Pathophysiology Flashcards
1
Q
H pylori
A
- a helical gram-negative rod with 4-6 flagella that resides in gastric-type epithelium within or beneath the mucous layer; this location protects the bacteria from acid
- shape and flagella aid its movement through the mucous layer & it produces enzymes that help it adapt to the hostile environment
- eg urease which can split urea into ammonia and bicarb, creating an alkaline microenvironment
- 4 potential mechanisms described for H-pylori induced GI injury
- release of toxic products that cause local injury
- breakdown products from urease (eg ammonia)
- cytotoxins (VacA and CagA - vacuolating cytotoxin antigen and cytotoxin-assoc gene A antigen)
- a mucinase that degrades mucus & glycoproteins
- phospholipases that damage epithelial cells & mucous cells
- platelet-activating factor which causes mucosal injury & thrombosis in the microcirculation
- induction of a local mucosal immune response
- attracts neutrophils & monocytes which then produce numerous proinflam cytokines & ROS
- increased gastrin levels w increase in acid secretion
- basal & stimulated gastrin levels are significantly increased, presumably secondary to a decrease in somatostatin release from antral D cells bc of infection w H pylori
- during acute phase of H pylori infection, acid secretion is decreased
- w chronic infection, H pylori has trophic effects on ECL & G cells, which can result in acid hypersecretion
- however, if oxyntic glands are destroyed by chronic infection, will get hypoacidity
- gastric metaplasia in duo
- likely a protective response to decreased duo pH –> allows H pylori to colonise duodenum & cause duodenitis & ulcers
- release of toxic products that cause local injury
- H pylori can lead to gastric adenocarcinoma via the Correa hypothesis which is a multistep process
- theory that there’s a pathway of transformation from normal mucosa –> gastritis –> chronic atrophic gastritis –> intestinal metaplasia –> dysplasia
- one particular strain - Cag-A +ve H pylori strain - has a higher assoc w gastric ca (this strain particularly common in Japan)
- Also strong association between mucosa-associated lymphoid tissue (MALT) lymphoma & H pylori infection - regression of these lymphomas demonstrated after eradication of H pylori
- Test with: mucosal biopsy (urease assay or histo) = gold standard; or serum antibodies
- to check for eradication: stool antigen or urea breath testing
2
Q
Wound healing
A
Healing progresses through 3 overlapping phases - inflammation, proliferation and maturation
- inflammation:
- injury leads to platelet adhesion & activation w clot formation (coagulation pathways, PAF)
- stops bleeding but also provides a matrix rich in growth factors and chemokines that acts as a scaffold for migrating leukocytes and stromal cells - within 24hrs, neutrophils appear at the margins & begin to degrade debris and sterilise wound
- inflammation involves IL-1, IL-2, IL-8; chemotaxis involves LB4, C5a, chemokines
- proliferation: VEGF, PDGF, TGF-b, IFN-y, macrophages
- migration and expansion of parenchymal cells (re-epithelialisation), endothelial cells (angiogenesis) and connective tissue cells
- within 1-2 days of wound healing (and peaking at 5-7 days), proliferating fibroblasts and endothelium form granulation tissue, a highly vascularised loose connective tissue
- within 2-4 days, neutrophils are largely replaced by macrophages, which then become the key cellular elements in clearing debris and directing subsequent angiogenesis and ECM deposition
- granulation tissue provides a framework for subsequent scar formation
- maturation:
- eventually granulation tissue scaffolding is converted into a scar composed of fibroblasts & collagen; 2 weeks after the injury the dominant feature is collagen deposition w regression of the vasculature (fibroblasts, MMPs)
- granulation tissue ultimately converted into a rel avascular scar depleted of inflammation & covered by intact epithelium
- wound contraction is a feature of larger wounds, accomplished by myofibroblasts w the synthetic features of fibroblasts & the contractile capacity of SM cells; will cause surface area of wound to be reduced
- eventually granulation tissue scaffolding is converted into a scar composed of fibroblasts & collagen; 2 weeks after the injury the dominant feature is collagen deposition w regression of the vasculature (fibroblasts, MMPs)
3
Q
Acute pancreatitis
A
- an inflammatory process occuring within the exocrine tissue of the pancreas characterised by an inflammatory infiltrate which can progress ot a serious systemic inflammatory state
- no matter the inciting event, there is an unregulated activation of trypsin within acinar cells, leading to an autodigestive injury to the pancreas with local inflammation
- the protective intracellular mechanisms that prevent trypsinogen activation are overwhelmed
-
calcium influx caused by various signals eg increased pressure within the panc duct, ETOH metabolites or NF-KB causes zymogen granules and lysosomes to coalsece inside acinar cells which allows trypsin to be activated by lysosomal enzyme cathepsin B
- can also be genetic anomalies which inhibit the protective anti-activation process (ie instability of zymogens & lysosomes) - PRSS1 and SPINK1
- release of activated trypsin does 2 things:
- 1) leads to activation of more trypsin and other panc enzymes; intrapanc release of active pancreatic enzymes leads to pancreatic autodigestion –> cycle of active enzymes damaging more cells & destruction spreading along the gland and into peripanc tissues
- there is injury to vascular endothelium resulting in microcirculation injury w vasoconstriction, decreased oxygenation & progressive ischaemia, increased vasc permeability & swelling of gland
- 2) activates other enzyme cascades incl complement, kallikrein-kinin, coagulation and fibrinolysis
- leads to leukocyte chemoattraction, release of cytokines and oxidative stress (TNF, IL-1, IL-6, IL-8, arachidonic acid metabolites, proteolytic and lipolytic enzymes and ROS)
- these substances also interact w pancreatic microcirculation to activate endothelial cells, increase vasc permeability & induce thrombosis and haemorrhage which can cause tissue hypoxia and contribute to panc necrosis (though 80% only get pancreatitis not necrosis)
- 1) leads to activation of more trypsin and other panc enzymes; intrapanc release of active pancreatic enzymes leads to pancreatic autodigestion –> cycle of active enzymes damaging more cells & destruction spreading along the gland and into peripanc tissues
- in some pts there is a systemic inflammatory response from the release of activated panc enzymes & cytokines - fever, ARDS (from microvasc thrombosis +/- activated phospholipase A which digests lecithin, a major component of surfactant), myocardial depression & shock, central haemodynamic dysfunction from 3rd spacing –> CV & renal dysfunction, GI dysfunction from decreased visceral perfusion, hypocalcaemia (from saponification, hormonal imbalance, intracellular translocation), other metabolic abnormalities eg low or high glucose/DKA
- bacterial translocation can occur; after 7-10 days pts transition through to a phase where there is downregulation of immune system which is why infections peak 2-3 weeks after onset
4
Q
Carcinoid syndrome
A
- a term applied to constellation of sx mediated by various hormonal factors elaborated by some well-diff NETs of digestive tract & lungs which synthesise, store & release a variety of polypeptides, biogenic amines and prostaglandins
- >90% of pts w carcinoid have metastatic disease, typically to liver
- carcinoid syndrome affects <10% of pts w NETs
- primarily assoc w metastatic tumours originating in the midgut; hindgut and foregut NETs uncommonly produce carcinoid syndrome
- bc of firstpass metabolism of the vasoactive peptides responsible for carcinoid syndrome, hepatic mets or extra-abdo disease are necessary to elicit the syndrome
- classic description: vasomotor, cardiac, GI manifestations
- episodic attacks of cutaneous flushing, bronchospasm, diarrhoea & vasomotor collapse, also hepatomegaly & cardiac lesions most commonly right-sided heart valvular disease
- humoral factors considered to contribute include serotonin, 5-HT (precursor of serotonin), histamine, dopamine, tachykinin, kallikrein, substance P, prostaglandin & neuropeptide K
- carcinoid crisis = life-threatening form of carcinoid syndrome usu precipitated by a specific event eg anaesthesia, surgery or chemo
- manifestations include intense flush, diarrhoea, tachycardia, hyper/hypotension, bronchospasm, altered metnal status
- sx usu refractory to fluid resus & vasopressors
- other functioning NETs of SB that produce specific clinical syndromes = comparatively rare
- gastrinoma of duo - ZES (15% of gastrinomas in duo)
- rarer: duodenal somatostatinomas, paragangliomas, high-grade NECs (rarely functioning)
5
Q
Small bowel obstruction
A
- obstruction –> onset of vigorous SB peristalsis (both prox & distal to obstruction) to try & propel luminal contents past obstructing point –> colicky pain, usu in central abdo
- can account for sometimes initial diarrhoea
- later intestine becomes fatigued & dilates; contractions become less frequent & less intense
- proximal dilatation of intestine and with time, bowel wall becomes oedematous, with loss of normal absorptive function & fluid is sequestered into bowel lumen; this & fluid loss thorugh vomiting –> hypovolaemia
- loss of hydrogen & chloride ions –> alkalosis, hypochloraemia & hypokalaemia (from renal compensation)
- ischaemic necrosis of bowel most commonly caused by twisting of bowel and/or its mesentery around an adhesive band or intestinal attachments; alternatively if bowel dilation is excessive, as intraluminal pressure increases in bowel, venous pressure is eventually surpassed –> oedema & congestion –> intramural vessels of SB become compromised so perfusion to intestine reduced –> ischaemia –> necrosis and perforation if process not interrupted
- –> worsened, continuous (cf colicky) pain followed by perforation if left
- if blood supply remains intact & bowel decompressed by vomitign & NG drainage, peristalsis will stop & colicky pain ceases, leaving dilated, non-functioning bowel
- flora of SB changes dramatically in both type of organism (most commonly E coli, Strep faecalis & Klebsiella) & quantity increases markedly
- increased bacteria translocating to mesenteric LNs & even systemic organs
- bacterial translocation amplifies local inflammatory response in gut –> intestinal leakage & increased systemic inflammation +/- systemic sepsis & multiorgan failure
- other consequences of bowel obstruction include increased abdo pressure, decreased venous return & elevation of diaphragm, compromising ventilation
6
Q
Adhesions
A
Adhesions can be primary or secondary (post-op or related to inflammation eg Crohn’s, previous diverticulitis)
- The body deposits fibrin onto injured tissues as part of the body’s healing process after surgery
- Usually local plasminogen activators initiate lysis of fibrin strands within 3days of their formation & mesodermal cells regenerate as early as 5 days after injury. Inadeqaute fibrinolysis due to decreased mesothelial plasminogen activity allows fibroblastic proliferation to produce fiborus adhesions.
- surgery diminishes fibrolytic activity dramatically by increasing levels of plasminogen activator inhitiors and by decreasing tissue oxygenation; fibrinolysis can also be impaired by
- thermal injury
- desiccation
- ischaemia
- foreign bodies
- blood
- bacteria
- some drugs
7
Q
TEG
A
TEG = thromboelastogram - this is a viscoelastic haemostatic assay that measures the global viscoelastic properties of whole blood clot formation under low shear stress; it shows the interaction of platelets with the coagulation cascade (aggregation, clot strengthening, fibrin cross-linking and fibrinolysis)
(Treatment goes in alphabetical order)
R (reaction time) = time to first significant clot formation
- If prolonged means decreased factors – give FFP (CLOTTING FACTORS) or prothrombinex
K value = achievement of certain clot firmness
- If prolonged means lack of fibrinogen – given CRYO or fibrinogen
A (alpha angle) = kinetics of clot development (rate at which fibrin cross-linking occurs)
- If reduced means lack of fibrinogen – give CRYO or fibrinogen
MA (maximum amplitude) = maximum strength of clot (formed by fibrinogen crosslinking with platelets)
- If reduced means reduced platelet count and/or function – give PLATELETS or DDAVP
LY30 (percent lysis 30 minutes after MA)
- If prolonged = increased clot breakdown – give TXA
8
Q
Necrotising soft tissue infection
A
- Necrotising soft tissue infections include necrotizing forms of fasciitis, myositis and cellulitis
- Characterized by fulminant tissue destruction, systemic signs of toxicity and high mortality
- Usually begins via a break in the mucocutaneous barrier; usually the skin
- Bacteria, aided by pathogenic factors such as hyaluronidase, lipase, collagenase (many sp.), streptokinase and M-proteins (GAS), and alpha-toxin (clostridial sp.) spread throughout the layers of the skin
- Local inflammatory change also promotes microvascular occlusion which facilitates further spread of the infection
- Necrotising fasciitis can be polymicrobial (type 1), which involves gas in the soft tissue, or monomicrobial (type 2)
- Type 1 tends to occur in older people and those with underlying comorbidities esp T2DM, PVD
- Typically involves at least 1 anaerobic species (eg bacteroides, clostridium) + enterobacteriaese (eg E coli, Enterobacter, Klebsiella) + one ore more facultative anaerobic strep
- Type II may occur in any age & in healthy people
- Usually GAS or other beta-haemolytic strep; in half no clear portal of entry and likely haematogenous translocation from throat to site of blunt trauma or muscle strain
- Vibrio vulnificus – Injury + sea water or contaminated oysters
- Aeromonas hydrophila – injury + fresh water
- Type 1 tends to occur in older people and those with underlying comorbidities esp T2DM, PVD
- Necrotising myositis can be clostridial myonecrosis (gas gangrene) or necrotizing myositis due to strep (group A or other beta-haemolytic strep)
- Necrotising cellulitis can be clostridial or nonclostridial anaerobic (polymicrobial) – both involve gas in soft tissue
- M protein is an important virulence determinant of GAS; necrotizing infection caused by GAS strains with M types 1&3 = assoc w strep toxic shock syndrome in ~50% of cases
- GAS strains of these & other serotypes can produce pyrogenic exotoxins which induce cytokines, contributing to shock, tissue destruction and organ failure
- GAS infection is more often associated with septic shock requiring treatment with inotropes or vasopressors
9
Q
Pilonidal disease
A
- An acquired disease resulting from a foreign body reaction to extruded hair in the skin; most commonly at the upper part of the natal cleft of the buttocks, but other areas eg umbilicus and interdigital spaces can be affected
- Presence of hair in the gluteal cleft seems to play a central role in the pathogenesis: as a person sits/bends, the natal cleft stretches, damaging or breaking hair follicles & opening a pore or ‘pit’
- debris and loose hairs from this region tend to gather towards the natal cleft due to anatomy and suction of buttocks on movement
- These hairs migrate into pits/pores and get trapped foreign body reaction and keratin plugs/other debris may contribute further to inflammation creation of sinus tracts
- Cavities may contain hair, debris & granulation tissue; pilonidal cavities aren’t true cyst and lack a fully epithelialized lining, however the sinus tracts may become epithelialized
- Sinuses can become secondarily infected forming an abscess which may rupture spontaneously or require operative drainage
10
Q
Hydradenitis suppurativa
A
A chronic, inflammatory skin disorder of the folliculopilosebaceous units characterised by the development of inflammatory nodules, pustules, sinus tracts and scars, primarily in intertriginous areas (groin & axillae, also inframammary, perineal & perianal areas)
Traditionally has been considered the result of occlusion of apocrine glands by keratotic debris leading to bacterial proliferation, suppuration and spread of inflammation to surrounding subcut tissues. Subcut tracts and pits develop; infected tissues ultimately become fibrotic & thickened
11
Q
Bilirubin metabolism
A
- Although cholesterol, bile salts & phospholipids play important role in nutritional homeostasis, bile also serves as a major route of exogenous and endogenous toxin disposal – eg disposal of bilirubin
- Bile pigments, eg bilirubin, are breakdown products of haemoglobin and myoglobin
- Heme is cleaved to biliverdin by heme oxygenase
- Biliverdin is cleaved to unconjugated bilirubin by biliverdin reductase
- Bilirubin and biliverdin = two main pigments of bile
- Uncong bilirubin is insoluble so travels in circulation bound to albumin
- Albumin-bili complex enters hepatic sinusoidal blood, enters space of Disse and dissociates
- Free bilirubin taken up by hepatocytes and conjugated with glucuronic acid, then secreted into bile as bilirubin diglucuronide – if biliary excretion impaired, conj bili can re-enter circulation (causing conj hyperbilirubinaemia and jaundice)
- Conj bilirubin is reduced by bacterial enzymes in gut into urobilinogens
- 80% excreted in faeces (as stercobilinogen and urobilinogen)
- 20% reabsorbed in TI & returned to liver à re-excreted into bile
- small amount ‘escapes’ enterohepatic circulation and is excreted in urine
- functions of bile secretion from liver:
- excretion of toxins and metabolites from liver
- absorption of nutrients from intestinal tract
12
Q
Bile acid circulation
A
- bile salts (eg cholic acid and deoxycholic acid) originally created from cholesterol in liver & secreted into bile canaliculi
- initially lipid soluble
- conjugated to glycine or taurine to make them water soluble (ampipathic – ie have hydrophilic & hydrophobic poles)
- bc ampipathic, tend to aggregate around droplets of lipid (triglycerides and phospholipids) to form micelles – dispersion of food fat into micelles provides increased surface area for action of pancreatic lipase, which actually digests the triglycerides, and is able to reach the fatty core through gaps between the bile salts
- conjugated bile salts are actively reabsorbed in TI and colon
- bacteria deconjugate some bile salts to make them lipid soluble, which can be passively reabsorbed in gut
- 95% reabsorbed mainly in TI & recycled into enterohepatic circulation up to 10x per day
- 5% lost daily – restored by hepatic synthesis
13
Q
Gallstone formation
A
- bile = 97-98% water, 0.7% bile salts, 0.2% bilirubin, 0.51% fats (cholesterol, fatty acids and phospholipids), and inorganic salts
- gallstones form due to imbalance of 3 key products in the bile; bile salts, phospholipids and cholesterol
- 3 major factor explain most gallstone formation:
-
supersaturation of secreted bile which causes crystallisation
- cholesterol precipitates out into crystal when the amount of cholesterol exceeds the capacity of bile salts & phospholipids to contain it in micelles
- increased unconjugated bilirubin as a result of increased enterohepatic circulation of bili from excessive breakdown of RBCs –> increased bilirubin conc in bile –> precipitation of calcium bilirubinate to form black pigmented stones
- nucleation: crystal formation is further accelerated by pronucleating agents, including glycoproteins & immunoglobulins/mucin
- hypomotility increases stasis in the GB, leads to absorption of water and concentrated bile; also allows more time for solutes to precipitate
-
supersaturation of secreted bile which causes crystallisation
- once formed, the stones persist and enlarge or consolidate over time
- pts with ileal disease/post resection can get
- pigment stones from increased bile salt delivery to the colon (increased enterohepatic cycling)
- or cholesterol stones bc of excessive bile salt excretion in faeces & diminished bile salt pool so cholesterol precipitates out
- brown pigment stones occur due to stasis within CBD with associated bacterial infection usually – obstruction, Caroli’s disease, PSC, biliary infection; mostly seen in south-east asia
14
Q
GORD
A
- GORD = troublesome symptoms or complication caused by the reflux of gastric contents into oesophagus
- mechanisms that stop reflux include:
- 10mmHg protective-pressure gradient spans stomach & oesophagus
- intrinsic oesophageal mechanisms
- LOS (together w diaphragmatic sphincter = HPZ) – basal tone, adaptive pressure changes
- Intrinsic epithelial resistance
- Acid clearance
- Extrinsic oesophageal mechanisms
- Diaphragmatic sphincter/R crus (together w LOS = HPZ)
- Distal oesophageal compression – when GOJ firmly anchored in abdo cavity, increased intra-abdo pressure is transmitted to GOJ which prevents spontaneous reflux of gastric contents
- Angle of His – ‘flap valve’ – when stomach gets full, fundus pushes against oesophagus
- Mucosal rosette
- Phreno-oesophageal ligament – anchors oesophagus within +ve pressure environment
- Reflux occurs when gastric pressure overwhelms the HPZ, though whether they are received as symptomatic = modulated by oesophageal sensitivity and volume, composition and clearance time of refluxate
- Pathological reflux episodes due to 3 primary mechanisms:
- Inappropriate TLOSRs
- A persistently hypotensive LOS (frequently assoc w hiatus hernia bc of displacement of GOJ into mediastinum)
- Transient increases in intra-abdo pressure
15
Q
Zenker’s diverticulum
A
- a form of false, pulsion diverticula of posterior mucosa between the 2 parts of the inferior constrictor - thyropharyngeus above & cricopharyngeus below (Killian’s dehiscence/triangle which is devoid of muscle in posterior wall)
-
aetiology: ?result of loss of tissue elasticity & muscle tone w age, along w abnormal motility which increases intraluminal pressures, as well as the sphincter muscle becoming non-compliant & fibrotic w age
- as diverticulum enlarges, mucosal & submucosal layers dissect down left side of oesophagus into superior mediastinum, posteriorly along prevertebral space
16
Q
OPSI
A
- spleen contains numerous antigen-presenting cells and T and B-cells
- it is the only organ in which some bacteria (particularly bacteria with a polysaccharide capsule) can be effectively identified and destroyed; spleen is involved in the opsonisation of encapsulated organisms and splenic macrophages attack and destroy these encapsulated organisms
- these substances resist antibody binding and opsonisation in the rest of the body
- spleen is also an early site of IgM production - important in the acute clearance of pathogens from the bloodstream via opsonisation
- loss of the spleen puts patients at increased risk of infection from: Pseudomonas, Strep pneumoniae, Haemophilus influenza, Neisseria meningitides, E. coli, Salmonella, Klebsiella, group-B strep and Bordatella pertussis (Please SHiNE my SKiS and bordatella)
- in the follicle of the white pulp, infectious antigens and blood-borne pathogens are presented by antigen-presenting cells
- this process initiates the activation of T-cells and B-cells, which eventually leads to production of opsonising antibodies (IgG)
- after opsonisation, macrophages, dendritic cells and neutrophils phagocytose the antigen
- asplenism therefore leads to increase risk of overwhelming sepsis, particularly secondary to encapsulated bacteria
- children are at highest risk - avoid splenectomy in <6yrs if possible
- those who have a splenectomy for haematological reasons are at higher risk, rather than traumatic splenectomy
- how to mitigate risk:
- avoid splenectomy where possible
- deliver vaccines pre-op by at least 2 weeks where possible; 14 days post-op following emergent splenectomy
- patient education
- medic alert bracelet
- back pocket script to start if feel unwell
- prophylactic abx (amoxycillin 250mg daily - case-by-case (age, immune status)
- children until 5 or for one year
- immunosuppressed children to at least 18
- adults - 1-3yrs
17
Q
Choledochal cysts
A
- Babbitt’s theory is based on an abnormal biliopancreatic confluence, where the main ducts join abnormally proximal to the ampulla of Vater
- This theory postulates that the long common channel allows mixing of the pancreatic and biliary juices, which then activates pancreatic enzymes
- These active enzymes cause inflammation and deterioration of the biliary duct wall, leading to dilation
- Furthermore, greater pressures in panc duct can further dilate weak-walled cysts
- Competing theories suggest that choledochal cysts are purely congenital in nature, resulting from aganglionosis similar to Hirchsprung’s disease
18
Q
Life cycle of entamoeba histolytica in humans
A
- Ingested as cysts via faecal to oral route
- Incubation for 2-4 weeks (may be longer)
- Excystation in the small bowel
- Trophozoites colonise large bowel
- Invade colon – amoebic dysentery
- Invade porto-venous system – abscess
19
Q
Microscopic consequences of splenectomy (on blood film)
A
- Howell-Jolly bodies (nuclear fragments)
- Heinz bodies (Hb deposits)
- Pappenheimer bodies (Fe deposits)
- Target cells (increased surface membrane to cell volume ratio)
- Siderocytes (iron not bound to Hb)
- Acanthocytes
- Transient leucocytosis
- Transient thrombocytosis
- Peristent lymphocytosis and monocytosis
20
Q
PPIs
A
- Parietal cells in the gastric antrum and cardia express a proton pump on their luminal surface
- This H+/K+ ATPase secretes H+ into the lumen of the stomach, reducing the pH
- Insertion and activity of the H+/K+ ATPase is under neurohormonal control via the vagus nerve, acetylcholine and gastrin
- PPIs irreversibly bind & inhibit the H+/K+ ATPase on the parietal cell
- They are the optimum medical therapy as they reduce expression of the final common pathway of all three variables in acid production
21
Q
Sepsis and classification
A
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. All sepsis has organ dysfunction by definition; SIRS as a term has fallen out of fashion.
Qsofa identifies patients with suspected infection at risk of poor outcomes typical of sepsis (prolonged LOS or in hospital mortality) based on the presence of 2/3 of any of RR >22, SBP<100, altered mentation - mortality risk of 10% in general hospital population.
SOFA (sequential organ failure assessment) scores 6 organ systems from 0-4 - resp, coag, liver, cardio, CNS, renal - score of 2 or more suggests presence of organ dysfunction. Dysfunction in 2 or more systems = MODS.
Septic shock = a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality (is assoc w in hosp mortality >40%) - requirement of vasopressors to maintain map >65, and serum lactate >2 in abscence of hypovolaemia
Triggering infectious agent sets off inflammatory cascade:
- Macrocirculatory changes (nitric oxide)
- Microcirculatory changes (glycocalyx disruption, endothelial dysfunction, microvascular thrombosis)
- Inflammation (SIRS and CARS - dysregulated inflammatory response)
- Coagulation (triggered by cytokines or tissue factor)
- Neurally-mediated immunosuppression
- Mitochondrial dysfunction
22
Q
Achalasia
A
- a primary disorder of oesophageal motility characterised by
- impaired/absent relaxation of LOS with
- abnormal peristalsis of the body - oesophagus is either flaccid, shows pan-oesophageal pressurisations or spastic activity
- type I = median IRP > upper limit normal, 100% failed peristalsis, minimal pressurisation within oesophagus
- type II = median IRP > upper limit normal, no normal peristalsis, panoesophageal pressurisation with ≥20% swallows
- type III = median IRP >upper limit normal, no normal peristalsis, premature contractions with ≥20% swallows
- primary form - due to loss of ganglion cells in myenteric (Auerbach) plexus - more common
- pathophys remains unclear but what is clearly described is an inflammatory infiltrate at the level of the myenteric plexus –> progressive neuronal loss & destruction of the nitric oxide releasing neurohormonal cells responsible for coordinating relaxation –> subsequent loss of peristalsis and appropriate LOS relaxation
- precipitating cause of this not clear although possibly an autoimmune response triggered by a viral infection eg HSV-1
- results in hypertension of LOS & failuer of LOS to relax on pharyngeal swallowing as well as pressurisation of oesophagus, oesophageal dilation and resultant loss of progressive peristalsis
- secondary form
- Chagas’ disease - in South America, caused by Trypanosoma cruzi infection (by bite from infected bug) –> long-term neurological disorders w diffuse ganglion cell involvement (incl destruction of myenteric plexus) –> abnormal motility –> disease in multiple organs, incl cardiomyopathy, megacolon, megaureter and megaoesophagus
- pseudoachalasia = rare presentation of malignancy at GOJ
- classic triad: dysphagia, regurgitation, weight loss
- also chest pain, aspiration pneumonias/lung abscess/bronchiectasis
- later SCC - 8% over 20yrs - chronic stasis with long-standing retained undigested fermenting food in body of oesophagus –> ulceration & continuous irritation of. mucosa –> dysplasia –> SCC
- adenoca can also occur but less common
- management
- aimed at relieving functional obstruction caused at LOS (while minimising risk of reflux) but none able to address issure of reduced motility in oesophageal body so all palliative treatments
- non-operative:
- SL nitrogen, CCBs, nitrogens - temporary relief in few pts (can cause SM relaxation at LOS sphincter but only partially effective, come w side-effects & not used routinely in clincial practice
- endoscopic
- balloon dilatation = most effective non-surgical Rx - involves stretching cardia w 30-40mmHg balloons to disrupt the muscle at the LOS - balloons specially designed for achalasia & different technique to dilating for other conditions; as balloon is dilated a waist can be seen at the pathologically ocntracted LOS & insufflation usu continues til this waist disappears
- 20-35% incidence of GORD, 2-5% risk of perf, 70% effective but 50% symptomatic again after 1-10yrs
- more effective than botox in longterm
- botox = directly into LOS; blocks acetylcholing release, prevents SM ocntraction, effectively relaxes LES
- effective in 85% but 40-50% have recurrent sx by 6mo
- causese inflammation at GOJ tha tmakes subsequent myotomy more difficult; therefore mostly used in elderly/poor surgical candidates who aren’t fit for pneumatic dilatation and the risk of perforation
- peroral endoscopic myotomy (POEM)
- mucosal incision at point prox to where myotomy planned to commence; develop submucosal plane and divide circular muscle fibres in the distal oesophagus down to the stomach; close mucosal defect at end of procedure
- excellent rates of improvement after dysphagia in short-term
- disadvantage = not combined w antireflux procedure & has significant reflux rate
- balloon dilatation = most effective non-surgical Rx - involves stretching cardia w 30-40mmHg balloons to disrupt the muscle at the LOS - balloons specially designed for achalasia & different technique to dilating for other conditions; as balloon is dilated a waist can be seen at the pathologically ocntracted LOS & insufflation usu continues til this waist disappears
- surgical
- Modified Heller myotomy +/- partial fundoplication (to prevent post-op reflux)
- do a lap single anterior myotomy with a partial fundoplication - divide all circular fibres of lower oesophagus (usu 6-8cm) & ~1-2cm on stomach/cardia
- Oesophagectomy occasionally required for end-stage disease or malignancy
- consider if symptomatic w tortuous/mega-oeosophagus, sigmoid oesophagus, failure of >1 myotomy or reflux stricture that isn’t amenable to dilatation
- Modified Heller myotomy +/- partial fundoplication (to prevent post-op reflux)
23
Q
Tension pneumothorax
A
- pathophysiology of a tension pneumothorax involves air from an injured lung or airway being trapped within the pleural cavity, resulting in loss of normal negative intrapleural pressure
- a tension pneumothorax occurs when there is a valve mechanism at the site of the leak allowing air to enter but not escape from the pleural cavity
- it is characterised by complete lung collapse, tracheal deviation and mediastinal shift leading to respiratory distress but also decreased venous return to the heart, decreased cardiac output and hypotension
- respiratory decompensation occurs as a rseult of lung injury and changes to pulmonary blood flow and gaseous exchange resulting in hypoxaemia, hypercapnia and respiratory acidosis
- the clinical features are dyspnoea, tachypnoea, hypotension, tachycardia and decreased PaO2
- there is usually asympmetrical expansion of the thorax, the percussion note on the side of the pneumothorax is hyper-resonant and the breath sounds are markedly reduced/absent
- trachea and apex beat are deviated away from the side of the pneumothorax and there is often clinical cyanosis and distension of neck veins
- the diagnosis is clinical and xray confirmation shouldn’t be awaited
24
Q
Underwater seal drain
A
- an underwater seal drain (UWSD) allows drainage of haemopneumothorax and restores negative pressure in the pleural space to allow lung expansion
- it has a three-chamber unit, including:
- a collection chamber (receives tube from patient)
- an underwater seal which acts as a one way valve to allow air to escape but not return to the chest
- a suction chamber that places -20cmH2O negative pressure to the pleural space
- the depth of water determines the negative pressure of the chamber
- draw it (p373 white book)
25
Q
Inflammation
A
- A pathophysiological mechanism of host defence against harmful stimuli
- Tissue injury and infection leads to release of PAMPs and DAMPs
- Host immune cells (via pattern recognition receptors) recognise these which elicits a signalling cascade resulting in the release of pro-inflammatory cytokines (TNFa, IL-1, IL-6, IL-8), chemokines (ICAM-1, VCAM-1) and nitric oxide
- Fever
- PMNs become activated and migrate to site of injury; release of mediators by PMNs at site of infection = responsible for cardinal signs of local inflammation: warmth and erythema due to local vasodilation and hyperaemia, and protein-rich oedema due to increased microvascular permeability
- Neutrophils are phagocytic cells defending against pathogens; mechanisms of defence include engulfing and destroying offending microorganism, secretion of antimicrobial peptides & release of neutrophil extracellula rtraps which aid in pathogenesis clearance but may also promote inflammation and tissue damage in sepsis; crucial role in DIC and intravascular thrombosis
- This process is highly regulated by a mixture of pre-inflammatory and anti-inflammatory mediators secreted by macrophages; if mediators balance each other out and infectious insult is overcome, homestasis will be restored –> end result = tissue repair and healing
26
Q
Anaphylaxis
A
Exaggerated systemic response to allergen, characterised by vasodilation, vascular permeability, smooth muscle spasm and cellular infiltrate
An example of type 1 hypersensitivity
Driven by IgE binding to allergen and activating mast cells and basophils, with release of primary mediators (histamine, bradykinin, prostaglandins) and secondary mediators (leukotrienes).
27
Q
DIC
A
Acquired consumptive coagulopathy characterised by microvascular thrombosis leading to organ dysfunction.
Exposure of blood to procoagulant susbtances (TF) leads to widespread coagulation and tissue ischaemia. Depletion of clotting factors leads to bleeding.
Diagnosis includes
- Low plt
- Low fibrinogen
- Increased PT and APTT
- Increased D-Dimer
- Schistocytes (haemolysed red cells)
28
Q
Suture duration
A
- Monocryl
- 50% at 1 week
- Absorbed in 3 months
- Vicryl (Polyglactin)
- 75% strength at 2 weeks, 50% at 3 weeks
- Absorbed in 3 months
- PDS
- 70% at 2 weeks, 50% at 4 weeks
- Absorbed at 6-8 months
- Maxon
- 80% at 2 weeks, 60% at 4 weeks
- Absorbed by 6 months
- (combines prolonged strength of PDS and good handling and knotting of Vicryl)
- Chromic gut:
- loses strength in 10-14 days
- digested by 2-3 months
29
Q
Shock
A
- A state of organ/systemic hypoperfusion, with resultant cellular hypoxia, cellular death and dysfunction of organs
- 3 broad phases:
- Compensated
- Decompensated/reversible
- Irreversible
- Multiple aetiologies, broadly classified as:
- Obstructive
- Distributive
- Hypovolaemic
- Cardiogenic
- Common pathophysiology is cellular hypoxia due to inadequate oxygen delivery. This leads to:
- Cell membrane ion pump dysfunction
- Intracellular oedema
- Leakage of cellular contents
- Inadequate regulation of cellular pH
- This progresses on the systemic level leading to:
- Acidosis
- Lactataemia
- Endothelial dysfunction
- Inflammation
- This is compounded by neurohumoral mechanisms to defend central end-organ perfusion at the expense of peripheral perfusion.
- Sympathetic activation and vasoconstriction
- Renin-angiotensin-aldosterone system
30
Q
MODS
A
- Progressive organ dysfunction in acutely ill pt - is at severe end of severity of illness spectrum of both infectious (sepsis, septic shock) and non-infectious conditions (eg SIRS from pancreatitis)
- Defined as an alteration in 2 or more organs’ function such that homeostasis cannot be maintained
- May be primary (due to inciting tissue injury) or secondary (due to host response)
- A hypometabolic, immunosuppressed state with clinical and biochemical evidence of decreased function of the body’s organ systems
No universially accepted criteria for individual organ dysfunction in MODS, but the organ-specific parameters used in SOFA are commonly used to diagnose MODS
• CNS - GCS
• Cardiovascular – hypotension, inotrope requirement
• Coagulation - platelets
• Renal - creatinine
• Respiratory - paO2/FiO2
• Liver – bili
All scored from 0 - 4
31
Q
SIRS
A
- A dysregulated host inflammatory response to an injury or infection
- A combination of humoral and cellular immune responses, cytokine release, and activation of the complement pathway; thought to be associated with an imbalance between the pro-inflammatory and anti-inflammatory cascades
- Injury leads to production of proinflammatory cytokines (IL-1, IL-6, IL-8, TNFa, IFN-y)
- These cytokines spill over into the circulation in order to amplify the inflammatory response and lead to recruitment of macrophages, lymphocytes and platelets to the area
- Usually there’s homeostasis that occurs with a compensatory anti-inflammatory response mediated by IL-4 and IL-10 - inhibit production of the inflammatory cytokines
- But if no homeostasis then a significant systemic reaction occurs - leads to activation of various different cascades - release of further cytokines, prostaglandins, activation of leukotriene and complement pathways, fever, sympathetic stimulation, RAS activation, vasoactive compound release, as well as alteration in coagulation leading to end-organ microthrombosis
- Consequent endothelial damage and vascular permeability leads to organ dysfunction
32
Q
Atherosclerosis
A
- endothelial injury (from pro-inflammatory substances in bloodstream e.g. LDL and glycated Hb, haemodynamic forces, toxins & infectious agents) –> decreased NO production and increased permeability, and increased expression of leukocyte adhesion molecules which increases adherence of macrophages & other leukocytes
- permeability of endothelium allows entry of leukocytes & lipoproteins to subendothelial space
- plaque formation:
- fatty streaks (focal thickening of intima w accumulation of foam cells which are lipid-laden macrophages)
- deposition of layers of matrix (ECM) around layered macrophages, T cells, SMCs
- lesions become a well defined lipid core with a fibrous cap which begins to compromise arterial lumen and protrude into it (foam cells at centre of developing atheroma become necrotic & form a central lipid core; shoulder regions contain SMCs, macrophages and other leukocytes)
- vasa vasorum from nearby adventitia in-grows to supply the lesion, weakening the walls & causing remodelling
- fibrous plaque (smooth muscle hypertrophy, collagen formation and consolidation of deep lipid core - may have relatively thin surface, vulnerable to rupture)
- intra-plaque haemorrhage (plaque neovascularisation results in spontaneous haemorrhage and subsequent rupture with thrombo-embolism)
- coronary, carotid & aortoiliac lesions tend to occur at branch points, however obstructive SFA plaque tends to develop in distal portion of vessel (generally straight w few branches - but anatomic compression by adductor tendons at adductor hiatus which limits compensatory arterial dilation to growing plaque)
- Inciting events include proinflammatory substances in the vasculature, including glycated Hb and LDLs, and shear forces from turbulent blood flow (eg at junctions)
- Endothelial injury leads to accumulation of lipid-laden macrophages.
- Platelet aggregation, fibroblast and smooth muscle activation leads to a raised lesion with a fibrous cap, calcification, lipid-rich necrotic core and intimal smooth muscle hypertrophy
33
Q
Portal venous gas
A
Mucosal breakdown leads to extrusion and intravasation of intestinal gas, with contribution from translocation of gas-forming bacteria
34
Q
Haemorrhagic shock stages
A
I: 0-15% (<750mL)
II: 15-30% (750-1500mL)
III: 30-40% (1500-2000mL)
IV: >40% (>2000mL)
35
Q
Complement cascade*
A
JC
A series of proteins involved in the innate immune response to antigen. These exist in the serum as precursor molecules - stimuli including antigen-antibody binding, direct microbe binding or mannose-binding lectin. Common result is activation of C3, C5 and formation of the membrane attack complex.
Actions are:
- Formation of membrane attack complex (via the classical pathway)
- Opsonisation for phagocytosis (via the alternative pathway)
- Inflammation, attracting macrophages and leucocytes (via the Lectin pathway)
36
Q
How does radiotherapy work
A
Formation of free radicals leads to DNA damage
Tumour cells lack DNA repair mechanisms and so are destroyed, whereas normal cells can repair DNA and recover
37
Q
Radiation enteritis
A
Acute effects due to:
• GI epithelium has a high proliferation rate -> susceptible to injury from radiation & chemo
• Loss of mucosal stem cells in Crypts of Lieberkuhn either directly or as a result of microvascular damage, so decreased cellular reserves for intestinal villi
• Consequent mucosal denudation with associated intestinal inflammation, oedema, shortened villi and decreased absorptive area
Occur within hours of irradiation. Should repopulate within days and symptoms should resolve within 2 weeks
Late effects (\>3 months) are due to: • Progressive obliterative vasculitis of the blood vessels within the bowel wall and submucosal fibrosis -\> eventually vascular thrombosis, vascular insufficiency & chronic intestinal ischaemia • Mucosal ulcerations can occur -\> perforation, fistulas or abscess formation • As ulcers heal, can be fibrosis w narrowing of intestinal lumen & stricture formation/obstruction • Stasis can --\> SB bacterial overgrowth • These chronic changes can impair absorption of fats, carbs, proteins, bile salts & vit B12 -\> loss of water, electrolytes & proteins in SB - Lactase degradation can be impaired --\> increased bacterial fermentation & associated flatulence, abdominal distension & diarrhoea - Bile salt resorption may be impaired --\> increased amounts of conjugated bile salts in colon --\> bile salts then deconjugated by bacteria --\> intraluminal water retention w resultant diarrhoea
NB large intestine generally believed to be less radiosensitive than SB; when radiation injury does involve colon, pts can develop a pancolitis that mimics inflammatory bowel disease
38
Q
Angiodysplasia
A
Dilated ectactic submucosal vessels thought to be due to obstruction of smaller vessels in submucosa
39
Q
Hydatid disease
A
A hydatid liver cyst is caused by an infection with Echinococcus granulosus most commonly, and rarely Echinococcus multilocularis parasite. E granulosus resides as an adult tapeworm in the SB of the definitive host (the dog). Humans are an accidental host and ingest the eggs of the E. granulosus through faecal route. Eggs then release larvae in the GI tract due to an interaction with bile salts and trypsin. Larvae then penetrate into wall of jejunum and are transported via portal circulation to liver, or via lymphatics to lung, where these larvae develop into hydatid cysts. Cysts then enlarge asexually, producing protoscolices which are contained in brood capsules, as well as daughter cysts, which fill the cysts. When the organ containing the cysts are ingested by the definitive host (dog), the protoscolices evaginate and the scolices attach to the intestine of the dog and develop into adult tapeworms which completes the life cycle. Usually intermediate host is the sheep; we are accidental hosts.
40
Q
Splenomegaly
A
V: splenic vein thrombosis, haemangiosarcoma, portal hypertension
I: malaria, HIV, abscess, TB
T: rupture/pseudocyst
A: ITP, AHA, Sarcoid, SLE, Felty’s syndrome
M: lysosomal storage disease, amyloidosis
I: hypersplenism
N: lymphoma, leukaemia, secondary deposit, myelofibrosis
C: spherocytosis, elliptocytosis
D: cyst
41
Q
ARDS
A
- an inflammatory injury to the lung endothelium and epithelium
- leads to increase in lung vascular and epithelial permeability, and the passage of protein-rich oedema fluid into the airspaces
- lung injury is caused by neutrophil- and platelet-dependent damage to the endothelial and epithelial barriers
- resolution of ARDS is delayed because the lung epithelial barrier injury prevents removal of the alveolar oedema fluid and deprives the lung of surfactant
- initial injury can be compounded by ventilator-associated lung injury
- criteria:
- lung injury of actue onset
- bilateral opacities on chest imaging not explained by other pulmonary pathology
- respiratory failure not explained by heart failure or volume overload
- decreased arterial PaO2/FiO2 ratio
- mild ARDS: 201-300
- Moderate ARDS: 101-200
- Severe ARDS: ≤100
- high mortality
- many survivors develop chronic lung disease, with the damaged lung healing by fibrosis
42
Q
Trauma lethal triad/diamond
A
- Lethal triad = hypothermia, acidosis, coagulopathy
- Trying to avoid these, as well as treating them
- Lethal diamond = add hypocalcaemia
- Independently assoc w high risk of mortality outside of its effects on coagulopathy alone
- Acidosis
- Effects
- Reduces contractility & CO
- Vasodilation & worsening hypotension
- Impaired metabolic function & coagulation
- Vasopressor & other catecholamines don’t work as well
- BD of ≥6 is strongly assoc w
- Need for MT & mortality
- ICU days
- ARDS & MODS
- Pts tend to have elevated BD BEFORE their BP drops to classic ‘hypotension’ levels
- Effects
- Hypothermia
- Develops at some point in up to 57% of trauma pts
- Independently assoc w 3x odds of death when adjusted for age, ISS, mechanism, BP
- In ISS <25:
- Temp >34 = 7% morality
- <34C = 40%
- <32C = 100%
- effects
- metabolism: shivering -> oxygen consumption (increases proportion of anaerobic metabolism & therefore lactic acid production) -> acidosis
- CNS: confusion -> coma
- Cardiac: vasoconstriction; and AF -> VF -> cardiac arrest
- Resp: RR, bronchospasm; and decreased resp drive -> apnoea
- GI: motility decreased
- Blood cells: platelet dysfunction; coagulation enzymes impaired -> coagulopathy
- Renal: cold diuresis
- Coagulopathy
- All above relate to coagulopathy, ultimately the most important aspect
- Non-surgical bleeding difficult to control
- Documented linear relationship with mortality
- Many different types of coagulopathy; trauma-induced coagulopathy is different to other types
- Combination of tissue injury -> endothelial glycocalyx injury
- Significant role for protein C as well
- Risk is that there is a proportion of these pts who are already coagulopathic and we don’t want to worsen things by giving them resuscitation-induced-coagulopathy
- Hypocalcaemia
- Decreases liver’s ability to metabolise citrate -> more calcium being bound & less available in the blood
43
Q
Damage control resus*
A
- Lethal triad = hypothermia, acidosis, coagulopathy
- Trying to avoid these, as well as treating them
- Lethal diamond = add hypocalcaemia
- Independently assoc w high risk of mortality outside of its effects on coagulopathy alone
- Acidosis
- Effects
- Reduces contractility & CO
- Vasodilation & worsening hypotension
- Impaired metabolic function & coagulation
- Vasopressor & other catecholamines don’t work as well
- BD of ≥6 is strongly assoc w
- Need for MT & mortality
- ICU days
- ARDS & MODS
- Pts tend to have elevated BD BEFRORE their BP drops to classic ‘hypotension’ levels
- Effects
- Hypothermia
- Develops at some point in up to 57% of trauma pts
- Independently assoc w 3x odds of death when adjusted for age, ISS, mechanism, BP
- In ISS <25:
- Temp >34 = 7% morality
- <34C = 40%
- <32C = 100%
- effects
- metabolism: shivering à oxygen consumption (increases proportion of anaerobic metabolism & therefore lactic acid production) à acidosis
- CNS: confusion à coma
- Cardiac: vasoconstriction; and AF à VF à cardiac arrest
- Resp: RR, bronchospasm; and ¯resp drive à apnoea
- GI: motility ¯
- Blood cells: platelet dysfunction; coagulation enzymes impaired à coagulopathy
- Renal: cold diuresis
- Coagulopathy
- All above relate to coagulopathy, ultimately the most important aspect
- Non-surgical bleeding difficult to control
- Documented linear relationship with mortality
- Many different types of coagulopathy; trauma-induced coagulopathy is different to other types
- Combination of tissue injury à endothelial glycocalyx injury
- Significant role for protein C as well
- Risk is that there is a proportion of these pts who are already coagulopathic and we don’t want to worsen things by giving them resuscitation-induced-coagulopathy
- Hypocalcaemia
- Decreases liver’s ability to metabolise citrate à more calcium being bound & less available in the blood
- Damage control resus = a systematic group of concepts of resuscitation that are utilized in an attempt to reduce ongoing blood loss and minimize the exacerbating underlying metabolic processes until definitive haemorrhage control can be achieved
- 3 main tenets to it:
- permissive hypotension
- haemostatic resuscitation (how we should resuscitate pts to minimize the effects of worsening the acute coagulopathy)
- early haemorrhage control/DCS
- involves:
- rapid diagnosis – trying to identify the group early that are going to benefit most from these interventions
- limit crystalloids
- early 1:1:1 transfusion strategy
- permissive hypotension
- rapid anatomic control
- antifibrinolytics
- DCR doesn’t stop when get to theatre, and also DCS is part of DCR
- Permissive hypotension
- Allow SBP/MAP to fall low enough to minimize bleeding, but high enough to maintain vital tissue perfusion (cardiac & neurological)
- Avoiding disruption of the clot formed
- Low BP is not the target, it is a compromise – don’t TRY to reduce BP
- Haemorrhage control is the goal (not hypotension)
- Remains controversial & not completely widely accepted
- Animal studies
- Variable interpretation of meaning & use
- Prolonged retrieval times
- Use in those w brain & spinal cord injuries
- Appropriate targets for that individual? Some peoples version of hypotension might be normal for them, but other people who are relatively normotensive that might be quite low for them
- Primarily applicable to penetrating trauma
- If using in blunt trauma would have to be clear that dealing with a specific group of people that have a short time to likely definitive surgical/radiological intervention so risk/benefit ratio would mean that permissive hypotension likely ok
- Targets differ: ?European guidelines (guidelines differ)
- Target MAP of 50-60mmHg in pts w/o TBI/SCI
- Target 80-90mmHg in pts w confirmed or suspected TBI/SCI
- Some recommendations go further and say if a pt has a palpable radial pulse in the pre-hospital setting that’s enough; or alternatively if mentating
- Haemostatic resuscitation – 3 main concepts
- Minimize the use of crystalloids
- Balanced blood product transfusion
- Management of acute coagulopathy of trauma
- IV fluids
- Minimize the amount of all non-blood product or oxygen carrying capacity fluids
- Excessive use of crystalloids been shown to worsen outcomes in trauma
- As little as 500mL
- How?
- Hyperchloraemic acidosis which tends to worsen their coagulation profile
- Dilution of remaining coagulation factors
- What if you don’t have blood available?
- Ideal fluid of choice unclear, but likely not 0.9% NaCl
- ATLS has reduced their recommended initial 2L to 1L
- Doesn’t stop after leave ED – intraop important too
44
Q
C diff
A
- spore forming, anaerobic, gram +ve bacteria
- faecal oral transmission
- in setting of disrupted colonic microbiome from antibiotic use which causes proliferation of c diff
- pathogenic mechanism:
- cytotoxin A: damages mucosa, villous tips
- cytotoxin B: endocytosis and induces apoptosis of epithelial cells
- leads to inflammatory response and SIRS
- forms pseudomembrane: fibrin, dead neutrophils, bacteria, mucous
45
Q
Abdominal compartment syndrome
A
- ACS is a sustained intra-abdominal pressure of >20mmHg, associated with new organ dysfunction
- affects multiple organ system
- GI issues due to direct pressure on the bowel as well as reduced splanchnic blood flow –> tissue hypoxia, can lead to mesenteric thrombosis and bowel wall ischaemia, predisposes to translocation of bacteria
- renal impairment due to direct compression of renal parenchyma and renal vein leading to increased renal vascular resistance, decreased renal blood flow and decreased urinary output
- cardiovascular compromise
- compression of IVC and portal vein reduces venous return –> hypotension and reduced stroke volume
- increased intrathoracic pressure due to elevated diaphragm can cause compression of pericardium and decreased LV end-diastolic volume
- hypotension worsens the renal impairment and activates RAAS leading to arterial constriction
- respiratory compromise
- reduced compliance of diaphragm against increased pressure within abdomen
- increases airway pressures and causes decreased tidal volumes
- can cause compressive atelectasis and VQ mismatch –> resultant hypoxia and acidosis
- increased intracranial pressure - impaired venous return causes increased ICP and decreased cerebral perfusion - can cause worsening cognitive impairment and delirium
- hepatic impairment
- decreased portal blood flow –> decreased mitochondrial function in liver and decreased lactate clearance
- reduced blood flow to abdominal wall - impaired healing
- SIRS
- increased risk of DVT due to decreased venous return from lower limbs
46
Q
Diabetic foot infection
A
- there are a number of different contributing mechanisms that predispose patients to these
-
arterial issues
- microvascular disease - hyperglycaemia causes vasoconstriction, inflammation and thrombosis; reduced endothelial NO, increased ROS, ‘advanced glycation endproducts’ all cause thickened capillaries; contributes to nerve issues
- macrovascular disease
- these lead to ischaemia, contribute to ulceration and secondary infection, and reduce ability of foot to heal from infection/repetitive trauma b/c can’t increase blood supply needed to heal
-
nerve issues
-
sensory neuropathy due to disease of vasa nevorum from microvascular disease and hyperglycaemia
- loss of protective pain sensation and proprioception
- repetitive microtrauma to joints & pressure points on skin b/c not sensing and moving the foot like they normally would –> damage
-
autonomic neuropathy - warm, dry foot
- denervation of sweat glands leads to dry skin & cracks
- opens AV shunts whihc increase blood flow to limb but shunts blood away from skin capillaries –> functional local skin ischaemia
-
motor neuropathy
- atrophy of intrinsic muscles –> guttering, altered foot shape, clawed toes & prominent MT heads –> change in weight distribution & eventual dislocation of MTP heads –> increased foot pressures & subsequent ulceration
- diabetes commonest cause of Charcot foot
- visual impairment - contributes to trauma and ulceration
-
sensory neuropathy due to disease of vasa nevorum from microvascular disease and hyperglycaemia
-
tissue effects of hyperglycaemia
- chronic hyperglycaemia –> glycosylation of proteins and collagen bundles become thickened & cross-linked –> alters mechanics of walking, high plantar pressures
- impaired chemotaxis & phagocytosis (leukocyte dysfunction due to chronic glycosylation of neutrophils)
- ideal bacterial substrate
- i.e. leads to higher risk of infection and difficulty dealing w infection when it does occur
47
Q
VTE
A
- Virchow’s triad
- endothelial injury due to e.g.
- surgery
- trauma
- lines, venepuncture
- hypercoagulability, e.g.
- malignancy
- thrombophilia syndromes
- nephrotic syndrome
- pregnancy and post-partum
- trauma incl surgery
- venous stasis due to e.g.
- immobility
- prolonged surgery
- varicose veins
- venous hypertension
- venous obstruction
- endothelial injury due to e.g.
48
Q
Goitre
A
- goitre = enlarged thyroid gland
- diffuse if evenly enlarged
- multinodular = enlarged, diffusely heterogeneous thyroid gland comprised of multiple nodules of varying sizes
- iodine deficiency = most common cause of goitre worldwide
- primary from low iodine intake
- secondary from diet (goitrogens eg brassica family or excess fluoride/calcium) or drugs (iodine, lithium, amiodarone)
- in places where significant iodine deficiency doesn’t exist, multinodular goitre, chronic autoimmune (Hashimoto’s) thyroiditis and Graves’ disease more common
- in iodine deficiency or chronic autoimmune thyroiditis, increase in TSH secretion = predominant cause of goitre
- most patients with sporadic nontoxic multinodular goitres have normal serum TSH concs; goitre prob caused by several growth factors (incl TSH) that act over time on thyroid follicular cells that have different synthetic and growth potentials
- often fhx of goitre, suggesting that genetic factors may also play a role
- result = diffuse and later multinodular thyroid enlargement; nodularity occurs due to haemorrhage and scarring and involution of the gland, leading to irregular nodularity
- some nodules eventually become autonomous due to activating mutations in TSH receptor or G proteins within the thyroid follicular cells, and others may undergo cystic degeneration
- in Graves’: TSH receptor antibodies (TRAb) stimulate the TSH receptor to cause thyroid growth and excessive hormonal secretion
- 2 stages in development of MNG which may be separated by long period of time eg decades
- early stimulus for generalised thyroid hyperplasia = iodine deficiency/goitrogens/genetic predisposition
- second stage = due to focal somatic mutations
- although most mutations result in enlarged colloid follicles, focal hyperplasia, hypertrophy, adenoma or even carcinoma can all contribute to the MNG
- over time these nodules undergo haemorrhage, cystic degeneration, necrosis +/- fibrosis and calcification
49
Q
Vasopressors*
A
50
Q
Thyroid storm
A
- A severe thyrotoxic state which may be precipitated by illness or a procedure in an un or undertreated patient
- characterised by severe tachycardia, hypo or hypertension, fever, confusion, vomiting and adrenergic overstimulation to the point of mania and coma with potential for arrhythmias and cardiovascular collapse
- treatment is with
- rapid fluid replacement
- cooling
- high dose PTU
- beta blockers
- iodine solution
- steroids
- cardiac monitoring
- in life-threatening situations, plasmaphoresis or plasma exchange may be effective in reducing T4 & T3 levels
51
Q
Hypercalcaemic crisis*
A
52
Q
Dupuytron’s contractures
A
- fibroblastic proliferation and collagen deposition in the palmar fascia
- leads to contracture and the development of nodules and cords in the palmar fascia
53
Q
Acute limb ischaemia
A
Acute phase:
Insufficient substrate (glucose) delivery and insufficient oxygen delivery
Local anaerobic metabolism leads to lactic acidosis
Failure of ATP pumps: cellular damage with K+ release, cytokine release, and oedema due to increased membrane permeability
Oedema further impairs oxygen delivery, bacterial infections may be superimposed, especially in the context of pre-existing disease
Compartment syndrome is caused when local compartmental pressure becomes greater than perfusion pressure.
Reperfusion phase:
Generation of oxygen free radicals; attach to FAs in the phospholipid membrane and cause mechanical and functional derangements
Revascularisation results in sudden venous return of blood with anaerobic metabolitse, low pH and high K conc
Reperfusion of large mass of ischaemic tissue –> systemic inflammatory response; may lead to multiple organ dysfunction & failure (hypotension and arrythmias), K+ may cause arrhythmias
Renal function may be furhter impaired by myoglobinuria (helped by maintaining good diuresis)
Revasc of ischaemic muscle can lead to considerable swelling within fascial compartments of legs –> increased compartment pressures causing venous compression, worsening oedema & if not treated promptly, permanent neurological insult. Pts at highest risk of this = prolonged ischaemia or ischaemia from embolic source.
54
Q
Dumping syndrome
A
- early dumping syndrome up to 50% after RYGB
- rapid onset usu within 15mins
- result of rapid emptying of food into SB & bc of hyperosmolality of food, rapid fluid shifts from plasma into bowel occur –> hypotension & SNS response
- colicky abdo pain, diarrhoea, nausea, tachycardia
- avoid foods high in simple sugar content & replace w diet consisting of high-fibre, complex carb & protein rich foods; also small frequent meals & separate solids from liquid intake by 30mins
- usu self-limiting and resolves within 7-12wks
- late dumping syndrome/reactive hypoglycaemia 1-2%
- usu 1-3hrs after ingestion of carb-rich meal, typically months to yrs after surgery
- neuroglycopenic sx (dizziness, fatigue, diaphoresis, weakness) assoc w low serum glucose levels; exact aetiology uncertain but prob includes combo of late dumping, beta cell hyperfunction and exaggerated incretin response
- same dietary modification as above
55
Q
PSC
A
A progressive, obliterative fibrosis (same as radiation enteritis) of the intra and extrahepatic biliary tree, causing strictures, secondary cholangitis and progressive liver failure
56
Q
Chronic liver failure
A
Many causes; all associated with gradual and incremental loss of liver cell mass and function, due to chronic or repeated cell injury and attempts at repair. There’s a fibrosis and scarring process associated with this regeneration and repair, that leads to the clinical condition of cirrhosis, with a typically small, shrunken, irregular liver and an increased risk of HCC development.
Cycles of necrosis, fibrous scarring & regeneration –> distortion of microcirculation of liver & disturbances to liver cell perfusion (hepatocellular injury and necrosis) –> fibroblast activity –> collagen deposition (esp in space of Disse) –> loss of fenestrations in sinusoidal endothelial cells –> Cirrhosis
ETOH –> hepatic steatosis –> alcoholic hepatitis –> cirrhosis
on biopsy: hepatocellular necrosis, PMN infiltration, presence of Mallory bodies
- lactic acidosis & hypoglycaemia bc of impaired Cori cycle
- build up of ammonia bc of impaired nitrogen homeostasis
- immune function compromised as liver’s phagocytic and synthetic capacity impaired
- portal hypertension +/- varices
- ascites
- coagulopathy/thrombocytopaenia
- hepatic encephalopathy
- hepatorenal syndrome (vasoactive changes in arterial circulation –> decreased GFR)
- bacterial infection & hepatic encephalopathy = leading causes of death
- HCC
57
Q
Amoebic liver abscess
A
Entamoeba histolytica (parasite). Faecal oral spread; humans ingest cysts orally and then trophocytes are released and multiply in the colon (espec caecum) - which causes diarrhoea in ~30% - then these trophocytes reach liver by portal venous and lymphatic circulation or sometimes by direct extension through colon wall –> peritoneum –> liver capsule.
58
Q
Portal hypertension
A
A combination of two things;
- An increase in the vascular resistance to portal flow - due to an architectural distortion in the liver (increased passive resistance secondary to fibrosis and regenerative nodules) and also an imbalance in the endogenous vasoconstrictors which are increased (norepinephrine, endothelin etc) & vasodilator nitric oxide which is decreased - increases hepatic vascular tone through contraction of myofibroblasts/activated stellate cells/vascular smooth muscle cells of intrahpeatic veins.
- An increase in portal blood flow due to progressive splanchnic arteriolar vasodilation/splanchnic hyperaemia (most of the medications for portal HTN are aimed at reducing this increased splanchnic blood flow)
59
Q
Ascites in chronic liver failure
A
- increase in portal venous pressure causing splanchnic vasodilatation which alters the capillary pressures and permeability –> fluid leakage into peritoneal space
- also increased lymphatic pressure leading to transudation and leakage of lfuid from lymphatic system
- low plasma protein from reduced production of proteins in liver –> reduced osmotic pressure of plasma –> less fluid removed from extravascular sites and more fluid leaking from blood vessels
- also increased sodium and water retention in chronic liver failure due to reduced circulating plasma volumes and pooling of blood in splanchnic system –> messaging to kidneys to activate JGA –> increased aldosterone and ADH levels via activation of RAAS
60
Q
Cholangitis
A
biliary obstruction causes cholestasis and increased pressure in biliary system –> leads to infection and cholangiovenous reflux, causing translocation of bacteria from the biliary system into the venous system –> systemic sepsis
61
Q
Chronic pancreatitis and chronic pain in pancreatitis
A
- a benign inflammatory disease characterised by irreversible fibrosis and atrophy of pancreatic parenchyma secondary to repeated injury resulting in altered structure and function, both endocrine and exocrine
- aetiology
- most common is chronic alcohol abuse
- Toxin + metabolites - alcohol, smoking, Tg, Ca, medications
- Idiopathic
- Genetic - SPINK1, PRSS1, CF
- Autoimmune - IgG4
- Recurrent and severe: post-necrotic severe AP
- Obstructive - SOD, divisum
- multiple theories for pathogenesis; no one really knows; does seem to be common pathway of an initial insult with injury which is often recurrent, followed by an attempt at healing through fibrosis & regeneration
- 2 hit hypothesis:
- pre-existing acute pancreatitis risk factor that initiates first acute hit of pancreatitis
- abnormal repsonse to that pancreatitis –> chronic inflammation & progression to chronic pancreatitis
- this fits with necrosis-fibrosis pathway theory which is that multiple episodes of acute pancreatitis -> duct distortion & altered pancreatic secretions that over time lead to loss of panc parenchyma & fibrosis
- toxic metabolite hypothesis:
- alcohol, tobacco & other environmental factors damage acinar cells which results in their chronic destruction
- several products of alcohol metabolism eg fatty acid ethyl esters & ROS cause fragility of intraacinar organelles, such as zymogen granules & lysosomes, which -> abnormal panc enzyme activation inside acinar cells
- acetaldehyde, another alcohol metabolite, causes direct acinar injury
- NB alcohol also directly activates pancreatic stellate cells which produce fibrosis
- ductal blockade theory
- protein plugs that form in panc ducts, diffuse fibrosis, increased viscosity of panc juice, stone formation, calcification –> increased ductal pressure –> acinar cell autodigestion & inflammation –> chronic pancreatitis
- thought that alcohol also works through this pathway bc reduces bicarb & water secretions in ductal secretions making it thicker & more likely to clog ductal system
- oxidative stress theory
- oxidative stress causes free radical generation within acinar cells -> membrane lipid oxidation & activation of inflammatory pathways -> fibrosis
- exocrine failure due to
- loss of acinar cells
- fibrosis and strictures within ductal system from chronic scarring that stop the flow of any panc juices that may be required
- leads to steatorrhoea & requirement for replacement panc enzymes
- ≥90% of gland needs to be dysfunctional before steatorrheoa, diarrhoea & other sx of malabsorption
- endocrine function
- islet cells initially preserved but over time get progressive atrophy -> endocrine dysfunction
- chronic pain related to chronic pancreatitis; number of mechanisms (intra and extra-pancreatic)
- increased pressure within ductal system/parenchyma due to obstructive-type pathophysiologies –> pain
- inflammatory involvement of intra-panc nerve fibres - neuro-immune reaction - inflammatory cells infiltrate round the nerves
- increase in number of nerve fibres in fibrotic panc tissue
- increased amounts of neurotransmitters in afferent panc nerves
- aberrant CNS perception of pain
- other complications:
- biliary stricture where distal aspect of CBD passes through panc head
- duo stenosis & GOO due to fibrosis & scarring here
- pseudocysts espec in setting of disruption of panc duct
- false aneurysms of visceral vessels can form leading to bleeding which may be acute presentation
- portal & splenic vein occlusion due to chronic inflammation –> extrahepatic portal HTN that can present as haematemesis & melaena
- pancreatic ascites
- pancreatic fistula
- risk factor for pancreatic ductal adenocarcinoma
62
Q
ITP
A
- Immune thrombocytopenic pupura
- Auto-antibodies against the membrane glycoproteins on the platelets that labels the platelets for destruction in the spleen
- Treatment
- medical: observation, steroids or immunoglobulins, or cytotoxic agents (eg rituximab)
- indications for surgery: resistant to medical treatment, incomplete responder, severe drop in platelets <10 for 6 weeks, pregnancy if plt <30 and not responding to treatment
- 80% cured, 15% partial, 5% failure (accessory spleen or rupture)
