Rabdomiolisis

Lancet 2009;373:154

Dr Ricardo Fadi
Unidad Neuromuscular
Departamento de Neurologa
Facultad de Medicina
Pontificia Universidad Catlica de Chile

Rabdomiolisis historia
NUMEROS 11:31-34
31 Y vino un viento de Jehov, y trajo codornices del mar, y las dej sobre
el campamento, un da de camino a un lado, y un da 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 da y toda la noche, y
todo el da siguiente, y recogieron codornices; el que menos, recogi diez
montones; y las tendieron para s a lo largo alrededor del campamento.
33 An estaba la carne entre los dientes de ellos, antes que fuese
masticada, cuando la ira de Jehov se encendi en el pueblo, e hiri
Jehov al pueblo con una plaga muy grande.
34 Y llam el nombre de aquel lugar Kibrot-hataava,
por cuanto all sepultaron al pueblo codicioso.
Billis AG. Acute renal failure after a meal
of quail. Lancet 1971; 298:702

1500 AC app

Rabdomiolisis historia
Intoxication 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.
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)

Coturnix coturnix

Rabdomiolisis historia
Cicuta acutica (Cicuta maculata) vs cicuta
venenosa (Conium maculatum)

Conium maculatum: Cicutina o coniina

Neurotoxina que bloquea receptores
colinrgicos nicotnicos

399 AC

Rabdomiolisis historia
Primera descripcin del
sndrome de aplastamiento.
Terremoto en Messina,
Sicilia 1909

History of the crush syndrome: from

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

Rabdomiolisis historia

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

Primera descripcin del sndrome del

compartimiento. Wilson en su msculo tibial
anterior durante la expedicin de Scott
(30 Enero 1912)
Freedman BJ. Dr. Edward Wilson of the Antarctic.
Proc R Soc Med 1954;47:183

Rabdomiolisis
Rabdomiolisis: ruptura rpida de clulas musculares con entrada masiva
de componentes intracelulares potencialmente txicos a la circulacin
Tra clsica: paresia, mialgia, pigmenturia
Menos del 10% presenta trada clsica.
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 ao (1)

1. Natural history of exertional rhabdomyolysis: a population-based analysis.

Muscle Nerve 2010;42:48791

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

Rabdomiolisis: clinica
Msculos sensibles y edematosos
Debilidad muscular
Orinas color t mioglobinuria
Considerar debilidad por otras causas: miopata del paciente crtico,
parlisis peridica, sGB, miopata aguda no necrotizante
Considerar que debilidades focales pueden ser neuropatas por
compresin secundarias a aplastamiento

Rabdomiolisis: clinica
CK sobre 16.000 aumenta riesgo de falla renal
75% causa adquirida
Adultos
Abuso drogas (34%)
Farmacos (11%)
Trauma (9%)
Crisis convulsiva (7%)
60% pacientes: dos o mas causas

Rhabdomyolysis: Review of the literature Neuromuscular Disorders 2014;24:651659

Rabdomiolisis: clinica
Nios
Miositis virales (38%)
Trauma (26%)
Dermatomiositis (5%)
Intoxicacin farmacolgica (4%)
Ejercicio (4%)
Alt. Metablicas (4%)

Rhabdomyolysis: Review of the literature Neuromuscular Disorders 2014;24:651659

Rabdomiolisis: clinica
Causas comunes
No recurrente en adultos:
alcohol y drogas, convulsiones, compresin muscular (aplastamiento
e inmobilidad)
No recurrente en nios:
trauma, coma hiperosmolar, infecciones (influenza, CMV, EBV,
estrepto hemoltico, VIH, Salmonella, Legionella), distona
Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine 2005;84:377

Miopata subyacente o defecto metablico muscular 10%

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

14

CK
Promedio/medi
ana

223/157

734/478

1226/567

667/486

499 reclutas. Ninguno hizo rabdomiolisis (paresia, CK elevada, mioglobinemia y/o

mioglobinuria. Rango de CK: 34-35056

Rabdomiolisis: clinica
Complicaciones:
Insuficiencia renal aguda
Hipercalemia
Hipocalcemia
Inflamacin heptica
Arritmias y paro cardaco
CID
Sndrome del compartimiento
10%- 40% de pacientes desarrollan IRA, y 15% de los casos de IRA
pueden ser atribudos a rabdomiolisis

Rhabdomyolysis: Review of the literature Neuromuscular Disorders 2014;24:651659

Rabdomiolisis

Rabdomiolisis: causas adquiridas

Exertion (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; ravers hematuria
Crush (2)
External weight; prolonged immobility (including coma, Parkinsons disease);
exaggerated lithotomy position and other surgical positions; pseudo-crush
syndrome (torture victims, child abuse); pneumatic antishock garment
Ischemia (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 syndrome
Metabolic (1, 3, 4)
Hypokalemia; diabetic ketoacidosis; nonketotic hyperglycemic/hyperosmolar
states; hyper/hyponatremia; hypophosphatemia; hypothyroidism; near drowning;
renal tubular acidosis; pancreatitis; Crohns disease with elemental diet
Extremes of body temperature (1, 2, 4)
Fever; burns; hypothermia (exposure, hypothyroidism)

Rabdomiolisis: causas adquiridas

Drugs and toxins
Metabolic (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; alteplase
Hypokalemia (1, 4)
Amphotericin; carbenoxolone; glycirrhizate (licorice); itraconazole; laxative abuse;
methylxanthines (caffeine, theophylline);thiazides and other kaliuretics
Ischemia (4)
Aminocaproic acid; cocaine; vasopressin
Autoimmune (2, 4)
Cyclosporin; famotidine; levodopa; nonsteroidals; penicillamine; phenylbutazone;
phenytoin; trimethoprimsulfamethoxazole
Membrane 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 adquiridas

Drugs 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 uncertain
Amiodarone; blowpipe dart poisoning; chromium picolinate; Haff disease; isoniazid;
kidney beans; lamotrigine; nicotinic acid;
peanut oil; pentamidine; valproate

Rabdomiolisis: causas hereditarias

Glycolytic/glycogenolytic (4)
Myophosphorylase deficiency (McArdles disease)
Phosphofructokinase deficiency
Phosphoglycerate kinase deficiency
Phosphoglycerate mutase deficiency
Lactate dehydrogenase (LDH)-A deficiency
Phosphorylase b kinase deficiency
Debrancher enzyme
Fatty acid oxidation (4)
Carnitine palmitoyl transferase (CPT) II deficiency
Carnitine deficiency
Short/medium/long/very long-chain and multiple
acyl-coenzyme A dehydrogenase deficiencies
Electron transfer flavoprotein (ETF) deficiency
ETF dehydrogenase deficiency
Ketoacyl CoA thiolase deficiency
Trifunctional enzyme deficiency
Long-chain fatty acid -oxidation defects (incompletely characterized)

Rabdomiolisis: causas hereditarias

Krebs cycle (4)
Aconitase deficiency
Lipoamide dehydrogenase deficiency
Pentose phosphate pathway (4)
G6PDH deficiency
Purine nucleotide cycle (4)
Myoadenylate deaminase deficiency
Mitochondrial respiratory chain (4)
Succinate dehydrogenase/complex II deficiency
Complex III deficiency (cytochrome b mutations)
Coenzyme Q10 deficiency, ? nuclear gene dysregulation
Cytochrome c oxidase deficiency (COX I and III mutations)
Mitochondrial tRNA point mutations
Multiple mitochondrial DNA deletions, ? nuclear gene
dysregulation
Uncharacterized mitochondrial myopathies

Rabdomiolisis: causas hereditarias

Malignant hyperthermia (MH) susceptibility (5, 6)
Familial MH (RYR1, CACNA1S mutations)
Central core disease
Duchenne and Becker dystrophies
Myotonic dystrophy
Myotonia congenita
SchwartzJampel syndrome
King syndrome
CPT II deficiency
Satoyoshi syndrome
Other
Abnormal sarcolemma composition in muscular dystrophies, Miyoshi myopathy (1)
Sarcoplasmic Ca++-ATPase deficiency (Brodys myopathy) (3)
Myofilamentous cylindrical spiral myopathy (?/2)
MarinescoSjogren syndrome
Familial recurrent myoglobinuria
Idiopathic recurrent myoglobinuria

Rabdomiolisis

Rabdomiolisis: patrones clinicos

Distrofia muscular: mialgia por ejercicio, hipertrofia, debilidad fija, CK
en reposo alta.
Alt. metabolismo del glucgeno: inicio al inicio de ejercicio,
isomtrico, fenmeno de segundo viento.
Alt. oxidacin cidos grasos: despus de ejercicio prolongado, ayuno,
infecciones, fro, estrs.
Estatinas: descargas miotnicas durante rabdomiolisis.
Mitocondrial: acido lctico alto en reposo o ejercicio leve.
Mutaciones en RYR1: ejercicio en calor hmedo.

Rabdomiolisis: clinica
Causa hereditaria mas probable cuando hay historia familiar,
episodios mltiples, rabdomiolisis con ejercicio mnimo o ayuno
Primera dcada:Lipin-1
Dficit de miofosforilasa (McArdle)
Dficit de carnitina palmitoiltransferasa II (CPT II)
Idioptico

Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia.

J Inherit Metab Dis 2012;35:119
LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.
Hum Mut 2010;31:1564

Rabdomiolisis: fisiopatologa
Msculo 40% peso corporal 40% del agua total
Contiene el pool mas grande de bombas de ATPasa-Na/K
Daos menores de msculo pueden dar alteraciones
mayores de volmenes y contenidos de LEC y LIC
Msculo necrtico o daado puede absorber fluidos a
gran velocidad, de manera que el total del volumen
extracelular puede quedar secuestrado en msculo en
horas despus del dao, desencadenando shock
hipovolmico
Msculos contiene el 75% del K corporal. Hiperkalemia
puede ser severa y letal

Rabdomiolisis: fisiopatologa
Hipovolemia en rabdomiolisis entre las mas severas vistas en
medicina (otras sangramiento arterial, gran quemados). El shock
hipovolmico hiperkalemico es causa de letalidad prevenible.
Alteraciones volumen/electrolitos que causan shock en rabdomiolisis.
-redistribucin de LEC al msculo daado
-produccin excesiva de NO en msculo daado
-hiperkalemia efectos crono e inotrpicos negativos en corazn y
produce vasodilatacin
-hipocalcemia agrava dao cardiotxico
-acidosis lctica (alt. respiracin celular) vasodilata y efecto
inotrpico negativo

Rabdomiolisis: fisiopatologa
Msculo daado libera mioglobina y purinas (se transforma en cido
rico)
Mioglobina y acido rico independientemente o en combinacin son
nefrotxicos, especialmente en oliguria y aciduria
Msculo 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 maratn (hiperkalemia principal causa de muerte precoz en
terremotos y avalanchas). Paro cardaco hiperkalmico puede ocurrir
en una hora despus del dao
Calcio ev, usado para prevenir dao cardaco por hiperkalemia es
dudoso en rabdomiolisis, porque se absorbe en msculo y
aumenta dao

Rabdomiolisis historia/fisiopatologa

Rabdomiolisis historia/fisiopatologa

Crush Injuries with Impairment of Renal Function.

Bywaters EG, Beall D.
Br Med J. 1941 Mar 22;1(4185):427

Rabdomiolisis historia/fisiopatologa

Crush Injuries with Impairment of Renal Function.

Bywaters EG, Beall D.
Br Med J. 1941 Mar 22;1(4185):427

Rabdomiolisis historia/fisiopatologa
Bywaters mostr que mioglubinuria se asoci a dao renal con
orina acdica pero no con orina alcalina
Hacia el final de la Segunda Guerra Londres fue bombardeado de
nuevo. Bywaters report que en 95 de 186 pacientes con
rabdomiolisis por aplastamiento fue posible prevenir dao renal
agudo con rehidratacin abundante y bicarbonato
(BMJ 1990;301:1412)
En 2003 terremoto en Turka 16 adultos jvenes (23 +/- 13 aos)
with rabdomiolisis por aplastamiento sobrevivieron con
resucitacin con fluidos precoz. Solo 4 hicieron dao 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/da desarrollaron falla renal aguda
Shimazu, T. et al. Fluid resuscitation and systemic complications in crush
syndrome: 14 Hanshin-Awaji earthquake patients. J. Trauma 1997;42:641
Oda, J. et al. Analysis of 372 patients with crush syndrome caused by the
Hanshin-Awaji earthquake. J. Trauma 1997;42:470

Rabdomiolisis: estudio

Rabdomiolisis:
estudio

Pediatr Nephrol (2010) 25:718

Rabdomiolisis: estudio

Neuromuscular Disorders 2014;24: 651659

Rabdomiolisis: estudio

Neuromuscular Disorders 2014;24: 651659

Rabdomiolisis: estudio

Neuromuscular Disorders 2014;24: 651659

Rabdomiolisis: estatinas

Incidence of myopathic events in patients taking statins at

1.5%-5.0%
however, in clinical practice, these rates have varied from 0.3%33%

The Ochsner Journal 2015;15:5869

Rabdomiolisis: estatinas

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

Rabdomiolisis: estatinas
FDA NEWS RELEASE
For Immediate Release: Feb. 28, 2012
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA announces safety changes in labeling for some cholesterollowering drugs
Important safety changes to the labeling for some widely used cholesterollowering 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 persons
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

Rabdomiolisis: estatinas
The 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.

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

Rabdomiolisis: estatinas
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.

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

Rabdomiolisis: estatinas

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

Rabdomiolisis: estatinas
Polimorfismos en estos dos genes asociados a alto riesgo de
rabdomiolisis por estatinas:
SLCO1B1 protena responsable por captacin heptica de estatinas
COQ2 protena responsable de sntesis coenzimo Q10
No hay evidencia todava para apoyar chequeo farmagenmico
rutinario

Rabdomiolisis: estatinas

Anti-NCAM Anti-HMGCR
Muscle biopsy from a subject with statin-associateimmunemediated necrotizing myopathy and anti-HMGCR
autoantibodies (hematoxylineosin stain). This biopsy shows
abundant myofiber degeneration and necrosis in the
absence of a prominent lymphocytic infiltrate

Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies

Muscle Nerve 2013;48:477
Antibodies against HMGCR in patients with statin-induced myopathy
Arthr Rheumatism 2011;63:713

Rabdomiolisis: estatinas

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

Rabdomiolisis: estatinas
Miopatia Txica

SINAM

incidencia

frecuente

rara

Debilidad proximal

infrecuente

comn

Max. CK

normal o leve

1000-50000

Factor riesgo
gentico

SNP en SLCO1B1

HLA-DRB1 11:01

Tiempo/ Estatinas

sigue al inicio, termina al

discontinuar

Puede aparecer despus de aos de

uso. No mejora al discontinuar

Anti-HMGCR

(-)

(+)

EMG

normal

miopata con ondas (+)

MRI

normal

mioedema

Biopsia

no especfica

necrosis con minima inflamacin

Terapia

retiro droga

inmunosupresin

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