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Management of intradialytic hypertension: The ongoing challenge

Article  in  Seminars in Dialysis · March 2006

DOI: 10.1111/j.1525-139X.2006.00140.x · Source: PubMed

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 UNRESOLVED ISSUES IN DIALYSIS

Management of Intradialytic Hypertension:

Blackwell Publishing Inc

The Ongoing Challenge

Joline Chen, Ambreen Gul, and Mark J. Sarnak
Division of Nephrology, Department of Medicine, Tufts-New England Medical Center, Boston, Massachusetts

ABSTRACT

There is no widely accepted definition of intradialytic hyper- sympathetic nervous system, increased circulating vasoactive
tension. Arbitrary clinical definitions have included an increase substances resulting in peripheral vasoconstriction, erythropoietin
in blood pressure during or immediately after hemodialysis, a use, and fluctuations in electrolytes and removal of antihyperten-
rise in blood pressure during the second or third hour of dialysis, sive medications during the dialysis procedure. Management
and an increase in blood pressure that is resistant to ultrafiltra- strategies of intradialytic hypertension are based on expert
tion. To date, no studies have evaluated the prevalence and opinion using the pathophysiologic principles described above.
prognostic importance of intradialytic hypertension. The We conclude that additional epidemiologic, basic science, and
pathogenesis of intradialytic hypertension is complex and is interventional studies are needed to further elucidate the preva-
due in part to extracellular fluid volume expansion, increased lence, prognostic importance, pathophysiology, and potential
cardiac output, activation of the renin-angiotensin system and the treatment of intradialytic hypertension.

There are extensive data on the prevalence and poten- This definition was used in a review by Fellner (2);
Address correspondence to: Mark J. Sarnak, MD, MS, Box 391, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111, or e-mail: msarnak@tufts-nemc.org.

tial causes of hypertension in dialysis patients. There is no further details were provided.
also significant literature on the prevalence, causes, and An increase in blood pressure that is resistant to
potential treatments of intradialytic hypotension. In this ultrafiltration. Several authors have used the term
review we focus on the definition, epidemiology, and “paradoxical” to emphasize the infrequent and counter-
potential causes and treatments of intradialytic hyperten- intuitive nature of the response to ultrafiltration; that is,
sion. We conclude that there are very little data on this an increase rather than a decrease in blood pressure.
topic and further inquiry is needed. For example, Cirit et al. (3) used the definition of
postultrafiltration blood pressure that exceeded the
preultrafiltration blood pressure in more than half of
Epidemiology the sessions.
As noted above, these definitions are for the most
Clinical Definition
part arbitrary, and the level of blood pressure and the
To our knowledge, there is no widely accepted definition timing and duration of hypertension during the course of
of intradialytic hypertension. In fact, there is not even a dialysis have not been strictly defined. In this review we
consensus as to what absolute level of blood pressure is focus broadly on hypertension that appears resistant to
required to meet the definition of intradialytic hyperten- ultrafiltration and which occurs during or immediately
sion, whether the phenomenon is primarily systolic or after the dialysis procedure.
diastolic, and whether it requires an increase in blood
pressure during the dialysis session. A few definitions,
Prevalence
however, have been used in clinical studies and have
emerged from review articles, and include the following: To our knowledge, the prevalence of intradialytic
Any increase in mean arterial blood pressure (MAP) hypertension has not been systematically studied in a
of 15 mmHg or more during or immediately after large and generalizable dialysis population. This is partly
hemodialysis (1). due to the lack of a well-accepted definition of the phe-
Hypertension during the second or third hour of dialy- nomenon. One survey of dialysis patients noted that over
sis after significant ultrafiltration has taken place. a 2-week period, 8% of treatments were associated with
an increase in MAP of 15 mmHg or more, during or imme-
diately after dialysis (1). Other authors have noted an increase
Address correspondence to: Mark J. Sarnak, MD, MS, Box
391, Tufts-New England Medical Center, 750 Washington of 20–30% in the incidence of new onset or exacerbated
St., Boston, MA 02111, or e-mail: msarnak@tufts-nemc.org. hypertension with the use of recombinant erythropoietin
Seminars in Dialysis —Vol 19, No 2 (March–April) 2006 (4), while Mees (5) noted that 5–15% of hemodialysis
pp. 141–145 patients have hypertension resistant to ultrafiltration.
141
142
Prognostic Importance
It is unknown whether intradialytic hypertension is
associated with any short- or long-term adverse outcomes.
Most studies that have evaluated the importance of blood
pressure have in fact considered pre- and postdialysis
systolic and diastolic blood pressures. For example, data
from a large not-for-profit dialysis provider (Dialysis Clinic,
Inc.) demonstrated that patients with a postdialysis sys-
tolic blood pressure above 180 mmHg or postdiastolic
blood pressure above 90 mmHg had a 1.96- and 1.73-fold
increased risk of cardiovascular mortality, respectively
(6). If postdialysis blood pressure can be used as a proxy
for intradialytic hypertension, these data would suggest
that intradialytic hypertension might be associated with
adverse consequences.
Pathogenesis
Intradialytic hypertension is thought to be due to exces-
sive activation of the renin-angiotensin system (RAS)
and the sympathetic nervous system (SNS) in response
to rapid ultrafiltration. Izzo and Campese (7) postulated
that “excessive reflex activation of the SNS and the RAS
caused by rapid or exaggerated reduction in venous
return and cardiac preload, results in an activation of the
cardiopulmonary baroreflexes, which in turn causes
central sympathetic stimulation.” This theory has not
been tested and continues to be debated. Most authors,
however, believe that the pathogenesis is more complex
and includes consideration of extracellular fluid volume
status, composition of dialysate, peripheral vascular
resistance, as well as activation of the RAS and SNS. In
the following sections we discuss each of these potential
pathogenic mechanisms in more detail (Table 1).
Volume Overload
Volume overload is recognized as the primary cause for
sustained and difficult-to-control hypertension in dialysis
patients. For example, infusion of volume expanders
during hemodialysis to maintain a high estimated dry
weight can contribute to hypertension, while removal of
fluid usually normalizes blood pressure. Leypoldt et al.
(8) evaluated the relationship between intradialytic fluid
removal and pre- and postdialysis blood pressure in 468
patients enrolled in the Hemodialysis (HEMO) study.
For each 5% decrease in plasma volume, predialysis and
postdialysis systolic blood pressure decreased by 1.50
mmHg and 2.56 mmHg, respectively, with a greater effect
TABLE 1. Potential causes of intradialytic hypertension
Volume overload
Increased cardiac input
Stimulation of renin-angiotensin system
Activation of sympathetic nervous system and effects of vasoactive
peptides
Electrolyte changes during dialysis
Increase in hematocrit and blood viscosity with ultrafiltration
Removal of antihypertensive medications
Chen et al.
on systolic blood pressure than diastolic blood pressure.
However, the reduction in blood pressure with ultrafiltra-
tion is not linear and is patient specific (9). For example,
van der Sande et al. (10) demonstrated that patients with
heart failure, as opposed to those without heart failure,
were more likely to reduce their blood pressure for an
equivalent decrease in plasma volume.
Because of the imprecise estimate of dry weight in
dialysis patients, as well as difficulty in reaching the goal
dry weight, several authors have suggested that hyper-
volemia itself may be an important cause of intradialytic
hypertension. Cirit et al. (3) selected seven patients who
had blood pressure variation according to their definition
noted earlier (Clinical Definition section) during the 2
weeks prior to study intervention. These patients all had
echocardiographic evidence of cardiac dilatation and
were treated with repeated intensive ultrafiltration. With
this intervention, mean systolic and diastolic blood pres-
sure decreased by 46 mmHg and 22 mmHg, respectively,
while body weight decreased by 6.7 kg. The authors con-
cluded that a paradoxical increase in blood pressure was
not a consistent phenomenon and that hypervolemia per
se was an important cause for both baseline predialysis
hypertension as well as the intradialytic rise.
Increased Cardiac Output
Gunal et al. (11) hypothesized that intradialytic
hypertension may be due to an increase in cardiac output,
particularly in those patients with large weight gains and
cardiac dilatation. The authors performed echocardio-
graphy on six patients unresponsive to antihypertensive
medication or ultrafiltration and noted an improvement
in mean cardiac index from 3.8 L/min to 4.8 L/min and
in MAP from 107 mmHg to 118 mmHg after a mean
fluid removal of 2.5 L. With continuation of ultrafiltra-
tion, MAP was reduced to 90 mmHg. The proposed
hypothesis by these authors was that patients with cardio-
myopathy and volume overload were initially on the
descending limb of the Frank-Starling curve (see Fig. 1).
With initial ultrafiltration, patients shifted to the left and
upward on the curve. The cardiac index subsequently
increased, resulting in an increase in cardiac output and
blood pressure. With additional ultrafiltration, the patient
moved down the ascending limb of the curve and the
blood pressure normalized. This intriguing observation
awaits further confirmation.
Fig. 1. Frank-Starling curve.
 MANAGEMENT OF INTRADIALYTIC HYPERTENSION
Renin-Angiotensin System
One of the more commonly accepted theories for
intradialytic hypertension is ultrafiltration resulting in
overshoot of counterregulatory activation of RAS, result-
ing in excessive stimulation of renin and angiotensin II
production. For the most part, patients with kidney
failure retain the functional integrity of the RAS, demon-
strated by increases in renin in response to volume deple-
tion. An increase in renin is likely to occur in those with
high baseline levels of renin (12). The response of renin
to ultrafiltration is, however, blunted and not consis-
tent among all dialysis patients (5). Fellner (2) observed
that patients with tubulointerstitial disorders or who had
undergone bilateral nephrectomies were less likely to
develop intradialytic hypertension and hypothesized that
this may be due to decreased activity of the RAS in these
patients.
One interventional study evaluated whether treatment
with an angiotensin-converting enzyme (ACE) inhibitor
decreased intradialytic hypertension (13). The authors
evaluated six patients with a marked increase in blood
pressure during hemodialysis, with an associated increase
in plasma renin activity in four of the six patients.
Administration of 50 mg of captopril at the beginning of
the hemodialysis session improved blood pressure control
in those with and without elevated plasma renin activity
levels.
Sympathetic Nervous System (SNS)
The SNS plays an important role in hypertension among
dialysis patients and may also contribute to intradialytic
hypertension. Campese et al. (14) demonstrated that in
rats with 5/6 nephrectomy, the turnover rate of norepi-
nephrine was increased in brain nuclei that are involved
in blood pressure control. In fact, selective renal deaffer-
entiation prevented both the hypertension and the
increased norepinephrine turnover rate in hypothalamic
nuclei.
Similar findings may also be present in humans. For
example, human subjects with chronic kidney disease
and hypertension demonstrate increased peripheral SNS
activity measured by microneurography (15). In addition,
this increased activity normalizes after nephrectomy.
Some have proposed that renal damage may activate a
renal afferent pathway, which connects with integrative
brain structures, resulting in increased SNS activity and
subsequently increased blood pressure.
Koomans et al. (16) demonstrated increased sympa-
thetic activity in dialysis patients. Their findings consisted
of increased plasma catecholamine levels, rapid changes
in plasma concentrations upon postural changes, increased
sensitivity to norepinephrine, as well as enhanced hypoten-
sive response to adrenergic inhibitors such as clonidine,
debrisoquine, or total autonomic blockade.
It is important to acknowledge, however, that circulating
levels of catecholamines are not consistently associated
with hypertension, and we are not aware of studies that
demonstrate changes in pre- and postdialysis catecholamine
levels. Furthermore, it remains unknown whether changes
in levels are associated with intradialytic hypotension.
143
Other Vasoactive Substances
Three vasoactive substances that play an important
role in sympathetic activity, peripheral vasoconstriction,
and blood pressure control (including potentially intradi-
alytic hypertension) are nitric oxide, asymmetric dimeth-
ylarginine (ADMA), and endothelin-1 (ET-1). Nitric
oxide is a natural antagonist of catecholamine and its
inhibition results in sympathetic activation. Nitric oxide
synthase is present in specific areas of the brain involved
in the neurogenic control of blood pressure. In animal
models of chronic kidney disease, nitric oxide availability
is decreased due to inhibition by ADMA, an endogenous
inhibitor of nitric oxide synthase.
Increased levels of ADMA cause an increase in
peripheral vascular resistance and blood pressure, and in
fact, ADMA has been shown to be an independent
predictor of left ventricular hypertrophy, cardiovascular
mortality, and all-cause mortality in dialysis patients (17,18).
Endothelin-1 is a vasoconstrictor peptide, also produced
by endothelial cells, which acts on vascular smooth mus-
cle to regulate peripheral vascular resistance. Some, but
not all studies have found higher concentration of ET-1 in
hypertensive hemodialysis patients compared to normo-
tensive subjects (19–22).
Raj et al. (23) conducted a study evaluating the role of
nitric oxide and ADMA in intradialytic blood pressure
variation. Twenty-seven hemodialysis patients were divided
into three groups based on their blood pressure response
during dialysis. Group 1 included patients with stable
blood pressure during dialysis, group 2 had dialysis-
induced hypotension, and group 3 had intradialytic
hypertension, defined as those who were normotensive
or hypertensive at the initiation of dialysis, but experi-
enced an increase in MAP of ≥ 15 mmHg during dialysis.
Nitric oxide, ADMA, and ET-1 were measured. Results
revealed that the nitric oxide level was not significantly
correlated with MAP change, and ADMA levels were
not different between groups 2 and 3. ET-1 concentra-
tions, however, significantly decreased in group 2 and
increased in group 3. The balance between nitric oxide
and ET-1 may therefore be an important contributor to
the complex regulation of peripheral vascular resistance,
arterial pressure, and paradoxical hypertension during
dialysis.
Sodium, Potassium, and Calcium Flux
Changes
Hypernatremic dialysate may be used to avoid exces-
sive sodium losses associated with ultrafiltration and
may prevent cardiovascular instability. However, hyper-
natremic dialysis can lead to thirst, increase fluid intake
between dialysis treatments, and worsening hypertension.
In rats, relative hypokalemia may stimulate renin secre-
tion independent of changes in volume status. It remains
unknown whether this has any effect on blood pressure
regulation in humans during the dialysis procedure.
Increased ionized calcium during the dialysis proce-
dure may in theory increase myocardial contractility,
cardiac output, and therefore blood pressure. Similarly
an increase in ionized calcium may increase peripheral
144 Chen et al.
resistance and through this mechanism increase blood
pressure.
There are, however, very few studies that have
evaluated or supported these hypotheses. Fellner et al.
(24) studied eight patients who were dialyzed with three
different calcium dialysate concentrations. They noted
increased systolic and diastolic blood pressure, stroke
volume, and cardiac output with higher calcium dialysate
concentrations. Systemic vascular resistance, however,
was not different between the groups. Other studies have
demonstrated that despite increases in ionized calcium
during dialysis that lead to increased cardiac contractility
and cardiac output, there is no associated increase in
blood pressure (25,26).
Erythropoietin Use
The prevalence of hypertension in dialysis patients has
increased an estimated 20–30% since the widespread
use of recombinant erythropoietin. Several potential
mechanisms have been proposed for this association,
including increased hematocrit, increased viscosity,
increased peripheral vascular resistance, and increased
ET-1 levels.
Neff et al. (27) demonstrated that transfusion of dialy-
sis patients over a 6- to 12-week period to a hematocrit of
50% resulted in increased peripheral vascular resistance
with markedly increased blood pressure and associated
decreased cardiac output. Patients who are treated with
erythropoietin and have increased hematocrit would
be expected to have similar hemodynamic responses.
However, dialysis patients may have attenuated autoregu-
latory response to increased peripheral vascular resis-
tance and cardiac output may not decrease accordingly
(2,28).
The increased hematocrit is also associated with
increased whole blood viscosity, and this together with
a potential direct pressor effect of erythropoietin might
further increase peripheral vascular resistance and worsen
hypertension (29). Finally, erythropoietin receptors have
been found on endothelial cells, thus stimulation of ET-1
may result from erythropoietin treatment (30).
To our knowledge there are no published clinical reports
showing a direct association between erythropoietin use
and intradialytic hypertension. Hypothetically, with high
ultrafiltration rates during dialysis, the absolute increase
and rate of increase in hematocrit and blood viscosity
might lead to an increase in peripheral vascular resistance
TABLE 2. List of antihypertensive medications that are removed by dialysis
Drug class Extensively removed by dialysis
Sympatholytics Methyldopa
α, α/ β antagonists
β-receptor antagonists Atenolol, metoprolol, nadolol
ACE inhibitor Captopril, enalapril, lisinopril,
perindopril, ramipril
Angiotensin II receptor antagonists
Calcium channel blockers None
Vasodilators Minoxidil, diazoxide, nitroprusside
Modified with permission from Amerling et al. (1) and Daugirdas and Ing (31).
and subsequently an increase in the likelihood of intradi-
alytic hypertension.
Removal of Antihypertensive Medications
Removal of antihypertensive medications during the
dialysis procedure can precipitate intradialytic hypertension.
Table 2 provides a list of antihypertensive medications
that are removed by dialysis (1,31).
Management of Intradialytic Hypertension
The following principles are extrapolated from the
pathophysiology described in the previous section. We
acknowledge, however, that there are few interventional
studies that have evaluated the effectiveness of these
strategies and most are based on expert opinion
(1,2,4,5,13,16).
Control of Intravascular Volume
Rigid regulation of intravascular volume with dietary
salt and fluid restriction as well as maintenance of “dry”
weight is essential. Patients should be counseled against
large interdialytic weight gain, and if a short duration of
ultrafiltration is insufficient, prolonged ultrafiltration
periods may be required to reduce excess volume.
Blockade of the SNS and RAS
Bilateral nephrectomy remains an option, but is cur-
rently only very rarely required. As noted above, use of
ACE inhibitors (and presumably angiotensin II receptor
blockers) may improve intradialytic hypertension. Other
classes of adrenergic receptor blockers such as α- and
β-blockers should be considered, although their efficacy
for this particular indication has not been shown. Similarly
central sympathetic inhibitors such as α-methyldopa and
clonidine have been shown to lower blood pressure and
catecholamine levels in patients with kidney disease.
However, their use in the treatment of intradialytic
hypertension has not been demonstrated.
Compared with conventional thrice-weekly hemodialysis
sessions, short daily dialysis or nocturnal long dialysis
may provide better blood pressure control through avoid-
ance of large intradialytic weight gains. In preliminary
studies, these novel forms of dialysis have also been
shown to reduce peripheral sympathetic activity (32).
Not extensively removed by dialysis
Clonidine, guanabenz
Prazosin, labetalol, terazosin
Popranolol, pindolol, esmolol, bisoprolol, carvedilol, acebutalol
Fosinopril
Losartan, candesartan
Amlodipine, diltiazem, felodipine, isradipine, nifedipine, verapamil
Hydralazine
 MANAGEMENT OF INTRADIALYTIC HYPERTENSION
Modulation of the Dialysate
In dialysis patients with severe hypertension we would
recommend avoidance of “extremes” of hypernatremic
dialysate. A lower calcium bath may be considered if other
interventions are unsuccessful, however, as noted above,
there are few data to support this contention.
Avoidance of High Hematocrit
If patients have large weight gains and high predialysis
hematocrits, we would consider allowing the predialysis
hematocrit to decrease so as to avoid the potential for large
increases in blood viscosity and increases in peripheral
vascular resistance during the dialysis procedure.
Remedying the Intradialytic Removal of
Antihypertensive Medications
As previously discussed, many antihypertensive
medications may be removed during the procedure. If a
patient experiences intradialytic hypertension and some
of the hypertensive agents are dialyzable, a change in the
hypertensive agent should be considered.
Conclusion
Intradialytic hypertension is a well-recognized
phenomenon, although its pathophysiology and management
have not been extensively studied. Furthermore, there is
no accepted definition or prevalence data and no studies
that have evaluated its prognostic importance.
The existing literature suggests that volume overload,
decompensated cardiac physiology, the RAS and SNS,
electrolyte changes, and erythropoietin use may play a role
in the pathophysiology of intradialytic hypertension.
Removal of antihypertensive medications by dialysis may
also be an important precipitating factor.
We would recommend additional epidemiologic, basic
science, and interventional studies to more thoroughly
evaluate the mechanisms, importance, and potential
treatments of intradialytic hypertension.
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