Background Myocardial reoxygenation injury following asphyxia in neonates is common. Matrix metalloproteinase-2 activation is associated with myocardial ischemic-reperfusion injury and stunning. Previous in vitro, ex vivo, and small animal studies have demonstrated the cardio-protective qualities of doxycycline, a known inhibitor of matrix metalloproteinase-2, however, large animal models demonstrating this effect are lacking. We hypothesized that doxycycline would improve cardiac recovery and systemic hemodynamics in asphyxiated newborn piglets.
Methods Piglets (1–5 days old) were acutely instrumented for continuous monitoring of heart rate, cardiac output [CO], mean systemic and pulmonary arterial pressures (SAP and PAP, respectively). After stabilization, 2hrs of normocapnic alveolar hypoxia (10–15% oxygen) was induced followed by 4hrs of normoxic reoxygenation (21% oxygen). Piglets were blindly randomized to receive either normal saline or doxycycline (3, 10, or 30mg/kg) intravenously 5 minutes into reoxygenation (n=7/group). Sham-operated piglets (n=5) received no hypoxia-reoxygenation.
Results Asphyxiated piglets demonstrated acidosis (pH=7.04± [SD]0.08), hypotension (SAP=31±3mmHg), and cardiac dysfunction (CO= 58±8% of normoxic baseline). Doxycycline had dose-related improvements in CO and stroke volume (30 mg/kg: 86±8% and 79±15% of normoxic baseline vs. 65±7% and 50±13% in controls, respectively [both p<0.05]), with no significant change in heart rate compared to controls. Furthermore, SAP was higher and PAP/SAP ratio was lower than those of controls (p<0.05), with no difference in PAP.
Conclusions In an established swine model of neonatal hypoxia-reoxygenation, post-resuscitation administration of intravenous doxycycline improves cardiac recovery with beneficial hemodynamic effects in systemic and pulmonary circulations.
Funded by Canadian Institutes of Health Research (CIHR).