ICS State of the Art 2015

1. Paradigms, Dogmas and
Evidence in Critical Care
Rinaldo Bellomo
ANZIC RC
Monash University
Melbourne

2. “Physicians are quite as intolerant as theologians.
They never had the power of burning at the stake
for medical opinions, but they certainly have
shown the will”
HB Stowe 1866

3. Human illusions
• We believe in free will (a philosophical, relativity
theory, quantum physics, neuro-cognitive,
electrophysiological, 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” therapies that, are
biological fact and if applied in the ICU, affect
survival – Is this another illusion?

4. Harrison’s textbook of internal medicine 1978
Management of myocardial infarction
• Rest in bed for 6 weeks
• Toilet use only after 2 weeks
• Avoid beta-blockers
• Lignocaine infusion to suppress ectopic beats
• No angiography (unstable plaque)
• Oxygen to all
• All gone !!

5. Fundamental truth
“The amount of energy
necessary to refute
bullshit is an order of
magnitude bigger than to
produce it”

6. • Rivers
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

7. Millions of dollars and pounds!
15 times the number of patients
as in River’s study to
“vanquish the beast”

8. The subtle game of guidelines, paradigms and
dogmas
• Paradigms of what is right develop over time through
advocacy even when evidence is poor
• They are then transformed into guidelines by
“experts” who have specific career/vested interests in
one or more of these paradigms
• Guidelines then get published in key specialty journals
• Once published and endorsed by colleges or societies
evidence-poor paradigms become prevailing dogma
• Violation of dogma can lead to public or professional
shaming or even legal action!

9. Guidelines or “guidelies”?
• Uncertainty is rarely embraced or even
accepted or estimated
• The reason for having guidelines is specifically
to grade and promote evidence even when
the evidence is so poor it might as well be
absent
• Influence of pharmaceutical companies is
never far away

10. CCM Paradigms promoted by guidelines over
time
• Give monoclonal anti-endotoxin antibodies in sepsis
• Normalize glucose to avoid risks of hyperglycemia
• Give protein C in severe sepsis
• Give albumin to brain trauma patients
• Decompress the brain when intracranial pressure is high
• Feed early
• Resuscitate septic children with lots of fluids
• Give high dose renal replacement therapy to improve outcome
• Use starch to resuscitate

13. HA-1A approved by FDA for use in humans!!!
JAMA. 1993 May 5;269(17):2221-7.
A controlled trial of HA-1A in a canine model of gram-negative septic shock.
Quezado ZM, Natanson C, Alling DW, Banks SM, Koev CA, Elin RJ, Hosseini JM, Bacher
JD, Danner RL, Hoffman WD.
Source Department of Critical Care Medicine, National Institutes of Health, Bethesda, MD
20892.
Abstract
OBJECTIVE:
To investigate the therapeutic efficacy and microbiological and physiological effects of a
human IgM monoclonal antibody (HA-1A) directed against the lipid A component of
endotoxin in a canine model of sepsis that simulates the cardiovascular abnormalities of
human septic shock.
DESIGN:
Blinded, placebo-controlled 28-day trial.
INTERVENTIONS:
Purpose-bred beagles were implanted with an intraperitoneal clot infected with Escherichia
coli O111:B4. At clot placement, animals received HA-1A (10 mg.kg-1), control human IgM
antibody (10 mg.kg-1), or control human serum albumin intravenously. All animals were
given antibiotic and fluid therapy.

14. RESULTS:
Only two (15%) of 13 animals in the HA-1A group, compared with eight (57%)
of 14 control animals (combined control human IgM antibody and control
human serum albumin groups) (P = .05), survived 28 days. At 24 hours, the
HA-1A group had lower mean arterial pressure (P = .04) and cardiac index (P =
.004) and higher lactate levels (P = .05) compared with the combined-controls
group. In addition, these parameters in the HA-1A group were significantly
more predictive of death. The HA-1A and combined-controls groups had similar
significant increases in the level of endotoxemia and bacteremia. Studies of
toxic effects showed no harmful effects of control human IgM antibody in
infected animals or HA-1A in non-infected animals.
CONCLUSION:
In a canine model of E coli sepsis, HA-1A did not alter levels of bacteremia or
endotoxemia and actually decreased survival. If these data are relevant to
human septic shock, HA-1A therapy should be limited until the conditions under
which this monoclonal antibody has beneficial or deleterious effects are more
completely defined
The arrival of doubt!

15. The end of dogma
•2199 patients
•621 had gram negative bacteremia
•In these 621 mortality was: 32% (placebo) vs. 33% HA-1A (p=0.86)
•In patients without gram negative bacteremia: 37 vs. 41% (p=0.07)

16. Aim for normoglycemia to save lives – really?

18. Give protein C in sepsis – its levels are low! – really?

19. For $ 15,000/patients
…..not much value!

20. Albumin resuscitation in TBI patients: it helps decrease cerebral edema – really?

22. Decompress the brain in increased ICP states post TBI –really?

25. Feed early – nutrition is essential – really?

30. Let’s give glutamine – they are all deficient – really?

32. Let’s give all septic children lots of fluids –
It’s self evident they need it !!
It is recommended by SCCM guidelines!

33. hours
days

35. Let’s increase dialysis intensity: more must be better

37. Let’s use starch for fluid resuscitation: large colloids are best!!

45. Figure 1: Distribution of the Fragility Index of multicenter randomized trials in critical care medicine
reporting significant effects of on an intervention on mortality *.

46. Why does all this happen?
Are doctors particularly stupid?
• Doctors have to make decisions
• They 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)
• Medical hierarchy – doctros need to show they
know stuff other doctors do not know
• Need to feel important – the “thank God you are
here syndrome”!

49. 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.

50. Rational astrology
• The beliefs that support many practices in critical care medicine
may represent a well-founded characterizations of reality.
• But most of us act as if those beliefs are true regardless of own
judgments or evidence, especially when giving advice or making
decisions for other people.
• Critical Care Medicine largely remains a rational astrology.
• We hope that our truth-seeking institutions will create
convergence between the beliefs we behave as if were true and
those that actually are true.
• But we behave as if they are true regardless
(if you don’t believe me see latest NEJM fluid resuscitation in sepsis comments by
readers during the sepsis articles series)

53. So what’s the truth….does EPO decrease mortality in TBI?

54. What if I showed you this?

55. …and this?
(it was them trauma patients what did it)

56. And what if I showed you this?

57. It was them trauma patients again!

58. And what if I showed you this?
Diffuse TBI + Multitrauma

59. And this?
IMPACT-TBI = International Mission of Prognosis and Analysis of Clinical trials in Traumatic Brian Injury

60. Table 3: IMPACT-adjusted hazard ratios
for mortality at 6 months, EPO doses as
time-dependent variable
HR for mortality at 6 months (95%CI)
Number of doses P value
1 0.62 (0.36-1.08) 0.09
2 0.31 (0.12-0.78) 0.01
…and this?
So….what is the truth?

61. Oscar Wilde on “Truth”
• The truth is never pure and rarely simple
• I can believe anything provided that it’s quite
incredible
• Experience is merely the name men give to their
mistakes
• A little sincerity is a dangerous thing, a great deal of
it is absolutely fatal
• If you want to tell people the truth, make them
laugh, otherwise they will kill you

62. Don’t worry: you are safe!
• Luckily, all these concerns relate only to critical care medicine
(CCM) in other countries.
• They have nothing to do with CCM in the UK.
• Unlike other countries, UK intensivists read the relevant 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 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 country !