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(+)Stephen J. Traub, MD, FACEP Assistant Professor of Medicine, Harvard Medical School, Division of Toxicology, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts MUDPILES and Beyond: Closing the Gap Emergency physicians are familiar with the pneumonic MUDPILES in the evaluation of the patient with high anion gap metabolic acidosis. Challenging cases will be presented to elevate the diagnosis and management of metabolic acidosis and help get your head out of the mud. • Review the approach to patients with metabolic acidosis. • Present challenging cases of patients with metabolic acidosis. • Review the treatment of causes of metabolic acidosis. • Outline a stepwise approach to the work up of anion gap acidosis. MO-45 Monday, October 5, 2009 3:00 PM - 3:50 PM Boston Convention & Exhibition Center (+)No significant financial relationships to disclose Goals • Review (and discard) MUDPILES • Derive and discuss an alternative approach (KULT) to an elevated anion-gap acidosis • Utilize a case-based approach to evaluate patients with an elevated anion gap acidosis • Discuss selected acid-base abnormalities Traditional Teaching: MUDPILES • Methanol • Uremia • DKA • Paraldehyde • INH • Lactate • Ethylene Glycol • Salicylates Anions and Cations Ions: charged species • In human blood, anions = cations Cations • Major: Sodium (Na+) • Minor: Potassium (K+) Anions • Major: Chloride (Cl-), Bicarbonate (HCO3-) • Minor: Phospate, Sulfate, Urate, Lactate What is the Anion Gap? • Useful relationship among major ions • Na+ - (Cl- + HCO3-) : The ANION GAP • Usually 12-14 meq/L Buffering and the Anion Gap • Endogenous acids are normally eliminated • When elimination is overwhelmed, buffers preserve acid-base balance • Bicarbonate system most important • (HCO3-) + (H+) Æ CO2 + H2O o Note the loss of bicarbonate ion • Decrease in bicarbonate = elevated gap • Anion gap = Na+ - (Cl- + HCO3-) Traditional Teaching: MUDPILES • Methanol • Uremia • DKA • Paraldehyde • INH • Lactate • Ethylene Glycol • Salicylates MUDPILES: Positives • Easy to remember MUDPILES: Negatives • Makes you think of methanol first o How often do you really see this? • Incomplete o Where is alcoholic ketoacidosis? • Somewhat misleading o INH produces acidosis via lactate • No thought to pathophysiology, no direction to workup MUDPILES Revisited • Methanol • Uremia • DKA • Paraldehyde • INH • Lactate • Ethylene Glycol • Salicylates Toxin Uremia Ketones Toxin Lactate Lactate Toxin Toxin A different approach . . . • Ketones o Diabetic, Alcoholic and Starvation Ketoacidosis Acetoacetate, Beta-hydroxybutyrate • Uremia o Renal failure (usually creatinine > 5 mg/dL) Phosphates, sulfates, other organic acids • Lactate o Sepsis, then other (long) differential diagnosis • Toxins* o Toxic alcohols, aspirin Formic acid and oxalic acid; salicylic acid The KULT Workup • Is the patient ketotic? o Urine dipstick or blood testing • Is the patient uremic? o Serum creatinine • Does the patient have an elevated lactate? o Serum lactate testing • Is this toxic alcohol or salicylate poisoning? o Direct testing The KULT Workup • Arterial or Venous Blood Gas • Basic Metabolic Panel • Urine or Serum Ketones • Serum Lactate • Aspirin Level • Occasionally: Toxic Alcohol Testing The KULT Workup: Postives • Mnemonic suggests stepwise approach • Mnemonic based on pathophysiology • Mnemonic logically drives testing • Common things come first • Uncommon things come last The KULT Workup: Negatives • You will be the only one doing this CASE PRESENTATION History of Present Illness 37 year-old alcoholic presents with vomiting and upper abdominal pain. He states that he has been binging on alcohol and not eating. Poorly compliant with medications. Depressed over recent breakup with fiancé. PMH/Meds/All/Soc • IDDM x 23 years • Medications: Insulin • Allergies: NKDA • Social: Alcoholic, Unemployed Jeweler ROS • Cough, Suicidal Thoughts Physical Exam P 121 BP 93/52 RR 22 T 100.0 PO 97% HEENT: NCAT Cardiac: RRR without MRG Lungs: Scattered crackles Abd: Soft and nontender, normal BS Neuro: Tired appearing but nonfocal Laboratory: As presented Alcoholic Ketoacidosis • Decrease in dietary carbohydrates o Decreased levels of circulating insulin o Increased levels of glucagon • Direct effects of ethanol o Decreased gluconeogenesis o Increased lipolysis Halperin, Metabolism 1993 Alcoholic Ketoacidosis • Clinical Presentation o Vomiting o Abdominal pain o Tachypnea and Hyperpnea • Treatment o Glucose o Intravenous fluids o Cessation of ethanol Uremia • Many minor acid products (sulfates, phosphates) are renally cleared • Uremia (typically BUN >50, Cr > 5.0) leads to a failure to clear these acids • Anion Gap acidosis ensues Uremia: Workup and Disposition • Resuscitate o Address electrolytes (K+) as necessary • Determine cause o Prerenal o Renal o Postrenal • Admit for further evaluation Uremia: Emergent Dialysis--AEIOU • Acidosis • Electrolyte abnormality (usually K+) • Intoxication with dialyzable drug • Overload of fluid (pulmonary edema) • Uremia (symptomatic): AMS Lactate: Sepsis and Lactate • Lactate reflects severity even when controlling for clinical parameters o In normotensive patients Lactate > 4.0 mmol/L: 15% mortality Lactate < 4.0 mmol/L: 2.5% mortality Howell, Intensive Care Medicine 2007 Sepsis Treatment: Early Goal Directed Therapy • Supplemental Oxygen +/- intubation • Central Venous Pressure Monitoring • Mean Arterial Pressure Monitoring • Central Venous Oxygenation Monitoring • 34% Reduction in Mortality Rivers, New England Journal of Medicine 2001 Lactic Acidosis: Increased Production • Enhanced metabolic rate o Seizures, exercise, shivering • Hypoperfusion o Hypovolemia, isolated organ ischemia • Decreased oxygen delivery o Pulmonary, anemia, dyshemoglobinemias • Toxin-induced mitochondrial dysfunction o Anti-retrovirals (zidovudine, stavudine) Lactic Acidosis: Decreased Clearance • Parenchymal hepatic dysfunction • Toxin-induced o Metformin Cyanide Toxicity • Alteration in mental status • Unexplained, profound metabolic acidosis Cyanide: Treatment • Hydroxocobalamin Complexes cyanide to form Vitamin B12 o o Dose: 5 g IV • Sodium thiosulfate o Promotes detoxification via rhodanese o Dose: 50 cc IV of 25% solution Toxic Alcohols • Cause initial intoxication when ingested • Metabolized to devastating acidic species o Methanol Æ Formic Acid Retinal toxicity o Ethylene Glycol Æ Æ Oxalic Acid Renal failure Toxic Alcohols: Initial Treatment • Alkalinization o NaHCO3 1-2 meq/kg bolus, then o 132 meq NaHCO3 in 1 L D5W @ 250 cc/h • Fomepizole o 15 mg/kg loading dose, then 10 mg/kg q 12h • Cofactors o Folic acid, 50 mg IV o Thiamine, 100 mg IV o Pyridoxine, 50 mg IV Toxic Alcohols: Definitive Treatment • Hemodialysis o Persistent metabolic acidosis o Evidence of end-organ damage o Elevated alcohol level (> 50 mg/dL) Not as hard and fast as it used to be The KULT Approach: Pitfalls • Lactate often complicates the picture o Lactate present in many states (i.e. DKA) o Oxalate and lactate may cross-react • The acidosis of aspirin is multifactorial o Some lactate o Some ketones • Don’t miss the forest for the trees o This is a guidance, not a rigid recipe Final Thoughts: The KULT approach • Blood Gas to define acid-base imbalance • Ketones: to rule out DKA, SKA, AKA • Uremia: BUN/Cr to assess for this • Lactate to rule out this entity (with its own ddx) • Toxin consideration o Toxic alcohols o Aspirin References • • • Halperin ML, Hammeke M, Josse RG, Jungas RL. Metabolic acidosis in the alcoholic: a pathophysiologic approach. Metabolism. 1983 Mar;32(3):308-15. Howell MD, Donnino M, Clardy P, Talmor D, Shapiro NI. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med. 2007 Nov;33(11):1892-9. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. 8/31/2009 Beyond MUDPILES: Join the KULT Stephen J. Traub, Traub, MD, FACEP Assistant Professor of Medicine, Harvard Medical School Division of Toxicology and Department of Emergency Medicine, Beth Israel Deaconess Medical Center Boston, MA USA Goals Review (and discard) MUDPILES Derive and discuss an alternative approach (KULT) to an elevated anionanion-gap acidosis Utilize a case case--based approach to evaluate patients with an elevated anion gap acidosis Discuss selected acidacid-base abnormalities Traditional Teaching: MUDPILES Methanol Uremia DKA Paraldehyde INH Lactate Ethylene Glycol Salicylates 1 8/31/2009 Anions and Cations Ions: charged species In human blood, anions = cations Cations Major: Sodium (Na+) Minor: Potassium (K+) Anions Major: Chloride (Cl (Cl-), Bicarbonate (HCO3-) Minor: Phospate Phospate,, Sulfate, Urate, Urate, Lactate What is the Anion Gap? Useful relationship among major ions Na+ - (Cl- + HCO3-) : The ANION GAP Usually 1212-14 meq/L meq/L Buffering and the Anion Gap Endogenous acids are normally eliminated When elimination is overwhelmed, buffers preserve acid acid--base balance Bi b Bicarbonate t system t mostt important i t t (HCO3-) + (H+) Æ CO2 + H2O Note the loss of bicarbonate ion Decrease in bicarbonate = elevated gap Anion gap = Na+ - (Cl- + HCO3-) 2 8/31/2009 Traditional Teaching: MUDPILES Methanol Uremia DKA Paraldehyde INH Lactate Ethylene Glycol Salicylates MUDPILES: Positives Easy to remember MUDPILES: Negatives Makes you think of methanol first How often do you really see this? Incomplete Wh Where is i alcoholic l h li ketoacidosis k t ketoacidosis? id i ? Somewhat misleading INH produces acidosis via lactate No thought to pathophysiology No direction to workup 3 8/31/2009 MUDPILES Methanol Uremia DKA Paraldehyde INH Lactate Ethylene Glycol Salicylates MUDPILES Methanol Uremia DKA Paraldehyde INH Lactate Ethylene Glycol Salicylates Toxin Uremia Ketones Toxin Lactate Lactate Toxin Toxin A different approach . . . Ketones Uremia Lactate Toxins 4 8/31/2009 A different approach . . . Ketones Diabetic, Alcoholic and Starvation Ketoacidosis Acetoacetate,, BetaAcetoacetate Beta-hydroxybutyrate Uremia Renal failure (usually creatinine > 5 mg/dL mg/dL)) Phosphates, sulfates, other organic acids Lactate Sepsis, then other (long) differential diagnosis Toxins* Toxic alcohols, aspirin Formic acid and oxalic acid; salicylic acid The KULT Workup Is the patient ketotic? ketotic? Urine dipstick or blood testing Is the patient uremic? S Serum creatinine ti i Does the patient have an elevated lactate? Serum lactate testing Is this toxic alcohol or salicylate poisoning? Direct testing The KULT Workup Arterial or Venous Blood Gas Basic Metabolic Panel Urine or Serum Ketones Serum Lactate Aspirin Level Occasionally: Toxic Alcohol Testing 5 8/31/2009 The KULT Workup Positives Mnemonic suggests stepwise approach Mnemonic based on pathophysiology Mnemonic logically drives testing Common things come first Uncommon things come last Negatives You will be the only one doing this Case Presentation History of Present Illness 37 year year--old alcoholic presents with vomiting and upper abdominal pain. He states that he has been binging on alcohol and not eating Poorly compliant with medications eating. medications. Depressed over recent breakup with fiancé. 6 8/31/2009 PMH/Meds/All/Soc Past Medical History IDDM x 23 years Medications Insulin Allergies NKDA Social Alcoholic Unemployed Jeweler ROS Cough Suicidal Thoughts Physical Exam P 121 BP 93/52 RR 22 T 100.0 PO 97% HEENT: NCAT Cardiac: RRR without MRG Lungs: Scattered crackles Abd:: Soft and nontender, Abd nontender, normal BS Neuro:: Tired appearing but nonfocal Neuro 7 8/31/2009 Scenario 1 Initial Laboratory Testing ABG: 7.25/92/26/16 138 4.3 102 Pnd 14 Pnd 92 13.8 12.4 37.1 158 Laboratory ABG: 7.25/92/26/16 138 4.3 102 Pnd 14 Pnd Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 13.8 12.4 37.1 158 Neg 4+ Neg Neg 1+ Neg Neg 8 8/31/2009 Laboratory ABG: 7.25/92/26/16 138 4.3 102 14 14 1.0 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 Neg 4+ Neg Neg 1+ Neg Neg 13.8 12.4 37.1 158 Lactate: 1.0 mmol/L mmol/L Salicylate:: ND Salicylate Ketoacidosis Diabetic Ketoacidosis Unlikely at this glucose level Starvation Ketoacidosis P Possible ibl Alcoholic Ketoacidosis Perfect presentation Alcoholic Ketoacidosis Decrease in dietary carbohydrates Decreased levels of circulating insulin Increased levels of glucagon Direct effects of ethanol Decreased gluconeogenesis Increased lipolysis Halperin,, Metabolism 1993 Halperin 9 8/31/2009 Alcoholic Ketoacidosis Clinical Presentation Vomiting Abdominal pain Tachypnea yp and Hyperpnea yp p Treatment Glucose Intravenous fluids Cessation of ethanol Scenario #2 Laboratory ABG: 7.25/92/26/16 138 4.3 102 Pnd 14 Pnd 92 13.8 12.4 37.1 158 10 8/31/2009 Laboratory ABG: 7.25/92/26/16 138 4.3 102 Pnd 14 Pnd Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 13.8 12.4 37.1 158 Neg Neg Neg Neg 1+ Neg Neg Laboratory ABG: 7.25/92/26/16 138 4.3 102 63 14 5.9 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 13.8 12.4 37.1 158 Neg Neg Neg Neg 1+ Neg Neg Laboratory ABG: 7.25/92/26/16 138 4.3 102 63 14 5.9 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili Neg Neg Neg Neg 1+ Neg Neg 92 13.8 12.4 37.1 158 Lactate: 1.0 mmol/L mmol/L Salicylate:: ND Salicylate 11 8/31/2009 Uremia Many minor acid products (sulfates, phosphates) are renally cleared Uremia (typically BUN >50, Cr > 5.0) leads to a failure to clear these acids Anion Gap acidosis ensues Uremia Resuscitate Address electrolytes (K+) as necessary Determine cause Prerenal P l Renal Postrenal Admit for further evaluation Acute Renal Failure: Emergent Dialysis A E I O U 12 8/31/2009 Acute Renal Failure: Emergent Dialysis Acidosis Electrolyte abnormality (usually K+) Intoxication with dialyzable drug Overload of fluid (pulmonary edema) Uremia (symptomatic): AMS Scenario #3a Laboratory ABG: 7.25/92/26/16 138 4.3 102 Pnd 14 Pnd 92 13.8 12.4 37.1 158 13 8/31/2009 Laboratory ABG: 7.25/92/26/16 138 4.3 102 Pnd 14 Pnd Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 13.8 12.4 37.1 158 Neg Neg Neg Neg 1+ Neg Neg Laboratory ABG: 7.25/92/26/16 138 4.3 102 14 14 1.0 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 13.8 12.4 37.1 158 Neg Neg Neg Neg 1+ Neg Neg Laboratory ABG: 7.25/92/26/16 138 4.3 102 14 14 1.0 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili Neg Neg Neg Neg 1+ Neg Neg 92 13.8 12.4 37.1 158 Lactate: 7.3 mmol/L mmol/L 14 8/31/2009 Laboratory ABG: 7.25/92/26/16 138 4.3 102 14 14 1.0 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili Neg Neg Neg Neg 1+ Neg Neg 92 13.8 12.4 37.1 158 Lactate: 7.3 mmol/L mmol/L Salicylate:: ND Salicylate Chest X X--Ray Sepsis and Lactate Lactate reflects severity even when controlling for clinical parameters In normotensive patients Lactate > 4.0 4 0 mmol mmol/L: /L: 15% mortality Lactate < 4.0 mmol mmol/L: /L: 2.5% mortality Howell, Intensive Care Medicine 2007 15 8/31/2009 Sepsis Treatment: Early Goal Directed Therapy Supplemental Oxygen +/+/- intubation Sepsis Treatment: Early Goal Directed Therapy Supplemental Oxygen +/+/- intubation Central Venous Pressure Monitoring Maintain CVP 88-12 mm Hg (IV fluids) Sepsis Treatment: Early Goal Directed Therapy Supplemental Oxygen +/+/- intubation Central Venous Pressure Monitoring Mean Arterial Pressure Monitoring Maintain MAP 6565-90 mm Hg ((vasopressors vasopressors)) 16 8/31/2009 Sepsis Treatment: Early Goal Directed Therapy Supplemental Oxygen +/+/- intubation Central Venous Pressure Monitoring Mean Arterial Pressure Monitoring Central Venous Oxygenation Monitoring Maintain SCVO2 > 70% Transfusion if hematocrit < 30% Dobutamine if hematocrit > 30% Sepsis Treatment: Early Goal Directed Therapy Supplemental Oxygen +/+/- intubation Central Venous Pressure Monitoring Mean Arterial Pressure Monitoring Central Venous Oxygenation Monitoring 34% Reduction in Mortality Rivers, New England Journal of Medicine 2001 Lactic Acidosis Increased Production Enhanced metabolic rate Seizures, exercise, shivering Hypoperfusion yp p Hypovolemia,, isolated organ ischemia Hypovolemia Decreased oxygen delivery Pulmonary, anemia, dyshemoglobinemias Toxin--induced mitochondrial dysfunction Toxin Anti--retrovirals (zidovudine Anti zidovudine,, stavudine) stavudine) 17 8/31/2009 Lactic Acidosis Decreased Clearance Parenchymal hepatic dysfunction Toxin--induced Toxin Metformin Scenario #3b: Chest X X--Ray Scenario #3b ABG: 7.25/92/26/16 Lactate: 7.3 Patient becomes abruptly unresponsive Intubated Repeat ABG: 7.15/12/98/12: 100% Simultaneous VBG: 7.13/16/63/12: 92% Repeat Lactate: 13.1 18 8/31/2009 Cyanide Toxicity Alteration in mental status Unexplained, profound metabolic acidosis Role of the mitochondria (Cyt = cytochrome) NADH FADH2 Cyt bII Cyt cII Cyt aII NAD+ FAD Cyt bIII Cyt cIII Cyt aIII H2O ½ O2 19 8/31/2009 Effect of Cyanide NADH FADH2 Cyt bII Cyt cII Cyt aII NAD+ FAD Cyt bIII Cyt cIII Cyt aIII H2O ½ O2 Cyanide Laboratory Electroplating Cyanide: Treatment 20 8/31/2009 Cyanide: Treatment Hydroxocobalamin Complexes cyanide to form Vitamin B12 Dose: 5 g IV S di Sodium thi thiosulfate lf t Promotes detoxification via rhodanese Dose: 50 cc IV of 25% solution Scenario #4 ABG: 7.25/92/26/16 138 4.3 102 Pnd 14 Pnd 92 13.8 12.4 37.1 158 Scenario #4 ABG: 7.25/92/26/16 138 4.3 102 Pnd 14 Pnd Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 13.8 12.4 37.1 158 Neg Neg Neg Neg 1+ Neg Neg 21 8/31/2009 Scenario #4 ABG: 7.25/92/26/16 138 4.3 102 14 14 1.0 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 13.8 12.4 37.1 158 Neg Neg Neg Neg 1+ Neg Neg Scenario #4 ABG: 7.25/92/26/16 138 4.3 102 14 14 1.0 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili 92 13.8 12.4 37.1 158 Lactate: 1.0 mmol/L mmol/L Neg Neg Neg Neg 1+ Neg Neg Scenario #4 ABG: 7.25/92/26/16 138 4.3 102 14 14 1.0 Urine Dip Glucose Ketones Leuk Est Nitrite Protein RBC Bili Neg Neg Neg Neg 1+ Neg Neg 92 13.8 12.4 37.1 158 Lactate: 1.0 mmol/L mmol/L Salicylate:: ND Salicylate 22 8/31/2009 Scenario #4 Scenario #4 Toxic Alcohols Cause initial intoxication when ingested Metabolized to devastating acidic species Methanol Æ Formic Acid R ti l ttoxicity Retinal i it Ethylene Glycol Æ Æ Oxalic Acid Renal failure 23 8/31/2009 Toxic Alcohols: Initial Treatment Alkalinization NaHCO3 11-2 meq/kg meq/kg bolus, then 132 meq NaHCO3 in 1 L D5W @ 250 cc/h F Fomepizole i l 15 mg/kg loading dose, then 10 mg/kg q 12h Cofactors Folic acid, 50 mg IV Thiamine, 100 mg IV Pyridoxine, 50 mg IV Toxic Alcohols: Definitive Treatment Hemodialysis Persistent metabolic acidosis E id Evidence off endend d-organ damage d Elevated alcohol level (> 50 mg/dL mg/dL)) Not as hard and fast as it used to be The KULT Approach: Pitfalls Lactate often complicates the picture Lactate present in many states (i.e. DKA) Oxalate and lactate may crosscross-react Th acidosis The id i off aspirin i i iis multifactorial ltif t i l Some lactate Some ketones Don’t miss the forest for the trees This is a guidance, not a rigid recipe 24 8/31/2009 Final Thoughts The KULT approach Blood Gas to define acidacid-base imbalance Ketones:: to rule out DKA, SKA, AKA Ketones Uremia: BUN/Cr to assess for this Lactate to rule out this entity (with its own ddx ddx)) Toxin consideration Toxic alcohols Aspirin 25
