Pathophysiology of endotoxin shock in the primate

Cavanagh, Denis; Rao, P. S.; Sutton, David; Bhagat, B.; Bachmann, P.

doi:10.1016/0002-9378(70)90535-1

Cited by 85 publications

(41 citation statements)

References 30 publications

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“…After studying the effect of endotoxin on the renal function of dogs, Hinshaw et al (15) concluded that the effect of endotoxin on kidneys is primarily vascular. Cavanagh et al (11) observed a decrease in the renal artery flow of baboons after endotoxin treatment. Bradley (7) reported that the effects of endotoxin in kidneys appeared to be secondary to disseminated intravascular coagulation.…”

Section: Discussionmentioning

confidence: 97%

Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin

Bergeron¹,

Bergeron²

1986

Antimicrob Agents Chemother

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Multiple factors may modify the pharmacokinetics of aminoglycosides and increase their nephrotoxic potential. In this study, we investigated the influence of Escherichia coli endotoxin on the renal handling of several aminoglycosides and one cephalosporin. Drug levels in the renal parenchyma, as well as several parameters of renal function and histology, were compared in rats treated with endotoxin (0.25 mg/kg) and normal rats treated with either gentamicin (10 mg/kg), netilmicin (10 mg/kg), tobramyin (10 mg/kg), amikacin (50 mg/kg), or cephalothin (100 mg/kg). Blood pressure and pulse rate were recorded. Endotoxin was associated with a decrease in the half-life and in the apparent volume of distribution of gentamnicin. The endotoxin-injected animals accumulated significantly (P < 0.05) more aminoglycosides in their kidneys than the normal animals. The amount of cephalothin recovered in the renal parenchyma was identical in both groups. Slight decreases in the glomerular filtration rate and renal plasma flow were observed after endotoxin treatment. Blood pressure and cardiac frequency were minimally affected by endotoxin. No histological lesions were observed by light microscopy in animals receiving endotoxin. Thus, endotoxin modifies the renal handling of aminoglycosides in the absence of any major physiological disturbance or histological change. By increasing the total amount of drug within the kidneys, endotoxin might increase the nephrotoxic potential of aminoglycosides.Previous studies done in our laboratory revealed that the intrarenal distribution of gentamicin was disturbed in experimental pyelonephritis due to Escherichia coli (5). A greater accumulation of drug was observed in the cortex and medulla of pyelonephritic animals than in the kidneys of noninfected animals. Pyelonephritic kidneys were also shown to be more susceptible tp'the nephrotoxic potential of gentamicin than normal kidneys (2). Pyelonephritic animals treated with gentamicin showed signs of renal damage which were more striking than those observed in normal treated rats. We considered the possibility that endotoxin liberated during antibiotic therapy (13, 25) might have disturbed the intrarenal pharmacokinetics of gentamicin and acted concomitantly with gentamicin on tubular cells to potentiate the toxicity of this antibiotic. The purpose of the present study was to evaluate the influence of endotoxin on the intrarenal distribution of aminoglycosides.MATERIALS AND METHODS Experimental model: distribution studies. Female SpragueDawley rats weighing 175 to 200 g were used for all experiments. Sixteen groups of 5 to 11 animals were anesthetized by a single intraperitoneal injection of sodium pentobarbital (45 mg/kg), followed 2 h later by a second dose of 20 mg/kg. Four animals, two controls and two endotoxintreated rats, were used in parallel each day. Catheters were inserted into the right jugular vein for infusion of solutions. E. coli 0127:B8 endotoxin (0.25 mg/kg; Difco Laboratories, Detroit, Mich.) or normal saline was infused intr...

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Section: Discussionmentioning

confidence: 97%

Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin

Bergeron¹,

Bergeron²

1986

Antimicrob Agents Chemother

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“…Endotoxin infused in our animals could have enhanced the uptake of vancomycin and therefore disturbed its handling by the kidneys. Endotoxin is known to be liberated locally or Saline systemically during antibiotherapy for gram-negative bacteo Endotoxin rial infections in human patients (25) and to induce physiological changes (6,10,16,22 (14) have observed an increase in the apparent volume of distribution of gentamicin-induced pyrexia in rabbits. These changes might be the result of an altered rate of tissue perfusion or tissue binding of the drug induced by fever (14).…”

Section: Methodsmentioning

confidence: 99%

Intrarenal distribution of vancomycin in endotoxemic rats

Ngeleka

Auclair

Tardif

et al. 1989

Antimicrob Agents Chemother

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We previously observed that the intrarenal distribution of aminoglycosides was modified by Escherichia coli endotoxin in the absence of any major renal physiological disturbance or histological changes. In the present study, we evaluated the role of E. coli endotoxin on the intrarenal distribution of vancomycin. At the beginning of the experiment, female Sprague-Dawley rats were infused intravenously with saline (control) or endotoxin (0.25 mg/kg) during 15 min. Thereafter, saline was constantly infused for the following 4 h. Two hours after the beginning of the infusion, animals were injected intravenously with a single dose of vancomycin (20 mg/kg).The drug levels in serum; renal cortex, medulla, and papilla; and urine were evaluated from 0.08 to 24 h after injection. Analysis of the area under the curve of the drug concentration in the different kidney components versus time showed a higher accumulation of vancomycin in the renal cortex and medulla in the endotoxininfused rats than in the normal rats (P < 0.01). Endotoxin was associated with an increase in the half-life in serum (P < 0.01) and a lower elimination rate constant. The total clearance of vancomycin from plasma was significantly decreased in endotoxin-treated rats (P < 0.01). These results demonstrate that endotoxin modifies the renal handling of vancomycin.Vancomycin is a glycopeptide antibiotic with potent activity against gram-positive bacteria which may increase the nephrotoxic potential of aminoglycosides. The early preparation introduced in the 1950s had many impurities (14). During that period, although the nephrotoxic potential was not clearly established, up to 25% of patient were reported to have increased azotemia (29). When less toxic antistaphylococcal antibiotics, including the semisynthetic penicillins and cephalosporins, appeared, vancomycin use drastically diminished; but the emergence of methicillin-resistant staphylococci has prompted the resurgence of its use (27). The currently available compound has been purified and is believed to be less toxic than the parent compound. The incidence of nephrotoxicity with the new vancomycin has been less than 8% (11,23,27). In animals, large doses of antibiotics are needed to induce renal damage, and the mechanism of renal toxicity has not been determined. It seems that vancomycin accumulates within the renal parenchyma and induces an interstitial nephritis and proximal tubular necrosis.Endotoxin, an important constituent of the cell wall of gram-negative bacteria, has been classified as a major offender that is responsible for many complications associated with severe infections, including septic shock and renal failure. Endotoxin, which is liberated in infected patients and released in excess during antibiotic therapy (25), is able to modify the hemodynamic status of the host (13), to activate the immunological and inflammatory processes (6), to induce vasoconstriction (28), and to act directly on target cells and organelles to induce cell injuries (15,18).Previous experimental studies fr...

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“…The purpose of the present study was to evaluate adrenergically related mechanisms which might account for the eventual depression of myocardial function occurring from 2-6 h after administration of endotoxin or live E. coli organisms, as reported by Goodyer (1967), Cavanagh et al (1970), Hinshaw et al (1972c, 1973, Parratt (1973), Parratt & Winslow (1974), and Greenfield, Jackson, Elkins, Coalson & Hinshaw (1974). It was hoped that similar mechanisms to those observed in certain mammalian species might also apply to an understanding of the development of heart dysfunction in clinical septic shock (Siegel et al, 1967(Siegel et al, , 1972Bell & Thal, 1970;Cann et al, 1972;Nishijima et al, 1973).…”

Section: Discussionmentioning

confidence: 96%

Myocardial Failure With Altered Response to Adrenaline in Endotoxin Shock

Archer

Black

Hinshaw

1975

British J Pharmacology

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1 There is a growing concensus that myocardial performance in the early stages of experimental endotoxic and septic shock is relatively normal; however, recent reports have identified an intermediate phase of shock when myocardial dysfunction is clearly apparent. 2 The mechanism of dysfunction has become a subject of intense investigation. A current view is that altered myocardial responsiveness to circulating catecholamines may play an important role in the dysfunction observed after endotoxin administration. The present studies, in which an isolated working heart preparation of the dog was used, were designed to test this hypothesis. This particular experimental preparation was selected to provide an adequate interpretation of results; cardiac output, afterload, and concentrations of adrenaline reaching the coronary vascular bed were controlled in all experiments. Responses to infusions of adrenaline were recorded in the 'steady-state' condition. Control (non-shocked) heart responses to adrenaline were highly reproducible in terms of inotropic, chronotropic and coronary vascular behaviour. 3 Results from the study document myocardial dysfunction within 4-6 h following an LD70 endotoxin administration on the basis of increased left ventricular end diastolic pressure (LVEDP), decreased cardiac power and myocardial efficiency, and depressed negative and positive dP/dt parameters. 4 Findings suggest significantly altered responsiveness of the myocardium to infused adrenaline at rates of 1, 2, and 5 pg/min with concentrations between 10 and 1 ng/ml blood. LVEDP was elevated while calculated power and efficiency parameters remained significantly below control values during infusion of adrenaline in endotoxin-treated hearts. Depressions of responsiveness were interpreted to occur on the basis of failure to restore positive and negative dP/dt to normal values and depressed coronary blood flow responses during adrenaline administration. Increases in coronary flow were regularly less in experimental hearts than the controls. Heart rate responses to adrenaline in both failing and non-failing hearts were identical. 5 In conclusion, it is suggested that myocardial contractile and relaxation characteristics and coronary vascular responses to adrenaline infusion are depressed in endotoxin shock during the period of demonstrated myocardial dysfunction. No distinct causal relationships were observed between the ailtered myocardial responsiveness and pathogenesis of heart dysfunction since myocardial dysfunction and altered responsiveness to adrenaline were generally observed together. Myocardial oedema formation after endotoxin as previously reported by this laboratory may bear a relationship to the depressed negative dP/dt response to adrenaline.

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Pathophysiology of endotoxin shock in the primate

Cited by 85 publications

References 30 publications

Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin

Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin

Intrarenal distribution of vancomycin in endotoxemic rats

Myocardial Failure With Altered Response to Adrenaline in Endotoxin Shock

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