Medicine Flashcards
What is pulmonary hypertension?
Mean PAP of >25mmHg at rest or > 30 with exercise
Pulmonary venous hypertension is defined as an elevated PCWP > 18
What causes pulmonary hypertension?
Classified according to the World Symposium on Pulmonary Hypertension
Group 1 -due to causes that lead to structural narrowing of the vessels. idiopathic, drug and toxin induced, due to collagen vascular disease, portal hypertension, HIV, congenital heart disease or schistosomiasis, pulmonary veno-occlusive disease, persistent pulmonary hypertension of the new born
Group 2 - secondary to left-sided heart disease - LVSD, LVDD, valvular diseasr, cardiomyopathies
Group 3 - secondary to lung disease or hypoxaemia - CIOPD, ILD, OSA, chronic altitude exposure, alveolar hypoventilation disorders, developmental lung disease
Group 4 - secondary to chronic VTE
Group 5 - due to multifactorial mechanismshaem disorders e.g. SCA, sarcoid, glycogen storage disorders
What is the pathophysiology of pulmonary hypertension?
There are 3 underlying processes
1. Increased flow:
-Left-to-right shunting
-Back up of flow due to LV dysfunciton or valvular heart disease. Results in vascular smooth muscle remodelling and compensatory hypertenison to drive flow forward
2. Puomonary arterial hypertension
- endothelial dysfunction - results in decreased vasodilator production e.g. NO.
- hypoxic pulmonary vasoconstriction
3. Small pulmonary vessel structural change or destruction. e.f. VTE - causing obstruction and increased resistance to flow
-
What ECG changes might you see in a patient with pulmonary hypertension?
Signs of RVH
- p - pulmonale in II and V1 (RA en largement)
- RAD
- Tall R wave V1 and V2
- RBBB
- RV strain pattern - ST depression and TWI in V1-3 in the inf leads
How is pulmonary hypertension managed in the ICU?
Manage underlying cause
- LTOT for advanced CIOPD - reduces HPVC and i proves RV SV and CO
- NIV - for COPD/OSA
- Pulmonary endarterectomy - for pulmonary veno-occlusive disease
- Anti-coagulation for chronic VTE
Medical therapies include
Diuresis - manage RV failure and volume overload
Vasodilators - improve CO by decreasing RV overload - prostacyclins, endothelin-receptor antagonists, phosphodiesterase inhibitors
What is the mortality rate in patients with severe pulmonary hypertension admitted to GICU?
Requirement for inotropic support may be associated with a mortality of 50%
Describe the pathophysiology of right ventricular failure
- RV tolerates increases in preload easily
- tolerates increases in afterload poorly
- sudden increases in PVR increases RVEDP and increases RV work. The raised RVEDP decreases pulmonary perfusion. The flow profile then begins to look like the LV - i.e happening in diastole
- RV dilates to maintain SV
- crescent shape is lost and the IV septum bulges into LV. LV filling then becomes reduced. This is known an ventricular interdependence
- This results in systemic hypoperfusion and a further decrease in coronary perfusion. Unless the RV is offloaded a vicious cycle ensues leading to circulatory failure and death.
What are the causes of right ventricular failure?
Intrinsic RV failure (normal PVR) - RV infarction, cardiomyopathy.
RV failure with increased PVR - PE, pulmonary hypertension, increased PVR (e.e. hypercapnia, acidosis, norad), LVAD implantation
RV with volume overload - LV failure, L-R intracardiac shunting
What are the signs of RHF?
Peripheral oedema, raised JVP, tender hepatomegaly, pansystolic TR murmur, 3rd HS, loud p2 due to raised PAP. Giant V waves if there’s TR.
What might the ECG show in RHF?
RAD RBBB RV strain pattern - ST depression and TWI in V1-3 S1Q3T3 if PE May be normal
What might the CXR show in patients with RHF?
PA dilatation
Oligaemia of affected lung (Westermark’s sign)
What might the ECHO show in RHF?
Dilated poorly functioning RV TR Hypertrophy Septal bulging RV hypokinesia with apical sparing may suggest PE (McConnell's sign)
How should you manage a patient with RHF?
- optimise fluid status. If PVR is high offload with diuretics
- reduce PVR - oxygen, correct pH and CO2, optimise lung volume (PVR is minimal at FRC), consider pulmonary vasodilators e.g. NO, sildenafil
- improve RV function - modify vent settings to offload the RV - avoid high intrathoracic pressures, limit mean airway pressures
- Maintain CPP (DBP > RVEDP). Low dose vaso has a better PVR profile than norad
- add inotrope if TAPSE < 16mm. Adrenaline raises PVR, dobutamine increases CO and causes pulmonary vasodilatation, PDE3 inhibitors e.g. milrinone causes inodilation
- treat co-existing LVF
What is acute liver failure?
Rare, life-threatening illness
Normally in patients without pre-existing liver disease
What are the 3 key features of acute liver failure?
Jaundice, encephalopathy and coagulopathy
What is the classification of acute liver failure?
The O’Grady classification system categorises ALF based on the interval between onset of jaundice and development of encephalopathy
Hyperacute: < 1 week
Acute: 1-4 weeks
Subacute: 4-12 weeks
What are the causes of acute liver failure?
Infective - Hep A-E, HSV, CMV, VZV, EBV
Drugs - paracetamol, phenytoin, valporate, isoniazid, chemo, ecstasy
Toxins - amanita phalloides mushroom
Malignancy - primary/secondary
Vascular - Budd-Chiari (hepatic vein thrombosis), ischaemic hepatitis (hypotension, hypoperfusion, hypoxia-related)
Pregnancy-related: HELLP syndrome, fatty liver
Metabolic disease: Wilson’s disease
Other: Seronegative hepatitis, autoimmune
In paracetamol toxicity, what are the King’s College criteria for liver transplant in acute liver failure?
ph< 7.3
OR
INR > 6.5 and Cr > 300 and grade 3 or 4 encephalopathy
In non-paracetamol ALF what are the Kings criteria for transplant?
INR > 6.5 Or Any three of -age < 11 or > 40 -non hep A,non-hep B or and idiosyncratic drig reaction -not hyperacute -INR > 3.5 -bili> 300
How does acute liver failure present?
malaise, nausea, jaundice with encephalopathy developing over varying time intervals.
It is associated with high cardiac output and low SVR making septic shock a differential
How is encephalopathy graded?
West Haven criteria
Grade 1 - lack of awareness, anxiety or euphoria, shortened attention span
Grade 2 - lethargy or apathy, disorientation in time, personality change, inappropriate behaviour
Grade 3 - Somnolence to semi-stupor, confusion, gross disorientation, remains responsive to verbal stimuli
Grade 4 - Coma
What are the potential mechanisms of renal failure in acute liver failure?
- ATN (most common) secondary to hypovolaemia, hypotension or hypoperfusion, or nephrotoxins e.g. paracetamol
- Secondary to underlying disease e.g. glomerulonephritis in hep b and c
- Intra-abdominal hypertension due to ascites
- Hepatorenal syndrome
What is the ICU management of acute liver failure?
Early referral to a tertiary centre
- I+V for reduced GCS. Avoid high PEEP if possible to avoid increasing hepatic portal venous pressure and ICP
- CV - targeted fluid resus aiming to avoid worsening cerebral oedema, vasopressor to maintain MAP 60-65 and CPP 60-80
- Neuro - head elevation, sedate, avoid hypotension, avoid hypoxia and hypercapnia, avoid fever, normal BM. Mannitol or hypertonic saline for intracranial hypertension
- Renal - may need RRT to avoid fluid overload and acidosis
- Coagulation - product replacement in active bleeding, but not routinely.
What is the mechanism of liver injury in paracetamol overdose?
The metabolite N-acetyl-p-benzoquinone imine (NAPQI) causes the hepatotoxicity.
Normally paracetamol is metabolised by glucoronidation and sulphation. A small amount is metabolised to NAPQI which is then detoxified by glutathione.
In paracetamol OD more is shunted down this route as the glucuronidation and sulphation become saturated, glutathione becomes depleted and the NAPQI builds up causing widespread hepatocyte damage.
What increases your risk for hepatotoxicity following paracetamol OD?
Cytochrome enzyme induction - chronic ETOH, enzyme inducing drugs e.g. carbamazepine, barbituates, rifampicin, isoniazid, st johns wort
2. Glutathione depletion - malnutrition, anorexia, existing liver injury
How is paracetamol OD treated and why?
N-acetylcysteine is a precursor for glutathione
Should be administered within 8 hours
What are the causes of cirrhosis?
Toxins - alcohol
Infective - hep b and c
Drugs - methotrexate, amiodarone
Cholestatic conditions - PBC, PSC
Autoimmune - autoimmune hepatitis
Hereditary - wilsons disease, haemochromatosis, alpha-1 antitrypsin deficiency, type IV glycogen storage disease
Vascular - Budd-Chiari syndrome, veno-occlusive disease
Other - non-alcoholic fatty liver disease
What scoring systems predict mortality in cirrhosis?
Child Pugh
Meld
Describe the Child Pugh scoring system
Encehalopathy Ascites Bilirubin Albumin INR Number of points correlates with a 1 year and 5 year % survival
Describe MELD
Predicts mortality in hospitalised patients
Calculation based on bilirubin, INR and Cr
Why do patients with cirrhosis get admitted to ICU?
Variceal bleeding Encephalopathy Alcoholic hepatitis AKI Severe sepsis
What is the in hospital mortality for patients with cirrhosis?
> 50%
65-90% in those with severe sepsis requiring organ support
What is portal hypertension?
Portal pressure > 10%
A/w development of a porto-systemic collateral venous circulation, ascites and splenomegaly
Diagnosed clinically
How is variceal bleeding managed?
Volume resuscitation Vasoconstrictors e.g. terlipressin OGD and band ligation Antibiotics Sengstaken-Blakemore tube if there is failure to control bleeding until repeat OGD or TIPPS
What is TIPPS?
Transjugular intrahepatic portosystemic stent shunt.
Endovascular procedure that establishes communication between the inflow portal vein and the outflow hepatic vein, using a stemt
Reduces portal pressures in patients with complications due to portal hypertension e.g. variceal bleeding and diuretic refractory ascites
What is hepatorenal syndrome?
Renal failure affecting patients with cirrhosis or fulminant liver failure
It is a pre-renal AKI that is unresponsive to fluid therapy
There is abnormal autoregulation with renal vasoconstriction and dilation of splanchnic vessels
What are the diagnostic criteria for hepatorenal syndrome?
- Cirrhosis with ascites
- Cr > 133
- No improvement in Cr after 2 days of diuretic withdrawal and volume expansion with albumin
- Absence of shock
- Absence of nephrotoxins
- Absence of renal parenchymal disease
What are the types of hepatorenal syndrome?
Type 1 - rapidly progressive decline in renal function, carrying a mortality > 50%
Type 2 - More indolent, a/w diuretic resistant ascites
A trial of treatment with terlipressin and plasma expansion with albumin should be considered. TIPSS will improve renal function. Definitive treatment is with transplant
What is SBP?
Ascitic fluid infection
Normally occurs in patients with cirrhosis and ascites
How might SBP present?
Fever
Hypotension
Abdo pain
Altered mental status
What are the features of hepatopulmonary syndrome?
Intrapulmonary shunting and hypoxia in patients with cirrhosis
Dyspnoea and hypoxia are worse in the upright position
Carries a poor prognosis and is an indication for orthotopic liver transplant in suitable candidates
What are the causes of chest pain?
- Myocardial ischaemia
- Pleuritic chest pain - pneumonia, PE, musculoskeletal
- Aortic dissection
- Pericarditis
5, Gastro-oesophaeal - GORD, dyspepsia
What differentiates MI from angina?
Pain > 20 mins not relieved by nitrates
More likely MI if a/w sweating/nausea/vomiting
Severity - worst pain ever, feeling of impending doom
Describe the pain a/w aortic dissection
Very sudden onset and severe at outset
May have a tearing quality
Often startes in the anterior chest, spreads to neck and then the back over a few minutes
Can start as neck pain - if originating in the arch
Or interscapular pain in those of the descending aorta
What causes pleurisy?
Pneumonia
PE
Pneumothorax
Describe pericardial pain
Worse on inspiration, central, positional ion nature, typically relieved on sitting up.
What are the causes of oedema?
Bilateral - CCF Hepatic failure Renal failure Nephrotic syndrome Malnutrition Immobility Drugs e.g. NSAIDS, calcium channel blockers Unilateral -lymphatic obstruction -venous obstruction e.g. DVT -cellulitis -localised immobility - ruptured bakers cyst
Describe Virchow’s triad
3 factors necessary for the formation of a thrombus
- statis/turbulence of blood flow
- injury to endothelium
-alterations in coagulability
VTE pften occurs in areas of vascular trauma e.g. in response to indwelling devices, or in regions of poor flow
What are the risk factors for VTE?
Venous statis - immobility, long travel, varicose veins
Endothelial injury - indwelling devices, surgery, trauma, burns
Hypercoagulability - malignancy, pregnancy and puerperium, obesity, past hx VTE, drugs e.g. COC, HRT, chemo, smoking, ageing, thrombophilia e.g. factor V leiden, activated protein c resistance, antiphospholipid syndrome, antithrombin and protein c and s deficiencies
How are PEs classified?
- Massive - where theres BP < 90 for at least 15 mins or requiring inotropic support, pulseless, profound bradycardia
- Submassive - PE with RV dysfunction or myocardial necrosis
What might an ECHO show in acute PE?
RV overload and dysfunction
McConnell’s sign - reduced RV free wall contracility with sparing of the apex
What guidelines are there to aid management of PE?
The European Society of Cardiology 2014
Describe the ESC guidelines on the diagnosis of PE
Is CTPA immediately available - if yes proceed to this
If not then ECHO
If there is no RV dysfuction then unlikely PE
If there is RV dysfuction and CTPA unavailable or patient unstable then treat as PE.
How are PEs treated?
- Anticoag - UFH is preferred initial mode
- Thrombolysis - is first line reperfusion therapy, surgical embolectomy may be needed in those with CI to systemic thrombolysis or where thrombolysis has failed to improve the haemodynamic status.
Is there any evidence to support thrombolysis in PE treatment?
The PEITHO trial was an RCT comparing IV tenecteplase plus heparin with just heparin. Patients needed to have evidence of RV dysfunction
There was improved all cause mortality at 7 days, although there were significantly more major bleeding complications in the thrombolysis group including intracerebral.
How can VTE be prevented?
- General measures - mobilise and hydrate
- Non-pharmacological - TEDS, ICDs
- Pharmacological - UFH, LMWH, NOACs
What is heparin?
A large polysaccharide
Naturally occurring anticoagulant
Exerts its effects by binding to endogenous an antithrombin III. This then inhibits factor Xa and IIa
Cleared by the reticuloendothelial system
Describe LMWH
Short chain polysaccharides Work in a similar way to UFH They have a lower risk of bleeding and Complications such as HIT than UFH. Renally excreted No monitoring is required
What is protamine?
Reverses UFH
1mg neutralises 100units of UFH
Give slowly to avoid pulmonary hypertension
May partially revers LMWH but its effects are inconsistent
What causes isolated APTT rise?
Haemophilia A - (factor VIII deficiency) Haemophilia B (Factor IX deficiency) Factor XI deficiency Factor XII deficiency Heparin Antiphospholipid syndrome Artifact
What are the contraindications to heparin?
Allergy
Previous HIT
Active major bleeding or risk of serious bleeding
Platelets < 50
Coagulopathy
Recent neuraxial blockade - don’t do within 12 hours of UFH admin, can be given 4 hours after uncomplicated neuraxial blockade.
What is HIT?
Heparin-induced thrombocytopenia
- Type 1: non-immune mediated, more common, occurs within 3 days of treatment, platelet count 100-150, no bleeding or thrombosis complication, resolves spontaneously
- Type 2: Immune mediated, IgG to heparin/platelet factor 4 complex causes platelet activation and results in arterial and venous thrombosis, 0/6% of patients treated with heparin, more common with UFH, 5-10 days after starting treatment, platelets fall to ~ 50 or by 50%, thrombosis occurs in 20-50%, skin necrosis in up to 20%
How do we diagnose HIT?
-Calculate a pre-test probability
-On the basis of this carry out a test after consulting haematologist
Pre-test probabilty is based on fall in platelets, timing, thrombosis and potential other causes. (the 4T’s)
How is HIT managed?
It’s a prothombotic state
Heparin should be stopped
Alternative anticoag should be started
-Argatoban is the first line choice - it’s a direct thrombin inhibitor and only licensed for use in HIT
-or dabigatran, danaparoid, fondaparinux
-Avoid giving platelets
-warfarin worsens skin necrosis and should be given until plateletns are > 150
-Avoid further heparin for 100 days. No IgM antibodies are produced so the body doesn;t have immunological memory
What is the aetiology of valvular lesions?
- Congential e.g. adult survivors of CHD, or bicuspid aortic valve which predisposes to early calcific aortic stenosis
- Rheumatic fever- causes scarring, thickening and calcification of valves. Mitral > aortic. Rare in developed countries
- Degenerative - acquired calcific aortic stenosis in elderly
- Infective - endocarditis causing destruction of leaflets and chordal rupture
- Prosthetic - artificial valves may degenerate or leak as a result of valve dysfunction or dihiscence or surgical sutures
What is encephalitis?
Inflammation of the brain paraenchyma - normally caused by viruses gaining access to the CNS via haematogenous spread
What are the symptoms of encephalitis?
Personality change Headaches Confusion Seizures including status Focal neurology Coma
What are the caused of encephalitis
Viruses - HSV-1, enterovirus, VZV, EBV, Rabies, CMV
Bacteria, fungi and TB
It can also occur secondary to an nautoimmune process e.g. anti-NMDA receptor or anti-gamma-aminobutyric acid (GABA)-B receptor encephalitis
How is encephalitis diagnosed?
History and exam
Bloods - FBC,(WCC may help differentiate from bacterial meningitis)
- CRP,
- U+Es, LFTs, TFTs (other causes of confusion)
- coag (may have DIC, may need LP)
- blood cultures
- autoimmune serology
-consider HIV
Imaging - CT brain, MRI
EEG
LP - if not contraindicated - cell count and Gram stain, cytology, viral PCR, biochem, culture, autoantibiodies
What are the differential diagnoses of encephalitis?
- Infection - meningitis, cerebral abscess, sepsis, HIV
- Vascular - CVA/TIA, intracranial haemorrhiage, posterior reversible encephalopathy syndrome (PRES)
- Malignancy - primary incl lymphoma, metastases
- Toxin/metabolic encephalopathy - hepatic encephalopathy, uraemia, thyroid crisis, electrolyte disturbance, illicit drugs e.g. cocaine, MDMA, LSD, overdose, seritonin syndrome
- Autoimmune - anti-NMDA or anti-GABA-B receptor encephalitis, vasculitis, cerebral lupus, acute disseminated encephaomyelitis (ADEM) e.g. secondary to viral infection or post rabies vaccine
- Other - non-convulsive status epilepticus
How is encephalitis treated?
ABCDE
Aciclovir 1-mg/kg tds for 14 days
3rd gen cephalosporin to cover bacterial meningitis may be needed
What is the prognosis of encephalitis?
If untreated 80% mortality
If treated 10% mortality
Complication rate is high with memory loss, behavioural and personality changes, speech problems or epilepsy
What are the LP findings in bacterial meningitis?
Opening pressure - high Turbid CSF:plasma glucose low (<50%) Protein (g/l) high >1 Cell count > 1000 per mm3 WCC differential - poly morphs
What are the LP findings in viral meningitis/encephalitis?
Opening pressure normal/high Appearance - gin clear CSF:plasma glucose normal Protein normal Cell count < 500 WCC differential lymphocytes
What are the LP findings in fungal meningitis/encephalitis?
Opening pressure - very high Appearance - fibrin web CSF:plasma glucose - low/normal Protein - high (0.2-5) Cell count 100-500 WCC differential lymphocytes
What are the causes of acute shortness of breath at rest?
Cardiovascular - LVF, acute PE, mitral stenosis
Respiratory - acute severe asthma, exac COPD, pneumonia, pneumothorax, ARDS, anaphylaxis, inhaled foreign body
Other - psychogenic hyperventilation, fever, metabolic acidosis, neurological disease
What are the causes of chronic breathlessness on effort?
CV - chronic heart failure, angina, chronic PE
Resp - COPD, pleural effusion, interstitial lung disease, bronchial cancer, lymphangitis carcinomatosis
Other - physical deconditioning, obesity, anaemia, neurological disease
What are the causes of cough?
Upper resp - URTI, rhinosinusitis, smoking, drugs
Lung disease - Ca, COPD, bronchiectasis, parenchymal lung disease, asthma, bronchitis, foreign body
Cardiac - LVF
Oesphagus - reflux
What are the causes of haemoptysis?
Common - bronchitis, pnuemonia, Ca, bronchiectasis, PE, LVF
Less common - bronchial ademona, mycetoma, vascular malformations, bleeding diasthesis, vasculitis (Wegeners, Goodpastures), connective tissue disease, endometriosis, spurious e.g. nose bleed
What causes wheeze?
Asthma COPD Bronchiectasis Large airway obstruction Pulmonary oedema
What does a polyphonic wheeze indicate?
Multiple simultaneous different pitched sounds occurring during expiration.
Caused by COPD and asthma
What does a fixed monophonic wheeze indicate?
Localised narrowing of a single airway
Might indicate bronchial carcioma
What do respiratory ‘squarks’ mean?
Opening of previously collapsed airway
Typical of extrinsic allergic alveolitis
What protein level in a pleural effusion indicates transudate vs exudate?
Protein < 30 g/dL - transudate
> 30 (or pleural serum protein raito 0.5) indicates exudate
What pH of a pleural effusion would be consistent with empyema?
pH < 7.2
What are the common causes of a transudative pleural effusion?
Cardiac failure
Nephrotic syndrome
Hepatic cirrhosis
Hypoalbuminaemia (malnutrition, chronic disease, malabsrption)
What are the uncommon causes of transudative pleural effusions?
Pericardial constriction
Meig’s syndrome (Ovarian fibroma)
Myxoedema
What are the common causes of exudative pleural effusion?
Bacterial pneumonia
Carcinoma
Mesothelioma
What are the less common causes of exudative pleural effusion?
TB Haemothorax Pancreatitis Sub-phrenic abscess Autoimmune disease Chylothorax Yellow nail syndrome (abnormal lymph drainage leading to yellow nails, pleural effusion and lymphoedema)
How should pleural effusions be investigated?
CXR Confirm pleural effusion may require USS Aspirate - LDH, pH, cytology CT thorax Pleural biopsy TFTs, u+es, LFTs, albumin ECHO
What LDH level is consistent with a pleural effusion being a transudate vs an exudate?
LDH < 200u = transudate
LDH > 200u (or pleural/serum ratio > 0.6) = exudate
What are the causes of pnuemothoraces?
Primary - implies normal lung and due to a ruptured pleural bleb
Secondary - occurs in association with underlying lung disease. Rupture of the visceral pleura results in communication between airway and pleural space
Traumatic
What is a closed pneumothorax?
The leak closes as the lung deflates so the amount of air escaping into the pleural space in limited, pleural pressure remains negative and resolution occurs slowly even without treatment
What is an open pneumothorax?
Occurs when persistent communication between the airway and the pleura develops (bronchopleural fistula), which is seen as a persistent bubbling of the chest drain
-The lung cannot re-expand and there is significant risk of infection being transmitted from the airway
How is a pneumothorax managed?
Small pnemothoraces in asymptomatic patients may required no treatment
Trial of aspiration is appropriate larger pneumothoraces and where patients are symptomatic - if unsuccessful ICD will be needed.
Surgical treatment may be required if non-resolving e.g. pleural abrasion or pleurectomy
Should not travel on an aeroplane for 3 months.
What is diarrhoea?
According to the WHO it’s the passage of 3 or more loose or liquid stools per day
Of type 6 or 7 stool as per the Bristol Stool Chart
What is the incidence of diarrhoea in ITU?
25-50%
What is the pathophysiology of diarrhoea?
Imbalance of water and solute transport in the GIT resulting from osmosis, secretion, inflammation or dysmotility
What are the causes of diarrhoea in ITU?
Infective causes
- bacterial e.g. e.coli, salmonella, campylobacter jejuni, clostridium difficile, Shigella
- viral e.g. noravirus, rotavirus
- fungal e.g. candida
- protozoal e.g. cryptosporidia, giardia lamblia
Non-infective
- IBD
- Drug related e.g. NG feed, antibiotics, oral magnesium, laxatives, chemo, alcohol, antacids
- mesenteric ischaemia
- bacterial overgrowth
- short gut syndrome
- post ileus recovery or overflow diarrhoea
- food intolerance
- others e.g. anxiety, IBS
What is osmotic diarrhoea?
Failure of the GIT to absorb osmotically active solutes - meaning that water is retained within the gut lumen e.g. NG feed associated diarrhoea
What is secretory diarrhoea?
Increased secretion or reduced absorption of salt and water across the gut mucosa, often results in large volume diarrhoea, doesn’t improve with starvation.
e.g. enterotoxin production e.g. Vibrio cholerae and laxatives
What is inflammatory diarrhoea?
Loff of integrity of the GI mucosa due to inflammation resulting in impaired absorption of bowel contents and exudative fluid loss
Bloody diarrhoea may result if it affects the large bowel
e.g. IBD
What is dysmotility diarrhoes?
Rapid transit time throught the GIT and the water and electrolytes from the small bowel overwhelm the absorptive capacity of the colon
e.g. post ileus.
What are the problems with ongoing diarrhoea in an ICU patient?
Patient-related -increased risk of pressure sores, increased risk of infection Organisational -significant workload for the staff - infection control risk -patients may require isolation
How would you manage a patient with diarrhoea?
ABCDE approach as needed
1. History - travel, exposure, onset, duration, characteristics, systemic symptoms, drug hx,
2. Exam - hydration status, abdo tenderness/peritonism, PR - exclude overflow
3. Investigations - blood tests, stool - MC+S, C.diff, virology, cysts, ova and parasites
4. Radiology - AXR if c.diff and abdo tenderness, erect CXR if perf suspected, CT abdo may be warranted
5. Surgical review - if significant abdo tenderness, immunosupporessed
Treatment - largely supportive , treat infections, chage type of NG feed, bowel management system, meticulous infection control, loperamide can be used if infection and overflow have been excluded
What is Clostridium difficile?
Anaerobic, spore-forming Gram positive bacillus.
It produces 2 toxins: toxin A (an enterotoxin, which causes fluid sequestration from the bowel) and toxin B ( a cytotoxin which is detected by the CDT test)
It’s a common and serious nosocimial infection often arising in situations where the patients normal gut flora have been eradicated
It produces copious, offensive, watery stools with a characteristic odour. The spores are not killed by alcohol gel
What are the risk factors for C.difficile infection?
1 Age > 60
- Broad spec antibiotics
- Underlying malignancy
- Albumin < 25
- Renal disease
- Pulmonary disease
- PPI
How would you approach a patient with confirmed C.diff?
Isolation
Inform infection control
Full barrier precautions
Hand washing with soap and water
oral or parenteral metronidazole or oral vancomycin
It can progress to fulminant pseudomembranous colitis in 20% with a mortality near 20%. Patients are at risk of developing toxic megacolon and perforation.
Fluid and electrolyte management.
What is acute coronary syndrome?
A spectrum or ischaemic events that follow sudden coronary artery occlusion. It’s initiated by stress-induced rupture of small, eccentric (i.e non-circumferential), non-occlusive, complex atherosclerotic plaques with lipd-rich cores and thin fibrous caps
Plaque rupture stimulates thrombus formation, vasospasm and arterial occlusion. The duration and degree of occlusion determine the severity of the ischaemia and results in a specturm of conditions from unstable angina, NSTEMI and STEMI
What is unstable angina?
Describe the occlusion of a coronary artery of limited extent and duration which causes ischaemia but not necrosis.
Cardiac enzymes don’t rise and there is no STE
What is an NSTEMI?
Occlusion of a coronary artery that is temporary, incomplete or alleviated by collateral vessels.
This limits ischaemia and necrosis to subendocardium causing cardiac enzyme release but not STE
What is a STEMI?
Coronary artery occlusion that causes transmural cardiac ischaemia
What does the RCA supply?
Main supply to the RV and AVN
Occlusion causes inferior (posterior) MI
What does the LAD supply?
Supplies larger territory - LV, septum and apex. Occlusion causes anterior MI
What factors limit O2 supply to the coronaries?
- CA narrowing - e.g. vasospasm, plaque thrombosis
- Reduced CA flow - e.g. HTN, tachycardia, increased LVEDP, LVH
- Reduced O2 carrying capacity
What factors increase O2 demand to the heart?
- Tachycardia
- Increased LV afterload/mass
- Increased RV afterload
- Increased contractility
What are the early complications of MI?
< 7 days
- arrythmias
- pericarditis
- papillary muscle or free wall rupture
- VSDs
- heart failure
What are the late complications of MI?
> 7 days
- mural thrombus over damaged myocardium (+/-VTE)
- autoimmune pericarditis (dresslers syndrome)
What is the pathophysiology of sickle cell disease?
- Due to a mutation on position 6 on the B-haemoglobin gene on chromosome 11 (valine substituted in place of glutamate), resulting in production of haemoglobin-S.
- It’s autosomal recessive
-Patients who are homozygous for the recessive allele (HbSS) have severe disease phenotype. Both homozygous and heterozygous confer resistance to malaria.
-HbS is less soluble compared to HbA with a tendancy to polymerise. This is worsened by hypoxia. The HbS polymers form within RBCs causing the classic sickle shape. These abnormal cells break down more rapidly leading to haemolysis and also cause microvascular occlusion, thrombosis and distal infarction.
The disease becomes clinically apparent between 3-6 months of age when there is a change form fetal to adult haeoglobin.
At what PaO2 does HbS sickle?
Homozygotes sickles at sats < 85% (PO2 5.2-6.5) and heterozygotes at S < 40% (PO2 3.2-4)
What types of sickle cell crisis are there?
- Vasoocclusive
- Sequestration
- Aplastic
Describe a vaso-occlusive sickle cell crisis
- Acute chest syndrome - due to pulmonary infarction. Acute illness with fever and/or resp symptoms in the presence of new pulmonary infiltrate. Presentation similar to pneumonia, high risk of respiratory failure and progression to ARDS. Leading cause of mortality in adults.
- Stroke - occurs in 10% of children with SCD
Leading cause of paediatric mortality in SCD, may be prevented by regular transfusions - Long bone ischaemia and avascular necrosis
- Abdo pain - due to visceral ischaemia
- AKI
Managed with rest, O2, IV fluids, analgesia, +/- broad spec abx, exchange transfusion
Describe a sequestration sickle cell crisis
Occurs mostly in kids
Caused by splenic sequestration
Presents with worsening anaemia, hypotension and a rapidly enlarging spleen
By adulthood most patients have infarcted their spleen and require immunisation and antibiotic prohylaxis
Managed with fluid resus and cautious transfusion
Describe an aplastic sickle cell crisis
Red cell aplasia caused by paravovirus B19 infection of folate deficiency
Managed with transfusion
What investigations should be performed in sickle cell disease?
- FBC (typically hb 60-90 and reticulocytosis)
- Blood film - sickling, target cells, Howell-Jolly bodies (normally filtered out by a functioning spleen)
- Sickledex test - confirms presence of HbS but doesn’t differentiate homo- or heterozygous
- Haemoglobin electrophoresis - Gold standard, detects different types of Hb and their relative proportions
What are the indications for an exchange transfusion?
Acute chest syndrome Stroke Acute hepatic sequestration MOF - Should be managed by the haematologists aiming Hb 90-100, with < 30% HbS
What is thalassaemia?
Caused by an abnormality in the transcription of either a- or b-globin genes, leading to excessive production of the other. These chains may precipitate within the red cell causing haemolysis and anaemia
In health 4 a-globin genes and 2 b-globin genes exist. The disease becomes clinically apparent at 3-6 months when fetal haemoglobin is taken over by adult haemoglobin
What is alpha-thalassaemia?
The deletion of between one and 4 of the genes from alpha globin. Clinical severity varies with deletion of all 4 being incompatible with life
What is beta-thalassaemia?
Usually due to a single gene mutation resulting in reduced production of b-globin chains. The excess alpha chains combine with the available beta-globins, delta globins and gamma globins. As a result abnormal amounts of HbA2 (delta chains) and HbF (gamma chains) are formed. The heterozygous state is known as minor (mild hypochromic, microcytic anaemia) and the homozygous as major (profound anaemia, transfusion dependent)
What special considerations should be given to the critically ill patient with beta-thalassaemia major?
- Transfusion support
- Infection control - pts may have had a splenectomy to reduce transfusion requirements, continue prophylaxis, increased risk of overwhelming sepsis.
- Yersinia infection - may occur in the presence of iron overload, have a high index of suspicion in patients with diarrhoea
- Iron-overload. May be associated with underlying hepatic impairment and cardiomyopathy, treat with desferrioxamine to chelate iron.
What is factor V Leiden?
An essential protein in the coagulation cascade and is required to produce thrombin.
It is usually inactivated by activated protein C (APC), thus preventing excessive clot formation.
What is factor V Leiden disorder?
An autosomal dominant condition with incomplete penetrance in which the sufferer produces a mutated form of factor V.
APC is unable to degrade the abnormal form and this results in ongoing clot formation.
Pts normally present with VTE.
What is antiphospholipid syndrome (APS)?
An autoimmune hypercoagulable state caused by the presence of antiphospholipid antibodies
It typically presents with arterial or venous thromboembolism or pregnancy-related complications e.g. miscarriages, still birth, IUGR, preterm labour, pre-eclampsia
It may be primary or secondary to other autoimmune disease esp SLE
What are the diagnositic criteria for antiphospholipid syndrome?
- One clinical event
- 2 antibody tests at least 3 months apart that confirm the presence of lupus anticoagulant or anti-b2-glycoprotein-1 antibodies
How is antiphospholipid syndrome managed?
Aspirin or anticoagulation
Plasma exchange in catastrophic APS
What is the pathophysiology of haemophilia?
Deficiency of specific coagulation factors
Inherited in an x-linked recessive fashion, hence only affecting males. There are 2 types:
A - deficiency of factor VIII
B - deficiency of factor IX
Disease severity is based on quantification of clotting factor levels (mild 5-50%, moderate 1-5%, severe < 1%)
How do patients with haemophilia present to the ICU?
Severe bleeding
Complications of haemorrhage or massive transfusion
unrelated
The most common presentations are haemarthroses and muscle haematomas
How are haemophiliacs managed on ICU?
Even in the absence of bleeding they should still receive their usual clotting factor concentrate to maintain factor levels > 50%. If interventions are planned the dose should be increased.
TXA can also be given and desmopressin (DDAVP) may be used to increase factor VIII in patients with mild haemophilia A
What is Von Willebrand’s disease?
The most common hereditary coagulopathy
Autosomal dominant inheritance and is characterised by quantitative or more rarely qualitative deficiency of vWF
Under normal circumstances vWF is produced by platelets and vascular endothelium. It’s required for platelet adhesion to the subendothelium and also binds to factor VIII and prevents its breakdown.
What are the types of von Willebrand’s disease?
Type 1 - AD, accounts for 85%. Results in a mild-mod deficiency
Type 2 - AD, accounts for about 15%. Functional defect of vWF subclassified into type 2A, 2B, 2M (rare) and 2N (rare)
Type 3 - AR, rare, severe deficiency of vWF (< 1%)
How does von Willebrand’s disease usually present and how is it managed?
Mucosal bleeding - e.g. dental extraction, epistaxis, menorrhagia, PPH
Managed with prophylactic DDAVP and factor VIII concentrate
What is DIC?
Dysregulated host response to various triggers
- an acquired syndrome characterised by the intravascular activation of coagulation with loss of localisation arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction.
What triggers DIC?
Sepsis
Trauma
Obstetric - AFE, placental abruption, pre-eclampsia, septic abortion, PPH
Describe the pathophysiology of DIC
Excessive thrombin generation
Accelerated thrombinogenesis occurs alongside excessive fibrinolysis, resulting in a heterogenous clinical presentation involving simultaneous thrombosis and bleeding.
In health thrombin regulates pro and anticoagulant pathways
In the presence of a severe and persistent trigger, thrombin generation become excessive and normal regulatory mechanisms are overwhelmed. The localisation of thrombogenesis is lost and clot is disseminated systemically.
Additionally the underlying trigger often causes endothelial dysfunction with NO depletion, which results in uninhibited platelet activation. The fibrinolytic pathways work to counteract this clot formation and plasmin activation results in the generation of large numbers of fibrin-degradation products
What are the clinical features of DIC?
Bleeding-related - ecchymosis and petechiae may become widespread, bleeding from venepuncture sites and wounds. Mucosal bleeding may occur due to hyperfibrinolysis and can result in GI or urinary tract haemorrhage
Thrombosis-related
-AKI
-Hepatic dysfunction
-Resp failure - alveolar haemorrhage, PEs, ARDS
-CNS dysfunction - large vessel occlusion, neuro obtundation, SAH, multiple cortical and brainstem haemorrhages and infarcts
How is DIC diagnosed?
Low platelet count
FDP/d-dimer
Fibrinogen
PT
Scoring system based on the above. A score of 5 or more is diagnostic.
TEG may also be useful.
How is DIC managed?
ABCDE aproach
Treat underlying condition
1. Blood products - RBCs, FFP aim INR < 1.5, plts aim > 50, cryo or fibrinogen concentrate aim fibrinogen > 1-1.5
2. Thromboprophylaxis - should be seriously considered
3. TXA should be avoided - hyperfibrinolysis is secondary to excess thrombin generation and it a physiological response to mitigate the uncontrolled thrombin generation. Inhibiting excess fibrinolysis with antifibrinolytic agents may be harmful in DIC.
What are the common causes of interstitial lung disease?
Upper lobe predominant
- Coal-workers pneumoconiosis
- Histiocytosis
- Allergic bronchopulmonary aspergillosis
- Ankylosing spondylitis
- Radiation pneumonitis
- Tuberculosis
- Silicosis
- Sarcoidosis
Lower lobe predominant
- Cryptogenic fibrosing alveolitis (idiopathic pulmonary fibrosis)
- Asbestosis
- RA
- Drugs
- Scleroderma
How is ILD classified?
- Known cause/association - CT disease, occupational disease/drug side effects
- Idiopathic interstitial pneumonia
- Granulomatous disease - sarcoid, hypersensitivity pneumonitis
- Other - lymphangioleiomyomatosis, Langerhans cell histiocytosis, eosinophilic pneumonia, pulmonary alveolar proteinosis
What are the subcategories of idiopathic interstitial pneumonias?
- Major idiopathic interstitial pneumonias
- Unclassifiable
- Rare - idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis
How is idiopathic pulmonary fibrosis diagnosed?
Diagnosis of exclusion
It’s the most common ILD
Mortality is significantly worse than other types of ILD
Requires:
1. Clinical assessment - symptoms, drug history, environmental exposure
2. Radiological investigation - CXR, HRCT - ground glass opacity, reticular shadowing with traction bronchiectasis and honey comb lung
3. Tissue biopsy if diagnostic uncertainty
What pharmacological treatment is available for ILD?
- Immunosuppressants (not useful in IPF)
- corticosteroids, cyclophosphamide, azathioprine, methotrexate, mycophenylate, ciclosporin, mycophenylate, anti-TNF e.g. infliximab - Antifibrotic agents - slow the rate of loss of lung function. Pirfenidone and nintedanib
- Oxygen therapy - slows down the rate of progression of associated pulmonary hypertension, but confers no survival advantage
When does the BTS recommend oxygen therapy in those with ILD?
- Resting PaO2 < 7.3
2. Resting PaO2 < 8 in the presence of peripheral oedema, polycythaemia or evidence of pulmonary hypertension
What non-pharmacological therapies are available for managing ILD?
- Pulmonary rehabilitation - improves breathlessness, exercise capacity and health-related QoL
- Manage co-morbidities - reflux is heavily implicated in the progression of IPF; pulmonary arterial hypertension
- Mange acute exacerbations
- Lung transplant - the only therapy proven to extend life expectancy in ILD
How is an exacerbation of ILD managed?
ABCDE approach
- investigations - bloods, CXR, HRCT, CTPA if PE possible; ECHO - CCF may be the cause plus assess right heart; bronchoscopy and BAL to exclude infection.
- Pharmacological management - pulsed methylpred
- NIV - it’s use is not supported by evidence unless a rapidly reversible cause is found
- I+V: high risk of VILI - high PEEP, recruitment maneuvres and prone ventilation should be avoided.
- ECMO as a bridge to transplant
- Lung transplant
How is angina managed?
- Nitrovasodilators - effective but tolerance develops unless there’s a nitrate free period daily
- Beta-blockers - improve prognosis. They enhabce diastolic myocardial perfusion by slowing heart rate and lower heart wall tension by reducing preload (+/- afterload)
- Calcium channel antagonists - useful if beta-blockers are contra-indicated. They relieve coronary vasospasm but some cause tachycardia (e.g. nifedipine) and are negative inotropes. Only CCA that slow heart rate (e.g. diltiazem) are given as monotherapy
- Revascularization
How is unstable angina/NSTEMI managed?
- Nitrates, beta-blockers +/- CCA
- Antiplatelet therapy - aspirin reduces MI and sudden death by 50%. Clopidogrel - decreases mortality by ~20% and is combined with aspirin for at least 30 days
- Consider PCI if medical therapy fails
How is STEMI managed?
Early reperfusion limits infarct size and reduces hospital mortality from 13% to < 10%
1. Immediate management - pain relief (reduces preload, lowers o2 consumption), oxygen, nitrates (reduce pain, infarct size and heart failure), aspirin (reduces mortality), clopidogrel, beta-blockers (reduces infarct size, arrythmias and mortality). Don’t delay revascularisation.
ACEI - reduce heart failure and improve remodelling in high-risk patients
Inotropes if cardiogenic shock
PCI within 90 mins of onset is the preferred revascularisation
Thrombolysis - most effective within 2 hours but benefit persists for 12. Reduces mortality by 25%
What causes vomiting?
- Metabolic - hypercalcaemia, Addisons disease, uraemia
- Inflammatory - visceral inflammation e.g. pancretitis, remote infection e.g. LRTI
- Drugs - cytotoxics, analgesic, antibiotics
- Neurogenic - intracranial tumours, painful stimuli, psychogenic, vestibulococchlear disease
- GI - obstruction, gastroenteritis
What are the causes of primary adrenal insufficiency?
a) autoimmune conditions,
b) infection (TB, disseminated fungal infections, HIV can cause necrotising adrenalitis secondary to CMV or infiltration by Mycobacterium avium-intracellulare or Kaposirs sarcoma)
c) Cancer - primary or metastatic
d) drugs e.g. etomidate, ketoconazole
e) other e.g. critical illness related corticostreoid insufficiency, adrenal glad haemorrhage, granulomatous and amyliod infitration, irradiation, iron deposits
What are the causes of secondary/tertiary adrenal insufficiency?
HPA axis suppression secondary to exogenous steroids
Hypothalamic or pituitary failure - malignancy, haemorrhage, infarction (Sheehan’s syndrome)
What is Addisons disease?
Failure of the adrenal cortex to secrete cortisol, which results in failure of the negative feedback to the pituitary and continual ACTH production.
MSH and ACTH share the same precursor molecule, hence MSH is also increased, leading to characteristic hyperpigmentation of the skin and buccal mucosa
How is adrenal insufficiency diagnosed?
- Cortisol and ACTH levels
- in primary adrenal failure cortisol is inappropriately low with a very high ACTH
- in secondary or tertiary failure both cortisol and ACTH will be low - The standard test for adrenal function is the Synacthen test. Failure of Synacthen to increase cortisol indicates adrenal insufficiency. The test is not affected by dexamethasone. A negative result rules out primary hypoadrenalism but not secondary
- Adrenal antibiodies and imaging may be useful in determining the cause
What are the clinical features of an Addisonian crisis?
CV - high output distributive shock
Neuro - lethargy, fatigue, extreme weakness, headache, dizziness, confusion, LoC
GI - D+V, abdo pain
Cutaneous - hyperpigmentation of skin in primary
Biochemical - Low sodium, high K, metabolic acidosis, hypoglycaemia
Other - autoimmune disease may be a/w other AI diseases e.g. pernicious anaemia or Grave’s disease
How is an acute Addisonian crisis managed?
ABCDE aproach
May initially be mistaken for septic shock
1. Initial resus - IV access, bloods for electroytes, glucose, cortisol, ACTH, fuid resus.
2. Replace glucocorticids and mineralocorticoids: 200mg hydrocortisone, followed by 100mg every 6 hours. MCs aren;t required acutely. Consider fludrocortisone with advice from endocrinology after fluid resus.
3. Invasive monitoring
4. Identify likely cause
What urine changes may occur in kidney disease and what do they indicate?
Frothy urine - proteinuria
Dark urine - myoglobinuria of rhabdo or hamoglobinuria of haemolysis
Recurrent intermittent frank haematuria - IgA glomerulonephritis in young people or cancer in older people. Glomerular bleeding is normally present throughout the stream.
What casts might be present in urine and what do they indicate?
Red cell casts - indicate glomerular bleeding
White cell casts - suggest acute infection
Hyaline casts and granular casts are normal
Fatty casts - nephrotic syndrome
Waxy casts - occur in dilated tubules in chronic renal failure
What are the effects of glomerular damage?
Reduced GFR Proteinuria Haematuria Hypertension Oedema
What is the pathological classification of glomerular disease?
- Proliferative disease - abnormal proliferation of cells within the glomerulus
- Membranous disease - the basement membrane is thickened and damaged
- Membranoproliferative disease
- Vasculitis
Glomerular disease may be focal (affects only some glomeruli), diffuse (affects all the glomeruli), segmental (affects only part of the glomerulus|) or global (affects the whole glomerulus)
What are the 5 major syndromes produced by glomerular disease?
- asymptomatic proteinuria or haematuria resulting from mild damage
- Acute glomerulopnephritis (acute nephritis syndrome) - consists of haematuria, acute fall in glomerular filtration, sodium and water retention and hypertension
- Chronic glomerulonephritis - slow progressive damage often with proteinuria, haematuria and hypertension
- Rapidly progressive glomerulonephritis - rapid renal failure with oliguria, haematuria and proteinuria
- Nephrotic syndrome - heavy proteinuria leading to hypoalbuminaemia and oedema
What diseases of the glomerular basement membrane are there?
- Minimal change nephropathy
- Focal segmental glomerulosclerosis
- Membranous nephropathy
What is minimal change nephropathy?
- accounts for 90% of nephrotic syndrome in children and 20% in adults
- in kids its a/w atopy and often follows an URTI
- responds to steroids + ciclosporin if relapses
- renal impairment doesn’t occur
- can be caused by NSAIDS
What is focal segmental glomerulosclerosis?
Accounts for 15% of adult nephrotic syndrome
Can cause hypertension and haematuria
Focal and segmental scarring is seen and the scars contain immunoglobulins and complement
Some respond to steroids
Many patients eventually develop ESRF and the disease can recur after transplant
Obesity is a recognised cause
HIV can cause a variant
What is membranous nephropathy?
Most common cause of nephrotic syndrome in adults
Proteinuria and often renal impairment
Usually idiopathic but can occur secondary to SLE, malignancy, hep B, or secondary to gold or penicillamine
It’s a/w autoantibodies against PLA2R phospholipase A2 receptor in blood and in deposits in the glomeruli
Some respond to steroids
The majority eventually develop ESRF
What types of proliferative glomerulonephropathy are there?
Mesangiocapillary glomerulonephritis IgA nephropathy (Bergers disease) Henoch-Schonlein purpura Diffuse proliferative glomerulonephritis Crescentic glomerulonephritis
Describe IgA nephropathy
Worldwide it’s the commonest primary glomerular disease
Typically presents as a young male presenting with macroscopic haematuria 1-2 days after an URTI
\Can also present with microscopic haematuria, proteinuria and renal impairment
Usually have raised IgA levels
Nearly 1/3 develop ESRF and recurrence can occur post transplant
What is Henoch-Schonlein purpura?
Mainly affects kids under 10
Typically presents with a purpuric rash on ankles, buttocks, and elbows, abdo pain and renal disease
Haematuria, proteinuria, hypertension, fluid retention and renal impairment sometimes with nephrotic syndrome
Most recover fully without treatment
What are the characteristics of microscopic polyangitis (MPA)?
skin
renal
joint
lung
What are the characteristics of granulomatosis with polyangiitis (GPA) (formally Wegeners) ?
ENT
Lung
Renal
What are the characteristics of eosinophilic granulomatosis with polyangiitis (EGPA)?
(Previously Churg-Strauss)
Asthma, eosinophilia
What are the characteristic features of polyarteritis nodosa (PAN)?
Hypertension
mononeuritis multiplex
gut/kidney/cerebral ischaemia
What are the small vessel vasculitides?
- ANCA associated vascullitis (AAV)
- microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiits (EGPA) - Immune complex vasculitis
- anti-GBM disease, cryoglobulinaemic vasculitis, IgA vasculitis
What are the medium sized vasculitidies?
Polyarteritis nodosa
Kawasaki disease
What are the large vessel vasculitidies?
Giant cell arteritis
Takayasu arteritis
What is Goodpasture’s syndrome?
Caused by antibodies against the glomerular basement membrane and the alveolar basement membrane of the alveoli which trigger inflammation
This causes a vasculitis with rapidly progressive crescentric glomerulonephritis which can lead to acute renal failure and lung haemorrhage
If untreated patients die from pulmonary haemorrhage or renal failure
treatment involves plasma exchange and immunosuppression
Most patients recover if treated early and relapse is uncommon
Describe primary systemic vasculiitis
Produce necrotizing inflammation of vessels and often affect the kidneys, resp tract, joints, skin and nervous system.
Classified according to the size of the vessel affected
What is c-ANCA?
Anti-neutrophil cytoplasmic antibodies
Patients with GPA have cyctoplasmic or C-ANCA reactivity against proteinase 3
What is p-ANCA?
Perineuclear or p-ANCA
Present in MPA
Describe the renal impairment in SLE
Classified by the WHO and modified by the International association of nephrology
Type 1 - minimal change on light microscopy
2 - mesangial proliferative
3 - focal proliferative
4- diffuse proliferative
5 - membranous
6 - advanced sclerosis
The renal presentation depends on the lesion but is typically nephrotic syndrome or renal impairment
There are usually double-stranded DNA and low complement levels
ESR is typically raised.
What is cryoglobulinaemia?
Cryoglobulins are immunoglobulins that preceipitate in the cold and may cause small vessel cryoglobulinaemic vasculitis
Occur in inflammatory or neoplastic diseases e.g. myeloma, lymphoma, mulitsystem autoimmune disease and chronic infection.
Presents with purpuric rash, arthraligia, peripheral neuropathy and glomerulonephritis
What 3 pathological processes lead to proteinuria?
- Overflow - secondary to increased plasma levels e.g. myeloma (Bence Jones Proteins), haemoglobinuria, myoglobinuria and inflammation
- Decreased tubular reabsorption - tubulointerstitial disease
- Filtration leak within the glomerulus e.g. glomerulonephritis, diabetes, amyloidosis
What level of urine protein is consistent with nephrotic syndrome?
> 3.5g/24 hours
or PCR >350mg/mmol or 40mg/mg
What are the clinical features of nephrotic syndrome?
Oedema
Urine may be frothy
Prothrombotic state - DVT, renal vein thrombosis
Hypertension
Hyperlipidaemia
Hypoalbuminaemia
Renal impairment and increased risk of a pre-renal injury
Decreased immunity - possibly because IgG is lost in the urine - increased risk of infection esp pneumococcal
Most common causes are minimal change glomerulonephritis in kids and membranous nephropathy or focal segmental glomerulosclerosis in adults
How is nephrotic syndrome normally managed?
Depends on the underlying cause
Kids are normally given steroids as it’s most likely to be due to a minimal change nephropathy
Adults normally undergo biopsy
ACEI and ARBs may reduce proteinuria
Oedema is treated with sodium restriction and diuretics
Anti-coagulation may be needed in cases of severe proteinuria
What are the causes of nephrotic syndrome?
- Glonerulonephritis -a) minimal change disease, b) membranous nephrophathy, c) focal segmental glomerulosclerosis, d) proliferative IgA nephropthy, post infective, SLE
- Diabetic nephropathy
- Myeloma nephropathy
- Amyloid nephropathy
- Genetic mutations (rare) - podicin, nephrin, laminin B2, CD2AP
What is acute interstitial nephritis?
Acute diffuse renal inflammation
Rapid deterioration in renal function
Usually asymptomatic but if drug induced there may be maculopapular rash, fever, eosinophilia.
Lumbar pain can also occur
There may be mild proteinuria, microscopic haematuria, white cell casts and eosinophils in the urine
USS - slighlty enlarged kideys
Treatment involves stopping causative drugs, treating infection and steroids.
Good prognosis
What causes acute interstitial nephritis?
Main cause is an allergic drug reaction esp to NSAIDS, PPIs, allopurinol, diuretics, antiretroviral drugs, penicillins, cephalosporins, rifampicin and sulfonamides.
Systemic or renal infection can cause an acute interstitial nephritis as can gout.
Also SLE, cryoglobinaemia and transplant rejection.
Why do patients with renal tubular acidosis develop a metabolic acidosis?
Those with proximal tubule damage develop bicarbonaturia alongside phosphateuria, glycosuria.
Thos with distal tubular damage also have impaired bicarbonate reabsorption plus aldosterone-regulated sodium reabsorption and potassium excretion.
What are the three layers of the glomerular filtration barrier?
- Endothelial cells -the glomeular capillary wall is thin with numerous 70nm pores filled with negatively charged glycoprotein
- Glomerular basement membrane - specialised capillary basement membrane has three layers and contains negatively charged glycoproteins atta ched to a 3D framework of collagen and other proteins
- Epithelial cells of Bowman’s capsule - the epithelial cells or podocytes have long projections from which foot processes arise and attach to the urinary side of the GBM.Foot processes from different podocytes interdigitate, leaving filtration slits on 25-65nm between them. The pores are the key selective barrier in the filtration process and prevent the passage of larger molecules such as albumin.
What substances are actively reabsorbed in the PCT?
Sodium Potassium Calcium Phosphate Glucose Amino acids Water There is also endocytic uptake of filtered proteins
What makes up the juxtaglomerular apparatus?
Macula densa
Extraglomerular mesangial cells
Granular cells
What hormones act on the kidneys?
Vasopressin
Natriuretic peptides
Parathyroid hormone
FGF23 (produces by bone osteoclasts and promotes phosphate excretion and inhibits vitamin d production
What hormones are produced by the kidneys?
Renin
Erythropoietin
Vitamin D
Prostaglandins
What does anuria suggest?
Total anuria is rare
Suggests urethral or bilateral ureteric obstruction, a severe rapidly progressive glomerulonephritis or aortic or bilateral renal arterial occlusion
How much does the glomerular filtration rate have to decrease by to start to get an increase in urea and creatinine?
It needs to fall to 30ml/min from a normal value of 130ml/min
What causes increase and decreased urea?
Increase with high protein intake and catabolic states and decrease with liver disease or overhydration.
Urea is freely filtered but there is some tubular reabsorption which is increased by dehydration or reduced renal perfusion, creating a greater elevation of urea than creatinine
How much blood do the kidneys receive?
1000ml/min, which is 20% of cardiac output
How is renal blood flow regulated?
- Autoregulation
- > myogenic reflex and tubuloglomerular feedback - Renin-angiotensin II system
- Prostaglandins
- Vasoactive peptides
- > bradykinin, natriuretic peptides, endothelin, vasopressin, adrenomedullin - Other regulatory pathways
- > renal nerves, dopamine, nitric oxide, adenosine
Describe control of renal blood flow - autoregulation
- Myogenic reflex - stretching of the BV wall causes reflex vasoconstriction, which reduces flow
- Tubuloglomerular feedback - a rise in glomerular pressure increases GRF and therefore tubular flow rate, this reduces time available for sodium and chloride reabsorption in the LoH. The higher tubular sodium and chloride concentrations are detected by the macula densa cause the juxtaglomerular apparatus to release adenosine. Adenosine acts on A1 receptors to cause afferent arteriolar vasconstriction, which reduces GFR.
Adenosine also promotes proximal tubule sodium reabsorption
Describe how the renin-angiotensin II system affects renal blood flow
The JGA releases renin in response to a drop in afferent arteriolar pressure, a fall in tubular flow rate, or a fall in tubular sodium and chlorodie concentration at the macular densa. Other stimuli include sympagthetic nerve stimulation and a fall in antiotensin II levels
Renin promotes production of angiotensin II which acts via AT1 receptors to vasoconstrict afferent and efferent arterioles. The dominant effect is on efferent arteriolar constriction, so the GFR is increased.
How do prostaglandins affect renal blood flow?
Many peripheral vasoconstrictors, esp angiotensin II, vasopressin, endothelin and noradrenaline stimulate the renal production of vasodilating prostaglandins such as PGE2 and PGI2 (prostacyclin). This protects the kidney from severe vasoconstriction.
Why does glomerular filtration occur?
Due to the hydraulic pressure gradient between the glomerular capillaries and Bowman’s space exceeding the opposing oncotic pressure
The hydraulic pressure is influenced by the state of vasoconstriciton of both the afferent and efferent arterioles. The oncotic pressure gradient reflects the difference in the concentration of osmotically active components between plasma and the filtered fliud. As larger plasma proteins are not filtered the oncotic pressure tends to oppose filtration.
What is renal artery stenosis?
Narrowing of the renal arteries causing reduced RBF and GFR, renal ischaemia, hypertension and sodium/water retention.
Mainly caused by atherosclerosis in older people and by fibromuscular dysplasia in younger patients.
Can be bilateral and atherosclerosis can cause complete occlusion.
Diagnosis is suspected where there is elevated ur and Cr, hypokalaemia and unequal kidney sizes on US.
What are the causes of renal artery stenosis?
- Atherosclerosis
- > normally vascular disease elsewhere
- > accounts for the majority
- Fibromusclar disease
- Large vessel vasculitis (Takayasu arteritis), neurofibromatosis, pressure from renal artery aneurysms and extrinsic pressure
What are the possible clinical features of renal artery stenosis?
- Hx of atherosclerosis or risk factors
- Hypertension
- Carotid/femoral/femoral bruits
- Pulmonary oedema
- Absent radial/ankle pulses
- Peripheral oedema
- Hyperternsive/embolic retinopathy
Why to patients with renal artery stenosis get hypertension?
Decreased renal perfusion stimulates the JXA to release renin, which enhances angiotensin II production
AngII causes HTN by systemic vasoconstriction and by stimulating aldosterone release - which promotes salt and water retention.
What happens to GFR in renal artery stenosis?
AngII vasoconstricts the efferent arteriole > the afferent. This reduces renal blood flow but maintains GFR.
If you then inhibit angII (ACEI or A2RB) then this removes the efferent vasoconstriction, causing a fall in GFR.
Why is renal artery stenosis associated with ankle oedema?
Bilateral renal artery disease causes enhanced proximal tubular sodium reabsorption
Contributary factors include a fall in renal blood flow, stimulation of the proximal tubule Na/H exchanger by angII and stimulation of the distal tubular sodium reabsorption by aldosterone
Aldosterone also promotes potassium secretion, which can cause hypokalaemia unless there is renal impairment.
Where in the kidneys is sodium reabsorbed?
65% - proximal tubule
25% - thick ascending limb of LOH
5% - distal convoluted tubule
2-5% collecting tubules and ducts
Where in the kidney do the diuretics work?
Furosemide - the Na/2Cl/K co-transporter on the apical membrane in the thick ascending loop of henle
Thiazides - the Na/Cl co-transporter on the apical membrane in the distal convoluted tubule
Amiloride - the epithelial sodium channel in the principal cells of the collecting ducts
Describe the water handling of the proximal tubule
The PCT is highly water permeable
Water follows the ions by osmosis
Describe water handling in the loop of henle
The descending limb is permeable to water but not ions
The ascending limb in permeable to ions but not water
Na and Cl are transported out of the thick ascending limbs into the interstitium, which raises its osmolarity, which in turn promotes water movement out of the descending limb
Within the loop 25% of filtered sodium is absorbed but only 10% of water, producing a dilute urine and hypertonic medullary
Describe water handling by the distal tubules
Water isn’t absorbed but ions are - further diluting the tubular fluid
Describe water handling by the collecting system
Water permeability at this level is controlled by ADH
Describe vasopressin
Made in the SON and PVN of the hypothalamus
Its packaged in granules which pass down to the posterior pituitary where the vasopressin is released by exocytosis
Osmoreceptors in the hypothalamus detect a rise in osmolality and trigger vasopressin release.
Vasopressin binds V2 receptors on the collecting ducts resulting in water channels to fuse with the apical membrane esp AQP2
Vasopressin also binds to V1 receptors on vascular smooth muscle and it enhances the effect of aldosterone on sodium reabsorption in the kidney
What are the actions of angiotensin II?
It promotes apical Na/H exchange and therefore sodium reabsorption
It also causes thirst and stimulates aldosterone production, vasopressin release, and renal and systemic vasoconstriction
When is renin released?
when there is a fall in circulating volume, which increases renal sympathetic activity. reduces afferent arteriolar tension, and reduces sodium chloride delivery to the macula densa.
What is the action of aldosterone?
It diffuses into the principal cells of the collecting duct and binds to receptors in the cytosol. This then promotes transcription of new apical sodium and basolateral Na/K ATPases.
This increases sodium reabsorption.
It’s mainly regulated by the renin-angiotensin II system
What are the key features of diabetes insipidus?
Central DI - not enough vasopressin is released bu the pituitary - occurs after head injury/brain tumours etc
Nephrogenic - the kidneys don’t respond to VP which may be genetic or occur secondary to low K, high Ca, lithium, amphotericin, gentamicin.
There is polyuria and polydipsia
Plasma osmolality and sodium are high and urine na and osmolality are low.
In central DI DDAVP (a vasopressin agonist) is useful but has no effect in nephrogenic.
What are the key features of SIADH?
Too much vasopressin
May occur secondary to tumours, surgical stress
Plasma osmolality and sodium are low
Urine osmolality and sodium are inappropriately high
Treat by restricting fluid intake - the kidney will still excrete some water and will eventually eliminate excess water.
Why are CCF, liver cirrhosis and nephrotic syndrome a/w generalised oedema?
Generalised oedema occurs where body volume is increased
In these conditions renal sodium handling mechanissm are intact but the kidney receives neuro-endocrine signals that promote sodium and water retention (perceived hypovolaemia)
CCF - low BP stimulates arterial baroreceptors
Liver cirrhosis - low vascular resistance causes low BP, caused by splanchnic vasodilatation and AV shunts, due ton increased NO.
Nephrotic syndrome - less well understood. Low plasma protein levels result in increased interstitial fluid, thus reducing circulating volume and triggering a volume-conserving response.
What are the volume-conserving responses in perceived hypovolaemia?
Increased sympathetic activity promotes sodium reabsorption in the PCT and reduces RBF. This lowers afferent arteriolar pressure, promotes renin secretion, resulting in angiotensin II, which further promotes PCT sodium reabsorption.
It also triggers aldosterone release which increases DCT sodium reabsorption
Describe potassium handling by the kidneys
Most potassium that is filtered is reabsorbed.
Potassium is then secreted into the tubular lumen in the collecting tubule and ducts.
Na/K ATPase on the basolateral membrane of principal cells drives K into the cell. The K can the leave via channels on the apical memebrane, the rate of which depends on the filtrate potassium being kept low. A high flow rate means that more K is secreted and excreted.
How does aldosterone affect Na and K?
It promotes the synthesis of Na/K ATPases and the insertion of more into the basolateral membrane.
It also stims apical sodium and potassium channel activity, increasing sodium reabsorption and potassium secretion.
How does blood pH level effect K handling in the kidneys?
K secretion is reduced in acute acidosis and increased in alkalosis
Chronic metabolic alkalosis is usually associated with a low potassium level.
What is the effect of magnesium on potassium in the kidneys?
Mg can reduce K secretion into the tubules.
In Mg deficiency this doesn’t happen and so more K is secreted into the tubule.
Therefore Mg deficiency can cause low K. It’s difficult to correct K without replacing Mg
How do diuretics affect K handling in the kidney?
All increase flow rate which increases K secretion
- Thiazides: reduce Na reabsorption in the DCT. K reabsorption depends on Na reabsorption so is reduced
- Furosemide: Inhibit K reabsorption
- Spironolactone: Antagonises aldosterone and so reduces K secretion
- Amiloride: blocks apical sodium entry into principal cells, reducing available Na for Na/K ATPase, which normally drives secretion.
Describe proximal renal tubular acidosis (type 2)
Relatively rare
Occurs when H secretion and bicarb reabsorption fails
May occur as part of Fanconi’s syndrome where is a/w other defects in tubule function - glucose, phosphate or urate reabsorption
Caused by genetics or nephrotoxics eg myeloma light chains
Bicarb is lost in the urine, causing metabolic acidosis
As plasma levels decrease, there is less bicarb filtered and the distal tubules can keep up with reabsorbing this lower amount. At this stage an acid urine can be excreted and therefore a severe acidosis doesn’t develop.
The lost bicarb takes sodium and water with it resulting in volume depletion, triggering aldosterone release, with resulting hypokalaemia
Describe distal renal tubular acidosis (type 1)
H+ secretion in the distal tubule and collecting ducts is impaired.
Acidic urine therefore cannot be made and a severe metabolic acidosis is produced
It can be divided into whether there is hyperkalaemia or not.
Describe hypokalaemic distal RTA
K is secreted instead of H
Describe hyperkalaemic distal RTA
Abnormally reduced K and H secretion
Hyperkalaemia worsens the acidosis
What are the pre-renal causes of AKI?
Inadequate cardiac function
Circulatory volume depletion
Obstruction of the arterial supply
-> the resulting renal ischaemia can cause acute tubular necrosis
What are the post-renal causes of AKI?
Obstruction to urine flow causing back pressure which inhibits filtration
The subsequent swelling compresses blood vessels causing ischaemia
Causes include stones, tumours or strictures and external compression e.g. from a mass or a fibrotic process.
What are the renal causes of AKI?
Glomerular disease (e.g. rapidly progressive glomerulonephritis, Goodpastures, vasculitis and proliferative glomerulonephritis)
Tubulointerstitial disease
Drugs (e.g. aminoglycosides, NSAIDS, ACEI/ARB, cephalosporins, amphotericin B, aciclovir, ciclosporin, tacrolimus, contrast)
Toxins (e.g. heavy metals, haemoglobin, myoglobin, calcium, myeloma (light chain precipitation in tubules)
What is the pathophysiology of acute tubular necrosis?
- Most AKI results from ATN
- Usually arises in the context of renal hypoperfusion with renal ischaemia in combination with other factors e.g. sepsis or nephrotoxic drugs
- Its a/w tubular cell death and shedding of the tubular lumen, resulting in tubular blockage, which raises tubular pressure and stops glomerular filtration
- exacerbated by many factors including disordered regulation of vascular tone after an initial ischaemic event
- Levels of vasoconstrictors are high and vasodilators low
- Initially na reabsorption is low, increasing Na conc at the macula densa causing further vasoconstriction due to release of adenosine
What disease does anti-GBM antibodies suggest?
GoodPastures syndrome
Pt may also have pulmonary haemorrhage
What disease does ANCA suggest?
Vasculitis
What tests suggest a diagnosis of myeloma?
Bence Jones protein (antibody free light chains) in the urine
Monoclonal band in the plasma
What are the features of uraemic syndrome?
Anaemia Confusion Coma Asterixis Seizures Pericardial effusion Itch Bone disease Uraemic frost
What are the metabolic features of chronic kidney disease?
Anaemia due to inadequate erythropoietin Low calcium and high PTH (unless tertiary hyperparathyroidism is present) High phosphate High Potassium, urea and creatinine Acidotic
What are the 2 types of renal bone disease?
- High turnover bone disease - where there is an excess of PTH (secondary hyperparathyroidism), which stimulates bone reabsorption and the new bone that replaces it has disordered collagen. Caused by phosphate retention and low vit D production
- Low turnover - PTH levels are low, bone turnover is low and there is osteomalacia with poorly mineralised bone. Occurs if calcium intake is high enough to suppress PTH..
What is the mechanism of action of ciclosporin?
Inhibits calcineurin, which normally dephosphorlyates the transcription factor NFAT, allowing it to enter the nucleus and promote expression of cytokines, esp IL-2.
Ciclosporin therefore inhibits IL-2 and T cell activation.
What are the side effects of ciclosporin?
Nephrotoxicity hyperkalaemia hypomagnesaemia hypertension hepatotoxicity gum hyperplasia hirsutism
How does azathioprine work?
It inhibits purine metabolism and therefore nucleic acid synthesis and cell proliferation, esp in lymphocytes and neutrophils
What are the side effects of azathiprine?
infection
pancreatitits
bone marrow depression
How does tacrolimus work?
Binds to FKBP immunophilins to form a complex that inhibits calcineurin and so has similar effects to ciclsporin
What are the side effects of tacrolimus?
nephrotoxicity
hypertension
impaired glucose tolerance/DM
What are the early complications of renal transplant?
- Poor renal function - may be due to acute rejection, ciclosporin toxicity or ATN due ton pre-revascularised ischaemia
- Vascular rejection is often more aggressive and needs plasma exchange to rtemove the antibodies
- CMV infection - causes fever, retinopathy, hepatitis, enteritis, pneumonitis and low plts
What are the chronic complications of renal transplant?
Chronic rejection HTN Hyperlipidaemia Skin cancer Post-transplant lymphoproliferative disease (a lymphoma like disease caused by EBV)
