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Individualized parenteral nutrition is frequently used in neonatal period because of specific nutritional needs of preterm neonates which are not always covered by industrially produced parenteral nutrition. This review summarizes the risks of physicochemical instability associated with parenteral nutrition preparation in order to make recommendations to secure this mode of preparation.

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UNLABELLED: During the first days of life, hyperkalemia can affect 30 to 60% of very low birth weight infants free of acute renal insufficiency (i.e. nonoliguric hyperkalemia). The place of the kidney in the regulation of the potassium homeostasis of VLBW remains badly specified. OBJECTIVE: To evaluate the rate and the mechanisms of hyperkalemia in infants born at less than 32 weeks' gestation. METHODS: A prospective study was conducted in 33 preterm infants (BW=1289+/-382 g; GA=28.8+/-1.7 weeks). Fifteen consecutive 8-hour urine collections were performed for each infant from the 8th hour of life (495 periods). A plasma sample was obtained at the end of each urine collection. Sodium, potassium and creatinine were measured in urine and blood samples as often as possible. RESULTS: Plasma potassium concentrations varied significantly over the 15 successive periods with an initial value (P1) of 4.55+/-0.80 mmol/l, a peak on P3 (4.94+/-0.81 mmol/l) and the lowest value on P13 (3.88+/-0.42 mmol/l). Hyperkalemia (plasma potassium>6.0 mmol/l) was observed in 4 infants (12%) and in 1.2% of the periods. The cumulative potassium balance (output-input) was negative over the first 7 periods (-1.97 mmol/kg), and afterwards became positive (from P8 to P15:+1.57 mmol/kg). Over the first 3 days, plasma potassium concentrations were positively correlated (p<0.01) with urinary excretion of potassium, clearance of potassium, fractional excretion of potassium, and negatively with endogenous creatinine clearance. CONCLUSION: In the first days of life, very low birth weight infants present an increase in kalemia associated with a negative potassium balance indicating a intracellular to extracellular potassium shift rather than a lower renal potassium excretion.

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Diuretics are frequently used in preterm infants in various situations such as patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia or neonatal renal insufficiency. However, the beneficial effects reported in the literature are usually transient, without any obvious effect on important parameters such as duration of oxygen dependency, ventilator dependency, length of hospital stay, long-term outcome, or mortality. Moreover, these drugs may induce water-electrolyte disorders especially when used for a long-term period. Thus, we recommend a systematic analysis of the beneficial/risk ratio before any use of these drugs.

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In adult patients, a recent physiological approach for the osmoregulatory system based on body fluid tonicity (the so-called effective osmolality) seems to provide better information on water movements than does the classical body fluid osmolality. To evaluate whether plasma or urinary tonicities could give a better assessment of osmoregulation than plasma and urine osmolalities in sick preterm infants cared for in a NICU. A prospective study was conducted in 30 preterm infants (BW=1284+/-377 g; GA=28.8+/-1.7 weeks). Fifteen consecutive 8-h urine collections were performed for each infant from the 8th h of life (450 periods). A plasma sample was obtained at the end of each urine collection. Sodium, potassium, creatinine, osmolality and tonicity were measured or calculated in urine and blood samples as often as possible. Hypernatremia (PNa=146-149 mmol/l) was observed in seven infants (23.3%) and in 5.9% of the periods. Fifty-three percent of the infants and 20.4% of the periods presented with plasma hyperosmolality (>300 mosmol/kg H2O). The relationship between Posm and PNa was significant, but the clinical relevance was weak (r(2)=0.411; P<0.001). Plasma osmolality (Posm) positively correlated with urine osmolality (Uosm), but did not correlate significantly with CH2O/100 ml GFR. Plasma tonicity (2x(PNa+PK)) positively correlated with both urine tonicity (2x(UNa+UK)) and effective water clearance (EWC/100 ml GFR). On an individual basis, the linear relationship between urine and plasma osmolalities was significantly weaker than the relationship between urine and plasma tonicities. This study suggests that the calculation of plasma and urine tonicities allows a better assessment of water movements in body fluid compartments than plasma and urine osmolalities.

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OBJECTIVE: To assess incidence and clinical risk factors of chronic oxygen dependency (COD) among survivors who were born at or before 31 weeks' gestation. METHODS: This prospective, multicenter study enrolled 802 infants who were born at or before 31 weeks' gestation and admitted to 8 level III neonatal intensive care units in northern and eastern France from January 1 through December 31, 1997. Need for oxygen to maintain oxygen saturation between 92% and 96% was assessed at 28 days of life and at 36 and 42 weeks' postconceptional age (PCA). Stepwise logistic regression analysis was used to identify the incidence of COD and the risk factors related to its occurrence. RESULTS: The mortality rate was 14%. Antenatal corticotherapy was administered to 51% of patients, surfactant therapy to 76% of the ventilated patients, and high-frequency oscillatory ventilation at day 1 to 32%. At 28 days and 36 and 42 weeks' PCA, respectively, 25%, 15%, and 6% of survivors had COD. After adjustment for intercenter variations, we identified the significant risk factors for COD at these dates: a low gestational age, a high score on the Clinical Risk Index for Infants, intrauterine growth restriction, and surfactant treatment. CONCLUSION: COD incidence was high at 28 days of life but decreased dramatically by 42 weeks' PCA. This study confirmed previously reported risk factors and underlined the importance of intrauterine growth restriction and the Clinical Risk Index for Infants as significant risk factors.

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BACKGROUND: Cisapride administration for 48 hours has been shown to increase heart rate corrected QT (QTc) interval in preterm neonates. Accumulation of the drug because of liver enzyme immaturity has been suggested to be the reason. If this is correct, a longer survey of QTc interval should disclose an increase even in term neonates. OBJECTIVE: A prospective survey of the effects of cisapride on QTc interval in term neonates administered cisapride. SETTING: Neonatal Unit of the University Hospital of Dijon, France. DESIGN: QTc interval was determined just before and 48 hours, seven days, and 15 days after the start of treatment. SUBJECTS: Twenty one term newborn infants (mean gestational age 39.3 weeks) given the recommended dose of cisapride (0.2 mg/kg, four times a day). RESULTS: Administration of cisapride caused a significant increase in QTc interval (p < 0. 01). The mean value increased from 0.397 before treatment to 0.418 after 48 hours, 0.431 by day 7, and 0.447 by day 15. A QTc interval exceeding 0.450 was found in six neonates: three at 48 hours, one at day 7, and two at day 15. In two infants, withdrawal of the drug was associated with normalisation of the QTc interval. CONCLUSIONS: These results support the hypothesis of cisapride accumulation in newborns due to enzymatic immaturity and indicate that QTc interval should be monitored in neonates receiving this drug.

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OBJECTIVE: Prospective recording of IV nicardipine efficacy and safety as a first-line antihypertensive drug in neonates. PATIENTS: Twenty neonates (15 preterm) with systemic hypertension due to steroids administration (n = 14), polycystic kidney disease (n = 1), renal vein thrombosis (n = 1), coarctation of aorta (n = 1) or from an undetermined cause (n = 3). INTERVENTIONS: The initial nicardipine dosage was 0.5 microg/kg/min in 17 patients. The maximal nicardipine dosage was 0.74+/-0.41 microg/kg/ min (0.5-2.0). The duration of treatment was 14.6+/-11.6 days. RESULTS: Systolic blood pressure significantly decreased after 3, 6, 12, 24 and 48 h of nicardipine treatment (-20+/-11%, -19+/-10%, -20+/-8%, -20+/-10% and -20+/-12%, respectively). The decrease in blood pressure remained significant over the subsequent days of treatment. No hypotension or other clinical side effects were observed. CONCLUSIONS: Both additional pharmacokinetic and pharmacodynamic studies remain mandatory to improve the dosage regimens and assess the efficacy and safety of nicardipine infusion in hypertensive neonates.

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We previously developed a model of acute cyclosporine A (CsA)-induced vasomotor nephrotoxicity in rabbits. In the present study, we evaluated the role of endothelin (ET), angiotensin II (AII) and adenosine in this experimental model. All animals received CsA (25 mg/kg/day) for 5 days. Renal function parameters were first measured in a 30-min period, showing renal insufficiency in all animals. Then, rabbits were administered bosentan (10 mg/kg; antagonist of ET(AB) receptors), perindopril (20 microg/kg; angiotensin-converting enzyme inhibitor), or theophylline (1 mg/kg; adenosine receptor blocker at micromolar concentrations). After a 40-min equilibration period, renal function was assessed again for 30 min. Bosentan, perindopril and theophylline significantly reduced renal vascular resistance (-28+/-5%, -39+/-7% and -8+/-3%, respectively), and improved renal blood flow (+38+/-15%, +66+/-16% and +20+/-5%), glomerular filtration rate (+33+/-9%, +52+/-13% and +50+/-8%) and diuresis (+48+/-9%, +76+/-19% and +73+/-14%). Filtration fraction was unchanged with bosentan, decreased with perindopril (-10+/-9%) and increased with theophylline (+24+/-5%). The overall results suggest that ET, AII and adenosine are involved in the acute renal failure induced by CsA. We conclude that CsA administration for 5 days induced a vasomotor nephropathy with ET- and adenosine-mediated afferent arteriolar constriction as well as ET- and AII-mediated efferent arteriolar constriction.

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Chronic cyclosporine A (CsA) nephrotoxicity has been widely assessed but only few studies have described acute nephrotoxicity. As CsA is now used for short periods, we developed an experimental model of acute CsA-induced nephrotoxicity. Renal clearances of inulin and para-aminohippurate were assessed in 35 New Zealand rabbits. Group 1: control, no treatment; group 2: CsA 25 mg/kg per day in 0.5 ml/kg per day for 5 days; group 3: vehicle Cremophor-EL, 0.5 ml/kg per day for 5 days; group 4: follow-up, the same as group 2, then CsA discontinuation for 31 days. Compared with group 1, CsA significantly decreased glomerular filtration rate (GFR), renal blood flow (RBF), and diuresis, with a significant increase in renal vascular resistance (RVR). The proportional fall in GFR (-32.3%) and RBF (-33.1%) suggests both pre- and postglomerular vasoconstriction. Discontinuation of CsA in group 4 led to normalization of RVR with improvement of other renal function parameters. Compared with group 1, Cremophor-EL induced no significant changes but an increased RBF. Microvacuolization of proximal tubule epithelial cells was the sole histological abnormality observed only in group 2. The overall results suggest that CsA induced a vasomotor acute renal failure which was not due to Cremophor-EL. This effect was partly reversible after discontinuation of treatment.

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The renal effects of acute hypoxemia and the ability of perindoprilat, a potent angiotensin-converting enzyme inhibitor, to prevent these effects were assessed in 31 anesthetized and mechanically ventilated newborn (5 to 8 d of age) rabbits. Renal blood flow (RBF) and GFR were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In eight normoxemic rabbits (group 1), the i.v. infusion of saline did not change renal and hemodynamic functions. In eight additional rabbits, acute hypoxemia (PaO2= 40 mm Hg) induced a significant decrease in mean blood pressure (-8+/-2%), RBF (-36+/-3%), and GFR (-31+/-3%) and an increase in renal vascular resistance (+50+/-12%). A third group of newborn animals (n=7) was used to determine the renal effects of perindoprilat administration (20 microg/kg) under normoxemic conditions. RBF significantly increased (+15+/-2%) and renal vascular resistance significantly decreased (-15+/-3%), whereas GFR, mean blood pressure, and filtration fraction did not change significantly. In group 4 (n=7), perindoprilat infusion completely prevented the hypoxemia-induced alterations in GFR and renal vascular resistance and partially prevented the fall in RBF. These results demonstrate that angiotensin II modulates the renal immature microcirculation and that inhibition of its formation effectively prevents the hypoxemia-induced decrease in GFR.

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OBJECTIVE: Comparison of three neonatal hemo(dia)filters (FH22, Gambro; Minifilter Plus, Amicon; Miniflow 10, Hospal) for removal of urea by venovenous hemofiltration (HF) and venovenous hemodiafiltration (HDF). DESIGN: Filters were successively used for HF with two different blood flows (Qb = 8.3 and 16.6 ml/ min) and for HDF with the two different blood flows and four dialysate flows (Qd = 0.5, 1.0, 2.0, and 3.0 l/h). SUBJECTS: 21 anesthetized adult New Zealand White rabbits infused with urea. MAIN RESULTS: Urea clearance was significantly increased by HDF compared to HF regardless of blood flow, dialysate flow, and the hemo (dia)filter type except in the FH22 group, when blood flow was high and dialysate flow was 0.5 or 1.0 l/h. The FH22 filter allowed the best urea clearance during HF at high blood flow. During the HDF procedures, the Miniflow 10 allowed the highest urea clearance regardless of blood flow and dialysate flow.

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Three preterm infants presented with both severe or moderate arterial hypertension and dehydration due to increased water and sodium urinary excretion. In patient 1, water and sodium wasting were extremely severe and peaked at 575 ml/kg per day and 73 mEq/kg per day, respectively. In all infants, urinary water and sodium excretion dramatically decreased when hypertension resolved. The overall clinical data suggest a pressure natriuresis phenomenon.

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Eight preterm infants were given intravenous nicardipine, a calcium channel blocker, to treat systemic hypertension (renal artery thrombosis (n = 3); dexamethasone for management of bronchopulmonary dysplasia (n = 2); unexplained (n = 3). Nicardipine doses ranged from 0.5 to 2.0 micrograms/kg/min and were given for three to 36 days (mean (SD) 15.9 (10.3) days). Systolic blood pressure had significantly decreased after 12 and 24 hours of nicardipine treatment (-17 (17)% and -21 (10)%, respectively). Diastolic blood pressure significantly decreased after 24 hours of treatment (-22 +/- 16%). The decrease in blood pressure remained significant over the subsequent days of treatment. No hypotension or other clinical side effects were observed. It is concluded that intravenous nicardipine could be a first line treatment for hypertension in preterm infants.

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AIM: Prospective survey of the effects of cisapride on QTc interval in neonates given cisapride. METHODS: QTc interval was determined just before and 2.9 (0.9) days after outset of the treatment in 49 neonates treated with cisapride between 1 August 1995 and 29 February 1996. RESULTS: Cisapride significantly increased QTc interval (p = 0.0001), and this was higher when birthweight or gestational age were lower. The prolongation of QTc interval above the arbitrary value of 0.450 (n = 7) was clinically asymptomatic and was significantly more common in the infants born with a gestational age < or = 33 weeks (n = 6). CONCLUSION: The findings indicate that cisapride accumulates in less mature neonates. Further pharmacokinetic studies are needed.

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OBJECTIVE: We compared the ability of peritoneal dialysis, hemofiltration, and continuous hemodiafiltration to remove infused ammonium chloride. STUDY DESIGN: Anesthetized adult rabbits received an intravenous infusion of ammonium chloride. Two methods of removal of ammonium chloride were performed in each animal and compared. In group 1 (n = 6), peritoneal dialysis (dialysate = 75 ml.kg-1) and continuous arteriovenous hemofiltration (CAVH) with a polysulfone 800 cm2 hemofilter (Minifilter Plus; Amicon Division, W. R. Grace & Co., Danvers, Mass.) were simultaneously performed for 40 minutes. In group 2 (n = 6), peritoneal dialysis and continuous arteriovenous hemodiafiltration (CAVHD) (dialysate flow = 1000 ml.hr-1) were simultaneous performed for 40 minutes. In group 3 (n = 6), CAVH and CAVHD were performed successively in random order for 30 minutes each. RESULTS: Animals had high and stable ammonium chloride and glutamine plasma levels during the experimental procedure. No significant difference in ammonium chloride clearance was observed between PD and CAVH (group 1). In comparison with PD or CAVH, CAVHD resulted in significantly higher clearances of ammonium chloride (40% +/- 10% vs 96% +/- 34%, respectively) and of glutamine (195% +/- 17% vs 77% +/- 25%, respectively). CONCLUSION: The overall results indicate that CAVHD should be considered for hyperammonemia when peritoneal dialysis is indicated but unfeasible or inefficient.

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In the newborn rabbit, acute normocapnic hypoxemia increases the renal vascular resistance, leading to renal hypoperfusion and decreased glomerular filtration rate. Endothelin is a potent vasoconstrictor peptide, produced by vascular endothelial cells, which could play a role as a mediator of the hypoxemia-induced renal dysfunction. To test this hypothesis, experiments were performed in 24 anesthetized and mechanically ventilated newborn rabbits. Renal blood flow and glomerular filtration rate were determined by the clearance of p-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 newborn rabbits (group 1), a bolus injection of 5 nmol.kg-1 of endothelin caused a marked increase in mean blood pressure and renal vascular resistance leading to a significant fall in glomerular filtration rate (-12 +/- 4%) and renal blood flow (-16 +/- 3%). A second group of animals (n = 8) confirmed the neutralizing activity of the endothelin-1 antiserum in vivo. In spite of pretreatment with endothelin-1 antiserum, hypoxemia induced an increase in renal vascular resistance (+40 +/- 18%; p < 0.05) associated with a significant fall in glomerular filtration rate (-18 +/- 7%) and renal blood flow (-29 +/- 6%) in 8 newborn rabbits (group 3). The present results suggest that endothelin-1 does not mediate the hypoxemia-induced renal changes.

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Endothelin is a potent vasoconstrictor peptide produced by vascular endothelial cells which could play a role in the physiological regulation of the renal microcirculation. To test this hypothesis, experiments were performed in 24 anaesthetized and mechanically-ventilated newborn rabbits. In 8 newborn rabbits (group 1), a bolus injection of 5 nmol/kg endothelin caused a marked increase in mean blood pressure (MBP) and renal vascular resistance (RVR), leading to a significant fall in glomerular filtration rate (GFR) (by 12% +/- 4%) and renal blood flow (RBF) by 16% +/- 3%). A second group of animals (n = 8) was used for testing the in vivo neutralizing activity of an endothelin-1 antiserum. The antiserum was thereafter infused into 8 additional newborn rabbits (group 3) in order to define the role of endogenous endothelin in modulating the function of the immature kidney. The antiserum induced a surprising increase in RVR (by 34% +/- 9%, P < 0.05) associated with a fall in GFR (by 21% +/- 4%, P < 0.05) and RBF (by 25% +/- 4%, P < 0.05), while the filtration fraction and MBP remained unchanged. The occurrence of a vasoconstrictive response to both high-dose endothelin and to its antiserum could be explained by the recent demonstration that high levels of endothelin lead to renal vasoconstriction, while lower levels induce renal vasodilatation. The present results suggest that endogenous endothelin is active at low levels under normal conditions and that this peptide plays a role in the physiological control of renal function, but not MBP.

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The renal effects of endothelin-1 were investigated in 16 anesthetized and mechanically ventilated newborn rabbits. Renal blood flow and glomerular filtration rate were determined by the clearance of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In eight newborn rabbits, a bolus injection of 5 nmol.kg-1 of endothelin-1 caused an initial fall in mean arterial blood pressure followed by a gradual, significant increase in mean arterial blood pressure that lasted for 45 min. The dramatic increase in renal vascular resistance (+28 +/- 4%) induced by endothelin led to a fall in glomerular filtration rate (-12 +/- 4%) and renal blood flow (-16 +/- 3%). In spite of the reduction of glomerular filtration rate and renal blood flow, urine flow and sodium excretion rates increased significantly (+20 +/- 5% and +49 +/- 9%, respectively). In eight additional newborn rabbits, a bolus injection of 1 nmol.kg-1 of endothelin--a dose that usually induces marked renal and systemic vasoconstriction in adult models--did not affect systemic or renal hemodynamics. In conclusion, endothelin induces renal and systemic vasoconstriction and affects water and sodium homeostasis during the neonatal period. These effects occur under higher doses than those used in adult animals. This age difference in systemic and renal responsiveness is probably mediated by receptor immaturity and/or interference of high levels of counteracting hormones present during the neonatal period.

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