Delivering Prolonged Intensive Care to a Non-human Primate: A High Fidelity Animal Model of Critical Illness

Abstract

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 35–54% 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.

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

“…Overall, animals 2–4 (NHP2, NHP3, and NHP4) demonstrated remarkably similar clinical courses. The first infected animal (NHP1) had a more complex course secondary to a ventilator-associated pneumonia (VAP) as well as a renal tubular acidosis unrelated to the EBOV infection [8]. These complications delayed time to infection compared to NHP2–4 to allow for treatment of the VAP with antibiotics prior to infection.…”

“…Furthermore, given the ethical implications of NHP research, we felt it appropriate to ensure each experiment had an optimized chance of achieving the experimental outcome, rather than focus on having sufficient power to compare specific intervention types. The use of sedation medications may have had an impact on cardiovascular function, although we previously demonstrated that these medications were safe for long-term use (beyond the 10th day), exceeding the experimental window [8].…”

“…We previously described our model for non-human primate (NHP) intensive care [8]. In brief, rhesus macaques were managed continuously by bedside teams and study physicians in a biosafety level 4 (BSL4) environment.…”

Haemostatic Changes in Five Patients Infected with Ebola Virus

“…As mentioned above, patients with EVD may develop DIC, organ failure, sepsis or other complications so treatment is complex. In recent years studies providing intensive care levels of supportive care to non-human primates infected with Ebola virus, including fluid and electrolyte management for virus induced sepsis have been attempted [33] and Maj AP. Cardile, personal communication as we continue to try and find ways to manage this complex disease.…”

Nonhuman primate species as models of human bacterial sepsis

“…Significant resources and expertise are especially essential for NHP experiments involving intravenous infusions, phlebotomy, or vital sign measurements; these procedures generally require sedation, which when administered to septic animals can worsen cardiopulmonary instability (similar to patients). While such sepsis experiments have been reported for chimpanzees 40 , baboons 70 , and rhesus macaques 113 , they have required provision of ICU-level support (e.g., mechanical ventilation, vasopressors, fluids). An alternative strategy involves inserting and tethering indwelling intravascular catheters or vital sign recording devices to a harness worn by the animal 19,114 .…”