David Mazer

Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: A position statement of the Canadian Cardiovascular Society

UNLABELLED Acute coronary syndrome (ACS) guidelines recommend that most patients receive dual antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) at the time of presentation to prevent recurrent ischemic events. Approximately 10% of ACS patients require coronary artery bypass grafting surgery (CABG) during the index admission. Most studies show that patients who receive ASA and clopidogrel within five days of CABG have an increase in operative bleeding. Current consensus guidelines recommend discontinuation of clopidogrel therapy at least five days before planned CABG to reduce bleeding-related events. However, high-risk individuals may require urgent surgery without delay, to reduce the risk of potentially fatal ischemic events. The present multidisciplinary position statement provides evidence- based recommendations for the optimal use of dual antiplatelet therapy to balance ischemic and bleeding risks in patients with recent ACS who may require urgent CABG. RECOMMENDATIONS 1. All ACS patients should be considered for dual antiplatelet therapy with ASA and clopidogrel at the earliest opportunity, despite the possibility of a need for urgent CABG. 2. For patients who have received clopidogrel and ASA, and require CABG: * Those at high risk of an early fatal event (eg, with refractory ischemia despite optimal medical treatment, and with high-risk coronary anatomy (eg, severe left main stenosis with severe right coronary artery disease), should be considered for early surgery without discontinuation of clopidogrel. * In patients with a high bleeding risk (eg, previous surgery, complex surgery) who are also at high risk for an ischemic event, consideration should be given to discontinuing clopidogrel for three to five days before surgery. * Patients at a lower risk for ischemic events (most patients) should have clopidogrel discontinued five days before surgery. 3. For patients who have CABG within five days of receiving clopidogrel and ASA, the risk of major bleeding and transfusion can be minimized by applying multiple strategies before and during surgery. 4. Patients who receive clopidogrel pre-CABG for a recent ACS indication should have clopidogrel restarted after surgery to decrease the risk of recurrent ACS. 5. For patients with a recent coronary stent, the decision to continue clopidogrel until the time of surgery or to discontinue will depend on the risk and potential impact of stent thrombosis. Restarting clopidogrel after CABG will depend on whether the stented vessel was revascularized, the type of stent and the time from stent implantation. Clopidogrel should be restarted when hemostasis is assured to prevent recurrent acute ischemic events.

Effects of Resuscitation Fluid on Neurologic Physiology After Cerebral Trauma and Hemorrhage

BACKGROUND The current standard of care for fluid resuscitation of hemorrhagic hypotensive patients involves the use of crystalloid solutions. Traumatic brain injury (TBI) is often associated with hemorrhage and hypotension, which can contribute significantly to morbidity and mortality. Guidelines for the choice of fluid resuscitation and the use of red blood cell transfusions are not yet clear in the context of brain injury. METHODS Various fluid resuscitation strategies were evaluated in Sprague-Dawley rats using fresh blood, normal saline, hypertonic saline, and albumin fluid resuscitation protocols. Mean arterial blood pressure (MAP) and cerebral oximetry were assessed in hemorrhaged groups and the mean population spike amplitudes (PSA) from the hippocampus were examined in fluid percussion injured (FPI) animals subject to hemorrhage and fluid resuscitation. RESULTS MAP in control animals, hemorrhage and hemorrhage + albumin treated groups was 82.4 +/- 1.5 mm Hg, 55.7 +/- 1.5 mm Hg, and 97.0 +/- 3.4 mm Hg, respectively. Arterial PaO2 was higher in albumin-treated animals relative to other fluid alternatives. Regional tissue oxygen tension (PbrO2) levels in hemorrhaged animals reached significantly higher levels in albumin treated group compared with in normal saline and hypertonic saline (p < 0.001, p = 0.034, respectively). After FPI+hemorrhage, PSA values in albumin- resuscitated animals were significantly higher than in normal saline-resuscitated animals (p = 0.012). CONCLUSIONS The results of normal saline resuscitation, relative to other fluid alternatives, suggest that a re-evaluation of current treatment strategies in hemorrhagic hypotensive TBI patients is warranted. Albumin demonstrated the greatest beneficial effects on neurophysiology endpoints over crystalloid alternatives. These data suggests that albumin resuscitation may play an important role in the treatment of hemorrhagic hypotension and TBI.

Effect of Pneumoperitoneum on Renal Tissue Oxygenation and Blood Flow in a Rat Model

OBJECTIVES To determine the correlation between the renal blood flow (RBF) and tissue oxygenation (PO(2)) at varying intra-abdominal pressures (IAPs) and to compare the effects on renal blood flow from carbon dioxide-induced pneumoperitoneum. METHODS Carbon dioxide pneumoperitoneum was established in Sprague-Dawley rats (n = 6). Licox oxygen/temperature tissue probes were laparoscopically inserted into the renal parenchyma, with the renal PO(2) and RBF recorded every 30 seconds while the IAP was gradually increased. Microprobes measuring the RBF, mean arterial pressures and serum pH were placed into the parenchyma to compare the effects of carbon dioxide pneumoperitoneum (n = 7) with that of open surgery (n = 6) and medical air pneumoperitoneum (n = 6). RESULTS Renal PO(2) was inversely related to the IAP (P < .001). Despite the reduction in IAP, the renal PO(2) in the recovery phase was lower than at baseline (P = .045). The renal PO(2) and RBF changed in a virtually identical pattern at varying levels of IAP (P > .05). The RBF significantly declined with a pneumoperitoneal pressure of 15 and 20 mm Hg (P = .022), regardless of the gas used to create the pneumoperitoneum. A partial reversal of the RBF occurred with a decrease of the IAP. The RBF in the open surgical arm remained unchanged. Although both the serum pH and the mean arterial pressure were inversely proportional to the IAP (P < .001), the mean arterial pressure was depressed to the greatest extent in the medical air group (P = .02). CONCLUSIONS These results have demonstrated that elevated IAP secondary to pneumoperitoneum causes significant renal hypoxia and decreased RBF. Additionally, this experiment has demonstrated the use of the Licox probes in monitoring the renal PO(2) and established a novel method for evaluating the effects of IAP on the kidney.

Hemolink™, an o-raffinose cross-linked haemoglobin-based oxygen carrier, does not affect activation and function of human platelets in whole blood in vitro

Summary. Haemoglobin‐based oxygen carriers (HBOCs) are anticipated to be safe and efficient alternatives to RBC transfusions. Haemoglobin (Hb) raffimer (Hemolink™; Hemosol, Toronto, ON, Canada) is polymerized human Hb, cross‐linked with o‐raffinose. As administration of cell‐free Hb may affect blood cells and tissues, this study was focused on evaluating effects of Hb raffimer on human platelets in whole blood in vitro. Citrated blood from healthy donors was incubated with Hb raffimer to achieve raffimer concentrations of 2–50 vol percentage (2–50 g/l). Platelet activation, phosphatidylserine exposure and microparticle generation were measured by flow cytometry. Aperture closure time on collagen/ADP‐ and collagen/epinephrine‐coated membranes was determined by a platelet function analyser (PFA‐100®). We found that addition of Hb raffimer to blood samples up to 50 vol % did not affect human platelets as measured by various markers of platelet activation (CD42b, CD41, PAC‐1, CD62, CD63), procoagulant activity (annexin V) and microparticle formation; differences between Hb raffimer‐ and lactated Ringers‐diluted blood were not significant. Similarly, no adverse effect of Hb raffimer on closure time was observed at concentrations up to 50 vol %, in comparison with Ringers solution. These data indicate that exposure of human blood to high concentrations of Hb raffimer in vitro did not cause platelet activation nor affect platelet function.

Impact of arterial and arteriovenous renal clamping with and without intrarenal cooling on renal oxygenation and temperature in a porcine model.

BACKGROUND As laparoscopic partial nephrectomy increases in prominence, more needs to be understood about the combined effect of the pneumoperitoneum and renal ischemia during tumor resection. The purpose of this study is to investigate the effect of combined renal hilar clamping (arterial only versus arteriovenous) and retrograde intrarenal cooling on renal temperature and oxygenation in a porcine laparoscopic partial nephrectomy model. MATERIALS AND METHODS Under general anesthesia, laparoscopic access with intra-abdominal pressure of 15 mm Hg to the left renal hilum was obtained. Licox tissue oxygenation and temperature probes were placed into the kidney transcutaneously; measurements were taken every 30 seconds. After establishing baseline readings, either the artery alone (n=18) or the artery and vein (n=18) were clamped for 30, 60 or 90 minutes (n=12 each). During vascular clamping, retrograde, intrarenal cooling was performed with ice cold saline infused via a percutaneously placed ureteric catheter in 18 pigs. Changes in renal pO2 and temperature were analyzed with repeated measures ANCOVA in SPSS 16. RESULTS Retrograde cooling decreased renal parenchyma to 75.8% of baseline temperature (27.9 degrees C) within 15 minutes. There were no differences in cooling whether arterial or arteriovenous clamping was used (p=0.79). In uncooled animals, there was no significant difference in the decrease in renal pO2 during the clamp phase (p=0.18) or during the recovery phase (p=0.52). During the recovery phase, renal pO2 in uncooled animals was significantly higher than in those who received cooling (p=0.01). Animals who underwent hilar clamping for extended periods (60 and 90 min) had a slower recovery of renal pO2 to baseline than those with hilar clamping for 30 minutes (p=0.04) CONCLUSION Retrograde intrarenal cooling can reliably cool the porcine kidney to 28 degrees C, regardless of whether arterial or arteriovenous clamping is used. Renal pO2 is not significantly different between animals that undergo artery only versus en bloc hilar clamping. Pigs that were provided with retrograde cooling had a slower return of pO2 to baseline following release of hilar clamps, possibly due to hypothermic vasospasm. Clamp durations greater than 60 minutes were also associated with slower return of renal oxygenation to baseline.

Can we develop a Canadian Perioperative Anesthesiology Clinical Trials Group

In Canada, research in the field of anesthesiology has been restricted mainly to the domains of basic science and applied physiology. Despite being of valuable scientific relevance and importance, most of this research evaluates physiologic outcomes or surrogate clinical outcomes rather than clinically significant outcomes that could change the way in which we practice. While many medical specialties have appreciated the importance of evaluating outcomes, such as mortality, quality of life, length of stay or efficiency of care, anesthesiology has lagged behind. One of the main reasons Canadian anesthesiology has been slow to embrace outcome studies is the delayed development of a collaborative network of anesthesia investigators to advance multicentre clinical research projects. Clinical research is at a turning point and is rapidly evolving, not only in Canada but worldwide. We strongly believe that Canadian anesthesiologists are capable of markedly improving their research capacity by fostering collaborative outcome-driven research. We further believe that such research can and will change clinical practice. In order to attain this goal, we have initiated a collaborative research network, the Perioperative Anesthesiology Clinical Trials (PACT) group. The PACT group is a collaborative group of Canadian academic anesthesiologists with an interest in the design, implementation, conduct, and publication of multicentre clinical trials in anesthesiology and perioperative medicine. The aim of the PACT initiative is to help anesthesiology clinician investigators 1) to identify and investigate clinically relevant questions in anesthesiology and perioperative medicine; 2) to build research programs that answer their research questions; 3) to structure and conduct quality research with sound methodology; 4) to facilitate collaboration amongst various investigators across Canada so as to conduct multicentre research; 5) to acquire peer-reviewed funding from granting agencies; and finally 6) to execute and publish their results in high-impact peer-reviewed journals. The primary focus of the PACT initiative is to generate knowledge in perioperative anesthesia by providing a forum for the development and implementation of multicentre clinical trials that are designed to answer research questions. It is anticipated that the forum will have a fundamental impact on the practice of anesthesiology and perioperative medicine. In addition, the PACT group will provide mentoring to new investigators as a collaborative network and will facilitate the dissemination of research knowledge, best practices, and standardization of practice parameters, thereby informing the practice of anesthesiology and ensuring its continued advancement as a profession. R. Hall, MD S. Beattie, MD D. Cheng, MD P. Choi, MD A. Y. Denault, MD D. Mazer, MD W. A. C. Mutch, MD A. F. Turgeon, MD H. Yang, MD Perioperative Anesthesiology Clinical Trials Group Steering Committee, Halifax, NS, Canada

Assessment of safety and efficacy of mesenchymal stromal cell therapy in preclinical models of acute myocardial infarction: a systematic review protocol

BackgroundDespite advances in treatment, acute myocardial infarction (MI) is still associated with significant morbidity and mortality, especially in patients with extensive damage and scar formation. Based on some promising preclinical studies, there is interest in the use of mesenchymal stromal cells (MSCs) to promote cardiac repair after acute MI. However, there is a need for a systematic review of this evidence to summarize the efficacy and safety of MSCs in preclinical models of MI. This will better inform the translation of MSC therapy for acute MI and guide the design of a future clinical trial.Methods/designA systematic literature search of MEDLINE, Embase, and BIOSIS Previews will be conducted. We will identify comparative preclinical studies (randomized and non-randomized) of myocardial infarction that include animals given MSC therapy versus a vehicle/placebo. The primary outcome will be left ventricular ejection fraction. Secondary and tertiary outcomes will include death, infarct size, measures of cardiac function, biochemical outcomes, and MSC retention and differentiation. Risk of bias will be assessed using the Cochrane Risk of Bias Tool. Subgroup analyses will be performed to measure how various sources of preclinical study heterogeneity affect the direction and magnitude of the primary outcome. We will meta-analyze data using inverse variance random effects modeling.DiscussionThis systematic review of preclinical evidence will provide a summary of the efficacy and safety of MSCs in animal models of MI. The results will help determine whether sufficient evidence exists to conduct a clinical trial in humans and inform its design.

Nutritional supplementation with MyoVive® repletes essential cardiac myocyte nutrients and reduces left ventricular size in patients with left ventricular dysfunction

BACKGROUND Congestive heart failure depletes the myocardium of carnitine, coenzyme Q10 (CoQ10), and taurine--substances known to influence mitochondrial function and cell calcium. We hypothesized that feeding patients a nutritional supplement that contained carnitine, CoQ10, and taurine would result in higher myocardial levels of these nutrients and improve left ventricular function. METHODS Forty-one patients who underwent aortocoronary artery bypass with an ejection fraction < or =40% at referral were randomly assigned to a double-blind trial of supplement or placebo. Radionuclide ventriculography was performed at randomization and before surgery. Surgical myocardial biopsies, adjusted for protein content, were analyzed for carnitine, CoQ10, and taurine levels. RESULTS The groups were well matched. Minor exceptions were supplement group versus placebo group for digoxin use (7 vs 0, respectively; P =.009) and age (62 +/- 11 years vs 69 +/- 5 years, respectively; P =.04). There were significantly higher levels in the treated group compared with the placebo group for myocardial levels of CoQ10 (138.17 +/- 39.87 nmol/g wet weight and 56.67 +/- 23.08 nmol/g wet weight; P =.0006), taurine (13.12 +/- 4.00 micromol/g wet weight and 7.91 +/- 2.81 micromol/g wet weight; P =.003), and carnitine (1735.4 +/- 798.5 nmol/g wet weight and 1237.6 +/- 343.1 nmol/g wet weight; P =.06). The left ventricular end-diastolic volume fell by -7.5 +/- 21.7 mL in the supplement group and increased by 10.0 +/- 19.8 mL in the placebo group (P =.037). CONCLUSIONS Supplementation results in higher myocardial CoQ10, taurine, and carnitine levels and is associated with a reduction in left ventricular end-diastolic volume in patients with left ventricular dysfunction before revascularization. Because the risk of death for surgical revascularization is related to preoperative left ventricular end-diastolic volume, supplementation could improve outcomes.

Special Article Toronto critical care medicine symposium report

ConclusionCritical care provides constant challenges to the practitioner whose attempt to remain up to date is made more difficult by the breadth and amount of new information available. This critical care symposium aptly captured bench-to-bedside areas of interesting new basic research, reviewed clinical trials with potential practical impact on day-to-day practice, and revisited older scientific questions (such as steroids in sepsis) which are now being re-evaluated in a new light.