3/19/2009

1

ObjectivesObjectives

•• Volume regulation entails the physiology ofVolume regulation entails the physiology of•• Volume regulation entails the physiology of Volume regulation entails the physiology of salt content regulationsalt content regulation

•• The edematous states reflect the The edematous states reflect the pathophysiology of salt content regulationpathophysiology of salt content regulation

•• The mechanisms of normal volume regulation The mechanisms of normal volume regulation e ec a s s o o a o u e egu a oe ec a s s o o a o u e egu a omediate the pathophysiology of the mediate the pathophysiology of the edematous statesedematous states

ObjectivesObjectives

•• Serum sodium concentration reflects theSerum sodium concentration reflects theSerum sodium concentration reflects the Serum sodium concentration reflects the physiology of water metabolismphysiology of water metabolism

•• Hypo and hypernatremia reflect the Hypo and hypernatremia reflect the pathophysiology of water metabolismpathophysiology of water metabolism

•• The mechanisms regulating normal water The mechanisms regulating normal water g gg gmetabolism mediate the pathophysiology of metabolism mediate the pathophysiology of hypo and hypernatremiahypo and hypernatremia

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2

Case SummaryCase Summary

Hx of rheumatic feverHx of rheumatic fever etiology ofetiology ofHx of rheumatic feverHx of rheumatic fever etiology of etiology of CHFCHF

DOE, SOB, ralesDOE, SOB, rales pulmonary pulmonary edemaedema

Pedal edema, abd girthPedal edema, abd girth peripheral peripheral eda ede a, abd geda ede a, abd g pe p e ape p e aedemaedemaweightweight

Question~ why edema?Question~ why edema?

Case SummaryCase Summary

Hx of rheumatic feverHx of rheumatic fever etiology ofetiology ofHx of rheumatic feverHx of rheumatic fever etiology of etiology of CHFCHF

DOE, SOB, ralesDOE, SOB, rales pulmonary pulmonary edemaedema

Pedal edema, abd girthPedal edema, abd girth peripheral peripheral eda ede a, abd geda ede a, abd g pe p e ape p e aedemaedemaweightweight

Serum [Na] = 128 meq/LSerum [Na] = 128 meq/L

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3

70 kg subject:70 kg subject:Total body water 42LTotal body water 42LTotal body water 42LTotal body water 42L

2/3 Intracellular 2/3 Intracellular 28L28L1/3 Extracellular 1/3 Extracellular 14L14L

2/3 interstitial 2/3 interstitial 9L9L1/3 intravascular1/3 intravascular 5L5L1/3 intravascular1/3 intravascular 5L5L

Low ECFLow ECF Nl ECFNl ECF Expanded ECFExpanded ECF

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4

HH22OOdeficitdeficit

HH22OOexcessexcess

HH22OOHH22OO

excessexcess22deficitdeficit

excessexcess

133133140140147147

[Na][Na]

140140133133140140147147

Low ECFLow ECF Nl ECFNl ECF Expanded ECFExpanded ECF

[Na] = 150[Na] = 150Lose NaLose Na Gain HGain H22OO

EuvolemicEuvolemic

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Tonicity and Serum [Na]Tonicity and Serum [Na]

•• Cell membranes are freely permeable to waterCell membranes are freely permeable to water•• No osmotic gradients exist between fluid No osmotic gradients exist between fluid

compartmentscompartments•• The tonicity of the intravascular compartment The tonicity of the intravascular compartment

reflects the tonicity of all fluid compartmentsreflects the tonicity of all fluid compartments•• The calculated serum osmolality is given by:The calculated serum osmolality is given by:([Na]x2) + ([K]x2) + [([Na]x2) + ([K]x2) + [glucgluc] + [] + [BUNBUN]]([Na]x2) + ([K]x2) + [([Na]x2) + ([K]x2) + [glucgluc] + [] + [BUNBUN]]

1818 2.82.8= (140x2) + (4x2) + = (140x2) + (4x2) + 9090 + + 1212

1818 2.82.8= 280 + 8 + 5 + 4= 280 + 8 + 5 + 4

Free WaterFree Water

•• [Na] reflects balance of H[Na] reflects balance of H O relative to saltO relative to salt•• [Na] reflects balance of H[Na] reflects balance of H22O relative to saltO relative to salt•• HH22O input and output must be assessed but O input and output must be assessed but

again relative to salt input and outputagain relative to salt input and output•• Concept of “Free HConcept of “Free H22O”:O”:

one L 1/2 NS =one L 1/2 NS =one L 1/2 NS one L 1/2 NS 1/2 L NS + 1/2 L salt free H1/2 L NS + 1/2 L salt free H22OO

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Determinants of TonicityDeterminants of Tonicity

Free HFree H O intake vs free HO intake vs free H O excretion + free HO excretion + free H OOFree HFree H22O intake vs. free HO intake vs. free H22O excretion + free HO excretion + free H22O O losseslosses

OralOral UrineUrine RespiratoryRespiratoryIntravenousIntravenous CutaneousCutaneousIntravenousIntravenous CutaneousCutaneous

VolumeVolume ConcentrationConcentration

Urinary SpaceUrinary Space

Glomerular Glomerular CapillariesCapillaries

Proximal TubuleProximal Tubule

Peritubular CapillariesPeritubular CapillariesJGAJGA

Afferent Afferent ArterioleArteriole

Efferent Efferent ArterioleArteriole

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Free HFree H22O excretionO excretion Free HFree H22O retentionO retentionDeliveryDelivery Medullary gradientMedullary gradient

GFR (Scr)GFR (Scr)GFR (Scr)GFR (Scr)Proximal reabsorptionProximal reabsorption Collecting duct Collecting duct

HH22O permeabilityO permeabilityDiluting segment Diluting segment

Collecting DuctCollecting DuctHH22O permeabilityO permeability

VasopressinVasopressin

•• Antidiuretic hormone: neurohypophysealAntidiuretic hormone: neurohypophyseal•• VV22--receptor: collecting ductreceptor: collecting duct

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12001200

14001400

25%25%

< 1%< 1%sm/L

)sm

/L)

Urinary Concentration and DilutionUrinary Concentration and Dilution

% water remaining

300300

600600

900900

3%3%

1% 1%

MaximalMaximalADHADH

Osm

olar

ity (m

Os

Osm

olar

ity (m

Os

35%35%15%15% 10%10%No ADHNo ADH

Proximal Proximal tubuletubule

Henle’s Henle’s looploop

DistalDistaltubuletubule

Cortical Cortical collectingcollecting

ductduct

MedullaryMedullarycollectingcollecting

ductduct

pvnpvn

dsds

nhnhahah

ococ

sonsonoror

ntsntsbrbr

opop

3/19/2009

9

1212

1010

n (p

g/m

l)n

(pg/

ml)

88

66

44

22asm

a Va

sopr

essi

nas

ma

Vaso

pres

sin

ThirstThirst

22

00

270270 280280 290290 300300 310310

Plasma Osmolality (mOsm/kg)Plasma Osmolality (mOsm/kg)

Pla

Pla

14001400

12001200

Osm

/kg)

Osm

/kg)

10001000

800800

600600

400400

Urin

e O

smol

ality

(mO

Urin

e O

smol

ality

(mO

200200

00

00 11 22 33 44 55 1010 1515

Plasma AVP (pg/ml)Plasma AVP (pg/ml)

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HyponatremiaHyponatremia(Hypoosmolar states)(Hypoosmolar states)

•• Intake of free H2O > renal output + insensibleIntake of free H2O > renal output + insensible•• Intake of free H2O > renal output + insensible Intake of free H2O > renal output + insensible losseslosses

•• Failure to make a large volume of dilute urineFailure to make a large volume of dilute urine–– Failure to deliverFailure to deliverFailure to deliverFailure to deliver–– Failure to diluteFailure to dilute–– Failure to suppress ADHFailure to suppress ADH

NormalNormal Congestive Heart FailureCongestive Heart FailureGCGC PTCPTC PTCPTCGCGC

rere

A.A. B.B.

ΔΔPP

ΔπΔπ

Arb

itrar

y P

ress

urA

rbitr

ary

Pre

ssur

Uni

tsU

nits

OO OO OO OOII II II II

ΔΔPP

ΔπΔπ

ΔπΔπ

EffEff

ΔΔPP

ΔπΔπ

ΔΔPP

RPFRPF RPFRPF

GFRGFRGFRGFR

Eff Eff ArtArt

Eff Eff ArtArt

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11

pvnpvn

dsds

nhnhahah

ococ

sonsonarar

ntsntsbrbr

opop

10001000

600600400400

200200sin

(pg/

ml)

sin

(pg/

ml)

10010060604040

2020

10106644la

sma

Vaso

pres

sla

sma

Vaso

pres

s

44

22

11

00 1515 3030 4545

% Decrease in Mean Arterial % Decrease in Mean Arterial PressurePressure

PP

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12

PressurePressure

BasalBasal

2525

2020sin

sin

VolumeVolumeBasalBasal

OsmolalityOsmolality

2020

1515

1010

55Plas

ma

Vaso

pres

Plas

ma

Vaso

pres

(pg/

ml)

(pg/

ml)

00

--3030 --2020 --1010 00 +10+10 +20+20

% Change% Change

PP

1010

88

essi

nes

sin

Hypovolemia orHypovolemia orHypotensionHypotension

Hypervolemia orHypervolemia orHypertensionHypertension

--2020--1515

--1010NN

+10+10+15+15

+20+20

66

44

22

00Pla

sma

Vaso

pre

Pla

sma

Vaso

pre

pg/m

lpg

/ml

00

260260 270270 280280 290290 300300 310310 320320 330330 340340

Plasma OsmolalityPlasma OsmolalitymOsm/kgmOsm/kg

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Hyponatremia in CHFHyponatremia in CHFFree water intake has exceeded free water outputFree water intake has exceeded free water outputWhy has the kidney failed to make a large volume of diluteWhy has the kidney failed to make a large volume of diluteWhy has the kidney failed to make a large volume of dilute Why has the kidney failed to make a large volume of dilute

urine?urine?

ThirstThirst AIIAII

Distal delivery Distal delivery AIIAII

Dilution at TALDilution at TAL DiureticsDiureticsHypokalemiaHypokalemia

ADHADH Volume Stimulus to ADHVolume Stimulus to ADH

150150 Heart100100

1919181817171616151514141313121211111010998877665544332211Day of Experiment

TIVCTIVCConstrictionConstriction

IncreaseIncreaseConstrictionConstriction

ReleaseReleaseConstrictionConstriction

5050

150150

100100Rate

100100

9090

8080

7070

Mean AorticMean AorticPressurePressure(mmHg)(mmHg)

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14

2020

1515

1010

55

00

PlasmaPlasmaRenin ActivityRenin Activity

(mg/ml/h)(mg/ml/h)

vity

vity

150150

6060

2525

Pla

sma

Ren

in A

ctiv

Pla

sma

Ren

in A

ctiv

(ng/

ml/h

r)(n

g/m

l/hr)

2525

1010

55

22

11

Pretreatment Serum Na Concentration (mEq/l)Pretreatment Serum Na Concentration (mEq/l)

0.50.5

0.20.2

124124 128128 132132 136136 140140 144144 148148

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Cardiac OutputCardiac Output

LVEDPLVEDP

Cardiac Cardiac OutputOutput

LVEDPLVEDP

3/19/2009

16

8080

100100

2020

4040

6060%

Sur

viva

l%

Sur

viva

l p<0.001p<0.001

Na >130 (n=163)Na >130 (n=163)

Na ≤ 130 (n=40)Na ≤ 130 (n=40)

00 66 1212 1818 2424 3030 3636

2020

00

MonthsMonths

Hyponatremia with Increased Hyponatremia with Increased ADHADH

•• Volume stimulusVolume stimulus•• Volume stimulusVolume stimulus

•• Syndrome of Inappropriate ADHSyndrome of Inappropriate ADH

•• Certain drugs endocrinopathiesCertain drugs endocrinopathies•• Certain drugs, endocrinopathiesCertain drugs, endocrinopathies

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PitressinPitressinRestrict HRestrict H22OO

140140

130130

120120

Serum [Na]Serum [Na]mEq/LmEq/L

33

200200

100100Urinary Sodium Urinary Sodium

mEq/daymEq/day

10001000

500500

UrinaryUrinaryOsmololityOsmololity

mOsm/kgHmOsm/kgH22OO

DaysDays

5757

5454

22 44 66 88 1010 1212

Body Weight Body Weight kg kg

33

22

11

Urine VolumeUrine VolumeL/dayL/day

–– Bronchogenic carcinomaBronchogenic carcinoma –– LymphomaLymphomaEctopic ADH Production from TumorsEctopic ADH Production from Tumors

Etiology of SIADHEtiology of SIADH

–– Adenocarcinoma of pancreasAdenocarcinoma of pancreas–– Adencarinoma of duodenumAdencarinoma of duodenum–– Carcinoma of ureterCarcinoma of ureter

–– TuberculosisTuberculosis–– PneumoniaPneumonia–– Aspergillosis with cavitationAspergillosis with cavitation

–– Hodgkin’s diseaseHodgkin’s disease–– ThymonaThymona

–– Lung abscessLung abscess–– Chronic chest infectionChronic chest infection

Pulmonary Disease Associated with SIADHPulmonary Disease Associated with SIADH

SIADH i C t l N S t DiSIADH i C t l N S t Di–– Brain tumorBrain tumor–– EncephalitisEncephalitis–– MeningitisMeningitis–– Brain abscessBrain abscess–– Head injuryHead injury

–– Subarachnoid hemorrhageSubarachnoid hemorrhage–– LandryLandry--GuillainGuillain--Barre syndromeBarre syndrome–– Systemic lupus erythematsusSystemic lupus erythematsus–– Acute intermittent porphyriaAcute intermittent porphyria

SIADH in Central Nervous System DiseaseSIADH in Central Nervous System Disease

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Approach to HyponatremiaApproach to Hyponatremia

ADH despite SADH despite SNaNaRenal Failure

ECF and intravascularECF and intravascular DrugsDrugscompartments depletedcompartments depleted(diarrhea)(diarrhea) EndocrinopathiesEndocrinopathies

SIADHSIADH

Often UOften UNa Na “nl U“nl UNaNa” ” CrCr

SIADHSIADHECF expanded butECF expanded but tumorstumorsintravascular compartmentintravascular compartment pulmonarypulmonaryarterially underfilled (CHF)arterially underfilled (CHF) CNSCNS

BUN/CrBUN/Cr

VasopressinVasopressin

•• Antidiuretic hormone VAntidiuretic hormone V22--receptor: receptor: collecting ductcollecting duct

•• Vasopressor hormone VVasopressor hormone V11--receptor: receptor: vascular smooth musclevascular smooth muscle

3/19/2009

19

8080

9090

100100

iam

eter

iam

eter

Efferent Arteriole of RatEfferent Arteriole of Rat

3030

4040

5050

6060

7070

% re

duct

ion

in lu

men

di

% re

duct

ion

in lu

men

di

--1414 --1313 --1212 --1111 --1010 --99 --88 --77 --66 --55

Agonist (log M)Agonist (log M)

00

1010

2020

130

120120

Average Changes in Blood Pressure and Pulse Rate in Nine Average Changes in Blood Pressure and Pulse Rate in Nine Normal Persons During Intravenous Administration of PitressinNormal Persons During Intravenous Administration of Pitressin

110110

100100

9090

8080

7070

60606060

5050

4040

3030

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828 3030

Systolic Blood PressureSystolic Blood PressureDiastolic Blood PressureDiastolic Blood PressurePulse RatePulse Rate

Time (minutes)Time (minutes)

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Vasopressin in Vasodilatory ShockVasopressin in Vasodilatory Shock

•• Exogenous vasopressin is a potent pressorExogenous vasopressin is a potent pressorExogenous vasopressin is a potent pressorExogenous vasopressin is a potent pressor•• Endogenous vasopressin is deficientEndogenous vasopressin is deficient•• Vasopressin restores pressor responsiveness Vasopressin restores pressor responsiveness

by inhibiting vasodilatory mechanismsby inhibiting vasodilatory mechanisms

Vasopressin In Vasodilatory ShockVasopressin In Vasodilatory Shock88

00

00

0.000.00

55

0.040.04

140140

88

00

00

0.000.00

55

0.040.04

140140

NEPINEPIμμg/ming/min

EPIEPIμμg/ming/min

AVPAVPU/minU/min

NEPINEPIμμg/ming/min

EPIEPIμμg/ming/min

AVPAVPU/minU/min

140140

120120

100100

140140

120120

100100

SAPSAPmmHgmmHg

SAPSAPmmHgmmHg

8080

150150

100100

5050

00

8080

150150

100100

5050

00

UUml/hml/h

UUml/hml/h

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2424 2626 2828

Time (hours)Time (hours)

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21

Effect of Vasopressin in Septic Shock in ManEffect of Vasopressin in Septic Shock in Man(n=10)(n=10)

ControlControl AVPAVP

160160

140140

120120SBPSBP

( H )( H ) 120120

100100

8080

(mmHg)(mmHg)

88

77

66

55

COCO(L/min)(L/min)

55

15001500

10001000

500500

SVRSVR(dyne • sec/cm(dyne • sec/cm55))

NorepinephrineNorepinephrine(median)(median)

32 32 μμg/ming/min 0 0 μμg/ming/min

0.020.02

0 000 00

AVPAVPU/minU/min

Discontinuation of Vasopressin in FirstDiscontinuation of Vasopressin in FirstProspective Patient in Vasodilatory Septic ShockProspective Patient in Vasodilatory Septic Shock

120120

100100

0.000.00

SAPSAPmmHgmmHg

U/minU/min

8080

11 22 33 44 55 66

Time (hour)Time (hour)

3/19/2009

22

140140

Discontinuation of Vasopressin in 6 of 10 PatientsDiscontinuation of Vasopressin in 6 of 10 Patientsin Vasodilatory Septic Shockin Vasodilatory Septic Shock

120120

100100

SAPSAP(mmHg)(mmHg)

100100

8080AVPAVP No AVPNo AVP AVPAVP

Vasopressin in Vasodilatory ShockVasopressin in Vasodilatory Shock

• Exogenous vasopressin is a potent pressor• Endogenous vasopressin is deficient• Vasopressin restores pressor responsiveness

by inhibiting vasodilatory mechanisms

3/19/2009

23

2525

3030

3535

Septic ShockSeptic Shock(n=19)(n=19)

Cardiogenic ShockCardiogenic Shock(n=12)(n=12)

1515

2020

2525

22.7 22.7 ±± 2.22.2

AVPAVPpg/mlpg/ml

00

55

1010

3.1 3.1 ±± 0.40.4

Vasodilatory Shock States with Vasopressin Vasodilatory Shock States with Vasopressin Deficiency and HypersensitivityDeficiency and Hypersensitivity

•• Septic shockSeptic shock•• Septic shockSeptic shock•• CPBCPB--induced vasodilatory shockinduced vasodilatory shock•• MilrinoneMilrinone--induced vasodilatory shockinduced vasodilatory shock•• Brain deathBrain death•• Irreversible shockIrreversible shock•• Irreversible shockIrreversible shock

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ControlControl AVPAVPPressor AntagonistPressor Antagonist ControlControl AVPAVP

Pressor AntagonistPressor Antagonist

140140 WaterWater--diuresingdiuresing FluidFluid--depriveddeprived

130130

120120

MAPMAP(mm Hg)(mm Hg)

110110

100100

NSNS pp < 0.005< 0.005

•• Vasopressin sensitivity is a regulatedVasopressin sensitivity is a regulated

A Speculation:A Speculation:

•• Vasopressin sensitivity is a regulated Vasopressin sensitivity is a regulated phenomenonphenomenon

•• Vasopressin hypersensitvity is observed Vasopressin hypersensitvity is observed when vasopressin sensitivity is activated in a when vasopressin sensitivity is activated in a state of vasopressin deficiencystate of vasopressin deficiency

3/19/2009

25

100100

9090AVPAVPNENE

100100

9090AVPAVPNENE

met

erm

eter

met

erm

eter

Efferent and Afferent Arterioles of RatEfferent and Afferent Arterioles of Rat

8080

7070

6060

5050

4040

3030

2020

1010

8080

7070

6060

5050

4040

3030

2020

1010

% R

educ

tion

in L

umen

Dia

m%

Red

uctio

n in

Lum

en D

iam

% R

educ

tion

in L

umen

Dia

m%

Red

uctio

n in

Lum

en D

iam

00--1414 --1313 --1212 --1111 --1010 --99 --88 --77 --66 --55

Agonist (Log M)Agonist (Log M)

00--1414 --1313 --1212 --1111 --1010 --99 --88 --77 --66 --55

Agonist (Log M)Agonist (Log M)