Objectives:To review mechanisms underlying sepsis-induced cardiac dysfunction in general and intrinsic myocardial depression in particular.Data Source:MEDLINE database.Data Synthesis:Myocardial depression is a well-recognized manifestation of organ dysfunction in sepsis. Due to the lack of a general

Mechanisms of sepsis-induced cardiac dysfunction

Sepsis is characterized by a severe inflammatory response to infection, and its complications, including acute kidney injury, can be fatal. Animal models that correctly mimic human disease are extremely valuable because they hasten the development of clinically useful therapeutics. Too often, however, animal models do not properly mimic human disease. In this Review, we outline a bedside-to-bench-to-bedside approach that has resulted in improved animal models for the study of sepsis — a complex disease for which preventive and therapeutic strategies are unfortunately lacking. We also highlight a few of the promising avenues for therapeutic advances and biomarkers for sepsis and sepsis-induced acute kidney injury. Finally, we review how the study of drug targets and biomarkers are affected by and in turn have influenced these evolving animal models.

/pdf/animal-models-of-sepsis-and-sepsis-induced-kidney-injury-3kwa2ipc9j.pdf

Animal models of sepsis and sepsis-induced kidney injury

Septic shock is one of the leading causes of acute kidney injury. The mechanisms of this injury remain mostly unknown notably because of the lack of data on renal histological lesions in humans. Kidney biopsy was performed immediately post-mortem in consecutive patients who died of septic shock. Comparisons were made with specimens from eight patients who died of trauma on scene and nine ICU patients that died of non-septic causes. Nineteen septic patients were included, 11 were male, and age was 72 ± 12 years. Anuria occurred in all patients 2.2 ± 1.4 days before death. Seven patients had disseminated intravascular coagulation. In all patients we observed (1) acute tubular lesions whose intensity correlated with blood lactate concentration; (2) intense infiltration by leukocytes, mainly monocytic, in glomeruli and interstitial capillaries as compared to controls; (3) presence of tubular cell apoptosis proved by the presence of apoptotic bodies (2.9% of tubular cells) significantly more frequently than in controls and confirmed by TUNEL and activated caspase-3 staining. Arteriolar/arterial thromboses were observed in only 4 of 19 patients, without any association with presence of disseminated intravascular coagulation. Kidney lesions in septic shock go beyond those associated with simple acute tubular injury, notably capillary leukocytic infiltration and apoptosis. Vascular thrombosis, however, did not appear to play a major role in the majority of patients. The extent to which these lesions are specific to sepsis or are common to all multi-organ failure independent of its cause is yet to be elucidated.

/pdf/histopathology-of-septic-shock-induced-acute-kidney-injury-1neeu6bcw5.pdf

Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic infiltration

Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome.

Objective: To describe temporal changes in mitochondrial function during the septic process, including the recovery phase. Design: Literature review. Subjects: Clinical studies and laboratory models. Main Results: Biochemical and ultrastructural mitochondrial abnormalities have been recognized in in vivo, ex vivo, and in vitro laboratory models of sepsis for >30 yrs. Short-term models show variable effects on mitochondrial function and structure; this is likely related to differences in model design, including species, organs studied, degree of septic insult, and degree of resuscitation. Longer-term models more consistently reveal mitochondrial dysfunction and damage. There is a rebound increase in oxygen consumption and resting energy expenditure in the recovery phase of sepsis. This could reflect mitochondrial recovery (biogenesis) that may restore the energy supply needed to fuel restorative metabolic processes and enable patient survival. Conclusion: Mitochondrial dysfunction seems to be intrinsically involved in the pathogenesis of multiple organ failure. As a consequence of a progressive decrease in energy availability, metabolism must decrease or the cell will die. The interplay between adenosine 5'-triphosphate supply and demand, dictated by the degree of mitochondrial dysfunction and the level of metabolic shutdown (analogous to a hibernation-type response), seems to be crucial in determining outcome. Further studies are needed to confirm this hypothesis.

Mitochondrial function in sepsis: Acute phase versus multiple organ failure

Hepatic cellular injury following lethal Escherichia coli bacteremia in rats.

Mechanisms of subcellular dysfunction of the liver in sepsis are still obscure. The present study investigates changes in oxidative phosphorylative activity and calcium-induced respiration of rat liver mitochondria following live Escherichia coli injection (E coli, Serotype: 0--18. A 1.25--1.5 X 10(9)/100 gm body wt inoculum of E coli bacteria was injected via the tail vein, causing a 100% mortality rate within 24 hours after injection. In order to determine alteration of liver mitochondrial membrane permeability, serum ornithine carbamoyltransferase activity was measured following E coli injection. This activity increased ten to 100-fold over that of controls with time following injection. However, the yield of liver mitochondria from treated rats, estimated by the amount of collected mitochondrial protein and the recovery rate of succinate dehydrogenase activity in the final mitochondrial suspensions, was not significantly different from that of controls. Mitochondrial oxidative phosphorylative activity measured using glutamate as a substrate was enhanced throughout all period to death (P less than 0.01 at three and six hours, P less than 0.05 in the fatal stage) and was associated with concomitant increases in respiratory control ratios. Similar results were obtained using beta-hydroxybutyrate as a substrate. This enhancement was accompanied by an increase in 2-4-dinitrophenol-stimulated ATPase activity (160% at three hours and 130% in the fatal stage). Calcium-induced stimulation of mitochondrial respiration as well as initial calcium uptake rate linked to respiration, using glutamate as a substrate, were higher in liver mitochondria from rats with E coli treatment than in those of controls throughout all periods (P less than 0.01 or less). These results suggest the coexistence of hyperfunctioning as well as deteriorated mitochondria following lethal treatment with E coli.

A study of oxidative phosphorylative activity and calcium-induced respiration of rat liver mitochondria following living Escherichia coli injection.

The only limit to the use and application of the autopsy in research is the imagination of the investigator. As pathologists, it would appear that we have really neglected this powerful tool in recent decades and have undersold the potentiality of this method. As we hope to have made evident by the foregoing discussion, the field of research utilizing autopsy tissues is truly as broad as medicine itself, and if developed properly, becomes an indispensable part of the fabric of on-going research in areas of carcinogenesis, environmental disease, atherosclerosis, and aging.

The use and application of autopsy in research.

In acute renal failure in man following shock and trauma, an amazing discrepancy was found between the complete breakdown of renal function and the very modest histological and ultrastructural changes in "immediate autopsy" patients, even in those who sustained septic shock. Although, from this limited number of studies no satisfactory interpretation of the pathogenesis of acute renal failure can be deduced from the structural changes found, the findings do indicate that hypoxia plays a key role in aggravating the structural changes that induce permanent cell damage in man following shock of various etiologies including septic shock.

Ultrastructural study on kidney cell injury following various types of shock in 26 immediate autopsy patients.

The effects of hypothermia on survival time and ECGs were investigated in hemorrhagic-shocked rats. Acute blood loss corresponding to LD84 was achieved within 1 min through cannulation of the carotid artery. Immediately following the hemorrhagic episode, extracorporeal cooling was performed by placing the animals, with ice packs attached to their lateral sides, in a cold water bath. Rewarming was achieved by removing the ice packs and resetting the temperature of the water bath to 37 degrees C. With this system, the survival time of the hemorrhagic rats was lengthened from 40 to 60 min without rewarming and to 123 min with rewarming. ECGs showed sinus bradycardia, prolonged PR and QRS intervals, AV block, and finally ventricular fibrillation in both the control and hemorrhagic groups during extracorporeal cooling. During rewarming, the above ECG changes returned to normal in the control group as did body temperature. In contrast, animals in the hemorrhagic group did not survive. Body temperature in this group began to rise toward normal, and above ECG changes showed slight but not complete improvement. It is concluded that extracorporeal cooling can lengthen the survival time of hemorrhagic-shocked rats and that recovery of the disturbed conduction system is a prerequisite for survival from severe hypothermia.

Effect of hypothermia on survival time and ECG in rats with acute blood loss.

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