to detect subtle abnormalities in systolic or diastolic ventricular function that could precipitate progressive ischemic cardiac injury. Twenty-three patients undergoing elective abdominal aortic operations (14 patients with abdominal aortic aneurysm [AAA] and nine patients with aortoiliac occlusive disease [AIOD] ) had hemodynamic and nuclear ventriculographic measurements performed preoperatively, during aortic clamping, and immediately after aortic declamping. No differences were found in the hemodynamic response to operation between patients with AAA or AIOD. Volume loading was performed at each time period to assess ventricular function. Myocardial performance (the relation between cardiac index and end-diastolic volume index) and systolic function (the relation between systolic blood pressure and end-systolic volume index) were depressed during aortic clamping (p less than 0.05), suggesting decreased contractility, but returned to baseline values after declamping. Diastolic compliance (the relation between pulmonary capillary wedge pressure and end-diastolic volume index) decreased after declamping (p less than 0.05), suggesting early myocardial ischemia. The decrease in diastolic compliance rendered pulmonary capillary wedge pressure a poor index of left ventricular preload after declamping. Higher pressures were required to maintain adequate diastolic volumes. Despite careful hemodynamic monitoring, potentially ischemic ventricular dysfunction was found during abdominal aortic operation.

LET THE CELLS SPEAK : NEUTROPHILS AS BIOLOGIC MARKERS OF THE INFLAMMATORY RESPONSE

These questions are inherently complex, since the septic process involves the concerted interplay of multiple dynamic biochemical and physiological cascades that manifest in an unpredictable and highly variable manner. Simpli~ed models of the host immune response in critical illness have been proposed [1–4], but not tested or validated in a manner that permits them to be of use in clinical decision-making. The value of any proposed model is to provide mechanistic insights and to identify targets for intervention that can be manipulated in a predictable manner to achieve clinical bene~t. Trauma has been a popular model of the in_ammatory response since the onset of injury is well-de~ned, and the inciting insult readily identi~able. Patrick et al. [1] have described a two hit model of an initial dysfunctional in_ammatory response following major trauma, which contributes to the development of multiple organ dysfunction (Figure 1). Sequential neutrophil priming plays a pivotal role in the genesis of remote organ injury. Faist et al. [2] have proposed a model relating monocyte/macrophage and T-cell interactions to the development of an anergic state following trauma; disruption of the normal balance between TH1 and TH2 lymphocyte subsets which serves as both a marker, and a potential mechanism for developing anergy (Figure 2). Both models describe early and late phases of the immune response: an early phase of systemic in_ammation that can be exacerbated by a secondary insult, with resultant progression to a later and potentially lethal immunosuppressed or anergic state. An important assumption of these models is that the exaggerated or prolonged early pro-in_ammatory phase triggers a compensatory anti-in_ammatory response which may shift the immune balance to a suppressed phenotype [5]. This anergic state not only predisposes the host to nosocomial infection, but previously immunocompetent effector cells such as granulocytes become injurious due to super activation [6–8], uncoordinated function [9–11] and/or delayed apoptosis [12]. Models of trauma which delineate the course of immune competence, provide useful parallels in other clinical scenarios such as ischemia-reperfusion, or systemic infection. A logical prediction from these models is that anti-in_ammatory therapies which blunt the hysteresis of the pro-in_ammatory cytokinemic phase would be bene~cial at an early stage, but potentially lethal during the anergic phase. Similarly, interventions designed to augment the immune response in the anergic phase could exacerbate the cytokinemic proin_ammatory state and contribute to a deleterious outcome for the patient. De~ning the immune status prior to therapeutic intervention may therefore be of critical importance to selection of therapy. There is a recognized need for markers which can rapidly identify: 1) the inciting insults, 2) the immunological staging of the patient and 3) the immune response to therapy. Circulating levels of in_ammatory mediators of acute in_ammation such as interleukin 6 [13], procalcitonin [14], or C reactive protein [15] may provide clinically useful information about the state of activation of the host septic response. Previous studies have shown that the measurement of sustained plasma pro-in_ammatory cytokines such as TNF-a and IL-6 rather than their peak concentrations identify those patients who develop multiple organ dysfunction and death [16]. An alternative apporach to the use of levels of in_ammatory mediators as diagnostic markers is to analyze the responses of the cellular effectors of an in_ammatory response—to let the cells speak for themselves. As the foot soldiers of acute in_ammation, neutrophils are ideally suited to ful~ll this role.

A Clinically Relevant Small-Animal Model of Skeletal Muscle Ischemia-Reperfusion Injury

Animal models of skeletal muscle ischemia-reperfusion injury have led to a better understanding of the pathophysiology of this condition and are necessary for the evaluation of potential therapeutics. This study presents a new, well-controlled model of ischemia-reperfusion that more accurately simulates acute arterial occlusions in humans. In rabbits, a whole hindlimb is rendered reversibly ischemic by occlusion of primary and collateral arterial inflow and then reperfused for an extended period of 48 h. Ischemic injuries are standardized by defining and controlling ischemic time, limb temperature, and the extent of collateral circulation. We have characterized this model by measuring anterior tibial and soleus muscle necrosis and edema formation in groups of animals subjected to 4 h of ischemia at either 32 or 36 degrees C, with one of two extents of collateralization and with or without muscle compartment release (fasciotomy). Our results indicate the following: (1) muscle necrosis is significantly worsened by restricting the extent of collateral blood supply or by elevating ischemic temperature; (2) anterior tibial muscle is inherently more sensitive than soleus muscle to ischemic injury; (3) fasciotomy may reduce muscle necrosis by more than 50%; and (4) the amount of edema present in muscles is an unreliable indicator of actual muscle necrosis. We conclude that this new model is a practical, well-controlled, and clinically relevant preparation useful for the investigation of ischemic muscle injury.