Clinical review: Practical approach to hyponatraemia and hypernatraemia in critically ill patients

Disturbances in sodium concentration are common in the critically ill patient and associated with increased mortality. The key principle in treatment and prevention is that plasma [Na+] (P-[Na+]) is determined by external water and cation balances. P-[Na+] determines plasma tonicity. An important exception is hyperglycaemia, where P-[Na+] may be reduced despite plasma hypertonicity. The patient is first treated to secure airway, breathing and circulation to diminish secondary organ damage. Symptoms are critical when handling a patient with hyponatraemia. Severe symptoms are treated with 2 ml/kg 3% NaCl bolus infusions irrespective of the supposed duration of hyponatraemia. The goal is to reduce cerebral symptoms. The bolus therapy ensures an immediate and controllable rise in P-[Na+]. A maximum of three boluses are given (increases P-[Na+] about 6 mmol/l). In all patients with hyponatraemia, correction above 10 mmol/l/day must be avoided to reduce the risk of osmotic demyelination. Practical measures for handling a rapid rise in P-[Na+] are discussed. The risk of overcorrection is associated with the mechanisms that cause hyponatraemia. Traditional classifications according to volume status are notoriously difficult to handle in clinical practice. Moreover, multiple combined mechanisms are common. More than one mechanism must therefore be considered for safe and lasting correction. Hypernatraemia is less common than hyponatraemia, but implies that the patient is more ill and has a worse prognosis. A practical approach includes treatment of the underlying diseases and restoration of the distorted water and salt balances. Multiple combined mechanisms are common and must be searched for. Importantly, hypernatraemia is not only a matter of water deficit, and treatment of the critically ill patient with an accumulated fluid balance of 20 litres and corresponding weight gain should not comprise more water, but measures to invoke a negative cation balance. Reduction of hypernatraemia/hypertonicity is critical, but should not exceed 12 mmol/l/day in order to reduce the risk of rebounding brain oedema.

Th is case story illustrates common and important problems in managing the hyponatraemic patient. First, the initial 0.9 % NaCl approach is inadequate to ensure a rapid and controllable response [10]. Second, no measures to avoid overcorrection are taken, and he gets hypernatraemia despite being in the ICU [8]. Th ird, hyponatraemia often has multiple causes [11]. Fourth, nothing is done to identify the mechanisms of hyponatraemia [12].
Th is review takes a practical approach to the critically ill patient with dysnatraemia.

Plasma [Na + ] is determined by water and electrolytes
Knowledge about what determines P-[Na + ] is crucial for understanding the mechanisms behind dysnatraemia and how to correct/prevent these disorders. Within a population of heterogeneous patients, Edelman and colleagues [13] demonstrated that P-[Na + ] is determined by exchange able cations (eNa + and eK + ) and total body water (TBW) according to Equation 1: eNa + + eK + P-[Na + ] = α × ------+ β Equation 1 TBW where α and β are the coeffi cients from the linear regression.
Equation 1 is not readily useful at the bedside; however, it was recently demonstrated that it is valid in the individual and that changes in P-[Na + ] can be determined by the external balances of water and cations (Na + + K + ) [14]. Th e simplifi ed version (Equation 2) where α = 1 and β = 0 provides a good estimate of the P-[Na + ] changes and is useful for planning fl uid and electrolyte treatment in the individual patient [14][15][16]: [Na + ] 1 × TBW + Δ(Na + + K + ) [Na + ] 2 = ----------------Equation 2 TBW + ΔTBW where [Na + ] 1 is the initial plasma concentration and [Na + ] 2 is the concentration that results from the change in the external balances of water (ΔTBW) and cations (Δ(Na + + K + )). Equation 2 is fundamental in understanding changes in P-[Na + ]. It is, therefore, also fundamental in practical patient treatment. It is important, however, to keep in mind that the impending output side of the water and cation balances can only be guessed. Frequent measurement of output (especially diuresis) and P-[Na + ] is necessary and input of fl uids must be adjusted dynamically.
Equations 1 and 2 assume that plasma tonicity is determined by P-[Na + ]. Th is is true in hypernatraemia and, by far, in the most common hyponatraemic conditions. Translocational hyponatraemia is an exception. In this condition osmotically active substances confi ned to the extracellular/plasma compartment cause a shift of water from the intracellular compartment. In this situation, the resulting hyponatraemia is hypertonic. Th e most frequent clinical condition is hyperglycaemia (P-[Na + ] is reduced approximately 0.4 mmol/l per mmol/l increase in P-[Glc] (or a reduction of 2.4 meq/l per 100 mg/dl increase)) [17], but the condition can also be caused by mannitol. Pseudohyponatraemia is an unusual measurement fl aw in patients with hyperlipaemia/hyperproteinaemia whose plasma tonicity is normal. In the rest of this article, 'hyponatraemia' refers to hyponatraemia where plasma tonicity is decreased.

Regulation of P-[Na + ]
P-[Na + ] is tightly regulated between 135 and 145 mmol/l primarily by water intake (thirst) and renal water excretion [15]. Of lesser quantitative importance, P-[Na + ] is regulated by the kidney's regulation of cation excretion via the renin-angiotensin-aldosterone system. Th irst is stimulated when P-[Na + ] increases a few percent [18]. It is also stimulated by a decrease in the eff ective circulating volume, which is the part of the extracellular volume (ECV) that eff ectively perfuses the tissue [19]. Arginine vasopressin (vasopressin, or antidiuretic hormone (ADH)) reduces renal water excretion. Vasopressin binds to the V 2 -receptor in the collecting duct. Th is promotes traffi cking of aquaporin 2 to the apical membrane and passive water reabsorption to the hypertonic medullary interstitium [20]. Vasopressin secretion is stimulated when P-[Na + ] increases [18]. Vasopressin release can also be stimulated non-osmotically by a reduced eff ective circulating volume, stress, pain, nausea, vomiting, various drugs and exercise.
Irrespective of vasopressin, the kidney's ability to excrete water is infl uenced by solute intake (protein/urea and cations) since the urine volume is the solute excretion divided by the urine osmolality: solute excretion urea + electrolytes urine volume = ----------= ----------urine osmolality urine osmolality A low solute intake reduces urine solute excretion and thereby urine volume despite maximally diluted urine. In contrast, a high protein/urea intake or generation will increase the urine volume. However, urea does not directly determine P-[Na + ] (according to Equation 2). Th is is so because in the whole body perspective, urea eventually crosses cell membranes and therefore is an ineff ective osmolyte that does not contribute to water fl ux between cells and extracellular volume [15].
Altogether, the renal eff ects infl uencing P-[Na + ] are gathered in excretion of electrolyte-free water [21]: where U[Na + ] and U[K + ] are urine Na + and K + con centrations. If electrolyte free water clearance (cH 2 O e ) is positive, the urine increases P-[Na + ]; and if cH 2 O e is negative, urine decreases P-[Na + ].

Part l: hyponatraemia
In a patient with hyponatraemia, it must fi rst be determined whether acute correction is required. Th is decision is made based on the patient's symptoms at a time when the mechanisms causing the hyponatraemia are rarely known. Th e discussion of hyponatraemia therefore begins with the symptoms and possible interventions (initial approach shown in Figure 1). Next, the mechanisms and fi nal diagnostics are discussed.
Hyponatraemia with severe symptoms: airway, breathing, circulation and 3% NaCl bolus therapy Severe hyponatraemia symptoms (Table 1) are believed to be caused by cerebral oedema. Th is corresponds well with cellular swelling as the extracellular tonicity decreases [22]. Intracranial pressure (ICP) rises when the brain cells swell in the rigid skull. An effl ux of excitatory neurotransmitters (for example, glutamate) as a response to cell swelling [23] or decreased chloride conductance caused by the corresponding, low plasma [Cl -] might also, in part, explain the symptoms [24]. Because severe cerebral symptoms indicate ongoing brain damage and a substantial risk of incarceration, treatment should normally not be delayed by cerebral CT scanning as was the case in the case story [25]. Crucially, secondary brain damage caused by hypoxia, hypercapnia and hypoperfusion should ardently be avoided with an ABC approach [10,26]. Next, immediate ICP reduction is best induced with one or more boluses of 2 ml/kg 3% NaCl (or a corresponding amount of more hypertonic NaCl) given intravenously/intraosseously [27][28][29]. Th e eff ect is immediate, and bolus doses may be repeated at 5-minute intervals. One 2 ml/kg 3% NaCl bolus causes a controllable rise in P-[Na + ] of about 2 mmol/l (Example 1 in Box 1). Cerebral symptoms decrease when P-[Na + ] increases by 4 to 6 mmol/l [27][28][29]. Infusion of 0.9% NaCl should not be used to acutely increase P-[Na + ] as in the case story: such an infusion does not cause an immediate, controllable increase in P-[Na + ], and 0.9% NaCl might worsen the hyponatraemia in SIADH (see SIADH section and Box 1). Vaso pressin V 2 -receptor antagonists are not recommended: V 2 -receptor antagonists do not induce a controllable and fast increase in P-[Na + ] and the induction/worsening of hypovolemia can be hazardous [30].
Cerebral disease, hepatic encephalopathy and sedation can cause severe symptoms similar to those of hyponatraemia [31], but a slight P-[Na + ] increase will not worsen these conditions [32,33]. However, the clinician must always consider other conditions if the patient fails to respond, and a maximum of three boluses should be given (complete awakening cannot be anticipated if the patient has suff ered elevated ICP/seizures for hours [29]).
Th ere is no set P-[Na + ] level below which severe symptoms arise. Cerebral symptoms have been described at P-[Na + ] levels between 125 and 130 mmol/l [34,35]. A MRI study in pigs demonstrated that cellular swelling in the brain oedema corresponds with the relative reduction in P-[Na + ] [22]. Th is indicates that it is the relative reduction and its speed that are clinically interesting and not an arbitrarily defi ned absolute P-[Na + ] value [36]. Hence, a P-[Na + ] reduction from 160 to 128 mmol/l induces as much osmotic stress to the brain as a reduction from 113 to 90 mmol/l (illustrated in the case story). Th is also implies that patients with intracranial pathology (for example, intracranial bleeding, tumour or oedema) have an increased risk of cerebral deterioration if brain cells swell and that they may need correction at a higher P-[Na + ] (for example, P-[Na + ] = 135 mmol/l). Bolus treatment is therefore instituted based on the patient's symptoms and not on the basis of an arbitrarily defi ned P-[Na + ] value.

Cerebral symptoms determine treatment, not the assumed time course
Treatment should be guided by the patient's symptoms and not by the assumed acute (<48 hours) or chronic nature of hyponatraemia. Classifi cation of acute versus chronic hyponatraemia is based on brain-adaptive responses to hyponatraemia. Patients with days of hyponatraemia have fewer cerebral symptoms than patients with newly developed hyponatraemia [37]. Th is has been linked with cerebral volume regulation [38,39]. Adaption to sustained hyponatraemia by loss of organic osmolytes has also been proposed to increase the risk of OD (formerly known as central pontine myelinolysis) when correcting hyponatraemia [40][41][42][43]. OD is a devastating clinical condition with progressive quadriplegia, dysarthria, dysphagia and alterations of consciousness days after hyponatraemia correction, and it is proposed to be due to cell shrinkage and/or water diff usion diff erences in the brain [22,44]. Alcoholism, malnutrition, hypo kalaemia, liver failure and malignant disease increase the risk of OD [45].
Th ese observations lie at the root of the distinction between acute and chronic hyponatraemia in treatment protocols [46,47]. Th is distinction is arbitrary, though, and diffi cult to implement in practice. First, asymp tomatic chronic hyponatraemic patients bear the highest risk of symptomatic hyponatraemia, that is, acute worsening of chronic hyponatraemia with looming brain oedema (for example, as in the case story) [48]. Second, it is diffi cult to determine the time frame of hyponatraemia in the comatose patient brought to the emergency department (for example, as in the case story). Finally, OD has been demonstrated in case reports after correction of acute (<48 h) hyponatraemia, so cautious correction is also important in these cases [42,49].

Measures to avoid P-[Na + ] overcorrection
Avoiding overcorrection is pivotal to diminish the risk of OD (see the case story). No prospective studies have established an absolutely safe and defi nitive speed for correction of hyponatraemia. In retrospective studies, OD has been seen in patients corrected with more than 12 mmol/ l day and not in less rapidly corrected patients [41,43,50]. In a small clinical MRI study, OD lesions were seen in patients corrected with more than 10 mmol/l/day [42].
Because OD is more likely when the patients are corrected by more than 12 mmol/l/day, it seems reasonable, in the light of the brain's adaption mecha nisms, not to correct at a faster pace, even though there is no absolutely safe rate. Conservative therapeutic goals for correction of 8 mmol/l in 24 hours, 14 mmol/l in 48 hours and 16 mmol/l in 72 hours have been proposed [51]. Th erefore, only three 2 ml/kg 3% NaCl bolus doses should be given to patients with severe symptoms [51,52].
Brisk diuresis is the most common cause of overcorrection even without sodium input [51,53]. Diuresis can be counteracted by administering water and, if necessary, using desmopressin [54]. Hypokalaemia correc tion can contribute to P-[Na + ] overcorrection. If renal replacement therapy is necessary (for example, fl uid overload or hyperkalaemia), P-[Na + ] changes can be controlled by lowering the Na + concentration in the replacement fl uid to the desired P-[Na + ] level by adding water (note that this will also reduce the concentration of all other components in the fl uid) [55] or by reducing the blood fl ow [56].
Response to a bolus is observed aŌer 5 minutes: if symptoms decrease, go to "no severe symptoms"; if severe symptoms persist, infuse a maximum of three boluses. Corresponding amounts of more concentrated NaCl can be used.

Mechanisms and treatment of hyponatraemia without severe symptoms
Th e population of hyponatraemia patients in the ICU without severe symptoms comprises two groups: one initially with severe symptoms stabilized with bolus therapy and one initially not having severe symptoms. In these patients, treatment must be individualized and the underlying mechanisms identifi ed for safe and lasting correction. Traditional classifi cations according to volume status are of little use in clinical practice since hypo-and normo volaemia cannot be reliably separated [57,58], and multiple combined causes are common so a simple scheme cannot be used (see the case story) [11,59]. Mechanisms causing hyponatraemia are often revealed by the patient's treatment response [60]. Importantly, the initial mechanisms causing hyponatraemia may be evanescent and a rapid P-[Na + ] increase may occur. In all patients with hyponatraemia spot urine for urine osmolality and U-[Na + ] determination should be sampled as fast as possible and preferably before treatment.
Th e mechanisms causing hyponatraemia are discussed in the following sections and summarized in Figure 2.

Hyponatraemia despite suppressed vasopressin
Young, normally functioning kidneys have an enormous capacity to excrete water (1 l/h), so excessive water input (polydipsia, infusion of hypotonic fl uids or absorption of irrigant solutions) must exceed 1 l/h to produce hyponatraemia. Much less water ingestion can produce hyponatraemia when the kidney's ability to excrete water is reduced. In beer potomania and severe malnutrition (for example, due to chronic disease like cancer or anorexia nervosa), a low solute intake (protein and cations) decreases the kidney's ability to excrete water as pure water cannot be excreted [15,61]. Th is is a possible contributing mechanism in the case story. Th e kidney's diluting capacity is also reduced independently of vasopressin [62] with decreased delivery of fl uid to the distal nephron. A reduction in the glomerular fi ltration rate with increasing age, various drugs (Table 2) and various disease states (for example, reduced eff ective circulating volume) will therefore render the patient more vulnerable to water ingestion. Treatment should address these mechanisms: reduce water intake (avoid hypotonic fl uids), improve nutrition and restore kidney function.

Thiazide-induced hyponatraemia
Th iazide-induced hyponatraemia (TIH) is common and may have contributed to the hyponatraemia in the case story [50,63]. Th e mechanisms by which some individuals (females more than males) develop TIH are not clear [63]. In contrast to loop diuretics, thiazides do not reduce the medullary concentration gradient in the kidneys necessary for concentrating the urine, but reduce NaCl transport in the diluting segment of the nephron. Desalination is a necessary consequence of thiazides [64], but whether this results in overt hyponatraemia is dependent on other partly unknown factors. A preexisting urine dilution defect (old age, medications like NSAIDs) may be worsened by thiazides independently of the vasopressin levels [65]. One study proposes increased thirst as a mechanism for TIH [66]. However, a small decrease in eff ective circulating volume with nonosmotically stimulated thirst/vasopressin-secretion may also contribute. Following TIH, a substantial risk of overcorrection looms.

Optimize eff ective circulating volume in hypervolaemic conditions
In conditions with increased ECV/plasma volume (congestive heart failure, cirrhosis, nephrotic syndrome and sepsis), hyponatraemia is caused by non-osmotic stimulation of vasopressin and thirst due to a reduced eff ective circulating volume. Stigmata and the patient's history may help the diagnosis. Optimizing the haemodynamics is the cornerstone of treatment in this situation. Th e underlying conditions can occasionally be improved, such as by angiotensin-converting-enzyme (ACE) inhibitors in heart failure [67] and the use of spironolactone in advanced liver disease [68]. P-[Na + ] is corrected with water restriction (avoid hypotonic fl uids) and loop diuretics [68]. Treatment with V 2 -receptor antagonists seems rational, but a randomized trial has shown no survival benefi ts [69], and overcorrection may occur [70]. Hypertonic saline infusion (improves eff ective circulating volume) together with loop diuretics has been shown to be eff ective sometimes in refractory heart failure and ascites [33].

Restore eff ective circulating volume in conditions with hypovolaemia
In hypovolaemia conditions, loss of total body solutes (Na + and K + ) results in a reduced eff ective circulating volume, non-osmotic vasopressin secretion and thirst. In this situation, hypotonic fl uid ingestion/infusion causes hyponatraemia. Diff erentiating these conditions from SIADH can be challenging because the reduced eff ective circulating volume (and ECV) is diffi cult to determine clinically [57,58].
Extra-renal causes of solute loss are diagnosed by the patient's history (bleeding, gastrointestinal loss, exercise [71] and sweating) and by U-[Na + ] <30 mmol/l in spot urine; however, exceptions exist (concurrent use of diuretics, compensating renal loss of NaHCO 3 in metabolic alkalosis (vomiting) or mineralocorticoid insuffi ciency).
Th e solute loss can also have renal causes. TIH has previously been discussed as a potential cause. Other renal mechanisms are osmotic diuresis, salt-losing nephro pathy including mineralocorticoid defi ciency, and cerebral salt wasting (CSW).
CSW is a condition with reduced eff ective circulating volume and unexplained/inappropriate natriuresis. Th e mechanisms leading to it are not clear [72,73]. Diagnostic diffi culties are rooted in the problem of determining the eff ective circulating volume and in the fact that the neuro intensive patient (for example, traumatic brain injury, subarachnoid haemorrhage) receives large amounts of normal and hypertonic saline to avoid hypovolaemia and hyponatraemia [74]. Th is sodium loading induces natriuresis in the normal kidney [75,76]. Inadequate release of brain natriuretic peptide has been proposed as a contributing mechanism in CSW [77].
Renal causes of hyponatraemia result in high U-[Na + ] levels and may have characteristics similar to those of SIADH. Responses to infusion of 1 to 2 l 0.9% NaCl can help clarify the diagnosis. Increased P-[Na + ] favours ECV/Na + defi cit: sodium, and to a lesser extent water, is retained, which increases P-[Na + ]. Additionally, normal saline restores the eff ective circulating volume and reduces the non-osmotic stimulus of vasopressin secretion. Unchanged or decreased P-[Na + ] makes SIADH  likely: the patient with SIADH is normally in sodium balance (output is refl ected in input) and the infused Na + is excreted. However, the urine is concentrated and urine cations are generally higher than the 0.9% NaCl (308 mOsm) resulting in retention of water and a decrease in P-[Na + ] (cH 2 Oe is negative) (Example 2 in Box 1) [15]. Infusions of 0.9% NaCl must increase ECV by 1 to 2 l and the infusion speed must therefore exceed ongoing losses [78].

Hyponatraemia induced by diuretics may entail a fractional excretion of uric acid (FE-UA = (U-[uric acid] × P-[creatinine])/(U-[creatinine] × P-[uric acid]))
below 8% [79]. However, CSW and SIADH can both have an FE-UA >12%, and it may be necessary to distinguish between the two conditions in terms of their response to water restriction or a vasopressin V 2 -receptor antagonist (FE-UA and P-[Na + ] is normalized in SIADH) [80]. However, this approach is not recommended in the neurointensive patient because it involves a substantial risk of worsening the hypovolaemia [74]. A practical approach is to control P-[Na + ] with 0.9% NaCl and hypertonic NaCl in the neurointensive patient [81].
Once the diagnosis is established, the underlying disease should be treated and the balances, including potassium and water defi cit, should be restored. Abolition of the non-osmotic stimulus of vasopressin secretion involves a substantial risk of overcorrection caused by brisk diuresis.

Syndrome of inappropriate antidiuretic hormone
Non-osmotic vasopressin secretion and abnormal thirst are present in SIADH despite a normal eff ective circulating volume [78,[82][83][84][85]. In the critically ill patient, the mechanisms of inappropriate vasopressin secretion and thirst are heterogeneous. Th is may be due to various drugs (Table 2), malignant disease, central nervous system disorders (infection, bleeding, thrombosis, spaceoccupying disorders, psychosis and generalised disorders), pulmonary disorders (infection, asthma, respirator treatment) or other causes (general anaesthesia, postoperative nausea, pain and stress) [78,86]. Th ese causes of SIADH may be divided into self-limiting mecha nisms with an inherent risk of overcorrection when the vasopressin stimuli are abolished, and persis tent conditions, for example, a paraneoplastic phenome non that, in the absence of vasopressin V 2 -receptor antagonist treatment, will rarely be overcorrected.
Other hyponatraemia mechanisms are likely to co-exist in the critically ill patient (for example, thiazide therapy, low solute intake, renal impairment), and it is important to determine and correct these causes. Urine investigation (U-Osm and U-Na + ) is important, although it is not always performed [12]. U-Na + can be low in SIADH with a low salt intake. Failure to increase P-[Na + ] with 1 to 2 l 0.9% NaCl intravenously is a practical way of tracing SIADH without inviting the risk of circulatory collapse (Example 2 in Box 1). Plasma uric acid below 238 μmol/l (<4 mg/dl) and FE-UA above 12% also likely suggest SIADH [79].
When a reduced eff ective circulating volume has been ruled out and persistent SIADH is a likely diagnosis, the cornerstone is investigation and treatment of its underlying causes. In the critically ill patient, the input side of Equation 2 is controlled and hyponatraemia may be corrected with water restriction and avoidance of hypotonic fl uids. Loop diuretics and increased solute intake (for example, 0.5 to 1 g/kg/day urea in the gastric tube [89]) can be used to increase water excretion. Compliance problems with urea administration in the critically ill patient seem small, and urea (as ineff ective osmolytes) has been shown to reduce the risk of OD in experimental studies [90]. If SIADH persists, vasopressin V 2 -receptor antagonists may be the most eff ective option in terms of correcting P-[Na + ]. However, lack of studies in the

Exclude adrenal and thyroid insuffi ciency
In adrenal insuffi ciency with glucocorticoid defi ciency, the hyponatraemia mechanisms include an increased vasopressin/thirst response [92] and a decreased eff ective circulating volume [93]. In the critically ill patient with suspected adrenal insuffi ciency, a random serum cortisol and plasma adrenocorticotropic hormone is obtained followed by 100 mg hydrocortisone intravenously. A serum cortisol level above 700 nmol/l (25 μg/dl) virtually excludes adrenal insuffi ciency [94,95]. If this is inconclusive, low-dose adrenocorticotropic hormone stimulation should be performed after cessation of hydro cortisone (details in Figure 2). Hypothyroidism is occasionally associated with hyponatraemia. Th e mechanisms are unclear. Fluid retention, impaired cardiac and renal function are likely [96]. Patients should be screened with plasma thyroidstimulating hormone and T4 [95].

Part 2: hypernatraemia
Why did the man in the case story develop hypernatraemia while staying in the ICU and how could it have been prevented? Hypernatraemia is less common than hyponatraemia, but the patient is generally more ill and has a higher mortality [3]. Th e initial approach is ABC management followed by treatment of underlying diseases and restoration of the distorted physiology. Th e discussion of hypernatraemia therefore addresses fi rst the mechanisms, then treatment. Th e discussion of the mechanisms addresses situations of water and solute loss, pure water loss and increased total body solutes. Multiple combined causes are common. Mechanisms and treatment are summarized in Figure 3.

Hypernatraemia with water and solute loss
Th is condition arises by a negative water balance exceeding a concomitant negative cation balance (Equation 2). Th e resulting hypovolaemia is the most common condition in hospitalised hypernatraemic patients [97].
Diminished water intake is a pivotal mechanism of increased P-[Na + ] [97]. Individuals at risk of insuffi cient drinking often have an altered mental status (critical illness, sedation, neurological impairment) or they are intubated patients, infants [98] or geriatric patients [99].
An enhanced water above salt loss contributes to hypernatraemia. Fever is a common contributing factor [21,97,100]. A high loss through the skin can result from a high temperature in the environment, from exercise or wounds (for example, burns). Gastrointestinal loss of hypotonic fl uid is increased by diarrhoea (for example, infection, lactulose).
A renal concentrating defect frequently contributes to hypernatraemia. Several mechanisms are responsible for this. Loop diuretics contribute, especially in the critically ill patient [21]. Osmotic diuresis (U-Osm >300 mOsm with hypernatraemia) can be induced by hyperglycaemia. Osmotic urea diuresis is seen with excessive protein nutrition and protein wasting and diagnosed by increased electrolyte-free water excretion [101]. Mannitol also induces osmotic diuresis. A renal concentrating defect is seen with kidney insuffi ciency. Rare causes are hypercalcaemia and potassium depletion.
Th e patient is treated by restoring the ECV and water defi cit (Example 3 in Box 1).

Hypernatraemia with pure water loss
Th is condition develops when the water balance is negative and the cation balance is normal. Th e reduction in ECV is far less than with a concomitant salt loss. Diminished water intake is obligatory [102]. Individuals with reduced water intake (infants, old, debilitated patients) will have appropriate, maximally concentrated urine. Patients with a functionally decreased vasopressin response to hypertonicity (central or nephrogenic diabetes insipidus) only develop hypernatraemia when water intake is restricted (for example, critical illness). Diabetes insipidus occasionally develops in the critically ill patient (for example, by traumatic brain injury and late-phase septic shock) and U-Osm is inappropriately low. In rare situations, the set point for osmolality is directly increased due to cerebral disease resulting in essential hypernatraemia and reduced thirst at a given sodium concentration.
Treatment is restoration of the water defi cit (Example 3 in Box 1). Water loss in central diabetes insipidus can be reduced with desmo pressin. Treatment of nephrogenic diabetes insipidus is challenging and may comprise drug evaluation, correction of hypercalcaemia or hypokalaemia and low-solute diet to decrease urine volume and thiazides.

Hypernatraemia with increased total body solute
Hypernatraemia with increased ECV develops when the cation balance is positive, which is frequently observed in ICU-acquired hypernatraemia [6,21]. Increased input of cations is mandatory. Th is is seen in conjunction with correction of water loss with 0.9% NaCl. Also, correction of hypokalaemia with hypertonic potassium-containing solutions (for example, 0.9% NaCl added 40 mmol KCl) may contribute to hypernatraemia. Hypernatraemia can be induced therapeutically with hypertonic saline to reduce ICP [103] or as a side eff ect seen with NaHCO 3 treatment. In healthy individuals, an increased salt load is excreted in the urine [75,76]. Natriuresis can be diminished in the critically ill patient with a reduced eff ective circulating volume and a low glomerular fi ltration rate [104]. A diagnosis of solute overload is made from the history, water-and cation balances and, if available, weight changes. Salt intoxi cation outside the hospital is rare, but may arise by suicide attempts with soya sauce and by inappropriate administration of solute in nursery homes [105].
Treatment consists of creating a negative cation balance by reducing the cation input and increasing the cation output with diuretics or, rarely, dialysis.

Symptoms and correction of hypernatraemia
Hypernatraemic patients are generally critically ill and it may be diffi cult to determine whether cerebral symptoms stem from hypernatraemia (decreased level of consciousness, irritability, hyper-refl exia, spasticity and seizures) or the underlying disease.
Th e fi rst principle in treatment is ABC. Circulatory collapse/hypoperfusion is treated with infusion of 0.9% NaCl according to haemodynamic parameters ( Figure 3) [106]. Th is should be paralleled by investigation and treatment of the underlying mechanisms (for example, insulin, antibiotics and antipyretics). Clinical evaluation of volume status is notoriously imprecise, and the only sign may be cerebral symptoms in the elderly/infant [98,99]. Next, total body solute cannot be measured in a clinical setting. Simple measures can be helpful (for example, history, weight, accumulated fl uid/electrolyte balances and electrolyte-free water clearance to diagnose the mechanisms behind the hypernatraemia (Figure 3)). Finally, the water/cation balance is restored.
Too rapid P-[Na + ] correction can provoke seizures, probably from cerebral oedema [107][108][109][110]. Th is has been linked with the brain cells' adaption to the hypertonic state by accumulation of solute [108]. Th e relative reduction in tonicity results in cellular swelling. However, failure to correct the hypernatraemia is associated with higher mortality [111,112]. No optimal correction rate has been determined, but it has been suggested that it should not exceed 0.5 mmol/l/h [107]. A practical  Overgaard-Steensen and Ring Critical Care 2013, 17:206 http://ccforum.com/content/17/1/206 approach is to decrease P-[Na + ] 5 to 6 mmol/l the fi rst hours (1 mmol/l/h) and then slow down the correction rate so the total correction is 12 mmol/l in 24 hours (0.5 mmol/l/h) [97,98]. Th e change in tonicity is important. Th e measured P-[Na + ] must therefore be corrected for any hyperglycaemia.
In hypernatraemia with water loss, the water correction rate can roughly be estimated from: [Na + ] corrected ΔTBW = TBW × ( --------1) Target  In severe cases with renal failure, renal replacement therapy should be instituted. Here, the Na + content in the replacement fl uid/dialysate must be increased to the desired P-[Na + ] by NaCl addition to avoid overly rapid correction [55].

Conclusion
Dysnatraemia is common in the critically ill patient and is associated with increased mortality. Th e case story illustrates common and important treatment problems in the hyponatraemic patient. Th e key principle in treatment and prevention is that P-[Na + ] is determined by external water and cation balances. First, the patient should be treated according to an ABC approach to diminish secondary organ damage. Next, symptoms are critical when handling a patient with hyponatraemia. Severe symptoms are treated with 2 ml/kg 3% NaCl bolus infusions irrespective of the proposed time course. Th e goal is to reduce cerebral symptoms. Th e bolus therapy gives an immediate, controllable rise in P-[Na + ]. A maximum of three boluses are given. In hyponatraemic patients, any correction exceeding 10 mmol/l/day must be avoided to reduce the risk of OD. Reduced vasopressin action and brisk diuresis are the most common mechanism and they must be counteracted by increasing water input and, if necessary, by desmopressin. Th e risk of overcorrection is associated with the mechanisms causing hyponatraemia. Traditional classifi cations according to volume status are notoriously diffi cult to apply in clinical practice. Moreover, multiple mechanisms are common and may easily be mixed. More than one mechanism must therefore be investigated for safe correction.
First and foremost, the patient in the case story develops hypernatraemia in the ICU because the problem is not addressed. Pivotal is treatment of the underlying diseases and restoration of the distorted water and salt balances based on knowledge of what determines P-[Na + ]. Multiple combined mechanisms are common and must be identifi ed. Importantly, hypernatraemia is not only a matter of water defi cit, and treatment of a critically ill patient with an accumulated fl uid balance of 20 litres and corresponding weight gain is not more water, but a negative cation balance. Reduction of P-[Na + ]/plasma tonicity in hypernatraemia is important, but should not exceed 12 mmol/l/day to reduce the risk of rebounding brain oedema.