Rhabdomyolysis - Differential Diagnosis Framework Rhabdomyolysis = Destruction of skeletal muscle with leakage

Rhabdomyolysis - Differential Diagnosis Framework and Management Summary Causes of Rhabdomyolysis: • Trauma: - Immobilization - Crush injury - Compartment syndrome - Electrical injury • Exertional: - Hyperthermia/Heat exhaustion, Heat injury, Heat stroke - Metabolic myopathies - Excess exertion/training - Seizures - Malignant hyperthermia - Neuroleptic malignant syndrome • Nontraumatic Nonexertional: - Electrolytes - Toxins - Drugs - Statins - ETOH - Infection - Viral (HIV, Influenza, TSS, Herpes, Coxsackie, etc) - Endocrine: Hypo/Hyperthyroidism - Autoimmune: Polymyositis/Dermatomyositis Clinical Features: • Triad of symptoms: - Muscle pain - Weakness - Dark urine • Other symptoms: - Malaise - Muscle swelling - Fever - Tachycardia - N/V - Abdominal pain Labs: • CPK 5X ULN • AST/ALT Elevation 4:1 ratio (AST declines > ALT) • AKI: BUN/Cr ↑ • Aldolase ↑ • LDH ↑ • Hyperkalemia • Hyperphosphatemia • Hypocalcemia/Late - Hypercalcemia • Hyperuricemia • Hyponatremia • HAGMA • Late complication: DIC • CPK - if doesn’t decline - suspect continued muscle injury or compartment syndrome • Myoglobinuria: UA positive for blood with no RBC’s, + myoglobin AKI Mechanism: 1. Shift of extracellular fluid into injured muscles - HYPOTENSION → renal vasoconstriction → decreased renal perfusion → renal ischemia 2. Cast formation: Renal tubular obstruction 3. Direct myoglobin nephrotoxicity to kidney tubular cells 4. Heme associated free radicals - oxidative injury Treatment: 1. Treatment of underlying disease 2. Prevent Prerenal azotemia: Isotonic fluid/Lactated ringers - Initial rate: 1-2 L/hour with goal urine output: 200 ml/hr 3. Monitor potassium and calcium several times per day until stable 4. Loop diuretics for fluid overload 5. Dialysis for severe hyperkalemia or ATN 6. Allopurinol for hyperuricemia if levels > 8 mg/dL #Rhabdomyolysis #Differential #Diagnosis #Management #causes #treatment #nephrology

Causes of Rhabdomyolysis - Differential Diagnosis • Drugs & Toxins (Statins, alcohol, cocaine) • Direct Muscle Damage (Trauma/crush injury, burns, extreme exercise) • Muscle Hypoxia (Prolonged immobilization) • Infections (Influenza, HIV, Legionella, S. pyogenes, Clostridium) • Temperature (Heat stroke, malignant neuroleptic syndrome) • Inflammatory Muscle Disease (myositis) • Metabolic Disorders (Diabetic ketoacidosis, hypothyroidism) • Genetic Defects (Deficiencies in glycolytic enzymes or lipid metabolism, mitochondrial) - BWH Medicine Chiefs @BrighamChiefs #Rhabdomyolysis #Differential #Diagnosis #Causes

Rhabdomyolysis - Differential Diagnosis and Management Summary Trauma: • Immobilization, Crush iniury, Compartment syndrome, Electrical injury Exertional: • Hyperthermia/Heat exhaustion, Heat iniury, Heat stroke, Metabolic myopathies, Excess exertion/training, Seizures, Malignant hyperthermia, Neuroleptic malignant syndrome Nontraumatic nonexertional: • Electrolytes, Toxins. Drugs (Statins), ETOH Infection (Viral- HIV, Influenza, TSS, Herpes, Coxsackie etc), Endocrine (Hypo/Hyperthyroidism), Autoimme (polymyositis/Dermatomyositis) AKI - Pathophysiology: 1. Shift of extracellular fluid into injured muscles -> HYPOTENSION -> renal vasocontriction-> decreased renal renal ischemia 2. Cast formation: Renal tubular obstruction 3. Direct myoglobin nephrotoxicity 4. Heme associated free radicals- oxidative iniury Treatment: 1. Prevent Prerenal azotemia: Isotonic saline 2. Iinitial rate: 1-2 L/hour with goal urine output: 200ml/hr 3. Monitor potassium and calcium several times per day until stable 4. Loop diuretics for fluid overload 5. Dialysis for severe hyperkalemia or ATN 6. Allopurinol for hyperuricemia if levels > 8mg/dL See updated Rhabdomyolysis Schema here: https://www.grepmed.com/images/10725 #Rhabdomyolysis #Differential #Diagnosis #Management #Summary #causes #treatment

Creatine Kinase - Causes of Elevated CK Levels Acute CK Elevation (Pain > Weakness): • RHABDOMYOLYSIS - Drugs: cocaine, amphetamines, alcohol - Medications: statins, fibrates, colchicine, daptomycin - Illness: viral (COVID19, CMV/EBV, HIV), clostridial spp, mycoplasma, staph, strep) - Seizures: Trauma, burns, hyperthermia, immobility • Critical Illness Myopathy (ICU, steroids, mechanical ventilation) • Myocardial infarction, Acute renal injury, Strenuous exercise Subacute to Chronic Causes (Weakness > Pain): • PROXIMAL MUSCLE WEAKNESS - Endocrine: Hypo/hyperthyroidism, acromegaly - Electrolytes: hypo- phos, kalemia, calcemia, natremia - Muscular dystrophy - Metabolic Myopathies - Neuromuscular disorders - Vit D/E deficiency - Medications- Statins, fibrates, colchicine, daptomycin - Chronic Illness: HIV, Trichinella, toxoplasmosis - Inflammatory myopathy: dermatomyositis, polymyositis, necrotizing myopathy - Autoimmune: mixed connective tissue disorder, SLE • PROXIMAL AND DISTA: Inclusion body myositis • ASYMPTOMATIC: Macro CK Ann Marie Kumfer @AnnKumfer #Creatine #Kinase #Elevated #CK #differential #diagnosis #rhabdomyolysis

Heat Illnesses and Heat Stroke - Differential Diagnosis Framework Heat Cramps: • Muscle pain or spasm - legs, arms or abdomen • Due to: - Strenuous exercise in the heat - Dehydration - Loss of sodium/Potassium - Extreme environmental conditions - Neurogenic fatigue Heat Rash: • Small red bumps/blisters on the skin • Areas that stay wet from sweat Heat Injury: • Exertional heat illness → Hypernatremia & end organ damage without neuro manifestations • Organ involvement: Muscles, Kidneys, Liver • Labs: - Metabolic acidosis - Rhabdomyolysis - AKI - Liver failure Heat Syncope / Exercise Associated Collapse: • Pathophysiology: Volume depletion → Decreased vasomotor tone → Postural hypotension → Syncope • Signs/Symptoms: - Lightheadedness - Tunnel vision - Pale and sweaty skin - Decreased pulse rate - Core temp normal/mildly elevated Heat Exhaustion: • Inability to maintain adequate cardiac output due to strenuous physical exercise and environmental heat stress • Criteria: - Athlete - difficulty continuing with exercise - Core body temp 101-104 degrees F - No significant CNS dysfunction • Other manifestations: - Tachycardia & hypotension - Extreme weakness - Dehydration and electrolyte losses - Ataxia and coordination problems - syncope/lightheadedness - Profuse sweating, pallor, “prickly heat” sensations - Headache - Abdominal cramps, N/V, diarrhea - Persistent muscle cramps Exertional Heat Stroke: EMERGENCY • Multi-system illness: 1. CNS dysfunction (encephalopathy) 2. Organ and tissue damage (AKI, Liver injury, Rhabdomyolysis, Thermal cardiomyopathy, ARDS, DIC) 3. High body temperatures • Criteria: - Core temp > 104 F - CNS dysfunction: • Disorientation, Headache, Irrational behavior, Irritability, Emotional instability, Confusion, Altered consciousness, Coma/seizure • Other Findings: - Tachycardia, Hyperventilation, Dizziness, Nausea, Vomiting, Diarrhea, Weakness, Profuse sweating, Dehydration, Dry mouth, Thirst, Muscle cramps, Loss of muscle function, Ataxia • Lab Findings: - Mild coagulopathy - Possible DIC - Mild lactic acidosis - CPK elevation - Hypoglycemia - Hypocalcemia - Hyperkalemia #heat #illness #differential #diagnosis #causes #stroke #heatstroke

Acute Kidney Injury - AKI Workup Algorithm and Differential Diagnosis Baseline Investigations: full blood count with differential, urine dipstick, urine microscopy / urinary sediment, renal ultrasonography, serum calcium Optional: urinary electrolytes, urea, uric acid, osmolarity If cause of AKI remains unclear AND hypovolaemia and obstruction excluded OR any of the above investigations abnormal: consider the following investigations depending on clinical context and signs • Glomerulonephritis / Vasculits: ANCA, ANA, Anti-GBM, Anti-ds-DNA, C3/C4, ENA, immunoglobulins, cryoglobulins, hepatitis serology, HIV serology, renal biopsy • Interstitial nephritis: eosinophilia, eosinophiluria, renal biopsy • Abdominal compartment syndrome: intravesicular pressure • TTP / HUS: fragmentocytes, LDH, platelets, reticulocytes, haptoglobin, bilirubin • Rhabdo-myolysis: CK, myoglobin • Myeloma: serum / urine, protein-electrophoresis, renal biopsy • Sepsis: sepsis screen, including blood culture, urine culture, inflammatory markers • Cardio-renal syndrome: troponin, CK-MB, NT-proBNP, cardiac imaging #Acute #Kidney #Injury #AKI #Workup #Algorithm #Differential #Diagnosis #nephrology #causes

Hyperthermic Toxidromes Five toxidromes may present with overlapping features: hyperthermia, rhabdomyolysis, altered mental status/seizures. • Sympathomimetic - Excess release of monoamines (epi, NE, DA, 5HT) leading to overstimulation of adrenergic receptors. • Anticholinergic - Blockade of muscarinic Ach receptors impairs acetylcholine signaling in the CNS, on cardiac & smooth muscle, and on sweat glands. • Serotonin Syndrome - Excessive release of 5HT, usually due to combination of 2 or more serotoninergic meds. Rarely it can occur with a single serotonergic agent. • Neuroleptic Malignant - Ideosyncratic reaction to dopamine blockers (e.g. anti-psychotic) or due to abrupt cessation of dopamine agonists (e.g. Parkinson’s Tx) • Malignant Hyperthermia - Rare pharmacogenetic disease caused by genetic susceptibility (AD mutations in ryanodine receptor) & triggered by inhaled anesthetics by Nick Mark MD @nickmmark #Hyperthermic #Toxidromes #comparison #table #diagnosis #differential #toxicology

Weakness - Differential Diagnosis Framework Approach To Weakness: • Non-neuromuscular disorder (Cardiac, pulmonary etc) • CNS -> PNS -> NMJ -> Muscle • Muscle weakness (generalized, distal, proximal, or localized) 1. Upper Motor Neuron Impairment: • Acute stroke syndromes • Space occupying lesions of the central nervous system: Brain tumor • Lesions of the spinal cord • Inflammatory: Vasculitis • Infectious: Brain abscess • Toxic/drug: Radiation • Metabolic/endocrine: Vitamin B12 deficiency • Congenital leukodystrophies 2. Lesions Of The Peripheral Nervous System: • Symmetric polyneuropathy: DM • Mononeuropathy: Nerve compression • Mononeuritis multiplex (DM, Vasculitis-polyarteritis nodosa) • Toxic/drug: Lead • Neoplastic: Paraneoplastic syndrome • Inflammatory: Myeloma/amyloid • Infectious: Leprosy 3. Neuromuscular Junction: • Exercise-induced weakness: Fatiguability - Consider NMJ • Nerve Side Presynaptic: - Lambert-Eaton - Isaacs' syndrome - Tick-paralysis - Botulism - Aminoglycosides - Envenomation (venom from animal bites) • Synaptic Cleft: - Organophosphate toxicity - Carbamate toxicity • Muscle Side: - Postsynaptic: Myasthenia Gravis - Lack of UMN/LMN signs - Lack of sensory changes - Common pattern: Symmetric proximal weakness Myopathy: • Inflammatory disorders: Polymyositis • Immune mediated necrotizing myopathy • Autoimmune: Inclusion body myositis • Endocrinopathies: Hypothyroid • Metabolic myopathies: Hypoglycemia • Drugs and toxins: Steroids, Statins, amiodarone, Alcohol • Infections: - Viral - Influenza, parainfluenza, Coxsackie, HIV, CMV, EBV - Bacterial - Pyomyositis, Lyme myositis • Rhabdomyolysis • Neoplastic: Malignancy-associated myositis • Genetic: Muscular dystrophies Work Up: • Chem: CPK aldolase, lactate dehydrogenase, and the aminotransferases • Serology: - Anti-Ro/SSA, anti-La/SSB, anti-Sm, and anti-RNP - (Myositis) anti-histidyl-t-RNA synthetase [anti-Jo-1] - (Vasculitis) ANCA titers, hepatitis B and C serologies, and cryoglobulins • PNS, NMJ, Nerve: Nerve conduction and electromyographic (EMG) studies • MRI: Inflammation of the muscle • Muscle Biopsy: Dermatomyositis, polymyositis, inclusion body myositis, certain drug-induced myopathies, the muscular dystrophies, or vasculitis #Weakness #Differential #Diagnosis #neurology

Hyperkalemia - Differential Diagnosis Framework PseudoHyperkalemia: • Lab error • Traumatic venipuncture • Hemolysis, thrombocytosis, leukocytosis • Clenching of fist during phlebotomy High Suspicion for Hyperkalemia: • CKD • Poorly controlled DM • Chemotherapy • Burns • Trauma/Crush injury • Blood transfusion • HTN and edema • Jaundice/Hemolytic reactions Common Drugs Causing Hyperkalemia: • Digoxin • K sparing diuretics • NSAIDs • ACE Inhibitors • Recent IV potassium • Beta blockers • Antibiotics: amoxicillin • Heparins • Tacrolimus • TMP-SMZ • Penicillin G Intracellular Shift: • K release due to cell lysis: - Hemolysis - Transfusion reaction - Tumor lysis syndrome - Rhabdomyolysis, burns, trauma - Ischemic colonic necrosis • K release with intact cell membrane - Beta adrenergic receptor blockers - Succinylcholine - Hyperosmolar states (Uncontrolled diabetes, glucose infusions) - Metabolic acidosis - Hyperkalemia Periodic paralysis - Insulin deficiency or resistance Impaired Renal Excretion: • Addison’s disease/Hypoaldosteronism • Acquired hyporeninemic hypoaldosteronism • Mineralocorticoid deficiency • Renal insufficiency/Failure • SLE • Type IV RTA • Renal hypoperfusion Increased K Intake: 1. Medications 2. K supplement 3. Blood transfusion 4. TPN 5. Food - Avoid in CRF: • Dried fruits, Seaweed, Nuts, molasses, Avocados, Lima beans • Vegetables: spinach, potatoes, tomatoes, broccoli, carrots • Fruits: kiwis, mangoes, oranges, bananas, cantaloupe Updated Version Here: https://www.grepmed.com/images/12834 #hyperkalemia #differential #diagnosis #causes #potassium #high #nephrology

Hyperkalemia - Differential Diagnosis Framework PseudoHyperkalemia: • Lab error • Traumatic venipuncture • Hemolysis, thrombocytosis, leukocytosis • Clenching of fist during phlebotomy High Suspicion for Hyperkalemia: • CKD • Poorly controlled DM • Chemotherapy • Burns • Trauma/Crush injury • Blood transfusion • HTN and edema • Jaundice/Hemolytic reactions Common Drugs Causing Hyperkalemia: • Digoxin • K sparing diuretics • NSAIDs • ACE Inhibitors • Recent IV potassium • Beta blockers • Antibiotics: amoxicillin • Heparins • Tacrolimus • TMP-SMZ • Penicillin G Intracellular Shift: • K release due to cell lysis: - Hemolysis - Transfusion reaction - Tumor lysis syndrome - Rhabdomyolysis, burns, trauma - Ischemic colonic necrosis • K release with intact cell membrane - Beta adrenergic receptor blockers - Succinylcholine - Hyperosmolar states (Uncontrolled diabetes, glucose infusions) - Metabolic acidosis - Hyperkalemia Periodic paralysis - Insulin deficiency or resistance Impaired Renal Excretion: • Addison’s disease/Hypoaldosteronism • Acquired hyporeninemic hypoaldosteronism • Mineralocorticoid deficiency • Renal insufficiency/Failure • SLE • Type IV RTA • Renal hypoperfusion Increased K Intake: 1. Medications 2. K supplement 3. Blood transfusion 4. TPN 5. Food - Avoid in CRF: • Dried fruits, Seaweed, Nuts, molasses, Avocados, Lima beans • Vegetables: spinach, potatoes, tomatoes, broccoli, carrots • Fruits: kiwis, mangoes, oranges, bananas, cantaloupe #hyperkalemia #differential #diagnosis #causes #potassium #high #nephrology