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:

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)

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.

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)

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.

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.

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.

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 Lancet, Volume 352, Issue 9123, 18 July 1998, Pages 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.

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.

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.

• Uses of urinary electrolytes:
   

  • Urinary sodium is used to investigate hyponatremia and oliguria
    • In hyponatremia, it should be low.
      • If it is not low, there is either some sort of sodium wasting process (eg. polyuric phase of ATN, or cerebral salt wasting) or the urine is highly concentrated (eg. SIADH)
    • In oliguria due to hypovolemia, it should be low (sodium retention is a normal response to hypovolemia)
    • Fractional sodium excretion in ATN should be > 2%
    • Fractional sodium excretion in pre-renal azotaemia  is <1%
  • Urinary chloride is used to ibvestigate metabolic alkalosis
    • In non-renal causes of metabolic alkalosis, urinary chloride is low
    • In metabolic alkalosis due to mineralocorticoids or diuretics, urinary chloride is high
  • Urinary potassium is used to investigate hypokalemia
    • In hypokalemia, urinary potassium should be low
    • igh urinary potassium in hypokalemia is a sign of an RTA (type 1 or 2), duretic effect or hyperaldosteronism
  • Urinary anion gap is used to investigate metabolic acidosis
    • In non-renal causes of metabolic acidosis, the UAG should be negative (or at least zero)
    • In renal tubular acidosis, the UAG is positive
  • Urinary osmolality
    • Acts as a measure of urinary concentrating capacity
    • The lowst value possible is about 40 mOsm/kg; the highest is around 1400 mOsm/kg
    • Urinary osmolal gap can be used instead of the urinary anion gap in the diagnosis of metabolic acidosis.

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 - if administered early in SBP - reduces the incidence of renal impairment and death.

Albumin for volume replacement in paracentesis

• Albumin prevents paracentesis-associated circulatory dysfunction.

Albumin as an adjunct in hepatorenal syndrome

• When combined with terlipressin, albumin infusion is an effective strategy to prolong survivalin hepatorenal syndrome while waiting for liver transplantation.
• Albumin alone is not as effective.

Albumin for extracorporeal detoxification in liver failure

• 20% albumin is used as a molecular adsorbent in the Molecular Adsorpent Recirculation System (MARS) which can be used as a bridge to transplant.

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.

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.

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.

College Answer

Discussion

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

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.

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:

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

College Answer

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.

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)

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")

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:

Na⁺ Deficit = 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.

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:

College Answer

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").

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:

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:

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:

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.

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 - if administered early in SBP - reduces the incidence of renal impairment and death.

Albumin for volume replacement in paracentesis

• Albumin prevents paracentesis-associated circulatory dysfunction.

Albumin as an adjunct in hepatorenal syndrome

• When combined with terlipressin, albumin infusion is an effective strategy to prolong survivalin hepatorenal syndrome while waiting for liver transplantation.
• Albumin alone is not as effective.

Albumin for extracorporeal detoxification in liver failure

• 20% albumin is used as a molecular adsorbent in the Molecular Adsorpent Recirculation System (MARS) which can be used as a bridge to transplant.

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.

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:

• Hypertonic saline is probably better than mannitol
• Brain Trauma Foundation Guidelines do not recommend it, but they have not been updated since 2007.

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

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.

College Answer

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.

• Adrenal insufficiency
• Refeeding syndrome
• Tumour lysis syndrome
• Ethylene glycol toxicity

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.

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)

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.

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.

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

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.

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

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.

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.

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:

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:

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.

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.

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).

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.

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:

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.

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

​

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):

c) ibid.

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.

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.

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:

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.

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.

College Answer

a)

Classify hyponatraemia:

• Hypertonic
• Isotonic
• Hypotonic

Further subdivide hypotonic:

• Hypervolaemic
• Euvolaemic
• Hypovolaemic

Serum Na⁺ < 135 mmol/L

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:

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.

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.

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.

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.

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.

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. 

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:
    • Thiazides
    • Amiloride (Knoers et al, 1990)
    • NSAIDs, eg. ibuprofen (Libber et al, 1986)

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?

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 

College answer

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.

College answer

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

College answer

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.

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"

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.

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:

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.

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.