Keith H. Marks

Indomethacin Disposition and Indomethacin-Induced Platelet Dysfunction in Premature Infants

Indomethacin failed to produce permanent ductal closure in any of four premature infants with patent ductus arteriosus to whom the drug was given. Indomethacin half-lives measured in two premature infants were 21 and 24 hours, respectively, much longer than in full-term newborns or adults. Platelet function, as measured by platelet aggregation, was grossly abnormal for two to four days after indomethacin administration, normal values returning only by the ninth and tenth days. Gastrointestinal bleeding and transient renal dysfunction occurred in one infant. Measurement of plasma indomethacin concentrations in sick, low-birthweight infants could help guide indomethacin dose and dosage interval, prevent drug accumulation, and reduce toxicity. Further studies of potential toxicity seem to be indicated before instituting widespread indomethacin administration for ductal closure in premature infants.

Urinary excretion of prostaglandin E following the administration of furosemide and indomethacin to sick low-birth-weight infants.

Urinary excretion of prostaglandin E was measured in seven sick low-birth-weight infants. Four had severe hyaline membrane disease and one had chronic bronchopulmonary dysplasia; all received furosemide. Two infants had patent ductus arteriosus and received indomethacin. Following administration of furosemide, urine volume and the excretion rates of sodium and calcium were significantly increased; such changes were not seen following the administration of indomethacin. Prostaglandin E excretion rate was increased from 0.4 +/- 0.04 to 1.3 +/- 0.2 ng/mg Cr (mean +/- SEM) following administration of furosemide, but decreased in two patients following administration of indomethacin. The present results demonstrate that furosemide enhances urinary excretion of prostaglandin E by mechanisms which may reflect an increase in prostaglandin synthesis, a decrease in prostaglandin renal metabolism, or both. Indomethacin, which is a prostaglandin synthetase inhibitor, decreases the urinary excretion of prostaglandin E. These observations suggest that furosemide therapy in patients receiving indomethacin may be ineffective.

The accuracy and precision of an open-circuit system to measure oxygen consumption and carbon dioxide production in neonates.

ABSTRACT: We measured the oxygen consumption, carbon dioxide production, and respiratory quotient during the combustion of a known mass of anhydrous ethanol and methanol to assess the accuracy of an open-circuit flowthrough system. Continuous measurements were made of the mass of alcohol burned, the velocity of gas flow through the apparatus, and simultaneous measurements of the fractional concentration of oxygen, carbon dioxide and nitrogen of the inlet and outlet gas using paramagnetic oxygen analyzer, infrared carbon dioxide meter, and mass spectrometer. Standard respiratory and stoichiometric equations were used to calculate the oxygen consumption, carbon dioxide production and RQ for the mass of absolute alcohol combustion per unit time. In a series of 12 consecutive laboratory experiments (on 7 days), the measured values of gas exchange (similar to the rate of respiratory gas exchange by an infant of 1-4 kg) were in agreement within 5% of the true values for ethanol and methanol combustion, confirming the validity of the open-circuit method. The paramagnetic oxygen analyzer and the mass spectrometer gave similar oxygen consumption results and differed very little when the rate of absolute alcohol combustion was used to quantify the accuracy of the complete measurement system. A positive measurement error was observed for the carbon dioxide production results from both the IR meter and mass spectrometer, with the result that the respiratory quotient measurements were 3.4-4.7% higher than the true value. The mass spectrometer gave more precise oxygen consumption results, whereas smaller variance of carbon dioxide production measurements was observed using the infrared CO2 meter. The sources of error and methods to reduce the overall system error were considered. By using a rigorous set of calculations we showed that the rate of combustion of a known mass of absolute alcohol was a suitable laboratory method for validation of respiratory gas exchange measurements made in the neonate.

Day-to-Day Energy Expenditure Variability in Low Birth Weight Neonates

ABSTRACT: We estimated the metabolic rate of 13 low birth weight infants over a 9-day period, using indirect calorimetry in conjunction with serial measurements of oxygen consumption, carbon dioxide production, and total urinary nitrogen excretion. The mean percent error for oxygen consumption and carbon dioxide production measurements (determined by alcohol combustion experiments) assignable to the open-circuit system was 0.4 and 3.8%, respectively. Error in the total urinary nitrogen excretion measurement was <1% by the Kjeldahl technique. In the clinical setting, however, the range of deviation of measured oxygen consumption, carbon dioxide production and total urinary nitrogen excretion was ±12, 12, and 15% of the mean value respectively for an individual patient under standardized controlled conditions. The variability of metabolic rate between infants may be as much as 76%. Factors that had a small effect on metabolic rate were difficult to detect because of the variability inherent in the short-term measurement of metabolic rate. It was virtually impossible to control the sources of variation in the resting metabolism of low birth weight neonates over extended experimental periods. Day-to-day variations in resting energy expenditure may explain, in part, the widely different growth rates of premature infants receiving similar caloric intakes.

Thermal head wrap for infants

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Precise control of nitric oxide concentration in the inspired gas of continuous flow respiratory devices.

Inhaled NO has become widely used for diagnosis and therapy of pulmonary hypertension. The potential hazards of NO inhalation include the formation of methemoglobin, formation of NO2, and generation of free radicals in the presence of humidity and oxygen. Careful monitoring of NO and NO2 concentration, and titration of the dose according to a patients clinical response is essential to minimize toxicity. This paper describes a formula and method that permits calculation and precise control of NO concentration in the inspired gas. The accuracy of the delivery system was assessed by a comparison of calculated and measured NO and NO2 concentrations in a continuous flow ventilator circuit. A comparison of electrochemical detector (ECD) versus chemiluminescence detector (CLD) monitoring techniques showed agreement between the instruments within ∼2 ppm, with the ECD averaging a higher reading than the calculated or CLD measured values. We deemed a 2 ppm discrepancy between instruments clinically acceptable, and concluded that the instruments could be used interchangeably for clinical purposes to measure NO, and that the ECD was preferable to CLD for measuring NO2. Details about the equipment are given and techniques are discussed to avoid the risk of inhalation of toxic concentrations of NO and NO2. This method provides the possibility of using inhaled NO with appropriate safety precautions in the range 0–60 ppm in a variety of continuous flow respiratory devices. Pediatr Pulmonol. 1996; 22:182–187.

A SIMPLE DEVICE FOR REDUCING INSENSIBLE WATER LOSS (IWL) IN LOW BIRTH WEIGHT INFANTS

IWL was measured in 5 non-distressed premature infants, 1-4 days old, by a multiple weighing technique using an electronic balance inside an incubator. The babies were studied naked before and after being covered with a transparent “thermal blanket” made from plastic packing material. Operative incubator temperature was within the thermoneutral zone and relative humidity between 25 and 40%. Consecutive three hour Δ weight measurements were made 30-60 minutes after gavage milk feeds. IWL was determined as Δ weight. Pulmonary water loss, assumed to be constant, was excluded from the calculation. Consecutive paired iWL studies:Use of the thermal blanket produced a 70% mean reduction in IWL and a net caloric saving of 27 kcal/kg/day (t=3.4; p<.01). There was minimal interference with nursing care. The results indicate that (1) the simple insulating blanket used is a highly effective means of reducing IWL, (2) the caloric saving achieved by reducing IWL and evaporative heat loss may be an important determinant of intact survival in the high-risk infant.

A WARMING MATTRESS FOR PREMATURE INFANTS

We measured temperatures and metabolic rate of healthy infants (gestational age 28-33 wks and postnatal age 2-26 days) in contact with a heated water mattress. Infants were randomized with/without the mattress ≥8 hrs in a single wall forced convection incubator, unrestrained, diapered and supine. Tmattress (35.2±.1°C) was regulated by continuous circulation of H2O through a thermostatically controlled bath. Mid-inc air temp (Ta) was within the thermoneutral range. No humidity was added to inc. Heating effects measured q half hrly: skin temp at 6 sites → mean skin temp (Ts), esophageal temp (Te), heart rate (HR), resp rate (RR) and O2 consumption (VO2) at the end of each period. N=10 patients. Results(mean±SD): No mattress vs mattress p value by paired t-test: Ta (°C) 32.4±1.3 vs 31.6±0.9 p<0.05; Ts (°C) 35.3±0.3 vs 36.3±0.3 p<0.01; Te (°C) 36.5±0.3 vs 37.2±0.4 p<0.01; HR (beats/min) 155±8 vs 161±10 p<0.01; RR (breaths/min) 41±6 vs 48±8 p<0.01; VO2 (ml/kg/min) STPD 5.33±1.4 vs 4.94±1.55 NS. Results indicate that heat storage occurred due to alteration of balance between body heat production and losses. To determine the rate of dry (sensible) heat exchange we used a metabolic simulator, an electrically-heated 10 cm diam sphere. At a representative incubator Ta of 31.5°C and simulator Ts of 35°C, the dry heat loss was reduced from 60 W/m2 to 35 W/m2 on the heated pad. This was brought about by a combination of heat conduction to the simulator and decreased radiation losses from the simulator to the surrounding mattress.

FUROSEMIDE (FS) IN HYALINE MEMBRANE DISEASE (HMD)

We conducted a random blind study to assess the effect of IV FS 2 mg/kg or 5% DW in 0.25 NaCl (control) on interstitial fluid mobilization and cardiorespiratory function in 7 infants with HMD. Criteria for entry into the trial were: peripheral edema and FiO2>.4 to maintain PaO2>50 torr. Echocardiogram and multiple gas analyses were performed in the 2 hours preceding and following the treatment. Results (mean ± SD):In spite of the diuresis, measurements of dynamic skinfold thickness did not confirm mobilization of subcutaneous interstitial water. We conclude that FS has a potent diuretic effect in infants with HMD but it does not improve cardiorespiratory function acutely. This may be due to failure to mobilize pulmonary interstitial fluid in the time period tested.

CALCIUM HOMEOSTASIS IN EXCHANGE TRANSFUSION

The effect of exchange transfusion (ET) on plasma ionized calcium (Ca++) was studied in 27 exchange transfusions on 19 infants using CPD blood. The addition of 0.1 g Ca gluconate per 100 ml exchanged did not prevent a fall in Ca++ in term or preterm infants (Group I). ET was then performed with 0.5 g CaCl2 (Group II) or 0.1 g CaCl2 (Group III) added to 450 ml heparinized CFD blood. In Group iI Ca++ and total Ca increased markedly during the ET, the total Ca reaching 15.5 rag/100 ml in one case. However, Ca levels were normal within 30 minutes of the end of the ET. In Group III, although Ca++ levels in the donor blood were very low (0.6±0.21 mg/100 ml) the fall in Ca++ was abolished during ET in term infants. Nevertheless, the decline in Ca++ could not be prevented in the preterm infants although total Ca increased. Mechanisms of Ca homeostasis during ET are complex and it may not be possible to achieve normal Ca++ levels without excessive elevation of total Ca. However, addition of Ca to the donor blood will prevent the fluctuation in Ca++ seen with intermittent Ca administration. In addition, it appears that in vitro titration of donor blood with CaCl2 to normocalcemic levels should not be used as a means of determining the appropriate dose of Ca in ET.