Rheoencephalographic evidence of complement activation-related cerebrovascular changes in pigs

Abstract

Intravenous administration of Doxil and other liposomes in pigs can cause severe cardiopulmonary and hemodynamic abnormalities, including pulmonary hypertension, systemic hypotension, falling cardiac output and tachy- or bradycardia with arrhythmia, ventricular fibrillation and cardiac arrest. The phenomenon, which is due to complement activation by the liposome membranes, suggests a model for acute hypersensitivity reactions (manifested in hyper- or hypotensive episodes, chest pain, dyspnea) caused by liposomal drugs in patients. However, some other manifestations (e.g., anxiety, confusion, headache) could not be readily explained by changes in systemic circulation, pointing to possible direct effects of complement activation on the cerebrovascular system. The goal of the present study was to explore liposome-induced changes and changes related to complement activation in cerebral blood flow (CBF) using rheoencephalography (REG), the measurement of changes of electrical impedance in the skull. REG measurements were performed on anesthetized pigs (n = 24 pigs, 57 liposome injections, 19 types of liposomes). Systemic (SAP) and pulmonary arterial pressure, cardiac output, EKG, REG were recorded on a PC. Data were processed off-line. Following liposome infusion, pig SAP decreased robustly, and the changes described above were again observed (massive pulmonary hypertension, systemic hypotension and severe cardiac abnormalities, including falling cardiac output and tachy- or bradycardia with arrhythmia). A significant, transient decrease in REG pulse amplitudes occurred in 40 of 51 cases. A 78.43% decrease in REG amplitude was observed, which lasted only a few seconds. This transient decrease preceded the actual onset of circulatory shock, before changes in pulmonary and systemic arterial pressures, and also preceded a decrease of CO2 levels in exhaled air. In about half of the animals (51.9%), REG pulse amplitude first decreased then increased, an indication of transient cerebral vasoconstriction and vasodilatation, which occurred while SAP was low or falling. In 48.1% of the animals, REG amplitude remained depressed or decreased further. In 26.3 % of the animals, both types of CBF response to cardiovascular shock induced by liposomes were observed. Different liposomes produced no qualitative differences in cardiovascular reactions; increased doses of all liposomes elicited severe reactions. In the Doxil subgroup (n=12), the decrease in REG pulse amplitude was statistically significant (P = 0.003) after Doxil administration; average amplitude decrease was 42.5 16.5 %, and the CBF response was autoregulatory in 91.6 % (11 out of 12). This study gives direct evidence of cerebrovascular changes caused by liposome administration. The fact that the CBF decrease preceded the CO2 decrease during the reaction supports our hypothesis that liposome infusion has a direct impact on cerebrovascular reactivity.