Given emerging evidence of rapid non-genomic cytoprotective effects of triiodothyronine (T3), we evaluated the resuscitative efficacy of two nanoparticle formulations of T3 (T3np) designed to prolong cell membrane receptor-mediated signaling.
Swine (n = 40) were randomized to intravenous vehicle (empty np), EPI (0.015 mg/kg), T3np (0.125 mg/kg), or T3np loaded with phosphocreatine (T3np + PCr; 0.125 mg/kg) during CPR following 7-min cardiac arrest (n = 10/group). Hemodynamics and biomarkers of heart (cardiac troponin I; cTnI) and brain (neuron-specific enolase; NSE) injury were assessed for up to 4-hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis.
Compared with vehicle (4/10), the rate of ROSC was higher in swine receiving T3np (10/10; p < 0.01), T3np + PCr (8/10; p = 0.08) or EPI (10/10; p < 0.01) during CPR. Although time to ROSC and survival duration were comparable between groups, EPI was associated with a ∼2-fold higher post-ROSC concentration of cTnI vs T3np and T3np + PCr and the early post-ROSC rise in NSE and neuronal injury were attenuated in T3np-treated vs EPI-treated animals. Analysis of hippocampal ultrastructure revealed deterioration of mitochondrial integrity, reduced active zone length, and increased axonal vacuolization in EPI-treated animals vs controls. However, the frequency of these abnormalities was diminished in animals resuscitated with T3np.
T3np achieved a ROSC rate and post-ROSC survival that was superior to vehicle and comparable to EPI. The attenuation of selected biomarkers of cardiac and neurologic injury at individual early post-ROSC timepoints in T3np-treated vs EPI-treated animals suggests that T3np administration during CPR may lead to more favorable outcomes in cardiac arrest.
Abbreviations:ANOVA (analysis of variance), CPP (coronary perfusion pressure), CPR (cardiopulmonary resuscitation), cTnI (cardiac troponin I), EPI (epinephrine), LDH (lactate dehydrogenase), LV (left ventricular), NSE (neuron-specific enolase), PCr (phosphocreatine), PEA (pulseless electrical activity), PLGA (polylactic acid-co-glycolic acid), ROSC (return of spontaneous circulation), T3 (triiodothyronine), T3np (triiodothyronine nanoparticles), TEM (transmission electron microscopy), VF (ventricular fibrillation)
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Published online: February 15, 2023
Accepted: February 8, 2023
Received in revised form: February 6, 2023
Received: October 11, 2022
Publication stageIn Press Journal Pre-Proof
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