Age and sex differences in brain gene expression in neonatal rats.

Gene expression in the central nervous system is highly region-specific. We tested the hypothesis that certain developmental biomarkers could be detected in the whole brain or in cortical, subcortical or cerebellar structures. Brain gene expressions of male and female rats at birth, 3 days, and 10 days of age were measured by microarray technique ( approximately 10 K genes; n=9/category). We found 53 significantly up-regulated and 8 down-regulated genes at 10 days of age, relative to birth and 3 days of age. The whole brain, however, showed no significant sex differences in gene expression patterns up to 10 days of age. Ten genes with the highest up-regulation, and 5 down-regulated genes were further confirmed by quantitative real-time PCR (Q-PCR), using the whole brain, cortices, subcortical structures, and cerebellum. The Q-PCR confirmed genes are known to be involved in neuronal differentiation, axonal myelination and growth, neurotransmission and glycolytic pathways. With a few exceptions, the expression levels of Q-PCR confirmed genes were significantly different in the whole brain, compared to other regions. In a separate study, we tested the potential utility of the Q-PCR confirmed genes, as whole brain biomarkers, after a six-hour exposure to hyperoxia (>98% oxygen breathing) in 10 days old rats. This relatively mild oxidative challenge created a 3.5-fold increase in the expression of T-cell receptor beta Variable 8.3b, known to have regulatory function during development. We suggest that genes displaying significant expression in the whole brain, regardless of their origin, could be used to screen normal brain development in neonatal rat models of experimental neurology.

ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents.

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral oedema; only a minority of deaths in DKA are attributed to other causes. Cerebral oedema occurs in about 0.3-1% of all episodes of DKA, and its aetiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral oedema, and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes.

Pulmonary and extrapulmonary effects of increased colloid osmotic pressure during endotoxemia in rats.

OBJECTIVES: We tested the hypothesis that an increase in the blood colloid osmotic pressure (COP) that is maintained during early-stage endotoxemia may decrease fluid flux across capillaries and may reduce pulmonary and multiple-organ edema. DESIGN: Prospective study. SETTINGS: Research laboratory in a hospital. SUBJECTS: Male albino Sprague-Dawley rats. INTERVENTIONS: Rats were anesthetized with pentobarbital, underwent tracheotomies, were cannulated in the femoral vein and artery, and were randomly assigned to the following four groups comprising 11 rats each: group I, controls (saline solution treatment); group II, albumin treatment (three doses of 1 g/kg 25% human albumin every 2 h); group III, endotoxin treatment with a single IV dose of 4 mg/kg endotoxin; and group IV, endotoxin and albumin-treatment (4 mg/kg endotoxin plus albumin treatment). Experiments lasted for 6 h while fluid intake was equally maintained in all groups. MEASUREMENTS AND RESULTS: COP and other variables were measured every 2 h. To determine the water content of an organ, after the rat was killed, the lung, heart, kidney, intestine, and liver were removed. Albumin treatment alone (group II) generated significant increases in COP (maximum, 58% from the baseline measurement) but did not change the water content of the organ, compared with saline solution-treated controls. Endotoxin-treated rats (group III) developed significant reductions in COP, with significant increases in pulmonary, renal, and heart water content compared with controls. Albumin treatment in endotoxemic rats (group IV) significantly increased the COP without improving the endotoxemia-induced organ edema. Pulmonary edema, however, was increased further, compared with endotoxemia alone. CONCLUSIONS: COP elevation by albumin administration during the early stage of endotoxemia does not ameliorate pulmonary or multiple-organ edema and may aggravate pulmonary edema.

Effects of arteriovenous extracorporeal therapy on hemodynamic stability, ventilation, and oxygenation in normal lambs.

OBJECTIVE: To evaluate hemodynamic stability and gas exchange in a neonatal animal model of pumpless arteriovenous extracorporeal membrane oxygenation (AV-ECMO) with extracorporeal shunt flow of up to 15% of cardiac output during variable ventilation and oxygenation. DESIGN: Prospective study. SETTING: Research laboratory in a hospital. SUBJECTS: Seven lambs (5.5 +/- 0.6 kg, mean +/- sd). INTERVENTIONS: The lambs initially were anesthetized by 50 mg/kg ketamine intravenously. After tracheostomy, the lambs were mechanically ventilated and paralyzed by using 1 mg/kg vecuronium bromide followed by 0.1 mg.kg(-1).hr(-1). One femoral vein was cannulated with a pulmonary artery flotation catheter and used for cardiac output and pulmonary artery pressure measurements. A femoral artery was cannulated for measuring mean arterial blood pressure, measuring heart rate, and blood sampling for gas exchange analyses. Finally, the right internal jugular vein and carotid artery were cannulated and used for the AV-ECMO. Normothermia (38 +/- 0.5 degrees C), fluid balance (5 mL.kg(-1).hr(-1) normal saline), and anesthesia (5 mg.kg(-1).hr(-1), intravenous ketamine) were maintained. Ventilator settings were adjusted to establish a baseline Paco2 (25-35 mm Hg) at an Fio2 of 0.4. The AV-ECMO circuit was established by using a hollow fiber oxygenator, primed with maternal sheep blood (150-200 mL). MEASUREMENTS AND MAIN RESULTS: The physiologic effects of the AV-ECMO shunt were evaluated at 15, 25, and 40 mL.kg(-1).hr(-1) ECMO flow, corresponding roughly to 4%, 8%, and 15% of the cardiac output values. The baseline minute volume was maintained during stepwise increases in arteriovenous shunt. A significant increase in endogenous cardiac output occurred at arteriovenous shunt of 25 and 40 mL.kg(-1).hr(-1) (analysis of variance followed by Tukey-Kramer multiple comparisons test), which was attributed to a significant increase of 30% in the heart rate. Effective cardiac output (difference between the thermodilution value and the AV-ECMO flow rate) and mean arterial blood pressure were not significantly changed. CO2 removal, measured at 15% arteriovenous shunt, was significantly increased with decreasing ventilation to 25% and 50% of the baseline (analysis of variance and Tukey-Kramer test). Oxygenation through the membrane was measured after reducing inspired Fio2 from 0.4 to 0.21, 0.15, and 0.10 with 15% arteriovenous shunt and baseline minute ventilation. Oxygen delivery by the oxygenator was significantly increased at Fio2 of 0.10, providing a maximum of 19.5% of the total oxygen consumption at an arterial hemoglobin-oxygen saturation of 60%. CONCLUSIONS: Healthy lambs are capable of maintaining effective cardiac output in the presence of moderate arteriovenous shunts (15%). AV-ECMO may provide efficient ventilatory support in the neonatal population with hypercapnia. The amount of oxygen delivery with AV-ECMO depends on arterial desaturation.

Intratracheal pulmonary ventilation versus conventional mechanical ventilation: continuous carinal pressure monitoring at low and high flows and frequencies.

We continuously measured proximal and carinal pressures at low and high flow rates and frequencies during conventional mechanical ventilation (CMV) and intratracheal pulmonary ventilation (ITPV), using an artificial lung. The proximal peak inspiratory pressure (PIP), carinal PIP, proximal positive end expiratory pressure (PEEP), and carinal PEEP, or negative end expiratory pressure (NEEP), were measured during simulated CMV and ITPV. Two levels of frequency (30 and 90 per min) and two gas flow rates (3 and 6 L/min) were examined, in both dry and humid states (four combinations of gas flow and frequency at each state). The gas flow and inspiratory time were held constant throughout the CMV and ITPV trials. Humidification of the ventilatory circuit during ITPV prevented the accurate measurement of carinal pressures. This problem was solved by introducing a continuous "bias flow" of 11 ml/min into the pressure monitoring line. A combination of low gas flow and low frequency with CMV showed no significant differences between the proximal and carinal PIP, as well as the proximal and carinal PEEP. The same combination with ITPV, however, resulted in a significantly lower carinal PIP and PEEP, compared to proximal PIP and PEEP. Carinal PIP and PEEP during ITPV were also significantly lower than those observed during CMV with a low flow and low frequency rates. During both CMV and ITPV, using a combination of a high flow rate with a high breathing frequency, carinal PIPs were significantly lower than proximal PIPs. ITPV, however, generated much larger differences between proximal and carinal PIPs than the CMV. A significant NEEP was generated at the carinal level during ITPV with high flow rates, both with high and low frequencies. The NEEP did not occur with a low gas flow, in combination with either a low frequency or a high frequency. The "bias flow" had no significant effect on carinal pressures. In conclusion, ITPV, compared with CMV, generates a significantly lower carinal PIP, but it may also generate carinal NEEP. For safety reasons, therefore, it is essential to monitor carinal pressures continuously in patients treated with ITPV.

Decreased urinary citrate excretion in type 1a glycogen storage disease.

OBJECTIVES: To quantify urinary citrate and calcium excretion and systemic acid-base status in patients with type 1a glycogen storage disease (GSD1a) and to investigate their relationship to renal complications. STUDY DESIGN: Fifteen patients (7 male and 8 female; age range, 3--28 years) were studied during annual evaluations of metabolic control. All were treated with intermittent doses of uncooked cornstarch. Hourly blood sampling and a 24-hour urine collection were obtained while subjects followed their usual home dietary regimen. RESULTS: All but the youngest subject had low levels of citrate excretion (mean 2.4 +/- 1.8 mg/kg/d; 129 +/- 21 mg citrate/g creatinine). Normally, urinary citrate excretion increases with age; however, in patients with GSD1a, a strong inverse exponential relationship was found between age and citrate excretion (r = -0.84, P <.0001). Urinary citrate excretion was unrelated to markers of metabolic control. Hypercalciuria occurred in 9 of 15 patients (mean urinary calcium/creatinine ratio, 0.27 +/- 0.15) and was also inversely correlated with age (r = -0.62, P =.001). CONCLUSIONS: Hypocitraturia that worsens with age occurs in metabolically compensated patients with GSD1a. The combination of low citrate excretion and hypercalciuria appears to be important in the pathogenesis of nephrocalcinosis and nephrolithiasis. Citrate supplementation may be beneficial in preventing or ameliorating nephrocalcinosis and the development of urinary calculi in GSD1a.

First-phase insulin release during the intravenous glucose tolerance test as a risk factor for type 1 diabetes.

OBJECTIVE: To determine the relationship between first-phase (1 minute + 3 minutes) insulin production during the intravenous glucose tolerance test (IV-GTT) and risk factors for developing type 1 diabetes. STUDY DESIGN: Relatives of persons with type 1 diabetes (n = 59,600) were screened for islet cell antibodies (ICAs). Subjects who had positive screening results underwent IV-GTT (> or =2 times), repeat ICA screening, insulin autoantibody (IAA) screening twice, and an oral glucose tolerance test. RESULTS: Of the 59,600 subjects in the study, 2199 (3.69%) had positive findings on initial ICA test. IV-GTTs were performed in 1622 subjects, with children <8 years having the lowest first-phase insulin release (FPIR) and subjects 8 to 20 years of age having the highest FPIR. The FPIR was lower for subjects with a confirmed positive ICA test result or a positive IAA test result, subjects with higher titers of ICA or IAA, and subjects who had an abnormal (impaired or diabetic) oral glucose tolerance test result. CONCLUSION: FPIR in the IV-GTT correlates strongly with risk factors for development of type 1 diabetes.

Insensible water loss during extracorporeal membrane oxygenation: an in vitro study.

To measure insensible fluid loss from silicone membrane oxygenators during extracorporeal membrane oxygenation (ECMO), an in vitro system was used. A standard neonatal ECMO circuit (Avecor) was connected to a noncompliant reservoir, which was then primed with normal saline. The experiment was conducted by using two silicone oxygenators (Avecor 0.4 and 0.8 m2), three gas flow rates (0.5, 1.0, and 2.0 L/min) (sweep), and two fluid flow rates (200 and 400 ml/min). Two methods were used to measure the water loss. One method was to replace the water to the noncompliant circuit by using a calibrated burette, and the other method was to collect condensed water after cooling the postmembrane sweep gas to 0 degrees C. The influence of the amount of sweep, fluid flow rate, size of membrane, and inlet and outlet sweep gas temperatures on measured water loss was statistically determined. The amount of water loss correlated with sweep (r2 = 0.81; p<0.00001) but was not related to the fluid flow rate, membrane size, or inlet and outlet sweep gas temperature. The average daily fluid loss measured with replacement and collection methods for each liter of sweep per minute were 72.0+/-12.6 and 62.3+/-10.0 ml, respectively. This information may be applied to clinical practice to accurately manage fluid balance in the sick neonate on ECMO.

Effect of hypothermia on ventilation in anesthetized, spontaneously breathing rats: theoretical implications for mechanical ventilation.

OBJECTIVE: To test if hypothermia, induced by a sustained pentobarbital anesthesia, in rats can reduce ventilatory demands without compromising pulmonary gas-exchange efficiency. DESIGN: Prospective study. SETTING: Research laboratory in a hospital. SUBJECTS: One group of 11 female Sprague Dawley rats. INTERVENTIONS: The rats were anesthetized with 45 mg/kg pentobarbital, tracheostomized and intubated; their femoral veins and arteries were cannulated. After surgery, anesthesia and fluid balance were maintained (10 mg/kg per h pentobarbital, and 5 ml/kg per h saline, i.v.). Rectal temperature, mean arterial blood pressure (MAP), and heart rate (HR) were continuously monitored. The respiratory variables and gas-exchange profiles were determined at 38 degrees C (normothermia), and during stepwise hypothermia at 37, 35, 33, 31 and 29 degrees C. The arterial pressure of carbon dioxide (PaCO2), pH and arterial pressure of oxygen (PaO2) during hypothermia were corrected at body temperature. MEASUREMENTS AND RESULTS: Graded systemic hypothermia, with maintained anesthesia, produced a strong correlation between reduction in the respiratory frequency and rectal temperature (r2 = 0.55; p < 0.0001; n = 66). The minute volume was significantly reduced, starting at 35 degrees C, without significant changes in the tidal volume (repeated measures of analyses of variance followed by Dunnett multiple comparisons test). No significant changes occurred in the PaCO2, pH, PaO2, hemoglobin oxygen saturation, the calculated arterial oxygen content and estimated alveolar-arterial oxygen difference during mild hypothermia (37-33 degrees C). The PaO2, however, was significantly reduced below 31 degrees C. The MAP remained stable at different levels of hypothermia, whereas HR was significantly reduced below 33 degrees C. CONCLUSIONS: Mild hypothermia in rats, induced by a sustained pentobarbital anesthesia, reduces ventilation without compromising arterial oxygenation or acid-base balance, as measured at body temperature. Theoretically, our observations in spontaneously breathing rats imply that a combination of mild hypothermia with anesthesia could be safely utilized to maintain adequate ventilation, using relatively low minute ventilation. We speculate that such a maneuver, if applied during mechanical ventilation, may prevent secondary pulmonary damage by allowing the use of lower ventilator volume-pressure settings.

Urinary lactate excretion to monitor the efficacy of treatment of type I glycogen storage disease.

The purpose of this study was to investigate the usefulness of urinary lactate measurements to assess the adequacy of dietary treatment in patients with type I glycogen storage disease (GSD-I). We determined the correlation of urine and blood lactate concentrations in 21 GSD-I patients during 24-h admissions to the General Clinical Research Center (GCRC) during which hourly blood samples and aliquots of every void were obtained. In all but 1 patient, we found a good correlation between blood lactate concentrations and urinary lactate excretion. One patient did not excrete lactate in significant amounts despite elevated blood lactate concentrations. In 17 patients, the highest blood lactate concentrations occurred during the night. Markedly elevated nighttime average blood lactate concentrations above 3.5 mmol/l resulted in a urinary lactate concentration above the normal limit of 0.067 mmol/mmol creatinine in the first morning urine specimen. Mildly elevated nighttime blood lactate concentrations (between 2.2 and 3.5 mmol/l) led to urinary lactate concentrations that were either normal or moderately elevated. All patients with normal blood lactate concentrations during the night also had normal first morning urinary lactate concentrations. The degree of urinary lactate excretion in relation to blood lactate concentrations varied by individual. Urinary filter paper specimens, collected at home during the night and in the morning and mailed to the laboratory, were used to monitor the dietary compliance of 5 GSD-I patients at home over a period of 6 to 9 weeks prior to their GCRC admissions. These data suggested variable degrees of dietary control. In conclusion, the urinary lactate concentration is a useful parameter to monitor therapy of GSD-I patients at home. To be interpretable, the baseline urinary lactate concentration in relation to the blood lactate concentration has to be determined.

Intratracheal pulmonary ventilation in a rabbit lung injury model: continuous airway pressure monitoring and gas exchange efficacy.

OBJECTIVES: To compare carinal pressures vs. proximal airway pressures, and gas exchange efficacy with a constant minute volume, in lung-injured rabbits during conventional mechanical ventilation (CMV) and intratracheal pulmonary ventilation (ITPV); and to evaluate performance of a prototype ITPV gas delivery and continuous airway pressure monitoring system. DESIGN: Prospective controlled study. SETTING: Animal research laboratory at a teaching hospital. SUBJECTS: Sixteen adult female rabbits. INTERVENTIONS: Anesthetized rabbits were tracheostomized with a multilumen endotracheal tube. Anesthesia and muscle relaxation were maintained continuously throughout the study. Proximal airway pressures and carinal pressures were recorded continuously. The injection port of the multilumen endotracheal tube was used for the carinal pressure monitoring. To prevent obstruction of the port, it was flushed with oxygen at a rate of 11 mL/min. CMV was initiated with a pressure-limited, time-cycled ventilator set at an FiO2 of 1.0 and at a flow of 1.0 L/kg/min. The pressure limit of the ventilator was effectively disabled. A normal baseline for arterial blood gases was achieved by adjusting the inspiratory/expiratory time ratios. ITPV was established using a flow of 1.0 L/kg/min through a reverse thrust catheter, at the same baseline and inspiratory/expiratory ratio. Carinal positive end-expiratory pressure was maintained at a constant value of 2 cm H2O by adjusting the expiratory resistance of the ventilator circuit Lung injury was achieved over a 30-min period by three normal saline lavages of 5 mL/kg each. After lung injury, all animals were consecutively ventilated for 1 hr with CMV, for 1 hr with ITPV, and again for 1 hr with CMV. Six rabbits were ventilated at 30 breaths/min (group 1), and ten rabbits were ventilated at 80 breaths/min (group 2). Four rabbits in group 2 were subjected, 1 hr after return to CMV from ITPV, to another session of ITPV, with positive end-expiratory pressure gradually being increased to 4, 6, and 8 cm H2O for 15 mins each. RESULTS: No significant differences were observed in carinal peak inspiratory pressure between CMV and ITPV modes, at both low and high frequencies of breathing, indicating that the inspired tidal volume remained constant during both modes of ventilation. Significant gradients were noted between proximal airway and carinal peak inspiratory pressure during ITPV but not during CMV. Initiation of ITPV, at a flow of 1.0 L/kg/min, required an increase in the ventilator expiratory resistance to maintain a constant level of positive end-expiratory pressure (2 cm H2O) as measured at the carina. During ITPV, the PaCO2 was significantly reduced by 20% at 30 breaths/min (p < .05) and by 22% at 90 breaths/min (p < .01), compared with CMV. Arterial oxygenation was significantly enhanced with a positive end-expiratory pressure of 6 and 8 cm H2O (p < .05 and .001, respectively), compared with a positive end-expiratory pressure of 2 cm H2O during ITPV. All components of the new prototype gas delivery and airway pressure monitoring system functioned without failure, at least for 3 hrs of the CMV, ITPV, and CMV trials. CONCLUSIONS: ITPV in saline-lavaged, lung-injured rabbits at breathing frequencies of 30 and 80 breaths/min, compared with CMV at the same minute ventilation, can improve CO2 exchange. During ITPV, significant pressure gradients can develop between carinal and proximal airway pressures. Continuous carinal pressure monitoring is therefore necessary for the safe clinical application of ITPV. Reliable carinal pressure monitoring can be achieved by adding a small bias flow through the carinal pressure monitoring port. Although ITPV can remove CO2 from injured lungs efficiently, simultaneous addition of positive end-expiratory pressure can further improve arterial oxygenation.

Oxygen-carrying capacity during 10 hours of hypercapnia in ventilated dogs.

OBJECTIVE: To test if a relatively long-term exogenous hypercapnia, equivalent to those maintained during permissive hypercapnia, can persistently increase oxygen-carrying capacity in ventilated dogs. DESIGN: Prospective study. SETTING: Research laboratory in a hospital. SUBJECTS: Six mongrel dogs (3 males; 3 females). INTERVENTIONS: The dogs were anesthetized (30 mg/kg pentobarbital, i.v.), intubated, and cannulated in one femoral artery, one femoral vein, and the right jugular vein. The mean arterial blood pressure, heart rate, and mean pulmonary artery pressure were continuously recorded. Anesthesia, fluid balance, and normothermia were maintained. Arterial hypercapnia was generated by the addition of 60 torr dry CO2 (8 kPa) to the inspired air for 10 hrs, continuously. All subjects were paralyzed (vecuronium bromide) and ventilated with room air, while the ventilator settings were kept constant. MEASUREMENTS AND MAIN RESULTS: Arterial and venous gas exchange profiles, hemoglobin concentration, oxygen saturation, oxygen content, cardiac output, and oxygen consumption were determined, before, during, and after 10 hrs of hypercapnia, periodically. Both hemoglobin concentration and oxygen content were gradually increased during hypercapnia and reached significant levels at 8 and 10 hrs of hypercapnia, respectively. These increases continued up to 2 hrs after termination of hypercapnia. The PaO2/FIO2, as an index of arterial oxygenation, was significantly increased during the first 3 hrs of hypercapnia and then remained at the normoxic level up to 10 hrs of hypercapnia. No significant changes occurred in the mean arterial blood pressure and oxygen consumption. The heart rate and cardiac output were significantly reduced at 4 and 8 hrs of hypercapnia, respectively. The mean pulmonary artery pressure was increased throughout the hypercapnic trial. CONCLUSIONS: A relatively long-term exogenous hypercapnia can significantly increase oxygen-carrying capacity in normal ventilated dogs. Whether this effect can occur during permissive hypercapnia because of controlled ventilation in patients warrants investigation.

Variability in systemic arterial pressure during closed- and open-bridge extracorporeal life support: an in vitro evaluation.

OBJECTIVE: To compare fluctuations in systemic arterial pressure (SAP) resulting from changes in systemic vascular resistance (SVR) during closed- and open-bridge extracorporeal life support (ECLS). DESIGN: In vitro laboratory study. SETTING: Physiology laboratory of a tertiary care pediatric hospital. METHODS: A standard neonatal ECLS circuit with simulated SAP was established using normal saline as circulating fluid. Our reference setting included an extracorporeal flow rate of 300 mL/min, a simulated SAP of 60 mm Hg, and a postoxygenator pressure of 150 mm Hg. The simulated SVR was modified by changing the degree of occlusion of the arterial catheter distal to the bridge. For this purpose, we used a graduated clamping device. Subsequently, the pressure changes were measured at four ports in the circuit. They were located as follows: a) on the venous tubing of the circuit between the bridge and the reservoir; b) on the arterial tubing of the circuit between the heat exchanger and the bridge; c) between the first and the second resistance clamps on the arterial tubing of the circuit for monitoring the simulated systemic arterial pressure; and d) at the reservoir. The experiment was repeated with various extracorporeal flow rates to the reservoir (100-300 mL/min) and through the bridge (100-300 mL/min using a custom-made clamp). Variations in the simulated SAP created by varying degrees of occlusion and flow rates were compared with repeated measures analysis of variance followed by the Tukey-Kramer test. MEASUREMENTS AND MAIN RESULTS: The open-bridge ECLS significantly reduced the variations in the simulated SAP by 15% to 45% (p < .001) compared with the closed-bridge. During closed-bridge ECLS, flashing of the bridge resulted in a decrease in the SAP and transient reversal of flows through the arterial and venous cannulae. CONCLUSIONS: Open-bridge ECLS decreases the fluctuations in the SAP that occur because of changes in the SVR. Open-bridge ECLS prevents transient iatrogenic changes in blood flow and blood pressure, caused by flashing of the bridge. Other potential advantages and disadvantages of the open-bridge ECLS are discussed. The application of prolonged open-bridge ECLS to the patients needs to be evaluated in animal models.

Vancomycin dosage requirements among pediatric intensive care unit patients with normal renal function.

PURPOSE: The purpose of this study was to determine a vancomycin dosage regimen among pediatric intensive care unit (PICU) patients with normal renal function resulting in desired peak and trough serum concentration and to determine the predictability of vancomycin peak concentrations based on reported trough concentrations. MATERIALS AND METHODS: The medical records of all PICU patients who received vancomycin over a 12-month period were identified through a hospital computer search and were obtained from the hospital's Department of Medical Records. Demographic and laboratory data as well as the patient's vancomycin dosing history were recorded. Patients who lacked appropriately timed vancomycin peak and trough concentrations or who exhibited renal dysfunction were excluded from the study population. The optimal vancomycin dose and the predictability of peak concentrations based on trough concentrations were assessed. RESULTS: A total of 135 patients were identified as having received vancomycin therapy during their PICU hospitalization between June 1997 and June 1998. Fifty-nine patients were excluded due to renal dysfunction or inappropriate vancomycin concentrations resulting in 76 patients representing our study population. The initial mean dose of vancomycin was 47 mg/kg/day resulting in a mean peak and trough serum concentration of 19 and 6 microg/mL, respectively. A mean of 2.2 (range, 1 to 5) and 2.1 (range, 1 to 5) peak and trough serum concentrations were reported for each patient, respectively. A mean of 1.1 (range, 0 to 4) dosing changes per patient was noted resulting in a final mean dose of 60 mg/kg/day corresponding to a mean peak and trough serum concentration of 26 and 8 microg/mL, respectively. A vancomycin trough concentration >5 microg/mL was highly predictive for a corresponding peak concentration >20 microg/mL (P > .0001). Eighty percent of the trough concentrations <5 microg/mL were associated with peak concentrations <20 microg/mL, whereas 81% of trough concentrations >5 microg/mL were associated with corresponding peak concentrations >20 microg/mL. CONCLUSIONS: PICU patients required higher doses of vancomycin than are typically prescribed to achieve conventionally accepted peak and trough vancomycin serum concentrations. In the absence of renal impairment, we recommend an initial dosage regimen of 60 mg/kg/day divided every 8 hours. Vancomycin trough concentrations are highly predictive of corresponding peak concentrations and therefore may negate the need to obtain routine peak concentrations.

Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy.

The glycogen storage diseases are caused by inherited deficiencies of enzymes that regulate the synthesis or degradation of glycogen. In the past decade, considerable progress has been made in identifying the precise genetic abnormalities that cause the specific impairments of enzyme function. Likewise, improved understanding of the pathophysiologic derangements resulting from individual enzyme defects has led to the development of effective nutritional therapies for each of these disorders. Meticulous adherence to dietary therapy prevents hypoglycemia, ameliorates the biochemical abnormalities, decreases the size of the liver, and results in normal or nearly normal physical growth and development. Nevertheless, serious long-term complications, including nephropathy that can cause renal failure and hepatic adenomata that can become malignant, are a major concern in GSD-I. In GSD-III, the risk for hypoglycemia diminishes with age, and the liver decreases in size during puberty. Cirrhosis develops in some adult patients, and progressive myopathy and cardiomyopathy occur in patients with absent GDE activity in muscle. It remains unclear whether these complications of glycogen storage disease can be prevented by dietary therapy. Glycogen storage diseases caused by lack of phosphorylase activity are milder disorders with a good prognosis. The liver decreases in size, and biochemical abnormalities disappear by puberty.

Nitric oxide and nitrogen dioxide concentrations during in vitro high-frequency oscillatory ventilation.

PURPOSE: The purpose of this study was to measure nitric oxide (NO) and nitrogen dioxide (NO2) concentrations, at various ventilatory settings and sampling sites, during in vitro inhaled NO and high-frequency oscillatory ventilation therapy [iNO-HFOV]. MATERIALS AND METHODS: We used a high-frequency oscillatory ventilator (model 3100A, SensorMedics, Yorba Linda, CA), a test lung (model VT-2A Ventilator Tester, Bio-Tek Instruments, Inc., Winooski, VT), nitric oxide delivery and NO/NO2 monitoring (Pulmonox II, Pulmonox, Tofield, Canada), and scavenging systems in this study. The ventilator frequency, amplitude, and inspired oxygen concentration were systematically changed at a fixed flow of NO. The concentrations of NO and NO2, sampled at four sites, were determined by an electrochemical method (Pulmonox II). The NO and NO2 concentrations were measured at the proximal part of the inspiratory limb (site 1), near the Y-piece (site 2), the carina of the test lung (site 3), and the bellows of the test lung (site 4). RESULTS: The concentration of NO decreased significantly (P < .001) from the proximal port (site 11 of the inspiratory circuit (86.16 +/- 0.38 ppm) through the lung bellows (site 4) (70.08 +/- 0.23 ppm). The concentration of NO2 increased significantly (P < .001) from site 1 (3.25 +/- 0.04 ppm) through site 4 (19.4 +/- 0.19 ppm). However, the total concentration of NO + NO2 (NOx) remained unchanged at both site 1 and site 4. Increasing the frequency and amplitude of the ventilator significantly altered NO and NO2 concentrations. The NO2 concentration increased significantly (P < .0001) from 5.6 ppm to 18.1 ppm at site 4 when the fraction of inspired oxygen was increased from 0.25 to 0.93. The NO2 concentration also increased significantly (P < .0001) from 0.6 ppm to 18.7 when NO concentrations were independently increased from 12 ppm to 80 ppm. CONCLUSIONS: During HFOV, the concentrations of NO and NO2 vary between sampling sites and also are influenced by the frequency, amplitude, and inspired oxygen concentration. NO2 concentrations in the lung were significantly increased above commonly accepted toxic concentrations during ventilation with high concentrations of NO (80 ppm) and high fractional concentrations of oxygen. The excessive increase in NO2 concentration at the "alveolar" level in our test lung model warrants confirmation in an in vivo model.

Experimental critical care in rats: gender differences in anesthesia, ventilation, and gas exchange.

OBJECTIVE: To compare normative ventilatory and gas-exchange data and anesthetic requirements in male and female rats subjected to critical care conditions. DESIGN: Prospective study. SETTING: Critical care research laboratory in a hospital. SUBJECTS: Twenty-two age-matched young male and female rats (Sprague-Dawley, Long Evans strain). INTERVENTIONS: Anesthesia was induced with 65 and 45 mg/kg pentobarbital in male and female rats, respectively. The rats were then tracheostomized and cannulated in one femoral vein and artery. Anesthesia was maintained using 8-15 mg/kg/hr pentobarbital (iv) and controlled by continuous hemodynamic monitoring. MEASUREMENTS AND MAIN RESULTS: Normoxic baselines for breathing frequency, tidal volume, minute volume, inspiratory-to-expiratory ratio, inspiratory drive (tidal volume/inspiratory time), respiratory system compliance, peak airway pressure, and gas-exchange profiles were established. Ventilatory and gas-exchange responses to oxygen and CO2 were then determined by exposure to 10 mins of hyperoxia (100% oxygen), two levels of mild and severe hypercapnic hyperoxia (inspired Pco2 of 30 and 60 torr; 4 and 8 kPa), and two levels of mild and severe normocapnic hypoxia (inspired PO2 of 81 and 48 torr; 10.7 and 6.3 kPa). The average anesthetic requirement (during a 5- to 6-hr experiment) was 30% less in the female rats than in the male rats (p < .05). Female rats showed significantly lower breathing frequency, minute volume (mL/min/kg), and inspiratory drive (mL/kg/sec) during hyperoxia, mild and severe hypercapnia, and mild hypoxia. Pulmonary peak airway pressure was significantly lower in the female rats, consistent with a significantly higher weight-indexed compliance during all exposures. The female rats also had significantly higher inspiratory-to-expiratory ratio and higher PaCO2 with lower pH during normoxia, hyperoxia, and mild hypercapnia. These gender differences had no effect on PaO2, which was similar in all exposures. CONCLUSIONS: There are significant gender differences in ventilation, gas exchange, and anesthetic requirements in rats subjected to critical care conditions. The gas-exchange values observed in these spontaneously breathing rats may represent the optimal levels attainable during pentobarbital anesthesia with normal lungs. They may serve as standards for ventilator settings in the rat models used for critical care studies.