OSMOLALITY

Osmolality is the measure of osmoles of solute per kilogram of solvent and includes both permeant (e.g. urea) and impermeant solutes (e.g. sodium) and thus osmolality may change due to both water movement and the movement of permeant solute. Osmolarity is the measure of osmoles per litre of solute and thus is temperature-dependent. Osmolality is temperature-independent. Normal plasma osmolality is in the range of 275–295 mosmol/kg. Plasma osmolality can be estimated from several equations.¹ The formula of Worthley et al.² below is both simple and correlates well with measured values.³

All units of solute are mmol/l.

Where a patient is markedly uraemic, a value of 8 mmol/l is substituted for the actual urea. Actual osmolality may differ markedly from estimated osmolality in the presence of unmeasured, osmotically active solutes such as mannitol, ethanol, bicarbonate, lactate and amino acids. Whenever concern exists that a patient may be hyper- or hypo-osmolal, osmolality should be measured by assessing the freezing-point depression of the plasma or urine. Increasing the osmolality results in depression of the freezing point.

The osmolal gap is the difference between the calculated and measured osmolality in plasma or urine.The normal osmolal gap is < 10 mosmol/l. An increased osmolal gap indicates the presence of an unmeasured osmotically active solute.

TONICITY

Tonicity describes the ability of a solution of impermeant solute (such as sodium) to cause the movement of water between itself and another fluid compartment. It may be considered an index of the water concentration rather than the solute concentration as the solute is impermeant. The tonicity of plasma is largely determined by its sodium content, the main solute in extracellular fluid, which is not freely permeable to cross into the intracellular space. This characteristic facilitates the control of extracellular fluid volume through the regulation of sodium balance.

It is possible for a solution to be both hypotonic and iso-osmolar. Dextrose solution 5% is an example of this; the solution contains no impermeant solute (assuming no absence of insulin, glucose freely enters the cell), but is iso-osmolar with the intracellular milieu.

SOLUTE AND WATER INTAKE AND LOSSES

In order to understand disorders of osmolality, tonicity, fluid balance and urine output, it is necessary to be aware of the essential physiological mechanisms which maintain the fluid and osmolal states of the body in health. Assuming a normal diet, in a 75-kg man, every day there is an obligatory loss of around 800 mmol of solute – approximately 300 mmol of urea and 500 mmol of cations and anions. The maximum concentrating ability of the healthy kidney is around 1200 mosmol/kg; consequently, a minimum of 666 ml of urine a day is required to excrete osmotically active solutes. Additionally, insensible losses of water (respiratory water, faecal water and sweat) approximate to 10 ml/kg per day and this rises markedly with fever and hot dry climates. Thus obligatory water losses of around 1.5 l/day arise due to insensible losses and obligatory solute excretion.

NORMAL URINARY OSMOLALITY

In health, urinary osmolality is usually maintained between 500 and 700 mosmol/kg. As the obligatory solute load to be excreted is relatively constant in value, urine osmolality will fall in response to an increased intake in free water and rise in response to dehydration or water restriction (Figure 51.1). The minimum osmolality of urine achievable inhumans is around 25 mosmol/kg. Diuresis refers to the passage of a high volume of urine (> 1.5 ml/kg per hour) and may be transient or persistent, physiological or pathological. The production of > 3 l/day is arbitrarily defined as polyuria. Water diuresis occurs when the total solute in the urine excreted per day is within the normal range but the osmolality of the urine passed is low. An osmotic or solute diuresis occurs when the total solute passed per day is higher than normal, and the urine passed is usually iso-osmolar to plasma if the extracellular fluid volume is expanded or hyperosmolar if the patient is hypo- or euvolaemic.

Figure 51.1 Urine output rises and urine osmolality falls in health as a function of increasing water intake. Assuming normal solute ingestion, normal solute excretion (around 800 mmol/day) is preserved between water intakes of 1.5 and 32 litres/day.

PLASMA OSMOLALITY AND PLASMA VOLUME REGULATION

Changes in plasma osmolality and changes in plasma volume can occur in tandem or independently of one another. Although normal plasma osmolality lies in a population range of 275–295 mosmol/kg (265–285 mosmol/kg in pregnancy), individuals tend to vary less than ± 1% around their set value. In pregnancy this set value falls but the limited variability around it does not. The body regulates osmolality and volume by separate mechanisms. Water balance and osmolality are maintained via osmoreceptors which mediate their control via control of thirst and ADH production. Control of the plasma volume is maintained via volume receptors and sodium receptors, which mediate their actions through the sympathetic nervous system, the renin–angiotensin–aldosterone system and atrial natriuretic peptide (ANP). Additionally, the volume receptors have inputs to the hypothalamus via which they too can mediate ADH release and the sensation of thirst.

THIRST

In health fluid intake is determined by the sensation of thirst and the subsequent ingestion of fluid; a plasma osmolality of > 290 mosmol, elevated angiotensin II concentration, sympathetic nervous system activation and circulating volume depletion of 5–10% are all associated with the onset of thirst. Fluid and solute excretion are largely regulated through the kidney, although some solutes such as ethanol and glucose are largely cleared through metabolism rather than excretion.

In the intensive care unit (ICU), the patient loses control over intake of fluids and solute and frequently has impaired excretory mechanisms. Thus both volume and solute homeostasis may become heavily dependent upon the skills of attending clinicians.

OSMORECEPTORS AND OTHER INPUTS TO THE SUPRAOPTIC AND PARAVENTRICULAR NUCLEI

Detection of osmolality occurs largely at osmo- (Na⁺) receptors sited around the anterior aspect of the third ventricle of the brain. These are sensitive to plasma osmolality and cerebrospinal fluid sodium concentration. Hypertonic saline is a more potent stimulus than equi-isotonic equiososmolar solutions of other solutes.⁴ These osmoreceptors link to the cells of the paraventricular nuclei (PVN) and supraoptic nuclei (SON), the sites of ADH synthesis. The axons of the cells in the PVN and SON form part of the pituitary stalk linking the hypothalamus to the pituitary gland in which they terminate. A smaller proportion of the axons terminate in the median eminence where they release ADH and oxytocin, which is transported to the anterior lobe of the pituitary by portal vessels. The ADH and oxytocin so released cause release of adrenocorticotrophic hormone (ACTH) and prolactin respectively; the ADH acts synergistically with corticotrophin-releasing factor (CRF) but is also believed to have ACTH secretagogue properties in its own right.^5,6

Direct inputs from the sympathetic nervous system to the PVN and SON can stimulate ADH release via α-adrenoreceptors. Other central osmoreceptors lie outside the blood–brain barrier in the subfornical organ and come into contact with plasma. It is believed that ANP and angiotensin II⁷ act via these receptors to inhibit or elicit ADH synthesis and ADH release and to modify the sensation of thirst. Additional osmoreceptors in the mouth, stomach and liver are believed to play a role in the anticipation of an osmolal load following ingestion of food and can pre-emptively stimulate ADH synthesis in the hypothalamus.

As the baroreceptor and osmoreceptor inputs to the PVN and SON are distinct, it is possible to lose the normal ADH response to hyperosmolality but maintain a normal ADH response to hypovolaemia.⁸ Additionally, in animal experiments, when hypotension increases the basal plasma ADH concentration, there is a simultaneous resetting of the osmomolality–plasma ADH response curve in an attempt to preserve osmoregulatory function from the new higher baseline.⁹ If this did not occur, the ADH response to hypotension would always result in the development of a hypo-osmolal state in addition to causing vasoconstriction.

The normal response of osmoreceptors to changing plasma osmolality in terms of ADH is illustrated in Figure 51.2. At plasma osmolalities of < 275 mosmol/kg, the osmoreceptors remain hyperpolarised and virtually no ADH release occurs via them. At osmolalities > 295 mosmol/kg, the osmoreceptors are maximally depolarised and plasma concentrations of ADH of > 5 pg/ml are attained. Other inputs and influences upon ADH release are summarised in Figure 51.3 and Table 51.2.

Figure 51.2 Plasma antidiuretic hormone (ADH) and plasma osmolality in health and partial cranial diabetes insipidus.

Figure 51.3 A schematic representation of anatomical and physiological connections of the supraoptic and paraventricular nuclei (SON and PVN), the principal sites of antidiuretic hormone (ADH) synthesis within the hypothalamus. Blue arrows represent the transport of ADH or its precursor between anatomically distinct sites. Baroreceptor inputs into these nuclei travel via the vagus nerve to reach the central nervous system. Whilst the majority of ADH produced in the SON and PVN is transported to the posterior pituitary (PP) for storage, some is transported to the median eminence (ME) then onwards to the anterior pituitary (AP), where it acts synergistically as a secretagogue for adrenocorticotropic hormone (ACTH). APo, area postrema; SFO, subfornical organ; CRF, corticotrophin-releasing factor.

Table 51.2 Factors influencing antidiuretic hormone (ADH) release

ANTIDIURETIC HORMONE/ARGININE VASOPRESSIN (AVP)

ADH (8-arginine vasopressin) is a nine-amino-acid peptide which differs from oxytocin at only two residues but shares the disulphide bond between the first and sixth ones. This similar structure and conformation results in some cross-reactivity at receptors and in function.¹⁰ It is synthesised in the SON and PVN, bound to neuorophysin, transferred through axons to the posterior pituitary gland and stored in granules prior to release. Synthesis to replace any released stores is a rapid process (1–2 hours from synthesis to storage) and patients with damage to the pituitary can achieve near-normal plasma concentrations of ADH, in terms of osmoregulatory function, via release of newly synthesised ADH via the axons terminating in the median eminence. However, the higher plasma concentrations associated with hypovolaemia cannot be achieved. Normal osmoregulatory plasma ADH concentrations are in the range of 1–8 pg/ml but rise as high as 40 pg/ml in hypovolaemic patients under the influence of the sympathetic nervous system, baroreceptor responses and angiotensin II.

Once released from the pituitary, ADH has a plasma half-life of around 10–35 minutes.¹¹ It is metabolised by hepatic and renal vasopressinases and around 10% of the active hormone is excreted unchanged in the urine.

VOLUME RECEPTORS

Volume homeostasis takes precedence over sodium homeostasis and so rises and falls in sodium will occur in order to preserve the circulating volume. In euvolaemic patients sodium homeostasis is maintained. Sodium concentration is detected by both the osmoreceptors of the subfornical organ outside the blood–brain barrier and also by the juxtaglomerular apparatus which secretes renin in response to reduced GFR and a lower sodium load in the tubule.²³

The predominant determinants of sodium balance, however, are the high-pressure baroreceptors in the pulmonary veins, left atrium, carotid sinus and aortic arch.²⁴ Reduced stretch of these receptors increases sympathetic nervous system activity and activation of the renin–angiotensin–aldosterone system, resulting in reduced sodium excretion (via reduced GFR) and increased reabsorption of sodium in the proximal and distal convoluted tubules. Additionally, release of ADH can be stimulated, resulting in concomitant water retention. Conversely, stretch of the baroreceptors will result in a fall in sodium retention through reduced activity of the sympathetic nervous and renin–angiotensin–aldosterone systems. Stretch additionally results in the release of ANP and a natriuresis through reduced sodium reabsorption in the distal convoluted tubule and collecting duct. ADH release is reduced by the fall in sympathetic nervous tone from the baroreceptors. ADH secretion may also be inhibited by the action of ANP on cerebral osmoreceptors lying outside the blood–brain barrier.²⁵

The role of low-pressure baroreceptors in the systemic venous circulation and right atrium is less clearly defined. When venodilatation occurs, as is seen in sepsis, or when there is a reduction in cardiac output, reduced baroreceptor signalling in the high-pressure system will result in both sodium and water retention, as outlined previously. This will expand the extracellular fluid compartment and potentially cause tissue oedema. As sepsis resolves, venous tone is restored, capillary leak reduces, an increase in the loading of the high-pressure baroreceptors results and a natriuresis takes place. Patients may become transiently polyuric as they clear the excess salt and water accumulated whilst shocked. During this physiological diuresis, plasma osmolality remains tightly within the normal range, provided that renal concentrating mechanisms have not been injured during the septic episode or by drug administration.

CONGENTIAL CDI

Congenital CDI is rare and usually inherited as an autosomal-dominant characteristic which results from mutations of the gene encoding an ADH precursor – preprovasopressin neurophysin II. The onset of the disease may occur anywhere between 1 year of age and middle adult life and is associated with the final destruction of the ADH-producing cells due to an accumulation of the abnormal ADH precursor. Until the destruction of the SON and PVN cells occurs, ADH secretion (facilitated by expression of the normal gene) and regulation of plasma osmolality are often unaffected.

ACQUIRED CDI

Acquired CDI may be transient or permanent and can arise due to an absolute (complete) or relative (incomplete) lack of ADH. Complete central DI is usually associated with lesions above the level of the median eminence in the SON or PVN or of the neurohypophyseal stalk whereby the production of ADH in the hypothalamus is terminated.²⁶ Permanent central DI tends to be associated with transecting, obliterating or chronic inflammatory lesions, whereas transient DI is more likely to be associated with acute inflammatory or oedematous lesions with some recovery of ADH secretion occurring as the inflammation or oedema resolves. An exception to this is the transient DI seen following excision or destruction of the posterior pituitary; ADH produced in the hypothalamus can still be released into the systemic circulation from capillaries in the median eminence.

In the past the majority of acquired non-traumatic CDI was categorised as idiopathic but it has become apparent that the majority of these cases are associated with abnormality of the inferior hypophyseal arterial system²⁷ or autoimmune reactivity against ADH-producing cells.²⁸ These findings may indicate causality or association.

When the normal release of ADH into the circulation in response to rising plasma osomolality is reduced or absent, inappropriately high urine volumes are passed and the urine osmolality becomes inappropriately low for the state of water depletion being suffered by the patient. Where ADH is entirely absent from the circulation, over 20 litres of very dilute urine (25–200 mosomol/kg) per day may be produced. If patients are unable to drink freely (most ICU patients) or their thirst mechanisms are impaired, profound dehydration will result very rapidly unless appropriate interventions are made by the physician.

Where ADH deficiency is relative rather than absolute, it is possible for the patient to concentrate the urine partially and values of 500–800 mosmol/kg would not be atypical. However, these osmolalities are inappropriately low relative to the plasma osmolality. In partial ADH deficiency volumes of urine as low as 3 l/day may be evidenced. These are still inappropriately high when assessed in terms of the solute excretion of the patient but are more difficult to recognise as being due to DI as there are many other causes of diureses of this magnitude. Additionally, extrinsic stimulants of ADH release (see Table 51.2) may have an antidiuretic effect, further complicating the diagnosis.

The plasma osmolality measured in central DI is usually in the higher regions of the normal range or very slightly supranormal. It is remarkably constant in those with free access to water and intact thirst mechanisms as they will drink huge quantities of water to regulate and maintain their water balance. Hyperosmolality or hypernatraemia suggest impaired sensation of thirst or inability to access water (see water deprivation test later) and can also be seen if patients are administered large quantities of isotonic saline or Hartmann’s solution to replace their hypotonic urine losses. If unrecognised and untreated, hyperosmolality and hypernatraemia may result in death.

CDI is usually associated with reduced production of ADH or damage to the normal release mechanisms of ADH. However, there can be dysfunction of the osmolality-sensing mechanism at receptor or intracellular signalling levels whilst actual ADH production and storage are normal. It is possible to have a normal release of ADH in response to baroreceptor detection of hypotension but subnormal release in response to hyperosmolality. This has been described in association with chronic hypernatraemia.²⁹

The main recognised causes of central DI are listed in Table 51.3. A particularly common cause of DI seen in the ICU is traumatic or postsurgical brain injury. Transsphenoidal surgery for treatment of suprasellar tumours can result in DI in 10–70% of patients; the frequency parallels the magnitude of the tumour being removed. Additionally, transcranial surgery may cause the development of DI in the absence of a fall in plasma ADH. This is postulated to be due to the release of a hypothalamic ADH precursor which acts as a competitive antagonist of both ADH and synthetic analogues. The presence of a competitive antagonist effectively creates an endocrinologice picture similar to NDI with normal or high plasma ADH levels but an inappropriate diuresis of dilute urine.

Table 51.3 Causes of cranial diabetes insipidus

* Doczi T, Tarjanyi J, Kiss J. Syndrome of inappropriate antidiuretic syndrome after head injury. Neurosurgery 1982; 10: 685–8.

† Repaske DR, Medlej R, Gulteken EK et al. Heterogeneity in clinical manifestation of autosomal dominant neurohypophyseal diabetes insipidus caused by a mutation encoding Ala¹-Val in the signal peptide of the arginine vasopressin/neurophysin II/copeptin precursor. J Clin Endocrinol Metab 1997; 82: 51–6.

Following surgery or traumatic brain injury, several different patterns of polyuria can be seen: immediate permanent or transient polyuria, initial normal or low urine production followed by transient or permanent polyuria, or initial low followed by normal urine output. Additionally, a classical triphasic pattern of urine output may be observed with: