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Hyperkalemia in End-Stage and Management12

Michael Allon3

Renal

Disease:

Mechanisms

M. Allon. Nephrology University of Alabama Center, Birmingham,

Research and at Birmingham Alabama


1995;

Training Center, and VA Medical

(J. Am. Soc. Nephrol.

6:1134-1

142)

ABSTRACT Clinical investigations in the past few years hove enhanced the understanding of the mechanisms of hyperkalemia in patients with ESRD. The results of these studies have led to modifications In the acute treatment and prevention of hyperkalemia in this patient population. They have confirmed the efficacy of intravenous insulin, while raising doubts about the utility of intravenous bicarbonate, for the acute treatment of hyperkalemia. Moreover, the fradrenergic agonist albuterol has been shown to be a useful adjunct to insulin for acutely lowering plasma potassium. Finally, there has been enhanced recognition of nondietary factors that can predispose to hyperkalemla In patients with ESRD, including prolonged fasting and the use of noriselective p-adrenergic blockers. These new insights may improve the clinical management of hyperkalemla in patients with renal failure. Key Words: Potassium,
bonate

insulin,

albuterol,

epinephrine,

bicar-

temporizing measures are used. Mter the myocardium is stabilized with intravenous calcium, therapy is directed at decreasing plasma potassium acutely, by shifting potassium from the extracellular to the intracellular fluid compartment. Until recently, the administration of intravenous insulin and bicarbonate was recommended uniformly to promote this shift. Only in the past few years have these textbook recommendations been examined critically In carefully designed, prospective studies. These investigations have confirmed the efficacy of insulin, while casting doubts about the utility of bicarbonate therapy. Moreover, these studies have established 13-adrenergic agonists as useful adjuncts to insulin for the acute treatment of hyperkalemla. The following section will examine some of the studies that have led to a change in our thinking. To understand the rational treatment and prevention of hyperkalemia in ESRD patients. It is necessary to understand the physiologic mechanisms that regulate potassium homeostasls. Extracellular potassium concentration Is determined by two distinct regulatory systems (3) (Figure 1). The first system maintains external potassium balance by regulating potassium excretion according to dietary intake. On a typical American diet containing approximately 100 mmol of potassium per day, 90 to 95 mmol Is excreted by the kidneys and 5 to 10 mmol is excreted by the gut. The excretion of an acute potassium load is a relatively slow process, requiring several hours for completion (4). In ESRD patients, there is an adaptive Increase in potassium excretion by the gut (5-9). Nevertheless, this adaptation is insufficient to compensate for the loss of renal excretory capacity. The second homeostatic system maintains internal potassium balance by regulating potassium shifts between the intracellular and extracellular fluid compartments. Internal balance can be achieved much faster than external balance: an acute potassium load Is shifted into the cells within minutes (2). Total body potassium is about 3.300 mmol. Only 2% (about 65 mmol) Is in the extracellular fluid compartment, whereas 98% Is in the intracellular fluid compartment, primarily in skeletal muscle and to a lesser extent In liver. This uneven distribution means that relatively small shifts of potassium from the intracellular to the extraceilular fluid compartment can produce severe hyperkalemla. Conversely, relatively small potassium shifts from the extracellular to the intracellular fluid compartment can produce a marked decrease in plasma potassium. Extrarenal
potassium disposal (shifts from the extracellular to

ecent review articles have discussed in depth the pathogenesis and management of potassium disorders in patients with ESRD (1,2). The goal of this editorial review Is to focus primarily on recent clinical investigations that have enhanced our understanding of potassium homeostasis in hemodialysls patients and to consider their Implications for the treatment and prevention of hyperkalemla in dialysis patients.

ACUTE TREATMENT PATIENTS


The ESRD definitive patients

OF HYPERKALEMIA

IN ESRD
in by

treatment of severe hyperkalemia is the removal of excess potassium


Because a 1- to 2-h
Accepted
in part

emergent ysIs often


1

hemodialysis. Involves
7, 1995.

the delay,
1995. 27th

initiation of dialmore Immediate

Received

February
Society
Birmingham,

April 26,
at

2The
American

manuscript

was

presented

the

annual

meeting
1994).

of

the

3Corresponderrce
Street,
Journal

ot Nephroiogy in Orlando to Dr. M. Ailon, Division


AL 35294.

(October of Nephroiogy,

26-29,

668 LHR, 701 South

19th

1046.6673/0604-1

134$03.00/0
American 1995 by the

of

the

Society
American

Copyright

of Nephrology Society of Nephrology

the

intracellular

fluid

compartment)

assumes

a criti-

1134

Volume

Number

1995

Allon

Plasma mmol/L

Potassium,

B,carbonate

Epoephr.ne

insuhn/glucose

-1

O-

STOOL 5-10E/day

D,aiyss

-1

5O 10 20 30
of

1#{149}

Figure 1. Internal and external potassium balance In humans. Reproduced with permission from Ref. 3. Gl, gastrointestinal; RBC, red blood cells.

40
Treatment,

50

60
mm

Duration

role in the defense against hyperkalemia In ESRD patients. The two major physiologic factors that stimulate extrarenal potassium disposal are insulin and epinephrine. Flatman and Clausen (10) observed the stimulation of potassium Influx in isolated skeletal muscle fibers incubated with insulin or epinephrine. Simultaneous exposure to both hormones produced an additive effect on potassium Influx, suggesting different cellular mechanisms. These observations would suggest that both insulin and epinephrine may be useful for the treatment of hyperkalemia In dialysis patients. Whereas Insulin is routinely used for this purpose in clinical practice. epinephrine is not. The potassium-lowering effect of insulin in normal individuals is well established and dose dependent; It is increased progressively, going from moderate physcal iologic doses to high physiologic doses to phannaco-

Figure 2. Changes in plasma potassium during the Intravenous infusion of 8.4% bicarbonate, epinephrine, or Insulin In glucose and during hemodialysis. Values represent means SE. Reproduced with permissIon from Ref. 16.

logic doses (11). The effect of insulin on potassium uptake Is distinct from that of eplnephrine. because p-adrenergic blockade does not attenuate the decrease in plasma potassium during insulin administration (12,13). Several studies have documented the efficacy of intravenous insulin in the acute treatment of hyperkalemia in ESRD patients (14-17) (Figure 2). The magnitude of decrease in plasma potassium after insulin administration In hemodialysis patients is comparable to that obtained in normal controls (14). Interestingly, the effect of insulin on cellular potassium uptake can be dissociated from its effect on glucose uptake. This dissociation was demonstrated In an elegant clinical study that measured plasma potassium In the brachial artery and vein of normal controls before and during a continuous infusion of insulin into the brachial artery (18). Insulin increased
the arteriovenous gradIent for both potassium and

glucose.

However,

the

concomitant

Infusion

of

ouabaln with insulin prevented the stimulation of potassium uptake, without affecting glucose uptake. Thus, the effect of Insulin on potassium uptake appears to be mediated by enhanced activity of the Na-K pump, whereas the stimulation of glucose uptake is achieved by a membrane-bound glucose transporter (19). These two effects of insulin are often dissociated In hemodialysis patients. As a result, ESRD patients are relatively resistant to the glucose-lowering effect of insulin (20-22), yet responsive to Its potassium-lowering action (14). When treating hyperkalemia, dextrose is routinely administered in conjunction with Insulin, to avoid the anticipated hypoglycemia. Because exogenous glucose stimulates endogenous insulin secretion, one might be tempted to administer dextrose alone. Such an approach is ill advised in the emergent situation. If endogenous insulin Is not secreted (as might occur in insulin-dependent diabetics or in patients with inadequate insulin reserve), the resulting hyperglycemia Is likely to aggravate the hyperkalemla (23-26). An acute worsening of hyperkalemia Is not unique to hyperglycemia; any maneuver that increases plasma osmolalIty promotes potassium shifts from the intracellular to the extracellular fluid compartments. Thus, for example, acute Infusions of mannitol, hypertonic saline, and hypertonic arginine in dialysis patients also raise plasma potassium acutely (27-29). The hyperkalemic effect of hyperosmolality Is independent of changes in plasma insulin, cartecholamines, or acid-base status (28). Epinephrlne at physiologic doses produces hypokalemla acutely In normal controls (30-34). The stimu-

Journal

of the American

Society

of Nephrology

1135

Hyperkalemia

in ESRD

of extrarenal potassium disposal by epinephrine is mediated by J3-2 adrenergic receptors. It is prevented by /3-2 selective blockers and by nonselective /3 blockers, but not by /3-1 selective blockers (30.32,35). The ability of intravenous /3-2 agonists to induce hypokalemla in normal IndivIduals (36,37) suggests their potential utility for acute therapy of hyperkalemla in hemodlalysls patients. Montoliu eta!. (38) first reported that intravenous albuterol (0.5 mg),
latlon
a /3-2 agonIst, acutely lowers plasma potassium in

hemodialysls patients. The effect was maximal (1.1 mmol/L reduction) at 30 mm and was sustained for at least 3 h. In several patients, hyperkalemic electrocardiographic changes resolved after the administration of albuterol alone, in the absence of Intravenous calcium or any other measures to lower plasma potassium. Subsequent studies have confirmed the efficacy of Intravenous albuterol In the acute treatment of hyperkalemla In patients with renal failure (17,39,40). Neither albuterol nor any other /3-2 selective agonist Is available for Intravenous use In the United States. However, selective (3-2 agonists are available in nebulized form for the treatment of asthma. Moreover,
nebullzed albuterol (and other /3-agonists) produces

eightfold higher than those used to treat asthma. raising concerns about potential adverse cardiovascular effects. The mean increase in heart rate in our double-blinded study was 6 beats/min with 10 mg of albuterol and 8 beats/min wIth 20mg of albuterol (45) (Figure 3). There were no significant changes in blood pressure, and no patient developed chest pain or arrhythmias. Several subsequent investigations have similarly reported stable blood pressures and clinically insignificant Increases in heart rate after the nonblinded administration of albuterol at similar nebulized doses to ESRD patients (15,40,46). An increase in plasma glucose after intravenous and nebulized albuterol has been observed in a number of studies, but this has not been clinically significant (-2 to 3 mmol/L). A direct comparison between intravenous (0.5 mg) and nebullzed (10 mg) albuterol in ESRD patients revealed a similar magnitude of decrease in plasma potassium (40). The onset of the potassium-lowering effect was somewhat slower with the nebulized drug than with the intravenous form. On the other hand,
nebulized aibuterol produced less tachycardia than

hypokalemla in normal controls (4 1-44). Indicating significant systemic absorption of the inhaled drug. To determine whether nebulized albuterol was useful for the acute treatment of hyperkalemla in ESRD patients, we studied ten hemodialysis patients In a double-blinded, crossover trial (45). Each subject received 10 or 20 mg of nebulized albuterol or nebulized placebo (saline) inhaled over 10 mm. Plasma potasslum decreased by about 0.6 mmol/L after 10 mg of albuterol and by about 1.0 mmol/L after the 20-mg dose (Figure 3). A significant decrease In plasma potassium was first noted after 30 mm. Albuterol was equally efficacious in diabetic and nondlabetic patients. In contrast, nebulized placebo did not lower plasma potassium. Subsequent studies have confirmed the utility of nebulized albuterol (10 to 20 mg) In lowering plasma potassium acutely (15.40,46). -J The doses of albuterol required to achieve a significant reduction in plasma potassium are fourfold to

the intravenous form. Thus, nebulized albuterol may be safer than the intravenous form in patients with known or suspected coronary artery disease. It Is Important to note that a subset of ESRD patients are refractory to the potassium-lowering effect of albuterol (K 0.4 mmol/L). In various studies, these have ranged from 20 to 40% of dialysis patients studied (15,40.45). Similarly. even pharmacologic doses of epinephrine do not lower plasma potassium in some dialysis patients (47.48). The reason for this resistance has not been elucidated. Because we cannot prospectively Identify which patients are resistant to albuterol, It Is critical to treat severe hyperkalemla with intravenous insulin, as well as albuterol. The potassium-lowering effect of albuterol in ESRD patients Is additive to that of insulin. We found that Intravenous insulin (10 U bolus) and albuterol (20 mg nebulized over 10 min) each lowered plasma potassium by approxImately 0.6 mmol/L, whereas in combination, they lowered plasma potassium by about 1.2

I
Figure 3. The effect of nebulized
1136

30

60
Time,

90 minutes

120

TIme,

minutes

albuterol in doses of 10 mg (solid bar) or 20 mg (stippled bar) or of nebulized placebo (open bar) on the plasma potassium concentration (left panel) and heart rate (right panel) of hemodlalysis patients. Values represent means SE. P < 0.05 versus nebulized placebo. p < 0.05 versus 10 mg of albuterol. Adapted from Ref. 45.

Volume

6-

Number

1995

Allon

mmol/L (15). A similar additive effect has also been reported with intravenous albuterol and Insulin (17). This additive effect is consistent with the in vitro observations in isolated skeletal muscle fibers (10). Albuterol may also attenuate insulin-induced hypoglycemia in hemodialysis patients. Dextrose is administered routinely with intravenous Insulin to prevent the predictable hypoglycemia. Nevertheless, hypoglycemia (frequently asymptomatic) may be a common event after such therapy. For example, we documented hypoglycemia (plasma glucose < 3 mmol / L) in 9 of 12 hemodialysis patients 1 h after they received 10 U of regular insulin and 25 g of dextrose as an intravenous bolus (15). The high incidence of hypoglycemia may reflect, in part, a defect in the activation of counterregulatory sympathetic discharge m ESRD patients (49). When nebulized albuterol was given concurrently with the same regimens of insulin and dextrose, only 2 of 10 patients developed hypoglycemia. This salutory action of albuterol is likely mediated by the $3-adrenergic stimulation of gluconeogenesis (50). In contrast to /3-adrenergic stimulation, which enhances potassium influx into the cells, a-adrenergic stimulation enhances potassium efflux out of the cells (51.52). Hence, the effect of epinephrine, a mixed aand /3-blocker, on plasma potassium reflects the relative effects of a- and /3-adrenergic stimulation on
plasma potassium. Hemodialysls al. (34) (0.015 patients are that
resis-

?
E

0.41

Alpha

Beta

cm

0.2

#{149} Transplant

___
Dialysis

Control

-0.8 0.01 0.02

II!
0.04

Pure Alpha
0.8
0

E E
to 0 a.

0.6 0.4 0.2

a, cm C
to

C 0

0.0 0.01 0.02 0.04

tant For

to the potassium-lowering example, Gifford et


dose of epinephrine

effect

of epinephrlne.
a low

found

kg per min) lowered plasma potassium by about 0.4 mmol/L In normal controls but had no effect in hemodialysis patients. Similarly, Blumberg et at. (16) observed no significant change In plasma potassium during the infusion of epinephrine at high physiologic doses (0.05 pg/kg per min) in hemodIalysis patients (Figure 2). These findings are in contrast to the potassium-lowering effects of /3-2 agonists in ESRD patients, suggesting a possible imbalance between a- and /3-adrenergic effects on potassium In dialysis patients.
physiologic To evaluate this possibility, we gave ESRD patients and normal controls at three physiologic

g/

-J
0

E
E E
tn
U,

a 0
0.

C a, C r
to

cm

a graded
doses

(33).

In normal

controls,

Infusion of epinephrmne (0.01 to 0.04 ,.tg/kg per mm) increasing doses of epmnephgreater decreases in hemodialysis in pa-

0.01 Epinephrine

0.02

0.04

dose (ig/kgJmin)

rifle produced plasma potassium.

progressively In contrast,

Figure
(means

4. Changes

SE) from

in serum potassium concentration baseline during the infusion of Intrave-

tients, epmephrine at the lowest dose actually increased plasma potassium, suggesting a predominant a-adrenergic effect. Even the highest dose of epinephnine did not significantly decrease plasma potassium
in ESRD patients (Figure 4). To indirectly assess the

nous epinephrine at three doses in normal controls, hemodialysIs patients, and renal transplant patients (serum creatmine <2 epinephrlne

a-adrenergic component of epinephrine, the identical infusion protocol was repeated during concurrent /3 blockade with propranolol. a-Adrenergic stimulation raised plasma potassium in a dose-dependent manner in both experimental groups. The magnitude of this increase was significantly greater. however, in dialysis patients (0.7 mmol/L) than in normal controls (0.3 mmol/L). Finally, the concomitant infusion of the

plus f3-adrenerglc stimulation), the middle panel shows the effect of epmnephrlne during $3 blockade (pure a effect), and the lower panel shows the calculated pure /3 effect. The changes in potassium in the upper and middle panels were signifIcantly (P < 0.05)
(a-

mg/mi). alone

The

upper

panel

shows

the

effect

of

different In the dialysis patients as compared with those in the controls and transplant patients. Reproduced with per-

mission from Ref. 2.

Journal

of the

American

Society

of Nephrology

1137

Hyperkalemia

in ESRD

a-blocker phentolamine overcame the resistance to the potassium-lowering effect of epinephrine in the dialysis patients (33). In summary, these studies suggest that the resistance to the potassium-lowering
effect of epmnephrmne In hemodlalysis patients Is due to

Whether
ate

a similar synergism exists between adrenerglc agonists is unknown. The removal of potassium by hemodialysis
and (3-2 by the

bicarbonis largely

determined

between
sures that

the

plasma
acutely

an enhanced a-adrenerglc response. Interestingly, this acquired resistance Is reversed after successful renal transplantation (2) (FIgure 4). Bicarbonate therapy has long been assumed to be effective for the acute treatment of hyperkalemia In dialysis patients. It is presumed that the metabolic
acidosls stimulating lar to the of renal net failure potassium promotes shifts hyperkalemia from the intracelluby

potassium concentration and the dlalysate shift potassium from

gradient (62,63). Meathe extracel-

lular duce

extracellular alkallnization should effect of acute acid


Inconsistent. (1to 3-h) plasma

fluid reverse infusion

compartment this action. on plasma


of animals, mineral organic

and However, potassium


the acids

that the is
acute raises no

to the intracellular fluid compartment will rethis gradient and thereby attenuate potassium removal by the subsequent dialysis treatment. Such an effect of insulin is suggested by studies demonstrating less dialytic potassium removal with glucosecontaining dialysate as compared with glucose-free dialysis (64). Thus, one might anticipate that aggressive therapy with insulin and albuterol for hyperkalemia may attenuate the removal of potassium in the subsequent dialysis treatment. Such a phenomenon
might potentially lead to a rebound hyperkalemia

In nephrectomlzed administration whereas

several

hours

after

the

dialysis

session.

potassium,

acids

have

effect (53-56). The effect of acute acid administration on plasma potassium in dialysis patients has not been reported. Acute (1- to 3-h) bicarbonate administration to nephrectomlzed animals has lowered plasma potassium in some studies (56,57), but not in others (54,55). SodIum bicarbonate infusion in hyperkalemic
dialysis patients lowers plasma potassium after 6 to 24 h (58). However, to be useful for acute therapy, the changes should occur within about 1 h. Blumberg et a!. (16) found that neither hypertonic nor isotonic

PREVENTION
Given
potassium clearly

OF HYPERKALEMIA

IN ESRD PATIENTS

central role of the kidneys in maintaining homeostasis. dietary potassium restriction plays an Important role in the prevention As nephrologists, we whenever we encounter
patients. We then ask

the

of

hyperkalemia. dietary excess


in hemodialysis

tend to assume hyperkalemia


the dietitians to

intravenous bicarbonate in hemodlalysis patients tion. This was in contrast


and hemodlalysis to lower

lowered plasma potassium during 60 mm of observato the abifity of both insulin


plasma potassium (Figure

2). Even 3 h after intravenous or Isotonic) administration, decrease in plasma potassium


spite substantial Increases

bicarbonate (hypertonic there was no significant in ESRD patients, dein plasma bicarbonate

(59). In fact, serial plasma potassium measurements for 6 h after bicarbonate administration found the earliest decrease at 4 h (60). In summary, although bicarbonate administration lowers plasma potassium chronically In ESRD patients. It does not do so in a
timeframe useful for the emergent treatment of hy-

provide the patients with appropriate dietary guidelines. It Is important, however, to recognize some nondietary factors that may predispose to hyperkalemia in hemodialysls patients. Thus, for example, there is convincing evidence for the impairment of extrarenal potassium disposal in ESRD patients. In a recent study, we gave fasted hemodialysis and control subjects a small oral potasslum load (0.25 mmol/kg, or about 20 mmol for an 80-kg patient). The mean increase in plasma potassium was substantially greater In hemodialysis patients than in controls (0.8 versus 0.4 mmol/L) and

perkalemia. Of course, bicarbonate therapy Is still indicated for the acute management of severe metabolic acidosis. A recent abstract suggested that bicarbonate administration may potentiate the potassium-lowering action of Insulin in hemodialysis patients (61).
Whereas bicarbonate administration by Itself had no

could not all be accounted for by renal excretion (65). Similar observations were reported by Fernandez et at. (66). These clinical observations in ESRD patients are also in agreement with the impairment of ouabamninhibitable rubidium uptake by skeletal muscle from uremic rats (67,68). Patients do not usually eat potassium by itself. They
eat foods that contain drate. The endogenous potassium, insulin as well that is as carbohyreleased in

potassium after 60 min In eight hemodialysis patients, It enhanced the potassium-lowering effect of insulin. Plasma potassium was decreased by 0.6 mmol/L after insulin alone and by 1.0 mmol/L after insulin plus bicarbonate. The cellular mechanism of this synergIsm Is unexplained but may Involve pH-dependent changes in the insulin receptor. If this study Is confirmed, It may provide a rationale for the administration of bicarbonate for the acute treatment of hyperkalemla in ESRD patients.

significant

effect

on plasma

response to the carbohydrate promotes extrarenal potassium disposal. We found that the ingestion of 50 g of glucose along with an oral potassium load (0.25 mmol/kg) attenuated the mean rise In plasma potassium from 0.8 to 0.3 mmol/L (65). If one assumes that the extracellular fluid compartment is approximately 20% of total body water and that all the ingested potassium (0.25 mmol/kg) remains in the extracellular fluid compartment, then one would predict a 1.25 mmol/L increase in plasma potassium. The actual measured increases suggest that endogenous insulin
approximately doubles extrarenal potassium dis-

1138

Volume

Number

1995

Allon

posal.
constitutes

from

36

to after

76%. an oral

Thus,

dietary
against

carbohydrate
life-threatening load in dialysis
0

a major

defense

4.8

hyperkalemia patients.

potassium

The ability of exogenous insulin to lower plasma potassium acutely has been discussed earlier. What Is less well appreciated is that even the low circulating

,g.
E
U,
U,

4.6

4.2

insulin concentrations present during prolonged fasting constitute an important defense against hyperkalemia. Thus, the Inhibition of endogenous insulin secretion in normal, fasting controls results in a
significant insulin increase levels may in plasma potassium (69). be particularly important hyperkalemia is suggested in dialysis Fasting in the patients.

U,
0

a.
U,

3.8
3.6 3.4
-I

E
.!
0.

0)

#{149}

defense against This conclusion

somatostatin
a greater

administration in plasma than in control animals (68). The decrease in plasma insulin
increase transition from is not sufficient a postprandial to raise plasma

by the finding that acute to fasting rats produced potassium in uremic rats that occurs in the

12

18

state to a fasting state potassium In Individ-

30,

uals with normal excess potassium to the extracellular


the kidneys. tion, however, In

renal function (70). that is shifted from fluid compartment


the absence prolonged

Presumably, the intracellular is excreted

the by
to

.E
0,

20

of renal excretory fasting may predispose

func-

hyperkalemia. Thus, Gifford et a!. (34) fasted nondlabetic hemodlalysis patients and normal controls for 26 h. Plasma potassium increased by about 0.5 mmol / L in ESRD patients but did not change in the controls. This observation suggests that prolonged fasting may be an Important cause of hyperkalemia
when hemodialysis diagnostic procedure. patients are fasted for surgery or a

I
the

i:
V
I
#{149}

6 Hours

12 of Fasting

18

To be

determine prevented

by

whether fasting hyperkalemia exogenous insulin, we


patients potassium

could fasted 10
mea(70).

nondiabetic sured serial

hemodialysis plasma

for 18 h and concentrations

On a second continuous

occasion, the same patients received a infusion of 10% dextrose with 20 U of regular insulin per liter, infused at 50 mL/min (or 1 U of insulin/h). This insulin infusion regimen doubled
fasting pletely sium doses plasma insulin from 10 to 20 mU/L prevented the 0.6 mmol/L increase observed during fasting (Figure 5). of exogenous insulin can potentially and comin potasEven low

Figure 5. Serial plasma potassium and Insulin concentrations during an 18-h fast in hemodlalysis patients In the absence (solid squares) or presence (open squares) of a continuous physiologic infusion of insulin (1 U/h) with dextrose (5 glh). Values represent means SE for 10 patIents. p < 0.05 and P < 0.01 versus the value at 6 h of fasting; P < 0.01 versus
corresponding value In the control experiment. Repro-

duced
fasting

with permission
plasma Insulin

from Ref. 70.


concentrations, thereby pro-

produce evaluate whether exogenous glufasting hyperkalemla. by stimulating endogenous Insulin secretion, we restudied some patients with an infusion of 10% dextrose alone. This attenuated the rise in plasma potassium during prolonged fasting but was not as effective as dextrose with insulin (70). Hyperkalemla is much less common In patients on continuous ambulatory peritoneal dialysis than In hemodialysis patients (71). This Is due, in part, to the hypoglycemia. cose can prevent To
continuous removal of potassium with continuous

moting extrarenal potassium disposal (72,73). Because /3-2 agonists decrease plasma potassium, one might expect /3-blockers to increase plasma potas-

sium. This is not a significant problem in individuals with normal renal function, because potassium transferred from the intracellular to the extracellular fluid compartment can be excreted by the kidneys. In the absence of renal excretory function, /3 blockade can aggravate hyperkalemia in ESRD patients. Thus, for example, a 10-day course of propranolol, a nonselective /3-blocker, increased predlalysis potassium by 0.7

ambulatory peritoneal dialysis. However, another contributory factor Is the continuous absorption of glucose from the dialysate, which results in increased

mmol/L In a group of hemodialysis patients. trast, the /3-1 selective blocker atenolol did crease plasma potassium in the same group
tients (74). Similarly, exercise-induced

In connot inpa-

of hyperkalemla

in ESRD

patients

is augmented

by

the

nonselective

Journal

of the American

Society

of Nephrology

1139

Hyperkalemia

in ESRD

/3-adrenergic
the /3-1

blocker
selective

propranolol
blocker metoprolol

but prescribe

is not
(75)

affected
(Figure

by
6).

TABLE 1. Changing concepts in the management hyperkalemia in dialysis patients Conventional Wisdom New Wisdom

of

Thus, one should preferentially blockers in dialysis patients.

/3-1 selectIve

A recent abstract described the potential utility of chronic oral 13-adrenerglc administration (albuterol, 2 mg twice daily) In the prevention of hyperkalemla in hemodialysis patients (76). The predialysis plasma potassium was decreased by 0.6 mmol/L after 2 wk of

Bicarbonate decreases plasma potassium acutely.


-

oral
from and

albuterol.
the study

However,
because

3 of the

12 patients

withdrew
palpitations Insulin decreases plasma

Bicarbonate is not effective for acute therapy of hyperkalemla. Albuterol decreases plasma potassium acutely.
Insulin decreases plasma

of unacceptable

tremor. Further studies are indicated to evaluate this prophylactic measure In hemodialysis patients with persistent hyperkalemia not responsive to dietary potassium restriction. Mlneralocorticolds play an important role In maintaining potassium and humans fed homeostasis In normal animals

potassium

acutely.

potassium

acutely,

and

Hyperkalemia
dietary

is due to

excess.

i.

a high-potassium diet by enhancing renal potassium excretion (77,78). In addition, there is conflicting experimental evidence on the effect of mmeralocorticolds on extrarenal potassium disposal (2). Sugarman and Brown (79) studIed the effect of chronic mineralocortlcold administration on the dis-

albuterol has an additive effect. Hyperkalemia may be due to dietary excess, but fasting and $3-blockers are also important factors.

TABLE 2. Treatment in dialysis patients: Acute Treatment


1. Calcium gluconate,

and prevention of hyperkalemia specific guidelines


10% solutIon,
10- to 20-mi iv

of Severe Hyperkalemia

Exercise

Recovery

bolus. May be repeated every 5 mm, if electrocardiographic appearance does not improve.
2. Regular insulin, bolus, followed 10 U + 50 ml of 50% dextrose, by 10% dextrose 0 50 mL/mln as iv until

0.6

0.5

dialysis initiated. 3. Albuterol (5 mg/mi), mm. 4. Acute hemodialysis Prevention

10 to 20 mg, nebulized

over 10 bath.

against

a low potassium

0.4

0.3
Ut

0.2
*

*
0.1

of Hyperkalemia potassium restriction, 40 to 50 mmoi/day or 1.5 to 2.0 g/d. 2. Avoidance of nonselective /3-blockers. If 13-blockers are clinically indicated, use /3-1-selective blockers, e.g., atenolol or metoprolol. 3. During prolonged fasting in diabetic dialysis patients, infuse: 10% dextrose + 10 U of regular insulin/I 0 50
1. Dietary mi/h. During prolonged fasting in nondiabetic

0.0

dialysis

patients,
-0.1

infuse: 10% dextrose

0 50 mL/h.

-0.2

posal of patients. blunted


0 10

an

acute

potassium

load

in

The the

prior increase

exogenous
deoxycorticosterone

administration potassium
the

hemodialysis of the
for 60 h

mineralocorticoid
-0.3

acetate

in

plasma

after

an

20

30
Time,

40
minutes

50

60

70

acute tration

potassium of the

load. aldosterone

Conversely, antagonist

prior adminisspironolactone

Figure 6. Time course of change in plasma potassium concentration in dialysis subjects during exercise alone (open circles), exercise plus propranolol (closed circles), and exercise plus metoprolol (closed triangles). All values represent mean SE. P < 0.05 versus control study. P < 0.05 versus
metoprolol study. Reproduced with permission from Ref. 75.

augmented the hyperkalemic response to the potassium load. These intriguing observations suggest that exogenous mineralocorticoids may be a useful modality for the prevention of hyperkalemia in hemodialysis patients. In summary, clinical investigations performed In the past few years have enhanced our understanding of

1140

Volume

Number

4-

1995

Alion

the

mechanisms

of hyperkalemia
the guidelines of hyperkalemia for the

in ESRD
acute

patients.
and of
16.

As a result, prevention

treatment

lin-mediated potassium healthy subjects. Am 15.

uptake J Physiol hemodlalysIs

may need intravenous


mia ties associated remains

in hemodlalysis patients to be revised (Tables 1 and 2). The utility calcium and insulin for acute hyperkalewith electrocardiographic unchallenged. In contrast, abnormalithe efficacy

Allon

M, Copkney

C: Albuterol

of hyperkalemia in 1990:38:869-872. Blumberg A, Weidinann

is normal in uremic and 1984;246:El74-E180. and insulin for treatment patients. Kidney Int S. Gnadinger M: Effect

of various
of 17.

therapeutic

P, Shaw approaches

on plasma

potassium

intravenous perkalemia
Albuterol,

appears lowering whereas


Important

bicarbonate for the treatment of hyis not supported by prospective studies. in either intravenous or nebulized form, to be a useful adjunct to the potassiumaction of intravenous insulin. Finally, dietary potassium restriction remains an
measure for the prevention of hyperkale-

18.

19.

mia, we have become more aware of nondietary contributing to hyperkalemia, including fasting and nonselective /3-blockers.

factors prolonged

20. 21.

ACKNOWLEDGMENTS
The author individuals
patients: Copkney, gratefully

to
Nancy

his

acknowledges Investigations
Linda

the contributions of the following of potassIum homeostasis In ESRD


Dansby, Azlta Takeshian. Charles

Shanklin.

22. 23. 24. 25.

and

Robert

Dunlay.

REFERENCES
1. Salem MM, Rosa RM, Baffle DC: Extrarenal potassium tolerance In chronic renal failure: Implications for the treatment of acute hyperkalemia. Am J Kidney DIs 1991; 18:42 1-440. 2. Allon M: Treatment and prevention of hyperkalemia in end-stage renal disease. Kidney mt 1993:43:1197-1209. 3. DeFronzo RA, Bia M. Extrarenal potassium homeostasis. In: Seldin DW, Gleblsch G. Eds. The Kidney. Physiology and Pathology. New York: Raven Press; 1985: 1179-1206. 4. Kurtzman NA, Gonzalez J, DeFronzo RA, Giebisch G: A patient with hyperkalemla and metabolic acidosis. Am J Kidney Dis 1990;15:333-356. 5. Hayes CP, McLeod ME, Robinson RE: An extrarenal mechanism for the maintenance of potassium balance In severe chronic renal failure. Trans Assoc Am Phys 1967; 80:207-2 16. 6. Basil C, Hayslett JP. Binder HJ: Increased large Intestinal secretion of potassium in renal insufficiency. Kidney mt 1977;12:9-16. 7. Sandle GI, Galger E, Tapster S. Goodship THJ: Evidence for large Intestinal control of potassium homeostasis In uremic patients undergoing long-term dialysis. Clin Sd 1987:73:247-252. 8. Panese S. Martin RS, Virginillo M, Litardo M, Arrizurieta E, Hayslett JP: Mechanism of enhanced transcellular potassium secretion In man with chronic renal failure. Kidney mt 1987;3 1:1377-1382. 9. Martin RS, Panese S. Virginillo M, et at.: Increased secretion of potassium in the rectum of humans with chronic renal failure. Am J Kidney Dis 1986:8:105-110. 10. Flatman JA, Clausen T: Combined effects of adrenaline and Insulin on active electrogenlc Na+-K+ transport In rat soleus muscle. Nature 1979:281:580-581. 11. DeFronzo RA, Felig P. Ferrannini E, Wahren J: Effect of graded doses of Insulin on splanchnlc and peripheral potassium metabolism In man. Am J Physlol 1980:238: E421-E427. 12. Massara F, Camanni F. Molinatti G: Effect of propranolol on some adrenalineand Insulin-induced metabolic changes In man. Acta Diabetol Lat 1975:12:41-51. 13. Mlnaker KL, Rowe JW: Potassium homeostasis dunn hyperinsulinemia: effect of insulin level, b-blockade, an age. Am J Physiol 1982:242:E373-E377. 14. Alvestrand A, Wahren J, Smith D, DeFronzo RA: Insu-

and major regulating factors In terminal renal failure. Am J Med 1988:85:507-5 12. Lens XM, Montollu J, Cases A, Campistol JM, Revert L: Treatment of hyperkalemia In renal failure: Salbutamol v Insulin. Nephrol Dial Transplant 1989:4:228-232. Ferrannini E, Taddei S. Santoro D, et aL: Independent stimulation of glucose metabolism and Na+-K+ exchange by insulin in the human forearm. Am J Physlol 1988;255:E953-E958. Hirshman MF, Goodyear U, Wardzala U, Horton ED, Horton ES: Identification of intracellular pool of glucose transporters from basal and insulin-stimulated rat skeletal muscle. J Biol Chem 1990:265:987-99 1. SmIth D, DeFronzo RA: Insulin resistance in uremia mediated by postblnding defects. Kidney mt 1982:22: 54-62. Alvestrand A, Mujagic M, Wajngot A, Efendlc 5: Glucose Intolerance In uremic patients: The relative contributions of Inpaired beta-cell function and Insulin resistance. Clin Nephrol 1989:31:175-183. Hager SR: Insulin resistance of uremia. Am J Kidney Dis 1989:14:272-276. Vlberti GC: Glucose-induced hyperkalemia: A hazard for diabetics? Lancet 1978:1:690-691. Nicolis GL, Kahn T, Sanchez A, Gabrllove JL: GlucoseInduced hyperkalemla In diabetic subjects. Arch Intern
Med 1981:141:49-53.

26.

Goldfarb S. Cox M, Singer I, Goldberg M: Acute hyperkalemia Induced by hyperglycemia: Hormonal mechanisms. Ann Intern Med 1976:84:426-432. Sunderlin FS, Anderson GH, Streeten DHP, Blumenthal SA: The renin-angiotensin-aldosterone system In diabetic patients with hyperkalemia. Diabetes 1981:30:
335-340.

27.

Moreno

28.

M, Murphy C. Goldsmith C: Increase in serum potassium resulting from the administration of hypertonic mannitol and other solutions. J Lab Clin Med 1969:73:291-298. Conte G, Dal Canton A, Iniperatore P. et at.: Acute increase in plasma osmolality as a cause of hyperkalemia In patients with renal failure. Kidney Int 1990:38:
301-307.

29.

30. 31.

Hertz P. Richardson JA: Arginine-induced hyperkalemia in renal failure patients. Arch Intern Med 1972:130: 778-780. Brown MJ, Brown DC, Murphy MB: Hypokalemla from beta2-receptor stimulation by circulating eplnephrlne. N

Engl J Med 1983:309:1414-1419. Brown RS: Extrarenal potassium


Int 1986:30:116-127.

homeostasis.

Kidney

32.
33. 34. 35.

Struthers

AD, Reid JL: Adrenaline

causes
stimulation.

hypokalemla
Clin Endo-

In man by beta-2 adrenoceptor crlnol 1984:20:409-414. Allon M, Shanklin N: Adrenergic


nal potassium disposal In men

modulation of extrarewith end-stage renal

disease. Kidney Int 1991:40:1103-1109. Gifford JD, Rutsky EA, Kirk KA, McDanIel HG: Control of serum potassium during fasting In end-stage renal disease. Kidney Int 1989:35:90-94. Struthers AD, Reid JL, Whitesmith R. Rodger JC: The
effects of cardioselective and non-selective beta-

adrenoceptor
36.

blockade

on the hypokalemic

and
hormones

cardioin

vascular responses to adrenomedullary man. Clin Sd 1983:65:143-147. VIncent HH, Boomsma F. Man in t Veld Wenting GJ, Schalekamp MADH: Effects

AJ, Derkx FHM, of selective and

nonselective
37.

beta-agonists
J Cardlovasc JBD,

on

plasma
Pharmacol

potassium
1984:6:107-

and

noreplnephrine. 114. Nevifie A, Palmer

Murchison

LE: Metabolic

Gaddle J, May CS, Palmer KJV, effects of salbutamol: Compar-

Journal

of the

American

Society

of Nephrology

1141

Hyperkalemia

in ESPD

Ison 38. 39.

of aerosol

and

Intravenous

administration. L:

Bnit Med 60. Arch

with

end-stage

renal

disease.

Miner

Electrolyte

Metab

J 1977:1:413-414.
Montoilu J, Lens XM, Revert effect of albuterol for hyperkalemla
Intern

Potassium-lowering in renal failure.

1991:17:297-302. Blumberg A, Weidmann bicarbonate administration

P. Ferrari P: Effect of prolonged on plasma potassium in ter-

Med

1987:147:713-717.

minal 61.

renal

failure.

Kidney

Int 1992:41:369-374.

40.

41. 42.

Murdoch IA: Dos Anjos R, Haycock GB: Treatment of hyperkalemla with intravenous salbutamol. Arch Dis Child 1991:66:527-528. Liou HH, Chiang SS, Wu SC, et at.: Hypokalemic effects of Intravenous Infusion or nebulizatlon of salbutamol In patients with chronic renal failure: Comparative study. Am J Kidney DIs 1994:23:266-271. Lipworth BJ, Tregaskis BF, McDevitt DG: Betaadrenoceptor responses to inhaled salbutamol in the elderly. Br J Clin Pharmacol 1989:28:725-729. Lipworth BJ. McDevitt DG, Struthers AD: Prior treatment with diuretic augments the hypokalemic and electrocardiographic effects of Inhaled albuterol. Am J Med 1989:86:653-657.

62.

63. 64.

Kim HJ. Park CH. Ahn YH, Kang CM, Park HC: Synergistic effect of sodium bicarbonate and insulin In glucose in the therapy of hyperkalemia accompanied by metabolic acidosis [Abstract). J Am Soc Nephrol 1994:5:369. Williams AJ, Barnes JN. Cunningham J, Goodwin FJ, Marsh FP: Effect of diahysate buffer on potassium removal during hemodlalysis. Proc Eur Dial Trans Assoc 1984:21:209-214. Sherman RA, Hwang ER. Bernholc AS, Eisinger RP: Variability in potassium removal by hemodlalysis. Am J
Nephrol 1986:6:284-288.

Ward RA, Wathen RL, Williams TE, dialysate composition and intradlalytlc

base
135.

and

potassium

changes.

HardIng GB: Hemometabolic, acidKidney Int 1987:32:129-

43.
44.

Haalboom

JRE.

Deenstra

M. Struyvenberg

A: Hypoka1985:1:

lemla Induced by Inhalation of fenoterol. Lancet 1125-1127. Wong CS, Pavord ID, Williams J, Britton JR.

65. 66.
In for

field AE: Bronchodilator,


45.

cardiovascular,

and

Tattershypokale-

mid effects of fenoterol. salbutamol, and asthma. Lancet 1990:336:1396-1399. Allon M. Dunlay R, Copkney C: Nebullzed

tenbutaline albuterol

acute
46. Intern Montollu

hyperkalemla
Med

in patients

on

hemodlalysis.
JM, Revert

Ann
L:

67.

1989:110:426-429. J, Almirall J, Ponz

E. Campistol in

Treatment

of hyperkalemla modulation

47.
48.

mol inhalation. MartInez Vea


adrenerglc
in terminal Yang WC,

renal failure with salbutaJ Intern Med 1990:228:35-37. M, Montollu J, Andreu L, et aL: Betaof extrarenal potassium extrarenal disposal
YL, Baffle

68. 69.

uremia. Proc EDTA 1982:19:756-760. Huang TP. Ho LT, Chung HM, Chan

49.
50.

DC: Beta-adrenergic-medlated disposal in patients with end-stage of propranolol. Miner Electrolyte 193. Adrogue HJ: Glucose homeostasls

potassium

renal
Metab and
MW,

disease:
the

Effects
70.

1986:12:186-

kidney.

Kid71.

ney Int 1992:42:1266-1282.


Rizza RA, Cryer PE, Haymond

ergic cose 51.

mechanisms production

for the effects and clearance

Gerich JE: Adrenof epinephrIne on gluIn man. J Chin Invest

1980:65:682-689.

Williams ME, Rosa RM. Silva P. Brown RS. Epstein PH: Impairment of extrarenal potassium disposal by alphaadrenerglc stimulation. N EngI J Med 1984:311:145149. Williams amine ME. Gervino EV, Rosa RM, modulation of rapid potassium N EngI J Med 1985:312:823-827.

72.

52.

et aL: Catecholshifts during ex-

73.

53.
54.

55.

56.

ercise. Swan RC, Pitts RF: Neutralization of Infused acid by nephrectomized dogs. J Chin Invest 1955:34:205-212. Tobln RB: Varying roles of extracellular electrolytes In metabolic acidosis and alkalosis. Am J Physlol 195: 1958.685-692. Poole-Wilson PA. Cameron IR: Intracellular pH and K+ of cardiac and skeletal muscle in acldosis and alkalosls. Am J Physlol 1975:229:1305-13 10. Keating RE. Weicbselbaum TE. Alanis M. Margraf HW,

74.

75. 76.

Elman
57. 58.

R: The

movement

of potassium

during

experi-

mental acidosis and alkalosis in the nephrectomlzed dog. Surg Gynecol Obstet 1953:96:323-330. Swan RC, Axelrod DR. Seip M, Pltts RF: Distribution of sodium bicarbonate infused into nephrectomlzed dogs. J Clin Invest 1955:34:1795-1801. Fraley DS. Adler 5: Correction of hyperkalemla by bicarbonate despite constant blood pH. Kidney mt 1977:12:

77.
78.

Allon M, Dansby L, Shanklin N: Glucose modulation of the disposal of an acute potassium load In patients with end-stage renal disease. Am J Med 1993:94:475-482. Fernandez J, Oster JR. Perez GO: Impaired extrarenal disposal of an acute oral potassium load In patients with endstage renal disease on chronic hemodlalysis. Miner Electrolyte Metab 1986:12:125-129. Bonilla S. Goecke IA, Bozzo 5, Alvo M, Michea L, Marusic ET: Effect of chronic renal failure on Na,KATPase alpha-i and alpha-2 mRNA transcription in rat skeletal muscle. ,.J Chin Invest 1991:88:2137-2141. Goecke IA, Bonilla 5, Marusic ET, Alvo M: Enhanced Insulin sensitivity In extrarenal potassium handling In uremic rats. Kidney Int 199 1:39:39-43. DeFronzo RA. Sherwin RS, Diffingham M: Influence of basal insulin and glucagon secretion on potassium and sodium metabolism: Studies with somatostatin in normal dogs and In normal and diabetic human beings. J Clin Invest 1978:61:472-479. Allon M, Takeshian A, Shanklin N: Effect of Insulinplus-glucose Infusion with or without epinephrine on fasting hyperkalemia. Kidney Int 1993:43:212-217. Tzanialoukas AH, Avasthi PS: Temporal profile of serum potassium concentration In nondiabetic and diabetic outpatients on chronic dialysis. Am J Nephrol 1987:7: 101-109. Armstrong VW, Creutzfehdt W. Ebert R, Fuchs C, Hilgers R, Scheler F: Effect of dialysate glucose load on plasma glucose and glucoregulatory hormones In CAPD patients. Nephron 1985:39:141-145. Wideroe TE, Smeby LC. Myking OL, Wessel-Aas T: Glucose, insulin, and C-peptlde kinetics during continuous ambulatory peritoneal dialysis. Proc EDTA 1983: 20:195-200. Arrizabalaga P. Montoilu J, Martinez Vea A, Andreu L, Lopez Pedret J, Revert L: Increase in serum potassium caused by beta-2 adrenergic blockade In terminal renal failure: Absence of mediation by insulin or aldosterone. Proc Eur Dial Transplant Assoc 1983:20:572-576. Castellino P. Bia M, DeFronzo RA: Adrenergic modulation of potassium metabolism in uremia. Kidney Int 1990:37:793-798. Castro MCM, Freitas IF, Marcondes M, Sabbaga E: Prolonged beta adrenergic stimulation-A new way to reduce serum potassium concentration In hemodlalysis [Abstract]. Kidney Int 1994:46:1738. Field MJ, Glebisch GJ: Hormonal control of renal potassium excretion. Kidney mt 1985:27:379-387.
Stanton B,

Pan

L, Deetjen

H, Guckian

V. Giebisch

G:

354-360.
59. Guttierez R, Schlesslnger F, OsterJR, Rietberg B, Perez GO: Effect of hypertonic versus Isotonic sodium bicarbonate on plasma potassium concentration in patients 79.

Independent effects induction of potassium Invest 1987:79:198-206. Sugarman A, Brown potassium tolerance: ney Int 1988:34:397-403.

of aldosterone adaptation

and potassium on In rat kidney. J Chin aldosterone patients. in Kid-

RS: The role of Studies in anephrlc

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Volume

6 . Number

. 1995

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