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.