1. Fluids and Electrolytes

2. Body Fluids Water is the major constituent of living cells Water is the major constituent of living cells Extracellular and intracellular fluids are largely water Extracellular and intracellular fluids are largely water A loss of 25% of body water can lead to death A loss of 25% of body water can lead to death

3. Electrolytes Compounds that form ions when dissolved in water Compounds that form ions when dissolved in water Na + - primary cation of extracellular fluid Na + - primary cation of extracellular fluid –Retains fluid in the body, generates and transmits nerve impulses, maintains acid- base balance, regulates enzyme activities, and regulates osmolarity and electroneutrality

4. Electrolytes K + - primary cation of intracellular fluid K + - primary cation of intracellular fluid –Regulates acid-base and water balance, important in protein synthesis, carbohydrate metabolism, muscle building, and the nervous system Ca ++ Ca ++ –Important in bone formation, muscle contraction, and blood coagulation

5. Electrolytes Mg ++ - 2 nd most abundant cation in intracellular fluids Mg ++ - 2 nd most abundant cation in intracellular fluids –Helps maintain normal nerve and muscular function, transmission of impulses, and steady heart rhythms

6. Serum electrolyte level Na – 135-145 mEq/L Na – 135-145 mEq/L Cl - 95-108 mEq/L Cl - 95-108 mEq/L K – 3.5-5 mEq/L K – 3.5-5 mEq/L Ca – 4.5-5.8 mEq/L Ca – 4.5-5.8 mEq/L Mg – 1.5-2.5 mEq/L Mg – 1.5-2.5 mEq/L

7. Electrolytes Cl - Cl - –Transports CO 2, forms HCl in the stomach, retains K +, maintains osmolarity H + H + –Determines the acidity and alkalinity of body fluids

8. Tonicity Measures the amount of dissolved particles in relation to body fluids Measures the amount of dissolved particles in relation to body fluids Hypotonic – lower concentration of dissolved particles Hypotonic – lower concentration of dissolved particles Hypertonic – higher concentration of dissolved particles Hypertonic – higher concentration of dissolved particles Isotonic – same concentration of dissolved particles (0.9% sodium chloride) Isotonic – same concentration of dissolved particles (0.9% sodium chloride)

9. Electrolyte disorders Abnormal electrolytes Abnormal electrolytes –primary disease state –secondary consequence of a multitude of diseases –iatrogenic problems are very common Important Important –maintenance of cellular homeostasis –cardiovascular physiology - BP –renal physiology –electrophyssiology - heart, CNS

10. Some clinical examples Haemorhage - accidents, surgery Haemorhage - accidents, surgery Poor intake - elderly Poor intake - elderly Increased losses - pyrexia, heat Increased losses - pyrexia, heat Diabetes insipidus Diabetes insipidus Diabetes mellitus Diabetes mellitus Diuretic therapy Diuretic therapy Endocrine disorders - ADH, aldosterone Endocrine disorders - ADH, aldosterone

11. Important Concepts Concentrations Concentrations Compartments Compartments Contents Contents Volumes Volumes Rates of gain & loss Rates of gain & loss

12. Concepts ICF 28L ECF 14L Plasma + Interstitial Intake Excetion Normally the system is maintained in equilibrium Changing any factor causes a new steady state to be reached

13. Decreasing the volume - 4L ICF 26L ECF 10L Plasma + Interstitial Intake Excetion This will raise the concentration of any solute

14. Increasing the excretion of a solute ICF 28L ECF 14L Plasma + Interstitial Intake Excretion This will decrease the solute concentration

15. Body Fluid Distribution Water[Na] [K] (L)(mmol/L) (mmol/L) ECF Vascular31405 Vascular31405 Interstitial161405 Interstitial161405ICF Intracellular2310150 Intracellular2310150 TOTAL42

16. Loss of Isotonic Solutions Haemorrhage

17. Compensatory mechanisms Physiological Physiological –Thirst –ADH –Renin / Angiotensin system Therapeutic Therapeutic –Intravenous therapy –Diuretics –Dialysis

18. Replacement of loss of 2L of isotonic fluid ICF 28L ECF 12L ICF 29L ECF 13L ICF 28L ECF 14L With isotonic fluid No change in [Na] No fluid redistribution With hypotonic fluid Fall in [Na] Fluid redistribution

19. Replacement of loss of 3L of hypotonic fluid With isotonic fluid [Na] slightly increased No fluid redistribution With hypotonic fluid [Na] restored Fluid redistribution ICF 26L ECF 13L ICF 28L ECF 14L ICF 26L ECF 16L ICF 26L ECF 16L ICF 26L ECF 16L

20. Clinical Problems Hyponatraemia Hyponatraemia –Too little Na in ECF –Excess water in ECF Hypernatraemia Hypernatraemia –Too little water in ECF –Too much Na in ECF Dehydration Dehydration –Water deficiency –Fluid (Na and water) depletion

21. Disorders of Potassium Potassium reference range - 3.6 to 5.0 mmol/L Potassium reference range - 3.6 to 5.0 mmol/L Values 6.0 are potentially dangerous Values 6.0 are potentially dangerous –Cardiac conduction defects –Abnormal neuromuscular excitability Clinical Problems are common Clinical Problems are common Many are iatrogenic and avoidable Many are iatrogenic and avoidable

22. Potassium Distribution Total Total NaK mmol NaK mmol Plasma1405 2%70 Interstitial fluid1405 Intracellular fluid10150 98%3400 Intake 60 - 200 mmols/d

23. Relationship of Potassium to Hydrogen Ions K+ and H+ exchange across cell membrane K+ and H+ exchange across cell membrane Both bind to negatively charged proteins (eg Hb) Both bind to negatively charged proteins (eg Hb) Changes in pH cause shifts in the equilibrium Changes in pH cause shifts in the equilibrium –acidosis - potassium moves out of cells -> hyperkalaemia –alkalosis - potassium moves into cells -> hypokalaemia Conversely Potassium depletion and excess can affect acid- base status

24. Causes of Hyperkalaemia Artefactual Artefactual –Delay in sample analysis –Haemolysis –Drug therapy - Excess intake Renal Renal –Acute Renal Failure –Chronic Renal Failure Acidosis (intracellular exchange) Acidosis (intracellular exchange) Mineralocorticoid Dysfunction Mineralocorticoid Dysfunction –Adrenocortical failure –Mineralocorticoid resistance - eg spironolactone Cell Death Cell Death –Cytoxic therapy

25. Treatment of Hyperkalaemia Correct acidosis if this is cause Correct acidosis if this is cause Stop unnecessary supplements / intake Stop unnecessary supplements / intake Give Glucose & insulin Give Glucose & insulin –Drives potassium into cells Ion exchange resins Ion exchange resins –GIT potassium binding Dialysis Dialysis –short and long-term

26. Causes of Potassium Depletion Low intake Low intake Increased urine loss Increased urine loss –diuretics / osmotic diuresis –tubular dysfunction –mineralocorticoid excess GIT losses GIT losses –vomiting –diarrhoea / laxatives –fistulae Hypokalaemia without depletion Hypokalaemia without depletion –alkalosis –insulin / glucose therapy.

27. Effects of Potassium depeletion (< 2.5 mmol/l) Acute changes in ICF/ECF ratios Acute changes in ICF/ECF ratios –Neuromuscular: lethargy, muscle weakness, heart arrhythmias lethargy, muscle weakness, heart arrhythmias Chronic losses from the ICF Chronic losses from the ICF –Neuromuscular: lethargy, muscle weakness, heart arrhythmias lethargy, muscle weakness, heart arrhythmias –Kidney: polyuria polyuria alkalosis - increase renal HCO3 production alkalosis - increase renal HCO3 production –Vascular: –Gut:

28. Detection of Potassium Depletion History: History: –diarhoea, vomiting, drugs (diuretics, digoxin) –symptoms of lethargy / weakness –cardiac arythmias Electrolytes investigation: Electrolytes investigation: –hypokalaemia –alkalosis - raised HCO 3

29. Treatment of Potassium Depletion Prevention Prevention –Adequate supplementation Replacement of deficit Replacement of deficit –oral-48 mmol/day + diet –IV-< 20 mmol/L Monitor plasma potassium regularly especially: Monitor plasma potassium regularly especially: –Diuretic therapy –Digoxin use –Compromised renal function –In support of IV resuscitation (eg DM Ketacidosis)

30. IV Therapy Goal: provide sufficient water and electrolytes to maintain fluids and excrete waste products Goal: provide sufficient water and electrolytes to maintain fluids and excrete waste products Solvent in IV solutions is water Solvent in IV solutions is water

31. IV Therapy Goal: provide sufficient water and electrolytes to maintain fluids and excrete waste products Goal: provide sufficient water and electrolytes to maintain fluids and excrete waste products Solvent in IV solutions is water Solvent in IV solutions is water D5W = 5 g of Dextrose in 100 ml of water D5W = 5 g of Dextrose in 100 ml of water NS = 0.9 g of NaCl in 100 ml of water NS = 0.9 g of NaCl in 100 ml of water

32. Crysrtaloids Normal Saline (NS) (0.9% NaCl) Normal Saline (NS) (0.9% NaCl) Hypertonic saline (3% NaCl) Hypertonic saline (3% NaCl) Lactated Ringer’s (na, Cl, K, Ca, Lactate) Lactated Ringer’s (na, Cl, K, Ca, Lactate) D5W (5% dextrose) D5W (5% dextrose)

33. Colloids Dextran Dextran Hetastarch Hetastarch 5 and 25 % Albumin 5 and 25 % Albumin

34. Crysrtaloids and collloids: indication Acute liver failure Acute liver failure Acute nephrosis Acute nephrosis Adult respiratory disterss syndrome Adult respiratory disterss syndrome Burns Burns Cardiopulmonary bypass Cardiopulmonary bypass Hypoproteinemia Hypoproteinemia Reduction of the risk of DVT Reduction of the risk of DVT Renal dialysis Renal dialysis Shock Shock

35. Acid-Base Homeostasis Kidneys Output Lungs Maintenance of Normal [H + ] Buffers MetabolismInput

36. Acid production total CO 2 25 mol/day total CO 2 25 mol/day unmetabolised acids50 mmol/day unmetabolised acids50 mmol/day plasma [H + ]40 nmol/L plasma [H + ]40 nmol/L

37. Buffering Systems Haemoglobin Haemoglobin BicarbonateBicarbonate PhosphatePhosphate ProteinsProteins AmmoniaAmmonia Misc organic acidsMisc organic acids

38. Integrated approach to acid-base

39. Acidosis Metabolic Alkalosis Acidosis Respiratory Alkalosis Acid-Base Pathology

40. 4 % Sodium hydrocarbon Acidosis treatment - 4 % Sodium hydrocarbon Alkalosis treatment – Citric acid Alkalosis treatment – Citric acid

41. Coagulation Modifiers Agents.

42. Blood Clotting Anticoagulants Anticoagulants –Prevent clot formation by inhibiting clotting factors

43. Blood Clotting Anticoagulants Anticoagulants –Prevent clot formation by inhibiting clotting factors Antiplatelets Antiplatelets –Reduce risk of clot formation by inhibiting platelet aggregation

44. Blood Clotting Anticoagulants Anticoagulants –Prevent clot formation by inhibiting clotting factors Antiplatelets Antiplatelets –Reduce risk of clot formation by inhibiting platelet aggregation Fibrinolytics Fibrinolytics –Dissolve clots already formed

45. Clotting Cascade

46. If any factor in the cascade is missing, blood will not clot (hemophilia) If any factor in the cascade is missing, blood will not clot (hemophilia)

47. Clinical Thrombosis >2.5 million cases of deep venous thrombosis (DVT) per year >2.5 million cases of deep venous thrombosis (DVT) per year >600,000 cases of pulmonary embolism (PE) per year >600,000 cases of pulmonary embolism (PE) per year >50,000 deaths per year from PE >50,000 deaths per year from PE PE contributes to another 150,000 deaths per year PE contributes to another 150,000 deaths per year > 11,000 postsurgical PE deaths per year > 11,000 postsurgical PE deaths per year

48. Venous Thrombi Usually form in areas of slow blood flow, surgical or vein injuries, large venous sinuses, or pockets formed by valves in deep veins Usually form in areas of slow blood flow, surgical or vein injuries, large venous sinuses, or pockets formed by valves in deep veins If the clot breaks off, it can travel to the lung causing pulmonary embolism (PE) If the clot breaks off, it can travel to the lung causing pulmonary embolism (PE)

49. DVT Deep vein thrombosis above the knee is the most serious and may be fatal Deep vein thrombosis above the knee is the most serious and may be fatal

52. Risk Factors for DVT Age over 40 Age over 40 Bed rest over 4 days Bed rest over 4 days Estrogen combined with nicotine Estrogen combined with nicotine High dose estrogen therapy High dose estrogen therapy Major illness Major illness Obesity Obesity Parturition Parturition Pregnancy Pregnancy Previous DVT Previous DVT Surgery Surgery Trauma Trauma Varicose veins Varicose veins

53. Laboratory Testing Certain lab tests must be done on patients who are on anticoagulant therapy Certain lab tests must be done on patients who are on anticoagulant therapy

54. Laboratory Testing Partial thromboplastin time (PTT) – affected by heparin Partial thromboplastin time (PTT) – affected by heparin APTT – Activated Partial thromboplastin time Prothrombin Time (PT) – affected by warfarin Prothrombin Time (PT) – affected by warfarin International Normalized Ration (INR) International Normalized Ration (INR) Hematocrit Hematocrit

55. Anticoagulant Agents argatroban argatroban bivalirudin (Angiomax) bivalirudin (Angiomax) fondaparinux (Arixtra) fondaparinux (Arixtra) heparin heparin lepirudin (Refludan) lepirudin (Refludan) warfarin (Coumadin) warfarin (Coumadin) Drug List

56. THE IDEAL ANTICOAGULANT 1) Would be effective for prophylaxis of clots, prevention of clot extension, and clot lysis 2)Would be able to be given orally and parenterally 3)Would be inexpensive 4)Would be devoid of side effects 5)Would have a long half-life 6)Would be easy to monitor or not require monitoring 7)Would not interact with food or other medications 8)Would be rapidly and easily reversible

57. heparin Inhibits thrombin formation preventing clots from forming Inhibits thrombin formation preventing clots from forming Only anticoagulant that does not cross the placenta Only anticoagulant that does not cross the placenta Given for prophylaxis of DVT in postoperative, bedridden, obese patients, and others Given for prophylaxis of DVT in postoperative, bedridden, obese patients, and others

58. HEPARIN Description 1)Discovered in 1916 by McLean; isolated from liver, thus the name heparin 2)Anionic glycosaminoglycan available as calcium or sodium salt 3)Molecular weight 15,000 D (avg.) 4)Prepared from porcine intestinal mucosa and bovine lung 5)Does not cross placenta 6)Little interaction with other medications 7)IV or SC administration only 8)Reversible with protamine (1 mg/200 U heparin)

59. HEPARIN Action 1)Binds to and potentiates antithrombin III 2)Heparin-antithrombin III complex inactivates thrombin (factor IIa) and factor Xa 3)Secondary effect against platelet function

60. Plasminog en Activator PAI* Plasmin  2 Anti-plasmin XII XI IX X V II I Fibrin VIIIVII  Inhibitory  Activating * Plasminogen Activator Inhibitor Antithrombin III

61. HEPARIN Indications Full Dose: 5000 U or 80 U/kg IV bolus, followed by 1200-1600 U/hr adjusted to therapeutic range 1)Acute deep venous thrombosis 1)Acute deep venous thrombosis 2)Pulmonary emboli 2)Pulmonary emboli 3)Unstable angina and myocardial infarction 3)Unstable angina and myocardial infarction Low Dose:5000 U sq q12 h 1)Postoperative prophylaxis of any major abdominal, thoracic, gynecologic, or orthopedic procedure 1)Postoperative prophylaxis of any major abdominal, thoracic, gynecologic, or orthopedic procedure 2)Immobilized medical patients >40 yrs. with CHF, CVA, malignant disease 2)Immobilized medical patients >40 yrs. with CHF, CVA, malignant disease 3)Prophylaxis for underlying hypercoagulable state 3)Prophylaxis for underlying hypercoagulable state Other Dose: 1)Extracorporeal bypass 1)Extracorporeal bypass 2)Hemodialysis 2)Hemodialysis 3)After thrombolytic therapy 3)After thrombolytic therapy

62. HEPARIN Contraindications 1)Thrombocytopenia 2)Aspirin or alcohol use 3)Hepatic or renal disease 4)Other platelet dysfunction 5)GI bleeding 6)Tumors, esp. CNS

63. HEPARIN (6) Side Effects 1)Major side effect is bleeding 2)Osteoporosis with prolonged use 3)Thrombocytopenia

64. LEPIRUDIN 1)Recombinant form of hirudin 2)Highly specific direct thrombin inhibitor 3) Not associated with HIT 4) Short half-life 1-2 hours 5) Monitored by APTT or ecarin clotting time 6) Crosses placenta in rats, would not use in pregnancy at present 7) No antidote

65. PENTASACCHARIDE fondaparinux (Arixtra) 1) New type of anticoagulant 2) Indicated for DVT prophylaxis in orthopedic surgery 3) Dose is 2.5 mg SC qd 4) ? benefit in HIT

66. ARGATROBAN 1)Synthetic molecule 2)Direct thrombin inhibitor 3)Not associated with HIT 4) Monitored by APTT, also prolongs PT 5) Must be dose reduced in hepatic failure 6) Half-life 40-50 min. 7) No antidote 8) Dose: 2 microgm/kg/min IV adjusted to 2 microgm/kg/min IV adjusted to 1.5-3.0 x baseline APTT 1.5-3.0 x baseline APTT

67. Low-Molecular-Weight Heparins: dalteparin (Fragmin) dalteparin (Fragmin) enoxaparin (Lovenox) enoxaparin (Lovenox) tinzaparin (Innohep) tinzaparin (Innohep) Drug List

68. LOW MOLECULAR WEIGHT HEPARIN General 1) Molecular weight 3,000- 7,000 D 2)Inhibits factor Xa rather than thrombin 3)Factor Xa assay used for monitoring 4)Administered subcutaneously 5)Probably less antigenic than standard heparin 6)Recommended for prophylaxis and treatment 7)Enoxaparine, dalteparin, and tinzaparin available in U.S.

69. LOW MOLECULAR WEIGHT HEPARIN Monitoring 1) PT, APTT not usually prolonged 2) May be monitored with anti-factor Xa assay

70. warfarin (Coumadin) Prevents production of vitamin K-dependent clotting factors Prevents production of vitamin K-dependent clotting factors Prevents future clots with no effect on existing clots Prevents future clots with no effect on existing clots Should not be taken with ASA or NSAIDs Should not be taken with ASA or NSAIDs

71. Vitamin K-antagonists of the coumarin type and vitamin K

72. COUMADIN Description 1)Isolated by Link in 1939 after previous observation that cattle developed bleeding disorder after ingestion of spoiled clover 2)Is 4-hydroxycoumarin compound, similar in structure to vitamin K 3)Administered p.o., rapid GI absorption 4)Crosses placenta easily 5)Interacts with a variety of drugs 6)Hereditary resistance has been described

73. COUMADIN Actions 1) Blocks the carboxylation of the vitamin K dependent clotting proteins, factors II VII, IX, and X, maintaining them in their inactive forms 2) Also blocks the anticoagulant proteins C and S

74. COUMADIN Laboratory 1)Prolongs the PT and APTT 2)PT and International Normalized Ratio (INR) used for monitoring

75. INTERNATIONAL NORMALIZED RATIO (INR) Ideal INR depends on clinical situation ISI = Sensitivity Index for thromboplastin INR = PATIENT PT CONTROL PT ISI

76. COUMADIN Contraindications 1)Pre-existing hemostatic defects 2)GI bleeding 3)CNS hemorrhage 4)Pregnancy, esp. 1st trimester

77. COUMADIN Side Effects 1)Hemorrhage 2)Unmasking of underlying anatomic lesion 3)Surreptitious use 4)Fetal abnormalities 5)Skin necrosis with deficiencies of proteins C or S usually on 3rd to 8th day of therapy

78. COUMADIN- INDUCED SKIN NECROSIS COUMADIN- INDUCED SKIN NECROSIS 1)Usually occurs on days 3-8 after initiation of Coumadin 1)Usually occurs on days 3-8 after initiation of Coumadin 2) More common in females (75%) 2) More common in females (75%) 3)Most common on the breast, buttocks, or extremities, occ. on penis in males 3)Most common on the breast, buttocks, or extremities, occ. on penis in males 4)Not predictable by history or protein C level 4)Not predictable by history or protein C level

79. COUMADIN Dosing 1)Usual recommendation is 5 mg initial daily dose 2)Larger loading dose not beneficial 3) Should be continued for at least 3-6 months after initial DVT, 1 yr. for recurrent thrombi, and indefinitely for atrial fibrillation and prosthetic valves 4)Must be aware of changes in concomitant drugs and diet

80. COUMADIN Interactions POTENTIATORS:SulfasPhenylbutazoneCimetidineOmeprazoleAmiodarone Anabolic steroids ANTAGONISTS:BarbituratesRifampinPenicillinsAntacids

81. Antiplatelet Agents aspirin aspirin clopidogrel (Plavix) clopidogrel (Plavix) ticlopidine (Ticlid) ticlopidine (Ticlid) Drug List

82. ANTIPLATELET THERAPY Aspirin Indications 1)Stroke, TIA 2)MI, recurrent MI 3)Unstable angina

83. Inhibitors of platelet aggregation

84. Presystemic inactivation of platelet cyclooxygenase by acetylsalicylic acid

85. TICLOPIDINE 1)Interferes with platelet-fibrinogen binding 2)Exerts its action for the life of the platelet 3)May prolong bleeding time 4)Useful for coronary artery stents and CVA 5)Methylprednisolone may reverse its effect 6)Associated with TTP, neutropenia, and diarrhea

86. clopidogrel (Plavix) Blocks ADP receptors and prevents platelet adhesion and aggregation Blocks ADP receptors and prevents platelet adhesion and aggregation Used to prevent MI and stroke Used to prevent MI and stroke Major side effect is bleeding Major side effect is bleeding

87. CLOPIDOGREL 1)Interferes with GP IIb/IIIa binding site 2)Exerts its action for the life of the platelet 3)May prolong bleeding time 4)Indicated for prevention of MI, CVA, and vascular death in pts with ASCD 5)Fewer side effects than ticlopidine 6)Dose: 75 mg qd

88. Antiplatelet Agents Glycoprotein Antagonists: abciximab (ReoPro) abciximab (ReoPro) eptifibatide (Integrilin) eptifibatide (Integrilin) tirofiban (Aggrastat) tirofiban (Aggrastat) Drug List

89. Abciximab (ReoPro) 1)Human-mouse monoclonal Ab 2)Binds to GP IIb/IIIa receptor on platelets 3)Half-life 10 min. 4)May block receptor for 10 days 5)Indicated for prevention of closure of coronary vessels after angioplasty 6)May cause thrombocytopenia 7)Used with heparin and ASA

90. Fibrinolytic Agents alteplase (Activase) alteplase (Activase) reteplase (Retavase) reteplase (Retavase) streptokinase (Streptase) streptokinase (Streptase) tenecteplase (TNKase) tenecteplase (TNKase) urokinase (Abbokinase) urokinase (Abbokinase) Drug List

91. Fibrinolytic Agents Dissolve existing emboli or thrombi Dissolve existing emboli or thrombi Indications: Indications: –DVT –Acute peripheral occlusion –Acute MI with embolization –PE –Coronary embolus