Effects of sodium bicarbonate on striated muscle metabolism and intracellular pH during endotoxic shock.

The effects of HCO3Na load on acid-base balance and muscle intracellular bioenergetics have been investigated using 31P-magnetic resonance spectroscopy in an experimental model of endotoxinic shock. Anesthetized, mechanically ventilated, and paralyzed rats (n = 16) were given an intravenous bolus of Escherichia coli lipopolysaccharide (15 mg/kg). When shock was established they were randomly assigned to receive either HCO3Na intravenously (2 mmol/kg in 2 min) or an equimolar saline injection. Lipopolysaccharide induced a significant decrease in the levels of mean arterial pressure (58 +/- 6 vs. 120 +/- 8 mmHg), arterial pH (7.20 +/- .03 vs. 7.35 +/- .01), intracellular pH (6.86 +/- .04 vs. 7.08 +/- .01), a marked hyperlactatemia (7 +/- 3 vs. 1.2 +/- .2 mmol/L) and a drop in the phosphocreatine-inorganic phosphate ratio. In the bicarbonate-loaded rats, mean arterial pressure further decreased whereas it remained unchanged in the saline group. Bicarbonate increased arterial pH and PaCO2 transiently. In the saline group, arterial pH decreased and PaCO2 remained stable. In both groups, intracellular pH and high energy phosphates had a similar evolution. In this model of septic shock, partial correction of arterial pH using HCO3Na did not reduce the metabolic cellular injury in skeletal muscle. Based on these results, HCO3Na may be of limited therapeutic value in severe septic metabolic acidosis.

Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, on lactate metabolism and muscle high energy phosphates during endotoxic shock in rats.

Overproduction of NO by an inducible NO synthase (iNOS) plays a role in the pathophysiology of septic shock. In such situations, NOS inhibition might be of therapeutic value, although detrimental side effects possibly related to inhibition of constitutive NOS have been reported. The use of L-canavanine, a selective inhibitor of iNOS, might be more suitable. The aim of the study was to compare in a rodent endotoxic shock the effects of saline (2 mL/h), N(G)-methyl-L-arginine(L-NMMA) (10 mg/kg/h) and L-canavanine (100 mg/kg/h) on muscle intracellular pH (pHi) and intracellular bioenergetic patterns (ATP, phosphocreatine/inorganic phosphate ratio) using in vivo 31P magnetic resonance spectroscopy (31P MRS). Three groups of anesthetized, mechanically ventilated and paralyzed rats received an intravenous infusion of 15 mg/kg of endotoxin. A fourth time-matched control group (n = 8) received 2 mL/h of saline. Mean arterial pressure, femoral blood flow, arterial blood gases, lactate, nitrate level, and 31P nuclear magnetic resonance (31P MRS) measurements were acquired at onset (T = 0), 90 min (T = 90), and 180 min (T180) after the endotoxin challenge. Femoral oxygen delivery was calculated as the product of femoral blood flow (mL/min) and arterial oxygen content. Endotoxin induced a marked decrease in arterial pressure and femoral oxygen delivery and an increase in lactate level. Intracellular pH and phosphocreatine/inorganic phosphate ratio decreased. ATP level did not change. Both L-NMMA and L-canavanine reversed the endotoxin-induced decrease in arterial pressure. L-NMMA attenuated the decrease in femoral oxygen delivery and the increase in lactate level while these were corrected by L-canavanine. Considering 31P MRS derived bioenergetic indices, the endotoxin-induced decrease in pHi and Pcr/Pi was attenuated by L-NMMA and corrected by L-canavanine. In conclusion, in a rodent model of endotoxinic shock, the continuous infusion of L-canavanine, a selective iNOS inhibitor, improved the systemic hemodynamic parameters and the intracellular bio-energetic patterns estimated by in vivo 31P MRS. To the contrary, the continuous infusion of both constitutive and inducible NOS inhibitor L-NMMA was not followed by the same achievement.

Tonicity balance, and not electrolyte-free water calculations, more accurately guides therapy for acute changes in natremia.

The usual way to decide why hyponatremia or hypernatremia has developed and to plan goals for its therapy is to analyze events in electrolyte-free water (EFW) terms. We shall demonstrate that an EFW balance does not supply this information. Rather, one must calculate mass balances for water and sodium plus potassium separately (a tonicity balance) to understand the basis for the change in natremia and the proper goals for its therapy. These points are illustrated with a clinical example.

Comparison of systemic and regional effects of dobutamine and dopexamine in norepinephrine-treated septic shock.

OBJECTIVES: To compare the effects of dobutamine and dopexamine on systemic hemodynamics, lactate metabolism, renal function and the intramucosal-arterial PCO(2) gap in norepinephrine-treated septic shock. DESIGN: A prospective, interventional, randomized clinical trial. SETTING: Adult medical/surgical intensive care unit in a university hospital. PATIENTS: After volume resuscitation, 24 patients were treated with norepinephrine alone titrated to obtain a mean arterial pressure of 75 mmHg and a cardiac index greater than 3. 5 l/min(-1). m(-2). INTERVENTIONS: Patients were randomized to receive an infusion of dobutamine (n = 12) (5 microg/kg per min) or dopexamine (n = 12) (1 microg/kg per min). MEASUREMENTS AND MAIN RESULTS: Baseline measurements included: hemodynamic parameters, renal parameters (diuresis, creatinine clearance and urinary sodium excretion), gastric mucosal-arterial PCO(2) gap, arterial and mixed venous gases and arterial lactate and pyruvate levels. These measurements were repeated after 1 (H(1)), 4 (H(4)) and 24 (H(24)) h. No difference was found between dobutamine and dopexamine among H(0) and H(1), H(4) and H(24) values for hemodynamics. Dobutamine and dopexamine at low doses had no significant effect on mean arterial pressure, heart rate, cardiac index, oxygen delivery, oxygen consumption and pulmonary artery occlusion pressure. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. After 4 and 24 h lactate concentration decreased in the dobutamine group from 2.4 +/- 1 mmol/l to 1.7 +/- 0. 7 mmol/l and 1.5 +/- 0.4 mmol/l, respectively, while it increased in the dopexamine group from 2.3 +/- 1 mmol/l to 2.7 +/- 1 mmol/l after 4 h and returned to baseline values after 24 h (2.2 +/- 0.6). After 24 h the lactate/pyruvate ratio decreased in the dobutamine group from 15 +/- 5 to 12 +/- 3 (p < 0.05) while it was unchanged in the dopexamine group (from 16 +/- 6 to 17 +/- 4). Arterial pH increased in the dobutamine group from 7.35 +/- 0.05 to 7.38 +/- 0.07 (p < 0. 05) while it was unchanged in the dopexamine group (from 7.34 +/- 0. 01 to 7.35 +/- 0.10). The PCO(2) gap decreased after 1 and 4 h in both the dobutamine and dopexamine groups (p < 0.05 with respect to baseline). When looking at individual responses, however, patients from both groups exhibited an increased gastric PCO(2) gap. No difference was found between dobutamine and dopexamine for renal parameters. CONCLUSIONS: In norepinephrine-treated septic shock, low doses of neither dobutamine nor dopexamine caused significant effects on systemic hemodynamics and renal function and both dobutamine and dopexamine inconsistently improved the PCO(2) gap. The present results support the need for individual measurement of the effects of catecholamine on the PCO(2) gap.

Acute hyponatremia in the perioperative period: insights into its pathophysiology and recommendations for management.

Our purpose is to review the topic of acute postoperative hyponatremia by focusing on pertinent aspects of the physiology of water and solute excretion. Four areas will be highlighted: an examination of the source of addition of electrolyte-free water, an exploration of the basis for the very large natriuresis that occurs during cerebral salt wasting following neurosurgery, possible reasons to explain why acute postoperative hyponatremia may pose a greater risk for young women [Ayus and Arieff 1996, Ayus et al. 1992, Arieff 1986, Wijdick et al. 1991], and issues related to treatment of acute hyponatremia.

Variations in plasma sodium concentration in post-operative patients depend on an electrolyte-free water balance, part of a tonicity balance.

BACKGROUND: There is an inverse relationship between changes in the concentration of sodium in plasma (PNa) and intracellular fluid (ICF) volume. Intakes and losses of sodium (Na), potassium (K) and water can be divided into two volumes: isotonic and electrolyte-free water (EFW). Calculations of these volumes assess a tonicity balance, a tonicity imbalance results in a change of PNa: when EFW is added to body fluids, PNa decreases. Moreover, the concept of EFW permits a good understanding of the renal contribution to the defence of body tonicity. PURPOSE: To illustrate that the measurement of a tonicity balance provides the best estimate of changes in PNa in an ICU setting. METHODS: Twenty-two patients were admitted to the Post-Operative Intensive Care Unit. We investigated how well changes in EFW balance correlated with PNa variations and what is the best formula to calculate EFW in this setting. RESULTS: PNa changes depend on EFW balance; there is no significant relationship with other classical factors such as urinary osmolality or Na-free water. CONCLUSION: The utility of a tonicity balance is demonstrated. A formula is derived facilitating at the bedside the prediction of changes in PNa following fluid therapy: PNa2 = [(PNa1.TBW) + balance (Na + K)]/[TBW + balance H2O]. PNa changes can be understood and/or modified exclusively by a careful measurement of intakes and losses of Na, K and water.

[Central pontine myelinolysis: apropos of an oligosymptomatic form]. / Myélinolyse centropontine: à propos d'une forme paucisymptomatique.

The authors report a case of paucisymptomatic central pontine myelinolysis (CMP). A 66 years old female had severe hypochloronatremia and hypokaliemia due to diuretic. Despite a slow hydroelectrolytic correction, she presented with dumbness and seizure. CT scan showed hypodensity of protuberance and magnetic resonance imaging (MRI) shown hypersignal of protuberance and undercortex, compatible with central and extra pontine myelinolysis. The long term clinical outcome was good, as MRI's data. Rapid and important correction of severe hyponatremia should be the most important factors of demyelination, secondary to interference with cerebral adaptation mechanisms to hypoosmolality. These factors were not present in this case.

[Treatment of severe hyponatremia by restricted water intake]. / Traitement des hyponatrémies graves par restriction hydrique.

The outcomes of 23 patients admitted to a medical intensive care unit for severe hyponatraemia (less than 120 mEq/l) associated with neurological disorders were reviewed. All patients had restricted water intake combined with a sodium intake adjusted to the natriuresis, and some received a loop diuretic. The mean correction rate during the first 48 hours was slow (greater than 12 mmol/l.24 h) in 16 cases and fast (less than or equal to 12 mmol/l.24 h) in 7 cases. Following biochemical cure, 2 patients in the fast correction group had an unfavourable outcome: one died for an unknown reason, the other developed pontine myelinosis. A review of the literature did not provide evidence that a certain rate of correction was better than the other, but it showed that an excessive rise in natraemia or an overcorrection of hyponatraemia was dangerous. Slow correction of hyponatraemia, usually obtained with water intake restriction, may be recommended.

[A new concept to explain dysnatremia: the tonicity balance of entries and exits]. / Un nouveau concept pour expliquer les dysnatrémies: le bilan de la tonicité des entrées et des sorties.

Plasma sodium concentration, or natremia, results from three main factors: exchangeable sodium (Na+), exchangeable potassium (K+) and total body water (H2O). Its alterations often imply a change in cell volume. Understanding dysnatremias is essential for the treatment and prevention of hydromineral disorders. Extra-cellular fluid tonomoles consist almost exclusively of Na+ salts. Their dilution is the tonicity. K+ is an essential tonomole for intra-cellular fluid tonicity. The balance between intra and extracellular tonicities depends on water movements and is responsible for changes in intra- and extracellular fluid volumes. Cell volume is therefore depending on the tonicity balance. A change in body tonicity (which is not osmolality) can be correctly and rapidly appreciated by measuring the (Na+ + K+) and H2O balances. Clinical cases emphasize the misleadings resulting from the free-water clearance calculation or the only measurements of urinary losses. They also demonstrate that tonicity balance provides indications for therapy whereas analyses based upon electrolyte-free water do not. Intakes should be quantified with the same care than losses. The units used must be coherent to allow a quick and easy understanding at the bedside. Tonicity balance should be taught and Na+ + K+ and H2O balances should be routinely utilized by practitioners, dieticians and nurses in the concerned pediatrics, in particular intensive care, internal medicine, nephrology, pediatry and anesthesiology.

Functional renal maturation in rat neonates after prenatal exposure to furosemide.

We investigated the pattern of functional renal maturation and electrolyte handling on postnatal day 1, (PD1), day 5 (PD5), and day 12 (PD12) in rat neonates, after mothers were given furosemide during pregnancy. The drug was administered (75 mg/kg per day i.p.) on day 7-11 (organogenesis) and 14-18 (nephrogenesis) of gestation. On PD1 and PD5, there was a disturbance of the urinary concentrating ability with a hyperdiuresis and an over-stimulated ionic exchange, mainly the distal sodium reabsorption. From PD1 to PD12, a progressive functional recovery in electrolyte handling appeared. However, on PD12, when nephrogenesis was achieved, the renal concentrating defect remained. We discuss the possibility of a drug-induced delay in the development of the loop of Henle, leading to functional and morphological adaptations of already developed parts of the nephron.

[Experimental study of nephrotoxicity: effects, on the newborn rat kidney, of aminoglycoside administration during gestation]. / Etude expérimentale d'une néphrotoxicité: effets, sur le rein du rat nouveau-né, de l'administration d'aminoglycosides durant la gestation.

Treatment of the pregnant rat with aminoglycosides provokes nephrotoxicity in the newborn. This study compares the effects of three antibiotics belonging to this group: gentamicin (same day dose administered in one or two injections according to the groups), sisomicin and dibekacin, all administered during the last phase of gestation. Newborns were tested the day after birth, creatinine clearance was measured and then the kidneys were removed for histopathological examination. Functional variations (diuresis, creatinine clearance) and histological alterations of glomerula and tubules were observed. Slight differences suggest that, depending on the antibiotic used, intra-cellular nephrotoxic mechanisms are not completely identical. The modifications which occur after the administration of aminoglycosides, lead us to believe that further studies on the possible fetal nephrotoxic effects of drugs taken by mothers during gestation should be undertaken.

Transplacental effects of gentamicin on endocytosis in rat renal proximal tubule cells.

Changes in kidney maturation in utero have been reported after gentamicin administration to pregnant rats. While the proteinuria commonly observed could be related to modifications of the glomerular basement membrane, perturbed renal protein handling could be accounted for by changes in the proximal tubular cells. Therefore, we studied the effect of gentamicin on the renal handling and transport of proteins in proximal tubular cells using the horseradish peroxidase, a fluid-phase marker, as a probe. Gentamicin was administered intraperitoneally to pregnant Wistar rats (75 mg/kg body weight per day) and neonatal kidneys were studied 1 day after birth. In proximal tubular cells of the deep cortical area, containing the fully matured nephrons of neonates, the transport and digestion of reabsorbed peroxidase was considerably reduced compared with controls where peroxidase reached lysosomes after endocytosis. Urinary protein excretion increased in treated animals. We conclude that gentamicin, entering the proximal tubular cells via the endocytic pathway, decreases the tubular reabsorption of proteins, thus increasing urinary protein excretion.

In-utero gentamicin-induced nephrotoxicity in rats.

Aminosides lead to a well-known nephrotoxicity. The possibility of the developing kidney being altered in utero after the pregnant mother's administration has been investigated. We gave gentamicin (75 mg/kg/day) to pregnant rats during periods of organogenesis (days 7-11) and the beginning of glomeruli differentiation (days 14-18). A group of nonpregnant females was also treated for the same period and at the same time each day. Gentamicin-treated mothers presented only minor modifications of the blood biology with no acute renal failure when treated nonpregnant females have a hypercreatininemia. The deep cortical area, containing the fully formed nephrons of neonates, presented less glomeruli that were differentiated in the gentamicin group than in the control group. Moreover with both light and electron microscopy, glomeruli and proximal tubules showed evidences of nephrotoxicity in the juxtamedullary cortex. This finding of an in utero aminoside nephrotoxicity demonstrates the possible toxicity of gentamicin on fetus kidneys when given during the pregnancy.

[Hyponatremia, toward a logical approach: the balance of tonicity]. / Hyponatrémies, pour une attitude logique: la balance de la tonicité.

Derangements in plasma sodium concentration are best analyzed by carefully determining entries and output for water, sodium and potassium, that is, by calculating a tonicity balance. Five clinical hyponatremic examples are discussed: the beer drinker has a severe deficit in total body sodium: the elderly female patient treated with a thiazide needs to be firstly repleted in potassium; the hypertensive transplanted patient with a multidrug treatment requires an increase of the urinary electrolyte-free water which has been obtained by the oral administration of urea; the post-operative hyponatremic cases (cases 4 and 5) are complex and involve a desalination phenomenon. Close observation, repeated determinations of electrolytes in plasma, urine and entries, together with measurements of water input and output, will allow the tonicity balance of the patient to be understood and thus occasional tragedies such as observed in cases 4 and 5 to be prevented.

Rat neonates renal function after beta-receptors and adrenoceptors blockade during pregnancy.

Pregnant Wistar rats were given by subcutaneous route 1 of 3 different adrenoreceptor blockers, 2 of them mainly beta-blockers. P5 and P7 group received propranolol (5 and 7 mg/kg respectively), L10 and L20 groups received labetalol (10 and 20 mg/kg) and B5 group received betaxolol (5 mg/kg). Drugs were given daily from the 7th to the 16th day of gestation. A control group received saline injections. 16 out 24 treated mothers delivered prematurely on the 21st day of gestation. Functional renal parameters were studied in neonates on the first day of life. Renal function of the full term rats prenatally exposed were compared with controls. Average body weight was higher in P5 but lower in L10-L20-B5 groups. Diuresis increased in L20. Creatinine clearance, urinary/plasmatic creatinine ratio and urea clearance decreased in L10-L20 groups and fractional excretion of H2O increased in L20. Thus these adreno- and beta-blockers given to pregnant rats induced a shorter gestation. Moderate functional renal effects were observed in all neonates.

Effective water clearance and tonicity balance: the excretion of water revisited.

OBJECTIVE: To demonstrate (1) that hyponatremia is usually due to an inappropriately low rate of excretion of electrolyte-free water and (2) that the measure "effective water clearance" (EWC) provides better information about renal defence of the body tonicity than does the classic measure free-water clearance, and to provide the rationale for calculating a "tonicity balance," which involves using water and sodium plus potassium intakes and their renal excretion to reveal the basis for changes in body tonicity. DESIGN: Prospective study. PARTICIPANTS: Four normal subjects with no conditions affecting excretion, 10 patients with advanced congestive heart failure (CHF) and 5 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). INTERVENTION: Normals and patients were administered a standard water load (20 mL per kg of body weight) during 45 minutes, and blood and urine samples were taken before, during and after the load was given. MAIN OUTCOME MEASURES: Urine and blood sodium and potassium concentrations, osmolar clearance, free-water clearance, electrolyte clearance and EWC. RESULTS: The water load was excreted rapidly by normals, more slowly by patients with CHF, and not at all by patients with SIADH. The EWC was positive in normals and those with CHF, but negative in those with SIADH. In patients with CHF, the EWC, but not the free-water clearance, helped explain why hyponatremia was corrected after the water load was given. CONCLUSIONS: In subjects with abnormal water excretion, the EWC provides the physiologic explanation for the renal role in variations in natremia. The authors propose a bedside evaluation of renal water and electrolyte handling that takes into consideration the role of urinary potassium in body tonicity. Changes in body tonicity can be explained by a "tonicity balance," a calculation in which the source and the net balance of sodium, potassium and water are considered.

Does the in-utero exposure to furosemide delay the renal maturation?

Two groups of pregnant Wistar rats were constituted, one treated with Furosemide IP and one with saline. The drug was given on days 7-11 and 14-18 of the pregnancy. Litters from the two groups were not different in number of pups, body weight, and/or kidney weight, but exposed in-utero neonates, studied shortly after birth, exhibited a significant lower number of differentiated glomeruli than those of the control group. As well as the difficulty of explaining this phenomenon, this condition raises the problem of a possible compensation by the postnatal nephrogenesis, which is important in the rat, and leads to the question of what will be the total amount of nephrons for the adult life in species with or without complete in utero nephrogenesis.

Gentamicin administered during gestation alters glomerular basement membrane development.

Gentamicin during gestation alters glomerular basement membrane development. A drug-induced nephrotoxicity was described for neonates after gentamicin was given intraperitoneally to pregnant Wistar rats; glomerular alterations and changes in permselectivity were important. We investigated the ultrastructure of the glomerular basement membrane (GBM), the arrangement of anionic sites, and the urinary proteins at two ages, with 1-day- and 12-month-old control and prenatally exposed animals. For neonates, the pattern of glomerular differentiation was similar, anionic sites were made of heparan sulfate proteoglycans, and the GBM had the same total thickness in both groups. After transplacental gentamicin exposure, the lamina densa was larger; the laminae rarae were thinner; the density of anionic sites was increased; the levels of hydroxyproline, sulfate, and hexuronic acid in the kidney were increased; and the immunoelectrophoresis of urinary proteins was abnormal. For adults, prenatal exposure to gentamicin led to altered juxta-medullary glomeruli with a larger GBM and abundant anionic sites, especially in the lamina densa, and to a protein excretion different from that of controls. Thus, gentamicin administered during pregnancy leads to permanent alterations of the GBM with modifications of both the layers and the anionic sites, possibly because of a perturbed protein metabolism. These altered glomeruli are at risk during life and could be the starting point for a kidney disease.

Glomerular alterations in rat neonates after transplacental exposure to gentamicin.

Alterations of tubules and glomerules have been reported previously in kidneys of rat neonates after aminoglycosides were given to the mother during gestation. Here, we have studied the effects of gentamicin on the development of the glomerular basement membrane (GBM). Pregnant Wistar female rates were treated with gentamicin. Deliveries occurred normally. Using electron microscopy, we looked at the deepest glomerules of the kidneys of 1-day-old neonates: myeloid bodies were found in podocytes, and the GBM appeared thicker and denser than in controls. Anionic ferritin, injected intravenously crossed the GBM in prenatally gentamicin-exposed animals, but not in controls. Furthermore, urine electrophoresis showed the presence of proteins normally found only in the urine of fetuses 2 days before birth. We suggest then, that in utero exposure to gentamicin leads to a delay of renal maturation and that the GBM is altered in juxtamedullary nephrons while it is normally differentiated and functioning in controls. Thus exposure to drugs before birth could be harmful to the GBM.