Systemic and Neuropathologic Effects of E. coli Endotoxin in Neonatal Dogs

Abstract

Summarytional 2 0 4 samples of arterial blood were obtained hourly forThe acute systemic and neuropathologic effects of E. coli endotoxin were determined in neonatal dogs. Administration of sublethal (LDo), moderate (LD50), or lethal (LDlo0) doses of endotoxin produced significant arterial hypotension, metabolic (lactic) acidosis, and hypoglycemia. Neuropathologic changes consisted of widespread inflammation in both grey and white matter; however, necrotic lesions were found only in forebrain white matter.determination ofplasma glucose and lactate levels by fluorometric analysis according to the method of Lowry and Passoneau (19). Body temperature was monitored by means of a rectal thermocouple (Yellow Springs) and maintained by a servo-controlled heating lamp. After insertion of the catheter, halothane was withdrawn and the animals allowed to spbntaneously breathe room air. The wound was sutured and periodically infiltrated with xylocaine, 1%. A low (LDo), moderate (LD~o), or high (LDIoo) Bacterial infections in the human infant are an important cause of subsequent mental retardation, cerebral palsy, and epilepsy (18,22,23,25). The morbidity and mortality associated with perinatal bacterial infections have been attributed to bacterial endotoxin, a lipopolysaccharide component of the bacterial cell wall. Because administration of endotoxin to laboratory animals mimics human septicemia (1,4,8,14), the systemic and neuropathologic disturbances induced by endotoxin are of considerable interest.Studies by Gilles et al. (12) have shown that administration of E. coli endotoxin to newborn kittens produces extensive brain injury. The acute systemic changes occurring during neonatal endotoxemia have not been described in detail. We, therefore, undertook a series of experiments in neonatal dogs to determine the acute neuropathologic changes occurring during endotoxemia as well as the critical physiologic and and metabolic parameters (blood pressure, heart rate, arterial blood gases, glucose, and lactate levels), which might be associated with those neuropathologic changes. Although these systemic parameters have not been studied during endotoxemia in the neonatal dog, they have been shown to be important predictors of mortality in the endotoxintreated adult dog (5,9,17,20). MATERIALS AND METHODSDose-response curve. Mongrel dogs, 1-10 days of age, were selected because their state of neurologic development at birth resembles that of the human infant of approximately 34-40 wk gestation (16). Trials were conducted in 16 animals to determine the dose of E. coli endotoxin that would result in 0, 50, and 100% mortality when injected subcutaneously. A lyophilized preparation of endotoxin from E. coli 055:B5 (Difco Laboratories) was chosen because this organism is a pathogen for human neonates, may be transmitted by nursery personnel (28), and has been previously used in neuropathologic experiments (12).Systemic responses to graded endotoxemia. The physiologic and metabolic responses of the animals were examined before and after ...

Neurobiology of Periventricular Leukomalacia in the Premature Infant

“…Thus, a distinct disturbance of vascular endothelium can be produced by endotoxin, as observed in brains of newborn kittens that developed PVL after endotoxin injection (122,164,165). Additionally, endotoxin has been shown to cause arterial hypotension in newborn dogs, in sublethal doses, and to produce in the same animals periventricular WM injury (166). Moreover, in the model the deficits in blood flow and metabolism produced in cerebral WM by hemorrhage-induced hypotension were similar to those produced by endotoxin-induced hypotension.…”

Models of Fetal Brain Injury, Intrauterine Inflammation, and Preterm Birth

“…However, these neonatal dogs had necrotic lesions only in the forebrain white matter. 40 Recently developed models aim to connect the impact of maternal inflammation and fetal exposure to the inflammatory milieu (animal models of maternal inflammation-induced fetal injury are depicted in Table I). Yoon et al 41 introduced E. coli into the cervix of pregnant rabbits on gestational day 21/22 and observed that all kits with evidence of intrauterine infection had white matter damage.…”

Timing of Neutrophil Depletion Influences Long-Term Neuroprotection in Neonatal Rat Hypoxic-Ischemic Brain Injury

“…Experimentally induced intrauterine infection causes brain damage in neonatal rabbits (54,55), and the administration of endotoxin to neonatal animals is associated with injury to the periventricular white matter (56,57). Notably, the periventricular white matter has very low blood flow even under normal conditions and the density of blood vessels in the white matter is lowest at around 28 wk gestation, about the same time that incidence of periventricular leukomalacia peaks (58,59).…”