1. Homeostasis. l Definition : Processes by which bodily equilibrium is maintained constant. l Examples of Bodily homeostasis: »temperature »blood pressure »heart rate »blood glucose level, etc. »body fluid composition

2. BODY FLUID COMPARTMENTS l General Goal: To describe the major body fluid compartments, and the general processes involved in movement of water between extracellular and intracellular compartments.

3. The Body as an Open System l “Open System”. The body exchanges material and energy with its surroundings.

4. Water Steady State. l Amount Ingested = Amount Eliminated

5. Water Ingestion l Drinking (1.4 L/day). l Water contained in Food (0.85L/day). l Metabolism----> CO 2 and H 2 O (0.35 L/day).

6. Water Elimination l Urinary loss (1.5 L/day). l Fecal loss (0.2 L/day). l Insensible H 2 O loss (0.9 L/day) l Sweat Losses. l Pathological losses.  vascular bleeding (H 2 0, Na + )  vomiting (H 2 0, H + )  diarrhea (H 2 0, HCO 3 - ).

7. Electrolyte (Na +, K +, Ca ++ ) Steady State. Electrolyte (Na +, K +, Ca ++ ) Steady State. l Amount Ingested = Amount Excreted. l Normal entry: Mainly ingestion in food. l Clinical entry: Can include parenteral administration.

8. Electrolyte losses l Renal excretion. l Stool losses. l Sweating. l Abnormal routes: e.g.. vomit and diarrhea.

9. Metabolized Substances. l Chemically altered substances must also be in balance l Balance sheet: conservation between substrates and end products.

10. Compartment. l DEFINITION. A non-specific term to refer to a region in the body with a unique chemical composition or a unique behavior. l Distribution of substances within the body is NOT HOMOGENEOUS.

11. Compartment Properties. l Can be spatially dispersed. l Separated by membranes l Epithelial (or endothelial) barriers (cells joined by tight junctions)

12. II. EXPRESSING FLUID COMPOSITION

13. Gram Molecular Weight (GMW). l Mole (mol) (6.02x10 23 molecules). l Atomic weight in grams l Molecules: sum atomic weight individual atoms.

14. Physiological Molecular Weights

15. Expressing Fluid Composition l Percentage l Molality l Molarity l Equivalence

16. Percent Concentrations: (Solute / Solvent) x 100 l Body solvent is H 2 O  1 ml weighs 1 g. l (weight/volume) percentages (w/v). l (weight/weight) percentages (w/w). l Clinical chemistries: mg % or mg / dl.

17. Molality. l Concentration expressed as: moles per kilogram of solvent. l Rarely used

18. Molarity (M). l Concentration expressed as: moles per liter of solution. l Symbol “M” means moles/liter not moles. l Physiological concentrations are low. » millimolar (mM) = 10 -3 M » micromolar (  M) = 10 -6 M » nanomolar (nM) = 10 -9 M » picomolar (pM) = 10 -12 M

19. Electrochemical Equivalence (Eq). l Equivalent -- weight of an ionic substance in grams that replaces or combines with one gram (mole) of monovalent H + ions. l Physiological Concentration: milliequivalent.

20. Electrochemical Equivalence (Eq). l Monovalent Ions (Na +, K +, Cl - ):  One equivalent is equal to one GMW.  1 milliequivalent = 1 millimole l Divalent Ions (Ca ++, Mg ++, and HPO 4 2- )  One equivalent is equal to one-half a GMW.  1 milliequivalent = 0.5 millimole

21. Complications in Determining Plasma Concentrations. l Incomplete dissociation (e.g. NaCl). l Protein binding (e.g. Ca ++ ) l Plasma volume is only 93% water.  The other 7% is protein and lipid. »Hyperlipidemia »Hyperproteinemia.

22. III. Distribution and Composition of Body Fluid Compartments

23. Fig 2: Body Water Distribution CELL WATER 36%25 L ECF 24%17 L RBC DENSE CONNECTIVE 4.5%3 L BONE 3% 2 L INTERSTITIAL FLUID COMPARTMENT 11.5%8 L PLASMA WATER 4.5% 3 L TRANSCELLULAR WATER 1.5%1 L Input

24. Total Body Water Individual variability = f ( lean body mass)  55 - 60% of body weight in adult males  50 - 55% of body weight in adult female  ~42 L For a 70 Kg man.

25. Extracellular Water vs. Intracellular Water l Intracellular fluid  ~36% of body weight  25 L in a 70 Kg man. l Extracellular fluid  ~24% of body weight  17 L in a 70 Kg man.

26. Major Extracellular Fluid Compartments (11L of ECF) l Plasma (blood minus the red and white cells)  ~3 L in a 70 Kg man  ~4.5% of body weight. l Interstitial space (between organ cells)  ~8 L in a 70 Kg man  ~11.5% of body weight.

27. Minor Extracellular Compartments (6 L of ECF) l Bone and dense connective tissue l Transcellular water (secretions)  digestive secretions  intraocular fluid  cerebrospinal fluid  sweat  synovial fluid.

28. Blood is Composed of Cells and Plasma. l Hematocrit (Hct).  Fraction of blood that is cells.  Often expressed as percentage. l Plasma volume = Blood volume x (1-Hct).

29. Ingress and Egress l Plasma water  Ingested nutrients pass through plasma on way to cells  Cellular waste products pass through plasma before elimination l Interstitial space.  Direct access point for almost all cells of the body  Exception -- red and white blood cells

30. Solute Overview: Intracellular vs. Extracellular Solute Overview: Intracellular vs. Extracellular l Ionic composition very different l Total ionic concentration very similar l Total osmotic concentrations virtually identical

31. Major Ionic Species l Principle cations  Extracellular: Na +  Intracellular: K + l Principle anions  Extracellular: chloride and bicarbonate.  Intracellular: proteins, aa’s, and phosphates »inorganic (HPO 4 2-, H 2 PO 4 - ) »organic (amino acids and ATP).

32. Figure 3: Summary of Ionic composition Interstitial H2OH2O Plasma H2OH2O Cell H2OH2O

33. IV. PROTEINS, OSMOTIC CONCEPTS, DONNAN MEMBRANE EQUILIBRIUM IV. PROTEINS, OSMOTIC CONCEPTS, DONNAN MEMBRANE EQUILIBRIUM

34. Net Osmotic Force Development l Semipermeable membrane. l Movement some solute obstructed. l H 2 O (solvent) crosses freely. l End point:  Water moves until solute concentration on both sides of the membrane is equal.  OR, an opposing force prevents further movement.

35. Osmotic Pressure (  ). l The force/area tending to cause water movement. S S S S SS S S S S S SS  p

36. Glucose Example Gl Gl GlGl Gl Gl GlGl Initial Final 10 L 15 L5 L

37. Osmotic Concentration. l Proportional to the number of osmotic particles formed. l Assuming complete dissociation:  1.0 mole of NaCl forms a 2.0 osmolar solution in 1L.  1.0 mole of CaCl 2 forms a 3.0 osmolar solution in 1L.

38. Osmotic Concentration l Physiological concentrations:  milliOsmolar units most appropriate.  1 mOSM = 10 -3 osmoles/L

39. Biological membranes are not impermeable to all solutes. l Endothelial Cell Barriers  All ions can freely cross the capillary wall.  Only proteins exert important net osmotic forces. l Cell Membrane Barriers  Membrane pumps effectively keep Na + from entering cells, thus forming a virtual barrier.  Proteins can’t escape the cell interior.

40. Gibbs-Donnan Membrane Equilibrium. l Proteins are not only large, osmotically active, particles, but they are also negatively charged anions. l Proteins influence the distribution of other ions so that electrochemical equilibrium is maintained.

41. Figure 5: Donnan’s Law l The product of Diffusible Ions is the same on the two sides of a membrane. 33 K + 33 Cl - 67 K + 50 Pr - 17 Cl - Step 2 66 Osmoles134 Osmoles 50 K + 50 Cl - 50 Pr - Initial 100 Osmoles Final 33 ml67 ml 33 K + 33 Cl - 67 K + 50 Pr - 17 Cl - Total Volume 100 ml Ions Move H 2 O moves

42. Measurement of Body Fluid Compartments l Based on concentration in a well-mixed compartment: Concentration = Amount Injected Volume of Distribution

43. Measurement of Body Fluid Compartments l Requires substance that distributes itself only in the compartment of interest. V d = Amount Injected - Amount Excreted Concentration after Equilibrium

44. Total Body Water (TBW) l Deuterated water (D 2 O) l Tritiated water (THO) l Antipyrine

45. Extracellular Fluid Volume (ECFV) l Labeled inulin l Sucrose l Mannitol l Sulfate

46. Plasma Volume (PV) l Radiolabeled albumin l Evans Blue Dye (which binds to albumin)

47. Compartments with no Compartment-Specific Substance Compartments with no Compartment-Specific Substance l Determine by subtraction:  Intracellular Fluid Volume (ICFV). ICFV = TBW - ECFV  Interstitial Fluid Volume (ISFV). ISFV = ECFV - PV

48. VI. PRINCIPLES OF H 2 O MOVEMENT BETWEEN BODY COMPARTMENTS Intracellular vs. Extracellular

49. Principles of Body Water Distribution. l Body control systems regulate ingestion and excretion:  constant total body water  constant total body osmolarity l Osmolarity is identical in all body fluid compartments (steady state conditions)  Body water will redistribute itself as necessary to accomplish this.

50. Intra-ECF Water Redistribution Plasma vs. Interstitium l Balance of Starling Forces acting across the capillary membrane.  osmotic forces  hydrostatic forces l Discussed in more detail later in course

51. Intracellular Fluid Volume l ICFV altered by: changes in extracellular fluid osmolarity. l ICFV NOT altered by: iso-osmotic changes in extracellular fluid volume. l ECF undergoes proportional changes in:  Interstitial water volume  Plasma water volume

52. Primary Disturbance: Increased ECF Osmolarity l Water moves out of cells  ICF Volume decreases (Cells shrink)  ICF Osmolarity increases l Total body osmolarity remains higher than normal. (Of Course, because...)

53. Primary Disturbance: Decreased ECF Osmolarity l Water moves into the cells  ICF Volume increases (Cells swell)  ICF Osmolarity decreases l Total body osmolarity remains lower than normal.  (Of Course, because...)

54. Plasma Osmolarity Measures ECF Osmolarity l Plasma is clinically accessible. l Dominated by [Na + ] and the associated anions l Under normal conditions, ECF osmolarity can be roughly estimated as: P OSM = 2 [Na + ] p 270-290 mOSM

55. Clinical Laboratory Measurement. l Includes contributions from glucose and urea. l Contribution from glucose and urea normally small.  Glucose normally 60-100 mg/dl  BUN normally 10-20 mg/dl

56. Clinical Laboratory Measurement.

57. Effective Osmolarity. l Urea (BUN) crosses cell membranes just as easily as water.  [BUN] E = [BUN] i  No effect on water movement

58. Effective Osmolarity.

59. Osmolar Gap. l P osm (measured) - P osm (calculated) l Suggests the presence of an unmeasured substance in blood.  e.g. following ingestion of a foreign substance (methanol, ethylene glycol, etc.)

60. VII. EXAMPLE CALCULATIONS l Strategy for solving infusion problems l Use for Workshop

61. Strategy for solving infusion problems. l Osmolarity is the same in all compartments.  Calculate the initial total body solute as: (Plasma Osmolarity) x (Total Body Water).  Calculate the initial extracellular solute as: (Plasma Osmolarity) x (Extracellular Volume)  Calculate the new total body solute as: Previous Amt. + Amt. Added.  Calculate the new total body water as: Old TBW + Added Water.  Calculate the new total body osmolarity as: New Total Body Solute divided by New TBW.  Calculate the new extracellular solute as: Old Extracellular Solute + Added Extracellular Solute.  Calculate the new extracellular volume as: New Extracellular Solute divided by New Total Body Osmolarity.  Calculate new intracellular volume as: New TBW - New Extracellular Volume.  If desired, estimate New [Na]p as: New body osmolarity divided by 2.

62. Problem 1: l Initial conditions: ICF = 25 L, ECF = 17 L, [Na]p = 140 mEq/L. l Calculate the effect on ICFV, ECFV, and Plasma Na +  Ingestion of 420 mEq NaCl. l Answers: ICF = 23.3 L, ECF = 18.7 L, [Na]p = 150 mEq/L.

63. Problem 2: l Initial conditions: ICF = 25 L, ECF = 17 L, [Na]p = 140 mEq/L. l Calculate the effect of each on ICFV, ECFV, and Plasma Na +.  Imbibing and absorbing 1.5 L of H2O. l Answers: ICF = 25.9 L, ECF = 17.6 L, [Na]p = 135 mEq/L.

64. Problem 3: l Initial conditions: ICF = 25 L, ECF = 17 L, [Na]p = 140 mEq/L. l Calculate the effect of each on ICFV, ECFV, and Plasma Na +.  Infusing 1.5 L of isotonic saline. l Answers: ICF = 25.0 L, ECF = 18.5 L, [Na]p = 140 mEq/L.

65. VIII. Common Clinical Conditions Affecting Body Water and Electrolytes l Read on your own l Relate to the Principles we have discussed

66. Extracellular Sodium l Hypernatremia: Decreased ICF l Hyponatremia: Increased ICF (cell swelling). l Hyperglycemia:  glucose acts as an effective osmole  Induce hyponatremia and cell shrinkage  Cell shrinkage, not the hyponatremia, needs correcting.

67. Example Conditions causing Hypernatremia Example Conditions causing Hypernatremia l Increased insensible water loss. l Excessive Sweat Loss. Normally, sweat is mainly water with only a little sodium. l Central or nephrogenic diabetes insipidus. Decreased ADH secretion or responsiveness to ADH.

68. Example Conditions causing Hyponatremia »Large water ingestion. »Syndrome of Inappropriate ADH Secretion (SIADH). Too much ADH leads to water retention, hyponatremia, and excretion of concentrated urine.

69. Increased ECF volume l Increased central venous pressure (bulging of the jugular veins) in conjunction with edema is often indicative of increased extracellular fluid volume. l If osmolarity is normal, the intracellular volume is probably normal.

70. Decreased ECF Volume. l Main danger is hypovolemia which ultimately decreases tissue perfusion. l Clinical presentation includes:  Dry mucous membranes  Lack of urination  Tenting of skin  Slow capillary refill.

71. Isotonic decreases in ECFV l Little direct effect on cell volume. l Fluid lost has same osmolarity as ECF. l Volume loss stimulates thirst and ADH secretion. l Results in water retention and occasionally, secondary hyponatremia. l Examples:  Vomiting.  Diarrhea.  Bleeding.  Burns. Direct loss of interstitial fluid. In addition there is protein loss, so plasma compartment contracts.

72. SOLUTIONS USED CLINICALLY FOR VOLUME REPLACEMENT THERAPY

73. Types of Solutions Types of Solutions l Isotonic Solutions --> n.c. ICF l Hypertonic Solutions --> Decrease ICF l Hypotonic --> Increase ICF

74. Dextrose Solutions l Glucose is rapidly metabolized to CO 2 + H 2 O. l The volume therefore is distributed intracellularly as well as extracellularly.

75. Saline solutions. l Come in a variety of concentrations: hypotonic (eg., 0.2%), isotonic (0.9%), and hypertonic (eg. 5%).

76. Dextrose in Saline. l Again available in various concentrations. l Used for simultaneous volume replacement and caloric supplement.

77. Plasma Expanders. l Dextran which is a long chain polysaccharide. l Solutions are confined to the vascular compartment and preferentially expand this portion of the ECF.