Michelle Chew

Tissue Injury and the Inflammatory Response to Pediatric Cardiac Surgery with Cardiopulmonary Bypass: A Descriptive Study

Background There are few detailed descriptions of the inflammatory response to cardiac surgery with cardiopulmonary bypass (CPB) in children beyond 24 h postoperatively. This is especially true for the antiinflammatory cytokines and the extent of tissue injury. The aim of the current study was to describe the inflammatory and injury responses in uncomplicated pediatric cardiac surgery with CPB, where methylprednisolone and modified ultrafiltration (MUF) were used. Methods Blood samples were collected up to 48 h postoperatively. Cytokines (tumor necrosis factor-&agr; and interleukin-6, -1&bgr;, -10, and -1ra), complement (C3d and C4d) and coagulation system (prothrombin activation fragments 1 and 2 and antithrombin III) activation, neutrophil elastase, and the resulting tissue injury (creatine kinase, lactate dehydrogenase, alanine transaminase, amylase, and &ggr;-glutamyl transferase) were measured. Results The proinflammatory cytokine release varied widely, in contrast to a clear-cut antiinflammatory response. Cytokine concentrations did not decrease immediately after MUF, and no rebound increases later in the postoperative period were observed. The coagulation system, but not complement, was activated. There was a late release of C-reactive protein. Tissue injury could be quantified biochemically without evidence of hepatic or pancreatic dysfunction. Conclusion In this group of uncomplicated subjects, the antiinflammatory cytokine and tissue injury responses were well defined, in contrast to a variable proinflammatory cytokine release. This was accompanied by activation of the coagulation system but not of complement. Concentrations of inflammatory mediators did not decrease immediately after MUF, and there was no evidence for rebound release later in the postoperative period.

Plaque pathology and coronary thrombosis in the pathogenesis of acute coronary syndromes

Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden coronary death. Therefore, for event-free survival, the vital question is not why atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicated by life-threatening thrombosis. Therefore, we have to focus on plaque composition and vulnerability to rupture and plaque thrombogenicity rather than on plaque size and stenosis severity. The risk for plaque disruption depends more on plaque vulnerability (plaque type) than on degree of stenosis (plaque size). Lipid-rich and soft plaques are more vulnerable and prone to rupture than collagen-rich and hard plaques. They are also highly thrombogenic after disruption because of high content of tissue factor. There seems to be three major determinants of a plaques vulnerability to rupture: 1) the size and consistency of the lipid-rich atheromatous core, 2) the thickness of the fibrous cap covering the core, and 3) ongoing inflammation and repair processes within the fibrous cap. Lipid accumulation, cap thinning, lack of smooth muscle cells (smc), and macrophage-related inflammation destabilize plaques, making them vulnerable to rupture. In contrast, smc-related healing and repair processes stabilize plaques, protecting them against disruption. Plaque size or stenosis severity tell nothing about a plaques vulnerability. Many vulnerable plaques are invisible angiographically due to their small size and compensatory vascular remodeling.

Effect of modified ultrafiltration on the inflammatory response in paediatric open-heart surgery: a prospective, randomized study

Modified ultrafiltration (MUF) is often used in conjunction with paediatric cardiac surgery with cardiopulmonary bypass (CPB) and is thought to improve clinical outcome. It is unclear whether these improvements (if any) are due to the removal of inflammatory mediators. In this prospective study, 18 children aged 12-24 months undergoing uncomplicated cardiac surgery with methylprednisolone added in the pump prime were randomized to receive CPB with ( n = 10) and without ( n = 8) MUF. Cytokines (TNFα, IL-6, IL- 1β, IL-10, IL-1ra), complement split products (C3d, C4d) and coagulation system activation (F1+ 2, ATIII) were measured pre-, peri- and up to 48 h postoperatively. For clinical outcome, the alveolar-arterial oxygen (A-a) gradient, transfusion requirement, drain loss, mean blood pressure and requirement for inotropic support were registered up to 24 h postoperatively. Our results show an improvement in postoperative oxygenation as well as a tendency towards decreased drain loss and improved haemodynamics in the MUF group. There were no intergroup differences detectable for TNFα, IL-1β, IL-1ra, complement and coagulation markers. We conclude that MUF in itself does not significantly influence TNFα, IL-1β, IL-1ra and the complement and coagulation profiles in children undergoing cardiac surgerywith CPB. Despite this, there was some evidence for improved clinical outcome. Our results do not support that MUF improves postoperative organ function by modulation of the measured markers of inflammation.

Freunds adjuvant alone is antiatherogenic in apoE-deficient mice and specific immunization against TNFα confers no additional benefit

TNFalpha participates in the pathogenesis of atherosclerosis. The effect of immunization against TNFalpha on development of advanced vascular lesions in atherosclerosis-susceptible apoE-deficient mice was investigated. At 5-7 weeks of age, animals received immunization with either Freunds adjuvant and a recombinant antigenic TNFalpha molecule (TNF106), Freunds adjuvant alone, or no immunization. All mice received a Western-type high-fat diet for 12 weeks. Aortic sinus lesion area was determined by microscopic morphometry, the total aortic arch cholesterol content was determined by gas chromatography, and antibodies against TNFalpha, malondialdehyde-modified low density lipoprotein, or heat shock protein 60, were assessed by ELISAs. Immunization with TNF106 induced high-titered circulating antibodies against TNFalpha (n=23), and these antibodies were not detected in mice immunized with Freunds adjuvant alone (n=22), or in non-immunized control animals (n=25). After 12 weeks, the atherosclerotic lesion size was significantly reduced in immunized animals, whether they had been immunized with TNF106 or Freunds adjuvant alone, and the total lesional cholesterol content was decreased in mice immunized with TNF106. There were no correlations between circulating antibody titers and plaque size, total aortic arch cholesterol content, or plasma lipid levels, respectively. Administration of Freunds adjuvant alone can thus reduce formation of mature atherosclerotic lesions in apoE-deficient mice and this response is not modified by specific immunization against TNFalpha.

Endogenous morphine is produced in response to cardiopulmonary bypass in neonatal pigs

Background: Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response. Endogenous morphine production has previously been demonstrated in humans after cardiac surgery with CPB. It has been hypothesized that morphine plays a role as an anti‐inflammatory mediator in the systemic inflammatory response. The aim of this study was to investigate if the CPB procedure in itself elicits an endogenous morphine production in neonatal pigs.

Intravenous Magnesium Reduces Infarct Size After Ischemia/Reperfusion Injury Combined with a Thrombogenic Lesion in the Left Anterior Descending Artery

Experimental studies have demonstrated that intravenous magnesium (Mg) can protect the ischemic myocardium and has an antithrombotic effect. In patients with myocardial infarction, the reperfusion injury is complicated by the presence of a thrombogenic area in the affected coronary artery that may cause repetitive thrombus formation and embolization. We investigated the effect of Mg on infarct size in a randomized study in pigs. Myocardial infarction was induced by a 50-minute mechanical occlusion of the left anterior descending artery combined with an arterial injury, which stimulated a dynamic thrombus formation with emboli shedding on reperfusion. Magnesium sulfate (6 mmol/20 min plus 3 mmol/h) or saline was started at 30 minutes after coronary occlusion. Real-time ventricular pressure-volume loops were generated from the left ventricle by using a microtip pressure manometer and a conductance catheter. Platelet accumulation in the myocardium was evaluated by using 111In-labeled platelets. After 4 hours of reperfusion, the infarct size/area at risk ratio in the placebo group was 46+/-0.06% (n=8) compared with 22+/-0.07% (n=6) in the Mg-treated animals (P=0. 03). Ejection fraction decreased significantly in the control group but not in the Mg-treated animals (P=0.03). Platelet accumulation in the myocardium did not change significantly between the Mg- and placebo-treated animals (placebo group, 191+/-19%; Mg group, 177+/-29%; NS). The present study demonstrates that intravenous Mg infusion is able to reduce infarct size by >50% and preserve the ejection fraction in this model where ischemia/reperfusion injury was evaluated in the presence of a thrombogenic area in the nutrient artery.

Does modified ultrafiltration reduce the systemic inflammatory response to cardiac surgery with cardiopulmonary bypass

Cardiopulmonary bypass (CPB) is associated with an accumulation of total body water and a systemic inflammatory response syndrome (SIRS), which, in turn, is associated with organ dysfunction and postoperative morbidity. It has been suggested that modified ultrafiltration (MUF) may be capable of reducing SIRS and improving clinical outcome by filtering out the inflammatory mediators generated during CPB. This paper reviews the data regarding the use of MUF in paediatric and adult settings. Specifically, three issues will be considered: 1) Does MUF improve clinical outcome? 2) Does MUF reduce the systemic inflammatory response to cardiac surgery with CPB? 3) Is MUF more effective than conventional ultrafiltration in improving clinical outcome?

Neutrophils and platelets accumulate in the heart, lungs, and kidneys after cardiopulmonary bypass in neonatal pigs

OBJECTIVE Cardiac surgery with cardiopulmonary bypass elicits a systemic inflammatory response. An exaggerated response is associated with organ dysfunction and increased morbidity and mortality. DESIGN The aim of the present study was to investigate whether the cardiopulmonary bypass procedure in itself results in accumulation of isotope-labeled platelets, polymorphonuclear neutrophils, and fibrinogen at organ levels in neonatal pigs and to monitor changes in organ function. SETTING Pediatric cardiopulmonary bypass setup with 60 mins of aortic cross-clamp time and 120 mins of hypothermic cardiopulmonary bypass time. SUBJECTS Thirty piglets were allocated to sternotomy alone (sham group, n = 15) or to sternotomy and cardiopulmonary bypass (n = 15). MEASUREMENTS AND MAIN RESULTS Isotope-labeled autologous polymorphonuclear neutrophils, platelets, and commercially available fibrinogen were infused, and the specific accumulation at organ level was measured in a gamma counter 4 hrs after termination of cardiopulmonary bypass. Concomitant changes in oxygenation index and cardiac output were registered. Animals exposed to cardiopulmonary bypass showed a significantly higher technetium-99m-polymorphonuclear neutrophil accumulation in the lungs and kidneys, whereas indium-111-platelets accumulated in the heart and kidneys compared with the sham group. There was a significantly larger increase in oxygenation index and significantly larger decrease in cardiac output between the pre- and postcardiopulmonary bypass period in the cardiopulmonary bypass group compared with the sham group. CONCLUSIONS The cardiopulmonary bypass procedure without cardiac surgery elicits organ dysfunction in terms of impaired respiratory and hemodynamic function. Platelets and polymorphonuclear neutrophils were entrapped in the heart, lungs, and kidneys of cardiopulmonary bypass animals, indicating that cell accumulation may contribute to the developing organ dysfunction.

Pediatric cardiac output measurement using surface integration of velocity vectors an in vivo validation study

ObjectiveTo test the accuracy and reproducibility of systemic cardiac output (CO) measurements using surface integration of velocity vectors (SIVV) in a pediatric animal model with hemodynamic instability and to compare SIVV with traditional pulsed-wave Doppler measurements. DesignProspective, comparative study. SettingAnimal research laboratory at a university medical center. SubjectsEight piglets weighing 10–15 kg. InterventionsHemodynamic instability was induced by using inhalation of isoflurane and infusions of colloid and dobutamine. MeasurementsSIVV CO was measured at the left ventricular outflow tract, the aortic valve, and ascending aorta. Transit time CO was used as the reference standard. ResultsThere was good agreement between SIVV and transit time CO. At high frame rates, the mean difference ± 2 sd between the two methods was 0.01 ± 0.27 L/min for measurements at the left ventricular outflow tract, 0.08 ± 0.26 L/min for the ascending aorta, and 0.06 ± 0.25 L/min for the aortic valve. At low frame rates, measurements were 0.06 ± 0.25, 0.19 ± 0.32, and 0.14 ± 0.30 L/min for the left ventricular outflow tract, ascending aorta, and aortic valve, respectively. There were no differences between the three sites at high frame rates. Agreement between pulsed-wave Doppler and transit time CO was poorer, with a mean difference ± 2 sd of 0.09 ± 0.93 L/min. Repeated SIVV measurements taken at a period of relative hemodynamic stability differed by a mean difference ±2 sd of 0.01 ± 0.22 L/min, with a coefficient of variation = 7.6%. Intraobserver coefficients of variation were 5.7%, 4.9%, and 4.1% at the left ventricular outflow tract, ascending aorta, and aortic valve, respectively. Interobserver variability was also small, with a coefficient of variation = 8.5%. ConclusionsSIVV is an accurate and reproducible flow measurement technique. It is a considerable improvement over currently used methods and is applicable to pediatric critical care.

DOPPLER FLOW MEASUREMENT USING SURFACE INTEGRATION OF VELOCITY VECTORS (SIVV): IN VITRO VALIDATION

Blood flow measurement using an improved surface integration of velocity vectors (SIVV) technique was tested in in vitro phantoms. SIVV was compared with true flow (12-116 mL/s) in a steady-state model using two angles of insonation (45 degrees and 60 degrees ) and two vessel sizes (internal diameter = 11 and 19 mm). Repeatability of the method was tested at various flow rates for each angle of insonation and vessel. In a univentricular pulsatile model, SIVV flow measured at the mitral inlet was compared to true flow (29-61 mL/s). Correlation was excellent for the 19-mm vessel (r(2)= 0.99). There was a systematic bias but close limits of agreement (mean +/- 2 SD = -24.1% +/- 7.6% at 45 degrees; +16.4% +/- 11.0% at 60 degrees ). Using the 11-mm vessel, a quadratic relationship was demonstrated between between SIVV and true flow (r(2) = 0.98-0.99), regardless of the angle of insonation. In the pulsatile system, good agreement and correlation were shown (r(2) = 0.94, mean +/- 2 SD = -4.7 +/- 10.1%). The coefficients of variation for repeated SIVV measurements ranged from 0.9% to 10.3%. This method demonstrates precision and repeatability, and is potentially useful for clinical measurements.