Cerebrovascular Involvement in Liposome—Induced Cardiopulmonary Distress in Pigs

Abstract

The public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing the burden, 14. ABSTRACT Intravenous administration of liposomes, including Doxil, can cause severe life threatening hemodynamic changes in pigs. The reaction is due to complement activation, and it is characterized by massive pulmonary hypertension, systemic hypotension and severe cardiac abnormalities including falling cardiac output, tachy-or bradycardia with arrhythmia. There were no data suggesting the involvement of cerebrovascular changes in this reaction, however clinical observations allowed this hypothesis. Here we measured the accompanying changes during liposome infusion by monitoring pulsatile electrical impedance (rheoencephalogram -REG) on the skull (n = 24 pigs, 57 trials, 19 types of liposomes). A transient but significant decrease of REG pulse amplitudes followed the injection of liposomes (78.43 % in the total sample, and 91.66 % in the Doxil subgroup; P = 0.003, n = 12), indicating the involvement of cerebrovascular reaction during liposome infusion.

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

“…Table 1 lists 30 experimental studies [15, which utilized the pig model to analyze the cardiopulmonary adverse effects of different nanoparticles (NPs) or other agents. Some of these studies highlighted the concordance of HSR symptoms in pigs and hypersensitive patients [25][26][27][28][29]32,33,[46][47][48], others addressed the mechanism of HSRs [15,[21][22][23][24][25][26][27][28][29][30][31][32][33]36,[41][42][43][44][45][46][47], and yet others focused on the prevention of HSRs by pharmacological intervention [15], or by optimizing the structure [24,44] or administration protocol [24,37,48] of NPs. Importantly, many of these studies were initiated mainly for preclinical safety evaluation of nanomedicines [15,22,23,30,31,35,…”

Studies in Rheoencephalography (REG)

“…Based upon the above-mentioned facts, we hypothesized the involvement of cerebrovascular change during liposome infusion. Further details see [54,111]. This study can be an animal model of human vasospam.…”

Thoracic, peripheral, and cerebral volume, circulatory and pressure responses to PEEP during simulated hemorrhage in a pig model: a case study

“…Earlier studies [ 31 , 32 ] made an initial effort to establish pathophysiological correlates to REG [ 30 , 34 ] but did not mention CBF AR. Previous studies documented that REG reflects cerebrovascular reactivity [ 40 ], has a correlation to ICP [ 35 , 38 ], laser Doppler flow [ 39 ], carotid flow [ 40 ] and can be used for patient monitoring instead of ICP [ 42 ]. It was documented that REG indicated cerebral vasospasm before systemic reaction caused by complement activation/cytokine storm in pigs [ 42 ].…”

“…Previous studies documented that REG reflects cerebrovascular reactivity [ 40 ], has a correlation to ICP [ 35 , 38 ], laser Doppler flow [ 39 ], carotid flow [ 40 ] and can be used for patient monitoring instead of ICP [ 42 ]. It was documented that REG indicated cerebral vasospasm before systemic reaction caused by complement activation/cytokine storm in pigs [ 42 ]. We described multimodal CBF AR changes during hemorrhage and various SAP changes in pigs [ 43 ].…”