In vivo oral efficacy of levofloxacin for treatment of systemic Pseudomonas aeruginosa infections in a murine model of septicemia.

The in vivo efficacies of levofloxacin and ciprofloxacin in lethal, systemic Pseudomonas aeruginosa infections in mice were compared. MICs of levofloxacin and ciprofloxacin ranged from 0.5 to 2.0 micrograms/ml and from 0.12 to 1.0 microgram/ml respectively. Infecting doses ranged from 5.0 x 10(1) to 3.2 x 10(3) CFU per mouse, depending on the isolate. Test fluoroquinolones were administered orally at 1 h (single dose) or at 1 and 3 h (divided dose) postinfection, with 10 infected mice used for each of six concentrations of each fluoroquinolone tested (1 to 40 mg/kg of body weight) in each dosing regimen. Whether given in a single or a divided dose, the total daily dose was the same for each fluoroquinolone. For mice treated 1 h postinfection with levofloxacin and ciprofloxacin, the effective doses for 50% of the infected mice ranged from 2.09 to 13.80 mg/kg and from 2.34 to 11.22 mg/kg, respectively, and for those treated 1 and 3 h postinfection, the effective doses for 50% of the infected mice ranged from 3.71 to 16.98 mg/kg and from 2.95 to 13.18 mg/kg, respectively. Although the potency varied for both levofloxacin and ciprofloxacin among all strains of P. aeruginosa tested, there were small differences within the same strain for levofloxacin and ciprofloxacin when given in the same dosing regimen. Levofloxacin proved nearly as effective as ciprofloxacin against a systemic P. aeruginosa infection in mice.

Investigation of electrophysiologic mechanisms for the antiarrhythmic actions of R 56865 in cardiac glycoside toxicity.

R 56865 is an experimental compound that has been shown to ameliorate the effects of cardiac glycoside toxicity and myocardial ischemia. We evaluated the direct electrophysiological effects of R 56865 and its effects on the electrophysiological sequelae of ouabain toxicity in vivo and in vitro. In normal anesthetized dogs, R 56865 alone at doses of 0.04 to 0.16 mg/kg i.v. had no effect on atrial, AV nodal, or ventricular conduction times and refractoriness, but at doses of 0.64 to 2.5 mg/kg it tended to increase these parameters. In ouabain-pretreated dogs, R 56865 (0.08 to 0.32 mg/kg i.v.) dose-relatedly reduced ouabain-induced ventricular arrhythmias. In normal isolated canine Purkinje fibers, R 56865 (1-10 microM) reduced Vmax at short pacing cycle lengths and decreased the action potential duration at concentrations of 0.1 to 10 microM. R 56865 at concentrations through 10 microM had no significant effect on normal action potentials of canine ventricular muscle and slow response action potentials in guinea pig papillary muscles. In Purkinje fibers exposed to toxic concentrations of ouabain, R 56865 (1 microM) reduced the delayed after depolarization (DAD) amplitude and inhibited triggered activity. R 56865 had no effect on normal automaticity in canine Purkinje fibers at 1 microM, but 10 microM significantly slowed it. R 56865 at 10 microM did not affect isoproterenol-enhanced automaticity and only slightly reduced barium-induced abnormal automaticity that occurred at reduced membrane potentials. These results demonstrate that R 56865 reverses cardiac glycoside-induced arrhythmias in anesthetized dogs at doses that do not significantly affect conduction or refractoriness. Suppression of ouabain-induced DAD and triggered activity in isolated Purkinje fibers, at concentrations not affecting normal or abnormal automaticity, may be the mechanism of R 56865's antiarrhythmic actions in vivo. Suppression of DAD does not appear to be associated with blockade of voltage-dependent calcium channels, but R 56865 may prevent intracellular sodium overload by limiting excessive sodium entry during ouabain intoxication.

Behavioral performance of rats following neonatal hypoxia-ischemia.

The behavioral performance of rats subjected in the neonatal period to hypoxia-ischemia at either 37 degrees C or 21 degrees C was compared to that of sham-ligated animals. Performance on complex motor tests was significantly delayed only in the hypoxic-ischemic 37 degrees C rats. However, cognitive testing disclosed significant delay of spatial learning in animals subjected to hypoxia-ischemia at 21 degrees C and those with gross infarction at 37 degrees C. There was enhanced avoidance learning in the animals with gross infarction in the hypoxia-ischemia 37 degrees C group. Hypoxic-ischemic damage in the neonatal rat at 37 degrees C results in transient delay of complex motor skills, but longer lasting cognitive changes. Hypoxia-ischemia during hypothermia produces no motor deficits, although there may be similar alterations in learning.

31P nuclear magnetic resonance study of the effect of hypoxemia on neonatal status epilepticus.

Prolonged neonatal seizures are often accompanied or exacerbated by hypoxemia. To determine the effects of hypoxemia on neonatal status epilepticus, we determined cerebral blood flow and cerebral metabolic state in groups of neonatal dogs subjected to hypoxia, to seizures during normoxia, or to seizures during hypoxia. The compensatory increase in cerebral blood flow was greatest in animals subjected to seizures during normoxia and somewhat less pronounced in animals made hypoxic. However, blood flow failed to increase in forebrain structures when animals were subjected to the combination of seizures and hypoxia. Accordingly, levels of adenosine triphosphate in forebrain (measured both by in vitro enzymatic analysis and by in vivo phosphorus-31 nuclear magnetic resonance spectroscopy) were depleted to the greatest degree in animals who were seizing while hypoxic. In addition, brain glucose was significantly reduced only in the seizure-hypoxia group. Systemic factors such as hypoxemia may play a critical role in the disruption of cerebral energy balance during neonatal status epilepticus.

Cardiac dysfunction during status epilepticus in the neonatal pig.

Cardiovascular complications frequently occur during status epilepticus. To determine the changes in systemic and pulmonary arterial pressure, cardi output, and left ventricular contractility during seizures, 1-week-old pigs were intubated, paralyzed, mechanicall entilated, and catheterized with a Swan-Ganz catheter. Seizures were induced with intravenous bicuculline. Early changes consisted of significant systemic and pulmonary arterial hypertension. After 2 hours of seizures, the animals developed progressive systemic hypotension and decreased cardiac output. M-mode echocardiography disclosed a decrease in left ventricular contractility. Cardiac tissue frozen in situ showed a significant increase in lactate and reductions in glucose, triglyceride, and adenosine triphosphate levels. Prolonged seizures in the neonatal pig result in cardiac dysfunction, which may play a role in the development of epileptic brain damage.

31P NMR study of cerebral metabolism during prolonged seizures in the neonatal dog.

The effects of prolonged bicuculline-induced seizures on cerebral blood flow and metabolism were determined in paralyzed, mechanically ventilated neonatal dogs. Transient changes occurring early in the course of status epilepticus included significant arterial hypertension, hypocarbia, elevation of plasma norepinephrine levels, and decline in brain glucose concentration. Cerebral blood flow remained elevated throughout the 45 minutes of seizure. Determination of cerebral metabolite values by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy and by in vitro enzymatic analysis of frozen brain samples showed significant decreases in the level of phosphocreatine and relatively less change in ATP values. Progressive intracellular acidosis occurred, coincident with elevation of brain lactate concentrations. We conclude that the physiological and metabolic alterations that occur during prolonged seizures are not uniform, but change with time. Any hypothesis advanced to explain the mechanism of neuronal injury during prolonged seizures must take into account these temporally related changes.

Physiologic and metabolic alterations associated with seizures in normoxic and asphyxiated neonatal dogs.

The effect of asphyxia on seizures was determined in neonatal dogs. In normoxic (paralyzed and ventilated) neonatal dogs, bicuculline-induced seizures produced significant elevations of arterial blood pressure, PO2, glucose, lactate, and epinephrine. Cerebral blood flow increased severalfold; brain glucose, adenosine triphosphate (ATP), and phosphocreatine (PCr) did not decrease significantly. In contrast, seizures during asphyxia were associated with hypoxia, hypotension, hypercarbia, and acidosis. Significant cerebral ischemia developed. Brain glucose, ATP, and PCr were significantly depleted. Complete oxygen deprivation during neonatal seizures exhausts brain energy stores, which leads to cessation of seizure activity.

Naloxone exacerbates hypoxic-ischemic brain injury in the neonatal rat.

Recent reports suggest that naloxone, an opiate antagonist, may adversely affect the asphyxiated fetus. We found that naloxone exacerbated hypoxic-ischemic brain injury in the 7-day-old rat subjected to unilateral common carotid artery ligation and hypoxia. Moreover, there was no amelioration of systemic acidosis or brain edema in naloxone-treated animals compared to animals treated with saline solution. High doses of naloxone may reduce the resistance of the fetus to hypoxic stress.

Cerebral physiological and metabolic effects of hyperventilation in the neonatal dog.

To clarify the changes that occur during marked hypocarbia in the neonate, we measured brain blood flow and metabolite levels after 90 minutes of hyperventilation in neonatal dogs. Brain blood flow decreased significantly in diencephalon, brainstem, and spinal cord but not in cerebral cortex or white matter. There was no substantial change in the electroencephalogram. Lactate concentrations, both in telencephalon and in superior sagittal sinus blood, increased significantly, although there was no alteration in levels of ATP or phosphocreatine. Marked hypocarbia in the neonatal dog produces an elevated brain lactate level that may be related to changes in glycolytic rate rather than to tissue ischemia or hypoxia.

The effects of sodium bicarbonate on brain blood flow, brain water content, and blood-brain barrier in the neonatal dog.

To explore the relationship between cerebral hemorrhage in the newborn and administration of sodium bicarbonate, we gave a standard dose of sodium bicarbonate (5 mEq/kg) to neonatal dogs and then assessed changes in cerebral blood flow, brain water content, and the blood-brain barrier. This dose of sodium bicarbonate produced no increase in blood pressure or cerebral blood flow and no alteration in blood-brain barrier. However, infusion of sodium bicarbonate did cause hyperosmolality and hypernatremia and a significant decrease in brain water content. Cerebral hemorrhage in the neonate associated with infusions of sodium bicarbonate may be related to shifts in brain water rather than to changes in blood pressure or cerebral blood flow.

Effects of steroidal and nonsteroidal antiinflammatory agents in neonatal endotoxemia.

The effects of steriodal and nonsteroidal antiinflammatory agents on mortality, plasma glucose and lactate levels, and pathologic alterations associated with Escherichia coli endotoxemia were assessed in neonatal rats. Animals were first injected subcutaneously with either high (LD95) or moderate (LD35) doses of endotoxin and immediately thereafter were administered either saline, dexamethasone, indomethacin, or glucose. Animals treated with saline or glucose developed significant hypoglycemia and hyperlactacidemia. Dexamethasone and indomethacin ameliorated the fall in glucose and the rise in lactate during high dose but not moderate dose endotoxemia. Pathologic changes consisting of widespread inflammation and hepatic necrosis were most marked in the saline- and indomethacin-treated animals. Only dexamethasone significantly reduced mortality at either LD95 or LD35 doses of endotoxin. We conclude that dexamethasone may reduce mortality in endotoxic shock through mechanisms other than simple amelioration of changes in plasma glucose.

Effects of dexamethasone in hypoxic-ischemic brain injury in the neonatal rat.

To clarify the effects of corticosteroids in neonatal hypoxic-ischemic brain injury, 7-day-old rats were subjected to unilateral common carotid artery ligation and hypoxia (Levine procedure) after being injected subcutaneously with saline, low-dose dexamethasone (4 mg/kg) or high-dose dexamethasone (40 mg/kg). Neither low-dose nor high-dose dexamethasone ameliorated the brain edema, lactacidemia, or hypoglycemia associated with hypoxia-ischemia. In addition, dexamethasone did not alter the pattern of neuropathologic damage or reduce the fall in brain high-energy phosphates. Finally, high-dose dexamethasone-treated animals experienced significantly more mortality than did either saline- or low-dose dexamethasone-treated animals. In this model of neonatal hypoxia-ischemia, dexamethasone did not confer any significant cerebral protection.

The effect of graded hypothermia on hypoxic-ischemic brain damage: a neuropathologic study in the neonatal rat.

To investigate the relationship between neuropathologic damage and cerebral metabolic alterations during hypothermia in the neonatal animal, 7 day old Sprague-Dawley rats were subjected to unilateral common carotid artery ligation and hypoxia at 37 degrees C, 29 degrees C, and 21 degrees C. At 37 degrees C, animals had extensive infarction of tectum and ipsilateral cerebral hemisphere, and marked depletion of brain ATP. At 29 degrees C, there was no significant change in brain ATP; neuropathologic damage was limited to a few areas of necrosis in the deeper layers of cerebral cortex. No histologic injury was seen in the 21 degrees C group of rats. Profound hypothermia may prevent cerebral edema and visible neuropathologic damage associated with hypoxic-ischemic injury by decreasing cerebral metabolic demands. Moderate hypothermia confers a partial, but incomplete degree of protection; whereas during normothermia, the full extent of hypoxicischemic injury is manifest.

Systemic and neuropathologic effects of E. coli endotoxin in neonatal dogs.

The acute systemic and neuropathologic effects of E. coli endotoxin were determined in neonatal dogs. Administration of sublethal (LD0), moderate (LD50), or lethal (LD100) 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.

Is the academic pediatric neurologist an endangered species?

Some argue that the physician-researcher is an endangered specie and that the 'bedside connection' is severely strained. Our survey of recent graduates of pediatric neurology training programs does not substantiate this. Almost one-half of graduating pediatric neurology residents are embarking on full-time, university-based careers. Laboratory experience seems to play a decisive role in career orientation, confirming the intention of those interested in an academic career, and dissuading those who ultimately decide on private practice. Finally, a large number of young pediatric neurology trainees have taken additional years of fellowship training, although primarily in clinical neurology. This survey indicates that even more people would be inclined toward fellowship training if stipends were somewhat higher. In summary, despite considerable uncertainties about grant support and low salaries, a substantial number of graduates of pediatric neurology training programs are planning careers as physician-researchers.

Selective reduction of blood flow to white matter during hypotension in newborn dogs: a possible mechanism of periventricular leukomalacia.

The cerebrovascular response of newborn animals to hypotension has not been defined on a regional basis. Using an autoradiographic technique employing 14C-iodoantipyrine as indicator, we studied the cerebral physiological responses of newborn dogs to hypotension induced by exsanguination or by administration of Escherichia coli endotoxin. Regional cerebral blood flow (rCBF) to all gray matter structures was preserved, even at mean arterial pressures as low as 20 mm Hg. In contrast, rCBF to periventricular and occipital white matter decreased significantly during severe hypotension. The selective hypoperfusion of cerebral white matter during severe hypotension may provide a mechanistic explanation for the pathogenesis of periventricular leukomalacia.