Content

Pain: the arrival of anaesthesia - William T. G. Morton, a Boston dentist, first used ether to extract teeth painlessly. - On 16 October 1846, at the Massachusetts General Hospital, he gave the first public demonstration of ether anaesthesia while the surgeon John Collins Warren removed a tumour from a patient's neck. The theatre is still called the Ether Dome. - Consequence: surgeons no longer had to operate in seconds. Slower, more careful and more ambitious operations became possible. Infection: from observation to theory to practice - Ignaz Semmelweis (Vienna, 1840s) noticed that puerperal fever killed far more women on the ward staffed by doctors and students, who came straight from the autopsy room, than on the midwives' ward. Hand washing with chlorinated lime cut mortality dramatically. His colleagues rejected the idea and he died in a psychiatric asylum in 1865. - Louis Pasteur (1860s) showed that fermentation and putrefaction are caused by living microorganisms. This is the germ theory of disease. - Joseph Lister (1867) applied Pasteur's work to surgery. He used carbolic acid (phenol) on wounds, dressings and instruments, and compound fractures stopped turning septic. This is antisepsis: killing germs already present. Exam focus: the sequence is observation (Semmelweis), theory (Pasteur), surgical application (Lister).

William Stewart Halsted (Johns Hopkins) - Developed the radical mastectomy for breast cancer in the 1890s. - Introduced rubber surgical gloves. - Taught gentle tissue handling, meticulous haemostasis and careful dissection. - Created the structured surgical residency model still used today. Theodor Billroth (Vienna) - Pioneer of gastrointestinal surgery. - Performed the first successful gastrectomy for gastric cancer (1881). - His two reconstructions are still named after him: Billroth I: gastroduodenostomy. Billroth II: gastrojejunostomy. Emil Theodor Kocher (Bern) - Made thyroid surgery safe and reproducible. - Championed strict asepsis. - Received the Nobel Prize in Physiology or Medicine in 1909 for his work on the thyroid gland, the first surgeon to do so. - Several eponyms survive: the Kocher manoeuvre (mobilising the duodenum) and the Kocher incision (right subcostal). Asepsis in practice today: - sterilised instruments and drapes - surgical hand scrub, gowns, gloves and masks - a controlled theatre environment with laminar airflow and restricted traffic Exam focus: be able to define antisepsis and asepsis and give one name linked to each.

1. Preoperative phase - Study the underlying disease: diagnosis, stage, and indication for surgery. - Evaluate comorbidities: heart, lungs, kidneys, liver, diabetes, nutrition, drugs. - Assess surgical risk and decide whether the expected benefit outweighs it. 2. Admission to the ward - Administrative procedures: registration, informed consent, the medical record. - Patient preparation: fasting, skin preparation and, where needed, bowel preparation. - Prophylaxis: antibiotic, thromboembolic, and stress ulcer prophylaxis where indicated. 3. Postoperative phase - Monitor vital parameters: heart rate, blood pressure, oxygen saturation, temperature, urine output, central venous pressure. - Check drains, the central venous catheter, the nasogastric tube and the urinary catheter. - Support the response to surgical stress: fluids, analgesia, nutrition, mobilisation. - Detect complications early. Clinical tip: most avoidable postoperative harm begins as a missed detail in phase 1, such as an unreported anticoagulant, unrecognised malnutrition or an undiagnosed heart condition.

Emergency surgery - Immediate danger to life. - The intervention cannot wait, so there is no time for preparation beyond resuscitation. - Examples: ruptured abdominal aortic aneurysm, massive haemorrhage after trauma, tension haemothorax. Urgent surgery - A threat to life, but surgery can be done within about 3-6 hours. - This allows basic preparation: blood tests, group and crossmatch, fluid resuscitation, correction of electrolytes and coagulation, antibiotics. - Examples: perforated peptic ulcer, strangulated hernia, acute appendicitis with peritonitis. Elective surgery - A planned, scheduled operation. - Allows a full evaluation of surgical risk and detailed preparation: optimising comorbidities, nutritional support, stopping or bridging drugs, prehabilitation. - Examples: cholecystectomy for symptomatic gallstones, most cancer resections. Why it matters: - Emergency surgery carries a much higher risk of death and complications than the same operation done electively. - Patients arrive unprepared, often septic or hypovolaemic, with electrolyte and acid-base disorders. - For this reason, scoring systems add an emergency modifier (for example the E suffix on the ASA class).

Medical record (kept by doctors) - Personal data and informed consent. - History and physical examination at admission. - Clinical progress notes: daily evolution, events, decisions and their reasons. - Pharmacological therapy: every drug with dose, route, timing and prescriber. - Operative report, anaesthetic chart, results of tests. - Discharge letter. Nursing record (kept by nurses) - Nursing progress notes: care given, patient's condition, problems. - Vital signs charted over time (heart rate, blood pressure, temperature, respiratory rate, oxygen saturation, pain score). - Fluid balance chart: all intake and output. - Drain outputs, wound checks and pressure area care. Electronic medical record - Most hospitals now use electronic records. - Advantages: legibility, instant sharing between teams, automatic alerts for allergies and interactions, and audit trails. Good documentation habits: - Date, time and signature on every entry. - Record what you saw, what you thought and what you did. - Never alter a previous entry. Add a dated correction instead.

The five variables 1. Type of disease: acute (for example peritonitis), chronic (for example gallstones) or neoplastic. Cancer adds catabolism, malnutrition and a prothrombotic state. 2. Age: elderly or young adult (see the geriatric note below). 3. Type and mode of intervention: major or minor, elective or urgent, open or minimally invasive. 4. Type of anaesthesia: general, regional (spinal or epidural) or local. General anaesthesia stresses heart and lungs the most. 5. General condition: comorbidities and functional reserve. Conditions associated with increased surgical risk: - Geriatric and neonatal age. - Cardiovascular disease: ischaemic heart disease, heart failure, arrhythmias, valve disease. - Respiratory disease: COPD, asthma, obstructive sleep apnoea, smoking. - Liver failure and cirrhosis: coagulopathy, poor healing, ascites, encephalopathy. - Kidney failure: fluid and electrolyte problems, altered drug clearance. - Diabetes: infection, poor healing, silent ischaemia. - Obesity and malnutrition: both impair healing and raise complication rates. - Current medications: immunosuppressants, anticoagulants and antiplatelets, corticosteroids. Exam focus: when asked about surgical risk, list the five variables first, then the high-risk conditions.

Laboratory tests - Full blood count (white cells, red cells, haemoglobin, haematocrit, platelets): anaemia, infection, platelet count before surgery and neuraxial anaesthesia. - Biochemistry: glucose, urea and creatinine (kidney), AST, ALT, ALP, GGT, bilirubin, LDH (liver and biliary tree), albumin and total protein (nutrition, liver synthesis), sodium, potassium, chloride, magnesium and calcium (electrolytes). - Coagulation (PT/INR, aPTT, fibrinogen): bleeding risk, liver function, anticoagulant effect. - Inflammatory markers (C-reactive protein, sometimes procalcitonin): a baseline for postoperative comparison and evidence of active infection. - Viral markers (HBV, HCV, HIV): protect staff and patients, and guide management in liver disease. - Pseudocholinesterase: low activity prolongs the effect of succinylcholine, the neuromuscular blocker. Undetected, the result is prolonged apnoea after anaesthesia. - Blood group and antibody screen: needed before any operation that might require transfusion. - Arterial blood gas (pH, PaO2, PaCO2, HCO3-): in lung disease, major surgery or critically ill patients. Instrumental tests - Chest X-ray: baseline in lung or heart disease, and for comparison with postoperative films. - Pulmonary function tests: before lung resection, or in severe COPD. - ECG: standard in adults with cardiac risk and in older patients. - Echocardiogram: ventricular function and valve disease. - Stress test (exercise or pharmacological): for suspected ischaemia in patients with poor functional capacity before high-risk surgery. Clinical tip: a patient who can climb two flights of stairs without stopping (about 4 metabolic equivalents) has adequate functional capacity for most operations. This single question often tells you more than a long list of tests.

Why elderly patients are at higher risk: 1. More comorbidities: cardiovascular, respiratory and renal disease, and metabolic disorders such as diabetes. 2. Physiological ageing of organs and systems, which reduces homeostatic reserve: - lower cardiac output reserve - lower lung compliance and a weaker cough - lower glomerular filtration rate - blunted thirst - reduced immune response The result: an older patient tolerates hypotension, fluid shifts and infection poorly. Most common postoperative complications in the elderly: - infections, especially pneumonia and urinary tract infection - pulmonary embolism - hypovolaemic shock, because they tolerate fluid loss poorly and signs appear late - myocardial infarction, often silent - postoperative delirium and loss of independence (important in practice) Assessing biological age: - Frailty: weight loss, weakness, slowness, exhaustion, low activity. - Functional status: activities of daily living. - Cognition and nutritional status. - Polypharmacy. Exam focus: say "biological age versus chronological age" and explain it with one example.

Why use scores at all? - To speak a common language across teams and hospitals. - To estimate risk and share it honestly with the patient. - To compare outcomes between centres fairly. - To trigger escalation, for example admission to intensive care. Map of the scores in this course: - ASA physical status (American Society of Anesthesiologists, 1963): all surgical patients, before surgery. - APACHE, APACHE II and APACHE III (Acute Physiology and Chronic Health Evaluation; 1981, 1984, 1991): patients in intensive care. - Trauma Score, Injury Severity Score and Glasgow Coma Scale: trauma patients. - Ranson score: severity of acute pancreatitis. - MODS score (Multiple Organ Dysfunction Syndrome): septic shock and organ failure. Limitation common to all: a score describes a population, not an individual. Use it to support clinical judgement, not replace it.

Classes (current wording, with the original 1963 idea in brackets): - ASA I: a normal healthy patient. - ASA II: mild systemic disease without functional limitation (for example well-controlled hypertension, a smoker, mild obesity). - ASA III: severe systemic disease that limits activity but is not incapacitating (for example poorly controlled diabetes, COPD, morbid obesity, stable angina). - ASA IV: severe systemic disease that is a constant threat to life (the original "requiring constant treatment for survival"; for example recent myocardial infarction, severe heart failure, sepsis). - ASA V: a moribund patient not expected to survive with or without the operation, operated on as a last resort (for example a ruptured aortic aneurysm in shock). - ASA VI: a declared brain-dead patient whose organs are being removed for donation (added later). - Suffix E: emergency surgery (for example ASA III-E). Strengths: - Quick, universal, needs no tests. - Correlates well with postoperative morbidity and mortality. Weaknesses: - Subjective, so two assessors may disagree. - Ignores the operation itself and the patient's age. Exam trap: ASA grades the patient, not the procedure.

Components 1. Acute Physiology Score: 12 variables, each scored 0-4 according to how far it is from normal. - rectal temperature - mean arterial pressure - heart rate - respiratory rate - oxygenation (A-a gradient if FiO2 is 0.5 or more; PaO2 if FiO2 is below 0.5) - arterial pH - serum sodium - serum potassium - serum creatinine (points doubled in acute renal failure) - haematocrit - white blood cell count - Glasgow Coma Scale (scored as 15 minus the GCS) 2. Age points: rising from 0 (44 years or less) to 6 (75 years or more). 3. Chronic health points: for severe organ insufficiency (cirrhosis, severe heart failure, severe COPD, dialysis) or immunocompromise. More points are given after emergency surgery or for non-operative patients than after elective surgery. Total range: 0 to 71. Predicted mortality rises steadily with the score. Scores above about 25 carry a high risk of death, with mortality around 50% or more in many series. Uses: - Stratifying ICU patients. - Comparing ICU performance. - Selecting patients for trials. - In acute pancreatitis, an APACHE II of 8 or more suggests severe disease. Clinical tip: APACHE II is a snapshot of the first day. It is not designed to be recalculated daily to track progress, although many units do so informally.

Glasgow Coma Scale (GCS) Eye opening (E, 1-4): 4 spontaneous 3 to voice 2 to pain 1 none Verbal response (V, 1-5): 5 oriented 4 confused 3 inappropriate words 2 incomprehensible sounds 1 none Motor response (M, 1-6): 6 obeys commands 5 localises pain 4 withdraws from pain 3 abnormal flexion (decorticate) 2 extension (decerebrate) 1 none Severity of head injury: 13-15 mild 9-12 moderate 3-8 severe Always report the components (for example E2 V3 M5 = 10), not just the total. Trauma Score (Revised Trauma Score, RTS) - A physiological score used in triage. - Uses three variables: GCS, systolic blood pressure and respiratory rate, each coded 0-4. - A lower score means a worse condition and predicts mortality. Injury Severity Score (ISS) - An anatomical score. - Each injury is graded with the Abbreviated Injury Scale (AIS) from 1 (minor) to 6 (unsurvivable), in six body regions. - ISS = the sum of the squares of the highest AIS in the three most severely injured regions. - Range 0-75. Any AIS of 6 automatically gives an ISS of 75. - An ISS above 15 defines major trauma. Exam focus: physiological scores (GCS, RTS) versus anatomical scores (ISS). Combining both (the TRISS method) predicts survival best.

Ranson criteria (classic, non-gallstone version) At admission: - age over 55 years - white cells over 16,000/mm3 - blood glucose over 200 mg/dL (11 mmol/L) - LDH over 350 IU/L - AST over 250 IU/L Within 48 hours: - haematocrit fall of more than 10 percentage points - blood urea nitrogen rise of more than 5 mg/dL - serum calcium below 8 mg/dL (2 mmol/L) - PaO2 below 60 mmHg - base deficit over 4 mEq/L - estimated fluid sequestration over 6 litres Interpretation: 0-2 gives low mortality; 3-4 about 15%; 5-6 about 40%; 7 or more approaches 100% in the original series. Memory aid for the admission criteria, "GA LAW": Glucose, Age, LDH, AST, WBC. MODS score (Multiple Organ Dysfunction Syndrome, Marshall score) Six organ systems, each scored 0-4: - respiratory: PaO2/FiO2 ratio - renal: serum creatinine - hepatic: serum bilirubin - cardiovascular: pressure-adjusted heart rate - haematological: platelet count - neurological: Glasgow Coma Scale Total 0-24. Mortality rises with the score and with the number of failing organs. It is used in septic shock and severe pancreatitis to follow organ failure day by day. Clinical tip: in pancreatitis, persistent organ failure (lasting more than 48 hours) is what defines severe disease in modern classifications. MODS-type scoring captures exactly that.

The components covered in this course: 1. Antibiotic prophylaxis: against surgical site infection. 2. Skin preparation: against infection from skin bacteria. 3. Bowel preparation: against infection from intestinal bacteria in gastrointestinal surgery. 4. Hospital hygiene protocols: against cross-infection and multidrug-resistant organisms. 5. Antithromboembolic prophylaxis: against deep vein thrombosis and pulmonary embolism. 6. Stress ulcer prophylaxis: against bleeding from stress gastritis in critically ill patients. The subsections below take each one in turn. For every measure, know its aim, how it works, its timing, and when it is not needed.

Core parameters and what they tell you - Heart rate: tachycardia is often the first sign of bleeding, pain, fever, a leak or pulmonary embolism. - Blood pressure: falls late in hypovolaemia, especially in young patients who compensate well. - Respiratory rate and oxygen saturation: rising respiratory rate is an early, underrated warning sign. - Temperature: fever, or hypothermia (worse bleeding, more infection). - Urine output: the best bedside measure of organ perfusion. The target is at least 0.5 mL/kg/hour. - Central venous pressure: helps guide fluids when a central line is present. - Drain output: its volume and appearance. - Pain and level of consciousness. The subsections below cover where the patient is monitored and the devices they come back with.

Normal recovery of motility after abdominal surgery: - small bowel: within about 24 hours - stomach: 24-48 hours - colon: 48-72 hours (the last to recover) Passing flatus and then stool marks the return of colonic function. Mechanisms 1. Neurogenic - Opening and handling the peritoneum activates spinal and sympathetic inhibitory reflexes (the peritoneo-enteric reflex). - Sympathetic activity inhibits acetylcholine release in the myenteric plexus, and acetylcholine is the main excitatory transmitter of gut motility. Motility falls. 2. Inflammatory - Handling the bowel activates macrophages in the muscular layer. - Leukocytes are recruited and cytokines and nitric oxide are released, which inhibit smooth muscle for days. - This is the main reason ileus outlasts the operation. 3. Pharmacological - Opioids act on mu receptors in the enteric nervous system, reducing propulsion and secretion. 4. Hormonal - Stress hormones, including corticotropin-releasing hormone (CRH), inhibit gut motility. 5. Metabolic - Hypokalaemia, hypomagnesaemia, hyponatraemia and fluid overload with bowel-wall oedema all prolong ileus. Expected duration: physiological ileus lasts a few days. Gastric distension and failure of bowel function lasting about 4-7 days is prolonged ileus and needs a search for a cause (leak, abscess, electrolytes, obstruction).

Clinical picture: - abdominal distension, often diffuse - nausea and vomiting, with large nasogastric aspirates - no flatus or stool - a quiet or silent abdomen on auscultation - discomfort rather than colicky pain X-ray: gas distributed through both small and large bowel, without a clear transition point. Management 1. Nil by mouth, or reduce oral intake, until function returns. 2. Nasogastric decompression if there is vomiting or marked distension. 3. Early mobilisation. 4. Opioid-sparing analgesia: - epidural analgesia in open surgery - paracetamol and NSAIDs - peripheral mu-receptor antagonists (for example alvimopan) where available 5. Correct electrolytes (especially potassium and magnesium) and avoid fluid overload. 6. Rule out a secondary cause if ileus is prolonged: anastomotic leak, intra-abdominal abscess, haematoma, pancreatitis, or mechanical obstruction. CT is the test of choice. 7. Nutrition: consider parenteral nutrition if oral intake is not expected for about 7 days. Prevention (ERAS principles): - minimally invasive surgery - avoiding routine nasogastric tubes and fluid excess - early oral feeding - early mobilisation - chewing gum - opioid-sparing analgesia

Functional (adynamic, paralytic) ileus: causes The neural control of the gut or the smooth muscle itself is impaired. 1. Peritonitis. 2. Abdominal surgery. 3. Reflexes from extraperitoneal organs (for example renal colic from the ureter, ovarian torsion, retroperitoneal haematoma). 4. Spinal cord injury. 5. Drugs: morphine and other opioids, psychotropic drugs (anticholinergic effects), muscle relaxants. 6. Haemoperitoneum. 7. Electrolyte imbalance, especially hypokalaemia. Pathways: peritonitis, spinal trauma and surgery act through spinal autonomic reflexes. Drugs and electrolyte imbalance act directly on the myenteric plexus and smooth muscle. Mechanical obstruction: causes - Obstruction (the lumen is blocked but the blood supply is intact): - in the lumen: gallstone ileus, bezoar, faecal impaction - in the wall: tumour, stricture, Crohn's disease - outside the wall: adhesions (the most common cause of small-bowel obstruction in operated abdomens), external compression - Constriction or strangulation (the blood supply is compromised): - incarcerated hernia - volvulus - intussusception - adhesive band with closed-loop obstruction This is a surgical emergency: ischaemia, then necrosis and perforation. Side by side Paralytic ileus: - pain mild, constant - bowel sounds absent or reduced - gas throughout small and large bowel - no transition point on CT - conservative treatment Mechanical obstruction: - colicky pain, vomiting early if proximal - high-pitched, tinkling bowel sounds early, silent late - dilated loops above a transition point, collapsed bowel below - surgery if strangulated or if conservative treatment fails Warning signs of strangulation: - constant (no longer colicky) pain - fever, tachycardia - peritonism - raised lactate and white cells - reduced bowel-wall enhancement on CT

The stress response - Hormones: - catecholamines, cortisol and glucagon rise - ADH (vasopressin) and aldosterone rise - insulin resistance develops - Effects: hyperglycaemia, fat breakdown (lipolysis) and muscle protein breakdown (for gluconeogenesis and acute-phase proteins), plus sodium and water retention (low urine output in the first 24-48 hours is partly physiological). - Inflammation: cytokines (IL-1, IL-6, TNF) drive fever, the acute-phase response and catabolism. - Phases: a short "ebb" phase (reduced metabolism, first hours), a catabolic "flow" phase (days), then an anabolic recovery phase (weeks). Daily energy requirement = basal metabolic rate + physical activity + the specific dynamic action of food (the energy used to digest and absorb nutrients). Caloric and protein needs (course table, for a 70 kg patient) - Normal condition: 20-27 kcal/kg/day (1,400-1,890 kcal). Nitrogen 0.12 g/kg/day, about 0.75 g protein/kg. - Postoperative, uncomplicated: 30-35 kcal/kg/day (2,100-2,450 kcal). Nitrogen 0.20 g/kg/day, about 1.25 g protein/kg. - Critically ill: 40-45 kcal/kg/day (2,800-3,150 kcal). Nitrogen 0.30 g/kg/day, about 1.9 g protein/kg. Conversion: 1 g of nitrogen = 6.25 g of protein. Clinical tip: in the first days of critical illness, deliberately feeding a little less than the full target avoids overfeeding (hyperglycaemia, fatty liver, excess CO2 production). Protein targets matter more than calories for preserving muscle.

Indications (course list) 1. Preoperative malnutrition, for example from intestinal obstruction, or anorexia and dysphagia from upper GI tumours (oesophagus, stomach, pancreas). 2. Normal nutritional status, but the patient is not expected to eat for more than about 7 days. 3. Hypercatabolic status: sepsis, hepatic failure, major trauma, burns. Recognising malnutrition - unintentional weight loss (more than 10% in 6 months is significant) - BMI below 18.5 - low albumin (also a negative acute-phase protein, so interpret with care) - reduced intake - muscle wasting - screening tools such as NRS-2002 or MUST In severely malnourished patients, 7-14 days of preoperative nutritional support before elective major surgery reduces complications. Refeeding syndrome - In severely malnourished patients, feeding restarted too fast causes insulin-driven shifts of phosphate, potassium and magnesium into cells. - Result: arrhythmias, heart failure, respiratory failure. - Prevention: start slowly, give thiamine first, and monitor phosphate daily.

Parenteral nutrition (PN) Total parenteral nutrition (TPN): - volume about 2,500-3,000 mL/day - about 1,800-2,000 kcal/day - requires central venous access, because the solution is hyperosmolar (up to about 900 mOsm/L and above) - a balanced mix of glucose, lipids, amino acids, electrolytes, vitamins and trace elements, often "all-in-one" bags Peripheral parenteral nutrition (PPN): - volume about 3,000 mL/day - maximum about 1,500 kcal/day - a peripheral vein is enough, because glucose concentration and osmolarity are lower - short-term or supplementary use; risk of thrombophlebitis Started in the immediate postoperative period when indicated. Monitoring: blood glucose, serum electrolytes (including phosphate and magnesium), triglycerides, liver function, fluid balance. Complications: - catheter infection and thrombosis - hyperglycaemia - liver steatosis and cholestasis - gut mucosal atrophy Enteral nutrition (EN) Access: - nasogastric or nasojejunal tube - gastrostomy (surgical or PEG) - jejunostomy, often placed during upper GI surgery Requirement: a functioning gastrointestinal tract. In the course's setting, typically where there is no fresh intestinal anastomosis at risk; feeding beyond an anastomosis through a jejunostomy is common. Advantages: - maintains mucosal trophism and gut barrier function - reduces bacterial translocation and infectious complications - more physiological, cheaper, safer Typically started low (about 1,000 kcal/day in the course) and increased as tolerated. Complications: - diarrhoea - aspiration - tube displacement or blockage - abdominal distension Side by side - Route: PN into a vein; EN into the gut. - Gut barrier: PN leads to mucosal atrophy; EN maintains it. - Infection risk: higher with PN (catheter sepsis); lower with EN. - Cost: higher with PN; lower with EN. - Use: PN when the gut is not working or not accessible; EN whenever the gut is functional.

Sequence 1. Sips of clear water, then clear liquids (tea, broth). 2. Semi-liquid and soft foods. 3. A low-residue diet: little fibre at first, so the bowel and any anastomosis are not overloaded. 4. Progressive reintroduction of fibre and calories. Principles - Small, frequent meals: about 5 meals per day. - Low-sodium diet where fluid retention is an issue, for example in cirrhosis or ascites after liver surgery. - Watch for nausea, vomiting and distension. These mean returning to an earlier step. ERAS note: after many elective operations, including colorectal resection, oral fluids and food are given on the day of surgery or the day after. Early feeding is safe and speeds the return of bowel function.

Body water compartments (70 kg adult) - Total body water is about 60% of body weight, about 42 L. - Intracellular fluid: about two thirds (28 L). - Extracellular fluid: about one third (14 L), divided into interstitial fluid (about three quarters) and plasma (about one quarter, about 3.5 L). Measurable losses - Urine: 1,500-2,000 mL/day. Oligoanuria is 0-400 mL/day. - External drains. - Nasogastric tube. - Faeces: about 200 mL/day once bowel function resumes. Insensible (unmeasurable external) losses: 500-1,000 mL/day - About 75% through the skin (perspiration), about 25% through the lungs. - Increased by fever (about 2.5 mL/kg/day for each degree Celsius above normal), hyperventilation and sweating. Unmeasurable internal losses (third-space shifts) - Into the intestinal lumen: paralytic ileus. - Into tissues: oedema, and sequestration at sites of surgical trauma. - Inflammatory processes (peritonitis, pancreatitis). - Effusions: pleural, peritoneal (ascites), pericardial. This fluid is lost to the circulation even though body weight does not fall. Daily requirements - Course figure: basal needs of about 3,000-3,500 mL/day in the postoperative patient, including the usual extra losses. - For comparison, pure maintenance in a healthy adult is often calculated as 25-30 mL/kg/day, with measured and third-space losses added on top. - Needs rise with haemorrhage, ascites, third-space accumulation, prolonged paralytic ileus and fever.

The Starling equation, in words Net filtration = filtration coefficient x [(capillary hydrostatic pressure - interstitial hydrostatic pressure) - reflection coefficient x (capillary oncotic pressure - interstitial oncotic pressure)] Symbols as on the slides: P is hydrostatic pressure, pi (π) is colloid osmotic pressure, c means capillary, i means interstitium. What each term means clinically - Capillary hydrostatic pressure (Pc) rises with fluid overload, heart failure and venous obstruction, so more fluid is filtered and oedema follows. - Plasma oncotic pressure (pi c) depends mainly on albumin. It falls in malnutrition, liver failure, nephrotic syndrome and after dilution with crystalloids, so less fluid is reabsorbed and oedema follows. - Capillary permeability (the filtration coefficient, and a fall in the reflection coefficient) rises in sepsis, burns and the inflammatory response to surgery. Proteins leak out, and fluid follows. This is the basis of third-spacing. - Lymphatic drainage removes filtered fluid. When it is overwhelmed, oedema accumulates. Why it matters after surgery - The inflammatory response makes capillaries leaky, so infused crystalloid partly leaves the vessels. - Giving large volumes to "fill" a leaky circulation causes tissue and bowel-wall oedema, prolonged ileus, poor anastomotic healing and pulmonary oedema. - Hence modern goal-directed, restrictive-but-adequate fluid strategies.

Intake 1. Infusion therapy, with electrolyte supplements as needed: - normal saline 0.9% (Na+ 154, Cl- 154 mmol/L): useful for replacing gastric losses; large volumes cause hyperchloraemic acidosis - glucose solutions (5% dextrose): distribute as free water and supply little energy - Ringer's acetate or lactate: balanced crystalloids, closer to plasma - branched-chain amino acid solutions, for example in liver failure 2. Blood product transfusions: red cells, plasma, platelets, albumin. 3. Oral or enteral intake, by mouth or nasogastric tube once the patient can feed. Output - Urine, measured through the urinary catheter. - Abdominal drains: serum, protein-rich fluid and blood components. - Nasogastric tube: variable, depending on how long ileus lasts. Gastric juice is rich in H+ and Cl-. - Insensible losses: sweat and breathing, increased by fever. - Faeces, once bowel function resumes. Practical routine - Chart intake and output every hour or every shift, and total them every 24 hours. - Weigh the patient daily if possible. - Check electrolytes and creatinine daily in the first days. - Replace measured losses with fluids of similar composition (like for like).

Dehydration (hypovolaemia) Signs: - dry mucous membranes, intense thirst - reduced urine output: oliguria, then anuria - psychomotor agitation, then apathy and clouding of consciousness - a small, rapid pulse, sometimes with rhythm disturbances - tachypnoea - hypotension (late), slow capillary refill - low central venous pressure (near or below 0 mmHg) Laboratory: raised haematocrit and urea (urea rises more than creatinine), concentrated urine. Management: - Replace volume with crystalloids: give a bolus, reassess, repeat. - Replace specific losses: saline and potassium for gastric losses, balanced solutions for intestinal or biliary losses, blood for haemorrhage. - Treat the cause (bleeding, ileus, fistula). Fluid overload (hyperhydration) Signs: - weight gain, peripheral and sacral oedema - distended jugular veins - raised central venous pressure (above about 10 mmHg) - dyspnoea, basal crackles - chest X-ray: congested hila, then pulmonary oedema and pleural effusions - low sodium from dilution Causes: excessive infusion, renal failure, heart failure, and the postoperative antidiuretic state. Management: - Restrict fluids. - Promote diuresis with loop diuretics (furosemide). - Reduce cardiac workload. - Manage renal insufficiency, with dialysis if needed. Side by side Dehydration: - mucosa dry - urine low and concentrated - CVP low - chest X-ray clear Overload: - oedema - urine variable (low in renal or heart failure) - CVP high - chest X-ray congested Exam trap: low urine output happens in both. The CVP, the chest, the neck veins and the fluid chart tell them apart.

Clavien-Dindo classification - Grade I: any deviation not needing drugs (other than antiemetics, antipyretics, analgesics, diuretics, electrolytes, physiotherapy), or surgical, endoscopic or radiological intervention. Wound infections opened at the bedside are included. - Grade II: needs drugs beyond those allowed in grade I, blood transfusion or parenteral nutrition. Example: pneumonia treated with antibiotics. - Grade III: needs surgical, endoscopic or radiological intervention. IIIa: without general anaesthesia (for example percutaneous drainage). IIIb: under general anaesthesia (for example relaparotomy). - Grade IV: life-threatening, needing intensive care. IVa: single-organ dysfunction (including dialysis). IVb: multi-organ dysfunction. - Grade V: death of the patient. - Suffix "d": disability persisting at discharge. The Comprehensive Complication Index (CCI) combines all of a patient's complications into one score from 0 to 100. Why grade? - It allows honest reporting. - It allows comparison between surgeons, centres and techniques. - It allows audit.

Respiratory - Atelectasis: the most common early complication after abdominal surgery, from pain, shallow breathing and secretions. Prevent it with analgesia, physiotherapy and incentive spirometry. - Pulmonary oedema: from fluid overload or cardiac failure. - Respiratory failure: from pneumonia, aspiration, ARDS or pulmonary embolism. Cardiovascular - Hypovolaemic shock: from bleeding or losses. - Cardiogenic shock: from myocardial infarction or arrhythmia. - Septic shock: from a leak, abscess or pneumonia. - Deep vein thrombosis and pulmonary embolism. Infection - Surgical site infections: superficial, deep, or organ/space (abscess). - Distant infections: pneumonia, urinary tract infection, catheter-related bloodstream infection, C. difficile. Gastrointestinal - Anastomotic dehiscence (leak): typically days 5-7, with fever, tachycardia, pain, peritonism and changed drain fluid. - Haemorrhagic (stress) gastritis. - Intestinal obstruction: prolonged ileus, early adhesions, internal hernia. Renal - Acute renal failure. Prerenal causes are commonest (hypovolaemia, hypotension); also nephrotoxic drugs, contrast, sepsis; post-renal from a blocked catheter (flush it first). Fever after surgery: a timeline to guide the search (classic teaching) - First 48 hours: the inflammatory response to surgery, atelectasis; rarely early necrotising wound infection or transfusion reaction. - Days 3-5: pneumonia, urinary tract infection, catheter-related infection. - Days 5-7: anastomotic leak, wound infection, intra-abdominal abscess. - After day 7: deep collections, DVT or pulmonary embolism, drug fever, C. difficile. Non-infectious causes also exist: drug reactions, transfusion, thrombosis, pancreatitis, adrenal insufficiency.

1. Put Semmelweis, Pasteur and Lister in order and say what each contributed. What is the difference between antisepsis and asepsis? 2. Define emergency, urgent and elective surgery, with the time window and one example of each. 3. List the five variables that determine surgical risk. 4. Why is pseudocholinesterase measured before surgery? 5. A patient has well-controlled hypertension and is having a large colectomy. What is their ASA class, and why is that not a contradiction? 6. Name six of the physiological variables in APACHE II. Over which time window are they measured? 7. Calculate the GCS: eyes open to pain, confused speech, localises pain. 8. List the five Ranson criteria at admission. How many positive criteria define severe pancreatitis? 9. When exactly is prophylactic antibiotic given, and when is a second dose needed? 10. Which wound classes need prophylaxis, and when does prophylaxis become therapy? 11. Which antibiotic would you give for an elective colectomy, and why? 12. Name the three elements of Virchow's triad and one surgical example of each. 13. Why are H2-antagonists or sucralfate preferred to PPIs for stress ulcer prophylaxis in this course? 14. What acid-base disorder follows large nasogastric losses? And large T-tube losses? 15. Milky fluid appears in an abdominal drain. What is the likely cause, and how do you confirm it? 16. Give three mechanisms of postoperative paralytic ileus and four treatment measures. 17. List three features that distinguish mechanical obstruction from paralytic ileus. 18. What are the three indications for postoperative artificial nutrition? 19. Compare TPN and PPN: access, volume, calories. 20. List the measurable and insensible losses, with daily volumes. 21. How do you tell dehydration from fluid overload when both present with low urine output? 22. A patient needs radiological drainage of an abscess under local anaesthesia. What Clavien-Dindo grade is this?

1. Semmelweis (1840s): hand washing prevents puerperal fever. Pasteur (1860s): germ theory. Lister (1867): carbolic acid antisepsis in surgery. Antisepsis kills germs already present; asepsis keeps germs away from the wound. 2. Emergency: immediate danger to life, operate at once, no preparation (for example ruptured aortic aneurysm). Urgent: within 3-6 hours, basic preparation possible (for example perforated ulcer). Elective: scheduled, full workup (for example cholecystectomy for gallstones). 3. Type of disease, age, type of intervention, type of anaesthesia, general condition and comorbidities. 4. Low activity prolongs the action of succinylcholine and causes prolonged apnoea after anaesthesia. 5. ASA II. ASA grades the patient's health, not the size or risk of the operation. 6. Any six of: temperature, mean arterial pressure, heart rate, respiratory rate, oxygenation, arterial pH, sodium, potassium, creatinine, haematocrit, white cell count, GCS. The worst values in the first 24 hours in the ICU. 7. E2 V4 M5 = 11. 8. Age over 55, white cells over 16,000, glucose over 200 mg/dL, LDH over 350 IU/L, AST over 250 IU/L. Three or more means severe. 9. At induction, about 30 minutes before incision (within 60 minutes). Redose if surgery lasts more than about 3 hours or blood loss exceeds about 1.5 L. 10. Clean-contaminated always. Clean only with an implant, CNS access, or catastrophic consequences of infection. In contaminated and dirty-infected surgery, antibiotics are therapy. 11. Cefoxitin, or cefazolin plus metronidazole, to cover Enterobacteriaceae and anaerobes. 12. Stasis (immobility under anaesthesia). Endothelial injury (pelvic dissection). Hypercoagulability (the acute-phase response, cancer, dehydration). 13. PPIs abolish gastric acidity, allowing bacterial overgrowth, respiratory infection and C. difficile, and they cost more. H2-antagonists reduce acid without abolishing it; sucralfate protects the mucosa without changing pH. 14. Nasogastric: hypochloraemic, hypokalaemic metabolic alkalosis. T-tube (bile): metabolic acidosis from bicarbonate loss. 15. A chyle leak from lymphatic injury. Confirm with high triglycerides in the drain fluid. 16. Mechanisms: neurogenic sympathetic reflexes, inflammation of the muscular layer, opioids, stress hormones such as CRH, electrolyte disturbance. Treatment: nasogastric decompression if needed, early mobilisation, reduced opioids, correction of potassium and magnesium, avoiding fluid overload, and investigating prolonged cases. 17. Colicky pain, high-pitched bowel sounds, a transition point with collapsed distal bowel on imaging (and possible signs of strangulation). 18. Preoperative malnutrition, expected lack of oral intake for more than 7 days, a hypercatabolic state. 19. TPN: central line, about 2.5-3 L, about 1,800-2,000 kcal/day. PPN: peripheral vein, about 3 L, at most about 1,500 kcal/day. 20. Measurable: urine 1.5-2 L, faeces about 200 mL, plus drains and nasogastric output. Insensible: 500-1,000 mL (skin 75%, lungs 25%), plus about 2.5 mL/kg/day for each degree of fever. 21. CVP, neck veins, oedema, chest X-ray (clear or congested), weight and the cumulative fluid chart. 22. Grade IIIa.

Key concepts - Adult hepatocytes are normally quiescent (in the G0 phase) but keep the ability to divide. - After partial hepatectomy they re-enter the cell cycle in a coordinated way. Mass, not shape, is restored: the remnant enlarges, and the resected lobes do not grow back. - Regeneration stops when the liver-to-body-weight ratio needed for the body's metabolic demands is reached. This is sometimes called the hepatostat. Phases 1. Priming: cytokines (TNF-alpha, IL-6), largely from Kupffer cells, move hepatocytes from G0 to G1. 2. Proliferation: growth factors drive DNA synthesis and division, above all hepatocyte growth factor (HGF), plus epidermal growth factor (EGF) and TGF-alpha. Hepatocytes divide first, followed by biliary cells, endothelial cells and stellate cells. 3. Termination: TGF-beta and matrix signals stop growth once the target mass is reached. The role of portal blood flow - After resection, the whole portal flow passes through a smaller liver. - The rise in flow and shear stress per gram of tissue, together with the growth factors and nutrients carried in portal blood, is a main trigger of regeneration. - This is why diverting portal flow away from one part of the liver (portal vein embolisation or ligation) makes the other part grow. The same principle underlies all the regeneration techniques in this chapter. What impairs regeneration: - cirrhosis and fibrosis - steatosis - cholestasis - recent chemotherapy - older age - diabetes - sepsis A liver that cannot regenerate needs a larger remnant.

The planes that divide the liver - Three vertical planes, each containing a hepatic vein: - The middle hepatic vein lies in Cantlie's line, which runs from the gallbladder fossa to the inferior vena cava. It divides the right hemiliver from the left hemiliver. This functional midline is NOT the falciform ligament. - The right hepatic vein divides the right anterior section (segments V and VIII) from the right posterior section (segments VI and VII). - The left hepatic vein, with the umbilical fissure and falciform ligament, divides the left lateral section (segments II and III) from the left medial section (segment IV). - One horizontal plane, at the level of the portal bifurcation, separates upper segments from lower ones (VIII above V, VII above VI, II above III, IVa above IVb). The segments, numbered clockwise when the liver is seen from the front: - I: caudate lobe. It sits behind, next to the vena cava, receives branches from both right and left pedicles, and drains directly into the vena cava through short hepatic veins. It is therefore often spared in Budd-Chiari syndrome and enlarges. - II and III: left lateral section. - IV: left medial section (IVa superior, IVb inferior). - V and VIII: right anterior section. - VI and VII: right posterior section. Glissonean pedicles - Inside the liver, portal vein, artery and bile duct travel together, wrapped in a sheath of Glisson's capsule. - Surgeons can clamp a pedicle and watch the corresponding territory change colour. This defines the resection line. Exam trap: the anatomical right and left lobes (divided by the falciform ligament) are not the same as the functional right and left hemilivers (divided by Cantlie's line). Segment IV is anatomically in the "right lobe" but functionally belongs to the left liver. Clinical tip: real portal branching varies between patients, and the segment borders are not flat planes. This is why 3D reconstruction and intraoperative ultrasound matter.

Non-anatomical resection (wedge) - Removes the tumour with a rim of healthy tissue, ideally with a clear margin (R0). - Spares as much parenchyma as possible. - Suited to small, superficial lesions, especially colorectal metastases. - Useful in cirrhotic livers where parenchyma must be saved. Anatomical resection - Removes one or more Couinaud segments along their natural borders, after controlling the corresponding portal pedicle. - Advantages: - removes microscopic tumour spread along the portal branches (important in HCC, which invades portal radicles) - leaves no devascularised tissue at the margin - usually bleeds less along the cut surface Choosing between them depends on: - tumour biology: HCC favours anatomical resection; metastases allow parenchyma-sparing resection - tumour size and position - quality and volume of the liver that will remain Clinical tip: parenchyma-sparing surgery keeps more options open. It allows repeat resection if metastases recur, which is common.

Terminology (Brisbane 2000): hemiliver means hepatectomy; section means sectionectomy; segment means segmentectomy. Resections from small to large: - Wedge resection: non-anatomical. - Segmentectomy: one Couinaud segment (for example segmentectomy VI). Bisegmentectomy: two adjacent segments. - Left lateral sectionectomy (the classic "left lobectomy"): segments II and III. Also the standard graft in living donation to small children. - Left hepatectomy: segments II, III and IV (plus I if the caudate is included). - Right hepatectomy: segments V, VI, VII and VIII. - Central hepatectomy (mesohepatectomy): segments IV, V and VIII. It removes a central tumour and spares both lateral parts of the liver. Technically demanding, with two cut surfaces. - Extended right hepatectomy (right trisectionectomy): segments IV-VIII (plus I if needed). Leaves only the left lateral section, often less than 25% of the volume. - Extended left hepatectomy (left trisectionectomy): segments II, III, IV, V and VIII. Leaves only the right posterior section. Key surgical steps of a major hepatectomy: 1. Exploration, with intraoperative ultrasound to confirm resectability. 2. Mobilisation of the liver. 3. Hilar dissection: isolation and division of the portal vein branch, hepatic artery branch and bile duct of the side to be removed (inflow control). 4. The demarcation line appears. 5. Control of the hepatic vein (outflow). 6. Parenchymal transection, often with intermittent clamping of the whole hilum (the Pringle manoeuvre) and low central venous pressure anaesthesia to reduce bleeding. 7. Haemostasis and a check for bile leaks. Exam focus: be able to list the segments removed in each resection. Know that the size of what remains, not of what is removed, determines safety.

1. Intraoperative ultrasound (IOUS) - The surgeon's "eyes inside the liver", and the gold standard for intraoperative staging. - Finds small lesions missed on preoperative imaging, often changing the plan. - Maps the tumour against the hepatic veins and portal pedicles. - Guides anatomical resection: the portal branch feeding a segment can be punctured and injected with dye, or compressed, to stain the territory. - Guides the transection plane and ablation needles in real time. 2. 3D vessel reconstruction - CT or MRI data rebuilt into a 3D model of the liver, tumours, vessels and bile ducts. - Uses: - calculates the volume of each territory and of the future liver remnant - simulates the resection - identifies anatomical variants - helps explain the operation to the team and the patient - Can be shown as a screen model, a 3D print, or augmented reality in theatre. 3. Minimally invasive liver surgery (MILS): laparoscopic and robotic - Advantages over open surgery: - less blood loss - less pain - shorter hospital stay - fewer wound complications - faster return to normal activity - In cirrhosis it also means less postoperative ascites and decompensation, because the abdominal wall collaterals and lymphatics are preserved. - Oncological results are comparable in experienced hands. - Difficulty scores help select cases as surgeons progress. Minor resections of anterolateral segments are easiest; posterosuperior segments and major hepatectomies are hardest. 4. Indocyanine green (ICG) fluorescence - ICG is a dye taken up by hepatocytes and excreted into bile. It fluoresces in near-infrared light. - Tumour detection: given days before surgery, it is retained in HCC and around metastases, making small superficial lesions glow. - Segment demarcation: injected into a portal branch (positive staining), or given intravenously after clamping a pedicle (negative staining), it outlines the segment. - Shows bile ducts and bile leaks on the cut surface. - As a function test: the ICG retention rate at 15 minutes (ICG-R15, normally below 10%) measures liver functional reserve before resection.

How the FLR is measured - CT volumetry: segment the liver on CT, calculate the volume of the part that will remain, and express it as a percentage of total functional liver volume (excluding tumour). - An alternative is standardised FLR, relative to a total liver volume estimated from body surface area. - Function matters too: two livers with the same volume may work very differently. Function can be measured with ICG clearance or hepatobiliary scintigraphy. Minimum safe FLR - Healthy liver: more than 25-30%. - Liver with fibrosis, marked steatosis or after prolonged chemotherapy (which can injure the liver: sinusoidal obstruction syndrome from oxaliplatin, steatohepatitis from irinotecan): more than 40%. - Cirrhosis: major resection is usually avoided. When resection is done in selected Child-Pugh A patients, at least 40-50% is required. If the FLR is insufficient, the options are: - a smaller or parenchyma-sparing resection - ablation instead of resection - inducing growth of the remnant before surgery (the next section)

Definition - Commonly defined as an increased INR and increased bilirubin on or after postoperative day 5, relative to normal limits. This is the definition of the International Study Group of Liver Surgery (ISGLS). - The "50-50 criteria": on day 5, prothrombin time below 50% and serum bilirubin above 50 micromol/L (about 2.9 mg/dL) predict high mortality. ISGLS grades - A: abnormal tests, but no change in clinical management. - B: change in management without invasive treatment, for example albumin, plasma, diuretics. - C: invasive treatment needed, for example ventilation, dialysis, vasopressors, or salvage transplantation. Clinical picture - rising jaundice - coagulopathy - ascites (and high drain output) - encephalopathy - renal failure - infection (the failing liver is also an immune organ) Risk factors - Patient: cirrhosis, fibrosis, steatosis, cholestasis, chemotherapy injury, diabetes, older age. - Surgical: small FLR, extended resection, massive blood loss and transfusion, prolonged clamping (ischaemia-reperfusion), venous outflow or portal inflow problems in the remnant. Management: mostly supportive. Correct coagulopathy only for bleeding, treat infection aggressively, give nutrition, and consider transplantation only in very selected cases. Prevention through proper selection is everything.

Why cirrhosis changes everything - Fewer functioning hepatocytes and impaired regeneration. - Portal hypertension: bleeding, ascites, poor healing. - Coagulopathy. - Higher risk of liver failure after even small resections. Assessment 1. Child-Pugh score: bilirubin, albumin, prothrombin time or INR, ascites, encephalopathy. Class A 5-6 points, B 7-9, C 10-15. 2. MELD score: bilirubin, INR and creatinine (MELD-Na adds sodium). Higher values mean worse function. For resection, a MELD of 10 or less is favourable. 3. Portal hypertension: - Direct measurement: hepatic venous pressure gradient (HVPG). Clinically significant portal hypertension is an HVPG of 10 mmHg or more. - Indirect signs: platelets below 100,000/mm3, splenomegaly, oesophageal varices, ascites. 4. Dynamic function tests: ICG-R15 (up to about 10% allows major resection; higher values restrict the extent). 5. FLR volume by CT. Indications according to international hepatology guidelines (EASL, AASLD, APASL) - The ideal candidate for resection of HCC is Child-Pugh A with a single tumour, good performance status, and no clinically significant portal hypertension. - Some guidelines accept limited resections in patients with mild portal hypertension if the resection is small or done by minimally invasive surgery. - When liver function is too poor for resection, transplantation or ablation are considered (chapters 3 and 5). Clinical tip: in cirrhosis, the laparoscopic approach reduces postoperative ascites and liver decompensation. This has widened the indications for resection.

Portal vein embolisation (PVE) - Technique: an interventional radiologist reaches the portal vein through the skin and liver and occludes the branches of the side to be resected (for example the right portal vein, plus segment IV branches before a trisectionectomy), using particles, coils or glue. - Effect: - the embolised side shrinks (atrophy) - the non-embolised side (the future remnant) enlarges, typically by about 10% of total liver volume in absolute terms - most growth happens within 3-6 weeks - Selection value: the degree of hypertrophy (the kinetic growth rate) tests the liver's capacity to regenerate. A liver that does not grow after PVE is unlikely to survive a major resection. - Limitations: - the waiting time, during which the tumour can progress - insufficient growth in damaged livers Portal vein ligation (PVL) - The same principle, done surgically. Often part of the first stage of a two-stage hepatectomy.

Two-stage hepatectomy - Typical setting: bilateral colorectal liver metastases too extensive for one operation. - Stage 1: clear the future remnant (usually the left liver) of metastases by limited resection or ablation, and ligate (or later embolise) the right portal vein. - Interval of about 4-8 weeks: the remnant grows, and chemotherapy may be given. - Stage 2: right or extended right hepatectomy. - Drop-out: a proportion of patients (often around a quarter to a third) never reach stage 2, because of tumour progression or insufficient growth. ALPPS: Associating Liver Partition and Portal vein Ligation for Staged hepatectomy - Stage 1: - ligate the portal vein of the side to be removed - divide (partition) the liver parenchyma along the future resection line - clear the remnant of tumours The partition cuts the collateral vessels between the two sides, so the remnant receives all portal flow and grows extremely fast. - Hypertrophy: often 40-80% within about 7-14 days. - Stage 2: complete the resection in the same hospital stay. - Advantages: - very rapid, large growth - very few patients fail to reach stage 2 - Disadvantages: - higher morbidity and mortality, especially in older patients and in stage 1 - the "volume" gained may be functionally immature (function lags behind volume) Refined variants (partial partition, minimally invasive ALPPS) reduce the risk. Side by side Two-stage hepatectomy: - time to stage 2: weeks to months - degree of growth: moderate - stage 2 completion: lower (drop-out from progression) - risk: lower per stage ALPPS: - time to stage 2: 1-2 weeks - degree of growth: large and rapid - stage 2 completion: high - risk: higher, especially at stage 1

Principle - Blocking both portal inflow and venous outflow of the liver to be removed increases the shift of function and flow to the future remnant. It also prevents the arterial-portal compensation that can blunt hypertrophy after portal vein embolisation alone. Technique - Percutaneous, in one or two sessions. - Embolise the right portal vein, then the right hepatic vein (and sometimes accessory inferior right hepatic veins). - Extended LVD also embolises the middle hepatic vein. Results - Faster and greater growth than portal vein embolisation alone, with a better functional gain. - Tolerance is similar to portal vein embolisation. Where it fits: an option between portal vein embolisation (slower, safer) and ALPPS (fastest, riskiest), especially when time or liver quality is an issue.

The volume-outcome relationship - For major hepatectomy, as for pancreatic and oesophageal surgery, hospitals and surgeons performing more procedures have lower postoperative mortality. - Mechanisms: - experienced surgeons and anaesthetists - dedicated hepatology, intensive care and interventional radiology available around the clock - standardised pathways - above all, lower "failure to rescue": the complication rate may be similar, but fewer complicated patients die - Policy consequence: centralising complex hepatobiliary surgery in specialised units. Clinical tip: when a complication such as bile leak, bleeding or liver failure appears, what saves the patient is the speed and quality of the team's response. That depends on experience.

1. What is the main haemodynamic trigger of liver regeneration, and how do surgeons exploit it? 2. Name three growth factors or cytokines involved in regeneration, and the factor that ends it. 3. Which vessel lies in Cantlie's line, and what does it divide? 4. List the segments of the left lateral section, the right anterior section and the right posterior section. 5. Why does the caudate lobe often enlarge in Budd-Chiari syndrome? 6. Which segments does a right hepatectomy remove? A central hepatectomy? A right trisectionectomy? 7. Why is anatomical resection preferred for HCC? 8. Give three uses of intraoperative ultrasound. 9. Give three uses of indocyanine green in liver surgery. 10. What is the minimum FLR in a healthy liver, and in a liver after heavy chemotherapy? 11. Define post-hepatectomy liver failure and state the 50-50 criteria. 12. What does an HVPG of 10 mmHg or more mean, and what indirect signs suggest it? 13. How does portal vein embolisation work, and what does a lack of growth afterwards tell you? 14. Compare a two-stage hepatectomy with ALPPS on speed, growth, completion rate and risk. 15. What is liver venous deprivation? 16. What is "failure to rescue", and why does it explain the volume-outcome relationship?

1. Increased portal flow and shear stress per gram of the remnant. Surgeons exploit it with portal vein embolisation or ligation, ALPPS and venous deprivation. 2. TNF-alpha, IL-6, HGF, EGF, TGF-alpha. TGF-beta ends it. 3. The middle hepatic vein. It divides the right from the left hemiliver. 4. Left lateral: II and III. Right anterior: V and VIII. Right posterior: VI and VII. 5. It drains directly into the vena cava through short hepatic veins, so it escapes the outflow block. 6. Right hepatectomy: V-VIII. Central: IV, V, VIII. Right trisectionectomy: IV-VIII. 7. HCC spreads along portal branches. Removing the whole portal territory removes microscopic satellites. 8. Detecting occult lesions, mapping the tumour against vessels, guiding the transection plane and segment staining, guiding ablation. 9. Tumour detection, segment demarcation (positive or negative staining), finding bile leaks, the ICG-R15 function test. 10. 25-30% in a healthy liver. 40% or more after heavy chemotherapy, or with fibrosis or steatosis. 11. Increased INR and bilirubin on or after postoperative day 5. The 50-50 criteria: PT below 50% and bilirubin above 50 micromol/L on day 5. 12. Clinically significant portal hypertension. Indirect signs: platelets below 100,000, splenomegaly, varices, ascites. 13. It diverts portal flow to the remnant, which enlarges over 3-6 weeks. No growth means poor regenerative capacity and a high risk of liver failure. 14. Two-stage: weeks, moderate growth, more drop-out, lower risk. ALPPS: 1-2 weeks, large growth, high completion, higher morbidity and mortality. 15. Combined embolisation of the portal vein and the hepatic vein of the side to be removed. It gives faster, greater growth of the remnant. 16. Death after a complication that occurred. High-volume centres rescue complications more successfully, so fewer patients die.

Benign - Cystic: simple cyst, hydatid (echinococcal) cyst, and others. - Solid: - haemangioma (the most common) - focal nodular hyperplasia (FNH) - hepatocellular adenoma Primary malignant - Hepatocellular carcinoma (HCC): by far the most common primary liver cancer. - Cholangiocarcinoma (intrahepatic). - Rarer tumours: angiosarcoma and other mesenchymal tumours. Secondary (metastases) - Colorectal, neuroendocrine and other primaries. - The liver is filtered by portal blood from the gut, which explains why gastrointestinal cancers metastasise there so often. Clinical scenarios in which a liver lesion appears 1. Incidental finding on imaging done for another reason. This is the most common, and most such lesions are benign. 2. Symptoms: pain, a mass, jaundice, or, rarely, rupture with bleeding. 3. Surveillance of a patient at risk (cirrhosis, chronic hepatitis B): the aim is to find HCC early. 4. Staging or follow-up of a known cancer elsewhere: the question is whether this is a metastasis. Exam focus: the same lesion is read differently depending on the scenario. A 2 cm arterially enhancing nodule means one thing in a young woman with a normal liver, and something very different in a patient with cirrhosis.

Two cystic lesions are covered here: - Simple cyst: congenital, common, harmless. Treated only if symptomatic, by deroofing. - Hydatid cyst: parasitic. It needs medical therapy and careful surgery, because spilling it is dangerous. The first question for any cystic lesion: does it look "pure" on imaging?

Haemangioma: the most common. Peripheral nodular centripetal enhancement. Treated only for symptoms, doubt, growth or rupture. FNH: central scar, women around 40, no malignant potential. No treatment if typical. Adenoma: young women on the pill. Can bleed and become malignant. Management depends on sex, size, growth and subtype.

HCC on a cirrhotic liver (the majority) - Chronic hepatitis C and B. - Alcohol-related liver disease. - MASLD (metabolic dysfunction-associated steatotic liver disease, previously NAFLD) and its progressive form MASH: a rapidly growing cause. - Haemochromatosis and other metabolic diseases. - Cirrhosis itself is the strongest risk factor, whatever its cause. The yearly incidence of HCC in cirrhosis is a few percent. HCC on a non-cirrhotic ("healthy") liver - Hepatitis B: the virus integrates into the host DNA and is carcinogenic even without cirrhosis. - Aflatoxin B1: a mycotoxin from Aspergillus contaminating stored grain and peanuts. It causes a characteristic TP53 mutation and acts in synergy with hepatitis B. Common in sub-Saharan Africa and East Asia. - MASLD: can lead to HCC even before cirrhosis. - Malignant transformation of an adenoma. - Fibrolamellar carcinoma: a distinct variant in young people. Why this matters - In a non-cirrhotic liver, tumours are often discovered late and large, but major resection is well tolerated. - In cirrhosis, the tumour may be small, but liver function limits every treatment.

Surveillance - Who: - all patients with cirrhosis who would be fit for treatment - selected non-cirrhotic hepatitis B carriers (by age, ethnicity, family history) - advanced fibrosis in some guidelines - How: abdominal ultrasound every 6 months. This interval reflects the tumour's doubling time. Alpha-fetoprotein (AFP) is often added. - Aim: find HCC at a size where curative treatment is possible. Non-invasive diagnosis (in cirrhosis) - Why it works: as a nodule becomes malignant, its blood supply shifts from portal to arterial ("arterialisation"). - Hallmarks on multiphase contrast CT or MRI: 1. Arterial phase hyperenhancement (APHE): the lesion lights up more than the liver. 2. Washout: on portal venous or delayed phase it becomes darker than the liver. 3. Supporting features: an enhancing capsule, growth over time. - Nodules of 1 cm or more with these features can be diagnosed as HCC without biopsy. - Nodules under 1 cm: repeat ultrasound in 3 months. - Biopsy is needed when imaging is not conclusive, and always in a non-cirrhotic liver. Exam trap: these non-invasive criteria apply only to patients at high risk (cirrhosis). In a healthy liver, arterial enhancement plus washout can also be an adenoma or metastasis.

Categories - LR-NC: not categorisable, because image quality is poor or phases are missing. - LR-1: definitely benign. - LR-2: probably benign. - LR-3: intermediate probability of malignancy. - LR-4: probably HCC. In the course material this is further split into 4A and 4B. - LR-5: definitely HCC. Split into 5A and 5B by size and features in the course material. - LR-M: probably or definitely malignant, but not HCC-specific (for example cholangiocarcinoma or combined tumours). Needs biopsy. - LR-TIV (called LR-5V in older versions, as on the slides): tumour in vein, meaning enhancing soft tissue inside a vein. Major features used to assign the category: - nodule size - arterial phase hyperenhancement - non-peripheral washout - enhancing capsule - threshold growth (an increase of 50% or more in 6 months or less) What each result means: - LR-1 and LR-2: routine surveillance. - LR-3: repeat imaging in 3-6 months. - LR-4: multidisciplinary discussion, repeat imaging or biopsy. - LR-5: treat as HCC. - LR-M: biopsy.

Edmondson-Steiner grading - Grade I: well differentiated, cells close to normal hepatocytes. - Grade II: moderately differentiated, trabecular or pseudoglandular pattern, larger nuclei. - Grade III: poorly differentiated, marked nuclear atypia, giant cells. - Grade IV: undifferentiated, little resemblance to liver, loss of trabecular pattern. Higher grade means worse prognosis and higher risk of recurrence. Vascular invasion - Microvascular invasion (MVI): - tumour cells in small vessels of the tumour capsule or surrounding liver - seen only on histology - a key predictor of recurrence after resection and transplantation - more likely with large tumours, multiple nodules, high AFP and poor differentiation - one reason to prefer anatomical resection - Macrovascular invasion: - tumour thrombus in the portal vein (or hepatic veins) - visible on imaging - classifies the disease as advanced - generally excludes transplantation Clinical tip: before surgery MVI cannot be seen. AFP, tumour size and number are used as surrogates when choosing between resection and transplantation.

The options, from most to least curative: - transplantation - resection - ablation - intra-arterial therapies (TACE, radioembolisation) - systemic therapy The following subsections explain: - who can have a resection - why and when transplantation is chosen - how the locoregional and systemic therapies work and when they are contraindicated

1. Name the three main groups of liver tumours and one example of each. 2. What are the imaging features of a simple cyst on ultrasound, CT and MRI? 3. Why does aspiration alone fail to cure a symptomatic simple cyst? What is the standard operation? 4. Describe the life cycle of Echinococcus granulosus. Which is the definitive host? 5. What is the main intraoperative danger with a hydatid cyst, and how is it prevented? 6. What is the enhancement pattern of a haemangioma? 7. List four indications for surgery for a haemangioma. 8. What is a central scar, and in which two lesions is it found? 9. Why can an adenoma bleed? Which subtype has the highest risk of malignant transformation? 10. Describe the management of an adenoma in a man, and in a woman. 11. Give four risk factors for HCC in a non-cirrhotic liver. 12. How often, and with what test, are patients with cirrhosis surveyed? 13. What two imaging features allow a diagnosis of HCC without biopsy, and in which patients? 14. What does LR-M mean, and what do you do with it? 15. What is microvascular invasion, and why does it matter? 16. List the criteria for resection of HCC in a cirrhotic patient. 17. State the Milan criteria. 18. What is downstaging? What is drop-out? 19. Why is TACE contraindicated in portal vein thrombosis? 20. Put these in the order of the therapeutic hierarchy: TACE, resection, systemic therapy, transplantation, ablation.

1. Benign (haemangioma), primary malignant (HCC), secondary (colorectal metastasis). 2. Ultrasound: anechoic with a thin wall and posterior enhancement. CT: water density, no enhancement. MRI: T1 hypo, T2 very hyper. 3. The epithelial lining keeps secreting fluid, so the cyst refills. The standard operation is laparoscopic deroofing (fenestration). 4. Adult worm in the dog's gut, eggs in faeces, ingested by sheep or humans (intermediate hosts), larvae in the liver or lung, dog eats infected offal. The dog is the definitive host. 5. Spillage of cyst contents, causing anaphylaxis and seeding. Prevented with preoperative albendazole, scolicide-soaked packs, and careful technique (or pericystectomy). 6. Peripheral nodular (discontinuous) enhancement with progressive centripetal fill-in. It stays bright on late phases. 7. Symptoms, diagnostic doubt, growth over 1 cm per year, rupture (or Kasabach-Merritt syndrome). 8. A fibrous scar containing an abnormal artery. Found in FNH and fibrolamellar HCC. 9. It has thin-walled arteries and no portal tracts. The beta-catenin (exon 3) subtype has the highest risk. 10. Man: resect. Woman: stop the pill and lose weight, MRI at 6 months, resect if 5 cm or more or grown by 20% or more. Resect beta-catenin adenomas regardless. 11. Hepatitis B, aflatoxin, MASLD, adenoma (and the fibrolamellar variant). 12. Ultrasound every 6 months, with or without AFP. 13. Arterial phase hyperenhancement and washout, in patients with cirrhosis (high risk) and nodules of 1 cm or more. 14. Probably malignant but not specific for HCC. Biopsy it. 15. Tumour cells in small vessels, seen only on histology. It predicts recurrence after resection and transplantation. 16. Child-Pugh A, MELD 10 or less, varices F1 or less, platelets 100,000 or more, and an adequate remnant. 17. One nodule up to 5 cm, or up to 3 nodules each up to 3 cm, with no vascular invasion or extrahepatic spread. 18. Downstaging: treating a tumour beyond criteria to bring it within them. Drop-out: progression beyond criteria while waiting, leading to removal from the list. 19. With the portal vein blocked, the hepatic artery is the liver's only blood supply. Embolising it can cause liver necrosis and failure. 20. Transplantation, resection, ablation, TACE, systemic therapy.

Donation after brain death (DBD) - Death is declared on neurological criteria. Ventilation and circulation are maintained artificially until procurement. - Organs are perfused with oxygenated blood up to the moment of cold perfusion, so the quality is best. - About 90% of deceased donors (course data). Donation after circulatory death (DCD) - Death is declared after the heart has stopped irreversibly. - The organs suffer a period of warm ischaemia before preservation begins. - Fewer than 10% of donors, but increasing in many countries (see the DCD section). Living donation - Kidney: the most common living donation. About 11% of kidney transplants in the course data (2019). - Liver: a part of the liver (left lateral section for children, right or left hemiliver for adults). About 1.8% of liver transplants in the course data (2019). - Advantages: - planned surgery - excellent graft quality - short cold ischaemia - Disadvantage: a healthy person undergoes major surgery with no personal medical benefit. Donor safety is the absolute priority.

History - 1959: Mollaret and Goulon describe "coma dépassé" (a state beyond coma) in 23 patients kept alive by ventilators, with no brain function. - 1968: the Harvard ad hoc committee defines irreversible coma as a new criterion for death. - Since then, most countries have accepted death determined by neurological criteria. Coma vs death, side by side Coma: - nature: dynamic, can improve or worsen - brain function: reduced but partly present - brainstem reflexes: may be present - spontaneous breathing: may be present - reversible: potentially Brain death: - nature: static - brain function: absent in the whole brain - brainstem reflexes: all absent - spontaneous breathing: absent (apnoea test positive) - reversible: never Causes of brain death - Stroke and intracranial haemorrhage: about 65-70% of cases (the largest group). - Head trauma. - Anoxic injury (for example after cardiac arrest). - Others: tumours, infections. Mechanism: rising intracranial pressure exceeds arterial pressure, cerebral blood flow stops, and the brain dies.

Prerequisites - A known cause of severe brain injury, documented by imaging. - Exclusion of confounders: - hypothermia - sedative or paralysing drugs - severe metabolic or endocrine disturbances - shock The board (collegio medico) - An anaesthetist-intensivist, a forensic physician (medico legale), and a neurologist (or neurophysiologist). - None of them can be part of the transplant team. Observation period (as taught) - Adults and children over 5 years: 6 hours. - Children aged 1-5 years: 12 hours. - Infants under 1 year: 24 hours. The criteria are verified at least twice: at the start and at the end of the period. What is verified 1. Unconsciousness (deep coma). 2. Absence of brainstem reflexes (next note). 3. Absence of spontaneous breathing: a positive apnoea test. 4. Electrical silence of the brain on EEG. 5. In some circumstances (for example infants, or confounding factors that cannot be excluded), absence of cerebral blood flow must be shown, for example by perfusion scintigraphy or angiography. The time of death is the moment the first set of criteria is recorded, not the end of observation. This is legally important.

Brainstem reflexes (afferent and efferent cranial nerves) - Pupillary light reflex: II (afferent), III (efferent). Pupils fixed and unreactive (usually mid-size or dilated). - Corneal reflex: V afferent, VII efferent. Touching the cornea produces no blink. - Oculocephalic reflex ("doll's eyes"): VIII afferent, III, IV and VI efferent. Turning the head, the eyes move with it and stay fixed in the orbit, with no counter-movement. Do not perform it if the cervical spine is unstable. - Vestibulo-ocular reflex (cold caloric test): about 50 mL of ice-cold water (around 4 °C) is instilled into each ear, after checking the eardrum is intact. There is no eye movement. - Gag (pharyngeal) reflex: IX, X. - Cough reflex with tracheal suction: X. - No motor response in the cranial nerve territory to painful stimuli. Spinal reflexes may persist and do not exclude brain death. Apnoea test 1. Pre-oxygenate with 100% oxygen. 2. Disconnect from the ventilator (or reduce to CPAP), supplying oxygen into the trachea. 3. Let the PaCO2 rise to 60 mmHg or more, with the pH falling (acidosis). 4. Observe for any breathing movement. 5. Positive (consistent with brain death) if there is no breathing at the target PaCO2. Stop the test if the patient becomes haemodynamically unstable or desaturates. EEG: electrical silence (isoelectric) for a set recording time under standardised conditions. Exam trap: persistent spinal reflexes (for example the "Lazarus sign") do not exclude brain death. Absent brainstem reflexes plus apnoea are what count.

The three options (as taught) 1. Consent recorded: donation proceeds (the family is informed). 2. Refusal recorded: no donation. 3. No declaration: the family (spouse, cohabiting partner, adult children, parents) can oppose donation. How a person records their will - at the local health authority - at the town hall when renewing an identity card - through donor associations (for example AIDO) - with a signed and dated declaration carried with personal documents Principles - The diagnosis of death is completely independent from the transplant process. - Families are approached with dedicated communication by trained staff. Refusal rates depend heavily on how the request is made. - The identity of donors and recipients is kept anonymous from each other.

The Italian classification (national guidelines, 2005; as taught) 1. Unacceptable risk: organs cannot be used. Examples: - HIV infection - HBsAg positive with HDV co-infection - active malignancy with a high risk of spread - active untreatable systemic infections 2. Increased but acceptable risk: an infectious agent or tumour is present, but the organ is used because the recipient's clinical urgency outweighs the risk (for example a patient who would otherwise die soon). 3. Calculated risk: the pathogen is known, and the organ goes to a recipient with the same infection or protected against it. Examples: - HCV-positive donor to an HCV-positive recipient (today also often HCV-negative recipients, since antivirals are available) - HBsAg-positive donor to an HBsAg-positive or vaccinated recipient - anti-HBc-positive donor (especially the liver) to an HBsAg-positive or anti-HBs-positive recipient, with prophylaxis - bacteraemia treated with targeted antibiotics for at least 24 hours 4. Non-assessable risk: some evaluation elements are missing (for example incomplete history or unavailable tests), so the risk cannot be fully quantified. 5. Standard risk: no risk factors emerged from the evaluation. Assessment always includes: - medical and social history, including risk behaviours - physical examination - serology and nucleic acid tests - imaging - inspection of the organs at procurement, with biopsy of any suspicious lesion The recipient is informed and must consent to receive an organ outside the standard category.

Steps 1. Incision: median sternotomy and laparotomy (xipho-pubic). 2. Inspection of all organs to exclude unsuspected disease. 3. Preliminary dissection, the "warm phase": isolate the aorta and the vena cava or iliac vessels, and identify variant arteries. 4. Cannulation of the aorta (and often the portal system for the liver). 5. Systemic heparin, aortic cross-clamp. This is when cold ischaemia begins. 6. Cold perfusion with preservation solution. The abdomen and chest are filled with ice slush. Blood is vented through the vena cava. 7. Removal in the order: heart, lungs, liver, pancreas, intestine, kidneys. 8. Back-table preparation. Vessel grafts (iliac arteries and veins) are kept for vascular reconstruction. 9. Packing: triple sterile bags in ice, with labelled samples (blood, lymph nodes, spleen for tissue typing). Teamwork - Several surgical teams (thoracic, abdominal) coordinate at the same procedure, with anaesthesia supporting the donor until cross-clamp. Donor management before procurement - Brain death causes haemodynamic instability, diabetes insipidus, hypothermia and coagulopathy. - Active management (fluids, vasopressors, hormone replacement) preserves organ quality.

Ischaemia-reperfusion injury (IRI) - During ischaemia: - there is no oxygen, so ATP falls and anaerobic metabolism leads to acidosis - ion pumps (Na+/K+ ATPase) fail, causing cell swelling - calcium accumulates - enzymes are activated - At reperfusion: - oxygen generates free radicals - endothelial damage, platelet and leucocyte activation, and microcirculatory failure follow - Consequences: - graft dysfunction or primary non-function - more rejection - biliary complications in the liver Principles of cold preservation 1. Rapid cooling (in situ perfusion plus surface ice) slows metabolism. 2. Flushing out blood prevents clotting in the microcirculation. 3. The solution must prevent cell swelling (impermeant molecules), buffer acidosis, prevent oxidative damage, and supply substrates to regenerate ATP. Preservation solutions - Collins solution: the first, an intracellular-type solution (high potassium). - University of Wisconsin (UW, or Belzer, sold as Viaspan): the gold standard for abdominal organs, especially the liver and pancreas. Contains lactobionate and raffinose (impermeants), hydroxyethyl starch (colloid), glutathione and adenosine. - HTK (Custodiol): a histidine buffer with low viscosity, which flushes easily. - Celsior: an extracellular-type solution, developed for the heart and also used for abdominal organs. Static cold storage: the organ sits in solution at 0-4 °C, in ice. Simple and cheap, but offers no ongoing support.

Cold ischaemia time: from cold perfusion in the donor to reperfusion in the recipient. Accepted limits (as taught) - Heart: 6 hours. - Lungs: 6 hours. - Liver: up to 18 hours (ideally below 8-12). - Pancreas: up to 24 hours (ideally less, because the pancreas is sensitive). - Kidneys: up to 36 hours (ideally below 24). Consequences - Geography: hearts and lungs must be transplanted near the donor. Kidneys can travel much further. - This is why thoracic organs are removed first, and why the recipient's operation is scheduled around the donor procurement. Warm ischaemia (at body temperature without flow) is far more damaging than cold ischaemia. In DCD donors it adds to the cold time. A second warm ischaemia happens during implantation (from removal from ice to reperfusion). Exam focus: "heart and lungs 6 h, liver 18, pancreas 24, kidney 36". The more sensitive the organ, the shorter the time.

Other ways to increase available grafts: - Split liver: one deceased donor liver divided into two grafts, typically one for a child and one for an adult (chapter 5). - Living donation: kidney and partial liver. - Dual kidney transplantation from older donors: both kidneys go to one recipient, to provide enough nephron mass. The following sections cover each strategy and its specific risks.

1. What proportion of deceased donors are DBD, and why are their organs the best quality? 2. Who described "coma dépassé", when, and in how many patients? 3. Give three differences between coma and brain death. 4. What is the most common cause of brain death? 5. Who makes up the Italian brain death board? 6. What are the observation times for an adult, a 3-year-old and a 6-month-old? 7. For each brainstem reflex, name the afferent and efferent cranial nerves. 8. Describe the cold caloric test. 9. At what PaCO2 is the apnoea test valid? 10. When is the legal time of death in brain death? 11. What are the three options for recording consent? 12. List the five donor risk levels, with one example each. 13. In what order are organs removed at procurement, and why? 14. By how much does metabolism fall for each 10 °C of cooling? 15. What are the maximum cold ischaemia times for heart, liver, pancreas and kidney? 16. Name four preservation solutions. Which is the gold standard for the liver? 17. Describe the Maastricht categories I-IV. 18. What is the Italian no-touch period, and why does it matter? 19. Why are the bile ducts so vulnerable in DCD livers? 20. Classify machine perfusion by temperature. What does normothermic perfusion allow that hypothermic does not?

1. About 90%. The organs are perfused with oxygenated blood until cold perfusion (no warm ischaemia). 2. Mollaret and Goulon, 1959, 23 patients. 3. Coma is dynamic, reversible, and may have reflexes or breathing. Brain death is static, irreversible, with no brainstem reflexes and no spontaneous breathing. 4. Stroke and intracranial haemorrhage (about 65-70%). 5. An intensivist, a forensic physician and a neurologist, none from the transplant team. 6. Adult: 6 hours. 3-year-old: 12 hours. 6-month-old: 24 hours. 7. Pupillary: II and III. Corneal: V and VII. Oculocephalic: VIII and III, IV, VI. Vestibulo-ocular: VIII and III, IV, VI. Gag: IX and X. Cough: X. 8. About 50 mL of ice-cold water (around 4 °C) is instilled into each ear, after checking the eardrum. No eye movement is consistent with brain death. 9. At 60 mmHg or more. 10. When the first set of criteria is recorded (the start of observation). 11. Consent recorded, refusal recorded, or no declaration (the family may then oppose). 12. Unacceptable (HIV). Increased but acceptable (a tumour with an urgent recipient). Calculated (HCV-positive to an HCV-positive recipient). Non-assessable (missing history). Standard (no risk factors). 13. Heart, lungs, liver, pancreas, intestine, kidneys. The thoracic organs tolerate cold ischaemia least. 14. About 1.5-2 times. 15. Heart 6 hours, liver 18 hours, pancreas 24 hours, kidney 36 hours. 16. Collins, UW (Belzer/Viaspan), HTK (Custodiol), Celsior. UW is the gold standard for the liver. 17. I: dead on arrival. II: unsuccessful resuscitation. III: awaiting arrest after withdrawal of treatment. IV: arrest in a brain-dead donor. 18. 20 minutes of continuous flat ECG. It causes long warm ischaemia, so NRP and machine perfusion are needed. 19. Their blood supply comes only from the hepatic artery (peribiliary plexus), and they are very sensitive to warm ischaemia. This leads to ischaemic cholangiopathy (NAS/ITBL). 20. Hypothermic 3-14 °C, subnormothermic 15-34 °C, normothermic 35-37 °C. Normothermic perfusion keeps the organ working, so its function can be tested (bile, lactate) before transplant.

Emergency (super-urgent) indications (as taught) 1. Acute liver failure. 2. Primary non-function (PNF) of a transplanted liver, within 10 days of transplantation. 3. Hepatic artery thrombosis (HAT), within 15 days of transplantation. 4. Liver failure after hepatectomy or liver trauma. 5. Severe liver injury after cholecystectomy (for example combined bile duct and vascular injury with liver necrosis). Acute liver failure - Definition: encephalopathy plus coagulopathy (INR 1.5 or more) within 8 weeks of the onset of symptoms, with no previous liver disease. - Subtypes by interval from jaundice to encephalopathy: hyperacute (up to 7 days), acute (8-28 days), subacute (over 4 weeks). Hyperacute cases, often paracetamol, have more cerebral oedema but better spontaneous survival. - Causes: - drugs: paracetamol (acetaminophen) overdose, the most common in the UK and USA; idiosyncratic drug reactions - viral hepatitis: A, B (including reactivation), E, herpes viruses - Amanita phalloides (mushroom) poisoning - Wilson's disease (acute presentation) - autoimmune hepatitis - Budd-Chiari syndrome - acute fatty liver of pregnancy, HELLP - ischaemic hepatitis - indeterminate cause - Main cause of death: cerebral oedema with intracranial hypertension, and multi-organ failure or sepsis. King's College criteria (for listing) - Paracetamol: arterial pH below 7.3 after resuscitation, OR all three of INR above 6.5, creatinine above 300 micromol/L, and grade 3-4 encephalopathy. - Non-paracetamol: INR above 6.5, OR any three of: - age below 10 or above 40 - unfavourable cause (non-A non-E hepatitis, drug reaction) - jaundice more than 7 days before encephalopathy - INR above 3.5 - bilirubin above 300 micromol/L

Main elective indications 1. Cirrhosis with decompensation or poor liver function: - viral (HCV, HBV) - alcohol-related, after a period of abstinence and addiction assessment - MASLD/MASH: now a leading indication - autoimmune hepatitis 2. Cholestatic diseases: - primary biliary cholangitis (PBC) - primary sclerosing cholangitis (PSC) - secondary biliary cirrhosis - in children, biliary atresia (the most common paediatric indication) 3. Tumours: - HCC within Milan criteria or downstaged (chapter 3) - selected hilar cholangiocarcinoma (protocols) - unresectable colorectal liver metastases in highly selected protocols - neuroendocrine metastases 4. Metabolic diseases: - Wilson's disease - haemochromatosis - alpha-1 antitrypsin deficiency - familial amyloidosis (FAP) - primary hyperoxaluria - urea cycle defects 5. Vascular: Budd-Chiari syndrome. 6. Complications that impair quality of life, even with preserved function: - refractory ascites - recurrent encephalopathy - hepatopulmonary syndrome - untreatable pruritus in cholestatic disease When to refer: at the first decompensation (ascites, variceal bleeding, encephalopathy, jaundice), or at a MELD of about 15 or more, where transplantation begins to offer a survival benefit.

Absolute contraindications - Extrahepatic malignancy (except some treated cancers with a long disease-free interval). - HCC with macrovascular invasion or extrahepatic spread. - Uncontrolled sepsis or active infection outside the liver. - Severe cardiac or pulmonary disease (for example severe portopulmonary hypertension with mean pulmonary pressure above about 50 mmHg that does not respond to treatment). - Active alcohol or drug abuse. - Lack of social support, or inability to comply with lifelong treatment. - Irreversible brain damage. - AIDS (not HIV infection itself, which is treated and no longer a contraindication). Relative contraindications - Advanced age (usually above about 70), frailty, severe malnutrition or sarcopenia. - Morbid obesity. - Extensive portal and mesenteric vein thrombosis. - Previous complex abdominal surgery. - Chronic kidney disease (may lead to combined liver-kidney transplantation). - Moderate portopulmonary hypertension. - Psychiatric disease that is not controlled. Clinical tip: many relative contraindications can be corrected (weight loss, rehabilitation, treating infection, abstinence programmes). The patient is then reassessed.

Components - Hepatology: cause and severity of liver disease; Child-Pugh and MELD; complications. - Imaging: - CT or MRI of the liver (tumour staging, vascular anatomy, portal vein patency) - chest CT and bone scan when HCC is present - Cardiovascular: - ECG and echocardiography (including pulmonary pressure) - stress test or coronary angiography according to risk - Respiratory: - pulmonary function - arterial blood gas - screening for hepatopulmonary syndrome (bubble echocardiography) - Kidneys: function and cause of any dysfunction (hepatorenal syndrome). - Infections: - serology (HIV, HBV, HCV, CMV, EBV, VZV, toxoplasma) - tuberculosis screening - vaccinations - dental check - Cancer screening appropriate for age. - Nutrition and frailty. - Psychosocial and addiction assessment, and family support. - Blood group and body size, needed for matching.

The formula - MELD = 3.78 x ln(bilirubin mg/dL) + 11.2 x ln(INR) + 9.57 x ln(creatinine mg/dL) + 6.43. - Values below 1 are set to 1. Creatinine is capped at 4 (and set to 4 if the patient is on dialysis). - MELD-Na adds serum sodium, because hyponatraemia independently predicts death. - Newer versions (MELD 3.0) add sex and albumin. What it means - Range 6-40. A higher score means a higher 3-month mortality without transplant. - Objective, reproducible, laboratory-based. Allocation by MELD - Introduced in the USA in February 2002, replacing a system based largely on waiting time and Child-Pugh ("sickest first" instead of "first come, first served"). - It reduced deaths on the waiting list. Limits: MELD does not capture the risk of some patients. MELD exceptions give extra points for: - HCC (risk of drop-out, not of liver failure) - cholestatic diseases with recurrent cholangitis or pruritus (PBC, PSC) - metabolic diseases where liver function is normal but the disease is systemic (for example familial amyloidosis, primary hyperoxaluria) - hepatopulmonary syndrome and portopulmonary hypertension - refractory ascites and recurrent encephalopathy, in some systems Exam trap: Child-Pugh includes subjective elements (ascites, encephalopathy) and has a ceiling effect. MELD is purely objective. That is why MELD replaced Child-Pugh for allocation.

Matching criteria - ABO compatibility (identical or compatible). HLA matching is not required for the liver. - Size: donor and recipient weight and height, to avoid a graft that is too large or too small. - Clinical priority, measured by MELD or MELD-Na plus exception points. Levels of priority (as taught) 1. National emergency: acute liver failure, and early primary non-function or hepatic artery thrombosis (see indications). These patients receive the first compatible liver in the country. 2. Macro-area urgency: MELD or MELD-Na 29 or more. Priority within the macro-area (a group of regions sharing organs). 3. Elective: all other patients, allocated by the regional or centre programme according to MELD and exceptions. Principles - Fairness (priority to those most at risk of dying) must be balanced with utility (the best use of each organ). - Allocation is supervised nationally (Centro Nazionale Trapianti) with regional coordination.

Incision - The classic incision is the "Mercedes" incision: bilateral subcostal with an upward midline extension. A J-shaped or reversed-L incision is also common. Recipient hepatectomy - Mobilisation of the liver, and dissection of the hilum (hepatic artery, portal vein, bile duct divided high). - In cirrhosis with portal hypertension, this is the phase with the most bleeding (collaterals, coagulopathy). Conventional (caval replacement) - The retrohepatic inferior vena cava is clamped above and below the liver and removed with it. - The donor liver is implanted with its own cava: suprahepatic caval anastomosis and infrahepatic caval anastomosis. - Clamping the cava halves venous return, which can cause hypotension. Venovenous bypass (femoral and portal to axillary vein) can maintain return and decompress the splanchnic circulation. Piggyback (caval preservation) - The liver is separated from the cava by dividing the short hepatic veins. The recipient's cava stays in place. - The donor's suprahepatic cava is joined to the recipient's hepatic vein orifices (or to the cava side-to-side). - Advantages: - caval flow is maintained, so the haemodynamics are more stable - usually no bypass is needed - shorter warm ischaemia Order of implantation 1. Caval or hepatic vein anastomosis. 2. Portal vein anastomosis, then reperfusion of the graft (end of cold ischaemia). 3. Arterial anastomosis. 4. Biliary anastomosis. Reperfusion syndrome: at unclamping, cold, acidotic, potassium-rich blood reaches the heart, causing hypotension, bradycardia and even arrest. The anaesthetist must be ready.

Portal vein - Standard: end-to-end anastomosis between donor and recipient portal veins. - Portal vein thrombosis (common in cirrhosis). Options by extent: 1. Thrombectomy (eversion endovenectomy), then standard anastomosis. Suited to partial or recent thrombosis. 2. Jump graft: a donor iliac vein graft from the superior mesenteric vein (or a large collateral) to the donor portal vein, bypassing the thrombosed segment. 3. Cavoportal hemitransposition: when the whole splanchnic system is thrombosed, the donor portal vein is connected to the recipient's inferior vena cava. This perfuses the graft with systemic blood, but portal hypertension is not relieved. 4. Extreme cases: multivisceral transplantation. Hepatic artery - Standard: end-to-end anastomosis, often at the level of the gastroduodenal artery bifurcation, using a branch patch. - When the recipient artery is inadequate (dissected, small, or after previous chemoembolisation): - an aortic conduit: a donor iliac artery graft from the infrarenal (or supraceliac) aorta to the donor artery - the recipient's splenic artery as the source - Donor arterial variants (for example a replaced right hepatic artery from the superior mesenteric artery, or a left from the left gastric) are reconstructed on the back table before implantation. Clinical tip: the hepatic artery is the only blood supply to the bile ducts. Any arterial problem shows up as biliary disease.

Duct-to-duct (choledocho-choledochostomy) - The donor common bile duct is joined end-to-end to the recipient's duct. - Advantages: - physiological - preserves the sphincter of Oddi, which reduces reflux and cholangitis - allows ERCP access later - T-tube: a Kehr T-tube placed through the anastomosis. - Pros: decompresses the duct, gives access for cholangiography, lets bile output be monitored. - Cons: leaks when it is removed, and cholangitis. - Practice varies between centres. Roux-en-Y hepaticojejunostomy - The donor duct is joined to a defunctioned loop of jejunum. - Indications: - diseased recipient duct (PSC, where the duct may be the site of disease or cancer) - biliary atresia - size mismatch - retransplantation - split or living donor grafts with small ducts - Disadvantages: - no ERCP access (percutaneous transhepatic access is needed instead) - risk of cholangitis from reflux

Why it was developed - Children need small grafts, and small donors are rare. Before split livers, many children died on the waiting list. - Reduced-size liver (cutting down an adult liver and discarding the rest) solved size but wasted liver. Splitting gives two usable grafts. Classic split (as taught) - Left lateral graft: segments II and III, about 25-30% of the volume, for a child. - Extended right graft: segments I and IV-VIII, about 70-75%, for an adult. - Full right/left split (right hemiliver V-VIII and left hemiliver II-IV) for two adults. Only with large donors and small recipients. Graft size - The graft-to-recipient weight ratio (GRWR) must be at least about 0.8-1%. For example, a 70 kg recipient needs a graft of at least about 560-700 g. - Too small: small-for-size syndrome (portal hyperperfusion, cholestasis, ascites, graft failure). - Too large in a child: the abdomen cannot be closed, and the graft is compressed. Techniques - Ex situ: split on the back table after procurement. - In situ: split in the donor while the circulation is intact, which gives less bleeding and shorter cold ischaemia. Donor selection: young, stable donors with a healthy liver. Technical points - The vessels (artery, portal vein, bile duct) must be shared between the two grafts. Usually the main trunks stay with one graft, and the other gets branches. - Biliary complications are more frequent than with whole grafts, because of the cut surface.

Grafts - Adult to child: left lateral section (II-III). - Adult to adult: right hemiliver (V-VIII) gives enough volume, but a larger resection for the donor. The left hemiliver (II-IV) is safer for the donor but may be too small for the recipient. - Graft-to-recipient weight ratio: at least about 0.8%. - The donor remnant must be at least about 30-35% of the donor's liver volume. Donor evaluation - Voluntary, informed consent without pressure. An independent donor advocate is often required. - Blood group compatible, healthy, usually aged 18-60. - Imaging: - CT volumetry (graft and remnant volume) - vascular and biliary anatomy - steatosis assessment (MRI, sometimes biopsy) - Medical and psychological assessment. Donor risk - Morbidity 20-40% (mostly minor; bile leak is the most common). - Mortality about 0.1-0.5% for right lobe donation. Lower for left lateral section. Advantages for the recipient - Transplant at the right moment, before deterioration or tumour drop-out. - Excellent graft quality, very short cold ischaemia. Especially important in Asia, where deceased donation is limited.

Primary non-function - The graft never functions after transplantation: - very high transaminases - lactic acidosis - coagulopathy that does not correct - no bile production - encephalopathy - kidney failure - Incidence about 2-5%. - Risk factors: donor steatosis, old donor, long cold ischaemia, DCD. - Treatment: urgent retransplantation, with emergency priority within 10 days. - Early allograft dysfunction (EAD) is a milder form, which may recover. Hepatic artery thrombosis (HAT) - The most important vascular complication. Incidence about 2-5% in adults, higher in children. - Early HAT (the first weeks): - fulminant graft necrosis, or massive bile duct necrosis (bile leak, abscess) - treatment: urgent revascularisation (thrombectomy, re-anastomosis) or retransplantation - emergency priority within 15 days - Late HAT: may be silent because collaterals develop, or present with ischaemic cholangiopathy. - Screening: Doppler ultrasound daily in the first days. Other vascular complications - Hepatic artery stenosis: treated with angioplasty or stent. - Portal vein thrombosis or stenosis: thrombectomy, stent, anticoagulation. - Caval or hepatic vein outflow obstruction (more likely with piggyback): ascites, graft congestion. Treated with angioplasty or stent.

Bile leak (1.3-10%, as taught) - Sites: - the anastomosis - the T-tube exit site (after removal) - the cut surface in split or living grafts - Early. - Treatment: - ERCP with a stent (duct-to-duct) - percutaneous drainage - surgery for large leaks or leaks caused by arterial thrombosis Anastomotic stricture (4-9%, as taught) - A narrowing at the anastomosis, usually within the first year. - Causes: technical issues, local ischaemia, earlier leak. - Treatment: - ERCP with repeated balloon dilation and stenting - PTC dilation if ERCP is not possible (for example Roux loop) - Roux-en-Y hepaticojejunostomy if these fail Non-anastomotic stricture (5-15%, as taught) - Multiple strictures in intrahepatic or hilar ducts, away from the anastomosis. - Causes: - hepatic artery thrombosis - long cold ischaemia time - DCD donor (warm ischaemia) - rejection - CMV infection - recurrent PSC - ABO incompatibility - Treatment: - endoscopic or percutaneous dilation for dominant strictures - often retransplantation when diffuse Other - Bile casts and stones (sludge), from ischaemia and cholestasis. - Sphincter of Oddi dysfunction.

Clinical picture - Often asymptomatic, found through raised transaminases, gamma-GT, alkaline phosphatase and bilirubin. - Sometimes fever, malaise, myalgia, graft tenderness, reduced bile output. Diagnosis - Rule out vascular problems (Doppler), biliary problems (imaging) and infection (CMV). - Liver biopsy is the gold standard. Histology: the classic triad 1. Mixed portal inflammatory infiltrate (lymphocytes, eosinophils, neutrophils). 2. Endotheliitis (subendothelial inflammation of portal or central veins). 3. Bile duct inflammation and damage. Severity (Banff grading): mild, moderate, severe, using the Rejection Activity Index (RAI). Treatment 1. Mild: increase maintenance immunosuppression (tacrolimus levels). 2. Moderate-severe: methylprednisolone boluses (for example 1 g intravenously, as taught, or 500-1000 mg for about 3 days). 3. Steroid-resistant: anti-lymphocyte antibodies (for example anti-thymocyte globulin). Basic immunosuppression - A calcineurin inhibitor (tacrolimus, cyclosporine). - Mycophenolate. - Steroids (tapered off over months). - mTOR inhibitors (everolimus, sirolimus) to spare the kidneys or in HCC patients. Exam focus: the liver is immunologically "privileged" compared with the kidney or heart. Acute rejection rarely causes graft loss if treated.

Features - Progressive cholestasis: rising alkaline phosphatase, gamma-GT and bilirubin, with jaundice. - Histology: - loss of small interlobular bile ducts in more than 50% of portal tracts (ductopenia) - foam-cell obliterative arteriopathy in larger arteries (often not seen on biopsy) Risk factors - repeated or unresolved episodes of acute rejection - low immunosuppression (poor adherence) - CMV infection - some underlying diseases (autoimmune) Treatment - Increase immunosuppression (switch to tacrolimus if on cyclosporine, add an mTOR inhibitor). Early cases may respond. - Advanced cases: retransplantation. Side by side Acute rejection: - frequency: up to 70% - timing: first weeks (peak week 2) - target: portal tract, veins, bile ducts (inflammation) - reversible: usually Chronic rejection: - frequency: about 3% - timing: months (median month 6) - target: loss of bile ducts, obliterative arteriopathy - reversible: rarely

1. Recurrence of the original disease - HCV: universal recurrence before direct-acting antivirals. Now cured with antiviral therapy. - HBV: prevented with antivirals, with or without hepatitis B immunoglobulin. - Alcohol: relapse into drinking. Needs follow-up by an addiction service. - MASLD: often recurs with metabolic syndrome. - Autoimmune diseases (PBC, PSC, AIH): recur in a proportion of patients. - HCC: recurrence risk depends on the tumour's biology and stage (chapter 3). 2. De novo malignancy (as taught) - The overall relative risk of cancer is about 4.3 compared with the general population. For solid organ tumours, about 4.4. - Skin cancers (especially squamous cell carcinoma): relative risk about 70. - Also: post-transplant lymphoproliferative disorder (PTLD, EBV-related), head and neck and lung cancers (smoking, alcohol), and colorectal cancer in PSC. - Needs lifelong cancer screening and sun protection. 3. Infections - First month: surgical and hospital-acquired bacterial infections. - 1-6 months: opportunistic infections: CMV (the most important), Pneumocystis, fungi. - Later: community infections. Prophylaxis and vaccination are needed. 4. Cardiovascular and metabolic disease - Immunosuppressants cause hypertension, diabetes, dyslipidaemia and weight gain. - Cardiovascular disease becomes a leading cause of late death. 5. Chronic kidney disease - Mainly from calcineurin inhibitor nephrotoxicity. - Strategies: lower tacrolimus doses, combined with mycophenolate or an mTOR inhibitor. Survival - Survival is recorded in registries: the European Liver Transplant Registry (ELTR), and centre series such as the 749 patients of Ancona in the course data. - Modern survival rates are about 85-90% at 1 year, 75-80% at 5 years, and around 60-70% at 10 years, depending on indication and era.

1. List the five emergency indications for liver transplantation, with their time limits where relevant. 2. Define acute liver failure. 3. Name five causes of acute liver failure. 4. State the King's College criteria for paracetamol-induced ALF. 5. Give four elective indications and four absolute contraindications. 6. Which three variables make up MELD? What does it predict? 7. Why did MELD replace Child-Pugh for allocation? 8. Give three kinds of patients who receive MELD exception points. 9. What are the three levels of allocation priority in Italy? 10. What is the difference between conventional and piggyback hepatectomy? 11. What are the options for reconstructing the portal vein in portal vein thrombosis? 12. When is a Roux-en-Y hepaticojejunostomy used instead of a duct-to-duct anastomosis? 13. Which segments make up each graft in a classic split? What volume percentage does each have? 14. What is the minimum graft-to-recipient weight ratio? 15. What is primary non-function? How is it treated? 16. Why does hepatic artery thrombosis cause biliary complications? 17. List five causes of non-anastomotic biliary strictures. 18. Describe the histological triad of acute rejection. 19. How is acute rejection treated, step by step? 20. Compare acute and chronic rejection. 21. What is the relative risk of skin cancer after transplantation? 22. Why is chronic kidney disease common after liver transplantation?

1. ALF, PNF within 10 days, HAT within 15 days, liver failure after hepatectomy or trauma, severe injury after cholecystectomy. 2. Encephalopathy and coagulopathy within 8 weeks of the first symptoms, in a patient with no previous liver disease. 3. Paracetamol, viral hepatitis (A, B, E), Amanita mushroom, Wilson's disease, autoimmune hepatitis, drug reactions, Budd-Chiari. 4. pH below 7.3 after resuscitation, OR all three of INR above 6.5, creatinine above 300 micromol/L, and grade 3-4 encephalopathy. 5. Elective: decompensated cirrhosis, HCC within Milan, PBC or PSC, Wilson's or other metabolic disease. Absolute contraindications: extrahepatic cancer, HCC with macrovascular invasion, uncontrolled sepsis, active substance abuse, severe cardiopulmonary disease. 6. Bilirubin, INR, creatinine. It predicts 3-month mortality without transplant. 7. MELD is objective, continuous and without a ceiling effect. It predicts mortality better and allows "sickest first" allocation. 8. HCC, cholestatic diseases with complications, metabolic diseases (amyloidosis, hyperoxaluria), hepatopulmonary syndrome. 9. National emergency, macro-area urgency (MELD or MELD-Na 29 or more), elective. 10. Conventional: the recipient cava is removed and replaced with the donor cava (with or without bypass). Piggyback: the recipient cava is preserved and the donor liver attached to it (flow maintained). 11. Thrombectomy, a jump graft from the SMV using donor iliac vein, cavoportal hemitransposition (multivisceral transplant in extreme cases). 12. Diseased duct (PSC), biliary atresia, size mismatch, retransplantation, small ducts in split or living grafts. 13. Left lateral (II-III): 25-30%. Extended right (I, IV-VIII): 70-75%. 14. About 0.8-1%. 15. A graft that never works after reperfusion. Treated by urgent retransplantation (emergency priority within 10 days). 16. The bile ducts are supplied only by the hepatic artery. 17. HAT, long cold ischaemia, DCD, rejection, CMV, recurrent PSC, ABO incompatibility. 18. Portal inflammatory infiltrate, endotheliitis, bile duct damage. 19. Increase immunosuppression, then methylprednisolone boluses (1 g), then anti-lymphocyte antibodies if steroid-resistant. 20. Acute: up to 70%, early (peak week 2), inflammatory, usually reversible. Chronic: about 3%, around month 6, bile duct loss and arteriopathy, rarely reversible. 21. About 70. 22. Calcineurin inhibitor (tacrolimus, cyclosporine) nephrotoxicity.