Electrolyte disorders in the critically ill

INTENSIVE CARE

Electrolyte disorders in the critically ill

Learning objectives After reading this article, you should be able to: C recognize the multiple aetiologies of electrolyte abnormalities of the critically ill C identify the signs and symptoms of the various electrolyte abnormalities C prescribe (describe?) appropriate management (plans?) of abnormalities, in particular the management of different types of dysnatraemia

Sing Chee Tan Ross Freebairn

Abstract Electrolyte disorders are extremely common in the critically ill patient. Competent analysis and management of these is essential in providing quality intensive care. This article provides a review of and guide to the aetiology, analysis, and management of major electrolytes disorders in the critically ill.

Specific electrolytes

Keywords Calcium; chloride; critically ill; dysnatraemia; electrolytes;

The normal values and effects of deficits and excesses of common electrolytes are listed in Table 1.

fluid; magnesium; phosphate; potassium; sodium Royal College of Anaesthetists CPD Matrix: 1A01, 1A02, 2A05, 2C01, 3C00

Sodium Sodium is the primary extracellular cation, and is a major contributor to serum osmolarity. Serum sodium levels are tightly regulated by thirst and the kidneys, although maintenance of plasma volume takes precedence over serum levels in hypovolaemic states. The prevalence of dysnatraemias in the intensive care unit (ICU) approaches 49%, and are independent risk factors for increased mortality, leading to their incorporation into severity scoring systems such as APACHE II. Sodium has osmotic and electrostatic activity so dysnatraemias need to be interpreted in the context of the patient’s volume status, and serum and urinary osmolality to determine the likely cause and management.

Introduction Electrolyte disorders are extremely common in the critically ill patient. Competent analysis and management of these is essential in providing quality intensive care. Electrolyte disorders represent:  aids to the diagnosis of the nature of the illness  markers of disease severity and prognosis  indicators of total body deficit or excess. Many electrolyte disturbances can be managed directly by increasing or decreasing intake, or encouraging loss. However, generalizing this approach to all electrolyte disturbances is oversimplistic for the following reasons: 1. Serum (or plasma) levels do not always reflect total body stores. For example, in diabetic ketoacidosis (DKA), there is usually a total body deficit of potassium, yet serum levels are elevated. Utilizing serum levels alone would not identify the deficit requiring replacement. 2. Electrolyte abnormalities may be secondary to underlying pathological processes requiring definitive treatment. 3. ‘Correction’ of a specific electrolyte abnormality may not improve a patient’s condition, and may even worsen their outcome, or mask the underlying problem. 4. Protocols for correction of electrolyte abnormalities serve as a starting point, but cannot replace serial clinical and biochemical reassessment, and need to be tailored to the individual patient. 5. All electrolytes are strong ions or weak acids; as such electrolyte disturbances and their correction may alter the overall acid-base status by altering the strong ion difference (SID). This can be assessed with blood gas data.

Hypernatraemia Aetiology: in the outpatient population hypernatraemia is usually the result of water deficit relative to total body sodium. However, in the ICU population excess total body sodium due to administration of hypertonic fluid is not uncommon. Excess hypotonic fluid losses often occur due to diarrhoea, vomiting or nasogastric losses, and central or nephrogenic diabetes insipidus. These losses are often replaced with a comparatively hypertonic fluid such as 0.9% saline. Sustained hypernatraemia occurs when there is impaired renal excretion of the excess sodium, access to free water is restricted or when the thirst mechanism is absent. Management: hypernatraemia raises serum osmolarity and leads to fluid shifts from intracellular to extracellular compartments. The brain reacts by generating idiogenic solutes to restore cell volume, whilst the serum hypertonic state remains. Following correction of hypernatraemia, it may take several days for these accumulated solutes to disperse; if correction occurs too rapidly, the resultant reduction in serum osmolarity may lead to cerebral oedema and irreversible neurological injury. For this reason, correction by less than 0.6 mmol/litre/hour or 10e15 mmol/litre in a 24-hour period is recommended. Hypotonic fluid such as free water or 0.45% saline in the lowest volume required should be used.

Sing Chee Tan MB BS M.Med (ClinEpi) is an Intensive Care Registrar at Ng Teng Fong General Hospital, Singapore. Conflicts of interest: none declared. Ross Freebairn MB ChB FANZCA FRCPE FCICM is a Consultant Intensive Care Physician at Hawke’s Bay Hospital, Hastings, New Zealand. Conflicts of interest: none declared.

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Ó 2016 Published by Elsevier Ltd.

Please cite this article in press as: Tan SC, Freebairn R, Electrolyte disorders in the critically ill, Anaesthesia and intensive care medicine (2016), http://dx.doi.org/10.1016/j.mpaic.2016.11.011

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The normal physiologic ranges of the common electrolytes and effects of deficit or excess Electrolyte

Normal values (mmol/litre)

Effect of excess

Effect of deficit

Sodium

136e145

Potassium

3.5e5.0

Cerebral haemorrhage and venous thrombosis, altered mental status, seizures and coma. Cerebral oedema if corrected too quickly Peaked t-waves, widened QRS, ventricular arrhythmias, cardiac arrest. Flaccid paralysis (especially in hyperkalaemic familial periodic paralysis)

Neuromuscular excitability (e.g. hyperreflexia), altered mental status, lethargy, irritability, seizures and coma. Demyelination syndromes if corrected too quickly. Depressed ST segments, biphasic t-waves, prominent uwaves/tachyarrhythmias. Muscle weakness, tetany and cramping, rhabdomyolysis, ileus, respiratory failure, polyuria with secondary polydipsia. Tetany, diffuse encephalopathy, seizures, hyperreflexia, laryngospasm, dehydration secondary to hypercalcaemic nephrogenic diabetes insipidus

Cation

Calcium

Total 2.10e2.60, Neurological (headache, fatigue, apathy, confusion), ionized: gastrointestinal (pain, constipation, vomiting), renal 1.10e1.35 (polyuria, nephrolithiasis, renal failure) cardiovascular (arrhythmia’s, short QT interval and atrioventricular or bundle branch block) and skeletal (pain, arthralgia) Magnesium 0.6e1.2 Prolonged PR interval, widened QRS, hyporeflexia, respiratory depression, cardiac arrest Anion Chloride Phosphate

95e105 0.8e1.5

Possible acute renal impairment Symptoms of acute hypocalcaemia, acute tubular necrosis, ectopic calcification

Muscle weakness, tetany, hyperreflexia, seizures, cardiac arrhythmias. Often associated with hypocalcaemia and hypokalaemia. Unknown-/related to associated abnormality Below 0.32 mmol/litre: respiratory muscle dysfunction, left shift of oxyhaemoglobin dissociation curve, myocardial dysfunction, arrhythmia’s, myopathy, encephalopathy, irritability, seizures, coma, rhabdomyolysis, haemolytic anaemia.

Table 1

in hyperglycaemia glucose exerts an osmotic force, causing a dilutional hyponatraemia that is both hyperosmolar and hypertonic. Differentiating the causes of hyponatraemia requires assessment of fluid status along with serum and urine sodium and osmolality. Hypervolaemic hyponatraemia is often due to impaired water excretion by the kidneys. Hypovolaemic hyponatraemia is often due to concurrent sodium and water loss via renal or extrarenal mechanisms.

Hyponatraemia Aetiology: hyponatraemia can occur in the setting of low, normal, or high total body water (Table 2). Pseudohyponatraemia may also occur in presence of other osmotically active solutes. For example,

Potential causes of the different types of hyponatraemia Fluid state in hyponatraemia

Hypovolaemia

C C C C C

C

Euvolaemia

C

C

C C C C

Hypervolaemia

C C C C

Diarrhoea/vomiting Diuretics Osmotic diuresis Aldosterone deficiency Third space losses (e.g. burns, pancreatitis) Cerebral/renal salt wasting Syndrome of Inappropriate anti-diuretic hormone Stress response (e.g. postoperative, trauma) Head injury Positive pressure ventilation Hypothyroidism Cortisol deficiency Congestive cardiac failure Cirrhosis Nephrotic syndrome Renal failure

Clinical features: symptoms (Table 1) occur when sodium derangement is severe and/or occurs rapidly. Signs and symptoms relate predominantly to central nervous system (CNS) dysfunction, and are not usually seen until serum sodium falls below 120 mmol/litre, although severity is also related to the speed of development. Acute hypotonic hyponatraemia poses the highest risk of cerebral oedema and tentorial herniation. Management: the urgency of correction of hyponatraemia depends upon the presence and severity of symptoms. In mild hypovolaemic hyponatraemia, 0.9% saline is usually sufficient to correct serum sodium. In hypervolaemic hypervolaemia (e.g. SIADH), fluid restriction may be appropriate. In either case, correction of hypontraemia should progress at the rates outlined in Box 1. Convulsions, unconsciousness, self-induced water intoxication, and hyponatraemia associated with intracranial pathology are medical emergencies that demand prompt correction with

Table 2

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Causes of potassium disorders

Recommended maximum rate of correction of hyponatraemia4 C C C

Hypokalaemia

6e8 mmol/litre in 24 hours, 12e14 mmol/litre in 48 hours, 14e16 mmol/litre in 72 hours.

Decreased intake C C

Box 1

C

C

hypertonic saline. Hypertonic saline should be administered to raise serum sodium by 4e6 mmol/litre, with the goal of reducing cerebral symptoms. If hypertonic saline is unavailable, or there is concern regarding fluid overload, frusemide can be used to limit volume expansion. Vasopressin receptor antagonists, which act to increase free water loss, are another treatment option. Serum levels above 120 mmol/litre are unlikely to cause of significant symptoms, and correction above this level should employ conservative measures such as identifying and treating the underlying cause, and proceed at slower correction rates (Box 1). There is significant morbidity and mortality associated with rapid correction of hyponatraemia. Osmotic demyelination syndrome (ODS), including central pontine myelinolysis, is perhaps the most dangerous and well-known complication. Although the risk of ODS is increased with rapid correction of hyponatraemia, it may still occur following slow correction. ODS has been observed following eunatraemic hyperosmolar hyperglycaemia, suggesting a hypertonic insult as the underlying mechanism, leading to extracellular fluid shifts and cellular dysfunction and demyelination. Symptoms can range from reversible gait ataxias to spastic quadriparesis, pseudobulbar palsy, and impaired consciousness with variable reversibility. Treatment is mainly supportive, although animal studies into drugs that prevent or reduce the risk of ODS have been promising. Formulae guiding the correction of hyponatraemia generally consider the patient as a closed system, ignoring ongoing fluid losses. Hence, these formulae may result in wide discrepancies in sodium levels and should only be used as an initial starting point; subsequently, regular measurements of serum sodium levels are required to avoid over-correction. If inadvertent over-correction occurs, serum sodium may be lowered using desmopressin and/or hypotonic solutions.

Hyperkalaemia Increased intake C Oral or IV intake C Red cell transfusion

Transcellular shift

Gastrointestinal  Diarrhoea  Vomiting  Nasogastric losses Renal  Drugs: diuretics, steroids, amphotericin  Excess mineralocorticoid activity (e.g. Conn’s syndrome)  Renal tubular acidosis

Decreased loss C Renal failure C Drugs: potassium sparing diuretics C Angiotensin converting enzyme inhibitors

C C C C

Alkalosis Drugs Insulin Beta-agonists

Transcellular shifts C Acidosis C Tumour lysis syndrome Rhabdomyolysis C Burns

Table 3

insulin and glucose. Although protocols usually recommend a bolus of 10 U of insulin/25 g of dextrose, this may be cause hypoglycaemia in certain patients, such as those with renal impairment or on CRRT. Beta agonists such as salbutamol (administered intravenously or inhaled) induce tachycardia and should be used with care in patients with cardiac disease. Sodium bicarbonate is no longer recommended due to a lack of efficacy, but may be beneficial in patients with concurrent metabolic acidosis. Renal loss of potassium can be facilitated with loop and thiazide diuretics, whilst haemodialysis or filtration may be required in renal failure. Potassium-binding agents such as sodium polystyrene sulfonate (SPS) do not have a role acutely, although they facilitate longer term lowering of potassium levels. Although SPS should be avoided in critically ill patients due to the risk of gastrointestinal side effects such as colonic necrosis, newer agents may have a more favourable side effect profile.

Potassium Potassium is the principle intracellular cation, with only 2% located extracellularly. Total body potassium is regulated renally, with 90% of daily potassium loss occurring in the urine under influence of aldosterone. In renal failure there is enhanced excretion through the bowel. The balance between extra- and intracellular potassium levels are dependent on the Na/K adenosine triphosphate (ATPase) pump, and passive leak across the cell membrane. Both renal losses and transmembrane potassium balance are influenced by factors such as medications and pH changes (Table 3).

Hypokalaemia: slow replacement at 10e30 mmol/hour is usually recommended. Maintenance of potassium balance may be magnesium dependent and hence should also be measured, as combined deficiency is common and may precipitate cardiac arrhythmias. The usual maximum recommended intravenous dose is 30 mmol/hour. In life-threatening arrhythmias, 2 mmol/ minute for 10 minutes, followed by 10 mmol over 5e10 minutes can be administered under continuous cardiac monitoring.

Management Hyperkalaemia: emergency management of hyperkalaemia involves stabilizing the myocardial membrane with calcium (gluconate or chloride), then shifting potassium intracellularly with

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Malnutrition Alcoholism

Increased losses

Chloride Chloride is the body’s major extracellular anion. It is regulated via the kidneys, gut and skin. In health over 99% of filtered

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chloride is reabsorbed in the distal tubule. With growing interest in Stewart’s approach to acidebase analysis, there is increasing recognition of role of chloride in acid-base physiology, where it is a major determinant of the strong ion difference (SID) and thus the hydrogen ion concentration. Chloride concentration should always be interpreted together with sodium, as concurrent sodium and chloride derangement (hyperchloraemia with hypernatraemia) will not alter the SID, and therefore not affect the acid-base balance.

Management Management should follow specific protocols where applicable, for example during continuous renal replacement therapy. Hypercalcaemia: treatment of hypercalcaemia should be guided by the severity of symptoms and the urgency of correction. Intravenous rehydration with 0.9% saline provides both volume replacement and additional sodium to augment urinary coexcretion of sodium and calcium. Calcitonin is useful in the treatment of severe hypercalcaemia, as it has a relatively rapid onset of action and is usually well tolerated. It reduces bone resorption but also has a mild calciuric effect. Bisphosphonates act by inhibiting osteoclast mediated bone resorption; given as a single intravenous infusion, results are seen in 24e48 hours and the therapeutic effect may last for several weeks. Glucocorticoids are only useful in cases of hypercalcaemia caused by endogenous overproduction of calcitriol (125-dihydroxyvitamin D). Diuretics such as frusemide should be avoided unless needed to correct excess fluid administration.

Hyperchloraemia Aetiology: the administration of chloride-rich fluids or total parenteral nutrition (TPN) is one major cause of hyperchloraemia in the ICU. Other mechanisms include free water loss through diarrhoea, fever, burns and diabetes insipidus, or increased renal chloride reabsorption in renal failure, renal tubular acidosis and medications such as acetazolamide. Despite an observed association between hyperchloraemia and increased morbidity and mortality, it is unclear whether hyperchloraemia contributes to, or is merely associated with critical illness.

Hypocalcaemia: despite an observed association between hypocalcaemia and increased ICU morbidity and mortality, correction of hypocalcaemia remains controversial. Hypocalcaemia will usually self-correct after a few days, and replacement does not improve the rate of normalization or mortality. Nonetheless, acute symptomatic hypocalcaemia may be treated with intravenous calcium gluconate 10% (10e20 ml) or calcium chloride 10% (5 ml) over 2e3 minutes. If required, infusions of calcium gluconate or chloride can also be administered to maintain an ionized calcium level greater than 0.8 mmol/litre. Identification and correction of co-existing magnesium, phosphate or vitamin D abnormalities are important as well.

Management: the use of balanced-salt solutions in place of normal saline reduces the risk of hyperchloremic acidosis. However, interventional studies have failed to demonstrate any corresponding reduction in renal impairment or mortality. Correction of hyperchloraemic acidosis is possible with loop diuretics or sodium bicarbonate, although the benefit of this is controversial. Hypochloraemia Aetiology: hypochloraemia can occur through chloride loss (e.g. vomiting or diuretic therapy) or excess water gain (e.g. hypotonic fluid replacement, congestive heart failure, and syndrome of inappropriate anti-diuretic hormone). Deficiencies in other electrolytes including sodium, potassium and calcium often coexist.

Magnesium Magnesium is the second most abundant intracellular cation, and is involved in neuroendocrine responses to stress, protein manufacture and mitochondrial function, and modulates calcium channel function in the cardiovascular system. Serum magnesium levels are regulated by reabsorption of urinary magnesium.

Management: treatment is generally only required when hypochloraemia is a primary disorder rather than a compensatory mechanism; in hypovolaemia replacement with sodium chloride is recommended.

Hypermagnesaemia Aetiology: hypermagnesemia is relatively less common in ICUs, and is usually secondary to renal failure or excessive supplementation. It may lead to muscle weakness and is associated with a prolonged duration of ventilation.

Calcium Calcium is involved numerous physiological processes, including neural transmission, muscular contraction, and coagulation. Calcium levels are regulated by hormones acting on the intestine, bone, and kidney. Although total serum calcium levels are frequently measured, ionized calcium is the physiologically active form and should be monitored directly, as it is influenced by pH, lactate, and bicarbonate levels.

Management: patients in renal failure may require dialysis to lower serum magnesium. Patients with normal renal function should quickly return to normal serum levels when the source of excess magnesium is stopped, due to its high renal clearance.

Aetiology Calcium levels are affected by sepsis, blood transfusions, renal failure, and renal replacement therapy, particularly when citrate anticoagulation is used. Rhabdomyolysis can precipitate deposition of intracellular calcium producing lowered ionized and total serum calcium levels.

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Hypomagnesaemia Aetiology: hypomagnesaemia in the ICU has a prevalence of up to 61%, and is independently associated with increased mortality. As 99% of total body magnesium is stored intracellularly and in bone and cannot be readily mobilized, even small losses may result in hypomagnesaemia.

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Management: hypomagnesaemia in high risk or symptomatic patients should be corrected with intravenous magnesium sulphate (20e60 mmol/24 hours) to keep serum magnesium 1.0e1.5 mmol/litre. A slow infusion is preferred due to the slow tissue redistribution and high renal clearance. Patients with mild deficits or ongoing losses may benefit from enteral supplementation, although this is limited by the low bioavailability of magnesium.

replaced intravenously at 5e20 mmol/hour, up to 100 mmol/day to keep serum phosphate levels greater than 0.8 mmol/litre. There is considerable controversy on the management of asymptomatic hypophosphataemia, and should be guided by the suspected cause (e.g. total body deficit versus transcellular shifts). Where possible, oral replacement should be preferred over IV formulations, to minimize the risk of overcorrection or precipitation of calciumephosphate complexes. A

Phosphate Phosphate is an intracellular anion and is essential for numerous cellular functions, such as ATP production and neurohumoral signalling. Total body phosphate is regulated via gastrointestinal and renal mechanisms, whilst serum phosphate levels reflect a balance of intra and extracellular flux and may be influenced by physiological factors such as pH, catecholamine levels, or carbohydrate metabolism. The significance of abnormal levels depends on the underlying cause and the presence of symptoms; urinary phosphate measurement is particularly useful in determining the cause of derangement.

FURTHER READING Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. CJASN 2015 Jul 7; 10: 1257e72. Geerse DA, Bindels AJ, Kuiper MA, Roos AN, Spronk PE, Schultz MJ. Treatment of hypophosphatemia in the intensive care unit: a review. Crit Care 2010; 14: R147. Handy JM, Soni N. Physiological effects of hyperchloraemia and acidosis. Br J Anaesth 2008; 101: 141e50. Lloyd P, Freebairn R. Using quantitative acid-base analysis in the ICU. Crit Care Resusc 2006, Mar; 8: 19e30. Maier JD, Levine SN. Hypercalcemia in the intensive care unit: a review of pathophysiology, diagnosis, and modern therapy. J Intensive Care Med 2015 Jul; 30: 235e52. Mohd Yunos N, Bellomo R, Story D, Kellum J. Bench-to-bedside review: chloride in critical illness. Crit Care 2010; 14: 226. Oude Lansink-Hartgring A, Hessels L, Weigel J, et al. Long-term changes in dysnatremia incidence in the ICU: a shift from hyponatremia to hypernatremia. Ann Intensive Care 2016 Mar 17; 6 [Internet]. [cited 2016 Jun 14]. Overgaard-Steensen C, Ring T. Clinical review: practical approach to hyponatraemia and hypernatraemia in critically ill patients. Crit Care 2013; 17: 206. Reddy S, Weinberg L, Young P. Crystalloid fluid therapy. Crit Care 2016; 20: 59. Steele T, Kolamunnage-Dona R, Downey C, Toh C, Welters I. Assessment and clinical course of hypocalcemia in critical illness. Crit Care 2013; 17: R106. Sterns RH, Grieff M, Bernstein PL. Treatment of hyperkalemia: something old, something new. Kidney Int 2016 Mar; 89: 546e54. Takagi H, Sugimura Y, Suzuki H, et al. Minocycline prevents osmotic demyelination associated with aquaresis. Kidney Int 2014 Nov; 86: 954e64. Velissaris D, Karamouzos V, Pierrakos C, Aretha D, Karanikolas M. Hypomagnesemia in critically ill sepsis patients. J Clin Med Res 2015 Dec; 7: 911e8.

Hyperphosphataemia Aetiology: hyperphosphataemia occurs when either the phosphate load exceeds the kidneys’ maximal rate of excretion or when there is increased resorption of filtered phosphate in the proximal tubules. Tissue breakdown (e.g. rhabdomyolysis) or cellular shifts, as seen in lactic and ketoacidosis, can also lead to high serum levels. Oral phosphate bowel preparations have also been implicated in severe and sometime fatal calcium and phosphate disturbances. Management: with normal renal function hyperphosphataemia is self-correcting within 24 hours. Severe or symptomatic hyperphosphataemia in the setting of renal failure requires dialysis. Hypertonic glucose can be used to drive phosphate (and potassium) into cells. Hypophosphataemia Aetiology: hypophosphataemia may reflect a total body deficit due to excessive renal or gastrointestinal losses or reduced absorption, or may be secondary to intracellular shifts. Although it may be due to a number of conditions such as sepsis and alkalosis, it is commonly seen in the ICU as a result of refeeding syndrome. Management: patients who are symptomatic or have severe hypophosphataemia (<0.32 mmol/litre) should have phosphate

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Please cite this article in press as: Tan SC, Freebairn R, Electrolyte disorders in the critically ill, Anaesthesia and intensive care medicine (2016), http://dx.doi.org/10.1016/j.mpaic.2016.11.011