Before you open an answer
Write it first, then mark it
The expanded teaching below is deliberately fuller than a 10-mark script. Write a timed answer before opening each model; the rapid-answer panel then shows what to prioritise under examination conditions, and the self-marking map shows where the marks sit.
These three questions were supplied for a teaching session rather than taken from a paper, so no sitting or question number is claimed for them. Where a genuine past MMed question covers the same material, it is listed under the stem with its real year, and where an examiner critique exists for that question its requirements are quoted at the head of the answer.
Four investigations in the critically ill patient
Supplied practice question · no mark allocation printed
- Briefly outline the role of the following investigations in critically ill patients:
- serum ammonia
- serum globulin
- urine osmolarity
- C-reactive protein
View model answerQuestion first · answer when ready
i. Serum ammonia
What earns the marks
| Where it comes from | Colonic bacterial urease acting on urea, and enterocyte glutaminase; about 85% reaches the liver in portal blood. |
|---|---|
| How it is cleared | Periportal urea cycle as the high-capacity route, perivenous glutamine synthetase as the scavenger, skeletal muscle as a reserve sink. |
| Normal value | Roughly 11–35 µmol/L in adults, laboratory-dependent. State a number. |
| What a high value tells you | Hepatocellular failure, portosystemic shunting, or a non-hepatic cause; in acute liver failure it grades the risk of cerebral oedema. |
| What it cannot tell you | It does not grade encephalopathy in cirrhosis, and it is not a test of synthetic function. |
| Pre-analytical trap | Tourniquet, delay, warmth and haemolysis all raise it falsely. |
Ammonia is a product of nitrogen metabolism, generated mainly by colonic bacterial urease acting on urea and by glutaminase in the enterocyte, with about 85% delivered to the liver in portal venous blood. The liver clears it by two routes in series: the urea cycle in periportal (zone 1) hepatocytes, which is high capacity but low affinity, and glutamine synthetase in perivenous (zone 3) hepatocytes, which is low capacity but high affinity and scavenges what escapes. Skeletal muscle provides a further sink. Normal serum ammonia is approximately 11–35 µmol/L, though the reference range is laboratory-specific.
In the critically ill it is used for three things. It supports the diagnosis of hepatic encephalopathy and, in unexplained coma, identifies hyperammonaemia arising outside the liver. In acute liver failure it is the best-validated biochemical predictor of intracranial hypertension: a persistently high arterial ammonia identifies the patient at risk of cerebral oedema and herniation, and a rising value argues for escalation. It also monitors treatment — lactulose, rifaximin, protein and nitrogen load, and renal replacement therapy in severe hyperammonaemia. It is not a test of synthetic function and correlates poorly with the clinical grade of encephalopathy in cirrhosis.
Where ammonia comes from and how it is removed
Ammonia exists in equilibrium between the gas NH3 and the ion NH4+, with a pKa of about 9.2, so at physiological pH the great majority is the charged NH4+. The uncharged fraction is what crosses the blood–brain barrier, which is why alkalosis worsens encephalopathy: raising the pH shifts the equilibrium towards the diffusible species. This single fact links a routine arterial blood gas to a neurological deterioration, and it is the sort of connection the examiners describe as clinical correlation.
| Urea cycle | Glutamine synthetase | |
|---|---|---|
| Location | Periportal (zone 1) hepatocytes; mitochondrion then cytosol | Perivenous (zone 3) hepatocytes, the last cells the blood meets |
| Kinetics | High capacity, low affinity | Low capacity, high affinity |
| Product | Urea, excreted by the kidney | Glutamine, non-toxic and re-usable |
| Function | Bulk disposal of the portal nitrogen load | Scavenges the residue, setting the final venous concentration |
| Vulnerability | Congenital enzyme deficiency; valproate; severe hepatocellular loss | Zone 3 is the first area injured by hypoxia or hypotension |
Commonly lost: Candidates did not state normal values and did not relate the result to liver failure or to a clinical context.
What it is used for in the critically ill
| Role | What it answers | How the result is used |
|---|---|---|
| Diagnosis of hepatic encephalopathy | Is this altered consciousness hepatic? | A normal ammonia in an undrugged patient makes hepatic encephalopathy unlikely, so its value is largely in exclusion. |
| Risk of intracranial hypertension | In acute liver failure, which patient will develop cerebral oedema? | A sustained high arterial ammonia is the best-validated biochemical predictor. Commonly quoted thresholds are above roughly 100 µmol/L for severe encephalopathy and above roughly 150–200 µmol/L for intracranial hypertension. Treat these as risk gradients, not switches. |
| Unexplained coma without liver disease | Is there a non-hepatic hyperammonaemia? | Identifies an adult-presenting urea cycle disorder, valproate toxicity, asparaginase, a urease-producing urinary infection with stasis, or a portosystemic shunt. These are treatable and otherwise easily missed. |
| Monitoring | Is treatment working? | Serial values track the response to lactulose, rifaximin, nitrogen restriction, correction of precipitants and renal replacement therapy. |
| Prognosis | How severe is the hepatic failure? | Contributes to the assessment of acute liver failure alongside INR, lactate, pH and creatinine, none of which it replaces. |
Limitations, and the pre-analytical trap
- Sampling error is the commonest cause of a high result. A prolonged tourniquet, fist clenching, haemolysis, a warm sample or a delay before separation all raise the measured value. Blood should be taken free-flowing, placed on ice and analysed promptly.
- Arterial is preferable to venous in acute liver failure, since muscle extracts ammonia and a peripheral venous sample underestimates what the brain sees.
- It does not grade encephalopathy in cirrhosis. The correlation between the ammonia concentration and the West Haven grade is poor, because chronic exposure produces astrocytic adaptation.
- It is not a liver function test in the synthetic sense. Synthetic function is measured by INR, albumin and glucose. A raised ammonia with a normal INR points to shunting or to a non-hepatic cause.
Suggested self-marking map
Educational allocation. This question prints no mark scheme, so the split shown is derived from the stem and is not presented as the official one.
ii. Serum globulin
What earns the marks
| What it is | A calculated value: total protein minus albumin, roughly 20–35 g/L. |
|---|---|
| What it contains | α₁, α₂, β and γ fractions; the γ fraction is immunoglobulin. |
| The key contrast | Albumin is hepatic; immunoglobulin is not. The two therefore move independently. |
| What the ratio tells you | A reversed albumin:globulin ratio points to chronic liver disease or a paraproteinaemia. |
| Critical-care use | Separates synthetic failure from protein loss; contributes to the anion gap and to drug binding. |
| Limitation | Crude, slow to change, and never interpreted without the albumin beside it. |
Serum globulin is not measured directly. It is total protein minus albumin, normally about 20–35 g/L against an albumin of 35–50 g/L, giving an albumin:globulin ratio of roughly 1.2–2.0. Electrophoresis separates it into α1 (α1-antitrypsin), α2 (haptoglobin, caeruloplasmin, α2-macroglobulin), β (transferrin, complement C3) and γ (immunoglobulins).
The point that makes it useful is one of origin. Albumin and the α and β globulins are synthesised by the liver; immunoglobulins are synthesised by plasma cells and are not. The two therefore dissociate in disease, and the pattern of that dissociation is the information. In chronic liver disease albumin falls through synthetic failure while γ-globulin rises, because portosystemic shunting delivers gut antigen past a reticuloendothelial system that would otherwise clear it — so the ratio reverses. In protein-losing states both fall together. In myeloma the globulin rises alone.
The fractions, and where each is made
| Fraction | Principal members | Source | Behaviour in inflammation |
|---|---|---|---|
| Albumin | Albumin, 35–50 g/L | Liver | Falls. A negative acute-phase protein, and also lost to capillary leak and dilution. |
| α1 | α1-antitrypsin, α1-acid glycoprotein | Liver | Rises. α1-acid glycoprotein binds basic drugs. |
| α2 | Haptoglobin, caeruloplasmin, α2-macroglobulin | Liver | Rises, except haptoglobin, which falls when it is consumed binding free haemoglobin in haemolysis. |
| β | Transferrin, complement C3, β2-microglobulin | Liver | Mixed; transferrin falls, complement rises. |
| γ | IgG, IgA, IgM, IgE, IgD | Plasma cells, not the liver | Slow to change; a polyclonal rise reflects chronic antigenic stimulation rather than an acute insult. |
Reading the pattern
| Albumin | Globulin | A:G ratio | Interpretation in the critically ill |
|---|---|---|---|
| Low | High | Reversed | Chronic liver disease: synthetic failure plus polyclonal γ rise from portosystemic shunting of gut antigen. |
| Low | Low | Preserved | External loss or dilution: nephrotic syndrome, protein-losing enteropathy, extensive burns, large-volume crystalloid resuscitation. |
| Low | Normal or mildly high | Low | Acute inflammation: albumin is a negative acute-phase protein and capillary leak redistributes it; α and β fractions rise. |
| Normal | Very high | Reversed | Paraproteinaemia. Consider myeloma with its hypercalcaemia, renal failure and hyperviscosity, all of which change anaesthetic management. |
| Normal | Low | High | Hypogammaglobulinaemia: recurrent infection, and relevant to the immunosuppressed or post-transplant patient. |
Why an anaesthetist cares
- Acid–base. Plasma proteins are net anionic at physiological pH and form the largest part of the unmeasured anion. Hypoalbuminaemia therefore lowers the apparent anion gap and can conceal a lactic or ketoacidosis entirely. The usual correction adds about 2.5 mmol/L to the anion gap for every 10 g/L the albumin falls below 40 g/L. In the Stewart approach the same fact appears as a fall in Atot, producing a metabolic alkalosis that offsets a coexisting acidosis.
- Drug binding. Acidic drugs bind albumin; basic drugs bind α1-acid glycoprotein, an α1-globulin that rises in critical illness. So in sepsis the free fraction of an acidic drug such as phenytoin rises while the free fraction of a basic drug such as bupivacaine or lidocaine falls. Total concentrations mislead in opposite directions.
- Calcium. Roughly 40% of plasma calcium is protein-bound, almost all to albumin, so ionised calcium must be measured directly rather than inferred from a total in the critically ill.
- Oncotic pressure. Albumin generates about 75–80% of plasma colloid osmotic pressure; globulins contribute the remainder despite their comparable mass, because oncotic pressure depends on particle number and globulins are larger.
Suggested self-marking map
Educational allocation. This question prints no mark scheme, so the split shown is derived from the stem and is not presented as the official one.
iii. Urine osmolarity
What earns the marks
| Define it correctly | Osmolality, mosmol/kg of water, is what is measured; osmolarity, mosmol/L of solution, is what the stem says. |
|---|---|
| Normal range | 50–1200 mosmol/kg, the span of maximal dilution to maximal concentration. |
| What it measures | The product of ADH action and an intact medullary gradient — two things, not one. |
| Use in oliguria | Separates a concentrating, hypoperfused tubule from an isosthenuric, injured one. |
| Use in hyponatraemia | Separates appropriate ADH suppression from inappropriate ADH secretion. |
| Limitation | Never read alone; confounded by diuretics, osmotic agents, CKD and sepsis. |
Begin by correcting the term. Osmolarity is mosmol per litre of solution; osmolality is mosmol per kilogram of solvent, is independent of temperature, and is what an osmometer measures by depression of freezing point. Urine is reported as osmolality, and in dilute biological fluids the two are numerically close.
Urine osmolality spans 50 to 1200 mosmol/kg. It is the product of two separate things: circulating ADH, which inserts aquaporin-2 into the collecting duct, and an intact medullary concentration gradient built by countercurrent multiplication and preserved by the vasa recta. Either can fail independently, which is why the number is read as a test of both.
In the critically ill it answers three questions. In oliguria, is the tubule concentrating (hypoperfusion, urine above 500 mosmol/kg) or isosthenuric (established tubular injury, below 350)? In hyponatraemia, is ADH appropriately off (urine below 100 mosmol/kg) or inappropriately on? In polyuria, is this a water diuresis (dilute urine, diabetes insipidus) or a solute diuresis (urine near 300 mosmol/kg with a high solute output from glucose, urea, mannitol or contrast)?
The oliguric patient
| Index | Prerenal, tubule intact | Acute tubular necrosis | Why |
|---|---|---|---|
| Urine osmolality | Above 500 mosmol/kg | Below 350 mosmol/kg | Concentrating ability requires living tubular cells and a medullary gradient. |
| Urine sodium | Below 20 mmol/L | Above 40 mmol/L | Avid, aldosterone-driven sodium reabsorption against failed reabsorption. |
| Fractional excretion of sodium | Below 1% | Above 2% | Corrects the urine sodium for how concentrated the urine is. |
| Fractional excretion of urea | Below 35% | Above 50% | Remains valid on loop or thiazide diuretics, when FeNa does not — the single most useful substitution at the bedside. |
| Urine:plasma osmolality ratio | Above 1.5 | About 1.0, isosthenuric | Expresses the same information as a ratio rather than an absolute. |
Read the question: These indices are a probability statement, not a diagnosis. Sepsis-associated acute kidney injury frequently shows prerenal indices with structurally injured kidneys, and the distinction is often only clear in retrospect. An answer that presents the table as definitive is describing a textbook rather than a patient.
The hyponatraemic patient
Here the logic runs the other way. The healthy response to a low plasma osmolality is to switch ADH off and excrete maximally dilute urine. So:
- Urine osmolality below 100 mosmol/kg — ADH is appropriately suppressed. The problem is water intake exceeding excretory capacity, or a solute intake too low to carry the water: primary polydipsia, or beer potomania and the tea-and-toast diet.
- Urine osmolality above 100 mosmol/kg — ADH is on. Now assess volume status. If the patient is euvolaemic with a urine sodium above 30 mmol/L, normal thyroid and adrenal function and no diuretic, this is consistent with SIADH. If hypovolaemic with a urine sodium below 30 mmol/L, ADH is being released appropriately for volume, and the correct treatment is salt and water rather than fluid restriction. The two are managed in opposite directions, and the urine osmolality with the urine sodium is what separates them.
What confounds it
- Diuretics raise urine sodium and abolish the FeNa, and loop diuretics dismantle the medullary gradient itself. Use the fractional excretion of urea.
- Osmotic agents — glucose, mannitol, urea, radiocontrast — raise urine osmolality without any concentrating work being done, and produce a solute diuresis that mimics neither pattern. In hyperglycaemia the osmotic diuresis drives a urine osmolality near or above plasma while the kidney is in fact losing free water.
- Chronic kidney disease fixes the urine osmolality near plasma regardless of the acute problem, so the indices lose their meaning.
- Age and protein intake both reduce maximum achievable concentration; a low-protein diet lowers the urea available to build the gradient.
- A single value with no plasma osmolality and no urine sodium answers nothing. This is the most common error and the reason the algorithm above starts where it does.
Suggested self-marking map
Educational allocation. This question prints no mark scheme, so the split shown is derived from the stem and is not presented as the official one.
iv. C-reactive protein
What earns the marks
| What it is | A pentraxin, hepatic, synthesised in response to IL-6; normal below about 5 mg/L. |
|---|---|
| What it does | Binds phosphocholine on damaged and microbial membranes, activates classical complement through C1q, opsonises. |
| Kinetics | Rises at 4–6 h, doubles about every 8 h, peaks at 36–50 h, half-life about 19 h and independent of cause. |
| Why the trend beats the value | Because the half-life is fixed, a falling CRP means the stimulus has gone. |
| Critical-care use | Post-operative complications, antibiotic duration, response to source control. |
| Limitation | Non-specific, lags the insult, and is blunted by liver failure and by steroids. |
CRP is an acute-phase protein of the pentraxin family, five identical subunits arranged in a ring, synthesised by the hepatocyte in response to interleukin 6, with IL-1 and TNF-α as secondary drivers. Normal is below about 5 mg/L. Its biological role is innate immune: it binds phosphocholine exposed on damaged cell membranes and on some bacterial surfaces, and activates the classical complement pathway through C1q, acting as an opsonin.
Its clinical value comes almost entirely from its kinetics. It begins to rise 4 to 6 hours after the insult, roughly doubles every 8 hours, peaks at 36 to 50 hours, and has a plasma half-life of about 19 hours that does not vary with the cause. Because clearance is fixed, the concentration is determined solely by the rate of synthesis, so the concentration tracks whether the stimulus is still present. That is why the trend is read rather than the number.
| Role | How it is used | The caveat |
|---|---|---|
| Detecting inflammation | A rise confirms a systemic inflammatory stimulus somewhere. Sensitive across causes. | Cannot distinguish infection from sterile inflammation. Surgery, trauma, burns, infarction, malignancy and autoimmune disease all raise it. |
| Post-operative surveillance | An uncomplicated major operation produces a predictable rise peaking on day 2 to 3 and falling thereafter. A failure to fall, or a second rise after day 3 to 4, suggests a complication such as an anastomotic leak or a collection. | The expected magnitude depends on the operation; the pattern, not the peak, is what is interpreted. |
| Guiding antibiotic duration | Serial measurements support stopping antibiotics when the trend has fallen convincingly, contributing to stewardship. | Procalcitonin has the stronger evidence base for this and falls faster; CRP lags. |
| Assessing source control | After drainage or debridement, a falling CRP supports adequate source control; a plateau argues for re-imaging. | The 19-hour half-life means a genuine fall takes 2 to 3 days to be convincing. |
| Prognosis | Persistently high values track ongoing inflammation and correlate with worse outcome. | Association, not a treatment target in itself. |
CRP against the other markers
| CRP | Procalcitonin | Lactate | |
|---|---|---|---|
| What it reflects | IL-6-driven hepatic acute-phase response | Ubiquitous transcription of CALC-1 in bacterial infection; suppressed by interferon-γ, hence lower in viral illness | Imbalance between production and clearance: hypoperfusion, adrenergic drive, impaired hepatic clearance |
| Begins to rise | 4–6 h | About 4 h | Minutes |
| Peak | 36–50 h | 6–24 h | No fixed peak |
| Half-life | About 19 h, constant | About 24 h; prolonged in renal failure | Minutes to hours, hepatic and renal clearance |
| Best question for it | Is the inflammatory stimulus resolving? | Is this bacterial, and can antibiotics stop? | Is this patient shocked now? |
| Main weakness | Slow and non-specific | Raised in major surgery, trauma, burns and renal failure without infection | Many non-hypoperfusion causes, including adrenaline and salbutamol |
The unifying point across all four investigations is the same one the examiners made about ammonia: each is a physiological variable with a normal range, a known time course and a defined failure mode, and each is interpreted against the clinical question rather than reported as a number. Two of them — ammonia and CRP — are made by the liver, so both are blunted by hepatic failure. Two of them — globulin and CRP — are protein responses to inflammation moving on quite different timescales. Urine osmolality is the only one that measures a function rather than a concentration, and it is the only one that needs two other results beside it to mean anything at all.
Suggested self-marking map
Educational allocation. This question prints no mark scheme, so the split shown is derived from the stem and is not presented as the official one.
The lower oesophageal sphincter in class 3 obesity
Supplied practice question · mark allocation as printed
- A 39-year-old female with class 3 BMI is scheduled for bariatric surgery. She gives a history of GERD which is well controlled.
- Describe the lower oesophageal sphincter (LOS). (3 marks)
- Describe the changes in LOS in this patient. (1 mark)
- Discuss all the factors influencing the resting LOS tone. (6 marks)
View model answerQuestion first · answer when ready
i. Describe the lower oesophageal sphincter
3 marksWhat earns the marks3 marks
| What kind of sphincter | Physiological, not anatomical: no discrete muscular thickening, identified by manometry rather than dissection. |
|---|---|
| Where and how big | The distal 2–4 cm of oesophagus, at the diaphragmatic hiatus, in tonic contraction. |
| Two components | Intrinsic oesophageal smooth muscle, vagal; extrinsic crural diaphragm, phrenic. |
| The pressure | 15–25 mmHg above intragastric. Barrier pressure is the difference, not the sphincter pressure. |
| The rest of the barrier | Angle of His and mucosal rosette, the intra-abdominal segment, the phreno-oesophageal ligament. |
| Its normal behaviour | Transient relaxations on swallowing and on gastric distension — physiological, not pathological. |
The LOS is a physiological rather than anatomical sphincter: there is no discrete muscular thickening to dissect, and it is defined by a high-pressure zone on manometry. It comprises the distal 2–4 cm of oesophageal circular smooth muscle, held in tonic contraction, sited at the diaphragmatic hiatus.
It has two components in series. The intrinsic sphincter is the oesophageal smooth muscle itself, innervated by the vagus — excitatory cholinergic fibres maintaining tone, and inhibitory non-adrenergic non-cholinergic fibres releasing nitric oxide and VIP to relax it. The extrinsicsphincter is the crural diaphragm, chiefly the right crus, innervated by the phrenic nerve, which clasps the oesophagus and adds a respiration-linked pressure that rises on inspiration.
Resting LOS pressure is 15–25 mmHg above intragastric pressure. Barrier pressure = LOS pressure − intragastric pressure, and it is barrier pressure, not sphincter pressure, that determines competence. Three further mechanical features complete the barrier: the acute angle of His with its mucosal rosette acting as a flap valve, the intra-abdominal segment of oesophagus that is compressed by any rise in intra-abdominal pressure, and the phreno-oesophageal ligament anchoring the junction. Normal function includes transient LOS relaxations, vagally mediated and triggered by gastric distension, which vent swallowed air and are the mechanism of physiological reflux.
The components of the barrier
| Component | What it is | Innervation | How it resists reflux |
|---|---|---|---|
| Intrinsic sphincter | Distal 2–4 cm of oesophageal circular smooth muscle, tonically contracted | Vagus: excitatory cholinergic; inhibitory NANC using nitric oxide and VIP | Generates most of the resting high-pressure zone. |
| Crural diaphragm | Right crus, forming a sling around the oesophagus at the hiatus — an external, striated sphincter | Phrenic | Adds pressure that rises with inspiration and with any expulsive effort, exactly when intra-abdominal pressure rises. |
| Angle of His | The acute angle at which the oesophagus meets the gastric fundus, with a mucosal rosette | Mechanical | A flap valve: gastric distension presses the fundus against the oesophageal opening and closes it further. |
| Intra-abdominal segment | The 2–3 cm of oesophagus lying below the diaphragm, therefore exposed to intra-abdominal rather than intrathoracic pressure | Mechanical | Self-sealing: a rise in intra-abdominal pressure compresses this segment as well as the stomach, so the barrier is partly defended against the very thing that threatens it. |
| Phreno-oesophageal ligament | Fascial attachment anchoring the junction within the hiatus | Mechanical | Keeps the intrinsic sphincter aligned with the crural sphincter, so the two act at the same level. |
Commonly lost: Candidates did not differentiate tone from competence, and did not define barrier pressure as the difference between LOS and gastric pressure.
Suggested self-marking map
Educational allocation against the printed marks, derived from the stem and the 2016 examiner critique. Not presented as the official marking scheme.
ii. Changes in the LOS in this patient
1 markWhat earns the marks1 mark
| The dominant change | Raised intra-abdominal and hence intragastric pressure reduces barrier pressure with the tone unchanged. |
|---|---|
| The structural change | Hiatus hernia is common in class 3 obesity and separates the intrinsic from the crural sphincter. |
| The functional change | More frequent transient LOS relaxations. |
| The conclusion | Reduced barrier pressure and reduced competence, so a high aspiration risk despite controlled symptoms. |
The dominant change is not a fall in sphincter tone. Class 3 obesity raises intra-abdominal pressure, and therefore intragastric pressure, so barrier pressure falls even though LOS pressure is unchanged. Three changes compound it: a high prevalence of hiatus hernia, which displaces the intrinsic sphincter above the hiatus so that it no longer acts at the same level as the crural diaphragm and which abolishes both the angle of His and the intra-abdominal segment; an increased frequency of transient LOS relaxations; and a larger fasting gastric volume with a greater distending stimulus.
The result is reduced barrier pressure and reduced competence. That her reflux is well controlled is a statement about symptoms on treatment, not about the barrier: acid suppression alters what refluxes, not whether it refluxes. She should be treated as being at high risk of aspiration at induction.
Two further points make this specific to her. She is presenting for bariatric surgery, so the operation itself will insufflate the abdomen: a pneumoperitoneum of 12 to 15 mmHg is a further, deliberate rise in intragastric pressure superimposed on an already reduced barrier, and it is applied under anaesthesia when tone is lowest. And the anaesthetic drugs used at induction — with the specific exception of suxamethonium and the anticholinesterases — reduce LOS tone, so barrier pressure is attacked from both directions at once.
Suggested self-marking map
Educational allocation against the printed marks, derived from the stem and the 2016 examiner critique. Not presented as the official marking scheme.
iii. Factors influencing resting LOS tone
6 marksWhat earns the marks6 marks
| Classify before you list | Mechanical, neural, hormonal, luminal, physiological state. A classified list scores; a jumble does not. |
|---|---|
| Mechanical | Intra-abdominal segment, angle of His, crural diaphragm, hiatus hernia, gastric volume, posture. |
| Neural | Vagal cholinergic excitatory; NANC inhibitory via NO and VIP; sympathetic α raises, β lowers. |
| Hormonal | Gastrin and motilin raise; secretin, CCK, glucagon, VIP, GIP and progesterone lower. |
| Luminal and dietary | Acidification raises; fat, chocolate, caffeine, alcohol and peppermint lower. |
| Physiological states | Pregnancy, obesity, the neonate, and hiatus hernia. |
Resting tone is the sum of five groups of influence. Mechanical: the length of the intra-abdominal segment, the angle of His, the crural diaphragm and its alignment with the intrinsic sphincter, gastric volume and pressure, and posture. Neural: tonic vagal cholinergic excitation through M3 receptors, opposed by inhibitory non-adrenergic non-cholinergic fibres releasing nitric oxide and VIP; sympathetic α-adrenergic activity increases tone and β-adrenergic activity reduces it. Hormonal: gastrin and motilin increase tone; secretin, cholecystokinin, glucagon, VIP, gastric inhibitory peptide, progesterone and oestrogen reduce it. Luminal and dietary: gastric acidification and a protein meal raise tone, while fat, chocolate, caffeine, alcohol and peppermint lower it. Physiological state: pregnancy, obesity, hiatus hernia and the neonatal period all reduce it.
Commonly lost: The examiners state plainly that this is a physiology paper, and that pharmacological agents named will earn no extra marks. Spend the six marks on the physiology; the drug table below is here because it matters clinically for this patient, not because it scores.
1. Mechanical and anatomical
| Factor | Effect on tone or barrier | Mechanism |
|---|---|---|
| Intra-abdominal segment length | Increases | A longer segment exposed to intra-abdominal pressure is compressed by it; by Laplace’s law a narrow tube is closed more readily than a wide one. |
| Angle of His | Increases | Flap-valve effect, reinforced as the fundus distends. |
| Crural diaphragm | Increases, phasically | Inspiratory contraction and any expulsive effort raise the pressure at the hiatus at the moment intra-abdominal pressure rises. |
| Hiatus hernia | Decreases | Separates the intrinsic sphincter from the crus so the two no longer act at one level, and abolishes the angle of His and the intra-abdominal segment. |
| Gastric distension | Decreases | Raises intragastric pressure and triggers transient relaxations through vagal stretch afferents. |
| Raised intra-abdominal pressure | Reduces barrier, tone unchanged | Obesity, pregnancy, ascites, bowel obstruction, pneumoperitoneum, lithotomy and Trendelenburg positioning. |
| Posture | Supine reduces the barrier | Removes the gravitational assistance that keeps gastric contents below the junction; the head-up position is protective at induction. |
| Nasogastric tube | Decreases | Splints the sphincter open across its lumen. |
2. Neural
| Pathway | Transmitter and receptor | Effect |
|---|---|---|
| Vagal excitatory | Acetylcholine at M3 on the smooth muscle, via myenteric neurones | Maintains resting tone. Vagotomy reduces it. |
| Vagal inhibitory (NANC) | Nitric oxide and vasoactive intestinal peptide | Produces swallow-induced relaxation and transient relaxations. The principal relaxant pathway. |
| Sympathetic | Noradrenaline at α-adrenoceptors | Increases tone. |
| Sympathetic | β-adrenoceptors | Decreases tone. |
| Enteric reflexes | Myenteric plexus, intrinsic | Coordinate relaxation with the arriving peristaltic wave; secondary peristalsis can be generated without central input. |
| Phrenic | Somatic, to the crus | The extrinsic component; unaffected by vagal disease. |
3. Hormonal and humoral
| Increase tone | Decrease tone |
|---|---|
| Gastrin | Secretin |
| Motilin | Cholecystokinin |
| Substance P | Glucagon |
| Pancreatic polypeptide | Vasoactive intestinal peptide |
| Histamine (H1) | Gastric inhibitory peptide |
| Prostaglandin F2α | Progesterone and oestrogen |
| α-adrenergic stimulation | Dopamine, nitric oxide, prostaglandin E2 |
4. Luminal and dietary
- Gastric acidification increases tone; alkalinisation reduces it. This is a negative-feedback loop — acid near the junction tightens the sphincter that keeps it out.
- A protein meal raises tone, through gastrin release.
- Fat, chocolate, caffeine, alcohol and peppermint lower it. Fat acts through CCK; chocolate and peppermint act directly on smooth muscle.
- Smoking lowers it, and also reduces salivary bicarbonate, so the refluxate is cleared less well.
5. Physiological and pathological states
| State | Net effect on the barrier | Mechanism |
|---|---|---|
| Pregnancy | Markedly reduced | Progesterone reduces tone; the gravid uterus raises intra-abdominal pressure; the junction is displaced by the enlarging uterus. Both halves of the subtraction move the wrong way. |
| Obesity | Reduced | Raised intra-abdominal pressure, more frequent transient relaxations, and a high prevalence of hiatus hernia. |
| Neonate | Reduced | Short intra-abdominal segment, obtuse angle of His, immature sphincter — hence physiological regurgitation. |
| Autonomic neuropathy | Reduced, with delayed emptying | Long-standing diabetes: vagal denervation lowers tone and gastroparesis raises residual volume. |
| Systemic sclerosis | Markedly reduced | Smooth muscle replaced by fibrous tissue; the sphincter cannot generate tone. |
| Achalasia | Increased, and fails to relax | Loss of the inhibitory NANC neurones, so the sphincter is hypertensive and non-relaxing while the body above it is full. A high tone here is a hazard, not a protection. |
Drugs — clinically relevant, but not scoring here
| Increase tone | Decrease tone | No significant effect |
|---|---|---|
| Metoclopramide | Volatile agents | Non-depolarising neuromuscular blockers |
| Suxamethonium | Propofol and thiopentone | |
| Anticholinesterases: neostigmine, edrophonium | Opioids | |
| Prochlorperazine, domperidone | Anticholinergics: atropine, glycopyrronium | |
| Cyclizine | Nitrates, calcium channel blockers, β2 agonists, tricyclics, alcohol |
Suggested self-marking map
Educational allocation against the printed marks, derived from the stem and the 2016 examiner critique. Not presented as the official marking scheme.
The hypothalamic–pituitary–adrenal axis in surgery, digestion and failure
Supplied practice question · mark allocation as printed
- Explain the role of hypothalamus–pituitary–adrenal (HPA) axis in the patient undergoing major surgery. (6 marks)
- How does HPA axis regulate digestion? (2 marks)
- List the potential presentation when HPA axis failed. (2 marks)
View model answerQuestion first · answer when ready
i. The HPA axis in major surgery
6 marksWhat earns the marks6 marks
| The afferent limb | Nociceptive and autonomic afferents from the wound, plus IL-6, IL-1 and TNF-α reaching the hypothalamus. |
|---|---|
| The axis itself | CRH with AVP → ACTH from POMC → cortisol from the zona fasciculata; 90% protein-bound. |
| What changes in surgery | Negative feedback fails and the diurnal rhythm is lost, so cortisol rises and stays up. |
| Magnitude and time course | Peaks 4–6 h, 3–5× baseline, proportional to severity, back to baseline by 24–48 h. |
| Metabolic effects | Gluconeogenesis and insulin resistance; protein catabolism; lipolysis. |
| Non-metabolic effects | Catecholamine sensitivity, mineralocorticoid sodium and water retention, immunomodulation. |
| Modification | Neuraxial block, high-dose opioid, laparoscopic technique, normothermia; etomidate suppresses synthesis. |
Afferent limb. Two signals reach the hypothalamic paraventricular nucleus: nociceptive and autonomic afferents from the site of injury, and cytokines — principally interleukin 6, with IL-1 and TNF-α — released by the wound and spilling into the systemic circulation.
The axis. The paraventricular nucleus releases corticotrophin-releasing hormone, with arginine vasopressin acting synergistically, into the hypophyseal portal system. Anterior pituitary corticotrophs release ACTH, cleaved from pro-opiomelanocortin. ACTH stimulates the zona fasciculata to synthesise cortisol from cholesterol. About 90% of plasma cortisol is bound to cortisol-binding globulin and albumin; the 10% that is free is the active fraction.
What surgery changes. Normally cortisol restrains its own release through short-loop feedback on the pituitary and long-loop feedback on the hypothalamus, in a diurnal rhythm peaking in the early morning. During major surgery the negative feedback fails and the rhythm is lost, so cortisol rises and stays high. Secretion increases from a basal 20–30 mg per day to as much as 75–150 mg per day, peaking 4 to 6 hours after incision at 3 to 5 times baseline, in proportion to the severity and duration of the insult, and returning to baseline over 24 to 48 hours in an uncomplicated case.
Why it matters. The response is adaptive but double-edged: it defends perfusion pressure and provides substrate, and it also causes the hyperglycaemia, catabolism, sodium and water retention and immunosuppression that worsen surgical outcome. Much of modern perioperative practice — regional anaesthesia, minimally invasive surgery, normothermia, carbohydrate loading — is aimed at attenuating it.
Time course
The effects of cortisol, classified as the examiners require
| Domain | Effect | Perioperative consequence |
|---|---|---|
| Carbohydrate | Stimulates gluconeogenesis; reduces peripheral glucose uptake; opposes insulin at the post-receptor level | Stress hyperglycaemia in proportion to the severity of trauma, compounded by reduced insulin secretion and raised glucagon. Associated with poor wound healing, wound infection and, in critical illness, worse outcome. |
| Protein | Mobilises amino acids from skeletal muscle for gluconeogenesis and for acute-phase protein synthesis | Negative nitrogen balance. Anabolism is inhibited first; catabolism follows after about 12 to 14 hours, and skeletal muscle loss can reach 0.5 kg per day after major surgery. Respiratory muscle loss predisposes to postoperative respiratory failure. |
| Fat | Stimulates lipolysis, releasing free fatty acids and glycerol | Glycerol feeds gluconeogenesis; free fatty acids become the dominant fuel, sparing glucose for the brain. |
| Cardiovascular | Permissive for catecholamine action — cortisol maintains vascular responsiveness to adrenergic agonists | Without it, widespread vasodilatation occurs. This is why adrenal insufficiency presents as catecholamine-resistant shock. |
| Renal and electrolyte | Intrinsic mineralocorticoid activity, reinforced by aldosterone released through the renin–angiotensin system | Sodium and water retention with potassium loss. Contributes to postoperative hypokalaemia and, with ADH and administered fluid, to fluid overload. |
| Immunological | Reduces capillary permeability, prostaglandin synthesis, cytokine release and leucocyte migration; stimulates CD8⁺ cytotoxic T cells, which suppress CD4⁺ helper cells | Restrains a damaging cytokine surge, at the price of increased susceptibility to invading pathogens. |
| Haematological | Contributes to a pro-coagulant state alongside the sympathetic response | Increased venous thromboembolic risk. |
Commonly lost: Candidates gave the metabolic functions of glucocorticoids but omitted the non-metabolic ones, and some could not separate glucocorticoids from mineralocorticoids. No marks were given for adrenal androgens or for medullary hormones.
How the response is modified
| Intervention | Effect on the axis | Why |
|---|---|---|
| Neuraxial blockade | Substantially attenuates it for surgery below the umbilicus; less effective for upper abdominal and thoracic surgery | Blocks the afferent limb before it reaches the hypothalamus. It cannot block the cytokine limb, which is why the attenuation is incomplete and why upper abdominal surgery escapes it. |
| High-dose opioid | Suppresses the axis; high-dose fentanyl can abolish the response | Central suppression of hypothalamic and pituitary output, at the cost of postoperative ventilation. |
| Etomidate | Inhibits synthesis for up to 8 hours after a single induction dose | Blocks 11β-hydroxylase in the adrenal cortex, reducing both cortisol and aldosterone synthesis. A single dose has not been shown to increase mortality; infusions were abandoned because they did. |
| Minimally invasive surgery | Reduces it | Less tissue injury, so a smaller cytokine limb. |
| Maintaining normothermia | Reduces it | Hypothermia is itself a stressor driving the axis. |
| Volatile and most other agents | Minimal effect | General anaesthesia obtunds the perception of the injury but not the afferent traffic that drives the axis. |
Suggested self-marking map
Educational allocation against the printed marks, derived from the stem and the October 2014 examiner critique. Not presented as the official marking scheme.
ii. How the HPA axis regulates digestion
2 marksWhat earns the marks2 marks
| CRH is the central mediator | Acting on CRF₁ and CRF₂ receptors, it inhibits the stomach and stimulates the colon. |
|---|---|
| Two opposite regional effects | Delayed gastric emptying and reduced acid secretion; accelerated colonic transit. |
| The sympathetic arm | Splanchnic vasoconstriction reduces motility, secretion and mucosal blood flow. |
| Cortisol on the mucosa | Maintains integrity at physiological concentrations; in excess causes ulceration. |
| Cortisol on absorption | Promotes mucosal maturation and enhances colonic sodium absorption. |
| It is bidirectional | The gut feeds back to the hypothalamus by vagal afferents — the brain–gut axis. |
CRH is the central mediator, and its effects are regionally opposite. Acting at CRF2 receptors in the stomach it delays gastric emptying and reduces acid secretion; acting at CRF1 receptors in the colon it stimulates colonic motility and defecation. This is the familiar physiology of stress: the meal stops moving out of the stomach while the colon empties. CRH is also anorexigenic, suppressing appetite. In parallel, hypothalamic activation of the sympathetic nervous system produces splanchnic vasoconstriction, reducing motility, secretion and mucosal blood flow.
Cortisol acts on the mucosa and on absorption. At physiological concentrations it is permissive for mucosal integrity and, through mineralocorticoid-receptor cross-activity, enhances sodium and water absorption in the colon; it also drives mucosal enzyme maturation, which is why antenatal glucocorticoids mature the neonatal gut. In excess it reduces prostaglandin synthesis and mucus production and predisposes to peptic ulceration. The axis is bidirectional: vagal afferents and the gut microbiota feed back to the hypothalamus, which is the brain–gut axis.
| Mediator | Site | Effect on digestion |
|---|---|---|
| CRH at CRF2 | Stomach | Inhibits gastric motility and emptying; reduces acid secretion. Delayed emptying matters directly to the anaesthetist: a stressed, injured or frightened patient has a full stomach for longer than the fasting interval suggests. |
| CRH at CRF1 | Colon | Stimulates propulsive motility and defecation; the stress-diarrhoea pattern. |
| CRH, central | Hypothalamic feeding centres | Anorexigenic — suppresses appetite and food intake. |
| Sympathetic outflow | Splanchnic circulation and enteric nervous system | Vasoconstriction with reduced mucosal blood flow, reduced motility and reduced secretion. Sustained, this contributes to gut mucosal ischaemia in shock. |
| Cortisol, physiological | Gut mucosa | Permissive for mucosal integrity; drives enzyme maturation, including neonatal lactase; enhances colonic sodium and water absorption through mineralocorticoid-receptor cross-activity. |
| Cortisol, excess | Gastric mucosa | Reduced prostaglandin and mucus production with impaired mucosal defence; peptic ulceration is a recognised feature of chronic glucocorticoid excess. |
| Afferent feedback | Vagus and the microbiota | Gut signals modulate hypothalamic CRH output, so the relationship runs in both directions. |
The perioperative consequence worth stating is the first row of the table. Pain, anxiety, trauma and opioids all delay gastric emptying through this pathway, so a standard fasting interval does not guarantee an empty stomach in a stressed or injured patient. That connects this part directly to Question 2: the same patient can have both a reduced barrier pressure and a fuller stomach than the fasting time implies.
Suggested self-marking map
Educational allocation against the printed marks, derived from the stem and the October 2014 examiner critique. Not presented as the official marking scheme.
iii. Presentation when the HPA axis fails
2 marksWhat earns the marks2 marks
| Acute: the crisis | Vasopressor-resistant shock, hypoglycaemia, hyponatraemia, hyperkalaemia, abdominal pain, fever, confusion. |
|---|---|
| Chronic | Fatigue, weight loss, anorexia, postural hypotension, nausea, salt craving. |
| Primary against secondary | Hyperpigmentation and hyperkalaemia occur only in primary failure. |
| Perioperative face | Failure to wean vasopressors, unexplained hypoglycaemia, and abrupt steroid withdrawal as the commonest cause. |
Acute failure — adrenal crisis. Hypotension and shock that is resistant to fluid and to vasopressors, because cortisol is permissive for catecholamine action; hypoglycaemia, from failed gluconeogenesis; hyponatraemia; hyperkalaemia and a metabolic acidosis in primary failure only; abdominal pain, nausea and vomiting; fever; confusion progressing to coma. Eosinophilia and lymphocytosis are supporting findings.
Chronic failure. Fatigue, weakness, anorexia, weight loss, postural hypotension, nausea, myalgia and arthralgia. In primary failure, salt craving and hyperpigmentation of skin creases, buccal mucosa and scars — because ACTH is high and shares a precursor, pro-opiomelanocortin, with melanocyte-stimulating hormone. Neither hyperpigmentation nor hyperkalaemia occurs in secondary or tertiary failure, where ACTH is low and aldosterone is preserved by the renin–angiotensin system.
In theatre and intensive care, it presents as failure to wean vasopressors, unexplained hypoglycaemia or persistent hyponatraemia. The commonest cause in surgical practice is not Addison’s disease but abrupt withdrawal of long-term exogenous corticosteroid, which suppresses the axis at the hypothalamus and pituitary.
| Primary (adrenal) | Secondary (pituitary) | Tertiary (hypothalamic) | |
|---|---|---|---|
| Typical cause | Autoimmune adrenalitis, tuberculosis, adrenal haemorrhage, metastases, meningococcal sepsis | Pituitary tumour, apoplexy, surgery, irradiation, Sheehan syndrome | Exogenous steroid withdrawal — much the commonest of all three |
| ACTH | High | Low | Low |
| Cortisol | Low | Low | Low |
| Aldosterone | Low — the zona glomerulosa is destroyed too | Preserved, driven by renin–angiotensin | Preserved |
| Hyperpigmentation | Yes — high POMC-derived peptides | No | No |
| Hyperkalaemia | Yes | No | No |
| Hyponatraemia | Yes — sodium loss plus water retention | Yes — through unsuppressed ADH, not sodium loss | Yes |
The presentations that matter perioperatively
- Shock that does not respond to noradrenaline. Cortisol is permissive for the vascular response to catecholamines; without it, vasodilatation persists at any dose. Escalating vasopressor requirement with no septic focus should prompt the thought.
- Unexplained intraoperative or postoperative hypoglycaemia, from failed gluconeogenesis and lost insulin antagonism.
- Failure to mount a stress response. The patient on long-term steroid who receives no perioperative supplementation may be entirely stable until the surgical stimulus demands a cortisol rise that the suppressed axis cannot produce.
- After etomidate, 11β-hydroxylase inhibition lasting up to 8 hours produces a transient, usually subclinical suppression — which matters most in the patient who is already critically ill.
- Critical illness–related corticosteroid insufficiency, where the axis is intact but the response is inadequate for the demand, presenting as the same vasopressor-dependent shock.
Suggested self-marking map
Educational allocation against the printed marks, derived from the stem and the October 2014 examiner critique. Not presented as the official marking scheme.