This document describes a case of statin-induced rhabdomyolysis in a 52-year-old man. He presented with chest pain and was found to have coronary artery disease, for which he underwent PCI. He developed complications including renal failure and was found to have markedly elevated CPK levels over 20,000. After two weeks, he was diagnosed with statin-induced rhabdomyolysis from his atorvastatin dose. He required continuous renal replacement therapy for over a week and his labs and symptoms gradually improved after stopping the statin. The case discusses the causes, presentation, and complications of rhabdomyolysis, including its association with hypernatraemia and potential liver injury.

1. Statin induced Myotoxicity
Rhabdomyolytic
Syndrome
Morbidity Case
Dr Asadullah Khan Soomro
Adult Cardiology department
Prince Sultan Cardiac Center Al-Ahsa.

3. Executive Summary
52 year saudi male newly diagnosed diabetes, admitted through
ER to our CCU on 31/12/2012 at around 4.05am .
He was referred from one of the secondary care hospital as ACS
for further management ,where he presented with H/O sudden
severe retrosternal ,prolonged chest pain with sweating ,woke
up from deep slumber at mid night.
In KFHH ER he developed heart failure and became hypoxic
therefore intubated & ventilated.
Chest X-ray showed normal heart size with pulmonary edema

4. Conti,
He was immediately transferred to cath lab & coronary angiogram
showed ,normal left main, LAD totally occluded proximaly,LCX,OM1
osteal 70%,OM2 good, distal LCX diffusely diseased. RCA totally
occluded after RV branch, fills retrogradely from left system, looks
chronic .
Primary PCI done to LAD with 2DES.
At the end of procedure developed monomorphic ventricular
tachycardia, which was reverted with single 150 jouls of DC shock,
had short CPR indeed.
He was hypotensive therefore IABP was inserted ,and shifted to CCU on
Amiodarone, dopamine , aggrastat,& lasix infusion.

5. Cont,
He remained critical ,but conscious, his intial CPK was 5887,MB,
617 ,with ratio of 10.4% ,creatnine was 133. Post PCI EKG
showed new RBBB with persistent ST elevation in leads V 4-6
.Still on IABP & on ventilator.( he was on clopidogrel, ASA ,
&40mg statin.
On 3rd Jan 2013 ,left sided weakness was noticed by nurses, at
night.
Next day 4th Jan on morning round at around 11 am it was
discovered that patient has developed stroke with left sided
hemiplegia, he was conscious but febrile ( 39C) he was on
ceftriaxone and tazocin,

6. CT brain was done on the same day, which was reported as small
hypodense lesion at left cerebellum , ( ? Old infarction), no mid
line shift ,no bleeding. Initially heparine was stopped and later after CT
brain ,restarted because of IABP.
Transthoracic echocardiogram did not showed apparent thrombus .
EKG showed RBBB, with persistent ST elevation in same leads.
his creatnine progresively increased from 133 to 215mg, CPK & MB ,
showed a downward trend for the next four days ,from 5887 to
794,MB from 617 to 59 ( yet not normalized, until 5th post MI day) )
.He was persistently hypernatraemic , ( Na,>150) seen by
nephrologist ,at this stage his HB,WBC,PLT and LFT remain stable.

7. Cont,
On 6th January ( 7th day of MI & statin) profile of cardiac enzymes
showed rising of CPK from 794 to 1043, MB, 60 ( ratio 7.5%),
creatnine 249, Na 156.
On 7th January pm ,CPK further increased to 2522,MB,75 ( ratio
2.9%), creatnine 206,Na, 162,K, 3.6,Ca, 1.8 platelets 100.
On 8th CPK further increased to 8926, MB,184 ( ratio, 2.0%)
creatnine 185, Na,164.K, 3.9, Ca 1.7
He remain on ionotropic support, he was extubated on 8th jan
2013.
Blood culture grew coagulase negative staphlococcus, and was
only susceptable to vancomycin, and was started

8. Cont,
IABP was tried to wean off but became hypotensive
60/30 on dopamine & levophed, he remain febrile
38C,ABG showed metabolic alkalosis, urinary out
put was 100-150ml/hour lasix infusion was reduced
from 5mg to 3mg/hour.
On 9th Jan became confused, developed hypotension
on dopamine & levophed, he was still febrile and
hypernatraemic.

9. Cont
On 12th jan because of persistent hypernatraemia ,he
was suspected for, diabetes insipidious,& pitutary
adenoma, seen by endocrinologist. After evaluation
,considered as sick thyroid, no DM insipidous,
discharged from his side and to be followed by
nephrologist for hypernatraemia. Results of hormonal
assays ( serum cotisol, ACTH, testosteron, FSH, LH &
prolactin) were with in normal range.
. Hepatitis Hbs, HCV& HIV remain negative

10. Cont,
He remain under care of nephrologist for renal failure and
hypernatraemia.
His CPK progressively incread to 18213, ( 9th jan) to, 21530,
38040 ,
On 15th jan highest peak of CPK 68405, renal function also
deteriorated ( from 168 to 322 & 404),Na 150,K
,4.9,Ca,1.7,Phos, 3.2, became oligouric , 30-40ml / hour and
later anuric at night .
Liver enzymes also increased significantly ( LDH,2640,GPT,824)
.

11. Cont,
On 16th jan , in acute renal failure, ( High creat,
Na, K Uric acid ,& posphorus, low Ca), he was
tachypnoeic ( ABG showed ,PH,7.3, PCO2,35,
PO2,95,Osat,97%, HCO3,18.6), Electively intubated
again.
He was reviewed by a nephrologist and first time CRRT
was started at 12.30pm.
Remain anuric on CRRT, however after dialysis, all
biochemical parameters started to regress , but CPK and
liver enzymes were still on higher side, despite on
CRRT,which was continued.

12. Until 19th jan ( 20th admission of day ,) he remain on 40mg
statin. ( undiagnosed rhabdomyolysis for two weeks)
At evening ,specialist on call evaluated the patient and first
time discover & diagnosed to have “statin induced
massive rhabdomyolyis”,& hepatic injury,
preceded by hypernatraemia, and progressed to acute
renal failure.
He was on ( HMG -co reductase inhibitor) statin( atorvastatin
40mg Qd, monotherapy) which was stopped ,& CRRT was
continued.
First time Urinary myoglobinurea done & came positive,
troponin T was negative .

13. Cont,
He remain anuric from 15th to 22nd jan,( 8 days) and ,on CRRT, which
was stopped on 23rd jan 5.20am ( on 8th day) because of
hypotension.
Subsequently on 24 th jan ,his 24 hour urinary out put became 2800,yet creatnine
was 171& 199,95 &55 electrolytes were stablized CPK became 278,136&97
LDH,476, 324& 264,GPT 131&98.
Urinary out put without dialysis remain between 2500 to 3000,with negative
balance of 700 to 1000ml.
On 2nd feb sputum culture grew Klebsiella pneumoni.
Still in CCU, conscious ,cardiologically compensated, renal function ,CPK
& liver enzymes have normalized, yet left sided dense hemiplegia, with
spiky fever.

14. LABORATORY
Admission
Hb, 15.8
Wbc, 16.0
PLT, 246,
INR, 0.94
Glucose, 28.5
BUN, 5.6
Creatn, 133
Uric acid, 277
GPT, 113
Alk.po4, 82
Tbil, 12.3
Tprot, 71.9
Albumin, 38
Admission
CPK, 5887
CK-MB
Cholest, 6.4
Trigly, 1.06
HDL, 2.09
LDL, 3.8
Na, 135
K, 3.6
Ca, 2.2

15. 31/12/2012
Admission
Day one
2/1/2013
Day
three
3/1/2013
Day
four
4/1/2013
Day
five
6/1/2013
Day
seven
7/1/2013
Day
eight
8,9,11/1/201
3
Day nine
12/1/2013
Day
thirteen
13/1/2013
Day
fourteen
CPK 5887 2044 895 794 1043 2522 8926
18213
21530
23036 38040
CKmb
ratio
617
10.4%
139
6.8%
59
6.5%
56
7.0%
60
5.7%
75
2.9%
184
2.0%
502
2.1%
Creatnin
e
133 170 157 215 249 206 185 128 165
Na/K 135/
3.4
150/3.
4
156/5.
1
155/3.
0
153/3.
8
162/3.
9
163/3.
9
156/4.
0
155
4.2
Vancomycin
level
Ibct
Iron
Sickling
positive
24 hour
Urinary
creatnine
Serum
osmolarity
Urine
protein/creat
ratio
Urine,Na
,K
Specific
gravity
9.3 26.9/3.6 Stool occult
blood
negative
10912 341.8 PCR( spot)
1.26
36/27.9 1.015

16. 15/1/2013
Day
sixteen
Oligo
uric/
Anuric
16/1/2013
Day
seventeen
CRRT
started
17/1/2013
Day eighteen
Anuric
19/1/2013
Day
twenty
Statin
stopped
20/1/2013
Day twenty
one
Anuric
21/1/2013
Day twenty
two
Anuric
22/1/2013
Day twenty
three
Anuric
23/1/2013
Day twenty
four
CRRT
Ended
24/1/2013
Day twenty
five
Urinary out
put
3195
CPK 68405
31242
20902 24371 12118 6786 2975 840 278 194
CKmb
ratio
1986
9.5%
2076
8.5%
302
2.4%
170
5.7%
111
2.9%
46
2.0%
67
2.1%
33
Creatnin
e
265 404 258 150 266 163 151 138 199
Na/K
Ca,phos
145/
4.8
150/4.9
1.7,3.2
137/4.
0
130/3.7
2.1.1.0
134/3.
8
133/3.
6
131/3.
5
137/4.
3
136
3.9
GPT/L
DH
824
2870
782
2739
803
2739
Troponin,
0.30
Urinay
myoglobib,
positive
340
560
131
297
Tbil,Tpro,Alb
,Uric acid
12.6,56,22
,548
8.3,53,21,
588
184 110 253 136 205 280

22. Discussion
Causes of High Creatine –phosphokinase
1) Cardiac 7) Metabolic
2) Skeletal 8) Auto-immune
3)Drugs 9) Heat stroke
4)Alcohol 10) Malignant hyperpyrexia
5)Infectious 11)Muscular dystrophy
12) Miscellaneous
6) Endocrine

23. Statin induced Myotoxicity
Rhabdomyolytic Syndrome
Statins are generally well tolerated, most cost effective& widely prescribed drugs
currently available for treatment of dyslipidaemia& coronary artery syndromes.
They are rapidly absorbed in 1-2 hours , & Mean plasma half life is
approximately 14hours. They under go metabolism via cytochrome P3A4 -A5.
98% Statins are bound to plasma proteins , because of this, haemodialysis is
not expected to significantly enhance statin clearance due to extensive drug
binding.
Statin induced myopathy occuring in 0.1% to 0.5% of population ,may
progress toward rhabdomyolysis while patients continue to take the drug.
The true incidence of statin associated rhabdomyolysis is not exactly clear because
of rarity of this condition.
The fatal rhabdomyolysis is rare, 0.12per one million

24. Cont,
Elevation in CK are conventionally used in the diagnosis of both
rhabdomyolysis & acute coronary syndromes, along with other
markers and may cause diagnostic confusion when both
conditions co-exist.
Skeletal muscle release of CK & MB generally remain elevated
for longer time, than myocardial release with temporal rise &
fall, rise after 4-8 hours and peak at 24 hours and decline after
48 to 72 hours.
Troponin may accurately distinguishes skeletal from cardiac
muscle damage.

25. Cont,
A frequent cause of drug induced Rhabdomyolysis today is
administration of HMG-CO, reductase inhibitors ,which are
most important & frequently prescribed cardiac drugs in ACS
due to their pleomorphic effect.
Rhabdomyolysis may range from asymptomatic subclinical rise in
CK to life threatening acute renal failure. In one of the study of
812 patients of statin induced rhabdomyolysis ,mean age was
64.4 yrs,35.5% were females.
The worst outcome reported were renal dysfunction in
17%,acute renal failure in 19.8%,dialysis in 5.2%,and death in
7.6% ( rhabdomyolysis is dose related 10mg statin 3.8% &
with 40mg 11.3%) .

26. Statin induced Myotoxicity
Rhabdomyolytic Syndrome
Skeletal muscle is a complex heterogenous mixture of cell types that
composes 40% adult body mass. CK,MM is abundantly present in skeletal
muscle,and is most specific test for diagnosis of rhabdomyolysis, typically
peaks 2-5 days after initial insult, CK remain in circulation longer than
myoglobin.
Rhabdomyolysis is literally dissolution of skeletal muscle, potentially life
threatening condition, may lead to fatal irreversible renal damage
through series of biochemical reactions. It is characterized by ,
1) Markedly elevated CPK > ten times ( >16000 likely to cause renal failure)
2) Myalgia, myositis & myopathy.
3) Dark( Port wine/ tea color) urine, due to myoglobinurea

27. Hypernatraemia & Rhabdomyolysis
Hypernatraemia in rhabdomyolysis is reported to be associated
as both cause and effect.
The pattern of persistent hypernatraemia with elevated CK raised
the suspicion of rhabdomyolysis in spite of the absence of other
clinical feature.
The persistent hypernatraemia caused by rhabdomyolysis guide us to
correct diagnosis.
The hypernatraemia in this setting should not be treated with free water
as in usual case of hypernatraemia and dialysis would be more
appropriate method of treatment.

28. Statins & liver
Mild increase in liver enzymes approximately occur
in 1-3%.Clinically important & idiosyncratic, liver
injury is probably very rare, and can be associated
with severe outcome, mostly occur 3-4 month after
statin treatment.
It can be cholestatic or hepatocellular injury
,and similar pattern of liver injury can be
reproduced on re-exposure.

29. Complications of Rhabdomyolysis
Early complications of rhabdomyolysis includes, electrolyte
abnormalties, like hypokalemia (causing cardiac arrhythmias and
possibly cardiac arrest), hypocalcemia, hypernatremia ,hyperkalemia
&hepatic dysfunction.
Late complications occuring after 12-24hours include acute renal
failure ( 4 to 33% due to direct toxic effect of myoglobin on epithelial
cells of proximal convoluted tubules, full recovery of renal function is common
irrespective of rhabdomyolysis cause, however mortality may still be as high as
8%.
Compartmental syndrome is rare but if not addressed with in 6-8 hours,
irreversible ischemic muscle & nerve damage may occur,
Finally disseminated intravascular coagulation ( DIC) and multi-organ failure are
dreaded complications in adults.

30. Precipitating Factors &Cautions.
1) Hepato-renal impairment
2) DM, Hypothyroidism
3) Personal or familial H/O hereditary muscular disorders
.
4) Previous H/O myotoxicity with statins or fibrates.
5) If CPK level are significantly elevated > 5times,or
concomitant drugs, fibrates, gemfibrozil, treatment
should not be started
6) Treatment should be stopped if > 10 times or evidence
of rhabdomyolysis.

31. Excess intracytoplasmic calcium causes muscle
destruction and fiber necrosis, leading to excessive
potassium, phosphate myoglobin, creatne kinase
and urate release in to systemic circulation
The most sensitive biochemical indicator ,a creatine
kinase reading at least 5 times higher than normal,
is the accepted diagnostic standard.
A ratio of blood urea nitrogen to serum creatinine of
6:1 or less indicates increased creatinine release
from skeletal muscle and renal dysfunction. An
increase or decrease in K, Po4 or Ca may occur,
depending on severity,duration & management of
rhabdomyolysis.

32. Management & prevention
The treatment goal is to stop muscle destruction. The following steps
should be taken,
1) Eliminate exposure to the toxic agent
2) Begin symtomatic treatment immediately in pts with acute
rhabdomyolysis.
3) Correct and controll hyponatraemia, hypernatraemia,
hyperglycaemia, hypocalcemia and decrease phosphorus.
4) Restore intravascular volume.
5) Alkalinizing the urine and mannitol may be effective in some patients
with acute renal failure. Patient with severe metabolic abnormalties
and renal dysfunction may require dialysis.

33. Conclusion
1) In hospital acquired acute renal failure if etiology is sorted out
,one can prevent iatrogenically induced renal injury ,and may
reverse the course of acute renal failure.
2) If rhabdomyolysis is recognized early & promptly treated , the
complications are preventable and syndrome has excellent
prognosis.
3) Finally patient, nurses,& doctors education should focus on
preventing and minimizing adverse effects of statins. It may cause
silent progressive renal failure ( days to year) therefore regular
monitoring in high risk patients is mandatory to avoid irreversible
renal failure.