Misc Paed

Question 1

Hypercalcaemia. What preliminary biochemical investigations would you request to narrow differential?

Answer 1

1. Urinary calcium excretion (elevation effectively rules out familial hypocalciuric hypercalcemia, a relatively common but usually asymptomatic cause of mild pediatric hypercalcemia caused by a mutation in the calcium-sensing receptor, that leads to increased renal tubular reabsorption of calcium and low urinary calcium and, in most cases, normal PTH values)
2. serum level of intact parathyroid hormone (PTH)
3. serum phosphate,
4. vitamin D
5. PTH-related protein (PTHrP)
6. TFT

Further tests:

Calcitriol: normal levels rule out infectious and noninfectious granulomatous disorders that could be
associated with ectopic production of vitamin D

Question 2

Hypercalcaemia. What rare cause should you consider in a neonate?

Answer 2

In the newborn, hypercalcemia may be caused by
subcutaneous fat necrosis, a rare entity of the
neonate that is usually associated with traumatic
delivery or perinatal asphyxia.

Question 3

Hypercalcaemia. Commonest causes in adults? Differential diagnosis in children?

Answer 3

Adults: primary hyperparathyroidism or malignancy

Hypercalcaemia differential in chldren:

1. Familial hypocalciuric hypercalcemia: a relatively common but usually asymptomatic cause of mild pediatric hypercalcemia caused by a mutation in the calcium-sensing receptor, that leads to increased renal tubular reabsorption of calcium and low urinary calcium and, in most cases, normal PTH values (ruled out by high urine calcium:creatinine ratio).
2. Primary hyperparathyroidism: is unusual in young children, with less than 0.5% of all cases manifesting before the patient is 10 years of age. Suppressed PTH rules this out.
3. Toxic effects of thiazide diuretics or other hypercalcemia- causing substances (e.g., lithium and vitamin A or D) - rule out by meticulous history taking and normal vitamin D levels.
4. Infections and noninfectious granulomatous disorders causing ectopic vitamin D production: ruled out by normal calcitriol.
5. Subcutaneous fat necrosis in the newborn: a rare entity of the neonate that is usually associated with traumatic delivery or perinatal asphyxia.
6. Hyperthyroidism, prolonged immobilization
   (>2 weeks), or malignant tumors can precipitate
   hypercalcemia that is due to a pathological increase of bone resorption.
7. Malignancy: Hypercalcaemia secondary to malignancy is rare in children, and when present, it is usually due to bone destruction either directly,
   by the tumor or tumor metastases, or after the
   production of lytic factors (e.g., PTHrP, interleukins,
   or prostaglandins).

Question 4

Hypercalcaemia. Describe normal calcium homeostasis.

Answer 4

The serum calcium level is determined mainly by the interplay of three dynamic processes: absorption from the gut, reabsorption by the kidneys, and bone remodeling. Two main calciotropic hormones orchestrate these processes through feedback-loop mechanisms: calcitriol (1,25-dihydroxyvitamin D3) enhances absorption from the small intestine, and parathyroid hormone (PTH) promotes calcium mobilization from the bones and reabsorption in the kidneys, causing an increase in serum calcium levels.

Question 5

Limp. How would you classify your differential? Causes of an antalgic gait?

Answer 5

1. Antalgic: trauma, infection (osteomyelitis, spondylodiskitis, Lyme disease acute synovitis, septic arthritis), osteochondrosis, inflammatory processes, vitamin D or C deficiency, and neoplasms.
2. Proximal muscle weakness: can cause Trendelenburg’s gait
3. Limb-length discrepancy, which causes a short-leg gait;
4. Diseases affecting the spinal pyramidal tracts,
   which can cause a spastic gait.

Question 6

Name two fractures common in toddlers that could explain an antalgic gait/refusal to weight bear. Examination findings of each?

Answer 6

1. Fracture of the tibia (toddler’s fracture)
2. nondisplaced physeal fracture of a long bone

• Radiographs are frequently normal, at least initially; abnormalities may appear after 2 weeks or so during the healing process.
• Tibial fractures are characterized by pain on palpation along the shaft of the tibia and pain with external rotation of the tibia relative to the femur.
• Physeal fractures are generally characterized by pain on palpation over the involved growth plate, with or without swelling in the region.

Question 7

What is Perthes disease and how does it typically present?

Answer 7

Legg–Calvé–Perthes disease, an osteochondrosis
of the femoral head in children, usually presents
with a painless limp; pain is elicited in the
hip during range-of-motion testing. There may
be no radiographic abnormalities initially; later,
radiographic findings may include subchondral
flattening of the femoral head, a feature that is
consistent with early osteonecrosis.

Question 8

Malignant differentials of bone pain/refusal to weight bear - name five? Radiographic findings in acute leukaemia?

Answer 8

1. Childhood leukemia is manifested with bone pain in 20% of the cases. Radiographic abnormalities include metaphyseal bands and osteopenia.
2. Intracranial and intraspinal tumors must be
   ruled out; patients with these tumors may present
   with headache or back pain, long-tract signs,
   and other neurologic abnormalities.
3. Ewing’s sarcoma is an uncommon cancer that can occur in this age group. Children generally present with constitutional symptoms, bone pain, and radiographic abnormalities within the diaphyseal region of long bones or within the pelvis.
4. Neuroblastomas from abdominal or other primary
   sites need to be ruled out by means of physical
   examination and imaging.
5. Eosinophilic granuloma of bone (Langerhans’-cell histiocytosis) can be manifested with vertebral collapse and pain.

Question 9

What is the characteristic plain film finding in Gaucher’s disease?

Answer 9

Erlenmeyer-flask deformity - flaring of the long bone
metaphyses due to interruption of normal
remodeling

Question 10

Malignancy-related hypercalcaemia: What proportion of adults with malignant tumours develop hypercalcaemia? Vs children? Cancers a/w hypercalcaemia in children?

Answer 10

• Adults with malignant tumors: approximately 20 to 30% develope hypercalcemia.
• Only 0.4 to 0.7% of pediatric cancer patients present with hypercalcemia.
• Hypercalcemia occurs in association with rhabdomyosarcoma, hepatoblastoma, some brain tumors, neuroblastoma, and hematologic cancers, including lymphoma and acute leukemia.
• In two large series, hypercalcemia was reported in 0.3 to 0.4% of patients with acute leukemia; all but one of the patients had acute lymphoblastic leukemia (ALL). It is interesting that most patients with hypercalcemia have bone pain as a prominent symptom, and patients with bone pain or hypercalcemia often do not have the striking
  abnormalities in the complete blood count
  that are typically present at the time of diagnosis
  of ALL. Thus, ALL should be considered in
  the differential diagnosis of bone pain or hypercalcemia in a child, even in the presence of a
  normal complete blood count.

Question 11

What sort of ALL is this? : Morphologic
examination of bone marrow aspirate smear reveal
a predominant population of small-to-mediumsize
cells that had finely dispersed nuclear chromatin,
small prominent nuclei, and scant basophilic
cytoplasm, features that are consistent with
blasts. According to flow-cytometric studies, the blasts are positive for the pan–B-cell marker CD19, CD10, and terminal deoxynucleotidyl transferase (an immature lymphoid marker) and weakly positive for CD45 (leukocyte common antigen), the mature B-cell marker CD20, and the stem-cell marker CD34.

Answer 11

These features are consistent with a precursor B-cell phenotype. The findings in the bone marrow and peripheral blood were diagnostic of B lymphoblastic leukemia.

Question 12

Aetiological Sieve

Answer 12

TIN CAN MED DIP

CONGENITAL

ACQUIRED

1. Traumatic
2. Inflammatory (physical, chemical, infective)
3. Neoplastic (benign or malignant, primary or secondary)
4. Circulatory
5. Autoimmune
6. Nutritional
7. Metabolic
8. Endocrine
9. Drugs
10. Degenerative
11. Iatrogenic
12. Psychosomatic

Question 13

Anatomical Sieve

Answer 13

Causes of Mechanical Bowel Obstruction

Extramural: adhesions, strangulated hernia, volvulus, extrisinc compression

Intramural: tumours, infarction, strictures, inflammation (eg Chrons)

Luminal: Impacted faeces, foreign body, large polyps, intussusception

Question 14

Path essay structure

Answer 14

1. Definition
2. Aetiology (incidence, age, sex, geography)/risk factors
3. Histology (macro and micro)
4. Clinical features (signs and symptoms)
5. Diagnosis (and differential)
6. Clinical staging (if appropriate)
7. Investigations/treatment/management
8. Complications
9. Prognosis

Question 15

RELATIONSHIP BETWEEN PLASMA SODIUM CONCENTRATION AND EXTRACELLULAR TONICITY

Answer 15

The plasma sodium concentration affects cell volume. The term “tonicity” describes the effect of plasma on cells — hypotonicity makes cells swell and hypertonicity makes them shrink. Hypernatremia always indicates hypertonicity. Hyponatremia usually indicates hypotonicity, but there are exceptions (e.g., hyperglycemic hyponatremia and pseudohyponatremia) that are not covered in this review.

Question 16

PLASMA SODIUM CONCENTRATION AND THE ELECTROLYTE AND WATER CONTENT OF THE BODY

Answer 16

Solute concentrations (osmolalities) must be equal inside and outside of cells because water channels (aquaporins) make cell membranes permeable to water.1,2 The “sodium pump” (Na+/K+–ATPase) functionally excludes sodium from cells, exchanging it for potassium by means of active transport. Although sodium is largely extracellular and potassium is intracellular, body fluids can be considered as being in a single “tub” containing sodium, potassium, and water, because osmotic gradients are quickly abolished by water movement across cell membranes. As such, the concentration of sodium in plasma water should equal the concentration of sodium plus potassium in total body water.

A substantial amount of sodium is bound to large polyanionic macromolecules called proteoglycans, which make up the ground substance of bone, connective tissue, and cartilage. The sodium concentration of cartilage is nearly twice that of plasma. The osmotic force created by the high sodium concentration (about 40 mm Hg for every difference in concentration of 1 mmol per liter) maintains the high water content in the tissue, allowing it to withstand pressures that can exceed 20,000 mm Hg during exercise.

When it became known that much of the sodium in the body is bound to bone, cartilage, and connective tissue, it was hypothesized that these tissues could serve as sodium reservoirs, taking up or releasing sodium in response to the needs of the body.6 Despite early evidence supporting the concept of a sodium reservoir,7-9 this theory lost favor10 and was not pursued for half a century. However, the past decade has seen renewed interest in stored sodium.11 In patients who consume high-salt diets, sodium can accumulate in the body, seemingly disappearing without a change in the plasma sodium concentration, body weight, or extracellular fluid volume.12 Sodium, potassium, and water balance do not always account for changes in the plasma sodium concentration during recovery from hyponatremia.13 Proteoglycans in skin serve as a sodium reservoir, and the number of negative charges available to bind sodium varies in response to the sodium concentration of interstitial tissue.14-16 In experiments in rats, chronic hyponatremia has been shown to be a more potent cause of osteopenia than vitamin D deficiency, and loss of sodium from bone exceeded the loss of calcium from bone. The activity of osteoclasts is increased in chronic hyponatremia owing to a direct effect of sodium and possibly vasopressin on these cells.17

In humans, chronic hyponatremia is associated with osteoporosis and fractures. During extreme-endurance athletic events lasting several hours, bone density decreases measurably, and the decrease in bone density correlates remarkably closely with changes in the plasma sodium concentration.17,18

Question 17

PLASMA SODIUM CONCENTRATION AND TONICITY BALANCE

Answer 17

To understand or roughly predict changes in the plasma sodium concentration, the overall tonicity of the diet and intravenous fluids and the overall tonicity of gastrointestinal fluids, sweat, and urine must be considered. Like the plasma sodium concentration, which is determined by the concentrations of sodium and potassium in body water, the tonicity of these fluids is defined by their concentrations of sodium plus potassium.

It is not possible to predict the effect of administering intravenous fluids on the plasma sodium concentration without considering concurrent urinary losses. The electrolyte concentration (sodium plus potassium) of urine, and not its osmolality (which includes electrolytes, urea, and glucose), determines the effect of urine on the plasma sodium concentration. Urine is hypotonic if its electrolyte concentration is lower than that of plasma; because it is partly composed of electrolyte-free water, excretion of hypotonic urine will increase the plasma sodium concentration. Conversely, urine is hypertonic if its electrolyte concentration is higher than that of plasma; excretion of hypertonic urine will lower plasma sodium concentrations.20

Isosmolar or hyperosmolar urine containing mostly urea (an end product of protein metabolism) may be nearly electrolyte-free.20,21 Excretion of urea owing to recovery from azotemia, catabolism, or a high-protein diet will cause hypernatremia unless there is replacement of the free water that has been lost.22 Because it increases excretion of electrolyte-free water, urea has been used to treat hyponatremia.23,24

Question 18

SODIUM AND THE BLOOD–BRAIN BARRIER

Answer 18

Sodium readily crosses systemic capillary membranes through clefts between endothelial cells. Consequently, in most tissues, the sodium concentrations of plasma and interstitial fluid are nearly identical, with a small difference created by intravascular albumin.1,25 In contrast, brain capillaries have tight endothelial junctions and are lined by astrocytic foot processes, creating a blood–brain barrier that sodium cannot cross Consequently, an abnormal plasma sodium concentration causes water to enter or leave brain tissue. Because of the confines of the skull, only a small degree of brain swelling or shrinkage is compatible with life.

Question 19

REGULATION OF THE PLASMA SODIUM CONCENTRATION

Where are osmoreceptors/tonicity receptors located and why?

• Hypothalamic neurons; not surprising since plasma sodium concentration affects brain volume

What are two stimuli that promote vasopressin release?

• Plasma sodium >135mmol/l
• Circulatory inadequacy/hypovolaemia

What is the mechanism of action of vasopressin?

• Once secreted, vasopressin binds to its V2 receptor on basolateral membranes of principal cells lining the renal collecting duct -> aquaporins are inserted into the luminal membrane, allowing water to flow out, attracted by the high solute concentration of the surrounding medullary interstitium.

What does the presence of dilute urine when plasma Na is >145mmol/l indicate?

• either deficient vasopressin secretion (as in neurogenic diabetes insipidus) or
• failure of the kidneys to respond to vasopressin (as in nephrogenic diabetes insipidus)

In what instances migh maximal dilution of urine fail to prevent hyponatraemia?

• water intake is extraordinarily large (>1 liter per hour) (e.g., in patients with schizophrenia who drink water compulsively) or
• the rate of urinary solute excretion is extremely low (e.g., in beer drinkers who eat very little)

Answer 19

Since the plasma sodium concentration affects brain volume, it is not surprising that the cell-volume receptors that are responsible for adjusting thirst and vasopressin secretion are located in the brain. Osmoreceptors, which are more accurately called tonicity receptors, are hypothalamic neurons that express transient receptor potential cation channel subfamily vanilloid member 1 (TRPV1) and member 4 (TRPV4) channels on their cell membranes.27,28

Transient receptor potential cation channels belong to a large family of molecules. They were first identified as photoreceptors in fruit flies and were later discovered to serve as receptors for a variety of sensations throughout nature.29 For example, transient receptor potential V (or vanilloid) (TRPV) channels respond to capsaicin, a vanilloid that causes the burning sensation associated with the ingestion of chili peppers. TRPV1, which is a member of the TRPV family of receptors, was identified in mutant Caenorhabditis elegans roundworms that did not avoid hyperosmotic environments. Insertion of a mammalian TRPV4 gene into the genome of mutant C. elegansroundworms restored normal worm behavior. The TRPV1 gene is required for normal functioning of isolated osmoreceptor neurons, and genetically engineered mice that lack genes for TRPV1 and TRPV4 have abnormal osmoregulation. Polymorphisms in genes encoding the TRPV4 channel have been identified in humans. Healthy aging men who are positive for the TRPV4 P19Spolymorphism are more likely to have mild hyponatremia than are men without this polymorphism.30

In normal osmoregulation, both thirst and vasopressin secretion are inhibited when the plasma sodium concentration is decreased below 135 mmol per liter. In the absence of vasopressin, urine osmolality decreases to as low as 50 mOsm per kilogram. In persons who consume a typical Western diet, with an output of urinary solute of about 900 mOsm daily, a urinary solute concentration of 50 mOsm per liter yields 18 liters of urine (750 ml per hour).20

Although individual responses vary,31 vasopressin is usually detectable at a plasma sodium concentration above 135 mmol per liter, and levels of vasopressin increase linearly with increasing sodium levels.32 The hormone may also be secreted in response to circulatory inadequacy,33 or it may be secreted “inappropriately,” and sometimes ectopically, with no osmotic or hemodynamic stimulus.34 (Vasopressin secretion without an osmotic or hemodynamic abnormality to account for it is termed “inappropriate.”34) Once secreted, vasopressin binds to its V2 receptor on basolateral membranes of principal cells lining the renal collecting duct.27 In the presence of vasopressin, aquaporins are inserted into the luminal membrane, allowing water to flow out, attracted by the high solute concentration of the surrounding medullary interstitium. When the plasma sodium level increases to approximately 145 mmol per liter, vasopressin levels are normally high enough to result in maximally concentrated urine (about 1200 mOsm per kilogram). The presence of a dilute urine when the plasma sodium concentration is above 145 mmol per liter implies either deficient vasopressin secretion (as in neurogenic diabetes insipidus) or failure of the kidneys to respond to vasopressin (as in nephrogenic diabetes insipidus) (see Case 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).27

However, even complete diabetes insipidus (with total absence of vasopressin or no tubular response to vasopressin) generally does not cause hypernatremia, because thirst prompts replacement of urinary losses of water.28 Hypernatremia develops if water is unavailable, if the urge to drink is impaired (hypodipsia), or if patients are too young, old, or sick to seek water themselves.35

Maximal dilution of urine prevents hyponatremia unless water intake is extraordinarily large (>1 liter per hour) (e.g., in patients with schizophrenia who drink water compulsively)36 or the rate of urinary solute excretion is extremely low (e.g., in beer drinkers who eat very little).20,37 Except in these scenarios, hypotonic hyponatremia is associated with an impaired ability of the body to dilute urine because of diminished sodium transport in renal-diluting sites (most commonly because of the use of diuretics),38 the presence of vasopressin,39,40 or, rarely, an inherited activating mutation of the vasopressin receptor.41 Because vasopressin, along with renin, angiotensin, aldosterone, and the sympathetic nervous system, participates in the neurohumoral response to inadequate circulation,33 vasopressin-mediated hyponatremia may complicate hypovolemia or states that lead to edema (e.g., heart failure and cirrhosis).40

Many causes of hyponatremia (e.g., hypovolemia, medications, cortisol deficiency, nausea, pain, or stress) are reversible — either by treatment or the passage of time.39 Once the cause of hyponatremia resolves, the normal osmoreceptor response to a low plasma sodium concentration inhibits vasopressin secretion, resulting in excretion of maximally dilute urine and resolution of hyponatremia.42,43

Administration of a vasopressin antagonist will also result in the excretion of dilute urine (also known as a “water diuresis” or “aquaresis”) despite the continued presence of vasopressin. Therefore, vasopressin antagonists increase the plasma sodium concentration and are approved by the Food and Drug Administration for the treatment of hyponatremia caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or by heart failure. 44

Question 20

HOW IS URINARY EXCRETION OF SODIUM RELATED TO THE PLASMA SODIUM CONCENTRATION?

Answer 20

Urinary excretion of sodium is relatively independent of plasma sodium levels; measurement of urinary sodium levels can help to distinguish between SIADH and hypovolemic hyponatremia.34,45,46 Excretion of sodium responds to intravascular volume, increasing with volume expansion and decreasing with volume depletion. Water retention due to SIADH expands extracellular fluid volume, resulting in increased urinary excretion of sodium despite hyponatremia.47

Excretion of sodium in SIADH restores normal extracellular volume, but hypertonic urinary losses also exacerbate hyponatremia.48 For this reason, SIADH should not be treated with isotonic solutions such as 0.9% saline or Ringer’s lactate, because infused sodium will be excreted in smaller volumes of urine, leading to net retention of electrolyte-free water. Such a sequence is common in patients with subarachnoid hemorrhage; saline is prescribed to maintain cerebral perfusion, but vasopressin released by neurologic injury concentrates the urine

Question 21

CAUSES OF RAPID CHANGES IN THE PLASMA SODIUM CONCENTRATION

Name a cause of rapid decrease in plasma sodium?

Name two causes of a rapid increase in plasma sodium concentration?

Answer 21

Rapid decrease in plasma sodium: amount of water ingested or infused exceeds the capacity of the kidneys to excrete free water.

Rapid increase in plasma sodium concentration:

• large amounts of concentrated salt are ingested or infused
• large, unreplaced losses of electrolyte-free water because of aquaresis or osmotic diuresis (most commonly due to glycosuria).

Loss or gain of approximately 3 ml of water per kilogram of body weight will change the plasma sodium concentration by approximately 1 mmol per liter.

Maximally dilute urine, whether resulting from untreated diabetes insipidus, spontaneous recovery from hyponatremia, or administration of a vasopressin antagonist, will increase the plasma sodium concentration by about 2.5 mmol per liter per hour.

In the absence of urinary loss of water, 1 ml of 3% saline per kilogram of body weight will increase the plasma sodium concentration by about 1 mmol per liter.51 Therefore, in a woman with a body weight of 50 kg, the increase in the plasma sodium level caused by a maximum water diuresis is similar to the increase caused by infusion of approximately 125 ml of 3% saline per hour.

Question 22

CONSEQUENCES OF AN ABNORMAL PLASMA SODIUM CONCENTRATION

Answer 22

Extreme hypotonicity ruptures cell membranes; extreme hypertonicity damages the cytoskeleton and causes breaks in DNA, ultimately leading to apoptosis.52 Given time, cells protect their volume and their survival by adjusting intracellular solute contents.53

Organic osmolytes are small intracellular molecules (e.g., glutamate, taurine, and myo-inositol) that are found throughout nature; their concentrations can vary without perturbing cell functions.54Hypotonicity promotes the release of osmolytes from cells through volume-sensitive leak pathways, while, concurrently, osmolyte-accumulating transporters (e.g., the taurine transporter TauT and the myo-inositol transporter SMIT) are down-regulated. With hypertonicity, TauT and SMIT are up-regulated.53,54 These adaptations allow cells to maintain intracellular solute concentrations that are equal to the osmolality of hypotonic or hypertonic plasma, with little change in cell volume. If severe hypernatremia develops over a period of minutes (e.g., after massive ingestion of salt that may occur in a suicide attempt), vascular injury created by a suddenly shrinking brain causes intracranial hemorrhage. Brain swelling from an abrupt onset of hyponatremia results in increased intracranial pressure, impairing cerebral blood flow and sometimes causing herniation (Figure 3). Adaptive changes in brain osmolytes permit survival, but they may also contribute to symptoms.55 For example, in acute hyponatremia, adaptive release of glutamate, an excitatory neurotransmitter, may increase the susceptibility to seizures; depletion of the transmitter from nerve terminals may account for some of the neurologic symptoms of chronic hyponatremia.

Although osmotic disturbances affect all cells, clinical manifestations of hyponatremia and hypernatremia are primarily neurologic, and rapid changes in plasma sodium concentrations in either direction can cause severe, permanent, and sometimes lethal brain injury. The foot processes of astrocytes, which encircle both brain capillaries and neurons, express aquaporins (such as aquaporin-4) that allow water to cross the blood–brain barrier.2 Astrocytes protect neurons from osmotic stress; in response to hypotonicity, a cell-to-cell transfer of taurine to adjacent astrocytes allows neurons to maintain their volume while astrocytes swell.56Within 24 to 48 hours after this transfer, astrocytes restore their volume through loss of organic osmolytes, but this makes them vulnerable to injury from rapid normalization of the plasma sodium concentration. Because of the down-regulation of transporters, recovery of lost brain osmolytes may take a week or longer.55,56 Therefore, rapid correction of hyponatremia is a hypertonic stress to astrocytes that are depleted of osmolytes, triggering apoptosis, disruption of the blood–brain barrier, and, eventually, brain demyelination57 (see the Supplementary Appendix). In experiments in animals, brain demyelination has been prevented by repletion of myo-inositol,58 by lowering the plasma sodium concentration again promptly (within 12 to 24 hours after rapid correction of hyponatremia),59 or by administration of minocycline (which prevents proliferation of glial cells).

Brain injury after rapid correction of chronic hyponatremia manifests as a biphasic illness called the osmotic demyelination syndrome: an initial reduction in symptoms is followed by a gradual onset of new neurologic findings (see Case 3 in the Supplementary Appendix).61 The clinical spectrum of the osmotic demyelination syndrome is broad and can include seizures, behavioral abnormalities, and movement disorders.62 The most severely affected patients become “locked in,” unable to move, speak, or swallow because of demyelination of the central pons. Although osmotic demyelination may cause permanent disability or death, many patients — even those who require ventilator support — have a full functional recovery.63 Acute hypernatremia may also cause brain demyelination, without the biphasic clinical course of the osmotic demyelination syndrome (Figure 3).64,65

Chronic hypernatremia, like chronic hyponatremia, causes a reversible encephalopathy. Particularly in infants, organic osmolytes gained in the adaptation to chronic hypernatremia are lost slowly. Therefore, rehydration resulting in rapid correction of chronic hypernatremia causes seizures and a bulging fontanelle indicating cerebral edema (Figure 3).35,66,67

A plasma sodium concentration that is even slightly outside the normal range increases the risk of death,68 but few deaths associated with abnormalities in the plasma sodium concentration are related to neurologic complications.69 The underlying disorders that produce an abnormal plasma sodium concentration may be responsible for excess mortality, but there may also be non-neurologic adverse consequences of prolonged osmotic disturbances, and observational studies have shown decreased mortality among hospitalized patients in whom the plasma sodium concentration was corrected.70 Taurine and myo-inositol, organic osmolytes that are lost from many cells in the adaptation to hyponatremia, are normally protective against oxidative injury.54 An experimental model of chronic SIADH in rats showed that prolonged hyponatremia resulted in hypogonadism, loss of body fat, skeletal-muscle sarcopenia, and cardiomyopathy.71

Question 23

CORRECTION OF AN ABNORMAL PLASMA SODIUM CONCENTRATION

Disorders of plasma sodium concentration expose cells to hypotonic or hypertonic stress. Although all cells are affected, clinical manifestations of hyponatremia and hypernatremia are primarily neurologic, and rapid changes in plasma sodium concentrations in either direction can cause severe, permanent, and sometimes lethal brain injury. Because the brain adapts to an abnormal plasma sodium level, excessive correction of a chronic disturbance can be injurious and should be avoided.

Answer 23

Aggressive interventions are indicated when the plasma sodium concentration has decreased or increased rapidly or when an abnormal plasma sodium concentration is causing severe symptoms. Therapy should be guided by frequent monitoring of the plasma sodium concentration and not by formulas alone.43

Fatal brain swelling — a rare complication of hyponatremia that clinicians are most concerned about — has only been reported in hyponatremic patients with intracranial disease and in a few specific conditions that cause the plasma sodium concentration to decrease rapidly, such as postoperative hyponatremia and self-induced water intoxication that develops over a few hours (Table 1). Because the brain cannot swell by much more than 5%, correction of hyponatremia by this amount would be expected to prevent the most serious complications of acute water intoxication; empirical observations support this prediction. An increase in the plasma sodium concentration of 4 to 6 mmol per liter is enough to reverse impending brain herniation or stop active seizures in patients with severe acute hyponatremia. Such an increase can be reliably achieved with 100-ml bolus infusions of 3% saline (2 ml per kilogram in small patients), administered at 10-minute intervals to a total of three doses, if necessary, to control symptoms.39 Milder symptoms of acute hyponatremia should be treated with enough 3% saline to avoid a worsening of hyponatremia because of delayed absorption of ingested water or excretion of hypertonic urine.72

Hyponatremia is usually a chronic condition and it should be presumed to be chronic when the actual duration is unclear; to reduce symptoms and improve potential outcomes, chronic hyponatremia should be corrected gradually with the use of fluid restriction, salt tablets, slow infusions of 3% saline, furosemide, urea, or vasopressin antagonists, or by treatment of the underlying cause. Severe symptoms of hyponatremia may require more aggressive initial interventions, but there is no need to increase the plasma sodium concentration by more than 4 to 6 mmol per liter per day. Regardless of how chronic hyponatremia is treated, inadvertent overcorrection, most commonly caused by excretion of dilute urine, is common and can be very dangerous (see Case 3 in the Supplementary Appendix).42,43 If the plasma sodium concentration is less than 120 mmol per liter, or if there are risk factors for osmotic demyelination, correction of the plasma sodium concentration by more than 8 mmol per liter per day should be meticulously avoided through replacement of lost water or prevention of water loss with desmopressin, a synthetic vasopressin. 42,73

Repeat therapeutic lowering of the plasma sodium concentration is justified if the correction of hyponatremia exceeds 8 mmol per liter per day and there are risk factors for osmotic demyelination or if the correction is 10 to 12 mmol per liter per day without these risk factors (Table 1)39,40,74,75— although the benefit of this strategy has not been confirmed in humans. To prevent inadvertent overcorrection (see Case 4 in the Supplementary Appendix), desmopressin can be administered preemptively, in anticipation of, rather than in response to, unwelcome urinary losses of water; hyponatremia is corrected with a slow infusion of 3% saline while the urine is kept concentrated with repeated doses of desmopressin.73

Limiting correction of chronic hypernatremia so that the plasma sodium concentration is decreased by less than 0.5 mmol per liter per hour reduces the risk of cerebral edema and seizures associated with rehydration.66 However, the fear of these complications, which have been reported only in young children, should not deter the aggressive rehydration of adults with acute hypernatremia to avoid brain hemorrhage or osmotic demyelination (Table 2).76 In contrast to the risk of inadvertent overcorrection in patients with hyponatremia, there is little risk of inadvertent overcorrection in patients with hypernatremia, and adults with hypernatremia are often undertreated.

Question 24

Pathogenesis of Osmotic Demyelination

• disruption of BBB due to rapid rise in plasma osmolality due to shrinkage of endothelial cells and alteration of tight junctions
• Loss of BBB may be due to astrocyte damanage. Astrocytes become depleted of organic osmolytes during adaptation to hyponatraemia, and become more vulnerable to osmotic stress themselves
• BBB disruption allows complement in, which is toxic to oligodendrocytes (responsible for myelination)

Answer 24

It is well accepted that rapid changes in the plasma sodium concentration can result in brain demyelination, but the precise mechanism underlying this injury is still under investigation. The discovery of bile pigment in the brains of jaundiced patients who died of central pontine myelinolysis led Norenberg to the idea that osmotically-induced disruption of the blood brain barrier might be the cause of the disorder. 1 This was an attractive hypothesis because it had been shown that a rapid rise in plasma osmolality opens the blood brain barrier (BBB), possibly by shrinking endothelial cells and altering their tight junctions.2,3 Norenberg’s hypothesis was supported by studies by Baker and co-workers which found that development of demyelination in the rat was associated with magnetic resonance indices of BBB disruption and that IgG and C3d were found after rapid correction of hyponatremia in areas of the brain undergoing osmotic demyelination. 4 Because complement is toxic to oligodendrocytes (the cells in the central nervous system involved in synthesizing, organizing and wrapping myelin around nerves), these findings suggested that a rapid increase in plasma sodium leads to BBB disruption, followed by an influx of complement into the brain, which then results in demyelination. More recently, Gangkam-Kengne and co-workers found that under some conditions, osmotic opening of the blood brain barrier could be dissociated from subsequent 3 demyelination and suggested that injury to astrocytes was the primary lesion in osmotic demyelination. 5 Studying the temporal relationship between astrocyte loss and myelin loss in a rat model of osmotic demyelination, these investigators found that astrocyte death precedes demyelination. Astrocytes, the most abundant cell type in the nervous system, regulate water homeostasis in the brain; these cells become depleted of organic osmolytes during the adaptation to hyponatremia, and loss of osmolytes make them more vulnerable to injury from osmotic stress. The foot processes of astrocytes encircle brain capillaries and interact with endothelial cells, oligodendrocytes, and microglia.6 There is evidence that alterations in astrocyte proteins, such as aquaporins, which regulate water and ion flux, directly affect the ability of oligodendrocytes to maintain myelin structure and integrity.7 Connexins connect astrocytes to each other and to oligodendrocytes in a network whose integrity is crucial for myelination and remyelination after demyelinative injury.5,7 In addition, astrocytes play an important role in inducing endothelial cells to form the tight junctions characteristic of the BBB8 and signaling between astrocytes and endothelial cells can lead to rapid and transient opening of the BBB. 6 Therefore, shrinkage and subsequent apoptosis of astrocytes could explain many of the phenomena that occur after rapid correction of chronic hyponatremia: transient opening of the blood brain barrier, loss of myelin-producing oligodendroytes and proliferation of microglia.

Question 25

Explain this. The physiology is pertinent to paeds.

A 57 year old woman with a 20 year history of bipolar disorder treated with lithium undergoes abdominal surgery and is given nothing by mouth beginning at midnight the night before her operation. Two days after surgery she becomes unresponsive. Perioperative input is 6250 ml 5% dextrose in lactated Ringer’s solution (sodium concentration 130 mmol per liter), and urine output is 5870 ml. Pre-operative plasma sodium was normal and 24 hours after surgery it is 168 mmol per liter. She is treated with 5% dextrose in 0.45% saline (sodium concentration 77 mmol per liter) at 100 ml per hr and plasma sodium increases to 175 mmol per liter over 8 hours. Urine osmolality is 159 mOsm per kilogram, urine sodium is 36 mmol per liter and urine potassium is 9 mmol per liter.

Answer 25

The patient has nephrogenic diabetes insipidus caused by long-term lithium therapy. Pre-operative plasma sodium was normal because thirst prompted her to replace urinary water losses. Perioperative fluids were nearly isotonic, providing her with almost no electrolyte-free water. Therefore, excretion of dilute urine without water replacement resulted in a rapid onset of severe hypernatremia with neurological symptoms. Treatment with 0.45% saline at 100 ml per hr was inadequate, because only 50 ml per hr of electrolyte-free water was provided, less than half the rate of urinary water losses. A rapid onset of severe hypernatremia risks osmotic demyelination and the plasma sodium should be rapidly re-lowered with a rapid infusion of 5% dextrose in water, combined with furosemide to eliminate the excess sodium given to her in the intravenous fluids.

Question 26

Explain this.

A 50 year old man is admitted with subarachnoid hemorrhage. He is treated with intravenous 0.9% sodium chloride (sodium concentration 154 mmol per liter) at 200 ml per hr, and plasma sodium gradually falls from normal to 125 mmol per liter. He is then treated with 4.5 liters of intravenous fluid having an average sodium concentration of 300 mmol per liter, and is given nothing by mouth. Despite therapy with hypertonic fluids, plasma sodium does not change. The 24 hour urine output is 4.8 liters, urine osmolality is 625 mOsm per kilogram, urine sodium 263 mmol per liter and urine potassium 24 mmol per liter.

Answer 26

This patient has the syndrome of inappropriate antidiuretic hormone secretion (SIADH) caused by subarachnoid hemorrhage. Vasopressin secreted in response to his acute neurological injury caused the urine to be concentrated (urine osmolality 625 mOsm per kilogram) despite the presence of hypotonic hyponatremia and large amounts of sodium were excreted in the urine because of volume expansion with isotonic saline. The plasma sodium concentration fell because the urine was hypertonic (urine sodium plus potassium concentration equals 287 mmol per liter). The sodium contained in two liters of isotonic saline can be excreted in just over one liter of hypertonic urine; the net effect is positive electrolyte-free water balance, weight gain and hyponatremia. Intravenous fluid with a sodium concentration of 7 300 mmol per liter was ineffective because the sodium plus potassium concentration of the infusate and its rate of input was nearly matched by the sodium plus potassium concentration of the urine and its rate of output. If urine output continues at its current rate and composition, infusion of 3% saline (sodium concentration 513 mmol per liter) at 100 ml per hour would approximately replace urinary sodium losses, allowing net electrolyte-free water loss which would increase the plasma sodium.

Question 27

Explain this.

A 30 year old woman with von Willebrand’s disease is treated with desmopressin before and after cholecystectomy to prevent bleeding. On the third hospital day, she has a major motor seizure. Plasma sodium concentration is 109 mmol per liter, urine osmolality is 325 millisomoles per kg, urine sodium is 114 mmol per liter and urine potassium is 9 mmol per liter. She is treated with 3% saline (sodium concentration 513 mmol per liter) at 100 ml per hour (2 ml per kg body weight per hour) for 5 hours and plasma sodium increases to 119 mmol per liter. During the next eight hours all fluid intake is withheld, the plasma sodium increases to 127 mmol per liter and she becomes fully alert and oriented. A repeat urine osmolality is 100 mOsm per kilogram and urine output is 600 ml per hr. The next day, plasma sodium is 139 mmol per liter. A day later she becomes unresponsive. Spastic quadriparesis and pseudobulbar palsy develops and, after two weeks, magnetic resonance imaging of the brain confirms the diagnosis of osmotic demyelination syndrome. The patient survives, with permanent, severe disabilities.

Answer 27

The patient developed symptomatic hyponatremia due to exogenous antidiuretic hormone (desmopressin). Because of severe symptoms, administration of 3% saline was indicated to increase plasma sodium by 4 to 6 mmol per liter. Absent urinary water losses, an increase of 10 mmol per liter would be expected, because 1 ml of 3% saline per kg body weight should increase the plasma sodium by approximately 1 mmol per liter and she was given 10 ml per kg. However, as the effect of desmopressin wore off and plasma hypotonicity suppressed endogenous vasopressin secretion, the urine became maximally dilute, and the plasma sodium continued to increase owing to urinary water losses. Three days of hyponatremia was sufficient time for brain cells to adapt; the large, rapid increase in plasma sodium (30 mmol per liter in 28 hours) caused osmotic demyelination, with a typical biphasic clinical course, and this resulted in permanent brain damage.

Question 28

Explain this.

A 60 year old man with a history of heavy beer drinking presents with confusion, weakness and falls 10 days after being started on hydrochlorthiazide for the treatment of hypertension. Serum sodium is 104 mmol per liter and serum potassium is 2.5 mmol per liter. Urine osmolality is 650 mOsm per kilogram and urine sodium is 10 mmol per liter. Hydrochlorthiazide is discontinued and he is treated with potassium supplements and 2 micrograms of desmopressin subcutaneously. Over the next six days, repeat doses of desmopressin are given every eight hours and he is also treated with an infusion of 3% saline that is adjusted to achieve a 4 mmol per liter daily increase in plasma sodium. When the plasma sodium concentration reaches 128 mmol per liter, desmopressin and 3% saline are discontinued. The patient’s symptoms resolve and his plasma sodium eventually returns to normal.

Answer 28

The patient has thiazide-induced hyponatremia with several risk factors for developing osmotic demyelination: plasma sodium less than 105 mmol per liter, hypokalemia, and alcoholism. Once the thiazide is discontinued, he is also at risk of developing a spontaneous water diuresis that could result in unintentional rapid correction of hyponatremia. Because of these risks, he was given desmopressin to prevent urinary water losses from developing. Repeated administration of desmopressin creates a state of iatrogenic SIADH and the plasma sodium is increased by administering hypertonic potassium chloride and sodium chloride. The goal of therapy for all patients with severe hyponatremia is a daily increase of 4 to 6 mmol per liter. Because of this patient’s added risk factors for developing osmotic demyelination syndrome, a 4 mmol per liter daily target was chosen.