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Question 6 - 2000, Paper 2

How  would  you  determine the  aetiology of  severe hypercalcaemia? List  the  treatments appropriate for each aetiology.

College Answer

Major causes of hypercalcaemia are: Increased calcium release from bone
•  erosion of  bone (malignant neoplasms eg. lung, breast, haematologic (include multiple myeloma), head & neerenal, prostate)
•  release of calcium from bone with immobilization
. •  humoral stimulation of calcium release (mainly PTH but also other hoonones)

Increased calcium intake
•  calcium supplements.milk alkali syndrome

Both of these are augmented by the presence of renal impairment.

Aetiology determined by combination of history.examination and investigations.

History and Examination
• clinical  features relate  to  symptoms  due  to  hypercalcaemia (protean)  and  those  due
underlying cause (specific or general of malignancy, immobilization, diet and medications)

Investigations
•  to confirm malignancy or bony involvement (Xrays of chest, spine etc.)
•  to assess bone turnover (alkaline phosphatase, urinary hydroxyproline)
•  to assess level of PTII

Treatment is dependent on underlying aetiology, but general measures are aimed at minimising calcium entry into and maximising exit from the circulation :

1.  Increased calcium excretion
•  volume resuscitation  to restore intravascular volume and tissue perfusion (usually normal saline, also inhibits calcium reabsorption in renal tubule)
•  frusemide (increase calcium filtration and decreased reabsorption). Aim? 200-300 m1/hr.
2.  Reducing calcium release
•  biphosphonates (eg. etidronate) are absorbed to hydroxyapatite crystals and inhibit bone resorption and formation and inhibit osteoclast activity. Administered intravenously; onset of action 24-48 hours.
•  calcitonin is less effective. Inhibits osteoclast activity and  increases calcium excretion.
Parenteral administration but faster onset of .11ction (6-24 hours).
•  plicamycin, gallium also used. Inorganic phosphate may be effective (multiple mechanisms)
but risks calcium precipitation
•  glucocorticoids  useful  in  some  scenarios   (excess  intake  or   production  of  Vit   D;
haematologic malignancies [tumouricidal effects])
3.  Others
•  correction of other electrolyte abnormalities (eg. K, Mg)
•  removal of offending drugs (eg. thiazides, Vitamins A & D, calcium)
• restriction of calcium intake
•  mobilisation (to reduce calcium release from bone)

Discussion

This question closely resembles Question 7 from the first paper of 2001 (A patient is admitted to ICU because of severe symptomatic hypercalcaemia. List the manifestations and common causes) and Question 9 from the second paper of 2013 (List the clinical features of severe symptomatic hypercalcaemia and outline the treatment of this condition).

Question 18.1 from the the first paper of 2011 also deals with hypercalcaemia of malignancy, but in the context of a clinical scenario.

Causes and consequences of hypercalcemia are treated in slightly greater detail elsewhere.

Thus:

Causes of Hypercalcemia

Primary endocrine causes

  • Primary hyperparathyroidism
  • Thyrotoxicosis
  • Adrenal insufficiency

Paraneoplastic causes

  • PTH-related protein
    • carcinoma of lung
    • oesophageal carcinoma
    • head and neck SCC
    • renal cell carcinoma
    • Breast cancer
    • Ovarian cancer
    • Bladder cancer
  • Ectopic 1,25-dihydroxyvitamin D
    • Lymphoma
  • Lytic bone lesions
    • Multiple myeloma
    • Breast cancer
    • Hematological malignancies
  • Phaeochromocytoma
  • VIP-secreting gastric adenoma

Granulomatous disease

  • Sarcoidosis
  • HIV
  • Tuberculosis
  • Histoplasmosis
  • Coccidioidomycosis
  • Leprosy

Drug-induced hypercalcemia

  • Vitamin D oversupplementation
  • Thiazide diuretics
  • Lithium carbonate
  • Oestrogens and HRT
  • Androgens 
  • Theophylline and aminophylline
  • Vitamin A
  • Aluminum toxicity
  • Total parenteral nutrition (TPN)

Random miscellaneous causes

  • Immobilization (eg. spinal injury)
  • Chronic renal failure
  • Milk alkali syndrome
  • Rhabdomyolysis
Clinical Manifestations of Hypercalcemia

Early manifestations (levels < 3.5mmol/L)

  • Constipation
  • Peptic ulcer exacerbation
  • Polyuria
  • Nephrogenic diabetes insipidus
  • Nephrolithiasis
  • Type 1 (distal) renal tubular acidosis
  • Shortened QT interval
  • Bone pain

Late manifestations (levels over 3.5mmol/L)

  • Pancreatitis
  • Renal failure (due to vasoconstriction)
  • Hypertension
  • Delirium, progressing to coma
  • Arrhythmia
  • Muscle weakness

Investigation of hypercalcemia

Causes such as renal failure and prolonged immobility can usually be ruled out (or in) immediately after meeting the patient. Similarly, one can easily look at their drugs and see whether something iatrogenic is responsible. Then, one is left with primary endocrine disturbances and malignancy.

Thus, one may wish to launch the following investigations:

  • Alkaline phosphatase
  • Serum PTH level
  • CK
  • Parathyroid hormone related peptide (PTHrp)
  • Serum Vitamin D metabolite levels
  • CXR - or better yet, CT chest - to look for obvious malignancy and granulomatous disease.

Management of hypercalcemia

  • Dilute serum calcium
    • Rehydration with IV fluids
  • Decrease calcium resportion from bone
    • Calcitonin
    • Bisphosphonates
    • Gallium nitrate
  • Decrease calcium resportion from renal tubule
    • Loop diuretics (this has fallen out of favour)
    • Calcitonin
  • Decrease calcium absorption from the gut
    • Corticosteroids (also they decrease the 1,25-dihydroxyvitamin D production by monocytes within granulomae)
  • Forcibly remove excess calcium from the circulation
    • Haemodialysis
    • EDTA administration (as chelating agent)

References

UpToDate has a nice chapter on this topic, for the paying customer.

 

Stewart, Andrew F. "Hypercalcemia associated with cancer." New England Journal of Medicine 352.4 (2005): 373-379.

 

Zawada Jr, E. T., D. B. Lee, and C. R. Kleeman. "Causes of hypercalcemia."Postgraduate medicine 66.4 (1979): 91-7.

 

Shane, Elizabeth, and I. Dinaz. "Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis, and management." Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Favus MJ (ed.). Philadelphia: Lippincott, Williams &Wilkins (1999): 183-87.

 

Endres, David B. "Investigation of hypercalcemia." Clinical biochemistry 45.12 (2012): 954-963.

Question 5 - 2001, Paper 1

A patient is admitted to ICU because of severe symptomatic hypercalcaemia.    List the manifestations and common causes.   It is found to be due to metastatic carcinoma  of the breast.  How should the hypercalcaemia be treated?

College Answer

(see J Am Soc Nephrol 2001; 12: S3-9) (a) Manifestations include

-kidney: polyuria, polydipsia, muscle weakness, oliguria, renal failure

-GIT   : anorexia, nausea, vomiting, constipation

-CNS   : weakness, lethargy and depression

-CVS   : hypertension, shortened QT

-Musculoskeletal: bone pain

Common causes:

-hyperparathyroidism (primary, secondary, tertiary)

-neoplasia (humeral)

-immobilisation

-sarcoidosis

-Vit D intoxication

-recovery stage of pancreatitis or rhabdomyolysis.

(b) Treatment, if due to metastatic carcinoma of breast:

-     rehydration with saline

-     frusemide if fluid overloaded

-     aggressive diuresis has a limited potential to remove calcium and may lead to renal dysfunction if inappropriate negative fluid balances ensues.

-     Bisphosphonates are first line therapy in malignancy. They prevent osteolysis

-     Calcitonin may be adjuvant

-     Haemodialysis may be necessary if acute oliguric renal failure occurs.

Discussion

This question closely resembles Question 8 from the second paper of 2000 (How  would  you  determine the  aetiology of  severe hypercalcaemia? List  the  treatments appropriate for each aetiology) and Question 9 from the second paper of 2013 (List the clinical features of severe symptomatic hypercalcaemia and outline the treatment of this condition).

Question 18.1 from the the first paper of 2011 also deals with hypercalcaemia of malignancy, but in the context of a clinical scenario.

Causes and consequences of hypercalcemia are treated in slightly greater detail elsewhere.

Causes of Hypercalcemia

Primary endocrine causes

  • Primary hyperparathyroidism
  • Thyrotoxicosis
  • Adrenal insufficiency

Paraneoplastic causes

  • PTH-related protein
    • carcinoma of lung
    • oesophageal carcinoma
    • head and neck SCC
    • renal cell carcinoma
    • Breast cancer
    • Ovarian cancer
    • Bladder cancer
  • Ectopic 1,25-dihydroxyvitamin D
    • Lymphoma
  • Lytic bone lesions
    • Multiple myeloma
    • Breast cancer
    • Hematological malignancies
  • Phaeochromocytoma
  • VIP-secreting gastric adenoma

Granulomatous disease

  • Sarcoidosis
  • HIV
  • Tuberculosis
  • Histoplasmosis
  • Coccidioidomycosis
  • Leprosy

Drug-induced hypercalcemia

  • Vitamin D oversupplementation
  • Thiazide diuretics
  • Lithium carbonate
  • Oestrogens and HRT
  • Androgens 
  • Theophylline and aminophylline
  • Vitamin A
  • Aluminum toxicity
  • Total parenteral nutrition (TPN)

Random miscellaneous causes

  • Immobilization (eg. spinal injury)
  • Chronic renal failure
  • Milk alkali syndrome
  • Rhabdomyolysis
Clinical Manifestations of Hypercalcemia

Early manifestations (levels < 3.5mmol/L)

  • Constipation
  • Peptic ulcer exacerbation
  • Polyuria
  • Nephrogenic diabetes insipidus
  • Nephrolithiasis
  • Type 1 (distal) renal tubular acidosis
  • Shortened QT interval
  • Bone pain

Late manifestations (levels over 3.5mmol/L)

  • Pancreatitis
  • Renal failure (due to vasoconstriction)
  • Hypertension
  • Delirium, progressing to coma
  • Arrhythmia
  • Muscle weakness

Management

  • Dilute serum calcium
    • Rehydration with IV fluids
  • Decrease calcium resportion from bone
    • Calcitonin
    • Bisphosphonates
    • Gallium nitrate
  • Decrease calcium resportion from renal tubule
    • Loop diuretics (this has fallen out of favour)
    • Calcitonin
  • Decrease calcium absorption from the gut
    • Corticosteroids (also they decrease the 1,25-dihydroxyvitamin D production by monocytes within granulomae)
  • Forcibly remove excess calcium from the circulation
    • Haemodialysis
    • EDTA administration (as chelating agent)

References

Laupacis, Andreas, and Dean Fergusson. "Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome." Anesthesia & Analgesia 85.6 (1997): 1258-1267.

 

Levi, Marcel, et al. "Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints." The Lancet 354.9194 (1999): 1940-1947.

Question 1 - 2001, Paper 2

A eighty (80) year old man needs volume replacement to treat hypotension secondary to biliary sepsis. Compare and contrast one colloid and one crystalloid solution that maybe used in this context.

College Answer

In marking this question it was realised that the candidates come from all parts of the world, especially Australia, Hong Kong and New Zealand. The choice of fluids reflected that diversity.

In  “comparing  and  contrasting”  it  was  expected  that  the  candidate  would  cover  content, manufacture, fate in the circulation, effects on organ function and idiosyncratic effects, not merely listing the properties but contrasting the properties within that list.

Eg. Normal Saline versus 4% Human Albumin (CSL).

Normal Saline is a sterile solution of 150mmol each of Na and Cl in I litre water whereas 4% albumin is prepared from human-donor, pooled blood by complex fractionation.   The albumin cannot be regarded as sterile, but is heated to 60o C for 10 hours and prepared at low pH. Prion transfer is feasible. It contains 140 mmol/L Na, 128 mmol/L Cl.

Saline would be expected to distribute 25% intravascularly and 75% interstitially whereas albumin, theoretically, is iso-oncotic and expands the vascular compartment by the administered volume. This may not be true in the critically ill with high albumin turnover and capillary leak.

Saline will have effects via expansion of the appropriate compartments and will lead to increased cardiac output proportionately. In large volumes it may lead to oedema formation, hypernatraemia and hyperchloraemic acidosis. On the other hand, colloid,eg albumin, in one meta-analysis has been associated with higher mortality. It also contains pre kalikrein activator (PKA) which, although present in low amounts, may produce hypotension and bradycardia in conjunction with ACEI use.

The half-life of albumin is said to be 20 days. The distribution half-life of saline is short (30mins) and elimination half-life will depend on the hormonal milieu (ADH, ANP, aldosterone levels) due to hypovolaemia and stress.

Cost : Saline- $1-2 per litre

Albumin – free to users in Australia, theoretical cost ~$80 for 500mls.

Discussion

Though this question is unique, it is difficult to come up with an answer which does not duplicate a series of other answers.

Instead, I will present here a copy of the table of colloid solutions (from Question 29, second paper of 2007) and a table of intravenous fluid content from the chapter on the applied physiology on fluid and electrolyte replacement.

A Comparison of Colloidal Volume Replacement Solutions
Property Albumin (20%) Gelofusine 4% Dextran (10%) Hydroxyethyl starch 6%
Drug class Endogenous protein Succynylated bovine gelatin Branched polysaccharide Amylopectin derivative
Molecular weight 69 000 Da 5 000 - 15 000 Da 14 000-18 000 Da 70 000 Da
Plasma halflife 24 hours 2.5 hours 12 hours 5 days
Elimination Degradation by reticuloendothelial system Renally excreted Renally excreted Some renally excreted,
some metabolised by the reticuloendothelial system
Plasma expansion as a percentage of infused volume 200-400% 70-80% 100-150% ~100%
Advantages

Antioxidant effects

Free radical scavenging effects

Protection of glycocalyx

Cheap

Relatively safe in renal failure

No limits on infused volume

Decreases the viscosity of blood, improving microcirculation

No risk of CJ disease

Cheap

Large maximum allowable volume

No risk of CJ disease

Lowest risk of anaphylactoid recations among non-albumin colloids

Disadvantages

Volume overload

Transfusion reaction

Expensive

Risk of CJ disease

Volume overload

Anaphylactoid reactions

Coagulopathy

Volume overload

Anaphylaxis

Coagulopathy

Interference with ABO crossmatch

Renal failure (ATN)

Volume overload

Anaphylactoid reactions

Coagulopathy

Accumulation

Renal failure

Increase in amylase


Fluid

osmolality

pH

dextrose

Cl-

HCO3

Na+

K+

Mg++

Ca++

lactate

citrate

acetate

gluconate

5% dextrose

278

3.5-6.5

278

-

-

-

-

-

-

-

-

-

-

10% dextrose

556

3.5-6.5

556

-

-

-

-

-

-

-

-

-

-

50% dextrose

2780

3.5-6.5

2780

-

-

-

-

-

-

-

-

-

-

Normal saline

300

4.0-7.5

-

150

-

150

-

-

-

-

-

-

-

20% saline

6840

4.0-7.5

-

3422

-

3422

-

-

-

-

-

-

-

Hartmanns

276

5.0-7.0

-

112

-

131

5

-

2

28

-

-

-

Plasma-Lyte 148

294

5.0-7.0

-

98

-

140

5

1.5

2

-

-

27

23

Albumin 20%

210-262

7.0

-

-

-

48-100

-

-

-

-

-

-

-

Packed cells

? 340

6.79

49

150

11

150

20

-

-

9

-

-

-

References

For a definitive treatment of all of this, you ought to pay homage to the gigantic and all-encompassing "Critical Care Nephrology" by Ronco Bellomo and Kellum (2009).

There is also extra stuff is from the Ronco et al article "The haemodialysis system: basic mechanisms of water and solute transport in extracorporeal renal replacement therapies" in Nephrol Dial Transplant ( 1998) 13 [Suppl 6 ]: 3–9.

Finally, the Gambro and Fresenius websites have been an excellent source of information.

Question 7 - 2002, Paper 2

List the causes of hyponatraemia in the intensive care patient  population, and outline your management of hyponatraemia.

College Answer

Causes are numerous. Lists should include:
Factitious: contaminated by hypotonic intravenous fluid
Isotonic: pseudohyponatraemia [hyperlipidaemia, hyperproteinaemia] Hypertonic: eg. hyperglycaemia, mannitol
Hypotonic:
•    water retention: SIADH, inappropriate antidiuresis [eg. hypovolaemia, cardiac failure, pain, post-operative, renal failure], psychogenic polydipsia, TURP syndrome
•    salt depletion: adrenocortical failure, diuretic excess

Management includes diagnosis and, if appropriate, specific treatment of underlying cause. Most patients are asymptomatic, with plasma Na > 120. Initial treatment with water restriction and isotonic saline is usually sufficient. More aggressive therapy (eg. hypertonic saline) is indicated if Na < 110, or if patient is symptomatic (eg. confusion, coma, seizures). Relationship of rate of correction of Na and risk of osmotic demyelination (central pontine myelinolysis) is controversial, but appears reduced if rate of correction of Na is less than 10-12 mmol/L (ie. :S 0.5 mmol/hr). Desmopressin (dDAVP) may be required to slow the rate of water excretion. Consider even administration of sterile water to lower sodium if rising too quickly.

Discussion

This question closely resembles Question 14 from the first paper of 2005.

The answer to it is reproduced below:

Potential causes:

This is essentially the content of Box 93.1 from Anthony Delaney and Simon Finfer's chapter for Oh's Manual.

Causes of Hyponatremia

Spurious result

Isotonic

  • High triglycerides
  • High serum protein
  • Glycine (TURP syndrome)

Hypertonic

  • Hyperglycaemia
  • Mannitol
  • Sorbitol
  • Maltose
  • Radiocontrast dye

Water retention

High urine sodium

  • Renal failure
  • Cirrhosis
  • Congestive cardiac failure
  • Diuretics (but not enough!)
  • SIADH

Low urine sodium

  • Psychogenic polydipsia
  • True hypovolemia

Sodium excretion

  • Post-ATN diuresis
  • Hypoaldosteronism
  • Diuretic excess
  • Cerebral salt wasting
  • Inappropriate fluid replacement (5% dex)

Diagnosis on the basis of the above lab tests and historical findings:

History

The following bits of historical information are important:

  • Medication history (diuretics, steroids, drugs which cause SIADH eg. SSRIs)
  • Fluid chart (has somebody been mindlessly charting dextrose)
  • Psychosocial history (is psychogenic polydipsia even a possibility; are they on a weird diet)
  • Alcohol history (liver disease, cirrhosis, beer potomania)
  • Oedema history (Ascites worse recently? Sleep on twenty pillows?)
  • Trauma history (cerebral salt wasting, pituitary injury)
  • Urine output (massive diuresis of HONK or ATN recovery phase, or oliguria or chronic renal failure)
  • Recent procedures: TURP, contrast CT, recent surgery, etc.

The following standard battery of tests can be launched; particularly if history is unhelpful, or one cannot bring oneself to interview the patient or their family.

  • Serum osmolality testing:
    • Hyperosmolar hyponatremia:
      • Hyperglycaemia
      • Mannitol therapy
      • Other unmeasured solutes, eg. glycine
      • Glycine (TURP syndrome)
    • Isoosmolar hyponatremia
      • High triglycerides
      • High serum protein
    • Hypoosmolar hyponatremia
      • Further investigations will be required to distinguish between water retention and sodium excretion.
  • Urinary sodium and urinary osmolality
    • Low urinary sodium: water retention disorders;
      • Polydipsia, beer potomania - low urine osmolality
      • true hypovolemia, heart failure, cirrhosis, nephrotic syndrome - high urine osmolality
    • High urinary sodium: sodium wasting disorders;
      • Acute renal failure, post-obstructive diuresis, polyuric phase of ATN - low urine osmolality
      • Thiazides, SIADH, cerebral salt wasting, hypoadrenalism, hypothyrodism - high urine osmolality

Treatment:

  • Reverse the reversible causes
  • Restore volume and sodium with isotonic saline (if appropriate)
  • If there are severe symptoms, hypertonic saline infusion is required.
  • Sodium replacement rate should not excess 12mmol/day, or about 0.5mmol/hr.

References

Lazaridis, Christos, et al. "High-Osmolarity Saline in Neurocritical Care: Systematic Review and Meta-Analysis*." Critical care medicine 41.5 (2013): 1353-1360.

Adrogué, Horacio J. "Consequences of inadequate management of hyponatremia." American journal of nephrology 25.3 (2005): 240-249.

Froelich, Matteus, et al. "Continuous hypertonic saline therapy and the occurrence of complications in neurocritically ill patients*." Critical care medicine 37.4 (2009): 1433-1441.

R J Martin Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes J Neurol Neurosurg Psychiatry 2004;75:iii22-iii28 doi:10.1136/jnnp.2004.045906

For all electrolyte abnormality questions, I refer to the Electrolyte Quintet series from the Lancet. In the sodium article by Kumar, there is a table (Panel 2) from which the college answer seems to be derived (with a couple of changes). I have used that panel as my model answer.

Sumit Kumar, Tomas Berl. Sodium.  The LancetVolume 352, Issue 912318 July 1998Pages 220-228

Laureno, Robert, and Barbara Illowsky Karp. "Myelinolysis after correction of hyponatremia." Annals of Internal Medicine 126.1 (1997): 57-62.

Lee, Eun Mi, et al. "Risk factors for central pontine and extrapontine myelinolysis following orthotopic liver transplantation." European neurology 62.6 (2009): 362-368.

Adams, Raymond D., MAURICE VICTOR, and ELLIOTT L. MANCALL. "Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients." AMA Archives of Neurology & Psychiatry 81.2 (1959): 154-172.

Brown, William D. "Osmotic demyelination disorders: central pontine and extrapontine myelinolysis." Current opinion in neurology 13.6 (2000): 691-697.

Harris, Cheryl P., J. J. Townsend, and J. Richard Baringer. "Symptomatic hyponatraemia: can myelinolysis be prevented by treatment?." Journal of Neurology, Neurosurgery & Psychiatry 56.6 (1993): 626-632.

Question 11 - 2004, Paper 1

Outline the role of urinary electrolytes in the assessment of the critically ill patient.

College Answer

Urinary electrolytes (sodium, potassium and chloride) can assist in the diagnosis of a number of electrolyte disturbances in ICU patients (especially where the intake of electrolytes is known and relatively controlled). This question does not refer to urinary pH or osmolality measurements. Some of the more commonly used example are included here. In assessing oliguria: a spot urinary sodium when low (<10 mmol/L) can indicate depleted extracellular volume and a pre-renal cause, whereas
>20 is more indicative of tubular damage. Hyponatraemia associated with extrarenal losses should be associated with a low spot urinary sodium (<10), whereas a higher level (>20) is more indicative of other causes (e.g. renal salt losing states, SIADH, and diuretic therapy). Fractional excretion of sodium can be calculated (100*UNa*PCr/PNa*UCr) but its ability to determine causes of oliguria (e.g. <1% implies pre-renal)is limited by sodium intake and diuretic therapy. Urinary chloride estimation is of most use when assessing normal anion gap metabolic acidosis. Renal tubular acidosis is associated with impaired urinary acidification (decreased ammonium excretion) and this is associated with a low urinary chloride (e.g. <10 mmol/L), a positive urinary anion gap (Na + K – Cl), and an inappropriately high urinary pH (e.g. >6). If the acidosis is due to extra-renal losses of bicarbonate, in the absence of renal failure the kidneys will excrete ammonium (and chloride) resulting in a negative urinary anion gap (as urinary Cl > Na + K). Urinary potassium concentration can also help with the cause of hypokalaemia. Renal loss is generally indicated by >20 mmol/L as iopposed to an extra-renal loss (<20 mmol/L).

Discussion

To present this topic systematically, one can either break it up into indications for urinary electrolyte testing, or into electrolytes tested (and the meaning of abnormal results). Both forms have a relevance.

A good article on this topic includes a table (Table 2.1) of urinary electrolyte results, their relevance, and the indications for the tests. I will repurpose some parts of this table for this answer.

Urinary Electrolytes according to Indication

Indication

Electrolyte

Meaning of results

Oliguria Na+ Na< 20mmol/L: appropriate conservation of sodium in the context of hypovolemia
Na>20mmol/L: renal failure, eg. ATN
Hyponatremia Na+ Na< 20mmol/L: appropriate conservation of sodium in the context of hyponatremia
Na>20mmol/L: renal salt wasting or water conservation, eg:
- cerebral salt wasting or SIADH
- adrenal insufficiency
- diuretic use
- osmotic diuresis eg. mannitol or glucose
Normal anion gap metabolic acidosis Urinary anion gap Positive: renal causes of NAGMA
Negative: gastrointestinal causes of NAGMA
Urinary osmolal gap In an acidaemic patient with NAGMA:
Lower than 150 mOsm/kg = urinary acidification defect (renal tubular acidosis)
Higher than 400 mOsm/kg = appropriate renal response to a non-renal cause of acidosis, eg. to diarrhoea.
Metabolic alkalosis Cl- 0-10: appropriate renal chloride conservation
- gastric chloride losses
- diuretic therapy (between doses)
- post hypercapnea alkalosis
>20: inappropriate renal chloride loss
- corticosteroid excess
- hypertension
- hyperaldosteronism 
Hypokalemia K+ Low urinary potassium: <5-10mmol/L
High urinary potassium: >15mmol/L
  • Renal tubular acidosis (Type 1 or 2)
  • Hyperaldosteronism
  • Corticosteroid excess
  • Diuretic therapy

Alternatively, you can organise it as a list. The list below is an adaptation of the table of contents for the chapter on urinary electrolytes, and clicking on the list items will take you to the Required Reading section where they are discussed in greater detail.

References

LITFL has an excellent summary.

 

There seems to only be one free fulltext article on this matter!

Reddi, Alluru S. "Interpretation of Urine Electrolytes and Osmolality." Fluid, Electrolyte and Acid-Base Disorders. Springer New York, 2014. 13-19.

The rest, you people have to pay for.

 

Schrier, Robert W. "Diagnostic value of urinary sodium, chloride, urea, and flow." Journal of the American Society of Nephrology 22.9 (2011): 1610-1613.

 

Harrington, John T., and Jordan J. Cohen. "Measurement of urinary electrolytes-indications and limitations." The New England journal of medicine 293.24 (1975): 1241.

 

Kamel, K. S., et al. "Urine electrolytes and osmolality: when and how to use them." American journal of nephrology 10.2 (1990): 89-102.

 

Kirschbaum, Barry, Domenic Sica, and F. Phillip Anderson. "Urine electrolytes and the urine anion and osmolar gaps." Journal of Laboratory and Clinical Medicine 133.6 (1999): 597-604.

Question 5 - 2004, Paper 2

Critically evaluate the role of albumin containing solutions in the management of the critically ill patient.

College Answer

The role of albumin containing solutions in the critically ill is becoming clearer with time, but is still controversial. Earlier meta-analyses of heterogeneous trials had suggested increased mortality with albumin administration. The recently published SAFE study confirmed that 4% albumin administration was “safe” when compared with normal saline in those critically ill patients who required fluid resuscitation, but did not suggest any specificindications. The specific predetermined and stratified subset of patients where there is still significant doubt is in patients with multiple trauma where there seemed to be worse outcomes in the albumin group (in a post-hoc analysis thought mainly in those patients with severe head injury). Two prospective RCTs have demonstrated specific situations where albumin may actually be of benefit: improved oxygenation in hypo-proteinemic patients with acute lung injury (Martin CCM 2002), and improved mortality in patients with spontaneous bacterial peritonitis (Sort NEJM1999).

Discussion

This question closely resembles Question 25 from the first paper of 2010.

The answer to it is reporduced below, to simplify revision

Albumin as a resuscitation fluid

  • Equivalent to saline in terms of mortality (SAFE study)

Albumin for resuscitation of septic shock

  • Slightly superior to saline in terms of mortality (on post-hoc subgroup analysis of the SAFE study)
  • Equivalent to saline in terms of mortality (ALBIOS trial)
  • Improves mortality of septic shock patients once hemodynamic stability has been achieved (also the ALBIOS trial).
  • According to a recent meta-analysis, the results of the available studies support safety, but suggest that albumin is "not robustly effective at reducing all-cause mortality".

Albumin for spontaneous bacterial peritonitis

Albumin for volume replacement in paracentesis

Albumin as an adjunct in hepatorenal syndrome

Albumin for extracorporeal detoxification in liver failure

Albumin as an adjunct to frusemide in ARDS

  • Albumin and frusemide together improve oxygenation in hypoproteinaemic ARDS patients
  • There is no mortality benefit, and robust evidence is lacking.

Albumin to aid water elimination in oedematous ICU patients

  • This practice is based on physiological principles, using albumin as an oncotic agent to attract water into the intravascular space to improve diuresis.
  • Proponents of this strategy admit that their recommendations "appear in open contrast with what is called “evidence-based medicine”".

Albumin is to be avoided in traumatic brain injury

  • Again from the SAFE study, in the same way as a post-hoc subgroup analysis revealed some benefit from albumin in sepsis, so did a similar subgroup analysis reveal some evidence of harm in patients with traumatic brain injury.

Much has been made of the findings of the SAFE study. The most recent ALBIOS study has supported the notion that albumin and saline are quivalent as resuscitation fluids. Furthermore, the authors found that the patients enrolled in early stages of sepsis did not demonstrate an early benefit, and that patients treated with albumin for longer tended to benefit more. This suggests that the benefit of albumin is derived not from a purely oncotic effect, but rather due to its ancillary functions as a nitric oxide modulator, antioxidant and anti-immunosuppressive. This is supported by the last salvo fired by Marik, who suggested that the contribution of albumin infusion to maintaining the integrity of the vascular endothelial glycocalyx is enough to support its role as "a reasonable intervention" in sepsis.

References

Question 14 - 2005, Paper 1

Outline your approach to the diagnosis and management of severe hyponatraemia.

College Answer

Severe hyponatraemia implies either a very low level (eg. < 120 mmol/L) or one associated with significant symptoms (eg. neurologic).   Approach should allow determination of aetiology by history, examination and simple investigations (and/or repetition of test).  An approach involves measurement of plasma osmolality, urine osmolality and urine sodium concentration. Causes are multiple, and include:

Factitious: contaminated by hypotonic intravenous fluid

Isotonic: pseudohyponatraemia (eg. hyperlipidaemia, hyperproteinaemia)

Hypertonic:  (eg.  hyperglycaemia, mannitol)  where  hypertonicity induces  movement  of water out of cells, and lowers Na by dilution. No specific treatment is usually required.

Hypotonic:

•    Water  retention:  (urinary  Na  is  usually  >  40  mmol/L)  SIADH,  inappropriate antidiuresis (eg. hypovolaemia, cardiac failure, pain, post-operative, renal failure), psychogenic polydipsia

•    Salt depletion: (urinary Na is low, eg.  < 20 mmol/L) adrenocortical failure, diuretic excess

Management includes diagnosis and, if appropriate, specific treatment of underlying cause. Most patients are asymptomatic, with plasma Na > 120.

Initial treatment obviously depends on the specific cause (eg. corticosteroids), but water restriction and isotonic saline is usually sufficient. More aggressive therapy (eg. hypertonic saline) is indicated if Na < 110, or if patient is symptomatic (eg. confusion, coma, seizures). Relationship of rate of correction of Na and risk of osmotic demyelination (central pontine myelinolysis) is controversial, but appears reduced if rate of correction of Na is less than 10-

12 mmol/L over the initial 24 hours (ie. < 0.5 mmol/hr). Desmopressin (dDAVP) may be required to slow the rate of water excretion. Consider even administration of sterile water to lower sodium if rising too quickly.

Discussion

This is an easy question for the sodium enthusiast.

Somewhere, a chapter about the diagnosis of hyponatremia is waiting for me to finish it. However, that classification and diagnostic algorithm is based around urine osmolality rather than volume assessment, and thus is not the canonical view. Classically, hyponatremia is separated into classifications according to serum osmolality and volume status. In the answer, the college goes even further towards raw practicality and separates hypoosmolar hyponatremia into disorders which waste sodium , and disorders which retain water.

In any case, this question calls for a systematic approach.

History

The following bits of historical information are important:

  • Medication history (diuretics, steroids, drugs which cause SIADH eg. SSRIs)
  • Fluid chart (has somebody been mindlessly charting dextrose)
  • Psychosocial history (is psychogenic polydipsia even a possibility; are they on a weird diet)
  • Alcohol history (liver disease, cirrhosis, beer potomania)
  • Oedema history (Ascites worse recently? Sleep on twenty pillows?)
  • Trauma history (cerebral salt wasting, pituitary injury)
  • Urine output (massive diuresis of HONK or ATN recovery phase, or oliguria or chronic renal failure)
  • Recent procedures: TURP, contrast CT, recent surgery, etc.

The following standard battery of tests can be launched; particularly if history is unhelpful, or one cannot bring oneself to interview the patient or their family.

Essential tests:

  • Serum osmolality (to classify the disorder)
  • Urine osmolality
  • Urinary sodium

Optional tests:

  • Serum triglycerides
  • Serum protein level
  • TFTs
  • LFTs
  • Urea and creatinine
  • Random cortisol
  • Short synacthen test

Potential causes:

This is essentially the content of Box 93.1 from Anthony Delaney and Simon Finfer's chapter for Oh's Manual.

Causes of Hyponatremia

Spurious result

Isotonic

  • High triglycerides
  • High serum protein
  • Glycine (TURP syndrome)

Hypertonic

  • Hyperglycaemia
  • Mannitol
  • Sorbitol
  • Maltose
  • Radiocontrast dye

Water retention

High urine sodium

  • Renal failure
  • Cirrhosis
  • Congestive cardiac failure
  • Diuretics (but not enough!)
  • SIADH

Low urine sodium

  • Psychogenic polydipsia
  • True hypovolemia

Sodium excretion

  • Post-ATN diuresis
  • Hypoaldosteronism
  • Diuretic excess
  • Cerebral salt wasting
  • Inappropriate fluid replacement (5% dex)

Diagnosis on the basis of the above lab tests and historical findings:

  • Serum osmolality testing:
    • Hyperosmolar hyponatremia:
      • Hyperglycaemia
      • Mannitol therapy
      • Other unmeasured solutes, eg. glycine
      • Glycine (TURP syndrome)
    • Isoosmolar hyponatremia
      • High triglycerides
      • High serum protein
    • Hypoosmolar hyponatremia
      • Further investigations will be required to distinguish between water retention and sodium excretion.
  • Urinary sodium and urinary osmolality
    • Low urinary sodium: water retention disorders;
      • Polydipsia, beer potomania - low urine osmolality
      • true hypovolemia, heart failure, cirrhosis, nephrotic syndrome - high urine osmolality
    • High urinary sodium: sodium wasting disorders;
      • Acute renal failure, post-obstructive diuresis, polyuric phase of ATN - low urine osmolality
      • Thiazides, SIADH, cerebral salt wasting, hypoadrenalism, hypothyrodism - high urine osmolality

Treatment:

  • Reverse the reversible causes
  • Restore volume and sodium with isotonic saline (if appropriate)
  • If there are severe symptoms, hypertonic saline infusion is required.
  • Sodium replacement rate should not excess 12mmol/day, or about 0.5mmol/hr.

References

Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med. 1987 Nov;83(5):905-8.

 

Milionis, Haralampos J., George L. Liamis, and Moses S. Elisaf. "The hyponatremic patient: a systematic approach to laboratory diagnosis."Canadian Medical Association Journal 166.8 (2002): 1056-1062.

 

Question 16 - 2006, Paper 2

Outline the methods available to estimate fluid balance in the critically ill patient  and briefly discuss their advantages  and limitations. (You may tabulate your answer)

College Answer

Method

Advantages

Limitations

Clinical – oedema, JVP,
skin turgor, hydration of tongue

Simple, easily done by the
bedside, not time consuming

Lack specificity

Intake–output chart

Simple method, reasonably
accurate in most patients

Labour intensive,
Insensible water losses not factored in, Losses through leaks in bed, drain disconnections and in the case of burns patients, severe evaporative water losses not taken into account

Body-weight

May be useful in
uncomplicated critically ill patients

Not routinely used in all
ICUs, time consuming, labour intensive, difficult in the ventilated patient, (zeroing has to be done properly with sheets and pillows), addition of moisture from perspiration
and spills can change baseline weight
Correlation with I-O charts not high.

CVP and PCWP

Used to predict
intravascular status

Significant limitations

EVLW

Shown to be of value in a
trial comparing it with PAC

Invasive technique

Research methods include
Bioelectrical impedance, determination of total body water and plasma volume using radionuclide techniques

Research tools, do not lend
themselves to serial measurements

Discussion

This question is identical to Question 16 from the second paper of 2009.

References

Question 25 - 2006, Paper 2

List 5 major causes and 3 important clinical manifestations of hypocalcaemia  in the critically ill patient.

College Answer

Aetiology

Calcium chelation (eg. alkalosis, citrate toxicity, tumour lysis, rhabdomyolysis)

Drug induced (eg. phenytoin, diphosphonates)

Hypoparathyroidism (eg. hypo and hypermagnesemia, sepsis, surgerical removal) Hypovitaminosis D (eg. inadequate intake, malabsorption, liver disease)

Reduced bone turnover (eg. osteoporosis, elderly, cachexia)

Clinical manifestations

Central nervous system (eg. circumoral and peripheral paraesthesia, muscle cramps, tetany, seizures, psychosis)

Cardiovascular (eg. arrhythmias, hypotension, inotrope unresponsiveness, prolonged QT intervals)

Respiratory (eg. apnoea, laryngospasm, bronchospasm)

Discussion

Causes of hypocalcemia and consequences of hypocalcemia are discussed in detail elsewhere.

Here, I will reproduce the tables for the aetiologies of hypocalcemia and its clinical manifestations.

Causes of Hypocalcemia

Low Parathyroid Hormone

  • Primary hypoparathyroidism (i.e. destruction of the parathyroid glands)
  • Post-operative hypoparathyroidism
  • Hungry bone syndrome
  • HIV infection
  • Haemochromatosis

 

High or normal Parathyroid hormone

  • Vitamin D deficiency
  • Hypomagnesemia
  • Hyperphosphataemia
  • Renal failure (pseudohypoparathyroidism)
  • Tumour lysis syndrome
  • Acute pancreatitis
  • Alkalosis
  • Depletion in coagulopathy

 

Drugs

  • Phenytoin
  • Fluoride toxicity
  • Foscarnet
  • EDTA
  • Citrate
  • Phosphate
  • Bisphosphonates
Clinical Manifestations of Hypocalcemia

Mild hypocalcemia

  • Generalised myalgia
  • Twitching, fasciculations
  • QT prolongation
  • Chvostek’s sign
  • Confusion, delirium, psychosis

Severe hypocalcemia

  • Carpopedal spasm (Trousseau’s sign)
  • Tetany and seizures
  • Papilloedema
  • Cardiac arrhythmias, esp. Torsades
  • Hypotension

References

UpToDate has a nice summary of this topic for the paying customer.

 

Cooper, Mark S., and Neil JL Gittoes. "Diagnosis and management of hypocalcaemia." BMJ: British Medical Journal 336.7656 (2008): 1298.

 

Tohme, J. F., and J. P. Bilezikian. "Hypocalcemic emergencies." Endocrinology and metabolism clinics of North America 22.2 (1993): 363-375.

 

Diercks, Deborah B., et al. "Electrocardiographic manifestations: electrolyte abnormalities." The Journal of emergency medicine 27.2 (2004): 153-160.

Question 16 - 2007, Paper 1

Write a short note on hypomagnesaemia.

College Answer

A common electrolyte abnormality in the ICU: 
Mg primary intracellular cation and plays a major·role in the transfer, storage and utilization of energy. 
Causes: diarrhoea, NG suction, TPN, RTA, alcoholism, malabsorption 
Drugs-amphotericin B, Aminoglycosides, Carbenicillins, diuretics. 
Pathophysiology: Mg deficiency leads to a drop in ICF potassium and a rise in ICF Na., leading to an elevation in the resting membrane potential. This leads to a rise in the inward Ca current and hence the enhanced neurological and cardiac irritability. 
Effects: Confusion, injtability, delirium, tremors, tachyanhytbmias, Torsade, 
refractory hypokalemia and hypocalcemia. 
Treatment: IV MgS04 in doses of 5-10 mmol/L, given slow IV. Repeated doses may 
be required. Rapid administration can lead to hypotension.

Discussion

There are few fellowship questions in this exam which ask the candidate to write a short note about anything. Understandably, somebody who was waiting to critically evaluate something or to discuss your management would have been taken aback by such a question. How does one structure a response?

Using this article, I have attempted a coherent answer.

Causes of hypomagnesaemia

  • Malnutrition/malabsorption
  • NG suction
  • Diarrhoea
  • Diuretics
  • Renal tubular acidosis
  • Aminoglycosides
  • Hyperparathyroidism
  • Diabetes
  • Alcoholism

Consequences of hypomagnesaemia

  • hypokalemia and hypocalcemia
  • tetany, muscle cramps
  • vertigo, nystagmus
  • delirium
  • ventricular arrhythmias, particularly Torsades de points
  • increased sensitivity to digoxin toxicity

Pathophysiology of cardiac consequences

  • Magnesium is required for the function of Na+/K+ ATPase.
  • Na+/K+ ATPase maintains the Na+ and K+ concentration gradients
  • If intracellular K+ concentration decreases, the cell membrane potential becomes less negative which increases its vulnerability to cardiac arrhythmias.

Management of hypomagnesaemia

  • Magnesium replacement
  • Amelioration of the aetiology of magnesium loss
  • Careful monitoring of rising levels

In greater detail, from the hypomagnesemia chapter:

Causes of Hypomagnesemia from Oh's Manual

Gastrointestinal disorders
  • Malabsorption syndromes
  • GIT fistulas
  • Short-bowel syndrome
  • Prolonged nasogastric suction
  • Diarrhoea
  • Pancreatitis
  • Parenteral nutrition

Endocrine disorders

  • Hyperparathyroidism
  • Hyperthyroidism
  • Conn’s syndrome
  • Diabetes mellitus
  • Hyperaldosteronism
Renal diseases
  • Renal tubular acidosis
  • Diuretic phase of acute tubular necrosis

Drugs

  • Alcohol
  • Aminoglycosides
  • Carbenicillin, ticarcillin
  • Amphotericin B
  • Diuretics
  • Cisplatin
  • Cyclosporine

A better way to organise the list of causes would be by pathophysiological disturbance, as below.

Causes of Hypomagnesemia ordered by Pathophysiology

Increased Loss

Gastrointestinal loss

  • GIT fistulas
  • Prolonged nasogastric suction
  • Diarrhoea
  • Pancreatitis

Renal loss

  • Renal tubular acidosis
  • Diuretic phase of acute tubular necrosis
  • Thiazide diuretics
  • Loop diuretics
  • Alcoholism
  • Hypercalcemia
  • Nephrotoxic drugs, eg. aminoglycosides, amphotericin, cyclosporin etc.
  • Primary renal magnesium wasting (a congenital disorder)

Sequestration and chelation

  • Pancreatitis (saponification in fat)
  • Post-operative (chelation with fatty acids)
  • Post cardiopulmonary bypass (adsorption into circuit)
  • Foscarnet (chelation)

Decreased intake

Poor intake

  • Fasted patient
  • Improperly prescribed parenteral nutrition

Poor absorption

  • Malabsorption syndromes, eg. coeliac disease
  • Short-bowel syndrome
  • Weird congenital disorders of selective magnesium malabsorption

Unclear association with low magnesium

  • Hyperthyroidism
  • Conn’s syndrome
  • Diabetes mellitus
  • Hyperaldosteronism

Clinical Features of Hypomagnesemia

Symptoms

Physical signs

  • Confusion
  • Delirium
  • Tremors
  • Seizures
  • Tachyarrhythmias (particularly VT and VF)
  • Tetany
  • Chvostek sign
  • Trousseau sign

ECG changes

  • Widening QRS complexes
  • Peaking T-waves (which vanish in very severe hypomagnesemia)
  • Prolonged PR interval

Associated biochemical abnormalities

  • Hypokalemia, refractory to replacement
  • Hypocalcemia
  • Low parathyroid hormone levels (in spite of hypocalcemia)
  • Low Vitamin D levels

References

Agus, Zalman S. "Hypomagnesemia." Journal of the American Society of Nephrology 10.7 (1999): 1616-1622.

Kutsal, Ebru, et al. "Severe hypermagnesemia as a result of excessive cathartic ingestion in a child without renal failure." Pediatric emergency care 23.8 (2007): 570-572.

SHILS, MAURICE E. "Experimental human magnesium depletion." Medicine 48.1 (1969): 61.

Grubbs, Robert D., and Michael E. Maguire. "Magnesium as a regulatory cation: criteria and evaluation." Magnesium 6.3 (1986): 113-127.

Martin, Kevin J., Esther A. González, and Eduardo Slatopolsky. "Clinical consequences and management of hypomagnesemia." Journal of the American Society of Nephrology 20.11 (2009): 2291-2295.

Chakraborti, Sajal, et al. "Protective role of magnesium in cardiovascular diseases: a review." Molecular and cellular biochemistry 238.1-2 (2002): 163-179.

Question 29 - 2007, Paper 2

Compare and contrast albumin and gelatins (Haemaccel and Gelofusin) as volume replacement fluids in the critically ill patient.

College Answer

Albumin

Haemaccel &
Gelofusin

Pharmacology

5% and 20%,
naturally occuring

Semisynthetic,
Produced from bovine collagen

Shelf life

1 yr shelf life at
room temperature

Long shelf lives

Indications for use

Used for treatment
of hypovolemia and hypoalbuminemia

Used for
hypovolemia

Published data

Proven to be
similar to crystalloids in SAFE study

Tendency for better
outcome in sepsis but worse outcome in head injured patients

No published data
in critical illness, regarded as safe, Haemaccel can’t be used with citrated blood

Side effects

No risk of
anaphylaxis, no effect on clotting

Lower risk of
anaphylaxis than haemaccel, no proven effect on clotting other than thro dilution

Complications

Risk of CJ disease

No risk or lesser
risk of CJ disease

Discussion

Physiological responses to concentrated human albumin and to Gelofusine are discussed in greater detail elsewhere. Haemaccel is not used locally, and thus I have never had very much interest in it (sorry, Haemaccel enthusiasts).

This question asks the candidate to compare and contrast them as volume replacement fluids in the critically ill patients. Sukanaya Mitra published a 2009 paper which goes some of the way towards answering this question for us; it summarises the key concepts, and expands on the range of colloids by also discussing the hydroxyethyl starches and dextrans.

Out of respect for this paper, I will make an attempt to summarise it into a table format.

A Comparison of Colloidal Volume Replacement Solutions
Property Albumin (20%) Gelofusine 4% Dextran (10%) Hydroxyethyl starch 6%
Drug class Endogenous protein Succynylated bovine gelatin Branched polysaccharide Amylopectin derivative
Molecular weight 69 000 Da 5 000 - 15 000 Da 14 000-18 000 Da 70 000 Da
Plasma halflife 24 hours 2.5 hours 12 hours 5 days
Elimination Degradation by reticuloendothelial system Renally excreted Renally excreted Some renally excreted,
some metabolised by the reticuloendothelial system
Plasma expansion as a percentage of infused volume 200-400% 70-80% 100-150% ~100%
Advantages

Antioxidant effects

Free radical scavenging effects

Protection of glycocalyx

Cheap

Relatively safe in renal failure

No limits on infused volume

Decreases the viscosity of blood, improving microcirculation

No risk of CJ disease

Cheap

Large maximum allowable volume

No risk of CJ disease

Lowest risk of anaphylactoid recations among non-albumin colloids

Disadvantages

Volume overload

Transfusion reaction

Expensive

Risk of CJ disease

Volume overload

Anaphylactoid reactions

Coagulopathy

Volume overload

Anaphylaxis

Coagulopathy

Interference with ABO crossmatch

Renal failure (ATN)

Volume overload

Anaphylactoid reactions

Coagulopathy

Accumulation

Renal failure

Increase in amylase


Evidence:

  • Albumin was found to be equivalent (in terms of mortality) to crystalloid (SAFE study)
  • Dextrans are the least favoured in critical illness (renal impariment, coagulopathy etc)
  • Gelatins are widely disliked due to the increased potential for anaphylactoid reactions
  • Hydroxyethyl starch has the least adverse effects, but its use has been discouraged by the findings of the CHEST study(increased rates of renal failure)

References

The albumin page and Gelofusine page are extensively referenced and I will not reproduce that stuff here.

 

Mitra, Sukanya, and Purva Khandelwal. "Are all colloids same? How to select the right colloid?." Indian journal of anaesthesia 53.5 (2009): 592.

 

Finfer, Simon, et al. "A comparison of albumin and saline for fluid resuscitation in the intensive care unit." N Engl j Med 350.22 (2004): 2247-2256.

 

Ertmer, Christian, et al. "Relevance of non-albumin colloids in intensive care medicine." Best Practice & Research Clinical Anaesthesiology 23.2 (2009): 193-212.

 

Myburgh, John A., et al. "Hydroxyethyl starch or saline for fluid resuscitation in intensive care." New England Journal of Medicine 367.20 (2012): 1901-1911.

Question 14.2 - 2009, paper 1

A 69 yo male with a history of previous pneumonectomy for lung carcinoma, is admitted with confusion.  There were no focal neurological signs on clinical examination.  Neck stiffness was not present. Contrast CT brain scan is normal
His initial plasma biochemistry is shown:

Na+

148 mmol/L

(134-145)

K+

3.7mmol/L

(3.5-5.0)

Cl-

109mmol/L

(97-107)

HCO3-

33mmol/L

(24-34)

Albumin

15 G/L

(35-40)

Urea

12.8 mmol/L

(3.1-8.1)

Creatinine

36 micromol/L

(60-100)

Ca++

2.59 mmol/l

(2.20-2.55)

Phosphate

0.86 mmol/L

(0.78-1.43)

Mg++

0.89 mmol/L

(0.67-1.05)

a)  What is the most likely cause of the confusion in this patient,  based on the above information? Justify your response.

List 4 therapies for the cause stated in a)

College Answer

Hypercalcemia (When corrected for albumin, the true calcium is higher).
Extra marks for recognising the inaccuracy of this correction

List 4 therapies for the cause stated in a)

Calciuresis (saline +/-frusemide)

Bisphosphonates
Calcitonin

Corticosteroids

NSAIDS

Mithramycin

Discussion

This question resembles Question 18.1 from the first paper of 2011- or rather, the answer to this question. Again, hypercalcemia is brought out.

In this case, however, it is "occult" hypercalcemia, obscured by the normal-looking numbers.

But, if one corrects for the albumin...

Corrected calcium = (0.02 × (normal albumin - patient's albumin)) + serum calcium

or

Ca++ = (0.02 × (40-15) + 2.59

Thus,

Ca++ = 3.09

This formula was first described by Payne et al in 1973.

In brief, these are the physiological aims for management of hypercalcemia, and the means to achieve them:

  • Dilute serum calcium
    • Rehydration with IV fluids
  • Decrease calcium resportion from bone
    • Calcitonin
    • Bisphosphonates
    • Gallium nitrate
  • Decrease calcium resportion from renal tubule
    • Loop diuretics (this has fallen out of favour)
    • Calcitonin
  • Decrease calcium absorption from the gut
    • Corticosteroids (also they decrease the 1,25-dihydroxyvitamin D production by monocytes within granulomae)
  • Forcibly remove excess calcium from the circulation
    • Haemodialysis
    • EDTA administration (as chelating agent)

References

Payne, R. B., et al. "Interpretation of serum calcium in patients with abnormal serum proteins." British Medical Journal 4.5893 (1973): 643.

Question 14.3 - 2009, paper 1

A 55 yo male with a history of significant alcohol intake presents with a 2-week history of lethargy. He takes no regular medications and has no other medical disorders. Clinically, he appears malnourished and euvolaemic. Investigations  reveal:

Plasma  
           Normal Range
Na+            115 mmol/L 134-143
K+ 3.7 mmol/L 3.5-5.0
Cl- 80 mmol/L   97-107
HCO3-   22 mmol/L 24-34
Urea 3.0 mmol/L   3.1-8.1
Creatinine 46 micromol/L 50-90
Glucose 4.1 mmol/L 4.4-6.8
Osmolality 241 mmol/Kg 274-289

Urine

Na+ <5mmol/L  
Osmolality 53 mmol/Kg  

a)  What is the most likely cause of the hyponatraemia?

College Answer

Water intoxication.

Discussion

This is a hypoosmolar hyponatremia with low urine osmolality and low urine sodium.

I.e. the kidneys are making an excellent effort to excrete copious amounts of water while preserving sodium, which means that not only is the renal response appropriate, but that the whole body systems are actively trying to defend tonicity. This is the sort of response one would expect from a sudden massive excess of water.

So. how did this happen?

Well: the differentials in this scenario would include

  • Psychogenic polydipsia
  • Beer potomania
  • Dietary solute deficiency ("crash diet potomania")

References

Hariprasad MK, Eisinger RP, Nadler IM, Padmanabhan CS, Nidus BD. Hyponatremia in psychogenic polydipsia. Arch Intern Med. 1980 Dec;140(12):1639-42.

Hilden T, Svendsen TL. Electrolyte disturbances in beer drinkers. A specific "hypo-osmolality syndrome". Lancet. 1975 Aug 9;2(7928):245-6.

Thaler SM, Teitelbaum I, Berl T. "Beer potomania" in non-beer drinkers: effect of low dietary solute intake. Am J Kidney Dis. 1998 Jun;31(6):1028-31.

Fox BD.Crash diet potomania. Lancet. 2002 Mar 16;359(9310):942.

Lipschutz JH, Arieff AI. Reset osmostat in a healthy patient. Ann Intern Med. 1994 Apr 1;120(7):574-6.

Question 14.4 - 2009, paper 1

A 76 yo female presents with seizures. She takes no regular medications. On examination she weighs 60kg, has no evidence of cardiac failure or liver disease, and appears euvolaemic. Her blood results in the emergency department reveal:

Plasma  
           Normal Range
Na+            110mmol/L 134-143
K+ 3.8 mmol/L 3.5-5.0
Cl- 81 mmol/L   97-107
HCO3-   24 mmol/L 24-34
Urea 5.7 mmol/L   3.1-8.1
Creatinine 36 micromol/L 50-90
Glucose 4.1 mmol/L 4.4-6.8
Osmolality 237 mmol/Kg 274-289

Urine

Na+ 23 mmol/L  
Osmolality 488 mmol/Kg  

a) What is the likely cause of the hyponatraemia?

b) Approximately how many mmol of NaCl would need to be given to raise her serum sodium to 120mmol/L? . Show your calculations.

College Answer

a) What is the likely cause of the hyponatraemia?
SIADH

b) Approximately how many mmol of NaCl would need to be given to raise her serum sodium to 120mmol/L? . Show your calculations.
An answer between300 – 360 mmol was acceptable) (Sodium deficit = TBW x (desired Na – Actual Na)
= 0.5/0.6 x 60 x (120-110) 
= 30/36 x 10
= 300/360)

Discussion

This is a hypoosmolar hyponatremia with a high urine osmolality and a high urine sodium.

The urine osmolality suggests that the kidneys are retaining water in spite of decreased body tonicity, and the inappropriately high urine sodium (>20mmol/L) suggests that are negligently wasting sodium. Of course, nobody is wasting anything - they are merely excreting a normal daily load (150-250mmol in the Western world), keeping up with intake.

This smells like SIADH.

Alternative differentials might include

  • Corticosteroid deficiency
  • Cerebral salt wasting
  • Thiazide diuretics
  • Hypothyroidism
  • Oliguric chronic renal failure

The question about sodium replacement relies on the candidate's ability to recall the formula for total body sodium deficit.

The formula is as follows:

NaDeficit = Total Body Water × Weight in kg × (desired Na+ - measured Na+)

( where TBW = 0.6 if male and 0.5 if female)

Thus, for this 60kg lady, the calculation would be:

(60) × (0.5) × (140-110) = 900mmol ... to bring the sodium back to a normal range

But, of course, a more sensible target would be a sodium level where seizures are no longer a problem. 120mmol/L would suffice. Thereafter, one can rely on water restriction to maintain the steady rise of body tonicity. In this case, the lady only needs 300mmol of sodium, which is two bags of isotonic saline.

References

Palmer, Biff F. "Hyponatremia in patients with central nervous system disease: SIADH versus CSW." Trends in Endocrinology & Metabolism 14.4 (2003): 182-187.

Milionis, Haralampos J., George L. Liamis, and Moses S. Elisaf. "The hyponatremic patient: a systematic approach to laboratory diagnosis."Canadian Medical Association Journal 166.8 (2002): 1056-1062.

Question 27 - 2009, paper 1

Compare and contrast the pharmacology of carbicarb, Sodium bicarbonate and THAM.

College Answer

Carbicarb is an equimolar combination of sodium carbonate and sodium bicarbonate, generates a smaller rise in CO2 than sodabicarb. More consistently increases intracellular pH, inconsistent effects on hemodynamics, not commonly used clinically.

Sodabicarb: 8.4% or 4.2% solution. Hyperosmolar, generates high CO2, can cause paradoxical acidosis in the presence of a low output, cause hypokalemia, alkalosis and left shift of the curve. Phlebitis when given peripherally. On the other hand, frequently used to treat a metabolic acidosis if pH < 7.1, improves vasopressor responsiveness, may have a role in decreasing contrast nephropathy.

THAM: commercially available weak alkali. Buffers H+ ions. Buffering not associated with a CO2 rise. Side effects include hyperkalemia, hypoglycemia, extravasation related necrosis, and hepatic dysfunction.

Discussion

Sodium bicarbonate pharmacology is discussed at length elsewhere. It is a dear and familiar product to most ICU trainees. The other two products are somewhat more exotic, and deserve a brief digression. For instance, carbicarb does not seem to be available in Australia.

As a table, the answer would look like this:

  Sodium bicarbonate Carbicarb THAM
Properties

An 8.4% (1mol/L) solution of NaHCO3 which offers 1000mmol/L of HCO3- and Na+ions.

An equimolar (300mmol/L) solution of Na2CO3 and NaHCO3which offers 666mmol/L of HCO3- ions, and 1000mmol/L of Na+ ions

An organic amine buffer, otherwise known as tris-hydroxymethyl-aminomethane, or tromethamine. The 3mol/L solution offers

Administration

Ideally IV, but can be given orally

IV only

IV only

Pharmacokinetics

Eliminated renally, as well as being converted to CO2 and exhaled (in process of buffering reactions). These two substances differ mainly in the amount of bicarbonate anion they add.

Rapidly eliminated by the kidney; 75% is excreted in the urine after 8 hours.

Adverse effects
  • Hypokalemia
  • Fluid overload
  • Hypercapnoea
  • Phlebitis
  • Hypokalemia
  • Fluid overload
  • Phlebitis
  • Fluid overload
  • Hypoglycaemia
  • Hyperkalemia
  • Phlebitis
  • Respiratory depression
  • Osmotic diuresis
Rationale for use

Sodium bicarbonate contributes HCO3which is a natural buffer, thus replenishing the buffer systems of the body in a state of acidosis.

The sodium carbonate component is supposed to act as a bicarbonae precursor, regenerating HCO3buffers without increasing the PaCO2.

THAM is a "third buffer" to complement the buffering capacity of endogenous HCO3and body protein.

At pH of 7.40, 30% of THAM is not ionized and therefore may penetrate cells and act as an intracellular buffer.

Indications
  • Metabolic acidosis with pH <7.10 and hemodynamic instability
  • Normal anion gap metabolic acidosis (esp. RTA)
  • Alkalinisation of urine to enhance the elimination of acidic drugs
  • Metabolic acidosis with hypercapnea
  • Viewed as an alternative to sodium bicarbonate for the treatment of metabolic acidosis

Contraindications

(or, situations in which it is known to be useless)

  • Hypokalemia
  • lactic aciosis
  • DKA
  • Hypokalemia
  • lactic aciosis
  • DKA
  • Uremia
  • Anuric renal failure

In neonates it is 
also contraindicated in chronic respiratory acidosis and salicylate intoxication.

References

The HOSPIRA booklet for THAM

 

Rhee, K. H., et al. "Carbicarb, sodium bicarbonate, and sodium chloride in hypoxic lactic acidosis. Effect on arterial blood gases, lactate concentrations, hemodynamic variables, and myocardial intracellular pH." CHEST Journal 104.3 (1993): 913-918.

 

Schmidt, G. A. "Treatment of Acidosis: Sodium Bicarbonate and Other Drugs."Anaesthesia, Pain, Intensive Care and Emergency Medicine—APICE. Springer Milan, 2002. 681-693.

 

Filley, G. F., and N. B. Kindig. "Carbicarb, an alkalinizing ion-generating agent of possible clinical usefulness." Transactions of the American Clinical and Climatological Association 96 (1985): 141.

Question 16 - 2009, Paper 2

Outline the methods available to estimate fluid balance in the critically ill patient  and briefly discuss their advantages and limitations. (You may tabulate your answer).

College Answer

Method

Advantages

Limitations

Clinical – oedema, JVP,
skin turgor, hydration of tongue

Simple, easily done by the
bedside, not time consuming

Lack specificity

Intake–output chart

Simple method, reasonably
accurate in most patients

Labour intensive,
Insensible water losses not factored in, Losses through leaks in bed, drain disconnections and in the case of burns patients, severe evaporative water losses not taken inot account

Body-weight

May be useful in
uncomplicated critically ill patients

Not routinely used in all
ICUs, time consuming, labour intensive, difficult in the ventilated patient, (zeroing has to be done properly with sheets and pillows), addition of moisture from perspiration and spills can change baseline weight
Correlation with I-O charts not high.

CVP/ PCWP/Echo

Used to predict
intravascular status

Significant limitations

EVLW

Shown to be of value in a trial comparing it with PAC

Invasive technique

Research methods include
Bioelectrical impedance, determination of total body water and plasma volume using radionuclide techniques

Research tools, do not lend
themselves to serial measurements

Discussion

This tabulated reponse is difficult to improve upon. It is reasonably comprehensive, and it remains within the realms of the achievable for a crazed exam candidate.

The college answer seems to ask about the estimation of total body water, rather than any other sort of fluid-related assessment. The candidate who carried on about estimation of fluid responsiveness would have been penalised.

The table mentioned above could be treated in a slightly more granular fashion, and I will attempt to do this with some references, expanding on some omitted details (for instance, it is perhaps insufficiently enlightening to simply say that the pulmonary artery catheter and CVP have "significant limitations").

Estimation of Fluid Balance in the Critically Ill Patient

Method

Advantages

Disadvantages

Clinical estimates
  • Cheap
  • Easily performed at the bedside
Fluid balance chart
  • Cheap
  • Easily performed at the bedside
  • Accuracy depends on accuracy or recording
  • Usually, cumulative balance records are inaccurate and tend to disagree with body weight measurements
  • This technique fails to estimate losses into incontinence pads, spilled secretions, sweat, evaporative losses from wounds, and losses via the lungs; in short "insensate" losses are forgotten.
Daily weights
  • Easily performed in the presence of specialised bed equipment
  • Accuracy depends on accuracy of recording
  • Requires expensive bed equipment
  • Requires attention to detail - one must ensure the same amount of bedding and on-bed equipment is with the patient each time, otherwise fluctuations in weight may occur. Usually, there is about 3.5kg of nonremovable hardware in the bed together with the patient.
  • Correlates poorly with bedside charts
  • Lack of evidence for cost-effectiveness
CVP
  • Easily performed at the bedside
  • Constant monitoring is possible
PAWP
TTE
  • Interpreter-dependent
  • Serial assessments across a series of clinicians may yield variation purely due to technique
  • Yields information regarding chamber filling volumes rather than total body fluid volume - and then you infer the fluid balance from this.
  • Not universally accepted as a method to assess intravascular volume
  • Only accurate when compared to the (known to be useless) clinical examination by an expert.
PAC or PiCCO EVLW
  • Invasive
  • Labour-intensive (thermodilution measurement)
  • Association with cardiac function makes it difficult to use lung water to estimate whole-body fluid balance
Bioimpedance
  • Experimental technique, yet to be validated
  • Does not agree with thermodilution measurements
  • Most of the available methods measure transthoracic bioimpedance, which relies on the absence of pleural effusion, and is usually useless in cardiac surgery or thoracic trauma
Tritium indicator dilution
 

References

Schneider, Antoine G., et al. "Estimation of fluid status changes in critically ill patients: Fluid balance chart or electronic bed weight?." Journal of critical care27.6 (2012): 745-e7.

Schoeller DA, van Santen E, Peterson DW, Dietz W, Jaspan J, Klein PD: Total body water measurement in humans with 18O and 2H labeled water. Am J Clin Nutr 1980, 33(12):2686-2693

Charra, Bernard. "Fluid balance, dry weight, and blood pressure in dialysis."Hemodialysis International 11.1 (2007): 21-31.

Stephan, F., et al. "Clinical evaluation of circulating blood volume in critically ill patients—contribution of a clinical scoring system†." British journal of anaesthesia 86.6 (2001): 754-762.

Chung, Hsaio-Min, et al. "Clinical assessment of extracellular fluid volume in hyponatremia." The American journal of medicine 83.5 (1987): 905-908.

Schneider, Antoine Guillaume, et al. "Electronic bed weighing vs daily fluid balance changes after cardiac surgery." Journal of critical care 28.6 (2013): 1113-e1.

Perren, A., et al. "Fluid balance in critically ill patients. Should we really rely on it?." Minerva anestesiologica (2011).

Wilson, John N., et al. "Central venous pressure in optimal blood volume maintenance." Archives of Surgery 85.4 (1962): 563-578.

Piccoli, Antonio, et al. "Relationship between central venous pressure and bioimpedance vector analysis in critically ill patients." Critical care medicine28.1 (2000): 132-137.

Marik, Paul E., Michael Baram, and Bobbak Vahid. "Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares." CHEST Journal 134.1 (2008): 172-178.

Mitchell, John P., et al. "Improved outcome based on fluid management in critically III patients requiring pulmonary artery catheterization." American Review of Respiratory Disease 145.5 (1992): 990-998.

Bethlehem, Carina, et al. "The impact of a pulmonary-artery-catheter-based protocol on fluid and catecholamine administration in early sepsis." Critical care research and practice 2012 (2012).

Schwann, Nanette M., et al. "Lack of effectiveness of the pulmonary artery catheter in cardiac surgery." Anesthesia & Analgesia 113.5 (2011): 994-1002.

Wheeler, A. P., et al. "Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury." N Engl J Med 354.21 (2006): 2213-2224.

Nguyen, Viviane TQ, et al. "Handheld echocardiography offers rapid assessment of clinical volume status." American heart journal 156.3 (2008): 537-542.

Schuller, D., et al. "Fluid balance during pulmonary edema. Is fluid gain a marker or a cause of poor outcome?." CHEST Journal 100.4 (1991): 1068-1075.

Marik, Paul E. "Hemodynamic parameters to guide fluid therapy." Transfusion Alternatives in Transfusion Medicine 11.3 (2010): 102-112.

Monnet, Xavier, et al. "Assessing pulmonary permeability by transpulmonary thermodilution allows differentiation of hydrostatic pulmonary edema from ALI/ARDS." Intensive care medicine 33.3 (2007): 448-453.

Mattar, J. A. "Application of total body bioimpedance to the critically ill patient. Brazilian Group for Bioimpedance Study." New horizons (Baltimore, Md.) 4.4 (1996): 493-503.

Foley, Kieran, et al. "Use of single-frequency bioimpedance at 50 kHz to estimate total body water in patients with multiple organ failure and fluid overload." Critical care medicine 27.8 (1999): 1472-1477.

Barry, Ben N., et al. "Lack of agreement between bioimpedance and continuous thermodilution measurement of cardiac output in intensive care unit patients."Critical Care 1.2 (1997): 71.

 

House, Andrew A., et al. "Volume assessment in mechanically ventilated critical care patients using bioimpedance vectorial analysis, brain natriuretic peptide, and central venous pressure." International journal of nephrology 2011 (2010).

Vincent, Jean-Louis, et al. "Clinical review: Update on hemodynamic monitoring-a consensus of 16." Crit Care 15.4 (2011): 229.

Question 21 - 2009, Paper 2

A 77 year old male undergoing transurethral prostatic resection under spinal anaesthesia becomes restless and agitated.  He is intubated and ventilated  in OT, the surgery is expedited, and he is transferred to ICU. His initial biochemistry profile is as follows:


Test

Value

Normal Range

Sodium*

113 mmol/L

135 – 145

Chloride*

87 mmol/L

100 -110

Potassium

4.5 mmol/L

3.2 - 4.5

Glucose

5.1 mmol/L

3.6 – 7.7

Urea

5.0 mmol/L

3.0 – 8.0

Osmolality (measured)

280 mOsm/kg

280 – 300

a)          Describe the important biochemical abnormalities.

b)         What is the likely cause of this confusional state?

c)         What transient neurological disturbance is likely in this clinical setting?

d)         List two confirmatory biochemical features (other than those from the table above).

e)         Do you believe hypertonic saline is indicated? Explain your reasoning.

21.2     Simultaneous arterial blood gas analysis is as follows:

Test

Value

FiO2

0.3

pH

7.33

pO2

93 mm Hg (7.4 kPa)

pCO2

33 mm Hg (4.4 kPa)

HCO3-*

16 mmol/L

Standard base excess*

-9.5 mEq/L

a)  Describe the acid- base status.

b)  What is the mechanism  of this disturbance?

21.3     After 7 hours, the biochemical profile is as follows:

Test

Value

Normal Range

Sodium*

130 mmol/L

135 – 145

Chloride

103 mmol/L

100 -110

Potassium

3.7 mmol/L

3.2 - 4.5

Glucose

5.5 mmol/L

3.6 – 7.7

Urea*

10.6 mmol/L

3.0 – 8.0

Osmolality (measured)

281 mOsm/kg

280 – 300

a)  What important changes have occurred since the initial profile, and how should they be interpreted?

b)  Your registrar is concerned that the sodium is correcting too rapidly. Is there a basis for this concern, and what should be done?

College Answer

A 77 year old male undergoing transurethral prostatic resection under spinal anaesthesia becomes restless and agitated.  He is intubated and ventilated  in OT, the surgery is expedited, and he is transferred to ICU. His initial biochemistry profile is as follows:


Test

Value

Normal Range

Sodium*

113 mmol/L

135 – 145

Chloride*

87 mmol/L

100 -110

Potassium

4.5 mmol/L

3.2 - 4.5

Glucose

5.1 mmol/L

3.6 – 7.7

Urea

5.0 mmol/L

3.0 – 8.0

Osmolality (measured)

280 mOsm/kg

280 – 300

a)          Describe the important biochemical abnormalities.

Severe normotonic hyponatraemia. The osmolar gap is increased to > 40 mOsm/kg (51 mosm/kg using 1.86*(Na + K) + urea + glucose, or 44 mOsm/kg using 2*Na + urea + glucose).

b)         What is the likely cause of this confusional state?

Absorption of glycine / water irrigation solution causing glycine neurotoxicity. Glycine is an inhibitory neurotransmitter. Increased plasma ammonia may contribute, but the encephalopathy isnot due to a primary increase in brain water.

c)         What transient neurological disturbance is likely in this clinical setting?

Visual impairment, blindness, sometimes fixed pupils. Should completely resolve in a few hours

d)         List two confirmatory biochemical features (other than those from the table above).

Hyperammonaemia, hyperglycinaemia, hyperserinaemia, metabolic acidosis.

e)         Do you believe hypertonic saline is indicated? Explain your reasoning.

None. The osmolality is normal. Hypertonic saline should only be considered if measured osmolality < 260 mOsm/kg (TE Oh p 967)

21.2     Simultaneous arterial blood gas analysis is as follows:

Test

Value

FiO2

0.3

pH

7.33

pO2

93 mm Hg (7.4 kPa)

pCO2

33 mm Hg (4.4 kPa)

HCO3-*

16 mmol/L

Standard base excess*

-9.5 mEq/L

a)  Describe the acid- base status.

Compensated metabolic acidosis – normal anion gap

b)  What is the mechanism  of this disturbance?

Water absorption (SID zero) reducing extracellular SID (in excess of ATOT dilution).

21.3     After 7 hours, the biochemical profile is as follows:

Test

Value

Normal Range

Sodium*

130 mmol/L

135 – 145

Chloride

103 mmol/L

100 -110

Potassium

3.7 mmol/L

3.2 - 4.5

Glucose

5.5 mmol/L

3.6 – 7.7

Urea*

10.6 mmol/L

3.0 – 8.0

Osmolality (measured)

281 mOsm/kg

280 – 300

a)  What important changes have occurred since the initial profile, and how should they be interpreted?

Osmolar gap now greatly reduced (to 16 mOsm/kg, or to 5 mOsm/kg using simple formula), indicating rapid glycine elimination. Sodium rapidly normalising, but plasma still normotonic

b)  Your registrar is concerned that the sodium is correcting too rapidly. Is there a basis for this concern, and what should be done?

Rapid sodium correction is to be expected during glycine elimination, and is safe provided no sudden changes in osmolality.

Discussion

The story given by the college makes one think immediately of the TURP syndrome, a cause of isoosmolar hyponatremia, which is seen less frequently these days because of a shift away from glycine-containing irrigation solutions.

a) The first part of the question asks about the important biochemical abnormalities. The college answer describes it as "normotonic hyponatremia". This is accurate, given that the given osmolality lies within the normal range of tonicity.

The osmolar gap is raised:

280 - (113 × 2 + 5.1 + 5) = 43.9

And so, this confirms one's instant impression that this a glycine-associated hyponatremia is causing this confusional state.

b) What is the likely cause of this confusional state?

Of the offered biochemistry values, only hyponatremia stands out.

However, it is not alone in the pathogenesis of this confusion.

Glycine itself has a well-known toxicity syndrome, and on top of that its metabolism by oxidative deamination can result in a massive excess of ammonia, with its own delirium-generating effects.

c)What transient neurological disturbance is likely in this clinical setting?

Traditionally, glycine toxicity causes blindness. Stupour and coma are also common. A good article on this topic has a table (Table 1) which lists other unpleasant CNS manifestations, including dilated unreactive pupils, seziures and paralysis.

d)List two confirmatory biochemical features (other than those from the table above).

Glycine toxicity is associated with the following biochemical changes, of which some have already been identified by the abovementioned test panel.

  • Hyponatremia
  • Hypoosmolarity
  • Hyperglycinaemia
  • Hyperammonaemia
  • Hyperserinaemia
  • Hyperoxalaemia
  • Metabolic acidosis: NAGMA due to absorption of fluid with a low strong ion difference, and HAGMA due to excess of oxalate and serine.

e) Hypertonic saline is not indicated in this setting; the serum sodium will return to normal when the glycine and free water have been eliminated, which does not take long. The neurological features of this syndrome are not due to cerebral oedema, but rather due to the direct neurotoxicity of the glycine, and thus one cannot call this "symptomatic hyponatremia".

21.2: The college asks us to interpret the ABG.

Let us do it systematically.

  1. The A-a gradient is high:
    PAO2 = (0.3 × 713) - (33 × 1.25) = 172.65
    Thus, A-a = ( 172.65 - 93) = 79.65mmHg.
  2. There is acidaemia
  3. The PaCO2 is compensatory
  4. The SBE is -9.5, suggesting a metabolic acidosis
  5. The respiratory compensation is adequate:
    the expected PaCO2 is (16 × 1.5) + 8 = 32mmHg
  6. The anion gap is slightly raised, but almost normal:
    (113+4.5) - (87+16) = 14.5
    The delta ratio suggests that there is a combined normal anion gap and high anion gap metabolic acidosis here.
    (14.5 - 12) / (24-16) = 0.31

This is a consequence of absorbing pure water (which has an SID of 0) as well as a minor contribution from oxalate and serine.

21.3

a)  What important changes have occurred since the initial profile, and how should they be interpreted?

The college now presents us with an essentially normal biochemical profile. The osmolar gap is now normal:

281 - (130 × 2 + 5.5 + 10.6) = 4.9

The glycine has therefore been eliminated.

b)  Your registrar is concerned that the sodium is correcting too rapidly. Is there a basis for this concern, and what should be done?

The panicky registrar needs to be calmly reassured. The elimination of glycine has resulted in the normalisation of sodium, which is as rapid in onset as the hyponatremia. Only chronic hyponatremia needs to be worried about. Because the serum osmolality remains essentially unchanged, there is no danger of cerebral oedema.

 

References

Rhymer JC, Bell TJ, Perry KC, Ward JP. Hyponatraemia following transurethral resection of the prostate. Br J Urol. 1985 Aug;57(4):450-2.

Hahn, R. G. "Serum amino acid patterns and toxicity symptoms following the absorption of irrigant containing glycine in transurethral prostatic surgery." Acta anaesthesiologica scandinavica 32.6 (1988): 493-501.

Roesch, Ryland P., et al. "Ammonia toxicity resulting from glycine absorption during a transurethral resection of the prostate." Anesthesiology 58.6 (1983): 577-578.

Glycine Toxicity page from The Anesthesia Practice Manual for Spectrum by Tom VerLee.

Gravenstein, Dietrich. "Transurethral resection of the prostate (TURP) syndrome: a review of the pathophysiology and management." Anesthesia & Analgesia 84.2 (1997): 438-446.

Hahn, R. G., and M. Rundgren. "Vasopressin and amino acid concentrations in serum following absorption of irrigating fluid containing glycine and ethanol."British journal of anaesthesia 63.3 (1989): 337-339.

Stewart, PA Hamilton, and I. M. Barlow. "Metabolic effects of prostatectomy."Journal of the Royal Society of Medicine 82.12 (1989): 725-728.

Beal, J. L., et al. "Consequences of fluid absorption during transurethral resection of the prostate using distilled water or glycine 1.5 per cent." Canadian Journal of Anaesthesia 36.3 (1989): 278-282.

Fitzpatrick, J. M., G. P. Kasidas, and G. Alan Rose. "Hyperoxaluria following glycine irrigation for transurethral prostatectomy." British journal of urology 53.3 (1981): 250-252.

 

Question 25 - 2010, Paper 1

Critically evaluate the use of albumin-containing solutions in critically ill patients.

College Answer

Albumin solutions are frequently used in critically ill patients for a variety of indications.

a) Volume replacement:  The SAFE study showed that using colloids was equivalent in efficacy and safety to crystalloids.

b) Hypoalbuminaemia: Clinical conditions that may benefit from albumin replacement for hypoalbuminaemia include:-

Patients with decompensated liver cirrhosis and spontaneous bacterial peritonitis. The administration of albumin results in a reduced incidence of renal failure and reduction in mortality.

Patients with Acute Lung Injury or ARDS.The study by Martin CCM 2005 shows that in patients who are hypoproteinaemic with ARDS, adding albumin to frusemide resulted in a significant improvement in oxygenation compared to frusemide alone. There was also a greater net negative fluid balance achieved and better haemodynamic stability in patients receiving albumin.

Head  injury:  The  clinical  conditions  in which  you  would  avoid  Albumin  replacement  is cerebral trauma where the SAFE subgroup  analysis reported increased  mortality at 28 days and 2 years.

Sepsis:  In the SAFE subgroup, a trend towards an improved outcome with albumin was noted as compared to saline

In Australia, albumin is cheap (free). It is also risk free, not associated with serious complications  such  as  coagulation  abnormalities  and  renal  failure  as  seen  with  other studies

Discussion

This question is a broad "what uses for albumin can you think of" sort of question. A couple of albumin enthusiasts (Caironi and Gattinoni) have published a good overview of this topic.

Firstly, to the most notable and obvious part.

Albumin as a resuscitation fluid

  • Equivalent to saline in terms of mortality (SAFE study)

Albumin for resuscitation of septic shock

  • Slightly superior to saline in terms of mortality (on post-hoc subgroup analysis of the SAFE study)
  • Equivalent to saline in terms of mortality (ALBIOS trial)
  • Improves mortality of septic shock patients once hemodynamic stability has been achieved (also the ALBIOS trial).
  • According to a recent meta-analysis, the results of the available studies support safety, but suggest that albumin is "not robustly effective at reducing all-cause mortality".

Albumin for spontaneous bacterial peritonitis

Albumin for volume replacement in paracentesis

Albumin as an adjunct in hepatorenal syndrome

Albumin for extracorporeal detoxification in liver failure

Albumin as an adjunct to frusemide in ARDS

  • Albumin and frusemide together improve oxygenation in hypoproteinaemic ARDS patients
  • There is no mortality benefit, and robust evidence is lacking.

Albumin to aid water elimination in oedematous ICU patients

  • This practice is based on physiological principles, using albumin as an oncotic agent to attract water into the intravascular space to improve diuresis.
  • Proponents of this strategy admit that their recommendations "appear in open contrast with what is called “evidence-based medicine”".

Albumin is to be avoided in traumatic brain injury

  • Again from the SAFE study, in the same way as a post-hoc subgroup analysis revealed some benefit from albumin in sepsis, so did a similar subgroup analysis reveal some evidence of harm in patients with traumatic brain injury.

Much has been made of the findings of the SAFE study. The most recent ALBIOS study has supported the notion that albumin and saline are quivalent as resuscitation fluids. Furthermore, the authors found that the patients enrolled in early stages of sepsis did not demonstrate an early benefit, and that patients treated with albumin for longer tended to benefit more. This suggests that the benefit of albumin is derived not from a purely oncotic effect, but rather due to its ancillary functions as a nitric oxide modulator, antioxidant and anti-immunosuppressive. This is supported by the last salvo fired by Marik, who suggested that the contribution of albumin infusion to maintaining the integrity of the vascular endothelial glycocalyx is enough to support its role as "a reasonable intervention" in sepsis.

References

McEvoy, Rinaldo Bellomo, et al. "The SAFE Study Investigators Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis." Intensive Care Med 37 (2011): 86-96.

 

Finfer, Simon, et al. "A comparison of albumin and saline for fluid resuscitation in the intensive care unit." N Engl j Med 350.22 (2004): 2247-2256.

 

Caironi, Pietro, et al. "Albumin replacement in patients with severe sepsis or septic shock." New England Journal of Medicine 370.15 (2014): 1412-1421.

 

Marik, Paul E. "Early Management of Severe Sepsis: Concepts and Controversies." CHEST Journal 145.6 (2014): 1407-1418.

 

Patel, Amit, et al. "Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality." BMJ 349 (2014): g4561.

 

Myburgh, John, et al. "Saline or albumin for fluid resuscitation in patients with traumatic brain injury." N Engl J Med 357.9 (2007): 874-884.

 

Bernardi, Mauro, Caterina Maggioli, and Giacomo Zaccherini. "Human albumin in the management of complications of liver cirrhosis." Crit Care 16.2 (2012): 211.

 

Gluud, Lise L., et al. "Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome." Hepatology 51.2 (2010): 576-584.

 

Sort, Pau, et al. "Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis." New England Journal of Medicine 341.6 (1999): 403-409.

 

Karvellas, Constantine J., et al. "Bench-to-bedside review: current evidence for extracorporeal albumin dialysis systems in liver failure." Crit Care 11.3 (2007): 215.

 

Martin, Greg S., et al. "A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury." Critical care medicine 33.8 (2005): 1681-1687.

 

Caironi, Pietro, and Luciano Gattinoni. "The clinical use of albumin: the point of view of a specialist in intensive care." Blood Transfusion 7.4 (2009): 259.

 

Question 1 - 2010, Paper 2

1.1; Briefly outline the rationale for the use of hypertonic saline in:

1)  Hyponatremia

2)  Traumatic brain injury

1.2; List the possible complications of hypertonic saline administration.

College Answer

1)  Hyponatremia

Hyponatremia

•    Severe hyponatremia (<120 mEq/L) can cause significant and permanent neurologic injury or death. In the event of seizures or acute collapse relatively rapid initial correction may be required.
•    There is evidence that the severity and duration of hyponatremia may be related to cerebro pontine myelinolysis, normal saline and fluid restriction may be inadequate to increase sodium levels appropriately.
•    Some conditions such as cerebral salt wasting or large GIT losses may result in losses that may not be able to be replaced by other means.

2)  Traumatic brain injury

Traumatic Brain Injury

•     The rationale for hypertonic saline compared with normal saline
•     Better compensates for blood loss
•     Improved CPP
•     Reduces harmful inflammatory responses
•     May prevent cerebral edema.
•     Can be used as a continuous infusion
•     Obviates the need for osmolality testing

Previous animal studies and smaller clinical trials suggested better outcomes in patients with TBI after use of hypertonic saline solution. The safety profile has been good, and some evidence suggests a potential survival benefit when hypertonic saline is given. However The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) has stopped enrollment of patients with severe traumatic brain injury (TBI) into a Resuscitation Outcomes Consortium (ROC) trial testing the effects of hypertonic saline solutions given before arrival at the emergency department. as early as possible after TBI.
1073 patients 6 month analysis – no difference.

1.2        List the possible complications of hypertonic saline administration.

•      Hypernatremia
•     Hyperchloraemic acidaemia
•     Renal failure
•     CCF/Pulmonary Oedema
•     Neurological   SAH
•     rebound intracranial H/T

•      Central Pontine Myelinolysis

Discussion

Hypertonic saline for hyponatremia

It is straightforward: one wants to replace the missing electrolyte.

However, it may not be the first line therapy.

In brief summary:

  • Sometimes, fluid restriction or other conservative measures may not be enough
  • Severe prolonged hyponatremia is not without consequences
  • Hyponatremia may have lifetheatening symptoms (such as coma and seizures), for which sodium replacement is the only sensible solution.
  • Symptomatic hyponatremia should be managed with the infusion of hypertonic saline, so as to contribute sodium without contributing volume.

Hypertonic saline for traumatic brain injury

Osmotherapy for control of increased intracranial pressure is discussed in greater detail elsewhere. In brief summary:

Complications of hypertonic saline therapy

One review of 3% saline among neuroICU patients has a nice table (Table 1) which lists the potential adverse effects of hypertonic saline administration. I will reproduce the relevant parts of this table below. As you can see, the college answer for this section relies significantly on a source either identical to this one, or very closely resembling it.

  • Hyperosmolarity
  • Overshoot hypernatremia
  • Congestive heart failure and pulmonary oedema
  • Hypokalemia
  • Normal anion gap metabolic acidosis
  • Coagulopathy
  • Phlebitis (hypertonic saline is a sclerosant)
  • Renal failure (due to vasoconstriction)
  • Decreased level of consciousness
  • Rebound intracranial hypertension
  • Seizures
  • Central pontine myelinolysis
  • Subdural and intraparenchymal hemorrhage

References

Lazaridis, Christos, et al. "High-Osmolarity Saline in Neurocritical Care: Systematic Review and Meta-Analysis*." Critical care medicine 41.5 (2013): 1353-1360.

Adrogué, Horacio J. "Consequences of inadequate management of hyponatremia." American journal of nephrology 25.3 (2005): 240-249.

Froelich, Matteus, et al. "Continuous hypertonic saline therapy and the occurrence of complications in neurocritically ill patients*." Critical care medicine 37.4 (2009): 1433-1441.

Question 25.1 - 2010, Paper 2

A 50 year old patients is admitted to the ICU for airway observation following a difficult  parathyroidectomy.   No  immediate   airway  problems   were  evident. About 24 hours later, the patient was noted to be in fast atrial fibrillation, and complained of difficulty in breathing with aches and pains.

a)  What is the likely explanation for the patient’s symptoms?

b)  Outline your management.

College Answer

a)  What is the likely explanation for the patient’s symptoms?

Hypocalcemia and possibly hypomagnesemia –e causing  muscle cramps, possible laryngospasm and AF from electrolyte abnormalities. Some patients suffer from the post operative hungry bone syndrome whereby the calcium goes into the bone because of lack of PTH.

b)  Outline your management.

•    Ca gluconate or chloride – bolus or infusion
•    Mg supplements
•    Anti-arrhythmics for AF

Discussion

The clinical features of hypocalcemia and the causes of hypocalcemia are discussed elsewhere. However, sophistication is not required to arrive at the answer here. This is a fairly straightforward pattern-recognition question, asking the candidate to recognise hypocalcemia as a possible complication of parathyroid surgery. The treatment, predictably, is the supplementation of calcium. One could go off on a tangent with AF management, and digress into a discussion of how one might want to replace calcium before attempting rate control with digoxin (digoxin being useless in the presence of hypocalcemia). However, this question is not worth enough marks for that.

References

Mittendorf, Elizabeth A., James I. Merlino, and Christopher R. McHenry. "Post-parathyroidectomy hypocalcemia: incidence, risk factors, and management."The American surgeon 70.2 (2004): 114-9.

Chopra, Deepak, Paul Janson, and Clark T. Sawin. "Insensitivity to digoxin associated with hypocalcemia." The New England journal of medicine 296.16 (1977): 917-918.

Question 12 - 2011, Paper 1

List the major biochemical abnormalities  that are usually associated with the following conditions:

a)   Adrenal insufficiency.

b)   Refeeding syndrome.

c)   Tumour lysis syndrome.

d)   Ethylene glycol toxicity.

College Answer

Adrenal Insufficiency

Hyponatraemia
Hyperkalaemia
Non anion gap acidosis Hypoglycaemia Hypercalcaemia

Refeeding Syndrome

Hypophosphataemia Hypokalaemia Hypomagnesaemia Hyperglycaemia

Tumour Lysis Syndrome

Hyperphosphataemia Hyperkalaemia Hypocalcaemia Hyperuricaemia Metabolic acidosis

Ethylene Glycol Toxicity

High anion gap acidosis High osmolar gap Hypocalcaemia

Discussion

The tabulated answer from the college is comprehensive, and would be difficult to improve upon.

Instead, I will offer links to detailed discussions of the abovementioned syndromes.

References

Cooper, Mark Stuart, and Paul Michael Stewart. "Adrenal insufficiency in critical illness." Journal of intensive care medicine 22.6 (2007): 348-362.

Khan, Laeeq UR, et al. "Refeeding syndrome: a literature review."Gastroenterology research and practice 2011 (2010).

Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.

Parry, Michael F., and Ronald Wallach. "Ethylene glycol poisoning." The American Journal of Medicine 57.1 (1974): 143-150.

 

Question 18.1 - 2011, Paper 1

The  blood  results  of a 75 year  old who  presents  with  lethargy,  confusion  and weight loss are shown below:

Patient value

Normal range

Sodium

141 mmol/L

135 – 145

Potassium

3.8 mmol/L

3.5 – 5.0

Chloride

100 mmol/L

97 – 109

Bicarbonate

29 mmol/L

24 – 32

Urea

11.5 mmol/L

3.0 – 8.0

Creatinine

150 µmol/L

70 – 110

Calcium

4.69 mmol/L

2.10 – 2.60

Phosphate

0.4 mmol/L

0.8 – 1.5

Albumin

44 G/L

38 – 48

a) What is the likely diagnosis?

b) What other biochemistry would you request and why?

c) Briefly explain the pathogenesis of the biochemical abnormalities.

d) Outline your management of this patient.

College Answer

a) What is the likely diagnosis?
Underlying malignancy

b) What other biochemistry would you request and why?
PTH to exclude primary hyperPTH – very high calcium indicates malignancy but patients with  malignancy  have  higher  incidence  of  hyperPTH  than  general  population  so  both conditions can co-exist

c) Briefly explain the pathogenesis of the biochemical abnormalities.

Hypercalcaemia:

Malignancy:

  • PTH rp (Parathyroid related peptide)
  • Ectopic PTH
  • Bone lysis

Increased PTH:

  • Leading to increased osteoclast activity leads to hypercalcaemia by bone reabsorption. It also acts at renal tubule to reabsorb Ca++ and increases conversion 25-OHD to 1,25 (OH)2D increases intestinal absorption of Ca++

Elevated urea and creatinine:

  • Secondary to hypovolaemia

d) Outline your management of this patient.

•    Fluid replacement with NS
•     Biphosphonates
•    Calcitonin
•    Steroids act by decreasing calcitriol
•    Dialysis
•    Treat underlying malignancy
•    Parathyroidectomy if raised PTH
•    (Diuretics no longer recommended)

Discussion

As for the diagnosis- the clue is in the age and the weight loss, and the college does sound as if they are asking for the one most likely diagnosis. But if one were to approach this on classical footing, one would be expected to regurgitate a small pool of differentials.

Causes of Hypercalcemia, by Pathophysiology

Primary endocrine causes

  • Primary hyperparathyroidism
  • Thyrotoxicosis
  • Adrenal insufficiency

Paraneoplastic causes

  • PTH-related protein
    • carcinoma of lung
    • oesophageal carcinoma
    • head and neck SCC
    • renal cell carcinoma
    • Breast cancer
    • Ovarian cancer
    • Bladder cancer
  • Ectopic 1,25-dihydroxyvitamin D
    • Lymphoma
  • Lytic bone lesions
    • Multiple myeloma
    • Breast cancer
    • Hematological malignancies
  • Phaeochromocytoma
  • VIP-secreting gastric adenoma

Granulomatous disease

  • Sarcoidosis
  • HIV
  • Tuberculosis
  • Histoplasmosis
  • Coccidioidomycosis
  • Leprosy

Drug-induced hypercalcemia

  • Vitamin D oversupplementation
  • Thiazide diuretics
  • Lithium carbonate
  • Oestrogens and HRT
  • Androgens
  • Theophylline and aminophylline
  • Vitamin A
  • Aluminum toxicity
  • Total parenteral nutrition (TPN)

Random miscellaneous causes

  • Immobilization (eg. spinal injury)
  • Chronic renal failure
  • Milk alkali syndrome
  • Rhabdomyolysis

One may wish to launch the following investigations:

  • Alkaline phosphatase
  • Serum PTH level
  • CK
  • Parathyroid hormone related peptide (PTHrp)
  • Serum Vitamin D metabolite levels
  • CXR - or better yet, CT chest - to look for obvious malignancy and granulomatous disease.

As for management, one would be well served to organise the response by the physiological aims of one's therapy:

  • Dilute serum calcium
    • Rehydration with IV fluids
  • Decrease calcium resportion from bone
    • Calcitonin
    • Bisphosphonates
    • Gallium nitrate
  • Decrease calcium resportion from renal tubule
    • Loop diuretics (this has fallen out of favour)
    • Calcitonin
  • Decrease calcium absorption from the gut
    • Corticosteroids (also they decrease the 1,25-dihydroxyvitamin D production by monocytes within granulomae)
  • Forcibly remove excess calcium from the circulation
    • Haemodialysis
    • EDTA administration (as chelating agent)

References

Question 5.1 - 2011, Paper 2

A 75-yr-old woman on Indapamide for Hypertension presented with seizures after a 7- day history of increasing lethargy. She was unwell, had dry mucus membranes and decreased skin turgor with a BP 88/50. Her serum sodium was 103 mmol/L. Outline your fluid management and discuss relevant physiology.

College Answer

a) This woman requires Hypertonic Saline for her hyponatremic encephalopathy.

b) She also requires isotonic fluid therapy (e.g. 0.9 % NaCl) to correct her Hypovolemia

Once volume repletion crosses the hypovolemic threshold for the adaptive excessive ADH

release that would have occurred (in part explaining her hyponatremia), there would be a

feed-back inhibition of the excess ADH release leading to massive aquaresis and the

increased free water excretion would help correct hyponatremia

Discussion

Why is this old woman hyponatremic?

This is a symptomatic hypovolemic hyponatremia, likely due to renal losses of both sodium and free water, associated with the use of indapamide (a thiazide diuretic).

Fluid management:

  • replacement of sodium (raising the serum level at a rate of 0.5-1 mmol/L per hour)
  • hypertonic saline infusion
  • replacement of free water.
  • Isotonic saline infusion

Relevant physiology:

  • Hypovolemia has resulted in excess ADH release in spite of hypo-osmolarity, because the baroreceptor reflex is a stronger stimulus for ADH release than the osmoreceptor reflex.
  • The excess ADH results in free water retention, which counteracts the attempts to increase sodium concentration with hypertonic saline
  • Once volume is restored, ADH release will decrease, and dilute diuresis will ensue
  • This loss of free water will assist the attempts to correct hyponatremia with hypertonic saline
  • Thus, volume replacement must occur together with sodium replacement.

References

For all electrolyte abnormality questions, I refer to the Electrolyte Quintet series from the Lancet. In the sodium article by Kumar, there is a table (Pane 2) from which the college answer for 5.2(b) seems to be derived (with a couple of changes). I have used that panel as my model answer.

Sumit Kumar, Tomas Berl. Sodium.  The LancetVolume 352, Issue 912318 July 1998Pages 220-228

SM Lauriat, T Berl: The Hyponatremic patients: practical focus on therapy. J Am Soc Nephrol 1997; 8: 1599–1607.

 

 

Question 5.2 - 2011, Paper 2

A 75-yr-old woman on Indapamide for Hypertension presented with seizures after a 7- day history of increasing lethargy. She was unwell, had dry mucus membranes and decreased skin turgor with a BP 88/50. Her serum sodium was 103 mmol/L.

By day 5 of her admission, the serum sodium has increased to 141 mmol/L. The antihypertensive therapy was adjusted and she was discharged home. Ten days after the initial presentation, she is readmitted with ataxia and confusion. On examination, the following findings were noted:

  • Afebrile GCS E4, M6, V4. 
  • No neck stiffness 
  • Tremor++, ataxia ++. 
  • Drooling of saliva + 
  • Brisk jaw jerk, bilaterally brisk reflexes, extensor plantar reflexes.
  • Full blood count: Nil significant 
  • LFT: normal. 


You are called to the ED to assess this patient as there are concerns that she might be an aspiration risk. 

a) List 2 likely differential diagnoses for her presentation. 
b) List 4 underlying predisposing conditions

College Answer

a)

Pontine demyelination is a differential given the recent history of rapid sodium replacement.

Brainstem stroke is an alternative explanation.

b)

Patients at increased risk of osmotic demyelination:

  • Alcoholics
  • Malnourished patients
  • Hypokalemic patients
  • Burns patients
  • elderly women on thiazide therapy
 

Discussion

Brainstem stoke? Really? But I suppose one must offer a differential.

A good article on pontine myelinolysis suggests that the pons is not unique and you can myelinolyse anywhere there is myelin. Typically, the early symptoms are dysartheria and dysphagia. They are followed by a flaccid quadriparesis.

The key issue is rate of correction. If the hyponatremia has lasted longer than 48 hours, we would be forced to call it "chronic". It takes brain cells about 48 hours to get rid of idiogenic osmoles and become isotonic with the hyponatremic extracellular fluid. However, once lost, those organic molecules take much longer to synthesise.

In short, your adaptation to hyponatremia is rapid, but your adaptation to a rising sodium is sluggish.

The result of bathing your neurons in a hypertonic solution is a shrinkage of those neurons. Water will easily cross the membrane into the hypertonic extracellular fluid, and the cells of the brain parenchyma will shrink and die.

The article mentioned above concludes with the sage advice that perhaps there is no such thing as a "maxiumum safe rate of replacement) but that most neurologists carry the figure of 10mmol/day in their head.

Risk factors for pontine myelinolysis?

Well. The first study (1959) which described this syndrome found it among alcoholic and malnourished patients. Later works extended the range of risk factors. In summary, they are as follows:

  • Alcoholism
  • Malnutrition
  • Other electrolyte disturbances (esp. hypokalemia)
  • Use of diuretics
  • Liver transplantation

References

R J Martin Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes J Neurol Neurosurg Psychiatry 2004;75:iii22-iii28 doi:10.1136/jnnp.2004.045906

For all electrolyte abnormality questions, I refer to the Electrolyte Quintet series from the Lancet. In the sodium article by Kumar, there is a table (Panel 2) from which the college answer seems to be derived (with a couple of changes). I have used that panel as my model answer.

Sumit Kumar, Tomas Berl. Sodium.  The LancetVolume 352, Issue 912318 July 1998Pages 220-228

Laureno, Robert, and Barbara Illowsky Karp. "Myelinolysis after correction of hyponatremia." Annals of Internal Medicine 126.1 (1997): 57-62.

Lee, Eun Mi, et al. "Risk factors for central pontine and extrapontine myelinolysis following orthotopic liver transplantation." European neurology 62.6 (2009): 362-368.

Adams, Raymond D., MAURICE VICTOR, and ELLIOTT L. MANCALL. "Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients." AMA Archives of Neurology & Psychiatry 81.2 (1959): 154-172.

Brown, William D. "Osmotic demyelination disorders: central pontine and extrapontine myelinolysis." Current opinion in neurology 13.6 (2000): 691-697.

Harris, Cheryl P., J. J. Townsend, and J. Richard Baringer. "Symptomatic hyponatraemia: can myelinolysis be prevented by treatment?." Journal of Neurology, Neurosurgery & Psychiatry 56.6 (1993): 626-632.

 

Question 20.1 - 2013, Paper 1

A 26-year-old male, admitted to the ICU 7 days ago following a traumatic brain injury, now has the following blood and urine results:

Test

Value

Normal Adult Range

Sodium*

128 mmol/L

135 – 145

Potassium

3.8 mmol/L

3.2 – 4.5

Chloride*

94 mmol/L

100 – 110

Bicarbonate*

19 mmol/L

24 – 32

Glucose

5.5 mmol/L

3.0 – 6.0

Urea

7.8 mmol/L

2.7 – 8.0

Creatinine*

120 μmol/L

65 – 115

Measured Osmolality*

267 mosmol/Kg

275 – 290

Urine Sodium

76

Urine Potassium

10

Urine Chloride

96

Urine Osmolality

350 mosmol/Kg

50 – 1200

Give two possible diagnoses and the rationale for your answer.

College Answer

SIADH

Cerebral salt wasting.

The presence of features that indicate hypovolaemia - low bicarb, high Cr and low plasma osmo and high anion gap .

Plus those indicating an ADH response – low plasma and high urine osmo.

Urine Na inappropriately high.

Discussion

Hyponatremia due to SIADH and CSW  is discussed in greated detail elsewhere.The combintion of traumatic brain injury and hyponatremia give rise to these two differentials almost involuntarily. This is a hypoosmolar hyponatremia with high urine osmolality and high urine sodium.

Urinary "osmo" (presumably, the examiner meant to finish typing "osmolality" but was called away to something very urgent) is relatively high, suggesting that there is a significant effect of ADH. This promotes SIADH as a differential. Consider that the serum osmolality is low, and the urine osmolality is high - obviously, the appropriate response to this situation would be to decreased ADH secretion and excrete buckets of dilute water-rich urine.

Urinary sodium sodium is also raised (i.e. over 40mmol/L), which suggests that for whatever reason, appropriate attempts to conserve sodium are not being made. This does not help to narrow the differentials very much, as it could be present in SIADH, cerebral salt wasting, hypoaldosteronism, hypoadrenalism, hypothyroidism, the polyuric phase of ATN, or with the use of thiazide diuretics. However, it excludes true hypovolemia (where efforts are made to conserve sodium).

Hypoaldosteronism and hypoadrenalism can be ruled out on the basis of a low serum potassium (it would normally be high in those situations). The polyuric phase of ATN normally has a more dilute urine, closer to 100mOsm/L. That leaves thiazides and hypothyroidism, which - though possible- have little relevance in the context of the history.

So, to discriminate between SIADH and cerebral salt wasting (both are a diagnosis of exclusion) one would have to examine the patient and decide whether they are underfilled (CSW) or euvolaemic (SIADH). This is the one situation in which the lazy man's approach to hyponatremia actually calls for a physical examination of the patient. The trick to discriminating between these two conditions lies in the ability to demonstrate that the body fluid volume is decreased. In both conditions the ADH level is elevated, but in cerebral salt wasting the ADH is elevated appropriately because the patient is hypovolemic, and so it cannot possibly be SIADH by definition.

References

Ashraf N, Locksley R, Arieff AI Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med. 1981 Jun;70(6):1163-8.

Kyu Sig Hwang, M.D. and Gheun-Ho Kim, M.D. Published online 2010 June 30. Thiazide-Induced Hyponatremia Electrolyte Blood Press. 2010 June; 8(1): 51–57.

Kovesdy CP. Significance of hypo- and hypernatremia in chronic kidney disease. Nephrol Dial Transplant. 2012 Mar;27(3):891-8.

Ahmed AB, George BC, Gonzalez-Auvert C, Dingman JF. Increased plasma arginine vasopressin in clinical adrenocortical insufficeincy and its inhibition by glucosteroids. J Clin Invest. 1967 Jan;46(1):111-23.

Schmitz PH, de Meijer PH, Meinders AE.Hyponatremia due to hypothyroidism: a pure renal mechanism. Neth J Med. 2001 Mar;58(3):143-9.

Hanna FW, Scanlon MF. Hyponatraemia, hypothyroidism, and role of arginine-vasopressin. Lancet. 1997 Sep 13;350(9080):755-6.

Cerdà-Esteve M, Cuadrado-Godia E, Chillaron JJ, Pont-Sunyer C, Cucurella G, Fernández M, Goday A, Cano-Pérez JF, Rodríguez-Campello A, Roquer J Cerebral salt wasting syndrome: review. .Eur J Intern Med. 2008 Jun;19(4):249-54

Question 7.3 - 2013, paper 2

A 61-year-old male, due to have a colonoscopy as an out-patient, is brought into the Emergency Department on the day of the procedure having been found collapsed at home, unresponsive with increased tone in his limbs.

Parameter

Patient Value

Normal Range

Urea

3.6 mmol/L

2.1 – 7.1

Creatinine

50 micromol/L*

53 – 97

Sodium

100 mmol/L*

136 – 146

Potassium

2.9 mmol/L*

3.5 – 5.1

Chloride

62 mmol/L*

98 – 107

Bicarbonate

35 mmol/L*

22 – 32

Glucose

5.0 mmol/L

3.0 – 6.0

 

a) What is the likely cause of the biochemical disturbance?
b) Briefly list the steps in your immediate management.

College Answer

a) Water intoxication secondary to bowel prep.

b)

  • Airway control and treat seizures as indicated.
  • Correct hypovolaemia.
  • Check serum osmolality (expected to be low).
  • Hypertonic saline to increase [Na+] by approx. 0.5 mmol/L/hour to achieve safe level to limit seizures (> 118 mmol/L) – balance between gradual increase in sodium and achieving safe level to limit seizures.
  • Correct hypokalaemia.
  • Fluid restriction.
  • Cease any medications that predispose to hyponatraemia (anti-depressants, thiazide diuretics, PPIs, ACEIs).
  • CT brain to assess for cerebral oedema.

Discussion

Hyponatremia is discussed in greater detail elsewhere.

In this electrolyte panel, the hyponatremia is the single most deranged electrolyte, and can account for seizures, which can in turn account for the increased tone. This sort of bowel-prep-associated hyponatremia is apparently a well-known complication of outpatient colonoscopy.

There are no fancy equations to apply in order to answer this question. Judging by the college answer, the examiners were interested in the candidate's understanding of sodium replacement for symptomatic hyponatremia.

If one were to approach the answer systematically, one might write something like this:

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history
  • Airway
    • Control the airway in view of uncosciousness; assess the need for urgent intubation
  • Breathing/ventilation
    • Maintain normoxia and normocapnea
    • Ensure a mandatory mode while the patient is obtunded
  • Circulatory support
    • Protect the myocardium by replacing potassium aggressively
  • Monitoring
    • careful monitoring of sodium during replacement
  • Specific investigations
    • Serum osmolality
    • Urinary sodium (should be low in water intoxication)
  • Specific management
    • Fluid restriction
    • Hypertonic saline administration to increase serum sodium

The college answer recommends to raise the sodium by no more than 0.5mmol/hr,to avoid pontine myelinolysis. However, in their answer to the very similar Question 24 from the first paper of 2016, the college recommend to raise the sodium level by 2-4% over 30 minutes if the patient is symptomatic, i.e. confused or having seizures. This  change in approach reflects a change in the multinational society recommendations: in the recent European guidelines (Spasovski et al, 2014) the guideline development group felt that the risk of brain oedema outweighs the risk of osmotic demyelination syndrome.

References

Frizelle, F. A., and B. M. Colls. "Hyponatremia and seizures after bowel preparation: report of three cases." Diseases of the colon & rectum 48.2 (2005): 393-396.

Salik, James M., and Paui Kurtin. "Severe hyponatremia after colonoscopy preparation in a patient with the acquired immune deficiency syndrome." The American journal of gastroenterology 80.3 (1985): 177-179.

Nagler, Jerry, David Poppers, and Meredith Turetz. "Severe hyponatremia and seizure following a polyethylene glycol-based bowel preparation for colonoscopy." Journal of clinical gastroenterology 40.6 (2006): 558-559.

Lien, Y. H., J. I. Shapiro, and L. Chan. "Study of brain electrolytes and organic osmolytes during correction of chronic hyponatremia. Implications for the pathogenesis of central pontine myelinolysis." Journal of Clinical Investigation88.1 (1991): 303.

Mohmand, Hashim K., et al. "Hypertonic saline for hyponatremia: risk of inadvertent overcorrection." Clinical Journal of the American Society of Nephrology 2.6 (2007): 1110-1117.

Laureno, Robert, and Barbara Illowsky Karp. "Myelinolysis after correction of hyponatremia." Annals of Internal Medicine 126.1 (1997): 57-62.

Question 9 - 2013, paper 2

a) List the clinical features of severe symptomatic hypercalcaemia and outline the treatment of this condition.

b) List four common causes of ionised hypocalcaemia and for each give the underlying mechanism.

College Answer

a)

  • Clinical features:
    • CNS and PNS
    • Confusion
    • Coma
    • Hypotonia
    • Hyporeflexia
    • Paresis
  • Renal findings
    • Renal stones
    • Volume depletion
    • Renal failure
  • GI findings
    • Constipation and fecal impaction
    • Pancreatitis
    • Gastric ulcer
  • Cardiac findings
    • Arrhythmias
    • Hypotension
    • Shortened QT interval

Signs related to underlying malignancy:

Treatment:

Treatment includes reduction of hypercalcaemia and treatment of underlying cause.

Measures for reduction of hypercalcaemia- (listing of agents adequate, doses & mechanism not expected)

Saline/frusemide diuresis- correction of dehydration with about 2L of fluid and 80mg Frusemide 2-4 hourly (only when volume has been adequately replaced) with replacement of urine losses with fluid & monitoring of potassium, calcium, phosphate and magnesium. Caution in cardiac or renal failure.

NB: Although use of frusemide is controversial/may not be beneficial, most current textbooks still include it.

  • Bisphosphonates- Disodium etidronate or pamidronate
  • Corticosteroids- especially if due to sarcoidosis or vit D toxicity
  • Calcitonin
  • Dialysis- Peritoneal or haemodialysis against calcium-free or low calcium concentration dialysate (citrate anticoagulation with CVVHDF)
  • (Gallium nitrate)- nephrotoxic
  • (Mithramycin)- contraindicated in renal or hepatic failure
  • (Octreotide)

b)

Causes of ionised hypocalcaemia – any 4 individual causes:

  • Decreased PTH activity:
    • Hypoparathyroidism
    • Pseudohypoparathyroidism
    • Hypomagnesaemia
  • Vitamin D deficiency:
    • Malabsorption of vitamin D/calcium- steatorrhoea
    • Vitamin D deficient rickets, osteomalacia in adults
  • Excess calcium losses/binding:
    • Rhabdomyolysis
    • Pancreatitis
    • Critical illness (burns, sepsis, toxic shock, etc.)
    • Frusemide and saline diuresis
    • Hyperphosphataemia
    • Citrate toxicity (CVVHDF)
    • Alkalosis / Hyperventilation
    • Fluoride toxicity
    • Oxalate poisoning
    • Tumour Lysis
    • Drugs – biphosphonates, calcitonin, phenytoin
  • Unknown mechanism:
    • Hypermagnesaemia

Discussion

Features of hypercalcemia are discussed elsewhere.

The table below is a satisfactory short summary:

Clinical Manifestations of Hypercalcemia

Early manifestations (levels < 3.5mmol/L)

  • Constipation

  • Peptic ulcer exacerbation

  • Polyuria

  • Nephrogenic diabetes insipidus

  • Nephrolithiasis

  • Type 1 (distal) renal tubular acidosis

  • Shortened QT interval

  • Bone pain

Late manifestations (levels over 3.5mmol/L)

  • Pancreatitis

  • Renal failure (due to vasoconstriction)

  • Hypertension

  • Delirium, progressing to coma

  • Arrhythmia

  • Muscle weakness

Management of hypercalcemia has indeed moved on since the frusemide diuresis days. All the positive evidence for this practice was published before bisphosphonates became available.

The college graciously allows the candidates to get by without mentioning drug doses.The modern medical approach to hypercalcemia is summarised as the following list, ordered by escalating invasiveness of therapy.

  • Volume restoration
  • Bisphosphonates
  • Calcitonin
  • Renal replacement therapy

Causes of hypocalcemia are discussed elsewhere. They are numerous. Though the college asks specifically about ionised hypocalcemia, they then give a list of all possible causes for this condition. In order to simplify revision, a table of causes is reproduced below:

Causes of Hypocalcemia

Low Parathyroid Hormone

  • Primary hypoparathyroidism (i.e. destruction of the parathyroid glands)
  • Post-operative hypoparathyroidism
  • Hungry bone syndrome
  • HIV infection
  • Haemochromatosis

 

High or normal Parathyroid hormone

  • Vitamin D deficiency
  • Hypomagnesemia
  • Hyperphosphataemia
  • Renal failure (pseudohypoparathyroidism)
  • Tumour lysis syndrome
  • Acute pancreatitis
  • Alkalosis
  • Depletion in coagulopathy

 

Drugs

  • Phenytoin
  • Fluoride toxicity
  • Foscarnet
  • EDTA
  • Citrate
  • Phosphate
  • Bisphosphonates

Ionised hypocalcemia in isolation is rare. It is seen in only one scenario: citrate toxicity. When citrate is used to chelate calcium, the total calcium is normal, but the ionised fraction is low. This is because measurement instruments which detect calcium will also measure citrate-calcium complexes in the serum, but the electrode which measures ionised calcium will only measure the free fraction, which decreases with citrate chelation.

References

Inzucchi, Silvio E. "Management of hypercalcemia." Postgraduate medicine115.5 (2004).

Ralston, S. H., et al. "Medical management of hypercalcemia." Calcified tissue international 74.1 (2004): 1-11.

Hästbacka, J., and V. Pettilä. "Prevalence and predictive value of ionized hypocalcemia among critically ill patients." Acta anaesthesiologica scandinavica 47.10 (2003): 1264-1269.

LeGrand, Susan B., Dona Leskuski, and Ivan Zama. "Narrative review: furosemide for hypercalcemia: an unproven yet common practice." Annals of internal medicine 149.4 (2008): 259-263.

UpToDate has a nice summary of this topic for the paying customer.

Cooper, Mark S., and Neil JL Gittoes. "Diagnosis and management of hypocalcaemia." BMJ: British Medical Journal 336.7656 (2008): 1298.

Tohme, J. F., and J. P. Bilezikian. "Hypocalcemic emergencies." Endocrinology and metabolism clinics of North America 22.2 (1993): 363-375.

Diercks, Deborah B., et al. "Electrocardiographic manifestations: electrolyte abnormalities." The Journal of emergency medicine 27.2 (2004): 153-160.

LITFL have an excellent point-form summary of citrate toxicity. Much of what we know about it is derived from the sorry experience of patients who were recipients of massive transfusions.

Uhl, L., et al. "Unexpected citrate toxicity and severe hypocalcemia during apheresis." Transfusion 37.10 (1997): 1063-1065.

Bushinsky, David A., and Rebeca D. Monk. "Calcium." The Lancet 352.9124 (1998): 306-311.

Schaer, H., and U. Bachmann. "Ionized calcium in acidosis: differential effect of hypercapnic and lactic acidosis." British journal of anaesthesia 46.11 (1974): 842-848.

Dzik, Walter H., and Scott A. Kirkley. "Citrate toxicity during massive blood transfusion." Transfusion medicine reviews 2.2 (1988): 76-94.

Question 7.1 - 2014, Paper 1

A 50-year-old patient was admitted to the ICU for airway observation following a difficult parathyroidectomy. No immediate airway problems were evident. About 24 hours later, the patient was noted to be in fast atrial fibrillation, and complained of difficulty in breathing with generalised aches and pains.

a) What is the likely explanation for the patient's symptoms?

b) List your specific management for this problem.

College Answer

a) Hypocalcaemia and possibly hypomagnesaemia causing muscle cramps, possible laryngospasm.

b)
 Ca gluconate or chloride – bolus or infusion.
 Mg supplements.
 Anti-arrhythmics for AF.

Discussion

That this is hypocalcemia, and that replacing calcium is the solution, does not require extensive discussion.

Post-parathyroidectomy hypocalcemia is the most likely guess for this disturbance, given that it's the complication everybody watches for whenever a patient's parathyroid glands have been surgically interfered with. It happens to some extent in over half of the patients undergoing this surgery (Mittendorf et al, 2004). Of the symptoms, the most common are "acral or perioral numbness and paresthesias, muscle cramps, or, in more severe cases, laryngeal stridor, tetany, generalized seizures, and cardiac arrhythmias". The difficulty breathing could also be pulmonary oedema. Lekas et al (2010) discussed how this might happen, pointing out the essential role of calcium in contractility and diastolic relaxation. 

Hypomagnesemia after parathyroid surgery is also a thing, albeit not as well-known. Jones et al (way back in 1973) described it in a way which makes it look much like severe hypocalcemia, which it is often associated with. By treating the mganesium, the symptoms disappear even if the calcium level is ignored. "Despite persistence of severe hypocalcaemia the acute restoration of the serum magnesium level to normal with intravenous therapy was accompanied by a striking alleviation of the clinical abnormalities" the authors remark. One cannot help but think that one should still think about replacing the missing calcium anyway (for one, the blood still needs to clot somehow).

References

Mittendorf, Elizabeth A., James I. Merlino, and Christopher R. McHenry. "Post-Parathyroidectomy Hypocalcemia: Incidence, Risk Factors, and Management/DISCUSSION." The American surgeon 70.2 (2004): 114.

Lekas, Poli, Patricia T. Goldenstein, and Joanne M. Bargman. "Myocardial dysfunction and pulmonary edema post parathyroidectomy: the role of hypocalcemia." Adv Perit Dial26.4 (2010): 125-129.

Jones, C. T., R. A. Sellwood, and J. M. Evanson. "Symptomatic hypomagnesaemia after parathyroidectomy." British Medical Journal 3.5876 (1973): 391.

Question 12.2 - 2014, paper 2

You are called to review a 54-year-old female who is obtunded, 5 days post total knee replacement. She has a history of hypertension and mild depression and is on regular medication for both conditions. She has no other known co-morbidities.

Her biochemistry profile is as follows:

Parameter Patient Value Normal Adult Range
Sodium 114 mmol/L* 135 – 145
Potassium 4.6 mmol/L 3.5 – 5.0
Chloride 87 mmol/L* 95 – 105
Bicarbonate 18 mmol/L* 24 – 32
Urea 6.6 mmol/L 2.9 – 8.2
Creatinine 72 µmol/L 70 – 120

a) What are the likely causes for these results in this patient?

b) Briefly outline how you will determine the underlying cause.

College Answer

a)
Inappropriate fluid therapy post op
SIADH (possible SSRI therapy)
Thiazide diuretic
Vomiting and/or diarrhoea
Salt-wasting (cerebral or renal)
Less likely as no other co-morbidity CCF, cirrhosis, hypoadrenalism, hypothyroidism (kidney failure
excluded from results)

b)
History of medications and fluid input/output
Clinical assessment of fluid status, presence of heart/liver failure
Serum osmolality
Urine osmolality and sodium
Random cortisol
TFTs

Discussion

a)

Causes of hyponatremia in this patient could include:

  • SIADH:
    • recent surgery
    • possible SSRI therapy
  • True hypovolemia
    • Underfilled post op
    • Vomiting post anaesthetic
    • Unable to drink (due to decreased level of consciousness)
  • Excess of sodium-poor fluid
    • Inappropriate fluid resuscitation choices, eg. 5% dextrose
  • Increased sodium excretion
    • Thiazide diuretic or spironolactone (has history of hypertension)
  • Unlikely:
    • Renal tubular acidosis
    • Hypothyroidism
    • Hypoadrenalism
    • Cerebral salt wasting

In general:

Causes of Hyponatremia

Spurious result

Isotonic

  • High triglycerides
  • High serum protein
  • Glycine (TURP syndrome)

Hypertonic

  • Hyperglycaemia
  • Mannitol
  • Sorbitol
  • Maltose
  • Radiocontrast dye

Water retention

High urine sodium

  • Renal failure
  • Cirrhosis
  • Congestive cardiac failure
  • Diuretics (but not enough!)
  • SIADH

Low urine sodium

  • Psychogenic polydipsia
  • True hypovolemia

Sodium excretion

  • Post-ATN diuresis
  • Hypoaldosteronism
  • Diuretic excess
  • Cerebral salt wasting
  • Inappropriate fluid replacement (5% dex)

b)

An approach to the diagnosis of a hyponatremia should involve the following structured steps:

  • History (including an audit of the medication chart and fluid orders)
  • Examination (focusing on volume status)
  • Investigations (most importantly, serum osmolality and urine soidum)

History: The following bits of historical information are important:

  • Medication history (diuretics, steroids, drugs which cause SIADH eg. SSRIs)
  • Fluid chart (has somebody been mindlessly charting dextrose)
  • Psychosocial history (is psychogenic polydipsia even a possibility; are they on a weird diet)
  • Alcohol history (liver disease, cirrhosis, beer potomania)
  • Oedema history (Ascites worse recently? Sleep on twenty pillows?)
  • Trauma history (cerebral salt wasting, pituitary injury)
  • Urine output (massive diuresis of HONK or ATN recovery phase, or oliguria or chronic renal failure)
  • Recent procedures: TURP, contrast CT, recent surgery, etc.

The following standard battery of tests can be launched; particularly if history is unhelpful, or one cannot bring oneself to interview the patient or their family.

Essential tests:

  • Serum osmolality (to classify the disorder)
  • Urine osmolality
  • Urinary sodium

Optional tests:

  • Serum triglycerides
  • Serum protein level
  • TFTs
  • LFTs
  • Urea and creatinine
  • Random cortisol
  • Short synacthen test

Potential causes:

This is essentially the content of Box 93.1 from Anthony Delaney and Simon Finfer's chapter for Oh's Manual.

Causes of Hyponatremia

Spurious result

Isotonic

  • High triglycerides
  • High serum protein

Hypertonic

  • Hyperglycaemia
  • Mannitol
  • Sorbitol
  • Maltose
  • Radiocontrast dye
  • Glycine (TURP syndrome)

Water retention

High urine sodium

  • Renal failure
  • Cirrhosis
  • Congestive cardiac failure
  • Diuretics (but not enough!)
  • SIADH

Low urine sodium

  • Psychogenic polydipsia
  • True hypovolemia

Sodium excretion

  • Post-ATN diuresis
  • Hypoaldosteronism
  • Diuretic excess
  • Cerebral salt wasting
  • Inappropriate fluid replacement (5% dex)

Diagnosis on the basis of the above lab tests and historical findings:

  • Serum osmolality testing:
    • Hyperosmolar hyponatremia:
      • Hyperglycaemia
      • Mannitol therapy
      • Other unmeasured solutes, eg. glycine
      • Glycine (TURP syndrome)
    • Isoosmolar hyponatremia
      • High triglycerides
      • High serum protein
    • Hypoosmolar hyponatremia
      • Further investigations will be required to distinguish between water retention and sodium excretion.
  • Urinary sodium and urinary osmolality
    • Low urinary sodium: water retention disorders;
      • Polydipsia, beer potomania - low urine osmolality
      • true hypovolemia, heart failure, cirrhosis, nephrotic syndrome - high urine osmolality
    • High urinary sodium: sodium wasting disorders;
      • Acute renal failure, post-obstructive diuresis, polyuric phase of ATN - low urine osmolality
      • Thiazides, SIADH, cerebral salt wasting, hypoadrenalism, hypothyrodism - high urine osmolality

References

Question 29 - 2015, Paper 1

Regarding sodium homeostasis in critically ill patients:

a)  Outline the pathophysiological mechanisms responsible for the hyponatraemia commonly seen in hepatic and renal failure. (20% marks)

b)  List the criteria essential for diagnosis of the syndrome of inappropriate antidiuresis (SIAD). (20% marks)

c)  List 4 drugs from separate classes that may cause SIAD. (20% marks)

d)  How would you distinguish SIAD from cerebral salt wasting syndrome (CSWS)? (20% marks)

e)  List two drugs that may be useful in the management of SIAD. (20% marks)

College Answer

a)

  • Hyponatraemia in the setting of ECF volume expansion.
  • Both however have reduced effective circulating arterial volume leading to increased AVP levels. In liver disease due to systemic vasodilatation and shunting and with CHF due to impaired cardiac output.
  • There is impaired excretion of solute free water caused in part by reduced GFR and reduced delivery of ultra filtrate to the diluting site in the nephron-renin angiotensin system is activated leading to sodium retention –overall water gain exceeds sodium gain

b)

  • Effective serum osmolality< 275mOsm/kg
  • Urine inappropriately concentrated( > 100mOsm/kg) in face of hypotonic plasma
  • Euvolaemic circulation
  • Urine sodium > 30mEq/l (accept any elevated value)
  • Absence of adrenal, thyroid or pituitary disease

c)

  • Antidepressants in particular SSRIs, TCA, MAOI
  • Anticonvulsants – carbamazepine, valproate, lamotrigine
  • Oncological agents – Vinca alkaloids, Melphalan, Methotrexate, and cyclophosphamide
  • Vasopressin analogues
  • Antidiabetics – chloropromamide
  • Other – opiates, NSAID, MDMA, interferon, amidarone, proton pump blockers

d)

  • Difficult – key difference is that patients with CSWS are volume /blood volume deplete with low CVP
  • Urine volume and sodium may be higher in CSWS than SIADH
  • Serum uric acid may be lower in SIADH than CSWS but is not consistent

e)
1. Demeclocycline
2. Tolvaptan / Conivaptan

Discussion

a) A more wordy answer as to why there is hyponatremia in hepatic and renal failure (which also works to explain CHF)

  • In hepatic and renal failure, there is loss of protein (by nephrotic syndrome or by decreased synthesis)
  • With loss of serum oncotic pressure, circulating arterial volume is decreased as fluid migrates into the interstitial compartment.
  • In addition to this, in severe liver disease the apparent decrease in circulating volume is exacerbated by portosystemic shunting
  • In response to this, there is a hypersecretion of ADH, which leads to increased water retention
  • Aldosterone is also released, increasing the reabsorption of sodium at the nephron
  • In liver disease, the concentration of both hormones is raised yet further by the impairment of their hepatic metabolism
  • The urine is usually concentrated, and the urinary sodium may be low.
  • The extracellular fluid volume expands, as does the total body sodium content; but water gain exceeds sodium gain
  • With renal failure, the capacity of the nephron to excrete water and dilute urine is further impaired by the decrease in glomerular filtration rate

b) From the chapter on Syndrome of inappropriate ADH secretion (SIADH):

Diagnostic Criteria for SIADH

  • Hypoosmolar hyponatremia
  • Urine osmolality greater than plasma osmolality
  • Urine sodium excretion greater than 20mmol/L
  • Normal renal, hepatic, cardiac, pituitary, adrenal and thyroid function
  • Absence of hypotension, hypovolemia, oedema and ADH-influencing drugs
  • Hyponatremia corrects with water restriction

c) ibid.

Drugs Associated with SIADH

  • carbamazepine
  • cyclophosphamide
  • phenothiazines
  • SSRIs
  • nicotine
  • tricyclics
  • vinca alkaloids eg. vincristine
  • interferon
  • cisplatin
  • MDMA
  • amiodarone
  • ciprofloxacin
  • sodium valproate
  • NSAIDs
  • Thiazides

d) How to tell SIADH from CSW? The trick is demonstrating that the extracellular fluid volume is reduced. With a reduced volume, the elevated vasopressin level is a sensible response to dehydration, whereas with volume expansion the vasopressin level is "inappropriate". Thus, the most important diagnostic criterion discriminating between SIADH and CSW is really the assessment of hydration.

In both conditions the ADH level is elevated, but only with euvolaemia is this "inappropriate" ADH seretion (and therefore it can then be called CSW). A heretical viewpoint (in which CSW does not exist) would call this SIADH with urinary sodium loss to compensate for daily maintenance intake, which gives the impression of salt wasting. 

e)

Drugs for management of SIADH include the following options:

  • Demeclocycline (oral)
  • Tolvaptan (oral)
  • Conivaptan (IV)
  • Lithium (oral)
  • Loop diuretics (oral or IV)
  • Urea (oral)

An excellent 2012 article by Peter Gross ("Clinical management of SIADH") discusses these options with satisfying detail.

References

Palmer, Biff F. "Hyponatremia in patients with central nervous system disease: SIADH versus CSW." Trends in Endocrinology & Metabolism 14.4 (2003): 182-187.

Cerdà-Esteve M, Cuadrado-Godia E, Chillaron JJ, Pont-Sunyer C, Cucurella G, Fernández M, Goday A, Cano-Pérez JF, Rodríguez-Campello A, Roquer J Cerebral salt wasting syndrome: review. .Eur J Intern Med. 2008 Jun;19(4):249-54.

Milionis, Haralampos J., George L. Liamis, and Moses S. Elisaf. "The hyponatremic patient: a systematic approach to laboratory diagnosis."Canadian Medical Association Journal 166.8 (2002): 1056-1062.

Gross, Peter. "Clinical management of SIADH." Therapeutic advances in endocrinology and metabolism (2012): 2042018812437561.

HANTMAN, DAVID, et al. "Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: an alternative treatment to hypertonic saline." Annals of Internal Medicine 78.6 (1973): 870-875.

Decaux, Guy, et al. "Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide." New England Journal of Medicine 304.6 (1981): 329-330.

Decaux, Guy, et al. "Treatment of euvolemic hyponatremia in the intensive care unit by urea." Critical Care 14.5 (2010): R184.

Forrest Jr, John N., et al. "Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone." New England Journal of Medicine 298.4 (1978): 173-177.

White, Martin G., and Christopher D. Fetner. "Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with lithium carbonate." New England Journal of Medicine 292.8 (1975): 390-392.

Rosner, Mitchell H. "Lixivaptan: a vasopressin receptor antagonist for the treatment of hyponatremia." Kidney international 82.11 (2012): 1154-1156.

Erickson, Kevin F., Glenn M. Chertow, and Jeremy D. Goldhaber-Fiebert. "Cost-effectiveness of tolvaptan in autosomal dominant polycystic kidney disease." Annals of internal medicine 159.6 (2013): 382-389.

Question 20.4 - 2015, Paper 2

The following biochemical profile is from a 65-year-old male who has been admitted to your Intensive Care Unit with a diagnosis of pancreatitis of unknown aetiology.

Parameter

Patient Value

Normal Adult Range

Sodium

124 mmol/L*

135 – 145

Potassium

4.3 mmol/L

3.2 – 4.5

Chloride

106 mmol/L

100 – 110

Bicarbonate

23 mmol/L

22

27

Urea

15.0 mmol/L*

3.0 – 8.0

Creatinine

340

μmol/L*

70

120

Glucose

5.8 mmol/L

3.0 – 7.0

Lipase

562

IU/L*

< 220

Total Calcium

2.3 mmol/L

2.15

– 2.6

Phosphate

1.25 mmol/L

0.70

– 1.40

Albumin

26 g/L*

33

47

Globulins

35 g/L

25

45

Total Protein

61 g/L

60

83

Total Bilirubin

20 μmol/L

4 – 20

Conjugated Bilirubin

4 μmol/L

1 – 4

g-Glutamyl transferase (GGT)

6 U/L

0 – 50

Alkaline phosphatase (ALP)

100

U/L

40

110

Lactate dehydrogenase (LDH)

380

U/L*

110 – 250

Aspartate aminotransferase (AST)

210

U/L*

< 40

Alanine aminotransferase (ALT)

100

U/L*

< 40

Measured Osmolarity

290 mOsm/kg

280 – 300

What blood test would you now order?

Give your reasoning.    (30% marks)

College Answer

Lipid profile.

The patient has low serum sodium but a normal measured osmolarity and hence has pseudohyponatraemia. His glucose and protein levels are not elevated. He therefore is likely to have hypertriglyceridemia, which may be the underlying cause of his pancreatitis.

Additional Examiners’ Comments:

20.4 was the least well answered section with many candidates failing to recognise pseudohyponatraemia.

Discussion

20.4 was the "least well answered section" because it was poorly worded, not because the candidates could not recognise hyponatremia. To ask" what test would you now order" is like asking "guess what the examiner is thinking".

However, the savvy candidate would have noticed a measured osmolality being offered.

They never give you a measured osmolality unless they expect you to do something with it.

The combination of a normal-ish osmolality and hyponatremia immediately rings alarm bells. Under virtually no conditions is hyponatremia iso-osmolar; the usual pattern is for the osmolality to drop as well as the sodium. An isoosmolar hyponatremia can only be one of two things, high triglycerides or high protein. Of these, the protein is available, and is normal - ergo, triglycerides are to blame.

It might seem that the historical tidbit about pancreatitis is virtually without purpose in this context.  However, a specific literature reference for the importance of recognising pseudohyponatremia is offered in the 1985 article by Howard et al. Six cases of hyperlipaemic pancreatitis are presented. Of the six patients, one was mistakenly resuscitated with hypertonic saline, with intracerebrally disastrous consequences.

So, what is the actual sodium level? You can calculate that. Fortgens and Pillay offer the following equation to correct sodium:

\("Correct" Na^+ = {"incorrect" Na^+ \times 0.93 \over [99.1 - (0.001 \times [lipid, mg/dL) - (0.7 \times protein, g/dL)] \div 100 }\)

If one plays with this equation, one finds that the effect of lipids on serum sodium measurement is actually rather trivial. For every 10g/L of triglycerides, the sodium level decreases only by  0.84 mmol/L. Thus, in order to be hiding a truly lifethreatening hypernatremia (eg. 150mmol/L), the patient in the college's case study would have to have a serum triglyceride level of 190g/L.

In other words, each litre of blood would have to be be 20% fat by weight. According to the Guiness Book of Records, the highest serum trigluceride level recorded belonged to Terry Culton (USA), who had a triglyceride reading of 3165 mg/dl, or 31.65g/L. This is clearly not much of a record, as the commenters on that page report their own horrific lipid levels as high as 9000 mg/dL, or 90g/L - which is not quite 20% w/v, but still enough to cause a significant sodium drop.

Interestingly, it is important to note that even though the old flame photometry method was the main source of this "pseudohyponatremia" in the pre-1990s literature, m modern analysers are not completely spared.  Modern high-volume pathology labs use various variants of ion-selective electrodes in automated analysers which should theoretically be immune to this error. The “direct” method, anyway, is immune (that is where the ISE membrane comes into direct contact with whole blood, like in an ABG analyser). However, those automated machines typically use the “indirect” method (because it prolongs ISE membrane life). This involves taking the patient’s blood, centrifuging out the red cells, and then diluting the plasma (usually by a factor of 10). This is the step which introduces a dilution error. Because the sodium is confined to the water volume in the sample, any dilution by a fixed amount will decrease the measured sodium concentration.

References

LADENSON, JACK H., FRED S. APPLE, and DAVID D. KOCH. "Misleading hyponatremia due to hyperlipemia: a method-dependent error." Annals of internal medicine 95.6 (1981): 707-708.

Howard, John M., and Jordan Reed. "Pseudohyponatremia in Acute Hyperlipemic Pancreatitis: A Potential Pitfall in Therapy." Archives of Surgery 120.9 (1985): 1053-1055.

Fortgens, Philip, and Tahir S. Pillay. "Pseudohyponatremia revisited: a modern-day pitfall." Archives of pathology & laboratory medicine 135.4 (2011): 516-519.

Question 24 - 2016, Paper 1

With respect to hyponatraemia:

a) Outline the classification and underlying causes. (50% marks)

a) Outline the specific treatment of severe hyponatraemia (i.e. sodium level < 120 mmol/L and/or associated with significant adverse symptoms). (50% marks)

College Answer

a)

Classify hyponatraemia:

  • Hypertonic
  • Isotonic
  • Hypotonic

Further subdivide hypotonic:

  • Hypervolaemic
  • Euvolaemic
  • Hypovolaemic

Serum Na+ < 135 mmol/L

What is serum osmolality?

Low (< 285 mOsm/kg)

Normal (285 – 295 mOsm/kg)

High (> 295 mOsm/kg)

Pseudohyponatraemia

Hyperlipidaemia

Hyperproteinaemia

Hyperglycaemia

Hypertonic infusions

Mannitol

Glucose

What is volume status?

What is urinary [Na+]?

< 20 mmol/L

> 20 mmol/L

Hypovolaemic

Vomiting

Diarrhoea

Skin losses 

excess sweating 3rd space losses  Burns

Pancreatitis

Obstruction

Diuretics

Renal tubular acidosis

Adrenal insufficiency

Normovolaemic

Water intoxication

Decreased solute intake

Renal failure

Hypothyroidism

Adrenal insufficiency

SIADH

Cerebral salt wasting

Hypervolaemic

Cirrhosis

Heart failure

Nephrotic syndrome

Acute renal failure Chronic renal failure

b)

Management is divided into 

  • Emergency and short term sodium elevation
  • Specific treatment of the underlying cause

Emergency treatment of sodium level

If the patient is symptomatic, then the serum sodium level needs to be urgently elevated by approximately 2- 4% e.g. 2.5 – 5 mmol/L (these are rough figures).

This is done by giving a specific sodium dose, which is usually in the form of hypertonic saline (e.g. 3%) to avoid any more excess water, over a brief period e.g. 30 minutes.

It is calculated by the following formula.

Sodium dose = Total body water x desired change in sodium level

For example in a 70 kg man, a total of 200 ml of 3% saline will raise the serum sodium by 2.5 mmol/L

Short-term sodium management

Once symptoms have resolved, the aim is to correct the sodium level by roughly 0.5 – 1.0 mmol/L per hour over the next 24 hours. And how this is done depends on the underlying cause.

Specific treatment of underlying cause:

  • Fluid restriction for water intoxication / SIADH
  • Fluid restriction for cardiac / liver failure
  • Fluid rehydration with appropriate fluids for vomiting / diarrhoea
  • Aggressive fluid resuscitation for significant fluid losses e.g. pancreatitis or burns
  • Stopping of offending medications e.g. diuretics
  • Thyroid replacement for hypothyroidism
  • Steroids for adrenal insufficiency
  • Arginine vasopressin receptor antagonists (e.g. conivaptan)

Discussion

a)

Mindlessly regurgitate the hyponatremia algorithm? Don't mind if I do. This is the "classical" approach:

The "classical" diagnostic algorithm for hyponatremia

In word form:

  • Causes of hyper-osmolar hyponatremia
  • Causes of iso-osmolar hyponatremia
  • Causes of hypo-osmolar hyponatremia:
    • With hypervolemia:
      • Congestive heart failure
      • Cirrhosis
      • Nephrotic syndrome
      • Acute renal failure
      • Chronic renal failure
    • With hypovolemia:
      • Hypovolemia
      • Diarrhoea
      • Vomiting
      • Sweating
      • Blood loss
      • Burns
      • Pancreatitis
      • Diuretics, eg. thiazides
      • Hypoaldosteronism (and spironolactone)
      • Renal tubular acidosis
      • Cerebral salt wasting
      • Osmotic diuresis
      • Ketonuria
      • Bicarbonate wasting in metabolic alkalosis
    • With euvolemia:
      • Psychogenic polydipsia
      • Beer potomania
      • Hypothyroidism
      • Hypoadrenalism
      • Glucocorticoid deficiency
      • SIADH

b)

In the management of severe (symptomatic) hyponatremia, the college were clearly after some sort of hypertonic saline protocol. The fact that the hyponatremia is being described as "severe" and "symptomatic" suggests that simple fluid restriction was not going to cut it. However, the alternative smust be mentioned. Thus:

  • Hypervolemic and euvolemic hyponatremia should be managed with fluid restriction
  • Hypovolemic hyponatremia must be managed with isotonic saline replacement
  • Hypertonic saline:
    • calculate the deficit:
      Sodium deficit = 0.6 ×body weight × (desired Na+ - current Na+)
    • Correct the deficit at a rate of change no more than 0.5mmol/L/hr.
  • Other strategies:
    • Loop diuretics
    • Hydrocortisone or fludrocortisone
    • SIADH-specific therapy:
      • Demeclocycline (oral)
      • Tolvaptan or satavaptan (oral)
      • Conivaptan (IV)
      • Lithium (oral)
      • Urea (oral)

Where it comes to a discussion of hyptertonic saline, the college recommend rapid corection of symptomatic hyponatremia, which is followed by slow correction of asymptomatic hyponatremia. This is consistent with the recent European guidelines (Spasovski et al, 2014). The guideline development group felt that the risk of brain oedema outweighs the risk of osmotic demyelination syndrome. Specifically, they recommend the infusion of 150ml of 3% saline over 20 minutes, then checking the sodium, and then repeating the infusion.

References

Spasovski, Goce, et al. "Clinical practice guideline on diagnosis and treatment of hyponatraemia." European Journal of Endocrinology 170.3 (2014): G1-G47.

David M., Arnold S. Berns, and Anthony D. Ivankovich. "Isotonic hyponatremia following transurethral prostate resection." Journal of clinical anesthesia 2.1 (1990): 48-53.

Question 13.2 - 2016, Paper 2

A 52-year-old male with a history of chronic alcohol abuse was brought to the Emergency Department with a reported change in his mental state for 3 - 4 days. He was drowsy and lethargic but communicated appropriately when roused. He did not appear dehydrated . The following are his blood results on presentation:

Parameter

Patient Value

Normal Adult Range

Sodium

116 mmol/L*

135 - 145

Potassium

2.9 mmol/L*

3.5 - 5.0

Chloride

67 mmol/L*

95 - 110

Bicarbonate

14 mmol/L*

22 - 32

Urea

2.9 mmol/L*

3.0 - 8.0

Creatinine

46 umol/L

45 - 90

Glucose

6.8 mmol/L

3.5 - 7.8

Phosphate

0.60 mmol/L*

0.65 - 1.45

Maqnesium

0.51 mmol/L*

0.70 - 1.05

Calcium adjusted

2.31 mmol/L

2.10 - 2.60

Albumin

34 q/L*

36 - 52

Bilirubin total

13 umol/L

< 18

Alanine aminotransferase

67 U/L*

< 35

Asoartate transaminase

80 U/L*

< 40

Alkaline phosphatase

148 U/L*

30 - 110

y-Glutamyl transferase

480 U/L*

< 40

Lipase

492 U/L*

< 95

Amylase

189 U/L*

< 130

Free T4

14.2 omol/L

12.0 - 31.0

Thyroid stimulatinq hormone

0.65 mU/L

0.50 - 5.00

Cortisol

1440 nmol/L*

150 - 700

B-Hvdroxvbutyrate

4.4 mmol/L*

< 0.4

Osmolality

254 mOsm/L*

275 - 295

Urine Chemistrv

Sodium

< 20 mmol/L

Potassium

37 mmol/L

Osmolality

198 mOsm/L

a) Give the likely diagnosis with the rationale for your decision. (25% marks)

b) Briefly outline your management of the hyponatraemia in this patient. (20% marks)

College answer

a) Beer potomania (alcoholic intoxication / ketoacidosis acceptable) 
History 
Abnormal LFTs with predominantly raised GGT 
Acidosis with elevated BOHB with normal glucose Low urine osmolality 
Normal endocrine profile 

 b) Likely chronic hyponatraemia so replace slowly < 10 mmol/24 hrs Stop non-essential fluids 
    At risk of seizures from alcohol withdrawal                
 

Discussion

Let us analyse the results in some detail.

This guy is a drinker, and his GGT is elevated, so... he has been drinking. 

After a few days of decreased level of consciousness he is not dehydrated, so ... he has been drinking a lot.

The bloods demonstrate hypoosmolar hyponatremia with a low usine osmolality and a low urine sodium. There are only a few conditions which can give rise to this:

  • Beer potomania
  • Psychogenic polydipsia
  • Excess 5% dextrose administration (psychogenic polydipsia by proxy, you might say)

Beer potomania is a case of dietary solute deficiency. Your water intake is excessive, but you eat virtually nothing containing salt. Lets say you are a degenerate beer-fiend, and your total nutritional intake consists of carbohydrate-rich, sodium-poor beer. Vast volumes are happily ingested. The carbohydrate from the beer is metabolised preferentially, leading to a suppression of protein catabolism. Low protein catabolism results in low urea levels, and with the sodium dropping, what solute can you excrete? None. The volume of urine drops. Each day you will excrete as little as 4 litres of maximally dilute urine. Obviously if you drink more than 4 litres of beer a day, hyponatremia will ensue. This phenomenon is not limited to American college students; ovolactovegetarians and people trying to lose weight too fast are also susceptible.

References

Hariprasad MK, Eisinger RP, Nadler IM, Padmanabhan CS, Nidus BD. Hyponatremia in psychogenic polydipsia. Arch Intern Med. 1980 Dec;140(12):1639-42.

Hilden T, Svendsen TL. Electrolyte disturbances in beer drinkers. A specific "hypo-osmolality syndrome". Lancet. 1975 Aug 9;2(7928):245-6.

Thaler SM, Teitelbaum I, Berl T. "Beer potomania" in non-beer drinkers: effect of low dietary solute intake. Am J Kidney Dis. 1998 Jun;31(6):1028-31.

Fox BD.Crash diet potomania. Lancet. 2002 Mar 16;359(9310):942.

Question 20.1 - 2017, Paper 1

The following venous blood results are from a 56-year-old patient presenting with abdominal pain.

Parameter

Patient Value

Adult Normal Range

Sodium

130 mmol/L'

135 - 145

Potassium

5.1mmol/L

3.5 - 5.0

Chloride

101 mmol/L

95 - 105

Bicarbonate

10 mmol/L

22 - 28

Creatinine

305 umol/L

50 - 100

Urea

75.6 mmol/L*

3.5 - 7.2

Glucose

5.2 mmol/L

3.5 - 6.0

Calcium corrected

2.05 mmol/L*

2.12 -2.62

Ionized Calcium

0.97 mmol/L*

1.14 -1.30

Phosphate

3.97 mmol/L*

0.73 - 1.37

Protein

66 g/L    -

61 - 83

Albumin

29 g/L*

35 - 50

Alkaline phosphatase

220 U/L•

30 - 110

y-Glutamyl transferase

30 U/L

< 40

Alanine transferase

27 U/L

< 35

Magnesium

0.83 mmol/L

0.75 -0.95

Interpret the biochemical results, giving underlying reasons to explain the abnormalities. 
(40% marks)

College answer

• Chronic renal failure with secondary hyperparathyroidism

• Elevated urea and creatinine  

• Decreased calcium, raised ALP and phosphate

• Dehydration or GI bleed

• Raised U:Cr  

• Mixed HAGMA and NAGMA

• Low HCO3 and delta ratio >1

• Chronic renal failure (uraemia and RTA)

• Acute on chronic renal failure (sepsis, dehydration, GI bleed etc.) 
 
(Other reasonable explanations were accepted.) 

Discussion

Let us dissect these results systematically:

  1. There is no gas exchange parameters, and we can make no comment about compensation.
  2. The bicarbonate is low, suggesting metabolic acidosis.
  3. The anion gap is raised (130+5.1 - 101 - 10 = 24.1); the expected gap is around 9.5 (given that the albumin is 29)
  4. The delta ratio is very near to 1.0, suggesting that this is a pure high anion gap metabolic acidosis. This can be accounted for by the presence of lactate and non-volatile acids of renal failure (sulfate, phosphate, urate)
  5. The creatinine and urea are raised, with a very high urea but only a moderately raised creatinine, suggesting that there is either significant dehydration or a prolonged period of subnormal renal function (giving time for the urea to accumulate).
  6. The phosphate is raised (likely as a result of renal failure). The other potential reasons for a raised phosphate may include rhabdomyolysis or other causes of large-scale cell death, eg.  hepatic necrosis. In this case the latter is unlikely because of relatively normal LFTs.
  7. The total and ionised calcium are low, which is likely to be the consequence of hyperphosphataemia.
  8. Alkaline phpsphatase is raised, suggesting there is some bone destruction taking place, which may be the result of secondary hyperparathyroidism. This gives the impresison of chronicity; i.e. the renal failure is at least of subacute onset.

The college do not ask for a diagnosis.

References

Question 5 - 2017, Paper 2

With respect to the use of hypertonic saline (HTS} in the critically ill, list the indications, mechanisms of action and outline the supporting evidence as well as the potential adverse effects.

College answer

The main indications for the use of hypertonic saline in the critically ill are: 
 
Osmotherapy to manage intracranial hypertension  
Correction of (symptomatic) hyponatraemia. 
Fluid resuscitation in hypovolaemic shock (uncommon) 
Burns resuscitation 
Has been used in tricyclic poisoning 
Mucolytic in nebulized form – e.g. for cystic fibrosis, induced sputum sample, used in bronchiolitis with positive trial evidence 
 
The range of concentrations of HTS used clinically varies from 1.8 – 30%.  Needs to be given via central venous access 
 
Mechanisms of action 
•    Marked osmotic shift of fluid from the intracellular to the interstitial and intravascular space.  
•    Reverses the increase in endothelial cell volume in shock and ischaemia, limiting capillary leak.  
•    Plasma viscosity is reduced by increased water content improving blood flow.  
•    Hypertonicity has a direct relaxant effect on vascular smooth muscle. End result is increased capillary blood flow. This may help counteract vasospasm in SAH.  
•    HTS induced increase in intravascular volume leads to an autoregulatory reduction in intracerebral blood volume. 
•    Increased cardiac output – increased preload, reduced PVR and SVR and reduced myocyte oedema. 
•    Immuno-modulatory effects and reduction of intestinal apoptosis in haemorrhagic shock 
 
Potential adverse effects 
Hypernatraemia 
Acute hyperosmolar state 
•    Osmotic demyelination syndrome 
•    Acute heart failure 
•    Pulmonary oedema 
•    Hyperchloraemic acidosis 
•    Hyperosmolar renal failure 
•    Dilutional coagulopathy 
 
Theoretical risks 
•    Increased rate of blood loss secondary to rapid volume expansion  
•    Reverse osmosis phenomenon in disrupted blood brain barrier with worsening cerebral oedema 
•    Severely dehydrated risk of worsening cellular dehydration 
•    Acute cerebral dehydration potentially result in shearing on bridging vessels and SAH 
 
Most of these risks are theoretical or can be avoided by careful use in patients with hyponatraemia and monitoring  
 
Evidence supporting use of HTS 
 
Fluid resuscitation 
Studies evaluating HTS in resuscitation in various shock states have shown benefit in outcomes including blood pressure, fluid balance and mortality. Comparison is difficult as different concentrations of HTS used, different case mix and other methodological issues. 
Concerns about potential of HTS to increase bleeding have not been proven. 
Overall HTS seems effective in increasing blood pressure in haemorrhagic shock. Its use in other forms of shock is not so well supported. 
 
Osmotherapy to control ICH 
Studies have evaluated HTS in traumatic brain injury and subarachnoid haemorrhage and used as either 7.5% boluses or 3% continuous infusions and HTS appears to be effective in reducing ICP. No evidence to suggest a better neurological outcome or survival benefit. 
 
Summary of clinical use 
 
Note: This template was long and complex and candidates were not expected to cover all the points in order to pass. 

Discussion

The potential adverse effects of hypertonic saline are common to all (or, most) of its various uses. These are listed in a nice review of 3% saline among neuroICU patients where a nice table (Table 1) lists the potential adverse effects of hypertonic saline administration. I will reproduce the relevant parts of this table below.

  • Hyperosmolarity
  • Overshoot hypernatremia
  • Congestive heart failure and pulmonary oedema
  • Hypokalemia
  • Normal anion gap metabolic acidosis
  • Coagulopathy
  • Phlebitis (hypertonic saline is a sclerosant)
  • Renal failure (due to vasoconstriction)
  • Decreased level of consciousness
  • Rebound intracranial hypertension
  • Seizures
  • Central pontine myelinolysis
  • Subdural and intraparenchymal hemorrhage

As for the indications mechanisms and evidence, this answer would certainly work well as a table, if only there were fewer columns. Fortunately, with the right monitor DerangedPhysiology is 1200 pixels wide. 

The Various Uses of Hypertonic Saline
Mechanism Evidence Advantages and disadvantages
As sodium replacement, for hyponatremia:

Replacement of the missing ion

The recent overview of published guidelines by Verbalis et al (2014) covers the recommendations for the use of hypertonic saline in symptomatic hyponatremia.

Ideal when fluid restriction is needed, eg. in SIADH.

Not ideal in situations where hypovolemia accompanies hyponatremia, i.e. when volume as well as sodium need to be replaced. 

As osmotherapy, for raised ICP:
Osmotic dehydration of brain tissue

The (2016)  publication of the BTF Guidelines was  unable to make a firm recommendation in favour of hypertonic saline.

A reasonably recent review (Lazarides et al, 2013) found a small statistically significant benefit for its use, as compared to mannitol.

Cheap, stable in storage, very rapid effect.

At least as potent as mannitol when it comes to reducing ICP

Less potential for hypovolemia than with mannitol

Safe endpoint (serum sodium around 145-155) is easily monitored with serial ABGs.

Needs central venous access, and should not be used if the patient is chronically hyponatremic

As a resuscitation fluid for shock:
Increased preload, some vasoactive properties 

Poor quality data in support (Oliveira et al , 2002)

No benefit in sepsis
(Ashfar et al, 2017)

Poor quality data and no benefit in trauma (de Crescenzo et al, 2017)

Smaller volume means less haemodilution (in trauma for example)

Small volume also means a more neutral fluid balance

All the haemodynamic and immunomodulatory benefits should also be helpful

For management of tissue oedema:
Improved diuresis

Paterna et al (2011) found some benefit in CCF patients.

Evidence is inconsistent and based on small scale studies.

Improved fluid balance

Potentially, better cardiac function 

May be frustrated by activation of the RAAS.

For cystic fibrosis, as an expectorant and mucolytic:
Multiple mechanisms 

Osmotic hydration of the mucus layer (i.e. attracting water into it) and disruption of mucus proteins.

Recommended for CF patients who can tolerate it (Elkins and Bye 2011)

Not very well investigated in other groups, eg. COPD

It's irritant, which the patients will not appreciate; but this promotes cough and improves secretion clearance

Routine frequent use may result in systemic absorption of sodium and chloride, which might not be desirable.

References

Lazaridis, Christos, et al. "High-Osmolarity Saline in Neurocritical Care: Systematic Review and Meta-Analysis*." Critical care medicine 41.5 (2013): 1353-1360.

Strandvik, G. F. "Hypertonic saline in critical care: a review of the literature and guidelines for use in hypotensive states and raised intracranial pressure." Anaesthesia 64.9 (2009): 990-1003.

Holmes, J. A. "Therapeutic Uses Of Hypertonic Saline In The Critically Ill Emergency Department Patient." EM Critical Care 3.1 (2013).

Oliveira, Roselaine P., et al. "Clinical review: Hypertonic saline resuscitation in sepsis." Critical care 6.5 (2002): 418.

Asfar, Pierre, et al. "Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial." The Lancet Respiratory Medicine 5.3 (2017): 180-190.

Pfortmueller, Carmen Andrea, and Joerg C. Schefold. "Hypertonic saline in critical illness-A systematic review." Journal of Critical Care 42 (2017): 168-177.

Paterna, Salvatore, et al. "Short-term effects of hypertonic saline solution in acute heart failure and long-term effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III (Class C)(SMAC-HF Study)." The American journal of the medical sciences 342.1 (2011): 27-37.

De Crescenzo, Claire, et al. "Prehospital hypertonic fluid resuscitation for trauma patients: A systematic review and meta-analysis." Journal of Trauma and Acute Care Surgery 82.5 (2017): 956-962.

Gunn, Mark L., et al. "Prospective, randomized trial of hypertonic sodium lactate versus lactated Ringer's solution for burn shock resuscitation.Journal of Trauma and Acute Care Surgery 29.9 (1989): 1261-1267.

Elkins, Mark R., and Peter TP Bye. "Mechanisms and applications of hypertonic saline." Journal of the Royal Society of Medicine104.1_suppl (2011): 2-5.

Question 5.2 - 2018, Paper 1

A 47-year-old, previously well, 70 kg male was admitted to the Emergency Department with agitation and confusion. Following catheterisation, his urine output in the next few hours was 300 — 350 ml/hr. The results of his blood tests are as follows:

Parameter

Patient Value

Adult Normal Range

Sodium

169 mmol/L*

135 - 145

Potassium 

4.6 mmol/L

105 mmol/L

Chloride

95 - 105

Bicarbonate

26.0 mmol/L

22.0 - 26.0

Glucose 

6.6 mmoI/L*

Urea

9.6 mmol/L*  

Creatinine

115 prnoI/L*

45 — 90

Magnesium

0.88 mmol/L

0.75 - 0.95

Albumin

28 g/L*

35 - 50

Protein

58 g/L*

60 - 80

Plasma osmolality

360 mmol/kg*

290 - 310

Urine specific gravity

1.005*

1 .010 - 1.030

a) What is the most likely diagnosis?           (10% marks)

b) How would you manage the hypernatremia?        (30% marks)

College answer

a)

Diabetes Insipidus

b)

  • Examination to assess fluid status, Cardiac status 
  • Specific therapy -  o 5%Dextrose or Sterile water administration with hourly Sodium Measurement- calculate water deficit and correct over time frame
    • Stop offending medications. If history of Lithium Intake-Lithium Levels 
    • Desmopressin or vasopressin 
    • Thiazides/Amiloride/Acetazolamide (if lithium)
    • Avoid rapid correction

Examiner Comments:

Management of diabetes insipidus was handled poorly, as some of the described fluid regimes were considered dangerous

Discussion

The major abnormalities are:

  • Hypernatremia
  • Hyperosmolarity with no osmolar gap 
  • Low albumin
  • Near maximally dilute urine

This is clearly diabetes insipidus. The urine findings and and the low osmolar gap rule out the interference of things like mannitol.

Management of diabetes insipidus consists of two major strategies:

1) Correct the water balance.

  • Calculate the water deficit:  total body water × (1- [140 ÷ serum sodium])
    In this guy's case, they gave you his weight (70kg). That gives him a total body water of 42L. Thus, he needs approximately 7.14 L of water.
  • Water should be corrrected as isotonic dextrose, but can also be given as pure water via the NG (infusion of sterile water is generally not done).

2) Interrupt the pathophysiology

  • If there is an obvious drug--related cause, stop the drugs (eg. the lithium suggested by the college. Then, either replace the ADH or stimulate its secretion:
    • Antidiuretic hormone analogues:
      • Arginine vasopressin
      • Desmopressin (DDAVP)
    • Antidiuretic hormone release stimulating drugs
      • Clofibrate
      • Clorpropamide
    • In case of nephrogenic DI:

References

Singer, Irwin, James R. Oster, and Lawrence M. Fishman. "The management of diabetes insipidus in adults." Archives of internal medicine 157.12 (1997): 1293-1301.

Libber, Samuel, Harold Harrison, and David Spector. "Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors." The Journal of pediatrics108.2 (1986): 305-311.

Knoers, N., and L. A. H. Monnens. "Amiloride-hydrochlorothiazide versus indomethacin-hydrochlorothiazide in the treatment of nephrogenic diabetes insipidus." The Journal of pediatrics 117.3 (1990): 499-502.

Question 7.2 - 2018, Paper 2

A 44-year-old patient is admitted post thyroidectomy for Graves’ disease. Seven years ago, she had gastric bypass surgery for obesity. Shortly after admission, her serum biochemical findings are:

Parameter

Patient Value

Adult Normal Range

Sodium 

136 mmol/L

135 – 145

Potassium  

5.0 mmol/L

3.5 – 5.0

Chloride 

103 mmol/L

95 – 105

Bicarbonate 

23.0 mmol/L

22.0 – 26.0 

Glucose 

5.8 mmol/L

3.5 – 6.0

Urea 

5.5 mmol/L

3.0 – 8.0

Creatinine  

80 μmol/L

45 – 90 

Magnesium

0.60 mmol/L*

0.75 – 0.95

Albumin 

35 g/L

35 – 50 

Protein 

74 g/L

60 – 80

Total bilirubin 

12 μmol/L

< 26

Aspartate aminotransferase (AST) 

34 U/L

< 35

Alanine aminotransferase (ALT)

40 U/L*

< 35

Alkaline phosphatase (ALP)

188 U/L*

30 – 110

γ-Glutamyl transferase (GGT)

45 U/L*

< 40

Calcium corrected 

1.80 mmol/L*

2.12 – 2.62

Phosphate 

0.7 mmol/L*

0.8 – 1.5

  1. Give two potential explanations for the abnormalities seen.               (10% marks)
  2. What clinical features might be associated with these abnormalities?       (20% marks)
  3. Outline your management.                                                              (40% marks)

College answer

a) Give two potential explanations for the abnormalities seen. 
Vit. D deficiency 
Hypoparathyroidism 
 
b) What clinical features might be associated with these abnormalities  

Hypocalcaemia is classically associated with 
Paraesthesias in perioral and acral areas 
Chvostek and Trosseau’s signs 
Muscle cramps, laryngeal spasm 
Irritability, confusion, seizures 
Prolonged QT, arrhythmias 
 
Hypomagnesaemia – some of above, also muscle weakness 
Hypophosphatemia – mild, unlikely to be associated with clinical features 
 
c) Briefly describe how you will manage this condition                     

IV Cal chloride or gluconate, IV Magnesium PO4 replacement 
Monitor ionised Ca level, if available. Check ECG for prolonged QT 
Avoid alkalosis – as it worsens neuromuscular irritability 
Oral Vitamin D3 (cholecalciferol) as soon as oral intake is allowed 
Oral Cal supplement (up to 1.5 – 2.0 grams/day) – preferable as Ca citrate Not Ca carbonate Oral Magnesium supplements 
If recalcitrant hypoCa, consider s/c parathyroid hormone (confirm adequate vit D level)

Check TFT, TSH – replacement T4 as needed. 

Discussion

Unlike a normal data interpretation question which asks the candidate to mindlessly produce a shopping list of abnormalities, this one expects a little more. The shopping list and salient features from the question are:

  • Post-thyroidectomy
  • Gastric bypass (thus, possible malabsorption)
  • Low magnesium, calcium and phosphate
  • Raised alkaline phosphatase, suggestive of increased bone turnover

The thyroidectomy story raises the possibility of hypoparathyroidism, which is an easy mark. To produce another differential, one might need to think somewhat laterally.  Possibilities relevant to this case might include:

  • Hypomagnesemia (after all, it is low)
  • Vitamin D deficiency due to malabsorption

More remote possibilities may include:

  • Consumption by osteoclastic bone metastases (alk phos)
  • Consumption of calcium by coagulopathy (from a massive transfusion? thyroidectomy can be a bloody surgery)

Clinical features, they ask?

Clinical Manifestations of Hypocalcemia

Mild hypocalcemia

  • Generalised myalgia
  • Twitching, fasciculations
  • QT prolongation
  • Chvostek’s sign
  • Confusion, delirium, psychosis

Severe hypocalcemia

  • Carpopedal spasm (Trousseau’s sign)
  • Tetany and seizures
  • Papilloedema, raised intracranial pressure
  • Cardiac arrhythmias, esp. Torsades
  • Hypotension

Clinical Features of Hypomagnesemia

Symptoms

Physical signs

  • Confusion
  • Delirium
  • Tremors
  • Seizures
  • Tachyarrhythmias (particularly VT and VF)
  • Tetany
  • Chvostek sign
  • Trousseau sign

ECG changes

  • Widening QRS complexes
  • Peaking T-waves (which vanish in very severe hypomagnesemia)
  • Prolonged PR interval

Associated biochemical abnormalities

  • Hypokalemia, refractory to replacement
  • Hypocalcemia
  • Low parathyroid hormone levels (in spite of hypocalcemia)
  • Low Vitamin D levels
Clinical Features of Hypophosphataemia

Neurological manifestations

  • Irritability
  • Hallucinations
  • Delirium
  • Seizures
  • Coma
  • Increased risk of osmotic demyelination

Cardiovascular manifestations

  • Impaired cardiac contractility, cardiomyopathy
  • Propensity towards arrhythmias

Biochemical abnormalities

  • Hypercalciuria
  • Increased bone resorption
  • Increased calcitriol (1,25-dihydroxyvitamin D)

Musculoskeletal manifestations

  • Weakness
  • Proximal myopathy
  • Dysphagia
  • Ileus
  • Slowed ventilator weaning
  • Rhabdomyolysis
  • Osteopenia and rickets (long term)

Haematological abnormalities

  • Decreased red cell 2,3-DPG levels (a left shift)
  • Increased RBC rigidity, and propensity to haemolysis
  • Impaired clot retraction
  • Leukocyte dysfunction
  • Thrombocytopenia

Management of hypocalcemia might seem as straightforward as replacing the calcium, but the college examiners make the fair point that this process can be more involved and occasionally requires extra thinking. A structured approach might resemble the following, which was borrowed from an excellent article by  Cooper and Gittoes (2008):

Acute replacement

  • IV replacement of calcium salt
  • Calcium chloride or gluconate, doesn't matter
  • Ensure magnesium and phosphate are replaced at the same time 

Medium term replacement

  • Oral calcium replacement
    • The college specifically recommend calcium citrate, "Not Ca carbonate",   in spite of the fact that the citrate appears to have lower oral bioavailability (Wang et al, 2014). According to UpToDate, both choices are available in exactly the same dose of elemental calcium. One possible reason for this (otherwise unexplainable) preference is the need for normal gastric pH to dissolve calcium carbonate tables, i.e. it is to be taken with food whereas calcium citrate is more suitable to an otherwise fasted post-operative patient. 
  • Vitamin D replacement
  • With intact parathyroid function:
    • Cholecalciferol (which is then converted to calcitriol in the kidney, provided parathyroid function is normal)
  • With impaired parathyroid function:
    •  Calcitriol, the hormonally active version of Vitamin D (without PTH around the oral cholecalciferol supplements will not be effective)
  • Both drugs will have positive effects:
    • Improve gut absorption
    • Improve release of calcium from bone
    • Decrease renal excretion

So, what might one do if in spite of ongoing calcium infusion the ionised calcium keeps dropping? That would probably be the "recalcitrant hypoCa" described by the examiners, who were presumably too busy to type "hypocalcemia" for the purposes of this model answer. "Recalcitrant hypoCa" is actually a real phenomenon which tends to occur in patients who have previously had gastric bypass procedures (Moore et al, 2013), as the patient in this question has done. It has no scientific definition, but some authors (eg. Ballal et al, 2017) seem to characterise it as a hypocalcemia which fails to respond to either vitamin D supplementation or intravenous calcium. Therre arre some treatment options open to these people:

  • Thiazide diuretics (which increase the renal reabsorption of calcium)
  • recombinant PTH 

References

Cooper, Mark S., and Neil JL Gittoes. "Diagnosis and management of hypocalcaemia." BMJ 336.7656 (2008): 1298-1302.

Wang, Haiyuan, Peter Bua, and Jillian Capodice. "A comparative study of calcium absorption following a single serving administration of calcium carbonate powder versus calcium citrate tablets in healthy premenopausal women." Food & nutrition research 58.1 (2014): 23229.

McKenzie, Travis J., et al. "Recalcitrant hypocalcemia after thyroidectomy in patients with previous Roux-en-Y gastric bypass." Surgery 154.6 (2013): 1300-1306.

Ballal, Devesh Sanjeev, et al. "Persistent recalcitrant hypocalcemia following total thyroidectomy: a management challenge." Malta Medical Journal 29.02 (2017).

Question 9.2 - 2019, Paper 1

A 69-year-old male with a history of previous pneumonectomy for lung carcinoma, is admitted with confusion. There are no focal neurological signs on clinical examination. Neck stiffness is not present. Contrast CT brain scan is normal. His initial plasma biochemistry is shown below:

Parameter

Patient Value

Adult Normal Range

Na+

148 mmol/L*

134 – 145

K+

3.7 mmol/L

3.5 – 5.0

Cl-

109 mmol/L*

97 – 107

HCO3-

33 mmol/L

24 – 34

Albumin

15 g/L*

35 – 40

Urea

12.8 mmol/L*

3.1 – 8.1

Creatinine

36 µmol/L*

60 – 100

Total calcium

2.59 mmol/L*

2.20 – 2.55

Phosphate

0.86 mmol/L

0.78 – 1.05

a)    What is the most likely cause of the confusion in this patent, based on the above information? Justify your response.    (10% marks)

b)    List four therapies for the cause stated in a).    (20% marks)
 

College answer

a)    Hypercalcemia (When corrected for albumin the true calcium is higher).

b)    Calciuresis (saline +/- frusemide)
•    Bisphosphonates
•    Calcitonin
•    Corticosteroids
•    NSAIDS
•    Mithramycin
 

Discussion

a)

To use a formula  first described by Payne et al (1973):

Corrected calcium = (0.02 × (normal albumin - patient's albumin)) + serum calcium

Thus, (0.02 × (40 - 15)) + 2.59 = 3.09mmol/L.

However, one needs to seriously question this value, and the use of the term "true calcium" to describe it. This 3.09 mmol/L is not the One True Calcium. The patient's actual serum calcium level is still the one reported in the blood results; it's not as if hypoalbuminaemia causes your blood sample to magically hide 0.50 mmol/L of calcium, and only to reveal them when the intensivist chants the appropriate incantations. The calcium value corrected for low albumin is a mathematical workaround from an era when calcium ion-selective electrodes were not widely available. Payne's formula calculates the calcium level your patient would have if their albumin were normal, so you can decide whether their ionised calcium might be high. Again, this is not a "true" calcium by any means. The patient's blood does not actually contain this much calcium. A much better calculation would have been to use an equation such as the ones tested by Mateu-de Antonio (2016), which use albumin and total calcium measurements to predict the ionised calcium value:

Ca2+ =  0.813 × CaTot0.5 - 0.006 × Alb0.75 + 0.079

(where albumin is represented in g/L).
Thus, in this case, ionised calcium would be (0.813 × 2.590.5 - 0.006 × 150.75 + 0.079) = 1.34 mmol/L, which is a mild hypercalcemia- elevated but potentially asymptomatic.

b)

In brief, these are the physiological aims for management of hypercalcemia, and the means to achieve them:

  • Dilute serum calcium
    • Rehydration with IV fluids
  • Decrease calcium resportion from bone
    • Calcitonin
    • Bisphosphonates
    • Gallium nitrate
    • Mithramycin (for malignant disease)
  • Decrease calcium resportion from renal tubule
    • Loop diuretics (this has fallen out of favour)
    • Calcitonin
  • Decrease calcium absorption from the gut
    • Corticosteroids (also they decrease the 1,25-dihydroxyvitamin D production by monocytes within granulomae)
  • Forcibly remove excess calcium from the circulation
    • Haemodialysis
    • EDTA administration (as chelating agent)

References

Mateu-de Antonio, Javier. "New predictive equations for serum ionized calcium in hospitalized patients." Medical Principles and Practice 25.3 (2016): 219-226.

Payne, R. B., et al. "Interpretation of serum calcium in patients with abnormal serum proteins." British medical journal 4.5893 (1973): 643.

Stewart, Andrew F. "Hypercalcemia associated with cancer." New England Journal of Medicine 352.4 (2005): 373-379.

Zawada Jr, E. T., D. B. Lee, and C. R. Kleeman. "Causes of hypercalcemia."Postgraduate medicine 66.4 (1979): 91-7.

Question 9.3 - 2019, Paper 1

A 55-year-old male with a history of significant alcohol intake presents with a 2-week history of lethargy. He takes no regular medications and has no other medical disorders. Clinically, he appears malnourished and euvolaemic. Investigations reveal the following:

Parameter

Patient Value

Adult Normal Range

Blood Results:

Na+

115 mmol/L*

134 – 143

K+

3.7 mmol/L

3.5 – 5.0

Cl-

80 mmol/L*

97 – 107

HCO3-

22 mmol/L*

24 – 34

Urea

3.0 mmol/L*

3.1 – 8.1

Creatinine

46 µmol/L*

50 – 90

Glucose

4.1 mmol/L*

4.4 – 6.8

Osmolality

241 mmol/kg*

271 – 289

Urine Results:

Na+

10 mmol/L

10 – 20

Osmolality

53 mmol/kg

40 – 1200

a)  What is the most likely cause of the hyponatraemia?                                       (15% marks)

College answer

a) Water intoxication/Beer potomania 

Discussion

Key features here are "degenerate alcoholic"  "malnutrition" and "euvolaemia". The undoubtedly vast intake of alcohol consists of essentially just water, as the alcohol is readily metabolised into CO2 and H2O.  The resulting water excess produces a hypoosmolar hyponatremia which remains euvolemic for as long as the drinking continues. The low urine sodium and minimal urinary osmolality (the lowest value possible is around 40 mmol/kg) suggests that the kidneys are responsibly retaining sodium and doing their best to dump water.

Apart from beer potomania and psychogenic polydipsia, this sort of thing can develop in case of a reset osmostat (eg. in old age), during pregnancy, and in people who embark upon weird crash diets.

References

Hariprasad MK, Eisinger RP, Nadler IM, Padmanabhan CS, Nidus BD. Hyponatremia in psychogenic polydipsia. Arch Intern Med. 1980 Dec;140(12):1639-42.

Hilden T, Svendsen TL. Electrolyte disturbances in beer drinkers. A specific "hypo-osmolality syndrome". Lancet. 1975 Aug 9;2(7928):245-6.

Thaler SM, Teitelbaum I, Berl T. "Beer potomania" in non-beer drinkers: effect of low dietary solute intake. Am J Kidney Dis. 1998 Jun;31(6):1028-31.

Fox BD.Crash diet potomania. Lancet. 2002 Mar 16;359(9310):942.

Lipschutz JH, Arieff AI. Reset osmostat in a healthy patient. Ann Intern Med. 1994 Apr 1;120(7):574-6

Question 9.4 - 2019, Paper 1

A 76-year-old female presents with seizures. She takes no regular medications. On examination she weighs 60 kg, has no evidence of cardiac failure or liver disease, and appears euvolaemic. Her results in the Emergency Department reveal the following:

Parameter

Patient Value

Adult Normal Range

Blood Results:

Na+

110 mmol/L*

134 – 143

K+

3.8 mmol/L

3.5 – 5.0

Cl-

81 mmol/L*

97 – 107

HCO3-

24 mmol/L

24 – 34

Urea

5.7 mmol/L

3.1 – 8.1

Creatinine

36 mmol/L*

50 – 90

Osmolality

237 mmol/kg*

274 – 289

Urine Results:

Na+

23 mmol/L*

10 – 20

Osmolality

488 mmol/kg

40 – 1200

  1. What is the likely cause of the hyponatraemia?                                                
    (10% marks)
  1. Approximately how many mmol of NaCl would need to be given to raise her serum sodium to 120 mmol/L? Show your calculations.                                              
    (20% marks)

College answer

a)    SIADH

b)    (An answer between 300 - 360 mmol was acceptable).
(Sodium deficit = TBW x (desired Na - Actual Na)
= 0.5/0.6 x 60 x (120-110)
= 30/36 x 10
= 300/360
 

Discussion

This is a hypoosmolar hyponatremia with concentrated urine and a high urine sodium. The college also told us the patient was euvolaemic. There are several possibilities which do not fit the scenario:

  • Diuretic therapy (thiazides) - but she's not on any regular meds
  • Polyuric phase of ATN - but her creatinine is normal
  • Chronic renal failure - but her creatinine is normal
  • Hypoadrenalism - but the potassium is not raised and there is no acidosis

It could still be

  • Hypothyroidism - 
  • Pan-hypopituitarism

These are less likely from the history; which is to say, if the college had wanted you to go down that road, they'd have given you red flags for myxoedema like hypothermia and bradycardia. SIADH is chosen by the examiners probably because cerebral salt wasting (the other possible cause of this electrolyte pattern) is less likely in somebody who has not had a severe head injury or intracranial haemorrhage. 

For a diagnosis of SIADH, one needs to have:

  • Hypoosmolar hyponatremia
  • Urine osmolality greater than plasma osmolality
  • Urine sodium excretion greater than 20mmol/L
  • Normal renal, hepatic, cardiac, pituitary, adrenal and thyroid function
  • Absence of hypotension, hypovolemia, oedema and ADH-influencing drugs
  • Hyponatremia corrected with water restriction

So, most of these are covered in the provided material. 

As for the calculation of the sodium deficit:

Sodium deficit = 0.6 ×body weight × (desired concentration - current concentration) 

The multiplier of body weight is 0.6 for men and 0.5 for women (whose fraction of body water is smaller). For this elderly 60kg woman, assuming you want to get her back to a sodium level of 135mmol/L the equation calls for 30L  × 10mmol = 300 mmol of sodium. 

References

Spasovski, Goce, et al. "Clinical practice guideline on diagnosis and treatment of hyponatraemia." European Journal of Endocrinology 170.3 (2014): G1-G47.

Milionis, Haralampos J., George L. Liamis, and Moses S. Elisaf. "The hyponatremic patient: a systematic approach to laboratory diagnosis."Canadian Medical Association Journal 166.8 (2002): 1056-1062.

Question 24.3 - 2019, Paper 1

A 54-year-old male presents with septic shock requiring vasopressor support and continuous renal replacement therapy for acute kidney injury (AKI).

His blood tests on presentation show:

Parameter

Patient Value

Adult Normal Range

FiO2

0.4

pH

7.15*

7.35 – 7.45

pO2

146.0 mmHg (19.5 kPa)

pCO2

42.0 mmHg (5.6 kPa)

35.0 – 45.0 (4.6 – 6.0)

SpO2

98%

Bicarbonate

14.0 mmol/L*

22.0 – 26.0

Base Excess

-13.6 mmol/L*

-2.0 – +2.0

Lactate

1.4 mmol/L

0.5 – 1.6

Sodium

104 mmol/L*

135 – 145

Potassium

4.0 mmol/L

3.5 – 5.0

Chloride

73 mmol/L*

95 – 105

Glucose

4.1 mmol/L

3.5 – 6.0

Urea

35.6 mmol/L*

3.0 – 8.0

Creatinine

947 µmol/L*

45 – 90

Albumin

28 g/L*

35 – 50

  1. With regards to his electrolytes, what is the concern about performing renal replacement therapy on this patient?                                                                   (10% marks)
  1. List three ways by which you could reduce this risk.                                          (40% marks)

College answer

  • a)

    Patient is hyponatraemic (duration unknown) -concern about rapid correction of Na causing osmotic demyelination syndrome (although uraemia may be protective) – should be aiming for 6-8 mmol/24 hrs which may be problematic if using standard bags (with normal Na levels) for CRRT as correction may occur more rapidly

    b)

  • CRRT at lower doses than usual i.e. very low flow rate to try to minimise speed of electrolyte correction and for short intervals only.
  • Add sterile water to dialysis or replacement fluid so that solution patient is being dialysed against has a lower sodium than standard solution (e.g. dilute to Na 117mmol/L or less – formulas exist to determine amount of sterile water to be added – candidates were not expected to know values/calculations)
  • Give the patient additional free water/5% dextrose intravenously while receiving CRRT (and remove this volume on circuit)

Examiners Comments:

 Part c - a lot of candidates focussed on the urea and potential disequilibrium syndrome rather than the far more concerning hypoatraemia and potential OSM.

Discussion

Interestingly, this ABG question did not specifically require the trainee to interpret the findings, which made it a time-wasting honeypot for people who did not read the question properly.

There is really not much to add to the college answer here. In essence, the standard dialysate which contains 145 mmol/L will correct this patient's sodium way too quickly. In fact, according to Bender et al (1998) standard IHD dialysis can raise the sodium by 5mmol/L per every hour of a 4-hour session. Obviously that's not ideal, and some strategies are required to keep the patient from developing osmotic demyelination.

Of all the possible resources to answer this question, the article by Rosner & Connor (2018) is so good that one might think one of the examiners has a subscription to th Clinical Journal of the American Society of Nephrology.  In short, the possible methods of mitigating the risk of myelinolysis in a hyponatremic dialysis patient are:

  • Avoid dialysis altogether. Sure, the patient is acidotic, but one could surely use some THAM to correct that, and there's no mention of fluid overload in the stem. 
  • Give sodium, then dialyse. If the patient needs dialysis but still passes some urine and is otherwise asymptomatic, one can spare 48-72 hours to bring the sodium up to a level where demyelination will not be such a massive risk (eg. 125mmol/L or so) and then carry on with dialysis as usual.
  • Use low dose dialysis. The dialysate flow rate can be turned down to the point where electrolyte exchange across the membrane is slow and gentle. The downside of this would be slower solute clearance, potentially so slow that it has no clinical benefit. As sodium ions are more likely to exchange across the membrane than the relatively larger urea molecules, one may find oneself in a position were no useful metabolic waste clearance has taken place, but the patient's sodium has corrected dangerously quickly anyway. Even if this dangerous outcome does not occur, one could still advance the logical argument that having pointless dialysis has zero advantage over having no dialysis.
  • Give systemic 5% dextrose. The patient will gain sodium via the circuit, so you give them water at the same time. This works just fine, so long as you keep giving enough 5% dextrose to keep up with the sodium exchange rate. With the dialysate flow low enough and the dextrose rate high enough, you should be able to achieve any desired rate of rise of sodium. Of course, this is not without its disadvantages. For one, that's 66 mmol/L of dextrose you're giving, which will have an undesirable effect on their BSL. Secondly, that's potentially several litres of extra fluid you are giving, which can't possibly be benign for this patient's circulatory system. Obviously at some later stage you will have to take that water out via the circuit, as the renally incompetent patient is probably not up to excreting it themselves. And when you take it out with the circuit, the sodium will go up again.  
  • Give sterile water or 5% dextrose into the return line of the circuit. That's functionally the same step as above, but one less access line.
  • Alter the sodium content of the dialysate. This takes some people out of their comfort zone, as one needs to create one's own bags of sterile dialysate. To quote the case report by Bender et al (1998)"Each 2 liters of dialysate was prepared by mixing 1 liter of 5% dextrose and 0.45% NaCl (half normal saline) with 1 liter of 0.675% NaCl (three-quarters normal saline) to which 50 mEq NaHCO3 was added; the final sodium concentration was thus 121 mEq/L"

References

Zepeda-Orozco, Diana, and Raymond Quigley. "Dialysis disequilibrium syndrome." Pediatric nephrology 27.12 (2012): 2205-2211.

Arieff, Allen I., et al. "Brain water and electrolyte metabolism in uremia: effects of slow and rapid hemodialysis." Kidney international 4.3 (1973): 177-187.

Bender, Filitsa H. "Successful treatment of severe hyponatremia in a patient with renal failure using continuous venovenous hemodialysis." American journal of kidney diseases 32.5 (1998): 829-831.

Wendland, Erik M., and Andre A. Kaplan. "A Proposed Approach to the Dialysis Prescription in Severely Hyponatremic Patients with End‐Stage Renal Disease." Seminars in dialysis. Vol. 25. No. 1. Oxford, UK: Blackwell Publishing Ltd, 2012.

Rosner, Mitchell H., and Michael J. Connor. "Management of severe hyponatremia with continuous renal replacement therapies." Clinical Journal of the American Society of Nephrology 13.5 (2018): 787-789.

Question 5.1 - 2019, Paper 2

A 62-year-old female with a history of obstructive sleep apnoea (OSA) is admitted to your ICU for monitoring after an orthopaedic procedure. The results of her routine post-operative blood tests are given below:

Parameter

Patient Value

Adult Normal Range

Sodium

144 mmol/L

135 – 145

Potassium

4.0 mmol/L

3.5 – 4.5

Bicarbonate

24 mmol/L

22 – 26

Urea

8.7 mmol/L*

3.0 – 8.0

Creatinine

88 μmol/L

45 – 90

Total Calcium

3.00 mmol/L*

2.15 – 2.55

  1. List four likely aetiologies for the hypercalcaemia. (20% marks)
  1. List four other specific blood tests you would order to investigate the cause.

(20% marks)

College answer

a)

  1. Primary hyperparathyroidism
  2. Malignancy (including myeloma)

Note 1) and 2) are the two commonest causes accounting for 90% cases. 0.5 mark for each of these

For the two other causes, any of:

  • Vitamin D toxicity
  • Granulomatous disorders (e.g. sarcoid)
  • Medications (Thiazides, Lithium etc)
  • Factitious (high albumin, dehydration)
  • Hyperthyroidism
  • Acromegaly
  • Phaeochromocytoma
  • Adrenal Insufficiency

Or any other recognised cause consistent with the stem.

b)

  1. Albumin OR ionised calcium
  2. PTH
  3. Vitamin D metabolites
  4. PTH related protein
  5. Tests for a specific cause – e.g. Thyroid function tests, Serum ACE etc.

Discussion

What are the most likely causes of this hypercalcemia? What do we know about the patient?

  • Middle-aged
  • Female
  • OSA
  • Needed some sort of bone surgery
  • Totally normal bloods, apart from calcium

The OSA story begs the question, is a large thyroid gland or retrosternal goitre causing the obstruction? Even weirder is the association between OSA and raised PTH levels, thought to be due to Vitamin D deficiency (Krasimirova et al, 2017). Anyway: the college examiners, in a rare paroxysm of assessment transparency, offered us the marking rubric for this question, and they clearly wanted the trainees to unfocus from the question stem and just give the most common community-prevalent causes of hypercalcemia. In fact, in their 2003 article, Carroll & Schade specifically state that "primary hyperparathyroidism and malignancy account for more than 90 percent of hypercalcemia cases". Other possible causes are listed below:

Causes of Hypercalcemia, by Pathophysiology

Primary endocrine causes

  • Primary hyperparathyroidism
  • Thyrotoxicosis
  • Adrenal insufficiency

Paraneoplastic causes

  • PTH-related protein
    • carcinoma of lung
    • oesophageal carcinoma
    • head and neck SCC
    • renal cell carcinoma
    • Breast cancer
    • Ovarian cancer
    • Bladder cancer
  • Ectopic 1,25-dihydroxyvitamin D
    • Lymphoma
  • Lytic bone lesions
    • Multiple myeloma
    • Breast cancer
    • Hematological malignancies
  • Phaeochromocytoma
  • VIP-secreting gastric adenoma

Granulomatous disease

  • Sarcoidosis
  • HIV
  • Tuberculosis
  • Histoplasmosis
  • Coccidioidomycosis
  • Leprosy

Drug-induced hypercalcemia

  • Vitamin D oversupplementation
  • Thiazide diuretics
  • Lithium carbonate
  • Oestrogens and HRT
  • Androgens
  • Theophylline and aminophylline
  • Vitamin A
  • Aluminum toxicity
  • Total parenteral nutrition (TPN)

Random miscellaneous causes

  • Immobilization (eg. spinal injury)
  • Chronic renal failure
  • Milk alkali syndrome
  • Rhabdomyolysis*

To order an ionised calcium level is reasonable, because this may reveal the true extent of the hypercalcemia (for instance, if the patient has little albumin on board, the majority of this "total" calcium will be in an ionised form, and the symptoms will be worse).

Additionally, the following investigations might be useful:

  • Alkaline phosphatase
  • Serum PTH level
  • CK
  • Parathyroid hormone related peptide (PTHrp)
  • Serum Vitamin D metabolite levels
  • CXR - or better yet, CT chest - to look for obvious malignancy and granulomatous disease.

References

UpToDate has a nice chapter on this topic, for the paying customer.

Krasimirova, Daniela, et al. "Parathyroid Hormone and Vitamin D Levels in Obstructive Sleep Apnea." (2017): PA2335.

Carroll, Marry F., and David S. Schade. "A practical approach to hypercalcemia." American family physician 67.9 (2003): 1959-1966.

Stewart, Andrew F. "Hypercalcemia associated with cancer." New England Journal of Medicine 352.4 (2005): 373-379.

Zawada Jr, E. T., D. B. Lee, and C. R. Kleeman. "Causes of hypercalcemia."Postgraduate medicine 66.4 (1979): 91-7.