a new perspective on hypokalemia
TRANSCRIPT
A New Perspective on Hypokalemia
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrologist
Steve Chen
K
PotassiumPotassium
Reference Range:3.5 – 5.1 meq/L
PotassiumPotassium
Hypokalemia is K+ < 3.5 meq/L
Symptoms & Signs of Symptoms & Signs of Hypokalemia Hypokalemia
Clinical Features(1)Clinical Features(1)– Symptoms at serum KSymptoms at serum K++ << 2.5 meq/L 2.5 meq/L– CardiovascularCardiovascular
Increased HTNIncreased HTN Orthostatic hypotensionOrthostatic hypotension DysrhythmiasDysrhythmias EKG abnormalitiesEKG abnormalities
– Flat T-waves, prominent U-waves, ST-segment Flat T-waves, prominent U-waves, ST-segment depressiondepression
Symptoms & Signs of Symptoms & Signs of HypokalemiaHypokalemia
Clinical Features (2):Clinical Features (2):– NeuromuscularNeuromuscular
Malaise, weakness, fatigueMalaise, weakness, fatigue Hyporeflexia, cramps, paresthesiasHyporeflexia, cramps, paresthesias
– RenalRenal Increased ammonia production Increased ammonia production
encephalopathyencephalopathy Decreased GFRDecreased GFR
– GastrointestinalGastrointestinal IleusIleus
Major Dangers of Hypokalemia Major Dangers of Hypokalemia
Cardiac arrhythmias Respiratory paralysis Hepatic encephalopathy
Immediate therapy: IV K supply on EKG 200meq/L in NS, 40 ~ 100meq/Hr, femoral vein 60meq/L in 1/2NS, 10 ~ 20meq/Hr, peripheral vein
Diagnosis of HypokalemiaDiagnosis of HypokalemiaIs the rate of excretion of K excessive ?
Excretion of K = Urine K x UV ﹝ ﹞If <15meq/D Extra-renal loss
poor intake, GI loss cellular shift remote vomiting, remote use of diuretics
If >15meq/D Renal loss High CCD flow if TTKG<2 : Osmotic diuresis High urine K ﹝ ﹞ if TTKG>4: Aldosterone plus; ongoing use of diuretics
Urinary potassium excretion < 15meq /D
Assess acid- base status
Metabolic acidosis Metabolic alkalosis
Lower gastrointestinal loss Diuretic, remote use Vomiting, remote K loss via sweat
Extra-renal Loss of Potassium
UKE >15 meq/day TTKG>4 TTKG<2
Metabolic Metabolic acidosis alkalosis +HTN
DKA Proximal RTA No hypertension(-HTN) Distal RTA Vomiting Bartter’s Diuretic abuse Hypomagnesemia
Renal Loss of Potassium
Aldosterone plus Fast Na
Osmotic diuresis
(Mineralocorticoid HTN)
Aldosterone plus Aldosterone plus lumen negative in CCDlumen negative in CCD
Fast Na reabsorption Slow Cl reabsorption
High or normal ECV
Low or high renin
No renal Na wasting
Low ECV
High renin
Renal Na wasting
Liddle syndrome
Amphotericin B
Adrenal Tumors, RAS, MH
Bartter-Gitelman syndrome
Mg depletion
Diuretic
Vomiting
Gitelman’s / Bartter’s Gitelman’s / Bartter’s syndromesyndrome
Gitelman’s Bartter’s
Molecular level ↓TSC in DCT ↓NKCC, ROMK, or Cl
Age at onset Teenage Children
Clinical Tetany Failure to thrive
Mimicked by Thiazides Loop diuretics
Plasma Mg ↓ ↓
D.D. Hypocalciuria Hypercalciuria
Uosm ↓
Transtubular K GradientTranstubular K Gradient
TTKG: to interpret urine K by adjusting ﹝ ﹞it for water reabsorption in renal medulla to reflect K in lumen of CCD﹝ ﹞
TTKG= Uk÷(Uosm/Posm) /Pk﹛ ﹜TTKG, physiological : 6 ~ 8
Trans-cellular shift
Hypokalemia with TTKG 2Hypokalemia with TTKG 2 ~~44
Shift of K into cellsShift of K into cells↑~↑~ 13.5meq/L if NaK-ATPase failed13.5meq/L if NaK-ATPase failed
Anabolism: growth, recovery from DKA, TPN, recovery from pernicious anemia
Acid-base disorder: ↑pH 0.1=↓0.2 ~ 1.7meq/L Acting via hormones: insulin, β2-agonist(↓0.5 ~
0.6meq/L), α-antagonist Hyperosmolality↓ 10 mosmol/Kg:↓ 0.4 ~ 0.8meq/L Exercise: ↑0.3 ~ 2.0meq/L
rebound hypokalemia: ↓0.5meq/L Others: Hypokalemic periodic paralysis Anesthesia? In animals
Therapeutic goalsTherapeutic goals
To correct potassium deficit
To minimize ongoing losses
To prevent life threatening complications
Therapeutic principlesTherapeutic principles
Safer to correct potassium via oral route
A decrement of 1mmol/l in plasma potassium may represent a total body k+ deficit of 200 to 400meq
Dextrose containing solutions avoided
When to treat…..?When to treat…..?
3.5 to 4 meq/L
Increase intake of potassium containing food.
3 to 3.5 meq/L
Only in high risk patients.
< 3 meq/L Needs definitive treatment.
Indications for K supplyIndications for K supply
Absolute Presence of symptoms: hypoventilation
Digitalis therapy
Therapy for DKA
Severe hypokalemia<2.0meq/L
Strong Myocardial disease
Anticipated hepatic encephalopathy
Anticipated ↑ of shift
Modest Development of glucose intolerance
Need for better antihypertensive control
Mild hypokalemia∞ 3.5meq/L
Food: 60meq KFood: 60meq K
Foods Weight(G)
Vegetables
Potatoes and beans
Peas
500
5000
Fruits
Banana
Orange
800
1200
Meats: beef and chicken 600
Oral potassiumOral potassiumSafer Potassium chloride preparation of choicePotassium bicarbonate and citrateMild to moderate hypokalemia: KCl 60 to 80
meq/day in 3 to 4 divided doses8 meq/tab
Oral K supplyOral K supply
Check bowel sounds first before SK 3 ~ 3.5meq/L: 60 ~ 80meq/DSK from 4 to 3 meq/L:
loss of 200 ~ 400meq K
IV potassiumIV potassiumSevere symptomatic hypokalemiaContinuous ECG monitoring & frequent k+
estimationNever give KCl directly IV.Rapid IV correction can cause dangerous
hyperkalemia.Use isotonic salineDo not mix with dextrose containing
solutions.
Preparation of IV KPreparation of IV K KCL
Diuretic or vomitingK citrate, KHCO3
DiarrheaK phosphate
give Pi < 6mmol/Hr to ensure K staying in ICF during anabolism TPN Recovery phase from DKA
IV K supplyIV K supply
GI problemsSevere hypokalemia < 2.0meq/LSevere symptoms: respiratory paralysis,
cardiac arrhythmia, hepatic encephalopathyTherapy for DKADigitalis therapy to keep SK > 4meq/LK deficit in SK 2meq/L: 400 ~ 800meq
Mutations(+) of renal Na Mutations(+) of renal Na channelschannels
Liddle syndrome: β and γ subunits of amiloride-sensitive ENaC
Glucocorticoid remediable aldosteronism(GRA) aldosterone synthase/11 β hydroxylase
Apparent mineralocorticoid excess(AME) mineralocorticoid receptor, 11 βhydroxystreoid dehydrogenase
Congenital adrenal hyperplasia(CAH) 11α hydroxylase/β hydroxylase
Progersterone induced hypertension(PIH) mineralocorticoid receptor
Aldosterone-ENaC Depolarizes Aldosterone-ENaC Depolarizes ROMK in CCD ROMK in CCD
E Na C
ROMK
Na K ATP aseDepolarize
+
Aldosterone+
Na
KV2R
AquaporinH2O CaSR
CaSR
Progesterone in renal collecting duct Progesterone in renal collecting duct not just a sex hormone anymorenot just a sex hormone anymore
Progesterone+
KH
PR bound progesterone
HKα2 mRNA
Mineralocorticoid HTNMineralocorticoid HTN
Causes Diagnostic parametersLiddle Amiloride test
GRA 18-hydroxycortisol(U)
AME(↓11βHSDH) Cortisol/cortisone(U)
CAH(↓11β hydroxylase) Deoxycorticosterone (U)
↓ 17αhydroxylase Deoxycorticosterone(U)
↑Mineralocorticoid receptor mutation Spironolatone test?
DOC-producing adenoma DOC(U); MRI Aldosterone-producing tumor Renin/aldosterone: supine/erect
MRI
Secondary hyperaldosteronism Renin; MRA
Liddle’s GRA AMEMolecular level ↑ENaC
in CCD Chimeric gene: ACTH-driven mineralcorticoid
synthesis
↓11β-HSDH in principal cells
Age at onset Young Young adult Children
Clinical HTN HTN,severe HTNMimicked by AMB Mineralcorticoids Licorice;
carbenoxolone
Plasma Mg N N N
D.D. Amiloride test
Dexamethasone suppression test;18-hydroxycortisol(U)
Cortisol/cortisone(U); THF+5αTHF/THE(U)
Liddle’s GRA AMEMolecular level ↑ENaC
in CCD
Chimeric gene: ACTH-driven mineralcorticoid
synthesis
↓11β-HSDH in principal cells
Age at onset Young Young adult Children
Clinical HTN HTN,severe HTNMimicked by AMB Mineralcorticoids Licorice;
carbenoxolone
Plasma Mg N N N
D.D. Amiloride test
Dexamethasone suppression test;18-hydroxycortisol(U)
Cortisol/cortisone(U); THF+5αTHF/THE(U)
Bartter’s syndrome in THAL Bartter’s syndrome in THAL
NKCC
ROMK
Na K ATP ase
Ca, Mg pH
Na/K
K
2Cl
CaSRNegative
Positive
ClC-Kb
2
1
3
Gitelman’s syndrome in DCT Gitelman’s syndrome in DCT
TSCNa
2Cl
V2R
Inactive TSC dimer TSC
monomer
AT1R
MR
SPAK
Ca-ATPase Ca
PTH
Feed forward
Feedback
TPP&HPPTPP&HPP TPP HPP
Duration 3~ 36H 1~ 4H
Clinical 20~ 50Y puberty
Interval Total weakness Often subclinical
Glucose-insulin Trigger only hyperthyroidism
Trigger at any time
Molecular Ion channel Ca channel
Therapy
Prophylaxis
K supply
PTU/ β-blocker
K supply
Acetazolamide
K supply in TPPK supply in TPP
Regimen 1: oral KCL, 0.2 ~ 0.4meq/Kg, repeat every 15 ~ 30 minutes
Regimen 2: IV bolus KCL, 0.1meq/Kg repeat every 5~ 10 minutes
Regimen 3: PO 32meq q2H or IV 20 ~40meq/2H in mannitol solution
Regimen 4: IV high dose proprandolol 3mg/Kg
CCD flow rateCCD flow rate
CCD flow rate∞osmole excretion rate under vasopressin action
CCD osmolality=cortical interstitial compartment=Plasma osmolality(Posm)
CCD flow rate= Urine osmoles/PosmUosm excretion= U osm / U Cr ﹝ ﹞ ﹝ ﹞
Estimate of UK excretion Estimate of UK excretion
UK excretion= U K x UV﹝ ﹞Ucr excretion= U Cr x UV ﹝ ﹞
if age<50 Ucr excretion=20mg/Kg x BW=1G/D
UK excretion= U K x UV / U Cr x ﹝ ﹞ ﹝ ﹞UV = U K / U Cr﹝ ﹞ ﹝ ﹞
70mmol K per 1.15g of Cr on a typical diet
Obligate loss of KObligate loss of K
Renal loss: 10meq/D≧Non-renal loss:
Sweat 10meq/L x 0.2 ~ 12L/D = 2 ~120meq/D Stool 100meq/L x 0.1L/D = 10meq/D Diarrhea 40 ~50meq/L
Vomiting-induced hypokalemiaVomiting-induced hypokalemiadue to urinary lossdue to urinary loss
Volume(L/D) K: meq/L
Gastric 1.5 10
Duodenal 3-8 15
Pancreas 0.5 5
Bile duct 0.5 5
Jejunal 3 5
Ileal 0.5 10
Vomiting/DiureticsVomiting/Diuretics
Urine electrolytes
Vomiting Diuretics
Na >20meq/L if recent
<10meq/L if remote
>20meq/L if recent
<10meq/L if remote
K TTKG↑if recent TTKG↑if recent
Cl <10~ 15meq/L >20meq/L if recent
<10meq/L if remote
HCO3 Abundant Zero CAI excluded
CKD and bone fracture CKD and bone fracture Nickolas et al: KI 2008 (Columbia University Medical Center) Nickolas et al: KI 2008 (Columbia University Medical Center)
Study GFR (ml/min) Fracture site Fracture risk Dukas et al < 65 Hip OR 1.57 (2005) Wrist OR 1.79 Vertebral OR 1.31Nickolas et al < 59 Hip OR 2.32 (2006)Ensrud et al 45-59 Hip HR 1.24 (2007) <45 HR 1.41 45-59 Trochanteric HR 3.69 <45 HR 5.04Jamal et al <45 Any fracture OR 1.3 (2007) Vertebral OR 2.5Friend et al <60 Hip HR 1.38 (2007)
Hypokalemia in magnesium deficiencyHypokalemia in magnesium deficiencyHuang et al: JASN 2007 (University of Texas Medical Center)Huang et al: JASN 2007 (University of Texas Medical Center)
Outward ROMK Driving Potassium
conductance force secretion
Mg replete + ++ ++
Mg deficient
Alone ++ + ++
+ Na delivery ++ ++ ++++
+ Aldosterone ++ ++ ++++
ROMK in intracellular magnesium ROMK in intracellular magnesium Huang et al: JASN 2007 (University of Texas Medical Center)Huang et al: JASN 2007 (University of Texas Medical Center)
CCT
E Na C
ROMK
Na K ATP aseDepolarize
+
UK 5mM CK 143mM
Aldosterone+
Na
KMg
Hypokalemia in magnesium deficiencyHypokalemia in magnesium deficiencyHuang et al: JASN 2007 (University of Texas Medical Center)Huang et al: JASN 2007 (University of Texas Medical Center)
CCT
E Na C
ROMK
Na K ATP aseDepolarize
+
Urine Blood
Aldosterone+
Na
K