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Myocardial Dysfunction after Pediatric Cardiac Surgery; Causes, Contributing Factors and a Potential Therapy.
J. R. Egan, T. L. Butler, C. G. Au, K. N. North, D. S. Winlaw. The Children's Hospital at Westmead, Sydney, Australia,
Objective
Low cardiac output state (LCOS) is the principle cause of morbidity and mortality following surgery for congenital cardiac disease. Myocardial ischemia/reperfusion injury, apoptosis, capillary leak syndrome and myocardial edema are potential causative or contributing factors.
We established a clinically relevant animal model to explore relationships between LCOS and expression of cell membrane proteins aquaporin-1 (AQP1 - involved in water transport) and dystrophin (responsible for cell-cell force transduction, and sensitive to ischemia).
We trialed a novel therapy, poloxamer 188 (P188, a membrane repair / protection agent used successfully in acute treatment of cardiac dysfunction in dystrophin deficient mice) in an attempt to reduce the severity of LCOS. P188 has previously been used in human sickle cell crises because of its membrane stabilization properties and low toxicity.
Methods
Eleven neonatal lambs were randomized to saline±P188 (300mg/kg IV load over 1hr prior to CPB and then a maintenance infusion of 30mg/kg/hr). Randomization was blinded and allocation concealed until completion. Lambs underwent 120min of CPB, moderate hypothermia, aortic cross clamping, intermittent cold blood cardioplegia and modified ultra filtration. Lambs were managed under anesthetic for 9 hours post CPB in a standardized way.
Seven hours post CPB, Evans blue was administered intravenously to quantify capillary leak. Hemodynamic (HR, BP, CVP) and biochemical data (venous and arterial blood gases, colloid osmotic pressure (COP), urea, creatinine, CK, albumin) were recorded. After sacrifice, the myocardium was assessed for i) water content by desiccation, ii) myocardial AQP1 expression by western blot and quantitative real time PCR, iii) dystrophin sub cellular localization by fractionation and western blot, and iv) apoptosis by TUNEL and caspase 3 western blot. Statistical analysis included mixed models for longitudinal hemodynamic data and Mann Whitney U test for comparisons between groups.
Results
Lambs receiving P188 had better hemodynamics, including significant elevations in mean and diastolic BP throughout the post CPB period (p<0.01) and required less inotrope (p<0.05). The initial post CPB lactate was lower in the P188 group (p<0.05), with a trend toward higher venous saturations and higher COP. There was significantly less Evans blue tissue uptake in those receiving P188 (p<0.05), indicating less capillary leak. The hearts of lambs receiving P188 were 1% drier and showed reduced AQP1 protein levels, although these did not reach statistical significance. There was no impact on dystrophin or markers of apoptosis and renal function remained normal.
Conclusions
In a clinically relevant lamb model, administration of P188 was associated with improved hemodynamics and less capillary leak following CPB, ischemia and reperfusion. Ischemia did not affect distribution of dystrophin and improved hemodynamics in the P188 group cannot be explained by acute repair or re-localization of dystrophin, unlike previous mouse models. Changes in AQP1 may, in part, underlie some of the changes observed with capillary leak. It is not yet known whether the beneficial effects of P188 relate to its ability to reduce capillary leak and myocardial edema, or by modulation of ischemia related pathways.
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