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Diarrhea and vomiting cause dehydration and electrolyte imbalance
Abstract
Normonatremic dehydration is by far the most common electrolyte imbalance. Hyponatremic and hypernatremic dehydration are less frequent and are caused by offering the patient hypotonic fluid in cases presenting hyponatremic dehydration or hypertonic and/or fluid containing high sodium concentration in cases presenting hypernatremic dehydration. Dehydration promotes vasoconstriction. Intravascular space contraction causes tissue hypoxia. The aerobic ATP production in mitochondria diminishes, the glycolytic ATP production is enhanced and its consumption yields high hydrogen and lactate concentration, causing acidemia. The production of activated oxygen species (AOS) increases in systemic arteries and diminishes in pulmonary arterioles. Acidemia and AOS open K ATP in systemic arteries. Potassium extrusion causes hyperpotassemia, hyperpolarization of miocytes and vasodilatation. In pulmonary arterioles acidemia and diminishing in AOS release cause closure of Kv, membrane depolarization and pulmonary vasoconstriction. Acidemia causes opening of Cl-C2 chloride channels and outward rectification. Imbalance in calcium, phosphate and magnesium is minimum. Oral or intravenous rehydration with balanced polyelectrolytic rehydration solution rehydrates successfully the diarrheic dehydrated patients presenting electrolyte and acid-base imbalance.
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The modulation of KATP channels during acidosis has an impact on vascular tone, myocardial rhythmicity, insulin secretion, and neuronal excitability.
Our previous studies have shown that the cloned Kir6.2 is activated with mild acidification but inhibited with high acidity.
The activation relies on His-175, whereas the molecular basis for the inhibition remains unclear. To elucidate whether the
His-175 is indeed the protonation site and what other structures are responsible for the pH-induced inhibition, we performed
these studies. Our data showed that the His-175 is the only proton sensor whose protonation is required for the channel activation
by acidic pH. In contrast, the channel inhibition at extremely low pH depended on several other histidine residues including
His-186, His-193, and His-216. Thus, proton has both stimulatory and inhibitory effects on the Kir6.2 channels, which attribute
to two sets of histidine residues in the C terminus.
Cystic fibrosis (CF) is a lethal inherited disease that results from abnormal chloride conduction in epithelial tissues. ClC-2 chloride channels are expressed in epithelia affected by CF and may provide a key "alternative" target for pharmacotherapy of this disease. To explore this possibility, the expression level of ClC-2 channels was genetically manipulated in airway epithelial cells derived from a cystic fibrosis patient (IB3-1). Whole-cell patch-clamp analysis of cells overexpressing ClC-2 identified hyperpolarization-activated Cl- currents (HACCs) that displayed time- and voltage-dependent activation, and an inwardly rectifying steady-state current-voltage relationship. Reduction of extracellular pH to 5.0 caused significant increases in HACCs in overexpressing cells, and the appearance of robust currents in parental IB3-1 cells. IB3-1 cells stably transfected with the antisense ClC-2 cDNA showed reduced expression of ClC-2 compared with parental cells by Western blotting, and a significant reduction in the magnitude of pH-dependent HACCs. To determine whether changes in extracellular pH alone could initiate chloride transport via ClC-2 channels, we performed 36Cl- efflux studies on overexpressing cells and cells with endogenous expression of ClC-2. Acidic extracellular pH increased 36Cl- efflux rates in both cell types, although the ClC-2 overexpressing cells had significantly greater chloride conduction and a longer duration of efflux than the parental cells. Compounds that exploit the pH mechanism of activating endogenous ClC-2 channels may provide a pharmacologic option for increasing chloride conductance in the airways of CF patients.
El objetivo de este estudio fue comprobar la seguridad y eficacia de la solución recomendada por Pizarro para el tratamiento parenteral de la deshidratación. Se hidrataron 50 niños con edad promedio de 10.3 ± 8.1 meses. De ellos 31 fueron hombres y 19 mujeres; 27 (54%) presentaban desnutrición y 45 (90%) habían recibido hidratación oral. Se programó la corrección del déficit con 25 ml/kg/hora. Se tomaron muestras de sangre para sodio, potasio, glicemia y gases arteriales al ingreso y cuando ya los niños estaban hidratados. Todos los niños se hidrataron sin complicaciones. Peso al ingreso: 6.63 ± 2.85 kg. Peso ganado: 5.18 ± 2.59%. Volumen de solución utilizado: 105.8 ± 45.8 ml/kg. Tiempo de hidratación: 4.32 ± 2.13 horas. Sodio al ingreso 139.32 ± 9.03 mmol/l. Sodio final: 137.1 ± 7.62 mmol/l. Potasio al ingreso : 4.10 ± 1.06 mmol/l. Potasio final: 4.22 ± 0.76 mmol/l. pH al ingreso: 7.25 :t 0.197. pH final: 7.34 :t 0.088. Glicemia al ingreso: 122.18 ± 66.31 mg/dl. Glicemia final: 117.46 ± 47 mg/dl. Se concluyó que la Solución de Pizarro es útil y segura para conseguir la hidratación de niños deshidratados por enfermedad diarreica cuando no se la puede alcanzar por vía oral.
A clinical trial was carried out with 126 male patients over 2 years of age suffering from diarrhoea requiring intravenous rehydration, 80 of the patients suffering from cholera and 46 from non-cholera diarrhoea. A new "diarrhoea treatment solution" (DTS) containing sodium at a concentration of 118 mmol/litre and glucose at 44 mmol/litre was compared with the usual Dacca intravenous solution (DS) which has a sodium concentration of 133 mmol/litre and contains no glucose. The other constituents and their concentrations were the same in both solutions. All the patients responded well clinically and made an uneventful recovery. Oral water intake measured during the first 24 h was higher in the group receiving the DS. This group also excreted a significantly higher quantity of sodium in the urine. A significant fall in the level of blood glucose from the admission values occurred in both the groups; the fall was relatively less in the DTS group, this solution containing 44 mmol of glucose per litre. Further work is required to find the optimum concentration of glucose in the solution for infants and young children.
Pediatric cholera has often had higher morbidity and mortality than adult cholera when treated in the same fashion. Because children have a greater need for free water and, in addition, produce cholera stools which are appreciably lower in sodium concentration than adult stools, the use of isotonic or hypertonic intravenous solutions designed for adults has been held partially responsible for the higher figures. Moreover, such solutions often contain insufficient dextrose, potassium, and alkali for optimal treatment of pediatric cholera. A pediatric cholera replacement solution (PCRS) formulated to overcome these problems was field tested in double blind fashion against lactated Ringer's solution in children with acute cholera. PCRS resulted in more rapid return of normal potassium and bicarbonate values, over-came the tendency toward hypoglycemia, and reduced the need for oral fluids. Despite its hypotonic composition and high potassium content, it produced neither hyponatremia nor hyperkalemia. The utility and safety of plasma specific gravity as a means of objectively quantitating the degree of dehydration in children is emphasized.
Stewart in 1983 (Can J Physiol Pharmacol 1983: 61: 1444) reintroduced plasma buffer base under the name “strong ion difference” (SIDl. Buffer base was originally introduced by Singer and Hastings in 1948 (Medicine (Baltimore) 1948: 27: 223). Plasma buffer base, which is practically equal to the sum of bicarbonate and albuminate anions, may be increased due to an excess of base or due to an increased albumin concentration. Singer and Hastings did not consider changes in albumin as acid-base disorders and therefore used the base excess, i. e., the actual buffer base minus the buffer base at normal pH and pCO2, as measure of a non-respiratory acid-base disturbance. Stewart and followers, however, consider changes in albumin concentration to be acid-base disturbances: a patient with normal pH, pCO2, and base excess but with increased plasma buffer base due to increased plasma albumin concentration get the diagnoses metabolic (strong ion) alkalosis (because plasma buffer base is increased) combined with metabolic hyperalbuminaemic acidosis. Extrapolating to whole blood, anaemia and polycytaemia should represent types of metabolic alkalosis and acidosis, respectively. This reveals that the Stewart approach is absurd and anachronistic in the sense that an increase or decrease in any anion is interpreted as indicating an excess or deficit of a specific acid. In other words, a return to the archaic definitions of acids and bases as being the same as anions and cations.
TREK-1 is a member of the novel structural class of K(+) channels with four transmembrane segments and two pore domains in tandem (1,2). TREK-1 is opened by membrane stretch and arachidonic acid. It is also an important target for volatile anesthetics (2,3). Here we show that internal acidification opens TREK-1. Indeed, lowering pH(i) shifts the pressure-activation relationship toward positive values and leads to channel opening at atmospheric pressure. The pH(i)-sensitive region in the carboxyl terminus of TREK-1 is the same that is critically involved in mechano-gating as well as arachidonic acid activation. A convergence, which is dependent on the carboxyl terminus, occurs between mechanical, fatty acids and acidic stimuli. Intracellular acidosis, which occurs during brain and heart ischemia, will induce TREK-1 opening with subsequent K(+) efflux and hyperpolarization.
To assess effects of smooth muscle energy state and intracellular pH (pH(i)) on pulmonary arterial tone during hypoxia, we measured ATP, phosphocreatine, P(i), and pH(i) by (31)P-NMR spectroscopy and isometric tension in phenylephrine-contracted rings of porcine proximal intrapulmonary arteries. Hypoxia caused early transient contraction followed by relaxation and late sustained contraction. Energy state and pH(i) decreased during relaxation and recovered toward control values during late contraction. Femoral arterial rings had higher energy state and lower pH(i) under baseline conditions and did not exhibit late contraction or recovery of energy state and pH(i) during hypoxia. In pulmonary arteries, glucose-free conditions abolished late hypoxic contraction and recovery of energy state and pH(i), but endothelial denudation abolished only late hypoxic contraction. NaCN had little effect at 0. 1 and 1.0 mM but caused marked vasorelaxation and decreases in energy state and pH(i) at 10 mM. These results suggest that 1) regulation of tone, energy state, and pH(i) differed markedly in pulmonary and femoral arterial smooth muscle, 2) hypoxic relaxation was mediated by decreased energy state or pH(i) due to hypoxic inhibition of oxidative phosphorylation, 3) recovery of energy state and pH(i) in hypoxic pulmonary arteries was due to accelerated glycolysis mediated by mechanisms intrinsic to smooth muscle, and 4) late hypoxic contraction in pulmonary arteries was mediated by endothelial factors that required hypoxic recovery of energy state and pH(i) for transduction in smooth muscle or extracellular glucose for production and release by endothelium.
Objective: This study determines whether acid-base data obtained in the emergency department correlate with outcome from major vascular injury. Design: Observational, retrospective record review of trauma patients requiring vascular repair (torso or extremity, January 1988 to December 1997). Data included age, Injury Severity Score, injury mechanism, survival, laboratory profiling, calculated anion gap, strong ion difference, and strong ion gap. Patients were divided into survivors and nonsurvivors with comparison by Student's t-test; significance was assumed for p less than or equal to .05. Multivariate logistic regression was used for further analysis of univariate predictors of mortality, and receiver operator characteristic curves were generated for mortality from each variable. Setting: Urban level I trauma facility. Patients: Trauma patients requiring vascular repair of torso or extremity injury. Interventions: None. Measurements and Main Results: Both nonsurvivors (n = 64) and survivors (n = 218) were similar with respect to age (31 +/- 9 vs. 31.5 +/- 10.5, p = 0.15) and injury mechanics (81% penetrating in survivors vs. 83% penetrating in nonsurvivors, p = .71). Nonsurvivor Injury Severity Score exceeded that of survivors (27.5 +/- 7.8 vs. 12.4 +/- 9.4, p < .001). Nonsurvivor pH (7.06 +/- 0.15 vs. 7.34 +/- 0.08, p < .001) and apparent strong ion difference (31.38 +/- 4.39 vs. 37.53 +/- 3.86, p < .001) were significantly lower, whereas nonsurvivor standard base excess (-17.9 +/- 5.1 vs. -2.9 +/- 4.4 mEq/L, p < .001), lactate (11.1 +/- 3.6 vs. 3.6 +/- 1.5 mmol/L, p < .001), anion gap (28.2 +/- 4.1 vs. 15.6 +/- 3.1, p < .001), and strong ion gap (10.8 +/- 3.2 vs. 2.4 +/- 1.8, p < .001) were higher. All but one nonsurvivor had initial emergency department pH less than or equal to7.26, standard base excess less than or equal to -7.3 mEq/L, lactate less than or equal to5 mmol/L, and strong ion gap less than or equal to5 mEq/L. All of the acid-base descriptors were strongly associated with outcome, but the strong ion gap discriminated most strongly with an area under the receiver operator characteristic of 0.991 (95% confidence interval, 0.972-0.998). Conclusions: The initial emergency department acid-base variables of pH, base deficit, lactate, anion gap, apparent strong ion difference, and strong ion gap discriminate survivors from nonsurvivors of major vascular injury. The strong ion gap is most strongly predictive of mortality following major vascular trauma.
In the first known incidence of a mass salt poisoning of infants, the case fatality rate was 6 of 14 exposed. Five died before the situation was recognized. All five whose brains were examined at autopsy showed hemorrhagic encephalopathy consistent with previous reports of salt poisoning in humans and animals. Eleven of 14 of these infants manifested neurological symptoms. Peritoneal dialysis was attempted in four patients, three of whom survived despite severe illness in two of them. The technique proved feasible under ordinary hospital conditions and may be instrumental in the recovery of patients. Some suggestions for improvement have come from the experience.
The inward rectifier K+ channel Kir2.3 is inhibited by hypercapnia, and this inhibition may be mediated by decreases in intra- and extracellular pH. To understand whether Kir2.3 has two distinct pH sensors and whether cytosol-soluble factors are involved in the modulation of this channel during intracellular acidification, single channel currents were studied by expressing Kir2.3 in Xenopus oocytes.In excised inside-out patches, Kir2.3 currents had a high baseline channel open-state probability (Po, at pH 7.4) with a strong inward rectification. Single channel conductance at hyperpolarizing membrane potential was about 17 pS with 150 mM K+ applied to both sides of the membrane. The channel showed a substate conductance of about 8 pS.Reduction of intracellular pH (pHi) produced a fast and reversible inhibition of single channel Kir2.3 currents in inside-out patches. The extent of this inhibition is concentration dependent. A clear reduction in Kir2.3 currents was seen at pHi 7.0, and channel activity was completely suppressed at pHi 6.2 with mid-point inhibition (pK) at pH 6.77.The effect of low pHi on Kir2.3 currents was due to a strong inhibition of Po and a moderate suppression of single channel conductance. The pK values for these single channel properties were pH 6.78 and 6.67, respectively.The decrease in Po with low pHi resulted from an increase in the channel mean closed time without significant changes in the mean open time. Substate conductance was not seen during low pHi.Decrease in extracellular pH (pHo) also caused inhibition of single channel activity of Kir2.3 currents in excised outside-out patches. This effect, however, was clearly different from that of pHi: the pK (pH 6.70) was about 0.1 pH units lower; more than 50 % channel activity was retained at pHo 5.8; and low pHo affected mainly single channel conductance.These results therefore indicate that (1) there are two distinct pH sensors in Kir2.3, (2) different mechanisms are involved in the modulation of Kir2.3 through these two pH sensors, and (3) cytosol-soluble factors do not appear to be engaged in this modulation.
Five patients with severe acidosis and pulmonary oedema complicating cholera were seen at the Cholera Research Laboratory, Dacca, in a two-year period. All had had inadequate treatment. Their disease resulted in acidosis prior to admission; only the two who subsequently survived received volumes of sodium bicarbonate solutions sufficiently large to repair completely their acidosis. Saline alone worsened pulmonary congestion, while alkali appeared to relieve it despite the accompanying volume expansion. These observations are consistent with the known redistribution of blood to the central circulation in acidosis. Timely and proper treatment of cholera will avert this syndrome, when use of isotonic sodium bicarbonate sufficient to correct acidosis may be very helpful.
The nationwide introduction of oral rehydration therapy to Egypt has led to improvement in diarrhoea case management and a fall in infant and child mortality. With the wider use of oral rehydration solution (ORS) prepared from packets, the incidence of hypernatraemia (serum sodium greater than 150 mmol/l) in inpatients with dehydration seen at Abu El-Reeche Hospital, Cairo, increased between 1980 and 1984. Systematic surveillance of hypernatraemia in the outpatient rehydration unit began in late 1984, and we report trends in hypernatraemia and analyses of key variables affecting its incidence in dehydrated children. In 1980, 17 of 100 children sampled had hypernatraemia and 2 had severe hypernatraemia (ie, serum sodium greater than 165 mmol/l). The frequency in inpatients peaked at 49% of 222 children in 1984 (19% with severe hypernatraemia). Between 1986 and 1989, at least 1000 dehydrated outpatients were surveyed each year; by 1989 the incidence of hypernatraemia had fallen to around 10% (2% severe hypernatraemia). The rise and decline coincided with increasing use of ORS and then increasing ability of mothers to mix the solution correctly. Hypernatraemia was positively related to the quantity of ORS taken, severity of dehydration, nutritional status, and the cooler season, and negatively related to age and duration of diarrhoea. Explanations for our findings include improved use of ORS and better case-management. Good practice promoted through the mass media has facilitated these changes; if the standard of ORS use is not maintained, there may be a case for reducing the sodium content of ORS.
To emphasise the dangers of inappropriate rehydration fluids in the treatment of gastroenteritis.
A two-year-old girl was admitted to hospital in shock and unconscious. She had a 36-hour history of diarrhoeal illness and had received Lucozade. Therapy with this hypertonic fluid resulted in worsening diarrhoea and seizures. On examination she had hypernatraemic dehydration and decorticate posturing.
An intravenous line was inserted, stable plasma protein solution was given, and she was admitted to the intensive care unit. Anticonvulsant and antibiotic therapy were begun. Significant neurological impairment was still evident after 14 days, at which time shw was discharged from hospital. Six months later she had made a good recovery, with no persisting neurological deficit.
The inappropriate use of hypertonic fluids in gastroenteritis may be associated with significant electrolyte imbalances and neurological sequelae.
Maintenance of homeostasis of inner ear fluids and biochemical integrity of inner ear tissue are essential for proper functioning of the auditory and vestibular end organs. Although various regulatory mechanisms exist in a different portion of the labyrinth, the inner ear is known to respond to systemic challenges. The association of Meniere's syndrome with an imbalance of inner ear fluid homeostasis has been hypothesized for the past century. Among many factors, the effects of hormonal imbalance on inner ear fluid composition and inner ear function have however scarcely been studied. The purpose of this study was to explore the relationship between the autonomic nervous system and inner ear function and possible mechanisms of functional disturbances in an experimental condition. An infusion of supraphysiologic amounts of epinephrine, a stress related hormone, resulted in an elevation of osmolality in serum and perilymph. Furthermore, the infusion of epinephrine resulted in elevation of threshold, prolongation of latency, and depression of amplitude in the compound action potential of the auditory nerve. These findings were most marked at high frequencies. We hypothesized that the epinephrine-induced hearing loss was brought about by an increase in perilymphatic osmolality, as well as by the ionic imbalance caused by the osmotic gradient. Since emotional stress has been implicated as a mechanism of inducing a Meniere's attack, evaluation of the relationship between the autonomic system and cochlear function may contribute to the understanding of possible mechanisms of inner ear dysfunction caused by hormonal imbalances.
Tissue hypoxia is frequently seen in critically ill patients and it perhaps predisposes these patients to development of multiple system organ failure. In cellular terms, hypoxia is characterized by decreases in the intracellular concentration of oxygen, leading to a decline in aerobically produced adenosine triphosphate (ATP). The deficit arising from unequal levels of cellular ATP requirements and aerobic ATP production is partially satisfied by anaerobic sources of ATP, including glycolysis, the creatine kinase reaction, and the adenylate kinase reaction. These reactions can set in motion cellular mechanisms that ultimately may lead to cellular dysfunction and death. A clear understanding of the relative importance of these reactions is impossible to acquire from global measures of oxygen delivery and oxygen consumption; therefore, the clinical monitoring of tissue oxygenation also should include the measurement of metabolically relevant, organ-specific variables.
We studied urinary acidification daily during the hospital course of 16 infants with acute gastroenteritis and metabolic acidosis. Urine pH value on admission was higher than 5.5 in 14 (87%) patients. We hypothesized that inappropriate urinary acidification was due to sodium deficiency and inadequate sodium delivery to the distal nephron. Forty-one urinary samples were collected during metabolic acidosis. The mean pH of 24 urine samples with sodium concentration less than 10 mmol/L was significantly higher than the pH of 17 samples with sodium concentration greater than 10 mmol/L (6.04 +/- 0.06 vs 5.19 +/- 0.1; p less than 0.001). The urine ratios of titratable acid to creatinine and of total acidity to creatinine were significantly higher in urine samples containing more sodium (p less than 0.02), whereas the ammonium/creatinine ratio was not. After administration of furosemide or correction of the sodium deficit, appropriate acidification was observed. We conclude that impaired urinary acidification is frequently found during metabolic acidosis in infants with acute gastroenteritis and results from a sodium deficit rather than from transient distal renal tubular acidosis.
We used 31P spectroscopy to determine whether administration of a neutralizing dose of bicarbonate in rabbits with lactic acidosis caused a paradoxical brain intracellular acidosis. Ten 10- to 16-day-old rabbits were anesthetized with 0.75% halothane/oxygen and their lungs mechanically ventilated. Metabolic acidosis was induced by decreasing PaO2 to 25 to 35 mm Hg for 1 to 2 hours until the base deficit was 10 to 15 mEq/L. Cerebral ischemia was prevented by maintaining arterial blood pressure at +/- 20% of control value with a venous infusion of epinephrine. Hypoxia was then terminated by administration of 100% oxygen, which was continued for the remainder of the study. After 15 minutes 100% oxygen, 5 mEq/kg 4.2% bicarbonate was administered to five animals; 5 minutes later the same dose was repeated. Control rabbits were given equal volumes of saline solution. In all animals, arterial pH decreased from 7.43 +/- 0.06 to 7.25 +/- 0.08 (SE) during hypoxia, and brain intracellular pH from 7.22 +/- 0.06 to 7.09 +/- 0.09 (SE). Both pH values remained low during reoxygenation. Bicarbonate administration normalized arterial pH (7.41 +/- 0.03), whereas treatment with saline solution did not (7.23 +/- 0.01, P less than 0.05). PaCO2 rapidly increased by 10 mm Hg in the bicarbonate group, and remained elevated; it was unaffected by saline solution administration. Brain intracellular pH in the bicarbonate group increased by 0.12 U over 40 minutes, but intracellular pH in the saline solution group decreased 0.05 pH U (P less than 0.05) over the same period. We conclude that administering a total dose of 10 mEq/kg sodium bicarbonate to neonatal rabbits recovering from hypoxic lactic acidosis increases arterial pH, brain intracellular pH, and PaCO2; it does not produce paradoxical intracellular acidosis in the brain.
Tetanic convulsions are not uncommon among severely dehydrated children in the developing countries. This raises the question whether these children have disturbances in the homeostasis of divalent ions. Serum values are reported of calcium, magnesium, phosphorus, sodium and potassium, as well as blood pH in children below 3 years of age with acute watery diarrhoea and with an estimated weight loss of about 10%. The study was performed on dehydrated children with (DC) or without (D) convulsions. Values were obtained on admission and following rehydration therapy (RT). On admission serum calcium was low in both D and DC children. Serum phosphorus was likewise elevated in both D and DC children. Serum magnesium was slightly elevated in the DC but not in the D group. No patient had hypernatremia. During RT, serum calcium increased significantly and serum phosphorus decreased significantly in D and DC children. Serum calcium showed a significant inverse correlation with serum phosphorus and a significant direct correlation with blood pH. Treatment of DC children with i.v. calcium and i.m. magnesium had no immediate effect on the convulsions. Our conclusion is that severely dehydrated children will develop hypocalcemia. The cause may be a redistribution of calcium into the cells, parallelled by a redistribution of phosphorus from the intra- to the extracellular space.
The effects of a Shiga toxin derived from Shigella dysenteriae Type 1, Strain 60R, and a Shiga-like toxin from the enterohemorrhagic Escherichia coli O157:H7, Strain 933, were studied in the in vivo rabbit ileal loop model. The effects of both toxins were similar and resulted in severe villus blunting by 18-24 hours after exposure. With both toxins, a dose effect was noted; and the lesions, first detected at 2 hours after inoculation, became more severe over time. Both toxins appeared to act directly and selectively on the mature columnar absorptive epithelium of the intestinal villus, which resulted in the premature expulsion of these cells from the lateral villus wall, with a decrease in the villus/crypt ratio. The goblet mucous cells remained attached and frequently formed clusters on the blunt villus apices. The crypt epithelium underwent a rapid proliferation and maintained the epithelial integrity. The ultrastructural changes observed in the toxin-injured villus absorptive cells suggested that these cells underwent a process of apoptosis, rather than necrosis. These findings suggest that both toxins act in vivo in the small intestine on a specific cell population, the mature, differentiated absorptive villus epithelium.
Alterations in serum ionized and total calcium, magnesium, and phosphate concentrations, during recovery from acute dehydrating gastroenteritis, were studied. Fifteen children with acute dehydrating gastroenteritis had serum concentrations of ionized and total calcium, magnesium, phosphate, sodium, potassium, chloride, urea, creatinine, and albumin, as well as acid-base status, evaluated during rehydration and up to 72-h postadmission. The total serum calcium corrected for albumin did not change significantly during rehydration and remained within the normal range. Although serum ionized calcium fell significantly at 24 and 72 h, its concentration was not sufficiently decreased to cause symptomatic hypocalcemia. Serum ionized calcium correlated significantly with pH (r = -0.57), bicarbonate (r = -0.63), and albumin (r = +0.65), but not with total serum calcium, magnesium, and phosphate. Serum magnesium remained within the normal range during the study period. Serum phosphate was increased on admission (2.64 +/- 0.77 mmol/L), decreased by 12 h (to 0.84 +/- 0.32 mmol/L), and then followed by a gradual increase. This study suggests that changes in serum ionized calcium in dehydrating gastroenteritis are not of clinical significance. However, changes in serum phosphate concentration need further evaluation.
Hyponatremia and hypernatremia are among the most common electrolyte disorders. Since the plasma sodium level is determined by the ratio between the total quantity of effective solutes (primarily sodium and potassium salts) and the total body water, abnormalities in the plasma sodium level must be produced by a change in one or more of these parameters. In most patients, alterations in body water are of primary importance because the plasma sodium level is normally regulated by changing water intake and water excretion. Measurement of free water excretion has traditionally been calculated by using a formula that includes the urine osmolality. However, urea is a major urinary solute but does not contribute to regulation of the plasma sodium level, since it is an ineffective osmole. As a result, urinary solute excretion is best expressed as 2 X UNa+K. Making this important correction allows solute and water intake and excretion to be compared, thereby leading to a better understanding of both the development and correction of disturbances in the plasma sodium level.
This paper reports on 1330 infants, from birth to 24 months old, suffering from diarrhoea and moderate to severe dehydration who were hospitalized in Tehran University Hospital over a period of 11 months. Fifteen per cent of them had signs of shock and 36% had marasmus. All patients were treated orally in two phases: rehydration therapy and maintenance therapy. For rehydration, an isotonic fluid (sodium 80 mmol l-1, potassium 20 mmol l-1) was administered at a rate of 40 ml kg-1 h-1 until all signs of dehydration disappeared. Following complete hydration, the patients were discharged and maintenance therapy was performed at home, by mothers, administering Maintenance Solution (sodium 40 mmol l-1, potassium 30 mmol l-1) ad libitum. Intravenous fluids were not used, even in severe dehydration. The efficacy and safety of this regimen were confirmed by rapid and successful rehydration in 99.7% of the patients and correction of a wide variety of electrolyte abnormalities present on admission, though some relapsed. The study suggests that this protocol could be employed in varied types and severities of dehydration and electrolyte abnormalities, and could also be used in both well nourished infants and in those with severe marasmus. It also demonstrates that mothers can serve as effective health workers and can perform successful maintenance therapy. Nine per cent of treated children required readmission to hospital within 24 h of discharge and a further 8% were hospitalized elsewhere with recurrent symptoms.
Determination of electrolytes in the stools of 58 children with cholera from the Philippines revealed losses which are substantially different from those found in adults with cholera. Fæcal losses of sodium, chloride, and bicarbonate are lower, and fæcal losses of potassium are higher than in adults. Intravenous solutions for replacement therapy are commonly devised on the basis of the adult losses, and their use in pædiatric cholera provides more sodium and chloride than is lost in the child's stool. Furthermore, such regimens rely too heavily on the oral route for administration of " free " water. Most of the morbidity and mortality seen in pædiatric cholera may be due to over-replacement of sodium losses and failure to provide " free " water intravenously.
The distribution of cardiac output was measured in various stages of hemorrhagic shock in unanesthetized dogs by microspheres labeled with five different isotopes. The microspheres were injected sequentially through a previously implanted left atrial catheter at the following times: control, early hypotension, late hypotension, and one hour as well as eight hours after return of the shed blood. Cardiac output was independently measured by the indicator dilution method at the time of each microsphere injection. Regional blood flows measured with microspheres were expressed in terms of the absolute values and as the percent distributions of the cardiac output. The early response to hemorrhage consisted of a redistribution of flow favoring the heart and brain, which have the least alpha adrenergic innervation. Later in hypotension, the percent cardiac output to the heart and arterial inflow to the liver and diaphragm increased further; this secondary change may be attributed to metabolic vasodilatory factors. Immediately after the return of the shed blood, organ blood flow changed in the opposite direction to the initial response. Eight hours after infusion, there were further increases in the blood flow to organs which had not immediately returned to control values. The data support the concept of participative roles of metabolic vasodilatory influences, increased metabolic requirements, and continued operation of neural and hormonal factors in the posttransfusion period.
The hemodynamic effects of hypovolemia and acidosis were studied in 23 patients with cholera. Studies were made before and during fluid replacement and administration of alkali.
The major hemodynamic abnormalities encountered before rehydration can be ascribed to a reduction in circulating blood volume. Hypovolemia was associated with a reduction in cardiac output, blood pressures, and central blood volume. Restoration of blood volume returned these variables toward normal.
The chief effect of acidosis appeared to be a redistribution of blood from the peripheral to the central circulation; consequently, central blood volume, lesser circulation pressures, and cardiac output were relatively well maintained despite hypovolemia. Fluid administration without correction of acidosis favored a disproportionate increase in central blood volume, while reduction in hydrogen ion concentration attending fluid replacement resulted in a more even distribution of the circulating blood volume and reduced the possibility of engorgement of the pulmonary bed.
It is postulated that this redistribution of blood stems from peripheral venoconstriction and a reduction in the capacity of venous reservoirs induced by acidosis.
Quantitative analysis of ionic solutions in terms of physical and chemical principles has been effectively prohibited in the past by the overwhelming amount of calculation it required, but computers have suddenly eliminated that prohibition. The result is an approach to acid-base which revolutionizes our ability to understand, predict, and control what happens to hydrogen ions in living systems. This review outlines that approach and suggests some of its most useful implications. Quantitative understanding requires distinctions between independent variables (in body fluids: pCO2, net strong ion charge, and total weak acid, usually protein), and dependent variables [( HCO-3], [HA], [A-], [CO(2-)3], [OH-], and [H+] (or pH]. Dependent variables are determined by independent variables, and can be calculated from the defining equations for the specific system. Hydrogen ion movements between solutions can not affect hydrogen ion concentration; only changes in independent variables can. Many current models for ion movements through membranes will require modification on the basis of this quantitative analysis. Whole body acid-base balance can be understood quantitatively in terms of the three independent variables and their physiological regulation by the lungs, kidneys, gut, and liver. Quantitative analysis also shows that body fluids interact mainly by strong ion movements through the membranes separating them.
Accurate evaluation of extracellular fluid acid-base status used to be a rather formidable task. However, with the availability of automated clinical testing, this evaluation is now readily performed on any hospitalized child. The following discussion will be limited to various aspects of metabolic acidosis with a brief review of normal and abnormal physiology. A practical approach to the diagnostic work-up of an acidotic child will also be discussed. Several more detailed discussions of acid-base homeostatic mechanisms are available for the reader who is interested in pursuing this subject.1-5
Acidosis, as used in this article, will refer to an abnormal increase in circulating acid with an accompanying decrease in the buffering capacity of the blood as manifest by a low serum bicarbonate level. Acidosis that ultimately exceeds the body's compensatory buffering mechanisms leads to an increase in extracellular fluid (ECF) H+ concentration such that pH is reduced below 7.35. This state is referred to as acidemia.
NORMAL ACID-BASE PHYSIOLOGY
The normal arterial blood pH is maintained at 7.40 (H+ = 39.8 mEq/liter) and ranges between 7.35 and 7.45. When this pH value drops below the normal range, acidemia is present.6 Acidosis (excess circulating acid) may or may not be accompanied by a fall in pH (acidemia) because the body can compensate for a drop in blood pH by combining some of the excess H+ with bicarbonate to form carbonic acid and then CO2, which is eliminated through the lungs by increased ventilation. Since this compensatory process is limited by the amount of bicarbonate available for the reaction with H+, only prolonged or severe acidosis may lead to acidemia.
(1) To determine the incidence of hyponatremic seizures in infants, (2) to compare the severity and outcome of seizures in hyponatremic and normonatremic patients, and (3) to evaluate the utility of clinical predictors of hyponatremia.
Retrospective chart review of infants who presented to an urban pediatric emergency department from 1988 through 1993.
Patients who experienced seizures while in the ED. These patients were divided into hyponatremic and normonatremic groups.
Hyponatremia was the cause of seizures in 70% of 47 infants younger than 6 months who lacked other findings suggesting a cause. Median seizure duration was longer in hyponatremic patients (30 versus 17 minutes; P = .007), with a greater incidence of status epilepticus (73% versus 36%; P = .02) and fewer patients with seizures lasting less than 10 minutes (9% versus 36%; P = .04). Emergency intubation was performed more often in hyponatremic patients (12% versus 0%; P = .009). The median temperature was lower in hyponatremic infants than in normonatremic patients (35.5 degrees C versus 37.2 degrees C; P = .0001). Exact logistic-regression methods identified temperature of 36.5 degrees C or less as the best predictor of hyponatremic seizures, with an OR of 64 (95% CI, 8 to 1,026).
Hyponatremia should be strongly suspected in an infant less than 6 months old with seizures and a temperature of 36.5 degrees C or less.
Neurologic symptoms due to electrolyte disorders are common, occurring in patients with diarrhea, diabetes mellitus, head injury, renal failure, and many other disorders, especially in infants and the elderly. The clinical syndromes of dehydration and overhydration, often first detected in measurements of plasma sodium or osmolality, are among the most frequent causes of the neurologic symptoms, which include irritability, seizures, lethargy, and coma. There are multiple hormonal and neurogenic mechanisms to maintain total body water and the concentration of solutes (osmolality) within narrow limits. Interruption of these homeostatic mechanisms leads to the retention or loss of either water or solute; . . .
A case of severe hypernatremic dehydration (sodium, 191 mmol/L) with associated severe hyperkalemia (potassium, 11.2 mmol/L) and hyperosmolality (502 mOsm/kg) is described in a 3-month-old infant secondary to acute infection with rotavirus. The patient was managed with i.v. fluid resuscitation in conjunction with intracranial pressure monitoring and was discharged well and without any permanent sequelae. Review of the literature reveals the case described to be the most profound example of hypernatremic dehydration with a favorable outcome reported from diarrheal illness. Strategies for management of hypernatremic dehydration are discussed.
The ClC-2 chloride channel is probably involved in the regulation of cell volume and of neuronal excitability. Site-directed mutagenesis was used to understand ClC-2 activation in response to cell swelling, hyperpolarization and acidic extracellular pH. Similar to equivalent mutations in ClC-0, neutralizing Lys566 at the end of the transmembrane domains results in outward rectification and a shift in voltage dependence, but leaves the basic gating mechanism, including swelling activation, intact. In contrast, mutations in the cytoplasmic loop between transmembrane domains D7 and D8 abolish all three modes of activation by constitutively opening the channel without changing its pore properties. These effects resemble those observed with deletions of an amino-terminal inactivation domain, and suggest that it may act as its receptor. Such a 'ball-and-chain' type mechanism may act as a final pathway in the activation of ClC-2 elicited by several stimuli.
Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidney to the action of arginine-vasopressin (AVP); it may be due to genetic or acquired causes. Recent advances in molecular genetics have allowed the identification of the genes involved in congenital NDI. While inactivating mutations of the vasopressin V2 receptor are responsible for X-linked NDI, autosomal recessive NDI is caused by inactivating mutations of the vasopressin-regulated water channel aquaporin-2 (AQP-2). About 70 different mutations of the V2 receptor have been reported, most of them missense mutations. The functionally characterized mutants show a loss of function due to defects in their synthesis, processing, intracellular transport, AVP binding, or interaction with the G protein/adenylyl cyclase system. Thirteen different mutations of the AQP-2 gene have been reported. Functional studies of three AQP-2 mutations reveal impaired cellular routing as the main defect. The great number of different mutations with various functional defects hinders the development of a specific therapy. Gene therapy may, however, eventually become applicable to the congenital forms of NDI. At present all gene-therapeutic approaches lack safety and efficiency, which is of particular relevance in a disease that is treatable by an adequate water intake. The progress with regard to the molecular basis of antidiuresis contributes to the understanding of acquired forms of NDI on a molecular level. Recent data show that lithium dramatically reduces the expression of AQP-2. Likewise, hypokalemia reduces the expression of this water channel. The exact mechanisms leading to this reduced expression of AQP-2 remain to be determined.
The role of Ca2+-activated K+-channel, ATP-sensitive K+-channel, and delayed rectifier K+-channel modulation in the canine pulmonary vascular response to hypoxia was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured with vascular occlusion techniques. Under normoxia, the Ca2+-activated K+-channel blocker tetraethylammonium (1 mM), the ATP-sensitive K+-channel inhibitor glibenclamide (10(-5) M), and the delayed rectifier K+-channel blocker 4-aminopyridine (10(-4) M) elicited a small but significant increase in pulmonary arterial pressure. Hypoxia significantly increased pulmonary arterial and venous resistances and pulmonary capillary pressure and decreased total vascular compliance by decreasing both microvascular and large-vessel compliances. Tetraethylammonium, glibenclamide, and 4-aminopyridine potentiated the response to hypoxia on the arterial segments but not on the venous segments and also further decreased pulmonary vascular compliance. In contrast, the ATP-sensitive K+-channel opener cromakalim and the L-type voltage-dependent Ca2+-channel blocker verapamil (10(-5) M) inhibited the vasoconstrictor effect of hypoxia on both the arterial and venous vessels. These results indicate that closure of the Ca2+-activated K+ channels, ATP-sensitive K+ channels, and delayed rectifier K+ channels potentiate the canine pulmonary arterial response under hypoxic conditions and that L-type voltage-dependent Ca2+ channels modulate hypoxic vasoconstriction. Therefore, the possibility exists that K+-channel inhibition is a key event that links hypoxia to pulmonary vasoconstriction by eliciting membrane depolarization and subsequent Ca2+-channel activation, leading to Ca2+ influx.
Rabbit and human ClC-2G Cl- channels are voltage sensitive and activated by protein kinase A and low extracellular pH. The objective of the present study was to investigate the mechanism involved in acid activation of the ClC-2G Cl- channel and to determine which amino acid residues play a role in this acid activation. Channel open probability (Po) at +/-80 mV holding potentials increased fourfold in a concentration-dependent manner with extracellular H+ concentration (that is, extracellular pH, pHtrans), with an apparent acidic dissociation constant of pH 4.95 +/- 0.27. 1-Ethyl-3(3-dimethylaminopropyl)carbodiimide-catalyzed amidation of the channel with glycine methyl ester increased Po threefold at pHtrans 7.4, at which the channel normally exhibits low Po. With extracellular pH reduction (protonation) or amidation, increased Po was due to a significant increase in open time constants and a significant decrease in closed time constants of the channel gating, and this effect was insensitive to applied voltage. With the use of site-directed mutagenesis, the extracellular region EELE (amino acids 416-419) was identified as the pH sensor and amino acid Glu-419 was found to play the key or predominant role in activation of the ClC-2G Cl- channel by extracellular acid.
The discovery of aquaporin membrane water channels by Agre and coworkers answered a long-standing biophysical question of how water specifically crosses biologic membranes, and provided insight, at the molecular level, into the fundamental physiology of water balance and the pathophysiology of water balance disorders. Of nine aquaporin isoforms, at least six are known to be present in the kidney at distinct sites along the nephron and collecting duct. Aquaporin-1 (AQP1) is extremely abundant in the proximal tubule and descending thin limb, where it appears to provide the chief route for proximal nephron water reabsorption. AQP2 is abundant in the collecting duct principal cells and is the chief target for vasopressin to regulate collecting duct water reabsorption. Acute regulation involves vasopressin-regulated trafficking of AQP2 between an intracellular reservoir and the apical plasma membrane. In addition, AQP2 is involved in chronic/adaptational regulation of body water balance achieved through regulation of AQP2 expression. Importantly, multiple studies have now identified a critical role of AQP2 in several inherited and acquired water balance disorders. This concerns inherited forms of nephrogenic diabetes insipidus and several, much more common acquired types of nephrogenic diabetes insipidus where AQP2 expression and/or targeting are affected. Conversely, AQP2 expression and targeting appear to be increased in some conditions with water retention such as pregnancy and congestive heart failure. AQP3 and AQP4 are basolateral water channels located in the kidney collecting duct, and AQP6 and AQP7 appear to be expressed at lower abundance at several sites including the proximal tubule. This review focuses mainly on the role of AQP2 in water balance regulation and in the pathophysiology of water balance disorders.
The aim was to improve the measurement of both the time course and amplitude of anoxia-induced KATP-channel current (IKATP) in isolated heart cells to specify the role of these channels in the time course of K+ accumulation in the ischemic myocardium.
Ionic currents in isolated ventricular heart cells of the mouse were measured with a patch clamp technique under normoxic conditions (atmospheric pO2), during wash-out of oxygen, and under anoxic conditions (pO2 < 0.2 mmHg). During the measurement, the actual pO2 in the close proximity of the cell was determined with an optical technique by exciting Pd-meso-tetra(4-carboxyphenyl)porphin with light flashes of 508-570 nm and evaluating the quenching kinetics of the emitted phosphorescence signal at 630-700 nm. These quenching kinetics steeply depend on pO2 and can be evaluated best at pO2 values near 0 mmHg.
Out of 28 cells, 23 cells started to develop IKATP at pO2 values between 0 and 0.4 mmHg, i.e. in the range of the level of half maximum activity of the cytochrome oxidase. The remaining five cells developed IKATP between 0.4 and 1.8 mmHg. With respect to the time course, 18 out of 27 cells started to develop IKATP within the first minute after pO2 had decreased to values below 0.2 mmHg. The amplitude of IKATP induced by anoxia and various metabolic inhibitors was large, 29 +/- 12 and 48 +/- 21 nA (+40 mV), respectively. The anoxia-induced IKATP was significantly smaller than IKATP induced by metabolic inhibitors. During the pulses of 50 ms duration to +40 mV, the amplitude of IKATP decayed and, after clamping back to -80 mV, IKATP generated large tail currents. This suggests a notable change in the concentration gradient of K+ ions in the time range of tens of milliseconds.
The results in isolated myocytes indicate that KATP channels open sufficiently rapidly after starting anoxia and generate sufficiently large conductance at maintained anoxia to explain both the time course and magnitude of the ischemic K+ accumulation if an appropriate counter-ion flux is available.
Adenosine is known to play an important role in the regulation of coronary blood flow during metabolic stress. However, there is sparse information on the mechanism of adenosine-induced dilation at the microcirculatory levels. In the present study, we examined the role of endothelial nitric oxide (NO), G proteins, cyclic nucleotides, and potassium channels in coronary arteriolar dilation to adenosine. Pig subepicardial coronary arterioles (50 to 100 microm in diameter) were isolated, cannulated, and pressurized to 60 cm H(2)O without flow for in vitro study. The arterioles developed basal tone and dilated dose dependently to adenosine. Disruption of endothelium, blocking of endothelial ATP-sensitive potassium (K(ATP)) channels by glibenclamide, and inhibition of NO synthase by N(G)-nitro-L-arginine methyl ester and of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one produced identical attenuation of vasodilation to adenosine. Combined administration of these inhibitors did not further attenuate the vasodilatory response. Production of NO from coronary arterioles was significantly increased by adenosine. Pertussis toxin, but not cholera toxin, significantly inhibited vasodilation to adenosine, and this inhibitory effect was only evident in vessels with an intact endothelium. Tetraethylammonium, glibenclamide, and a high concentration of extraluminal KCl abolished vasodilation of denuded vessels to adenosine; however, inhibition of calcium-activated potassium channels by iberiotoxin had no effect on this dilation. Rp-8-Br-cAMPS, a cAMP antagonist, inhibited vasodilation to cAMP analog 8-Br-cAMP but failed to block adenosine-induced dilation. Furthermore, vasodilations to 8-Br-cAMP and sodium nitroprusside were not inhibited by glibenclamide, indicating that cAMP- and cGMP-induced dilations are not mediated by the activation of K(ATP) channels. These results suggest that adenosine activates both endothelial and smooth muscle pathways to exert its vasodilatory function. On one hand, adenosine opens endothelial K(ATP) channels through activation of pertussis toxin-sensitive G proteins. This signaling leads to the production and release of NO, which subsequently activates smooth muscle soluble guanylyl cyclase for vasodilation. On the other hand, adenosine activates smooth muscle K(ATP) channels and leads to vasodilation through hyperpolarization. It appears that the latter vasodilatory process is independent of G proteins and of cAMP/cGMP pathways.
The existence of a proton-selective pathway through a protein is a common feature of voltage-gated proton channels and a number of molecules that play pivotal roles in bioenergetics. Although the functions and structures of these molecules are quite diverse, the proton conducting pathways share a number of fundamental properties. Conceptual parallels include the translocation by hydrogen-bonded chain mechanisms, problems of supply and demand, equivalence of chemical and electrical proton gradients, proton wells, alternating access sites, pK(a) changes induced by protein conformational change, and heavy metal participation in proton transfer processes. An archetypal mechanism involves input and output proton pathways (hydrogen-bonded chains) joined by a regulatory site that switches the accessibility of the bound proton from one 'channel' to the other, by means of a pK(a) change, molecular movement, or both. Although little is known about the structure of voltage-gated proton channels, they appear to share many of these features. Evidently, nature has devised a limited number of mechanisms to accomplish various design strategies, and these fundamental mechanisms are repeated with minor variation in many superficially disparate molecules.