Rhabdomyolysis and Severe Muscle Weakness Secondary to Colistin Therapy

Abstract

Rhabdomyolysis is a clinical condition that causes renal failure up to 40%. Rhabdomyolysis may be traumatic or nontraumatic. Colistin (polymyxin E) is an effective antibiotic. Nephrotoxicity is a frequently encountered side effect. The nephrotoxic effect of colistin is thought to be associated with increased membrane permeability, cell swelling and lysis, and the development of acute tubular necrosis. Here, we report a case of nontraumatic rhabdomyolysis associated with the use of colistin. There is only one report of rhabdomyolysis secondary to colistin in the literature, and there is no report of a case developing severe tetraparesis, as in our case.

• rhabdomyolysis
• colistin
• muscle weakness
• acute renal failure

INTRODUCTION

Necrosis of the muscle cells that occurs as a result of a sudden elevation of intracellular calcium and sodium concentrations is called rhabdomyolysis. Organ damages and metabolic derangements occur when the cellular contents of damaged or necrotized muscle cells are released into the extracellular area.¹ Kidneys are primarily affected during rhabdomyolysis, and acute renal failure (ARF) occurs in ∼40% of cases.²

Colistin (polymyxin E) is an effective antibiotic that was used often in the treatment of gram-negative infections in the 1980s. However, nephrotoxicity is a frequently encountered side effect,³ and for this reason, it has not been used very often in clinical settings in the years following the introduction of third-generation cephalosporins.³ Nevertheless, as resistance to the third-generation cephalosporins has developed in recent years, the use of colistin has come to be reconsidered.^3,4 The nephrotoxic effect of colistin is thought to be associated with increased membrane permeability, cell swelling and lysis, and the development of acute tubular necrosis.^3,5 Renal failure associated with rhabdomyolysis has been reported in only one case.⁶

Our purpose in this article is to report the case of a patient who developed rhabdomyolysis serious enough to cause tetraparesis and kidney failure after using colistin. There is only one report of rhabdomyolysis secondary to colistin in the literature, and there is no report of a case developing severe tetraparesis, as in our case. In that sense, our case is unique.

CASE HISTORY

A 49-year-old woman presented to our emergency department with a complaint of high fever, fatigue, and hemoptysis. During the emergency room examination, she was found to be conscious but with impaired orientation and cooperation; her temperature was 38.5°C, pulse was 92/min, arterial pressure was 130/60 mmHg, and respiration rate was 55/min; her conjunctivae were pale; and rales were detected in the lungs bilaterally up to the middle zones. Her other system examinations were normal. The laboratory test results were blood urea nitrogen (BUN) of 58 mg/dL, creatinine of 5.6 mg/dL, hemoglobin of 8.2 g/dL, platelets of 110,000 U/L, and white blood cells of 12,600/uL. Blood gas results were pH of 7.49, PCO₂ of 26 mmHg, PO₂ of 72 mmHg, HCO₃ of 21 mmol/L, and O₂ SAT of 97%. Complete urinalysis density was 1006, and the protein level was 30 mg/dL. The other laboratory tests are provided in Table 1. Pulmonorenal syndrome was suspected, as the patient, who was found to have a bilateral infiltration in her chest radiography, also had kidney dysfunction with acute respiratory failure. Intubation was performed, due to the patient’s tachypnea. Then, blood, urine, and tracheal aspirate cultures were collected. As the patient had a history of dealing with animal breeding, a sample was collected and sent for Hantavirus testing. Piperacillin–tazobactam 2 × 2.25 g intravenous therapy was initiated, because pneumonia could not be excluded. Samples were sent for antiglomerular basement membrane antibody, antinuclear antibody (ANA), Anti-dsDNA, and perinuclear antineutrophil cytoplasmic cell antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) tests to exclude other possible causes of pulmonorenal syndrome. Then, the patient, whose hemoptysis was continuing, was administered a single dose of cyclophosphamide 1 g and methylprednisolone 1 g i.v. for 3 days. During intensive care monitoring of the patient, occasional hemodialysis support was given according to her biochemical data and physical examination results. During this process, Hantavirus results were confirmed and, because the other autoimmune markers were negative, the immunosuppressive therapy was discontinued. A Hantavirus infection was considered to be responsible for the current clinical condition of the patient, and she was given supportive treatment and monitored. The patient’s fever decreased to normal on the 4th day of monitoring, and she remained anuric for 5 days; urination started on the 6th day. Her creatinine decreased to 0.9 mg/dL on the 10th day. The patient had fever again on the 15th day of her monitoring and, due to the growth of Acinetobacter in her tracheal aspirate culture, a colimycin 3 × 150 mg i.v. therapy was initiated. On the second day of the colimycin therapy, the patient’s fever subsided and she was extubated. Her physical examination was normal during extubation, but the level of creatinine increased on the 4th day of colimycin therapy, the urine color darkened, and the patient developed myalgia, with generalized muscle weakness of all four extremities. On neurological examination, muscle power was assessed as Grade II/V in the bilateral upper limbs and Grade I/V in the bilateral lower limbs on the Medical Research Council scale. There was no involvement of bulbar muscle, cranial nerve, or sphincter. Deep tendon reflexes were absent in all four extremities, and plantar responses were bilateral flexor. Sensory examination was normal. Nerve conduction studies revealed decreased compound motor action potential (CMAP) with normal distal latencies and conduction velocities in all four extremities, and preserved sensory nerve action potentials. Needle electromyography (EMG) study demonstrated fibrillation potentials, polyphasic, short duration, and low-amplitude motor unit potentials both in the proximal and distal muscles of all extremities, consistent with myopathy. Rhabdomyolysis was considered, because the patient’s creatine phosphokinase (CPK) level was 1370 U/L and myoglobin level was 2716 ng/mL. The levels of K, P, and uric acid were 5.4 mmol/L, 7.5 mg/dL, and 8.8 mg/dL respectively. The patient’s thyroid function tests were normal. The patient continued to urinate 2.5–3 L during this process, and she was given appropriate fluid support together with urine alkalization. The kidney function tests of the patient deteriorated after the colistin therapy; therefore, the therapy was discontinued on the 6th day. Three days after the discontinuation of the therapy, the patient’s BUN and creatinine levels started to decline, and muscle strength in her extremities began to improve. A 3-week follow-up later showed a marked improvement in muscle strength—Grade IV+/V in all four extremities. Follow-up nerve conduction tests and needle EMG revealed an improvement in CMAP (within normal limits near the lower limit), preserved sensory nerve action potentials, and absence of fibrillation potentials with mild myopathic pattern. CPK and myoglobulin levels were 17 U/L and 24.62 ng/mL, respectively.

Table 1.  Biochemical parameters of the patient.

	At the time of admission	At the time of extubation	At the time of colistin initiation	On the 4th day of colistin therapy	At the time of discharge
BUN (mg/dL)	58	37	39	112	30
Cr (mg/dL)	5.6	0.9	0.8	3.81	0.8
Na (mmol/L)	137	138	141	126	142
K (mmol/L)	3.1	3.8	3.5	5.4	3.8
Ca (mg/dL)	8.9	8.6	8.7	9.0	9.03
P (mg/dL)	4.9	3.15	2.4	7.5	3.4
TP (g/dL)	6.2	5.6	5.7	6.0	6.3
Alb (g/dL)	3.2	3	3	2.8	3.3
UA (mg/dL)	7.9	4.5	2.7	8.8	5.0
CK (U/L)	37			1370	50
Myg (ng/mL)				2716	35
Hb (g/dL)	8.2	8.2	7.7	10.2	8.6
WBC (U/L)	12,600	5300	16,700	16,500	6300
PLT (U/L)	110,000	104,000	90,000	244,000	237,000
CRP (mg/dL)	26.6	4.78	19.0	0.98	0.77
PH	7.49	7.42			7.43
PCO2 (mmHg)	26	35			37
PO2 (mmHg)	72	90			90
HCO3 (mmol/L)	21	22			24
O2 SAT	97	96			96

Note: BUN, blood urea nitrogen; Cr, creatinine; TP, total protein; Alb, albumin; Ca, calcium; P, phosphorus; CK, creatine kinase; Na, sodium; K, potassium; UA, uric acid; WBC, white blood cells; Hb, hemoglobin; PLT, platelets; Myg, myoglobin; CRP, C-reactive protein.

DISCUSSION

Rhabdomyolysis is a clinical condition that develops when cells swell and lysis as a result of intracellular increases of Ca and Na contents, due to increased permeability of the muscle cell membranes.¹ Release of the substances concentrated in muscle cells that lysis leads to organ damage. When the intracellular contents are released, hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, myoglobinuria, and a decline in pH are observed. Rhabdomyolysis may be traumatic or may occur due to nontraumatic causes, such as toxins, drugs, and infections, as well as hereditary, metabolic, and immunologic reasons and muscle ischemia.^1,7 Although its classical symptoms are muscle pain, muscle weakness, and darkening urine color, muscle weakness and pain may not be seen in nearly half of the patients. High levels of CPK and blood urine myoglobin in laboratory tests support the diagnosis.^1,7 The occurrence of kidney failure during rhabdomyolysis has been linked to many causes, but the most frequent mechanisms are renal vasoconstriction, tubular obstruction, and lipid peroxidation damage.^1,2 We considered nontraumatic rhabdomyolysis associated with the use of an antibiotic (colistin) in our patient, as there was an impairment of kidney function, development of muscle weakness, and a rise in myoglobulin and CPK levels after 4 days of using colistin.

Polymyxin E (colistin) had been used effectively to treat gram-negative infections for many years, but its use was later suspended due to its nephrotoxic side effect and the invention of third-generation cephalosporins. However, the use of this antibiotic has come to be reconsidered, due to the occurrence of multidrug-resistant Pseudomonas and Acinetobacter strains.^3–5 The mechanism blamed for the pathogenesis of its nephrotoxicity is swelling and lysis of the cells due to increased permeability of the cell membrane for ions such as Na and Ca. Acute tubular necrosis can also develop.³ We thought, in our case, that the mechanisms that caused or contributed to the renal damage were associated with rhabdomyolysis, as there was a weakening of muscles and an increase in CPK and myoglobin levels. There is only one report of rhabdomyolysis associated with colistin in the literature⁶ and our patient is the second such case to be reported. Furthermore, the tetraparesis (muscle power Grade II/V in the bilateral upper limbs and Grade I/V in the bilateral lower limbs) caused by rhabdomyolysis was quite severe in our patient, and there is no report in the literature of a case progressing with such severe tetraparesis. We think the pathogenesis of the rhabdomyolysis caused by colistin is the swelling of the muscle cells due to increased permeability of the cell membrane and the resulting lysis, similar as in its nephrotoxic effect.^3,6 The risk factors that facilitate the development of nephrotoxicity due to colistin include the presence of basal renal damage, the use of nephrotoxic drugs such as nonsteroidal antiinflammatory drugs and various antibiotics, serum albumin level, and dose of colistin.^3,8

We determined that the factors facilitating the renal damage due to colistin in our patient could be hypoalbuminemia and a history of ARF in the recent past. Tetraparesis occurred in the patient on the 4th day of colistin therapy, 2 days after the discontinuation of steroids, recovery from Hantavirus infection, and disconnection from the mechanic ventilator. For this reason, we determined that the present condition could be secondary to colistin and that the present comorbidities could be the factors facilitating the rhabdomyolysis.

Urine alkalization, appropriate hydration, and removal of the cause of rhabdomyolysis are accepted approaches today in treating rhabdomyolysis.⁹ We discontinued colistin therapy in our patient and administered urine alkalization and hydration. This process resulted in the recovery of kidney function, without the need for hemodialysis.

In conclusion, although the use of colistin is being reconsidered today, its nephrotoxic effect, which caused discontinuation of its use years ago, should be borne in mind. Moreover, it may be appropriate to include rhabdomyolysis in the traditionally known pathogenesis of nephrotoxicity. Weakness of muscles may be overlooked, especially in patients under sedation for whom the use of colistin is necessary in intensive care. Because this may cause a delay in extubation of such patients, a prolonged stay in the hospital, and ultimately, an increase in their mortality and morbidity, such patients should be monitored for urine color and quantity with respect to rhabdomyolysis. In addition, their CPK and myoglobulin levels, as well as kidney functions, should be checked at regular intervals.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.