DISCUSSION
Patients with rhabdomyolysis usually present with myalgia, weakness, dark urine (myoglobinuria), and prodromal systemic symptoms like fever and malaise [2]. Rhabdomyolysis itself as the presenting feature of an otherwise asymptomatic COVID-19 infection, is rare [7]. Diagnosis of rhabdomyolysis is made by consistent clinical features and serum CK potassium and phosphate, all released from lysed myocytes. Hypocalcemia can occur secondary to intravascular calcium-phosphate binding. However, this patient did not have any electrolyte abnormalities. Increased creatinine above the baseline, indicates pigment-induced AKI, which this patient had [2, 3]. A diagnosis of myoglobinuria is suggested by dipstick positive for blood (by detecting myoglobin), but no RBCs on microscopy, and simultaneously elevated CK and transaminases in blood (to differentiate from haemoglobinuria) [8].
Rhabdomyolysis is managed by aggressive intravenous fluid resuscitation to prevent or treat AKI, with careful titration to the urine output. It may be prudent to consider the volume status of the patient as well. In this particular case, it can be stated retrospectively that over-hydration should have been prevented, given the patient was already volume-overloaded at the time of presentation. Intravenous albumin supplementation alone may have been sufficient to increase intravascular volume. Whenever CK levels are more than 30,000 IU/L, forced alkaline diuresis with sodium bicarbonate is a good option, whereby the urine is alkalinized to prevent precipitation of myoglobin in the distal convoluted tubules. Treatment of the cause and treating electrolyte abnormalities are also important [2, 9, 10].
The patient in this case had a few risk factors for the development of rhabdomyolysis such as medications (atorvastatin, levetiracetam and antipsychotics), statin-cyclosporine interaction resulting in elevated statin levels, and hypothyroidism. He also had hypoalbuminemia secondary to FSGS, which is a poor prognostic factor, increasing the risk of AKI in rhabdomyolysis [3]. The patient had no documented evidence of rhabdomyolysis in the past. Furthermore, the potential triggers he had for rhabdomyolysis were injury due to the fall, possible seizure, and the incidentally discovered COVID-19 infection. However, the likely etiology is the COVID-19 infection, and in the trailing discussion, we have tried to rule out all other possible triggers.
The fall episode as described by the patient did not sound seizure-related, and he did not recount any recent episode of seizure. Creatine kinase levels in rhabdomyolysis secondary to seizure activity peak within 24-72 hours and the rate of decline is also relatively constant, decreasing by about 39 per cent of the previous day’s value, in a regular downward trend [5]. In this patient the CK was already or had peaked before admission. Two days after the fall, CK was 11671 and rose to 13539 the day after, then dropped by 27.4 per cent in a day to 9699, suggesting an irregular pattern. Furthermore, the rhabdomyolysis was unlikely to have been caused by the fall itself, as the patient neither sustained significant muscle injury nor was he immobilized for long. Most cases of rhabdomyolysis, severe enough to cause AKI, are seen in patients who fall unconscious and are unable to move for many hours and develop enough trauma to the muscles just from body weight. This patient sustained minimal trauma from the fall, without being immobile on the floor for any length of time. Also, high levels of CK were seen on the same day as the fall and thereafter only trended downwards. Muscle injury induces a rise-peak-fall type of CK pattern, hence making it unlikely to be the trigger here [2]. The patient had also complained of increasing bilateral lower extremity swelling with pain over a few days before admission, suggesting that rhabdomyolysis likely predates his admission. In addition, his raised ESR with subsequent falling trend, points more towards infection versus inflammatory state. Thus, COVID-19 was the most likely trigger for rhabdomyolysis.
Of the risk factors predisposing the patient to rhabdomyolysis, atorvastatin with concomitant use of cyclosporine appears the most important. Statins are well-known to cause a spectrum of myopathies, ranging from myalgia to rhabdomyolysis [11]. The risk of rhabdomyolysis with statin is usually within one month after its onset or when the dose is intensified. Our patient was taking the same dose of statin for many years. However, considering that he is also on cyclosporine, which has pharmacokinetic interactions with statins and increases statin levels, the risk is increased more than with statin alone. Also, his cyclosporine dose was increased a month before his admission, given the sub-therapeutic levels. Atorvastatin has been reported to cause rhabdomyolysis when used along with cyclosporine, and its pharmacokinetic and pharmacological properties make such a drug interaction likely [12]. Levetiracetam may also cause rhabdomyolysis as one of its rare side effects, but it’s usually observed within three days of initiation of the drug [13, 14]. This patient has been taking levetiracetam for years. However, levetiracetam levels were found to be elevated in this patient, almost double the therapeutic maximum, which could be due to impaired excretion in the setting of AKI. Rhabdomyolysis is a rare complication of hypothyroidism but is only seen if the patient is not adherent to treatment, which is not the case here [15]. Lastly, the patient was on antipsychotics, which are known to cause rhabdomyolysis even in the absence of neuroleptic malignant syndrome [16, 17]. Both aripiprazole and risperidone have been implicated in this regard [18, 19]. However, the patient had been taking them for a few years, hence they are unlikely to be the cause of rhabdomyolysis.