High Anion Gap Metabolic Acidosis

1
High Anion Gap Metabolic Acidosis

• Dr Chaitanya Vemuri

2
Introduction

• Systemic arterial pH 7.35 7.45
• Maintained by extracellular intracellular
  chemical buffering together with respiratory and
  renal regulatory mechanisms
• Control of PaCo2 CNS Respiratory System
• Control of plasma HCO3- by Kidneys stabilize pH
  by excretion / retention of acid / alkali

3
Introduction

• Acid H Donor
• Base H Recipient
• p H Negative Logarithm of H
• Buffer Weak Acid / Salt that can accept /
  release H

4
Maintainence Of Homeostasis

• Buffers Act immediately Mops up H
• Lungs Control Co2 excretion
• Kidneys Control plasma HCO3- , excrete H

5
Buffers

• Extracellular HC03- / H2CO3
• Intracellular HPO4, Hb, Proteins
• HA- Na HCO3 Na A
  H2CO3
• Excreted by lungs CO2
  H2O

6
Role Of Lungs

• Hyperventilation Wash out of Co2
• Hypoventilation Retention of Co2

7
Proximal Tubule
Tubular lumen
Blood
Tubular Cell
HCO3-
HCO3- H
H
HCO3-
H2CO3
H2CO3
CO2
H2O
CO2 H2O
Reabsorption of HCO3-
8
Blood
Tubular lumen
Tubular cell
CO2 H2O
HPO4-
HCO3- H
H
HCO3
H 2PO4-
Formation of titratable acidity
9
Blood
Tubular Cell
Tubular lumen
Glutamine
NH4
HCO3-
NH3 H
HCO3-
Ammonium secretion
10
Henderson Hasselbach Equation

• p H 6.1 log ( HCO3- / H2CO3 )
• p H 6.1 log ( HCO3- / Pa Co2 x0.0301 )

11
pH depends on the ratio of HCO3- and PCO2
(Does not depend on the absolute values of each)
Basis of compensation
HCO3- and PCO2 need to move in the same
direction
12

• In a Simple Acid Base Disorder
  
• Pa Co2 and HCO3- move together in same
  direction
• In a Mixed Acid Base Disorder
• PaCo2 and HCO3- move in opposite directions

13
Simple Acid Base Disorders
DISORDER p H Primary Event Compensation
METABOLIC ACIDOSIS HCO3- PCO2
METABOLIC ALKALOSIS HC03- PCO2
RESPIRATORY ACIDOSIS PCO2 HCO3-
RESPIRATORY ALKALOSIS PCO2 HCO3-
14
Base excess response to acid/base physiology

• Henderson/hasselbach equation is not linear .
• Non linearity prevents this equation from
  quantifying the exact amount of bicarbonate
  deficit in metabolic acidosis
• So this led to development of SEMIQUANTITATIVE
  approach Base Excess
• BE ( HC03 24.4 2.3 X Hgb 7.7 x pH
  7.4 ) X
• ( 1- 0.023 x Hgb )
• BE gives amount of HCO3 to be added or subtracted
  to restore 1 L of whole blood to pH 7.4 at PCo2
  40 mm Hg

15
Metabolic Acidosis

• Defined as a low arterial pH ( normal 7.35 7.45
  ) and a low serum bicarbonate concentration
  ( normal 22 28 mEq/L
  )
• 3 major mechanisms
• Increased acid generation
• Loss of bicarbonate
• Diminished renal acid excretion

16
Increased acid generation

• Lactic acidosis
• Ketoacidosis diabetic, alcoholic, starvation
• Ingestions methanol, ethylene glycol,
  salicylates, toluene, paraldehyde

17
Loss of Bicarbonate

• Diarrhoea
• Ureteral diversion as ureters are implanted into
  sigmoid colon or short loop of ileum
• Proximal Renal Tubular Acidosis ( Type 2 RTA )
  proximal bicarbonate reabsorption is
  impaired

18
Diminished Renal Acid Excretion

• Renal failure
• Distal Renal Tubular Acidosis ( Type 1 RTA )

19
Dilutional Acidosis

• Refers to a fall in serum bicarbonate
  concentration that is solely due to expansion of
  extracellular fluid volume
• The fall in serum bicarbonate is less than
  predicted from the degree of volume expansion,
  presumbly due to contributions from intracellular
  and bone buffers
• Administration of large volumes of IV Fluids that
  does not contain bicarbonate or an anion
  that can be metabolized to bicarbonate . Eg
  lactate

20
In Metabolic Acidosis

• Respiratory compensation results in
  1.2 mm Hg fall in PCo2 for
  every 1 mEq/L reduction in HCO3
• This response begins within first 30 minutes and
  is complete by 12 24 hrs
• An inability to generate this hyperventilatory
  response is generally indicative of significant
  underlying respiratory disease

21

• Normal respiratory response ( Kussmaul Breathing
  ) to metabolic acidosis is decrease in PCo2
• This is given by WINTER EQUATION
• PCo2 1.5 x ( observed HC03-) ( 8 /- 2 )
• PCo2 should approximate the last two digits of pH
  
• Eg pH 7.25
• PCo2 should be close to 25 mm Hg

22
Metabolic Acidosis

• Normal Anion Gap Metabolic Acidosis
• High Anion Gap Metabolic Acidosis

23
Anion Gap

• Represents Unmeasured Anions in plasma
• Serum AG Measured Cations Measured Anions
• Serum AG Na ( Cl HCO3 )
• Normal AG 10 12 mEq/L
• Some physicians include K . Then normal range
  increases by 4 mEq/L
• Serum AG ( Na K ) ( Cl HCO3 )

24
Anion Gap

• Unmeasured anions include
• Anionic proteins
• Phosphate
• Sulfate
• Organic anions

25
Decreased AG

• Increase in unmeasured cations
• Addition of cations like Lithium to blood
  in Lithium Intoxication
• Addition of cationic immunoglobulins to blood
  in plasma cell dyscrasias
• Decrease in anionic albumin in plasma
  nephrotic syndrome
• Decrease in anionic charge of albumin by acidosis
  
• Hyperviscosity Hyperlipidemia underestimation
  of Na Cl conc

26
Increased AG

• Increase in unmeasured anions - commonly
• Decrease in unmeasured cations ( calcium,
  magnesium, potassium ) rare
• Increase in anionic albumin
• Increase in acid anions acetoacetate, lactate

27
Met.Acidosis Normal Albumin High AG

• Non Chloride Containing Acids that contain
• Inorganic ( phosphate, sulfate )
• Organic ( ketoacidosis, lactate, uremic organic
  anions )
• Exogenous ( salicylate, ingested toxins with
  org.acids )
• Unidentified anions

28
? Anion Gap / ? HCO3 Ratio

• AG is elevated in Met.acidosis in which anion
  accompanying H is not Chloride
• causes Lactic acidosis , Ketoacidosis
• The degree to which AG rises in relation to fall
  in HCO3 varies with the cause of acidosis

29
? Anion Gap / ? HCO3 Ratio

• gt 1 Lactic acidosis
• Almost 1 1 Ketoacidosis
• 11 or less
• D-Lactic Acidosis
• Toluene ingestion
• CKD tubular damage

30
HIGH ANION GAP METABOLIC ACIDOSIS
31
Causes

• Lactic Acidosis
• Ketoacidosis Diabetic, Alcoholic, Starvation
• Toxins Ethylene Glycol, Methanol, Salicylates,
• Propylene Glycol, Pyroglutamic
  acid
• Renal Failure Acute / Chronic ( Uremia )

32
Lactic Acidosis

• Most common cause of metabolic acidosis in
  hospitalized patients
• Plasma lactate concentration gt 4 mEq/L
• Lactic acid derived from metabolism of pyruvic
  acid
• Lactic acid generated from
• Glucose via Glycolytic Pathway
• Deamination of Alanine

33
Lactic acid

• Rapidly buffered by extracellular HCO3 - to
  generate lactate
• In liver kidney lactate is metabolized back
  to pyruvate Co2 , H2O or Glucose
• Excess lactate Increase Lactate Production
• Diminished Lactate
  Utilization
• Enhanced Pyruvate production
• Reduced Pyruvate conversion to Co2,H20 or Glucose
• Altered redox state within cell pyruvate
  lactate

34
Types

• Type A Lactic Acidosis
• Type B Lactic Acidosis
• D- Lactic Acidosis

35
Type A Lactic Acidosis
Impaired tissue oxygenation
in shock / cardiopulmonary arrest

• Severe Hypoxia
• Severe Asthma
• Carbon monoxide poisoning
• Severe anemia
• Regional hypoperfusion

• Hypovolemic shock
• Cholera
• Septic shock
• Cardiogenic shock
• Low output heart failure
• High output heart failure

36
Type B Lactic Acidosis
Toxin induced impaired cellular metabolism
Findings of systemic hypoperfusion are not
apparent

• Diabetes mellitus with metformin
• Malignancy leukemia lymphoma
• Thiamine deficiency
• Riboflavin deficiency
• Alcoholism
• Seizures

• HIV infection
• Catecholamine excess
• Mitochondrial toxins
• Intracellular phosphate depletion IV Fructose
• IV Xylose
• IV Sorbitol

37
Treatment

• Overall mortality 60 70
• But approaches 100 with coexisting
  hypotension
• Underlying condition initiating the disruption in
  normal lactate metabolism should be corrected
• Septic shock control of underlying infection
• Hypovolemic shock volume resuscitation
• Bicarbonate infusion little value

38
Treatment

• Alkali therapy ( Na HCO3 ) advocated for
  acute severe acidemia ( pH lt7.15 )
  to improve cardiac
  function lactate utilization
• IV 50-100 mEq NaHCO3 over 30 45 min
  during initial 1 -2 hrs of therapy
• s/e paradoxical depression of cardiac
  performance
• worsen acidosis
• fluid overload
• hypernatremia

39
Treatment

• A reasonable approach to infuse NaHCO3
  sufficient to raise arterial pH to no more than
  7.2 over 30 40 min
• Tromethamine
• Carbicarb lactic acidosis d/t cardiopulmonary
  arrest
• Dichloroacetate
• Dopamine is preferred to epinephrine for pressure
  support

40
D-Lactic Acidosis

• Occurs in patients with jejunoileal bypass
• small
  bowel resection
• short
  bowel syndrome
• In Colon - Glucose, Starch D-Lactic acid
• absorbed
  to systemic circulation
• not metabolized by L-Lactate
  dehydrogenase
• Thus D-Lactate is slowly metabolized in humans

41
Factors overproduction of D-Lactic acid

• Overgrowth of gram positive anaerobes
  lactobacilli produce D-Lactic acid
• Relatively very little glucose starch is
  delivered to colon because of extensive small
  intestinal absorption.
• However, the delivery of these substances is
  markedly enhanced when small bowel is bypassed /
  removed / diseased

42
Clinical features

• Usually asymptomatic elevated d-lactic acidosis
• Episodic metabolic acidosis ( after carbohydrate
  meal )
• Characteristic neurological abnormalities like
• Confusion
• Cerebellar ataxia
• Slurred speech
• Loss of memory

43
Diagnosis

• Increased anion gap
• Normal serum lactate
• Negative Ketones
• One / more of following
• Short bowel or other malabsorption syndrome
• Acidosis that is preceeded by food intake and
  resolves with discontinuation
• Characteristic neurologic symptoms and signs

44

• Special enzymatic assay D-Lactate dehydrogenase
  and measures generation of NADH as lactate is
  converted to pyruvate
• Urinary Anion Gap may be positive
• Ammonium excretion is best estimated by
  measurement of urine osmolal gap.

45
Treatment

• Acute Sodium Bicarbonate administration
• Oral antimicrobials Metronidazole
• Neomycin
• Vancomycin
• Low Carbohydrate diet

46
Ketoacidosis

• Diabetic Ketoacidosis
• Alcoholic Ketoacidosis
• Starvation Ketoacidosis

47
Diabetic Ketoacidosis

• One of the most serious acute complications of
  diabetes mellitus
• In DKA
• Metabolic acidosis often major finding
• S.Glucose lt800mg/dl
• but may exceed 900mg/dl in pts who are comatose

48
Diabetic Ketoacidosis

• Caused by increased fatty acid metabolism
• Accumulation of ketoacids
  (
  acetoacetate, betahydroxybutyrate )
• Usually occurs in Insulin dependent DM in
  association with
• Cessation of insulin
• Intercurrent illness infection,
  gastroenteritis,
• pancreatitits,
  myocardial infarction

49

• Accumulation of ketoacids increased Anion Gap
• Accompanied by Hyperglycemia ( gt 300 mg/dl )
• ? AG ? HCO3 - 11
• But may decrease in well hydrated patient with
  normal renal functions
• Insulin prevents the production of ketones
• Bicarbonate therapy is rarely needed except when
  there is severe acidemia ( pH lt 7.1 ) in
  limited amounts

50
Clinical features

• Evolves rapidly over 24 hrs
• Early signs nausea , vomiting, abd pain,
  hyperventilation
• As hyperglycemia worsens neurological symptoms
  appear
• Lethargy, focal deficits, obtundation, seizures
  coma

51
Evaluation

• Vitals
• Cardiorespiratory status
• Mental status
• Assess volume status vitals, skin turgor,
  mucosa , Urine vol
• Serum Glucose, Na , K , EKG
• BUN , Creatinine , Urine analysis , Urine ketones
• Plasma Osmolality
• Blood C/S , Urine C/S , CXR

52
Management

• Stabilize airway, breathing, circulation
• Large Bore IV Access ( 16 G )
• Monitor vitals, ECG, Pulse oximetry
• Monitor hourly S.Glucose
• S.Na, S.K, Plasma Osmolality, Venous Ph every 2
  4 hrs
• Determine the cause and treat underlying cause of
  DKA

53
Replete Fluid Deficit

• Give several liters of Isotonic saline as rapidly
  as possible to pts with signs of shock
• Give isotonic saline _at_ 15 20 ml/kg/hr, in
  absence of caridac compromise , for first few
  hours to hypovolemic pts without shock
• After Intravascular volume is restored , give one
  half isotonic saline _at_ 4 15 ml/kg/hr if
  corrected s.sodium is normal / elevated.
• Isotonic saline is continued if hyponatremia is
  
• Add dextrose to saline solution when s.glucose
  reaches 200mg/dl

54
Replete K deficits

• Regardless of initial measured s.potassium , pts
  with DKA have large total body potassium deficit
• Initial K lt 3.3 mEq/L hold insulin
• K
  20-30mEq /L/hr iv until K gt 3.3
• initial K 3.3 5.3 mEq/L IV K 20-30 mEq/L
• 
  maintain K b/w 4 -5 mEq/L
• Initial K gt 5.3mEq/L do not give K
• check S.K
  every 2 hrs

55
Insulin

• Do not give insulin if initial K is below
  3.3mEq/L , replete K first
• Regular insulin 0.1units/kg IV Bolus
• 0.1 units/kg/hr
  continuous iv infusion
• Regular insulin no bolus
• 0.14 units/kg/hr
  continuos iv infusion
• Continue insulin infusion until ketoacidosis is
  resolved, s.glucose lt 200 mg/dl then s/c
  insulin is begun

56
Sodium Bicarbonate pH lt 7.00

• If arterial pH 6.90 7.00 50mEq NaHCO3 10
  mEq KCl in 200ml sterile water over 2 hrs
• If arterial pH lt 6.90 100mEq NaHCO3 20 mEq
  KCl in 400 ml sterile water over 2 hrs

57
Alcoholic Starvation Ketoacidosis

• Ketoacidosis often due to uncontrolled diabetes
  mellitus
• Insulin deficiency increases lipolysis free
  fatty acid delivery to liver
• Glucagon excess promotes conversion of FFA into
  Ketoacids in liver
• Similar metabolic alterations occur in
  combination of alcohol ingestion poor dietary
  intake or fasting alone

58
Alcoholic Starvation Ketoacidosis

• In alcoholics . Decreased
  carbohydrate intake
• reduces insulin secretion ,
  increases glucagon
• increased ketoacid
  formation
• alcohol induced inhibition of
  gluconeogenesis
• stimulation of
  lipolysis

59
Clinical features

• History of alcohol abuse
• Presenting with unexplained HAGMA and ketonemia
• Acidosis can be severe in alcoholic ketoacidosis
• Plasma Glucose in AKA normal / low / elevated
• Ketoacids do not exceed 10 mEq/L with prolonged
  fasting alone HCO3 - gt 14 mEq/L

60
AKA is usually complicated by

• Hypoperfusion induced Lactic Acidosis
• Metabolic Alkalosis resulting from Concurrent
  Vomiting
• Chronic Respiratory Alkalosis induced by
  underlying alcoholic liver disease
• So mixed acid base disorders are common

61
AKA

• Chronic alcoholics develop ketoacidosis when
  alcohol consumption is abruptly curtailed and
  nutrition is poor
• Usually associated with binge drinking, vomiting,
  abdominal pain, starvation and volume depletion
• Acidosis d/t elevated ketoacids predominantly
  BETA HYDROXYBUTYRATE

62
AKA Diagnosis

• Demonstration of ketonemia / ketonuria
• Nitroprusside ketone reaction
• A 4 reaction with serum diluted 11 is
  strongly suggestive of ketoacidosis .
• This detects acetoacetate but not
  betahydoxybutyrate
• So this test becomes increasingly positive as
  pt improves
• S.Creatinine Usually Normal
• S.Insulin low
• Triglycerides, Glucagon, Cortisol, GH Elevated

63
Treatment

• Acidemia in all forms of ketoacidosis largely
  corrects spontaneously as treatment of underlying
  disease allows regeneration of bicarbonate from
  metabolism from ketoacid anions
• In AKA / Starvation Ketoacidosis goal is
  achieved by
• IVF Dextrose and saline solutions
• Dextrose ( 5 ) Increase Insulin / Decrease
  Glucagon
• 0.9 NS to repair the fluid deficit

64

• Thiamine 100 mg IV / IM prior to any glucose
  containing solutions
• Correct Hypophosphatemia
• Hypokalemia
• Hypomagnesemia

65
Salicylate Induced Acidosis

• Aspirin and other Salicylates
• Mechanisms
• Inhibition of cyclooxygenase results in decreased
  synthesis of prostaglandins,prostacycline,thrombox
  anes
• Stimulation of CTZ in medulla nausea ,
  vomitings
• Activation of respiratory center in medulla
  resp alkalosis
• Interference with cellular metabolism met
  acidosis

66
Clinical features

• Early symptoms tinnitus, vertigo
• fever
• vomitings,
  diarrhoea
• Severe intoxication altered mental state
• coma
• non
  cardiogenic pulmonary edema
• death

67
Laboratory Investigations

• Plasma salicylate gt 40 mg/dl associated with
  toxicity
• Plasma salicylate check 2 hrly
• gt100 mg/dl associated with increased mortality
• absolute indication for
  hemodialysis
• S.Creatinine aspirin excreted by kidneys
• Mild elevation in s.creatinine hemodialysis
• S.Potassium Correct Hypokalemia if present
• Coagulation Studies Prolonged PT

68
Treatment

• Avoid Intubation if possible
• Volume resuscitate unless cerebral / pulmonary
  edema if present
• Administer multiple doses of activated charcoal
• Administer supplemental glucose in patients with
  altered mental status
• Alkalanize with Sodium Bicarbonate
• Hemodialysis

69
Hemodialysis

• Altered mental status
• Pulmonary Or Cerebral Edema
• Renal Insufficiency that interferes with
  salicylate excretion
• Fluid Overload that prevents the administration
  of sodium bicarbonate
• Plasma salicylate gt100 mg/dl
• Clinical deterioration despite aggressive
  supportive care

70
Toxin Induced Metabolic Acidosis
Osmolal Gap in Toxin Induced Acidosis

• Osmolal gap difference between measured and
  calculated plasma osmolality
• Calculated Plasma Osmolality
  2X Na
  Glucose / 18 bun / 2.8

71
In HAGMA

• Plasma Osmolal Gap A rapid screening test
• Markedly elevated Methanol ingestion
• Ethanol
  ingestion
• Ethylene Glycol
  ingestion
• Increased but less pronounced Lactic acidosis
• 
  Ketoacidosis
• 
  CKD

72
Other Possibilities Elevated OG

• Pseudohyponatremia due to
• Hyperlipidemia
• Hyperproteinemia
• Accumulation of osmolytes other than Na Salts,
  Glucose, Urea in plasma
• Infused Mannitol
• Radiocontrast media

73
Ethanol Ingestion

• Ethanol after absorption from git
  acetaldehyde
• 
  acetyl Co A
• 
  Co2
• Blood Ethanol gt500mg/dl HIGH MORTALITY
• Acetaldehyde levels are high Load is
  exceptionally high
• Inhibition of
  acetaldehyde dehydrogenase
• by Disulfiram,
  Sulfonylureas etc
• This causes severe toxicity

74
Ethanol ingestion

• Alcoholic ketoacidosis
• Lactic acidosis
• Treatment
• Treat alcoholic ketoacidosis / lactic acidosis

75
Ethylene glycol ingestion

• Central nervous system cranial neuropathies
• Cardiopulmonary and renal damage
• High anion gap metabolic acidosis
• L-Lactic acidosis
• High Osmolar Gap
• Diagnosis Oxalate crystals in urine
• HAGMA
• High Osmolar Gap

76
Treatment

• Osmotic diuresis
• Thiamine
• Pyridoxine
• Fomipezole ( 4 Methylpyrazole ) 7mg/Kg
  loading dose
• Ethyl alcohol
• Dialysis

77
Methanol ( Wood Alcohol ) Ingestion

• Optic nerve damage blurring of vision
• photophobia
• blindness
• CNS manifestations disinhibition , ataxia
• headache,
  vomiting, nausea
• drowsiness,
  obtundation, coma
• seizures
• Metabolic acidosis

78
Treatment

• General Supportive measures
• Ethanol
• Fomipezole
• Hemodialysis

79
Isopropyl alcohol( Rubbing alcohol ) ingestion

• Accidental oral ingestion / absorption through
  skin
• Isopropyl alcohol metabolized to Acetone
• Osmolar gap increases d/t accumulation of
  acetone, isopropyl alcohol
• Metabolic acidosis with increased osmolar gap
• Treatment supportive
• IV fluids / pressors /
  ventilatory support
• Hemodialysis severe intoxication ( gt 400 mg/dl
  )

80
Uremia Renal failure

• Advanced renal insufficiency converts
  hyperchloremic acidosis to a typical high AG
  acidosis
• Poor filtration Continued resorption of poorly
  identified uremic organic anions
  
  contributes to metabolic disturbance
• Uremic acidosis
• reduced rate of NH4 production and excretion
  
• d/t cumulative significant loss of renal
  mass

81

• HCO3 rarely falls to lt 15 mmol/L AG rarely gt
  20
• Acid retained in CRF is buffered by alkaline
  salts from bone.
• Phosphate balance is maintained as a result of -
• hyperparathyroidism decreases proximal
  absorption
• Increase in plasma phosphate as GFR declines.

82
Treatment Uremic acidosis

• Oral alkali replacement to maintain HCO3- gt
  20mEq/L
• 1-1.5 mEq/L /Kg/day
• Shohl Solution ( Sodium Citrate )
• Sodium Bicarbonate Tablets 325 650 mg
• Protein Restriction
• Sodium polystyrene sulfonate ( Kayexelate )
  therapy ( 15 30 g/day )

83
Thank You !