American Journal of Emergency Medicine 33 (2015) 123.e1-123.e3

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

journal homepage: locate/ ajem

Case Report

An unusual cause of rhabdomyolysis in emergency setting: challenges of diagnosis?,??,?

Abstract

Rhabdomyolysis is a rare phenomenon that may be challenging to recognize in an emergency setting. Drugs are one of the common causes. Trimethoprim-sulfamethoxazole is a commonly used antibi- otic effective in the treatment of upper and lower respiratory tract infections as well as renal, urinary, and gastrointestinal tract infections. It has variable side effects, ranging from mild symptoms of fatigue and insomnia to a potentially life-threatening Steven- Johnson syndrome and renal failure. Rhabdomyolysis is a rare complication of therapy with this drug and is commonly seen in Immunocompromised patients or those with an allogenic stem cell transplant. In this article, we report a case of rhabdomyolysis in an immunocompetent patient who has undergone treatment with trimethoprim-sulfamethoxazole and a possible Drug interaction with nonsteroidal anti-inflammatory drugs, with the latter acting as an aggravating factor of this complication.

Rhabdomyolysis is a syndrome that is characterized by necrosis of the skeletal muscle tissue and consequent release of cellular byproducts into the blood. From all the released components, the most dangerous is myoglobin, which can cause acute renal failure via its direct toxicity to the renal tubules. Rhabdomyolysis can be a consequence of various causes, which include genetic and metabolic myopathies, trauma, infections, electrical injuries, hyperthermia, autoimmune disorders, and adverse drug interactions [1,2]. This article presents a trimethoprim-sulfamethoxazole (TMP-SMX)- induced rhabdomyolysis in an immunocompetent patient, possibly aggravated by a drug interaction with Nonsteroidal anti-inflammatory drugs .

A 64-year-old man, 45-pack/year smoker, with no significant family history and a past medical history of urethral polyps, was admitted to the hospital due to a worsening bilateral Lower extremity pain, severely disturbed walking, and tea-colored urine. Patient stated that, 2 days earlier, he sought medical attention in the emergency department (ED) for the same pain and darkening of urine that have become more prominent over the past 7 days.

Further from his history, we learned that he self-medicated with Biseptol (TMP-SMX 40/800 mg) 3 tablets per day for 2 weeks due to a “self diagnosed” urinary tract infection . He explained that he previously had UTI, and a physician prescribed him a TMP-SMX treatment, which resolved the infection. When he experienced the

? Funding: There was no funding.

?? Conflicts of interest: We have no conflicts of interest to disclose.

? Verification: All the above-mentioned authors have had the access to the data and

have taken part in writing the manuscript.

same symptoms, he obtained TMP-SMX and self-medicated for a period of 2 weeks with a dosage as stated above. During therapy, he began to experience lower extremity pain. Pain was gradual and increasing in intensity, for which he sought medical attention in an ED. The analyses showed an aspartate aminotransferase 66 U/L, Creatinine kinase-MB 69 U/L, and an increased creatinine kinase (CK) level of 1524 U/L (reference range, 30-170 U/L). He was referred to a neurologist, who suspected polymyositis and scheduled an appoint- ment for further investigations in 2 days. During this time, the pain became more intense, and he decided to take some pain killer medication, which included ibuprofen 200 mg per day, celecoxib 200 mg per day, piroxicam 20 mg per day, Algocalmine (sodium metamizole 500 mg) 2 pills per day, and Antinevralgic (acetyl salycilic acid 250 mg + phenacetine 150 mg + caffeine 50 mg) 2 pills per day. He also consulted a rheumatology specialist, who prescribed him parenteral NSAIDs as follows: ketolorac 30 mg/mL, 2 vials per day, and meloxicam 15 mg, 2 vials per day.

Despite this treatment, the pain persisted and has become so severe that, upon seeking again medical attention, he could barely walk, having Intense pain in the lumbar region and in the legs, dark urine, and oliguria.

On admission, the patient was fully alert and oriented. On physical examination, his temperature was 37?C; blood pressure, 130/70 mm Hg; pulse, 90 beats per minute; and respiratory rate, 17 breaths per minute. Lower limbs showed signs of swelling and edema. The muscles of the lower back, glutes, thighs, and calves were tender to palpation bilaterally. Examination of head, eyes, ears, nose, and throat was unremarkable. The neck was supple and nontender to palpation. Patient denied any associated headache, Neck rigidity, and upper Extremity weakness or pain. Cardiovascular examination showed a normal S1 and S2. Lungs were clear to auscultation. No hepatomegaly or splenomegaly was appreciated. The initial laboratory analyses showed a CK of 64691 U/L, CK-MB 600U/L, elevated transaminases, lactate dehydrogenase, mild acidosis, hyponatremia, hypocalcemia, hyperuri- cemia, and normal blood urea nitrogen and Creatinine levels. Urinalysis showed presence of myoglobin. Electrocardiogram (ECG) was normal. Anti-Jo antibody and antinuclear antibodies were negative; thyroid function tests were all within normal limits. Skeletal muscle ultraso- nography showed an important bilateral edema of subcutaneous tissue with a fluid collection of 17 mm in the thighs and 11 mm in the legs. Muscular fibers showed normal structure. Muscle biopsy revealed muscle fibers without striations and a loss of homogeneity. Some areas showed presence of erythrocytes, without any other inflammatory cell infiltrates. Other tests performed excluded all possible causes of Nontraumatic rhabdomyolysis or myopathies, and we concluded the diagnosis of drug-induced rhabdomyolysis.

0735-6757/(C) 2014

123.e2 M. Petrov et al. / American Journal of Emergency Medicine 33 (2015) 123.e1–123.e3

Table

Creatinine kinase levels from the time of admission until hospital day 16

Trimethoprim-sulfamethoxazole and NSAIDs were discontinued on admission, and the patient was started on aggressive hydration with glucose 5% and 10%, saline solution 9%, mannitol, and furosemide, together with measures to correct electrolyte and acid- base disturbances. The evolution of CK is presented in Table. By hospital day 16, CK decreased within normal limits, patient’s status markedly improved, and he no longer reported any myalgias. At discharge, a Neurologic assessment showed no motor deficits and symmetrical +2 deep tendon reflexes without any superficial sensitivity modifications. There was moderate pain on compression of left and right thigh muscles and in the distal part of legs with mild peripheral sensitive polyneuritis. Ultrasound showed persistence of a minor bilateral posterior thigh and leg subcutaneous edema.

Rhabdomyolysis is a syndrome that occurs due to dissolution of the skeletal muscle tissue and consequent release of cellular byproducts into the blood [2]. From all the released components, the most dangerous is myoglobin, which can cause acute renal failure via its direct toxicity to the renal tubules.

Drug-induced rhabdomyolysis is a relatively common and a well-known side effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors when used in conjunction with fibrates [3] or even clarithromycin [4]. However, such condition is a rare complication of TMP-SMX therapy, with only a few cases having been documented.

Those predisposed to develop rhabdomyolysis are immunocom- promised patients. Recently, a first case has been documented in a nonimmunocompromised patient [5]. Our patient was immunocom- petent, and he has previously been successfully treated with a standard TMP-SMX dosage and reported no symptoms. However, during the second episode of his UTI, for which he self-medicated with TMP-SMX, he began to experience Muscle pain. The patient initially took NSAIDs for the pain produced most likely by the early rhabdomyolysis, and such decision further worsened his condition. His First visit to ED showed CK of 1524 U/L, and 2 days after addition of NSAIDs therapy, CK was 64691 U/L (Table).

Trimethoprim-sulfamethoxazole is a hepatic CYP2C9 inhibitor [6]. Therefore, drugs that are CYP2C9-dependent increase in concentra- tions when administered with it. Such drugs include amitryptyline, celecoxib, diclofenac, fluoxetine, fluvastatin, glipizide, glyburide, irbesartan, ibuprofen, losartan, naproxen, phenytoin, tamoxifen, tolbutamide, torsemide, and warfarin [3,6]. Based on those findings, we hypothesize that this adverse reaction might have been produced by the Drug-drug interaction with NSAIDs specifically at the levels of CYT2C8 and CYT2C9. However, further studies on this particular subject are needed.

Medical management of rhabdomyolysis concerns the mainte- nance of the vital functions. It is important to prevent any further damage from the Muscle breakdown. In addition, prevention and treatment of renal failure are crucial because it is the most common complication of this phenomenon. Hydration is the basis of treatment [2,7]. Normal saline should be given intravenously at a rate that maintains urine output at 1 mL/kg per hour or more. Fluid therapy will enhance the excretion of Toxic substances that may damage the kidneys. If renal failure is significant despite fluid therapy, renal dialysis may be considered. However, our case had an uncomplicated evolution with adequate hydration after interruption of offended drugs, without the need for hemodialysis, despite the high initial value of CK.

Frequent monitoring and correction of any serum electrolyte imbalances such as hyperkalemia are also recommended. Hyperka- lemia may lead to a Life-threatening arrhythmia, so continuous cardiac monitoring and frequent ECGs are indicated [8,9]. Our case did not experience any electrolyte changes, and the ECG remained normal during the hospital admission.

Although rare, rhabdomyolysis is a serious and potentially life- threatening complication of TMP-SMX treatment. Trimethoprim- sulfamethoxazole is a popular effective and inexpensive drug. It is associated with a range of adverse effects, some with fatal outcomes. The exact mechanisms for some of the adverse effects of TMP-SMX have not been defined yet. In addition, more studies are needed to understand the influence of pharmacokinetics on the metabolism of other drugs and their interactions, such as NSAIDs and TMP-SMX in this case [4]. Clinicians should be aware of the potential consequences when prescribing TMP-SMX. They should educate the patients about correct dosage, possible drug interactions, and adverse effects of the therapy.

To our knowledge, this is the second case of TMP-SMX-induced rhabdomyolysis in an immunocompetent patient who self-medicated with this drug. Complication of this therapy had a dramatic evolution after the concurrent self-administration of some NSAIDs. We emphasize the dangers of self-administration of these drugs, especially in countries where such agents can be obtained in pharmacies without any medical prescription.

Mikhail Petrov? Yan Yatsynovich

Internal Medicine Department, School of Medicine, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania

?Corresponding author. Grigore T. Popa University of Medicine and

Pharmacy, Iasi, Romania. Tel.: +40 751637766

E-mail address: [email protected]

M. Petrov et al. / American Journal of Emergency Medicine 33 (2015) 123.e1–123.e3 123.e3

Catalina Lionte MD, PhD Internal Medicine Department, School of Medicine, Grigore T. Popa University of Medicine and Pharmacy; Second Internal Medicine Clinic Sfantul Spiridon Regional Emergency Hospital, Iasi, Romania

http://dx.doi.org/10.1016/j.ajem.2014.05.041

References

1. Allison RC, Beosole DL. The other Medical causes of rhabdomyolysis. Am J Med Sci 2003;326(2):79-88.
2. Lionte C, Sorodoc L, Petris O, Sorodoc V, Bologa C, Anton G. Non-traumatic rhabdomyolysis in medical practice. Rev Med Chir Soc Med Nat Iasi 2009;113(4):1025-33.
3. Schreiber DH, Anderson TR. Statin-Induced Rhabdomyolysis. J Emerg Med 2006;31 (2):177-80.
4. Wagner J, Suessmair C, Pfister HW. Rhabdomyolysis caused by co-medication with simvastatin and clarithromycin. J Neurol 2009;256:1182-3.
5. Ainapurapu B, Kanakadandi, Uday B. Trimethoprim-Sulfamethoxazole Induced Rhabdomyolysis. Am J Ther 2013;21(3):e69-93.
6. Ho JM, Juurlink DN. Considerations when prescribing trimethoprim-sulfamethoxazole. CMAJ 2011;183(16):1851-8.
7. Coco TJ, Klasner AE. Drug-induced rhabdomyolysis. Curr Opin Pediatr 2004;16:206-10.
8. Camp NE. Drug- and toxin-induced rhabdomyolysis. In: Muller AA, editor. J Emerg Nurs 2009;35(5):481-2.
9. Guis S, Mattei JP, Cozzone PJ, Bendahan D. Pathophysiology and clinical presentations of rhabdomyolysis. Joint Bone Spine 2005;72:382-91.