A Porcine Sepsis Model With Numerical Scoring for Early Prediction of Severity

Abstract

IntroductionSepsis can lead to organ dysfunctions with disturbed oxygen dynamics and life-threatening consequences. Since the results of organ-protective treatments cannot always be transferred from laboratory models into human therapies, increasing the translational potential of preclinical settings is an important goal. Our aim was to develop a standardized research protocol, where the progression of sepsis-related events can be characterized reproducibly in model experiments within clinically-relevant time frames.MethodsPeritonitis was induced in anesthetized minipigs injected intraperitoneally with autofeces inoculum (n = 27) or with saline (sham operation; n = 9). The microbial colony-forming units (CFUs) in the inoculum were retrospectively determined. After awakening, clinically relevant supportive therapies were conducted. Nineteen inoculated animals developed sepsis without a fulminant reaction. Sixteen hours later, these animals were re-anesthetized for invasive monitoring. Blood samples were taken to detect plasma TNF-α, IL-10, big endothelin (bET), high mobility group box protein1 (HMGB1) levels and blood gases, and sublingual microcirculatory measurements were conducted. Hemodynamic, respiratory, coagulation, liver and kidney dysfunctions were detected to characterize the septic status with a pig-specific Sequential Organ Failure Assessment (pSOFA) score and its simplified version (respiratory, cardiovascular and renal failure) between 16 and 24 h of the experiments.ResultsDespite the standardized sepsis induction, the animals could be clustered into two distinct levels of severity: a sepsis (n = 10; median pSOFA score = 2) and a septic shock (n = 9; median pSOFA score = 8) subgroup at 18 h of the experiments, when the decreased systemic vascular resistance, increased DO2 and VO2, and markedly increased ExO2 demonstrated a compensated hyperdynamic state. Septic animals showed severity-dependent scores for organ failure with reduced microcirculation despite the adequate oxygen dynamics. Sepsis severity characterized later with pSOFA scores was in correlation with the germ count in the induction inoculum (r = 0.664) and CFUs in hemocultures (r = 0.876). Early changes in plasma levels of TNF-α, bET and HMGB1 were all related to the late-onset organ dysfunctions characterized by pSOFA scores.ConclusionsThis microbiologically-monitored, large animal model of intraabdominal sepsis is suitable for clinically-relevant investigations. The methodology combines the advantages of conscious and anesthetized studies, and mimics human sepsis and septic shock closely with the possibility of numerical quantification of host responses.

A chronic intermittent haemodialysis pig model for functional evaluation of dialysis membranes

“…Several methods of inducing renal failure in animal models have been reported, including drugs, sepsis, ureteral ligation, ischaemic recanalization and bilateral nephrectomy. [10][11][12][13] We chose nephrectomy as it provides a reliable and less time-consuming model of renal failure with very few individual differences. Regarding renal function in the present model, the serum Cr level before each dialysis was high and nearly constant, starting from POD 5.…”

An experimental porcine model of invasive candidiasis

“…They have been particularly useful in infectious disease research, as they are susceptible to many of the pathogens that also infect humans. Porcine models have been used to study viral infections, such as influenza, as well as bacterial infections, such as tuberculosis, pneumonia, wound infections, and sepsis [ 18 – 22 ]. Our model represents the first porcine IC model using monitoring and interventions relevant to intensive care, and could be an important first in the expanding use of porcine models.…”

Fluid resuscitation, but not inhaled nitric oxide, improves microcirculation in septic pigs

“…All methods were carried out in accordance with applicable Polish law and followed the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH) and Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) recommendations. 36,37 Throughout our research, care was taken to guarantee the maximum comfort of the animals. The depth of analgesia was adjusted to the level of pain stimuli and the depth of anesthesia was adjusted according to the level of consciousness.…”