intradialytic hypotension and hypertension: salt and water balance

ASN DIALYSIS CURRICULUM

ASN DIALYSIS ADVISORY GROUP

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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

1940’s – Kolff 1st successful dialysis in humans

1960’s – Salt and water removed mostly by diffusion/osmosis. Low sodium diet. Dialysate sodium of 126 meq/L. 70-90% of pts BP controlled

1970’s – improved dialyzer’s and machines allowed hydrostatic driven ultrafiltration. Development of “dialysis dysequilibrium” thought from osmotic dysequilibria or tonicity gradient between plasma and dialysate

1980’s –High-sodium bicarbonate dialysis introduced and improved patient comfort. kt/v introduced and dialysis adequacy based on urea removal. Dialysis treatment times reduced to 4-5 hrs 3x/week.

1990’s – average dialysate sodium rose from 132 to 140-145

2000’s – prevalence of HTN is 70-90%, mortality rates remain high

Presenter

Presentation Notes

Cells swell and cause symptoms as osmolality is lowered in ECF first and water fluxes into cells


The Balancing Act

Hypotonic “low” sodium dialysate

• lower incidence of hypertension

• higher patient discomfort

• intradialytic hypotension

Isotonic/hypertonic “high” sodium dialysate

• higher incidence of hypertension

• lower patient discomfort • intradialytic hypertension


Higher Sodium Dialysis

Higher pOsm

H O

Higher pOsm

Removal of Fluid from bothIC and EC

Thirst

IDWG

Interdialytic BPFewer Episodes of IDH, better dialysis compliance

Mobilization IC and EC2 2H O


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-


Plasma osmolality

THIRST ADH-Renal

_____________________________270 280 290 300

Normal Range

Hypothalamic Osmotic Sensor

Baroreceptor

Pituitary

Presenter

Presentation Notes

When osmolarity of ECF increases, osmoreceptor cells in the hypothalamis shrink and stimulates thirst. Volumetric thirst when the body loses salt and water triggers baroreceptors in the atria sense low cardiac return volume Pituitary gland releases ADH in response to increase osmolality and decreased filling pressures within the cardiac atria which acts as baroreceptor


Sodium Intake

Recommended salt (Nacl) intake is < 5 gm/day

• Na intake of 2 g/day or 85 mmol/day

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

139 mmol Na+

Na+

1 Liter water

1.5 grams of sodium included

Presenter

Presentation Notes

To convert mg of sodium to mmol or meq divide my MW of Na (23). To convert mg of salt to mg of sodium divide the mg by the percent of salt that is in sodium (23/58.5)=39.3%


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 vsactivity Na dialysate

Presenter

Presentation Notes

3 l UF is equal to 408 mmols sodium removed, about 9 gms sodium


Serum Sodium Activity Vs DialysateSodium Activity

Serum sodium activity

• Serum Na of 140 meq/L fails to take into consideration ~6% of plasma is colloidal protein/lipid

• 140 meq/L in 0.94L plasma water = plasma water sodium concentration 149 meq/L

Dialysis sieving

• Protein-induced transport asymmetry restricts sodium from isotonic flow across the dialysis membrane

• This Gibbs-Donnan effect results in hypotonic ultrafiltrate

• 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

__

___

__

___

_anion biał czanowy (10) Na+ Cl-protein anion (10)sodium cation (10)

(20)

__

___

__

___

_anion białczanowy (10)

Na+

Cl-Na+

Cl-

188

1212

protein anion (10)

Blood

DialysateBlood

Dialysate

Presenter

Presentation Notes

Proteins are not only large, osmotically active, particles, but they are also negatively charged anions. Proteins influence the distribution of other ions so that electrochemical equilibrium is maintained. With the osmotic force of proteins in plasma, the effective gradient favors the movement of sodium from dialysate to plasma even though the difference would be anticipated to favor movement to the dialysate


Higher interdialytic weight gain (driven by high sodium intake and high serum sodium) increases systolic BPeg, 5% interdialytic weight gain (3.5 kg) = 5 mmHg increase in prediaysis SBP

0

1

2

3

4

5

6

7

8

9

0 5 10

Predia

lysis Sy

stolic B

P (mmH

g)

%Interdialytic Weight Gain

*Adjusted for comorbid conditions, demographics, lab variables, medical compliance, and antihypertensive medications.

Inrig et al. Am J Kid Dis 50(1):108-118, 2007

Presenter

Presentation Notes

Observational study of 32,395 HD sessions in 442 patients followed for 6 months in a randomized trial of blood volume monitoring


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

Presenter

Presentation Notes

Current dialysis prescription most of na lost is convection. Previously was diffusion when dialysate na was 126 and UF rate was not able to be programmed into the machine… With onset of programmable machines, UF volume is set leading to a major advance in volume control. When larger dialyzer membranes came about, solute clearance can occur much quicker allowing urea removal to occur during shorter HD session. This resulted in larger osmolar shifts resulting dialysis dysequilibrium sundrome. Higher dialysate sodium was adopted in an attempt to minimize dysequilibrium


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 meq/L

Decreased Fixed decrease in Na, 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 titrationin Na based on dialysate conductivity

Sayarlioglu 18 Variable based on preHD NA

Decreased Decreased IVC 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


Every 1 mmol/L increase in plasma sodium was associated with a 1.91 mmHg increase in systolic BP, p<0.05

Acute Rises In Plasma Sodium Is Associated With Increases In BP

Adapted from Suckling et al. 81:407, 2012

Presenter

Presentation Notes

randomized crossover study looking at the effect of high vs. no salt intake on plasma sodium and BP. 2 period, randomized crossover study of the acute effect of high vs no salt intake on plasma sodium and BP 2 weeks of 6g/day salt intake 10 healthy subjects examined in GCRC for 10 hrs Soup (400 ml) with 6 grams salt vs soup with 0 gms salt Labs and BP every 15 minutes


Higher sodium impairs NO release and increases endothelial cell stiffness

Adapted from Oberleithner et al. Proc Natl Acad Sci USA 2007. 104:16281Oberleithner et al. Proc Natl Acad Sci USA 2009. 106:2829


Pathophysiology of BP changes during HD

Hypotension during HDDrop in plasma osmolality1

• Comparison of HD vs UF vshypertonic mannitol HD vsIsotonic mannitol HD• UF alone (with no change is osm) and

hypertonic mannitol HD avoided postdialysis hypotension

Impaired sympathetic response

Poor cardiac reserveRapid ultrafiltration rates with

impaired vascular reactivity

Dialysate to plasma tonicity gradient and ultrafiltration/plasma refilling

Hypertension during HD

1Henrich, KI:18:480, 1980

• Volume overload• Sodium loading• Sympathetic over-activity• Activation of the renin-angiotensin

aldosterone system• Endothelial cell dysfunction• Dialysis-specific factors

-net sodium gain-high ionized calcium-hypokalemia

• Medications-Erythropoietin stimulating agent -Removal of antihypertensive

medications• Vascular stiffness

Inrig, AJKD, 55:580, 2010


Causes of Intradialytic Hypotension

Hypotension

LACK OF VASOCONSTRICTION-warm dialysis solution-splanchnic vasodilation

-tissue ischemia-autonomic neuropathy

-antihypertensive medications

DROP IN ECFV -UFR too high (exceeds refill rate)

-low target weight-low dialysate Na (drop in osmolality)

-acetate dialysate

CARDIAC FACTORS-low cardiac output

-failure to increase HR-low dialysate calcium

Presenter

Presentation Notes

-talk about myocardial stunning!!! Drop in plasma osmolality1 Comparison of HD vs UF vs hypertonic mannitol HD vs Isotonic mannitol HD UF alone (with no change is osm) and hypertonic mannitol HD avoided postdialysis hypotension Henrich 2000


• The greater the gap between ultrafiltration and plasma refill from the interstitium, the greater the risk for hemodynamic complications

• Ultrafiltration rates that exceed the plasma refill rate (PRR) will increase the risk of hypotension, blood pressure instability, and complications during HD.

VascularSpace

Plasma Refill Rate

Intravascular

UFR

Extravascular

UFR d PRR

Ultrafiltration Rates

Wigneswaran, CHF solutions


Intradialytic hypotension defined by a nadir intradialytic systolic BP of <90 mmHg associated with higher mortality

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

• Post-hoc analysis of HEMO Study

• (+) IDH characterized as meeting specified IDH definition in at least30% of baseline treatments

• Nadir systolic BP <90 mmHg wasmost potently associated withmortality. Other definitions were notassociated with mortality.


45%

12%

14%

24%

Lightheadedness

Cramping

Hypotension Needing Nursing Intervention

No NursingIntervention

Steuer et al. Dial & Transplant (1996) 25:272

How Common is HemodynamicInstability During HD?


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

Hypertension

Excess Extracellular Volume

RAAS Overactivity

Endothelial Cell Dysfunction

High Endothelin-1 &

Low Nitric Oxide

Medications-ESA

-dialyzability of antihypertensives

High DialysateNa

High DialysateCa+

SNS over-activity

Presenter

Presentation Notes

Drop in plasma osmolality1 Comparison of HD vs UF vs hypertonic mannitol HD vs Isotonic mannitol HD UF alone (with no change is osm) and hypertonic mannitol HD avoided postdialysis hypotension Henrich 2000


6 Month Hospitalization or Mortality

SBP Increase e10 mmHg

SBP Decrease e10 mmHg

2.17

Reference

2-year Survival

Intradialytic Hypertension is Associated With Increased Morbidity and Mortality

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)

52.0%Systolic Blood

Pressure Decrease >10

mmHg

26.7%Systolic Blood

Pressure Change <10

mmHg 21.3%Systolic Blood

Pressure Increase >10

mmHg

HYPERTENSIVE =Systolic BP >140

mmHg pre HDOr

>130 mmHg post-HD

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


Carvedilol improves Intradialytic Hypertension

ΔSBP +15.0 mmHg

Inrig et al, cJASN, 7:1300, 2012

ΔSBP -3.8 mmHg

110

120

130

140

150

160

170

180

preHD SBP postHD SBP preHD SBP postHD SBP

Sys

tolic

BP

(m

mH

g)

Baseline After Carvedilol

The frequency of intradialytic hypertension declined from 77% (4.6/6) at baseline to 28% (1.7/6) of HD sessions at study end (p<0.0001)


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 intradialytichypertension

• Consider use of carvedilol for management of intradialytichypertension


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

intradialytic hypotension and hypertension: salt and water balance

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