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.

Characterization of Ebola Virus Risk to Bedside Providers in an Intensive Care Environment

“…The clinical course and outcome of all four animals in this experiment were remarkably similar despite the differences in viral challenge, treatment, and medical complications (previously published [16,23]). All Ebola-infected animals went through a period of initial compensated shock, occurring between 5 to 6 days post-infection (DPI) followed by uncompensated shock starting on 6 DPI, and leading to multi-system failure and death by 7 DPI, despite aggressive but judicious fluid, inotropic, and other intensive medical care.…”

The emergence of travel-related infections in critical care units

“…The effect of ICU-level supportive care interventions (fluid resuscitation, vasoactive medications, blood transfusions, hydrocortisone, and ventilator support) on the pathophysiology of EVD in rhesus macaques infected with a lethal dose of Ebola strain Makona C07 was studied. [ 76 ] The animals developed progressive MOF and shock before death. While the overall impact of supportive care on the observed pathophysiology in this highly lethal model was limited, some time-dependent positive responses were observed.…”

“…While the overall impact of supportive care on the observed pathophysiology in this highly lethal model was limited, some time-dependent positive responses were observed. [ 76 ] Although an Ebola virus-specific therapy has not been proven to be effective in clinical trials, the mortality rate has been dramatically decreased among patients with EVD who are managed with supportive intensive care in settings with large amounts of resources, enabling the avoidance of hypovolemia, correction of electrolyte imbalance, and provision of oxygen, ventilation, vasopressors, and dialysis. This experience emphasizes that in addition to evaluating specific medical treatments, improvements in the global capacity to provide supportive critical care to patients with EVD may be the greatest opportunity to outcome.…”

Immunotherapeutics for Ebola Virus Disease: Hope on the Horizon

“…A recent study on the implementation of supportive care in an intensive care unit on NHPs demonstrated that all supportive care measures did little to slow the disease progression with all NHPs reaching the terminal endpoint by around 7 dpi. 55 The time course of disease in NHP is compressed compared to that of human cases. However, this means that therapeutics to treat high-risk patients need to combat the ongoing viral replication as well as quell the systemic inflammatory response and organ failure.…”