Physiology of water balance and Hypernatremia

Distribution of body water
Functions of body water
Daily water balance
Plasma Osmolality
Water metabolism
Vasopressin
Stimuli for vasopressin release
Thirst
Hypernatremia
Approach to Hypernatremia

1. Physiology of water balance and Hypernatremic disorders Dr Abdullah Ansari SR Nephrology SGPGI Lucknow

2. Distribution of body water

3. Distribution of body water Water constitutes approximately 55% to 65% of body weight It varies with Age Gender Body fat Total body wateris distributed between the intracellular and extracellular fluid compartments

4. Body water content Body water content in percentage of a body weight is lowest in Well built man Fat woman Well nourished child Fat Man

5. An adult of 70 kg body

6. Distribution of TBW

7. Functions of body water

8. Functions of body water Involved in Biochemical reactions Water act as reactant in many hydrolytic reactions of metabolic pathways Transporting media of body: Transportation of nutrients and waste metabolites through aqueous media of blood and tissue floods Regulates body temperature

9. Functions of body water Water transports Hormones , Enzymes, and blood cells Water act as a solvent for Electrolytes and Non electrolytes Water Facilitates Digestion and promoting Elimination of ingested food Water serve as a tissue Lubricant

10. Daily water balance

11. Source Water intake (ml/day) Source Water output (ml/day) Ingested water 1400 Urine 1500 Water content of food 800 Skin Respiratory tract 500 400 Water of oxidation 300 Stool 100 Total: 2500 Total: 2500

12. Plasma Osmolality

13. Electrolytes In Body Fluid Compartments INTRACELLULAR EXTRACELLULAR Potassium Sodium Magnesium Chloride Phosphorous Bicarbonate

14. Osmotic equivalence Both ICF & ECF have an equivalent osmotic pressure despite different solute compositions Most biologic membranes are semipermeable (i.e. freely permeable to water but not to all aqueous solutes) Water flows across membrane to compartment with higher solute concentration  a steady state is reached  osmotic pressures have equalized

15. Osmolarity: The number of moles per liter of solution Osmolality: The number of moles per kg of Solvent Osmolality is preferred for biological systems, because it is temperature independent

16. Plasma Osmolality Sodium and its associated ions make the largest contribution (90%) for plasma Osmolality Osmolality is measured directly by Osmometer Osmometer is based on the depression of freezing point or vapor pressure which is related to the number of free solute particles of that solution

17. Plasma Osmolality Plasma osmolality can be calculated Both methods produce comparable results (the value obtained using this formula is within 1-2% of that obtained by direct osmometry)

18. Plasma osmolality vs t onicity Plasma osmolality is determined by all the particles dissolved in plasma while Plasma tonicity, i.e. “ effective osmolality ” is limited to only those particles that exert an osmotic effect The effective osmolality is the function of the relative solute permeability properties of the membrane separating the two compartments Urea contributes to plasma osmolality but does not confer tonicity because its high permeability allows for rapid equilibration across plasma membranes

19. Effective vs ineffective solutes Effective solutes Impermeable to cell membranes and restricted to ECF compartment (e.g. Na + , mannitol) They create osmotic pressure gradients across cell membranes, leading to the osmotic movement of water Ineffective solutes Freely permeable to cell membranes (e.g., urea, ethanol, methanol) They do not create osmotic pressure gradients across cell membranes and are not associated with such water shifts

20. Glucose as a unique solute At physiological conditions, glucose is taken up by cells via active transport mechanisms and acts as an ineffective solute But, under conditions of impaired cellular uptake (e.g. insulin deficiency), it becomes an effective extracellular solute

21. Water metabolism

22. Water homeostasis

23. Regulated vs unregulated water intake & excretion Unregulated water intake The intrinsic water content of ingested foods Consumption of beverages for taste ( eg tea), social or habitual reasons ( eg alcohol) Regulated water intake Fluids consumed in response to a perceived sensation of thirst Unregulated water excretion Insensible water losses, from sweating, respiration and gastro-intestinal losses The obligate amount of water that kidneys must excrete to eliminate solutes generated by body metabolism Regulated water excretion Renal excretion of free water in excess of the obligate amount necessary to excrete metabolic solutes

24. The determinants of unregulated water loss The water loss from the skin and lungs depends dress, temperature, humidity and exercise The rate of urine solute excretion, which cannot be reduced below a minimal obligatory level required to excrete the solute load

25. The volume of urine The volume of urine required depends on The solute load The degree of antidiuresis At basal level of urinary concentration (urine osmolality = 600 mOsm /kg), a typical solute load of 900 to 1200 mOsm /day, would require a total urine volume of 1.5 to 2.0 L for excretion At maximal antidiuresis (urine osmolality = 1200 mOsm /kg), the same solute load would require a minimal obligatory urine output of only 0.75 to 1.0 L/day

26. Vasopressin

27. Structure and synthesis It is a 9–amino acid cyclic peptide Synthesized by the supraoptic and paraventricular magnocellular nuclei in the hypothalamus The posterior pituitary “ neurohypophysis ” contains the distal axons of magnocellular neurons AVP has a half-life of 15-20 minutes and is rapidly metabolized in the liver and the kidney

28. Mechanism of Vasopressin Action AVP binds three types of receptors coupled to G proteins: The V2 receptor is primarily localized in CD and leads to an increase in water permeability through aquaporin 2 transporters V1a/V1 Vascular and hepatic V1b/V3 Anterior pituitary and pancreatic islet V2 Renal

29. Aquaporin transporters AQP1: Constitutively expressed and not regulated by AVP AQP2: AVP affects both short and long-term regulation

30. AVP regulation of AQP2 Short-term regulation: The “shuttle hypothesis” involves insertion of water channels from subapical vesicles into the luminal membrane The rapid and reversible increase in CD water permeability Long-term regulation: It involves AVP-mediated increased transcription of AQP2 related genes Occurs if AVP levels are elevated for >24 hours

31. Cellular mechanism of vasopressin action

32. Vasopressin and urea transporters AVP also stimulates urea transporters in the inner medullary CD Urea reabsorption increases inner medullary tonicity and driving force for water reabsorption Inner medullary CD

33. Stimuli for vasopressin release

34. The regulatory control of vasopressin release

35. Stimuli for Vasopressin release

36. Osmotic stimuli It efficiently maintain osmolality within 1-2% despite wide fluctuation in water intake The osmoreceptive cells termed as the “organum vasculosum of the lamina terminalis” are located in the anterior hypothalamus, near the circumventricular organ The plasma osmotic pressure is the most important stimulus under physiologic conditions

37. Vasopressin secretion in response to increases in plasma osmolality Below threshold  AVP secretion is suppressed to low or undetectable levels Above threshold  AVP secretion increases in direct proportion to plasma osmolality In general, each 1-mOsm/kg H 2 O increase in plasma osmolality causes an increase in the plasma AVP level, ranging from 0.4 to 1.0 pg /mL

38. Relationship of plasma osmolality, plasma vasopressin concentrations, urine osmolality, and urine volume The renal response (i.e. urinary osmolality) is linear to AVP levels from 0.5 to 5 pg /mL, after which urinary osmolality is maximal U rine volume is inversely related to urine osmolality Maximal antidiuresis is achieved after plasma osmolality increases by 5 to 10 mOsm /kg H 2 O (2−4%) above the threshold for AVP

39. The osmotic threshold The osmotic threshold for AVP secretion ranges from 280 to 290 mOsm / kg H 2 O Multiple factors can alter the sensitivity and/or set point of osmoregulation Genetic influences, individual differences in osmoregulation Acute changes in blood pressure, volume or both Aging, increases osmosensitivity Metabolic factors, such as Ca 2+ levels and various drugs Women have increased osmosensitivity , particularly during luteal phase of menstrual cycle

40. The pregnancy-associated resetting of osmoregulation The set point of the osmoregulatory system is reduced more during pregnancy The possible involvement of the placental hormone relaxin has been suggested Increased NO production by relaxin has been reported to increase vasodilation

41. Stimulation of osmoreceptor neurons Sodium and its anions, are the most potent solutes to stimulate AVP secretion and thirst Certain sugars like mannitol and sucrose are equally effective when infused intravenously In contrast, noneffective solutes like urea result in little or no increase in AVP levels The efflux of water and the resultant shrinkage of osmoreceptor neuron activates a stretch-inactivated, noncationic channel that initiates depolarization and firing of the neuron

42. NONOSMOTIC REGULATION: Hemodynamic Stimuli Small reductions (5-10%)  only minimal effects on plasma AVP levels Large reductions (20-30%)  exponential release of hormone many times higher than required to produce maximal antidiuresis Hypovolemia is a potent stimulus for AVP secretion

43. Osmotic stimuli vs hemodynamic Stimuli Moderate hypovolemia modulates the gain of the osmoregulatory responses The direct effects on thirst and AVP secretion occurring only during more severe hypovolemia The minimal effect of small changes in blood volume and pressure on AVP secretion contrasts sharply with the extraordinary sensitivity of the osmoregulatory system

44. Hemodynamic stimuli pathway “ Baroreceptors ” in the cardiac atria, aorta and carotid sinus Afferent nerve fibers  vagus and glossopharyngeal nerves  the nuclei of tractus solitarius  postsynaptic pathways to PVN and SON

45. NONOSMOTIC REGULATION: Drinking Drinking lowers plasma AVP before any appreciable decrease in plasma osmolality It occurs independently of the composition of fluid ingested Sensory afferents in the oropharynx  glossopharyngeal nerve

46. NONOSMOTIC REGULATION: Nausea The pathway mapped to the chemoreceptor zone in area postrema of brainstem It can be activated by a variety of drugs and conditions Apomorphine, morphine, nicotine and alcohol Vasovagal reactions, diabetic ketoacidosis, acute hypoxia and motion sickness The sensation of nausea, with or without vomiting, is the most potent stimulus to AVP secretion

47. Effect of nausea on vasopressin secretion The effect is instantaneous and extremely potent , even when the nausea is transient Pretreatment with fluphenazine, haloperidol or promethazine abolishes the response

48. NONOSMOTIC REGULATION: Hypoglycemia Acute hypoglycemia is a less potent but reasonably consistent stimulus 20% decreases in glucose are required to increase AVP levels significantly The triggering factor is likely intracellular deficiency of glucose or ATP The rise in plasma AVP is not sustained with persistent hypoglycemia

49. NONOSMOTIC REGULATION: Renin-Angiotensin-Aldosterone System Ang II stimulates AVP secretion at the circumventricular subfornical organ, in the third ventricle SFO neural pathways  SON and PVN  AVP secretion High level of plasma Ang II is required to stimulate AVP, may be active only under pharmacologic conditions

50. NONOSMOTIC REGULATION: Drugs

51. Drugs and Hormones That Affect Vasopressin Secretion Stimulatory Acetylcholine Nicotine Apomorphine Morphine (high doses) Epinephrine Isoproterenol Histamine Bradykinin Prostaglandin β- Endorphin 2-Deoxyglucose Angiotensin II Inhibitory Norepinephrine Fluphenazine Haloperidol Promethazine Opioid agonists Morphine (low doses) Ethanol Carbamazepine Muscimol Glucocorticoids Clonidine Phencyclidine

52. Thirst

53. Thirst The body’s defense mechanism to increase water consumption in response to perceived deficits of body fluids True thirst must be distinguished from other determinants of fluid intake such as taste, dietary preferences and social customs Thirst can be defined as a consciously perceived desire for water

54. Thirst mechanism Osmotic thirst: Stimulated by intracellular dehydration caused by increased osmolality of ECF Osmoreceptors located in the anterior hypothalamus Hypovolemic thirst: Stimulated by intravascular hypovolemia caused by losses of ECF Activation of baroreceptors and circulating Ang II Hypertonicity is clearly the most potent The actual perception of thirst occurs in the anterior cingulate cortex and insular cortex, which receive information from circumventricular organs via relay nuclei in the thalamus

55. Thirst mechanism

56. Osmotic thirst threshold An increase in plasma osmolality of 2-3% above basal levels produces a strong desire to drink The “osmotic thirst threshold ” averages approximately 295 mOsm /kg H 2 O This level is above the osmotic threshold for AVP release and approximates the plasma osmolality at which maximal concentration of urine is normally achieved

57. The thirst osmoreceptors The thirst osmoreceptors located in the anteroventral hypothalamus and OVLT Ineffective plasma solutes such as urea and glucose are ineffective at stimulating thirst, whereas effective solutes such as NaCl and mannitol can stimulate thirst A modest decline in plasma osmolality induces a sense of satiation

58. Hypovolemic thirst The threshold for producing hypovolemic thirst is significantly higher Sustained decreases in blood pressure or volume of at least 4-8% required The blunted sensitivity in humans represents an adaptation for the erect posture of primates, which predisposes them to wider fluctuations in blood pressures

59. Anticipatory thirst The best studied example is the increase in drinking that a few hours at the end of their awake period, which serves to maintain hydration during sleep period This may be mediated by vasopressin containing neurons in supra-chiasmatic nucleus , the brain nucleus controlling diurnal rhythms SCN neurons  pr oject to OVLT  excite thirst-activating neurons

60. Integration of vasopressin secretion and thirst Under normal physiologic conditions The sensitive osmoregulatory system for AVP secretion maintains osmolality by adjusting renal water excretion Stimulated thirst does not represent a major regulatory mechanism U nregulated fluid ingestion supplies adequate water in excess of true “need”

61. Integration of vasopressin secretion and thirst When unregulated water intake can’t adequately supply body needs in presence of plasma AVP levels sufficient to produce maximal antidiuresis Plasma osmolality rises to levels that stimulate thirst T hirst essentially represents a backup mechanism The advantage of freeing humans from frequent episodes of thirst

62. Integration of vasopressin secretion and thirst

63. Disorders of insufficient vasopressin or vasopressin effect Disorders of insufficient AVP or AVP effect are associated with inadequate urine concentration and increased urine output termed as “ polyuria ” Diabetes insipidus, is characterized by excretion of abnormally large volumes of urine ( diabetes ) that is dilute ( hypotonic ) and devoid of taste from dissolved solutes ( insipid ), in contrast to the hypertonic, sweet-tasting urine characteristic of diabetes mellitus (from the Greek, meaning honey)

64. Disorders of insufficient vasopressin or vasopressin effect If thirst mechanisms are intact: Thirst is stimulated with compensatory increases in fluid intake (“polydipsia”) This maintains normal plasma osmolality and serum electrolyte concentrations If thirst is impaired, or fluid intake is insufficient to compensate for the increased urine excretion: Hyperosmolality and hypernatremia can result

65. Disorders of insufficient vasopressin or vasopressin effect

66. Hypernatremia

67. Hypernatremia A state of total body water deficiency absolute or relative to total body Na + It can result from Water loss (diabetes insipidus) Hypotonic fluid loss (osmotic diarrhea) Hypertonic fluid gain (Na + containing fluids) Hypernatremia is defined as an increase in plasma Na + concentration >145 mEq /L

68. The renal concentrating mechanism The first defense mechanism against water depletion and hyperosmolarity Hypernatremia results from disorders of urine concentration

69. The importance of thirst Thirst is the most important defense mechanism in preventing hypernatremia Hypernatremia is seen primarily in patients who Can’t experience or respond to thirst normally due to impaired mental status ( older adult or critically ill patients ) Require others to provide fluid intake ( infants ) Individuals who are alert and have access to water should not develop hypernatremia

70. Development of hypernatremia

71. Hypernatremia and hyperosmolality

72. Hypernatremia and hyperosmolality

73. Cellular adaptation to hypernatremia

74. Brain shrinkage by hypernatremia Brain shrinkage can cause vascular tearing with cerebral bleeding, subarachnoid hemorrhage, and permanent neurologic damage or death Brain shrinkage is countered by the adaptive response

75. Signs and symptoms of hypernatremia Acute hypernatremia: nausea, vomiting, lethargy, irritability, restlessness, weakness, may progress to seizures and coma Chronic hypernatremia: (>48 hours) less neurological signs and symptoms because of brain adaptation

76. Mortality in hypernatremia Hypernatremia induces diverse effects in multiple organ systems Short-term mortality is approximately 50-60% Even mild hypernatremia has a 30-day mortality of > 20%

77. Question 1: Is the patient hypernatremia related to water deficit or gain of Na + ???

78. Diagnostic Approach in Hypernatremia U Na + <20 U Na + variable U Na + >20 U Na + >20 Tachycardia, orthostatic changes Edema Polyuria Polyuria

79. Question 1: Is the patient hypernatremia related to water deficit or gain of Na + ??? Patient’s hypernatremia is likely related to water deficit

80. Polyuric disorders Polyuric disorders can result from either Increase in C osm : loop diuretics, renal salt wasting, vomiting ( bicarbonaturia ), alkali administration, mannitol administration Increase in C water : excess ingestion of water (psychogenic polydipsia) or in abnormalities of renal concentrating mechanism (Diabetes Insipidus)

81. Water deprivation test Test procedure: Water intake is restricted till the patient loses 3-5% of body weight or till 3 consecutive hourly urinary osmolality values are within 10% of each other Caution to prevent excessively dehydration Aqueous vasopressin, 5 units given subcutaneously, and urinary osmolality measured after 60 minutes

82. Interpretation of w ater deprivation test

83. Caution for baseline hypernatremia By definition, the patient with baseline hypernatremia is hypertonic, with an adequate stimulus for AVP by the posterior pituitary Therefore, a water deprivation test is unnecessary in hypernatremia Water deprivation has the risk for worsening the hypernatremia

84. AVP and copeptin levels Measurement of circulating AVP by radioimmunoassay, or measurement of copeptin levels, is preferred to the tedious water deprivation test Under basal conditions, AVP levels are unhelpful because there is a significant overlap among the polyuric disorders Measurement after a water deprivation test is more useful

85. Copeptin is a 39 amino acid long peptide derived from C terminal of precursor protein of AVP

86. Copeptin measurement The levels of copeptin in the circulation correlate with those AVP Copeptin has advantages over AVP in terms of ex vivo stability of the marker the ease and speed of measurement

87. Hypernatremia management The goals of management are: Identification of the underlying cause(s) Correction of volume disturbances Correction of hypertonicity

88. Treatment of Hypernatremia

89. Question 2: Calculate the water deficit for serum Na + of 140 mEq /l…

90. Calculation of free water deficit

91. Question 2: Calculate the water deficit for serum Na + of 140 mEq /l… 42 x (168/140 - 1) = 8.4 l Add obligatory water output to the calculated infusate volume

92. Question 3: What is the choice of fluid ???

93. Question 3: What is the choice of fluid ???

94. Choice of fluid for correction The preferred route for administering fluids is the oral route or a feeding tube If neither is feasible, fluids should be given intravenously Hypotonic fluids include pure water, 5% dextrose and 0.45% sodium chloride The more hypotonic the infusate , the lower the infusion rate required Except in frank circulatory compromise , normal saline is unsuitable for managing hypernatremia

95. Question 4: How to estimate reduction in serum Na + with correction ???

96. Hypernatremia correction Rapid correction (abrupt fall in ECF tonicity) can outpace this regulatory volume decrease, causing cell swelling and irreversible damage

97. Hypernatremia correction Serum sodium should be slowly corrected at a maximal rate of 0.5 mEq /l per hr , typically replacing the free water deficit over 48-72 hours The plasma Na + should not be corrected by >10 mEq /l per day In acute cases ( <48 hours), it may be safe to correct at a rate of 1 mEq /l per hr , because accumulated electrolytes are rapidly extruded from brain cells

98. Question 4: How to estimate reduction in serum Na + with correction ??? The more hypotonic the infusate , the lower the infusion rate required Estimated reduction in serum Na + per liter of 0.45% NS = (77-168) / (42+1) = -2.12 mEq /l Total fluid required to correct 10 mEq /l over 24 hours = 10/2.12 = 4.72 l Rate of infusion = 4.72/24 = 0.197 l/ hr = 197 ml/ hr

99. Caution It must be emphasized that calculation of free water deficit is only an estimate based on several assumptions It is important to frequently assess plasma sodium to assure that the rate of correction is proceeding as planned

100. When is dialysis indicated in the treatment of hypernatremia? Hypernatremia in the setting of volume overload (e.g. heart failure, renal failure and pulmonary edema) Dialysis has advantages of quick removal of excess sodium and fluid Dialysis may be beneficial in management of acute severe hypernatremia E.g. a patient with serum sodium levels near 200 will remain hypernatremic for 5 days, if treated with conventionally with fluids, but with dialysis this period may be curtailed

101. Dialysis in the treatment of hypernatremia Intermittent hemodialysis machines can’t deliver dialysate sodium > 155 mEq /L CRRT may be advantageous in renal failure and chronic, extreme hypernatremia Changes in sodium are slower with CRRT due to lower delivered sodium dialysance with low flow rates of dialysate/replacement fluids and/or lower blood flow rates

102. CRRT in the treatment of hypernatremia

103. CRRT in the treatment of hypernatremia

104. CRRT in the treatment of hypernatremia

105. CRRT in the treatment of hypernatremia

106. For hypernatremia correction Go slow……