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Rabdomiolisis

Dr Ricardo FadićUnidad NeuromuscularDepartamento de NeurologíaFacultad de MedicinaPontificia Universidad Católica de Chile

Lancet 2009;373:154

Rabdomiolisis historiaNUMEROS 11:31-34

31 Y vino un viento de Jehová, y trajo codornices del mar, y las dejó sobre el campamento, un día de camino a un lado, y un día de camino al otro, alrededor del campamento, y casi dos codos sobre la faz de la tierra.

32 Entonces el pueblo estuvo levantado todo aquel día y toda la noche, y todo el día siguiente, y recogieron codornices; el que menos, recogió diez montones; y las tendieron para sí a lo largo alrededor del campamento.

33 Aún estaba la carne entre los dientes de ellos, antes que fuese masticada, cuando la ira de Jehová se encendió en el pueblo, e hirió Jehová al pueblo con una plaga muy grande.

34 Y llamó el nombre de aquel lugar Kibrot-hataava, por cuanto allí sepultaron al pueblo codicioso.

Billis AG. Acute renal failure after a meal of quail. Lancet 1971; 298:702

1500 AC app

Rabdomiolisis historiaIntoxication due to quail consumption is rarely seen. Such a toxicological syndrome (also called coturnism) occurs during the migration of quails from north to south, when they consume hemlock seeds.

Coturnix coturnix

Early writers used quail as the standard example of an animal that could eat something poisonous to man without ill effects for themselves.

Aristotle (On Plants 820:6-7),

Philo (Geoponics: 14: 24),

Lucretius (On the Nature of Things: 4: 639-640),

Galen (De Temperamentis: 3:4)

Rabdomiolisis historia

Conium maculatum: Cicutina o coniinaNeurotoxina que bloquea receptorescolinérgicos nicotínicos

399 AC

Cicuta acuática (Cicuta maculata) vs cicuta venenosa (Conium maculatum)


History of the crush syndrome: from the earthquakes of Messina, Sicily 1909 to Spitak, Armenia 1988. Am J Nephrol 1997;17:392

Primera descripción del síndrome de aplastamiento. Terremoto en Messina, Sicilia 1909

Captain Scott's expedition to the South Pole. Standing, left to right - Capt Lawrence Oates, Capt Robert Falcon Scott, PO Edgar Evans. Seated, left to right - Lt Henry Bowers, Dr Edward Adrian Wilson

Freedman BJ. Dr. Edward Wilson of the Antarctic. Proc R Soc Med 1954;47:183


Primera descripción del síndrome del compartimiento. Wilson en su músculo tibial anterior durante la expedición de Scott (30 Enero 1912)

Rabdomiolisis

Rabdomiolisis: ruptura rápida de células musculares con entrada masiva de componentes intracelulares potencialmente tóxicos a la circulación

Tría clásica: paresia, mialgia, pigmenturia

Menos del 10% presenta tríada clásica.

Mas del 50% no tiene paresia o mialgias, presentandose solo con mioglobinuria

26.000 casos reportados anualmente en EEUU.22.2 casos /100.000 reclutas por año (1)

1. Natural history of exertional rhabdomyolysis: a population-based analysis. Muscle Nerve 2010;42:487–91

Rabdomiolisis

American Heart Association: CK mayor 10x valor normal. Proposiciones entre 5x a 50x valor normal

Rabdomiolisis: clinica

Músculos sensibles y edematosos

Debilidad muscular

Orinas “color té” mioglobinuria

Considerar debilidad por otras causas: miopatía del paciente crítico, parálisis periódica, sGB, miopatía aguda no necrotizante

Considerar que debilidades focales pueden ser neuropatías por compresión secundarias a aplastamiento


CK sobre 16.000 aumenta riesgo de falla renal

75% causa adquirida

AdultosAbuso drogas (34%)Farmacos (11%)Trauma (9%)Crisis convulsiva (7%)

60% pacientes: dos o mas causas

Rhabdomyolysis: Review of the literature Neuromuscular Disorders 2014;24:651–659



Niños

Miositis virales (38%)Trauma (26%)Dermatomiositis (5%)Intoxicación farmacológica (4%)Ejercicio (4%)Alt. Metabólicas (4%)


Causas comunes

No recurrente en adultos:

alcohol y drogas, convulsiones, compresión muscular (aplastamiento e inmobilidad)

No recurrente en niños:

trauma, coma hiperosmolar, infecciones (influenza, CMV, EBV, estrepto β hemolítico, VIH, Salmonella, Legionella), distonía

Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine 2005;84:377

Miopatía subyacente o defecto metabólico muscular 10%

Rabdomiolisis

Dia entrenamiento

0 3 7 14

CK Promedio/mediana

223/157 734/478 1226/567 667/486

499 reclutas. Ninguno hizo rabdomiolisis (paresia, CK elevada, mioglobinemia y/omioglobinuria. Rango de CK: 34-35056

Serum creatine kinase after exercise: drawing the line between physiological response and exertional rhabdomyolisis. Muscle Nerve 2012;45:356-362



Complicaciones:

Insuficiencia renal agudaHipercalemiaHipocalcemiaInflamación hepáticaArritmias y paro cardíacoCIDSíndrome del compartimiento

10%- 40% de pacientes desarrollan IRA, y 15% de los casos de IRA pueden ser atribuídos a rabdomiolisis

Rabdomiolisis

Rabdomiolisis: causas adquiridasExertion (1, 2, 4)Exercise; “march myoglobinuria”; status epilepticus; delirium; psychosis; electric shock, electroconvulsive therapy; prolonged cardiopulmonary resuscitation and cardioversion; status asthmaticus; tetanus; prolonged myoclonus, dystonia or chorea;neuromyotonia; conga drumming; keyboard operation; raver’s hematuriaCrush (2)External weight; prolonged immobility (including coma, Parkinson’s disease); exaggerated lithotomy position and other surgical positions; “pseudo-crush” syndrome (torture victims, child abuse); pneumatic antishock garmentIschemia (4)Arterial occlusion; compartment syndrome; cardiopulmonary bypass; vena cava ligation; disseminated intravascular coagulation; sickle cell disease; air embolism; atrial myxoma; diabetes mellitus; increased capillary permeability syndromeMetabolic (1, 3, 4)Hypokalemia; diabetic ketoacidosis; nonketotic hyperglycemic/hyperosmolar states; hyper/hyponatremia; hypophosphatemia; hypothyroidism; near drowning; renal tubular acidosis; pancreatitis; Crohn’s disease with elemental dietExtremes of body temperature (1, 2, 4)Fever; burns; hypothermia (exposure, hypothyroidism)

Rabdomiolisis: causas adquiridasDrugs and toxinsMetabolic (1, 3, 4)Anticholinergics; antidepressants (all classes); antihistamines (diphenhydramine, doxylamine); arsenic; azathioprine; barbiturates; benzodiazepines; bezafibrate; carbon monoxide; clofibrate; cytotoxics; ethanol; ethylene glycol; fenfluramine; gemfibrozil;glutethamide; interferon; methanol; naltrexone; opiates; propofol; oxprenolol; labetolol; paracetamol; podophyllin; statins; zidovudine; isolated limb perfusion (multiple agents); streptokinase; alteplaseHypokalemia (1, 4)Amphotericin; carbenoxolone; glycirrhizate (licorice); itraconazole; laxative abuse; methylxanthines (caffeine, theophylline);thiazides and other kaliureticsIschemia (4)Aminocaproic acid; cocaine; vasopressinAutoimmune (2, 4)Cyclosporin; famotidine; levodopa; nonsteroidals; penicillamine; phenylbutazone; phenytoin; trimethoprim–sulfamethoxazoleMembrane effect (1, 2)Carbon tetrachloride; cimetidine; colchicine; didanosine; dyes; gasoline; hydrocarbons; herbicides; iron dextran; metal fumes;quinidine; solvents; detergents; succinylcholine; toluene; vecuronium, pancuronium (especially combined with high-dose steroids);snake/spider/hornet/bee/fugu/parrotfish venoms

Rabdomiolisis: causas adquiridasDrugs and toxins (2)

Agitation (2, 4)Hemlock (quail eaters); ketamine; lithium; loxapine; LSD; mercuric chloride; phencyclidine; salicylates; strychnine; terbutaline

Neuroleptic malignant syndrome (1, 2, 4)Butyrophenones; levodopa and dopamine agonist withdrawal; lithium; phenothiazines; pimozide; promethazine; thioxanthenes

Serotonergic syndrome (1, 2, 4)Amphetamines; Ecstasy; lithium; monoamine oxidase inhibitors; nefazodone; pethidine; selective serotonin reuptake inhibitors;tricyclic antidepressants; tryptophan; venlafaxine

Mechanism uncertainAmiodarone; blowpipe dart poisoning; chromium picolinate; Haff disease; isoniazid; kidney beans; lamotrigine; nicotinic acid;peanut oil; pentamidine; valproate

Rabdomiolisis: causas hereditariasGlycolytic/glycogenolytic (4)Myophosphorylase deficiency (McArdle’s disease)Phosphofructokinase deficiencyPhosphoglycerate kinase deficiencyPhosphoglycerate mutase deficiencyLactate dehydrogenase (LDH)-A deficiencyPhosphorylase b kinase deficiencyDebrancher enzyme

Fatty acid oxidation (4)Carnitine palmitoyl transferase (CPT) II deficiencyCarnitine deficiencyShort/medium/long/very long-chain and multipleacyl-coenzyme A dehydrogenase deficienciesElectron transfer flavoprotein (ETF) deficiencyETF dehydrogenase deficiencyKetoacyl CoA thiolase deficiencyTrifunctional enzyme deficiencyLong-chain fatty acid -oxidation defects (incompletely characterized)

Rabdomiolisis: causas hereditariasKrebs cycle (4)Aconitase deficiencyLipoamide dehydrogenase deficiency

Pentose phosphate pathway (4)G6PDH deficiency

Purine nucleotide cycle (4)Myoadenylate deaminase deficiency

Mitochondrial respiratory chain (4)Succinate dehydrogenase/complex II deficiencyComplex III deficiency (cytochrome b mutations)Coenzyme Q10 deficiency, ? nuclear gene dysregulationCytochrome c oxidase deficiency (COX I and III mutations)Mitochondrial tRNA point mutationsMultiple mitochondrial DNA deletions, ? nuclear genedysregulationUncharacterized mitochondrial myopathies

Rabdomiolisis: causas hereditariasMalignant hyperthermia (MH) susceptibility (5, 6)Familial MH (RYR1, CACNA1S mutations)Central core diseaseDuchenne and Becker dystrophiesMyotonic dystrophyMyotonia congenitaSchwartz–Jampel syndromeKing syndromeCPT II deficiencySatoyoshi syndrome

OtherAbnormal sarcolemma composition in muscular dystrophies, Miyoshi myopathy (1)Sarcoplasmic Ca++-ATPase deficiency (Brody’s myopathy) (3)Myofilamentous cylindrical spiral myopathy (?/2)Marinesco–Sjogren syndromeFamilial recurrent myoglobinuriaIdiopathic recurrent myoglobinuria

Rabdomiolisis

Rabdomiolisis: patrones clinicos

Distrofia muscular: mialgia por ejercicio, hipertrofia, debilidad fija, CK en reposo alta.

Alt. metabolismo del glucógeno: inicio al inicio de ejercicio, isométrico, fenómeno de “segundo viento”.

Alt. oxidación ácidos grasos: después de ejercicio prolongado, ayuno, infecciones, frío, estrés.

Estatinas: descargas miotónicas durante rabdomiolisis.

Mitocondrial: acido láctico alto en reposo o ejercicio leve.

Mutaciones en RYR1: ejercicio en calor húmedo.


Causa hereditaria mas probable cuando hay historia familiar, episodios múltiples, rabdomiolisis con ejercicio mínimo o ayuno

Primera década:Lipin-1

Déficit de miofosforilasa (McArdle)

Déficit de carnitina palmitoiltransferasa II (CPT II)

Idiopático

Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia.J Inherit Metab Dis 2012;35:119LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.Hum Mut 2010;31:1564

Rabdomiolisis: fisiopatología

Músculo 40% peso corporal 40% del agua total

Contiene el pool mas grande de bombas de ATPasa-Na/K

Daños menores de músculo pueden dar alteraciones mayores de volúmenes y contenidos de LEC y LIC

Músculo necrótico o dañado puede absorber fluidos a gran velocidad, de manera que el total del volumen extracelular puede quedar secuestrado en músculo en horas después del daño, desencadenando shock hipovolémico

Músculos contiene el 75% del K corporal. Hiperkalemiapuede ser severa y letal


Hipovolemia en rabdomiolisis entre las mas severas vistas en medicina (otras sangramiento arterial, gran quemados). El shock hipovolémico hiperkalemico es causa de letalidad prevenible.

Alteraciones volumen/electrolitos que causan shock en rabdomiolisis.

-redistribución de LEC al músculo dañado-producción excesiva de NO en músculo dañado-hiperkalemia efectos crono e inotrópicos negativos en

corazón y produce vasodilatación-hipocalcemia agrava daño cardiotóxico-acidosis láctica (alt. respiración celular) vasodilata y efecto inotrópico negativo


Músculo dañado libera mioglobina y purinas (se transforma en ácidoúrico)

Mioglobina y acido úrico independientemente o en combinación son nefrotóxicos, especialmente en oliguria y aciduria

Músculo es el principal regulador de niveles extracelulares de K. Alterado durante ejercicio puede producir hiperkalemia de 7 mmol en 1 minuto, cambios en EKG en 2 minutos y niveles de 9 mmol al final de un maratón (hiperkalemia principal causa de muerte precoz en terremotos y avalanchas). Paro cardíaco hiperkalémico puede ocurrir en una hora después del daño

Calcio ev, usado para prevenir daño cardíaco por hiperkalemia esdudoso en rabdomiolisis, porque se absorbe en músculo y aumenta daño

Rabdomiolisis historia/fisiopatología


Crush Injuries with Impairment of Renal Function.Bywaters EG, Beall D.Br Med J. 1941 Mar 22;1(4185):427


Crush Injuries with Impairment of Renal Function.Bywaters EG, Beall D.Br Med J. 1941 Mar 22;1(4185):427


Bywaters mostró que mioglubinuria se asoció a daño renal con orina acídica pero no con orina alcalina

Hacia el final de la Segunda Guerra Londres fue bombardeado de nuevo. Bywaters reportó que en 95 de 186 pacientes con rabdomiolisis por aplastamiento fue posible prevenir daño renal agudo con rehidratación abundante y bicarbonato (BMJ 1990;301:1412)

En 2003 terremoto en Turkía 16 adultos jóvenes (23 +/- 13 años) with rabdomiolisis por aplastamiento sobrevivieron con resucitación con fluidos precoz. Solo 4 hicieron daño renal agudo(J Am Soc Nephrol 2004;15:1862)

Rabdomiolisis: terapia

Suggested protocol for early vigorous fluid resuscitation in patients with rhabdomyolysis. This protocol is suitable for use in patients with prolonged coma and those with muscle crush injuries, in whom it should be initiated at the scene of the injury Nat Rev Nephrol 2011;7:416

Rabdomiolisis: terapia

Suggested protocol for early vigorous fluid resuscitation in patients with rhabdomyolysis. This protocol is suitable for use in patients with prolonged coma and those with muscle crush injuries, in whom it should be initiated at the scene of the injury Nat Rev Nephrol 2011;7:416

Rabdomiolisis: terapia (volumen) Nat Rev Nephrol 2011;7:416

Todos los pacientes heridos en terremotos que recibieron menos de 6 litros de fluidos/día desarrollaron falla renal agudaShimazu, T. et al. Fluid resuscitation and systemic complications in crush syndrome: 14 Hanshin-Awaji earthquake patients. J. Trauma 1997;42:641Oda, J. et al. Analysis of 372 patients with crush syndrome caused by the Hanshin-Awaji earthquake. J. Trauma 1997;42:470

Rabdomiolisis: estudio


Pediatr Nephrol (2010) 25:7–18


Neuromuscular Disorders 2014;24: 651–659





Rabdomiolisis: estatinas

Incidence of myopathic events in patients taking statins at1.5%-5.0%

however, in clinical practice, these rates have varied from 0.3%-33%

The Ochsner Journal 2015;15:58–69


Statin myotoxicity: A review of genetic susceptibility factors Neuromusc Dis 2014;24:4-15

Rabdomiolisis: estatinasFDA NEWS RELEASEFor Immediate Release: Feb. 28, 2012Media Inquiries: Erica Jefferson, 301-796-4988, [email protected] Inquiries: 888-INFO-FDAFDA announces safety changes in labeling for some cholesterol-lowering drugs Important safety changes to the labeling for some widely used cholesterol-lowering drugs known as statins are being announced today by the U.S. Food and Drug Administration.

These products, when used with diet and exercise, help to lower a person’s “bad” cholesterol (low-density lipoprotein cholesterol). The products include: Lipitor (atorvastatin), Lescol (fluvastatin), Mevacor (lovastatin), Altoprev (lovastatin extended-release), Livalo (pitavastatin), Pravachol (pravastatin), Crestor (rosuvastatin), and Zocor (simvastatin). Combination products include: Advicor (lovastatin/niacin extended-release), Simcor (simvastatin/niacin extended-release), and Vytorin (simvastatin/ezetimibe).

http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm293623.htm

mailto:[email protected]

Rabdomiolisis: estatinasThe changes to the statin labels are:

The drug labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins. FDA now recommends that liver enzyme tests should be performed before starting statin therapy, and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing this rare side effect

Statin labels will now include information about some patients experiencing memory loss and confusion. These reports generally have not been serious and the patients’ symptoms were reversed by stopping the statin. However, patients should still alert their health care professional if these symptoms occur.



Increases in blood sugar levels (hyperglycemia) have been reported with statin use. The FDA is also aware of studies showing that patients being treated with statins may have a small increased risk of increased blood sugar levels and of being diagnosed with type 2 diabetes mellitus. The labels will now warn healthcare professionals and patients of this potential risk.

Health care professionals should take note of the new recommendations in the lovastatin label. Some medicines may interact with lovastatin, increasing the risk for muscle injury (myopathy/rhabdomyolysis). For example, certain medicines should never be taken (are contraindicated) with Mevacor (lovastatin) including drugs used to treat HIV (protease inhibitors) and drugs used to treat certain bacterial and fungal infections.



Statin myotoxicity: A review of genetic susceptibility factors Neuromusc Dis 2014;24:4-15


Polimorfismos en estos dos genes asociados a alto riesgo de rabdomiolisis por estatinas:

SLCO1B1 proteína responsable por captación hepática de estatinas

COQ2 proteína responsable de síntesis coenzimo Q10

No hay evidencia todavía para apoyar chequeo farmagenómico rutinario


Muscle biopsy from a subject with statin-associateimmune-mediated necrotizing myopathy and anti-HMGCR autoantibodies (hematoxylin–eosin stain). This biopsy shows abundant myofiber degeneration and necrosis in the absence of a prominent lymphocytic infiltrate

Statin-associated autoimmune myopathy and anti-HMGCR autoantibodiesMuscle Nerve 2013;48:477Antibodies against HMGCR in patients with statin-induced myopathyArthr Rheumatism 2011;63:713

Anti-NCAM Anti-HMGCR


Statin induced necrotizing autoimmune myopathy. J Neurol Sci 2015;351:13-17


Statin induced necrotizing autoimmune myopathy. J Neurol Sci 2015;351:13-17

Miopatia Tóxica SINAMincidencia frecuente rara

Debilidad proximal infrecuente común

Max. CK normal o leve 1000-50000

Factor riesgo genético

SNP en SLCO1B1 HLA-DRB1 11:01

Tiempo/ Estatinas sigue al inicio, termina al discontinuar

Puede aparecer después de años de uso. No mejora al discontinuar

Anti-HMGCR (-) (+)

EMG normal miopatía con ondas (+)

MRI normal mioedema

Biopsia no específica necrosis con minima inflamación

Terapia retiro droga inmunosupresión