EMERGENCY CASE REPORT
Rhabdomyolysis and Acute Renal Failure David Ralph, MD Sacramento, Cafifornia
Three cases of rh abdomyolysis, two with acute renal failure, seen in a short period of time in an emergency department illustrate this increasingly recognized entity. Myoglobinuria may result from muscle trauma, ischemia, metabolic causes, druginduced injury or intrinsic muscle disorders. The diagnosis is easily made by the presence of an elevated creatine phosphokinase, positive orthotoluidine in the urine and pigmented urine casts. Failure to diagnose rhabdomyolysis early will result in increased morbidity and mortality from subsequent hyperkalemia, acute renal failure and hypocalcemia. These three cases illustrate the difficulty in predicting the eventual degree of renal failure from the initial assessment. Ralph D: Rhabdomyolysis and acute renal failure. JACEP 7:103-106, March, 1978. kidney failure, rhabdomyolysis; myoglobinuria.
INTRODUCTION Rhabdomyolysis is the lysis of muscle tissue from a traumatic, toxic or metabolic insult. Myoglobinuria results when enough myoglobin is released from damaged muscle to be excreted into the urine. Several recent papers 1-3 have stressed t h a t rhabdomyolysis, with or without associated acute r e n a l failure, is becoming more commonly recognized. The diagnosis can be easily made i n the emergency d e p a r t m e n t if the physician is aware of the situations predisposing to muscle necrosis. Often, such necrosis occurs in the absence of major t r a u m a . Three cases seen in our emergency d e p a r t m e n t w i t h i n a few months illustrate several aspects of this disorder.
CASE REPORTS C a s e N u m b e r One. A 20-year-old man, a weekend heroin user, fell asleep on his back on a pool table after injecting heroin. His lower legs dangled over the edge of the table. When he awoke 15 hours later both legs were n u m b and he came to the emergency department. The results of physical exam were n o r m a l except for the finding of bilateral sciatic and femoral nerve palsies. The legs were somewhat cool below the knees but distal arterial pulses were intact and there was no swelling. Both thighs were mildly tender but calves were not. There was no evidence of volume depletion. Original laboratory studies showed a hematocrit r e a d i n g of 51% and potassium 4.8 mEq/liter. Since initial a t t e n t i o n was focused on the neurological dysfunction, an emergency myelogram was obtained and was normal. However, the pat i e n t was unable to void after the myelogram. A Foley catheter was passed, yielding 100 cc of dark u r i n e t h a t was + 3 orthotoluidine-positive (Hematest for occult blood). A n occasional pigmented cast was noted b u t no red blood cells. BeCause of the pigmented urine, further studies were obtained t h a t showed a blood urea n i t r o g e n (BUN) of 49 mg/100 ml, c r e a t i n i n e clearance, 2.5 gm/24 hrs; Presented at the University Association for Emergency Medicine Annual Meeting in Kansas City, Missouri, May, 1977. Address for reprints: David Ralph, MD, Assistant Professor, Section of EmergencyMedicine, Department of Internal Medicine, UCD-SacramentoMedical Center, 2315 Stockton Boulevard, Sacramento, California 95817. 7:3 (Mar) 1978
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creatine phosphokinase (CPK), 1600 units ( n o r m a l < 200); total lactic dehydrogenase (LDH), 2055 (normal < 400); s e r u m g l u t a m i c - o x a l o a c e t i c t r a n s a m i n a s e (SGOT), 1390 (normal < 90); uric acid, 15.3; and calcium, 7.5 (normal 8.5 to 10.5)with n o r m a l albumin. E l e c t r o c a r d i o g r a p h (EKG) was normal. An orthopedic consultant found no evidence of a muscle comp a r t m e n t syndrome. A c e n t r a l venous pressure (CVP) line m e a s u r e d a pressure of 3 cm of w a t e r which rose to 10 after infusion of 37.5 gm of mannitol. Furosemide was injected i n t r a venously (IV) in a dose of 100 mg but no diuresis ensued. The p a t i e n t was a d m i t t e d to the hospital a n d had a prolonged hospital course (Table 1). He r e m a i n e d oliguric with a r a p i d l y r i s i n g c r e a t i n i n e level t h a t n e c e s s i t a t e d t h e i n s t i t u t i o n of h e m o d i a l y s i s on the fourth hospital day. D i a l y s i s was continued for seven additional days until the diuretic phase of acute r e n a l failure b e g a n and intrinsic renal function improved. S e r u m calcium was p e r s i s t e n t l y low, w i t h the phosphorus elevated, d u r i n g the first week. Calcium was given int r a v e n o u s l y several t i m e s for r e l i e f of severe muscle cramps. S e r u m potass i u m c o n t i n u e d n o r m a l . C P K rem a i n e d elevated for two weeks before r e t u r n i n g to normal. The BUN was still e l e v a t e d at the t i m e of discharge 25 days after admission. The p a t i e n t was lost to follow-up. C a s e N u m b e r T w o . A 50-yearold male alcoholic w i t h p r e v i o u s l y n o r m a l r e n a l f u n c t i o n e n t e r e d the emergency department complaining of intense r i g h t calf p a i n of 12 hours duration. He had been on a d r i n k i n g b i n g e for two w e e k s b u t d e n i e d t r a u m a or prolonged unconsciousness, a l t h o u g h he had spent considerable t i m e l y i n g on his couch. Physical e x a m i n a t i o n showed an e n l a r g e d n o n - n o d u l a r liver w i t h a 16 cm span, firm calves b i l a t e r a l l y with the r i g h t m e a s u r i n g 39 cm in circumference a n d the left 35 cm. Dorsalis pedis pulses and Achilles tendon reflexes were intact. H e m a t o c r i t reading was 51%, white blood cell count (WBC) 20,100 cu mm; sodium, 126 mEq/liter; potassium, 5.7 mEq/liter; BUN, 45, c r e a t i n i n e c l e a r a n c e , 3.4 gm/24 hours: uric acid, 12.7 mg/100 ml; calcium, 5.8 mg/100 ml; albumin, 4.2 gm/100 ml; and C P K g r e a t e r t h a n 155,000. E K G showed moderate peaking of precordial T waves. The u r i n e was d a r k w i t h t h r e e to six red cells and several pigmented casts per high power field. It t e s t e d + 3 o r t h o t o l u i d i n e - p o s i t i v e , a n d c o n t a i n e d +1 4o/104
Table 1 CASE 1 n 29-YEAR-OLD MAN
Day 1
3 4-12 14 24
CPK
Creatinine
BUN
K+
C a .++
1600 2.5 46 4.8 > 4000 12.2 114 4.6 Hemodialysis necessary, diuresis begins on day # 10 440 3.0 83 4.3 200 1.1 45 --
7.5 6.6 9.1 10.2
Table 2 CASE 2 -- 50-YEAR-OLD MAN
K+
CA + +
3.4 45 5.7 -5.1 57 6.8 15,000 11.6 131 4.7 -14.5 137 -Hemodialysis, diuresis begins on day #11 150 3.3 41 m
5.8 5.7 6.2
Day
CPK
1 2 4 7 8-9 20
> 155,000
Creatinine
BUN
--
10.7
Table 3 CASE 3 -- 74-YEAR-OLD MAN
Day
1 3 8
CPK
Creatinine
BUN
K+
Ca ++
10,300 1,800 200
1.4 0.9 1.0
62 51 12
4.6 4.2 3.8
9.0 8.6 8.7
p r o t e i n . T h e r e w a s no free h e m o globin in the plasma. The p a t i e n t was t a k e n to s u r g e r y where necrotic muscle was removed from the l a t e r a l a n d posterior comp a r t m e n t s of b o t h calves. F a s c i o t omies were performed on the r i g h t calf. D e s p i t e t r e a t m e n t w i t h m a n nito], and furosemide, and a fluid challenge, he r e m a i n e d oliguric w i t h only 15 cc of urine o u t p u t d u r i n g s u r g e r y (Table 2). H e m o d i a l y s i s w a s instit u t e d b r i e f l y on t h e s e v e n t h a n d e i g h t h days because azotemia led to a d e t e r i o r a t i o n of m e n t a l status. Resolution of the acute r e n a l failure began in the t h i r d week of hospitalization with g r e a t l y improved r e n a l function at discharge after 40 days. C r e a t i n e c l e a r a n c e w a s n o r m a l one m o n t h later. C a s e N u m b e r T h r e e . A 74year-old chronic male alcoholic was sent to the hospital after being found on his hotel room floor b y the manager. He said he h a d been b e a t e n and kicked d u r i n g a robbery three days
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before and had been unable to move from a p r o n e p o s i t i o n b e c a u s e of weakness and muscle soreness. His b l o o d p r e s s u r e f e l l f r o m 122/70 supine to 90/55 w h e n s i t t i n g and his pulse rate increased from 100 to 140 beats/minute. There were bruises around both orbits, the anterior thorax, and both knees. Neurological e x a m w a s n o r m a l e x c e p t for mild t r e m u l o u s n e s s and diffusely hyperactive deep t e n d o n reflexes. O r i g i n a l l a b o r a t o r y r e s u l t s showed h e m a t o c r i t reading, 57%; WBC, 13,000 cu mm; sodium 150 mEq/liter; potassium, 5.3 m E q / l i t e r ; B U N 62 m g / 1 0 0 ml; creatinine clearance, 1.4 gm/24 hrs; C P K 10,300 (MB f r a c t i o n < 2%). U r i n e w a s d a r k w i t h + 2 ort h o t o l u i d i n e r e a c t i o n a n d 0-3 red blood cells b u t no casts. The patient was given normal saline intravenously r a p i d l y u n t i l p o s t u r a l changes and tachycardia had disappeared. Diuretics and mannitol were not used. In spite of the m y o g l o b i n u r i a and e l e v a t e d C P K level, the p a t i e n t 7:3 (Mar) 1978
RHABDOMYOLYSIS - - C O M P L I C A T I O N S
CAUSES OF M Y O G L O B I N U R I A
I
Direct Muscle Trauma Crush injuries Burns Electric shock Status epilepticus Exercise, eg, squat jumps Ischemia Compression and compartment syndromes Arterial embolism Carbon monoxide poisoning Toxic - - Metabolic Alcoholism Snake and spider bites Heat stroke Malignant hyperthermia Hypothermia Hypokalemia Hypophosphatemia Diabetic k e t o a c i c l o s i s -
hyperosmolar coma Drug-Induced Heroin Amphetamines Others Polymyositis Intrinsic muscle disorders Phosphorylase deficiency Muscle infections Cause unknown (approx. 15%) Fig. 1. Many causes of rhabdomyolysis, often not due to direct trauma: Multiple mechanisms of injury 'may contribute to rhabdomyolysis, eg, ischemia, acidosis and trauma with severe exercise. had an uncomplicated hospital course (Table 3), except for a m i l d alcohol w i t h d r a w a l syndrome, and was discharged on the s e v e n t h day. DISCUSSION
Meyer-Betz first recognized myo g l o b i n u r i a in 1910. 4 A c u t e r e n a l failure due to crush injuries was described d u r i n g World W a r II. 1 M a n y causes of rhabdomyolysis, often not due to direct t r a u m a , have now been described (Figure 1). 3 M a s s i v e m u s c l e n e c r o s i s from t e a r i n g or b l u n t c r u s h i n j u r i e s is p r o b a b l y t h e b e s t k n o w n c a u s e of rhabdomyolysis, but some investigators 1 r e p o r t t h a t prolonged coma w i t h i m m o b i l i t y a n d m u s c l e comp r e s s i o n is a more c o m m o n cause. T h e s e l a t t e r c a s e s a n d t h o s e associated with seizures, amphetam i n e 5 or h e r o i n use, h e a t s t r o k e , carbon monoxide poisoning, and alcoholism are likely to pass undiag7:3 (M ar) 1978
Muscle InjUry
L
Release of Intracellular Contents
I CPK
I
Creatine and
I
I
{ K+ ~
I
Myoglobinuria
I
~ P04
/
Creatinine
~ Creatinine •
Renal Failure
CaPO4deposition Ca ++
Fig. 2. Complication of failure to diagnose rhabdomyolysis early. nosed unless the physician m a i n t a i n s a h i g h i n d e x of suspicion in t h e s e c l i n i c a l c i r c u m s t a n c e s . F a i l u r e to diagnose r h a b d o m y o l y s i s e a r l y will r e s u l t in i n c r e a s e d m o r b i d i t y a n d m o r t a l i t y from subsequent h y p e r k a lemia, acute renal failure, and hypocalcemia (Figure 2). Myoglobin is a h e m e - c o n t a i n i n g p i g m e n t w i t h a m o l e c u l a r weight of 17,000 t h a t is i m p o r t a n t for oxygen t r a n s p o r t in m u s c l e c e l l s r i c h in oxidative enzymes. If the serum conc e n t r a t i o n of the p i g m e n t exceeds the r e n a l t h r e s h o l d concentration of app r o x i m a t e l y 0.3 mg/100 ml, m y o g l o bin will a p p e a r in the urine. 1 Lysis o f as little as 200 gm of s k e l e t a l muscle m a y r e s u l t in m y o g l o b i n u r i a . 1 H e m o g l o b i n w i l l n o t a p p e a r as r e a d i l y in t h e u r i n e since it is a larger molecule. Skeletal muscle lysis also releases large q u a n t i t i e s of the enzyme C P K t h a t m a y be used as a m a r k e r of the severity of muscle injury. 3 S k e l e t a l muscle contains the MM isoenzyme of C P K w h e r e a s cardiac muscle c o n t a i n s both the MM a n d MB isoenzymes. SGOT a n d LDH are also r e l e a s e d d u r i n g muscle lysis b u t are not tissue specific as these e n z y m e s a r e f o u n d a l s o in m a n y other tissues. The m e c h a n i s m by which myoglobulin induces r e n a l injury is not clear. Light microscopy and immunofluorescence have d e m o n s t r a t ed myogtobin in t h e d i s t a l t u b u l e s and t u b u l a r lining cells in cases of r e n a l failure due to myoglobinuria. 6 Myoglobin may thus simply cause o b s t r u c t i o n of d i s t a l t u b e s or m a y a d d i t i o n a l l y d a m a g e k i d n e y s by in-
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ducing fibrin deposition on glomeruli or by d e c r e a s i n g r e n a l cortical blood flow. 3 In the e x p e r i m e n t a l and clinical s i t u a t i o n , m y o g l o b i n u r i a seems much more likely to cause r e n a l failure if t h e r e is an associated i n s u l t s u c h as h y p o t e n s i o n , acidosis', h y p o t h e r m i a , or hypoxia. 3 Thus, the degree of muscle t r a u m a alone will not n e c e s s a r i l y predict the s e v e r i t y of s u b s e q u e n t r e n a l damage. O u r cases i l l u s t r a t e the difficulties in p r e d i c t i n g the e v e n t u a l degree of r e n a l failure from the initial ass e s s m e n t . In case 3, a C P K of over 10,000 was accompanied by volume d e p l e t i o n in a n e l d e r l y m a n , y e t there was no evidence of prolonged r e n a l failure. In contrast, a y o u n g e r p a t i e n t (case 1) who h a d a l o w e r CPK a n d less i n i t i a l volume depletion a c c o r d i n g to clinical e x a m i n a tion, developed prolonged r e n a l failure r e q u i r i n g dialysis. P r o m p t volume expansion m i g h t have lessened his r e n a l injury. Because of this inab i l i t y to predict the clinical course,
MYOGLOBINURIA m DIAGNOSIS
Clinical suspicion (Figure 1) O rthotol uidi ne-positive urine (Hematest)
Pigmented urinary casts Elevated CPK Gel electrophoresis or immunodiffusion Fig. 3. Diagnosis of rhabdomyolysis in suspect clinical circumstances. 105/41
e a c h p a t i e n t m u s t be followed closely. The diagnosis of rhabdomyolysis can easily be made in a suspect clinical c i r c u m s t a n c e ( F i g u r e 3). Pigmented u r i n e is suggestive of myog l o b i n u r i a b u t p h o r p h y r i n s , beets and hemoglobin also discolor urine. 1 Visible p i g m e n t u r i a from myoglobin may be t r a n s i e n t , l a s t i n g only one or two days, and m a y have passed by the time a p a t i e n t p r e s e n t s to the physician. Pigmented casts are prese n t a n d the o r t h o t o l u i d i n e t e s t is positive in the p r e s e n c e of e i t h e r myoglobin or hemoglobin. However, if these two findings are accompanied by a n elevated CPK, myoglobinuria may be diagnosed. 2 D e m o n s t r a t i o n of myoglobinuria with either gel elect r o p h o r e s i s or i m m u n o d i f f u s i o n is d e f i n i t i v e b u t r e q u i r e s m o r e advanced methodology. The more l i f e - t h r e a t e n i n g seq u e l a of r h a b d o m y o l y s i s is a c u t e h y p e r k a l e m i a (case 2) due to release of i n t r a c e l l u l a r potassium from necrotic muscle cells. 2 The kidneys will u s u a l l y be able to excrete the extra p o t a s s i u m in t h e a b s e n c e of associated r e n a l failure, 2 b u t dialysis or exchange resins m u s t be employed if s i g n i f i c a n t r e n a l i m p a i r m e n t is present. H y p o c a l c e m i a (cases 1 a n d 2) often occurs early in the course of myoglobinuric renal failure and may be s y m p t o m a t i c . 2 U s u a l l y the hyp o c a l c e m i a is a c c o m p a n i e d by h y p e r p h o s p h a t e m i a . 2 R e l e a s e of large stores of i n t r a c e l l u l a r phosp h a t e m a y l e a d to d e p o s i t i o n of c a l c i u m - p h o s p h a t e in vessel w a l l s with c o n s e q u e n t h y p o c a l c e m i a and t e t a n y . 2 H y p e r c a l c e m i a d u r i n g the later resolution of the renal failure has occurred when such deposits are r e a b s o r b e d . 2 I n o r d e r to p r e v e n t metastatic calcification, calcium
42/106
salts should be reserved for administ r a t i o n of s e v e r e l y s y m p t o m a t i c cases. A r a p i d r i s e in the s e r u m c r e a t i n i n e , already elevated at the. time of admission in cases 1 and 2, can occur with r h a b d o m y o l y s i s because of the degradation of released i n t r a c e l l u l a r m u s c l e c r e a t i n e to creatinine. Serum creatinine rises at a n average of 2 mg/24 hrs in r e n a l f a i l u r e n o t caused by m y o g l o b i n u ria. 2 With myoglobinuria, however, the c r e a t i n i n e increases at g r e a t e r t h a n 2.5 mg/24 hr in most patients because of the increased c r e a t i n i n e load. 3 I m m e d i a t e t r e a t m e n t of the complications of rhabdomyolysis and associated r e n a l f a i l u r e is critical. The prognosis for recovery of renal function appears to be quite good in p a t i e n t s properly managed. Hyperk a l e m i a is the most c r i t i c a l e a r l y c o m p l i c a t i o n a n d m a y be a c u t e l y m a n a g e d w i t h b i c a r b o n a t e d or insulin-glucose infusion, if necessary. C a l c i u m a d m i n i s t r a t i o n is best avoided i n t r e a t i n g h y p e r k a l e m i a because of the p o t e n t i a l of i n d u c i n g m e t a s t a t i c calcifications. Exchange resins or dialysis may be necessary for d e f i n i t i v e c o n t r o l of h y p e r kalemia. Prompt correction of addit i o n a l i n s u l t s to r e n a l f u n c t i o n is m a n d a t o r y , i n c l u d i n g t r e a t m e n t of a c i d o s i s or t i s s u e h y p o x e m i a . In addition, a l k a l i n i z a t i o n of the urine may increase the solubility of myoglobin. Volume expansion has been effective i n e x p e r i m e n t a l c i r c u m stances 3 in reducing the incidence of a c u t e r e n a l f a i l u r e from r h a b domyolysis although no studies demo n s t r a t e the u s e f u l n e s s of t h i s app r o a c h once r e n a l f a i l u r e s u p e r vened. It seems reasonable, however, to assume t h a t e s t a b l i s h m e n t of proper r e n a l p e r f u s i o n is a n e c e s s a r y
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step t o w a r d s e l i m i n a t i n g f u r t h e r renal injury. Infusion of a solution of 25 gm of m a n n i t o l and 100 mEq of sodium bicarbonate per liter of D5W has been r e c o m m e n d e d for volume expansion a n d a l k a l i n i z a t i o n . 3 This should certainly be accompanied by careful m o n i t o r i n g of CVP or pulmon a r y arterial wedge pressure to prevent p u l m o n a r y edema from excess volume. The use of furosemide is controversial and potentially dangerous if given before volume expansion because it may worsen i n i t i a l volume depletion. Experimental studies 3 t h a t suggest a role for volume expansion indicate poorer results with any delay in therapy. Thus, it is essential t h a t the e m e r g e n c y p h y s i c i a n initiate prompt correction of a n y volume deficits if the clinical course of this disorder is to be modified.
REFERENCES 1. Rowland LP, Penn AS,: Myoglobinuria. Med Clin North A m 56:1233-1256, 1972. 2. Grossman RA, Hamilton, RW, Morse BM et ah Non-traumatic rhabdomyolysis and acute renal failure. N Engl J Med 291:807-811, 1974. 3. Medical Staff Conference. Rhabdomyolysis. West J Med 125:198-304, 1976. 4. Meyer-Betz F: Beobachtungen an einem eigenartigen mit muskell ahmungen verbundenen Fall von hamoglobinuric (observations on a peculiar case of hemoglobinur~a associated with muscle palsy). Deutsche Archiv Klinische Medizinische 101:85, 1910. 5. Kendrick WC, Hull AR, Knochel JP: Rhabdomyolysis and shock after intravenous amphetamine administration. A n n Intern Med 86:381-387, 1977. 6. Kagen L J: Immunofluorescent demonstration of myoglobin in the kidney. A m J Med 48:649-653, 1970.
7"3 (Mar) 1978
Rhabdomyolysis and Acute Renal Failure David Ralph, MD Sacramento, Cafifornia
Three cases of rh abdomyolysis, two with acute renal failure, seen in a short period of time in an emergency department illustrate this increasingly recognized entity. Myoglobinuria may result from muscle trauma, ischemia, metabolic causes, druginduced injury or intrinsic muscle disorders. The diagnosis is easily made by the presence of an elevated creatine phosphokinase, positive orthotoluidine in the urine and pigmented urine casts. Failure to diagnose rhabdomyolysis early will result in increased morbidity and mortality from subsequent hyperkalemia, acute renal failure and hypocalcemia. These three cases illustrate the difficulty in predicting the eventual degree of renal failure from the initial assessment. Ralph D: Rhabdomyolysis and acute renal failure. JACEP 7:103-106, March, 1978. kidney failure, rhabdomyolysis; myoglobinuria.
INTRODUCTION Rhabdomyolysis is the lysis of muscle tissue from a traumatic, toxic or metabolic insult. Myoglobinuria results when enough myoglobin is released from damaged muscle to be excreted into the urine. Several recent papers 1-3 have stressed t h a t rhabdomyolysis, with or without associated acute r e n a l failure, is becoming more commonly recognized. The diagnosis can be easily made i n the emergency d e p a r t m e n t if the physician is aware of the situations predisposing to muscle necrosis. Often, such necrosis occurs in the absence of major t r a u m a . Three cases seen in our emergency d e p a r t m e n t w i t h i n a few months illustrate several aspects of this disorder.
CASE REPORTS C a s e N u m b e r One. A 20-year-old man, a weekend heroin user, fell asleep on his back on a pool table after injecting heroin. His lower legs dangled over the edge of the table. When he awoke 15 hours later both legs were n u m b and he came to the emergency department. The results of physical exam were n o r m a l except for the finding of bilateral sciatic and femoral nerve palsies. The legs were somewhat cool below the knees but distal arterial pulses were intact and there was no swelling. Both thighs were mildly tender but calves were not. There was no evidence of volume depletion. Original laboratory studies showed a hematocrit r e a d i n g of 51% and potassium 4.8 mEq/liter. Since initial a t t e n t i o n was focused on the neurological dysfunction, an emergency myelogram was obtained and was normal. However, the pat i e n t was unable to void after the myelogram. A Foley catheter was passed, yielding 100 cc of dark u r i n e t h a t was + 3 orthotoluidine-positive (Hematest for occult blood). A n occasional pigmented cast was noted b u t no red blood cells. BeCause of the pigmented urine, further studies were obtained t h a t showed a blood urea n i t r o g e n (BUN) of 49 mg/100 ml, c r e a t i n i n e clearance, 2.5 gm/24 hrs; Presented at the University Association for Emergency Medicine Annual Meeting in Kansas City, Missouri, May, 1977. Address for reprints: David Ralph, MD, Assistant Professor, Section of EmergencyMedicine, Department of Internal Medicine, UCD-SacramentoMedical Center, 2315 Stockton Boulevard, Sacramento, California 95817. 7:3 (Mar) 1978
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creatine phosphokinase (CPK), 1600 units ( n o r m a l < 200); total lactic dehydrogenase (LDH), 2055 (normal < 400); s e r u m g l u t a m i c - o x a l o a c e t i c t r a n s a m i n a s e (SGOT), 1390 (normal < 90); uric acid, 15.3; and calcium, 7.5 (normal 8.5 to 10.5)with n o r m a l albumin. E l e c t r o c a r d i o g r a p h (EKG) was normal. An orthopedic consultant found no evidence of a muscle comp a r t m e n t syndrome. A c e n t r a l venous pressure (CVP) line m e a s u r e d a pressure of 3 cm of w a t e r which rose to 10 after infusion of 37.5 gm of mannitol. Furosemide was injected i n t r a venously (IV) in a dose of 100 mg but no diuresis ensued. The p a t i e n t was a d m i t t e d to the hospital a n d had a prolonged hospital course (Table 1). He r e m a i n e d oliguric with a r a p i d l y r i s i n g c r e a t i n i n e level t h a t n e c e s s i t a t e d t h e i n s t i t u t i o n of h e m o d i a l y s i s on the fourth hospital day. D i a l y s i s was continued for seven additional days until the diuretic phase of acute r e n a l failure b e g a n and intrinsic renal function improved. S e r u m calcium was p e r s i s t e n t l y low, w i t h the phosphorus elevated, d u r i n g the first week. Calcium was given int r a v e n o u s l y several t i m e s for r e l i e f of severe muscle cramps. S e r u m potass i u m c o n t i n u e d n o r m a l . C P K rem a i n e d elevated for two weeks before r e t u r n i n g to normal. The BUN was still e l e v a t e d at the t i m e of discharge 25 days after admission. The p a t i e n t was lost to follow-up. C a s e N u m b e r T w o . A 50-yearold male alcoholic w i t h p r e v i o u s l y n o r m a l r e n a l f u n c t i o n e n t e r e d the emergency department complaining of intense r i g h t calf p a i n of 12 hours duration. He had been on a d r i n k i n g b i n g e for two w e e k s b u t d e n i e d t r a u m a or prolonged unconsciousness, a l t h o u g h he had spent considerable t i m e l y i n g on his couch. Physical e x a m i n a t i o n showed an e n l a r g e d n o n - n o d u l a r liver w i t h a 16 cm span, firm calves b i l a t e r a l l y with the r i g h t m e a s u r i n g 39 cm in circumference a n d the left 35 cm. Dorsalis pedis pulses and Achilles tendon reflexes were intact. H e m a t o c r i t reading was 51%, white blood cell count (WBC) 20,100 cu mm; sodium, 126 mEq/liter; potassium, 5.7 mEq/liter; BUN, 45, c r e a t i n i n e c l e a r a n c e , 3.4 gm/24 hours: uric acid, 12.7 mg/100 ml; calcium, 5.8 mg/100 ml; albumin, 4.2 gm/100 ml; and C P K g r e a t e r t h a n 155,000. E K G showed moderate peaking of precordial T waves. The u r i n e was d a r k w i t h t h r e e to six red cells and several pigmented casts per high power field. It t e s t e d + 3 o r t h o t o l u i d i n e - p o s i t i v e , a n d c o n t a i n e d +1 4o/104
Table 1 CASE 1 n 29-YEAR-OLD MAN
Day 1
3 4-12 14 24
CPK
Creatinine
BUN
K+
C a .++
1600 2.5 46 4.8 > 4000 12.2 114 4.6 Hemodialysis necessary, diuresis begins on day # 10 440 3.0 83 4.3 200 1.1 45 --
7.5 6.6 9.1 10.2
Table 2 CASE 2 -- 50-YEAR-OLD MAN
K+
CA + +
3.4 45 5.7 -5.1 57 6.8 15,000 11.6 131 4.7 -14.5 137 -Hemodialysis, diuresis begins on day #11 150 3.3 41 m
5.8 5.7 6.2
Day
CPK
1 2 4 7 8-9 20
> 155,000
Creatinine
BUN
--
10.7
Table 3 CASE 3 -- 74-YEAR-OLD MAN
Day
1 3 8
CPK
Creatinine
BUN
K+
Ca ++
10,300 1,800 200
1.4 0.9 1.0
62 51 12
4.6 4.2 3.8
9.0 8.6 8.7
p r o t e i n . T h e r e w a s no free h e m o globin in the plasma. The p a t i e n t was t a k e n to s u r g e r y where necrotic muscle was removed from the l a t e r a l a n d posterior comp a r t m e n t s of b o t h calves. F a s c i o t omies were performed on the r i g h t calf. D e s p i t e t r e a t m e n t w i t h m a n nito], and furosemide, and a fluid challenge, he r e m a i n e d oliguric w i t h only 15 cc of urine o u t p u t d u r i n g s u r g e r y (Table 2). H e m o d i a l y s i s w a s instit u t e d b r i e f l y on t h e s e v e n t h a n d e i g h t h days because azotemia led to a d e t e r i o r a t i o n of m e n t a l status. Resolution of the acute r e n a l failure began in the t h i r d week of hospitalization with g r e a t l y improved r e n a l function at discharge after 40 days. C r e a t i n e c l e a r a n c e w a s n o r m a l one m o n t h later. C a s e N u m b e r T h r e e . A 74year-old chronic male alcoholic was sent to the hospital after being found on his hotel room floor b y the manager. He said he h a d been b e a t e n and kicked d u r i n g a robbery three days
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before and had been unable to move from a p r o n e p o s i t i o n b e c a u s e of weakness and muscle soreness. His b l o o d p r e s s u r e f e l l f r o m 122/70 supine to 90/55 w h e n s i t t i n g and his pulse rate increased from 100 to 140 beats/minute. There were bruises around both orbits, the anterior thorax, and both knees. Neurological e x a m w a s n o r m a l e x c e p t for mild t r e m u l o u s n e s s and diffusely hyperactive deep t e n d o n reflexes. O r i g i n a l l a b o r a t o r y r e s u l t s showed h e m a t o c r i t reading, 57%; WBC, 13,000 cu mm; sodium 150 mEq/liter; potassium, 5.3 m E q / l i t e r ; B U N 62 m g / 1 0 0 ml; creatinine clearance, 1.4 gm/24 hrs; C P K 10,300 (MB f r a c t i o n < 2%). U r i n e w a s d a r k w i t h + 2 ort h o t o l u i d i n e r e a c t i o n a n d 0-3 red blood cells b u t no casts. The patient was given normal saline intravenously r a p i d l y u n t i l p o s t u r a l changes and tachycardia had disappeared. Diuretics and mannitol were not used. In spite of the m y o g l o b i n u r i a and e l e v a t e d C P K level, the p a t i e n t 7:3 (Mar) 1978
RHABDOMYOLYSIS - - C O M P L I C A T I O N S
CAUSES OF M Y O G L O B I N U R I A
I
Direct Muscle Trauma Crush injuries Burns Electric shock Status epilepticus Exercise, eg, squat jumps Ischemia Compression and compartment syndromes Arterial embolism Carbon monoxide poisoning Toxic - - Metabolic Alcoholism Snake and spider bites Heat stroke Malignant hyperthermia Hypothermia Hypokalemia Hypophosphatemia Diabetic k e t o a c i c l o s i s -
hyperosmolar coma Drug-Induced Heroin Amphetamines Others Polymyositis Intrinsic muscle disorders Phosphorylase deficiency Muscle infections Cause unknown (approx. 15%) Fig. 1. Many causes of rhabdomyolysis, often not due to direct trauma: Multiple mechanisms of injury 'may contribute to rhabdomyolysis, eg, ischemia, acidosis and trauma with severe exercise. had an uncomplicated hospital course (Table 3), except for a m i l d alcohol w i t h d r a w a l syndrome, and was discharged on the s e v e n t h day. DISCUSSION
Meyer-Betz first recognized myo g l o b i n u r i a in 1910. 4 A c u t e r e n a l failure due to crush injuries was described d u r i n g World W a r II. 1 M a n y causes of rhabdomyolysis, often not due to direct t r a u m a , have now been described (Figure 1). 3 M a s s i v e m u s c l e n e c r o s i s from t e a r i n g or b l u n t c r u s h i n j u r i e s is p r o b a b l y t h e b e s t k n o w n c a u s e of rhabdomyolysis, but some investigators 1 r e p o r t t h a t prolonged coma w i t h i m m o b i l i t y a n d m u s c l e comp r e s s i o n is a more c o m m o n cause. T h e s e l a t t e r c a s e s a n d t h o s e associated with seizures, amphetam i n e 5 or h e r o i n use, h e a t s t r o k e , carbon monoxide poisoning, and alcoholism are likely to pass undiag7:3 (M ar) 1978
Muscle InjUry
L
Release of Intracellular Contents
I CPK
I
Creatine and
I
I
{ K+ ~
I
Myoglobinuria
I
~ P04
/
Creatinine
~ Creatinine •
Renal Failure
CaPO4deposition Ca ++
Fig. 2. Complication of failure to diagnose rhabdomyolysis early. nosed unless the physician m a i n t a i n s a h i g h i n d e x of suspicion in t h e s e c l i n i c a l c i r c u m s t a n c e s . F a i l u r e to diagnose r h a b d o m y o l y s i s e a r l y will r e s u l t in i n c r e a s e d m o r b i d i t y a n d m o r t a l i t y from subsequent h y p e r k a lemia, acute renal failure, and hypocalcemia (Figure 2). Myoglobin is a h e m e - c o n t a i n i n g p i g m e n t w i t h a m o l e c u l a r weight of 17,000 t h a t is i m p o r t a n t for oxygen t r a n s p o r t in m u s c l e c e l l s r i c h in oxidative enzymes. If the serum conc e n t r a t i o n of the p i g m e n t exceeds the r e n a l t h r e s h o l d concentration of app r o x i m a t e l y 0.3 mg/100 ml, m y o g l o bin will a p p e a r in the urine. 1 Lysis o f as little as 200 gm of s k e l e t a l muscle m a y r e s u l t in m y o g l o b i n u r i a . 1 H e m o g l o b i n w i l l n o t a p p e a r as r e a d i l y in t h e u r i n e since it is a larger molecule. Skeletal muscle lysis also releases large q u a n t i t i e s of the enzyme C P K t h a t m a y be used as a m a r k e r of the severity of muscle injury. 3 S k e l e t a l muscle contains the MM isoenzyme of C P K w h e r e a s cardiac muscle c o n t a i n s both the MM a n d MB isoenzymes. SGOT a n d LDH are also r e l e a s e d d u r i n g muscle lysis b u t are not tissue specific as these e n z y m e s a r e f o u n d a l s o in m a n y other tissues. The m e c h a n i s m by which myoglobulin induces r e n a l injury is not clear. Light microscopy and immunofluorescence have d e m o n s t r a t ed myogtobin in t h e d i s t a l t u b u l e s and t u b u l a r lining cells in cases of r e n a l failure due to myoglobinuria. 6 Myoglobin may thus simply cause o b s t r u c t i o n of d i s t a l t u b e s or m a y a d d i t i o n a l l y d a m a g e k i d n e y s by in-
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ducing fibrin deposition on glomeruli or by d e c r e a s i n g r e n a l cortical blood flow. 3 In the e x p e r i m e n t a l and clinical s i t u a t i o n , m y o g l o b i n u r i a seems much more likely to cause r e n a l failure if t h e r e is an associated i n s u l t s u c h as h y p o t e n s i o n , acidosis', h y p o t h e r m i a , or hypoxia. 3 Thus, the degree of muscle t r a u m a alone will not n e c e s s a r i l y predict the s e v e r i t y of s u b s e q u e n t r e n a l damage. O u r cases i l l u s t r a t e the difficulties in p r e d i c t i n g the e v e n t u a l degree of r e n a l failure from the initial ass e s s m e n t . In case 3, a C P K of over 10,000 was accompanied by volume d e p l e t i o n in a n e l d e r l y m a n , y e t there was no evidence of prolonged r e n a l failure. In contrast, a y o u n g e r p a t i e n t (case 1) who h a d a l o w e r CPK a n d less i n i t i a l volume depletion a c c o r d i n g to clinical e x a m i n a tion, developed prolonged r e n a l failure r e q u i r i n g dialysis. P r o m p t volume expansion m i g h t have lessened his r e n a l injury. Because of this inab i l i t y to predict the clinical course,
MYOGLOBINURIA m DIAGNOSIS
Clinical suspicion (Figure 1) O rthotol uidi ne-positive urine (Hematest)
Pigmented urinary casts Elevated CPK Gel electrophoresis or immunodiffusion Fig. 3. Diagnosis of rhabdomyolysis in suspect clinical circumstances. 105/41
e a c h p a t i e n t m u s t be followed closely. The diagnosis of rhabdomyolysis can easily be made in a suspect clinical c i r c u m s t a n c e ( F i g u r e 3). Pigmented u r i n e is suggestive of myog l o b i n u r i a b u t p h o r p h y r i n s , beets and hemoglobin also discolor urine. 1 Visible p i g m e n t u r i a from myoglobin may be t r a n s i e n t , l a s t i n g only one or two days, and m a y have passed by the time a p a t i e n t p r e s e n t s to the physician. Pigmented casts are prese n t a n d the o r t h o t o l u i d i n e t e s t is positive in the p r e s e n c e of e i t h e r myoglobin or hemoglobin. However, if these two findings are accompanied by a n elevated CPK, myoglobinuria may be diagnosed. 2 D e m o n s t r a t i o n of myoglobinuria with either gel elect r o p h o r e s i s or i m m u n o d i f f u s i o n is d e f i n i t i v e b u t r e q u i r e s m o r e advanced methodology. The more l i f e - t h r e a t e n i n g seq u e l a of r h a b d o m y o l y s i s is a c u t e h y p e r k a l e m i a (case 2) due to release of i n t r a c e l l u l a r potassium from necrotic muscle cells. 2 The kidneys will u s u a l l y be able to excrete the extra p o t a s s i u m in t h e a b s e n c e of associated r e n a l failure, 2 b u t dialysis or exchange resins m u s t be employed if s i g n i f i c a n t r e n a l i m p a i r m e n t is present. H y p o c a l c e m i a (cases 1 a n d 2) often occurs early in the course of myoglobinuric renal failure and may be s y m p t o m a t i c . 2 U s u a l l y the hyp o c a l c e m i a is a c c o m p a n i e d by h y p e r p h o s p h a t e m i a . 2 R e l e a s e of large stores of i n t r a c e l l u l a r phosp h a t e m a y l e a d to d e p o s i t i o n of c a l c i u m - p h o s p h a t e in vessel w a l l s with c o n s e q u e n t h y p o c a l c e m i a and t e t a n y . 2 H y p e r c a l c e m i a d u r i n g the later resolution of the renal failure has occurred when such deposits are r e a b s o r b e d . 2 I n o r d e r to p r e v e n t metastatic calcification, calcium
42/106
salts should be reserved for administ r a t i o n of s e v e r e l y s y m p t o m a t i c cases. A r a p i d r i s e in the s e r u m c r e a t i n i n e , already elevated at the. time of admission in cases 1 and 2, can occur with r h a b d o m y o l y s i s because of the degradation of released i n t r a c e l l u l a r m u s c l e c r e a t i n e to creatinine. Serum creatinine rises at a n average of 2 mg/24 hrs in r e n a l f a i l u r e n o t caused by m y o g l o b i n u ria. 2 With myoglobinuria, however, the c r e a t i n i n e increases at g r e a t e r t h a n 2.5 mg/24 hr in most patients because of the increased c r e a t i n i n e load. 3 I m m e d i a t e t r e a t m e n t of the complications of rhabdomyolysis and associated r e n a l f a i l u r e is critical. The prognosis for recovery of renal function appears to be quite good in p a t i e n t s properly managed. Hyperk a l e m i a is the most c r i t i c a l e a r l y c o m p l i c a t i o n a n d m a y be a c u t e l y m a n a g e d w i t h b i c a r b o n a t e d or insulin-glucose infusion, if necessary. C a l c i u m a d m i n i s t r a t i o n is best avoided i n t r e a t i n g h y p e r k a l e m i a because of the p o t e n t i a l of i n d u c i n g m e t a s t a t i c calcifications. Exchange resins or dialysis may be necessary for d e f i n i t i v e c o n t r o l of h y p e r kalemia. Prompt correction of addit i o n a l i n s u l t s to r e n a l f u n c t i o n is m a n d a t o r y , i n c l u d i n g t r e a t m e n t of a c i d o s i s or t i s s u e h y p o x e m i a . In addition, a l k a l i n i z a t i o n of the urine may increase the solubility of myoglobin. Volume expansion has been effective i n e x p e r i m e n t a l c i r c u m stances 3 in reducing the incidence of a c u t e r e n a l f a i l u r e from r h a b domyolysis although no studies demo n s t r a t e the u s e f u l n e s s of t h i s app r o a c h once r e n a l f a i l u r e s u p e r vened. It seems reasonable, however, to assume t h a t e s t a b l i s h m e n t of proper r e n a l p e r f u s i o n is a n e c e s s a r y
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step t o w a r d s e l i m i n a t i n g f u r t h e r renal injury. Infusion of a solution of 25 gm of m a n n i t o l and 100 mEq of sodium bicarbonate per liter of D5W has been r e c o m m e n d e d for volume expansion a n d a l k a l i n i z a t i o n . 3 This should certainly be accompanied by careful m o n i t o r i n g of CVP or pulmon a r y arterial wedge pressure to prevent p u l m o n a r y edema from excess volume. The use of furosemide is controversial and potentially dangerous if given before volume expansion because it may worsen i n i t i a l volume depletion. Experimental studies 3 t h a t suggest a role for volume expansion indicate poorer results with any delay in therapy. Thus, it is essential t h a t the e m e r g e n c y p h y s i c i a n initiate prompt correction of a n y volume deficits if the clinical course of this disorder is to be modified.
REFERENCES 1. Rowland LP, Penn AS,: Myoglobinuria. Med Clin North A m 56:1233-1256, 1972. 2. Grossman RA, Hamilton, RW, Morse BM et ah Non-traumatic rhabdomyolysis and acute renal failure. N Engl J Med 291:807-811, 1974. 3. Medical Staff Conference. Rhabdomyolysis. West J Med 125:198-304, 1976. 4. Meyer-Betz F: Beobachtungen an einem eigenartigen mit muskell ahmungen verbundenen Fall von hamoglobinuric (observations on a peculiar case of hemoglobinur~a associated with muscle palsy). Deutsche Archiv Klinische Medizinische 101:85, 1910. 5. Kendrick WC, Hull AR, Knochel JP: Rhabdomyolysis and shock after intravenous amphetamine administration. A n n Intern Med 86:381-387, 1977. 6. Kagen L J: Immunofluorescent demonstration of myoglobin in the kidney. A m J Med 48:649-653, 1970.
7"3 (Mar) 1978
