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Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model.

ABSTRACT: BACKGROUND:There are currently limited data for the use of specific antiviral therapies for the treatment of Ebola virus disease (EVD). While there is anecdotal evidence that supportive care may be effective, there is a paucity of direct experimental data to demonstrate a role for supportive care in EVD. We studied the impact of ICU-level supportive care interventions including fluid resuscitation, vasoactive medications, blood transfusion, hydrocortisone, and ventilator support on the pathophysiology of EVD in rhesus macaques infected with a universally lethal dose of Ebola virus strain Makona C07. METHODS:Four NHPs were infected with a universally lethal dose Ebola virus strain Makona, in accordance with the gold standard lethal Ebola NHP challenge model. Following infection, the following therapeutic interventions were employed: continuous bedside supportive care, ventilator support, judicious fluid resuscitation, vasoactive medications, blood transfusion, and hydrocortisone as needed to treat cardiovascular compromise. A range of physiological parameters were continuously monitored to gage any response to the interventions. RESULTS:All four NHPs developed EVD and demonstrated a similar clinical course. All animals reached a terminal endpoint, which occurred at an average time of 166.5?±?14.8?h post-infection. Fluid administration may have temporarily blunted a rise in lactate, but the effect was short lived. Vasoactive medications resulted in short-lived improvements in mean arterial pressure. Blood transfusion and hydrocortisone did not appear to have a significant positive impact on the course of the disease. CONCLUSIONS:The model employed for this study is reflective of an intramuscular infection in humans (e.g., needle stick) and is highly lethal to NHPs. Using this model, we found that the animals developed progressive severe organ dysfunction and profound shock preceding death. While the overall impact of supportive care on the observed pathophysiology was limited, we did observe some time-dependent positive responses. Since this model is highly lethal, it does not reflect the full spectrum of human EVD. Our findings support the need for continued development of animal models that replicate the spectrum of human disease as well as ongoing development of anti-Ebola therapies to complement supportive care.

SUBMITTER: Poliquin G

PROVIDER: S-EPMC6744539 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model.

Poliquin Guillaume G Funk Duane D Jones Shane S Tran Kaylie K Ranadheera Charlene C Hagan Mable M Tierney Kevin K Grolla Allen A Dhaliwal Amrinder A Bello Alexander A Leung Anders A Nakamura Cory C Kobasa Darwyn D Falzarano Darryl D Garnett Lauren L Bovendo Hugues Fausther HF Feldmann Heinz H Kesselman Murray M Hansen Gregory G Gren Jason J Risi George G Biondi Mia M Mortimer Todd T Racine Trina T Deschambault Yvon Y Aminian Sam S Edmonds Jocelyn J Sourette Ray R Allan Mark M Rondeau Lauren L Hadder Sharron S Press Christy C DeGraff Christine C Kucas Stephanie S Cook Bradley W M BWM Hancock B J BJ Kumar Anand A Soni Reeni R Schantz Darryl D McKitrick Jarrid J Warner Bryce B Griffin Bryan D BD Qiu Xiangguo X Kobinger Gary P GP Safronetz Dave D Stein Derek D Cutts Todd T Kenny James J Soule Geoff G Kozak Robert R Theriault Steven S Menec Liam L Vendramelli Robert R Higgins Sean S Liu Guodong G Rahim Niaz Md NM Kasloff Samantha S Sloan Angela A He Shihua S Tailor Nikesh N Gray Michael M Strong James E JE

Intensive care medicine experimental 20190913 1

<h4>Background</h4>There are currently limited data for the use of specific antiviral therapies for the treatment of Ebola virus disease (EVD). While there is anecdotal evidence that supportive care may be effective, there is a paucity of direct experimental data to demonstrate a role for supportive care in EVD. We studied the impact of ICU-level supportive care interventions including fluid resuscitation, vasoactive medications, blood transfusion, hydrocortisone, and ventilator support on the p ...[more]

PMID: 31520194

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Project description:Critically ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decrease quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders associated with ICU-acquired muscle weakness. Although there are no available treatments for the ICU-acquired muscle weakness, it has been demonstrated that early mobilization can improve its prognosis and functional outcomes. This study aims at improving our understanding of the effects of passive mechanical loading on skeletal muscle structure and function by using a unique experimental rat ICU model allowing analyses of the temporal sequence of changes in mechanically ventilated and pharmacologically paralyzed animals at durations varying from 6 h to 14 days. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle structure and function is likely a consequence of a reduced oxidative stress, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle structure and function associated with mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients. This study aims to unravel the effects of passive mechanical loading on skeletal muscle structure and function in an experimental rat ICU model at duration varying between 6h and 14 days. A total of 23 experimental female Sprague-Dawley rats were included in this study. The experimental rats were anaesthetized, treated with the neuromuscular blocking agent (NMBA) M-NM-1-cobrotoxin, mechanically ventilated and monitored for durations varying from 6h to 4 days (n=13), from 5 to 8 days (n=4), and from 9 to 14 days (n=6). The left leg of the animal was activated for 6 hours at the shortest duration and 12 hours per day at durations 12 hours and longer throughout the experiment, using a mechanical lever arm that produced a continuous passive maximal ankle joint flexions-extensions at a speed of 13.3 cycles per minute. Muscle biopsies were obtained from gastrocnemius muscle (proximal part) immediately after euthanasia, were quickly frozen in liquid propane cooled by liquid nitrogen, and stored at -80M-BM-0C. RNA was extracted.

Dataset Information

Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model.

Publications

Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model.

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