Basic principles of laboratory medicine : Dr R Sirkar

RHABDOMYOLYSISRHABDOMYOLYSIS

DR.S.C.COKA DR.S.C.COKA 2008 2008

CASECASE

•• 24 yr old male referred from 24 yr old male referred from NorthdaleNorthdale hospital with a diagnosis of Acute hospital with a diagnosis of Acute Renal Failure due to urinary retention(?)Renal Failure due to urinary retention(?)

HX:HX:10 days prior to presentation10 days prior to presentation-- 2 days 2 days hxhx of gastroenteritisof gastroenteritisvomittingvomitting –– 4 episodes over the 2 days.4 episodes over the 2 days.

non bilious, no non bilious, no haematemesishaematemesisoccurred post occurred post prandiallyprandially

DiarrhoeaDiarrhoea-- watery stools x4 episodes daily for the 2 dayswatery stools x4 episodes daily for the 2 daysno dysentery, no mucus in stoolsno dysentery, no mucus in stoolsassociated abdominal pain, not related to mealsassociated abdominal pain, not related to meals described described cramping in nature, no exacerbating factorscramping in nature, no exacerbating factors++veve hxhx of herbal medicine ingestion prior to the GEof herbal medicine ingestion prior to the GE

NO NO hxhx of of preceedingpreceeding upper respiratory tract infectionupper respiratory tract infectionNO change in frequency nor burning of NO change in frequency nor burning of micturitionmicturition. No change of urine . No change of urine colourcolour

History continuedHistory continued

Previously wellPreviously wellTested RVD negative in December 2007Tested RVD negative in December 2007No No hxhx of NSAID useof NSAID useNo No hxhx of recurrent of recurrent UTIsUTIsNo complaints of photosensitivity, rashes nor joint painsNo complaints of photosensitivity, rashes nor joint painsNo illicit drug usageNo illicit drug usageNo No hxhx of jaundice previouslyof jaundice previously

PMH and PSHPMH and PSH: nil: nilSHSH: sober habits: sober habits

security guardsecurity guard

ExaminationExamination

GeneralGeneral:: healthy lookinghealthy lookingweight 63.35kgweight 63.35kgBP 139/62 Pulse=71 all present and =, normal BP 139/62 Pulse=71 all present and =, normal volume RR=16 volume RR=16 b/mb/mapyrexialapyrexial , GR=3.6 , GR=3.6 mmol/lmmol/lno excoriations, no oral thrush nor no excoriations, no oral thrush nor LNsLNsno clubbing nor no clubbing nor leuconychialeuconychiaminimal pedal minimal pedal oedemaoedema but no pallorbut no pallordehydrateddehydratedno evidence of hypertensive retinopathyno evidence of hypertensive retinopathydiffusely tender muscles with no evidence of atrodiffusely tender muscles with no evidence of atrophy or phy or weakness. No heliotrope rash nor weakness. No heliotrope rash nor goitrensgoitrens papulespapulesno features of connective tissue disorderno features of connective tissue disorderno no ecchymosesecchymoses nor nor purpurapurpura

Systems examinationSystems examination

Respiratory systemRespiratory system::RR: 16 RR: 16 Breathing appeared shallowBreathing appeared shallowB/S= bilaterallyB/S= bilaterallyNo pleural effusionsNo pleural effusions

Cardiovascular systemCardiovascular system::Not in heart failure Not in heart failure Apex beat in 5ICS/ MCL Apex beat in 5ICS/ MCL S1S2 presentS1S2 presentNo murmursNo murmursNo pericardial friction rubNo pericardial friction rub

AbdomenAbdomenNot distendedNot distendedSoft but tender on deep palpation diffuselySoft but tender on deep palpation diffuselyNo No hepatosplenomegalyhepatosplenomegalyNo No ascitesascitesNo renal massesNo renal massesBS presentBS present

CNSCNSFully alert and orientatedFully alert and orientatedNo No meningismmeningismNo focal neurologyNo focal neurology

Urine Urine dipstixdipstix: dark urine: 2+ blood: dark urine: 2+ bloodno proteinno proteinno leucocytesno leucocytes

200mls of concentrated dark urine were in catheter200mls of concentrated dark urine were in catheterbag that had been placed 18 hrs before.bag that had been placed 18 hrs before.

Assessment:Assessment:24 yr old RVD negative male, previously well, with 24 yr old RVD negative male, previously well, with

documented renal failure and documented renal failure and haematuriahaematuriapreceededpreceeded by a bout of gastroenteritis and herbal by a bout of gastroenteritis and herbal medicine ingestion. Clinically he is dehydrated medicine ingestion. Clinically he is dehydrated and and acidoticacidotic with a moderately elevated blood with a moderately elevated blood pressure and evidence of a pressure and evidence of a myositismyositis. .

Differential DiagnosisDifferential Diagnosis

1.1. Acute renal failure due to Acute renal failure due to hypovolaemiahypovolaemia secondary to acute secondary to acute gastroenteritisgastroenteritis

2.2. Acute renal failure due to acute tubular necrosis secondary to Acute renal failure due to acute tubular necrosis secondary to herbal ingestionherbal ingestion

3.3. Post streptococcal Post streptococcal glomerulonephritisglomerulonephritis

4.4. Rapidly progressive Rapidly progressive glomerulonephritisglomerulonephritis

5.5. RhabdomyolysisRhabdomyolysis

Investigations:Investigations:

1.1. FBC:FBC:WCC 8.0 WCC 8.0 HbHb 12.6 PLT 36812.6 PLT 368

2.2. U+E:U+E:Na 120mmol/lNa 120mmol/lK K 6.496.49HCO HCO 19.319.3Urea Urea 71.271.2CreatCreat 14831483Ca 1.95Ca 1.95PhosPhos 2.69 2.69 Mg 1.05Mg 1.05

3.3. LFT:LFT:TP 53 ALB 23 GGT 70 ALT 473 LDP TP 53 ALB 23 GGT 70 ALT 473 LDP 88708870 CK CK 182918182918

4.4. Rapid HIV Rapid HIV ––VEVE HEP B HEP B --VEVE

5.5. ECGECG-- peaked T wavespeaked T waves

Investigations continuedInvestigations continued

BloodgasBloodgas: pH 7.31: pH 7.31pCO2 3.83 pCO2 3.83 kPakPapO2 12.12 pO2 12.12 kPakPaHCO3 17.8 HCO3 17.8 mmol/lmmol/lBE BE --8.3 8.3 mmol/lmmol/lO2sat 96.8 % at room air O2sat 96.8 % at room air Anion gap 18.1 Anion gap 18.1 mmol/lmmol/l

ASSESSMENT at this timeASSESSMENT at this time: 24 yr old male, RVD : 24 yr old male, RVD negative, negative, HepHep B rapid negative, in acute renal failure B rapid negative, in acute renal failure secondary to secondary to rhabdomyolysisrhabdomyolysis. Clinically he is . Clinically he is acidoticacidotic, , dehydrated and dehydrated and oliguricoliguric. Biochemistry . Biochemistry revealesreveales a a metabolic acidosis, metabolic acidosis, hyperkalaemiahyperkalaemia with with electrocardiographicelectrocardiographic changes. He is a candidate for changes. He is a candidate for haemodialysishaemodialysis

Acute managementAcute management1. 1. Central venous line placementCentral venous line placement

CVP reading was 8cm H2O. He was CVP reading was 8cm H2O. He was rehydratedrehydrated with normal salinewith normal salinevigorously, aiming to achieve a CVP=10vigorously, aiming to achieve a CVP=10--12cm12cm

2. 2. Potassium shift was commencedPotassium shift was commenced..He was also placed on He was also placed on salbutamolsalbutamol nebulisationnebulisation..

3. 3. Strict output and intake monitoring.Strict output and intake monitoring.

4. 4. Urine for MC+SUrine for MC+S was collected looking for was collected looking for pigmented casts.pigmented casts.

5. A 5. A renal ultrasoundrenal ultrasound was booked to assess kidney size and excludewas booked to assess kidney size and excludeobstruction.obstruction.

6. Placed on a 6. Placed on a renal diet.renal diet.

7. 7. TFT, TFT, collagen vascular screen tests were done.collagen vascular screen tests were done.

RhabdomyolysisRhabdomyolysis-- HaemHaem pigment pigment nephropathynephropathy

Syndrome Syndrome characterisedcharacterised by:by:--muscle necrosismuscle necrosis--release of intracellular potentially release of intracellular potentially nephrotoxicnephrotoxic contentscontentsinto the circulation.into the circulation.

Severity ranges from:Severity ranges from:--asymptomatic elevation of muscle enzymesasymptomatic elevation of muscle enzymes--life threatening cases with extreme muscle enzymelife threatening cases with extreme muscle enzymeelevation, electrolyte imbalances and acute renal failureelevation, electrolyte imbalances and acute renal failure

Causes of Causes of rhabdomyolysisrhabdomyolysis1. 1. Muscle injuryMuscle injury Trauma,Trauma, pressure necrosis,pressure necrosis,

electric shock, acute v. electric shock, acute v. dxdx

2. 2. MyofibreMyofibre exhaustionexhaustion seizures, excessivseizures, excessive exercise; e exercise; heat exhaustionheat exhaustion

3. 3. ToxinsToxins alcohol, cocaine, heroin, alcohol, cocaine, heroin, amphetamines, ecstasy, snake amphetamines, ecstasy, snake bitebite

4. 4. Electrolyte disturbancesElectrolyte disturbances hypokalaemiahypokalaemia, , hypophosphataemiahypophosphataemia,,excess water shiftsexcess water shifts

5.5. InfectionsInfections HIVHIV, , coxackiecoxackie, EBV, Salmonella, , EBV, Salmonella, StaphStaphLegionellaLegionella, Strep pneumonia, Strep pneumonia

6.6. FamiliaFamilial l malignant hyperthermia, malignant hyperthermia, McArdleMcArdle’’ss dxdx,,

7. 7. OtherOther Hypothyroidism, Hypothyroidism, polymyositispolymyositis,,dermatomyositisdermatomyositis

Causes examinedCauses examined1. 1. MyofibreMyofibre exhaustionexhaustion

--subclinicalsubclinical myoglobinaemiamyoglobinaemia, , myoglobinuriamyoglobinuria andandincreased CKincreased CK-- common post physical exertion.common post physical exertion.--risk factors for massive risk factors for massive rhabdomyolysisrhabdomyolysis during exertion:during exertion:* untrained individual* untrained individual* exertion in extremely hot/ humid conditions* exertion in extremely hot/ humid conditions* impairment of heat loss during sweating by use of Ach* impairment of heat loss during sweating by use of Ach* individual with sickle cell trait at high altitudes* individual with sickle cell trait at high altitudes* * hypokalaemiahypokalaemia caused by K loss from sweatingcaused by K loss from sweating

2. Drugs2. DrugsStatinsStatins::--Muscle toxicity remains concern.Muscle toxicity remains concern.

--MyopathiesMyopathies are common but are usually mild.are common but are usually mild.

--RhabdomyolysisRhabdomyolysis with ARF is not seen in patients without with ARF is not seen in patients without other risk factorsother risk factors--use of concurrent use of concurrent macrolidemacrolide antibiotics,antibiotics,digoxindigoxin, , antifungalsantifungals and and warfarinwarfarin..

In study of 252,460 patients treated with In study of 252,460 patients treated with statinsstatins the incidence of the incidence of rhabdomyolysisrhabdomyolysiswas 0.44was 0.44--10,000 patient years (95% CI)10,000 patient years (95% CI)Death due to Death due to statinstatin induced induced rhabdomyolysisrhabdomyolysis occurred at rate of 0,15 per million scripts occurred at rate of 0,15 per million scripts in the US .in the US .CervastatinCervastatin was was withdrwawnwithdrwawn from market as a result.from market as a result.

Biopsy of muscle Biopsy of muscle revealesreveales myonecrosismyonecrosis without without vasculitisvasculitis or inflammation.or inflammation.

In a In a pxpx who developed who developed rhabdomyolysisrhabdomyolysis secondary to secondary to statinstatin, these drugs should not be used. A trial, these drugs should not be used. A trialof of statinstatin therapy may be initiated if therapy may be initiated if rhabdomyolysisrhabdomyolysis occurred in the presence of a risk factor.occurred in the presence of a risk factor.

Non Non statinstatin lipid lowering therapy may also cause recurrence in patients wilipid lowering therapy may also cause recurrence in patients with th statinstatin inducedinducedrhabdomyolysisrhabdomyolysis

3. Electrolyte disorders3. Electrolyte disorders

-- HypophosphataemiaHypophosphataemia-- HyponatraemiaHyponatraemia-- HypokalaemiaHypokalaemia

Both Both hypophophataemiahypophophataemia end end hypokalaemiahypokalaemia may alsomay alsounderscore the severity of the total body deficiency of theseunderscore the severity of the total body deficiency of theseelectrolytes as there is release of these electrolytes from intrelectrolytes as there is release of these electrolytes from intracellularacellularstores during stores during myonecorosismyonecorosis..

HypophosphataemiaHypophosphataemia causes ATP production impairment resulting incauses ATP production impairment resulting inmuscle injury.muscle injury.

Peak elevation of CK may occur 48Peak elevation of CK may occur 48--96 hrs after the development of96 hrs after the development ofhyponatraemiahyponatraemia and may persist even after Na replacementand may persist even after Na replacement

4. Metabolic 4. Metabolic myopathiesmyopathies

RhabdomyolsisRhabdomyolsis may develop in individuals with abnormal muscle as inmay develop in individuals with abnormal muscle as ininherited disorders of inherited disorders of glycogenolysisglycogenolysis, , glycolysisglycolysis , , purinepurine and lipid metabolismand lipid metabolism

--accounts for a small %accounts for a small %--suspect in recurrent suspect in recurrent rhabdomyolysisrhabdomyolysis--77 patients with idiopathic 77 patients with idiopathic myoglobinuriamyoglobinuria had musclehad musclebiopsy. *enzyme deficiencies were identified in 36 biopsy. *enzyme deficiencies were identified in 36 pxpx

* * carnitinecarnitine palmitolytransferasepalmitolytransferase was the most was the most common common d/od/o in 17/36 followed by in 17/36 followed by myophosphorylasemyophosphorylasedeficiency.deficiency.

--result of deficiency is insufficient energy production in exerciresult of deficiency is insufficient energy production in exercisingsingmuscle with depletion of ATP and loss of muscle muscle with depletion of ATP and loss of muscle intergrityintergrity

Suspect in the ff casesSuspect in the ff cases1.1. Recurrent Recurrent rhabdomyolysisrhabdomyolysis after exertion/ viral illnessafter exertion/ viral illness2.2. HxHx of exercise intolerance with of exercise intolerance with recuurrentrecuurrent cramps and fatigue beginning in cramps and fatigue beginning in

childhoodchildhood3.3. Family Family hxhx of of rhabdomyolysisrhabdomyolysis in siblingsin siblings4.4. Normal strength during Normal strength during interictalinterictal periodsperiods

5. Malignant hyperthermia5. Malignant hyperthermia

Syndrome Syndrome characterisedcharacterised by:by:--feverfever--generalisedgeneralised muscular contraction and rigiditymuscular contraction and rigidity--metabolic acidosis and metabolic acidosis and rhabdomyolysisrhabdomyolysis--mostly occurs after inhalation of mostly occurs after inhalation of anaestheticanaesthetic agents in susceptibleagents in susceptiblepeoplepeople--mostly inherited as mostly inherited as autosomalautosomal dominant but recessive inheritancedominant but recessive inheritancehas been reportedhas been reported--may occur with other may occur with other myopathiesmyopathies egeg DuchennesDuchennes and central coreand central core

Defect may be in calcium binding by Defect may be in calcium binding by sarcoplasmicsarcoplasmic reticulum. An reticulum. An excess release of calcium occurs into the excess release of calcium occurs into the myoplasmmyoplasm in response toin response tov.ariousv.arious drugs.drugs.

6. Endocrine disorders6. Endocrine disordersa. Hypothyroidisma. Hypothyroidism--frequently associated with frequently associated with myalgiasmyalgias and mild to moderateand mild to moderateCK elevationsCK elevations--In one case report an individual with hypothyroidism In one case report an individual with hypothyroidism showed marked increases in CK and showed marked increases in CK and myoglobinuriamyoglobinuria afterafterexercise.exercise.

Postulate: deficiency of thyroid hormone impairsPostulate: deficiency of thyroid hormone impairsglycogenolysisglycogenolysis and places individual at risk during exerciseand places individual at risk during exercise

Rarely : hyperthyroidism due to increased cellular demands ofRarely : hyperthyroidism due to increased cellular demands ofhypermetabolichypermetabolic statestate

b. Diabetes during DKA secondary to electrolyte abnormalitiesb. Diabetes during DKA secondary to electrolyte abnormalities

c.c. PheochromocytomaPheochromocytoma secondary to vasoconstriction and muscle secondary to vasoconstriction and muscle ischaemiaischaemiadue to due to catecholaminescatecholamines

PathophysiologyPathophysiology of of rhabdomyolysisrhabdomyolysis

ATP depletion leads to ATP depletion leads to --intracellular Ca accumulationintracellular Ca accumulation-- proteases e.g. proteases e.g. calpaincalpain and and phospholipasephospholipase e.g. e.g.

PLA2 and other PLA2 and other degradativedegradative enzyme activationenzyme activation-- myofibril and membrane myofibril and membrane phospholipidphospholipid damage occursdamage occurs-- Mitochondrial injury generates O2 free radicals resulting in oxiMitochondrial injury generates O2 free radicals resulting in oxidative dative

stress.stress.-- Cell protection may occur by limited Ca delivery, decreased Cell protection may occur by limited Ca delivery, decreased

production of oxidative radicals and local acidosis.production of oxidative radicals and local acidosis.-- Reperfusion removes protective mechanism with resultant cell Reperfusion removes protective mechanism with resultant cell

damage.damage.-- MyoglobinMyoglobin gains access to systemic circulation and fluid gains access to systemic circulation and fluid

sequestration occurs leading to intravascular volume sequestration occurs leading to intravascular volume comtractioncomtraction..-- Sympathetic nervous system activation and RAS activation resultiSympathetic nervous system activation and RAS activation resulting ng

in renal vasoconstriction. in renal vasoconstriction. EndothelinEndothelin and and thromboxanethromboxane may play a may play a role.role.

-- MyoglobinMyoglobin--filtered to filtered to glomerulusglomerulus and is toxic to tubular cells.and is toxic to tubular cells.-- Precipitation of Precipitation of myoglobinmyoglobin and and tammtamm horsfallhorsfall protein and sloughed protein and sloughed

cells form obstructing casts in distal cells form obstructing casts in distal nephronnephron..

Clinical featuresClinical features

--patients may present with or without renal failurepatients may present with or without renal failure--volume depletion is prominent due to fluid sequestrationvolume depletion is prominent due to fluid sequestrationin musclein muscle-- Blood pressure may be preserved due to scavenging effect of Blood pressure may be preserved due to scavenging effect of

myoglobinmyoglobin on nitric oxideon nitric oxide-- Injured muscle may not be apparent and muscle pain may be Injured muscle may not be apparent and muscle pain may be

absentabsent-- In muscles confined to rigid compartments, a compartment In muscles confined to rigid compartments, a compartment

syndrome may ensuesyndrome may ensue-- CK usually > 10 000 u/mlCK usually > 10 000 u/ml-- HyperkalaemiaHyperkalaemia, , hyperphoshataemiahyperphoshataemia and and hyperuricaemiahyperuricaemia-- Lactic acidosis may occur due to anaerobic metabolismLactic acidosis may occur due to anaerobic metabolism-- Hypocalcaemia is typical in acute stage due to deposition in musHypocalcaemia is typical in acute stage due to deposition in musclecle-- HypercalcaemiaHypercalcaemia occurs during recovery with occurs during recovery with mobilisationmobilisation from from

musclemuscle-- Urine is red brown due to Urine is red brown due to myoglobinmyoglobin with pigmented casts on MCSwith pigmented casts on MCS-- Low fractional excretion of Na due to volume depletion.Low fractional excretion of Na due to volume depletion.

ManagementManagement

1.1. Aggressive volume repletionAggressive volume repletion-- typical regimen is normal saline typical regimen is normal saline initially at 1initially at 1--1.5L/h aiming for a urine output of 300mL/h1.5L/h aiming for a urine output of 300mL/h

2.2. Consider alkaline Consider alkaline mannitolmannitol diuresisdiuresis but only when UO is sufficient but only when UO is sufficient to prevent HCO3 and to prevent HCO3 and mannitlomannitlo accumulation in serumaccumulation in serumhalf normal saline with 75mmol/l NaHCO3 may be used as fhalf normal saline with 75mmol/l NaHCO3 may be used as fluid luid replacement aiming for urine pH>6.5 with replacement aiming for urine pH>6.5 with mannitolmannitol infusion at infusion at 10ml/hr10ml/hrBe careful of Be careful of metabolic alkalosismetabolic alkalosis..

3.3. HaemodialysisHaemodialysis

Patient progressPatient progress

Dialysis was commenced the next morning. Had 4 sessions. Dialysis was commenced the next morning. Had 4 sessions. Became Became polyuricpolyuric. Meticulous fluid balance was attempted.. Meticulous fluid balance was attempted.Urea and Urea and creatininecreatinine levels were within normal limits on FFDlevels were within normal limits on FFD

Ultrasound showed kidneys which were 10.3Ultrasound showed kidneys which were 10.3®®and 10.5 (L) respectively. No and 10.5 (L) respectively. No hydronephrosishydronephrosis..

Urine MCS showed epithelial castsUrine MCS showed epithelial casts

TFT and collagen vascular screen were normal. TFT and collagen vascular screen were normal.