Hiperkalemia.pptx

Pendekatan dan Tatalaksana
Hiperkalemia dan Kasus
dr. Muhammad Thaifur
PROGRAM PENDIDIKAN DOKTER SPESIALIS-1
BAGIAN/SMF ILMU PENYAKIT DALAM
FAKULTAS KEDOKTERAN UNVERSITAS SYIAH KUALA
BANDAACEH
2022

Pendekatan dan Penatalakasanaan
Hiperkalemia dan Kasus
dr. Muhammad Thaifur
Program Pendidikan Dokter Spesialis-1
Fakultas Kedokteran – Universitas Syiah Kuala
Banda Aceh
~ AUGUSTA UNIVERSITY

Outline
•
•
Define hyperkalemia
Be able to describe the pathophysiology and mechanisms
of the correction of hyperkalemia
Compare the different treatment modalities (both
pharmaceutical and non-pharmaceutical) for hyperkalemia
Contrast the current ‘old’ treatment options with the new
treatments that have been developed
•
•
(al AUGUSTA UNIVERSITY

Kalium
Intraseluler (98%) > ekstraseluler (2%)
Konsentrasi serum normal 3.5-5 mEq/ml
Penting untuk fungsi fisiologis tubuh
Elektrofisiologi
Kontraktilitas miokard
Ekskresi
Renal (~81 mEq/hari)
Gastrointestinal (kolon) (~9 mEq/hari)
Keringat (minimal)
Sumber diet utama (~75-100 mEq/hari)
•
•
•
•
•

Bans ices Fish
.
Beans Citrus Juice
Fish

Renal Potassium Handling
Renal Kalium Handling

Hiperkalemia ECG
Perubahan
•
•
Kalium serum >
Tanda dan Gejala
Kelemahan
5 mEq/L
Perubahan EKG
Paralisis asendens
Henti jantung asistolik
•

Risk
•
•
Factors
Usually due to more
Known risk factors
than one factor
–
–
–
–
Kidney disease
History of diabetes
Age
Medications
RAAS inhibitors Potassium-sparing diuretics
Trimethoprim/sulfamethoxazole Beta antagonists
Heparin Calcineurin inhibitors

(
Renin Angiotensin Aldosterone System (RAAS)

Treatment of hyperkalemia
• Depends on acuity of hyperkalemia
–
–
–
Cause
Symptoms and/or ECG changes
Potassium concentration;
aggressive therapy
>6.5 mEq/L may require more

Treatment methods
• Remove exogenous potassium sources
– Oral supplements
– Intravenous sources (i.e. potassium-containing
maintenance fluids)
Minimize dietary sources
Hold medications that may contribute to
hyperkalemia
– RAAS antagonists
– Potassium-sparing diuretics
•
•

Interstitial flud
0
@ @
@ ®
Treatment of acute hyperkalemia
Intracellular shift
• Insulin regular IV / Dextrose IV
• Beta agonists – Albuterol INH
• Sodium bicarbonate IV
ln1racellular
fluid
/
i

Treatment of acute hyperkalemia
Removal therapies
• Dialysis
• Loop diuretics
• Potassium binding therapies
–
–
–
Sodium Polystyrene Sulfonate
Patiromer
Sodium Zirconium Cyclosilicate (ZS-9)*

Intracellular shift
• Insulin (Regular IV)
– Activates the sodium/hydrogen exchange pump
•
•
Improves sodium/potassium adenosine triphosphatase function
Promotes the movement of potassium from the extracellular
intracellular space
to
• Dextrose (IV) – hypoglycemia associated with insulin
administration
• Calcium (IV) - Stabilizes the cardiac membrane

Insulin and Dextrose
– REGULAR Insulin 5-10 units intravenously
» Intravenous insulin faster onset than subcutaneous
– Dextrose 25-50 grams
•
•
Onset immediate
Duration ~30 minutes

Results of insulin use in hyperkalemia
• Decreases potassium by 0.65 + 0.09 mEq/L
• Maximum effect seen within
administration
1-2 hours of
• May cause hypoglycemia

Hypoglycemia
• Risk of hypoglycemia with insulin
– Exogenous insulin metabolized by the kidneys
• Half-life of insulin increased in renal failure
– Duration of effect 4-8 hours
– Cases of hypoglycemia in hyperkalemia
post dose
up to 6-7.5 hours

Albuterol and Insulin for Treatment of Hyperkalemia
in Hemodialysis Patients
Design Single-center cross over study
n=12 on hemodialysis with hyperkalemia (>5 mEq/L on 3 occasions during a
1 month period)
Insulin 10 units/25gm D50%, Albuterol 20mg inhaled over 10 min, and a
combination of both on one of three occasions
Outcomes Primary endpoint: Maximum decrease in serum potassium
Results Baseline serum potassium evels similar for all groups
0.65 (+0.09) mEq/L for insulin/dextrose
0.66 (+ 0.12) mEq/L or albuterol
1.21 (+ 0.19) mEq/L or combination
,
l
-
-
-
f
f
Lepage CJASN 2015
Design Single-centre, cross over study
N-12 on hemodialysis with hyperkalemia (>5 mEq/L on 3 occasions
during a 1 month period)
Insulin 10 units/25g D50%, Albuterol 20mg inhaled over 10 min, and a
combination of both on one of three occasion
Outcomes Primary endpoint: Maximum decrease in serum potassium
Results Baseline serum potassium levels similar for all groups
- 0.65 (±0.09) mEq/L for insulin/dextrose
- 0.66 (± 0.12) mEq/L for albuterol
- 1.21 (± 0.19) mEq/L for combination
Albuterol and Insulin for Treatmenet of Hyperkalemia
in Hemodialysis Patients

Sodium Bicarbonate
•
•
•
Hyperkalemia seen in acute acidosis
Increased blood pH drives K+ into
Conflicting data
cells
– Schwarz, 1959 (case series)
•
•
5% Sodium Bicarbonate
144-408 mEq over 2-4 hours
–
–
Corrected acidosis
Decreased K+
– Blumberg, 1988 (n=10)
• No change in K+ after 60 minute
sodium bicarbonate
infusion of isotonic and hypertonic

Removal Therapies

Dialysis
Hemodialysis - most effective method to remove excess potassium
Dialysate potassium concentration
– Two potassium (2K+) bath
– Zero potassium (0K+) bath
•
•
•
•
Used for short period in order to avoid hypokalemia
Reserved for severe symptomatic cases
• >100 mEq of potassium can be removed over 4 hours
–
–
–
Plasma-to-dialysate K+ concentration gradient
Blood and dialysate flow rates
Total body potassium

Diuretics
• Loop diuretics
– Furosemide IV
– Inhibits inward transport of potassium via the Na-K-Cl
transporter 2 channel in thick ascending limb
Requires residual renal function
Intermediate rapidity of action (15 min – 1 hr)
May give with fluids if volume depletion a concern
Co-
•
•
•

Potassium Binding Therapies

Sodium Polystyrene
Introduced in 1958
Sulfonate (SPS)
•
• No clinical studies to support
use when introduced
its
• First clinical studies
– Poor methodology
in 1961
SPS Si.lspension

Sodium Polystyrene Sulfonate (SPS)
•
•
Cation exchange resin
Cross-linked polymer with sulfone groups preloaded
with sodium
Exchanges Na+ for K+ in the large intestine
Can cause constipation
Available
•
•
•
–
–
–
Powder
Premixed solution 15gm/60ml
Enema in sorbitol
with 33% sorbitol

Sodium Polystyrene Sulfonate (SPS)
• Oral
– Dose: 15-60gm divided once to four times daily
Rectal
•
–
–
–
Use for patients who cannot take by mouth
30-60gm given once to twice daily
Retain for as long as possible, then
(2000ml)
irrigate with non-saline fluid

FDA warning (2009)
–
–
Cases of intestinal necrosis associated with SPS
Other serious GI adverse events
•
•
•
Bleeding
Ischemic colitis
Perforation
–
–
–
Do not use in patients with non-normal bowel function
Do not use in patients at risk for constipation or impaction
Concomitant sorbitol with SPS has been implicated in colonic
intestinal necrosis

Sodium retention
•
•
4.1mEq (~100mg) sodium per 1gm SPS
33% of sodium is exchanged and
retained
30gm SPS x 100mg Sodium = 3000mg
Sodium
3000mg Sodium x 0.33 = 1000mg
•
•
• May be problematic in patients who
sodium sensitive
are
–
–
Uncontrolled hypertension
Heart failure

Drug Interactions
•
•
•
•
•
Lithium
Thyroid products
Digoxin
Magnesium containing laxatives
Aluminum containing antacids
and antacids
FDADrugSafetyCommunication: FDA requires drug
interaction studies with potassium-lowering drug sodium
polystyrene sulfonate [10-22-15]

Secondary Prevention of Hyperkalemia With Sodium
Polystyrene Sulfonate in Cardiac and Kidney Patients on
Renin-Angiotensin-Aldosterone System Inhibition Therapy
Design Single center medical record eview of patients from 2005-2010
n=14 with CKD and heart disease on RAAS inhibitors and daily SPS
Outcomes Hospitalizations, electrolyte levels and symptoms possibly attributable to SPS
Results Total of 289 days of follow-up with no colonic necrosis or life-threatening events
attributed to SPS
Mild hypokalemia responding to dose reduction, no further hyperkalemia and no
withdrawal or reduction of RAAS inhibitor therapy
r
lfMJ
AUGUSTA
UNIVERSITY Chernin, Clin Cardiol 2012

Randomized Clinical Trial of Sodium Polystyrene
Sulfonate for the T eatment of Mild Hyperkalemia in
CKD
Design Single-center double-blind, randomized, placebo-controlled
n=33 with CKD and mild hyperkalemia (5-5.9 mEq/L)
Randomized to placebo or 30gm of SPS without sorbitol daily for 7 days
Outcomes Primary endpoint: Between group dif erence in mean K+ rom baseline to he
day after the last dose
Results SPS superior to placebo in reduction of mean serum K+ between groups;
1.07 mEq/L (95% C -1.37 to 0.71)
T end toward more hypomagnesemia, hypocalcemia, and constipation vs
placebo
r
,
f f t
I -
r
lfMJ
AUGUSTA
UNIVERSITY Lepage, CJASN 2015

New Alternatives

Patiromer

Patiromer
•
•
•
•
•
•
Non-absorbed polymer
Binds K+ in exchange for Ca++
Does not swell and does not require cathartic
Acts in distal colon
Powder for suspension to be taken orally
Single-use packets of 8.4gm, 16.8gm, 25.2gm

Effec of P iromer 0n Serum Potassium Leve in P tients
With Hyperk emi nd 1Di betic Kldney Dise se
The AMETHYST-ON Randomized Cliruca Trtal
Design Phase III, multicenter open-label, dose ranging trial,
n=306 outpatients with K+>5 with type 2 DM and Stage 3-4 CKD on RAAS
inhibitors
Stratified to mild (5-5.5 mEq/L) or moderate (5.6-5.9) hyperkalemia
Randomized to 4.2, 8.4gm 12.6gm mild) and 8.4gm, 12.6gm, 16.8gm (mod)
PO BID
Outcomes Primary endpoint: Mean change in K+ from baseline to week 4 or until dose
titration
Secondary endpoint: mean change in K+ from baseline to 52 weeks
Results Primary: Mean reduction of 0.35, 0.51, 0.55 (mild)
0.87, 0.97, 0.92 (moderate) p<0.001 for all vs baseline
Secondary: Significant eduction in K+ from baseline to 52 weeks
1
l
,
(
r
lfMJ
AUGUSTA
UNIVERSITY Bakris, JAMA 2015

• ld
ode rate
Results
~
w
CT
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4
d
Day 3
...
....
Treatme
nt
Follow-
up
o. of
patients
Hyperkale
mia
ild
oderat
e
218 204
199
83 83
73
19
2
70
17
5
6
5
16
8
6
2
16
1
6
2
16
1
6
2
16
3
6
1
15
8
5
3
15
6
5
3
15
1
5
3
14
8
5
2
149 145
131 126
9 49 48
7
5.
8
5.
6
5.
4
5.
2
5.
0
4.
8
4.
6
4.
4
4.
2
.L
Baseline 1 4 8 12 16 20 24 28 32 36
40 44 48 52
Day 3a
Study Visit, k
2
1c
3
Hyperkalemia
i

Adverse Drug Events
• 20% of patients experienced adverse drug events
–
–
–
–
Hypomagnesemia 8.6%
Hypokalemia 5.6%
Constipation 4.6%
Diarrhea 2.7%

he G A D
0 A of D c
s 2015 0. 3
Pa iro rrre r m i Kidney isease and Hyper alemia e
ce iv irr g RAAS Inhibitors
Design Multicenter single-blind, andomized, placebo-controlled, wo phase
n=243, Stage 3-4 CKD on > 1 RAAS inhibitor with chronic hyperkalemia 5.1-6.4)
Stratified to mild (5.1-<5.5) = 4.2gm o moderate (5.5-<6.5) = 8.4gm n initial phase,
then randomized o same dose or placebo for 8 weeks (withdrawal phase)
Outcomes Primary endpoint initial phase): mean change in K+ from baseline week 4
Primary endpoint withdrawal phase): Difference between patiromer and placebo in
median change in serum K+ from baseline week 4 of withdrawal phase
Results Primary (initial): Mean serum K+ change; 1.01 + 0.03 mEq/L (95%CI 1.07 to -0.95),
p<0.001)
Primary (withdrawal): Difference in median change in serum K+ rom baseline
week; 0.72 (95% C 0.46 to 0.99) p<0.001)
.
, r t
(
r i
t
(
(
-
-
- -
f -
I (
l,fgjJ
AUGUSTA
Weir, NEJM 2015
UNIVERSITY

Adverse Drug Events
•
•
47% of subjects with at least one ADE
Most common ADE were gastrointestinal
–
–
–
–
Constipation 11%
Diarrhea 3-4%
Nausea 3%
Hypokalemia 3%

Patiromer Black Box Warning

Drug Interactions
•
•
Twenty-eight drugs tested
50% of drugs tested demonstrated interaction
binding)
(>30%
• Cationic, anionic, and neutral drugs affected

Amlodipine Clopidogrel Allopurinol Digoxin
Ciprofloxacin Metoprolol Apixaban Phenytoin
Quinidine Warfarin Atorvastatin Spironolactone
Percent of Drug Bound
Cinacalcet Lithium Amoxacillin Glipizide
Levothyroxine Verapamil Aspirin Rivaroxaban
Trimethoprim Cephalexin Valsartan

Drug interactions, in vivo
vitro studies
studies on previously listed
•
•
Current labeling based on in
Company conducting in vivo
medications
– 12 of 14 drugs interacting in vitro were tested in vivo
• 3 drugs demonstrated “clinically meaningful” reduced
absorption when co-administered
–
–
–
Ciprofloxacin
Metformin
Levothyroxine
• When separated by 3 hours, no interactions present

Distribution
• Obtained by individual outpatients through two national
specialty pharmacies only
• Hospitals can
distributors
obtain through authorized specialty

Sodium Zirconium Cyclosilicate (ZS-9)

Sodium Zirconium Cyclosilicate (ZS-9)
•
•
Engineered crystalline lattice structure
Highly selective for monovalent
– Potassium (K+)
– Ammonium (NH4+) High
capacity (9x SPS)
Exchanges Na+ for K+
Soluble in aqueous solution
Not absorbed systemically
cations over divalent cations
•
•
•
•

A phase 2 study on the treatment of hyperkalemia in
patients with chronic kidney disease suggests that
the selective potassium trap, ZS-9, is safe and
efficient
Design Phase II, multicenter double-blind, placebo-controlled trial,
n=90 in-patients with stage III CKD and K+ 5-6 mEq/L
randomized 2:1 to 3 doses 0.3, 3 10gm) of ZS-9 or placebo PO TID x 48 hrs
Outcomes Primary endpoint: Rate of decline in K+ from baseline at 48 hours,
Secondary endpoint: Significant decrease from baseline in K+ at 1 hour
Results Primary: 10gm vs placebo (-0.92 (+ 0.52) mEq/L at 38 hours) p<0.0001)
Secondary: 10gm (-0.11 + 0.46 mEq/L) vs placebo (0.12 + 0.36 mEq/L),
p=0.02
,
( ,
(
lfMJ
AUGUSTA
UNIVERSITY Ash, Kidney Int 2015

Results
5.4
...-.. ..... Placebo --· 0.3 g ZS-
9
- · 3 g ZS-
9
1 O g
ZS-9
-
o
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w
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5.2
5.0
4.8
4.6
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0124 14
8 44 48
24 28 32 38
Time
(h)
(sJ AUGUSTA UNIVERSITY

Adverse Drug Events
•
•
•
•
No
No
No
serious adverse drug events
change in Mg++, Ca+, or Na+
hypokalemia
Gastrointestinal ADE in ZS-9
–
–
–
Vomiting 13%
Nausea 8%
Diarrhea 4%

I
L
odium Zirconium Cyclo ilicate
in Hyper alernia
Design Phase III, multicenter double-blind, placebo-controlled trial,
n=753 ambulatory outpatients with K+ 5-6.5 (63-71% on RAAS inhibitors)
Randomized to 4 doses o ZS-9 or placebo PO TID x 48 hours, then
normokalemic subjects andomized 1:1 to same dose daily or placebo for
days 3-14
Outcomes Primary endpoint: Exponential rate o change in serum K+ at 48 hrs
Secondary endpoint: Between group dif erence in mean absolute change in
K+
Results Primary: Mean exponential reduction of 0.3% with 10gm ZS-9 vs 0.09% or
placebo(<0.001)
Secondary: Mean absolute change in K+ of -0.73 for 10gm vs placebo
,
f
r
f
f
f
lfMJ
AUGUSTA
UNIVERSITY Packham, NEJM 2015

Primary Endpoint
2.5gm 0.16% p <0.001 -0.46 (-0.53 to -0.39)
10gm 0.30% p <0.001 -0.73 (-0.82 to -0.65)
Placebo 0.09% -0.25 (-0.32 to-0.19)
5gm 0.21% p <0.001 -0.54 (-0.62 to -0.47)
1.25gm 0.11% p >0.05 Not Reported

Adverse Drug Events
• Initial Phase
– ZS-9 12.9% vs placebo 10.8%
Maintenance Phase
– ZS-9 25.1% vs placebo 24.5%
Diarrhea (ZS-9 vs placebo)
– Initial phase: 1.8% vs 2.5%
– Maintenance phase: 1.7% vs 2.2%
Hypokalemia
– 2 cases with ZS-9
No edema
•
•
•
•

Original Investigation
Effect of Sodium Zirconium Cyclosilicat1e on Potassium
Lowering for 28 Days Among Outpatients With Hyperkalernla
The HARMONIZE Randomized Chnical Trial
Design Phase III, multicenter randomized, double-blind, placebo-controlled
n=258 adult ambulatory patients with K+ > 5.1 mEq/L
Open label treatment phase 10gm TID for 48 hours
If normokalemic, then randomized to 5,10,15 gm o placebo daily for 28 d
Outcomes Primary endpoint: Comparison of mean serum K+ levels between placebo
and each treatment group during days 8-29 of andomized phase
Secondary: proportion of patients who were normokalemic at 29 days
Results Maintenance: Mean between group dif erences n mean K+ for ZS-9 vs
placebo
= -0.3 mEq/L, -0.6 mEq/L, and -0.7 mEq/L
Secondary: 71%, 76% and 85% vs 48% or placebo (p=.01, 0.002, and
<0.001)
1 1
'
,
r
r
f i
f
lfMJ
AUGUSTA
UNIVERSITY Kosiborod, JAMA 2014

Adverse Drug Events
•
•
Comparable between ZS-9 and placebo
Edema (maintenance phase)
–
–
–
6% of 10gm
14.3% of 15gm
2.5% with placebo
• Gastrointestinal adverse events
– 9% in 15gm group vs 14% with placebo
Hypokalemia (maintenance phase)
•
–
–
–
10.7% of 15gm
9.8% of 10gm
none with placebo

FDA approval
• May 2016
–
–
–
–
FDA approval denied due to manufacturing issues
No additional clinical trials requested
Manufacturer states it is addressing the issues
Will appeal ruling with new anticipated approval 2017

New Agents
• Onset
– Patiromer 7 hours (-0.2 mEq/L)
– ZS-9 1 hour (-0.11 mEq/L)
•
•
•
•
Majority of
Most dealt
60-70% of
studies were in the ambulatory setting
with chronic hyperkalemia
subjects were on RAAS inhibitors
Most studies excluded stage 5 CKD (ESRD)

Sodium Polystyrene Sulfonate Established use in acute Variable onset
(SPS) treatment Risk of severe gastrointestinal
adverse events
Risk of Na+ etention
Possible revised drug interaction
profile
Non-selective for K+
Sodium Zirconium Shorter onset han Patiromer Possible problems with Na+
Cyclosilicate (ZS-9) More selective for K+ retention
Mild adverse drug events Unknown drug interaction profile
Comparison
• •
•
•
•
r
•
•
•
Patiromer •
•
•
•
Exchanges Ca++ for K+
Daily dosing for chronic use
Effective at reducing K+
Mild GI adverse drug events
Onset 7 hours
Drug interactions and inflexibility
of dosing
Potential non-selectivity for K+
•
•
•
•
t •
•

Sodium Polystyrene 454gm bottle $20.27/bottle 30gm
Sulfonate (SPS) powder $1.34
Cost
Sodium Polystyrene
Sulfonate (SPS) liquid
Sodium Polystyrene
Sulfonate (SPS) enema
Patiromer
15gm/60ml liquid
bottle
30gm/120ml
enema
8.4 gm packet
$ 11.25/bottle 30gm
$22.50
30gm
$56.70
16.8gm
$71.40
Unknown
$56.70 each
$35.70/packet
Sodium Zirconium
Cyclosilicate (ZS-9)
Unknown Unknown

Summary
• Newer binding therapies primarily studied for outpatient chronic use
• Newer agents may provide advantages over SPS in chronic patients
–
–
–
Lower rates of adverse effects
More selectivity for potassium
More rigorous efficacy data
• Based on onset of action, Patiromer likely unsuitable for acute treatment
hyperkalemia
of
• Use of ZS-9 for acute hyperkalemia needs to be investigated further
• The incidence of sodium retention and edema with ZS-9 requires further
investigation

Conclusions
• Niche drugs
– Outpatient for chronic hyperkalemia from RAAS
antagonists
Use for acute treatment of inpatient mild-moderate
hyperkalemia unclear and unstudied
•
– Patiromer unlikely effective due to 7 hour
– ZS-9 shorter onset
onset

Questions?

The
The
Treatment of Hyperkalemia:
Old and the New
Dwayne A. Pierce, PharmD, BCPS
Clinical Pharmacist-Nephrology/Internal Medicine
Augusta University Medical Center
Augusta, Georgia

Question 1
The treatment of hyperkalemia consists of two basic
methods: drive the potassium intracellularly and remove
potassium from the body.
A)
B)
True
False

Question 2
Which FDA approved potassium binding agent has a black
box warning concerning the binding of other medications
necessitating a separation of 6 hours from
A) Sodium Polystyrene Sulfonate
B) Patiromer
the agent?
C) Sodium Zirconium
D) Sorbitol
Cyclosilicate

Question 3
What adverse effect is most associated with the
combination of calcium/insulin/
treatment of hyperkalemia?
and dextrose for the
A)
B)
C)
D)
Athlete’s foot
Sneezing
Hypoglycemia
Headache

Hiperkalemia.pptx

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