J Am Board Fam Pract: first published as 10.3122/jabfm.3.4.265 on 1 October 1990. Downloaded from Asymptomatic Rhabdomyolysis Of Unknown Etiology Michael T Hagley, M.D., andJames H. Sorrell, M.D.

Abstract: A 7-year-old boy developed rhabdomyolysis with a peak creatine phosphokinase level of 261,400 lUlL after his appendectomy. These abnormalities occurred following a 2-3-day illness consisting of upper respiratory tract symptoms, fever, and abdominal pain mimicking acute appendicitis. At the time of operation, a normal appendix Was removed, and mesenteric lymphadenitis was noted. The myoglobinuria and elevation of creatine phosphokinase were transient, and the patient remained asymptomatic. We review various causes of right lower quadrant pain and rhabdomyolysis and address the roles of malignant hyperthermia and infectious agents. The possible cause of the phenomena observed in this patient is discussed. (J Am Board Fam Pract 1990; 3:265-9.)

A 7-year-old white boy was brought in January On physical examination, the patient's tem­ 1988 to a small-town hospital in Nebraska be­ perature was 38.9°C (I02.1°F); pulse, 120 beats cause he had abdominal pain, anorexia, and vom­ per minute; respirations, 18 breaths per minute; iting for several hours preceded by myalgia, sore and blood pressure, 110/70 mmHg. He appeared throat, and nonproductive cough of about 2-days' acutely ill. He had right-sided abdominal tender­ duration. His abdominal pain began in the epi­ ness that was most pronounced at McBurney's gastric area the afternoon of admission and by point. He had palpable, mildly tender cervical, evening was predominately in the right lower axillary, and inguinal lymph nodes. quadrant. He denied diarrhea, constipation, or His white cell count was 8.3 X 106/L (8300/fJ.L) rectal bleeding. with normal values for the differential leukocyte The patient was born after a full-term preg­ count. Hemoglobin and electrolytes were normal. nancy, and his vaginal birth was uncomplicated. He met all developmental milestones appropri­ Course of the Illness

ately and had no history of major illness. He used A diagnosis of appendicitis was made, and the http://www.jabfm.org/ no medications and had no allergies. The patient patient was taken to the operating room the same lived with his parents, an 8-year-old brother, and evening. He was given intravenous methahexital a 5-year,,",0Id sister in the town where the hospital sodium (BrevitaPM) and succinylcholine and was is located. The family had no cats, but they did intubated without difficulty. Anesthesia was own a properly vaccinated dog. maintained with nitrous oxide and fluothane. His Two cousins on opposite sides of the family body temperature was monitored throughout the were affected by cerebral palsy. One had trouble procedure, and no elevation above baseline was on 25 September 2021 by guest. Protected copyright. tolerating anesthetics, but this was not related to noted. An appendectomy was performed through malignant hyperthermia. No family members a right pararectus incision, splitting, not cutting, were affected by malignant hyperthermia or any the abdominal wall musculature. The appendix other musculoskeletal disease. appeared normal, an observation later confirmed by histological examination. The surgeon also noticed mesenteric lymphadenitis. The operation was completed in less than 1 hour; the patient From the Family Practice Residency Program, Barberton Citi­ was extubated and left the operating room in sat­ zens Hospital, Barberton, OH, and the Department of Psychia­ isfactory condition. try, George Washington University Medical Center, Washing­ ton, D.C. On the first postoperative day, the patient de­ At the time this case occurred, the authors were students at the scribed his urine as looking "like coke." Urinaly­ University of Nebraska Medical Center in Omaha, NE, and were sis showed 3 + to 4+ occult blood with 0-2 red under the supervision of the Department of Family Practice. Address reprint requests to Michael T. Hagley, M.D., Akron cells per high power field. On day 2, the urine City Hospital, 535 East Market Street, Akron, OH 44309. had returned to its normal color, and urinalysis

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sh()wed 1+ ()ccult hl()()d and 0-2 red cells per before undergoing an appendectomy because of high power tield. ;\ urine sample taken on day 2 right lower quadrant pain. llis appendix \vas nor­ was sent to a referral Iahoratory, which was un­ ma\, and he had mesenteric lymphadenitis. Post­ ahle t() determine whether it contained hemoglo­ operatively, he developed transient myoglobinu­ hin or my()glohin hecause of the small amount ria caused by rhabdomyolysis. llis recovery was present in the sample. uneventful, and he has remaint:d in good health. ()n postoperative day I, the patient's serum In the following discussion, we consider possi­ creatine ph()sph()kinase (ePK) was 13 7,OO() lUlL ble causes of the right lower creatinine concen­ simplified by the tlnding of l11t:senteric lymphad­ trations as well as urine output remained normal enitis during appendectomy and the absence of throughout hospitalization. On postoperative day evidt:nce of other disease processt:s (other than 2, serum haptoglobin was 11.9 giL (119 mg/dL), tht: rhahdomyolysis). and a direct Coombs' tt:st \vas negativt:. Mesenteric lymphadenitis refers to intlamma­ On postopt:rative day 1, tht: whitt: cell count tion of lymph nodes in the area of the Illt:soap­ was 16.2 X IOI)/L (16,200hd.), but on day 3, the pt:ndix. It frequently occurs following a viral white cell count was 3.0 X I ({)/L (3000!,.1:L) with type of upper rt:spiratory tract infection I and has ..J.O percent segmented nt:utrophils, 2 percent bet:n reported to occur in association \\lith inft:c­ hand neutrophils, 56 percent Iymphocytt:s, and 2 tions by adt:novirust:s, 1,2 parvovirus B Ph l inliu­ pt:rcent monocytes. On day 5, the whitt: cell enza, I Yersinia enterocolitica and Yeninia pseudotu­ count \vas 2.7 X J({)/L (2700/iJL) with normal berculosis,"" and Giardia lamblia.' I n addition, a values for the differential leukocyte count. number of organisms that product: a vt:ratoxin During his postoperative course, tlw patient thought to be responsible for hemolytic urt:mic had no complaints of muscular pain. lIe had a syndrome have been reported to cause acute ab­ temperature of 100-1 () 1OF on postoperative days dominal symptoms, usually in conjunction with I through 3 and \vas afebrile tht:rt:after. Ilis diarrht:a. These include Salmonella, Campy/o/Jacter, physical examination did not show muscular ten­ Yersinia, Pneumococcus, enterotoxic Hrcbericbia coli, http://www.jabfm.org/ derness or weakness. The patient was discharged Sbigel/a, and st:veral virust:s. 6 With tht: exct:ptions on postoperati ve day 7. of Yersillia"" and PIlC/lIl/OCOCCUS, I these organisms On postoperative day 13, the patient's ePK have not been reportt:d to occur in association was ..J.5 3 I elL. Although a repeat CPK level and a with mesenteric lymphadenitis. Although all of muscle biopsy might havt: bt:en useful in t:stab­ the above art: possible eaust:s, influenza A infec­ lishing a diagnosis, tlw attt:nding physician, aftt:r tion seemed bt:st for t:xplaining the patient's pro­ conft:rring with st:vt:ral consultants, electt:d not dromal symptoms of ft:ver, myalgia, and cough, on 25 September 2021 by guest. Protected copyright. til pursut: tht:st: tt:sts. At the time of follow-up, the presence of mesenteric lymphadenitis, and the patit:nt's part:nts wt:rt: intilfll1ed that malig­ the predominance of lymphocytes in the white nant hyperthermia was a possible cause of the cell ditFert:ntial postoperatively. In addition, the observed rhahdolll}-·olysis. They were advised condition occurred during the time of )Tar when that future surgery on the patient or family melll­ inllut:nza infections art: most common. bers should he undertaken only when clearly Analyzing tht: causes of rhabdomyolysis is a necessary and with appropriate precautions at a more diflicult task. The largest reported series of medical center \vhere anesthesiologists are t:xperi­ patients with rhabdomyolysis is by Callow, et enct:d in the trt:atnwnt of patients who might dt:­ a\.,:' who studied 77 patients during X7 t:pisodes velop malignant hyperthermia. of rhabdomyolysis. In half of the C1St:S with reli­ able histories, the patients did not complain of Discussion muscle pain. Swelling of the muscles was present \Vt: have prest:nted a 7-year-old boy \vho had a 2- in only ..J. of X7 cases at tht: time of admission and day history of upper respiratory tract symptoms became apparent after administration of intra-

~(,() JAHFP OCIOI'CJ"-I lecember I ()()() Vol., No. "" 4 Xlt . ,s. J Am Board Fam Pract: first published as 10.3122/jabfm.3.4.265 on 1 October 1990. Downloaded from venous fluids in 4 of 9 patients who were ob­ Because our patient developed rhahdomyoly­ served daily. Eleven patients had peak CPK lev­ sis after receiving succinylcholine and inhalation els greater than 20,000 JUIL with a range of anesthetics, we were concerned about the possi­ 24,000 to 238,000 lUlL. Thirty-three percent de­ bility of malignant hyperthermia (MH). This dis­ veloped acute renal failure. Eight patients died, order is usually inherited in an autosomal domi­ although 4 had major trauma, burns, or gangrene nant manner, although a less common variant, that were major contributing factors. associated with multiple congenitalllhnormalitics Numerous causes of rhabdomyolysis were iden­ and known as the King syndrome, is inherited as 19 tified, including excessive muscle exertion, direct an autosomal recessive trait. ,20 The pathophysi­ muscle trauma, ischemia, malignant hyperthermia, ology of MH is not well understood, but it seems . polymyositis, metabolic disorders, drug intoxica­ to involve excessive release of calcium into the tion, toxic injury, and genetic disorders. No etio­ sarcoplasmic reticulum following administration logical factor could be identified in 3 percent of the of succinylcholine and inhalation anesthetics. 21 cases. We considered several of these possibilities in Subsequently, the patient develops prolonged attempting to explain our patient's case. contraction of skeletal muscle, hyperthermia, aci­ The first was the possibility of direct operative dosis, marked muscle swelling, and increased lev­ muscle trauma, although this seemed unlikely, els of serum potassium, sodium, ionized calcium, because no muscle was incised. Several authors CPK, and myoglobin. Body temperature may in­ have reported postoperative increases in CPK,H,9 crease as rapidly as 1°C every 5 minutes. The but these elevations have been only in the range episode is usually fatal unless promptly recog­ of 200 to 700 lUlL. The possibility of muscle nized and appropriately treated. damage from ischemia because of muscle com­ Several cases of a similar syndrome involving pression intraoperatively was considered as well. muscle destruction and variable degrees of con­ We found 2 reports of this occurring. The first, 10 traction in the absence of hyperthermia follow­ reported in 1953, described myoglobinuria and ing use of inhalation anesthetics have been re­ renal failure in a 35-year-old, obese man who was portedY-25 In two of these reports, 22,23 patients in an extreme knee-chest position during a were difficult or impossible to intubate, had obvi­ 3-hour orthopedic procedure. In the second, II ous rigidity, and had severe muscle pain and following a 6-hour procedure in the same posi­ weakness postoperatively. One patient diedY In tion, the patient developed myoglobinuria, the two other reports,24,25 the signs were less obvious,

peak CPK level was 4555 lUlL. Both patients but both patients had no fasciculations after suc­ http://www.jabfm.org/ complained of lower extremity pain postopera­ cinylcholine was given and were difficult to intu­ tively. It is difficult to imagine that our 7-year­ bate. One patient25 suffered a cardiac arrest post­ old patient could have developed this sort of operatively but was successfully resuscitated. damage after just 40 minutes in a supine position, It is unlikely but not impossible that our pa­ particularly because he had no postoperative pain tient had an episode of MH. He obviously did not

other than that from his appendectomy incision. have a classic case, because he had no hyperther­ on 25 September 2021 by guest. Protected copyright. A number of drugs have been reported to cause mia (beyond his ekvated preoperative tempera­ rhabdomyolysis in one of three ways. Intoxica­ ture), rigidity, postoperative muscle pain, or evi­ tion from use of illegal drugs or alcohol can pro­ dence of metabolic abnormalities associated with duce unconsciousness and prolonged ischemia in MH. Even in the cases where there was evidence a limb that has been compressed for a number of of rhabdomyolysis without hyperthermia or ri­ hours. 12, 13 Drugs have also been reported to gidity, the patients, unlike the one we report, produce rhabdomyolysis by causing excessive showed abnormal reactions to succinylcholine 4 11i muscle contraction following overdosel - and and were difficult to intubate. Nevertheless, we hypersensitivity reactions. 17 In 2 reports,15,17 still cannot be absolutely sure that this does not CPK levels exceeded 200,000 lUlL. Succ~nylcho­ represent a rare variant of anesthetic- or succinyl­ line has also been reported to cause modest eleva­ choline-induced myopathy. A muscle biopsy and tions in CPK levels, presumably because of mus­ repeated CPK levels might have been helpful in cle fasciculations. III Our patient had no signs of establishing such a diagnosis, but these tests were drug toxicity or hypersensitivity. not obtained.

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Viral infection was another possihle cause of by appendectomy. Postoperatively, the patient rhahdoll1yolysis in our patient, hecause he had developed rhahdo1l1yolysis with a dramatic ele­ I! symptoms of an upper respiratory tract infection vation in serum CPK concentration. The exact I and cervical, axillary, inguinal, and mesenteric cause eluded LIS, hut a viral etiology was likely, lymphadenopathy. In addition, the patient's de­ namely, influcnza A. Because rhabdomyolysis is creasing white cell count with a lymphocyte pre­ a rare complication of influenza infections, we dominance was consistent with a viral infection. initially overlooked the need to obtain viral cul­ Unfortunately, no viral antihody titers or viral cul­ tures and acute antibody titers. We considered tures were obtained. However, the condition oc­ the need for a muscle biopsy and further CPK curred during a season when influenza A infections levels to evaluate for MH hut were unable to \vere most prevalent in Nehraska2{, and lowa.27 obtain these. I n the absence of these data, this We reviewed the literature on rhabdomyolysis patient will be considered as though he is suscep­ associated primarily with viruses and found IS tible to MH in the event that further surgery is published reports of 36 cases. The most com­ necessary. monly implicated virus was inliuenza,2H.l7 which accounted for 2() cases. Epstein-Barr virus was as­ References sociated with 4 cases,lH-.. I and herpes simplex type I. Bonard EC. Appendicites i\ virus. Helv Med Acta 2 was associated with 1 case. IH Adenovirus,"2 echo­ I %3; ~:~5-t-(,(). virus,"l Sbigella, .... aspergillosis,'" Stap/~ylococcus epi­ 2. Prince RL. Evidence for an aetiological role for dcrmidis/> and J'CJ~io1Jell(/ pncuJl1opbilia+> have all adenovirus type 7 in the mesenteric adenitis syn­ drome. ,\ledJ Aust 1979; 2:5(,-7. been reported in association with rhabdomyolysis. 3. l'vlorinet 1', Monsuez .1.1, Rogcr P, Perol Y. Parvovirus Finally, the various organisms that produce vera­ B I V associated with pseudoappendicitis lletterl. Lan­ toxin can cause rhabdomyolysis with or without cet 19H 7; 2: 14M. hemolytic uremic syndrome.(,·2o These include Sal­ 4. Jansson E, Wallgren CIt Ahvonen P. Ycrsillia L'IItcro­ moncl/a, Sb~f.{clla, Campylobaeter, Yersinia, Pneumo­ colitica ,IS a cause of acute mesenteric lymphadenitis. coccus, and enterotoxic El"cbcricbia coli. Patient ages Acta Paediatr Scand I%H; 57:HH-50. 11 29 were from 3 to 74 years. Peak CPK values were 5. Ray C, Escrihano .Ie, Foz 1'11, Vidal MT, Salvador R. l1 between 100 IU/LH and 200,000 IU/L. A number Mesenteric adenitis secondary to Giardia lamblia. of authors reported peak CPK values greater than Adult Dig Dis Sci 19HO; 25 :%H-7I. 40,000 IU/L. 11 ,HJH, .. o,-+2'''l,-+5 The mechanism of in- (,. Levin M, \Valters i\L\, Barratt, 'I'M. Hemolytic ure­ http://www.jabfm.org/ jury is unknown. mic syndrome. Ady Pediatr Infect Dis I 9H9; 4: 51-H2. The temporal relation between the mesenteric 7. (;abow PA, Kaehny WD, Kelleher SP. The spec­ trum of rhabdom),olysis. Med 19HZ; (,1 :141-52. lymphadenitis and rhabdomyolysis that occurred H. Irving AD, Kennedy D. Serum "cardiac" enzyme in our patient suggests the possibility of a com­ levels after Iaporatomy . .I Royal Col of Surg Edin­ mon cause. The veratoxin-producing organisms burgh 19H4; 29:252-3. mentioned above provide a plausible explanation 9. KraH't .I, Fink R Rosalki SB. Serum enzymes and because they have been associated with acute ab­ isocnzymes after surgery. Ann Clin Biochem 1977; on 25 September 2021 by guest. Protected copyright. dominal pain and rhabdomyolysis.(' However, 14:2,)~-(,. they are more commonly associated with hemo­ 10. Cordon BS, Newman \V. Lower nephron syndrome lytic uremic syndrome and diarrhea, neither of following prolonged knee-chest position . .I Bone which was present in our patient. We believe that Joint Surg 1953; 35 A:7(,4-H. an intluer1l',a A infection provided a particularly II. (;oldberg ,'vi, Stccker .IF Jr, Scarff .IE Jr, Wombolt satisfactory explanation because it was prevalent DC. Rhabdomvolvsis associated with urethral stric­ at the time of this patient's illness, can cause ture repair: report of a case. J U rol 19HO; 124: 7 30-1. 12. Crossman R,\, Hamilton RW, Morse BI\\, Penn AS. rhabdotnyolysis, and can probably cause mesen­ !\1ontraurnatic rhabdomyolysis and acute renal fail­ teric lymphadenitis. As interesting as these possi­ ure. N EnglJ Med 1974; 291:H07-11. bilities are, however, they remain speculative. I.l. Owen C\, Mubarak SJ, Hargens AR, Rutherford I., (;aretto LP, Akeson WI I. Intramuscular pressures Summary with limb comprcssion clarification of thc patho­ \Ve have presented a case of mesenteric lymphad­ genesis of the drug-induced muscle-compartment enitis mimicking acute appendicitis and treated syndrome. N EnglJ Med 1979; .WO: 1 ](i9-72.

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14. Barton CH, Sterling ML, Vaziri ND. Rhahdomyoly­ Myoglobinuria associated with influen7.a A infec­ sis and acute renal failure associated with phencyc­ tion. Ann Intern Med 1974; 80: 359-61. lidine intoxication. Arch Intern Med 1980; 140: 29. Cunningham E, Kohli R, Venuto RC. Influenza­ 568-9. associated myoglobinuric rcnal failure . .lAMA 1979; 15. Boyd RE, Brennan PT, Deng jF, Rochcster DF, 242:2428-9. Spyker DA. Strychnine poisoning. Recovery from 30. Zamkotf K, Rosen N. Influenza and myoglohinuria profound lactic acidosis, hyperthermia, and rhahdo­ in hrothcrs. NClll'ology 1979; 29: .HO-5. myolysis. Am j Med 1983; 74:507-12. 31. DiBona I'J, MorclIs DM. Rhahdomyolysis associated 16. Modi KB, Horn EH, Bryson SM. Theophylline poi­ with influenza A . .l Ped 1977; 91:943-5. soning and rhabdomyolysis I\etter]. Lancet 1985; 32. Rhabdomyolysis Iclinical conferencel. West j Med 2: 160-1. 1976; 125:298-.Hl4. 17. Engel jN, Mellul VG, Goodman DB. Phenytoin B. Berlin BS, Simon NM, Bovner RN. Myoglobinuria hypersensitivity: a case of severe acute rhabdomyol­ precipitated by viral infection. JAMA 1974; 227: ysis. Am j Med 1986; 81:928-30. 1414-5. 18. Plotz j, Braun J. Failure of "self-taming" doses of 34. Shenouda A, Hatch FE. Influenza A viral infection succinylcholine to inhibit increases in postoperative associated with acute renal failurc. Am j Mcd 1976; serum creatine kinase activity in children. Anesthesi­ 61:697-702. ology 1982; 56:207-9. 35. Middleton Pj, Alcxander RM, Szymanski MT. Se­ 19. Braunwald E, Issebacher Kj, Petersdorf RG, Wilson vere myositis during recovery from influenza. Lan­ jD, Martin jB, Fucci AS, eds. Harrison's principles cet 1970; 2:533-5. of internal medicine, II. New York: McGraw-Hili, 36. Simon NM, Rovner RN, Berlin BS. Acute myoglo­ 1987:47. binuria associated with type A2 (Hong Kong) influ­ 20. Gronert GA. Malignant hyperthermia. Anesthesi­ enza. JAMA 1970; 212: 1704-5. ology 1980; 53:395-423. 37. Morgensen.lL. Myoglobinuria and renal failure 21. Cantin RY, Poole A, Ryan jF. Malignant hyper­ associated with influenza. Ann Intern Med 1974; thermia. Oral Surg Oral Med Oral Pathol 1986; 62: 80: 362-3. 389-92. 38. Schlesinger jj, Gandara D, Bensch KG. Myoglobin­ 22. Cody jR. Muscle rigidity following administra­ uria associated with herpes-group viral infections. tion of succinylocholine. Anesthesiology 1968; 29: Arch Intern Med 1978; 138:422-4. 159-62. 39. Friedman 131, Libby R. Epstein-Barr virus infection 23. Schmitt HP, Simmendinger Hj, Wagner H, Yolk B, associated with rhabdomyolysis and renal failure. Busing CM, Stenzel M. Severe morphological Clin Pediatr 1986; 25: 2 28-9.

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Britt BA, eds. Second International Symposium Ma­ type 21 infection. Occurrence with pneumonia, on 25 September 2021 by guest. Protected copyright. lignant Hyperthermia. New York: Grune & Strat­ rhabdomyolysis, and myoglobinuria in an adult . ton, 1979:419-25. .lAMA 1979; 241:2420-1. 25. Caccia MR, Cerri C, Gravame V, et al. Myopathy 43 . .Iossclson j, Pula T, Sadler .IH. Acute rhabdomyoly­ with paroxysmal myoglobinuria and focal muscle sis associated with an echovirus 9 infection. Arch necrosis following enfluorane anaesthesia. j Neuro Intern Med 1980; 140:1671-2. Sci 1978; 39:61-9. 44. Hocking WG, Reza MJ. Nontraumatic rhabdomyol­ 26. Influenza update - United States. MMWR 1988; ysis and renal failure [letter]. N Engl.l Med 1975; 37:97. 292:979-80. 27. Update: influenza activity - United States. MMWR 45. el Nahas AM, Farrington K, Quyyumi S, Moorhcad 1988; 37:49. jF, Sweny P. Rhabdomyolysis and systemic infec­ 28. Minow RA, Gorbach S,johnson BLjr, Dornfeld L. tion. Br Med j 1983; 286:349-50.

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