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METABOLIC ACIDOSIS (Raised anion gap (Lactate (Sepsis and septic shock -…
METABOLIC ACIDOSIS
Raised anion gap
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Lactate
Classical classification: Type 1 - lactic acidosis with reduced tissue perfusion, Type 2 - lactic acidosis without reduced tissue perfusion
Mechanistic classification:
- increased glycolysis due to low ATP (hypoxia/ischaemia/anaemia/CO poisoning.
2.Increased glycolysis due to pro-glycolytic stimulus - catecholamine excess in shock, adrenoreceptor agonists.
3.Pyruvate dehydrogenase inactivity - thiamine deficiency, sepsis, inborn error.
- Defect of oxidative phosphorylation - cyanide, metformin, propofol, salicylate, iron.
- Defect of lactate clearance - liver failure
Is there such a thing as 'lactic acidosis? Production of lactate does not produce H+ ion. the hydrolysis of ATP does. Usually this is buffered by ADP but in highly active tissues ADP is rapidly re-converted to ATP leaving unbuffered H+. Therefore lactate production may coincide with acidosis rather than being the cause of it. Lactate is a strong ion and WILL cause an acidosis in solution BUT the levels of lactate required to do this are much higher than those usually assumed (in the region of 10).
Haemorrhagic shock - a 'pure' hypo perfusion state without mitochondrial dysfunction/cytokine influences. Lactate is produced by hypo perfused tissues but is also produced by aerobic glycolysis in other tissues (mainly muscle) in response to increased circulation catecholamines.
Hypoxia/anaemia/CO poisoning - you need to be extremely hypoxic/anaemic/CO poisoned for your lactate to rise as seen in Everest experiments where lactate did not change despite very low pO2.
Sepsis and septic shock - lactate undoubtedly causes an increase lactate. Only a small part of this results from hypoperfusion however. Causes are:
1.Microvascular stasis and shunting - due to micro thrombi, increased endothelial adhesion etc.
- Catecholamine induced glycolysis (esp. in skeletal muscle
- Mitochondrial dysfunction /pyruvate dehydrogenase inhibition due to cytokines and bacterial endotoxins
Can I use lactate to monitor resuscitation in sepsis?Lactate level does correlate with severity of sepsis and some evidence that targeting lacteate improves outcomes - Jansen et al 2010
Thiamine deficiency - in malnourished patients and those on long term Frusemide. Thiamine is a cofactor in pyruvate dehydrogenase activity.
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Renal
Failure to re-absorb HCO3-, minimal contribution in acidosis secondary to renal failure
Failure to acidify urine - much more significant contributor to acidosis in renal failure (same mechanism as RTA type 2). Remaining nephrons will compensate for loss of others up to a point but beyond that point Cl- builds up leading to acidosis
Failure of anion clearance - major contributor to acidosis in LATE renal failure. Sulfate, phosphate (elevated in ESRF - phosphate binders given), urate and hippurate
Ketones
Ketones are anions. Fatty acids are broken down to acetoacetate, B hydroxybutyrate and acetone in the context of low insulin, high glucagon +/- catecholamines. Alcoholic ketoacidosis occurs in as a result of raised lipolysis, high cortisol and catecholamines post binge. Mitochondria are also altered by metabolism of ETOH to produce more B hydroxybutyrate.
Salicylate overdose
2 mechanisms of acidosis - salicylic acid is acidic - lower pH means less is ionised and gains access to cells where it interferes with mitochondrial function and oxidative phosphorylation resulting in production fo ketone bodies.. May co-occur with metabolic alkalosis due to vomitting, bicarb. infusion (urinary alkalisation)
Iron overdose
Classed with cyanide, metformin and propofol as a cause of metabolic acidosis due to mitochondrial toxicity resulting in lactic acidosis. Iron damages delicate mitochondrial membranes and the enzymes of the electron transport chain.
Normal anion gap
Renal
RTA type 2
Caused by a failure of bicarb. retention mechanisms in proximal tubule (via carbonic anhydrase) this leads to loss of bicarb and retention of Cl-. Causes include ACETAZOLIMIDE, monoclonal gammopathy, aminoglycosides. FANCONI SYNDROME.
RTA type 1
Urinary chloride excretion is dependent on secretion of ammonia into distal renal tubule. Presence of NH4+ requires Cl- to maintain electroneutrality. Failure of NH4+ secreting mechanisms (H+ transporter or damage to distal tubule lead to inability to secrete Cl- in response to acidosis. Causes - hyperparathyroidism, sarcoidosis, cyclophosphamide, amphotericin B. Test for this by checkin urinary pH and anion gap.
RTA type 4
Hypoaldosteronism/hypoadrenalism causes type 4 RTA by causing renal sodium loss (eNAC channel) and impairing ammonia genesis and chloride secretion. Caused by spironolactone, critical illness, anything that interferes with the RAA system e.g. NSAIDs/diabetes/kidney disease or adrenal function e.g. exogenous steroids. Treatment is stop offending drug or give synthetic mineralocorticoid like Fludrocortisone.
GI losses
Diarrhoea
Large volume diarrhoea causes NAGMA and hyponakalaemidc hyponatraemia as large volumes of Na+ rich fluid are lost. This is again exacerbated by volume loss and decreased renal compensation.
High output stoma
Small bowel
Bicarb rich, chloride low secretions are reabsorbed along the ileum so ileostomy should be safe - however high output stomas will have flow that is too fast for re-absorption leading to NAGMA by a similar mechanism - exacerbated by de-hydration (slower renal compensation). Can also secrete chloride rich fluid leading to alkalosis.
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Hyperchloraemia
Normal saline intoxication - electroneutrality must be maintained. Na+, K+ and Cl- are all strong ions (independent variables) HCO3- is a weak ion (dependent variable) which incidentally determines pH. Adding Cl- forces a reduction in HCO3- and results in acidosis.
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