EDITORIALS
use of desferrioxamine given orally and parenterally to chelate excess iron along with other supportive measures has been responsible for a dramatic decrease in mortality from the 45 percent reported by Aldrich in 19585 to none in the present series of 26 patients. The success of treatment places greater responsibility on the health support facilities 'that are involved in making this medical care available with little loss in time after poisoning has occurred. The Poison Center in San Diego, for example, has provided a highly effective interphase between the lay public encountering such accidents and medical care facilities. One can anticipate an expanding role of such information facilities in answering the emergency health questions of the population at large. However, even in the best organized community, it is to be expected that early treatment of iron poisoning will not always occur, and that death will not always be avoided. The problem of prevention remains an important consideration. A reduction in the amount of iron prescribed for pregnant women (1 to 2 15 mg tablets per day taken apart from meals is ample to prevent iron deficiency), and the use of bottle tops which a child cannot easily open is also helpful. But why do people need to keep so much potentially dangerous iron in their bathroom cabinets? It must be the consequence of an iron depleted population, of the 10 to 20 percent of menstruating women with laboratory evidence of iron deficiency and the even greater proportion of pregnant women who would show iron deficiency if not given prophylactic iron therapy. But why does the human race have so much trouble with iron deficiency? External iron exchange in man is more limited than in other mammalian species, amounting to about 1 mg per day in men and 1.4 mg in women. The remarkable conservation of iron in itself may be a genetic adaptation to a limited iron supply and to the low availability of what iron is present.6 Recent studies of food iron availability indicate a poor absorption of vegetal iron as compared with that of meat. It has been suggested that iron balance may have been better in Homo sapiens in the days of prehistory when man lived largely off of migrating herds, that the present day diet derived largely from the cultivation of grain is a highly artificial one. Other factors such as decreased caloric consumption and practices of food preparation also contribute to reducing iron
312
OCTOBER 1976 * 125 * 4
intake. The establishment or reestablishment of an acceptable iron intake would be the definitive step to take in dealing with iron poisoning by removing the need for iron therapy. Those who express concern that fortification of food will increase the problem of chronic iron overload must give equal consideration to the deaths that occur from iron deficiency, from the complications of transfusions administered to anemic individuals with iron deficiency and from acute iron poisoning. It helps that the prognosis of both acute and chronic iron toxicity is improving through better treatment, but the underlying need for more adequate iron balance remains. CLEMENT A. FINCH, MD Professor and Head Division of Hematology Department of Medicine University of Washington School of Medicine, Seattle
REFERENCES 1. Whitten CF, Chen YC, Gibson GW: Studies in acute iron poisoning-il1. The hemodynamic alterations in acute experimental iron poisoning. Pediat Res 2:479-485, 1968 2. Reissmann KR, Coleman TJ: Acute intestinal iron intoxication-II. Metabolic, respiratory, and circulatory effects of absorbed iron salts. Blood 10:46-51, 1955 3. Oki K, Yoshioka S, Hayashi K, et al: Mitochondrial changes induced by iron absorption in the duodenal absorptive cells of rats. J Cell Biol 24:328-332, 1965 4. Cooper HA, Ekblad MD, Fairbanks VF: Emergency semiquantitative estimation of plasma iron concentration in acute iron poisoning. Am J Dis Child 122:19-21, 1971 5. Aldrich RA: Acute iron toxicity, In Wallerstein RO, Mettier SR (Eds): Iron in Clinical Medicine. Berkeley, University of California Press, 1958, pp 93-104 6. Cook JD, Finch CA: Iron nutrition (Medical Progress). West J Med 122:474-481, Jun 1975
Rhabdomyolysis DURING THE WINTER OF 1975-76, at least six cases of a "flu-like" illness with evident myositis were observed in the Dallas area. All showed classical evidence of rhabdomyolysis and myoglobinuria as noted in the patient presented in the Medical Staff Conference in this issue. In several of these patients, there was acute renal failure and it is noteworthy that these were the same patients in whom pronounced vomiting, diarrhea and volume depletion were seen. Thus, in our cases as well as in those previously cited' 2 volume depletion appeared to be the factor determining whether or not acute renal failure would supervene in the wake of myoglobinuria. Volume depletion, by increasing the concentration of the urine, would increase the concentration and presumably the nephrotoxicity of the heme pigment. Furthermore, in most patients who are volume depleted and catabolic, urine is intensely
EDITORIALS
acid. In this situation, urine of low pH could have at least two harmful effects. First, it could potentiate the nephrotoxicity of myoglobin.3 Second, in patients with muscle injury, uric acid commonly is overproduced. Acid and concentrated urine would also favor uric acid precipitation.4 Such cases of myoglobinuric acute renal failure have been observed sporadically in dialysis centers for many years. Before we recognized that rhabdomyolysis was a common disorder, the cause of acute renal failure in such cases was usually ascribed to "dehydration," unrecognized shock and the like. Besides occasional cases of "flu," I have observed one patient with typical type A infectious hepatitis in whom there was evidence of significant rhabdomyolysis. Findings on studies of a needle biopsy specimen from a tender muscle disclosed patchy fiber necrosis and lymphocytic infiltration. Based upon the ever-increasing number of clinical entities recognized to be associated with rhabdomyolysis (see Table 1 in the Medical Staff Conference), it would not seem surprising that nearly all viral illnesses with a myalgic prodrome will at least on occasion be associated with frank rhabdomyolysis and, when severe, acute tubular necrosis. In persons in whom acute rhabdomyolysis occurs, serum creatine phosphokinase (CPK) activity usually peaks within 12 to 24 hours and thereafter declines by approximately half each succeeding 48 hours.5 In contrast, in this patient CPK activity progressively rose. This suggests ongoing necrosis and appropriately there was concern about vascular compression in the lower extremities. In patients with rhabdomyolysis affecting the legs, the initial heat and swelling sometimes subside but then become notably accentuated on the second or third day. Timely recognition of this second-wave phenomenon is critical. In these cases, a fasciotomy can save a muscle, an extremity or a nerve. Injured skeletal muscle behaves in a fashion resembling that of a subdural hematoma. As its intracellular contents decompose, the muscle accumulates salt and water. If this occurs within a tight fascial compartment, secondary ischemic necrosis can occur. To explain this phenomenon, one can envision a process whereby intracellular substances such as proteins or blood decompose into smaller fragments. Having osmotic activity, they would promote movement of water and salt from the circulation in sufficient volume to induce a pronounced elevation of hydrostatic pressure. Quantitatively, the elevated os-
motic activity in a semirigid fascial compartment required to produce such an effect would be very small, that is, less than 10 mOsm per kg, since the hydrostatic pressure generated by each milliosmol is 17 mm of mercury. In some patients with this phenomenon, the erroneous diagnosis of thrombophlebitis is made. Homan's sign can be positive and many other features of phlebitis can occur.* Mistaken administration of anticoagulants could well intensify hemorrhage into the injured muscle. It is also notable that despite apparently extensive muscle necrosis, CPK activity in this patient was only modestly elevated. In young, healthy men in whom muscle necrosis develops, CPK activities in excess of 100,000 IU per ml commonly are seen.6 In contrast, extensive rhabdomyolysis in patients whose physical condition is poor or those with malnutrition may be associated with only modest elevations of CPK activity. Especially prominent examples are patients with alcoholic rhabdomyolysis. This is probably related to decreased CPK content of muscle.7 The only exception I raise to Dr. Humphreys' elegant discussion of rhabdomyolysis concerns the question of whether furosemide should be given in hope of ameliorating or preventing acute renal failure in patients with myoglobinuria. In contrast to Dr. Humphreys' recommendation, it is my opinion that furosemide may well be helpful. By interfering with sodium reabsorption in the ascending limb, it impairs the concentrating mechanism. By this means, the concentration of myoglobin in the urine would be less and accordingly there should be less nephrotoxicity. Second, by interfering with sodium reabsorption, renal tissue oxygen tension should increase.8 This also should theoretically decrease the potential nephrotoxicity of myoglobin.9 Of course, mannitol may exert a similar effect provided it reaches the nephron.8 In practice, one of the most important maneuvers in the management of extensive rhabdomyolysis is to replenish extracellular fluid deficits immediately since sizable quantities of fluid may be lost into injured muscle cells. In this sense, massive rhabdomyolysis resembles a severe burn. In some patients, up to 12 liters of saline may be required in the first 24 hours to maintain adequate blood pressure and satisfactury urine output.'0 Given a patient with myoglobinuria in *We have measured serum CPK activity in several patients with thrombophlebitis. So far, it has been normal.
severe
THE WESTERN JOURNAL OF MEDICINE
313
EDITORIALS
whom acute tubular necrosis has not yet developed, I would also favor the use of mannitol and furosemide simultaneously. On the other hand, I have become wary of using bicarbonate in these patients for two reasons. First, under such conditions, even large doses of sodium bicarbonate generally fail to alkalinize the urine. Second, systemic alkalinization with bicarbonate could conceivably favor deposition of calcium salts in injured muscle. At any rate, induction of a diuresis with mannitol and furosemide will usually serve to dilute the urine sufficiently to bring its pH above the critical value at which myoglobin nephrotoxicity should constitute a lesser problem. Rhabdomyolysis and myoglobinuria were once thought to be medical curiosities. Automation of muscle enzyme tests have shown unquestionably that rhabdomyolysis is extremely common, and in most large hospitals it has become recognized as one of the most common causes of acute renal failure. For this reason, it behooves all primary care physicians to be alert for this potentially serious disease. Early recognition of rhabdomyolysis is critical since the measures outlined by
314
OCTOBER 1976 * 125 * 4
Dr. Humphreys in the Medical Staff Conference may be lifesaving in these patients. JAMES P. KNOCHEL, MD Associate Chief of Staff for Research and Chief, Renal Section Veterans Administration Hospital Professor of Internal Medicine University of Texas Southwestern Medical School Dallas REFERENCES Minow RA, Gorbach S, Johnson BL Jr, et al: Myoglobinassociated with influenza A infection. Ann Intern Med 80: 1974 Morgensen JL: Myoglobinuria and renal failure associated influenza. Ann Intern Med 80:362, 1974 Bywaters EGL, Stead JK: The production of renal failure following injection of solutions containing myohaemoglobin. Quart J Exp Physiol 33:53, 1944 4. Knochel JP, Dotin LN, Hamburger RJ: Heat stress, exercise and muscle injury: Effects of urate metabolism and renal function. Ann Intern Med 81:321, 1974 5. Dawson DM, Alper CA, Seidman J, et al: Measurement of serum enzyme turnover rates. Ann Intern Med 70:799, 1969 6. Demos MA, Gitin EL, Kagen LJ: Exercise myoglobinemia and acute exertional rhabdomyolysis. Arch Intern Med 134:669, 1974 7. Suominen H, Forsberg S, Heikkinen F, et al: Enzyme activities and glycogen concentration in skeletal muscle in alcoholism. Acta Med Scand 196:199, 1974 8. Washington JA II, Holland JM: Urine oxygen tension: Effect of osmotic and saline diuresis and of ethacrynic acid. Am J Physiol 210:243, 1966 9. Braun SR, Weiss FR, Keller Al, et al: Evaluation of the renal toxicity of heme proteins and their derivatives: A role in the genesis of acute tubule necrosis. J Exp Med 131:443, 1970 10. Kendrick WC, Hull AR, Knochel JP: Rhabdomyolysis and shock following intravenous amphetamine administration. Clin Res 24:37A, 1976 (Accepted for publication, Ann Intern Med)
1. uria 359, 2. with 3.
use of desferrioxamine given orally and parenterally to chelate excess iron along with other supportive measures has been responsible for a dramatic decrease in mortality from the 45 percent reported by Aldrich in 19585 to none in the present series of 26 patients. The success of treatment places greater responsibility on the health support facilities 'that are involved in making this medical care available with little loss in time after poisoning has occurred. The Poison Center in San Diego, for example, has provided a highly effective interphase between the lay public encountering such accidents and medical care facilities. One can anticipate an expanding role of such information facilities in answering the emergency health questions of the population at large. However, even in the best organized community, it is to be expected that early treatment of iron poisoning will not always occur, and that death will not always be avoided. The problem of prevention remains an important consideration. A reduction in the amount of iron prescribed for pregnant women (1 to 2 15 mg tablets per day taken apart from meals is ample to prevent iron deficiency), and the use of bottle tops which a child cannot easily open is also helpful. But why do people need to keep so much potentially dangerous iron in their bathroom cabinets? It must be the consequence of an iron depleted population, of the 10 to 20 percent of menstruating women with laboratory evidence of iron deficiency and the even greater proportion of pregnant women who would show iron deficiency if not given prophylactic iron therapy. But why does the human race have so much trouble with iron deficiency? External iron exchange in man is more limited than in other mammalian species, amounting to about 1 mg per day in men and 1.4 mg in women. The remarkable conservation of iron in itself may be a genetic adaptation to a limited iron supply and to the low availability of what iron is present.6 Recent studies of food iron availability indicate a poor absorption of vegetal iron as compared with that of meat. It has been suggested that iron balance may have been better in Homo sapiens in the days of prehistory when man lived largely off of migrating herds, that the present day diet derived largely from the cultivation of grain is a highly artificial one. Other factors such as decreased caloric consumption and practices of food preparation also contribute to reducing iron
312
OCTOBER 1976 * 125 * 4
intake. The establishment or reestablishment of an acceptable iron intake would be the definitive step to take in dealing with iron poisoning by removing the need for iron therapy. Those who express concern that fortification of food will increase the problem of chronic iron overload must give equal consideration to the deaths that occur from iron deficiency, from the complications of transfusions administered to anemic individuals with iron deficiency and from acute iron poisoning. It helps that the prognosis of both acute and chronic iron toxicity is improving through better treatment, but the underlying need for more adequate iron balance remains. CLEMENT A. FINCH, MD Professor and Head Division of Hematology Department of Medicine University of Washington School of Medicine, Seattle
REFERENCES 1. Whitten CF, Chen YC, Gibson GW: Studies in acute iron poisoning-il1. The hemodynamic alterations in acute experimental iron poisoning. Pediat Res 2:479-485, 1968 2. Reissmann KR, Coleman TJ: Acute intestinal iron intoxication-II. Metabolic, respiratory, and circulatory effects of absorbed iron salts. Blood 10:46-51, 1955 3. Oki K, Yoshioka S, Hayashi K, et al: Mitochondrial changes induced by iron absorption in the duodenal absorptive cells of rats. J Cell Biol 24:328-332, 1965 4. Cooper HA, Ekblad MD, Fairbanks VF: Emergency semiquantitative estimation of plasma iron concentration in acute iron poisoning. Am J Dis Child 122:19-21, 1971 5. Aldrich RA: Acute iron toxicity, In Wallerstein RO, Mettier SR (Eds): Iron in Clinical Medicine. Berkeley, University of California Press, 1958, pp 93-104 6. Cook JD, Finch CA: Iron nutrition (Medical Progress). West J Med 122:474-481, Jun 1975
Rhabdomyolysis DURING THE WINTER OF 1975-76, at least six cases of a "flu-like" illness with evident myositis were observed in the Dallas area. All showed classical evidence of rhabdomyolysis and myoglobinuria as noted in the patient presented in the Medical Staff Conference in this issue. In several of these patients, there was acute renal failure and it is noteworthy that these were the same patients in whom pronounced vomiting, diarrhea and volume depletion were seen. Thus, in our cases as well as in those previously cited' 2 volume depletion appeared to be the factor determining whether or not acute renal failure would supervene in the wake of myoglobinuria. Volume depletion, by increasing the concentration of the urine, would increase the concentration and presumably the nephrotoxicity of the heme pigment. Furthermore, in most patients who are volume depleted and catabolic, urine is intensely
EDITORIALS
acid. In this situation, urine of low pH could have at least two harmful effects. First, it could potentiate the nephrotoxicity of myoglobin.3 Second, in patients with muscle injury, uric acid commonly is overproduced. Acid and concentrated urine would also favor uric acid precipitation.4 Such cases of myoglobinuric acute renal failure have been observed sporadically in dialysis centers for many years. Before we recognized that rhabdomyolysis was a common disorder, the cause of acute renal failure in such cases was usually ascribed to "dehydration," unrecognized shock and the like. Besides occasional cases of "flu," I have observed one patient with typical type A infectious hepatitis in whom there was evidence of significant rhabdomyolysis. Findings on studies of a needle biopsy specimen from a tender muscle disclosed patchy fiber necrosis and lymphocytic infiltration. Based upon the ever-increasing number of clinical entities recognized to be associated with rhabdomyolysis (see Table 1 in the Medical Staff Conference), it would not seem surprising that nearly all viral illnesses with a myalgic prodrome will at least on occasion be associated with frank rhabdomyolysis and, when severe, acute tubular necrosis. In persons in whom acute rhabdomyolysis occurs, serum creatine phosphokinase (CPK) activity usually peaks within 12 to 24 hours and thereafter declines by approximately half each succeeding 48 hours.5 In contrast, in this patient CPK activity progressively rose. This suggests ongoing necrosis and appropriately there was concern about vascular compression in the lower extremities. In patients with rhabdomyolysis affecting the legs, the initial heat and swelling sometimes subside but then become notably accentuated on the second or third day. Timely recognition of this second-wave phenomenon is critical. In these cases, a fasciotomy can save a muscle, an extremity or a nerve. Injured skeletal muscle behaves in a fashion resembling that of a subdural hematoma. As its intracellular contents decompose, the muscle accumulates salt and water. If this occurs within a tight fascial compartment, secondary ischemic necrosis can occur. To explain this phenomenon, one can envision a process whereby intracellular substances such as proteins or blood decompose into smaller fragments. Having osmotic activity, they would promote movement of water and salt from the circulation in sufficient volume to induce a pronounced elevation of hydrostatic pressure. Quantitatively, the elevated os-
motic activity in a semirigid fascial compartment required to produce such an effect would be very small, that is, less than 10 mOsm per kg, since the hydrostatic pressure generated by each milliosmol is 17 mm of mercury. In some patients with this phenomenon, the erroneous diagnosis of thrombophlebitis is made. Homan's sign can be positive and many other features of phlebitis can occur.* Mistaken administration of anticoagulants could well intensify hemorrhage into the injured muscle. It is also notable that despite apparently extensive muscle necrosis, CPK activity in this patient was only modestly elevated. In young, healthy men in whom muscle necrosis develops, CPK activities in excess of 100,000 IU per ml commonly are seen.6 In contrast, extensive rhabdomyolysis in patients whose physical condition is poor or those with malnutrition may be associated with only modest elevations of CPK activity. Especially prominent examples are patients with alcoholic rhabdomyolysis. This is probably related to decreased CPK content of muscle.7 The only exception I raise to Dr. Humphreys' elegant discussion of rhabdomyolysis concerns the question of whether furosemide should be given in hope of ameliorating or preventing acute renal failure in patients with myoglobinuria. In contrast to Dr. Humphreys' recommendation, it is my opinion that furosemide may well be helpful. By interfering with sodium reabsorption in the ascending limb, it impairs the concentrating mechanism. By this means, the concentration of myoglobin in the urine would be less and accordingly there should be less nephrotoxicity. Second, by interfering with sodium reabsorption, renal tissue oxygen tension should increase.8 This also should theoretically decrease the potential nephrotoxicity of myoglobin.9 Of course, mannitol may exert a similar effect provided it reaches the nephron.8 In practice, one of the most important maneuvers in the management of extensive rhabdomyolysis is to replenish extracellular fluid deficits immediately since sizable quantities of fluid may be lost into injured muscle cells. In this sense, massive rhabdomyolysis resembles a severe burn. In some patients, up to 12 liters of saline may be required in the first 24 hours to maintain adequate blood pressure and satisfactury urine output.'0 Given a patient with myoglobinuria in *We have measured serum CPK activity in several patients with thrombophlebitis. So far, it has been normal.
severe
THE WESTERN JOURNAL OF MEDICINE
313
EDITORIALS
whom acute tubular necrosis has not yet developed, I would also favor the use of mannitol and furosemide simultaneously. On the other hand, I have become wary of using bicarbonate in these patients for two reasons. First, under such conditions, even large doses of sodium bicarbonate generally fail to alkalinize the urine. Second, systemic alkalinization with bicarbonate could conceivably favor deposition of calcium salts in injured muscle. At any rate, induction of a diuresis with mannitol and furosemide will usually serve to dilute the urine sufficiently to bring its pH above the critical value at which myoglobin nephrotoxicity should constitute a lesser problem. Rhabdomyolysis and myoglobinuria were once thought to be medical curiosities. Automation of muscle enzyme tests have shown unquestionably that rhabdomyolysis is extremely common, and in most large hospitals it has become recognized as one of the most common causes of acute renal failure. For this reason, it behooves all primary care physicians to be alert for this potentially serious disease. Early recognition of rhabdomyolysis is critical since the measures outlined by
314
OCTOBER 1976 * 125 * 4
Dr. Humphreys in the Medical Staff Conference may be lifesaving in these patients. JAMES P. KNOCHEL, MD Associate Chief of Staff for Research and Chief, Renal Section Veterans Administration Hospital Professor of Internal Medicine University of Texas Southwestern Medical School Dallas REFERENCES Minow RA, Gorbach S, Johnson BL Jr, et al: Myoglobinassociated with influenza A infection. Ann Intern Med 80: 1974 Morgensen JL: Myoglobinuria and renal failure associated influenza. Ann Intern Med 80:362, 1974 Bywaters EGL, Stead JK: The production of renal failure following injection of solutions containing myohaemoglobin. Quart J Exp Physiol 33:53, 1944 4. Knochel JP, Dotin LN, Hamburger RJ: Heat stress, exercise and muscle injury: Effects of urate metabolism and renal function. Ann Intern Med 81:321, 1974 5. Dawson DM, Alper CA, Seidman J, et al: Measurement of serum enzyme turnover rates. Ann Intern Med 70:799, 1969 6. Demos MA, Gitin EL, Kagen LJ: Exercise myoglobinemia and acute exertional rhabdomyolysis. Arch Intern Med 134:669, 1974 7. Suominen H, Forsberg S, Heikkinen F, et al: Enzyme activities and glycogen concentration in skeletal muscle in alcoholism. Acta Med Scand 196:199, 1974 8. Washington JA II, Holland JM: Urine oxygen tension: Effect of osmotic and saline diuresis and of ethacrynic acid. Am J Physiol 210:243, 1966 9. Braun SR, Weiss FR, Keller Al, et al: Evaluation of the renal toxicity of heme proteins and their derivatives: A role in the genesis of acute tubule necrosis. J Exp Med 131:443, 1970 10. Kendrick WC, Hull AR, Knochel JP: Rhabdomyolysis and shock following intravenous amphetamine administration. Clin Res 24:37A, 1976 (Accepted for publication, Ann Intern Med)
1. uria 359, 2. with 3.
