Objectives Volume regulation entails the physiology of salt content regulation The edematous states reflect the pathophysiology of salt content regulation The mechanisms of normal volume regulation mediate the pathophysiology of the edematous states Objectives Serum sodium concentration reflects the physiology of water metabolism Hypo and hypernatremia reflect the pathophysiology of water metabolism The mechanisms regulating normal water metabolism mediate the pathophysiology of hypo and hypernatremia 1
Case Summary Hx of rheumatic fever DOE, SOB, rales Pedal edema, abd girth weight etiology of CHF pulmonary edema peripheral edema Question~ why edema? Case Summary Hx of rheumatic fever DOE, SOB, rales Pedal edema, abd girth weight etiology of CHF pulmonary edema peripheral edema Serum [Na] = 128 meq/l Question~ why hyponatremia? 2
7 kg subject: Total body water 42L 2/3 Intracellular 28L 1/3 Extracellular 14L 2/3 interstitial 9L 1/3 intravascular 5L Low ECF Nl ECF Expanded ECF 3
H 2 O deficit H 2 O excess H 2 O deficit H 2 O excess [Na] 147 14 133 14 147 14 133 Low ECF Nl ECF Expanded ECF Lose Na [Na] = 15 Gain H 2 O Euvolemic 4
Tonicity and Serum [Na] Cell membranes are freely permeable to water No osmotic gradients exist between fluid compartments The tonicity of the intravascular compartment reflects the tonicity of all fluid compartments The calculated serum osmolality is given by: ([Na]x2) + ([K]x2) + [gluc[ gluc] ] + [BUN[ BUN] 18 2.8 = (14x2) + (4x2) + 9 + 12 18 2.8 = 28 + 8 + 5 + 4 Free Water [Na] reflects balance of H 2 O relative to salt H 2 O input and output must be assessed but again relative to salt input and output Concept of Free H 2 O : one L 1/2 NS = 1/2 L NS + 1/2 L salt free H 2 O 5
Determinants of Tonicity Free H 2 O intake vs. free H 2 O excretion + free H 2 O losses Oral Intravenous Urine Respiratory Cutaneous Volume Concentration Glomerular Capillaries Urinary Space Proximal Tubule JGA Peritubular Capillaries Afferent Arteriole Efferent Arteriole 6
Free H 2 O excretion Delivery GFR (Scr( Scr) Proximal reabsorption Diluting segment Free H 2 O retention Medullary gradient Collecting duct H 2 O permeability Collecting Duct H 2 O permeability Vasopressin Antidiuretic hormone: neurohypophyseal V 2 -receptor: collecting duct 7
Urinary Concentration and Dilution Osmolarity (mosm mosm/l) 14 12 9 6 3 35% 25% 15% % water remaining Maximal ADH No ADH 3% 1% < 1% Proximal tubule Henle s loop Distal tubule Cortical collecting duct Medullary collecting duct pvn or son oc ds ah nh op br nts 8
Plasma Vasopressin (pg/ml) 12 1 8 6 4 2 Thirst 27 28 29 3 31 Plasma Osmolality (mosm/kg) 14 Urine Osmolality (mosm mosm/kg) 12 1 8 6 4 2 1 2 3 4 5 1 15 Plasma AVP (pg/ml) 9
Hyponatremia (Hypoosmolar states) Intake of free H2O > renal output + insensible losses Failure to make a large volume of dilute urine Failure to deliver Failure to dilute Failure to suppress ADH A. B. Normal GC PTC Congestive Heart Failure GC PTC RPF Arbitrary Pressure Units ΔP Δπ Δπ ΔP ΔP Δπ Δπ O I O I O I O I Eff Art GFR RPF ΔP Eff Art GFR 1
pvn ar son oc ah ds nh br op nts Plasma Vasopressin (pg/ml) 1 6 4 2 1 6 4 2 1 6 4 2 1 15 3 45 % Decrease in Mean Arterial Pressure 11
25 Pressure Plasma Vasopressin (pg/ml) 2 15 1 5 Volume Basal Osmolality -3-2 -1 +1 +2 % Change Plasma Vasopressin pg/ml 1 8 6 4 2 Hypovolemia or Hypotension -2-15 -1 N +1 +15 Hypervolemia or Hypertension +2 26 27 28 29 3 31 32 33 34 Plasma Osmolality mosm/kg 12
Hyponatremia in CHF Free water intake has exceeded free water output Why has the kidney failed to make a large volume of dilute urine? Thirst Distal delivery Dilution at TAL ADH AII AII Diuretics Hypokalemia Volume Stimulus to ADH Mean Aortic Pressure (mmhg) 1 9 8 15 1 5 Heart Rate 7 1 2 3 4 5 6 7 8 9 1 11 Day of Experiment 12 13 14 15 16 17 18 19 TIVC Constriction Increase Constriction Release Constriction 13
2 Plasma Renin Activity (mg/ml/h) 15 1 5 15 6 Plasma Renin Activity (ng ng/ml/hr) 25 1 5 2 1.5.2 124 128 132 136 14 144 148 Pretreatment Serum Na Concentration (meq/l( meq/l) 14
Cardiac Output LVEDP Cardiac Output LVEDP 15
1 % Survival 8 6 4 p<.1 Na >13 (n=163) 2 Na 13 (n=4) 6 12 18 24 3 36 Months Hyponatremia with Increased ADH Volume stimulus Syndrome of Inappropriate ADH Certain drugs, endocrinopathies 16
Serum [Na] meq/l Urinary Osmololity mosm/kgh 2 O Urinary Sodium meq/day 14 13 12 1 5 2 1 Pitressin Restrict H 2 O Urine Volume L/day 3 2 1 Body Weight kg 57 54 2 4 6 8 1 12 Days Etiology of SIADH Ectopic ADH Production from Tumors Bronchogenic carcinoma Adenocarcinoma of pancreas Adencarinoma of duodenum Carcinoma of ureter Pulmonary Disease Associated with SIADH Tuberculosis Pneumonia Aspergillosis with cavitation SIADH in Central Nervous System Disease Brain tumor Encephalitis Meningitis Brain abscess Head injury Lymphoma Hodgkin s s disease Thymona Lung abscess Chronic chest infection Subarachnoid hemorrhage Landry-Guillain Guillain-Barre syndrome Systemic lupus erythematsus Acute intermittent porphyria 17
Approach to Hyponatremia Renal Failure ADH despite S Na Often U Na nl U Na Cr ECF and intravascular Drugs compartments depleted (diarrhea) Endocrinopathies SIADH ECF expanded but tumors intravascular compartment pulmonary arterially underfilled (CHF) CNS BUN/Cr Vasopressin Antidiuretic hormone V 2 -receptor: collecting duct Vasopressor hormone V 1 -receptor: vascular smooth muscle 18
1 Efferent Arteriole of Rat 9 % reduction in lumen diameter 8 7 6 5 4 3 2 1-14 -13-12 -11-1 -9-8 -7-6 -5 Agonist (log M) Average Changes in Blood Pressure and Pulse Rate in Nine Normal Persons During Intravenous Administration of Pitressin 13 12 11 1 9 8 7 6 5 4 3 Systolic Blood Pressure Diastolic Blood Pressure Pulse Rate 2 4 6 8 1 12 14 16 18 2 22 24 26 28 3 Time (minutes) 19
Vasopressin in Vasodilatory Shock Exogenous vasopressin is a potent pressor Endogenous vasopressin is deficient Vasopressin restores pressor responsiveness by inhibiting vasodilatory mechanisms Vasopressin In Vasodilatory Shock NEPI μg/min EPI μg/min AVP U/min 8 5.4. 8 5.4. NEPI μg/min EPI μg/min AVP U/min 14 14 SAP mmhg 12 12 SAP mmhg 1 1 8 8 U ml/h 15 1 5 15 1 5 U ml/h 2 4 6 8 1 12 14 16 18 2 24 26 28 Time (hours) 2
Effect of Vasopressin in Septic Shock in Man (n=1) Control AVP 16 SBP (mmhg) 14 12 1 8 8 CO (L/min) 7 6 5 15 SVR (dyne sec/cm 5 ) 1 Norepinephrine (median) 5 32 μg/min μg/min Discontinuation of Vasopressin in First Prospective Patient in Vasodilatory Septic Shock AVP U/min.2. 12 SAP mmhg 1 8 1 2 3 4 5 6 Time (hour) 21
Discontinuation of Vasopressin in 6 of 1 Patients in Vasodilatory Septic Shock 14 SAP (mmhg) 12 1 8 AVP No AVP AVP Vasopressin in Vasodilatory Shock Exogenous vasopressin is a potent pressor Endogenous vasopressin is deficient Vasopressin restores pressor responsiveness by inhibiting vasodilatory mechanisms 22
35 Septic Shock (n=19) Cardiogenic Shock (n=12) 3 25 22.7 ± 2.2 AVP pg/ml 2 15 1 5 3.1 ±.4 Vasodilatory Shock States with Vasopressin Deficiency and Hypersensitivity Septic shock CPB-induced vasodilatory shock Milrinone-induced induced vasodilatory shock Brain death Irreversible shock 23
Control AVP Pressor Antagonist Control AVP Pressor Antagonist 14 Water-diuresing Fluid-deprived deprived 13 MAP (mm Hg) 12 NS p <.5 11 1 A Speculation: Vasopressin sensitivity is a regulated phenomenon Vasopressin hypersensitvity is observed when vasopressin sensitivity is activated in a state of vasopressin deficiency 24
Efferent and Afferent Arterioles of Rat % Reduction in Lumen Diameter 1 9 8 7 6 5 4 3 2 1 AVP NE % Reduction in Lumen Diameter 1 9 8 7 6 5 4 3 2 1 AVP NE -14-13 -12-11 -1-9 -8-7 -6-5 -14-13 -12-11 -1-9 -8-7 -6-5 Agonist (Log M) Agonist (Log M) 25