1

ObjectivesObjectives

•• Volume regulation entails the physiology of salt Volume regulation entails the physiology of salt content regulationcontent regulation

•• The edematous states reflect the The edematous states reflect the pathophysiologypathophysiologyof salt content regulationof salt content regulation

•• The mechanisms of normal volume regulation The mechanisms of normal volume regulation mediate the mediate the pathophysiologypathophysiology of the edematous of the edematous statesstates

ObjectivesObjectives

•• Serum sodium concentration reflects the physiology Serum sodium concentration reflects the physiology of water metabolismof water metabolism

•• Hypo and Hypo and hypernatremiahypernatremia reflect the reflect the pathophysiologypathophysiology of water metabolismof water metabolism

•• The mechanisms regulating normal water The mechanisms regulating normal water metabolism mediate the metabolism mediate the pathophysiologypathophysiology of hypo of hypo and and hypernatremiahypernatremia

2

Case SummaryCase Summary

HxHx of rheumatic feverof rheumatic fever etiology of CHFetiology of CHFDOE, SOB, DOE, SOB, ralesrales pulmonary edemapulmonary edemaPedal edema, Pedal edema, abdabd girthgirth peripheral edemaperipheral edema

weightweight

Question~ why edema?Question~ why edema?

Case SummaryCase Summary

HxHx of rheumatic feverof rheumatic fever etiology of CHFetiology of CHFDOE, SOB, DOE, SOB, ralesrales pulmonary edemapulmonary edemaPedal edema, Pedal edema, abdabd girthgirth peripheral edemaperipheral edema

weightweight

Serum [Na] = 128 Serum [Na] = 128 meqmeq/L/LQuestion~ why Question~ why hyponatremiahyponatremia??

3

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

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

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

Low ECFLow ECF NlNl ECFECF Expanded ECFExpanded ECF

4

HH22OOdeficitdeficit

HH22OOexcessexcess

HH22OOdeficitdeficit

HH22OOexcessexcess

133133140140147147

[Na][Na]

140140133133140140147147

Low ECFLow ECF NlNl ECFECF Expanded ECFExpanded ECF

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

EuvolemicEuvolemic

5

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 compartmentsNo osmotic gradients exist between fluid compartments•• The tonicity of the intravascular compartment reflects the The tonicity of the intravascular compartment reflects the

tonicity of all fluid compartmentstonicity of all fluid compartments•• The calculated serum The calculated serum osmolalityosmolality is given by:is given by:

([Na]x2) + ([K]x2) + [([Na]x2) + ([K]x2) + [glucgluc] + [] + [BUNBUN]]1818 2.82.8

= (140x2) + (4x2) + = (140x2) + (4x2) + 9090 + + 12121818 2.82.8

= 280 + 8 + 5 + 4= 280 + 8 + 5 + 4

Free WaterFree Water

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

relative to salt input and outputrelative to salt input and output•• Concept of Concept of ““Free HFree H22OO””::

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

6

Determinants of TonicityDeterminants of Tonicity

Free HFree H22O intake vs. free HO intake vs. free H22O excretion + free HO excretion + free H22O lossesO losses

OralOral UrineUrine RespiratoryRespiratoryIntravenousIntravenous CutaneousCutaneous

VolumeVolume ConcentrationConcentration

Proximal TubuleProximal Tubule

PeritubularPeritubular CapillariesCapillaries

Urinary SpaceUrinary Space

GlomerularGlomerularCapillariesCapillaries

JGAJGA

Afferent Afferent ArterioleArteriole

Efferent Efferent ArterioleArteriole

7

Free HFree H22O excretionO excretion Free HFree H22O retentionO retentionDeliveryDelivery MedullaryMedullary gradientgradient

GFR (GFR (ScrScr))Proximal Proximal reabsorptionreabsorption Collecting duct Collecting duct

HH22O permeabilityO permeabilityDiluting segment Diluting segment

Collecting DuctCollecting DuctHH22O permeabilityO permeability

VasopressinVasopressin

•• AntidiureticAntidiuretic hormone: hormone: neurohypophysealneurohypophyseal•• VV22--receptor: collecting ductreceptor: collecting duct

8

300300

600600

900900

12001200

14001400

35%35%

25%25%

15%15%

3%3%

< 1%< 1%

10%10%No ADHNo ADH

MaximalMaximalADHADH

Proximal Proximal tubuletubule

HenleHenle’’sslooploop

DistalDistaltubuletubule

Cortical Cortical collectingcollecting

ductduct

MedullaryMedullarycollectingcollecting

ductduct

Osm

olar

ityO

smol

arity

(( mO

smm

Osm

/L)

/L)

Urinary Concentration and DilutionUrinary Concentration and Dilution

% water remaining

ntsntsbrbr

opop

dsds

nhnhahah

ococ

sonsonoror

pvnpvn

9

ThirstThirst

1212

1010

88

66

44

22

00

270270 280280 290290 300300 310310

Plasma Plasma OsmolalityOsmolality ((mOsmmOsm/kg)/kg)

Plas

ma

Vas

opre

ssin

(pg/

ml)

Plas

ma

Vas

opre

ssin

(pg/

ml)

14001400

12001200

10001000

800800

600600

400400

200200

00

00 11 22 33 44 55 1010 1515

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

Urin

e U

rine

Osm

olal

ityO

smol

ality

(( mO

smm

Osm

/kg)

/kg)

10

HyponatremiaHyponatremia((HypoosmolarHypoosmolar states)states)

•• Intake of free H2O > renal output + insensible lossesIntake of free H2O > renal output + insensible losses

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

NormalNormal Congestive Heart FailureCongestive Heart FailureGCGC PTCPTC PTCPTCGCGC

ΔΔPP

ΔπΔπArb

itrar

y Pr

essu

reA

rbitr

ary

Pres

sure

Uni

tsU

nits

OO OO OO OOII II II II

A.A. B.B.

ΔΔPP

ΔπΔπ

ΔπΔπ

RPFRPF RPFRPF

GFRGFR GFRGFR

Eff Eff ArtArt

Eff Eff ArtArt

ΔΔPP

ΔπΔπ

ΔΔPP

11

ntsntsbrbr

opop

dsds

nhnhahah

ococ

sonsonarar

pvnpvn

10001000

600600400400

200200100100

60604040

2020

10106644

22

11

00 1515 3030 4545

% Decrease in Mean Arterial Pressure% Decrease in Mean Arterial Pressure

Plas

ma

Vas

opre

ssin

(pg/

ml)

Plas

ma

Vas

opre

ssin

(pg/

ml)

12

PressurePressure

VolumeVolumeBasalBasal

OsmolalityOsmolality

2525

2020

1515

1010

55

00

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

% Change% Change

Plas

ma

Vas

opre

ssin

Plas

ma

Vas

opre

ssin

(pg/

ml)

(pg/

ml)

--2020--1515

--1010NN

+10+10+15+15

+20+20

1010

88

66

44

22

00

Plas

ma

Vas

opre

ssin

Plas

ma

Vas

opre

ssin

pg/m

lpg

/ml

HypovolemiaHypovolemia ororHypotensionHypotension

HypervolemiaHypervolemia ororHypertensionHypertension

260260 270270 280280 290290 300300 310310 320320 330330 340340

Plasma Plasma OsmolalityOsmolalitymOsmmOsm/kg/kg

13

HyponatremiaHyponatremia in CHFin CHF

Free water intake has exceeded free water outputFree water intake has exceeded free water outputWhy has the kidney failed to make a large volume of dilute urineWhy has the kidney failed to make a large volume of dilute urine??

ThirstThirst AIIAII

Distal delivery Distal delivery AIIAII

Dilution at TALDilution at TAL DiureticsDiureticsHypokalemiaHypokalemia

ADHADH Volume Stimulus to ADHVolume Stimulus to ADH

1919181817171616151514141313121211111010998877665544332211Day of Experiment

TIVCTIVCConstrictionConstriction

IncreaseIncreaseConstrictionConstriction

ReleaseReleaseConstrictionConstriction

5050

150150

100100

HeartRate

100100

9090

8080

7070

Mean AorticMean AorticPressurePressure(mmHg)(mmHg)

14

2020

1515

1010

55

00

PlasmaPlasmaReninRenin ActivityActivity

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

Plas

ma

Plas

ma

Ren

inR

enin

Act

ivity

Act

ivity

(( ngng

/ml/h

r)/m

l/hr)

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

150150

6060

2525

1010

55

22

11

0.50.5

0.20.2

124124 128128 132132 136136 140140 144144 148148

15

Cardiac OutputCardiac Output

LVEDPLVEDP

Cardiac Cardiac OutputOutput

LVEDPLVEDP

16

00 66 1212 1818 2424 3030 3636

2020

00

4040

6060

8080

100100

MonthsMonths

% S

urvi

val

% S

urvi

val p<0.001p<0.001

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

Na Na ≤≤ 130 (n=40)130 (n=40)

HyponatremiaHyponatremia with Increased ADHwith Increased ADH

•• Volume stimulusVolume stimulus

•• Syndrome of Inappropriate ADHSyndrome of Inappropriate ADH

•• Certain drugs, Certain drugs, endocrinopathiesendocrinopathies

17

DaysDays

5757

5454

22 44 66 88 1010 1212

Body Weight Body Weight kg kg

33

22

11

Urine VolumeUrine VolumeL/dayL/day

200200

100100Urinary Sodium Urinary Sodium

mEqmEq/day/day

10001000

500500

UrinaryUrinaryOsmololityOsmololity

mOsm/kgHmOsm/kgH22OO

PitressinPitressinRestrict HRestrict H22OO

140140

130130

120120

Serum [Na]Serum [Na]mEqmEq/L/L

–– BronchogenicBronchogenic carcinomacarcinoma–– AdenocarcinomaAdenocarcinoma of pancreasof pancreas–– AdencarinomaAdencarinoma of duodenumof duodenum–– Carcinoma of Carcinoma of ureterureter

–– TuberculosisTuberculosis–– PneumoniaPneumonia–– AspergillosisAspergillosis with with cavitationcavitation

–– Brain tumorBrain tumor–– EncephalitisEncephalitis–– MeningitisMeningitis–– Brain abscessBrain abscess–– Head injuryHead injury

–– LymphomaLymphoma–– HodgkinHodgkin’’s diseases disease–– ThymonaThymona

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

–– SubarachnoidSubarachnoid hemorrhagehemorrhage–– LandryLandry--GuillainGuillain--BarreBarre syndromesyndrome–– Systemic lupus Systemic lupus erythematsuserythematsus–– Acute intermittent Acute intermittent porphyriaporphyria

EctopicEctopic ADH Production from TumorsADH Production from Tumors

Etiology of SIADHEtiology of SIADH

Pulmonary Disease Associated with SIADHPulmonary Disease Associated with SIADH

SIADH in Central Nervous System DiseaseSIADH in Central Nervous System Disease

18

Approach to Approach to HyponatremiaHyponatremia

ADH despite ADH despite SSNaNa

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

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

BUN/CrBUN/Cr

Renal Failure

Often Often UUNaNa ““nlnl UUNaNa”” CrCr

VasopressinVasopressin

•• AntidiureticAntidiuretic hormone Vhormone V22--receptor: receptor: collecting ductcollecting duct

•• VasopressorVasopressor hormone Vhormone V11--receptor: receptor: vascular smooth musclevascular smooth muscle

19

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

Agonist (log M)Agonist (log M)

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

% r

educ

tion

in lu

men

dia

met

er%

red

uctio

n in

lum

en d

iam

eter

Efferent Arteriole of RatEfferent Arteriole of Rat

130

120120

110110

100100

9090

8080

7070

6060

5050

4040

3030

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

Systolic Blood PressureSystolic Blood Pressure

Diastolic Blood PressureDiastolic Blood Pressure

Pulse RatePulse Rate

Time (minutes)Time (minutes)

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 Normal Persons During Intravenous Administration of PitressinPitressin

20

Vasopressin in Vasopressin in VasodilatoryVasodilatory ShockShock

•• Exogenous vasopressin is a potent Exogenous vasopressin is a potent pressorpressor•• Endogenous vasopressin is deficientEndogenous vasopressin is deficient•• Vasopressin restores Vasopressin restores pressorpressor responsiveness by responsiveness by

inhibiting inhibiting vasodilatoryvasodilatory mechanismsmechanisms

Vasopressin In Vasopressin In VasodilatoryVasodilatory ShockShock88

00

00

0.000.00

55

0.040.04

140140

120120

100100

8080

150150

100100

5050

00

88

00

00

0.000.00

55

0.040.04

140140

120120

100100

8080

150150

100100

5050

00

NEPINEPIμμg/ming/min

EPIEPIμμg/ming/min

AVPAVPU/minU/min

SAPSAPmmHgmmHg

UUml/hml/h

NEPINEPIμμg/ming/min

EPIEPIμμg/ming/min

AVPAVPU/minU/min

SAPSAPmmHgmmHg

UUml/hml/h

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

Time (hours)Time (hours)

21

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

ControlControl AVPAVP

160160

140140

120120

100100

8080

SBPSBP(mmHg)(mmHg)

88

77

66

55

COCO(L/min)(L/min)

15001500

10001000

500500

SVRSVR(dyne (dyne •• sec/cmsec/cm55))

NorepinephrineNorepinephrine(median)(median)

32 32 μμg/ming/min 0 0 μμg/ming/min

120120

100100

8080

0.020.02

0.000.00

11 22 33 44 55 66

Time (hour)Time (hour)

SAPSAPmmHgmmHg

AVPAVPU/minU/min

Discontinuation of Vasopressin in FirstDiscontinuation of Vasopressin in FirstProspective Patient in Prospective Patient in VasodilatoryVasodilatory Septic ShockSeptic Shock

22

140140

120120

100100

8080AVPAVP No AVPNo AVP AVPAVP

SAPSAP(mmHg)(mmHg)

Discontinuation of Vasopressin in 6 of 10 PatientsDiscontinuation of Vasopressin in 6 of 10 Patientsin in VasodilatoryVasodilatory Septic ShockSeptic Shock

Vasopressin in Vasopressin in VasodilatoryVasodilatory ShockShock

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

inhibiting vasodilatory mechanisms

23

00

55

1010

1515

2020

2525

3030

3535

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

CardiogenicCardiogenic ShockShock(n=12)(n=12)

3.1 3.1 ±± 0.40.4

22.7 22.7 ±± 2.22.2

AVPAVPpg/mlpg/ml

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

•• Septic shockSeptic shock•• CPBCPB--induced induced vasodilatoryvasodilatory shockshock•• MilrinoneMilrinone--induced induced vasodilatoryvasodilatory shockshock•• Brain deathBrain death•• Irreversible shockIrreversible shock

24

ControlControl AVPAVPPressorPressor AntagonistAntagonist ControlControl AVPAVP

PressorPressor AntagonistAntagonist

140140

130130

120120

110110

100100

NSNS pp < 0.005< 0.005

WaterWater--diuresingdiuresing FluidFluid--depriveddeprived

MAPMAP(mm Hg)(mm Hg)

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

•• Vasopressin Vasopressin hypersensitvityhypersensitvity is observed when is observed when vasopressin sensitivity is activated in a state of vasopressin sensitivity is activated in a state of vasopressin deficiencyvasopressin deficiency

A Speculation:A Speculation:

25

100100

9090

8080

7070

6060

5050

4040

3030

2020

1010

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

Agonist (Log M)Agonist (Log M)

AVPAVP

NENE

100100

9090

8080

7070

6060

5050

4040

3030

2020

1010

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

Agonist (Log M)Agonist (Log M)

AVPAVP

NENE

% R

educ

tion

in L

umen

Dia

met

er%

Red

uctio

n in

Lum

en D

iam

eter

% R

educ

tion

in L

umen

Dia

met

er%

Red

uctio

n in

Lum

en D

iam

eter

Efferent and Afferent Arterioles of RatEfferent and Afferent Arterioles of Rat