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The Problem with Physiology by Rinaldo Bellomo

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Critical care clinicians can change physiology with a number of tools. The can repeatedly, often and mercilessly change physiological variables. They can increase the blood pressure (or decrease it); they can increase cardiac output (or decrease it), they can increase cardiac filling pressures (or decrease them), they can increase glucose levels (or decrease them), they can increase positive fluid balance (or decrease it) and so on. This kind of “numerology” is attractive because the outcomes are tautological and clinicians feel powerful and effective. However, outside the obvious situations where physiology is so dangerously abnormal as to threaten life, such physiological manipulations have an unproven relationship with outcome. Importantly, patients do not care whether their cardiac output has been increased from 5L/min to 6 L/min. They only care whether they live or die, get out of hospital intact and return to their previous life. Thus, physiological gain is not patient centred. Moreover, all research focusing of the physiology of a specific intervention always and inevitably deals with the effect on a specific set of variables. For example and fluid bolus may or may not increase cardiac output for a while. Thus studies focus on identifying fluid responders for such purposes. However, no one studies the effect of such fluid bolus on anything other than hemodynamics. No one measures what the effect is on the immune system, cerebral edema, the glycocalyx, interstitial oxygen gradient, pulmonary congestion, body temperature, haemoglobin and white cell function etc. etc. Thus, all physiological studies are “blind” to the effects that their protagonists cannot or will not measure. In other words, the measurable is made important but the important may not be measured. Clinicians need to reflect on this before they become seduced by physiological manipulation.

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The Problem with Physiology by Rinaldo Bellomo

  1. 1. The Trouble with Physiology Rinaldo Bellomo ANZIC RC Monash University Melbourne
  2. 2. Human illusions • We believe in free will (a philosophical, relativity theory, quantum physics, neuro-cognitive, EEG, and blood flow MR-demonstrated impossibility) • We believe that we do is important (a historical, biological, paleontological, sociological and cosmic impossibility) • We believe there are “proven” physiological facts which, if applied in the ICU, will improve survival • Is this another illusion?
  3. 3. Harrison’s textbook of internal medicine 1978 Management of myocardial infarction • Physiology: Rest is good for the heart. Associated therapy: Rest in bed for 6 weeks • Physiology: Valsalva manoeuvre strains the heart. Associated therapy: Toilet use only after 2 weeks • Physiology: Beta-blockers decrease contractility. Associated therapy: Avoid beta-blockers • Physiology: Ectopic beats increase R on T risk Associated therapy: Lignocaine infusion to suppress them
  4. 4. Harrison’s textbook of internal medicine 1978 Management of myocardial infarction • Physiology: An unstable plaque will clot if touched. Associated therapy: No angiography • Physiology: Myocardial ischemia is due lack of lack of oxygen delivery to muscle. Associated therapy: Oxygen to all • All based on physiological thinking. All gone !! • We laugh at all this …but are we any better in critical care medicine?
  5. 5. Massive physiological belief • Sepsis = infection and organ failure • Sepsis Physiology = microvascular shunting • Physiological paradigm No 1 = organs must be failing because of shunting • Physiological paradigm No 2= Shunting must cause tissue hypoxia. Must fix tissue hypoxia. • Therapeutic implication = let’s increase oxygen delivery (Early Goal Directed Therapy)
  6. 6. Small (n=263); unblinded; PI involved in patient care, PI involved in patient selection; no information of method of randomization, de-facto interim analysis with each patient; High mortality in control group; implausible effect EGDT: Physiological salvation or mumbo-jumbo?
  7. 7. Fundamental truth “The amount of energy necessary to refute bullshit is an order of magnitude bigger than to produce it”
  8. 8. Millions of dollars and pounds! 15 times the number of patients as in River’s study to “refute belief” No salvation – Just illusion
  9. 9. CCM Paradigms promoted by physiological thinking • Physiology: Glucose levels are high in ICU patients • Associated therapy: Normalize glucose to avoid risks of hyperglycemia • Physiology: Protein C is low in sepsis and is being consumed • Associated therapy: Give protein C in severe sepsis • Physiology: Resuscitation with albumin decreases tissue edema • Associated therapy: Give albumin to brain trauma patients to decrease cerebral edema • Physiology: Very high Intracranial pressure can kill. So high intracranial pressure must be treated aggressively. • Associated therapy: Decompress the brain by craniectomy
  10. 10. Fix physiology Normalize glycaemia . All will be ok Really???
  11. 11. Give protein C in sepsis – its levels are low! – really?
  12. 12. For $ 15,000/patient …..not much value
  13. 13. Albumin resuscitation in TBI patients: it helps decrease tissue edema – really?
  14. 14. The effect of commercial 4% albumin on ICP in health sheep
  15. 15. Decompress the brain. Increased ICP is bad post TBI –really?
  16. 16. Awesome – we have reduced ICP big time!!
  17. 17. ICP physiology looks awesome !! Pity about the brain
  18. 18. More mad physiology…. • Physiology: Critically ill patients have increased caloric expenditure • Associated therapy: Feed early and aggressively • Physiology: Critically ill patients have low glutamine levels • Associated Therapy: Give lots of glutamine
  19. 19. Feed early – nutrition is essential – really? We can do it!!
  20. 20. The problem is…it’s a stupid thing to do
  21. 21. Caloric expenditure during critical illness is high Feeding early is a physiological priority. We can do it.
  22. 22. Oops! Another waste of time
  23. 23. Let’s give glutamine – they are all deficient – really?
  24. 24. More mad physiology • Physiology: Fluids can increase blood pressure. Children with sepsis have a low blood pressure. • Associated therapy: Resuscitate septic children with lots of fluids
  25. 25. Fluids for children – It’s self evident they need it !! It is recommended by SCCM guidelines! Oops….physiology just killed quite a few African kids! Mortality
  26. 26. More mad physiology • Physiology: Large artificial colloids can expand intravascular volume more than crystalloids and have longer intravascular dwell time • Associated therapy: Let’s use starch to resuscitate
  27. 27. Oops…. physiology just killed a few Scandinavians!
  28. 28. RRT: 21% higher with starch P=0.04 Adverse events: 90% higher! P<0.001 Ooops… Physiology just lost us a few Aussie and Kiwi kidneys (and they will be scratching themselves for years)
  29. 29. Why does all this happen? Are doctors particularly stupid? • Well…actually…yes • However…to be fair…doctors have to make decisions • The poor fools can’t tolerate the thought they actually do not know what they are doing • Physiological gain is seductive in ICU (but pretty much regularly misleading) • Physiological seduction is pretty much regularly associated with attribution bias
  30. 30. Attribution bias • Anecdotal and selective observations of favourable effects attributed to the intervention which lead to undue confidence in its effectiveness (sounds familiar?) • Physiology is particularly diabolical because it also carries a high chance of immediacy bias
  31. 31. Immediacy bias • The selective immediate observations of favourable effect attributed to the intervention which lead to undue weight being placed on such changes rather than others that are either invisible (because unmeasured or unmeasurable) or delayed • Sounds familiar?
  32. 32. IV fluid bolus: attribution and immediacy bias • IV fluids are given to patients during and after surgery to replace estimated losses. Such approach seems innocent enough (maybe) • But IV fluids are also given as “boluses” to deal with perceived physiological states based on clinical observations • Such boluses are common and perceived to have clinical value (they are given incessantly) …but…do they? • Are we dealing with attribution and immediacy bias?
  33. 33. You say…as long as we follow the physiology of “fluid responsiveness” all is just fine
  34. 34. Author Journal Year Diagnosis Patients, N Type of Fluid Volume Duration Indication FR assessment Variable FR, ∆ % Time from end of the bolus Device Feissel ICM 2007 sepsis 23 6% HES 8 mL / kg - VE CI ≥ 15% 30' TTE Lamia ICM 2007 ACF 24 Saline 500 ml 15' ACF SVI ≥ 15% 0 TTE Maizel ICM 2007 ACF 34 Saline 500 ml 15' ACF CO ≥ 12% 0 TTE Wyffels Anesth Analg 2007 Post Card Surg 32 6% HES 500 ml 20' VE CI ≥ 15% 0 PAC Auler Anesth Analg 2008 Post Card Surg 59 Lactated Ringer's 20 mL / kg 20' VE CI ≥ 15% 0 PAC Biasis Br J Anesth 2008 Post Liver Transp 40 Albumin 4% 20ml / BMI 20' ACF CI ≥ 15% 0 TOE, PAC Biasis CC 2009 ACF 34 Saline 500 ml 15' ACF SV-TTE ≥ 15% 0 TTE + Vigileo Monnet CCM 2009 ACF 34 Saline 500 ml 10' ACF CI ≥ 15% 0 PiCCO Thiel CC 2009 ACF 89 Saline,Ringer's Lactated and HES at least 500 ml rapid ACF SV ≥ 15% 0 TTE Benomar ICM 2010 Post Card Surg 75 Colloid 500 ml 15' VE CO - 3' Bioreactance Lakhal ICM 2010 ACF 102 Modified Gelatin 300 ml + 200 ml 18' + 12' ACF CO ≥ 15% 0 PAC, PiCCO Preau CCM 2010 sepsis/acute pancreatitis 34 6% HES 500 ml 30' VE SV ≥ 15% 0 TTE Guinot CC 2011 ARDS + vvECMO 25 Saline 500 ml 15' VE SV ≥ 15% 0 TTE Alas...another sad case of immediacy bias
  35. 35. The problem with immediacy bias Fluid bolus: it’s all over 15 minutes later!!! Change from baseline
  36. 36. Change in stroke volume index The problem with immediacy bias Change in ml/min/m2 All over in 20 minutes?
  37. 37. Do fluids actually do anything at all? Or is it just giving some “cold stuff” into people’s veins?
  38. 38. Oh dear!! It’s the temp, not the fluid The cold stuff makes you pee! Temp. associated changes in V/Q matching?
  39. 39. ANALYS UNDER HÄNDELSE 2 elapsed i sekunder sedan bolusstart Interaction P = 0.0003 Higher MAP with cold fluids – same amount Maria Cronjort et al cold
  40. 40. Interaction P = 0.001 Higher cardiac output with warm fluids – same amount warm
  41. 41. Interaction P = 0.01 Higher HR to increase CO with warm fluids – same amount warm
  42. 42. The physiological knowledge illusion
  43. 43. Overclaiming bias! – People (doctors) overclaim to the extent that they perceive personal expertise favourably
  44. 44. Overclaiming bias • People overestimate their knowledge sometimes claiming knowledge of concept, places. or people that do not exist • They overclaim to the extent that they perceive their expertise favourably • Self perceived knowledge in specific domains is specifically associated with overclaiming is such domains • Warning that some concept were fictitious does not reduce the relationship between self perceived knowledge and overclaiming • Boosting self-perceived expertise in geography led to asserion of familiarity with non-existent places (assocition b/w self-perceived expertise and impossible knowledge) • Does this remind you of anyone you know?
  45. 45. Is it all just Rational Astrology? • A rational astrology is a set of beliefs which one rationally behaves as if were true, regardless of whether they are in fact true. • Rational astrologies need not be entirely fake or false. • The essential characteristic is the indifference to truth or falsehood of the factors that compel one’s behavior. • Some rational astrologies may turn out to be largely true, and that happy coincidence can be a great blessing. • But they are still a rational astrologies to the degree the factors that persuade us to behave as though the beliefs are true are not closely related to the fact of their truth. • Some rational astrologies: fluid boluses are helpful in oliguria; vitamin C is good for you; breakfast is the most important meal of the day; oxygen is good for patients with myocardial infarction
  46. 46. Don’t worry: you are safe! • Luckily, all these concerns relate only to other doctors. They have nothing to do with doctors at SMACC. • Unlike other doctors, SMACC doctors read the relevant physiological literature in detail, consider biological plausibility, follow carefully evaluated evidence, are open-minded, balanced, carefully sceptical, and not unduly cynical. • They accept doubt with a smile and practice the known medicine of their time with the understanding that today’s physiological truth is tomorrow’s target of derision. • More importantly they enrol patients in high quality randomized controlled trials so that known medicine can be improved • How lucky are you to be such a doctor in such a group !

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