Nagoya J. Med. Sci. 54. 00 - 00, 1992

Invited Review Article

MECHANISM OF DIALYSIS-INDUCED HYPOTENSIONKENJI MAEDA, TAKAHIRO SHINZATO, SHIGERU NAKAI, ICHIRO TAKAI
and HIROYUKI KOBAYAKA W A
Department of Internal Medicine, The Branch Hospital, Nagoya University School of Medicine,
Nagoya 461, Japan

ABSTRACT
Dialysis-induced hypotension, the sharp decrease in blood pressure occurring during hemodialysis, remains one of the most difficult problems associated with hemodialysis even today. However, there is yet noestablished theory to explain the mechanism triggering dialysis-induced hypotension.
This review attempts to offer a consistent and cohesive source of information on the hemodynamics during dialysis-induced hypotension, and then analyzes etiologic factors in such hypotension reported by various
investigators. Finally, three hypotheses concerning the mechanism of dialysis-induced hypotension including
our own are introduced.

HEMODYNAMICS DURING DIALYSIS-INDUCED HYPOTENSION
The mean arterial blood pressure is the resultant product of cardiac output and total peripheral resistance. Therefore, dialysis-induced hypotension should be the result of lowered cardiac
output and/or a decrease in total peripheral resistance.
Maeda et al. l ) measured the hemodynamic parameters using the Swan-Ganz catheter immediately before and at the time of dialysis-induced hypotension, as well as after the bloodpressure recovered under appropriate treatment. They found that as the blood pressure sharply
fell, the cardiac output decreased but the total peripheral resistance failed to show any significant change. Azancot et al. 2) in the same type of research, reported that the cardiac output fell
but the total peripheral resistance remained unchanged at the time hypotension developed.
The absence of any compensatory increase in the total peripheral resistance in relation to thedecreased cardiac output, which is the common finding in either of the above investigations,
may reflect the fact that hypotension involves some sympathetic failure. (Heart rate did notchange at the time of dialysis-induced hypotension in either investigation.)
The decrease in cardiac output is the result of either lowered myocardial contractility or diminished venous return to the right atrium (or heart rate). Therefore, the decreased cardiac output
at the time of dialysis-induced hypotension can be due to either the sudden reduction of
myocardial contractility or diminished venous return. (As mentioned above, the heart rate does
not change during hypotension.)
Numerous investigators have demonstrated that, in the hypovolemic condition, changes inmyocardial contractility and heart rate do not exert much influence on the cardiac dynamics. In
unanesthetized sheep, for example, blockade of beta-adrenergic responses with propranolol had
little effect on the hemodynamic response to slow hemorrhage 3). In conscious dogs, cardiac denervation 4 ) or beta-adrenergic blockadeS) has a minimal effect on the hemodynamic response tohemorrhage. These findings suggest that the lowered cardiac output at the time of dialysis-

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Kenji Maeda et al.

induced hypotension does not result from an abruptly reduced myocardial contractility but froma sharply diminished venous return to the right atrium, since the hypotension usually occurs during a hypovolemic condition. Moreover, the decreased mean right atrial presure lJ and mean pulmonary arterial pressure 2) which occur at the time of hypotension, indicate that at least one
reason for the lowered cardiac output is the diminished venous return.
The reduced venous return to the right atrium must be due either to the rapid contraction ofblood volume or to some kind of blood redistribution. If the rapid contraction of blood volume
were the reason for the decrease in the venous return during dialysis-induced hypotension, it
could only be because of the hemoconcentration due to a fluid shift from the plasma compartment to the interstitial compartment. However, Maeda et aLI.O), based on their studies of thecontinuous hematocrit monitoring during hemodialysis, discovered that there was no rapid
hemoconcentration at the onset of hypotension. This finding suggests that the diminished venous
return at the time of dialysis-induced hypotension results from redistribution of blood due tosome dramatic and sudden increase in vascular capacity.
Splanchnic7•H) and cutaneous Y) circulations are extremely important blood reservoirs, the volume of which can contract during hypovolemia. Therefore, the abrupt redistribution of blood at
the time of hypotension would surely bring about extensive involvement of one or both of these
vascular beds. Recently, Nakai et aLIO) suggested that cutaneous circulation did not increase at
the time of dialysis-induced hypotension. Using an infrared ray monitoring system, theymeasured continuously the skin temperature during hemodialysis, only to find it did not rise but
rather fell when hypotension occurred.
Circulation in other organs may well increase at the time of dialysis-induced hypotension.
However, the compliance of the vascular beds of these organs is far lower than that of asplanchnic vascular bed. Hence, although no study to date has clearly demonstrated that thesplanchnic vascular bed is most extensively involved in redistribution of blood occurring at thetime of dialysis-induced hypotension, there is little reason to believe that the increased vascular
capacity in other organs is the main cause of redistribution of blood at the time of hypotension.
There are two mechanisms whereby the regional vascular capacity can be increased. One is areduction of venous wall tension. The actual decrease in venous wall tension II) and the elevation 12) of plasma levels of calcitonin-gene-related peptide, which is a vasodilatory substance,might suggest that the reduction of venous wall tension plays some role in the increased regional
vascular capacity occurring at the time of dialysis-induced hypotension. The other mechanism
for the increased regional vascular capacity is the elevation in venous bed distending pressure
due to the decrease in resistance vessel tone (De Jager-Krogh phenomenon)13,14.15). This elevation of distending pressure can cause prominent sequestration of blood in the venous bed andconsequent dimunition of venous return 16),ETIOLOGIC FACTORS IN DIALYSIS-INDUCED HYPOTENSION
In attempting to explain the cause of the hemodynamic changes at the time of hypotension
discussed above, the analysis of the various etiologic factors in dialysis-induced hypotension isextremely important. Here, we will discuss the main etiologic factors proposed to date.

1. Hypovolemia
Clinical experience has made it a matter beyond doubt that one most important factor in dialysis-induced hypotension is hypovolemia. However, Maeda et aLo) have demonstrated that such
hypotension is not the direct result of hypovolemia. In their study, they measured the hematocrit

3
MECHANISM OF DIALYSIS-INDUCED HYPOTENSION

value continuously during hemodialysis using the system they had developed, and found that
there was no contraction of blood volume at the time of dialysis-induced hypotension and thatthe hypotension occurred when the blood volume was more than 10% higher than the minimum
level in the course of hemodialysis.
The mechanism by which hypovolemia contributes to dialysis-induced hypotension remains
unknown. Hypovolemia may playa role in the dialysis-induced hypotension via one or anothersecondary step; or dialysis-induced hypotension may result from the combining of hypovolemiawith some sudden failure of a compensatory mechanism for entirely different reasons.
Hypovolemia can result when the ultrafiltration rate exceeds the plasma refilling rate (rate of
fluid shift from the interstitial compartment to the plasma compartment) 17. IX). Thus, not only thelarge and rapid ultrafiltration but the factors diminishing the plasma refilling rate are what
exacerbate the hypovolemia.
The two most important determinants of the plasma refilling rate, as reflected in Starling's
principle, are the static pressure gradient and the oncotic pressure gradient between the plasma
and the interstitial compartments through the capillary wall. Thus, the plasma refilling ratewould be lower in patients with a lower predialysis plasma protein concentration. The plasma
refilling rate is also affected by interstitial fluid volume. The contracted interstitial fluid volume
would translate into lower interstitial static pressure and higher interstitial oncotic pressure.
Hence, when the patient is close to "dry weight," the plasma refilling rate is lessl~).
A low dialysate sodium level serves to lower the plasma refilling rate through the greater ensuing dimunition of interstitial volume because of the fluid shift from the extracellular to the intracellular compartment 17.1X). Daugirdas et al. 20), for example, showed in their dog experimentsthat the plasma volume decreases more quickly when the dialysate sodium level is lower thanthe plasma sodium level. Kimura et al. IX ) demonstrated in human that the plasma volume decrease became marked and swift whenever a low sodium dialysate was used during the hemodialysis. Van Stone et al. 2l ) also showed that when the dialysate sodium concentration is below theplasma sodium concentration, there is a fluid shift from the extracellular to the intracellularcompartment.

2. Dialysate temperature
Employment of a warm dialysate results in unstable hemodynamics, while use of a cool dialysate leads to stabilization 22 .23 ). The core body-temperature rise resulting from the employment of
a warm dialysate leads to a resultant decrease in cutaneous resistance vessel tone and increased
cutaneous circulation; on the other hand, the core body-temperature fall resulting from the useof a cool dialysate leads to an increase in cutaneous resistance vessel tone and a decrease in cutaneous circulation. (The reader is referred to several excellent reviews on thermoregulatory
control of human cutaneous circulation 24 ' 26 ).)The experiments performed by Maggiore et al. 27) suggested that at least some of the hemodynamic differences between hemofiltration and hemodialysis 2X-30) are due to a thermal factor.
They indicated that standard hemofiltration using warmed replacement fluid was not always
thermically equivalent to conventional hemodialysis using a warmed dialysate. Thus, they compared hemodialysis with thermically equivalent hemofiltration in terms of vascular stability andfound that there were no significant differences in blood pressure between the two treatment
modes.

3. Autonomic insufficiency
It is well recognized that there is baroreflex arc dysfunction in hemodialysis patients 31 - 3X ). To
date, however, it remains a matter of controversy whether or not this autonomic insufficiency

4Kenji Maeda et al.

plays a role in triggering dialysis-induced hypotension. Kersh et al. 31) showed that on the basis of
the Valsalva maneuver and the amyl nitrate test, six of eight patients who suffered severe hypotension during hemodialysis had autonomic insufficiency. On the other hand, Nies et al. 32) reported no difference in the response to the valsalva maneuver between hypotension-prone andhypotension-resistant patients. Lilley et a1. 34 ) and Nakashima et a1. 39 ) found no difference between hypotension-prone and hypotension-resistant patients in terms of blood pressure response
to tilting. Thus, the autonomic insufficiency experienced by a substantial proportion of hemodialysis patients may not be the cause of dialysis-induced hypotension.
Maeda et a1. 40 ) made an interesting discovery based upon plasma catecholamine levels estimated from ultrafiltrate catecholamine levels: although the estimated plasma catecholamine levels rose significantly immediately before the onset of hypotension as compared with the time atwhich hemodialysis was begun, they decreased to the predialysis level when the hypotension occurred; and when the appropriate hypotension treatment was given and the crisis passed, theyagain rose to the pre-hypotension level. Based upon these results, the investigators considered
acute sympathetic failure to playa role in the dialysis-induced hypotension, and they hypothesized that this failure was separate from the autonomic insufficiency that hemodialysis patients already have outside of hemodialysis. The fact that at the time of dialysis-induced hypotension there was no compensatory elevation in the heart rate l ,2) may well suggest a connection between hypotension and acute sympathetic failure.

4. Decreasing plasma osmolality
Kobayashi et a1. 41 ) first reported that isolated ultrafiltration did not produce symptomatic hypotension, The result was later confirmed by Ing et aI. 42 ). Moreover, Bergstrom et a1. 43 ) and Keshaviah et a1. 44 ) demonstrated that isolated ultrafiltration was well tolerated but not when combined with diffusion, This series of observations demonstrates that diffusive solute transport
plays a key role in dialysis-induced hypotension, However, which aspect of diffusive solutetransport is responsible for dialysis-induced hypotension is as yet unclear.
A fluid shift from the extracellular to the intracellular compartment due to decreased plasma
osmolality may be one of the reasons for the unstable hemodynamics accompanying highly diffusive solute transport, In fact, Falls et a1. 45 ) and Oh et aI. 4 (') indicated in early studies that
hemodialysis provokes a fluid shift on the order of I to 1.5 liters from the extracellular to the intracellular compartment.
Sodium is the most important solute determining plasma osmolality. Thus, as discussed earlier, when the dialysate sodium concentration is lower than the plasma sodium concentration, a
fluid shift from the extracellular to the intracellular compartment results I7 ,IK.21J,21). Urea is another solute which substantially determines plasma osmolality. Even so, it has been believed that
decreased plasma urea concentration during hemodialysis does not affect the rate of plasma volume contraction, since it rapidly traverses various body water compartments 47 ,4K). However,there has been a recent report of a substantial rebound of plasma urea concentration immediately after completion of hemodialysis 49l . This finding would tend to indicate a substantial fluid
shift from the extracellular to the intracellular compartment due to the urea concentration gradient during very high-efficiency hemodialysis treatment.
In a mechanism involved in other than a fluid shift to the intracellular compartment, the decreased plasma osmolality could also exert some effect upon the hemodynamic stability.
Schultze et al. 50) found that low sodium dialysis elevated the concentration of prostaglandin E 2,
which is known to have venodilatory properties. Moreover, Kunze et al,5i) reported that actuechanges in plasma sodium concentration impair baroreceptor function in experimental animals.

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MECHANISM OF DIALYSIS-INDUCED HYPOTENSION

5. Ingestion offood
The association of food ingestion with dialysis-induced hypotension now has been well documented 52 .s3 ), and it is considered that feeding causes an obligatory increase in splanchnic
blood flow 54 ) and a consequent decrease in venous return.
6. Anemia
Sherman et al. 55) reported that patients with a low hematocrit appeared to be inordinately
susceptible to dialysis-induced hypotension, and the problem could be ameliorated by bloodtransfusion. The mechanism of the hematocrit effect has not be clarified.
Patients with low hematocrit have a high plasma volume in relation to their blood volume, so
the concentration rate of their plasma protein along with ultrafiltration is thought to become
slower. It is this delayed plasma protein concentration (slow rise of plasma oncotic pressure)
together with the lower plasma refilling rate which probably undermines hemodynamic stability
in patients with low hematocrit.
The blood viscosity increases exponentially with increasing hematocrit, and blood viscosity is
an important component of total peripheral resistance 56). For this reason, patients with severe
anemia may appear to be inordinately susceptible to dialysis-induced hypotension.
Furthermore, it may be that anemia plays a role in triggering hypotension during hemodialysis, since it modulates tissue ischemia in hypovolemia. (See the adenosine hypothesis proposed
later. )7. Acetate hemodialysis
It is known that acetate increases splanchnic blood flow through an adenosine-mediated actionS?). Moreover, some reports suggested that acetate causes vasoreiaxation 5H ) through a cyclic
AMP-related action 59). Thus, during acetate dialysis, increased venous capacity and reduced
total peripheral resistance may well be produced by a direct effect on the veins and by a vasorelaxant effect on splanchnic and cutaneous resistance vessels, which can contribute to hypotension during hemodialysis.

HYPOTHESES CONCERNING THE MECHANISMOF DIALYSIS-INDUCED HYPOTENSION
Some investigators have combined some of the above-mentioned etiologic factors in order tocreate a viable hypothesis concerning the mechanism of dialysis-induced hypotension. Two of
the previously proposed hypotheses and our own new one are herewith presented.

1. Interleukin -1 hypothesis
Exposure of whole blood to the cuprophane membrane causes the release of the anaphylatoxins C3a60 ) and C5a61 ). The thus-released C5a serves to stimulate monocyte production of interleukin-1 62 ,(3). And if interleukin-l is present in sufficient quantity in the circulating blood, it
could produce fever and shock.
Henderson et al. (4 ) hypothesized that such monocyte release of interleukin-l is the key factor
in terms of dialysis-induced hypotension, which may be modulated by hypovolemia, vasodilationby acetate, autonomic insufficiency and so on. The same investigators have maintained that their
hypothesis is supported by the fact that the 3- to 4-hour time lag6S ) from when the monocyte is
activated until the release of interleukin-l has peaked, coincides with the peak incidence ofdialysis-induced hypotension. They also explained that the difference in the incidence of6Kenji Maeda el ai.

hypotension between hemofiltration and hemodialysis is due to the reduced interleukin-l production during hemofiltration. They speculated that, during hemofiltration, there would bemuch less production of interleukin-l because of use of a noncellulosic membrane which has
little capacity to activate complement 6o /,J), and minimal rise in body temperature. (It has beenshown that an increase in body temperature enhances monocyte production of interleukin-lafter monocyte stimulation 65Ni ).)However, research results which contradict this hypothesis have recently been reported 67 ).

2. Thermal amplification hypothesis
Gotch et al. 6X ) have advanced the hypothesis that dialysis-induced hypotension results from
abrupt expansion of the cutaneous vascular bed as a means to disperse the heat build-up within
the body during the latter part of the hemodialysis session. This process is held to take place asfollows: If hypovolemia results because of ultrafiltration in the course of hemodialysis, the sympathetic tone increases correspondingly and the cutaneous circulation decreases. As a result, themetabolic heat produced during hemodialysis no longer can be dispersed from the skin surface,
thereby causing a gradual elevation in the core body-temperature. Once the core body-temperature reaches threshold during the latter part of a hemodialysis session, the cutaneous vessels suddenly open, leading to patient shock.
If this hypothesis were valid, at least until sweating developed the skin temperature should
rise together with the sudden increase in cutaneous circulation. However, Nakai et al. 10) recently
employed an infrared ray monitoring system to monitor skin temperature continuously in thecourse of hemodialysis. They found that even when dialysis-induced hypotension occurred there
was no corresponding elevation in skin temperature.
3. Adenosine hypothesis
We found it interesting that several important etiologic factors in dialysis-induced hypotension could result in tissue ischemia. For example, the hypovolemia due to large-volume ultrafiltration and use of low sodium dialysate obviously leads to tissue ischemia. Also, an increase in
cutaneous circulation associated with the employment of a warm dialysate inevitably redistributes blood to the skin from other organs, resulting in ischemia of orgrans other than skin.
Once highly metabolic organs become ishchemic through such mechanisms, adenosine, which
is a powerful vasorelaxant substance, is released('Y). Here, we posited the hypothesis explained inwhat follows, namely, that the adenosine released from hypoxic cells plays a key role in the development of dialysis-induced hypotension. When highly metabolic organs become ischemic, regional ATP synthesis is inhibited; and with hydrolysis of ATP, adenosine is released in those orgrans. Since adenosine inhibits Ca 2+ flux into vascular smooth muscle 711 ) and at the same time inhibits norepinephrine release from the nerve endings at the junction with vascular smoothmuscle71.72), resistance vessel tone falls in ischemic organs. This fall of resistance vessel tone
leads to elevation of vascular bed distending pressure and expansion of regional vascular capacity (De Jager-Krogh phenomenon) 13 15), especially in the splanchnic vascular bed 14). Accordingly, venous return to the right atrium diminishes markedlyI6). These pathophysiologicalchanges induced by adenosine conjoin with the underlying hemodynamic alteration induced byhypovolemia. Thus, the more tissue ischemia is aggravated, the more adenosine is released, anddialysis-induced hypotension finally results. It may be important that some acutely ill patients
evidence more adenosine release during hypotensive events compared with others, suggesting
more cellular hypoxia73-75). For the same reason that individual differences exist in purine metabolism among non-uremic patients during hypotensive events, the incidence of dialysis-induced
hypotension might differ with the individual.
07
MECHANISM OF DIALYSIS-INDUCED HYPOTENSION

Skin is a low metabolic organ. Therefore, even though the cutaneous circulation is reduced
dramatically, a drop in resistance vessel tone due to adenosine mechanism would not be induced. In fact, as long as the core body-temperature is not remarkably high, the skin resistancevessel tone increases because of normal baroreflex in the hypovolemic condition 76.77).
Thus, the rise in resistance vessel tone in the skin and the decrease in the resistance vessel
tone in other organs may mutually cancel each other out, leaving little change in the total peripheral resistance at the time dialysis-induced hypotension occurs.
This hypothesis is corroborated by our recent results, which indicate that, at the time of dialysis-induced hypotension, there was a pronounced elevation in the plasma level of inosine andhypoxanthine, both of which are adenosine metabolites7H ). Also, the fact that patients with low
hematocrit are susceptible to dialysis-induced hypotension'S) may be because the decreased red
blood cell mass results in further reduction of the O 2 delivery to various organs in hypovolemic
condition. Again, one may explain the association of food ingestion with dialysis-induced hypotension s2 .s3 ) in terms of an adenosine-mediated increase of splanchnic circulation accompanying such food intake 79 ). Moreover, at least part of the reason for the high incidence of hypotension during acetate dialysis may be increased splanchnic circulation through adenosine-mediatedaction S7 ). It is known that the blood pressure rises dramatically with rapid administration of only
100 to 200 ml of biological fluid. The reason for the remarkable effect of such a small volume of
biological fluid administration on dialysis-induced hypotension may be the rise in the resistancevessel tone and recovery from the inhibition of sympathetic neurotransmission in ischemic organs (e.g., intestines and liver) due to the decreased adenosine release. Fluid administered isthought to distribute mainly to the relatively dilated vascular bed.
It is the authors' hope that their adenosine hypothesis will be given careful consideration frommany different viewpoints in the days to come.

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