Covers topics of hypo/hyperkalemia, hypo/hypercalcemia and hypo/hypernatremia in an oncology setting.

1. Dyselectrolytemias
Dr Sunit Lokwani
D.M. 1st year
Medical Oncology
VIMS & RC, Bangalore

2. Study outline
• Basics/Introduction
• Pathophysiology
• Oncologica
• Cancer Drugs associated with the condition
• Management guidelines
• Current Trends in management.

3. Hypokalemia - Basics
• 3.5 – 5.0 meq/L
• Intake is normally 40 to 120 meq per day
• Symptom of another disease or condition, or a side effect of drug
therapy.
• Regulated by the kidneys
• Hormonal control - Aldosterone & Insulin
• Causes - Decreased potassium intake, Increased entry into
cells, increased gastrointestinal losses, increased urinary losses,
increased sweat losses, dialysis,plasmapheresis.
• “The severity of the manifestations of hypokalemia tends to be
proportionate to the degree and duration of the reduction in serum
potassium.”
• Manifestations -Severe muscle weakness or rhabdomyolysis , Cardiac
arrhythmias and ECG abnormalities, Renal abnormalities, Glucose
intolerance

6. Pathophysiology
• Alterations in the generation of the action potential.

7. Oncologica
• Potassium has been the ‘Katappa’ of hemato-oncology for time
immemorial – By your side always but tends to kill you if not
attended to.
• Commonly seen in cancer patients due to:
1. Paraneoplastic syndromes
2. Tumors causing ectopic release of ACTH
3. Cancer chemotherapy affecting Renal tubular function

8. Drugs
• Diuretics (carbonic anhydrase inhibitors, loop diuretics, thiazide
diuretics): Increased collecting duct permeability or increased
gradient for potassium secretion can result in losses
• Methylxanthines (theophylline, aminophylline, caffeine)
• Verapamil (with overdose)
• Quetiapine (particularly in overdose)
• Ampicillin, carbenicillin, high-dose penicillins
• Bicarbonate
• Antifungal agents (amphotericin B, azoles, echinocandins)
• Gentamicin
• Cisplatin
• Ephedrine
• Beta-agonist intoxication

9. Cisplatin
Methotrexate
Ifosfamide
Pamidronate
Cytosine
Anthracyclines
“Capecitabine”
Ondansetron

10. Management Guidelines
Treatment of hypokalemia has 4 facets, as follows:
• Reduction of potassium losses
• Replenishment of potassium stores
• Evaluation for potential toxicities
• Determination of the cause
Cohn JN, Kowey PR, Whelton PK, Prisant LM: New guidelines for potassium
replacement in clinical practice: A contemporary review by the National
Council on Potassium in Clinical Practice. Arch Intern Med 2000;160:2429–
2436.

11. Correction of Critical Hypokalemia July 15th, 2010
by reuben in electrolytes, glucose

12. Hyperkalemia - Basics
• 5.5-6.0 mEq/L – Mild
• 6.1-7.0 mEq/L – Moderate
• ≥7.0 mEq/L – Severe
• Total body potassium stores are approximately 3000 meq (50 to 55 meq/kg
body weight).
• The plasma potassium concentration is determined by the relationship among
potassium intake, the distribution of potassium between the cells and the
extracellular fluid, and urinary potassium excretion.
• Psudohyperkalemia – Faulty technique, Ion moving out of clotted cells, cases
of leukaemia with high Cell count at presentation, Metabolic acidosis

13. Pathophysiology/Etiology
DECREASED EXCRETION -
• Most common cause is Oliguric
renal failure.
• Primary adrenal disease (e g, Addison disease,
salt-wasting forms of congenital adrenal hyperplasia),
Hyporeninemic hypoaldosteronism,
Renal tubular disease (pseudohypoaldosteronism I[or II),
or
Medications (e g, ACE inhibitors, angiotensin II blockers, spironolactone or other
potassium-sparing diuretics).

14. INCREASED INTAKE
• Intravenous or oral potassium supplementation.
• Packed RBCs (PRBCs)transfusion
TRANSCELLULAR SHIFTS
• Acidosis most common cause
• Process that leads to cellular injury or death (eg, Tumor lysis
syndrome, massive hemolysis) can cause hyperkalemia
• Other causes include propofol ("propofol infusion
syndrome"),toxins (digitalis intoxication), succinylcholine,
beta-adrenergic blockade, strenuous or prolonged exercise,
insulin deficiency, malignant hyperthermia, and
hyperkalemic periodic paralysis

15. Oncologica
• Side effects of chemotherapy, breakdown of tumor cells, hormones produced
by certain types of tumors and extensive replacement of the adrenal glands
by tumors can all result in high potassium blood levels, according to the
“Manual of Clinical Oncology.”
• For ages, TLS has been the matter of concern for Haemato-oncologists.
• A part of focus in correcting Tumor lysis is focussed on Managing
hyperkalemia.

16. Drugs associated with..
• Potassium-sparing diuretics
• NSAIDs
• ACE inhibitors
• ARBs
• Direct renin inhibitors (eg, aliskiren)
• Cyclosporine or tacrolimus
• Antibiotics (eg TMP-SMX)
• Epsilon-aminocaproic acid (EACA)
• Oral contraceptive agents,
such as drosperinone

17. Treatment
STABILIZE MYOCARDIUM
• IV Calcium Gluconate (10 %) 0.5 mL/kg IV over 2-4 min,monitor for
bradycardia.May repeat.Has transient effect.
Indicated in all cases of severe hyperkalemia (ie, >7 mEq/L), especially when
accompanied by ECG changes

18. SHIFT K+ INTO CELL
• Regular insulin and glucose IV
2ml/kg 50% dextrose (1g/kg) and 0.1units/kg of regular Insulin over 5-10
minutes (mixed in same syringe) , can be repeated after 30 min.
Rapid action,Monitor sugar post insulin
• Beta-adrenergic agents, such as salbutamol neb. 2.5-5 mg or Epinephrine
(0.05 µg/kg per minute by intravenous infusion)
• Sodium bicarbonate(7.5%) IV
2 cc / kg slowly ,?Efficacy, repetition not recommended.
• A Cochrane review suggests that Dextrose/Insulin and salbutamol are the first
line therapies most supported by evidence, and that a combination of
the two therapies may be more effective than either alone.
(Mahoney BA, et al. Emergency interventions for hyperkalaemia. Cochrane Database Syst Rev 2005;(2):CD003235.)

19. INCREASE K EXCRETION
• Loop or thiazide diuretics work well if kidneys are functioning normally.
• Kayexalate(Cation Excange Resin): exchanges Na for k.
Dose: 1gm/kg/dose every 6 to 8 hrly PO/PR.
Pneumonic C BIG K Drop –
• C : Calcium Gluconate
• B: Bicarbonate
• I,G : Insulin and Glucose
• K: Kayexelate
• D: Diuretics and Dialysis

20. Hyponatremia - Basics
• Generally considered a disorder of water as opposed to disorder of salt i.e.it
usually Results from increased water retention.
• Hyponatremia, the most common electrolyte disorder in hospitalized patients
present seen in 15%-22% patients at admission.
• Normal physiologic measures allow a person to excrete up to 10 liters of water
per day which protects against hyponatremia
• Thus, in most cases, some impairment of renal excretion of water is present
• Maximum concentrating ability of kidney is approximately 800-1600mOsm/kg
Verbalis et al Hyponatremia Treatment Guidelines 2007/American Journal of Medicine (2007) Vol120 (11A),S1–S21

26. Oncologica
• “In patients with cancer, hyponatremia secondary to inappropriate secretion of
AVP (or ADH; syndrome of inappropriate antidiuretic hormone [SIADH] or
syndrome of inappropriate antidiuresis) occurs as a paraneoplastic syndrome,
or as a complication of therapy.
• SIADH is defined as a hypo-osmolar or dilutional hyponatremia with excessive
natriuresis.
• Hyponatremia occurs because AVP secretion continues even after plasma
osmolality falls
below the threshold
for AVP release.”
- DeVita Hellman Rosenberg Cancer
Principles and Practice of Oncology
10E

27. • Most frequently reported with small-cell lung cancer, head and neck
carcinomas, hematologic malignancies, and non–small-cell lung cancer.
• Drugs reported to cause SIADH include
• Cyclophosphamide
• Ifosfamide;
• The vinca alkaloids including vincristine, vinblastine, and vinorelbine;
• The proteasome inhibitor bortezomib;
• Carboplatin and Cisplatin,

28. THERAPY ADVANTAGES DISADVANTAGES
Fluid restriction Generally effective; inexpensive Noncompliance
Demeclocycline Consistently effective Reversible azotemia and
nephrotoxicity; polyuria
Lithium Effective in some patients Inconsistent effectiveness;
significant adverse effects
Loop diuretics (e.g. furosemide)
plus increased salt intake
Effective in some patients Imbalance between diuretic
action and salt ingestion
can lead to volume
depletion or overload
Urea Consistently effective Poor palatability; gastrointestinal
adverse effects;
development of azotemia at
higher doses
Hypertonic (3% or 5%) saline
with or without co-
administration of loop
diuretics
Corrects serum [Na+] Rate of correction is variable and
difficult to control; overly
rapid correction is
associated with
myelinolysis
VAPTANS Corrects sodium consistently Expensive, no long term
mortality benefit

29. • Na deficit = 0.6 x wt(kg) x (desired [Na] - actual [Na]) (mmol)
• 60 kg woman, serum Na 107, seizure and other symptoms
• Na deficit = 0.6 x (60) x (120 – 107) = 468 mEq
• Want to correct at rate 1.5 mEq/L/h: 13/1.5 = 8.7h
• 468 mEq / 8.7h = 54 mEq/h
• 3% NaCl has 513 mEq/L of Na
• 54 mEq/h = x
513 mEq 1L
• x = rate of 3% NaCl = 105 cc/h over 8.7h to correct serum Na to 120 mEq/h
• Note: Calculations are always at best estimates, and anyone getting
hyponatremia corrected by IV saline (0.9% or 3%) needs frequent serum
electrolyte monitoring

30. ADROGUE MADIAS FORMULA
• A value of 1 indicates that the entire increase in serum sodium
concentration can be accounted for by the administered hypertonic
saline.
• Hypertonic saline should be infused at rates lower than those
predicted by formulas with close monitoring of serum sodium and
urine output.
• Total body water is estimated as total body weight
– X 0.6 in children and nonelderly men,
– X 0.5 in nonelderly women and elderly men
– X 0.45 in elderly women.

33. Hypernatremia - Basics
 Plasma [Na+] >145 meq/L (a Hyperosmolar Condition)
 Primary Na+ gain or a Water Deficit due to -
o Impaired Thirst Response - Physical restrictions,or mentally impaired
patient
o Due to Water loss :-
1. Nonrenal Water Loss—Skin and respiratory tract(insensible),GI loss like
diarrhea mainly osmotic diarrhoea and viral gastroenteritis .
2. Renal water Loss - Either Osmotic Diuresis or DI.
• Osmotic Diuresis:-High osmolar feeds,and glycosurea,stress dose of
steroid.
• DI or NDI / CDI - Li, Demeclocycline, amphotericin, hypercalcemia,
Hypokalemia, medulary wash out and intrinsic renal ailment.
• Hypothalamic lesions which affect thirst function – Causes include tumors,
granulomatous diseases or vascular disease

34. Pathophysiology
• Urine Osmolaity >400 mosm/kg
– Renal losssevere hyperglacemiatranslocatinal hyponatrimia
progressive volume depletion from glucosuria lead to Hypernatrimia
– Non Rneal LossFluid Loss from excessive sweating, respirator tract or
bowel movements. Lactulose cause osmotic diarrohea with loss of free
water
Urine Osmolaity <250 msom/kg
– Hypernatrimia with dilue urine is charactersitc of DI.
– Central DI results from Inadequate ADH release
– Nephrogenic DI results from renal insensitivity to ADH

37. • If urine Osmolality is lower than serum
Osmolality then DI is present
– Administration of DDAVP(desmopressin) will
differentiate
• Urine Osmolality will increase in central DI, no response
in nephrogenic DI
DDAVGreatly enhanced ADH activity. Less vasopressor
activity. Longer DOA. (Synthetic analog of vasopressin-
posterior pituitary hormone).

38. Drugs
Drugs
• Lithium
• Amphotericin B (Fungizone)
• Demeclocycline (Declomycin)
• Methoxyflurane (Penthrane)
• Foscarnet (Foscavir)
Chronic tubulointerstitial disease
• Analgesic nephropathy
• Sickle cell nephropathy
• Multiple myeloma
• Amyloidosis
• Sarcoidosis
• Polycystic kidney disease
Electrolyte disorders
• Hypercalcemia
• Potassium depletion

39. Treatment of Hypernatremia
• First, calculate water deficit
• Water deficit = CBW x ((plasma Na/desired Na
level)-1)
• CBW = current body water assumed to be 50%
of body weight in men and 40% in women

40. •60 kg woman with 168 mEq/L
•How much water will it take to
reduce her sodium to 140 mEq/L
sample calculation:
Water deficit =
0.4 x 60 ([168/140]-1) = 4.8 L

41. Calculation continued
But how fast should I correct it?
• Same as Hyponatremia, sodium should not be
lowered by more than 12 mEq/L in 24 hours
– Overcorrection can lead to cerebral edema which can
lead to encephalopathy, seizures or death
• So what does that mean for our patient?
– The 4.8 L which will lower the sodium level by 28
should be given over 56-60 hours, or at a rate of 75-80
mL/hr
– Typical fluids given in form of D5 water

42. Hypercalcemia - basics
• Very common – aka “ The hypercalcemia of malignancy” –
incidence – upto 30% of cancer patients.
Bushinski and Monk (1998), Lancet, 352, p.307.

43. Hypercalcemia of Malignancy
• Lung, breast, and prostate cancer frequently invade
skeleton and destroy bone tissue
• Breast and lung cancer also cause hypercalcemia of
malignancy (HCM), without invading skeleton
• Multiple myeloma has skeletal complications in virtually
100% of cases
• Damage to skeleton usually late in course of disease
• Bone damage associated with considerable worsening in
patient’s quality of life

44. • The Catch here is
The symptoms of
hypercalcemia may overlap
With the symptoms of
Patient’s malignancy.

45. Stewart, A.F. (2005), NEJM, 352, p.374.

46. Mechanisms of HCM
(1) Humoral hypercalcemia- PTHrP mediated
From Horwitz, M.J., UpToDate
(2) Local osteolytic hypercalcemia
(3) 1,25-dihydroxyvitamin D mediated hypercalcemia.
(4) Coexisting primary Hyperparathyroidism
(2) Local osteolytic hypercalcemia

47. Pathophysiology
The vicious cycle of osteolytic
metastasis in breast cancer.
PTHrP in breast cancer- both
endocrine and paracrine
action.
Roodman, G.D. (2004), NEJM, 350,p.1660.

48. • It is most frequently encountered in patients with carcinomas of
the breast, lung, kidney, and head and neck, whereas
hypercalcemia with skeletal metastases is seen most often in
patients with multiple myeloma.
• Hypercalcemia present up to 30% at presentation.
• Purely osteolytic.
• Key factors; Interleukin 6, Interleukin 1, RANKL, MIP 1a and
osteoblastic dysfunction
(Roodman, 2004)
- DeVita Hellman Rosenberg Cancer Principles and
Practice of Oncology 10E

49. • Seymour and Gagel (1993), Blood, 82, p.1384.

50. Treatment
Intervention Adverse Effect
Hydration or calciuresis
Phosphate repletion
IV Bisphosphonates
Pamidronate Renal failue, flu-like syndrome
Zoledronate
Gluticorticoids
Mithramycin Myelosuppression, renal toxicity
Calcitonin Flushing, nausea
Gallium nitrate Renal failue
• Redrawn from Stewart, A.F. (2005), NEJM, 352, p.376.

51. Novel therapy: RANKL inhibitor
Inhibitor
www.rankligandincancer.com

52. Denosumab
• Human monoclonal IgG2 anitibody to RANKL.
• Currently2 Phase 3 studies: in subjects with CSC >
12.5mg/dL and not responding to recent treatment
with IV bisphosphonate.
• Pharmacokinetic goal: to maintain a constant level of
maximal suppression of bone resorption.
• Hypothesis: CSC 11.5mg/dL by day 10.
• Denosumab 120mg SC Q4W, with loading dose on
study days 8 and 15 to facilitate a rapid attainment of
steady-state.
AMG 162 protocol # 20070315, May 2010

53. calcium
40-45 %
ionized
40-45 %
albumin
bound
10%
complexed
citrate, sulphate
8.5–10.5 mg/dl
ECF
Filtration
5-7gr
Reabsorption
4.9-6.7gr
98%
Diet 0.5-1.5 gr
Absorption
0.25-0.5gr
Secretion
0.1-0.2gr
Feces
0.35-0.6gr
Resorption
0.3-0.5 g
Formation
0.3-0.5 g
Bone
1000 g
0.15-0.3 g/24h
• Total body Ca
1 to 1.5 kg
• 99%- skeleton
• 0.1% ECF
• rest intracellular
Hypocalcemia - Basics

54. Calcium
• An essential intracellular and extracellular cation
• Extracellular calcium is required to maintain normal
biological function of nervous system, the musculoskeletal
system, and blood coagulation
• Intracellular calcium is needed for normal activity of many
enzymes
• Preservation of the integrity of cellular membrane
• Regulation of endocrine and exocrine secretory activities
• Activation of compliment system
• Bone metabolism

55. Calcium (Ionized) - Roles
• In bone: calcium salts provide structural integrity
of the skeleton ( mineralization)
• Regulation of neuromuscular contractility
• Regulation of activity of many enzymes
• Cofactor in coagulation process ( factors VII, IX, X and
prothrombin)
• Cellular activities: second messenger, mediating
the effects of membrane signals on release or
secretory products (neurotransmitters, amylase,
insulin, aldosteron)

56. Calcium and Albumin
• 40-45% of circulating calcium is bound to albumin
• Change in serum albumin change in measured total
serum calcium concentration
• Calcium is bound to carboxyl groups in albumin, this
binding is highly pH dependent
• Acute acidosis binding ionized calcium
• Acute alkalosis binding ionized calcium
• A shift of 0.1 pH unit produces a change in ionized
calcium of 0.04 to 0.05 mmol/L ( 0.16-0.2 mg/dl)
• These changes are not reflected at the total calcium

57. Corrected calcium
• Correct calcium for albumin: Ca = measured
Ca + 0.8 for each mg/dl albumin below 4.0

58. Manifestations of Acute Hypocalcemia
• CNS
– Psychiatric disturbances
– Seizures
• Neuromuscular
– Tremor, twitching, movement disorders
– Positive Chvostek and Trousseau signs
– Carpopedal spasm
– Tetany
• Cardiac
– Q-T prolongation on ECG
– Ventricular Arrhitmia
– Heart block

59. ECG in Hypocalcemia
• Sinus rhythm with diffuse T wave inversion
• T waves -inverted, but of relatively normal width
• QT prolongation (The corrected qtc is 560 ms )
• Prolongation is in the ST segment rather than the T waves

60. Carpopedal Spasm

61. Signs & Symptoms: A 2-in-1 Reference for Nurses, Copyright © 2007 Lippincott Williams & Wilkins,
www.wrongdiagnosis.com/bookimages/14/4721.1.png

62. Trousseau sign:
(very uncomfortable and painful)
• A blood pressure cuff is
inflated to a pressure above
the patients systolic level.
• Pressure is continued for
several minutes.
• Carpopedal spasm:
* flexion at the wrist
* flexion at the MP joints
* extension of the IP joints
* adduction thumbs/fingers

63. The causes of hypocalcemia include the following:
• Hypoalbuminemia
• Hypomagnesemia
• Hyperphosphatemia
• Medications
• Post Surgical
• PTH deficiency or resistance
• Vitamin D deficiency or resistance
• Medications – Cisplatin, Combination therapy with 5-FU
and Leucovorin, Rx with Zometa, Foscarnet,
Denosumab, Ethylene glycol complexes with calcium,
Estrogen inhibits bone resorption, Aluminum and
alcohol suppress PTH.

64. Treatment of Acute Hypocalcemia
Calcium Repletion
• Promptly correct symptomatic or severe hypocalcemia
with cardiac arrhythmias or tetany with parenteral
administration of calcium salts
• Administer 1-2 ampules 10% calcium gluconate (93
mg/10 mL) in 50-100 mL of D5W over 5-10 minutes
then NS with 15 mg/kg of calcium
• Each 10 cc ampule of 10% calcium gluconate contains
1 gm of calcium gluconate but less than 100 mg of
calcium then therefore, if want to give 15 mg/kg
calcium to 70 kg pt, have to give 10 amps
• Measure serum calcium every 4-6 hours to maintain
serum calcium levels at 8-9 mg/dL

65. • Patients with cardiac arrhythmias or patients on
digoxin therapy need continuous ECG
monitoring during calcium replacement
because calcium potentiates digitalis toxicity.
• In case of extreme emergency: Calcium chloride
10% solution (273 mg/10-mL ampoule) delivers
higher amounts of calcium and has advantages
when rapid correction is needed, but it is very
irritating when administered intravenously and
probably only should be administered centrally.

66. Treatment of Acute Hypocalcemia
• Identify and treat the cause of hypocalcemia
and taper the infusion.
• Start oral calcium and vitamin D treatment
early. Patients with postparathyroidectomy
hungry bone disease, especially those with
osteitis fibrosa cystica, can present with a
dramatic picture of hypocalcemia.