DR. FATHI NEANACHIEF OF ORTHOPEDICS

DR. FAKHRY & ALRAJHY HOSPITALSAUDI ARABIA

NOVEBER, 30 - 2016

RhabdomyolysisCauses, Pathophysiology & Management

Rhabdo •Striated

Myo •Muscle

Lysis •Breakdown

RhabdomyolysisRhabdo •Striated

Myo •Muscle

Lysis •Breakdown

Breakdown of skeletal muscle fibers

Potentially life-threatening syndrome

Leakage of muscle contents into the circulation

• Tea or coca cola like urine : breakdown of muscle fibers, specifically the sarcolemma resulting in release of myoglobin -> may cause acute kidney injury or

renal failure• Oliguria : Shift of extracellular fluid into injured muscles -> hypovolaemia & under

perfusion of the kidneys

Rhabdo •Striated

Myo •Muscle

Lysis •Breakdown

First clue1- Tea or coca cola like urine

2- +ve urine myoglobin 3- Oliguria

History• First reported in 1881, in the German literature . • In 1910 Myer-Betz Syndrome, (German physician) - Triad:

Muscle Pain, Weakness, Brown Urine.

• World War II– First described in the victims of crush injury . Dr Bywaters described

patients during London Bombings (Battle of Britain 1941).– Oliguria, pigmented casts, limb oedema, shock & death.

• In 1943, in animal models, Bywaters & Stead identified myoglobin as the offending agent, & formulated the first treatment plan.

• In 1950 Korean War, dialysis reduces mortality rate from 84% to 53%.

• Natural Disasters – Earthquakes– 1976 Tangshan (near Beijing): 20% of 242,000 deaths due to

crush syndrome.– In 1995, British nephrologists introduced the Disaster Relief

Task Force to prevent acute renal failure.– 1999 Marmara (Turkey): 7.2 Richter scale earthquake. 12%

hospitalised patients had renal failure, 76% received dialysis, 19% fatality rate.

The incidence of rhabdomyolysis varies with

the underlying cause

Levels increase with disasters - eg, earthquakes & in war

zones

Rhabdomyolysis account for ~7- 8% of all new cases of

acute kidney injury

Epidemiology

Definitions• Rhabdomyolysis - destruction of striated

muscle (multiple causes)

• A crush injury is direct injury resulting from a crush

• A crush syndrome is the systemic manifestation of muscle cell damage

Resulting from 3 criteria Crushing, Prolonged pressure,

Devascularization

Also known as Traumatic rhabdomyolysis

Rhabdomyolysis

Why all the worry?

1- Acute Renal FailureARF

2- Sudden Cardiac Death among young athletes

SCD

3- Acute compartment syndrome ACS

Sequelae of ACS -> contractures, deformities, long life disability & even

amputationex. Volkmann contracture

Why all the worry?Devastating consequences is the answer

(ASA)

Mechanisms of ARF in rhabdomyolysis

• Hypovlemia -> renal vasoconstriction -> diminished renal perfusion

• Cast formation leads to tubular obstruction

• Direct Myoglobin nephrotoxicity

• Haeme produced free radicles - Oxidants

• When muscle is damaged, a protein pigment called myoglobin is released into the bloodstream and filtered out of the body by the kidneys.

• The broken down myoglobin may block

the structures of the kidney, causing damage such as acute tubular necrosis or kidney failure.

• Dead muscle tissue may cause a large amount of fluid to move from the blood into the muscle, leading to Hypovolemic shock. Causing reduced blood flow to the kidneys.

Rhabdomyolysis after an injury can be a cause ofSudden Cardiac Death among young athletes Usually in athletes, skeletal muscles are prone to injury either due to over exercises or any sports related injury

Sudden Cardiac Death among young athletes

Sarcolemma damage release the content of sarcoplasm of muscle cells including potassium ions (K+) -> Electrolyte

imbalance

->> Cardiac electrical activity changes may precipitateSudden Cardiac Arrest

Sudden efflux of potassium ions in the blood stream

+High catecholamine level

(exercises)

Mechanisms of SCD in rhabdomyolysis

Acute compartment syndrome

ACS = Critical increase of interstitial pressure within a confined closed fascial compartment

->> decline in the perfusion pressure to the compartment tissue

Without timely diagnosis & treatment ->> microvascular compromise , ischaemia & cellular necrosis

Ultimately permanent disability of the affected region.

Acute compartment syndrome

• Immediate fasciotomy & decompression of all tissues within the affected compartment

• Normal resting ICP is around 0 - 8 mmHg in adults & slightly higher (13 to 16 mmHg) in children

• DBP – ICP = >30mmhg –> surgical assessment ->

conservative -> normal muscle function at follow up - (McQueen and Court-Brown)

• DBP – ICP = < 30 -> (fasciotomy)

NB: Differential pressure = ( DBP) diastolic BP – (ICP) Intra compartment Pressure

Acute compartment syndrome

• DBP - ICP = >30mmhg –> Non-operative techniques to delay the onset of ischemia & preserve soft tissues.

• All restrictive dressings , tight pop cast should be loosened and removed.

• Extremity elevation to maximize venous return and minimize edema.

• Fracture reduction to limit ongoing soft tissue damage.

• AVI System

Severe deformity, chronic pain, paralysis & even amputation.

The best treatment is immediate Decompression Fasciotomies & prevention of late contractures

Deformities depend on the most fibrotic & ischemic muscles

Complications of A. compartment syndrome

late sequelae of A. compartment syndrome

Skeletal Muscle

Skeletal Muscle Cell

The sarcolemma is the cell membrane

of a muscle cell. The membrane is

designed to receive and conduct stimuli and surround The

sarcoplasm

Skeletal Muscle Cell function

Pathogenesis of Rhabdomyolysis 1• Compressive forces cellular

hypoperfusion hypoxia • Decrease in ATPase failure of ATPase

pump & sacrolemma leakage

• Lysed cell release inflammatory mediators • platelet aggregation

• Vasoconstriction

• increase vascular permeability

Electrolyte disturbancesHyperkalaemia Hypocalcaemia

HyperphosphatemiaHyperuricaemia

Metabolic acidosis

Pathogenesis of Rhabdomyolysis 2

Revascularization• Fluids trapped in damaged tissue

• Oedema of affected limb• Haemoconcentration and shock

(hypovolaemia)• Myoglobin, potassium, phosphate

enter venous circulation

Lysed cell releasePotassiumPhospate

Creatine kinaseMyoglobin

Lysed cell retainCa

water

Causes of Rhabdomyolysis (Muscle Breakdown)

Traumatic Nontraumatic

-Multiple Trauma-Crush Injury-Surgery-Coma-Immobilization

Exertional Non exertional

-Exertion-Heat illness-Seizures-Metabolic myopathies-Malignant hyperthermia-Neuroleptic Malignant Syndrome

-ETOH (ethyl alcohol Abuse)-Drugs ( statins, OTC, illicit) -Infection-Electrolytes

Causes• Trauma

• Exertion

• Infection – viral myositis

• Body temperature change:

heat stroke, hypothermia

• Connective tissue diseases

• Genetic defects: metabolic

disorders

• Drugs and toxins:

statins, OTC, illicit drugs

TABLE 1Medications and Toxic Substances That Increase the Risk of Rhabdomyolysis

HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LSD = lysergic acid diethylamide; MDMA = 3,4-methylene dioxymethamphetamine.

Direct myotoxicity

HMG-CoA reductase inhibitors, especially in combination with fibrate-derived lipid-lowering

agents such as niacin (nicotinic acid; Nicolar)

Cyclosporine (Sandimmune) Itraconazole (Sporanox)

ErythromycinColchicine

Zidovudine (Retrovir) Corticosteroids

Indirect muscle damage

Alcohol Central nervous system depressants

Cocaine Amphetamine

Ecstasy (MDMA) LSD

Neuromuscular blocking agents

Statins act by inhibiting HMG-CoA reductase(3-hydroxy-3-methyl-glutaryl-CoA Reductase)

All metabolic functions further down the pathway are affected (isoprenoids)

HMG-CoA reductase inhibitors

Clinical Mmanifestations of Rhabdomyolysis ?Range from asymptomatic to acute renal failure and DIC

Triad : muscle pain , weakness , dark urine

Systemic features• Coca-cola coloured urine

– Results from Myoglobinuria • General weakness• Confusion, unconsciousness• Fever, nausea/vomiting,

Tachycardia• Less frequent urination• In severe cases: AKI (acute kidney

injury) renal failure• Disseminated intravascular

coagulation

Additional symptomsOverall Malaise - Fatigue - Joint pain – Seizures - Weight gain

Local features• Muscle pain, swelling, stiffness &

tenderness• Bruising & compartment syndrome• Muscle & Limb weakness

Complications of Rhabdomyolysis

Early complications (< 12-72 hrs)

• Hypovolaemia• Hyperkalaemia• Hypocalcaemia

• Cardiac arrhythmias• Cardiac arrest

Late complications (< 12-72 hrs)

• Kidney damage• Acute tubular necrosis• Acute renal failure 15%

• DIC• ARDS• sepsis

Early or late complicationsAcute compartment syndrome

Laboratory Findings• Creatine kinase: >5x ULN (1500-100,000) (heart, brain,

skeletal muscle) Rises within 2 to 12 hours following the onset of muscle injury and

reaches its maximum within 24 to 72 hours. A decline is usually seen within three to five days of cessation of muscle injury1,2.

• Myoglobinuria• Hyperkalemia• Hyperphosphatemia• Hypocalcemia• Hyperuricemia

Laboratory Findings

High CPK levels may be seen in people who have:

Brain injury or strokeConvulsions

Delirium tremensDermatomyositis or polymyositis

Electric shock

Heart attackInflammation of the heart muscle

(myocarditis)Lung tissue death (pulmonary

infarction)

Creatine phosphokinaseCreatine phosphokinase (CPK) an enzyme found mainly in

heart, brain, skeletal muscle

Muscular dystrophiesMyopathy

Rhabdomyolysis

Other conditions that may give positive test results

include:HypothyroidismHyperthyroidism

Pericarditis following a heart attack

Prevention

• Balanced diet & exercise

• Risk: Antipsychotics, statin & fibrate medications for high

cholesterol , Selective serotonin reuptake inhibitors,

Zidovudine, Colchicine, lithium, Antihistamines, and several

others

• Don’t: Over exercising in extreme heat conditions, take drugs

& alcohol

• Keep: hydrated – electrolytes

How can I prevent Rhabdomyolysis

• Drink plenty of fluids after strenuous exercise to dilute the urine and flush the myoglobin out of the kidney

• Proper hydration is also

necessary after any condition or event that may involve damage to skeletal muscle

Treatment

• A B C• Fluids Early aggressive fluid resuscitation.• Electrolyte replacement.• Alkalinization of urine?• Treat hyperkalaemia• Treat underlying cause.• Fasciotomy.• Free radical scavengers and antioxidants

EMS Treatment

1. Immediately obtain intravenous access with a large-bore catheter.

2. Administer isotonic crystalloid 500 mL/h and then titrate to maintain a urine output of 200-300 mL/h.

Fluid Resuscitation• Give as much fluid as you would give a severely burned

patient.

• Optimal fluid and rate of repletion are unclear.• No studies comparing efficacy/safety of different types and rate of fluid

administration.

• Early and aggressive fluids (hydration) may prevent complications by rapidly remove myoglobin out of the kidneys. Administer

isotonic crystalloid fluids (Normal Saline or Lactated Ringer’s). • Studies of patients with severe crush injuries resulting in Rhabdomyolysis suggest that the prognosis is better when prehospital personnel provide FLUID

RESUCITATION!

Algorithm

Isotonic Saline-Initial Resuscitation: 1-2 L/hr -100-200 ml/hr (if hemolysis induced injury)-Correct electrolyte abnormalities

Titrate IVF UOP goal: 200-300ml/hr

Serial CK measurements

CK>5000

CK<5000 Stop Treatment

Bicarbonate, Mannitol, DialysisBicarbonate: Forced alkaline diuresis• May reduce renal heme toxicity

• May also decrease the release of free iron from myoglobin, the formation of vasoconstricting F2-isoprostanes, and the risk for tubular precipitation of uric acid3,4

• No clear clinical evidence that an alkaline diuresis is more effective than a saline diuresis in preventing AKI.

Mannitol: Forced diuresis• May minimize intratubular heme pigment deposition and cast formation, and/or by

acting as a free radical scavenger, thereby minimizing cell injury6,7.• Net clinical benefit remains uncertain, therefore, not routinely administered.

Dialysis• Use of dialysis to remove myoglobin, hemoglobin, or uric acid in order to prevent

the development of renal injury has not been demonstrated.

Free radical scavengers and antioxidants

• The magnitude of muscle necrosis caused by ischemia-reperfusion injury has been reduced in experimental models by the administration of free-

radical scavengers .• Many of these agents have been used in the early treatment of crush

syndrome to minimize the amount of nephrotoxic material released from the muscle

• Pentoxyphylline is a xanthine derivative used to improve microvascular blood flow. In addition, pentoxyphylline acts to

decrease neutrophil adhesion and cytokine release • Vitamin E , vitamin C , lazaroids (21-aminosteroids) and

minerals such as zinc, manganese and selenium all have antioxidant activity and may have a role in the treatment of the

patient with rhabdomyolysis

Prognosis of Rhabdomyolysis

• The outcome varies depending on the extent of kidney damage.

Source: Silberber, 2007

Automatic Positive Airway Pressure

Rhabdomyolysis is the breakdown of skeletal muscles

ATP depletion ->> increase in intracellular Ca2+ ->> triggering a series of proteolytic enzymes =>> myocyte destruction ->> leakage of cell components in blood stream (myoglobin, creatine kinase, K, P, electrolytes, etc.)

Summary and Conclusions

Summary and Conclusions • Excess myoglobin —>> precipitate in glomerular

filtrate —>> acute renal failure• Rhabdomyolysis accounts for an estimated 8-15% of

cases of acute renal failure

• The overall mortality rate for patients with Rhabdomyolysis is approximately 5%

• Rhabdomyolysis is more common in Males than in Females

• May occur in infants, toddlers, and adolescents

Summary and Conclusions

• High index of suspicion (coca-cola coloured urine, muscle pain, nausea, confusion)

• On scene treatment Aggressive fluid treatment Adequate monitoring

• Recognition & early

treatment of complications

Laboratory tests:

Plasma creatine kinase levels

Plasma potassium levels

urine myoglobin assay

Summary and Conclusions

• When rhabdomyolysis is suspected aggressive fluid resuscitation should started to prevent pigment nephropathy.

• Titrate to UOP 200-300cc/hr.

• The use of bicarbonate, mannitol, and dialysis: net clinical benefit has not been shown.

Keep always hydrated

Well supplemented with electrolytes & carbohydrates

Avoid drugs, alcohol, excessive heat & over-exercising

Summary and ConclusionsPrevention strategies

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