James P. Knochel

On the mechanism of rhabdomyolysis in potassium depletion

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.

Neuromuscular manifestations of electrolyte disorders

Abstract 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.

Epidemic classical heat stroke: Clinical characteristics and course of 28 patients

Patients with classical heat stroke are different in many ways from those with exertional injury; contrasts included difference in demographic factors, prior general health, in-hospital complications and laboratory abnormalities (lactate, liver enzymes, pH, electrolytes). Severe hyperkalemia, acute renal failure, rhabdomyolysis and disseminated intravascular coagulation often dominate the course of patients with exertional heat stroke but are uncommon in those with classical heat stroke (Table 4). While lactic acidosis is the rule in exertional injury, it is somewhat unusual in patients with classical heat stroke and when above 3 mmoles/L predicts a poor outcome or death. In spite of the advanced age and multiple medical problems of the patients with classical heat stroke, careful attention to early and aggressive cooling and scrutiny for potential complications can result in salvage of most patients.

Hypophosphatemia and rhabdomyolysis

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 <0.001). CPK activity rose from 66+/-357 to 695+/-1,288 IU/liter (P <0.001). Muscle phosphorus content fell further to 21.1+/-7.7 mmol/dg fat-free dry solids (P <0.001). Muscle Na and Cl contents became higher (P <0.01). Sections of gracilis muscle showed frank rhabdomyolysis.6 of the 23 phosphorus- and calorie-deprived dogs were also given 140 kal/kg per day but in addition, each received 147 mmol of elemental phosphorus. These dogs consumed their diet avidly and displayed no symptoms. They did not become hypophosphatemic, their CPK remained normal, and derangements of cellular Na, Cl, and H(2)O were rapidly corrected. The gracilis muscle appeared normal histologically in these animals. These data suggest that a subclinical myopathy may set the stage for rhabdomyolysis if acute, severe hypophosphatemia is superimposed. Neither acute hypophosphatemia nor rhabdomyolysis occur if abundant phosphorus is provided during hyperalimentation.

Hyperglucagonemia of Renal Failure

Elevation of plasma glucagon concentration has been observed in starvation and illnesses associated with increased catabolism such as diabetes mellitus and severe infections. Thus, we examined plasma glucose, immunoreactive insulin (IRI, microunits per milliliter) and glucagon (IRG, picograms per milliliter) responses to a beef meal (1 g/kg body wt) and intravenous glucose (1.5 g/min for 45 min) in patients with chronic renal failure (CRF). After the beef meal (n = 6), plasma glucose did not change, IRI rose from 10.1+/-1.2 to 16.3+/-1.1 (P < 0.01), and IRG rose from a fasting value of 225+/-26 to 321+/-40 (P < 0.01) by 90 min (mean+/-SEM). Intravenous infusion of glucose in CRF patients resulted in significant elevations and prolonged disappearance of plasma glucose and insulin when compared to control subjects (P < 0.01). Glucose infusion failed to suppress elevated plasma glucagon concentrations to normal levels.6 wk of chronic hemodialysis in five patients resulted in normal plasma glucose and insulin responses to the same intravenous glucose load. In contrast, plasma glucagon concentration remained unchanged after hemodialysis and there was no correlation of plasma glucagon levels with carbohydrate intolerance.

Reversible changes of the muscle cell in experimental phosphorus deficiency.

Both animal and human studies suggest that either phosphorus depletion or hypophosphatemia might have an adverse effect on muscle function and composition. Recently a possible deleterious effect was noted in patients with chronic alcoholism. In this unexplained disease, a variety of toxic and nutritional disturbances could affect the muscle cell, thus obscuring the precise role of phosphorus. Accordingly, we examined eight conditioned dogs for the possibility that phosphorus deficiency per se might induce an abnormally low resting transmembrane electrical potential difference (Em) and alter the composition of the muscle cell. Eight conditioned dogs were fed a synthetic phosphorus-deficient but otherwise nutritionally adequate diet plus aluminum carbonate gel for a 28-day period followed by the same diet with phosphorus supplementation for an additional 28 days. Sequential measurements of Em and muscle composition were made at 0 and 28 days during depletion and again after phosphorus repletion. Serum inorganic phosphorus concentration (mg/100 ml) fell from 4.2 +/- 0.6 on day 0 t0 1.7 +/- 0.1 on day 28. Total muscle phosphorus content (mmol/100 g fat-free dry wt [FFDW]) fell from 28.5 +/- 1.8 on day 0 to 22.4 +/- 2.1 on day 28. During phosphorus depletion, average Em (-mV) fell from 92.6 +/- 4.2 to 77.9 +/- 4.1 mV (P less than 0.001). Muscle Na+ and Cl- content (meq/100 g FFDW) rose respectively from 11.8 +/- 3.2 to 17.2 +/- 2.8 (P less than 0.01) and from 8.4 +/- 1.4 to 12.7 +/- 2.0 (P less than 0.001). Total muscle water content rose from 331 +/- 12 to 353 +/- 20 g/100 FFDW (P less than 0.05). A slight, but nevertheless, significant drop in muscle potassium content, 43.7 +/- 2.0-39.7 +/- 2.2 meq/100 g FFDW (P less than 0.05) was also noted. After 4 wk of phosphorus repletion, all of these measurements returned toward control values. We conclude that moderate phosphorus depletion can induce reversible changes in skeletal muscle composition and transmembrane potential in the dog, and it apparently occurs independently of profound hypophosphatemia.

The renal, cardiovascular, hematologic and serum electrolyte abnormalities of heat stroke

Abstract 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.

Diuretic-induced hypokalemia.

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.

Resting Skeletal Muscle Membrane Potential as an Index of Uremic Toxicity: A PROPOSED NEW METHOD TO ASSESS ADEQUACY OF HEMODIALYSIS

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.

Acute renal failure due to heat injury: An analysis of ten cases associated with a high incidence of myoglobinuria

Abstract 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.