rhabdomyolysis and acute renal failure

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, drug- induced 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 predict- ing the eventual degree of renal failure from the initial assessment. Ralph D: Rhab- domyolysis 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 resul ts when enough myoglobin is released from damaged muscle to be excreted into the urine. Several recent papers 1-3 have stressed that rhabdomyolysis, with or without associated acute renal failure, is becoming more commonly recognized. The diagnosis can be easily made in the emergency depar tment if the physician is aware of the s i tuat ions predisposing to muscle necrosis. Often, such necrosis occurs in the absence of major t rauma. Three cases seen in our emergency depar tment wi th in a few months i l lustrate several aspects of this disorder.

CASE REPORTS

Case 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 inject ing 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 normal except for the finding of bi la teral sciatic and femoral nerve palsies. The legs were somewhat cool below the knees but distal ar ter ial 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 hematocri t reading of 51% and potas- s ium 4.8 mEq/liter. Since ini t ia l a t ten t ion was focused on the neurological dysfunc- tion, an emergency myelogram was obtained and was normal. However, the pa- t i en t was unable to void after the myelogram. A Foley catheter was passed, yielding 100 cc of dark ur ine that was + 3 orthotoluidine-positive (Hematest for occult blood). An occasional pigmented cast was noted but no red blood cells. BeCause of the pigmented urine, fur ther studies were obtained tha t showed a blood urea n i t rogen (BUN) of 49 mg/100 ml, c rea t in ine 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 Emergency Medicine, Depart- ment of Internal Medicine, UCD-Sacramento Medical Center, 2315 Stockton Boulevard, Sacramento, California 95817.

7:3 (Mar) 1978 JACEP 103/39

creat ine phosphokinase (CPK), 1600 uni ts (no rmal < 200); to ta l lactic de- hydrogenase (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 ansaminase (SGOT), 1390 (normal < 90); uric acid, 15.3; and calcium, 7.5 (normal 8.5 to 10.5)wi th normal albu- min. Elec t rocard iograph (EKG) was no rma l . A n o r thoped ic c o n s u l t a n t found no evidence of a muscle com- p a r t m e n t syndrome. A cent ra l venous pressure (CVP) line measu red a pressure of 3 cm of wa te r which rose to 10 after infusion of 37.5 gm of man- nitol. Furosemide was injected in t ra- venously (IV) in a dose of 100 mg but no diuresis ensued.

The pa t ien t was admi t ted to the hospi tal and had a prolonged hospi ta l course (Table 1). He remained oliguric wi th a rap id ly r i s ing crea t in ine level t h a t necess i t a ted the i n s t i t u t i on of hemodia lys is on the fourth hospi tal day. Dia lys is was cont inued for seven a d d i t i o n a l days u n t i l the d i u r e t i c phase of acute renal fa i lure began and i n t r i n s i c r e n a l func t ion improved . Serum calcium was pers i s ten t ly low, wi th the phosphorus elevated, dur ing the first week. Calc ium was given in- t ravenous ly severa l t imes for r e l i e f of severe muscle cramps. Serum potas- s i u m c o n t i n u e d n o r m a l . C P K remained e levated for two weeks before r e tu rn ing to normal . The BUN was st i l l e leva ted at the t ime of discharge 25 days af ter admission. The pa t i en t was lost to follow-up.

C a s e N u m b e r Two. A 50-year- old male alcoholic wi th p rev ious ly n o r m a l r e n a l func t ion e n t e r e d the emergency d e p a r t m e n t compla in ing of intense r igh t calf pa in of 12 hours durat ion. He had been on a d r ink ing 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 though he had spent considerable t ime ly ing on his couch.

Physical examina t ion showed an en la rged non-nodular l iver wi th a 16 cm span, f i rm calves b i l a t e ra l ly wi th the r igh t measu r ing 39 cm in circum- ference and the left 35 cm. Dorsal is pedis pulses and Achi l les tendon reflexes were intact . Hematocr i t reading was 51%, whi te blood cell count (WBC) 20,100 cu mm; sodium, 126 mEq/l i ter; potassium, 5.7 mEq/l i ter ; BUN, 45, c rea t in ine c learance , 3.4 gm/24 hours: uric acid, 12.7 mg/100 ml; calcium, 5.8 mg/100 ml; a lbumin, 4.2 gm/100 ml; and CPK grea te r than 155,000. E K G showed moderate peak- ing of precordial T waves. The ur ine was da rk wi th three to six red cells and s e v e r a l p i g m e n t e d c a s t s pe r h igh power field. It t e s t ed +3 or tho to l - u id ine -pos i t ive , and c o n t a i n e d +1

Table 1 CASE 1 n 29 -YEAR-OLD M A N

Day

1 3 4-12 14 24

C P K Creat inine B U N K + Ca .++

1600 2.5 46 4.8 7.5 > 4000 12.2 114 4.6 6.6

Hemodialysis necessary, diuresis begins on day # 10 440 3.0 83 4.3 9.1 200 1.1 45 - - 10.2

Table 2 CASE 2 - - 50 -YEAR-OLD M A N

Day

1 2 4 7 8-9 20

C P K Creat inine B U N K + CA ++

> 155,000 3.4 45 5.7 5.8 - - 5.1 57 6.8 5.7

15,000 11.6 131 4.7 6.2 - - 14.5 137 - - - - Hemodialysis, diuresis begins on day #11 150 3.3 41 m 10.7

Table 3 CASE 3 - - 74 -YEAR-OLD M A N

Day C P K

1 10,300 3 1,800 8 200

Creatinine B U N K + Ca + +

1.4 62 4.6 9.0 0.9 51 4.2 8.6 1.0 12 3.8 8.7

pro te in . There was no free hemoglobin in the p lasma.

The pa t ien t was t aken to surgery where necrotic muscle was removed from the l a te ra l and poster ior com- p a r t m e n t s of bo th calves. Fasc io t - omies were performed on the r ight calf. Despi te t r e a t m e n t wi th man- nito], and furosemide, and a fluid chal- lenge, he r emained oliguric wi th only 15 cc of ur ine ou tput dur ing surgery (Table 2). H e m o d i a l y s i s was ins t i - t u t e d b r i e f l y on the s e v e n t h and e ighth days because azotemia led to a de ter iora t ion of men ta l s tatus. Reso- lut ion of the acute r ena l fai lure began in the th i rd week of hospi ta l iza t ion with grea t ly improved rena l function at discharge af ter 40 days. Crea t ine c l e a r a n c e was 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 74- year-old chronic male alcoholic was sent to the hospi tal af ter being found on his hotel room floor b y the man- ager. He said he had been bea ten and kicked dur ing a robbery three days

before and had been unable to move f rom a p rone p o s i t i o n b e c a u s e of weakness and muscle soreness. His b lood p r e s s u r e fe l l f rom 122/70 supine to 90/55 when s i t t ing and his pulse ra te increased from 100 to 140 b e a t s / m i n u t e . T h e r e were b r u i s e s a r o u n d bo th o r b i t s , t h e a n t e r i o r thorax, and both knees. Neurological e x a m was n o r m a l e x c e p t for mild t remulousness and diffusely hyperac- t ive deep tendon reflexes. Or ig ina l labora tory resu l t s showed hematocr i t reading, 57%; WBC, 13,000 cu mm; sodium 150 mEq/l i ter; potass ium, 5.3 m E q / l i t e r ; B U N 62 m g / 1 0 0 ml; c rea t in ine 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 was d a r k w i t h + 2 or- t 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 but no casts. The pat ient was g i v e n n o r m a l s a l i n e i n t r a v e - nously rap id ly un t i l pos tura l changes and t a c h y c a r d i a had d i s a p p e a r e d . D i u r e t i c s a n d m a n n i t o l were not used. In spite of the myoglobinur ia and e levated CPK level, the pa t ien t

4o/104 JACEP 7:3 (Mar) 1978

CAUSES OF MYOGLOBINURIA

Direct Muscle Trauma Crush injuries Burns Electric shock Status epilepticus Exercise, eg, squat jumps

Ischemia Compression and compart-

ment 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 u n c o m p l i c a t e d h o s p i t a l course (Table 3), except for a mi ld al- cohol w i thd rawa l syndrome, and was discharged on the seventh day.

DISCUSSION

Meyer-Betz first recognized my- o g l o b i n u r i a in 1910. 4 Acu te r e n a l fai lure due to crush injur ies was described dur ing World W a r II. 1 Many causes of rhabdomyolys is , often not due to direct t r auma , have now been described (Figure 1). 3

M a s s i v e musc le nec ros i s f rom 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 the bes t k n o w n cause of r h a b d o m y o l y s i s , b u t some inves - t igators 1 repor t t ha t prolonged coma wi th i m m o b i l i t y and musc le com- press ion is a more common cause. These l a t t e r ca se s a n d t h o s e as- s o c i a t e d w i t h s e i z u r e s , a m p h e t a - mine 5 or h e r o i n use, h e a t s t roke , carbon monoxide poisoning, and alcoholism are l ikely to pass undiag-

I CPK

RHABDOMYOLYSIS - - COMPLICATIONS

I Muscle InjUry

L Release of Intracellular Contents

I I I I I

Creatine { K + Myoglobinuria ~ P04 and ~ / Creatinine

~ Creatinine • Renal Failure CaPO4 deposition

Ca ++

Fig. 2. Complication o f failure to diagnose rhabdomyolysis early.

nosed unless the physic ian ma in t a in s a h igh index of suspic ion in these c l in i ca l c i r c u m s t a n c e s . F a i l u r e to diagnose rhabdomyolys i s ea r ly wil l 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 and mor ta l i ty from subsequent hyperka - l e m i a , a c u t e r e n a l f a i l u r e , a n d hypocalcemia (Figure 2).

Myoglobin is a heme-conta in ing p igment wi th a molecular weight of 17,000 tha t is impor t an t for oxygen t r a n s p o r t in m u s c l e ce l l s r i ch in oxidat ive enzymes. If the serum con- cent ra t ion of the p igment exceeds the renal th reshold concentra t ion of ap- p rox imate ly 0.3 mg/100 ml, myoglobin will appear in the urine. 1 Lysis of as l i t t le as 200 gm of ske le ta 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 wi l l no t a p p e a r as r e a d i l y in the u r i n e s ince i t is a l a r g e r m o l e c u l e . S k e l e t a l m u s c l e lysis also re leases large quant i t i es of the enzyme CPK tha t may be used as a m a r k e r of the sever i ty of muscle injury . 3 Ske le t a l muscle conta ins the MM isoenzyme of CPK whereas car- diac muscle conta ins both the MM and MB isoenzymes. SGOT and LDH are also re leased dur ing muscle lysis but are not t issue specific as these e n z y m e s a r e found a l so in m a n y other t issues.

The mechanism by which myo- globulin induces r ena l injury is not c l ea r . L i g h t m i c r o s c o p y a n d im- munofluorescence have demons t ra t - ed myogtobin in the d is ta l t ubu les and t u bu l a r l in ing cells in cases of rena l fa i lure due to myoglobinur ia . 6 Myoglob in m a y thus s imply cause obs t ruc t ion of d i s t a l t ubes or m a y addi t ional ly damage k idneys by in-

ducing f ibr in deposi t ion on glomerul i or by decreas ing r ena l cortical blood flow. 3 In the exper imenta l and clinical s i tua t ion , myog lob inur i a seems much more l ikely to cause rena l failure if the re is an associa ted insu l t s u c h as h y p o t e n s i o n , acidosis ' , hypothermia , or hypoxia. 3 Thus, the degree of muscle t r a u m a alone will not necessar i ly predict the sever i ty of subsequent rena l damage.

Our cases i l lus t ra te the difficul- t ies in predic t ing the even tua l degree of rena l fai lure from the in i t ia l as- s e s smen t . In case 3, a CPK of over 10,000 was accompanied by volume d e p l e t i o n in an e l d e r l y m a n , y e t there was no evidence of prolonged renal fai lure. In contrast , a younger p a t i e n t (case 1) who had a lower CPK and less in i t i a l volume deple- t ion according to c l in ica l examina - tion, developed prolonged rena l failure r equ i r i ng d ia lys is . Prompt volume expansion might have lessened his r ena l injury. Because of this ina- b i l i ty to predict the cl inical course,

MYOGLOBINURIA m DIAGNOSIS

Clinical suspicion (Figure 1) O rthotol uidi ne-posit ive urine

(Hematest) Pigmented urinary casts Elevated CPK Gel electrophoresis or immuno-

diffusion

Fig. 3. Diagnosis of rhabdomyolysis in suspect clinical circumstances.

7:3 (M ar) 1978 JACEP 105/41

each p a t i e n t m u s t be fol lowed 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 igure 3). Pig- mented ur ine is suggestive of myo- g l o b i n u r i a bu t phorphyr ins , beets and hemoglobin also discolor urine. 1 Visible p igmentur ia from myoglobin may be t ransient , las t ing only one or two days, and may have passed by the t ime a pa t i en t presents to the physician. Pigmented casts are present and the o r tho to lu id ine tes t is posi t ive in the presence of e i the r myoglobin or hemoglobin. However, if these two findings are accompanied by an elevated CPK, myoglobinuria may be diagnosed. 2 Demonstra t ion of myoglobinuria with either gel elec- t rophores is or immunod i f fu s ion is d e f i n i t i v e bu t r e q u i r e s more ad- vanced methodology.

The more l i f e - t h r e a t e n i n g se- que l a of r h a b d o m y o l y s i s is acu te hyperkalemia (case 2) due to release of in t race l lu lar potassium from necrotic muscle cells. 2 The kidneys will usual ly be able to excrete the extra p o t a s s i u m in the absence of associated renal failure, 2 but dialysis or exchange resins mus t be employed if s ign i f i can t r ena l i m p a i r m e n t is present.

Hypoca lcemia (cases 1 and 2) often occurs early in the course of myoglobinuric renal failure and may be symptomat ic . 2 U s u a l l y the hypoca l cemia 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 Re lease of large stores of i n t r a c e l l u l a r phospha t e may lead to depos i t i on of ca lc ium-phospha te in vessel wal ls with consequent hypocalcemia and te tany. 2 Hyperca lcemia du r ing the later resolution of the renal failure has occurred when such deposits are r eabso rbed . 2 In order to p r e v e n t m e t a s t a t i c ca l c i f i ca t ion , c a l c i u m

salts should be reserved for adminis- t r a t i o n of severe ly s y m p t o m a t i c cases.

A r ap id r i se in the s e r u m creat in ine , a lready elevated at the. t ime of admission in cases 1 and 2, can occur with rhabdomyolysis 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 creat inine rises at an average of 2 mg/24 hrs in renal fa i lure not caused by myoglobinuria. 2 With myoglobinuria, however, the crea t in ine increases at greater than 2.5 mg/24 hr in most pat ients because of the increased creat in ine 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 rena l fa i lure is critical. The prognosis for recovery of renal function appears to be quite good in pat ients properly managed. Hyper- k a l e m i a is the most cr i t ical ear ly compl ica t ion a nd may be acu te ly 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 in t rea t ing hyperkalemia because of the po ten t i a l of i n d u c i n g metas ta t ic calcifications. Exchange resins or dialysis may be necessary for d e f i n i t i v e con t ro l of hyper - kalemia. Prompt correction of addi- t i ona l i n su l t s to r ena l func t ion is mandatory , inc lud ing t r e a t m e n t of acidosis or t i s s u e h y p o x e m i a . In addition, a lkal inizat ion of the urine may increase the solubili ty of myoglobin. Volume expansion has been effective in e x p e r i m e n t a l c i rcum- stances 3 in reducing the incidence of acu te r e n a l f a i l u r e f rom rhabdomyolysis al though no studies demons t ra te the usefulness of th is ap- proach once r e n a l f a i l u re super - vened. It seems reasonable, however, to assume that es tab l i shment of prop- er r e n a l pe r fus ion is a necessa ry

step towards 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 manni to l and 100 mEq of sodium bicarbonate per l i ter of D5W has been recommended for volume expansion and alkal inizat ion. 3 This should certainly be accompanied by careful moni tor ing of CVP or pulmonary arter ial wedge pressure to pre- vent pulmonary edema from excess volume. The use of furosemide is con- troversial and potent ial ly dangerous if given before volume expansion because it may worsen ini t ia l volume dep le t ion . E x p e r i m e n t a l s t ud i e s 3 tha 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 in- itiate prompt correction of any 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. Rhabdo- myolysis. West J Med 125:198-304, 1976.

4. Meyer-Betz F: Beobachtungen an einem eigenartigen mit muskell ahmun- gen verbundenen Fall von hamoglobinur- ic (observations on a peculiar case of hemoglobinur~a associated with muscle palsy). Deutsche Archiv Klinische Medi- zinische 101:85, 1910.

5. Kendrick WC, Hull AR, Knochel JP: Rhabdomyolysis and shock after in- travenous amphetamine administration. Ann Intern Med 86:381-387, 1977.

6. Kagen L J: Immunofluorescent demon- stration of myoglobin in the kidney. A m J Med 48:649-653, 1970.

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rhabdomyolysis and acute renal failure

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