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Calciphylaxis is a rare and life-threatening condition of progressive cutaneous necrosis secondary to small and medium-sized vessel calcification previously described in patients with end-stage renal disease and hyperparathyroidism. Early diagnosis may be important in improving the poor outcome in these patients since early intervention may forestall the development of life-threatening complications. We describe a patient with Crohn's disease complicated by short-bowel syndrome and modest renal insufficiency (not requiring renal replacement therapy) who developed calciphylaxis. It appears that longstanding Crohn's disease and the short-bowel syndrome accelerated the development of calciphylaxis as the chronic renal disease was not end stage. Considering the possibility of calciphylaxis in this setting may avoid delaying the diagnosis and its consequences.

Each year, especially in the United States, young and middle aged men die from a variety of causes during or following intense physical exertion. For unknown reasons, death and disability as a consequence of physical effort are virtually unknown in women, despite the fact that they participate heavily in competitive sports. The most important complications of exhaustive exercise are shown in Table 1. Of these, rhabdomyolysis, especially if associated with exertional heat stroke, is one of the most devastating clinical illnesses that exists. The term rhabdomyolysis defines an injury to skeletal muscle cells of such severity that their contents leak into the circulation. The injury may be confirmed biochemically by demonstrating elevated concentrations of enzymes in serum that are specifically located in skeletal muscle cells (CK-MM, aldolase) or myoglobin. Myoglobin released into the circulation is filtered and excreted into the urine, so-called myoglobinuria. The latter invokes the risk of acute renal failure (pigment nephropathy). Exertional rhabdomyolysis is an exceptionally common event. It is probably experienced in mild form by everyone who has undergone some form of exercise training during their youth when it is expressed simply by stiff and tender muscles. If at that time someone happened to measure a serum CK value, it would be slightly to modestly elevated. Some of the most classic examples of frank exertional rhabdomyolysis occur among our most highly trained endurance runners. In the majority of cases, there is no history or other apparent evidence for myopathy before the event. In most who survive major episodes, subsequent muscle testing has shown no results that suggest a hereditary myopathy such as McArdle's Syndrome, carnitine palmityl transferase deficiency, or other myopathy. Because of this, it is assumed that any normal person may develop frank rhabdomyolysis provided the provocation is adequate. Provocative events consist of exhaustive exercise, especially when competitive, and particularly if the athlete musters his supreme effort to win during the last segment of a race. Hot or warm weather and a high relative humidity increase the risk enormously. Victims of this disorder often give a history that they continued to run despite cramping pain and "dead legs". Some of them continue to run despite obvious disorientation and confusion. Observers commonly recall that victims appeared pallid or gray as if their skin vessels had become constricted as a result of a massive discharge of norepinephrine or alternatively, their cardiac output and peripheral circulation had failed. It seems that it is this last burst of effort that often provides the coup de grace , so that the patient develops major and widespread soft tissue injury and in some cases, heat stroke as an associated illness. It is unfortunate that the gravity of acute exertional rhabdomyolysis is so often unappreciated by physicians who initially provide care for these patients. Although the victim may collapse and appear to recover quickly, in some of these, potentially fatal metabolic acidosis, hyperkalemia, disseminated intravascular coagulation and the acute respiratory distress syndrome may appear during the following 24 hours. The syndrome of rhabdomyolysis is given little attention in the major textbooks of internal medicine. Perhaps this is one of the reasons why the gravity of the illness is so commonly unappreciated at the onset when appropriate identification and treatment of its complications could be life saving. There is strong evidence that training induces a degree of resistance to development of exertional rhabdomyolysis as well as exertional heat stroke. Some of this evidence will be reviewed, but with emphasis on the fact that even a highly trained athlete can still develop exertional rhabdomyolysis. Following the review of the physiological mechanisms that help forestall injury incident to exertion, several cases will be presented that will highlight some of the devastating complications of exercise.

When patients present with acute onset of chest pain suggestive of myocardial ischemia, immediate clinical decisions regarding thrombolysis, percutaneous transluminal coronary angioplasty, or both are usually based on the history and abnormal electrocardiograms and confirmed by the presence of abnormally elevated cardiac enzymes. However, there are potential limitations of the electrocardiograms and initial cardiac enzymes in the diagnosis and confirmation of acute myocardial infarction. We describe the case of a patient who presented with an acute onset of chest pain and had a normal electrocardiogram and initial cardiac enzymes yet was found by transesophageal echocardiography to have a large myocardial infarction.

Hypercalcemia and electrolyte abnormalities are common problems in patients with malignancy. In this article we discuss the pathophysiology, clinical features, and management of hypercalcemia, which is the most common metabolic abnormality. We also analyze the electrolyte disturbances that occur in association with malignancy, including hyponatremia, hypokalemia, hypomagnesemia, hypophosphatemia, and hyperkalemia. Recognition and treatment of these disturbances are important parts of the management of patients with malignant disease.

Rhabdomyolysis is a common disorder that occurs as a primary disease or as a complication of a broad spectrum of other diseases. Although some cases are caused by hereditary metabolic or structural abnormalities of the skeletal muscle cell, the majority of cases occur in healthy persons as a result of exhaustive exercise, infections, intoxications, deficiency states, or trauma. Although the causes of rhabdomyolysis are diverse, current evidence suggests that there may be a common final pathway that mediates cellular injury. Thus some noxious factor, perhaps a drug that injures the plasma membrane of the cell, a toxin that activates a cytolytic enzyme, a factor that interferes with metabolism and disrupts the integrity of the skeletal muscle cell, a cytokine such as tumor necrosis factor, or simple hypoxia that reduces energy production by the cell, serves to increase cellular permeability to sodium ions. When sodium ions accumulate in the cytoplasm of the cell, an increase of cytosolic or mitochondrial calcium follows. Calcium activates a variety of proteolytic enzymes that injure the cell membrane, allowing efflux of cellular components into the circulation. The ability to identify some of these components, such as myoglobin or creatine kinase, facilitates clinical recognition of rhabdomyolysis. The cytosolic components released into the circulation, under appropriate conditions, may be life threatening, eg, release of potassium causes hyperkalemic cardiotoxicity. In this review, I attempt to describe a variety of factors that are known to be injurious to skeletal muscle cells and, when possible, describe the apparent mechanism whereby these factors result in injury and disruption of the muscle cell.

A 70-kg adult contains about 700 g of phosphorus. Eighty-five percent of this quantity is in bone, 14% in soft tissues, and the remainder is equally distributed between the teeth, blood, and extravascular fluids. The extracellular fluid pool of phosphorus is only about 600 mg.

Plasma exchange is the mainstay of therapy for thrombotic thrombocytopenia purpura. In this study, the authors retrospectively examined variables that may predict outcome in 18 patients with thrombotic thrombocytopenia purpura. They found that the time to first plasma exchange from admission and time to first dose of intravenous steroid are important in influencing outcome. A rise in platelets and a fall in lactic dehydrogenase 3 days after plasma exchange were also found useful in predicting survival. Therefore, early recognition and intervention in this disease is warranted.

To the Editor: Blackwater fever and acute tubular necrosis in malaria caused by Plasmodium falciparum are assumed to be results of hemoglobinuria. The following case suggests that myoglobinuria may...

To the Editor: We recently encountered a patient who survived ethylene glycol poisoning with an arterial-blood pH of 6.46. A 44-year-old woman drank approximately 720 ml of ethylene glycol in the form of antifreeze. She had previously attempted suicide by injecting the same substance into her buttocks. When admitted to the hospital, the patient was unresponsive and incontinent and was receiving ventilation. Her temperature was 37.1 °C (98.7 °F), her pulse 110 per minute, and her blood pressure 130/70 mm Hg. Her pupils were fixed and dilated, and she had no corneal, gag, or deep-tendon reflexes. The serum sodium level . . .

rior surface dust lead, interior house dust lead and childhood lead exposure in an urban environment. In: Hemphill DD, ed. Trace Substances in Environmental Health, XX: Proceedings of University of Missouri’s 20th Annual Conference, June 1986. Columbia: University of Missouri; 1987:322-332. 23. Environmental Protection Agency. Distribution of Soil Lead in the Nation’s Housing Stock. Washington, DC: Office of Pollution Prevention and Toxics. Environmental Protection Agency; 1996. Report No. EPA 747-R-96-003. 24. Department of Housing and Urban Development. Comprehensive and Workable Plan for the Abatement of Lead-Based Paint in Privately Owned Housing, Report to Congress. Washington, DC: Office of Policy Development and Research; 1990.

Uremia is the last of four progressive stages of renal disease. Symptoms are referable to major organ systems and appear to be intensified by high intake of crude dietary protein. In many respects uremia resembles systemic poisoning from a toxic substance, and many chemicals are now suspected, but not proved, to be causative agents. The hypometabolism and low body temperature commonly seen in advanced uremia could result from alterations in cellular sodium transport. These changes can be reversed by hemodialysis or renal transplantation.

Electrochemical disturbances of skeletal muscle cells in untreated uremia are characterized by an increase in the intracellular sodium and chloride content, a decrease in intracellular potassium, and a low resting membrane potential. In this study, we have reexamined the foregoing and, in addition, have examined the effects of hemodialysis. Three groups of patients were studied. In the first group of 22 uncomplicated uremic patients, whose creatinine clearance (Ccr) ranged from 2 to 12 cm(3)/min per 1.73 m(2), resting transmembrane potential difference (Em) of skeletal muscle cells was measured. In each of the nine patients whose Ccr ranged between 6.3 and 12 cm(3)/min, the Em was normal (i.e., -90.8+/-0.9 mV, mean+/-SEM). However, as Ccr dropped below 6.3 cm/min, the Em became progressively reduced and assumed a linear relationship with the Ccr. In the second study, nine individuals with end-stage renal disease, whose mean Ccr was 4.3 cm(3)/min, underwent measurement of Em and intracellular electrolyte concentration before and after 7 wk of hemodialysis. Before dialysis, the Em was -78.5+/-2.1 mV, intracellular sodium and chloride were elevated, and the intracellular potassium was reduced. After 7 wk of hemodialysis the Em rose to -87.8+/-1.3 mV, and the intracellular sodium, chloride, and potassium became normal. In the third study, seven patients who were stable on 6-h thrice-weekly dialysis were studied before and after reduction of dialysis to 6 h twice weekly. In those individuals whose Em remained normal after 6 wk, dialysis time was reduced further. On thrice-weekly dialysis the Em was -91.2+/-1.0 mV. With reduced dialysis, the Em fell to -80.1+/-0.8 mV (P < 0.001). In each case, the Em became abnormal before significant signs or symptoms of uremia were noted. These findings demonstrate that end-stage renal disease is associated with serious electrochemical changes in the muscle cell which are reversed by hemodialysis and recur when dialysis time is reduced. Thus, serial observations of muscle Em may be a potentially powerful tool to assess adequacy of dialysis therapy.

We have examined the effect of ethanol on muscle blood flow at rest and during electrically stimulated exercise in five normal dogs using the isolated gracilis muscle preparation. Under pentobarbital anesthesia and mechanical ventilation, ethanol (15% in 0.9% NaCl) infused at 4 mL/min for 2 hr produced an arterial blood concentration of 268 +/- 10 mg/dL (X +/- SEM). Resting muscle blood flow was 6.3 +/- 0.9 mL/min/100 gm in 8 dogs infused with saline alone. During stimulated contraction using supramaximal voltage at a rate of 5 stimuli/sec, respective mean flows for ETOH and saline dogs at 1, 5, 10, and 30 min were 35.5, 19.9, 27.7, 22.2, and 22.0, 20.0, 23.6, and 19.1 mL/min/100 gm. The 1-min flow rate for ethanol infused animals was significantly greater (P < 0.05) than that observed in saline infused animals. The remainder of the values were not significantly different. Potassium release from contracting muscle was normal. These observations do not support the theory that ethanol induces vasoconstriction in the vascular bed of skeletal muscle nor do they support the postulation that muscle cell ischemia plays a role in alcoholic myopathy.

Pruritus is a frequent and troublesome consequence of end-stage renal disease. We have surveyed 155 chronic dialysis patients and found pruritus to be a significant problem in approximately 70%. Seventeen patients reporting severe pruritus were treated thrice weekly with total body exposure to either UVA or UVB light. UVB light resulted in resolution of pruritus in all cases. UVA light was without significant effect. Skin biopsies obtained before and after UV phototherapy revealed elevated contents of calcium, magnesium, and phosphorus in all pruritic patients. The resolution of pruritus following UVB treatment was associated with a reduction of skin phosphorus to values comparable with nonpruritic uremics or healthy volunteers. Uremic pruritus may be due to increased skin divalent ion content resulting in microprecipitation of calcium or magnesium phosphate.

An incompletely defined interregulatory balance exists between potassium, insulin, and aldosterone. That potassium administration enhances and hypokalemia depresses aldoterone production is well known. It is not as well known that the same relationship exists between potassium and insulin. In a normal subject, acute hyperkalemia stimulates release of insulin from the pancreas. Potassium deficiency, on the other hand, may depress production of insulin. Both insulin and aldosterone, under appropriate conditions, may indirectly promote transfer of potassium ions from extracellular to intracellular fluid. In contrast, deficiency of either insulin or aldosterone, and expecially both, may favor development of hyperkalemia. Pharmacologically, glucagon, epinephrine, norepinephrine, and somatotropin may also influence transfer of potassium between extracellular and intracellular fluid. Their precise physiological roles in potassium homeostasis, however, are much less evident than that for insulin and aldosterone. It is the intention of this brief review to point out the salient effects and mechanisms whereby the foregoing substances affect potassium homeostasis and to point out physiologically important interrelationships wherever possible.

Diuretic therapy is the most common cause of potassium deficiency. Although the extent of potassium deficiency usually does not exceed 200 or 300 mEq, under appropriate circumstances such modest deficiency may have important consequences. Factors that tend to increase the incidence or severity of potassium deficiency in patients who take diuretics include high salt diets, large urine volumes, metabolic alkalosis, increased aldosterone production, and the simultaneous use of two diuretics that act on different sites in the renal tubule. There are many serious complications of potassium deficiency, including cardiac arrhythmias, muscle weakness, rhabdomyolysis, glucose intolerance, and several complications that result directly from increased ammonia production, such as protein and nitrogen wasting and hepatic coma. Emphasized herein are those conditions that impose potential danger in patients with mild hypokalemia. Important factors that identify specific causes of potassium deficiency and its treatment are discussed briefly.

The incidence of full-blown uremic syndrome is decreasing because most patients in renal failure are started on dialysis before the uremia becomes symptomatic. Research in the pathophysiology of ur...

Continued technological improvements in the quality of nutritional formulations and techniques for parenteral administration have resulted in a major improvement in patient care. The ability to provide all necessary nutrients by intravenous infusion, so-called total parenteral nutrition (TPN), has sustained life and growth in patients who otherwise would have died. Most adult patients who derive benefit from this procedure are those with disorders in which alimentary dysfunction precludes adequate nutrition to either save life or prevent serious disease. Included among these disorders are various forms of carcinoma of the gastrointestinal tract, esophageal stricture or stenosis, intestinal fistulae, severe pancreatitis, and the "short-bowel" syndrome. Perhaps one of its advantages has been to re-establish adequate nutritional vitality to patients who suffered life-threatening malnutrition and weight loss and who, following TPN, could undergo corrective surgical procedures. The purpose of this editorial review is to discuss several interesting and sometimes preventable complications that result from the use of TPN and, in addition, to point out several situations in which TPN used too enthusiastically might directly result in death. This will not be a comprehensive review of all complications one may encounter in patients undergoing TPN. Rather, emphasis will be placed on certain electrolyte disturbances, with special emphasis on phosphate deficiency and its resulting problems. Although infection, oxalosis, disturbances of carbohydrate and lipid metabolism and the potentially important disorders related to carnitine deficiency are of critical importance in patients undergoing TPN, they will not be reviewed in this editorial. The history of TPN has amusing as well as interesting facets. About 300 years ago, Sir Christopher Wren administered a mixture of ale, opium, and beer intravenously to animals. His intravenous set was a pig bladder and his needle was a quill from a feather [1]. His work may have unintentionally represented the pioneer effort in intravenous substance abuse. More seriously, it appears that the advent of modern TPN therapy began during World War II. A fascinating review describing treatment of starvation based on sound physiological and biochemical principles appeared in 1945 [2]. Participants at this conference detailed a number of interesting observations on prisoners of war subjected to protracted starvation. They pointed out that under such conditions, the bowel underwent atrophy to the extent that it seemed to consist of only its serous coat. This was probably the derivation of the term "cellophane bowel" applied to this condition in the modern literature. Those investigators recognized clearly that under such conditions the intestine would not tolerate food administered by mouth. Almost any food acted as an irritant, causing diarrhea and dehydration. They correctly assumed and showed that administration of nutrients intravenously for several days would apparently permit sufficient functional reconstitution of the gut so that oral administration of food could be tolerated. Our current knowledge that intestinal mucosal cells can repopulate themselves very rapidly corresponds to those earlier observations. Studies conducted in 1913 by Henriques and Anderson [3] demonstrated that nitrogen equilibrium could be achieved by administering hydrolysates prepared from pancreatic extracts of goat muscle. Before the end of World War II, hydrolysates of known amino acid composition were prepared from proteins digested in proteolytic enzymes derived from pork pancreas, papain, or by simple hydrolysis in sulphuric acid [4]. It was clearly recognized at that time that the drawback of sulphuric acid hydrolysis was its destruction of tryptophane. Amino acid solutions prepared by these techniques were successfully administered to many starved people. The most successful technique appeared to be intravenous administration of protein hydrolysate preparations for 1 to 3 days followed by oral ingestion of small quantities of a solution prepared from dried milk powder, glucose, and vitamins [5, 6]. Interest in TPN was rekindled in 1968 when Dudrick, Wilmore, Vars, and Rhoads [7] showed that by this technique, normal growth and development could be maintained in children for long periods of time.

An illustrative case of severe heat stroke complicated by acute renal failure, jaundice, acute myocardial infarction and marked hematologic abnormalities is presented. A review of the pertinent literature is included for the purpose of clarification of the diverse interrelationships of the various complications. Evidence is presented which suggests that total body potassium deficiency may be of etiologic importance in the genesis of heat stroke.

Ten patients with oliguric acute renal failure associated with various forms of heat injury were treated at the U. S. Army Surgical Research Unit during the period from 1958 through 1965. In contrast to the general impression that this complication of heat stroke is almost invariably fatal, seven of these patients survived, with complete clinical recovery of renal function. Also noteworthy was the high incidence of rhabdomyolysis and myoglobinuria, affecting four of the ten patients. Certain features in these cases, correlated with clinical and experimental findings reported by others, suggest that the development of heat stroke and rhabdomyolysis may possibly be related to a disordered potassium metabolism which appears in many subjects during heat acclimatization.

The effect of intensive physical exercise upon plasma levels of pancreatic glucagon was investigated in dogs and in man. In 7 dogs, treadmill exercise until collapse was invariably associated with a rise in plasma glucagon, which at the time of collapse averaged 426 pg/ml (sem ± 71), more than 4 times the baseline average of 111 pg/ml (sem ± 26) (p < 0.005). Glucose rose in parallel from 88 mg/100 ml prior to exercise (sem ± 2) to a peak of 105 mg/100 ml (sem ± 4) at collapse (p < 0.01). Hypoglycemia did not occur in any dog. Insulin remained unchanged but rose briefly soon after collapse. In 4 human volunteers exercised to exhaustion on a stationary bicycle glucagon rose from 68 pg/ml (sem ± 17) to 116 pg/ml (sem ± 14) 10 min after the exhaustion point (p < 0.02), and again glucose rose in parallel from a pre-exercise value of 93 mg/100 ml (sem ± 3) to 124 mg/100 ml (sem ± 8) during recovery. Insulin also rose during recovery. When dogs were exercised to collapse during a 15 mg/kg/min intravenou...

Rhabdomyolysis and myoglobinuria occur commonly in men who sustain environmental heat injury during intensive physical training in hot climates. These also occur in patients with potassium depletion. Since physical training in hot climates may be accompanied by serious losses of body potassium, the possibility was considered that performance of strenuous exercise when potassium deficient might enhance susceptibility to rhabdomyolysis. Potassium is released from contracting skeletal muscle fibers and its rising concentration in interstitial fluid is thought to dilate arterioles thereby mediating the normal rise of muscle blood flow during exercise. If potassium release from deficient muscle were subnormal, exercise would not be accompanied by sufficient muscle blood flow and rhabdomyolysis could occur by ischemia. This hypothesis was examined by comparing the effect of electrically stimulated exercise on muscle blood flow, potassium release, and histology of the intact gracilis muscle preparation in normal and potassium-depleted dogs. In normal dogs, muscle blood flow and potassium release rose sharply during exercise. In contrast, muscle blood flow and potassium release were markedly subnormal in depleted dogs despite brisk muscle contractions. Although minor histologic changes were sometimes observed in nonexercised potassium-depleted muscle, frank rhabdomyolysis occurred in each potassium-depleted animal after exercise. These findings support the hypothesis that ischemia may be the mechanism of rhabdomyolysis with exercise in potassium depletion.

Hematuria in patients with sickle cell trait might be related to sickling in the medullary vessels of the kidney. In vitro, hypertonicity, acidity, and anoxia may cause sickling. These conditions may also exist in the renal medulla of man. In two patients with long-standing hematuria associated with sickle cell trait, urinary hemoglobin loss consistently diminished or transiently stopped following urinary alkalinization or certain measures which theoretically diminish medullary tonicity and increase medullary oxygen tension. Transient cessation of hematuria also occurred repeatedly after an infusion of distilled water. This phenomenon may be related to red cell expansion and dilution of S-hemoglobin and supports experimental evidence that a critical concentration of S-hemoglobin is a prerequisite for sickling.

Three male patients developed a total of four episodes of acute rhabdomyolysis associated with documented cocaine intoxication (two caused "crack" and two caused by intravenous cocaine). Included is one patient who developed rhabdomyolysis after injecting cocaine and then redeveloped it 6 months later on "rechallenge." One of the four cases resulted in death related to severe hyperkalemia and ischemic bowel. The remaining three episodes followed a course of nonoliguric renal failure.

Elsewhere in this issue, Aubier and his associates report their observations on eight patients with hypophosphatemia-related diaphragm weakness and pulmonary insufficiency that improved after administration of potassium phosphate.1 An ever-increasing number of case reports have described respiratory muscle failure in critically ill patients with severe hypophosphatemia. The work of Aubier et al. supports the concept that hypophosphatemia may be a treatable cause of respiratory insufficiency. Profound muscle weakness with phosphorus depletion has been well described in both human beings and animals. Indeed, if one induces acute hypophosphatemia by hyperalimentation in an animal that has previously been subjected to weight loss . . .

Clinical observations suggest that overt rhabdomyolysis may occur if severe hypophosphatemia is superimposed upon a pre-existing subclinical myopathy. To examine this possibility, a subclinical muscle cell injury was induced in 23 dogs by feeding them a phosphorus- and calorie-deficient diet until they lost 30% of their original weight. To induce acute, severe hypophosphatemia in the animals after partial starvation, 17 of the dogs were given large quantities of the same phosphorus-deficient diet in conjunction with an oral carbohydrate supplement, which together provided 140 kcal/kg per day. After phosphorus and caloric deprivation, serum phosphorus and creatine phosphokinase (CPK) activity were normal. Total muscle phosphorus content fell from 28.0+/-1.3 to 26.1+/-2.5 mmol/dg fat-free dry solids. Sodium, chloride, and water contents rose. These changes resembled those observed in patients with subclinical alcoholic myopathy. When studied after 3 days of hyperalimentation, the animals not receiving phosphorus showed weakness, tremulousness, and in some cases, seizures. Serum phosphorus fell, the average lowest value was 0.8 mg/dl (P

Patients with end-stage renal disease display a variety of endocrine disturbances. In some instances, clearly recognizable endocrinopathies occur. More commonly, evidence of endocrine dysfunction consists only of laboratory abnormalities. Many of these are not associated with apparent disease.

Contracting muscle cells release K ions into their surrounding interstitial fluid, and some of these ions, in turn, enter venous plasma. Thereby, intense or exhaustive exercise may result in hyperkalemia and potentially dangerous cardiotoxicity. Training not only reduces hyperkalemia produced by exercise but in addition, highly conditioned, long-distance runners may show resting hypokalemia that is not caused by K deficiency. To examine the factors underlying these changes, dogs were studied before and after 6 wk of training induced by running on the treadmill. Resting serum [K] fell from 4.2 +/- 0.2 to 3.9 +/- 0.3 meq/liter (P less than 0.001), muscle intracellular [K] rose from 139 +/- 7 to 148 +/- 14 meq/liter (P less than 0.001), and directly measured muscle cell membrane potential (Em) in vivo rose from -92 +/- 5 to -103 +/- 5 mV (P less than 0.001). Before training, resting Em of isolated intercostal muscle in vitro was -87 +/- 5 mV, and after incubation in 10(-4) M ouabain, Em fell to -78 +/- 5 mV. After training, resting Em of intercostal muscle rose to -95 +/- 4, but fell to -62 +/- 4 mV during incubation in 10(-4) M ouabain. The measured value for the Em was not completely explained by the increased ratio of intracellular to extracellular [K] or by the potassium diffusion potential. Skeletal muscle sarcolemmal Na,K-ATPase activity (microM inorganic phosphate mg-1 protein h-1) increased from 0.189 +/- 0.028 to 0.500 +/- 0.076 (P less than 0.05) after training, whereas activities of Mg2+ -dependent ATPase and 5'nucleotidase did not change. In untrained dogs, exercise to the point of exhaustion elevated serum [K] from 4.4 +/- 0.5 to 6.0 +/- 1.0 meq/liter (P less than 0.05). In trained dogs, exhaustive exercise was associated with elevation of serum [K] from 3.8 +/- 0.3 to 4.2 +/- 0.4 (NS). The different response of serum [K] to exercise after training was not explainable by blood pH. Basal insulin levels rose from 7.0 +/- 0.7 microU/ml in the untrained dogs to 9.9 +/- 1.0 microU/ml (P less than 0.05) after training. Although insulin might have played a role in the acquired electrical hyperpolarization, the reduced exercise-produced hyperkalemia after training was not reversed by blockade of insulin release with somatostatin. Although the fundamental mechanisms underlying the cellular hyperpolarization were not resolved, our observations suggest that increased Na-K exchange across the sarcolemmal membrane, the increase of Na,K-ATPase activity and possibly increased electrogenicity of the sodium pump may all play a role in the changes induced by training.

A large variety of diseases encountered in clinical medicine are associated with symptoms suggestive of neuromuscular dysfunction. The myalgia of viral prodromes, the muscular cramps of hyponatremia and the weakness of potassium deficiency are well known examples. Although investigation of the myopathic components of these illnesses is fragmentary, those that have been examined show abnormalities compatible with subtle alterations of ion transport and, when sought out, histologic changes of muscle fiber injury or necrosis. Certain electrolyte and divalent ion deficiencies are likely to cause such findings, especially those related to potassium and phosphorus. The precise mechanism by which cellular injury occurs in electrolyte derangements has not been clearly elucidated. However, in potassium deficiency, for example, at least three potentially harmful effects occur: (1) abnormally low muscle blood flow with exercise; (2) suppression of glycogen synthesis and storage in muscle; (3) deranged ion transport. In consonance with these observations, it can be shown that once a muscle cell is injured, even when the injury is subclinical, superimposition of any stress that demands substantial expenditure of energy so as to deplete muscle energy stores can apparently precipitate frank rhabdomyolysis. The combined influence of exericise and fasting is a prime example. New information based upon observations in patients and limited experimental studies in animals suggests that skeletal muscle cells, under conditions of certain specific electrolyte derangement, show a common pattern of changes characterized by abnormal electrogenesis (abnormal resting transmembrane potential difference) and elevation of intracellular Na concentration. Such changes could well set the stage for irreversible cellular injury by another important mechanism. Thus, depression of the normally high concentration ratio of sodium ions between extracellular and intracellular fluids or depression of membrane potential could impair the normal exchange of extracellular sodium for intracellular calcium ions. Impressive evidence suggests that if calcium ions thereby attain a critical elevated value in the sarcoplasm, autodestructive proteases are activated that can destroy the cell. The field of interest concerning electrolyte and divalent ion disorders and their implication in rhabdomyolysis is newly emerging. In this paper, the current information on these disorders is reviewed. With license, considerable speculation will be inserted on those disorders not yet adequately examined.

Administration of nutrients after underfeeding is associated with a decline of serum inorganic phosphorus concentration (1). When nutrients are administered in excess and especially with inadequate quantities of phosphorus, hypophosphatemia is apt to become pronounced and is invariably associated with excretion of only trace quantities of phosphorus in the urine. The decline of serum phosphorus concentration and its simultaneous disappearance from the urine suggests that phosphorus is being taken up by cells. The site of phosphorus uptake with regard to specific tissues has not been determined. We have examined the effects of hypophosphatemia induced by hyperalimentation of the underfed dog. The results show that phosphorus deficiency appears rapidly in skeletal muscle during hyperalimentation. Significant deficiencies of total phosphorus content were also observed in bone, parathyroid glands and the liver. Phosphorus content did not change significantly in other tissues.

Potassium deficiency in chronic renal failure. That total body potassium depletion may occur in the presence of a normal or high serum K+ concentration in patients with end-stage renal disease is controversial. Since muscle K+ stores are the best single index of body potassium stores, we measured sketetal muscle water, Na+, K+ and Cl- content in volunteers, in patients with stable chronic renal failure (CRF) and in patients maintained on chronic hemodialysis (CHD). Skeletal muscle resting membrane potential (Em), measured in the anterior tibial compartment to facilitate calculation of intracellular electrolyte concentrations, was immediately followed by the procurement of muscle samples, obtained by percutaneous needle biopsy of the thigh. Chronic renal failure was associated with a high intracellular Na+ concentration; (20.4mEq/liter of intracellular water (ICW); normal = 11.4, P < 0.001), a low intracellular K+ concentration, (126mEq/liter of ICW; normal = 155, P < 0.001) and a low Em(-76.7 mv; normal =-86.7 mv, P < 0.001). After chronic hemodialysis for six weeks' duration, the intracellular electrolyte concentration returned to normal but the Em remained low (-75 mv). We conclude that K+ deficiency is common in advanced CRF despite a normal serum K+ concentration, and is corrected by hemodialysis.Déplétion en potassium dans l'insuffisance rénale chronique. La survenue éventuelle d'une déplétion en potassium en présence d'une concentration normale ou élevée de potassium plasmatique chez des malades atteints d'insuffisance rénale terminale est discutée. Du fait que le potassium musculaire est le meilleur index du potassium total nous avons mesuré les contenus du muscle squelettique en eau, Na+, K+ et Cl- chez des volontaires, des malades atteints d'insuffisance rénale chronique stable (CRF) et des malades soumis à l'hémodialyse itérative. Le potentiel de repos membranaire du muscle squelettique (Em) a été mesuré dans la loge tibiale antérieure afin de faciliter le calcul des concentrations intracellulaires. Les échantillons musculaires ont été prélevés immédiatement après, pour biopsie percutanée à l'aiguille de la cuisse. A l'insuffisance rénale chronique étaient associés une concentration intracellulaire élevée en Na+ (20,4mEq par litre d'eau intracellulaire (ICW): valeur normale: 11,4; P < 0,001); une concentration intracellulaire de K basse (126mEq par litre d'ICW, valeur normale: 155; P < 0,001) et une baisse de Em (-76,7 mv, valeur normale: -86,7 mv; P < 0,001). Après six semaines d'hemodialyse chronique les concentrations sont revenues à la normale mais Em est resté bas (-75 mv). Nous concluons que la déplétion en K+ est fréquente dans l'insuffisance rénale chronique avancée, en dépit d'une kaliémie normale, et qu'elle est corrigée par l'hémodialyse.

The effect of intravenously administered distilled water was examined alone and during alkalization in a patient with gross hematuria associated with the sickle cell trait. On each of 4 occasions hematuria ceased promptly after the infusion of distilled water. Bicarbonate therapy also consistently decreased hematuria.In vitro studies on erythrocytes from another patient with sickle ceil trait and hematuria demonstrated that slight increases in urinary pH similar to those that occur in the urine during alkalization can reverse or prevent erythrocyte sickling in the sickle cell trait.If patients with the sickle cell trait are hydrated adequately and have a good rate of urine flow distilled water can be given intravenously with virtually no danger of acute tubular necrosis secondary to erythrocyte hemolysis.

Publisher Summary This chapter describes the two mechanisms, blood flow and carbohydrate metabolism. Potassium (K) very likely exerts a regulatory influence on muscle blood flow during exercise. The resulting increase of muscle blood flow subserves the delivery of chemical substrates for contraction and facilitates the removal of heat and metabolites from the working muscle cells. A second metabolic effect relates to the role of K ions in carbohydrate metabolism, especially that of glycogen synthesis. As skeletal muscle occupies such a large proportion of total body mass in health, several investigators examined the role of K on carbohydrate metabolism in that tissue. The observation that venous K concentration was considerably less than the interstitial fluid K concentration represents an effect of mixing between interstitial fluid and capillary fluid and the reaccumulation of K ions from interstitial fluid back into muscle cells. These observations suggested that K release from contracting muscle cells is probably not simply a biological accident but rather represents a physiological mechanism contributing toward regulation of muscle blood flow during exercise.

The resting transmembrane potential of skeletal muscle (E(m)) is thought to be a function of the ratio of intracellular to extracellular potassium concentration ([K(i)]/[K(o)]). In potassium deficiency, the fall of [K(i)] is proportionately less than the fall of [K(o)], thus theoretically predicting a rise of E(m). To examine this theory and to characterize E(m) in kaliopenic myopathy, muscle composition and E(m) were measured during moderate (n = 5) and severe (n = 11) K deficiency in the dog and compared with measurements in the severely K-deficient rat (n = 10). Mean measured E(m) rose during moderate K deficiency in four of five dogs (-85.4 to -94.6 mV) and during severe K deficiency in the rat (-89.1 to -94.9 mV). Both values closely approximated the increase in E(m) predicted by the Goldman equation. In contrast, during severe K deficiency in the dog, a significant decline (P < 0.001) of mean E(m) to -55 mV was observed.Since skeletal myopathy and paralysis do not occur in the rat as a consequence of K deficiency, the observation that E(m) falls as paralysis occurs in the unexercised dog suggests that alteration of muscle membrane function may play a role in kaliopenic myopathy. Such an event could explain the ease with which frank muscle necrosis may be induced by exercise in the K-deficient dog.

Hypocalcemia is a well-recognized biochemical sign of major rhabdomyolysis. Early observations by Meroney and Herndon in soldiers with massive injury and rhabdomyolysis causing acute renal failure ...

We investigated the possible role of potassium deficiency, a recognized cause of myopathy, in the pathogenesis of experimental acute alcoholic myopathy (EAM) in the rat. Alcohol-treated animals receiving the same dietary potassium as controls developed mild hypokalemia; however, muscle potassium was preserved or elevated even in the presence of scattered muscle fiber necrosis. Increasing dietary potassium raised serum potassium but did not prevent EAM. These data indicate that hypokalemia in EAM is due to potassium redistribution between intra- and extracellular compartments rather than potassium deficiency, and confirm clinical observations that alcohol-induced muscle injury occurs independently of potassium deficiency.

The deleterious effects of ethanol on a variety of tissues may result largely from altered ion permeabilities and transport. Clinically relevant ethanol concentrations in blood increase the sodium permeability of the plasma membrane and depress active sodium transport by suppressing Na, K-ATPase activity. As a result, intracellular sodium concentration increases. The total tissue content of calcium increases. Important transport mechanisms deranged by ethanol probably include those regulating calcium-sodium and hydrogen-sodium exchange at the plasma membrane and calcium uptake by the sarcoplasmic reticulum. A modest decline in magnesium content of muscle occurs after chronic exposure to ethanol. This also has been associated with accumulation of calcium. After days to weeks of sustained ethanol intake, sodium pump activity, active sodium transport and tissue oxygen consumption increase. The cell membrane potential, initially lowered by alcohol, increases to supraphysiological levels. This is likely an electrogenic effect of increased sodium transport in response to a sodium leak. Eventually the earlier derangements in tissue composition, including retention of sodium, chloride, and calcium, and reductions in magnesium, potassium, and phosphate, slowly undergo correction. This biphasic response of injury and adaptation appears to depend upon adequate nutrition and the absence of other factors that can adversely affect cell function. That the Na, K-ATPase activity and oxygen consumption remain elevated suggests an ongoing sodium leak of the sarcolemmal membrane. Chronic ethanol-induced cell necrosis may be related to the increased intracellular calcium that accompanies the increase in sodium permeability. Conceivably, critically elevated concentrations of calcium in the cytoplasm may activate autolytic enzymes that in turn may be responsible for structural damage to the cell.