Dépret et al. Ann.

Intensive Care (2019) 9:32

https://doi.org/10.1186/s13613-019-0509-8

REVIEW Open Access

Management of hyperkalemia in the acutely

ill patient
François Dépret1,2,3, W. Frank Peacock5, Kathleen D. Liu6, Zubaid Rafique5, Patrick Rossignol4,7
and Matthieu Legrand1,2,3,4*

Abstract 
Purpose:  To review the mechanisms of action, expected efficacy and side effects of strategies to control hyper-
kalemia in acutely ill patients.
Methods:  We searched MEDLINE and EMBASE for relevant papers published in English between Jan 1, 1938, and July
1, 2018, in accordance with the PRISMA Statement using the following terms: “hyperkalemia,” “intensive care,” “acute
kidney injury,” “acute kidney failure,” “hyperkalemia treatment,” “renal replacement therapy,” “dialysis,” “sodium bicarbo-
nate,” “emergency,” “acute.” Reports from within the past 10 years were selected preferentially, together with highly
relevant older publications.
Results:  Hyperkalemia is a potentially life-threatening electrolyte abnormality and may cause cardiac electrophysi-
ological disturbances in the acutely ill patient. Frequently used therapies for hyperkalemia may, however, also be
associated with morbidity. Therapeutics may include the simultaneous administration of insulin and glucose (associ-
ated with frequent dysglycemic complications), β-2 agonists (associated with potential cardiac ischemia and arrhyth-
mias), hypertonic sodium bicarbonate infusion in the acidotic patient (representing a large hypertonic sodium load)
and renal replacement therapy (effective but invasive). Potassium-lowering drugs can cause rapid decrease in serum
potassium level leading to cardiac hyperexcitability and rhythm disorders.
Conclusions:  Treatment of hyperkalemia should not only focus on the ability of specific therapies to lower serum
potassium level but also on their potential side effects. Tailoring treatment to the patient condition and situation may
limit the risks.
Keywords:  Hyperkalemia, Intensive care, Emergency, Renal replacement therapy, Acute kidney injury

Background abnormalities [7, 8]. However, the actual causes of death

Hyperkalemia is a potentially life-threatening electro- in patients with hyperkalemia are poorly described, and
lyte abnormality [1–3]. Although there is no interna- the causal relationship between hyperkalemia and out-
tionally agreed upon definition for hyperkalemia, the come remains controversial.
European Resuscitation Council defines hyperkalemia The aim of this review is first to describe mecha-
as a plasma level > 5.5  mmol/L and severe hyperkalemia nisms and the risk–benefit ratio of different strategies
as > 6.5  mmol/L [4]. Hyperkalemia is associated with of hyperkalemia treatment and second, to propose a
poor outcomes in many different settings, including the tailored treatment strategy. This will include a discus-
acutely ill patient [5, 6]. In acute hyperkalemia, the pri- sion of the effectiveness as well as complications of renal
mary mortality risks are cardiac rhythm or conduction replacement therapy, limiting the risk of hypoglycemia
with judicious insulin and glucose administration, and
*Correspondence: [email protected]
the potential benefit and risks of hypertonic sodium
1
GH St‑Louis‑Lariboisière, Department of Anesthesiology and Critical bicarbonate.
Care and Burn Unit, St‑Louis Hospital, Assistance Publique-Hopitaux de
Paris, Paris, France
Full list of author information is available at the end of the article

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 2 of 16

Methods lowers membrane resistance, increases repolarizing

We searched MEDLINE and EMBASE for relevant currents, and shortens transmembrane action potential
papers published in English between Jan 1, 1938, and duration.
July 1, 2018, in accordance with the PRISMA State- While rising serum potassium initially increases con-
ment using the following terms: “hyperkalemia,” “inten- duction velocity, it decreases it at higher levels [20]. Clas-
sive care,” “acute kidney injury,” “acute kidney failure,” sic hyperkalemia electrocardiographic findings include
“hyperkalemia treatment,” “renal replacement therapy,” signs of hyperexcitability such as peaked T-waves (reflect-
“dialysis,” “sodium bicarbonate,” “emergency,” “acute.” ing a decrease in the threshold for rapid depolarization).
Reports from within the past 10  years were selected Further, altered conduction may manifest as PR prolon-
preferentially together with highly relevant older gation, loss of P-waves, QRS widening, bradycardia, and
publications. ultimately a sine wave rhythm due to action potential
shortening and prolongation of diastolic depolarization.
Association between hyperkalemia and outcomes Importantly, the correlation between potassium eleva-
The potassium ion (­ K+) is the most abundant cation in tion and electrocardiographic (ECG) changes is poor.
the body. There is an estimated total reserve of 3000– Severe hyperkalemia may manifest with minimal or
4000  mmol in adults, of which only 60  mmol (2%) are atypical ECG findings [1–3, 21], including nonspecific
extracellular [9]. Hyperkalemia is associated with poor ST segment modification or pseudo-Brugada syndrome
outcomes in many different settings: in the general (featuring wide QRS, elevation of the ST segment, J-point
population [5, 6], in patients with cardiac and renal elevation, T-wave inversion). On the contrary moderate
disease [10–13] and in critically ill patients [14]. In a hyperkalemia (< 6  mmol/L) may have life-threatening
retrospective study of hospitalized patients, Khana- ECG findings. The electrocardiographic manifestations
gavi et al. [5] found that acute kidney injury (AKI) and of hyperkalemia are largely influenced by rapid changes
prolonged hyperkalemia are independent predictors of of plasma concentration [7], the gradient of potassium
in-hospital mortality. In acute myocardial infarction, a across the myocardial cell membrane, the effect of other
serum potassium above 4.5 mmol/L is associated with a ions (i.e., sodium, calcium), as well as underlying cardiac
higher mortality [11]. More recently, Legrand et al. [15] disease [22]. Retrospective data found a higher mortal-
identified that a serum potassium > 4.5 mmol/L in heart ity rate in patients with hyperkalemia showing abnormal
failure patients admitted to the emergency department ECG findings [23]. Along these lines, chronically dialyzed
(ED) is associated with an increased risk of death. patients may show no ECG signs of hyperkalemia despite
The net effect is a U-shaped mortality curve associ- high serum potassium levels. Altogether, more than the
ated with potassium abnormalities [16–19]. Several absolute serum potassium level, therapeutic strategies
observational studies have identified hypokalemia as an should be guided by the cardiac consequences of hyper-
independent risk factor for poor outcome [13, 16–19]. kalemia identified on the ECG (Fig. 1).
This association raises concern regarding the potential
for overcorrection, as may occur with some fast-acting Causes of hyperkalemia in acutely ill patients
potassium-lowering agents. However, these associa- Factors associated with the development of hyperkalemia
tions do not mean causality and thresholds for treating can be classified into three categories, and include altered
hyperkalemia remain debated. renal clearance of potassium (e.g., chronic kidney disease,
acute kidney injury, renin–angiotensin–aldosterone sys-
Cardiac manifestations of hyperkalaemia tem inhibitor), release from the intracellular space (e.g.,
Although patients with hyperkalemia can present rarely hemolysis, rhabdomyolysis, tissue injury) and altered
with weakness progressing to flaccid paralysis, pares- transfer to the intracellular space (e.g., acidosis, insulin
thesias, or depressed deep tendon reflexes, the clinical deficit, β-adrenergic blockers, heparin) (Table 1). Hyper-
presentation of hyperkalemia is usually benign until kalemia in the patient with normal renal function is
cardiac rhythm or conduction disorders occur. Eleva- unusual and should prompt evaluation for pseudo-hyper-
tion of extracellular potassium has several effects on kalemia if no ECG abnormalities consistent with hyper-
myocardial electrophysiology that contribute to intra- kalemia are identified (false elevation of potassium due to
cardiac conduction disturbances. The intracellular to hemolysis occurring with blood draw and not reflective
extracellular potassium gradient lessens when extracel- of the patient’s plasma potassium concentration). While
lular potassium increases, thus decreasing the resting concomitant medications (e.g., potassium supplements,
membrane potential. Elevated extracellular potassium penicillin G, digoxin, nonsteroidal anti-inflammatory
also increases membrane permeability for potassium, drugs, renin–angiotensin–aldosterone system inhibitor,
amiloride, triamterene, trimethoprim, pentamidine) are
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 3 of 16

Fig. 1  Suggested algorithm for hyperkalemia treatment in the acutely ill. *In case of Digitalis intoxication or hypercalcemia. **Sodium zirconium
cyclosilicate and patiromer when available, kayexalate if not available. ESKD end-stage kidney disease, AKI acute kidney injury, CKD chronic kidney
disease, RRT​ renal replacement therapy

often a contributor to hyperkalemia, in our experience transfer into the cell and higher extracellular potassium
they are rarely the only cause in acute settings. levels. In this line, utilization of balanced solutions with
Since the potassium pool is mostly intracellular, altera- physiological concentrations of chloride (i.e., Ringers
tion of cellular potassium uptake can be a major con- lactate) prevents the development of mineral metabolic
tributors to hyperkalemia [24]. Hyperchloremic acidosis acidosis and is associated with lower serum potassium
is frequent in acutely ill patients [25]. According to the levels compared to NaCl 0.9% [25, 27, 28]. The effect of
Stewart’s theory, the main determinant of acid–base metabolic acidosis appears less prominent when organic
balance is the strong ion difference (SID), essentially acids accumulate (i.e., lactate, phosphate). This is because
determined by the difference between the strong cation organic acids can passively diffuse into the intracellular
(sodium) and the anions (chloride) [26]. A possible mech- compartment, resulting in a larger fall in intracellular pH.
anism to explain hyperkalemia related to hyperchloremic The fall of intracellular pH stimulates inward N ­ a+ move-
+ +
acidosis is that mineral acids (i.e., chloric) cannot freely ment and maintains ­ Na –K -ATPase activity, which
diffuse into the intracellular compartment, they decrease minimizes the extracellular accumulation of potassium
extracellular pH. Low extracellular pH decreases the [29]. Ultimately, the increased intracellular N­ a+ concen-
­Na+–H+ exchange and inhibits the inward movement tration leads to the intracellular entry of potassium [29].
of ­Na+. The subsequent fall in intracellular N ­ a+ reduces A special warning should be made with regards to the
­Na –K -ATPase activity, leading to a net decrease in ­K+
+ +
use of succinylcholine, classically used to induce paralysis
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 4 of 16

Table 1 Mechanisms contributing to  the  development show its efficacy and its indications are based on expert
of hyperkalemia opinion [34]. The effect should be immediate (within
Mechanisms contributing to the development of hyperkalemia 5 min) when any hyperkalemia-related ECG changes are
identified or suspected [33]. The protective effect may
Increased extracellular ­K+ Decreased ­K+ elimination
last between 30 and 60  min [35]. Calcium administra-
Tissue injury AKI tion in the case of hypercalcemia may be problematic.
 Hemolysis  Hypovolemia It also increased toxicity with digoxin overdose in ani-
 Rhabdomyolysis  Sepsis
 Tumor lysis syndrome Acidosis treatment
mal models [34]. However, this effect was found only at
K+ shift in extracellular space  RAAS inhibitor nonphysiologically high calcium concentrations [35]. The
 Mineral acidosis (i.e., hyperchoride  Calcineurine inhibitor use of calcium in cases of hyperkalemia associated with
acidosis)  Cardiac glycosides
 Succinylcholine
digoxin toxicity was not associated with life-threatening
Inability to enter into myocyte dysrhythmias or mortality in human studies [36–38].
 Diabetes mellitus Finally, calcium may cause tissue injury (i.e., skin necro-
 Hyperglycemia
 Hypertonicity
sis) in case of extravasation [39]. The recommended dose
 β2-receptor antagonists is 10–20 mL of a 10% calcium salt (e.g., 1–2 g of gluco-
 Aldosterone blockers nate or chloride).
 Cardiac glycosides
High acute iatrogenic ­K+ load
 Increased dietary intake Hypertonic sodium
 Blood transfusion Infusion of hypertonic sodium also increases the action
 Error of injection
potential rising velocity in isolated cardiomyocytes [42].
K+ potassium, RAAS renin–angiotensin–aldosterone system In 1960, Greenstein et al. [43] studied the effect of sodium
lactate, sodium bicarbonate, and sodium chloride on
ECG abnormalities induced by hyperkalemia in nephrec-
in acutely ill patients for rapid sequence intubation.
tomized dogs. Infusion of hypertonic sodium increased
Succinylcholine induces skeletal muscle cell depolari-
the action potential rising velocity, which was depressed
zation with an efflux of intracellular potassium by nico-
when isolated cardiomyocytes were exposed to increas-
tinic receptor activation. In a population of critically ill
ing concentrations of potassium [42]. Taken together,
patients, succinylcholine increased serum potassium on
these results suggest that hypertonic sodium acts as a
average 0.4  mmol/L (interquartile range 0–0.7  mmol/L)
membrane stabilizer and might be considered as an alter-
[30]. It should be avoided in patients with hyperkalemia
native to calcium in hyperkalemia-induced ECG changes
and in patients with up-regulation of nicotinic receptors,
when infusion of calcium is at risk. Furthermore, the
as they are at risk of greater potassium elevation. This
fluid loading associated with hypertonic sodium bicarbo-
includes those with anatomical denervation, prolonged
nate may increase the glomerular filtration rate and renal
administration of neuromuscular blocking drugs, burn
potassium excretion in volume-depleted patients.
injury, and prolonged immobilization [31]. Alternative to
succinylcholine are available in patients at risk of hyper-
Intracellular potassium transfer
kalemia (i.e., rocuronium).
Hypertonic sodium bicarbonate
Although the data supporting the use of sodium bicar-
Medical strategy bonate as a treatment for hyperkalemia are contro-
First‑line treatment in hyperkalemia with ECG
versial, it does have effects on serum potassium after
abnormalities: myocardial protection
infusion of hypertonic sodium bicarbonate. Some
Calcium salt
reported little effect on the potassium concentration
The intravenous administration of a calcium salt
in stable hemodialysis patients [44, 45]. In 1997, Ngugi
increases the cardiac threshold potential, the speed of
et  al. [46] observed that bicarbonate was less effective
impulse propagation and stabilizes the myocellular mem-
than salbutamol and insulin–dextrose in groups of 10
brane, thus causing almost immediate normalization of
patients with end-stage renal disease (i.e., not acutely
the ECG abnormalities (Fig. 2). In 1950, Merrill et al. [32]
ill). Others reported effects on serum potassium.
found a beneficial effect of intravenous calcium salt in 9
Schwarz et  al. [47] reported that an infusion of 144–
of 10 patients with hyperkalemia. Four years later, this
408  mmol of sodium bicarbonate over 2–4  h lowered
was confirmed by Chamberlain et al. [33], who reported
the serum potassium by 2–3  mmol/L in four patients
five cases of an immediate effect of intravenous calcium
with severe acidosis.
on ECG changes induced by severe hyperkalemia (from
In a recent randomized controlled trial (RCT), hyper-
8.6 to 10  mmol/L). There are no randomized studies to
tonic sodium bicarbonate (4.2%) was administered to
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 5 of 16

(See figure on next page.)

Fig. 2  Cardiac effect of hypertonic sodium and calcium salt during hyperkalemia. During hyperkalemia, resting membrane potential increases,
derecruiting the sodium voltage gate channel Nav1.5 (left panel). Calcium salts bind to calcium-dependent calmodulin and protein kinase II
(CaMKII) and activates the sodium voltage gate channel leading to an intracellular sodium entrance (right panel). Calcium salt restores the channel
activity though the calcium-dependent calmodulin (CaM), recruiting the voltage-gated channel Nav1.5, increasing the intracellular sodium
entrance, restore dV/dt phase 0 action potential and increase in the resting membrane potential. Hypertonic sodium increases extracellular sodium
concentration and “forces” intracellular sodium entrance (right panel). The bottom panel represents on the left the decrease of dV/dt phase 0 action
potential due to hyperkalemia (Bottom left panel), restored by either calcium or hypertonic sodium (Bottom rightpanel)(Adapted from [40, 41] with
authorization)

critically ill patients with severe metabolic acidaemia Insulin–dextrose

(pH < 7.2) [48]. There was no difference in the primary Insulin binds to the insulin receptor on skeletal mus-
outcome (composite of death from any cause by day 28 cle, activates the sodium–potassium adenosine triphos-
or 1 organ failure at day 7), but the sodium bicarbonate phatase, and leads to potassium transfer from the
group had significantly lower potassium concentra- extracellular to intracellular space (Fig. 3) [53]. Although
tions compared to the control group and required renal insulin–dextrose has never been tested versus placebo
replacement therapy less frequently. A more recent retro- for the treatment of hyperkalemia, it shows similar
spective study also reported improved survival in septic effects on serum potassium compared with salbutamol
patients with AKI stage 2 or 3 and severe acidosis treated in a study of 20 patients [46, 54] but with faster decrease
with sodium bicarbonates infusion [49]. However, the in serum potassium with insulin (i.e., 15 vs 30  min).
impact on serum potassium was not reported. Of note, combination of both further lowered serum
Metabolic alkalosis, hypernatremia, hypocalcemia, potassium compared to separate treatments. The major
and fluid overload are potential expected side effects of side effect of insulin is hypoglycemia, which has been
sodium bicarbonate (Table 2). Hypertonic sodium bicar- reported to occur up to 75% in subjects, depending of the
bonate can cause hypocalcaemia in a pH dependent protocol  [55, 56]. One of the few blinded ED studies of
manner and by direct calcium binding [50]. In the Jaber hyperkalemia management found a 17% rate of clinically
et al. [48] study, more patients in the bicarbonate group significant hypoglycemia after insulin–dextrose therapy
had ionized calcium lower than 0.9  mmol/L compared [53].
to patients in the placebo group (24% vs 15%, p = 0.0167) Several studies suggest that a lower bolus dose of
and 2 patients had a ionized calcium below 0.5 mmol/L in insulin may be safer. In 2 retrospective studies, similar
the bicarbonates group versus none in the placebo group. potassium-lowering effects were found with the admin-
Calcium is key for cardiac contractility. In an experimen- istration of either 5 or 10 U of insulin (and 25 g of dex-
tal model of lactic acidosis, Kimmoun et al. [51] reported trose), but a higher incidence of hypoglycemia occurred
improved myocardial elastance, aortic and mesenteric with the higher insulin dose [57, 58]. To limit hypogly-
vasoreactivity when sodium bicarbonate was combined cemia with the 10 U insulin dose required using 50 g to
with calcium compared to sodium bicarbonate alone. 60  g of dextrose [59]. Another strategy is to administer
Severe hypocalcemia can cause myocardial dysfunction weight-based insulin dosing (0.1 U/kg of body weight up
and therefore ionized calcium should be monitored and to a maximum of 10 U) to limit episodes of hypoglycemia
ionized hypocalcemia corrected after sodium bicarbo- without impacting potassium lowering [60]. Finally, using
nate infusion. Finally, even though sodium bicarbonate an infusion limited to 30 min led to a faster decrease in
has been suspected of causing intracellular acidosis, this potassium, but less hypoglycemia as compared to con-
has not been confirmed in  vivo [52]. We therefore rec- tinuous infusion [61]. Ultimately, because of the risk of
ommend to use hypertonic sodium bicarbonate (e.g., hypoglycemia, blood glucose should be measured on an
100–250  mL of 8.4% sodium bicarbonate over 20  min) hourly basis for at least 2 h, and potentially longer in the
in patients with metabolic acidosis (pH  < 
7.2) or in setting of renal failure [61]. While the risks of hypogly-
patients with a contraindication to calcium administra- cemia have long been recognized, the risk of hyperglyce-
tion (patients with hypercalcemia and/or severe digoxin mia is probably underappreciated. To summarize, using
intoxication), whether sodium bicarbonate is efficient in 5 U of insulin with 25 g of dextrose appears an effective
reducing serum potassium in patients without severe aci- and safe regimen. The impact of exogenous administra-
dosis and the impact of the mechanism of metabolic aci- tion of insulin and glucose on serum potassium and
dosis need further exploration. organ damage in this setting is unknown. Intravenous
administration of high doses of glucose to limit the risk
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 6 of 16
Table 2  Treatments of hyperkalemia
Type of treatment Effect on potassium plasma Administration Potential side effects Population at risk Preferred population
level

Myocardial protection
Calcium salt None 10–20 mL of calcium gluconate Hypercalcemia Digitalis intoxication or hyper- Hyperkalemia with ECG modifica-
10% i.v within 5 min calcemia tions
Dépret et al. Ann. Intensive Care

Hypertonic sodium (e.g., − 0.47 ± 0.31 mmol/L at 30 min 10–20 mL of sodium chloride Venous toxicity, increasing Hypervolemia, patients with Hyperkalemia with ECG modifica-
sodium bicarbonate) 20% i.v within 5 min or ­PaCO2 (due to bicarbonate) heart failure, hypernatremia, tions, patient with metabolic
100 mL of 8.4% i.v sodium patient with respiratory insuf- acidosis or AKI
bicarbonate ficiency (due to bicarbonate)
Intracellular potassium transfer
(2019) 9:32

Insulin dextrose − 0.79 ± 0.25 mmol/L at 60 min 5 UI of rapid insulin + 25 grams Hyperglycemia and hypogly- All patients Severe hyperkalemia with hourly
of dextrose over 30 min or cemia Critically ill patients at monitoring of plasma glucose
10 of rapid insulin +  g of increased of hyperglycemia- possible
dextrose or 0.5 U/kg of body related side effects
weight
Patients with acute neurologi-
cal disease
β2 mimetics − 0.5 ± 0.1 mmol/L at 60 min 10 mg nebulized salbutamol Tachycardia, arrhythmias, myo- Patients with ischemic cardi- Patient without heart failure,
cardial ischemia opathy angina or coronary disease
Increase plasma lactate level Patient under β blockers Spontaneously breathing patient
therapy
Elimination
Renal replacement therapy − 1 mmol/L within minutes High blood flow and dialysate Complications related to cath- Low availability of the tech- Severe renal failure, multiple
flow in hemodialysis, high eter (i.e., infection, thrombo- nique organ failure
ultrafiltration rate in hemo- sis, hemorrhage) Delay to initiate the treatment
filtration
Loop diuretics Unpredictable Variable Hypovolemia, hypokalemia, Hypovolemic patients Hypervolemic patients with
hypomagnesemia normal or moderately altered
renal function
Absorption
Sodium polystyrene sulfonate Unpredictable (no randomized 15 g one to four times per day Digestive perforation, hypocal- Patients with abnormal transit, Treatment of chronic hyper-
controlled trial in acute cemia, hypomagnesemia critically ill patients kalemia
hyperkalemia)
Patiromer 0.21 ± 0.07 mmol/L within 7 h 8.4–25.2 g per day Potential interaction with Patients with abnormal transit Treatment of chronic hyper-
(no randomized controlled co-administered drugs, kalemia
trial in acute hyperkalemia) hypomagnesemia, potential
long-term calcium disorder
ZS-9 0.6 ± 0.2 mmol/L within 2 h 10 g one to three times per day Edema Patients with abnormal transit Treatment of chronic and poten-
tially acute hyperkalemia
i.v intravenous, ECG electrocardiographic, β2 beta 2, ZS-9 sodium zirconium cyclosilicate
Page 7 of 16
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 8 of 16

Fig. 3  Action mechanisms of plasma lowering treatments by intracellular transfer. β-2 agonist (i.e., salbutamol) binds the β-2 receptor, insulin binds
insulin receptors and sodium bicarbonate ­(NaHCO3) induces an intracellular entrance of sodium through the ­Na+/H+ exchanger (NHE), all activate
the sodium–potassium adenosine triphosphatase ­(NaK+ ATPase) leading to a potassium transfer from the extracellular space to the intracellular
space

of hypoglycemia may induce severe hyperglycemia, and insulin resistance. We propose insulin–glucose as
which has been associated with organ damage, vascu- first-line treatment in patients with relative contraindi-
lar dysfunction and poor outcomes in different settings cation to β-2 agonists (Table 2) and patients with severe
(i.e., heart failure, sepsis, critically ill patients) [62–64]. hyperkalemia (i.e.,  ≥ 6.0 mmol/L or associated with ECG
Critically ill patients often present with hyperglycemia changes).
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 9 of 16

β‑2 agonists AKI to 1–1.5 mg/kg of furosemide in patients with AKI)

Salbutamol (e.g., albuterol) is effective at lowering potas- and only considered in patients with fluid overload after
sium, without differences between nebulized or intrave- excluding low intravascular volume and with close atten-
nous administration, in terms of its efficacy [65, 66] even tion to the amount of diuresis to avoid additional kidney
though effectiveness appears variable. However, salbuta- insults resulting from iatrogenic hypovolemia. Finally,
mol administered intravenously is associated with more close monitoring for potential side effects, including
cardiovascular side effects than the nebulized route [67]. the risk of secondary hypovolemia and other electro-
In one study of 10 patients treated with 10–20 mg salbu- lytes disturbances (i.e., dysnatremia, metabolic alkalosis,
tamol, the maximal decrease in potassium ranged from hypophosphatemia, hypomagnesaemia) is needed. To
0.4 to 1.22  mmol/L [65, 66]. The peak effect occurred conclude, except in patients with symptomatic fluid over-
between 60 and 90  min after administration, and the load, diuretics should not be considered as a therapy for
higher salbutamol dose was more efficient in lowering hyperkalemia.
potassium. Due to systemic effects of salbutamol, regard-
less of the route of administration, side effects, such as Gastro intestinal excretion
tachycardia may also be of concern in patients with heart Sodium polystyrene sulfonate (SPS)
failure or unstable angina. Finally, other consequences SPS exchanges sodium for calcium, ammonium, and
of β-2-agonists are hyperglycemia and increased plasma magnesium in addition to potassium in the colon (Addi-
lactate. Impacts of treatments with β-blockers or efficacy tional file  1: Figure S1) [72]. To date, no controlled tri-
in critically ill patients remain unexplored. Critically ill als in humans or animals have demonstrated that SPS
patients may present sympatho-adrenal activation (i.e., increases fecal potassium losses, and no studies on the
with tachycardia, vasoconstriction, hyperglycemia). We efficacy of SPS are available in the acute setting. How-
recommend the utilization of 10  mg nebulized salbuta- ever, serious gastrointestinal complications related to
mol as first-line therapy in nonsevere hyperkalemia in SPS, and attributed to sorbitol (co-administered with SPS
spontaneous breathing patients without tachycardia. to increase its delivery to the colon) have been described
[73]. These include intestinal perforations, especially in
patients with abnormal transit (e.g., patients in shock or
Increase potassium urinary excretion who are immediately postoperative). Furthermore, its use
Loop diuretics inhibit the NKCC2 channel at the apical has been associated with edema and increases in blood
surface of thick ascending limb cells along the loop of pressure-likely related to the fact that it exchanges potas-
Henle. NKCC2 is a sodium–potassium–chloride cotrans- sium for sodium. Due to its route of administration, its
porter that reabsorbs (directly and indirectly) up to 25% delayed and highly variable onset, and the potential for
of filtered sodium and chloride. Its blockade is respon- serious adverse side effects [35, 73], SPS is not a treat-
sible for most natriuretic effects of loop diuretics [68]. ment of choice in the acutely ill patient.
Loop diuretic administration via the intravenous route
is quickly followed by a similar dose dependent increase Emerging treatment alternatives
in both 24-h kaliuresis and natriuresis [69, 70]. The kaliu- Patiromer
retic effect is predominately a function of an increased Patiromer is a sodium-free, nonabsorbed, potassium-
tubular flow rate and a higher sodium concentration in binding polymer, approved in the USAUS and in the
the late nephron, both leading to an induction of the Na/ European union (EU) for management of hyperkalemia.
K+-ATPase that increases potassium excretion in the dis- In a recent meta-analysis of phase 2 and phase 3 trials,
tal tubules and collecting duct [70]. However, one major it was associated with a decrease in serum potassium of
drawback of diuretics is the unpredictable natriuretic 0.21 ± 0.07 mmol/L within 7 h [74, 75]. Its long term effi-
and kaliuretic effects, especially in patients with AKI or cacy and safety was also shown in a 52-week trial [76].
heart failure. These patients may be resistant to the diu- Side effects include minor gastrointestinal intolerance
retic and kaliuretic effects of diuretics, thus making this and hypomagnesemia (7.1%) and edema due to exchange
a poor strategy to control severe hyperkalemia. A “furo- of potassium for sodium [75]. Patiromer has not been
semide stress test” has been proposed in AKI patients clinically tested in the emergency setting. Whether this
to predict sustained AKI, with nonresponders defined compound may enable the maintenance of normoka-
as a urine output < 200 mL in the first 2 h after an infu- lemia in emergency room patients is currently being
sion of 1.0 or 1.5  mg/kg of furosemide [71]. In these tested (REDUCE study NCT: 02933450).
nonresponders, alternative strategies to control hyper-
kalemia should not be delayed. Furthermore, loop diuret-
ics should be titrated (0.2–0.4  mg/kg in patient without
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 10 of 16

Sodium zirconium cyclosilicate (ZS‑9) Renal replacement therapy and potassium dialysance

ZS-9 is a crystal that is highly selective for potassium Renal replacement therapies (RRT) include diffusive (i.e.,
and ammonium ions exchanging sodium for potas- hemodialysis), convective (i.e., hemofiltration) and mixed
sium [77]. A recent meta-analysis of phase 2 and phase modalities (e.g., hemodiafiltration) in the acute setting.
3 studies concluded that ZS-9 was effective in main- Potassium dialysance refers to the clearance of potassium
taining normokalemia with minor gastrointestinal side in various RRT modalities. Body potassium dialysance
effects and edema [75]. Even though ZS-9 has not been and potassium flux depends on the gradient of potas-
specifically compared to existing alternatives for treat- sium concentration between plasma and dialysate (or
ment of severe hyperkalemia in emergency conditions, infusate using hemofiltration), blood and dialysate flow
Kosiborod et  al. [78] recently described a subgroup through the circuit, the modality (hemodialysis, hemofil-
of 45 patients with severe hyperkalemia (> 6  mmol/L) tration, hemodiafiltration), and the dialyzer characteris-
who received a 10 g dose of ZS-9. The median time to a tics. Potassium mass transfer on the other side depends
serum potassium level < 6.0  mmol/L was 1.1  h, and the on treatment time and intracorporeal potassium kinet-
median time to a level ≤ 5.5 mmol/L was 4.0 h, suggesting ics (Fig.  4). Since potassium freely and totally diffuses
that this treatment might be considered in severe acute throughout the dialyzer membrane, it is rapidly and
hyperkalemia in patients with preserved gastrointesti- effectively removed during hemodialysis. In the setting
nal function. However, because of the lack of data in the of high blood and dialysate flow and low dialysate potas-
acute setting and its potential delayed onset of action, it sium concentration, serum potassium drops within min-
was not approved for acute hyperkalemia management utes of initiation. Since intracorporeal potassium kinetics
in either the US or in UE. An ongoing phase 2 study behave as a multi-compartmental model, serum potas-
(NCT03337477) is evaluating the short term efficiency of sium will decrease more slowly after 2 h of hemodialysis
ZS-9 plus insulin–dextrose versus insulin–dextrose alone and rebound after stopping the therapy. Of note, hyper-
in patients with acute hyperkalemia. osmolarity, or treatments shifting potassium from the
extracellular to the intracellular space before the dialysis
Renal replacement therapy session (i.e., β-2 agonists, sodium bicarbonate, insulin,
Indication of Renal replacement therapy glucose), will decrease potassium dialysance.
Severe hyperkalaemia is a key indication for renal Continuous RRT, including hemofiltration (i.e., con-
replacement therapy (RRT) (e.g., hemodialysis or hemo- vective technique), is the most frequently used modality
filtration) in acutely ill patients with AKI [8]. However, in the intensive care unit. Using convective techniques,
what potassium concentration or other clinical indica- flux of potassium through the membrane depends on the
tions (e.g., significant ECG changes) should serve as ultrafiltration rate and the serum potassium level (Fig. 4).
triggers for RRT remain debated [8]. However, the lit- When combined techniques are used (i.e., hemodiafil-
erature does however provide some guidance  [79]. In tration), elimination of potassium depends mostly on
a recent trial, a strategy of delayed RRT (with timing the diffusive transfer through the membrane. Continu-
of RRT determined by serum creatinine or urine out- ous low flow techniques have a slower decrease in serum
put) ultimately avoided RRT in many patients [80]. Not potassium concentrations, and the serum potassium
unexpectedly, medical treatment for hyperkalemia was will tend to approach dialysate (with diffuse techniques)
more frequent in the delayed group, but the incidence or infusate concentration (with convective techniques)
of arrhythmias did not differ between groups. Of note, within few hours after initiation without rebound.
patients with potassium > 6, or > 5.5  mmol/L despite Hemofiltration using mild to high cut-off membranes
medical treatment, were excluded, a factor limiting con- also allows higher myoglobin removal in patients with
clusions regarding acute therapy in those with the most rhabdomyolysis.
severe hyperkalemia. Another trial evaluated hypertonic RRT will naturally be a second line strategy. In our
sodium bicarbonate in critically ill patients with severe view, the choice of RRT modality will largely depend
acidaemia (pH  < 7.2). They reported the bicarbonate on the available techniques. The efficacy and tolerance
group had a lower serum potassium, less need for RRT, will however largely rely on RRT prescription. Using
and a longer delay to RRT in those patients ultimately short high efficiency dialysis (intermittent dialysis) will
requiring RRT [48]. Altogether these data suggest that require high blood and dialysate flow to remove sufficient
medical treatment of hyperkalemia (including hypertonic amount of potassium (e.g., blood flow 250  mL/min and
sodium bicarbonate in patients with metabolic acido- dialysate flow 500 mL/min) allowing rapid drop of serum
sis) may be safe in critically ill patients with mild hyper- potassium but with a risk a rebound after stopping RRT
kalemia. This medical treatment could avoid or delay (Fig. 4). Clearance of potassium using continuous hemo-
RRT onset in patients with AKI. filtration is proportional to ultrafiltrate rate (Fig.  4). We
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 11 of 16

Fig. 4  Action mechanisms of hypokalemic treatments by intracellular transfer. a Potassium dialysance, flux and plasma kinetic under short high
efficient hemodilaysis. b Potassium dialysance, flux and plasma kinetic under long low efficient hemodilaysis. c Potassium clearance, flux and
plasma kinetic under hemofiltration. K potassium, CVVHD continuous venovenous hemodialysis, CVVHF continuous venovenous hemofiltration
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 12 of 16

therefore advise a high ultrafiltration rate at the initiation situation might limit the risk of under or over-treating
of the technique (e.g.,  ≥ 45  mL/kg/h) when using this hyperkalemia [34].
modality. This ultrafiltration rate can be lowered when The evaluation of hyperkalemia should always include
serum potassium is controlled (e.g., 25 mL/kg/h). assessment for the rapid need of membrane stabilization
Both techniques expose the patient to the risk of sec- treatment (i.e., calcium or hypertonic sodium solutions)
ondary hypokalemia. Importantly, both hyperkalemia and should be considered in patients with cardiac con-
and a rapid decrease in serum potassium are associ- duction or rhythm abnormalities (Figs.  1  and 5). When
ated with cardiac events and sudden death in patients the clinical scenario and absence of ECG changes do
with end-stage kidney disease [81, 82]. Long inter- not support the likelihood of hyperkalemia, the potas-
dialytic periods expose patients to consequences of sium measurement should be repeated to exclude facti-
hyperkalemia and cardiac conduction disorders while tious hyperkalemia (or pseudo-hyperkalemia). A result
intradialytic periods and postdialytic periods are asso- of kalemia in delocalized biochemistry (i.e., blood gas
ciated to increase cardiac excitability and arrhythmic analyzer) could probably be used to detect hyperkalaemia
disorders. Rapid decreases in serum potassium using a and start a treatment in high-risk patients (e.g., patients
potassium dialysate concentration ≤ 2 mmol/L was asso- with severe metabolic acidosis, AKI or CKD).
ciated with a doubling of risk of sudden cardiac arrest Efficacy and tolerance of treatment may vary widely
in a recent study [82]. This arrhythmogenic propensity according to the clinical scenario (Table 2). Insulin–glu-
of RRT is enhanced by simultaneous combined stresses cose infusion appears to be appropriate for severe hyper-
including ischemia (hypovolemia), hypoxia, electro- kalemia due to its efficacy and reproducible lowering of
lyte changes (calcium, magnesium, citrate, acetate) and serum potassium levels, with close serum glucose mon-
potential removal of cardiac medications. Studies have itoring (Fig.  5). However, the impact of this regimen in
shown that the frequency of premature ventricular con- critically ill patients with insulin resistance or dysglyce-
tractions during dialysis is less common when using a mia remains unclear. Hypertonic sodium bicarbonate
dialysate potassium concentration of 2.0–3.0  mmol/L, combines fluid loading, cardiac membrane stabilization
compared ≤ 2.0 mmol/L [83]. More recently, Ferrey et al. and serum potassium lowering and is most appropriate
[84] examined the association of dialysate potassium in patients with severe metabolic acidosis, AKI and hypo-
concentration with all-cause mortality risk in chronic volemia. Aerosolized β-2 agonists are more easily used
hemodialysis patients. They observed that a dialysate in spontaneously breathing patients and appear to have
potassium concentration of 1  mEq/L was associated similar efficacy to the insulin–dextrose combination in
with higher mortality compared to higher concentra- lowering serum potassium. However, the use of β-2 ago-
tions. Taken altogether, these data suggest using a potas- nists in patients with cardiac hyperexcitability, baseline
sium dialysate concentration ≥ 2.0  mmol/L to avoid a high sympathetic activity or with unstable coronary dis-
too rapid drop in serum potassium using dialysis. Treat- ease is potentially associated with severe side effects or
ment of hyperkalemia using peritoneal dialysis has been decreased efficacy. In addition, efficacy in mechanically
described anecdotally and appears feasible when alterna- ventilated patients is unknown. Serial serum potassium
tives are not readily available [85]. Alternatives to prevent measurements after first-line treatment allow providers
rapid and profound drop of serum potassium is to use to assess the initial response and need for a second line
low flow techniques (i.e., continuous hemofiltration, con- strategy. RRT is usually required in patients with severe
tinuous hemodialysis or slow low efficiency or extended AKI with oliguria or anuria who are not expected to rap-
dialysis) (Fig. 4) once acute severe hyperkalemia has been idly recover (e.g., AKI unresponsive to hemodynamic
controlled. Continuous techniques will further largely optimization, unresponsive to diuretics), in patients with
prevent rebound of serum potassium observed after end-stage chronic kidney disease admitted for an acute
intermittent dialysis. Finally, extended or continuous ses- condition and in the setting of severe AKI and hyper-
sion with high flow should be considered in patients with kalemia (i.e.,  > 6.5  mmol/L) and in patients with hyper-
ongoing uncontrolled cause of hyperkalemia (i.e., rhab- kalemia resistant to medical therapy [8, 34].
domyolysis, tumor lysis syndrome). Finally, identification and treatment of the cause and
contributing factors of hyperkalemia should be per-
Who should be treated for hyperkalemia?
formed simultaneously. Identification of the cause of AKI
Even though hyperkalemia has been associated with and rapid correction of contributing factors of AKI may
mortality in different settings [5], the potential side allow faster recovery.
effects of hyperkalemia treatment should not be over-
looked. Tailoring treatment to the patient condition and
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 13 of 16

Fig. 5  First-line treatment of hyperkalemia. During hyperkalemia with ECG modifications, first-line therapy should consist on cardiomyocyte
stabilization using calcium salt or hypertonic sodium (red panel), second line therapy on treatment leading to a fast transfer of potassium from
extracellular to intracellular space using either insulin–glucose i.v, aerosol of β2 agonist and/or sodium bicarbonate (in case of metabolic acidosis
and hypovolemic patient) depending of the patient’s comorbidities and clinical status. Insulin–glucose is recommended as the first-line treatment
in severe hyperkalemia (i.e., above 6.5 mmol/L) but close glucose monitoring is mandatory. β2 agonists can be used in spontaneously breathing
patients but with safety concerns in patients with unstable angina or cardiac failure. Hypertonic sodium bicarbonate should probably be restricted
to hypovolemic patients with metabolic acidosis (blue panel). Strategies increasing potassium renal excretion decreases the total potassium
pool (i.e., hemodynamic optimization and correction of acute kidney injury or loop Henle diuretics in patients with fluid overload) (green panel).
Indications of renal replacement therapy are patients with severe acute kidney injury associated to severe hyperkalemia or persistent hyperkalemia
despite first-line medical treatment

Conclusion to the patient condition and situation will limit the risks
Recognition of hyperkalemia-related ECG changes is of treatments side effects. Efficacy and tolerance remain
central in the choice of strategy to treat the patient. however poorly explored in acute setting. There is a need
ECG changes should prompt urgent medical interven- for further research to evaluate both efficacy and side
tion including both cardiac protection and potassium- effects of different strategies in the acute setting.
lowering treatment. Tailoring treatment of hyperkalemia
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 14 of 16

Additional file Ethics approval and consent to participate

Not applicable.

Additional file 1: Figure S1. Gastrointestinal absorption site of ZS-9, SPS Funding
and patiromer. The majority of potassium is in the distal gastrointestinal Not applicable.
(GI) tract (e.g., the colon). Both sodium polystyrene sulfonate (SPS) and
patiromer are concentration dependent binding (with patiromer being
better than SPS). Since there is not relatively much potassium in the early Publisher’s Note
part of the GI tract, SPS and patiromer have less of an effect because there Springer Nature remains neutral with regard to jurisdictional claims in pub-
is less for them to bind. Furthermore divalent cation ­(Ca2+ and M­ g2+) are lished maps and institutional affiliations.
inadvertently pick up as well. On the contrary, sodium zirconium cyclosili-
cate (ZS9), which is much more attracted to potassium and more specific Received: 9 November 2018 Accepted: 22 February 2019
than SPS or patiromer (binding coefficient much higher), that it can bind
potassium in low concentration environments with less competition with
divalent cation, so it starts binding earlier in the GI tract.

References
Abbreviations 1. Mattu A, Brady WJ, Robinson DA. Electrocardiographic manifestations of
K+: potassium ion; AKI: acute kidney injury; ED: emergency department; ECG: hyperkalemia. Am J Emerg Med. 2000;18:721–9.
electrocardiographic; SID: strong ion difference; RCT​: randomized controlled 2. Freeman K, Feldman JA, Mitchell P, Donovan J, Dyer KS, Eliseo L, et al.
trial; NKCC: Na–K–Cl cotransporter; SPS: sodium polystyrene sulfonate; US: Effects of presentation and electrocardiogram on time to treatment of
USA; EU: European Union; ZS-9: sodium zirconium cyclosilicate; RRT​: renal hyperkalemia. Acad Emerg Med. 2008;15:239–49.
replacement therapy. 3. Montague BT, Ouellette JR, Buller GK. Retrospective review of the
frequency of ECG changes in hyperkalemia. Clin J Am Soc Nephrol.
Authors’ contributions 2008;3:324–30.
FD, ML: collected data, performed analysis and interpretation of the data and 4. Truhlář A, Deakin CD, Soar J, Khalifa GEA, Alfonzo A, Bierens JJ, et al. Euro-
drafted the manuscript. FP , KL , ZR , PR: performed analysis and interpretation pean resuscitation council guidelines for resuscitation 2015. Resuscita-
of the data and drafted the manuscript. All authors read and approved the tion. 2015;95:148–201.
final manuscript. 5. Khanagavi J, Gupta T, Aronow WS, Shah T, Garg J, Ahn C, et al. Hyper-
kalemia among hospitalized patients and association between duration
Author details of hyperkalemia and outcomes. Arch Med Sci. 2014;2:251–7.
1 6. Phillips BM, Milner S, Zouwail S, Roberts G, Cowan M, Riley SG, et al.
 GH St‑Louis‑Lariboisière, Department of Anesthesiology and Critical Care
and Burn Unit, St‑Louis Hospital, Assistance Publique-Hopitaux de Paris, Paris, Severe hyperkalaemia: demographics and outcome. Clin Kidney J.
France. 2 University Paris Diderot, Paris, France. 3 UMR INSERM 942, Institut 2014;7:127–33.
National de la Santé et de la Recherche Médicale (INSERM), Paris, France. 7. Winkler AW, Hoff HE, Smith PK. Electrocardiographic changes and
4
 F-CRIN INI-CRCT Network, Vandœuvre‑lès‑Nancy, France. 5 Henry JN Taub concentration of potassium in serum following intravenous injection of
Department of Emergency Medicine, Baylor College of Medicine, Houston, potassium chloride. Am J Physiol Leg Content. 1938;124:478–83.
TX, USA. 6 Department of Medicine, University of California, San Francisco, CA, 8. Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA, Goldstein SL,
USA. 7 CHRU‑Nancy, INSERM 1116, Université de Lorraine, CIC Plurithématique et al. Work group membership. Kidney Int. 2012;2:1.
1433, 54000 Nancy, France. 9. Lee Hamm L, Hering-Smith KS, Nakhoul NL. Acid-base and potassium
homeostasis. Semin Nephrol. 2013;33:257–64.
Acknowledgements 10. Jain N, Kotla S, Little BB, Weideman RA, Brilakis ES, Reilly RF, et al. Predic-
The author thanks Pr. Bernard Canaud for his advice on the role of renal tors of hyperkalemia and death in patients with cardiac and renal disease.
replacement therapy and editing of this part of the manuscript. Am J Cardiol. 2012;109:1510–3.
11. Goyal A, Spertus JA, Gosch K, Venkitachalam L, Jones PG, Van den Berghe
Competing interests G, et al. Serum potassium levels and mortality in acute myocardial infarc-
Dr. Dépret has nothing to disclose. Dr. Peacock reports grants and personal tion. JAMA. 2012;307:157.
fees from Astra Zeneca, grants and personal fees from Relypsa, outside the 12. Brunelli SM, Du Mond C, Oestreicher N, Rakov V, Spiegel DM. Serum
submitted work. Dr. Liu reports grants from NIH: National Heart, Lung and potassium and short-term clinical outcomes among hemodialysis
Blood Institute, grants from NIH: National Institute of Diabetes and Digestive patients: impact of the long interdialytic interval. Am J Kidney Dis.
and Kidney Disease, personal fees from Achaogen, personal fees from Durect, 2017;70:21–9.
personal fees from Z S Pharma, personal fees from Theravance, personal fees 13. Collins AJ, Pitt B, Reaven N, Funk S, McGaughey K, Wilson D, et al. Associa-
from Quark, personal fees from Potrero Med, other from Amgen, grants from tion of serum potassium with all-cause mortality in patients with and
American Society of Nephrology, grants from National Kidney Foundation, without heart failure, chronic kidney disease, and/or diabetes. Am J
grants from National Policy Forum on Critical Care and Acute Renal Failure, Nephrol. 2017;46:213–21.
personal fees from Baxter, outside the submitted work. Dr. Rafique reports 14. McMahon GM, Mendu ML, Gibbons FK, Christopher KB. Association
personal fees and other from AstraZeneca, grants and personal fees from Vifor, between hyperkalemia at critical care initiation and mortality. Intensive
outside the submitted work. Dr. Rossignol reports personal fees from French Care Med. 2012;38:1834–42.
National Research Agency Fighting Heart Failure (ANR-15-RHU-0004), personal 15. Legrand M, Ludes P-O, Massy Z, Rossignol P, Parenica J, Park J-J, et al.
fees from French PIA project «Lorraine Université d’Excellence» GEENAGE (ANR- Association between hypo- and hyperkalemia and outcome in acute
15-IDEX-04-LUE) programs, outside the submitted work. Dr. Legrand reports heart failure patients: the role of medications. Clin Res Cardiol Off J Ger
grants from French ministry of health, grants and nonfinancial support from Card Soc. 2018;107:214–21.
Sphingotec, personal fees from Fresenius, personal fees from Baxter-Hospal, 16. Hoss S, Elizur Y, Luria D, Keren A, Lotan C, Gotsman I. Serum potassium
and personal fees from Novartis, outside the submitted work. levels and outcome in patients with chronic heart failure. Am J Cardiol.
2016;118:1868–74.
Availability of data and materials 17. Ahmed A, Zannad F, Love TE, Tallaj J, Gheorghiade M, Ekundayo OJ, et al.
Not applicable. A propensity-matched study of the association of low serum potassium
levels and mortality in chronic heart failure. Eur Heart J. 2007;28:1334–43.
Consent for publication 18. Luo J, Brunelli SM, Jensen DE, Yang A. Association between serum potas-
Not applicable. sium and outcomes in patients with reduced kidney function. Clin J Am
Soc Nephrol. 2016;11:90–100.
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 15 of 16

19. Rossignol P, Girerd N, Bakris G, Vardeny O, Claggett B, McMurray JJV, concentration in patients with end-stage renal disease. Miner Electrolyte
et al. Impact of eplerenone on cardiovascular outcomes in heart failure Metab. 1991;17:297–302.
patients with hypokalaemia. Eur J Heart Fail. 2017;19:792–9. 45. Allon M, Shanklin N. Effect of bicarbonate administration on plasma
20. Lyons CJ, Burgess MJ, Abildskov JA. Effects of acute hyperkalemia on potassium in dialysis patients: interactions with insulin and albuterol. Am
cardiac excitability. Am Heart J. 1977;94:755–63. J Kidney Dis Off J Natl Kidney Found. 1996;28:508–14.
21. Aslam S, Friedman EA, Ifudu O. Electrocardiography is unreliable in 46. Ngugi NN, McLigeyo SO, Kayima JK. Treatment of hyperkalaemia by
detecting potentially lethal hyperkalaemia in haemodialysis patients. altering the transcellular gradient in patients with renal failure: effect of
Nephrol Dial Transplant. 2002;17:1639–42. various therapeutic approaches. East Afr Med J. 1997;74:503–9.
22. Burchell HB. Electrocardiographic changes related to disturbances in 47. Schwarz KC, Cohen BD, Lubash GD, Rubin AL. Severe acidosis and
potassium metabolism. J Lancet. 1953;73:235–8. hyperpotassemia treated with sodium bicarbonate infusion. Circulation.
23. Durfey N, Lehnhof B, Bergeson A, Durfey S, Leytin V, McAteer K, et al. 1959;19:215–20.
Severe hyperkalemia: Can the electrocardiogram risk stratify for short- 48. Jaber S, Paugam C, Futier E, Lefrant J-Y, Lasocki S, Lescot T, et al. Sodium
term adverse events? West J Emerg Med. 2017;18:963–71. bicarbonate therapy for patients with severe metabolic acidaemia in the
24. Kovesdy CP, Appel LJ, Grams ME, Gutekunst L, McCullough PA, intensive care unit (BICAR-ICU): a multicentre, open-label, randomised
Palmer BF, et al. Potassium homeostasis in health and disease: a controlled, phase 3 trial. Lancet. 2018;392:31–40.
scientific workshop cosponsored by the National Kidney Founda- 49. Zhang Z, Zhu C, Mo L, Hong Y. Effectiveness of sodium bicarbonate
tion and the American Society of Hypertension. J Am Soc Hypertens. infusion on mortality in septic patients with metabolic acidosis. Intensive
2017;11:783–800. Care Med. 2018. https​://doi.org/10.1007/s0013​4-018-5379-2.
25. Yunos NM, Kim IB, Bellomo R, Bailey M, Ho L, Story D, et al. The bio- 50. Cooper DJ, Walley KR, Wiggs BR, Russell JA. Bicarbonate does not improve
chemical effects of restricting chloride-rich fluids in intensive care. Crit hemodynamics in critically ill patients who have lactic acidosis. A pro-
Care Med. 2011;39:2419–24. spective, controlled clinical study. Ann Intern Med. 1990;112:492–8.
26. Stewart PA. Independent and dependent variables of acid-base con- 51. Kimmoun A, Ducrocq N, Sennoun N, Issa K, Strub C, Escanyé J-M, et al.
trol. Respir Physiol. 1978;33:9–26. Efficient extra- and intracellular alkalinization improves cardiovascular
27. O’Malley CMN, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, functions in severe lactic acidosis induced by hemorrhagic shock. Anes-
Mercer JS, et al. A randomized, double-blind comparison of lactated thesiology. 2014;120:926–34.
Ringer’s solution and 0.9% NaCl during renal transplantation. Anesth 52. Levraut J, Labib Y, Chave S, Payan P, Raucoules-Aime M, Grimaud D. Effect
Analg. 2005;100:1518–24. of sodium bicarbonate on intracellular pH under different buffering
28. Khajavi MR, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, conditions. Kidney Int. 1996;49:1262–7.
et al. Effects of normal saline vs. lactated Ringer’s during renal trans- 53. Ho K. A critically swift response: insulin-stimulated potassium and glu-
plantation. Ren Fail. 2008;30:535–9. cose transport in skeletal muscle. Clin J Am Soc Nephrol. 2011;6:1513–6.
29. Palmer BF. Regulation of potassium homeostasis. Clin J Am Soc Neph- 54. Allon M, Copkney C. Albuterol and insulin for treatment of hyperkalemia
rol. 2015;10:1050–60. in hemodialysis patients. Kidney Int. 1990;38:869–72.
30. Blanié A, Ract C, Leblanc P-E, Cheisson G, Huet O, Laplace C, et al. 55. Rafique Z, Kosiborod M, Clark CL, Singer AJ, Turner S, Miller J, et al. Study
The limits of succinylcholine for critically ill patients. Anesth Analg. design of Real World Evidence for Treatment of Hyperkalemia in the
2012;115:873–9. Emergency Department (REVEAL-ED): a multicenter, prospective, obser-
31. Strayer RJ. Succinylcholine, rocuronium, and hyperkalemia. Am J Emerg vational study. Clin Exp Emerg Med. 2017;4:154–9.
Med. 2016;34:1705–6. 56. Peacock WF, Miller J, Char D, Clark CL, Singer AJ, Rafique Z, et al. 1* Burden
32. Merrill JP, Levine HD, Somerville W, Smith S. Clinical recognition of hyperkalemia and treatment patterns in the Emergency Department
and treatment of acute potassium intoxication. Ann Intern Med. setting: results from the REVEAL-ED Study. Ann Emerg Med. 2016;68:S1.
1950;33:797. 57. LaRue H, Peksa GD, Shah S. A comparison of insulin doses for the treat-
33. Chamberlain MJ. Emergency treatment of hyperkalaemia. Lancet Lond ment of hyperkalemia in patients with renal insufficiency. Pharmacother J
Engl. 1964;1:464–7. Hum Pharmacol Drug Ther. 2017. https​://doi.org/10.1002/phar.2038.
34. Rossignol P, Legrand M, Kosiborod M, Hollenberg SM, Peacock WF, 58. McNicholas BA, Pham MH, Carli K, Chen CH, Colobong-Smith N,
Emmett M, et al. Emergency management of severe hyperkalemia: Anderson AE, et al. Treatment of hyperkalemia with a low-dose insulin
guideline for best practice and opportunities for the future. Pharmacol protocol is effective and results in reduced hypoglycemia. Kidney Int Rep.
Res. 2016;113:585–91. 2018;3:328–36.
35. Alfonzo AVM, Isles C, Geddes C, Deighan C. Potassium disorders—clinical 59. Coca A, Valencia AL, Bustamante J, Mendiluce A, Floege J. Hypoglycemia
spectrum and emergency management. Resuscitation. 2006;70:10–25. following intravenous insulin plus glucose for hyperkalemia in patients
36. Smith PK. Calcium and digitalis synergism: the toxicity of calcium with impaired renal function. PLoS ONE. 2017;12:e0172961.
salts injected intravenously into digitalized animals. Arch Intern Med. 60. Wheeler DT, Schafers SJ, Horwedel TA, Deal EN, Tobin GS. Weight-based
1939;64:322. insulin dosing for acute hyperkalemia results in less hypoglycemia: hyper-
37. Nola GT, Pope S, Harrison DC. Assessment of the synergistic relationship kalemia treatment and hypoglycemia. J Hosp Med. 2016;11:355–7.
between serum calcium and digitalis. Am Heart J. 1970;79:499–507. 61. Harel Z, Kamel KS. Optimal dose and method of administration of
38. Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in intravenous insulin in the management of emergency hyperkalemia: a
patients with digoxin toxicity. J Emerg Med. 2011;40:41–6. systematic review. PLoS ONE. 2016;11:e0154963.
39. Pacheco Compaña FJ, Midón Míguez J, de Toro Santos FJ. Lesions associ- 62. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and
ated with calcium gluconate extravasation: presentation of 5 clinical increased risk of death after myocardial infarction in patients with and
cases and analysis of cases published. Ann Plast Surg. 2017;79:444–9. without diabetes: a systematic overview. Lancet. 2000;355:773–8.
40. Robert T, Joseph A, Mesnard L. Calcium salt during hyperkalemia. Kidney 63. King JT, Goulet JL, Perkal MF, Rosenthal RA. Glycemic control and infec-
int. 2016;90:451–2. tions in patients with diabetes undergoing noncardiac surgery. Ann Surg.
41. Robert T, Burbach M, Joseph A, Mesnard L. Sodium is the secret re-agent 2011;253:158–65.
of bicarbonate therapy during hyperkalemia. Kidney Int. 2016;90:450–1. 64. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz
42. Ballantyne F, Davis LD, Reynolds EW. Cellular basis for reversal of M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med.
hyperkalemic electrocardiographic changes by sodium. Am J Physiol. 2001;345:1359–67.
1975;229:935–40. 65. Allon M. Nebulized albuterol for acute hyperkalemia in patients on
43. Greenstein S, Goldburgh WP, Guzman SV, Bellet S. A comparative analysis hemodialysis. Ann Intern Med. 1989;110:426.
of molar sodium lactate and other agents in the treatment of induced 66. Mandelberg A, Krupnik Z, Houri S, Smetana S, Gilad E, Matas Z, et al. Sal-
hyperkalemia in nephrectomized dogs. Circ Res. 1960;8:223–33. butamol metered-dose inhaler with spacer for hyperkalemia: How fast?
44. Gutierrez R, Schlessinger F, Oster JR, Rietberg B, Perez GO. Effect of How safe? Chest J. 1999;115:617–22.
hypertonic versus isotonic sodium bicarbonate on plasma potassium 67. Liou H-H, Chiang S-S, Wu S-C, Huang T-P, Campese VM, Smogorzewski
M, et al. Hypokalemic effects of intravenous infusion or nebulization of
Dépret et al. Ann. Intensive Care (2019) 9:32 Page 16 of 16

salbutamol in patients with chronic renal failure: comparative study. Am J 77. Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS. Characterization
Kidney Dis. 1994;23:266–71. of structure and function of ZS-9, a ­K+ selective ion trap. PLoS ONE.
68. Ellison DH, Felker GM. Diuretic treatment in heart failure. N Engl J Med. 2014;9:e114686.
2017;377:1964–75. 78. Kosiborod M, Peacock WF, Packham DK. Sodium zirconium cyclo-
69. Reyes AJ. Effects of diuretics on renal excretory function. Eur Heart J. silicate for urgent therapy of severe hyperkalemia. N Engl J Med.
1992;13:15–21. 2015;372:1577–8.
70. Reyes AJ. Renal excretory profiles of loop diuretics: consequences 79. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet.
for therapeutic application. J Cardiovasc Pharmacol. 1993;22(Suppl 2005;365:417–30.
3):S11–23. 80. Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Pons B, Boulet E, et al.
71. Chawla LS, Davison DL, Brasha-Mitchell E, Koyner JL, Arthur JM, Shaw AD, Initiation strategies for renal-replacement therapy in the intensive care
et al. Development and standardization of a furosemide stress test to unit. N Engl J Med. 2016;375:122–33.
predict the severity of acute kidney injury. Crit Care. 2013;17:R207. 81. Kovesdy CP, Regidor DL, Mehrotra R, Jing J, McAllister CJ, Greenland
72. Evans BM, Jones NC, Milne MD, Yellowlees H. Ion-exchange resins in the S, et al. Serum and dialysate potassium concentrations and survival in
treatment of anuria. Lancet Lond Engl. 1953;265:791–5. hemodialysis patients. Clin J Am Soc Nephrol. 2007;2:999–1007.
73. Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Gastrointestinal adverse 82. Pun PH, Lehrich RW, Honeycutt EF, Herzog CA, Middleton JP. Modifiable
events with sodium polystyrene sulfonate (kayexalate) use: a systematic risk factors associated with sudden cardiac arrest within hemodialysis
review. Am J Med. 2013;126:264.e9–24. clinics. Kidney Int. 2011;79:218–27.
74. Bushinsky DA, Williams GH, Pitt B, Weir MR, Freeman MW, Garza D, 83. Morrison G, Michelson EL, Brown S, Morganroth J. Mechanism and pre-
et al. Patiromer induces rapid and sustained potassium lowering in vention of cardiac arrhythmias in chronic hemodialysis patients. Kidney
patients with chronic kidney disease and hyperkalemia. Kidney Int. Int. 1980;17:811–9.
2015;88:1427–33. 84. Ferrey A, You AS, Kovesdy CP, Nakata T, Veliz M, Nguyen DV, et al. Dialysate
75. Meaney CJ, Beccari MV, Yang Y, Zhao J. Systematic review and meta-anal- potassium and mortality in a prospective hemodialysis cohort. Am J
ysis of patiromer and sodium zirconium cyclosilicate: a new armamentar- Nephrol. 2018;47:415–23.
ium for the treatment of hyperkalemia. Pharmacother J Hum Pharmacol 85. Roseman DA, Schechter-Perkins EM, Bhatia JS. Treatment of life-threat-
Drug Ther. 2017;37:401–11. ening hyperkalemia with peritoneal dialysis in the ED. Am J Emerg Med.
76. Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, et al. Effect 2015;33:473.e3–5.
of patiromer on serum potassium level in patients with hyperkalemia
and diabetic kidney disease: the AMETHYST-DN randomized clinical trial.
JAMA. 2015;314:151.