Pertaining to cancer

1. METABOLIC
EMERGENCIES
DR ANAND
Senior Resident
MEDICAL ONCOLOGY

2. • Metabolic emergencies continue to be an important
challenge for practicing oncologists. Whereas many of
these are well-known side effects of treatments and
individual cancers, others have emerged because of new
and innovative therapies.
• It is essential to anticipate and recognize early signs and
institute appropriate treatment to avoid severe
complications.

3. CONTENTS
• Tumour lysis syndrome
• Hyponatremia
• Hypercalcemia
• Lactic acidosis
• Hyperammonia

4. SODIUM DISORDER

5. TOTAL
BODY
WEIGHT
40%
SOLIDS
60%
FLUIDS
2/3RD ICF 1/3RD ECF
80%
INTERSTITIAL
FLUID
20%
PLASMA
DISTRIBUTION OF BODY
WATER

6. Osmotic
pressure
28 mmHg
Arteriolar
end
Venous end
Hydrostatic
pressure
(BP) 35 mm
Hg
Hydrostatic
pressure
(BP) 15
mm Hg
Net inward
pressure 7
mmHg
Net outward
pressure 10
mmHg
FORCES THAT MAINTAIN FLUID BALANCE
CAPILLARY
Osmotic
pressure
25 mm Hg
Osmotic
pressure
6.3 mm Hg
Osmotic
pressure 6.3
mm Hg

7. REGULATION OF BODY WATER
Increased
ECF water
Restoration of
ECF osmolality
Increased water
intake
Stimulation of
hypothalamic
centre
Renal
water
retention
Redistributi
on of water
from ICF
Stimulation of
vasopressin
release
Increased plasma
osmolality
Water loss

8. Overview of Na+ Reabsorption along the
Nephron
65% of filtered Na+ is reabsorbed
from the proximal tubule.
25% of filtered Na+ is reabsorbed
from the thick ascending limb.
5% of filtered Na+ is reabsorbed
from the distal tubule.
4-5% of filtered Na+ is reabsorbed
from the collecting duct.

9. Hyponatremia
Incidence and Etiology
Hyponatremia (serum sodium <135 mmol/L) is a common condition
affecting up to 47% of hospitalized cancer patients.
The incidence of moderate or severe hyponatremia (<130 mmol/L) is
less common (7.8%) but represents levels that are more likely to
be symptomatic (nausea, vomiting, pain, depression, fatigue, and
coma).
The causes of hyponatremia include the disease itself, concomitant
comorbidities, physical stress, and medication.

10. Clinical Features of Hyponatremia
• Acute and Severe –Symptomatic
• Chronic and Mild -Asymptomatic
Hyponatremia
Mild Moderate Severe
Anorexia
Headache
Nausea
Vomiting
Lethargy
Personality change
Muscle Cramps
Muscular
weakness
Confusion
Ataxia
Drowsiness
Diminished Reflexes
Convulsion
Coma & Death

11. It may be a prognostic factor, not only in the case of small-cell lung
cancer but also in other malignancies and is often the result of a
syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
This can occur due to ectopic secretion from the cancer itself or
antidiuretic hormone secretion induced by various medications
including vincristine, cyclophosphamide, opioids, and antidepressants.

12. Other causes hyponatremia include diarrhea and vomiting-induced
hypovolemic hyponatremia, which require volume repletion as a
primary treatment.
Plasma osmolality is closely related to sodium levels and is normally
tightly regulated in the range of 280 to 295mOsm/kg through thirst
perception, control of free water clearance in the kidney by ADH, and
renal sodium excretion regulated by atrial natriuretic peptide and the
renin–angiotensin system.
Therefore,inappropriate or ectopic secretion of either ADH or atrial
natriuretic peptide can result in hyponatremia.

13. Classification and differential diagnosis of
Hyponatremia

14. Screening, Diagnosis, and
Management
The finding of hyponatremia on a serum chemistry panel does
not necessarily constitute an emergency. However, an appropriate
workup should ensue to determine the cause.
Rapid onset of hyponatremia with refractory seizures and coma can
have a significant mortality, and profound hyponatremia is a true
oncology emergency.
Traditionally, hyponatremia can be classified as hypovolemic,
euvolemic, or hypervolemic; however, this is often difficult to assess
in clinical practice. Often, more than one mechanism is involved
in the disorder. The volume status can sometimes be determined
on a clinical basis and can be aided by simple plasma and urine
electrolytes.

15. Evaluation
Plasma osmolality =
2 Na (Glu/18 + BUN/2.8 )

16. SIADH
• While inappropriate AVP secretion
can occur with any cancer, it is 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 and its
isomeric analogue, ifosfamide; the
vinca alkaloids including vincristine,
vinblastine, and vinorelbine; the
proteasome inhibitor bortezomib;
as well as carboplatin and
cisplatin, although the later more
frequently cause renal salt wasting.

17. • Patients with small-cell lung cancer, hyponatremia, and without
measurable AVP have also been reported. In a fraction of these
patients, ectopic production of ANP mRNA and a peptide similar to
the bioactive 28-amino acid ANP form present in plasma has been
shown in tumors and leads to hyponatremia.
• Normally, ANP is produced, stored, and released by atrial myocytes
and binds to a specific set of receptors increasing renal sodium
excretion.

18. Besides SIADH and syndrome of inappropriate atrial natriuretic
peptide (SIANP) production, there is increasing awareness of an
alternate mechanism of salt loss referred to as cerebral salt wasting
syndrome (CSWS).
Two major criteria must be met for a diagnosis of CSWS:
1) a cerebral lesion and
2) high urinary excretion of Na+ and Cl– , in a patient with
contraction of the extracellular fluid volume.
 While the frequency of CSWS is less, it is important to make the
correct diagnosis as management is different
1. Aggressive fluid and electrolyte replacement
2. Mineralocorticoid supplementation (fludrocortisone 100–400 mg/d)

19. The acuity of onset of hyponatremia predicts for the risk of
complications, and identifying patients with an acute drop
in sodium levels (<48 hours) is probably the most important factor in
determining treatment.
In patients with chronic hyponatremia, there is a higher risk of
complications of overaggressive treatment, and it is probably in these
patients that vasopressin antagonists tolvaptan and conivaptan should
be used in an outpatient setting.

20. • High-risk individuals include those with a serum sodium level of <105
mmol/L, heavy alcohol intake, advanced liver disease, hypokalemia,
and malnutrition.
• Although the risk of mortality is increased with all degrees of
hyponatremia, deaths from neurologic complications including
cerebral edema and osmotic demyelination are rare.

21. Treatment
Hyponatremia
Hypovolemic Normovolemia Oedema
-Salt
-water
supplementation
-Water Restriction -No salt
-Water restriction
-Loop diuretics

23. GENERALGUIDELINES
• Na deficit = 0.6 x wt(kg) x (desired [Na] - actual [Na])
• When do we need to Rx quickly?
• Acute (<24h) severe (< 120 mEq/L) Hyponatremia
• Prevent brain swelling or Rx brain swelling
• Symptomatic Hyponatremia (Seizures, coma, etc.)
• Alleviate symptoms
• Initially treat “Quickly”: 3% NS, 1 mEq/kg/h until:
• Symptoms stop
• 3-4h elapsed and/or Serum Na has reached 120 mEq/L
• Then 0.5 mEq/L/h with 0.9% NS or simply fluid restriction.
• Aim for overall 24h correction to be < 10-12 mEq/L/d to prevent myelinolysis

24. • Acute Hypo-natremia with severe Neurological symptoms(headache,
nausea, and/or vomiting, seizures, obtundation , and central
herniation)
• Rate of plasma Sodium correction should be 0.5 -2 mEq/L/Hr for the
first 3-4 hrs or severe neurological symptom improves.
• <10-12 mEq /24Hr.

25. • Chronic asymptomatic Hyponatremia
-Rate of plasma Sodium correction should be
-< 0.5 to 1.0 mEq/L/Hr
-On first day < 10-12 mEq/L
-On First Two day < 18 mEq/L
->25 mEq/48 hrs or Until normo-natremia is at risk of ODS.
• Stop non-essential fluids, medications.
• Cause-specific treatment.
• Fluid restriction.

26. ADROGUE MADIAS FORMULA

27. Example -
• A 30kgs girl with serum sodium of 110meq/L
• Total body water = 30kgs * 0.5 = 15
• Change in serum sodium
• = infusate Na – serum Na / (Total body water+1)
• = 513 -110 / ( 15+1)
• = 25.18 meq/L

28. • So from the above equation – 25meq is corrected by
1Litre of 3% NaCl.
• But we need to correct Na by 10-12 meq in first 24hrs .
• So around 400ml of 3% NaCl will correct around 10meq.
• 400ml of 3% NaCl should be given in 24hrs and this can
be given @16ml/hr.

29. SIADH
• Severe hypo-natremia with
hypertonic saline.
• Fluid restriction- 0.5- 1 Lt per
day.
• Demeclocycline.
• Vaptans.

30. Tolvaptan has been studied in a small trial involving cancer patients
with hyponatremia. However, despite a superiority in correcting sodium
levels, there was no difference in mortality or length of stay. Therefore,
because of the expense of this agent, the use of vasopressin
antagonists has not been recommended yet for inpatient use.
• Care should be taken with sodium replacement and the treatment of
other forms of hyponatremia to not correct extremely low sodium
levels too rapidly because of the risk of osmotic demyelination.
• Osmotic demyelination can be avoided by correcting sodium at a rate
that does not exceed 8 mEq/L per day and, in high-risk patients, 4 to
6 mEq/L per day.

31. HYPERNATREMIA
• Hypernatremia is defined as an increase in the plasma
Na+ concentration to >145 m M .
• Mortality rates of as high as 40–60%
• Hypernatremia is usually the result of a combined water
and electrolyte deficit, with losses of H2O in excess of
Na+.
• Less frequently, the ingestion or iatrogenic administration
of excess Na+ can be causative, for example after IV
administration of excessive hypertonic Na+-Cl– or Na+-
HCO3–

32. Clinical feature
Osmolality
(mOsm/kg)
Manifestations
350–375 Restlessness,
irritability
375–400 Tremulousness, ataxia
400–430 Hyperreflexia,
twitching, spasticity
>430 Seizures and death

36. Example-
• 30kgs girl with 168 Sodium.
• Total body water – 30kgs * 0.5 = 15
• We will use 5% Dextrose solution for correction in this
patient.
• Change in serum sodium
= infusate Na – serum Na / (Total body water+1)
= 0-168 / (15 +1)
= -10.5

37. • So Change in serum Na by 1 litre of 5% Dextrose
solution is 10.5meq/L.
• We need to correct serum sodium by 10-12meq/L in
24hours.
• So we will give 1litre of 5% Dextrose solution in 24hours
– which can be given @40ml/hr.

38. Alternate Method
• First, calculate water deficit
• Water deficit =CBW X wt X ((plasma Na/desired Na level)-1)
• CBW = current body water assumed to be 60% of body
weight in men and 50% in women
• So let’s do a sample calculation:
• 30 kg girl with 168 mEq/L
• How much water will it take to reduce her sodium to 140 mEq/L

39. Calculation continued-
• Water deficit = 0.5x 30 ([168/140]-1} = 3 L
• But how fast should I correct it?
• Same as hyponatremia, sodium should not be lowered by
more than 10-12 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 3L 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.

40. CALCIUM DISORDER

41. Hypercalcemia
Incidence, Etiology, and Diagnosis
• Hypercalcemia is also a common problem in cancer patients,
occurring in 20% to 30% of all cancer patients at some point in their
disease course.
• The finding of hypercalcemia in a cancer patient often confers a poor
prognosis, with one series finding that most patients died within 30
days.
• The constellation of symptoms is well known to all students of
medicine who have learned the well-known mnemonic “stones,
bones, moans, abdominal groans, and psychiatric overtones.”
(nausea, vomiting, constipation, polyuria, and disorientation).

42. • Hypercalcemia can be divided into the following four types:
• 1. Local osteolytic hypercalcemia
• 2. Humoral hypercalcemia of malignancy (secretion of parathyroid
hormone–related peptide) –(MC- 80%)
• 3. 1,25-Dihydroxyvitamin D–secreting lymphomas
• 4. Ectopic hyperparathyroidism
• The main principles of treatment of hypercalcemia are targeting the
underlying malignancy, correction of dehydration with aggressive fluid
resuscitation, and prevention of bone resorption with
bisphosphonates and rank ligand inhibition.

44. Pathogenesis

46. It is usually best to categorize hypercalcemia patients into two groups: those
who can be treated less aggressively in an outpatient setting and those who
need hospitalization.

47. Management
• Therapeutic interventions depend on the presentation.
• Asymptomatic patients with a serum calcium level of ≤3.25 mmol/L
can be managed conservatively, whereas symptomatic patients or
those with a serum calcium level >3.25 mmol/L require immediate
aggressive measures.
• Although hydration results at most in only a mild (0.5 mmol/L [∼2
mg/dL]) decrease in serum calcium levels, it is a simple, rapid, and
effective intervention that can also preclude continued renal calcium
reabsorption.
• After adequate hydration, 20 to 40 mg of intravenous furosemide can
enhance calcium excretion.
• Together with hydration, bisphosphonates are the cornerstone of
therapy for malignancy-associated hypercalcemia.

48. • Bisphosphonates are based on a phosphorous-carbon-phosphorous
backbone, similar to pyrophosphate. The carbon replacing the central
oxygen renders the molecules resistant to hydrolysis, but allows the
retention of pyrophosphate-like inhibition of bone resorption. Their
mechanism of action is complex.
• Evidence indicates non– nitrogen-containing bisphosphonates such
as clodronate resemble pyrophosphate and are metabolized
intracellularly to nonhydrolyzable analogues of ATP that inhibit ATP-
dependent intracellular enzymes and are thus cytotoxic.
• Nitrogen-containing bisphosphonates (aminobisphosphonates),
including pamidronate, ibandronate, and zoledronate, impede protein
prenylation and bone resorption by osteoclasts by inhibiting the
mevalonate pathway (farnesyl diphosphate synthase) disrupting the
signaling functions of key regulatory proteins.

49. • Bisphosphonates have an onset of action of approximately 48hours
and a nadir in calcium levels of 5 to 7 days. Zoledronic acid, the
preferred agent, is given at a dose of 4 mg over 15 minutes and has
been shown to be superior to pamidronate. The average duration of
response is 32 days .
• Bisphosphonates are most effective in the therapy of hypercalcemia
associated with multiple myeloma, but are also efficacious in solid
tumors with skeletal metastases. They are somewhat less effective in
the treatment of patients with humoral-mediated hypercalcemia
because they have no effect on tubular calcium reabsorption
mediated by humoral factors, including PTHrP.

50. • Zolendronic acid can be given weekly for patients with persistent
hypercalcemia. It is a well-tolerated agent, but adverse events of mild
nephrotoxicity, flu-like syndrome, musculoskeletal pain, and
hypocalcemia have been reported. Osteonecrosis of the jaw is a
chronic side effect occurring in about 1% to 2% of patients.
• Calcitonin has the advantage of acting rapidly in 6 to 24 hours,can
be given prior to hydration, and is not nephrotoxic. However, it
exhibits rapid tachyphylaxis and can only be given for two doses.
Therefore, it should be used in severe hypercalcemia or in cases of
renal failure. Other agents such as gallium nitrate are rarely used
today.

51. • Osteoprotegerin (OPG) is a naturally occurring soluble receptor that
inhibits bone resorption by inhibiting osteoclast differentiation.
• OPG is part of a cytokine system that belongs to the tumor necrosis
factor superfamily. The components include the ligand RANKL
(receptor activator of nuclear factor-κΒ ligand), its specific receptor
RANK (receptor activator of nuclear factor-κΒ) and OPG, a soluble
“decoy” receptor.
• By binding to RANK, RANKL enhances bone resorption by
(1) increasing osteoclast formation from hematopoietic precursors,
(2) increasing osteoclast activity, and
(3) inhibiting osteoclast apoptosis.
• By acting as a “decoy,” intravenous administration of OPG has potent
hypocalcemic effects in murine models of humoral hypercalcemia.

52. • Denosumab, a fully human monoclonal antibody with a high affinity
and specificity for RANKL, is approved by the US Food and Drug
Administration “for prevention of skeletal-related events in patients
with bone metastases from solid tumors . . . but is not indicated for the
prevention of skeletal-related events in patients with multiple
myeloma.”
• Repeated doses of denosumab, 120 mg given subcutaneously, may
be effective in patients with hypercalcemia of malignancy who have
lost responsiveness to bisphosphonates.

54. • Mild hypercalcemia (≤3 mmol/L [12 mg/dL)]) can usually be managed
by hydration.
• Severe hypercalcemia (≥3.7 mmol/L [15 mg/dL]) requires rapid
correction. IV pamidronate, or zolendronate, or subcutaneous
denosumab should be administered. In addition, for the first 24–48 h,
aggressive sodium-calcium diuresis with IV saline should be given
and, following rehydration, large doses of furosemide or ethacrynic
acid, but only if appropriate monitoring is available and cardiac and
renal function are adequate.
• Intermediate degrees of hypercalcemia between 3 and 3.7 mmol/L
(12 and 15 mg/dL) should be approached with vigorous hydration and
then the most appropriate selection for the patient of the combinations
used with severe hypercalcemia.

55. LACTIC ACIDOSIS

56. Lactic acidosis
• Lactic acidosis is defined as a pH ≤7.35 with plasma lactate
concentration ≥5 mEq/L. It has been reported more frequently as a
complication of hematologic malignancies but can be a rare event in
solid tumors, often associated with liver metastases.
• Often, the acidosis is associated with an elevated anion gap, but in
cancer patients with poor nutrition and low albumin levels, the anion
gap may not be appropriately corrected.
• Lactic acidosis occurs when the production of lactate exceeds the
ability metabolize it. Overproduction is a result of circulatory,
respiratory, hematologic, or cellular dysfunction or collapse, whereas
underutilization can be a result of poor hepatic perfusion.

57. • Lactate is generated largely by anaerobic glycolysis (Embden-
Meyerhof-Parnas pathway).
• Cancer cells produce energy primarily through glycolysis because of
oncogene-driven metabolic reprogramming designed to promote
cancer cell survival (Warburg effect).
• Although cancer can result in lactic acidosis by itself, other serious
causes may also be present and will need to be concurrently
managed aggressively, including shock, heart failure, sepsis, hypoxia,
anemia, and various medication side effects
• Bicarbonate infusions are sometimes used as a temporary measure
to reverse acidemia, especially in patients with malignancies where
the underlying cause may not be rapidly reversible. In the absence of
proven outcomes data , however, such infusions should be used
judiciously.

59. HYPERAMMONEMIA

60. Hyperammonemia
Incidence, Etiology, and Diagnosis
• Cancer and its treatments can be causes of hyperammonemia and
hepatic encephalopathy. This represents an impairment of the mental
state because of impaired hepatic function and accumulation of
ammonia from the gut.
• The detailed pathogenesis and array of symptoms are varied and
complex, but in cancer patients, disorder of the blood–brain barrier
may be an important factor.
• Although the symptoms can be varied, severe findings such as
asterixis, confusion, somnolence, and coma define states requiring
emergent intervention.

61. • Patients suspected of having hepatic encephalopathy should also be
checked for other reversible causes including hypoxia, hypercapnia,
acidosis, uremia, medications (including rare side effects of novel
agents), electrolyte abnormalities, central nervous system metastases
or hemorrhage, and hypoglycemia.
• Serial measurements of ammonia levels are generally not
recommended during treatment because they often lag behind clinical
response. Because most patients show an improvement in clinical
symptoms within 48 hours of initiation of therapy, those who donot
recover should be evaluated for one of the differential causes listed
previously.

62. Management

63. • Patients who do not respond rapidly may need to be moved to a more
intensive care setting and require the assistance of hepatologists or
transplant teams. Medications such as rifaximin and neomycin can be
considered in refractory cases.
• Aggressive treatment of hypokalemia is important because this will
reduce renal production of ammonia. who do not recover should be
evaluated for one of the differential causes listed previously.

64. THANKYOU