{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:33:42Z","timestamp":1788363222099,"version":"build-2803163510"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,4,26]],"date-time":"2017-04-26T00:00:00Z","timestamp":1493164800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,4,26]],"date-time":"2017-04-26T00:00:00Z","timestamp":1493164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Critical care needs have been rising in recent decades as populations age and comorbidities increase. Sepsis-related admissions to critical care contribute up to 50% of volume and septic shock carries a 35\u201354% fatality rate. Improvements in sepsis-related care and mortality would have a significant impact of a resource-intensive area of health care delivery. Unfortunately, research has been hampered by the lack of an animal model that replicates the complex care provided to humans in an intensive care unit (ICU). We developed a protocol to provide full ICU type supportive care to Rhesus macaques. This included mechanical ventilation, continuous sedation, fluid and electrolyte management and vasopressor support in response to Ebolavirus-induced septic shock. The animals accurately recapitulated human responses to a full range of ICU interventions (e.g. fluid resuscitation). This model can overcome current animal model limitations by accurately emulating the complexity of ICU care and thereby provide a platform for testing new interventions in critical care and sepsis without placing patients at risk.<\/jats:p>","DOI":"10.1038\/s41598-017-01107-6","type":"journal-article","created":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T13:37:54Z","timestamp":1492695474000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Delivering Prolonged Intensive Care to a Non-human Primate: A High Fidelity Animal Model of Critical Illness"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8822-5882","authenticated-orcid":false,"given":"P. Guillaume","family":"Poliquin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia","family":"Biondi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlene","family":"Ranadheera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mable","family":"Hagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Bello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trina","family":"Racine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Allan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duane","family":"Funk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"BJ","family":"Hancock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray","family":"Kesselman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Mortimer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Grolla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaylie N.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Tierney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangguo","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darwyn","family":"Kobasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Strong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,26]]},"reference":[{"key":"1107_CR1","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1097\/CCM.0b013e3181b090d0","volume":"38","author":"NA Halpern","year":"2010","unstructured":"Halpern, N. A. & Pastores, S. M. Critical care medicine in the United States 2000\u20132005: an analysis of bed numbers, occupancy rates, payer mix, and costs. Crit Care Med \n                           38, 65\u201371, doi:10.1097\/CCM.0b013e3181b090d0 (2010).","journal-title":"Crit Care Med"},{"key":"1107_CR2","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1007\/s40273-015-0282-y","volume":"33","author":"B Tiru","year":"2015","unstructured":"Tiru, B. et al. The Economic and Humanistic Burden of Severe Sepsis. Pharmacoeconomics \n                           33, 925\u2013937, doi:10.1007\/s40273-015-0282-y (2015).","journal-title":"Pharmacoeconomics"},{"key":"1107_CR3","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1097\/01.CCM.0000194725.48928.3A","volume":"34","author":"J-L Vincent","year":"2006","unstructured":"Vincent, J.-L. et al. Sepsis in European intensive care units: Results of the SOAP study*. Critical Care Medicine \n                           34, 344\u2013353, doi:10.1097\/01.ccm.0000194725.48928.3a (2006).","journal-title":"Critical Care Medicine"},{"key":"1107_CR4","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","volume":"315","author":"M Singer","year":"2016","unstructured":"Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA \n                           315, 801\u2013810, doi:10.1001\/jama.2016.0287 (2016).","journal-title":"JAMA"},{"key":"1107_CR5","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1007\/s00011-016-0937-y","volume":"65","author":"CL Lakshmikanth","year":"2016","unstructured":"Lakshmikanth, C. L., Jacob, S. P., Chaithra, V. H., de Castro-Faria-Neto, H. C. & Marathe, G. K. Sepsis: in search of cure. Inflamm Res \n                           65, 587\u2013602, doi:10.1007\/s00011-016-0937-y (2016).","journal-title":"Inflamm Res"},{"key":"1107_CR6","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.ccm.2016.01.015","volume":"37","author":"EJ Seeley","year":"2016","unstructured":"Seeley, E. J. & Bernard, G. R. Therapeutic Targets in Sepsis: Past, Present, and Future. Clin Chest Med \n                           37, 181\u2013189, doi:10.1016\/j.ccm.2016.01.015 (2016).","journal-title":"Clin Chest Med"},{"key":"1107_CR7","doi-asserted-by":"publisher","first-page":"R47","DOI":"10.1186\/cc4858","volume":"10","author":"E Wiel","year":"2006","unstructured":"Wiel, E. et al. Activated protein C increases sensitivity to vasoconstriction in rabbit Escherichia coli endotoxin-induced shock. Crit Care \n                           10, R47, doi:10.1186\/cc4858 (2006).","journal-title":"Crit Care"},{"key":"1107_CR8","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2220\/biomedres.32.9","volume":"32","author":"S Jesmin","year":"2011","unstructured":"Jesmin, S. et al. Time-dependent expression of endothelin-1 in lungs and the effects of TNF-alpha blocking peptide on acute lung injury in an endotoxemic rat model. Biomedical Research \n                           32, 9\u201317 (2011).","journal-title":"Biomedical Research"},{"key":"1107_CR9","doi-asserted-by":"publisher","first-page":"143","DOI":"10.4161\/viru.26083","volume":"5","author":"MP Fink","year":"2014","unstructured":"Fink, M. P. Animal models of sepsis. Virulence \n                           5, 143\u2013153, doi:10.4161\/viru.26083 (2014).","journal-title":"Virulence"},{"key":"1107_CR10","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1056\/NEJMoa010307","volume":"345","author":"E Rivers","year":"2001","unstructured":"Rivers, E. et al. Early Goal-directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine \n                           345, 1368\u20131377 (2001).","journal-title":"New England Journal of Medicine"},{"key":"1107_CR11","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1056\/NEJMoa1404380","volume":"371","author":"ARISE Investigators","year":"2014","unstructured":"ARISE Investigators. Goal-directed resuscitation for patients with early septic shock. N Engl J Med \n                           371, 1496\u20131506, doi:10.1056\/NEJMoa1404380 (2014).","journal-title":"N Engl J Med"},{"key":"1107_CR12","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1056\/NEJMoa1401602","volume":"370","author":"ProCESS Investigators","year":"2014","unstructured":"ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med \n                           370, 1683\u20131693, doi:10.1056\/NEJMoa1401602 (2014).","journal-title":"N Engl J Med"},{"key":"1107_CR13","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1056\/NEJMoa1500896","volume":"372","author":"PR Mouncey","year":"2015","unstructured":"Mouncey, P. R. et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med \n                           372, 1301\u20131311, doi:10.1056\/NEJMoa1500896 (2015).","journal-title":"N Engl J Med"},{"key":"1107_CR14","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1164\/rccm.201512-2544CP","volume":"194","author":"HC Prescott","year":"2016","unstructured":"Prescott, H. C., Calfee, C. S., Thompson, B. T., Angus, D. C. & Liu, V. X. Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design. Am J Respir Crit Care Med \n                           194, 147\u2013155, doi:10.1164\/rccm.201512-2544CP (2016).","journal-title":"Am J Respir Crit Care Med"},{"key":"1107_CR15","doi-asserted-by":"publisher","first-page":"2868","DOI":"10.1172\/JCI39421","volume":"119","author":"K Doi","year":"2009","unstructured":"Doi, K., Leelahavanichkul, A., Yuen, P. S. & Star, R. A. Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest \n                           119, 2868\u20132878, doi:10.1172\/JCI39421 (2009).","journal-title":"J Clin Invest"},{"key":"1107_CR16","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1189\/jlb.0806542","volume":"81","author":"D Rittirsch","year":"2007","unstructured":"Rittirsch, D., Hoesel, L. M. & Ward, P. A. The disconnect between animal models of sepsis and human sepsis. J Leukoc Biol \n                           81, 137\u2013143, doi:10.1189\/jlb.0806542 (2007).","journal-title":"J Leukoc Biol"},{"key":"1107_CR17","doi-asserted-by":"publisher","first-page":"H2487","DOI":"10.1152\/ajpheart.00589.2007","volume":"293","author":"PC Minneci","year":"2007","unstructured":"Minneci, P. C. et al. A canine model of septic shock: balancing animal welfare and scientific relevance. Am J Physiol Heart Circ Physiol \n                           293, H2487\u20132500, doi:10.1152\/ajpheart.00589.2007 (2007).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"1107_CR18","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.jcrc.2015.09.032","volume":"31","author":"E de Montmollin","year":"2016","unstructured":"de Montmollin, E., Aboab, J., Ferrer, R., Azoulay, E. & Annane, D. Criteria for initiation of invasive ventilation in septic shock: An international survey. J Crit Care \n                           31, 54\u201357, doi:10.1016\/j.jcrc.2015.09.032 (2016).","journal-title":"J Crit Care"},{"key":"1107_CR19","first-page":"21","volume":"46","author":"CE Hotchkiss","year":"2007","unstructured":"Hotchkiss, C. E., Wang, C. & Slikker, W. Jr Effect of Prolonged Ketamine Exposure on Cardiovascular Physiology in Pregnant and Infant Rhesus Monkeys (Macaca mulatta). Journal of the American Association for Laboratory Animal Science \n                           46, 21\u201328 (2007).","journal-title":"Journal of the American Association for Laboratory Animal Science"},{"issue":"Suppl 3","key":"1107_CR20","doi-asserted-by":"publisher","first-page":"S1000","DOI":"10.1093\/infdis\/jir337","volume":"204","author":"MG Kortepeter","year":"2011","unstructured":"Kortepeter, M. G. et al. Real-time monitoring of cardiovascular function in rhesus macaques infected with Zaire ebolavirus. J Infect Dis \n                           204(Suppl 3), S1000\u20131010, doi:10.1093\/infdis\/jir337 (2011).","journal-title":"J Infect Dis"},{"key":"1107_CR21","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.ccm.2015.05.008","volume":"36","author":"MP Knauert","year":"2015","unstructured":"Knauert, M. P., Haspel, J. A. & Pisani, M. A. Sleep Loss and Circadian Rhythm Disruption in the Intensive Care Unit. Clin Chest Med \n                           36, 419\u2013429, doi:10.1016\/j.ccm.2015.05.008 (2015).","journal-title":"Clin Chest Med"},{"key":"1107_CR22","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1111\/j.1399-3089.2012.00713.x","volume":"19","author":"JI Lee","year":"2012","unstructured":"Lee, J. I. et al. Reference values of hematology, chemistry, electrolytes, blood gas, coagulation time, and urinalysis in the Chinese rhesus macaques (Macaca mulatta). Xenotransplantation \n                           19, 244\u2013248, doi:10.1111\/j.1399-3089.2012.00713.x (2012).","journal-title":"Xenotransplantation"},{"key":"1107_CR23","doi-asserted-by":"publisher","first-page":"S991","DOI":"10.1093\/infdis\/jir336","volume":"204","author":"H Ebihara","year":"2011","unstructured":"Ebihara, H. et al. Host Response Dynamics Following Lethal Infection of Rhesus Macaques with Zaire ebolavirus. Journal of Infectious Diseases \n                           204, S991\u2013999, doi:10.1093\/infdis\/jir336 (2011).","journal-title":"Journal of Infectious Diseases"},{"key":"1107_CR24","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1093\/infdis\/152.5.887","volume":"152","author":"SP Fisher-Hoch","year":"1985","unstructured":"Fisher-Hoch, S. P. et al. Pathophysiology of Shock and Hemorrhage in a Fulminating Viral Infection (Ebola). The Journal of Infectious Diseases \n                           152, 887\u2013894 (1985).","journal-title":"The Journal of Infectious Diseases"},{"key":"1107_CR25","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1111\/j.1600-0684.2009.00393.x","volume":"39","author":"TL Settle","year":"2010","unstructured":"Settle, T. L., Rico, P. J. & Lugo-Roman, L. A. The effect of daily repeated sedation using ketamine or ketamine combined with medetomidine on physiology and anesthetic characteristics in rhesus macaques. J Med Primatol \n                           39, 50\u201357, doi:10.1111\/j.1600-0684.2009.00393.x (2010).","journal-title":"J Med Primatol"},{"key":"1107_CR26","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1207\/S15327604JAWS0603_03","volume":"6","author":"SJ Schapiro","year":"2003","unstructured":"Schapiro, S. J., Bloomsmith, M. A. & Laule, G. E. Positive reinforcement training as a technique to alter nonhuman primate behavior: quantitative assessments of effectiveness. J Appl Anim Welf Sci \n                           6, 175\u2013187, doi:10.1207\/S15327604JAWS0603_03 (2003).","journal-title":"J Appl Anim Welf Sci"},{"key":"1107_CR27","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.vascn.2010.05.014","volume":"62","author":"S Authier","year":"2010","unstructured":"Authier, S., Haefner, P., Fournier, S., Troncy, E. & Moon, L. B. Combined cardiopulmonary assessments with implantable telemetry device in conscious freely moving cynomolgus monkeys. J Pharmacol Toxicol Methods \n                           62, 6\u201311, doi:10.1016\/j.vascn.2010.05.014 (2010).","journal-title":"J Pharmacol Toxicol Methods"},{"key":"1107_CR28","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1242\/dmm.000471","volume":"2","author":"D Bente","year":"2009","unstructured":"Bente, D., Gren, J., Strong, J. E. & Feldmann, H. Disease modeling for Ebola and Marburg viruses. Dis Model Mech \n                           2, 12\u201317, doi:10.1242\/dmm.000471 (2009).","journal-title":"Dis Model Mech"},{"key":"1107_CR29","unstructured":"Public Health Agency of Canada. Program Specific Guidelines in The Laboratory Safety Guidelines. Government of Canada, Ottawa (2004)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01107-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01107-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01107-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:53:57Z","timestamp":1671767637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01107-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,26]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["1107"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-01107-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,26]]},"assertion":[{"value":"24 November 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"1204"}}