http://www.kidney-international.
org
Pathogenesis and treatment of dialysis hypotension
W Sulowicz1 and A Radziszewski1
1
Department of Nephrology, Collegium Medicum, Jagiellonian University, Krakow, Krakow, Poland
Dialysis-induced hypotension (DIH) is a very serious clinical
problem. It is one of the most frequent complication in renal
replacement therapy which diminish patient’s quality of life,
and increases mortality in the dialyzed population. The main
mechanism of DIH is rapid reduction of blood volume owing
to ultrafiltration and decrease in extracellular osmolarity
during the dialysis session. Coexisting illnesses, especially
cardiovascular diseases, particularly common in older and
diabetic patients have an essential meaning in the
episodes of dialytic hypotension. Efficient treatment of DIH is
difficult owing to no generally accepted guidelines – is still
a great challenge to the nephrologist. Multilevel strategy
of DIH management includes emergency replacement
of intravascular volume in acute episodes of hypotonia,
accurate assessment of ‘dry weight’, education of the patient,
adequate hypertension treatment, and assessment methods
strictly related to hemodialysis procedure such as low
dialysate temperature, longer dialysis sessions or daily
dialysis, sodium profiling or application of the modern
dialysis technique as biofeedback equipment. There is also
a possibility for pharmacological treatment with the use of
such agents – as the well described midodrine, or other drugs
such as caffeine, effedrin, and vasopressin analogs. The new
class of drugs which can be a novel therapeutic option for
DIH treatment are adenosine receptor antagonists and
selective inhibitors of the inducible form of nitric oxide
synthase. Besides the discussed strategies, efficient treatment
of congestive heart failure, a common reason of hypotension
in uremic patients, should not be overlooked.
Kidney International (2006) 70, S36–S39. doi:10.1038/sj.ki.5001975
KEYWORDS: hemodialysis; hypovolemia; blood volume; dialysis hypo-
tension; mortality
Correspondence: W Sulowicz, Department of Nephrology, Collegium
Medicum, Jagiellonian University, 31-501 Krakow, ul. Kopernika 15 c, Poland.
E-mail: wladsul@mp.pl
S36
& 2006 International Society of Nephrology
Dialysis-induced hypotension (DIH) is a very, or even the
most frequent complication in renal replacement therapy. It
is usually associated with such symptoms as muscle cramps,
abdominal and chest pain, nausea and vomiting, dyspnea,
light-headedness, weakness, anxiety, vertigo, paleness, and
sweating which significantly diminish patient’s quality of life.
Dialysis hypotension is also an independent risk factor for
mortality in the dialyzed population.1 Correlation between
mortality and DIH in chronic hemodialysis patients in
comparison to the general population and well-known
traditional risk factors as hypertension and hypercholester-
olemia, has been referred to have paradoxical or reverse
epidemiology.2 Low blood pressure was shown to signifi-
cantly augment mortality in hemodialysis patients. Acute
intradialytic hypotonia reduces coronary blood flow. Con-
sequential myocardial ischemia may lead to heart failure,
cardiac arrhythmia, or even cardiac arrest. DIH and con-
comitant hypoperfusion, especially if recurrent, can damage
other vital organs such as the brain and gastrointestinal tract.
It may also contribute to chronic overhydration owing to an
inability to reach proper dry weight and is an obstacle to
provide adequate dialysis dose, which result in further
increase in morbidity and mortality.3
DEFINITION AND INCIDENCE
Dialysis hypotension may occur in one of three clinical
patterns: (i) acute (episodic) hypotension defined as a
sudden drop of systolic blood pressure below 90 mmHg or
of at least 20 mmHg with accompanying clinical symptoms,
(ii) recurrent – as detailed above but prevailing in a
minimum 50% of dialysis sessions, and (iii) chronic,
persistent hypotension in which interdialytic systolic blood
pressure is maintained at less than 90–100 mmHg.4 Intradia-
lytic hypotension occurs in 15–30% of conventional dialysis
treatments5 and in 35% of other extracorporeal techniques
like therapeutic apheresis.6 Owing to increasing number of
elder and diabetic patients in the hemodialysis population,
the incidence of acute DIH has reached up to 50%.7
Prevalence of the chronic form of dialysis hypotension,
specific for long-term dialyzed patients, is estimated to occur
in 3–5% of treated individuals.4
ETIOLOGY AND PATHOGENESIS
The mechanisms of DIH are complex. The predominant
factors of this manifestation seem to be aggressive reduction
of circulating blood volume owing to ultrafiltration, rapid
Kidney International (2006) 70, S36–S39
W Sulowicz and A Radziszewski: Pathogenesis and treatment of dialysis hypotension
decrease in extracellular osmolality associated with sodium
removal, and coexisting imbalance between ultrafiltration
and plasma refilling. Cardiac underfilling and impaired
cardiovascular compensatory mechanisms may trigger the
sympatico-inhibitory cardiodepressor Bezold–Jarish reflex.8
Some authors indicate the important role of several
vasoactive substances which may be synthesized or released
during dialysis, for example, cardiodepressive and vaso-
dilative adenosine or nitric oxide (NO) overproducted by
inducible synthase, similarly as in septic shock. Adenosine,
an endogenous purine nucleoside, is released by endothelial
cells and vascular myocytes during tissue ischemia. High
concentration of adenosine and its metabolites was observed
in hemodialyzed patients. This substance acts through
specific receptor stimulation and its effects are both
suppression of cardiac contractility and heart rate reduction,
artery relaxation, as well as decreased catecholamine and
renin release. Accumulation of adenosine may be just an
accompanying occurrence triggered by DIH-related ischemia,
but it is not likely to play a central role in pathogenesis of
sudden intradialytic hypotension.9 NO is an important
endogenous mediator of vascular responsiveness which is
synthesized in the endothelium. NO deficiency leads to severe
hypertension with its systemic complications and to dynamic
progression of atherosclerosis. On the contrary, high levels of
NO can be responsible for DIH owing to induction of rapid
vasodilation. NO-dependent mechanisms of DIH seem to be
related with the use of bioincompatible dialyzer membranes
and acetate dialysate.10
The etiology of DIH is multifactorial and depends on
patient-related factors, as well as on complications related to
the dialysis procedure. Hypotension occurs more frequently
in non-compliant patients, especially with too high inter-
dialytic fluid intake, as well as in persons eating just before or
during dialysis sessions. In elderly, demented patients, the
overdosage of antihypertensive drugs is also not rare.
Coexisting severe cardiovascular diseases, especially common
in older patients, can have an essential meaning in tend to
episodes of DIH. The most important among them are
advanced atherosclerosis, coronary heart disease, left ven-
tricular hypertrophy, numerous ventricular arrhythmias,
cardiomyopathy, congestive heart failure irrespective of its
etiology, and valvular heart diseases. Diabetes, the most
common reason of chronic renal failure also leads to
hypotonia because of its systemic complications as auto-
nomic and peripheral neuropathy, macroangiopathy, and
dynamical progression of atherosclerosis.11 Other commonly
coexisting diseases as amyloidosis or vasculitis can addition-
ally impair venous compliance considered as physiological
capacity of the vasculature to prevent venous pooling and
aberrant vasodilatation.12 One should take under considera-
tion that uremia per se is an independent risk factor for
autonomic dysfunction. Serum from uremic patients in-
creases vascular permeability for water and proteins,13 and
secondary hyperparathyroidism leads to calcification and
stiffness of the vessels.14 So-called iatrogenic reasons for DIH,
Kidney International (2006) 70, S36–S39
related directly to renal replacement therapy are also
numerous. The most important of them are incorrectly
estimated ‘dry weight’ resulting in too high filtration rate, low
sodium and calcium or high magnesium dialysate concen-
tration, dialysis with acetate buffer, non-biocompatible
materials used in production of dialysis equipment, high
temperature of dialysate, and chronic inflammation owing
to dialysis.15 Nowadays, air embolism and hemolysis rarely
lead to dialysis hypotonia.
MANAGEMENT AND PREVENTION
Efficient treatment of DIH is still a great challenge to the
nephrologists. Owing to a small number of comparative
studies, there are no generally accepted guidelines. Adequate
therapy is difficult and requires a multilevel strategy. Nephro-
logy nurses have the primary responsibility to prevent, detect,
and provide emergency interventions for DIH. Staff and
patients should therefore be well informed about possibility
of intradialytic hypotension, its symptoms and impact to
dialysis treatment.16 The emergency management of DIH
includes reduction or cessation of ultrafiltration rate and
reduction of blood flow rate. Patients should be placed in
the Trendelenburg position. Intravascular volume may be
replaced by intravenous infusion of natrium chloride (0.9%,
10%), glucose (10–40%), mannitol, dextran 70, hydroxyethyl-
starch, or more seldom albumin (5–20%). Theoretically,
albumin should be most effective owing to its oncotic
properties and expected influence on plasma refilling rate,
but a randomized, blinded, clinical trial has shown that very
expensive albumin is not superior to natrium chloride for the
treatment of DIH.17 One should remember that DIH
suspicion does not absolve physicians from an obligation to
undertake differential diagnostics. Primarily unrecognized
cardiac or pericardial disease, sepsis and gastrointestinal
bleeding must be excluded. Common strategies of long-term
treatment and prevention of DIH include accurate calculat-
ing and frequent assessment of ‘dry weight’, patient education
to avoid excessive interdialytic weight gain and no heavy
meals during or just before the dialysis, adequate hyper-
tension management – sometimes it is necessary to skip or
reduce drug dose on the day of dialysis session, use of
bicarbonate dialysate buffer and biocompatible membranes.
Not of any importance is effective anemia correction and
improvement of nutritional status. Other methods of DIH
treatment are strictly related to hemodialysis procedure. The
use of sodium modelling profiles, higher sodium concentra-
tion in dialysate – especially at the beginning of the procedure
and lower dialysis temperature are first therapeutic option for
hypotension-prone patients.4 Cool dialysis solution increases
blood pressure owing to increased total peripheral resistance,
increased cardiac contractility, and mobilization of pooled
venous blood to the central circulation.18 Patient’s body
temperature is lowered by about 11 and is generally well
tolerated, although several persons suffer from unacceptable
side effects such as chilling, shivering, or cramping. Inter-
mittent sodium administration, high sodium concentration
S37
 W Sulowicz and A Radziszewski: Pathogenesis and treatment of dialysis hypotension
in dialysate, and sodium profiling are most efficient and
well-tolerated procedures applied for episodic hypotension.
Their effect is explained by a stop of the rapid decline in
plasma osmolality and minimizing osmotic fluid loss into the
cells. The most common disadvantages of such methods are
increased thirst, interdialytic weight gain, hypertension
followed by increased morbidity. To avoid excessive sodium
load, modern ramping protocols are used and an essential
part of them is the reduction of sodium concentration at the
end of the dialysis session.19 Other simple maneuvers which
can be undertaken during the dialysis session to prevent DIH
are increase of calcium concentration in dialysate and
additional bicarbonate administration during dialysis to
better correct the acid/base status.20 Cardiovascular stability
can also be attained by extension of single dialysis sessions,
additional dialysis sessions, hemodiafiltration, linear decreas-
ing ultrafiltration profiling, or application of isolate ultra-
filtration at the first hour of dialysis. Very effective, but
unfortunately a very expensive proposal of DIH management
is a program of short, daily hemodialysis. This kind of
treatment seems to be beneficial in hypotension because of
lower decrease in serum osmolarity and ultrafiltration rate.
Additionally, daily hemodialyses provide essential improve-
ment in anemia treatment (reduction of rHuEPO dosage),
improve nutritional status, normalize blood pressure in
hypertensive patients, and significantly reduce ventricular
hypertrophy. These effects are prolonged and persist even
more than 12 weeks after daily treatment cessation. The only
possible drawbacks can be potential problems with patient’s
compliance and with vascular access. Unfortunately because
of its expensiveness, in most countries this treatment option
is not covered by national health insurance.21,22 Technologi-
cal advances which have taken place in modern renal
replacement therapy have given nephrologists many new
sophisticated tools for more efficient and safer treatment of
their patients. The newest devices (e.g. biofeedback equip-
ment) are able to continuously non-invasively monitor
changes in patients blood volume and pressure, to estimate
an individual critical relative blood volume, dynamics of
refilling, plasma conductivity, and ionic mass balance.
Moreover, based on the continuous stream of information,
concerning all these changes, equipment on-line adjusts both
dialysate conductivity and ultrafiltration rate. In certain
groups of patients, it is also possible to predict DIH episodes.
Some devices the so called ‘isotermic dialysis artificial
kidneys’ with blood temperature monitor are able to reduce
hypotensive episodes via extrapolation of patient’s core
temperature estimated from blood temperature and to keep
it stable by modifying dialysate temperature. All these
therapeutical advances seem to be the first step in creation
of optimal, physiological dialysis.23,24
DIH can also be treated and prevented with certain
pharmacological agents. A well-known and generally accepted
drug used for acute and persistent form of DIH manage-
ment is midodrine. Midodrine hydrochloride – prodrug –
that undergoes plasma enzymatic hydrolysis, is a selective
S38
peripheral a1-adrenergic agonist, which increases tonicity of
blood vessels, as well as stimulates venous blood flow. It is
very effective in patients suffering from serious heart diseases
and atherosclerosis. In chronic renal failure, its elimination is
almost identical as in healthy subjects; midodrine is also
effectively cleared by hemodialysis, therefore there is no need
for dose reduction. The drug is well tolerated, safe, and has
very few adverse side effects. Numerous studies indicate that
midodrine is able to blunt the blood pressure drop during
dialysis.25 Other drugs, commonly used to treat dialytic
hypotension, which have similar, but non-selective, a1/b1
agonistic effects are caffeine, ephedrine, and etilefrine. Their
application, as well as usage of vasopressine analogs is
burdened with many drawbacks such as tachycardia, cardiac
arrhythmia, and aggravation of coronary heart disease. Based
on the theory that DIH pathogenesis is similar to
neurocardiogenic and idiopathic orthostatic syncope, some
authors propose administration of serotonin re-uptake
inhibitors. Impairment in cardiopulmonary receptors and
arterial pressoreceptors is common in uremics, especially in
elderly and diabetics patients. A paradoxical withdrawal of
central sympathetic outflow in which serotonin pathways
participate seems to be an important mechanism of these
diseases. Sertraline hydrochloride, an antidepressive drug
primarily applied in psychiatric disorders, is effective in
prevention of DIH, especially in its persistent form. The
effect may be related to improved regulation in the
autonomic response to hypovolemic stress.26 A quite reason-
able solution, especially in patients with amyloidosis or after
nephrectomy, seems to be mineralocorticoid administration.
An additional benefit of this treatment is prevention of severe
hyperkalemia.27 The new class of drug, which can be a novel
therapeutic option in DIH management is FK352, adenosine
A1 receptor antagonist, reported as safe and moderately
effective. However, the exact role of adenosine in DIH
pathogenesis is unclear and guidelines for its correct
indications need to be settled and require further multicenter
studies.9,28 With reference to NO, the DIH pathogenesis
theory stated that L-arginine supplements in uremic patients
are attractive as a possibility in the correction of endothelial
dysfunction and vascular responsiveness. In the future,
selective inhibitors of inducible forms of NO synthase will
be found useful for treatment and prevention of DIH and
dialyzer membrane reactions.10 The matter of dispute is still
the effect of carnitine supplementation in the population
of patients on long-term dialysis therapy. Carnitine is known
as a metabolic cofactor essential for normal fatty acid
metabolism. Its deficiency may lead, among other things, to
Epo-resistance and hypotonia. Some authors propose
intravenous levocarnitine administration at the beginning
of dialysis session to prevent DIH; however, there are no
large-scale randomized trials to clearly confirm the effective-
ness of such therapy.29,30 Finally, the insistently recurrent
dialytic hypotension, resistant to all modifications of hemo-
dialysis procedures not responsive to pharmacological
treatment may be an indication to convert the patient into
Kidney International (2006) 70, S36–S39
W Sulowicz and A Radziszewski: Pathogenesis and treatment of dialysis hypotension
continuous peritoneal dialysis or to begin combined therapy
with both these methods. Besides the discussed strategies of
management, nephrologists should not forget about proper
congestive heart failure treatment in dialyzed patients that is
a common cause of hypotension. Its management includes
pharmacotherapy, as well as selected invasive cardiological
and cardiosurgical procedures, which increase cardiac output.
Revascularization methods such as percutaneous coronary
intervention (PTCA, stents) or coronary artery bypass
grafting are suitable to avoid hypotension owing to improve-
ment of contractility and ejection fraction of heart.
SUMMARY
Dialysis hypotension is a very important, multifactorial
clinical problem with tendency to increased incidence owing
to more elderly and diabetic patients on dialysis. The main
role in its prevention play: patients education to avoid
excessive interdialytic weight gain, accurate setting of ‘dry
weight’, adequate dosing of antihypertensive drugs, dialysis
modification (more frequent dialysis, sodium and ultrafiltra-
tion profiling, cool dialysate), midodrine treatment, and
perfect patients supervision by dialysis staff.
REFERENCES
1. Shoji T, Tsubakihara Y, Fujii M et al. Hemodialysis-associated hypotension
as an independent risk factor for two-year mortality in hemodialysis
patients. Kidney Int 2004; 66: 1212–1220.
2. Nurmohamed SA, Nube MJ. Reverse epidemiology: paradoxical
observations in haemodialysis patients. Neth J Med 2005; 63: 376–381.
3. Dasselaar JJ, Huisman RM, de Jong PE et al. Measurement of relative
blood volume changes during haemodialysis: merits and limitations.
Nephrol Dial Transplant 2005; 20: 2043–2049.
4. Dheenan S, Henrich WL. Preventing dialysis hypotension: a comparison of
usual protective maneuvers. Kidney Int 2001; 59: 1175–1181.
5. Daugirdas JT. Preventing and managing hypotension. Semin Dial 1994; 7:
276–283.
6. Stegmayr B, Ptak J, Wikstrom B et al. World apheresis registry: report of
2004 data. Ther Apher Dial 2005; 9: A38.
7. Santoro A, Mancini E, Basile C et al. Blood volume controlled hemodialysis
in hypotension-prone patients: a randomized, multicenter controlled trial.
Kidney Int 2002; 62: 1034–1045.
8. Daugirdas JT. Pathophysiology of dialysis hypotension: an update. Am J
Kidney Dis 2001; 38(Suppl 4): 11–17.
9. Imai E, Fujii M, Kohno Y et al. Adenosine A1 receptor antagonist improves
intradialytic hypotension. Kidney Int 2006; 69: 877–883.
10. Sarkar SR, Kaitwatcharachai C, Levin NW. Nitric oxide and hemodialysis.
Semin Dial 2004; 17: 224–228.
Kidney International (2006) 70, S36–S39
11. Sato M, Horigome I, Chiba S et al. Autonomic insufficiency as a factor
contributing to dialysis-induced hypotension. Nephrol Dial Transplant
2001; 16: 1657–1662.
12. Hoeben H, Abu-Alfa AK, Mahnensmith R et al. Hemodynamics in patients
with intradialytic hypotension treated with cool dialysate or midodrine.
Am J Kidney Dis 2002; 39: 102–107.
13. Harper SJ, Tomson CRV, Bates DO. Human uremic plasma increases
microvascular permeability to water and proteins in vivo. Kidney Int 2002;
61: 1416–1422.
14. Barth C, Boer W, Garzoni D et al. Characteristics of hypotension-prone
haemodialysis patients: is there a critical relative blood volume? Nephrol
Dial Transplant 2003; 18: 1353–1360.
15. Sklar A, Newman N, Scott R et al. Identification of factors responsible for
postdialysis fatigue. Am J Kidney Dis 1999; 34: 464–470.
16. Hossli SM. Clinical management of intradialytic hypotension: survey
results. Nephrol Nurs J 2005; 32: 287–291.
17. Knoll GA, Grabowski JA, Dervin GF et al. A randomized, controlled trial of
albumin versus saline for the treatment of intradialytic hypotension. J Am
Soc Nephrol 2004; 15: 487–492.
18. Yu AW, Ing TS, Zabaneh RI et al. Effect of dialysate temperature on central
hemodynamics and urea kinetics. Kidney Int 1995; 48: 237–243.
19. Song JK, Lee SW, Suh CK et al. Time-averaged concentration of dialysate
sodium relates with sodium load and interdialytic weight gain during
sodium-profiling hemodialysis. Am J Kidney Dis 2002; 40: 291–301.
20. Hampl H, Berweck S, Ludat K et al. How can hemodialysis-associated
hypotension and dialysis-induced symptoms be explained and controlled
– particularly in diabetic and arteriosclerotic patients? Clin Nephrol 2000;
53(Suppl 1): 69–79.
21. Goldfarb-Rumyantzev AS, Leypoldt JK, Nelson N et al. A crossover
study of short daily haemodialysis. Nephrol Dial Transplant 2006; 21:
166–175.
22. Okada K, Abe M, Hagi C et al. Prolonged protective effect of short daily
hemodialysis against dialysis-induced hypotension. Kidney Blood Press Res
2005; 28: 68–76.
23. Moret K, Aalten J, Wall Bake W et al. The effect of sodium profiling and
feedback technologies on plasma conductivity and ionic mass balance: a
study in hypotension-prone dialysis patients. Nephrol Dial Transplant
2006; 21: 138–144.
24. Donauer J. Hemodialysis-induced hypotension: impact of technologic
advances. Semin Dial 2004; 17: 333–335.
25. Prakash S, Garg AX, Heidenheim AP et al. Midodrine appears to be safe
and effective for dialysis-induced hypotension: a systematic review.
Nephrol Dial Transplant 2004; 19: 2553–2558.
26. Yalcin AU, Kudaiberdieva G, Sahin G et al. Effect of sertraline
hydrochloride on cardiac autonomic dysfunction in patients with
hemodialysis-induced hypotension. Nephron Physiol 2003; 93: 21–28.
27. Mercadal L, Petitclerc T. Effect of mineralocorticoids on interdialytic
weight gain in hemodialysis patients with perdialytic hypotension.
Hemodial Int 2005; 9: 338–340.
28. Franssen CMF. Adenosine and dialysis hypotension. Kidney Int 2006; 69:
789–791.
29. Handelman GJ. Debate forum: carnitine supplements have not been
demonstrated as effective in patients on long-term dialysis therapy. Blood
Purif 2006; 24: 140–142.
30. Schreiber BD. Debate forum: levocarnitine therapy is rational and justified
in selected dialysis patients. Blood Purif 2006; 24: 128–139.
S39