Evidence for a detrimental effect of bicarbonate therapy in hypoxic lactic acidosis.

Lactic acidosis, a clinical syndrome caused by the accumulation of lactic acid, is characterized by lactate concentration in blood greater than 5 mM. Therapy usually consists of intravenous sodium bicarbonate (NaHCO3), but resultant mortality is greater than 60 percent. The metabolic and systemic effects of NaHCO3 therapy of hypoxic lactic acidosis in dogs were studied and compared to the effects of sodium chloride or no therapy. Sodium bicarbonate elevated blood lactate concentrations to a greater extent than did either sodium chloride or no treatment. Despite the infusion of NaHCO3, both arterial pH and bicarbonate concentration decreased by a similar amount in all three groups of dogs. Additional detrimental effects of NaHCO3 were observed on the cardiovascular system, including decreases in cardiac output and blood pressure that were not observed with either sodium chloride or no treatment. Thus there is evidence for a harmful effect of NaHCO3 in the treatment of hypoxic lactic acidosis.

Studies on mechanisms of cerebral edema in diabetic comas. Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits.

To investigate the pathophysiology of cerebral edema occurring during treatment of diabetic coma, the effects of hyperglycemia and rapid lowering of plasma glucose were evaluated in normal rabbits. During 2 h of hyperglycemia (plasma glucose=61 mM), both brain (cerebral cortex) and muscle initially lost about 10% of water content. After 4 h of hyperglycemia, skeletal muscle water content remained low but that of brain was normal. Brain osmolality (Osm) (343 mosmol/kg H(2)O) was similar to that of cerebrospinal fluid (CSF) (340 mosmol/kg), but increases in the concentration of Na+, K+, Cl-, glucose, sorbitol, lactate, urea, myoinositol, and amino acids accounted for only about half of this increase. The unidentified solute was designated "idiogenic osmoles". When plasma glucose was rapidly lowered to normal with insulin, there was gross brain edema, increases in brain content of water, Na+, K+, Cl- and idiogenic osmoles, and a significant osmotic gradient from brain (326 mosmol/kg H(2)O) to plasma (287 mosmol/kg). By similarly lowering plasma glucose with peritoneal dialysis, increases in brain Na+, K+, Cl-, and water were significantly less, idiogenic osmoles were not present, and brain and plasma Osm were not different. It is concluded that during sustained hyperglycemia, the cerebral cortex adapts to extracellular hyperosmolality primarily by accumulation of idiogenic osmoles rather than loss of water or gain in solute. When plasma glucose is rapidly lowered with insulin, an osmotic gradient develops from brain to plasma. Despite the brain to plasma osmotic gradient, there is no net movement of water into brain until plasma glucose has fallen to at least 14 mM, at which time cerebral edema occurs.

Calcium metabolism of brain in acute renal failure. Effects of uremia, hemodialysis, and parathyroid hormone.

Studies were carried out to evaluate the changes in content of calcium and magnesium in brain during acute uremia in dogs. Ca content in gray and white matter of brain increased significantly after 3 days of acute uremia and this increment was prevented by thyroparathyroidectomy (TPTX). The administration of parathyroid extract (PTE) to normal dogs and TPTX uremic animals produced a significant rise in brain Ca. These changes were not related to alteration in the concentration of Ca in plasma or cerebrospinal fluid, to changes in calcium-phosphorus product, or to changes in blood pH. Furthermore, the infusion of large amounts of phosphate to vitamin D2-treated animals with suppressed parathyroid gland activity produced marked elevation in calcium-phosphorus product but no significant change in brain Ca. Also, uremia in vitamin D2-treated TPTX dogs failed to increase calcium content in brain despite marked elevation in calcium-phosphorus product. Hemodialysis significantly reduced Ca content of brain but the values were still significantly higher than normal. Mg content increased modestly only in the white matter of uremic dogs with intact parathyroid glands and in normal dogs and TPTX uremic dogs receiving PTE. The results indicate that (a) acute uremia of 3 days is associated with a marked rise of Ca content of brain and modest increment of Mg in certain parts of the brain, and (b) these alterations are not related to uremia, per se, but are dependent on the presence of excess parathyroid hormone. It is suggested that the neurological abnormalities noted in acute uremia may be related in part to the rise in the Ca content of brain.

Effects of dichloroacetate in the treatment of hypoxic lactic acidosis in dogs.

The metabolic and systemic effects of dichloroacetate (DCA) in the treatment of hypoxic lactic acidosis were evaluated in the dog and compared with the infusion of equal quantities of volume and sodium. Hypoxic lactic acidosis was induced by ventilating dogs with an hypoxic gas mixture of 8% oxygen and 92% nitrogen, resulting in arterial PO2 of less than 30 mmHg, pH below 7.20, bicarbonate less than 15 mM, and lactate greater than 7 mM. After, the development of hypoxic lactic acidosis dogs were treated for 60 min with either DCA as sodium salt or NaCl at equal infusions of volume and sodium. Dogs treated with DCA showed a significant increase of arterial blood pH and bicarbonate, and steady levels of lactate, whereas NaCl resulted in further declines of blood pH and bicarbonate, and rising blood lactate levels. Overall lactate production decreased during therapy with either regimen, but hepatic lactate extraction increased significantly with DCA, while it remained unchanged with NaCl. Tissue lactate levels in liver and skeletal muscle decreased significantly with DCA treatment but were unchanged with NaCl. Additionally, an increase in muscle intracellular pH was observed only in DCA treated dogs. A possible mechanism for the observed actions of DCA might be related to a significant increase in oxygen delivery to tissues. Such an effect was found with DCA administration, but was not observed with NaCl therapy. In conclusion, DCA therapy in hypoxic lactic acidosis has beneficial systemic effects compared with therapy with NaCl. DCA administration is accompanied by increases of blood pH and bicarbonate, a decrease in lactate production, and enhanced liver lactate extraction, and a lowering of tissue lactate levels.

Treatment of lactic acidosis with dichloroacetate in dogs.

Lactic acidosis is a clinical condition due to accumulation of H(+) ions from lactic acid, characterized by blood lactate levels >5 mM and arterial pH <7.25. In addition to supportive care, treatment usually consists of intravenous NaHCO(3), with a resultant mortality >60%. Dichloroacetate (DCA) is a compound that lowers blood lactate levels under various conditions in both man and laboratory animals. It acts to increase pyruvate oxidation by activation of pyruvate dehydrogenase. We evaluated the effects of DCA in the treatment of two different models of type B experimental lactic acidosis in diabetic dogs: hepatectomy-lactic acidosis and phenformin-lactic acidosis. The metabolic and systemic effects examined included arterial blood pH and levels of bicarbonate and lactate; the intracellular pH (pHi) in liver and skeletal muscle; cardiac index, arterial blood pressure and liver blood flow; liver lactate uptake and extrahepatic splanchnic (gut) lactate production; and mortality. Effects of DCA were compared with those of either NaCl or NaHCO(3). The infusion of DCA and NaHCO(3), delivered equal amounts of volume and sodium, although the quantity of NaHCO(3) infused (2.5 meq/kg per h) was insufficient to normalize arterial pH. In phenformin-lactic acidosis, DCA-treated animals had a mortality of 22%, vs. 89% in those treated with NaHCO(3). DCA therapy increased arterial pH and bicarbonate, liver pHi and cardiac index, with increased liver lactate uptake and a fall in blood lactate. With NaHCO(3) therapy, there were decrements of cardiac index and liver pHi, with an increase in venous pCO(2) and gut production of lactate. Dogs with hepatectomy-lactic acidosis were either treated or pretreated with DCA. Treatment with DCA resulted in stabilization of cardiac index, a fall in blood lactate, and 17% mortality. NaHCO(3) was associated with a continuous decline of cardiac index, rise in blood lactate, and 67% mortality. In dogs pretreated with NaCl, mortality was 33%, but all dogs pretreated with DCA survived. Dogs pretreated with DCA also had lower blood lactate and higher arterial pH and bicarbonate than did those pretreated with NaCl.Thus, in either of two models of type B experimental lactic acidosis, treatment with DCA improves cardiac index, arterial pH, bicarbonate and lactate, and liver pHi. The mortality in dogs with type B lactic acidosis was significantly less in DCA-treated animals than in those treated with other modalities.

Neurodiagnostic abnormalities in patients with acute renal failure.

Neurological abnormalities are a major cause of morbidity in patients with renal failure. The pathophysiology of these neurological changes is unclear, and the effects on them of dialysis and return of renal function have not been well studied. Studies were done in 31 patients who had acute renal failure (ARF), all of whom were either treated with dialysis within 5 days or did not survive. Studies on these patients included the electroencephalogram (EEG), motor nerve conduction velocity, and plasma Ca(++) and parathyroid hormone (PTH) levels. Studies were done at the time ARF was diagnosed, after stabilization on dialysis, during the diuretic phase of ARF, and 3 mo after recovery from ARF. In 16 patients with acute or chronic renal failure who did not survive and in nine patients without renal disease who died, measurements were made in brain of content of Na(+), K(+), Cl(-), Ca(++), Mg(++), and water. In patients with ARF for less than 48 h, despite the fact that there were only modest increases in plasma urea and creatinine, there were striking abnormalities in the EEG. The percent EEG power < 5 Hz+/-SE was 41+/-8% (normal = 2+/-1%), whereas the percent of frequencies > 9 Hz was only 22+/-6% (normal = 62+/-3%). These changes were unaffected by dialysis, but became normal with return of renal function and remained normal at 3 mo follow-up. The motor nerve conduction velocity was unaffected by either ARF or dialysis. In patients with ARF, the brain Ca(++) was 46.5+/-3.2 meq/kg dry wt, almost twice the normal value of 26.9+/-1.0 meq/kg dry wt (P < 0.001). The plasma PTH level was 3.2+/-0.6 ng/ml (normal < 1.5 ng/ml, P < 0.01). The increased brain Ca(++) was not related to an increased plasma (Ca(++)) (PO(4) (---)) product (r(2) = 0.14, P > 0.05). There was a small but significant decrement in brain Na(+) (P < 0.05), but brain water, K(+), and Mg(++) were unaffected by ARF.Thus, in patients with ARF for less than 48 h, the EEG is grossly abnormal and there are elevated levels of PTH in plasma. The PTH appears to have a direct effect on the brain, resulting in an increased brain Ca(++) content. The EEG abnormalities are unaffected by dialysis, but they become normal with return of renal function and remain normal after 3 mo follow-up. Thus, PTH may be a major uremic toxin, demonstrating evidence for central nervous system toxicity when there are only minimal abnormalities of other biochemical markers of ARF.

Abnormal sodium transport in synaptosomes from brain of uremic rats.

The causes of central nervous system (CNS) dysfunction in uremia are not well known and are not completely reversed by dialysis. This problem was investigated in synaptosomes, which are membrane vesicles from synaptic junctions in the brain. We measured Na uptake under conditions of control, veratridine stimulation, and tetrodotoxin inhibition, in synaptosomes from normal and acutely uremic (blood urea nitrogen, 250 mg/dl) rats. In the control state, maximal Na uptake was 2.2 +/- 0.2 and 1.9 +/- 0.3 nmol/mg of protein in normal and uremic synaptosomes, respectively. With veratridine stimulation, Na uptake was increased by 1.9 and 3.6 nmol/mg of protein in normal vs. uremic rats (P less than 0.001). The increased veratridine-stimulated Na uptake observed in uremia could be due either to increased membrane permeability to Na or decrease in the Na-K ATPase pump activity. To investigate this, we studied the Na-K ATPase pump function by evaluating uptake of K (using rubidium as a tracer), uptake of Na during ATP stimulation, and inhibition of Rb and Na uptake by ouabain. In uremic rats both Rb uptake and ATP-stimulated Na uptake were significantly less than in normals (P less than 0.005). This suggests a defect in the Na-K ATPase pump. Membrane permeability for Na was then evaluated both by measuring initial Na uptake, and with addition of valinomycin. No change in Na uptake pattern was observed with valinomycin, and initial Na uptake was not significantly different in normal versus uremic synaptosomes. These data show that (a) in uremic rats veratridine-stimulated Na accumulation is significantly greater than normal; (b) the increased Na accumulation observed in uremia appears to be due to alterations in Na-K ATPase pump activity; and (c) the altered Na accumulation observed is probably not due to a uremic environment, but may be secondary to a physiologic alteration in synaptosomal function due to the uremic state. These abnormalities may affect neurotransmission and may be associated with the CNS alterations observed in uremia.

Calcium transport abnormality in uremic rat brain synaptosomes.

Brain calcium is elevated in patients and laboratory animals with uremia. The significance of this finding is unclear. We evaluated calcium transport in brain of both normal and acutely uremic rats (blood urea nitrogen = 250 mg/dl) by performing studies in synaptosomes from rat brain cerebral cortex. Synaptosomes are vesicular presynaptic nerve endings from brain that contain mitochondria and are metabolically active. Two mechanisms of calcium transport were evaluated using radioactive 45Ca++ as a tracer. Both mechanisms were evaluated in the absence of exogenously administered parathyroid hormone (PTH). We first evaluated Na+-Ca++ exchange in vesicles that were loaded with NaCl in an external media containing 10 microM CaCl2. Both initial rates of calcium transport and equilibrium levels of calcium accumulation in synaptosomes prepared from uremic rats were significantly greater (P less than 0.005) than in normal. To assess calcium efflux, ATP-dependent calcium uptake (1 mM ATP) was studied in inverted plasma membrane vesicles loaded with KCl. In the uremic synaptosomes, a significant increase (P less than 0.005) in ATP-dependent calcium uptake was observed as compared with the normal. These studies show that (a) Calcium accumulation via the Na+-Ca++ exchanger is increased in synaptosomes prepared from uremic rat brain. (b) Calcium influx into inverted plasma membrane vesicles from uremic rats via the ATP-dependent calcium transport mechanism is increased when compared with normal. (c) The increased calcium accumulation in uremia by both Na+-Ca++ exchange and ATP-dependent calcium transport mechanism appears to be a result of increased synaptosomal membrane permeability to calcium. Both these abnormalities of calcium transport in uremia would tend to increase brain extracellular calcium in vivo. The defects observed in uremia do not appear to be readily reversible, and the relationship to PTH is presently unclear. These abnormalities may affect neurotransmission in the uremic state.

Changes in the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain electrolytes.

Studies were carried out in order to evaluate the effects of changes in brain calcium and the influence of parathyroidectomy and administration of parathyroid extract on the electroencephalogram (EEG) of normal and uremic dogs. Manual analysis of frequency and power distribution of the EEG in uremic dogs revealed a significant increase in both the percentage distribution and the area or power occupied by frequencies below 5 Hz. In addition, high amplitude bursts of delta activity were apparent in the uremic dog. These changes were largely prevented by parathyroidectomy before the induction of uremia, but the administration of parathyroid extract to either normal dogs, or to previously parathyroidectomized uremic dogs, induced EEG changes similar to those noted in uremic animals with intact parathyroid glands. In all groups of animals which showed EEG changes, brain content of calcium was significantly higher than in either normal dogs or previously parathyroidectomized uremic dogs. Changes in arterial pH and bicarbonate, or in the concentrations of Na+, K+, urea, or creatinine in plasma or cerebrospinal fluid were similar in uremic animals with intact parthyroid glands and in previously parathyroidectomized uremia dogs. The results indicate that the EEG changes found in dogs with acute renal failure require the presence of excess parathyroid hormone in blood, and they may be related to the observed changes in brain content of calcium.

Mechanisms of seizures and coma in hypoglycemia. Evidence for a direct effect of insulin on electrolyte transport in brain.

The mechanisms involved in the production of hypoglycemic coma were studied in rabbits. Measurements were made in brain, cerebrospinal fluid (CSF), and plasma of osmolality, Na(+), K(+), Cl(-), water content, exogenous insulin, glucose, lactate, and glutamate, while pH, Pco(2), Po(2), and bicarbonate were evaluated in arterial blood, 35 min after i.v. injection of insulin (50 U/kg), plasma glucose did not change, but brain K(+) content increased significantly. Grand mal seizures were observed in unanesthetized animals (+/-SD) 133+/-37 min after administration of insulin, at a time when brain glucose was normal, but brain tissue content of Na(+), K(+), osmoles, and water was significantly greater than normal. Coma supervened 212+/-54 min after insulin injection, at which time brain glucose, lactate, and glutamate were significantly decreased. At both 35 and 146 min after insulin administration, exogenous insulin was present in brain, but not in the CSF. After 208 min of insulin administration, animals were given i.v. glucose and sacrificed 35 min later. Most changes in the brain produced by hypoglycemia were reversed by the administration of glucose. Hypoxia (Po(2) = 23 mm Hg) was produced and maintained for 35 min in another group of animals. Hypoxia caused brain edema but did not affect brain electrolyte content. However, brain lactate concentration was significantly greater than normal. The data indicate that the seizures noted early in the course of insulin-induced hypoglycemia are temporally related to a rise in brain osmolality secondary to an increased net transport into brain of Na(+) and K(+), probably caused by insulin, per se. As hypoglycemia persists, there is also depletion of energy-supplying substrates (glucose, lactate, glutamate) in the brain, an event which coincides with the onset of coma. The brain edema observed during hypoxia is largely due to an increase in brain osmolality secondary to accumulation of lactate.

Renal bicarbonate wasting during phosphate depletion. A possible cause of altered acid-base homeostasis in hyperparathyroidism.

With hyperparathyroidism, serum bicarbonate (HCO(3) (-)) is low, urinary excretion of HCO(3) (-) is increased and the apparent T(m) for HCO(3) (-) is reduced. These findings have been ascribed to a direct renal action of parathyroid hormone (PTH). Since hypophosphatemia and phosphate depletion may occur in hyperparathyroidism, it is possible that phosphate depletion could account for the abnormal renal HCO(3) (-) handling. To test this possibility, renal reabsorption of HCO(3) (-) was evaluated in dogs before and after phosphate depletion. Serum HCO(3) (-) was significantly lower in phosphate depleted dogs than in normal animals, and serum HCO(3) (-) was directly related to serum phosphorus. Both the threshold at which HCO(3) (-) appeared in the urine and the T(m) for HCO(3) (-) were reduced during phosphate depletion. Intracellular pH of muscle was significantly higher in phosphate depleted dogs than in normals and the pH returned to normal after phosphate repletion. These data show that phosphate depleted dogs, which probably have physiological hypoparathyroidism, display abnormalities in both serum HCO(3) (-) and its renal handling which are similar to those seen in hyperparathyroidism, supporting the concept that the PTH-induced alterations in HCO(3) (-) homeostasis may be due to phosphate depletion. The latter could alter cell metabolism, resulting in reduced intracellular H(+) concentration, which may then impair H(+) secretion by the renal tubules and decrease their ability to reabsorb HCO(3) (-). Consequently, T(m) HCO(3) (-) and serum HCO(3) (-) fall.

Central nervous system pH in uremia and the effects of hemodialysis.

Rapid hemodialysis of uremic animals may induce a syndrome characterized by increased cerebrospinal fluid (CSF) pressure, grand mal seizures, and electroencephalographic abnormalities. There is a fall in pH and bicarbonate concentration in CSF, and brain osmolality exceeds that of plasma, resulting in a net movement of water into the brain. This syndrome has been called experimental dialysis disequilibrium syndrome. The fall in pH of CSF may be secondary to a fall of intracellular pH (pHi) in brain. Since changes in pHi can alter intracellular osmolality in other tissues, it was decided to investigate brain pHi in uremia, and the effects of hemodialysis. Brain pHi was measured by evaluating the distribution of 14C-labeled dimethadione in brain relative to CSF, while extracellular space was calculated as the 35504=/4 space relative to CSF. In animals with acute renal failure, brain (cerebral cortex) pHi was 7.06+/-0.02 (+/-SE) while that in CSF was 7.31+/-0.02, both values not different from normal. After rapid hemodialysis (100 min) of uremic animals, plasma creatinine fell from 11.8 to 5.9 mg/dl. Brain pHi was 6.89+/-0.02 and CSF pH and 7.19+/-0.02, both values significantly lower than in uremic animals (P less than 0.01), and there was a 12% increase in brain water content. After slow hemodialysis (210 min), brain pHi (7.01+/-0.02) and pH in CSF (7.27+/-0.02) were both significantly greater than values observed after rapid hemodialysis (P less than 0.01), and brain water content was normal. None of the above maneuvers had any effect on pHi of skeletal muscle or subcortical white matter. The data show that rapid hemodialysis of uremic dogs is accompanied by a significant fall in pH of CSF and pHi in cerebral cortex. Accompanying the fall in brain pHi is cerebral edema.

Hypoxic and ischemic hypoxia exacerbate brain injury associated with metabolic encephalopathy in laboratory animals.

Hypoxemia is a major comorbid factor for permanent brain damage in several metabolic encephalopathies. To determine whether hypoxia impairs brain adaptation to hyponatremia, worsening brain edema, we performed in vitro and in vivo studies in cats and rats with hyponatremia plus either ischemic or hypoxic hypoxia. Mortality with hypoxic hypoxia was 0%; with hyponatremia, 22%; and with hyponatremia+hypoxia, 100%. Hyponatremia in cats produced brain edema, with a compensatory decrease of brain sodium. Ischemic hypoxia also resulted in brain edema, but with elevation of brain sodium. However, when ischemic hypoxia was superimposed upon hyponatremia, there was elevation of brain sodium with further elevation of water. Outward sodium transport in cat cerebral cortex synaptosomes was measured via three major pathways through which brain osmolality can be decreased. After hyponatremia, sodium transport was significantly altered such that brain cell osmolality would decrease: 44% increase in Na(+)-K(+)-ATPase transport activity (ouabain inhibitable); 26% decrease in amiloride-sensitive sodium uptake. The change in veratridine-stimulated sodium uptake was not significant (P > 0.05). When ischemic hypoxia was superimposed upon hyponatremia, all of the cerebral adaptive changes induced by hyponatremia alone were eliminated. Thus, hypoxia combined with hyponatremia produces a major increase in brain edema and mortality, probably by eliminating the compensatory mechanisms of sodium transport initiated by hyponatremia that tend to minimize brain swelling.

Transient cerebral ischemia. Association of apoptosis induction with hypoperfusion.

Apoptosis is thought to be important in the pathogenesis of cerebral ischemia. The mechanism of apoptosis induction remains unclear but several studies suggest that it is preferentially triggered by mild/moderate microcirculatory disturbances. We examined in cats whether induction of apoptosis after 2.5 h of unilateral middle cerebral artery occlusion plus 10 h of reperfusion is influenced by the degree of cerebral microcirculatory disturbance. Quantitative monitoring over time of the disturbances of cerebral microcirculation in ischemic brain areas and evaluation of cytotoxic edema associated with perfusion deficits was achieved by using two noninvasive magnetic resonance imaging techniques: (a) high-speed echo planar imaging combined with a bolus of magnetic susceptibility contrast agent; and (b) diffusion-weighted imaging. Apoptosis-positive cells were counted in anatomic areas with different severity of ischemic injury characterized by magnetic resonance imaging, triphenyltetrazolium chloride, and hemotoxylin and eosin staining. The number of apoptosis-positive cells was significantly higher in anatomic areas with severe perfusion deficits during occlusion and detectable histologic changes 10 h after reperfusion. In contrast, in areas where perfusion was reduced but maintained during occlusion there were no detectable histological changes and significantly fewer apoptosis-positive cells. A similar number of cells that undergo apoptosis were shown in regions with transient or prolonged subtotal perfusion deficits. These results suggest that the apoptotic process is induced in the ischemic core and contributes significantly in the degeneration of neurons associated with transient ischemia.

Glycine-induced hypo-osmolar hyponatremia.

BACKGROUND: Hyponatremia is commonly observed following transurethral resection of the prostate or endometrial resection when the operative field is irrigated with hypotonic glycine. Although glycine-induced hyponatremia has been associated with brain damage, the mortality is low, and it has been suggested that the condition might not be hypo-osmolar and thus might not cause brain edema. OBJECTIVE: To determine if glycine-induced hyponatremia is a hypo-osmolar condition. METHODS: The study was a retrospective evaluation of 13 men who underwent transurethral resection of the prostate and 5 women who underwent transcervical endometrial resection at 2 university medical centers. In all patients, hypotonic glycine (200 mmol/L) was the irrigating solution. Measurements were made of the plasma sodium, osmolality, glucose, urea, glycine, and ammonia; and arterial pH, PO2 and PCO2. Mortality and the occurrence of respiratory arrest were recorded. Data are given as mean (+/- SE). RESULTS: The plasma sodium in 18 patients was 106 +/- 2 mmol/L and the measured osmolality was 235 +/- 5 mOsm/kg H2O. Glycine was measured as the difference between measured and calculated plasma osmolality and was 18 +/- 2 mmol/L. Four patients suffered respiratory arrest; all died. One patient had elevated blood ammonia (130 mumol/L) with a plasma sodium level of 110 mmol/L. She was treated with endotracheal intubation and respiratory support plus hypertonic sodium chloride, and recovered. The other 14 surviving patients were treated with hypertonic sodium chloride. CONCLUSIONS: Patients who undergo transurethral resection of the prostate or endometrial resection with hypotonic glycine as the irrigating medium can experience symptomatic hyponatremia that is hypo-osmolar and can be fatal. Therapy with hypertonic sodium chloride was associated with survival in 14 of 14 patients. Ammonia intoxication also can develop, and can be managed with respiratory support.

Biguanide-associated lactic acidosis. Case report and review of the literature.

PURPOSE: The biguanides are a class of oral hypoglycemic agents that are commonly used in the treatment of diabetes mellitus. Such agents include metformin, phenformin, and buformin. The use of phenformin was discontinued in the United States in 1976 because of probable association with lactic acidosis. However, metformin is currently in common use in many parts of the world. In this report, we describe a patient with severe lactic acidosis secondary to metformin administration, and review the literature relevant to biguanide-associated lactic acidosis. PATIENT: We describe a diabetic man with end-stage renal failure and diabetes mellitus who was hospitalized with life-threatening lactic acidosis (lactate, 10.9 mmol/L). Unbeknownst to the hospital staff, he was being treated with metformin, which had been prescribed in Indonesia. RESULTS: Arterial blood gas analysis revealed a pH of 6.76 and a bicarbonate level of 1.6 mmol/L prior to treatment. Following therapy, which included oxygen, volume expansion, other supportive therapy, and hemodialysis, the patient completely recovered and was discharged from the hospital. CONCLUSIONS: Lactic acidosis can complicate biguanide therapy in diabetic patients with renal insufficiency. We review the literature relevant to the pathogenesis and therapy of biguanide-associated lactic acidosis. Physicians who have completed their training after 1976 may not be familiar with metformin and other biguanides, but with the increasing numbers of immigrants to the United States, physicians should be aware of the potential complications of these medications.

Low-dosage heparin in rapidly progressive glomerulonephritis.

Two patients developed acute renal failure; creatinine clearances fell to 13 and 34 ml/min, respectively, and one patient was oliguric. Renal biopsies in both patients gave results that were compatible with rapidly progressive glomerulonephritis (RPGN). Both patients were treated with low-dosage heparin sodium infusion (8,000 units/day) and prednisone for two to four weeks, followed by oral anticoagulant (warfarin) and antithrombotic agents (dipyridamole). In the two patients, creatinine clearance rose to at least 60 ml/min, and no bleeding complications were observed. Repeat renal biopsy specimens that were obtained after three to six months of treatment showed no evidence of active glomerulonephritis in either patient, but there was extensive scarring and fibrosis. Low-dosage heparin infusion may arrest and partially reverse the renal failure associated with RPGN in some cases, while avoiding the bleeding complications that are frequently observed in patients treated with larger dosages of heparin.

Rapid inibition of basal and glucose-stimulated insulin release by xylazine.

Xylazine is a tranquilizer that is widely used in both biomedical research and veterinary medicine. We now report that in dogs, clinically effective doses of xylazine both markedly decrease basal insulin levels and completely abolish the rise in insulin produced by iv glucose. These changes in insulin levels lead to elevations of fasting plasma glucose and glucose intolerance. In contrast, glucagon levels are unchanged. These studies suggest that xylazine may be a useful agent in the study of glucose metabolism and beta-cell function.

Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes.

1. An attempt was made to evaluate the pathophysiology of symptoms of hyponatremia as related to changes in brain water and electrolytes. Studies were carried out in 66 hyponatremic patients and 5 groups of experimental animals. 2. In hyponatremic patients, symptoms (depression of sensorium, seizures) correlated well with plasma Na+ (r = 0.64, p less than .001), but there was substantial overlap. In patients with acute hyponatremia, all were symptomatic and 50% died. Among patients with hyponatremia of at least 3 days duration, sympatomatic patients had plasma Na+ (115 +/- 1 mEq/L) which was significantly less (p less than .001) than that of asymptomatic patients (plasma Na+ = 122 +/- 1 mEq/L). Among symptomatic patients, mortality was 12% and 8% had seizures, while none of the asymptomatic patients died or had seizures. 3. Among 14 patients with acute (less than 12 hrs) hyponatremia, the mean plasma Na+ was 112 +/- 2 mEq/L. All such patients had some depression of sensorium and four had grand male seizures. Seven of these patients were treated with hypertonic (862 mM) NaCl, while four were treated only with fluid restriction. Of the seven patients treated with hypertonic NaCl, five survived, while three of four patients treated with fluid restriction died. There was no evidence of circulatory congestion or cerebral damage in the patients treated with hypertonic NaCl. 4. Among rabbits with acute (2-3 hours) hyponatremia (plasma Na+ = 119 +/- 1 mEq/L), all had grand mal seizures and 86% died. All such animals had cerebral edema (brain H2O content 17% above control value) but brain content of Na+, K+ and Cl- was normal. 5. Rabbits with 3 1/2 days of hyponatremia (plasma Na+ = 122 +/- 2 mEq/L) appeared to be asymptomatic, even though brain water content was 7% above normal (p less than .01). 6. Rabbits with 16 days of more severe hyponatremia (plasma Na+ = 99 +/- 3 mEq/L) were weak, anorexic, lethargic and unable to walk. Brain water content was 7% above normal, although brain osmolality (218 +/- 12 mOsm/kg H2O) was similar to plasma (215 +/- 8 mOsm/kg). Brain content of Na+, K+, Cl- and osmoles was 17 to 37% less than normal values, so that the brain established osmotic equilibrium with plasma primarily by means of a loss of electrolytes. 7. These studies suggest that in patients with hyponatremia, symptoms and morbidity are only grossly correlated with either magnitude or duration of hyponatremia. Symptoms appear to correlate best with the interplay between a net increase in brain water versus a loss oof brain electrolytes. However, even asymptomatic animals have subclinical brain edema when plasma Na+ is below 125 mEq/L, and such edema may cause permanent brain damage. Thus, many patients with similar levels of plasma Na+, particularly when they are symptomatic, should probably be treated with hypertonic NaCl infusions.

Effects of glycerol administration on experimental brain edema.

The effects of glycerol on brain water and solute distribution in cerebral edema are not well known. In brail edema induced in dogs by focal freezing, tissue underlying the necrotic lesion had an elevated water content but the remainder of the brain was unaltered. Administration of glycerol to maintain plasma glycerol at about 35 mM dehydrated normal white matter, but water and solute contents of the edematous white matter were not changed. During the initial 3 hours of glycerol infusion, CSF pressure fell, but when the infusion was continued for 6 hours or more, a gradual rise in CSF pressure was observed. In three animals, the final CSF pressure was higher than preinfusion values. At this time, brain water content was significantly less than normal, but both CSF osmolality and glycerol concentration were higher than plasma. The data show that glycerol infusion can decrease intracranial volume towards normal by dehydration of normal, but not damaged, brain tissue. The rebound rise in CSF pressure observed during the continuous administration of glycerol cannot be explained by rehydration of brain tissue but may be related to alterations in CSF dynamics.