Euboxia and (Ab)Normality

WHAT IS EUBOXIA?

• ‘Euboxia‘ is the pathophysiological state whereby ‘all boxes on a pathology print-out are in the normal range’ (Reade, 2009).
• LITFL — Don’t put your patient in a box
• Reade MC (2009). Should we question if something works just because we don’t know how it works? Critical Care and Resuscitation, 11 (4), 235-6 PMID: 20001869
• Aberegg SK, O’Brien JM Jr. The normalization heuristic: an untested hypothesis that may misguide medical decisions. Med Hypotheses. 2009 Jun;72(6):745-8. doi:10.1016/j.mehy.2008.10.030. Epub 2009 Feb 23. PubMed PMID: 19231086.
  • Unfortunately I had somehow missed this reference and only discovered it after I gave this talk!
  • This paper defines the ‘normalisation heuristic’ as ” A… ‘‘rule of thumb” which encourages a general practice of normalizing abnormal biochemical and physiological parameters based on an explicit or implicit hypothesis that doing so confers net benefits to patients” and describes numerous examples of when it is wrong or causes harm.

Euboxia and abnormality smacc gold from precordialthump

WHAT IS NORMAL?

• Normal… for what? Context is everything!
• Usual or most frequent?
• Toward the middle of the bell curve? What about blue versus brown eyes?
• Homeostasis – yet there is a range of physiological behaviour that is acceptable, and phsiological systems adapt to external and internal factors
• Do we understand normal variation, what about the difference between disease and risk of disease?
• TILES M. The Normal and Pathological: The Concept of a Scientific Medicine. Br J Philos Sci (1993) 44 (4): 729-742 doi:10.1093/bjps/44.4.729
• WELLMAN M. The concept of normal in medicine. Can Med Assoc J. 1958 Jul 1;79(1):43-4. PubMed PMID: 13547028; PubMed Central PMCID: PMC1830141.

WHEN IS NORMAL BAD?

• First, normal is often good
  • when recovery is signified by a return to an individual’s ‘normal state’
  • e.g. normal (low, <35 cmH20) plateau pressures in mechanical ventilation of ARDS
• See #euBOXia twitter stream!
• Normal parameters misapplied
  • Is a MAP of 65 appropriate for all pateints with septic shock? What if the patient’s usual BP is 90/60, what if it is usually 160/90?
  • Panwar R, Lanyon N, Davies AR, Bailey M, Pilcher D, Bellomo R. Mean perfusion pressure deficit during the initial management of shock–an observational cohort study. J Crit Care. 2013 Oct;28(5):816-24. doi: 10.1016/j.jcrc.2013.05.009. Epub 2013 Jul 10. PubMed PMID: 23849541.
• Multiple parameters- which ones should be normalised?
  • e.g. in ventilated patients, should we target the PO2, the PCO2, the Pplat, the tidal volume – or something else?
  • easy to lose sight of ‘the big picture’
  • we tend to find quantitative measures more convincing than qualititative measures – ubt we can’t see the error bars
• Bogus biological basis
  • e.g. Urine output drop due to syndrome of APPROPRIATE ADH secretion, attempts to ‘improve’ this leads to waterlogged ICU patients
  • e.g. correcting PCO2 in metabolic acidosis
  • e.g. correcting PCO2 in asthma
  • e.g. dogma of bleeding patients being tachycardic – normal or bradycardia is common, especially if the patient is on a beta blocker!
  • e.g. reassured by a normal hematocrit in an acute bleed
  • e.g. normal WBC or Absolute Neutrophil count in sepsis often delays diagnosis. Suggests granulocyte failure due to overwhelming infection
  • e.g. normal cardiac output in a systemically vasodilated patient (e. septic or pregnant) – would expect high cardiac output ‘normally!’
• Normal saline 😉 See David Story’s smaccGOLD talk on ICN: Is chloride a poison?

IS MAKING IT NORMAL GOOD?

• surrogates and epiphenomena, e.g. ‘relative relative insufficiency’: “An example I came across recently concerns the ‘common knowledge’ (in other words, there is no convincing evidence that it is true) that having more than two relatives at the bedside of an ICU patient is a poor prognostic indicator (Reade, 2009). Unfortunately for euboxophiles, asking relatives to leave does not help the situation! The converse also appears to be true. A paucity of relatives relative to the severity of illness is suggestive of a bad outcome. Reade has termed this ‘relative relative insufficiency’, and correcting it by dragging relatives to the bedside doesn’t seem to be beneficial.” (from Don’t put your patient in a box)
• speed kills – rapid normalisation can be harmful e.g. correction of chronic hyponatraemia, refeeding syndrome, treating hypertension in acute stroke
• Fever may be protective: Fever, Friend or Foe?
• We correct the measurable, even minor ‘abnormalities’ e.g. electrolyte disturbance, which may not be beneficial…
• and may lead to side effects of treatment e.g. transfusion and the TRICC trial, CO2 retention from excessive O2 administration, intensive glucose control versus NICE-SUGAR
• Making a patient ‘look normal’ (e.g. fluid resuscitation) may be harmful! See FEAST trial:
  • Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T, Brent B, Evans JA, Tibenderana JK, Crawley J, Russell EC, Levin M, Babiker AG, Gibb DM; FEAST Trial Group. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483-95. doi: 10.1056/NEJMoa1101549. Epub 2011 May 26. PubMed PMID: 21615299.

HOW CAN ABNORMAL BE GOOD?

• Critical care has its orgins in anaesthesia, but anaesthesia was traditionally focused on the rapid normalisation of a patient have an acute surgical insult
• Critically ill patients are different, in the initial phase of illness they often need all the support they can get, but overtime they can adapt and a different approach is required
• Some abnormalities are simply physiological compensations e.g. low PCO2 in compensated metabolic acidosis
• Abnormal may really reflect normal variation, or be a chronic state to which the patient has become accustomed e.g. should we individualise BP targets based on presence or absence of chronic hypertension?
• Some measurements are just surrogates – ?ICP measurements in TBI:
  • Treatment of ICP with decompressive craniectomy – high ICP may have been an epiphenomenon, squash may have been replaced with stretch or the harms of therapy may have been too great
  • Cooper DJ, Rosenfeld JV, Murray L, Arabi YM, Davies AR, D’Urso P, Kossmann T, Ponsford J, Seppelt I, Reilly P, Wolfe R; DECRA Trial Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011 Apr 21;364(16):1493-502. doi: 10.1056/NEJMoa1102077. Epub 2011 Mar 25. Erratum in: N Engl J Med. 2011 Nov 24;365(21):2040. PubMed PMID: 21434843.
  • Chesnut RM, Temkin N, Carney N, Dikmen S, Rondina C, Videtta W, Petroni G, Lujan S, Pridgeon J, Barber J, Machamer J, Chaddock K, Celix JM, Cherner M, Hendrix T; Global Neurotrauma Research Group. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med. 2012 Dec 27;367(26):2471-81. doi: 10.1056/NEJMoa1207363. Epub 2012 Dec 12. Erratum in: N Engl J Med. 2013 Dec 19;369(25):2465. PubMed PMID: 23234472; PubMed Central PMCID: PMC3565432.
• Need to tailor to the person and the condition, e.g. permissive hypotension in penetrating trauma:
  • Bickell WH, Wall MJ Jr, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994 Oct 27;331(17):1105-9. PubMed PMID: 7935634. [Free Full Text]
• Context is everything, e.g. toxicology: aim for lower sats if paraquat or bleomycin toxicity, target pH 7.55 in TCa overdose, alkalinise the urine in salicylate overdose
• Consider adaptation
  • e.g. Stress-induced adaptation is well described in the setting of endurance athletes, high altitude mountaineering and other people exposed to chronic hypoxia
  • Stress-induced hyperglycemia may be adaptive: Marik PE, Bellomo R. Stress hyperglycemia: an essential survival response! Crit Care. 2013 Mar 6;17(2):305. [Epub ahead of print] PubMed PMID: 23470218
  • Multi-organ dysfunction Syndrome, the sine qua non of critical illness, may even be adaptive!: Mongardon N, Dyson A, Singer M. Is MOF an outcome parameter or a transient, adaptive state in critical illness? Curr Opin Crit Care. 2009 Oct;15(5):431-6. doi: 10.1097/MCC.0b013e3283307a3b. Review. PubMed PMID: 19617821

TAKE HOMES

• Don’t ask ‘is it normal?’, ask ‘is it optimal?’
• consider the big picture using all the information available about the patient
• inform our understanding with science: trials and physiology
• Physiology is often more complex than we realise and remember Orgel’s 2nd law: ’ Evolution is cleverer than you are’
• Embrace ‘dysboxia’ (when it is safe to do so)