Intra and Intradialytic Hypotension and Hypertension Inrig

ASN DIALYSIS ADVISORY GROUP
ASN DIALYSIS CURRICULUM

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Intradialytic Hypotension and

Hypertension: Salt and Water
Balance
Jula K Inrig, MD, MHS, FASN

Duke University Medical Center
Quintiles Global Clinical Research Organization
2
History Lesson in Hemodialysis

1940s Kolff 1st successful dialysis 1980s High-sodium bicarbonate
in humans dialysis introduced and improved
1960s Salt and water removed patient comfort. kt/v introduced
mostly by diffusion/osmosis. Low and dialysis adequacy based on
sodium diet. Dialysate sodium of urea removal. Dialysis treatment
126 meq/L. 70-90% of pts BP times reduced to 4-5 hrs 3x/week.
controlled 1990s average dialysate sodium
1970s improved dialyzers and rose from 132 to 140-145
machines allowed hydrostatic 2000s prevalence of HTN is 70-
driven ultrafiltration. 90%, mortality rates remain high
Development of dialysis
dysequilibrium thought from
osmotic dysequilibria or tonicity
gradient between plasma and
dialysate
The Balancing Act
Hypotonic low sodium Isotonic/hypertonic high

dialysate sodium dialysate
lower incidence of higher incidence of
hypertension hypertension
higher patient discomfort lower patient discomfort
intradialytic hypotension intradialytic hypertension
Higher Sodium Dialysis
Higher pOsm Higher pOsm
Mobilization IC and EC
H2O H2O
Thirst
Removal of Fluid from both IDWG

IC and EC
Fewer Episodes of IDH, Interdialytic BP

better dialysis compliance
Overview Sodium Balance
Sodium is the most abundant cation in human

extracellular fluid
Tight regulation of plasma osmolarity and

sodium in all terrestrial mammals
Total body sodium determines extracellular

fluid volume
Na+
Cl- or HCO3-
Pituitary
Hypothalamic Baroreceptor
Osmotic Sensor
Normal Range
_____________________________
270 280 290 300
Plasma osmolality
THIRST ADH-Renal
Sodium Intake
Recommended salt (Nacl) intake is < 5

gm/day
139 1
Na intake of 2 g/day or 85 mmol/day
mmol Liter
Na+ water
1.5 grams of sodium
included
Salt intake will raise osmolality and stimulate

thirst
8 gm salt = 3 g Na = 139 mmol Na= 1 L
intake
Weight gain of ~0.65 kg/day if limit to 5 gm
salt (Nacl) /day
Na+
Sodium Flux During HD
UF volume is set into machines regardless of sodium gradient
Removal of Na during HD
mostly due to convection (based on prescribed UF with Na removed from
filtered plasma)
3L UF = 408 mmols sodium (9 gms sodium removed)
partially due to diffusion (based on the gradient between plasma and the
dialysate)
Dialysate to patient sodium gradient

activity Na = activity coefficient Na x concentration sodium
Diffusion of Na is driven by the difference between activity Na blood vs
activity Na dialysate
Serum Sodium Activity Vs Dialysate

Sodium Activity
Serum sodium activity Dialysis sieving

Serum Na of 140 meq/L fails to Protein-induced transport asymmetry
take into consideration ~6% of restricts sodium from isotonic flow
plasma is colloidal protein/lipid across the dialysis membrane
140 meq/L in 0.94L plasma This Gibbs-Donnan effect results in
water = plasma water sodium hypotonic ultrafiltrate
concentration 149 meq/L Donnan effect predicts isonatric dialysis
will occur only if dialysate Na activity is
5-10 mmol less than plasma water
sodium activity
Gibbs-Donnan Membrane Equilibrium
Blood Dialysate
_ _
_ _
_ _
_ _
_ _
_ protein anion (10)

anion bia czano wy (10)
Na
+
Cl
-
(20)
sodium cation (10) Blood Dialysate
_ _
_ _
_ _
_ _
_ _
_ protein anion (10)

anio n biaczanowy (10)
+ +
Na 18 Na 12
-
Cl
-
8 Cl 12
Higher interdialytic weight gain (driven by high

sodium intake and high serum sodium) increases
systolic BP
eg, 5% interdialytic weight gain (3.5 kg) = 5 mmHg increase in
prediaysis SBP
9
8
Predialysis Systolic BP (mmHg)
7
6
5
4
3
2
1
0
0 5 10
%Interdialytic Weight Gain
Inrig et al. Am J Kid Dis 50(1):108-118, 2007 *Adjusted for comorbid conditions, demographics, lab
variables, medical compliance, and antihypertensive
medications.
Dialysate Sodium and BP in Dialysis
Obtaining adequate sodium balance and ECFV control

are essential for BP control
Crossover study of 11 HD patients assigned to 3
different dialysate Na prescriptions: time average
sodium 138 meq/L vs 140 meq/L vs 147 meq/L
Higher time average NA resulted in stepwise increase in thirst
scores, interdialytic weight gain and ambulatory blood pressure
in the interdialytic period
136/82 with Time-average Na 138 meq/L
Song et al, AJKD.

40:291, 2002
Trials of Effect of Changing Dialysate Na on BP

Reference N Dialysate Na Change BP effect Comments
Krautzig 8 140 135 meq/L Decreased Also dietary Na

restriction and fixed
Na decrease
Farmer 10 138-140 133-135 Decreased Fixed decrease in Na,
meq/L ABP measured
Kooman 6 140 136 meq/L NS Fixed decrease in Na
Ferraboli 14 140135 meq/L Decreased Fixed decrease in Na
De Paula 27 138135 Decreased Tailored decrease in
Na
Lambie 16 136variable Decreased Progressive titration
in Na based on
dialysate conductivity
Sayarlioglu 18 Variable based on Decreased Decreased IVC
preHD NA diameter
Krautzig. NDT. 13:552, 1998. Farmer, Nephrol. 5:237, 2000. Kooman, NDT. 15:554, 2000. Ferraboli, JASN (abstr) 13:211a,
2002. de Paula, KI 66: 1232, 2004. Lambie ASAIO J. 51:70, 2005. Sayarlioglu, Renal Fail 29:143, 2007
Effect of High Plasma Na
Potential pro-hypertensive effects of high Na independent of volemia

In a study of young dahl-sensitive rats, increasing plasma sodium increased
central sympathetic outflow1
Increased brain sodium and osmolality increased ANGII levels and
increased sympathetic outflow2
In vitro, high medium sodium concentrations results in hypertrophy of
cardiomyocytes and vascular smooth muscle3
Increased sodium concentration (from 135-145) in endothelial cell culture
medium produced significant endothelial cell stiffness and decreased NO
release in the presence of aldosterone4
1. Bealer. Am J Phys Heart Circ Physiol. 284:H559, 2003. 2. Campese. J Renin Ang Aldo 1:1083, 2000.
3. Gu et al. HTN 31:1083, 1998. 4. Oberleithner et al. Proc Natl Acad Sci USA. 104:16281, 2007 and
2009
Acute Rises In Plasma Sodium Is Associated With

Increases In BP
Every 1 mmol/L increase in plasma sodium was

associated with a 1.91 mmHg increase in systolic BP,
p<0.05 Adapted from Suckling et al. 81:407, 2012
Higher sodium impairs NO release and increases

endothelial cell stiffness
Adapted from Oberleithner et al. Proc Natl Acad Sci USA 2007. 104:16281
Oberleithner et al. Proc Natl Acad Sci USA 2009. 106:2829
Pathophysiology of BP changes during HD
Hypotension during HD Hypertension during HD

Drop in plasma osmolality1 Volume overload
Comparison of HD vs UF vs Sodium loading
hypertonic mannitol HD vs Sympathetic over-activity
Isotonic mannitol HD
Activation of the renin-angiotensin
UF alone (with no change is osm) and aldosterone system
hypertonic mannitol HD avoided
postdialysis hypotension Endothelial cell dysfunction
Impaired sympathetic Dialysis-specific factors
response -net sodium gain
Poor cardiac reserve -high ionized calcium
Rapid ultrafiltration rates with -hypokalemia
impaired vascular Medications
reactivity -Erythropoietin stimulating agent
Dialysate to plasma tonicity -Removal of antihypertensive
gradient and medications
ultrafiltration/plasma Vascular stiffness
refilling
1Henrich, KI:18:480, 1980 Inrig, AJKD, 55:580, 2010
Causes of Intradialytic Hypotension

DROP IN ECFV
-UFR too high (exceeds refill rate)
-low target weight
-low dialysate Na (drop in osmolality)
-acetate dialysate
LACK OF
VASOCONSTRICTION
CARDIAC FACTORS -warm dialysis solution
-low cardiac output -splanchnic vasodilation
-failure to increase HR -tissue ischemia
-low dialysate calcium -autonomic neuropathy
-antihypertensive medications
Hypotension
Ultrafiltration Rates
Extravascular
The greater the gap between ultrafiltration and Plasma

plasma refill from the interstitium, the greater the Refill
risk for hemodynamic complications Rate
Ultrafiltration rates that exceed the plasma refill rate
(PRR) will increase the risk of hypotension, blood
pressure instability, and complications during HD.
Intravascular
Vascular
Space
UFR
UFR d PRR
Wigneswaran, CHF solutions

Intradialytic hypotension defined by a nadir

intradialytic systolic BP of <90 mmHg associated with
higher mortality
Post-hoc analysis of HEMO Study
(+) IDH characterized as meeting

specified IDH definition in at least
30% of baseline treatments
Nadir systolic BP <90 mmHg was

most potently associated with
mortality. Other definitions were not
associated with mortality.
Flythe et al. JASN, 9/30/2014, : doi: 10.168

How Common is Hemodynamic

Instability During HD?
Hypotension Needing
Nursing Intervention
No Nursing 24%
Intervention
45%
14% Cramping
12%
Lightheadedness
Steuer et al. Dial & Transplant (1996) 25:272
Summary - Management of Intradialytic Hypotension
Intradialytic hypotension occurs in up to 30% of hemodialysis

sessions
Intradialytic hypotension is associated with increased
morbidity and mortality
Sequential UF is not routinely effective at preventing
intradialytic hypotension
Avoid hypertonic saline and sodium modeling due to risk of
sodium excess
Use other therapies for long-term management of intradialytic
hypotension: cooler temperature, longer dialysis sessions,
extra UF session, midodrine
Causes of Intradialytic Hypertension
High Dialysate
Na
Excess Extracellular Endothelial Cell RAAS Medications

Volume Dysfunction Overactivity -ESA
-dialyzability of
antihypertensives
High Endothelin-1
&
Low Nitric Oxide
High Dialysate SNS over-
Ca+ activity
Hypertension
Intradialytic Hypertension is Associated With

Increased Morbidity and Mortality
6 Month Hospitalization or Mortality 2-year Survival
SBP Increase SBP Decrease

e10 mmHg e10 mmHg
2.17
Reference
Inrig et al. KI, 71: 454-461, 2007 Inrig et al. AJKD. 54:881-890, 2009
Intradialytic Hypertension affects >20% of

Hemodialysis Sessions
Systolic Blood Pressure Patterns Over 6 Months (n=22,955 treatments)
26.7%
Systolic
Blood
Pressure
Change <10
HYPERTENSIVE =
mmHg 21.3% Systolic BP >140
Systolic Blood mmHg pre HD
Or
Pressure >130 mmHg post-
52.0% Increase >10 HD
Systolic Blood mmHg

Pressure
Decrease >10
mmHg
Van Buren et al. IJAO, 35:1031, 2012

Carvedilol improves Intradialytic Hypertension

The frequency of intradialytic hypertension declined from 77% (4.6/6) at
180
baseline to 28% (1.7/6) of HD sessions at study end (p<0.0001)
170
Systolic BP (mmHg)
160
SBP
150 +15.0
mmHg SBP -
140 3.8
mmHg
130
120
110
preHD SBP postHD SBP preHD SBP postHD SBP
Baseline After Carvedilol

Inrig et al, cJASN, 7:1300, 2012
Summary - Management of Intradialytic Hypertension
Intradialytic hypertension occurs in >20% of hemodialysis

sessions
Intradialytic hypertension is associated with increased
morbidity and mortality
First step in managing intradialytic hypertension is reduction
in dry weight
Avoid high dialysate-to-plasma sodium gradients as it may
case vasoconstriction and contribute to intradialytic
hypertension
Consider use of carvedilol for management of intradialytic
hypertension
Conclusion
Patients should be educated to minimize sodium intake between treatments (<2 gm/day)
Adequate sodium solute removal during HD is critical for BP control
Inadequate sodium solute removal can contribute to higher thirst, larger interdialytic
weight gains, and higher interdialytic BP burden
Both intradialytic hypotension and intradialytic hypertension are associated with higher
mortality
There are many cause of both intradialytic hypotension and hypertension

Intradialytic hypotension is dependent on UF, while intradialytic hypertension is not
Treatment options for intradialytic hypotension:

Extend treatment times, low dietary sodium intake, cool dialysate, midodrine
Treatment options for intradialytic hypertension:

Reduce dry weight, low dietary sodium intake, review dialyzable medications, consider
carvedilol, consider lowering dialysate sodium

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ASN DIALYSIS ADVISORY GROUP

ASN DIALYSIS CURRICULUM

Intradialytic Hypotension and

Jula K Inrig, MD, MHS, FASN

History Lesson in Hemodialysis

The Balancing Act

Hypotonic low sodium Isotonic/hypertonic high

Higher Sodium Dialysis

Higher pOsm Higher pOsm

Removal of Fluid from both IDWG

Fewer Episodes of IDH, Interdialytic BP

Overview Sodium Balance

Sodium is the most abundant cation in human

Tight regulation of plasma osmolarity and

Total body sodium determines extracellular

Recommended salt (Nacl) intake is < 5

Salt intake will raise osmolality and stimulate

Sodium Flux During HD

UF volume is set into machines regardless of sodium gradient

Dialysate to patient sodium gradient

Serum Sodium Activity Vs Dialysate

Serum sodium activity Dialysis sieving

Gibbs-Donnan Membrane Equilibrium

_ protein anion (10)

_ protein anion (10)

Higher interdialytic weight gain (driven by high

Dialysate Sodium and BP in Dialysis

Obtaining adequate sodium balance and ECFV control

Song et al, AJKD.

Trials of Effect of Changing Dialysate Na on BP

Krautzig 8 140 135 meq/L Decreased Also dietary Na

Effect of High Plasma Na

Potential pro-hypertensive effects of high Na independent of volemia

Acute Rises In Plasma Sodium Is Associated With

Every 1 mmol/L increase in plasma sodium was

Higher sodium impairs NO release and increases

Pathophysiology of BP changes during HD

Hypotension during HD Hypertension during HD

Causes of Intradialytic Hypotension

The greater the gap between ultrafiltration and Plasma

Wigneswaran, CHF solutions

Intradialytic hypotension defined by a nadir

Post-hoc analysis of HEMO Study

(+) IDH characterized as meeting

Nadir systolic BP <90 mmHg was

Flythe et al. JASN, 9/30/2014, : doi: 10.168

How Common is Hemodynamic

Summary - Management of Intradialytic Hypotension

Intradialytic hypotension occurs in up to 30% of hemodialysis

Causes of Intradialytic Hypertension

Excess Extracellular Endothelial Cell RAAS Medications

Intradialytic Hypertension is Associated With

6 Month Hospitalization or Mortality 2-year Survival

SBP Increase SBP Decrease

Intradialytic Hypertension affects >20% of

Systolic Blood mmHg

Van Buren et al. IJAO, 35:1031, 2012

Carvedilol improves Intradialytic Hypertension

Baseline After Carvedilol