Optimal position for a spinal tap in preterm infants.

Inasmuch as spinal taps in preterm infants are frequently accompanied by clinical deterioration, the optimal position for this procedure was investigated. Three positions were each randomly assigned for five minutes to 17 healthy preterm infants without a spinal tap actually being performed: (1) lateral recumbent with full flexion (flexed position), (2) lateral recumbent with partial neck extension (extended position), and (3) sitting with head support and spine flexion (upright position). Transcutaneous PO2 and PCO2 were monitored in all infants, minute ventilation (VI) in seven, and heart rate and blood pressure in ten infants. Mean transcutaneous PO2 decreased in each of the three positions. This decrease was significantly greater in the flexed (28 +/- 8 mm Hg) as compared with the extended (18 +/- 8 mm Hg, P less than .001) and upright (15 +/- 11 mm Hg, P less than .001) positions. Mean transcutaneous PCO2 increased only in the flexed position (3 +/- 4 mm Hg, P less than .005) and levels were still elevated five minutes after that position had been discontinued. The consistent decrease in transcutaneous PO2 was accompanied by a variable effect of positioning on VI and there were no episodes of airway obstruction or apnea greater than 10 seconds. Heart rate increased in each position whereas blood pressure remained unchanged. These data suggest that although hypoventilation may contribute to the observed decrease in transcutaneous PO2, ventilation/perfusion imbalance appears to be the major mechanism. As spinal taps performed in the widely accepted flexed position carry the greatest risk of potential morbidity, it is recommended that this position be modified with neck extension or that spinal taps be performed in the upright position.

Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants.

DESIGN AND METHODS: We hypothesized that treatment with recombinant human erythropoietin (r-HuEPO) would stimulate erythropoiesis and would thereby reduce the need for erythrocyte transfusions in preterm infants. We treated 157 preterm infants born at 26.9 +/- 1.6 weeks of gestation who weighed 924 +/- 183 g at birth with either subcutaneous r-HuEPO (100 U/kg/d, 5 days per week) or placebo for 6 weeks in a randomized, double-blind, controlled clinical trial. All patients received oral iron and were managed according to uniform conservative transfusion guidelines. RESULTS: Treatment with r-HuEPO was associated with fewer erythrocyte transfusions (1.1 +/- 1.5 per infant in the r-HuEPO group versus 1.6 +/- 1.7 per infant in the placebo group; P = .046) and with a reduction in the volume of packed erythrocytes transfused (16.5 +/- 23.0 mL versus 23.9 +/- 25.7 mL per infant; P = .023). Overall, 43% of the infants in the r-HuEPO group and 31% of placebo-treated infants were transfusion-free during the study (P = .18). The volume of blood removed for laboratory tests and the need for respiratory support at the start of treatment had major effects on transfusion requirements independent of r-HuEPO. Reticulocyte counts were higher during treatment in the r-HuEPO group (P = .0001), and r-HuEPO-treated infants had higher hematocrit values at the end of the study (32% versus 27.3% in the placebo group; P = .0001). We found no differences in the incidence of major complications of prematurity between the treatment groups. CONCLUSION: We conclude that treatment with r-HuEPO at a weekly dose of 500 U/kg stimulates erythropoiesis, moderates the course of anemia, is associated with a reduction in erythrocyte transfusions, and appears safe in very low birth weight preterm infants who are receiving iron supplements. Conservative transfusion criteria, minimization of phlebotomy losses, and treatment with r-HuEPO are complementary strategies to reduce erythrocyte transfusions in these infants.

An elevated hematogenous photosensitizer in the preterm neonate.

PURPOSE: Human blood contains low levels of protoporphyrin IX (PP IX), a photoactive compound that produces reactive oxygen species when exposed to light. It has been proposed that photoactivation of PP IX and subsequent generation of potentially tissue-damaging reactive oxygen may be a mechanism of retinal injury in retinopathy of prematurity (ROP). The purpose of this study is to determine an association between blood PP IX level and infant birth-weight and gestational age. METHODS: Erythrocyte PP IX levels were measured from the umbilical cord blood of 31 neonates, both full term and preterm. Birthweights and gestational ages were recorded. RESULTS: PP IX levels in infants weighing < 1000 grams (n = 7) average 200 micrograms/dl, which is significantly higher than PP IX levels in infants weighing > 1000 grams (125 micrograms/dl, n = 24; P < 0.02). CONCLUSION: Elevated PP IX levels may place preterm neonates at increased risk for photosensitizing retinal injury.

Blood-brain barrier permeability during dopamine-induced hypertension in fetal sheep.

Dopamine is often used as a pressor agent in sick newborn infants, but an increase in arterial blood pressure could disrupt the blood-brain barrier (BBB), especially in the preterm newborn. Using time-dated pregnant sheep, we tested the hypothesis that dopamine-induced hypertension increases fetal BBB permeability and cerebral water content. Barrier permeability was assessed in nine brain regions, including cerebral cortex, caudate, thalamus, brain stem, cerebellum, and spinal cord, by intravenous injection of the small tracer molecule [(14)C]aminoisobutyric acid at 10 min after the start of dopamine or saline infusion. We studied 23 chronically catheterized fetal sheep at 0.6 (93 days, n = 10) and 0.9 (132 days, n = 13) gestation. Intravenous infusion of dopamine increased mean arterial pressure from 38 +/- 3 to 53 +/- 5 mmHg in 93-day fetuses and from 55 +/- 5 to 77 +/- 8 mmHg in 132-day fetuses without a decrease in arterial O(2) content. These 40% increases in arterial pressure are close to the maximum hypertension reported for physiological stresses at these ages in fetal sheep. No significant increases in the brain transfer coefficient of aminoisobutyric acid were detected in any brain region in dopamine-treated fetuses compared with saline controls at 0.6 or 0.9 gestation. There was also no significant increase in cortical water content with dopamine infusion at either age. We conclude that a 40% increase in mean arterial pressure during dopamine infusion in normoxic fetal sheep does not produce substantial BBB disruption or cerebral edema even as early as 0.6 gestation.

Relationship of diaphragmatic contractility to diaphragmatic blood flow in newborn lambs.

We determined the relationship of diaphragmatic contraction rate to diaphragmatic blood flow (Qdi), metabolism, and contractility in nine open-chested mechanically ventilated newborn lambs. The diaphragm was paced for 15 min at slow (20/min) and fast (100/min) contraction rates each followed by a 30-min rest period. There was a mild reduction in transdiaphragmatic pressure (Pdi) during the slow contraction period accompanied by a shift to the right of the curve relating stimulation frequency (10-100 Hz) to Pdi. Pdi returned to control at the start of the fast contraction period, but then fell by 30% within 2 min with continued fast contraction rates. The frequency-Pdi curve was significantly shifted to the right. Qdi, O2 transport, and O2 consumption increased during slow contraction and to an even greater extent during fast contraction. Fractional O2 extraction reached an apparent maximum during slow contraction. Lactate efflux from the right phrenic vein during slow contraction remained unchanged from control. During fast contraction lactate efflux rose proportionately more than did O2 consumption. We conclude that the energy demands at fast rates of diaphragmatic contraction in newborn lambs cannot be met by aerobic metabolism alone despite increasing O2 transport to the diaphragm.

The human locus coeruleus and anxiogenesis.

Electrical stimulation of locus coeruleus (LC), via permanently implanted electrodes with confirmed localization and effectiveness, did not elicit any subjective or behavioral manifestations of anxiety. This is evidence against the hypothesis that LC is a mediator of anxiogenesis in man.

Rapid electroenzymatic measurement of lactate in microsamples of spinal fluid.

A lactate sensor, which makes possible rapid direct measurement of L-lactate in small samples of spinal fluid, has been developed. This enzyme electrode gives a linear current output as a function of hydrogen peroxide generated by a lactate oxygen oxidoreductase sandwiched between two membranes. The membranes serve to support the oxidase, prevent the diffusion of soluble electroactive species such as urate, ascorbate, and phenolic drugs such as acetaminophen, and to form a diffusion-limited path for the lactate. A 10 or 25 microL sample of spinal fluid is injected into a 350 microL thermostated chamber containing a suitable buffer and the electrode's sensing surface. The method has been tested by analysis of spinal fluid, with amounts of lactate up to 15 mmol/L, by comparison with a photoenzymatic method. A correlation coefficient of 0.999 was found. With a new cellulose ester membrane, acetaminophen levels up to 10 mmol/L did not interfere. A YSI glucose analyzer can be converted to a lactate analyzer by changing the O-ring mounted enzyme transducer membrane.

Prostaglandins and the developing kidney.

Prostaglandins PGE2, PGD2, PGI2, and PGF2 alpha, as well as thromboxanes and leukotrienes, are synthesized by the fetal and neonatal kidney. The major prostaglandin, PGE2, PGD2, and PGI2, increase RBF, free water clearance, urine flow, and natriuresis. Alterations in the synthetic and catabolic activity of renal prostaglandins with advancing gestational and postnatal age occur along with concomitant alterations in RBF, GFR, and water and electrolyte excretion, suggesting that the prostaglandins play an important role in renal functional development. Indomethacin treatment may affect both fetal and neonatal renal function. Long-term maternal indomethacin treatment may decrease fetal urine output enough to alter amniotic fluid volume. Neonatal indomethacin therapy may cause transient dose-related renal dysfunction characterized by a decrease in urine output, but this renal dysfunction also depends in part on dosage, timing of therapy, and the cardiovascular and renal status of the infant prior to treatment. New areas of research interest include urinary prostaglandins as a marker for development of essential hypertension, and the possible interaction between antenatal steroids and renal function in the newborn.

Stereotactic localization (with computerized tomographic scanning), biopsy, and radiofrequency treatment of deep brain lesions.

In eight patients stereotactic biopsy of deep brain lesions was performed. Adequate tissue was obtained, and the information helped considerably in planning further therapy. No significant complications occurred in these patients. In three of the cases, the stereotactic coordinates were determined from the computerized tomographic (CT) scan. In one patient, after biopsy, stereotactic radiofrequency (RF) lesions in the tumor resulted in temporary improvement.

Laparoscopically implantable nerve-stimulating electrode (LINSE): application to the cavernous nerve in acute and chronic canine models.

Using a new laparoscopic procedure, we investigated stimulation of the cavernous nerves to achieve erection in a canine model. The technique was developed during acute experiments in four dogs, following which, chronic studies (4- to 6-weeks survival after surgery) were undertaken in three dogs. A monopolar cuff electrode was inserted laparoscopically by a transperitoneal approach and placed around the cavernous nerve. The leads were brought out to the subcutaneous space, where they were attached to stimulation receivers that could be activated by an external radiofrequency transmitter. An intracavernous pressure elevation indicative of successful stimulation was obtained acutely in five of eight cavernous nerves in the four acute-study dogs and in four of six nerves in the three chronic-study dogs. The implanted equipment associated with four of six cavernous nerves failed mechanically in the chronic-study animals, such that only two receiver-electrode sites were intact at the time of sacrifice 4 to 6 weeks later. Transmitter-driven stimulation of one of these two sets produced an intracavernous pressure rise above 100 cm H2O. We present this technique as part of the continuing evolution of laparoscopy as both a research and a clinical tool. The present use of the laparoscopically implantable nerve-stimulating electrode is a new animal research tool and a potential first step in the human application of the technology.

Skin care management practices for premature infants.

OBJECTIVE: To describe current skin care practices for preterm infants in neonatal intensive care units in the United States. We hypothesized that there would be little consensus among facilities. STUDY DESIGN: Neonatal intensive care units (n = 823) listed in the 1996 United States Neonatologists Directory (American Academy of Pediatrics, Section on Perinatal Pediatrics) were sent a 28-question survey dealing with many aspects of neonatal skin care along with descriptive data about their neonatal intensive care unit. Descriptive data analysis was performed. RESULTS: A total of 305 surveys were returned (37% return rate); of these, 241 of the respondents reported admitting infants weighing < or = 1000 gm. Some neonatal skin care practices showed wide consensus (> 70%) (e.g., scrub procedure for staff; use of a skin barrier under tapes/adhesives), whereas other practices showed little consensus (< 30%) (e.g., routine surveillance cultures; use of Aquaphor). CONCLUSION: Consensus on skin care practices was not found among neonatal intensive care units. Data from this survey can be used to develop studies to examine whether certain skin care management practices can improve neonatal outcomes.

Evaluating patterns of morphine use in a neonatal intensive care unit after NEOPAIN.

OBJECTIVE: To test the hypothesis that use of morphine for sedation of ventilated premature neonates has not changed despite evidence-based recommendations. STUDY DESIGN: Retrospective chart review. RESULTS: Of 410 ventilated patients, 129 received a morphine infusion. The annual percentage of ventilated patients started on an infusion did not vary significantly from 2005-2010 (range: 27%-37%, mean: 32%, χ2 test for trend p = 0.60). Patients given morphine infusion had a lower median estimated gestational age at birth (26 0/7 weeks versus 27 6/7 weeks), and a lower median birth weight (762 versus 1010 grams). CONCLUSION: Use of morphine as a sedative and/or pre-emptive analgesic agent for critically ill, ventilated, premature neonates has not decreased at the study site despite evidence-based recommendations against this treatment approach. This is an area of care that may benefit from quality improvement interventions.

Gluconeogenesis by the fetal sheep liver in vivo.

Hepatic gluconeogenesis is an important source of glucose postnatally. Whether hepatic gluconeogenesis contributes to fetal glucose supply has not been studied directly in vivo. Previous studies of gluconeogenesis in fetal sheep have assessed total fetal glucose production, and the results have been controversial. To assess the specific role of the liver in gluconeogenesis in fetal sheep, we placed catheters in the right or left hepatic vein, umbilical vein and the inferior vena cava of six fetal sheep (mean gestational age 134 days) and infused a radioactive gluconeogenic substrate (14C-lactate or 14C-alanine) into the fetal inferior vena cava. We measured 14C-glucose radioactivity (dpm/ml) in the right or left hepatic vein and calculated the arteriovenous difference in 14C-glucose radioactivity (dpm/ml) across the right or left liver lobe. We found that only 0.35% of the 14C substrates perfusing either the right or the left hepatic lobe of the fetal liver were converted to 14C-glucose. Even when considerable glucose was released by the liver, the percentage of substrates converted to glucose remained very low (maximum 1.7%), indicating that gluconeogenesis did not contribute significantly to the glucose released. We conclude that gluconeogenesis by the fetal liver contributes negligibly to the glucose supply in fetal sheep.

Cerebral responses to acute maternal alcohol intoxication in immature fetal sheep.

Previous studies in mature fetal sheep have shown that alcohol depresses cerebral blood flow (CBF), cerebral O2 consumption (CMRO2), and cerebral glucose consumption (CMRglu). This effect earlier in gestation might contribute to the pathogenesis of fetal alcohol syndrome. Physiologic studies of immature fetal sheep have demonstrated lower CBF, CMRO2, and CMRglu as well as a blunted vasodilatory response to hypoxia compared with mature fetal sheep. The purpose of this study was to determine whether immature fetal responses to alcohol are blunted compared with near-term fetal responses. We studied seven immature fetal sheep in utero at 92 +/- 1 d gestation (term = 147 d) 2 d after placement of vascular catheters. Pure ethanol (1 g/kg) was infused i.v. to the mother over 1 h. We measured CBF and myocardial blood flow by radioactive microspheres and calculated CMRO2 and CMRglu using arterial and sagittal sinus O2 and glucose concentrations. At a fetal ethanol concentration of 33 + 8 mmol/L (150 +/- 37 mg/dL), there were no significant changes in CBF, CMRO2, or CMRglu. There was mild hypoglycemia (glucose concentration = 1.05 +/- 0.2 versus 1.33 +/- 0.2 mM baseline) and lactic acidemia (lactate concentration = 1.29 +/- 0.3 versus 1.07 +/- 0.2 mM baseline). Cardiovascular variables were unchanged as was myocardial blood flow. The immature fetal sheep brain shows no significant cerebrovascular and metabolic response to acute alcohol intoxication compared with mature fetal sheep. Mild hypoglycemia and lactic acidemia did develop. The reason for the developmental differences in response to alcohol and their relationship to fetal alcohol syndrome remain to be elucidated.

Oxygenation does not stimulate hepatic gluconeogenesis in fetal lambs.

We have previously shown that the healthy fetal lamb liver does not release glucose and does not demonstrate gluconeogenesis. Shortly after birth, however, the liver releases glucose both by glycogenolysis and by gluconeogenesis. Previously it has been suggested that increased oxygen availability stimulates hepatic gluconeogenesis at birth. To test this hypothesis, we increased fetal arterial blood pO2 by ventilating the fetus with high oxygen gas mixtures in utero. We placed intravascular catheters in the right or left hepatic vein, umbilical vein, inferior vena cava, and descending aorta and inserted a large polyvinyl tube into the trachea of seven fetal lambs at 134 +/- 2.2 days gestation. Studies were done several days after surgery. 14C-lactate was infused intravenously and 14C-glucose concentrations were measured in hepatic venous and umbilical venous blood during a control period, during ventilation with 5% CO2, 3% O2, 92% N2, and then during ventilation with 5% CO2 and 95% O2. The difference between these two measurements represented hepatic gluconeogenesis. Arterial blood glucose concentrations and blood gases were also measured during each study period. Ventilation with 3% O2 did not significantly change arterial PO2 but ventilation with 95% oxygen increased mean arterial pO2 from a control of 16.7 to 156.3 torr. Mean arterial blood glucose concentration increased significantly from a control of 11.9 to 17.6 mg/dl during ventilation with 3% O2 and to 19.1 mg/dl during ventilation with 95% O2. However, the hepatic-umbilical venous 14C-glucose concentration difference was not significant when control values were compared with each ventilation period. We conclude that an acute increase in fetal oxygenation does not stimulate hepatic gluconeogenesis in near-term fetal lambs.

Cerebral responses to maternal cocaine injection in immature fetal sheep.

Previous studies in near-term sheep have shown that maternal cocaine injection causes acute fetal cerebral vasodilation along with transient hypoxemia and hypertension. Preterm sheep fetuses have lower cerebral O2 consumption (CMRO2) and their cerebrovascular responses to hypoxemia are attenuated compared with near-term fetuses. We therefore tested the hypothesis that fetal cerebrovascular responses to maternal cocaine injection may also differ earlier in gestation. We studied nine immature fetal sheep at 0.65 gestation using the same experimental protocol we used in previous studies in near-term sheep. Fetal studies were done in utero, 2 d after vascular catheter placement. We measured cerebral blood flow (CBF) using microspheres, arterial and sagittal sinus O2 content, and cocaine concentrations. We calculated cerebrovascular resistance (CVR) as mean arterial blood pressure divided by CBF. Measurements were made before and 2, 5, and 15 min after a 2 mg/kg maternal cocaine injection. At 2 min, fetal Cao2 decreased (18 +/- 6%, mean +/- SEM), and there was cerebral vasoconstriction (CVR increased by 22 +/- 5%). At 5 min, CBF increased (19 +/- 9%), but because blood pressure increased also, CVR returned to baseline, and therefore there was no vasodilation compared with baseline. Furthermore, at 5 min there was a 22 +/- 6% decrease in Cao2 and a 21 +/- 6% increase in mean arterial blood pressure. There were no changes in CMRo2 throughout the study, but at 2 min, cerebral O2 delivery decreased. Differences in cerebrovascular responses to maternal cocaine injection earlier in gestation may be due to differences in vascular development and/or to developmental differences in responses to cocaine, cocaine metabolites, and/or to hypoxemia.

ECG/respiration monitor calibrator.

This paper describes an ECG/Respiration monitor calibrator used by the Biomedical Staff to check such units quickly, inexpensively and accurately. The calibrator can be constructed by the Biomedical Engineering Staff in one day for a parts cost of less than fifty dollars. Once the calibrator is connected to the patient cable of an ECG/Respiration monitor, the calibrator will generate concurrently a calibrated rate and amplitude ECG-pulse and respiration waveform.

Readiness-potentials preceding unrestricted 'spontaneous' vs. pre-planned voluntary acts.

The nature of readiness-potentials (RPs) that may be associated with fully endogenous, 'freely' voluntary acts was investigated. Restriction on when to act were eliminated and instructions fostered 'spontaneity.' The 'self-initiated' RPs exhibited in these conditions were categorizable into two (possibly three) types, all of which could be exhibited by the same subject. Type I had an early onset at about -1050 +/- 175 msec and a long ramp-like form, resembling self-paced RPs. In type II the main negative shift began at about -575 +/- 150 msec, and at about -240 +/- 50 msec in type III. Type II partially resembled the similarly timed NS' component in self-paced RPs. For acts produced at known, preset times, in which freedom of choice was eliminated but planning to act was required, RPs resembled self-initiated type I RPs and self-paced RPs. All RPs were maximal at the vertex, especially type II even though it was also bilaterally asymmetrical. These distributions suggest that cortical areas other than area 4 and 6 contribute importantly, especially to type II. All RPs, whether in self-initiated or pre-planned acts, appear related specifically to preparation for a motor action. When task-related skin stimuli replaced self-initiated movements, under similar conditions of attentiveness (and expectancy), there were either no or relatively small event-preceding-slow potential shifts. All post-stimulus P300 waves were very large. Two volitional processes are postulated: process I is associated with development of pre-planning or preparation to act in the near future (seconds), whether voluntary choice is present (type I RPs) or absent (pre-set RPs); process II, with an onset at roughly 0.5 sec before the act, is associated more uniquely with voluntary choice and with the more specific as well as endogenous urge or intention to act; it can be present in the comparative absence of or in sequence and overlapping with process I.

Cerebral blood flow and metabolism during and after prolonged hypocapnia in newborn lambs.

We studied the effects of prolonged (6 hours) hypocapnia and the abrupt termination thereof on cerebral blood flow and metabolism in six paralyzed, sedated (but not anesthetized) newborn lambs. Thirty minutes after institution of hyperventilation to an arterial carbon dioxide pressure of 15 +/- 2 torr, hyperventilation, cerebral blood flow had returned to baseline. Abrupt termination of hyperventilation after 6 hours resulted in a 110 +/- 71% increase in cerebral blood flow over baseline after 30 minutes of normocapnia. This cerebral hyperemia persisted for at least 90 minutes after hyperventilation was discontinued. Cerebral oxygen consumption did not change throughout the study. The posthypocapnia hyperemia noted in these animals after abrupt normalization of arterial carbon dioxide pressure may contribute to the increased risk of intracranial hemorrhage in newborn infants who are treated similarly in the management of pulmonary hypertension.