Zuur-Base Stoornissen INTRODUCTION AND DEFINITIONS. Acid - Base Balance. Topics. Acid-Base Disturbances

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1 Acid Base Balance ZuurBase Stoornissen Dr. M. Verhaegen Coassistenten Maintenance of a physiologic ph ([H + ]) is important for Oxygen transport Enzyme activity Biochemical reactions Cellular function Organ function Acidbase disturbances have adverse effects during anesthesia and surgery Anesthesia and surgery can disturb acidbase balance by Changes in ventilation Hemodynamic changes Intravenous fluid therapy Topics Introduction and definitions Regulation of [H + ] Immediate chemical response Ventilatory response Renal response Simple acidbase disturbances Respiratory acidosis Respiratory alkalosis Metabolic acidosis Metabolic alkalosis Interpretation of acidbase disturbances: A practical approach AcidBase Disturbances INTRODUCTION AND DEFINITIONS

2 Dissociation of Water H 2 O H + + OH [H + ] [OH ] K = [H 2 O] K w = [H + ] [OH ] = mmol/l Hydrogen Ion Plasma [H + ] is tightly regulated Normal plasma [H + ] 40 nmol/l [H + ] is conventionally expressed as ph ph is the negative logarithm of [H + ]: ph = log [H + ] K = dissociation constant (equilibrium constant) K w (= K x [H 2 O]) includes the concentration of water [H 2 O] does not vary much In pure water [H + ] = [OH ] = 10 7 mmol/l Acid An acid is a substance that increases [H + ] when added to a solution Strong acid Readily and irreversibly increases [H + ] Weak acid Less effect on [H + ] Base A base is a substance that decreases [H + ] when added to a solution Strong base Decreases [H + ] Weak base Less effect on [H + ] Acidosis and alkalosis Acidosis: a process that reduces blood ph (increases [H + ]) Alkalosis: a process that increases blood ph (reduces [H + ]) Acidosis and alkalosis refer to a primary process and its compensatory response altering arterial ph Acidosis and alkalosis can occur concomitantly Acidemia and alkalemia Acidemia: blood ph < 7.35 Alkalemia: blood ph > 7.45 Acidemia and alkalemia denote the net effect on arterial ph of primary processes and their compensatory physiologic responses Acidemia and alkalemia are mutually exclusive terms

3 Buffer (1) Buffer (2) A buffer minimizes changes in ph by either binding or releasing H + A buffer always consists of conjugate pairs A weak acid and its conjugate base HA A + H + Acid (HA): protonates excess base molecules Conjugate base (A ): binds excess H + Acetic acid: CH 3 COOH CH 3 COO + H + Bicarbonate: H 2 CO 3 HCO 3 + H + A weak base and its conjugate acid B + H 2 O BH + + OH Base (B): binds excess H + Conjugate acid (BH + ): protonates excess base molecules Ammoniak: NH 3 + H 2 O NH 4+ + OH Weak acid buffer: HA H + + A [H + ] [A ] K a [HA] K a = or [H + ] = [HA] [A ] The acid dissociation constant (K a ) indicates the strength of an acid Buffer (2) Weak acid buffer: HA H + + A [H + ] [A ] K a [HA] K a = or [H + ] = [HA] [A ] Negative logarithm Henderson Hasselbach equation [A ] ph = pk a + log [HA] The acid dissociation constant (K a ) indicates the strength of an acid Strong acid: almost completely dissociated in water Weak acid: not completely dissociated in water Smaller pk a stronger acid pk a is the ph at which an acid is 50% dissociated A buffer is most effective when pk a = ph HendersonHasselbach Equation The HendersonHasselbalch equation describes the relationship between the ph of a solution and the ratio of the concentration of a weak acid or weak base and its salt. [Conjugate base] ph = pk a + log [Weak acid] Bicarbonate buffer (H 2 CO 3 / HCO 3 ) [HCO 3 ] ph = pk a + log [H 2 CO 3 ] ph is related to the ratio between [H 2 CO 3 ] and [HCO 3 ]

4 AcidBase Disturbances: HendersonHasselbalch Approach Anion Gap (AG) (1) Metabolic or respiratory acidosis or alkalosis Metabolic acidbase disturbance: primarily affects HCO 3 Metabolic acidosis: HCO 3 Metabolic alkalosis: HCO 3 Respiratory acidbase disturbance (acute or chronic): primarily affects PaCO 2 Respiratory acidosis : PaCO 2 Respiratory alkalosis: PaCO 2 HH is a bicarbonatebased approach: HCO 3 is considered an independent variable Limitations of HH approach to acidbase disturbances Only an estimate of the magnitude of acidbase disturbances Alterations in [HCO 3 ] and [H + ] do not reflect the mechanism of the acidbase disturbances Does not explain complex acidbase disturbances AG = ([Na + ] + [K + ]) ([Cl ] + [HCO 3 ]) = Measured plasma cations Measured plasma anions = Unmeasured anions Unmeasured cations = meq/l Based on principle of electroneutrality in body fluids Routinely measured cations: Na +, K + Routinely measured anions: Cl, HCO 3 Unmeasured cations: Ca 2+, Mg 2+ Unmeasured anions: proteins (albumin), phosphate, sulphate, lactate Jeffrey A. Kraut, and Nicolaos E. Madias CJASN 2007;2: Anion Gap (AG) (2) Base Excess AG = ([Na + ] + [K + ]) ([Cl ] + [HCO 3 ]) Unmeasured ions: mostly anionic serum albumin AG decreases by ~ 0.25 meq/l for each 1 g/l decrease in plasma albumin concentration AG increases when the ion replacing HCO 3 is not measured E.g. lactic acid, keto acids Weaknesses of AG AG may be normal in the presence of unmeasured anions E.g. hypoalbuminemia and hypophosphatemia Corrected AG (hypoalbuminemia): Measured AG + [0.25 x (normal measured albumin g/l)] Use of HCO 3 in the equation [HCO 3 ] can change independently of metabolic disturbances (e.g. hyperventilation) Base excess (BE) is the amount of strong acid (BE > 0) or strong base (BE < 0) required to return 1 L of fully oxygenated blood to a ph of 7.4 (at 37 C and a PaCO 2 of 40 mmhg) Refers to the nonrespiratory (= metabolic) component of an acidbase disturbance Normal value: between 2 and 3 mmol/l A positive value indicates metabolic alkalosis A negative value indicates metabolic acidosis Graphically or electronically derived from a nomogram (SiggaardAndersen) or algorithm Utilizes plasma ph, blood PCO 2 and hemoglobin concentration

5 Stewart Approach to AcidBase Disorders Strong Ion Difference (SID) (1) Stewart approach = physicochemical approach 3 independent variables affect the dissociation of water [H + ] acidbase balance and ph Arterial partial pressure of carbon dioxide (PaCO 2 ) Strong ion difference (SID) Plasma concentration of nonvolatile weak acids (A Tot ) Plasma [HCO 3 ] is a dependent variable and therefore does not alter blood ph Dependent variables: [HCO 3 ], [CO 3 2 ], [OH ], [H + ], [HA], [A ] Strong ion difference (SID) = (Strong cations) (Strong anions) = ([Na + ]+[K + ]+[Ca 2+ ]+[Mg 2+ ]) ([Cl ]+[Lactate] +[Unmeasured anions]) = meq/l Strong ions dissociate almost completely Most abundant in extracellular compartment: Na + and Cl Other strong ions: K +, Mg 2+, Ca 2+, lactate SID is balanced by an equal amount of buffer base Bicarbonate, albumin, phosphate, Mg 2+ Ca 2+ K + Na + HCO 3 Weak acids (A ) (Alb, P i ) Unmeasured anions Cl, lactate Strong Ion Difference (SID) (2) Strong cations Mg 2+ Ca 2+ K + Na + HCO 3 A (Alb, P i ) Unmeasured anions Cl Lactate Strong ion difference (SID) Ca 2+ Strong anions SID = ([Na + ]+[K + ]+[Ca 2+ ]+[Mg 2+ ]) ([Cl ]+[Lactate]+[Unmeasured anions]) SID changes affect the dissociation of H 2 O ([H + ] and [OH ]) SID is an independent variable [H + ] and [OH ] are dependent Decreased SID Metabolic acidosis Massive volumes of NaCl 0.9 %: [Na + ] = 154 meq/l = [Cl ] and SID = 0 SID of plasma decreases (hyperchloremic metabolic acidosis) Severe diarrhea with mainly Na + and K + loss (without Cl ) Unmeasured anion increase (e.g. lactate) Increased SID Metabolic alkalosis E.g. gastric fluid loss: major ion is Cl (> strong cations) Hypochloremic alkalosis

6 Nonvolatile Weak Acids Classification of AcidBase Disorders (Stewart Approach) Nonvolatile weak acids (A ): Inorganic phosphates, albumin, other plasma proteins Weak acids are only partially dissociated Weak acids have not a great influence on the acidbase balance in healthy persons Hyperalbuminemia, hyperphosphatemia A increase SID decrease = Metabolic acidosis Hypoalbuminemia, hypophosphatemia A decrease SID increase = Metabolic alkalosis Acidosis Respiratory Increased PaCO 2 Hypoventilation Metabolic Decreased SID Increased Cl Decreased Na + /increased free water Increased A Tot Hyperphosphatemia Hyperalbuminemia Respiratory Decreased PaCO 2 Hyperventilation Alkalosis Metabolic Increased SID Decreased Cl Increased Na + /decreased free water Decreased A Tot Hypophosphatemia Hypoalbuminemia Analysis of Acidbase Balance Descriptive: based on the HendersonHasselbalch equation Interrelationship between PCO 2 and [HCO 3 ] Additionally: Anion gap calculation Quantitative: Stewart approach based on physical chemistry SID and A TOT, Strong ion gap are independent variables [HCO 3 ] is a dependent variable AcidBase Disturbances BUFFERING SYSTEMS: REGULATION OF HYDROGEN ION CONCENTRATION

7 Hydrogen Ion Concentration Buffering Systems Arterial blood and extracellular fluid: [H + ] = nmol/l Normal arterial ph = Blood ph between ([H + ] between 16 and 160 nmol/l) is compatible with life The body has a large buffering capacity to maintain a normal [H + ] despite a large amount of daily acid production Daily approximately mmol of CO 2 Mainly excreted by the lungs Daily meq of nonvolatile acid Mainly excreted though the kidneys Regulation of [H + ] Chemical response: fast Bicarbonate buffer Extracellular buffering system Protein buffer Intracellular buffering system Red blood cell: Hemoglobin buffer Respiratory buffering system: fast Renal buffering system: slow response, but nearly complete restoration of ph Reabsorption / excretion of HCO 3 Excretion of titratable acid Production of ammonia Bicarbonate Buffering System (1) Bicarbonate Buffering System (2) Carbonic anhydrase CO 2 + H 2 O H 2 CO 3 H + + HCO 3 Bicarbonate buffer: weak acid (proton donor) = H 2 CO 3 conjugate base (proton binding) = HCO 3 Carbonic anhydrase (in endothelium, erythrocytes and kidneys) greatly accelerates this reaction Major buffering system in extracellular fluid Responsible for 80 % of extracellular buffering Reponds to metabolic acidbase disturbances Carbonic anhydrase CO 2 + H 2 O H 2 CO 3 H + + HCO 3 HendersonHasselbach equation for bicarbonate buffer [HCO 3 ] ph = pk + log [H 2 CO 3 ] Dissociation constant pk = 6.4 CO 2 tension (PaCO 2 ) may be substituted for H 2 CO 3 [HCO 3 ] ph = pk + log 0.03 PaCO 2 Solubility coefficient for CO 2 = 0.03 Adjusted dissociation constant pk = 6.1

8 Bicarbonate Buffering System (3) Hemoglobin Buffering System (1) pk = 6.1: not close to the normal arterial ph of 7.4 The bicarbonate buffer is important Relatively high concentrations in extracellular fluid Kidneys and lungs have important influences on arterial ph by altering [HCO 3 ] /PaCO 2 ratio Lungs regulate PaCO 2 Kidneys regulate plasma [HCO 3 ] The bicarbonate buffer system easily adapts to changing acidbase conditions Most important buffering system for plasma CO 2 Histidine buffer Multiple buffering sites on imidazole side chains Histidine is an effective buffer from ph (pk a 6.8) A large fraction of extrapulmonary CO 2 is transported to the lungs as plasma HCO 3 Tissues: CO 2 diffuses into the RBC where it is eliminated as HCO 3 Lungs: HCO 3 enters the RBC (in exchange for Cl ) where it is converted to CO 2 which is released into the plasma and eliminated by the lungs. Hemoglobin Buffering System (2) Figure 213 Hemoglobin buffering system: Carbon dioxide freely diffuses into erythrocytes, where it combines with water to form carbonic acid, which rapidly deprotonates. The protons generated are bound up by hemoglobin. The bicarbonate anions are exchanged back into plasma with chloride Oxygenated and deoxygenated hemoglobin have different affinities for H + and CO 2 Deoxyhemoglobin (tissues) takes up more H + (3 times more) Facilitates removal of CO 2 from tissues Oxyhemoglobin (lungs) favors the release of H + Increased CO 2 production and elimination in the lungs A small amount of CO 2 is also directly buffered by hemoglobin (carbaminohemoglobin) and plasma proteins (carbamino proteins) Venous blood contains 1.68 mmol/l extra CO 2 over arterial blood Miller and Pardo, Basics of Anesthesia, 6th ed

9 Pulmonary Buffering System (1) Pulmonary Buffering System (2) Regulation by the lungs of CO 2 in ECF Central and peripheral chemoreceptors Central chemoreceptors (anterolateral surface of medulla) Respond to changes in ph of CSF Peripheral chemoreceptors (bifurcation of common carotid arteries, aortic arch) Respond to changes in ph, PaCO 2, PaO 2, and arterial perfusion pressure Most sensitive to PaO 2 Communication with central respiratory centers occurs via glossopharyngeal nerves PaCO 2 and ventilation response MV increases 1 4 L/min for every 1 mmhg increase in PaCO 2 For PaCO mmhg Exceptions: very high PaCO 2 (carbonarcosis) and very low PaCO 2 (apneic threshold) Wide interindividual variation There is no complete ventilatory correction Pulmonary response diminishes when ph approaches 7.4 Renal Buffering System Slow onset (12 24 h) Maximal effect after 5 d Mechanism compensating for alkalosis Excretion of large amounts of HCO 3 Mechanisms compensating for acidosis 1. Reabsorption of filtered HCO 3 2. Excretion of titratable acids 3. Production of ammonia Generation and reabsorption of HCO 3 Three mechanisms of renal compensation during acidosis to sequester hydrogen ions and reabsorb bicarbonate: (1) reabsorption of the filtered HCO3, (2) excretion of titratable acids, and (3) production of ammonia. Miller and Pardo, Basics of Anesthesia, 6th ed AcidBase Disturbances ACIDEMIA AND ALKALEMIA: PATHOPHYSIOLOGIC EFFECTS

10 Cardiovascular Metabolic Neurologic Respiratory Acidemia Arteriolar dilation Venoconstriction Increased pulmonary vascular resistance Impaired cardiac contractility Decreased hepatorenal blood flow Decreased threshold for arrhythmias Attenuation of responsiveness to catecholamines Increased oxyhemoglobin dissociation Inhibition of anaerobic glycolysis Reduction of ATP synthesis Insulin resistance Hyperkalemia Protein degradation Hyperphosphatemia Bone demineralization (chronic acidemia) Inhibition of metabolism and cellvolume regulation Intracranial pressure increase Obtundation, coma Muscle fatigue due to compensatory hyperventilation (metabolic acidosis) Alkalemia Arteriolar constriction Reduced coronary blood flow Decreased oxyhemoglobin dissociation Stimulation of anaerobic glycolysis Formation of organic acids Decreased ionized calcium Hypokalemia Hypomagnesemia Hypophosphatemia Tetany Seizures Lethargy Delirium Stupor Hypercapnia and hypoxemia due to compensatory hypoventilation (metabolic alkalosis) Acidemia: Adverse Effects (1) Hemodynamic effects: Result of balance between sympathoadrenal activation, direct vasoactive effects, and direct negative cardiac effects Mild acidemia: mild cardiovascular effects Mainly sympathoadrenal activation No significant effect on systemic vascular resistance, pulmonary vascular resistance, cardiac output, or systemic O 2 delivery Severe acidemia (ph < 7.20): significant adverse cardiovascular effects Direct cardiac depressant effects and decreased myocardial responsiveness to catecholamines predominate Decreased cardiac output Hypotension Decreased hepatorenal blood flow Acidemia: Adverse Effects (2) Acidemia and Anesthesia: Risks Severe acidemia (ph < 7.20) Significant adverse cardiovascular effects Hyperkalemia Movement of K + out of cells in exchange for extracellular H + Plasma [K + ] increase of 0.6 meq/l for each 0.10 decrease in ph Central nervous system effects (respiratory > metabolic acidosis) Severe acute intracellular acidosis: confusion, loss of consciousness, seizures Increased cerebral blood flow Increased intracranial pressure Hemodynamic instability Arteriolar vasodilatation Decreased cardiac output Exaggerated cardiovascular depressant effects of anesthetics Decreased response to vasopressors and inotropes Arrhythmias Increased intracranial pressure (respiratory acidosis) Hyperkalemia Insulin resistance and hyperglycemia Acidemia may augment nondepolarizing neuromuscular blockade Postoperative mechanical ventilation may be necessary In severe acidemia, consider postponing surgery until the underlying cause is treated, or until the patient is preoperatively optimized. However: surgery may be the treatment that is required

11 Alkalemia: Adverse Effects Alkalemia and Anesthesia: Risks Severe alkalemia (ph > 7.6) Arteriolar vasoconstriction Decreased cerebral blood flow Decreased coronary blood flow Neurological effects are more severe with respiratory alkalosis Acute hyperventilation lightheadedness, dizziness, confusion, myoclonus, flapping tremor, depressed consciousness, seizures Hypokalemia Movement of H + out of cells in exchange for extracellular K + Hypocalcemia Increased binding of calcium to albumin (available negative charges on albumin are increased in alkalemia) Hemodynamic instability Coronary vasospasm and risk of myocardial ischemia Hypocalcemia Arrhythmias Hypokalemia: reduced threshold for arrhythmias Reduction in CBF and risk of cerebral ischemia Particularly during hypotension Potentiation of nondepolarizing neuromuscular blockade Respiratory alkalosis prolongs the duration of opioidinduced respiratory depression Increased protein binding of opioids? AcidBase Disturbances SIMPLE ACIDBASE DISTURBANCES Simple AcidBase Disorders (HendersonHasselbalch Approach) Disorder Primary change Compensatory response Respiratory Acidosis Alkalosis Metabolic Acidosis Alkalosis PaCO 2 HCO 3 PaCO 2 HCO 3 HCO 3 HCO 3 PaCO 2 PaCO 2

12 Causes of Respiratory Acidosis Respiratory Acidosis Primary PaCO 2 increase H 2 O + CO 2 H 2 CO 3 H + + HCO 3 Hypercapnia Alveolar minute ventilation is inadequate relative to CO 2 production (MV can be decreased, normal or increased) Increased CO 2 production Decreased CO 2 elimination Increased rebreathing or absorption of CO 2 Risk of hypoxemia (hypoventilation) Increased CO 2 production Malignant hyperthermia Hyperthyroidism Sepsis Overfeeding Decreased CO 2 elimination Intrinsic pulmonary disease (pneumonia, ARDS, fibrosis, edema) Upper airway obstruction (laryngospasm, foreign body, OSA) Lower airway obstruction (asthma, COPD) Chest wall restriction (obesity, scoliosis, burns) CNS depression (anesthetics, opioids, CNS lesions) Decreased skeletal muscle strength (residual effects of neuromuscular blocking drugs, myopathy, neuropathy) Increased CO 2 rebreathing or absorption Exhausted soda lime Incompetent oneway valve Laparoscopic surgery (CO 2 pneumoperitoneum) ARDS = acute respiratory distress syndrome; CNS = central nervous sytem; COPD = chronic obstructive pulmonary disease; OSA = obstructive sleep apnea) Respiratory Acidosis: Compensatory Response [HCO 3 ] increase Limited acute compensatory response (within 6 12 h) Hemoglobin buffer Plasma [HCO 3 ] increase 1 meq/l for each 10 mmhg increase in PaCO 2 > 40 mmhg Expected [HCO 3 ] 24 + [(Measured PaCO 2 40) / 10] Exchange of extracellular H + for Na + and K + from bone and intracellular fluid The renal response to retain HCO 3 is very limited acutely Renal compensation (appreciable within hrs, maximal after 3 5 days) Plasma [HCO 3 ] increase 4 meq/l for each 10 mmhg increase in PaCO 2 > 40 mmhg Expected [HCO 3 ] x [(Measured PaCO 2 40) / 10] Chronic respiratory acidosis: evolution to nearly normal ph (increased PaCO 2 )

13 Respiratory Acidosis: Treatment (1) Respiratory Acidosis: Treatment (2) Causal treatment. Examples: Reduction of CO 2 production Status epilepticus: muscle paralysis TPN: reduced carbohydrate intake Thyroid storm: antithyroid medication Malignant hyperthermia: dantrolene, cooling Improving alveolar ventilation Bronchodilatation Reversal of narcosis Administration of a respiratory stimulant (doxapram) Improving lung compliance (diuretics) Mechanical ventilation may be indicated Severe acidosis (ph < 7.2) CO 2 narcosis Respiratory muscle fatigue Intravenous buffers are not indicated NaHCO 3 : transient PaCO 2 increase (H + + HCO 3 CO 2 + H 2 O) Buffers that do not increase PaCO 2 : no proven benefit Respiratory Acidosis: Treatment (3) Respiratory Alkalosis Acute respiratory failure superimposed on chronic respiratory acidosis Avoid overventilation Goal: return PaCO 2 to the patient s baseline PaCO 2 PaCO 2 = 40 mmhg in chronic respiratory acidosis will result in metabolic alkalosis Renal loss of HCO 3 Increased work of breathing In some patients, respiratory drive is dependent on PaO 2 Primary PaCO 2 decrease H 2 O + CO 2 H 2 CO 3 H + + HCO 3 Hypocapnia Generally, there is an inappropriate increase in alveolar ventilation relative to CO 2 production Increased minute ventilation Decreased CO 2 production Prolonged respiratory alkalosis: resetting of central chemoreceptors to a lower CO 2 level Active transport of HCO 3 out of the CSF

14 Causes of Respiratory Alkalosis Increased minute ventilation Hypoxia (high altitude, low FiO 2, severe anemia) Iatrogenic (mechanical ventilation) Anxiety and pain CNS disease (tumor, infection, trauma) Fever, sepsis Drugs (salicylates, progesterone, doxapram) Liver disease Pregnancy Restrictive lung disease Pulmonary embolism Decreased CO 2 production Hypothermia Skeletal muscle paralysis CNS = central nervous sytem Respiratory Alkalosis: Compensatory Response Decreased reabsorption of HCO 3 from renal tubules Increased urinary excretion of HCO 3 Acute respiratory alkalosis Plasma [HCO 3 ] decreases ~ 2 meq/l for each 10 mmhg decrease in PaCO 2 < 40 mmhg Expected [HCO 3 ] 24 2 x [(40 Measured PaCO 2 ) / 10] Chronic respiratory alkalosis: variable compensatory response Plasma [HCO 3 ] decreases (2 ) 5 meq/l for each 10 mmhg decrease in PaCO 2 < 40 mmhg Expected [HCO 3 ] 24 5 x [(40 Measured PaCO 2 ) / 10] Respiratory Alkalosis: Treatment Correction of the underlying disorder Mild alkalemia usually does not require treatment Severe acute respiratory alkalosis (ph > 7.60): intravenous drug therapy may be indicated Hydrochloric acid Arginine chloride Ammonium chloride

15 Metabolic Acidosis Primary decrease in [HCO 3 ] Consumption of HCO 3 by a strong nonvolatile acid Renal or gastrointestinal wasting of HCO 3 Rapid dilution of extracellular fluid with a fluid with a SID = 0 (e.g. NaCl 0.9 %) Traditionally, the differential diagnosis is based on the anion gap calculation 'Acidbase physiology' by Kerry Brandis from Metabolic Acidosis: Compensatory Response Anion Gap: Classification of Metabolic Acidosis Acute respiratory compensation decrease in PaCO 2 (hyperventilation) Starts minutes after the development of metabolic acidosis Results in a near normal ph (after hours) PaCO 2 decreases 1.2 mmhg for 1 meq/l decrease in [HCO 3 ] Expected PaCO 2 = 40 [1.2 x (24 [HCO 3 ])] (Winter s formula: Expected PaCO 2 = 1.5 x [HCO 3 ] + 8, range +/ 2) Renal compensation Increased reabsorption of HCO 3 Tubular secretion of H + in the urine Chronic metabolic acidosis (e.g. renal failure) Buffers present in bone are used loss of bone mass The anion gap represents the difference in charge between measured cations and measured anions. The missing negative charge is made up of weak acids (A ), such as albumin and phosphate, and strong unmeasured anions (UMAs), such as lactate. From Miller s Anesthesia, 8 th ed, Chapter 60 High anion gap metabolic acidosis Acid accumulation with HCO 3 being replaced by an unmeasured anion Normal anion gap metabolic acidosis GI or renal HCO 3 losses (HCO 3 is lost with Na + no change in AG) Administration of large volumes of NaCl 0.9% (> 30 ml/kg/hour) Dilution and excessive Cl administration

16 Causes of Metabolic Acidosis Anion gap acidosis M methanol, ethylene glycol U uremia L lactic acidosis = congestive heart failure, sepsis, cyanide toxicity E ethanol P paraldehyde A aspirin, isoniazid K ketones = starvation, diabetes mellitus Nonanion gap acidosis Administration of large volumes of 0.9% NaCl Gastrointestinal losses (diarrhea, ileostomy, neobladder, pancreatic fistula) Renal losses (renal tubular acidosis) Drugs (acetazolaminde) High Anion Gap Metabolic Acidosis (1) Metabolic acidosis and AG > meq/l Characteristic: increase in relatively strong nonvolatile acids HA H + + A H + consumes HCO 3 to produce CO 2 H + + HCO 3 H 2 CO 3 H 2 O + CO 2 Anions (A ) accumulate and take the place of HCO 3 in the extracellular fluid increased AG (A = unmeasured anion) Endogenous of nonvolatile acids Increased endogenous nonvolatile acid production (e.g. lactate) Failure to excrete endogenous nonvolatile acids (renal failure) Ingestion of exogenous nonvolatile acids Causes of High Anion Gap Metabolic Acidosis Increased production or retention of endogenous nonvolatile acids Renal failure (uremic) Ketoacidosis (diabetic, starvation) Lactic acidosis Mixed (nonketotic hyperosmolar coma, alcoholic) Inborn errors of metabolism Ingestion of toxin Salicylate Methanol Ethylene glycol Paraldehyde Toluene Sulphur Rhabdomyolysis High Anion Gap Metabolic Acidosis (2) Most common causes of high AG metabolic acidosis (1) Lactic acid Most common cause of high AG metabolic acidosis in hospitalized patients Increased production of lactate (anaerobic metabolism) Hypoxemia, hypoperfusion, inability to utilize O 2 (cyanide) Decreased utilization of lactate by the liver (and kidneys) Hypoperfusion, alcoholism, liver disease Ketoacidosis Common complication of type I diabetes mellitus Occurs also with starvation, alcoholic binges Free fatty acid metabolism Liver: FFAs are converted to ketoacids, acetoacetic acid and βhydroxyburyrate

17 High Anion Gap Metabolic Acidosis (3) Delta Ratio Most common causes of high AG metabolic acidosis (2) Renal failure Decreased acid excretion Decreased HCO 3 reabsorption High AG due to accumulation of suphates, phosphates, urate, and hippurate Ingestion of toxins Acidic metabolites or triggering of lactic acidosis Salicylate, methanol, ethylene glycol, paraldehyde Delta ratio = AG increase / [HCO 3 ] deficit Assessment of high anion gap metabolic acidosis A delta ratio < 1 indicates a greater [HCO 3 ] deficit than would be expected by the increase in AG A delta ratio > 2 indicates a lesser [HCO 3 ] deficit than would be expected by the increase in AG Delta Ratio Assessment Guideline < 0.4 Hyperchloremic normal AG acidosis Consider combined high AG and normal AG acidosis. However: DR is often < 1 in acidosis with renal failure. 1 2 High AG acidosis. > 2 Suggests high AG acidosis with concurrent metabolic alkalosis or with preexisting compensated respiratory acidosis. Always correlate the delta ratio with other evidence to support the diagnosis Normal Anion Gap Metabolic Acidosis (1) Normal Anion Gap Metabolic Acidosis (2) Metabolic acidosis and a normal anion gap Characteristic: hyperchloremic metabolic acidosis Plasma [Cl ] increase to replace lost HCO 3 Causes of normal AG metabolic acidosis Increased losses of HCO 3 (GI or renal) Rapid infusion of large amounts of NaCl 0.9 % Causes of Normal Anion Gap Metabolic Acidosis Increased gastrointestinal losses of HCO 3 Diarrhea Anion exchange resins Ingestion of CaCl 2, MgCl 2 Fistulas (pancreatic, biliary, or small bowel) Ureterosigmoidostomy or obstructed ileal loop Increased renal losses of HCO 3 Renal tubular acidosis Carbonic anhydrase inhibitors Hypoaldosteronism Rapid infusion of a large amount of NaCl 0.9 % Total parenteral nutrition (Cl salts of amino acids) Increased intake of Cl containing acids Ammonium chloride Lysine hydrochloride Arginine hydrochloride Causes of normal AG metabolic acidosis Abnormal gastrointestinal losses of HCO 3 Diarrhea Pancreatic or biliary fistulae Ureterosigmoidostomy Colon secretes HCO 3 in exchange for Cl Colon absorbs urinary ammonium (dissociates in NH 3 and H + ) Abnormal renal losses of HCO 3 Renal tubular acidosis Impaired H + secretion Impaired HCO 3 absorption Acetazolamide (Diamox )

18 Normal Anion Gap Metabolic Acidosis (3) Metabolic Acidosis: Treatment (1) Causes of normal AG metabolic acidosis Rapid infusion of NaCl 0.9 % SID = 0 Fast infusion of large volumes Parenteral nutrition: organic cations > organic anions Cl is commonly used as anion for the cationic amino acids Excessive administration of chloridecontaining acids Adrenal insufficiency Causal treatment if possible Lactic acidosis due to anaerobic metabolism Restoration of adequate oxygenation and tissue perfusion with oxygen, fluid resuscitation and circulatory support Diabetic ketoacidosis Correction of fluid deficit Insulin Potassium, phosphate, magnesium Methanol or ethylene glycol intoxication Ethanol Metabolic Acidosis: Treatment (2) Metabolic Acidosis: Treatment (3) NaHCO 3 therapy: controversial Consider when ph < (without a respiratory component) Other indications Acidosis with life threatening hyperkalemia Salicylate intoxication (alkalinization of urine) Acidosis and chronic renal insufficiency or renal tubular acidosis Therapy should always be guided using arterial blood gas measurements (goal: ph 7.2) Dosage of NaHCO 3 Calculated NaHCO 3 (meq) = (24 [HCO 3 ] s ) x 0.5 x body weight (kg) Generally 50% of the calculated dose is given initially Empirically A fixed dose of 1 meq/kg meq Aim: ph = 7.2 NaCO %: 1000 meq Na + /L, 2000 mosm/l Side effects

19 Metabolic Acidosis: Treatment (4) Metabolic Alkalosis Side effects of treatment with NaHCO 3 8.4% Increased production of CO 2 Intracellular acidosis and possibly electromechanical dissociation Hypernatremia and hyperosmolarity (1000 meq Na + /L, 2000 mosm/l) Hypervolemia, pulmonary edema Inhibition of peripheral chemoreceptors Decrease of hyperventilation, hypercapnia Negative inotropic effect Lactate has also a negative inotropic effect Hemoglobin: increased affinity for oxygen Primary increase in plasma [HCO 3 ] Increased HCO 3 reabsorption Hypovolemia Hypokalemia Hyperaldosteronism H + loss GI or renal losses Differential diagnosis Chloridesensitive metabolic alkalosis Urinary [Cl ] < meq/l Extracellular fluid depletion NaCl deficiency Chlorideresistant metabolic alkalosis Urinary [Cl ] > 20 meq/l Metabolic Alkalosis: Compensatory Response Pulmonary reponse: increase in PaCO 2 (hypoventilation) Expected PaCO 2 PaCO 2 increases 0.7 mmhg for every 1 meq/l increase in [HCO 3 ] Expected PaCO 2 = 40 + [0.7 x ([HCO 3 ] 24)] (Winter s formula: Expected PaCO 2 = 0.7 x [HCO 3 ] + 20, range +/ 5) Less predictable response than response to metabolic acidosis Progressive hypoventilation results in hypoxemia Hypoxemia activates O 2 sensitive chemoreceptors stimulating ventilation PaCO 2 usually does not rise above 55 mmhg in response to metabolic alkalosis Renal compensation by HCO 3 excretion is less efficient

20 ChlorideSensitive Metabolic Alkalosis ChlorideSensitive Metabolic Alkalosis (1) Urinary [Cl ] < meq/l Mechanism: depletion of extracellular fluid ( contraction alkalosis ) Na + reabsorption in the renal tubules With Cl to maintain electrical neutrality There is not enough Cl available to accompany all reabsorbed Na + HCO 3 ions that might otherwise have been excreted are reabsorbed Increased H + secretion to maintain electroneutrality Enhanced K + secretion Hypokalemia» Exchange of intracellular K+ for extracellular H+ Depletion of extracellular fluid Na + reabsorption in the renal tubules Cl absorption: insufficient to maintain electroneutrality H + secretion HCO 3 reabsorption K + secretion + + Hypokalemia ChlorideSensitive Metabolic Alkalosis (2) ChlorideSensitive Metabolic Alkalosis (3) Common causes Diuretics (furosemide, thiazides): most common cause NaCl depletion, hypokalemia Mild metabolic alkalosis Loss of gastric fluid (vomiting, nasogastric suctioning) [H + ]: meq/l [Na + ]: meq/l [K + ]: 15 meq/l [Cl ]: 200 meq/l Extracellular volume depletion Hypokalemia Marked metabolic alkalosis Other causes (cont.) Chloride diarrhea, villous adenoma Posthypercapnic alkalosis: rapid normalization of PaCO 2 after plasma [HCO 3 ] has risen in chronic respiratory acidosis High dose sodium penicillins Low chloride intake Infant formula containing Na + without Cl

21 ChlorideResistant Metabolic Alkalosis (1) ChlorideResistant Metabolic Alkalosis (2) Typically urinary [Cl ] > 20 meq/l Inappropriate increases in mineralocorticoid activity Na + retention Increased H + and K + secretion, increased HCO 3 reabsorption Metabolic alkalosis and hypokalemia Hyperaldosteronism, primary or secondary Liddle Cushing Licorice Bartter s syndrome Severe hypokalemia Massive blood transfusion Liver converts citrate into HCO 3 Hypercalcemia Milkalkali syndrome Alkali therapy (renal insufficiency) Metabolic Alkalosis: Treatment (1) Metabolic Alkalosis: Treatment (2) Treatment of underlying disorder Chloridesensitive metabolic alkalosis Intravenous saline (NaCl) Intravenous potassium (KCl) may be indicated Depending on the cause H 2 blocker therapy (in case of excessive loss of gastric fluid) Acetazolamide (edematous patients) Primary increase in mineralocorticoid activity Aldosterone antagonist (spironolactone) Severe metabolic alkalosis: ph > 7.60 Intravenous hydrochloric acid Ammonium chloride Arginine hydrochloride Hemodialysis

22 Assessment of AcidBase Disorders: A Practical Approach AcidBase Disturbances ASSESSMENT OF ACIDBASE DISORDERS: A PRACTICAL APPROACH Know the clinical context 1. Determine the ph: acidemia or alkalemia? 2. Is the primary cause respiratory or metabolic? 3. Is there a compensatory response? Is the compensatory response adequate? 4. Is it a simple or a mixed acidbase disorder? 5. If a primary respiratory process is present determine if it is acute or chronic. 6. If metabolic acidosis is suspected calculate the anion gap. High AG metabolic acidosis: calculate the delta ratio. 7. Correlate with the clinical context and identify the cause of the acidbase disturbance. Assessment of AcidBase Disorders: A Practical Approach 1. Determine the ph acidemia or alkalemia present? ph < 7.35: acidemia ph > 7.45: alkalemia ph : normal or more than one acidbase disturbance Assessment of AcidBase Disorders: Practical Approach 2. Is the primary cause of the acidbase disorder respiratory or metabolic? Disorder Primary change ph Respiratory acidosis alkalosis Metabolic acidosis alkalosis PaCO 2 PaCO 2 HCO 3 HCO 3 Respiratory pco 2 < or > 40 mmhg ph and PaCO 2 change in opposite directions from the normal values Metabolic [HCO 3 ] < or > 24 meq/l ph and [HCO 3 ] change in the same direction from the normal values

23 Assessment of AcidBase Disorders: A Practical Approach Assessment of AcidBase Disorders: A Practical Approach 3. Is there a compensatory response? Is the compensatory response adequate? Metabolic AcidBase Disturbances: Normal Compensatory Responses Disturbance Compensatory Response Expected change Metabolic acidosis ( [HCO 3 ]) PaCO mmhg decrease in PaCO 2 for every 1 meq/l decrease in [HCO 3 ] Metabolic alkalosis ( [HCO 3 ]) PaCO mmhg increase in PaCO 2 for every 1 meq/l increase in [HCO 3 ] 3. Is there a compensatory response? Is the compensatory response adequate? Assessment of AcidBase Disorders: A Practical Approach Assessment of AcidBase Disorders: A Practical Approach 4. Is it a simple or a mixed acidbase disorder? 1. In a simple acidbase disorder only one primary acidbase disturbance is present. A simple acidbase disorder is suspected if Changes of PaCO 2 and [HCO 3 ] occur in the same direction ( or ), indicating a compensatory response The measured compensatory response equals the calculated compensatory response 2. In a mixed acidbase disorder more than one acidbase disturbance is present. 4. Is it a simple or a mixed acidbase disorder? 2. In a mixed acidbase disorder more than one acidbase disturbance is present. A mixed acidbase disorder is suspected if The expected compensatory response does not occur The compensatory response is less than expected or too extreme The ph is normal, but PaCO 2 or [HCO 3 ] is abnormal. In a simple acidbase disorder the compensatory response never returns the ph to normal PaCO 2 and [HCO 3 ] change in opposite directions: one is elevated while the other is decreased High anion gap metabolic acidosis and a delta ratio > 2 or < 1. This indicates that the change in [HCO 3 ] is not proportional to the change in anion gap

24 Mixed metabolic disorders High anion gap and normal anion gap metabolic acidosis High anion gap metabolic acidosis and metabolic alkalosis Normal anion gap metabolic acidosis and metabolic alkalosis Mixed respiratory disorders Chronic respiratory acidosis with superimposed acute respiratory acidosis It is impossible to have concurrent respiratory acidosis and respiratory alkalosis Mixed respiratory metabolic disorders Chronic respiratory acidosis and high anion gap metabolic acidosis Chronic respiratory acidosis and metabolic alkalosis Respiratory alkalosis and metabolic acidosis Assessment of AcidBase Disorders: A Practical Approach 5. If a primary respiratory process is present determine if it is acute or chronic Respiratory acidbase disorder: acute or chronic? Acute process ph 0.08 for every 10 mmhg in PaCO 2 from 40 mmhg Chronic process ph 0.03 for every 10 mmhg in PaCO 2 from 40 mmhg Miller and Pardo, Basics of Anesthesia, 6th ed Respiratory AcidBase Disturbances: Normal Compensatory Responses Disturbance Response Expected change Respiratory acidosis ( PaCO 2 ) Acute [HCO 3 ] 1 meq/l increase in [HCO 3 ] for every 10 mmhg increase in PaCO 2 Chronic [HCO 3 ] 4 meq/l increase in [HCO 3 ] for every 10 mmhg increase in PaCO 2 Respiratory alkalosis ( PaCO 2 ) Acute [HCO 3 ] 2 meq/l decrease in [HCO 3 ] for every 10 mmhg decrease in PaCO 2 Chronic [HCO 3 ] 5 meq/l decrease in [HCO 3 ] for every 10 mmhg decrease in PaCO 2 Assessment of AcidBase Disorders: A Practical Approach 6. If metabolic acidosis is suspected calculate the anion gap High AG metabolic acidosis A high AG (> 20 meq/l) always indicates metabolic acidosis Nonvolatile acid accumulation, with HCO 3 being replaced by an unmeasured anion Normal AG metabolic acidosis Gastrointestinal or renal HCO 3 losses (HCO 3 is lost with Na + : no change in AG) Administration of large volumes of NaCl 0.9% (> 30 ml/kg/hour) SID = 0 Excessive Cl administration

25 Assessment of AcidBase Disorders: A Practical Approach Assessment of AcidBase Disorders: A Practical Approach 6. High AG metabolic acidosis: calculate the delta ratio Delta ratio = AG increase / [HCO 3 ] deficit Delta ratio < 1: the [HCO 3 ] deficit is greater than would be expected by the increase in AG Delta ratio > 2: the [HCO 3 ] deficit is less than would be expected by the increase in AG 7. Correlate with the clinical context and identify the cause of the acidbase disturbance Delta Ratio Assessment Guideline < 0.4 Hyperchloremic normal AG acidosis Consider combined high AG and normal AG acidosis. However: DR is often < 1 in acidosis with renal failure. 1 2 High AG acidosis. > 2 Suggests high AG acidosis with concurrent metabolic alkalosis or with preexisting compensated respiratory acidosis. Always correlate the delta ratio with other evidence to support the diagnosis Assessment of AcidBase Disorders: A Practical Approach Know the clinical context 1. Determine the ph: acidemia or alkalemia? 2. Is the primary cause respiratory or metabolic? 3. Is there a compensatory response? Is the compensatory response adequate? 4. Is it a simple or a mixed acidbase disorder? 5. If a primary respiratory process is present determine if it is acute or chronic. 6. If metabolic acidosis is suspected calculate the anion gap. High AG metabolic acidosis: calculate the delta ratio. 7. Correlate with the clinical context and identify the cause of the acidbase disturbance.