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. 2019 Sep 13;7(1):54.
doi: 10.1186/s40635-019-0268-8.

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

Guillaume Poliquin  1   2   3 , Duane Funk  4 , Shane Jones  1 , Kaylie Tran  1 , Charlene Ranadheera  1 , Mable Hagan  1   3 , Kevin Tierney  1 , Allen Grolla  1 , Amrinder Dhaliwal  5 , Alexander Bello  1 , Anders Leung  1 , Cory Nakamura  6 , Darwyn Kobasa  1   3 , Darryl Falzarano  7 , Lauren Garnett  1 , Hugues Fausther Bovendo  8 , Heinz Feldmann  9 , Murray Kesselman  2 , Gregory Hansen  10 , Jason Gren  1 , George Risi  11 , Mia Biondi  12   13 , Todd Mortimer  13 , Trina Racine  3   8 , Yvon Deschambault  1 , Sam Aminian  1 , Jocelyn Edmonds  1 , Ray Sourette  1 , Mark Allan  1 , Lauren Rondeau  1 , Sharron Hadder  1 , Christy Press  1 , Christine DeGraff  1 , Stephanie Kucas  1 , Bradley W M Cook  14 , B J Hancock  2   15 , Anand Kumar  3 , Reeni Soni  2 , Darryl Schantz  2 , Jarrid McKitrick  16 , Bryce Warner  1 , Bryan D Griffin  1 , Xiangguo Qiu  1   3 , Gary P Kobinger  3   8 , Dave Safronetz  1 , Derek Stein  1   3 , Todd Cutts  1 , James Kenny  1 , Geoff Soule  1 , Robert Kozak  17 , Steven Theriault  14 , Liam Menec  1 , Robert Vendramelli  1 , Sean Higgins  1 , Guodong Liu  1 , Niaz Md Rahim  1 , Samantha Kasloff  1 , Angela Sloan  1 , Shihua He  1 , Nikesh Tailor  1 , Michael Gray  1 , James E Strong  18   19   20
Affiliations

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

Guillaume Poliquin et al. Intensive Care Med Exp. .

Erratum in

  • Correction to: Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model.
    Poliquin G, Funk D, Jones S, Tran K, Ranadheera C, Hagan M, Tierney K, Grolla A, Dhaliwal A, Bello A, Leung A, Nakamura C, Kobasa D, Falzarano D, Garnett L, Bovendo HF, Feldmann H, Kesselman M, Hansen G, Gren J, Risi G, Biondi M, Mortimer T, Racine T, Deschambault Y, Aminian S, Edmonds J, Saurette R, Allan M, Rondeau L, Hadder S, Press C, DeGraff C, Kucas S, Cook BWM, Hancock BJ, Kumar A, Soni R, Schantz D, McKitrick J, Warner B, Griffin BD, Qiu X, Kobinger GP, Safronetz D, Stein D, Cutts T, Kenny J, Soule G, Kozak R, Theriault S, Menec L, Vendramelli R, Higgins S, Banadyga L, Liu G, Rahim MN, Kasloff S, Sloan A, He S, Tailor N, Albietz A, Pickering B, Wong G, Gray M, Strong JE. Poliquin G, et al. Intensive Care Med Exp. 2019 Dec 4;7(1):66. doi: 10.1186/s40635-019-0283-9. Intensive Care Med Exp. 2019. PMID: 31802320 Free PMC article.

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.

Keywords: Ebola; Fluid; Hydrocortisone; NHP; Pathophysiology; Supportive care; Vasoactives; Ventilatory support.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Cardiovascular vital sign trends and fluid Resuscitation. Trends in cardiovascular vital signs in relation to interventions. a–d NHP1–4, respectively. HR (measured in beats per minute) and MAP (measured in mmHg) are plotted on the left Y-axis. The vertical dashed line in a, b, and d represents the first detection of viremia (for NHP3 (c), first detection occurred earlier than this time scale). The vertical lines labeled “A” and “B” in those same panels represent the start of the first and second vasoactive medications, respectively. Cyan-shaded areas represent compensated shock while magenta-shaded areas represent decompensating shock. The vertical blue bars denote fluid rate in mL/kg/hour; bars significantly above the baseline represent fluid boluses. The initial high heart rate for NHP1 (a) is secondary to acidosis. Once the acidosis began to resolve, the heart rate stabilized until the onset of EVD-related illness
Fig. 2
Fig. 2
Effect of vasoactive medications on mean arterial pressure. Mean arterial pressure (solid colored lines plotted on the left Y-axis) compared to the VIS score (dashed lines plotted on the right Y-axis). The vertical dashed line labeled “A” denotes the start of vasopressin for NHP3. Note that the X-axis was truncated to focus on the late experimental stage for all four animals
Fig. 3
Fig. 3
Viral load in plasma over time. Viral load, represented as genome copies/milliter of plasma, as derived from amplification of viral RNA using the National Microbiology Laboratory in-house assay run against a full EBOV plasmid as quantification standard
Fig. 4
Fig. 4
Lactate values over time. This figure trends lactate values over time for the four infected animals. a–d NHP1–4, respectively. a–c The lactate values over time (in black) for NHP1, NHP2, and NHP3, respectively. The blue columns represent bolus fluids. The horizontal dotted lines represent the normal value range. The cyan-shaded areas represent compensated shock while the magenta-shaded areas represent decompensating shock
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  • Correction to: Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model.
    Poliquin G, Funk D, Jones S, Tran K, Ranadheera C, Hagan M, Tierney K, Grolla A, Dhaliwal A, Bello A, Leung A, Nakamura C, Kobasa D, Falzarano D, Garnett L, Bovendo HF, Feldmann H, Kesselman M, Hansen G, Gren J, Risi G, Biondi M, Mortimer T, Racine T, Deschambault Y, Aminian S, Edmonds J, Saurette R, Allan M, Rondeau L, Hadder S, Press C, DeGraff C, Kucas S, Cook BWM, Hancock BJ, Kumar A, Soni R, Schantz D, McKitrick J, Warner B, Griffin BD, Qiu X, Kobinger GP, Safronetz D, Stein D, Cutts T, Kenny J, Soule G, Kozak R, Theriault S, Menec L, Vendramelli R, Higgins S, Banadyga L, Liu G, Rahim MN, Kasloff S, Sloan A, He S, Tailor N, Albietz A, Pickering B, Wong G, Gray M, Strong JE. Poliquin G, et al. Intensive Care Med Exp. 2019 Dec 4;7(1):66. doi: 10.1186/s40635-019-0283-9. Intensive Care Med Exp. 2019. PMID: 31802320 Free PMC article.
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