Acid is also generated by
What are the main buffer systems in the intravascular, interstitial and intracellular compartments?
In the plasma the main systems are
Bicarbonate (HCO3−)
Phosphate (PO43−)
Plasma proteins
Globin component of haemoglobin
The bicarbonate system is predominantly interstitial, and cytoplasmic proteins are mostly intracellular
What does the Henderson–Hasselbalch equation describe?
This defines the relationship between dissociated and undissociated acids and bases
Which organ systems are involved in regulating acid–base balance?
Respiratory system: this controls PaCO2 through alterations in alveolar ventilation. CO2 indirectly stimulates central chemoreceptors (in the medulla oblongata) by releasing H+, which once it crosses the blood–brain barrier (BBB), dissolves in the cerebrospinal fluid (CSF)
Renal: this controls the [HCO3−] and is important for long-term control and compensation of acid–base disturbances
Haematology: the constituents of blood, e.g. plasma proteins and haemoglobin, serve as buffers
Rheumatology: H+ may exchange with cations from bone mineral. Also, carbonate in bone can be used to support plasma HCO3− levels
Gastrointestinal: the liver may generate HCO3− and NH4+ (ammonium) by glutamine metabolism. In the kidney tubules, ammonia excretion generates more bicarbonate
How does the kidney absorb bicarbonate?
There are three main methods by which the kidneys increase the plasma bicarbonate
Replacement
Tubule cells: can replace filtered bicarbonate and phosphate with bicarbonate that is generated in the tubular cells
Generation
Tubule cells: can generate de novo bicarbonate from glutamine that is absorbed by tubule cells
Define the base deficit (base excess)?
The base deficit is the amount of acid or alkali required to restore 1 L of fully oxygenated blood to a normal pH at a pCO2 of 5.3 kPa at 37°C. It helps to indicate if an acid–base disturbance is respiratory, metabolic or mixed, and usually ranges from −2 to +2 mmol/L.
What basic investigation provides information on acid–base balance?
This is the arterial blood gas (ABG), which is usually taken from venepuncture of the radial artery. It provides basic information, including pH, PaCO2 (4.5–6.0 kPa), HCO3− (22–28 mmol/L), PaO2 (10.5–13.5 kPa) and base excess. It should be interpreted in that order (see below). Other valuable information is lactate, indicating inadequate tissue perfusion (0–2 mmol/L) and glucose, as a guide to treatment in diabetic ketoacidosis.
How is knowledge of the PaO2 useful?
It provides a guide to tissue oxygenation, but should be interpreted compared to the FiO2. A relatively normal PaO2 but a high FiO2 can indicate problems diffusing oxygen from the alveolus into blood, e.g. inefficient gas exchange.
Describe some common acid–base disturbances on ABG analysis?
The pH influences the analysis of other variables if it is respiratory, metabolic, or mixed.
pH
Metabolic acidosis
What is metabolic acidosis?
This is an acid–base disturbance characterised by an increase in the total body acid (pH <7.35). There is also a fall of the serum bicarbonate to below the reference range.
In what ways may bicarbonate be lost in the cases of metabolic acidosis?
The bicarbonate may be
Excreted, e.g. vomiting, diarrhoea, fistulas or urine
Depleted through buffering an overwhelming H+ load
Impaired generation of bicarbonate
How may the causes of metabolic acidosis be classified?
The causes may be classified according to the anion gap
The anion gap ranges from ∼12 to 20 mmol/L and estimates the contribution of unmeasured ions, e.g. lactate, to help determine the cause of a metabolic acidosis.
Normal anion gap due to loss of bicarbonate (or ingestion of acid)
Gastrointestinal: this includes diarrhoea, pancreatic fistula, ileostomy and ingestion of acidifying agents, e.g. TPN and excess amino acids
Renal: losses of bicarbonate include renal failure, and tubular acidosis Type II and Type IV (hypoaldosteronism)
Chloride ions replace bicarbonate to ensure electrochemical neutrality, but can lead to a hyperchloraemia
Increased anion gap (increased exogenous or endogenous acid ingestion)
Ketoacidosis, e.g. DKA, starvation, alcoholism
Uraemia
Salicylate poisoning
Methanol intoxication
(A)ethylene glycol poisoning
Lactic acidosis, e.g. sepsis, shock, hypermetabolic state such as burns
The acronym KUSsMAuL is useful, particularly as Kussmaul’s respiration is a clinical sign of metabolic acidosis. Bicarbonate buffers the acid load. It is catalysed to CO2, and H2O, which is then excreted by the lungs.
What effects can acidosis have on body physiology?
Shift of the oxygen dissociation curve to the right, signifying a reduction of the haemoglobin molecule’s oxygen affinity. This increases tissue oxygenation
Resistance to the effects of circulating catecholamines
Pulmonary hypertension, as acidosis causes pulmonary vasoconstriction
Cardiac arrhythmias, due to both a direct effect and through development of hyperkalaemia
Increased sympathetic activity and paradoxical catecholamine resistance
What are the principles of management of any cause of metabolic acidosis?
The principles of management involve
Assessment: of the severity of the acidosis and resultant complications mentioned above
Management: of the underlying cause, e.g. fluids and insulin for DKA, emergency dialysis for renal failure
The use of bicarbonate is a controversial issue. It is more justified in cases of hyperchloraemic metabolic acidosis, where the primary problem is a loss of bicarbonate (see Lactic Acidosis), but renal involvement is important.
Metabolic alkalosis
What is the essential disturbance that defines a metabolic alkalosis?
The essential change is a primary increase in the serum bicarbonate to >28 mmol/L.
Which ions other than bicarbonate are implicated in the development of metabolic alkalosis?
The other ions are
Hydrogen ions (protons): loss of protons, e.g. by vomiting, leads to a compensatory increase in bicarbonate and, hence, alkalosis
Chloride ions: loss causes renal tubules to increase bicarbonate uptake in order to maintain electrochemical neutrality, as the loss of one leads to gain of the other
Potassium: loss of this ion leads to increased absorption of bicarbonate in the renal tubules. Also, this leads to increased cellular uptake of protons
Which organ system is most commonly involved in metabolic alkalosis?
Gut pathology is often implicated.
Give some examples of the causes of metabolic alkalosis
Excess bicarbonate ingestion
Gastrointestinal: e.g. milk–alkali syndrome
Iatrogenic: overtreatment of acidosis
Inappropriate acid loss (with gain of bicarbonate)
Gastrointestinal: persistent vomiting, e.g. pyloric stenosis, self-induced vomiting
Metabolic: any cause of hypokalaemia, as this shifts protons into cells
Endocrine: hyperaldosteronism
Iatrogenic: chloride loss, e.g. secondary to diuretic abuse
One other cause is contraction alkalosis due to rapid diuresis or fulminant liver failure. This increases bicarbonate absorption over chloride.
Describe the mechanism by which metabolic alkalosis develops in cases of pyloric stenosis
In the case of pyloric stenosis, metabolic alkalosis develops and is perpetuated by normal compensatory mechanisms
Gastric acid is a rich source of protons and chloride, which are both lost in vomit
There is a reduction of pancreatic juice secretion due to reduced acid load at the duodenum, which therefore retains bicarbonate
Volume depletion maintains the alkalosis by leading to bicarbonate absorption over chloride, e.g. contraction alkalosis
There is increased uptake of bicarbonate at renal tubules (response to a loss of chloride) in order to maintain electrochemical neutrality
Why may patients with a metabolic alkalosis develop poor tissue oxygenation?
There are two main reasons
Lactic acidosis
What are the defining features of lactic acidosis?
The important features include a metabolic acidosis (with varying degrees of compensation) and elevated serum lactate. The serum lactate level is normally <2 mmol/L, but with lactic acidosis, it may increase to >5 mmol/L.
How may the causes of lactic acidosis be classified?
The Cohen and Woods (1976) classification divides the causes thus
Type A: clinical evidence of inadequate tissue oxygenation
Anaerobic metabolism: e.g. sprinting, marathon running, seizures and lactate is produced from pyruvate
Shock (any cause): causing poor tissue perfusion and cellular hypoxia, worsening the anaerobic metabolism, e.g. mesenteric ischaemia, haemorrhagic shock
Reduced tissue oxygenation: tissue perfusion may be adequate but oxygen delivery and utilisation may be inadequate, e.g. carbon monoxide poisoning, extremely severe anaemia
Type B: no clinical evidence of inadequate tissue oxygenation
Type B1 (chronic diseases): including liver disease, renal failure, DKA, malignancy, short bowel syndrome
Type B2 (drug-induced): including paracetamol, salicylate overdose, metformin, adrenaline, alcohol intoxication, anti-retroviral medication
What are the essential findings on investigation?
The diagnostic features are an elevated serum lactate and the presence of an increased anion gap metabolic acidosis on ABG analysis in the face of known predisposing factors.
What are the principles of management of lactic acidosis?
The most important aspect of management is
Correcting the predisposing factor, e.g. support of the cardiac output in order to improve the tissue perfusion
What are the precautions and potential problems associated with bicarbonate therapy?
Some considerations must be made when using bicarbonate to reverse metabolic acidosis
Rate: bicarbonate must be infused slowly. It comes as a hypertonic 8.4% solution (or hypotonic 1.26% solution), which can alter myocardial contractility depending on the rate of infusion
Dose: it must be carefully titrated to the desired therapeutic end point, because of the risk of an overshoot metabolic acidosis
Complications can include
Electrolyte balance: calcium (and phosphate)
What is the normal level of serum calcium?
2.2–2.6 mmol/L.
What is the distribution of calcium in the body?
Ninety-nine per cent of calcium is found in bone, mostly as hydroxyapatite. One per cent is readily exchangeable as calcium phosphate salts.
In what state is calcium found in the circulation?
50% is unbound and ionised
45% is bound to plasma proteins
5% is associated with anions such as citrate and lactate
Which organ systems are involved in controlling serum calcium levels?
The main organ systems include the gut, kidneys and skeletal systems.
Name the hormones involved in controlling serum calcium
Major hormones
Other hormones include parathyroid hormone-related peptide (PTHrP), and magnesium and albumin also play a role. Magnesium prevents PTH release, potentially causing hypocalcaemia. Up to 40% of plasma calcium is bound to albumin. It is important that the unbound ionised form is measured, e.g. add 0.1 mmol/L to the level for every 4 g/L drop in albumin <40 g/L.
Briefly describe their effects
PTH (raised Ca2+ but low PO43−)
Bone: increases the synthesis of enzymes that break down bone matrix to release calcium and phosphate into the circulation. It also stimulates osteocytic and osteoclastic activity, leading to progressive bone reabsorption
Renal: increases renal phosphate excretion while reducing renal calcium loss. It also stimulates 1-α-hydroxylase activity in the kidney, increasing 1,25 dihydroxy-vitamin D3 (calcitriol), thus indirectly increasing calcium absorption
Vitamin D3 (cholecalciferol) metabolites (↑Ca2+ and ↑PO43− but ↓PTH release)
Bone: calcitriol increases both serum calcium and the calcification of bone matrix. It stimulates osteoblastic proliferation and protein synthesis
Renal: it promotes calcium and phosphate reabsorption
Gastrointestinal: it enhances gut absorption of calcium and phosphate
What are the clinical consequences of hypercalcaemia?
Renal: calculi due to hypercalcinuria, nephrocalcinosis and multi-focal calcium deposits in the renal parenchyma. Polyuria and polydipsia occur due to decreased tubular function. This can lead to dehydration, especially if there is associated vomiting
Gastrointestinal: dyspepsia and peptic ulceration due to increased gastric acid secretion stimulated by calcium and PTH. There is an increased risk of developing acute pancreatitis, and constipation is common
Bone: cysts can develop, osteitis fibrosa cystica and Brown’s tumours may occur
General medical: a non-specific series of symptoms can develop, e.g. tiredness, lethargy and organic psychosis, and, in severe cases, this can lead to coma
What ECG changes may be found?
The ECG changes are related to alterations in the membrane potential and cardiac conduction, and include
Shortened QT interval
Increased PR interval (progressing to heart block)
Flattened or inverted T-waves
Under what circumstances may a surgeon encounter a patient with hypercalcaemia?
The main reasons why a surgeon may encounter a hypercalcaemic patient are
Malignancy: a hypercalcaemia of malignancy may develop, e.g. bronchogenic carcinoma and pathological fractures due to secondary deposits
Endocrine: primary hyperparathyroidism, due to an adenoma of the parathyroid gland, requiring neck exploration, and tertiary hyperparathyroidism in renal transplant patients
General complications: urinary obstruction due to renal calculi, deranged physiology from acute pancreatitis and peptic ulceration
What are the differential diagnoses of abdominal pain in the hypercalcaemic patient?
Peptic ulceration (perforation may be present)
Renal colic from calculi
Acute pancreatitis
Constipation from reduced intestinal motility
What does the emergency management of hypercalcaemia involve?
Management of acute hypercalcaemia (>3.5 mmol/L), following immediate ABCDE assessment, involves
Commencing continuous cardiac monitoring
Fluid resuscitation by giving 3000 ml of normal saline in 24 hours. To prevent overload, CVP monitoring may be required. Furosemide can be given to help aid calcium diuresis and prevent overload
Urinary catheter to monitor fluid balance and urinary volumes, e.g. output should be >2000 ml/day
A bisphosphonate infusion can rapidly reduce the serum calcium, e.g. pamidronate, but should only be given once fully rehydrated
In all cases, identifying and treating the underlying cause by conducting basic laboratory investigations, e.g. PTH, is required. Surgery is required in those cases due to hyperparathyroidism.
What is the most important surgical cause of hypocalcaemia?
The most important surgical cause is after thyroid surgery, when there is inadvertent removal of the parathyroid glands.
Give some of the recognised features of hypocalcaemia?
The important clinical features are
Electrolyte balance: magnesium
What is the normal serum level of magnesium?
0.7–1.0 mmol/L.
What is the distribution of magnesium in the body?
Magnesium is the second most abundant intracellular cation after potassium. The total body magnesium is ∼25 g. Up to 65% is located in bone and only 1% is found in serum. Therefore, serum is a poor reflection of the total body store.
What purpose does magnesium serve?
Magnesium is an essential co-factor in a number of enzymes, notably in the transfer of phosphate groups, and protein synthesis. It is most conspicuously important for the normal function of the central nervous system, neuromuscular and cardiovascular systems.
What is the relationship between magnesium and serum calcium?
High magnesium levels prevent calcium cellular uptake, and for this reason hypermagnesaemia can lead to bradycardia and sluggish deep tendon reflexes.
Which organ is largely responsible for magnesium homeostasis?
The kidney is the major site for magnesium balance. It is freely filtered at the glomerulus, and reabsorbed mainly at the proximal convoluted tubule and the thick ascending limb of the loop of Henle.
What are the main causes of hypomagnesaemia?
Decreased intake
Starvation: e.g. alcoholism, malnutrition
How common is hypomagnesaemia in the hospital setting?
Hypomagnesaemia occurs in over 60% of the critically ill, most commonly associated with diuretic use.
How can hypomagnesaemia be recognised?
It may be difficult to recognise hypomagnesaemia due to its varied presentation. Recognised features include
Give some examples of the therapeutic role of magnesium-containing compounds
Anti-arrhythmic: can be used to achieve chemical cardioversion for acute AF
Acute MI: some studies suggest a survival benefit from early administration
Antacid: e.g. magnesium trisilicate, or hydroxide
Laxative: e.g. magnesium sulphate
Electrolyte balance: potassium
What is the normal level of serum potassium?
3.5–5.0 mmol/L.
What is the distribution of potassium in the body?
Ninety-eight per cent of potassium is intracellular at a concentration of ∼150 mmol/L, compared to ∼4 mmol/L in the serum.
How is potassium regulated?
There are a number of influential factors on serum potassium
Gastrointestinal
Diet: the Western diet may contain 20–100 mmol of potassium daily
Endocrine
Acid–base balance: potassium and H+ are exchanged at the cell membrane, producing reciprocal changes in concentration, e.g. acidosis leads to hyperkalaemia. Similarly, alkalosis can lead to hypokalaemia. Also, renal reabsorption of one causes excretion of the other
Tubular fluid flow rate: increased flow promotes potassium secretion, one method by which diuretics may cause hypokalaemia
What are the causes of hyperkalaemia?
Artefact, e.g. haemolysis in the blood bottle
Excess administration, e.g. IV fluids
Redistribution
Compartmental fluid shifts: due to injury, intravascular haemolysis, burns, rhabdomyolysis, tissue necrosis, massive blood transfusion
Reduced cellular uptake: e.g. insulin deficiency, acidosis
Decreased excretion
Renal: e.g. renal failure, potassium-sparing diuretics
Endocrine: e.g. Addison’s disease, mineralocorticoid resistance due to systemic lupus erythematosus (SLE)
What is the emergency management of hyperkalaemia?
The serum potassium must be re-checked to determine if it is a spurious finding. If it comes back as >6.5 mmol/L, following immediate ABCDE assessment, implement
Continuous cardiac monitoring
Stop all potassium-containing intravenous fluids, including Hartmann’s
Calcium gluconate (10 ml of 10%) is given IV over 10 min, which provides a short-term cardioprotective effect but does not decease the serum potassium
Give 5–10 U of insulin in 50 ml of 50% dextrose IV over 30 minutes, which increases cellular uptake of potassium
In all cases, treat the underlying cause and investigate renal function, as haemodialysis might be needed if the potassium is persistently high or if there is severe acidosis (pH <7.20). The use of bicarbonate is a specialist renal intervention as it can paradoxically exacerbate the acidosis.
What use does knowledge of the cardiac effects of potassium have for surgical practice?
Potassium-rich cardioplegic solutions are used to arrest the heart in diastole to permit cardiac surgery once cardiopulmonary bypass has been established.
What are the causes of hypokalaemia?
Artefact, e.g. drip arm sampling
Decreased intake
Starvation: e.g. alcoholism
Redistribution
Compartmental fluid shifts: including alkalosis and insulin excess
Increased excretion
Gastrointestinal losses: e.g. vomiting and diarrhoea, enterocutaneous fistula, mucin-secreting adenomas of the colon
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