1. Pathophysiology & Management of Acid Base and Common Electrolyte Imbalance in Critically ill Dr. Shalini Saini University College of Medical Sciences & GTB Hospital, Delhi

2. Acid Base Equilibrium What is Acid Base Equilibrium About? ? Buffers? Fixed Cation? Base Excess/ Deficit? Anion Gap?

3. Acid Base Equilibrium Acid Base Equilibrium is all about Maintenance of H + ion concentration of the ECF. Source of H + ion in Body: CO 2 from metabolism H + load from AA metabolism Strenuous Exercise  Lactic Acid Diabetic KA Ingestion of NH 4 Cl, CaCl 2 Failure of Kidneys to Excrete PO 4 --, SO 4 -- 12500 mEq/d 50 - 100 mEq/d

4. Some Basic Chemistry Definitions: Arrhenius(1903): – Acid: H + Donor in Solution – Base: OH - Donor in Solution Browsted and Lowry(1923): – Acid: Proton Donor – Base: Proton Acceptor

5. Some Basic Chemistry pH (Potenz or Power of Hydrogen): Sorenson Negative logarithm of H + ion concentration to the base of 10 Why pH? Normal H + ion conc: 0.00004meq/L or 40nEq/L or 4x10 -9 mol/L pH converts decimal numbers & takes away negative sign. Normal pH: 7.35-7.45 Normal H + Conc: 0.00002mEq/L – 0.0001 mEq/L

6. Acid Base Equilibrium: Solutions: When substances are added to water, 3 simple rules have to be satisfied at all time: 1.Electrical Neutrality 2.Mass conservation 3.Dissociation Equilibrium

7. Clinical Concepts : Base Excess : Amount of Acid or Alkali required to return plasma in vitro to normal pH under standard conditions( pH 7.4, PCO 2 40, temp 37 C) Standard BE: BE calculated for Anemic Blood (Hb = 6gm%). – Since Hb effectively buffers plasma & ECF to a large extent. Quantity of Acid or Alkali required to return plasma in-vivo to a normal pH under standard conditions

8. Siggard Anderson Normogram To calculate Base Excess

9. Acid Base Equilibrium: The Henderson-Hasselbalch Equation: H 2 CO 3 H + + HCO 3 - => K a = [H + ][HCO 3 ]/ H 2 CO 3 Taking Logarithm on both sides & Rearranging:  pH= pK a + log 10 [HCO 3 - ]/SX*PCO 2 pK a = 6.1, S = 0.03(solubility coefficient), PCO 2 = 40, HCO 3 =25 On putting values & solving, pH = 7.4 Significance: Includes components of both Metabolic & Respiratory Acid base disorders Value of any one variable can be determined if other two known. Mostly HCO 3 - is calculated pH determined by ratio of [HCO 3 - ]/PCO 2 Increase=> alkalosis, Decrease => Acidosis

10. Anion Gap: Estimate of relative abundance of unmeasured anions Footprint of metabolic acidosis UC & UA in electrochemical balance equation: Na + UC = (Cl + HCO 3 ) + UA Rearranging equation : UA-UC (AG) = [Na + ] - {[HCO 3 - ] + [Cl - ]} Normal Value: 8-12mEq/L ↑ AG reflects ↑ Unmeasured Anion Unmeasured Anions- Albumin,Phosphate, Sulphate, Organic acid. 1mg/dl fall in Albumin, AG↓ by 3meq/l High AG acidosis - Ketones, Lactate, Methanol. Normal AG acidosis - Diarrhea.

11. Clinical Concepts : Acid Base Equilibrium : Elimination of Acid Recovery/Regeneration of Base Mechanisms that keep pH stable  Buffering  Compensation  Correction

12. Clinical Concepts: Buffers: Definition : A substance that can bind or release H + ions in solution, thus keeping the pH of the solution relatively constant despite addition of large amounts of acid or base. For Buffer HA, HA H + + A - pH = pK a + log [A - ]/[HA] – When [A - ] = [HA], pH= pK, buffering capacity is maximum.

13. Clinical Concepts: Most buffers are weak acids (H + buffer) & their Na + Salts (Na + buffer) Strong Acids Buffered by Na + Buffer HCl + Na Buffer H + + Cl - +Na + + Buffer H Buffer + NaCl Strong Bases Buffered by H + buffer NaOH + H Buffer Na + + OH - + H + + Buffer Na Buffer + H 2 O Buffer Effectiveness Depends on: Quanitity – H 2 CO 3 /HCO 3 - - Most important Extracellular Buffer – Protein Buffers – Most important Intracellular Buffer pK a – Buffering capacity maximum when pH=pK a

14. Clinical Concepts: Buffers in ECF: Carbonate-Bicarbonate Buffer53% – Plasma (35%) – Erythrocyte(18%) Hemoglobin 35% Plasma Proteins7% Organic & Inorganic Phosphates5% Buffers in ICF: Intracellular Proteins H 2 PO 4 -HPO 4 - system Intracellular buffers are responsible for ~85% buffering in Met. Acidosis and ~35% in Met Alkalosis and almost complete buffering in Respiratory Acidosis and Alkalosis.

15. Clinical Concepts : Bicarbonate Buffer: HCl + NaHCO 3 - NaCl + H 2 CO 3 NaCl + H 2 O + CO 2 Useful only for Metabolic Acidosis Hb System: Both Respiratory & Metabolic Acidosis in ECF

16. Hemoglobin buffer Chloride Shift Buffers H + directly HCO 3 - diffuses out Cl diffuses in

17. Clinical Concepts: Protein Buffer: Predominant Intracellular Buffer – Large total concentration pK = 7.4 AA have Acidic & Basic Free radicals. COOH + OH - COO - + H 2 O. NH 3 OH + H + NH 3 + H 2 O Phosphate Buffer: pK = 6.8 Predominantly Intracellular Also in renal tubular HCl + Na 2 HPO 4 NaH 2 PO 4 + NaCl NaOH + NaH 2 PO 4 Na 2 HPO 4 + H 2 O

18. Clinical Concepts: Compensation: Pulmonary Compensation H + + HCO 3 - H 2 CO 3 CO 2 + H 2 O H + acts on medullary centres. – Metabolic Acidosis – Increased Ventilation – Metabolic Alkalosis – Depression of Ventilation Minute ventilation increases 1-4l/min for every 1mmHg increase in PaCO 2

19. Clinical Concepts: Renal Compensation: Mechanisms: 1.Reabsorption of filtered HCO 3 - (4000-5000 mEq/d) 2.Generation of fresh bicarbonate 3.Formation of titrable acid – (1mEq/Kg/d) 4.Excretion of NH 4 + in urine

20. PERITUBULAR BLOOD RENAL TUBULAR CELL GLOMULAR FILTRATE HCO 3 - + H + CO 2 HCO 3 - + H + HCO 3 - + H + HCO 3 - Na + HPO 4 2- Na + NH 3 Na + H 2 CO 3 CO 2 + H 2 O H2OH2O H 2 PO 4 - NH 4 + 1. NaHCO 3 2. NaHCO 3 3. NaHCO 3 MAJOR RENAL MECHANISMS RESPONSIBLE FOR H + EXCRETION/HCO 3 - RETENTION CO 2 can be obtained from blood or the tubular fluid Glutamine CO 2 CA

21. Acidemia or Acidosis? Alkalemia or Alkalosis? Any condition that disturbs acid -base balance by increasing H + through endogenous production,↓ buffering capaity, ↓ excretion, or exogenous addition is termed as ACIDOSIS Any condition that ↓ H + is termed as ALKALOSIS Acidemia or Alkalemia refer to net imbalance of H + in blood.

22. Defining acid base disorders DisorderPrimary changeCompensatory response Respiratory Acidosis Alkalosis ↑PaCO 2 ↓PaCO 2 ↑HCO 3 ↓HCO 3 Metabolic Acidosis Alkalosis ↓HCO 3 ↑HCO 3 ↓PaCO 2 ↑PaCO 2

23. Normal reference range pH7.35-7.45 HCO 3 - 22-26meq/l PaCO 2 35-45mmHg PaO 2 80-100mmHg Base excess/Deficit-2 to +2meq/l Anion gap8 to 12 meq/l A-aO 2 5-25mmHg SaO 2 96-100%

24. Prediction of Compensatory Responses on Simple Acid Base Disorders DisorderPrediction of Compensation Metabolic Acidosis For every 1mmol/l ↓ in HCO 3 - → 1mm Hg ↓ in PaCO 2 Expected PaCO 2 = 1.5 (HCO 3 - ) + 8 PaCO 2 should approach last two digits of pH Metabolic AlkalosisFor every 1 mmol/l ↑ in HCO 3 -,↑ PaCO 2 By 0.7mmHg Respiratory Alkalosis Acute[HCO 3 - ] will ↓ 2mmol/L per 10 mmHg ↓ in PaCO 2 Chronic[HCO 3 - ] will ↓ 4mmol/L per 10 mmHg ↓ in PaCO 2 Respiratory Acidosis Acute[HCO 3 - ] will ↑ 1mmol/L per 10 mmHg ↑ in PaCO 2 Chronic[HCO 3 - ] will ↑ 4mmol/L per 10 mmHg ↑ in PaCO 2

25. General approach to acid-base disorder pH Acidemia pH <7.35 Normal pH7.35-7.45 Alkalemia pH> 7.45 Normal or mixed disorder ↓HCO 3 ↑PaCO 2 Metabolic acidosis Respiratory acidosis ↑HCO 3 ↓PaCO 2 Metabolic alkalosis Respiratory alkalosis

26. Diagnosis of acid base disturbance Step - 1: Is there an acid – base disturbance ? look at PaCO 2 & HCO 3, whether in normal range. If normal range, no acid-base disturbance or rule out mixed disorder. If abnormal, proceed to step 2. Step-2: Is there acidemia or alkalemia? Step-3: What is primary acid base disorder? Step-4: Calculate the expected compensation? Determine whether actual value matches with the expected compensation. Matching of both confirms diagnosis of primary disorder.

27. Step 5 : Determine the presence of mixed acid-base Check the direction of changes- As per ‘ Rule of same direction ’, in simple acid-base disorder PaCO 2 & HCO 3 changes from normal in same direction. If changes occur in opposite direction; mixed disorder. If expected compensation > or < than calculated compensation; mixed. Check for anion gap : i.If high AG, High AG metabolic acidosis. ii.If normal AG, Non-AG metabolic acidosis.

28. Case scenario : A 66 year old man seen in emergency room. He has had 8 days of severe diarrhea, abdominal pain, & decreased intake, but adequate intake of liquids. His medical history is significant for diabetes & hypertension. Presently on enalapril, aspirin, atenolol, metformin. Physical examination: B.P 105/70, Pulse 72/min, R.R 32. Lab report: Na 136, K 3.9, Cl 114, HCO 3 13, creatinine 1.2, glucose 128 Urine: pH 6, Na 32, K 21, Cl 80 ABG: pH 7.27, PO 2 90, PCO 2 30  Which acid base disorder is present?

29. pH low & ↓ HCO 3 Metabolic acidosis. Respiratory compensation : Expected PCO 2 = 1.5 X 13 + 8 = 27.5 (Adequate) Anion Gap = 136– (114 + 13) = 9 (Normal) Non-AG Metabolic Acidosis

30. Metabolic acidosis Characterized by fall in plasma HCO 3 & fall in pH Causes : Normal Anion GapIncreased Anion Gap 1. Loss of HCO 3 Diarrhoea, CA inhibitors, Ureterosigmoidostomy,Proximal RTA 1. Metabolic disorders: Lactic acidosis, DKA, Alcoholic ketoacidosis 2. Failure to excrete H + Distal RTA 2. Addition of exogenous acids Salicylate/ methanol poisoning 3. Addition H + NH 4 CL infusion 3. Failure to excrete acid Acute/chronic renal failure

31. Clinical manifestations : Pulmonary changes- Kussmaul’s breathing( deep,regular,sighing respiration) Cardiovascular changes- if severe (pH<7.2), ↑ susceptibility for cardiac arryhthmias, ↓ response to ionotropes & secondary hypotension. Neurological changes- headache, confusion to coma. Other- Renal failure Diagnosis : ABG values - ↓ HCO 3, ↓ pH, compensatory ↓ PaCO 2

32. Treatment of Metabolic Acidosis : 1.Specific management of underlying disorder As a rule treat underlying disorder meticulously. It may be the only required treatment for mild to moderate acidosis & Non-AG acidosis. 2.Alkali therapy Reserved only for selective patients with Severe Acidemia (controversial) & for Non-AG Acidosis Indications : pH<7.2 with sign of shock or myocardial irritability. HCO 3 < 4meq/l Severe Hyperchloremic acidemia Goal: To return pH to about 7.2 & HCO 3 ↑ by 8-10meq/l. Amount of HCO 3 required= (Desired HCO 3 – Actual HCO 3 ) X0.3 X Bodywt. Half of the correction is given f/b repeat ABG after sometime.

33. Case scenario: ABG of a patient with CHF on frusemide pH 7.48, HCO 3 34 mEq/l, PaCO 2 48 mmHg pH  = alkalosis HCO 3  = s/o metabolic alkalosis PaCO 2  = s/o compensation Rise in PaCO 2 = 0.75 x rise in HCO 3 = 0.75 x (34-24) = 7.5 Expected compensation = 40+7.5= 47.5 mmHg ~ actual PaCO 2 s/o simple acid base disorder So patient has primary metabolic alkalosis due to diuretics

34. Metabolic alkalosis Characterized by ↑ HCO 3, ↑ pH,& compensatory ↑ in PaCO 2 Occurs when there is excess of buffers present, raising systemic pH. Clinical features : CNS- ↑ neuromuscular excitability leading to paresthesia, headache. CVS- hypotension & arrythmias Others- weakness, muscle cramps

35. Causes: Metabolic alkalosis by chloride handling Diagnosis : ↑ HCO 3,pH, compensatory ↑ PaCO 2 Serum potassium & chloride low Urinary chloride estimation useful for diagnosis Chloride sensitive (urine CL - <20meq/l) Chloride resistant (urine CL - > 40meq/L) GI Losses Nasogastric suction, vomiting, Rectal adenoma Hypertensive Renovascular hypertension, hyperaldosteronism Renal acid losses Penicillins, post-diuretic, Post-hypercapneic Normotensive Diuretics, administration of alkali

36. Treatment: Chloride sensitive- IV normal saline volume expansion Discontinue diuretics if possible H 2 blockers & PPI in case of nasogastric suction & vomiting Chloride resistant- Remove offending agent Replace potassium if deficit Extreme Alkalosis Hemodialysis HCl can also be used(Dose = ∆ HCO 3 X wt. X 0.5) ( infused at 0.1mmol/kg/hr)

37. Case scenario: Following sleeping pill ingestion, patient presented in drowsy state with sluggish respiration with rate of 4/min pH 7.1, HCO 3 28 mEq/l, PaCO 2 80 mmHg, PaO 2 42 mmHg pH  = acidosis PaCO 2  = s/o respiratory acidosis PaO 2  = moderate hypoxemia HCO 3  = s/o compensation Rise in HCO 3 = 0.1 x rise in PaCO 2 = 0.1 x (80-40) = 4 mEq/l Expected compensation = 28 mEq/l ~ actual PaCO 2 s/o simple acid base disorder So patient has primary respiratory acidosis due to respiratory failure, due to sleeping pills

38. Respiratory Acidosis Characterised by ↑ PaCO 2, ↓ pH, & compensatory ↑ HCO 3 Causes : Airway obstruction- Foreign body,Aspiration, Obstructive sleep apnea, Laryngospasm or Brochospasm. Neuromuscular disorders of respiration - Myasthenia gravis, Guillain-Barre syndrome, Tetanus, Botulism, Hypokalemia, Cervical spine injury, Obesity Central respiratiory depression - Drugs(Opiates, sedatives),Brain trauma Respiratory disorder - Severe Pulmonary edema, Asthma, ARDS, COPD, Pulmonary fibrosis.

39. Clinical presentation : Headache, confusion, irritability, delirium Severity relates with the rapidity of development of disturbance. Treatment: A.General measures 1. Major goal is to identify & treat underlying cause. 2. Establish patent airway & restore oxygenation. 3. If patient with chronic hypercapnia develops sudden ↑ PaCO 2, search for aggravating factor, vigrous treatment of pulmonary infection, brochodilator therapy, removal of secretions. B. Oxygen therapy 1. In Acute, major threat is hypoxia, so oxygen is supplemented. 2. In Chronic hypercapnia, oxygen therapy instituted carefully & in lowest possible concentration.

40. C.Mechanical Ventilatory Support 1. Patient selection : In acute acidosis, early use of ventilatory assistance advised. In chronic, a more conservative approach is advisable because of great difficulty in weaning. 2. Indications : Unstable,symptomatic or progressively hypercapneic. If signs of muscle fatigue Refractory severe hypoxemia Depression of respiratory centre 3. Rate of correction PaCO 2 should be gradual & target is usually patient’s prior stable level & in acute should be normal level. D.Alkali Therapy Avoid except in severe acidemia or severe bronchospasm.

41. CASE SCENARIO A 15 year old boy brought from examination hall in apprehensive state with complain of tightness in chest. pH 7.54, PCO 2 21, HCO 3 21 pH ↑ = s/o alkalosis ↓ PCO 2 = s/o respiratory alkalosis ↓ HCO 3 = s/o compensation expected compensation = 0.2 X (40- 21) = 3.8 expected HCO 3 = 24-3.8= 20.2 meq/l ~ actual HCO 3 s/o simple acid-base disorder. so, the patient has primary respiratory alkalosis due to anxiety.

42. Respiratory Alkalosis Characterised by ↓ PaCO 2 due to hyperventilation & leads to ↑ pH. Diagnosis : ↓ PaCO 2 (<35mmHg), ↑ pH, compensatory ↓ HCO 3 serum HCO 3 does not fall below 15meq/l unless metabolic acidosis is present. Causes: 1. Hypoxemia- Pulmonary disease( Pneumonia, Fibrosis, Edema,Emboli), CHF, Hypotension, Severe anemia, High altitude. 2. Direct stimulation of respiratory centre- Psychogenic or voluntray hyperventilation, Pain, Hepatic failure, Neurological disorder. Clinical features : Headache, arrythmias, tetany, seizures. Severity of hypocapnia constitutes grave prognosis.

43. Treatment Vigrous treatment of the underlying cause Mild alkalosis with few symptoms needs no treatment. As hypoxemia is common cause, oxygen supplememtation is essential.

44. Case scenario Known case of COPD develops severe vomiting pH 7.4, HCO 3 36meq/l, PCO 2 60mmHg pH normal = s/o either no acid –base disorder or mixed ↑ PCO 2 = s/o respiratory acidosis ( due to COPD) ↑ HCO 3 = s/o metabolc alkalosis ( due to vomiting) the patient has mixed disorder, respiratory acidosis & metabolic alkalosis. Normal pH can be due to end result of opposite changes caused by primary disorder.

45. Mixed Acid Base Disorders Difficult to diagnose Suspected whenever pH is normal or if apparent compensation is not adequate in a patient with known primary acid-base disorder. Mixed metabolic & respiratory acidosis occurs when respiratory compensation is insufficient. Gram- negative sepsis is a common cause of respiratory alkalosis & metabolic acidosis.

46. Summary: Acid Base Homeostasis is all about maintenance of normal H + concentration. Changes in acid base status of ECF have profound and often unpredicatable clinical and laboratory effects, more so during anaesthesia. pH scale is a negative logarithmic scale. Anion gap must always be calculated to decipher more accurately the complex acid-base disorders in critically ill patients. Bicarbonate therapy must be used with caution in view of it’s various deleterious effects.

47. References Miller’s Anesthesia, 7 th Edition Civetta, Taylor, Kirby; Critical care 4 th Edition Wylie And Churchill Davidson’s A Practice of Anaesthsia, 5 th Edition Morgan Michael, 4 th Edition Clinical Application of Blood Gases, Shapiro, 5 th Edition Harrison’s Principles of Internal Medicine, 16 th Edition

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