18 Blood gas analysis: Acid–base, fluid, and electrolyte disorders

The maintenance of acid-base homeostasis is necessary for normal cellular and organ function. Outside of normal physiological pH, essential intracellular functions are disrupted, and extremes of pH are life-threatening. Arterial blood gas (ABG) analysis is the most common point-of-care test in the ICCU, and is essential in the evaluation and monitoring of respiratory gas exchange, acid-base status and basic electrolyte concentrations. Water and electrolyte disorders are common in the intensive cardiac care unit, with patients presenting with either acute kidney injury, cardiac failure or both. It is essential that these are promptly diagnosed and treatment initiated to prevent metabolic decompensation. Therapeutic strategies range from simple electrolyte substitution and fluid management to extracorporeal filtration of excess fluid and electrolytes. We discuss these systematically.

Arterial blood gas (ABG) analysis is the most common point-of-care test (POCT) in the ICCU. It is essential in the evaluation and monitoring of respiratory gas exchange, acid–base status, basic electrolyte concentrations (serum potassium [K⁺], sodium [Na⁺], calcium [Ca²⁺]), plasma glucose, and osmolality. It is a relatively quick and easy test to perform.

It has long been established that deviation from the human body’s normal pH range can lead to intracellular metabolic derangement and reduced protein synthesis and transport activity, with significant physiological and clinical sequelae (see Table 18.1). pH derangement can also reduce the effect of pharmacological agents, leading to treatment and recovery difficulties. Examples of important agents affected by changes in pH include:

Treatment relies mainly on correcting the underlying pathology, thus demanding prompt diagnosis and management of the precipitating disease state, using clinical and biochemical indicators such as ABG analysis. Care should be taken to distinguish respiratory and metabolic disorders, and acute from chronic conditions with any physiological compensation that may have occurred.

The normal pH range in the human body is narrow (7.35–7.45). Enzyme reactions, protein synthesis, and ion channels are exquisitely dependent on the surrounding pH, and values of <6.8 and >7.8 are considered to be incompatible with life. Human metabolism produces either volatile (e.g. carbonic acid, H₂CO₃) or fixed acids (e.g. lactic and pyruvic acid). H₂CO₃ is the largest source of hydrogen ions (H⁺) in the human body and is a volatile (or respiratory) acid, in that it dissociates into either H⁺ ions and bicarbonate ions (HCO₃⁻) or CO₂ and water, with the respiratory acid (CO₂) subsequently being excreted by the lungs. To ensure that pH homeostasis is maintained, acids produced by the body must either be buffered (neutralized) or excreted. As H⁺ ions are needed for so many chemical processes in the body, the majority are buffered and recycled, rather than being permanently lost [2]. There are three main mechanisms by which buffering and excretion are achieved:

This is the collective term for multiple buffer pairs, activated immediately after the addition of an acid or alkali to prevent any change in the body’s normal pH. As the pK_a of a weak acid represents the pH at which equal quantities of the acid are in both the ionized and unionized form, the body’s most efficient buffers will have pK_as close to this normal pH to be able to buffer both acids and bases. The most common buffers are the bicarbonate–carbonic acid, phosphate, and plasma protein buffer systems.

This is responsible for over 50% of the buffering capacity of the body and is the main component of extracellular fluid (ECF) buffering (80%). It is particularly important due to its association with both of the other main buffer systems (respiratory and renal). H₂CO₃ is a weak acid, in equilibrium with HCO₃⁻, a weak base, in solution.

When excess H⁺ ions are added to the system, the equilibrium shifts to the left, with the formation of H₂CO₃ by the reaction of H⁺ ions with HCO₃⁻. When H⁺ ions are removed from the reaction (or excess base added, e.g. hydroxide ions (OH⁻)), the equilibrium shifts to the right, with the dissociation of H₂CO₃ to release H⁺ ions. Therefore, when a small quantity of H⁺ ions is added or removed from blood or ECF, the equilibrium is able to shift to maintain a relatively constant pH. The buffering capacity of this system is further enhanced by its coupling with the renal and respiratory systems, which can control the concentration of HCO₃⁻ and H₂CO₃ through the elimination of HCO₃⁻ and CO₂, respectively.

This system has a very low concentration and acts as an intracellular buffer; it also works within RBCs and the renal tubules to regulate pH. Phosphoric acid is a triprotic weak acid, with three possible dissociations, each with different pK_as. At the pH of the human body, the predominant buffer pair is dihydrogen phosphate (H₂PO₄⁻), as the weak acid, and hydrogen phosphate (HPO₄^2–) as the weak base. The equilibrium formed by these two ions in solution is:

The pK_a of H₂PO₄⁻ is 7.21, making the phosphate buffer system an ideal buffer in the human body.

Protein buffers in blood include both haemoglobin and plasma proteins. The plasma protein buffering system is the most abundant intracellular and ECF buffering pair but is responsible for only 15% of the body’s buffering capacity. Proteins can act as both acid and base buffers, depending on the pH of the solution they are in, as both their free carboxyl (acid) and free amine (base) groups dissociate in solution. At the normal pH of blood (7.34), proteins tend to act as weak acids [1].

Haemoglobin and oxyhaemoglobin are the second most abundant buffer pair. Whilst haemoglobin is found intracellularly, it is classed as an ECF buffer, as erythrocytes are confined to the ECF. As oxygenated blood passes through an organ’s capillary network, two main processes occur:

In the RBC, H₂CO₃ dissociates into H⁺ and HCO₃⁻. The HCO₃⁻ ions diffuse into plasma in exchange for chloride (Cl⁻) ions (the chloride shift) to retain electroneutrality, and reduced haemoglobin attracts H⁺ ions (binding them more readily than oxyhaemoglobin). This results in the formation of protonated haemoglobin (H-Hb), which is a weaker acid than H₂CO₃. The formation of the weaker acid results in a lower concentration of H⁺ ions in the erythrocyte (buffering).

When blood reaches the pulmonary capillaries, the presence of a high O₂ concentration favours O₂ binding and promotes the loss of H⁺ ions from H-Hb. Reduced haemoglobin is converted to oxyhaemoglobin, and H⁺ ions are released and buffered by the bicarbonate–carbonic acid system to form CO₂ and water. The aqueous CO₂ follows a concentration gradient into the blood, across the alveolar membrane and into the alveolar space, where it is eliminated during ventilation [2]. This system acts as part of the Bohr effect, this is a physiological phenomenon relating to haemoglobin’s oxygen binding – the capacity of which is inversely related to the acidity of the blood stream and the CO2 concentration. This facilitates O₂ transport via haemoglobin from the lungs and its subsequent offloading to metabolically active tissues to meet their O₂ demand.

Ventilation plays a major role in pH homeostasis by eliminating or conserving CO₂. The addition of H⁺ ions to blood activates the bicarbonate–carbonic acid buffer system, increasing H₂CO₃ concentration. This subsequently dissociates into CO₂ and water, and excess CO₂ then diffuses passively into the alveoli of the lungs and is eliminated. Peripheral chemoreceptors in the carotid and aortic bodies and central chemoreceptors in the medulla oblongata are stimulated by free H⁺ ions, CO₂ in plasma, and CO₂ in CSF, respectively, to increase respiratory rate and tidal volume, leading to greater minute ventilation and increased CO₂ elimination [3]. If the HCO₃⁻ concentration is increased (metabolic alkalosis), the CO₂ concentration increases to buffer the excess HCO₃⁻ (respiratory compensation). High HCO₃⁻ concentration therefore inhibits central and peripheral chemoreceptors, resulting in reduced minute ventilation (rate x tidal volume) and reduced CO₂ elimination. Therefore, by controlling the CO₂ concentration of blood, the respiratory system is capable of compensating for pH changes due to metabolic derangement. This system is quicker than the other major buffer systems, occurring in just minutes.

In contrast to the passive elimination of CO₂ by the respiratory system, the renal system more actively controls acid–base balance through several mechanisms:

The proximal tubule contributes to acid–base balance by reabsorbing HCO₃⁻ from the urine and the production of NH₄⁺. In response to a low pH, H⁺ ions are secreted into the urine either in exchange for Na⁺ ions via the Na⁺ -H⁺ antiporter or by using the H⁺ -ATPase active transport systems. HCO₃⁻ is simultaneously reabsorbed in exchange for Na⁺ ions. The overall effect is that HCO₃⁻ and Na⁺ ions are reabsorbed from the tubular lumen in exchange for H⁺ ions being secreted into the urine. The reabsorbed Na⁺ and HCO₃⁻ ions form NaHCO₃ in the tubule cells, which is then useable as a buffer. The reactions occur in reverse for increases in pH, leading to a net excretion of HCO₃⁻ ions [4].Phosphate (HPO₄^2–/H₂PO₄⁻) is a major titratable acid buffer. Excretion of titratable acids is dependent on the quantity of phosphate excreted by the kidneys, on intake (e.g. diet), and on phosphate resorption from bone. The rate of increase in phosphate is slow and cannot respond quickly to an increased acid load; however, NH₄⁺ production can. NH₄⁺ is produced by the proximal tubular cells from glutamine, in a reaction catalysed by glutaminase that also produces α-ketoglutarate. NH₄⁺ is then secreted into the tubular lumen but reabsorbed within the medulla (medullary recycling), during which time it dissociates to ammonia (NH₃) and H⁺ ions. NH₃ then diffuses into the collecting duct where it combines with free H⁺ ions to form NH₄⁺, which is then excreted in the urine. In acidotic states, this process can be amplified. Therefore, excess H⁺ secretion by H⁺-ATPase pumps in distal convoluted tubular cells, in response to an acid load, leads to greater NH₃ diffusion into the tubules and its combination with H⁺ to form NH₄⁺, and hence greater excretion of free H⁺ ions. HCO₃⁻ is simultaneously produced in the proximal tubules by the metabolism of α-ketoglutarate and is then transferred to the systemic circulation, demonstrating one of the most important functions of the kidney with regards to acid–base balance [4]. As a result of H⁺ and NH₄⁺ excretion, urine usually has a pH of approximately 6. Therefore, a particularly low urinary pH (high urine acidity) is a good indicator of renal compensation for a systemic acidosis; however, as all mechanisms are via active transportation, compensation is slow, taking days, rather than minutes.

The interdependence between pH, HCO₃⁻ concentration, and PaCO₂ is the basis for understanding and interpreting acid–base balance. These factors enable the differentiation of respiratory from non-respiratory acid–base disturbances, but not metabolic disturbances, as any change in PaCO₂ also causes a change in [HCO₃⁻]. To overcome these limitations, successive investigations led to the introduction of ‘standard bicarbonate’ and ‘buffer base [5], followed by the concept of ‘base excess’ (the concentration of H⁺ ions required to return the pH of blood to 7.4) [6]. Conversely, ‘base deficit’ defines the amount of strong base that must be added to restore normal pH to blood, assuming the blood sample is fully oxygenated, at a temperature of 37̊C, and that PaCO₂ is maintained at 40 mmHg. Base excess and [HCO₃⁻] will inform the clinician of the degree of acidosis/alkalosis (with or without pH change) but is not able to distinguish the underlying cause (HCO₃⁻ loss or consumption, unmeasured anions, etc.). Calculations of the anion gap (AG) can help with this differentiation.

The AG represents the concentration of all unmeasured anions subtracted from unmeasured cations in the plasma. Under normal circumstances, the majority of the gap is made up of negatively charged proteins; however, in complex or mixed metabolic acidotic conditions, acid anions (e.g. lactate, acetoacetate, and sulfate) may be produced that are not measured by usual laboratory methods. The H⁺ ions produced by these acids are buffered by HCO₃⁻, reducing the concentration of the measured anions, which, in turn, increases the proportion of these unmeasured anions, and the gap increases. The ‘gap’ refers to what we can only see by proxy in such circumstances. The predominant unmeasured extracellular cations are K⁺, Ca²⁺, and magnesium (Mg²⁺), and so the AG can be affected by increases or decreases in unmeasured cations or anions (see Table 18.2). A normal AG is <11 mEq/L, and a high gap usually indicates a metabolic acidosis. Using the AG can help to differentiate between HCO₃⁻ loss and consumption. An AG acidosis is also present, regardless of the pH or [HCO₃⁻], when the AG >20 mEq/L. Causes of alterations in the AG are shown in Table 18.3.

Normal AG acidosis results from a net increase in Cl⁻ concentration, secondary to a loss of HCO₃⁻. This is known as hyperchloraemic metabolic acidosis and is most commonly associated with:

However, in critically ill patients, the usefulness of the AG in interpreting acid-base disturbance is limited by the tendency for these patients to be hypoalbuminaemic. This leads to a reduction in the baseline AG.

This is caused by an increase in arterial PaCO₂ (hypercarbia) and may be secondary to hypoventilation, poor CO₂ clearance from damaged lung parenchyma and alveolar membrane integrity, or increased metabolism with increased CO₂ production (e.g. sepsis, burns). Overfeeding critical care patients, either enterally or parenterally, is a rare, but important, cause of increased CO₂ production.

Hypercarbia causes significant physiological changes. At low levels, there is generalized cardiovascular, respiratory, and autonomic stimulation. However, as PaCO₂ rises, this reverses to organ depression, the most important of which is the CNS, leading to drowsiness, respiratory depression, and eventually coma. An alveolar PACO₂ of >100 mmHg is incompatible with life when a patient is breathing room air, due to the associated severe hypoxaemia that will result from the high partial pressure of CO₂ in the alveolus. Other effects are shown in Table 18.4. Over a period of days, metabolic compensation occurs (↑ [HCO₃⁻] via renal excretion of H⁺).

Increased minute ventilation, by increasing either the rate or depth of ventilation, will result in reduced PaCO₂ and respiratory alkalosis. Without a ‘mixed’ acid–base disorder, a resultant metabolic compensation with ↓ [HCO₃⁻] production and reabsorption by the kidney will occur over several days. Table 18.5 lists the common causes.

HCO₃⁻ loss or reduced HCO₃⁻ production through renal dysfunction or the build-up of fixed acids through increased production/reduced excretion leads to metabolic acidosis. Respiratory compensation occurs through hyperventilation to reduce the PaCO₂. A clinical example of this is diabetic ketoacidosis (DKA) where the body attempts to counteract the pH change from acidic ketone bodies by increasing the depth and rate of respiration (Kussmaul breathing).

Increased [HCO₃⁻] through either HCO3⁻ gain or H+ ion loss causes raised blood pH. This is usually slow and accompanied by respiratory compensation, with an increase in PaCO₂ through hypoventilation. In cardiac care, one of the most common causes is chronic diuretic use. Loop diuretics block the Na⁺-K⁺-2Cl⁻ cotransport system in the thick ascending limb of the loop of Henle to inhibit Na⁺ and Cl⁻ reabsorption. The decrease in Cl⁻ reabsorption increases the luminal electronegativity of the distal tubules, leading to a compensatory influx of H⁺ and K⁺ ions into the urine and, over time, an increase in blood pH. Due to both cations being lost in the urine, this is termed hypokalaemic metabolic alkalosis.

A simple acid–base disturbance is where only one primary derangement is present and responsible for the altered pH. When more than one system is responsible for the disturbance, it is characterized as mixed. Respiratory compensation occurs within minutes and is completed within 24 hours; however, renal compensation starts within 6 hours, taking 4–5 days to be complete. Table 18.6 demonstrates the biochemical changes that are seen on ABG analysis in acute and chronic respiratory and metabolic disturbances.

In order to correctly interpret the acid-base disturbance, it is advisable to use a consistent approach (see [68] Figure 18.1). The normal values are shown in Table 18.7.

If the pH <7.35, then an acidaemia is present; if it is >7.45, an alkalaemia predominates. If it is normal, there is either no disturbance or a compensated or mixed state exists.

In relation to the pH change:

If PaCO₂ is high, it is important to gauge its chronicity by examining the ratio between the change in H⁺ ion concentration and PaCO₂ from their reference values:

(where: >0.8, acute; 0.3–0.8, acute on chronic; <0.3, chronic)

Respiratory compensation for metabolic disorders can be marked. This can be investigated using Winter’s formula to calculate the expected PaCO₂:

In general, respiratory compensation results in a 1.2 mmHg change in PaCO₂ for every 1.0 mEq/L change in plasma [HCO₃⁻], down to a minimum of 10–15 mmHg and a maximum PaCO₂ of 60 mmHg.

If it is >11 mEq/L, then the metabolic acidosis is due to one of the disorders noted in Table 18.4. If it is normal, then any metabolic acidosis is likely to be gastrointestinal or renal in origin.

This will help to differentiate renal tubulopathies from other causes of non-elevated AG acidosis.

Under normal conditions, the fluid and electrolyte contents within the cells of the body are maintained at a constant level, despite a constant flux in intake and cellular requirements. This equilibrium is maintained by control over intake, fluid, solute, and electrolyte shifts across these cells, and the capacity of the kidney to adjust excretion to match the intake and needs of the body. Disorders of water or electrolyte balance therefore can occur due to alterations in intake, utilization (including uptake, handling and release), or excretion.

The human body is essentially a large bag of salty water. Water itself has several chemical properties that make it extremely important for supporting life. It is the major solvent into which other molecules are dissolved in solution, and it has a high molar concentration and a small dissociation constant (K_w). Under normal conditions, the concentration of water within the human body is extremely high (55.5 mol/L at normal body temperature) [8], and it has the potential to dissociate to yield H⁺ ions. The importance of this is that water can provide the body with an almost endless supply of H⁺ ions, but, with a very small dissociation constant (K_w = 4.3), very little is actually dissociated.

Water constitutes about 60% of the total bodyweight of the average human. It occupies two main body compartments, with two-thirds in the intracellular fluid (ICF) and one-third in the ECF, the interstitial fluid and plasma, compartments. Total body water (TBW) is dependent upon age and sex, as its value is inversely proportional to total body fat. Water is regulated between the two main compartments by the permeability of cellular membranes. Most cellular membranes are relatively permeable to water; however, they are less permeable to other ions and molecules such as proteins. This causes an osmotic gradient between cells and compartments, allowing the movement of water across the membranes, down a concentration gradient, until equilibrium is achieved. This is the main mechanism by which cells maintain their fluid volume.

Movement of fluid across capillary membranes (i.e. between the vascular and interstitial spaces) is governed by the Starling equation. This relates hydrostatic and oncotic forces (Starling forces) to the rate of diffusion as follows:

(where K_f is the filtration coefficient (i.e. the water permeability), ΔP is the difference between the capillary and interstitial hydrostatic pressure, Δπ is the difference between the capillary and interstitial oncotic pressure and σ is a correction factor or reflection coefficient)

It is important to conceptualize this equation, as critical care patients may have significant fluid shifts from one compartment to another, due to alterations in either hydrostatic (congestive cardiac failure) and oncotic (hypoalbuminaemia) pressure gradients, combined with the loss of capillary membrane integrity, leading to the formation of oedema.

Water balance is regulated by intake and loss (urine, faeces, insensible loss). Plasma volume is approximately 4.5–5 L in a 70 kg male, with a normal 24-hour intake of 2–2.5 L (see Table 18.8). Fluid turnover by the kidney can vary markedly, from 0.5 L (the minimum to excrete the solute load) to over 20 L per day, to maintain a tight control over the ECF volume and electrolyte concentrations (and indirectly the interstitial and ICF volume). This homeostasis includes the cardiovascular and renal systems. In response to a reduced ECF volume, there will be a rapid alteration in heart rate, peripheral vascular resistance, and venoconstriction, mediated by catecholamine release, whilst the slower renal alterations include the activation of the renin–angiotensin–aldosterone pathway and increased aldosterone secretion, leading to salt and water retention and restoration of the ECF volume. Critically ill adult water requirements start at 30–35 mL/kg/day or 1–2 mL/kg/hour. These will need to be uptitrated in sepsis (capillary leak and relative hypovolaemia), septic shock, and burns. They may also need to be restricted in states of volume excess.

Disorders of water balance are either those of volume depletion (dehydration) or volume excess (fluid overload).

With mild volume depletion, the compensatory haemodynamic responses include; tachycardia, an increase in SVR, and an increase in venoconstriction of the venous capacitance vessels. Arterial blood pressure will be maintained. This response to maintain cardiac output will persist, until the ECF volume is normalized through renal mechanisms. In minor ECF depletion, there may be minimal clinical findings, apart from a raised heart rate. Moderate to severe ECF volume depletion will result in significant tachycardia and vasoconstriction, poor skin turgor, and increased capillary refill time, with a reduced urine volume. Severe ECF volume depletion will result in hypotension, mental obtundation, and oligo-anuria. These findings may be masked by the administration of cardiovascular medications, including β-blockers and diuretics. The common causes of volume depletion are shown in Table 18.9.

During extrarenal volume depletion, the renal system works to conserve Na⁺ and water, with a resultant reduction in urine output, increase in urinary osmolality (>450 mOsmol/kg), and reduction in urinary Na⁺ (<15 mEq/L). However, when the cause is an intrinsic renal pathology, the urine can be inappropriately dilute and have a high salt content (e.g. nephrogenic diabetes insipidus). High urinary Na⁺ (>20 mEq/L) can also be found with diuretic use and adrenal insufficiency.

Volume depletion can also be characterized as being isotonic, hypertonic, or hypotonic. The most common is isotonic and is characterized by the loss of both water and Na⁺ from the ECF in equal amounts (e.g. through poor intake, vomiting, or diarrhoea). As a result, there is no osmotic shift from the intracellular to extracellular space. Hypertonic dehydration occurs when water loss exceeds Na⁺ loss. This is characterized by an osmotic shift of water from the ICF to the ECF. This can occur due to an osmotic diuresis (e.g. hyperglycaemia in diabetes mellitus) and the use of diuretic drugs. It is also the form of volume loss that occurs in diabetes insipidus. Hypotonic volume loss results in an osmotic shift of water from the ECF to the ICF and can occur when volume depletion is treated with hypotonic solutions. It can also occur with diarrhoea (15% of cases) and salt-wasting syndromes. It is particularly dangerous, as water leaves the ECF into the ICF to equalize the osmotic gradient, causing oedema of tissues which can include cerebral tissue.

Treatment includes slow correction of the volume deficit and monitoring of electrolyte concentration. The choice of fluid to use for volume expansion is contentious; however, hypotonic solutions should be avoided, as these will worsen the imbalance in Na⁺ homeostasis and do not stay long in the extracellular space, worsening oedema. Hypertonic solutions are reserved for the treatment of cerebral oedema and should be managed by physicians with experience in neurointensive care and Endocrinologists.

This occurs when salt and water intake (irrespective of route) exceeds the capacity for excretion by the renal system. Na⁺ and water retention ensues that may be either primary in origin (e.g. renal and endocrine diseases) or secondary (e.g. heart failure and pregnancy) [7]. The overall effect is that capillary hydrostatic pressure is increased, leading to a net efflux of fluid from the ECF to the interstitial space. Tissue oedema may then ensue. In cardiac failure, poor cardiac output leads to the activation of the renin–angiotensin–aldosterone system (RAAS), leading to increased Na⁺ and water retention and an effective increase in ECF volume.

Volume excess can be further characterized as being isotonic, hypertonic, or hypotonic.

Hypotonic volume excess is the result of an excess of water (without concomitant Na⁺ excess). Most commonly, this is through polydipsia and water intoxication with other causes, including increased antidiuretic hormone (ADH) activity and liver failure. Iatrogenic causes include excessive administration of low-salt or salt-free solutions and the use of salt-poor solutions in prostate and bladder surgery (transurethral resection syndrome). With the elevation in ECF volume, capillary hydrostatic pressure is increased, and water diffuses from the ECF into the ICF space to balance the osmotic difference. This can lead to dilutional hyponatraemia and the potential for cerebral oedema via the swelling of neuronal tissue. An excess of water and Na⁺ in equal measures will result in isotonic volume excess, without any transport of fluid between the two compartments. Causes include excessive administration of isotonic solutions (particularly, in patients with anuric renal failure), cardiac failure, and other renal diseases. Symptoms might include cerebral irritation, confusion, hypertension, oedema, effusions, and pulmonary oedema. Hypertonic volume excess results when there is an excess of Na⁺ over water. This results in an increase in serum osmolality and an increase in the ECF volume. To restore the osmotic equilibrium, water diffuses from the ICF to the ECF, further increasing the ECF volume. Causes include the iatrogenic administration of hypertonic solutions, hypercortisolism (Cushing’s syndrome), hyperaldosteronism (Conn’s syndrome / mineralocroticoid excess) and exogenous steroid abuse. Symptoms are similar to isotonic volume excess, with agitation, reduced consciousness, and vomiting.

Treatment of volume excess is usually with restriction of fluid intake, salt restriction, and diuretics.

Maintenance of electrolyte concentrations within narrow limits is vital to maintain bodily functions. Electrolytes maintain the resting membrane potential of cells and the generation of action potentials and are vital in cotransport mechanisms throughout the body. Therefore, imbalances, even in single electrolyte concentrations, can have significant multiorgan effects, ranging from alterations in muscular contraction to arrhythmia. Fluid osmolality is also carefully maintained between body compartments within a narrow range (285–295 mOsmol/kg). This is calculated using the formula:

Increases in plasma osmolality will result in water flux between the ICF and ECF and the release of ADH, leading to increased water reabsorption in the collecting ducts and restoration of the osmolality to within its normal range. Large swings in osmolality lead to excessive fluid movements between the body compartments that can be harmful.

These are usually caused by a free water excess (hypernatraemia) or loss (hyponatraemia). Changes in Na⁺ concentration are more likely to cause changes in serum osmolality than any other electrolyte disturbance and therefore have the potential to cause significant fluid shifts.

This is defined as serum [Na⁺] <135 mEq/L, with severe hyponatraemia being <120 mEq/L, carrying with it a high risk of complications. In clinical practice, one may not be unduly concerned about mild hyponatraemia (130–135 mEq/L) as this can be just a sign of mild dehydration, the frail elderly or diuretic therapy. The management of patients with hyponatraemia begins with a good clinical history and examination, an understanding of the timeline of the change in serum sodium values and some basic tests to rule out obvious or worrying causes.

Low sodium is associated with reduced serum osmolality and, in acute falls of [Na⁺], marked fluid shifts may lead to cerebral oedema and neurological complications, including confusion, reduced level of consciousness, seizures, and coma. More chronic falls in [Na⁺] are better tolerated by patients due to gradual adjustment. Symptoms range from anorexia, nausea, abdominal cramps, and diarrhoea to oedema, muscle weakness, cramps and neurological sequelae.

Figure 18.2 demonstrates the different causes of hyponatraemia and the basic tenets of acute management. Stop any offending medications - where practical, discontinue the use of medications that may be causing or exacerbating hyponatraemia. The most common are thiazide diuretics, selective serotonin reuptake inhibitors, proton pump inhibitors, angiotensin?converting enzyme inhibitors and loop diuretics.

Hypovolaemic patients should be treated with 0.9% saline. In the critically ill with, the aim is to increase the serum [Na+] by a maximum of 0.5 mEq/L/hour. In these patients, the sodium deficit should be calculated as follows:

This deficit should then be replaced by isotonic saline.

Hypervolaemic hyponatraemia management should focus on treating the underlying cause to improve hyponatraemia. In these circumstances, water restriction may be all that is required or loop diuretics can be used that will produce a diuresis that exceeds the increased 24-hour urine sodium losses they produce and so can be used safely.

If a patient is euvolaemic, it is important to confirm that the patient has hypotonic hyponatraemia. Plasma and urine osmolality should be checked and if plasma osmolality is > 275 mOsm/kg, causes of hypertonic hyponatraemia, such as hyperglycaemia or mannitol infusions should be considered. If the urinary osmolality is < 100 mOsm/kg, primary polydipsia should also be considered.

If plasma osmolality is < 275 mOsm/kg, and the urine osmolality is > 100 mOsm/kg, urinary sodium concentration should be measured. SIADH is the likely diagnosis if urinary sodium is < 20 mmol/L. If urinary sodium is > 20 mmol/L, then the volume status of the patient needs to be reconsidered, as this usually reflects intravascular volume depletion.

Severe symptomatic sodium depletion (e.g. with neurological sequelae) is a medical emergency and patients should be moved to a Level 2 monitored environment. A consultant endocrinologist or nephrologist should be consulted as soon as possible. Treatment involves the use of hypertonic saline to gradually correct the hyponatraemia, with the goal of ensuring that the sodium level does not rise by more than 6 mmol/L in the first 6-hours or 10 mmol/L in the first 24-hours. Patients who have hyponatraemia for more than 48-hours are at risk of neurological sequelae if the correction of sodium occurs too rapidly, due to the development of osmotic demyelination (central pontine myelinolysis, CPM [38]).

Current UK national guidance is to start with 150 ml of 3% saline intravenously over 15 minutes [70]. If there is no clinical improvement, the dose should be repeated after 20 minutes. Serum sodium should then be checked at 6, 12, 24 and 48 hours to ensure that over-correction (serum sodium rise of 10 mmol/L or more in 24 h or less) has not occurred. If the sodium does rise excessively, then intravenous dextrose or desmopressin (e.g. DDAVP) may be required. The serum sodium does not need to be normalised with hypertonic saline; an increase of 4–6 mmol/L often leads to major clinical improvements.

SIADH is characterised by the presence of hypotonic hyponatraemia in the context of inadequately diluted urine (given the hypo-osmolality in plasma) [71]. The most common cause of hyponatraemia is the non-osmotic release of arginine vasopressin (AVP). The mainstay of SIADH treatment is fluid restriction; however, the degree of restriction will vary depending on the patient’s ability to excrete electrolyte-free water. This can be ascertained using the Furst formula.

Dilute urine may be considered to have an isotonic portion and an electrolyte-free water portion. The proportions of electrolyte-free water and isotonic urine can be measured by the ratio of effective solutes (principally sodium and potassium, with associated anions) between the plasma and the urine [72].

Restriction of water intake to less than the amount of electrolyte-free water excreted will cause plasma tonicity, and hence serum sodium, to rise. The amount of electrolyte-free water that can be cleared from the kidneys will therefore affect the patient’s response to fluid restriction. A clinically useful equation simplified by Furst et al. for estimating free-water clearance is the urine/plasma electrolyte ratio measured in a urine sample [73]:

Demeclocycline and lithium carbonate have been used to treat the syndrome of inappropriate antidiuretic hormone secretion (SIADH), on the basis of causing nephrogenic diabetes insipidus; however, renal toxicity and a slow onset limit their use [9, 74]. ADH Antagonists such as Tolvaptan are more effective and can be used in this context and their utility should be discussed with a consultant endocrinologist (insert reference: Grant, P. et al The diagnosis and management of inpatient hyponatraemia and SIADH. Eur J Clin Invest. 2015 Aug; 45(8): 888–894.).

The management options discussed above are represented in Figure 18.3.

The critically ill cardiac patient may occasionally present with an acute kidney injury and severe hyponatraemia (e.g. from excessive use of diuretics). In this scenario, haemodialysis or haemofiltration on the ICCU may be required to control fluid, electrolyte and acid base balance. However, during continuous venovenous haemofiltration (CVVH), serum electrolytes tend to equilibrate with their concentrations in the replacement fluid, the rate of which is under the influence of the concentration gradient between the plasm and replacement fluid [75]. In patients with severe hyponatraemia, rapid overcorrection may lead to cerebral oedema or CPM. To prevent these electrolyte shifts, the usual replacement fluid sodium concentration (usually 140 mmol/L) needs to be adjusted to allow for more gentle shifts.

For severe hyponatraemia (Na⁺ <125 mmol/L), the sodium concentration of the replacement fluid needs to be reduced by the addition of sterile water. As the patient’s plasma sodium level rises, the amount of sterile water can be reduced until equilibrium is reached. This requires regular checking of plasma sodium concentration, most usually by ABG.

This is defined as serum [Na⁺] >145 mEq/L). It is usually caused by excess water loss but can also be caused by excessive Na+ ingestion. Hypernatraemia can also be classified as hypervolaemic, euvolaemic, or hypovolaemic, depending on the volume status of the patient (see Figure 18.4) Symptoms and signs vary, depending on the rapidity of development and the severity of the disturbance. In hypovolaemic patients, features of dehydration will also be apparent. In severe hypernatraemia, CNS involvement can lead to cerebral agitation and restlessness, decreased reflexes, seizures, and coma.

Treatment is focused on diagnosing and managing the underlying disorder and fluid replacement therapy to treat accompanying dehydration. In hypovolaemic hypernatraemia, there is a Na⁺ deficit, in addition to the water deficit, and treatment includes an isotonic 0.9% saline infusion until the patient is euvolaemic. In other patients, 0.45% saline can be used. In non-severe hypernatraemia, free water may be used also as replacement. The same principles guiding the management of hyponatraemia should be used for the treatment of hypernatraemia, specifically the rate of decrease of serum [Na⁺]. In patients with central diabetes insipidus, synthetic arginine vasopressin (DDAVP) may be used, in conjunction with a specialist endocrinology opinion. In nephrogenic diabetes insipidus, salt restriction, in combination with a thiazide diuretic, may be successful.

K⁺ is the major cation in the ICF. Ninety-eight per cent of its total body store is within this compartment, with a normal range of 140–150 mEq/L, and amounts to approximately 3500 mEq. The ECF contains a much smaller amount, with a serum [K⁺] of 3.5–5.0 mEq/L. Approximately 65–75% of the total body K⁺ is stored in muscle. The ratio of intracellular to extracellular [K⁺] determines the resting membrane potential of the cell membrane, controlling the excitability of nerve and muscle cells, as well as contractility of skeletal, cardiac, and smooth muscle. The main method of maintaining plasma [K⁺] within normal limits is by rapid redistribution from the ECF to the ICF, under neuroendocrine control (e.g. insulin and catecholamines). Acid–base disorders are of profound importance in K⁺ homeostasis. Acidaemias cause a net movement of K⁺ out of cells and into the ECF (potentially to life-threatening levels), whilst the converse is true of alkalaemias.

This is defined as serum [K⁺] <3.5 mEq/L. It is usually caused by excessive loss, decreased intake, or a side effect of medications (e.g. diuretics). Common causes are shown in Table 18.10.

Signs and symptoms of hypokalaemia include:

Characteristic ECG changes include:

Treatment is based on replacement of the deficit. Severe hypokalaemia (<2.0 mEq/L) or a K⁺ deficit in patients at risk of arrhythmias will require IV correction, with ECG monitoring and potentially central venous access. Correction should not exceed 0.3 mEq/kg/hour, as, if exceeded, there is a risk of significant arrhythmia and cardiac arrest.

This is defined as serum [K⁺] >5.0 mEq/L and is usually caused by excessive intake, decreased elimination, or redistribution from the ICF to the ECF. Tissue trauma can result in a rapid release of large quantities of K⁺, leading to potentially life-threatening hyperkalaemia. As ECF [K⁺] increases, cellular membranes depolarize, and the ability for Na⁺ to be transported across the membrane to re-establish the resting membrane potential is reduced. Therefore, action potentials cease to be created. This leads to conduction defects, arrhythmias and characteristic ECG changes, and weakness in skeletal muscles. K⁺ levels of 7.0–8.0 mEq/L predispose patients to VF in 5% of cases, and levels of 10 mEq/L in 90% of cases. The most common causes are shown in Table 18.11. Signs and symptoms of hyperkalaemia include:

Characteristic ECG changes include:

Treatment depends on the level of hyperkalaemia—either emergency therapy or correction of the underlying disorder with restriction of dietary sources of K⁺. Emergency therapies include administration of:

Ca²⁺ and Mg²⁺ are cations whose serum concentrations are lower than their total body stores, as the majority is stored in bone. Only 0.1% of Ca²⁺ and 1% of Mg²⁺ are present in ECF [10]. In plasma, Ca²⁺ exists in three main forms: bound to plasma proteins (40%), bound to other anions such as phosphate and lactate (12%), or in the free ionized form (48%). Ca²⁺ balance is achieved primarily through parathyroid hormone action on bone, absorption from the intestinal tract, and excretion by the kidney. As the ionized Ca²⁺ is the active form, total serum Ca²⁺ needs to be adjusted for serum albumin. There is an interdependence between Mg²⁺ concentration and both Ca²⁺ and K⁺ concentrations, such that a reduction in the former leads to a reduction in both of the latter. Mg²⁺ deficiency can contribute to cardiac dysrhythmias, due to the hypokalaemia it produces. Symptoms and disorders caused by deranged Ca²⁺ and Mg²⁺ balance are shown in Table 18.12.

Treatment should always include the diagnosis and management of the underlying disorder. Acute symptomatic treatment of tetany requires an IV infusion containing Ca²⁺ ions (either calcium gluconate, gluceptate, or chloride). The usual dose is 100–200 mg of elemental calcium over 10 min in 50–100 mL of 5% dextrose, followed by an infusion containing 1–2 mg/kg/hour over 6–12 hours. Chronic hypocalcaemia may be treated with oral dietary supplementation. Depending on the underlying cause, vitamin D supplementation may also be required (particularly in children).

Treatment of symptomatic hypercalcaemia consists of rehydration (large volume of 0.9% saline), with the use of loop diuretics (which leads to Ca²⁺ ion excretion). For more chronic conditions, drugs that prevent Ca²⁺ mobilization from bone are used (e.g. bisphosphonates and calcitonin). Dialysis can also be used for patients with renal or heart failure with acute hypercalcaemia. Plicamycin, an antineoplastic antibiotic, can be used as a final therapy.

Symptomatic moderate to severe deficiency can be treated with IV administration for several days to replace depleted stores and plasma levels. Common treatment doses are 2 g magnesium sulfate (where 1 g = 8.3 mmol/L of Mg²⁺) in IV boluses, infused over 10–20 min, until the desired plasma concentration is achieved. Mg²⁺ is often used to treat arrhythmias (for its membrane-stabilizing action) and in the treatment of pre-eclampsia and eclampsia (for its hypotensive and membrane-stabilizing actions).

The interpretation of ABG sampling, together with that of fluid and electrolyte disturbances, is pivotal to the ongoing assessment of the critically ill patient. Although the compensatory systems of the body are complex, some basic principles apply that can be used to guide any intervention. The key, however, is to understand the underlying reason for the abnormality and treat the underlying cause, rather than the abnormal numbers per se. Future developments in POCT, which allows the analysis of regional acid–base and metabolic disturbances, are likely to significantly enhance the management of such critically ill patients.