Rhabdomyolysis In The Perioperative Period Henry Rosenberg MD

Rhabdomyolysis In The Perioperative Period Henry Rosenberg, MD Director, Department of Medical Education and Clinical Research Saint Barnabas Medical Center Livingston, NJ President of MHAUS Professor of Anesthesiology Mount Sinai School of Medicine

Goals And Objectives • Discuss pathophysiology of rhabdomyolysis • Describe the clinical implications of rhabdo • Discuss the differential diagnosis of perioperative rhabdo

Myoglobin And Myoglobinemia / Myoglobinuria • • Heme protein of 15, 500 mol weight Found in muscles of vertebrates Oxygen store/transfer Necessary for oxygen consumption / contraction / membrane integrity muscle

Myoglobin Appears Following Muscle Membrane Destruction • Many etiologies of muscle membrane destruction • 26, 000 cases of rhabdo each year in US

Rapid Test For Myoglobin • Urine dipstick for hemoglobin then check for RBCs -- sensitivity 80% • Urine dipstick for myoglobin -sensitivity 20% • CK over 10, 000

Pathophysiology Of Rhabdo • Energy supply not adequate to maintain membrane integrity because of low ATP – Increased demand — MH hyperthermia, exercise, seizures – Decreased production – Ischemia, metabolic disturbances, glycogen storage disease, propofol infusion • Direct membrane destruction – Toxins, e. g. infection – Drugs – Disease, eg. dystrophies

Factors Leading To Rhabdomyolysıs ABNORMAL MUSCLE METABOLISM • Myopathies, e. g. glycogen storage disease, CPTdeficiency MAXIMAL FUEL EXHAUSTION • Exercise, especially in heat environments • Seizures • Contractures secondary to drugs TRAUMA/ISCHEMIA • Crush injuries • Surgery • Compression

Manifestations Of Rhabdomyolysis • • • Brown or cola colored urine, heme pos, without RBC’S Myoglobinemia Myoglobinuria Elevated creatine kinase Elevated LDH; Decreased Ca++2 Incr P 04 Renal failure – ~50% of patients with rhabdo develop ARF • Causes 5 -25% of ARF

Pattern Of Myoglobin Release • Myoglobin appears within minutes or hours of injury • Myoglobin is cleared by the kidney rapidly • Creatine kinase appears after several hours • Peak CK is 14 -20 hours after injury • Brown urine appears when CK over ~10, 000 • Hyperkalemia often associated

Complications Associated With Myoglobinuria • • Renal Failure Muscle Swelling and Edema Compartment Syndrome Hyperkalemia, hypocalcemia

History Of Periop Rhabdo • 1960 s-70 s rhabdo associated with succ • Ryan found that 40% of children receiving succ develop myoglobinemia • Greater CK release with succ and inhalation agents 1970 s: Recognition of MH as cause of rhabdo • 1980 s: Recognition of occult myopathy and rhabdo • Drugs and rhabdo • Surgical causes of rhabdo

Succinylcholine And Myoglobin Release Ryan, Kagen and Hyman, 1971 Myoglobin Release in 1/30 Adults, 17/40 Children Tammisto, 1966; Innes, 1973; Plotz, 1982 Succinylcholine, Especially with Halothane Associated with CK Release, Myoglobinemia (Occasionally 40 fold Increase) Noguchi, 1993 Thiopental, Propofol Reduces Myoglobin Release

Innes. R and Stromme J, BJA(1973)45. 185.

CK Release In Children Having Routine Surgery Anesthesia Pre-Op CK 20 Min. Halo/succ 58 174 TPL (4 mg/kg)/succ 60 114 No succ 60 61 Myoglobin Release Anesthesia Pre-Op Mb 60 Min. Halo/succ 19 2192 TPL (4 mg/kg)/succ 19 796 No succ 22 40

Hyperkalemic Cardiac Arrest During Anesthetics In Infants And Children With Occult Myopathies Number of Patients 25 (92 % Male) Age Range 3 – 151 Months (Mean 45) Mortality 40 % DMD Diagnosed 7/8 Potassium Above 6 13 / 18 Succ Adm 60 % Myopathy dxed 9 / 15 Previous anes 32 % CK 118, 558 (2, 784 -174, 376) Larach, Rosenberg, Gronert, Allen Clinical Pediatrics 1997

Patients Predisposed To Myoglobinuria Heat Stroke Victims Status Epilepticus Drug/Alcohol Abusers Electrolyte Imbalance Psychoactive Drugs, NMS Infection Cholesterol Lowering Agents Major Trauma Myopathies MH Susceptibles Larach, Rosenberg, Gronert, Allen Clinical Pediatrics 1997

Pharmacologic Agents and Rhabdo Drugs of Abuse Pharmacologic Agents Alcohol Statins Ephedra Propofol MDMA Psychoactive Drugs Cocaine Haldol, SSRIs Amphetamines Steroids Anabolic steroids Succ Colchicine Zidurovine Many others, sporadically

Case Report • • • 46 yo extreme body builder 124 kg Received succ and sevo for peripheral surgery CK Post op 18, 870, Creatinine 1. 6 SGOT 448, SGPT 167 Drugs: – Testosterone – Fenofibrate, Zetia • No history of MH

Statins and Anesthesia • Few reports suggest a relation • Incidence of rhabdo in patients on statins: – High with fibrates: e. g. gemfibrizol and lovastatin: 5% • Most statins alone: ~`0. 2% – increased with various CYP 3 A 4 inhibitors – increased with age >65 • Should statins be discontinued prior to surgery?

Intrathecal Contrast Injection of water soluble, ionic contrast agent into CSF produces: • Ascending tonic –clonic syndrome, seizures, hyperthermia after 1 -2 hr delay • Loss consciousness, rhabdomyolysis • Diagnostic feature: contrast in cerebral ventricles on CT • Treatment is supportive

Neuroleptic Malignant Syndrome NMS is a potentially fatal, idiopathic hypermetabolic response to a variety of neuroleptics and dopamine receptor blocking agents. • Although peripheral manifestations include rhabdomyolysis and rigidity, the pathophysiologic changes occur in the CNS • Treatment with dantrolene, benzodiazepines, dopamine agonists have been effective

Principle Features of NMS • Hypermetabolic response to potent neuroleptics and to dopamine receptor blocking drugs • Incidence 0. 2% of those taking neuroleptics/antipsychotics • Onset may be gradual or slow • Not inherited • No animal model • Responsive to a variety of drug treatments

Signs of NMS • • • Leadpipe rigidity Altered mental state Hyperthermia Rhabdomyolysis Autonomic instability: tachycardia, hypo /hypertension

Serotonin Syndrome • Fever, acidosis, hypertension, rhabdomyolysis, delirium, following use of drugs that increase serotonin levels • Increase release: – Cocaine, Amphetamines, Meperidine, MDMA • Decrease uptake: – Tranylcypromine, Paroxetine, etc

Myopathies And Rhabdomyolysis • • Malignant Hyperthermia Muscular Dystrophy and Dystrophinopathies DMD, BMD, Myotonias CPT-2 Deficiency Disorders of Glycogen Metabolism Myophosphorylase def (Mc. Ardle’s) PFK, PGK other defects in Glycogenolysis Mitochondrial Myopathies

Myopathies And Rhabdo • • • Hypothyroid myopathy Polymyositis Denervated muscle CCD Myoadenylate Deeaminase Deficiency?

Other Disorders • • • Trauma per se Sepsis Seizures (status) Pheochromocytoma Ischemia/reperfusion New onset diabetes in adolescent

Patient Position As A Cause Of Rhabdomyolysis

Lithotomy Position and Rhabdo Compartment syndrome , rhabdomyolyis and risk of acute renal failure as a complications of the lithotomy position Bocca G et al. J of Nephrology. 2002: 15: 183 -5 Risk factors: • Obesity • Duration > 4 hrs • Hypotension • PVD

Gastric Bypass In The Morbidly Obese • 1. 4% of morbidly obese with laparascopic bypass surgery • Generally surgical times > 4 hrs

Prone Position: Vısceral Hypoperfusıon And Rhabdomyolysıs Ziser A. , Friedhoff R. Anesth Analg 1996; 82: 412 - 5

Rhabdomyolysis And Myonecrosis In A Patient In The Lateral Decubitis Position Mathes D. , Assimos Dg. Anesthesiology 1996; 84: 727 - 5

Major Surgery Per Se Does Not Seem To Cause Significant Rhabdo

Malignant Hyperthermia And Rhabdo • • Frequently seen with MH May appear early in the PACU May appear >12 hours May not be present at all – Dose of agent – Prompt recognition and rx – Genotype • May be the only sign of MH!!

Succ Induced MMR • Always associated with rhabdo • If CK >20, 000 usually associated with MHS or DMD

Rhabdomyolysis Post Anesthesia • 48 yo male(109 kg) for umbilical hernia repair. • Anesthetic was propofol and 180 mg succinylcholine, followed by nitrous oxide-isoflurane-fentanyl. • No problems intraoperatively. One hour case. • Three days post op readmitted for myalgia, malaise, vomiting • BUN 56 mg/dl, CK 12, 041 Mc. Kenny, K, Holman SJ. Anesthesiology 2002

Rhabdomyolysis Post Anesthesia • Patient diuresed and renal function returned to normal in fourteen days. • Contracture to 3%halothane: 1. 1 g, 1. 2 g • Contracture to 2 m. M caffeine: 0. 5 g, 1. 0 g • No histologic abnormality. No RYR mutation found

Similar case by Harwood and Nelson, Anesthesiology 1998

How Often Is Post Op Rhabdo A Sign Of MH? 3 / 475 hospitalized patients with rhabdo at JHU were found to have MHS(1993 -2001) Melli, G et al, Medicine 2005

A Variety Of Causes For Rhabdo Reported To MH Hotline • Source: MH hotline calls 1997 -1999 • 77/554 calls were for rhabdo – 26 thought to be MH – 7 with MMR after succ – ER and ICU : • NMS, diabetic acidosis, heat stroke , trauma, sepsis, CP bypass, direct pressure injury, hypoxic encephalopathy • Renal failure -2 • Death: 6—MH, hyperkalemia, hypoxic encephalopathy, sepsis, psychoactive drugs Brandom, Rosenberg, A&A. S 91, 2001

Myoglobinuria In The PACU • • Is it myoglobin or hemoglobin? Did the patient have a myopathy? What drugs were used? Succinylcholine, inhalation agents What position and for how long? Manifestation of malignant hyperthermia? Intraoperative sepsis?

Evaluation Of Elevated Ck / Rhabdomyolysis • • • How high was the CK? Is it in the range that is anticipated? Was the CK elevated preoperatively? What was the patient’s position? Ischemia? What medications was the patient taking?

Evaluation Of Elevated Ck / Rhabdomyolysis • Personal and family history of muscle disease/muscle cramps? • • Exercise related muscle problems? • Neurologic exam with EMG • Muscle biopsy – Structural abnormalities – Metabolic abnormalities – Halothane/caffeine contracture test

Creatine Kinase Post Surgery ALL SURGERY N 135 Peak CK (Mean + SD) 722 + 266 Neck 35 460 + 145 Thoracic 30 1260 + 320 Abdominal 38 760 + 106 Genitourinary 22 842 + 220 Orthopedic 10 540 + 180 ALL MI 100 852 + 120 Roberts R Arch Int Med 1976

Rhabdomyolysis And MH • Not present in all cases of MH • Dark urine appearing in PACU or at end of long case • Dark urine in association with MH episode • MMR is always associated with myoglobinuria • Post op myoglobinuria as a sign of MH

Can Post Op Ck Be Diagnostic For MH? • Not usually Creatine Kinase Alterations after Acute MH and Common Surgical Procedures Antognini, JF; Anesth Analg 81: 1, 1995 75% of MHS had CK in range of peak CK occurring as a result of surgery only!

Additional Causes Of Rhabdo In ICU • Disease state – – – ICU myopathy Sepsis Ischemia Hyperthermia per se Status epilepticus • Drugs – Neuroleptics, esp haloperidol – Propofol infusion

Treatment Of Rhabdomyolysıs • • • Hydration and Diuresis Alkalinization of the Urine Check for Elevated Potassium Follow CK Determine the Etiology

Conclusions • MH is only one of many causes of post op rhabdo • Rhabdo may occur from disease, drugs, position, trauma • Rhabdo may occur early or late • A thorough history of previous disorders and drugs is essential • Of all anesthetic drugs succ is most often implicated in rhabdo.

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