Namdar Manouchehri

Cyclosporine treatment improves cardiac function and systemic hemodynamics during resuscitation in a newborn piglet model of asphyxia: a dose-response study.

Objectives:Asphyxiated neonates often have myocardial depression, which is a significant cause of morbidity and mortality. Cardioprotective effects of cyclosporine have been observed in adult patients and animals with myocardial infarction. However, the cardioprotective effect of cyclosporine in neonates has not yet been studied. We hypothesize that cyclosporine will improve cardiac function and reduce myocardial injury in asphyxiated newborn piglets. Design:Thirty-six piglets (1–4 days old, weighing 1.4–2.5 kg) were acutely instrumented for continuous monitoring of cardiac output and systemic arterial pressure. After stabilization, normocapnic alveolar hypoxia (10% to 15% oxygen) was instituted for 2 hrs followed by reoxygenation with 100% oxygen for 0.5 hrs and then 21% for 3.5 hrs. A nonasphyxiated, sham-operated group was included (n = 4) to control for effects of the surgical model. Plasma troponin and myocardial lactate concentrations were determined as well as morphologic examinations. Setting:Neonatal asphyxia and reoxygenation. Subjects:Newborn (1–4 days old) piglets. Interventions:Piglets were block-randomized to receive intravenous boluses of cyclosporine A (2.5, 10, or 25 mg/kg) or normal saline (control) at 5 mins of reoxygenation (n = 8/group). Measurements and Main Results:Cardiac index, heart rate, systemic oxygenation, plasma troponin, and left ventricular lactate were measured. Hypoxic piglets had cardiogenic shock (cardiac output 40% to 48% of baseline), hypotension (mean arterial pressure 27–31 mm Hg), and acidosis (pH 7.04). Cyclosporine treatment caused bell-shaped improvements in cardiac output, stroke volume, and systemic oxygen delivery (p < .05 vs. controls). Plasma troponin and left ventricle lactate were higher in controls than that of 2.5 and 10 mg/kg cyclosporine-treated groups (p < .05). Although histologic features of myocardial injury were not different among groups, severe damage was observed in mitochondria of control piglets but attenuated in that of cyclosporine (10 mg/kg) treatment. Conclusions:Postresuscitation administration of cyclosporine causes preservation of cardiac function and attenuates myocardial injury in newborn piglets after asphyxia–reoxygenation. (Crit Care Med 2012; 40:–1244)

Postresuscitation cyclosporine treatment attenuates myocardial and cardiac mitochondrial injury in newborn piglets with asphyxia-reoxygenation.

Objectives:Cardiovascular dysfunction occurs in the majority of asphyxiated neonates and has been suggested to be a major cause of neonatal morbidity and mortality. We previously demonstrated that cyclosporine A treatment during resuscitation can significantly improve cardiovascular performance in asphyxiated newborn piglets. However, the mechanisms through which cyclosporine elicits its protective effect in neonates have not yet been fully characterized. We hypothesized that cyclosporine A treatment would attenuate myocardial and cardiac mitochondrial injury during the resuscitation of asphyxiated newborn piglets. Design:After acute instrumentation, piglets received normocapnic alveolar hypoxia (10% to 15% oxygen) for 2 hours followed by reoxygenation with 100% oxygen (0.5 hr) and then 21% oxygen (3.5 hr). At 4 hours of reoxygenation, plasma troponin level, left ventricle myocardial levels of lipid hydroperoxides, cytochrome-c, and mitochondrial aconitase activity were determined. Setting:Neonatal asphyxia and reoxygenation. Subjects:Twenty-four newborn (1–4 days old) piglets. Interventions:Piglets were randomized to receive an IV bolus of cyclosporine A (10 mg/kg) or normal saline (placebo, control) at 5 minutes of reoxygenation (n = 8/group). Sham-operated piglets (n = 8) underwent no asphyxia-reoxygenation. Measurements and Main Results:Asphyxiated piglets treated with cyclosporine had lower plasma troponin and myocardial lipid hydroperoxides levels (vs. controls, both p < 0.05, analysis of variance). Cyclosporine treatment also improved mitochondrial aconitase activity and attenuated the rise in cytosol cytochrome-c level (vs. controls, all p < 0.05). The improved mitochondrial function significantly correlated with cardiac output (p < 0.05, Spearman rank-correlation test). Conclusions:We demonstrate that the postresuscitation administration of cyclosporine attenuates myocardial and cardiac mitochondrial injury in asphyxiated newborn piglets following resuscitation.

Important returns on investment: an evaluation of a national research grants competition in emergency medicine.

OBJECTIVE We sought to examine scholarly outcomes of the projects receiving research grants from the Canadian Association of Emergency Physicians (CAEP) during the first 10 years of national funding (i.e., between 1996 and 2005). METHODS We sent email surveys to 62 emergency medicine (EM) researchers who received funding from CAEP. We focused our data collection on grant deliverables and opinions using a 1-7 Likert scale with regard to the value of the award. RESULTS Fifty-eight recipients responded to our survey. Grants were most commonly awarded to residents (21 [36%]), followed by senior (16 [28%]) and junior (13 [22%]) emergency staff. Twenty-six applicants from Ontario and 11 from Quebec received the majority of the grants. Overall, 51 projects were completed at the time of contact and, from these, 39 manuscripts were published or in press. Abstract presentations were more common, with a median of 2 abstracts presented per completed project. Abstract presentations for the completed projects were documented locally (23), nationally (39) and internationally (37). Overall, 19 projects received additional funding. The median amount funded was Can

Differential Hemodynamic Effects of Levosimendan in a Porcine Model of Neonatal Hypoxia-Reoxygenation

4700 with an interquartile range of

A comparison of combination dopamine and epinephrine treatment with high-dose dopamine alone in asphyxiated newborn piglets after resuscitation

3250-

Milrinone is preferred to levosimendan for mesenteric perfusion in hypoxia-reoxygenated newborn piglets treated with dopamine

5000. Respondents felt CAEP funding was critical to completing their projects and felt strongly that dedicated EM research funding should be continued to stimulate productivity. CONCLUSION Overall, the CAEP Research Grants Competition has produced impressive results. Despite the small sums available, the grants have been important for ensuring study completion and for securing additional funding. CAEP and similar EM organizations need to develop a more robust funding approach so that larger grant awards and more researchers can be supported on an annual basis.

Esophageal perforation after radiofrequency ablation for atrial fibrillation.

Background: Neonatal asphyxia can be complicated by myocardial dysfunction with secondary alterations in pulmonary and regional hemodynamics. Levosimendan is a calcium-sensitizing inotrope that may support cardiac output, but little is known regarding its differential hemodynamic effects in asphyxiated neonates. Methods: Mixed breed piglets (1–4 days old, weight 1.6–2.3 kg) were acutely instrumented. Normocapnic alveolar hypoxia (10–15% oxygen) was induced for 2 h, followed by reoxygenation with 100% (1 h) and then 21% oxygen (3 h). At 2 h of reoxygenation, after volume loading (Ringer’s lactate 10 ml/kg), either levosimendan (0.1 or 0.2 µg/kg/min) or D5W (placebo) was infused for 2 h in a blinded, block-randomized fashion (n = 7–8/group). The systemic, pulmonary and regional (carotid, superior mesenteric and renal) hemodynamics were compared. Results: At 0.1 and 0.2 µg/kg/min, levosimendan significantly increased cardiac output (121 and 123% of pretreatment, respectively) and heart rate, and decreased systemic vascular resistance without causing hypotension. Pulmonary arterial pressure and estimated pulmonary vascular resistance were significantly increased from pretreatment baseline in 0.1 but not 0.2 µg/kg/min levosimendan. Levosimendan infusion had no effects on regional hemodynamics. Myocardial efficiency but not oxygen consumption increased with 0.1 µg/kg/min levosimendan without significant effects on plasma troponin and myocardial lactate levels. Conclusions: In newborn piglets following hypoxia-reoxygenation injury, levosimendan improves cardiac output but has no marked effects in carotid, superior mesenteric and renal perfusion. It appears that various doses of levosimendan increase the cardiac output through different mechanisms. Further investigations are needed to examine the effectiveness of levosimendan as a cardiovascular supportive therapy either alone or in conjunction with other inotropes in asphyxiated neonates.

Infusing Sodium Bicarbonate Suppresses Hydrogen Peroxide Accumulation and Superoxide Dismutase Activity in Hypoxic-Reoxygenated Newborn Piglets

Background:When asphyxiated neonates require additional cardiovascular support to moderate doses of dopamine infusion, controversy exists on the differential hemodynamic effects of two approaches (adding a second inotrope vs. increasing dopamine dosage). We hypothesized that high-dose dopamine (HD) would be detrimental to systemic and regional perfusion as compared with dopamine and epinephrine (D + E) combination therapy using a swine model of neonatal hypoxia–reoxygenation (H-R).Methods:Twenty-seven piglets (1–4 d, 1.5–2.5 kg) were used for continuous monitoring of systemic arterial pressure (mean arterial pressure, MAP) and pulmonary arterial pressure (PAP), cardiac output (cardiac index, CI), and carotid (carotid artery flow index, CAFI), superior mesenteric (superior mesenteric artery flow index), and renal arterial flows. H-R piglets underwent 2 h of hypoxia followed by 2 h of reoxygenation before drug infusion (2 h).Results:The hemodynamics of H-R piglets deteriorated gradually after reoxygenation. HD and D + E infusions improved CI similarly (both groups vs. control; P < 0.05). Both regimens increased MAP (P < 0.05) but not PAP, with decreased PAP/MAP ratio in D + E piglets. Both regimens improved CAFI and superior mesenteric artery flow index, with decreased mesenteric vascular resistance in HD-treated piglets. No significant effect on renal perfusion was observed.Conclusion:In H-R newborn piglets treated with a moderate dose of dopamine, adding epinephrine or further increasing dopamine improved systemic hemodynamics similarly; these treatments have differential effects on the pulmonary and mesenteric circulations.

100 Cardioprotective Effects of Cyclosporine in a Newborn Piglet Model of Asphyxia: A Dose-Response Study

Introduction:There is little information regarding the comparative hemodynamic effects of adding milrinone or levosimendan to dopamine infusion in hypoxia-reoxygenated (H-R) newborns.Results:Severely hypoxic piglets had cardiogenic shock with depressed cardiac index (CI) and mean arterial pressure (MAP). The hemodynamics deteriorated gradually after initial recovery upon reoxygenation. Heart rate and CI improved with milrinone (D+M) and levosimendan (D+L) administration (P < 0.05 vs. control). Both regimens improved carotid arterial flow and carotid vascular resistance; D+M additionally improved superior mesentric arterial flow (all P < 0.05 vs. control). No effect was found on renal arterial flow or elevated lactate state with either regimen. D+M piglets also had a lower myocardial oxidized/reduced glutathione ratio (P < 0.05 vs. control).Discussion:In conclusion, adding milrinone or levosimendan to dopamine similarly improved systemic hemodynamics in H-R newborn piglets. Milrinone also improved mesenteric perfusion and attenuated myocardial oxidative stress.Methods:Twenty-eight piglets (1–4 d, 1.5–2.5 kg) were instrumented for continuous monitoring of systemic MAP and pulmonary arterial pressure (PAP), CI, and carotid, superior mesenteric, and renal arterial flows. Piglets were randomized with blinding to sham-operated, H-R control (saline), and H-R dopamine (10 μg/kg/min) with D+M or D+L groups. H-R piglets underwent H-R followed by 2 h of drug infusion after reoxygenation. Tissue was collected for biochemical/oxidative stress testing and histological analysis.

333 Cyclosporine and Regional Hemodynamics of Newborn Piglets Following Asphyxia-Reoxygenation: A Dose-Response Study

A 69-year-old man underwent left atrial radiofrequency ablation for atrial fibrillation. After 10 minutes, the procedure was terminated due to pericardial tamponade secondary to perforation during mapping. Pericardiocentesis resolved the tamponade. Ablation was completed one week later, and the patient was discharged. Two days later, he presented with odynophagia. Computed tomography demonstrated small bilateral pleural effusions. He was judged to be stable and was discharged again, but returned 2 days later with chest pain. He was found to have esophageal perforation with empyema, which was repaired using a muscle patch and esophageal stenting, successfully treating the lesion with minimal morbidity.