The Magnificent Seven

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The Magnificent Seven

• Chris Cairns
• SRI
• 2007

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Sepsis

• 25 deaths per 100,000 in Scotland
• Hospital mortality
• 47 in adults (MOF)
• 10 in children
• 5 yr mortality 74
• Patients with severe sepsis account for 45 of
  all ICU bed-days
• Considerable short and long term morbidity
• High cost US 120,000 at 5yrs

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In other words sepsis is bad!
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Historical Management of Sepsis

• ABC
• Antibiotics / surgery
• Goal directed therapy

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History of Goal directed therapy

• Shoemaker Arch. Surg. 1973
• Increased DO2, increased survival
• Vallet CCM 1993
• Dobutamine challenge test
• Ronco JAMA 1993
• Critical DO2 needed is less
• VO2 mirrors DO2
• Hayes NEJM 1994
• Goal directed approach leads to worse outcome in
  sepsis
• Hayes CCM, 1997
• Sub-group analysis
• Survivors can increase DO2 VO2 (reserve)
• Non-survivors reduced reserve, fail to increase
  VO2 with resus, O2 extraction falls with
  aggressive inotropes

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Why not that simple ?

• Not just about oxygen delivery
• Oxygen consumption also important
• Critically ill different from surgical patient
• Flogging the struggling patient does harm

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What goals work?

• High risk surgery
• Early intervention in Sepsis

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• High risk surgery or patients
• Three groups
• Control
• Invasive monitoring, fluids, adrenaline to
  increase DO2
• Invasive monitoring, fluid, dopexamine to
  increase DO2
• Improved outcome in treatment groups (15 reduced
  hospital mortality NNT 7)
• Less side effects with Dopexamine
• Most benefit from fluid

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But

• Poor control results
• Impractical?

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What do I do?

• Measure CO in theatre
• Give more fluid pre KNS
• Use dopexamine more

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Early intervention

• Six hours only in AE HDU (but its the first 6
  hours)
• More fluid (blood) earlier
• Less inotropes and ventilation later
• NNT 7

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But..

• Are you doing it?
• How easy is it?
• What does it cost?

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What do I do..

• Easy in ICU
• Use CV sats- more blood and dopexamine
• Measure CO less noradrenaline
• Difficult in HDU
• Difficult in AE
• Impossible on the wards?

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• Randomized, double-blind, placebo controlled
• Multicenter, international
• Strict patient selection patients with systemic
  inflam. organ failure due to acute infection.
• 96 hours of 24mcg/kg/hr activated protein C
• 28 day mortality used as primary endpoint

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Results

• All patients
• 28 day mortality Placebo 30.8 Treatme
  nt 24.7 (p0.005)
• Reduction in the relative risk of death of 19.4
• Absolute reduction in risk of death of 6.1
• NNT 16
• In MOF
• 28 day mortality
• Placebo 33.9
• Treatment 26.5
• NNT 13.5

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But..

• Is Lilly trying to take over the world?
• Is it worth the money?
• Do we need another trial first?
• How would randomize for another trial?

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Cost Effectiveness

• USA
• 48,800 per QALY overall
• 27,400 per QALY if APACHE II gt25
• UK
• 10,000 per QALY if same treatment effect as
  PROWESS
• ARR would have to drop to 2 to 3 before cost
  exceeded 30,000 per QALY (Davies in press)

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Cost Comparison

• aPC 10,000 per QALY
• Infliximab 100,000 per QALY
• rTPA 19,400 per QALY

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Current Situation

• Poor efficacy in
• Single organ failure (especially surgical
  patients)
• Usage
• ICS/SICS aPC appropriate for severe sepsis with
  2 or more organ failures
• ? APACHE gt25
• Variable usage
• Trial in the pipeline

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What do I do?

• Give to
• Septic shock
• 2 or more organ failures despite resuscitation
• Earlier rather than later

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aPC
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• Control BM 10 - 11 mmol/l
• Experimental 4.4 - 6.1 mmol/l

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But..

• Majority of patients post cardiac surgery
• Most benefit however
• Septic
• ICU for more than 3 days
• Non cardiac patients
• Trials awaited in general ICUs
• Benefit due to glycaemic control rather than
  insulin per se. (Van den Berghe, CCM, 2003)

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Intensive Insulin - Medical
Patients in ICU for 3 days
All patients
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What do I do?

• Currently
• Tight control as per Annane
• The future
• Not so sure!
• Await ANZICS study.

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Intensive Insulin Therapy
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Relative adrenal insufficiency

• Definition
• Difficult
• Admission cortisol lt25mcg/dl (690nml/l)
• Incidence
• 30 of all ICU patients
• 50-60 in sepsis
• Marik PE, Zaloga GP. Adrenal insufficiency in the
  critically ill. Chest 2002 1221784-1796.
• Marik PE, Zaloga GP. Adrenal insufficiency during
  septic shock. Crit Care Med 2003 31141-145.

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Annane, JAMA, 2002

• 300 patients with septic shock
• Hydrocortisone 50mg q6h
• ACTH test (high dose)
• Improved outcome in non-responders
• NNT (hospital mortality) 6
• Annane D, Sebille V, Charpentier C, et al. Effect
  of treatment with low doses of hydrocortisone and
  fludrocortisone on mortality in patients with
  septic shock. JAMA 2002 228862-871.

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Relative adrenal insufficiency

• Diagnosis
• Admission cortisol
• Cortisol if deterioration
• Management
• 50mg hydrocortisone q6h iv in septic shock
• Stop if result suggests cortisol level sufficient
  (lt25mcg/dl (690nml/l))

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Cheap easy. But

• Who gets them?
• For how long?
• ACTH?
• Random level?
• Harm?
• Is one trial enough?

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CORTICUS

• 500 patients
• 2002-2005
• Less sick than Annane study
• Sepsis for longer
• Non mortality difference
• Steroid vs placebo
• Responders vs non-responders

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What do I do?

• Give to
• Septic shock
• Resuscitate first
• Higher dose noradrenaline
• Random level pre first dose
• Stop
• Watch for response or level back
• Stop abruptly

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Steroids
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• 838 critically ill patients with Hb lt 9 within 72
  hrs of ICU admission
• Hb controlled to 7-9g or 10-12g
• Results
• ARR of 5.8 - Hospital mortality
• NNT 17
• No change in 30 day mortality (except if APACHE
  lt20, lt55 yrs restrictive better)
• MI or unstable angina ?

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But.

• Is anaemia better or transfusion harmful?
• J-L Vincent, JAMA, 2002, Transfusion associated
  with higher mortality.
• Leuco-depleted blood?
• Long term effects?
• Do we do what we think we do?
• Ischaemic heart disease?
• Wu, NEJM, 2001, Transfusion improved outcome in
  MI if admission Hct lt30.

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What do I do?

• Most patients
• Transfuse one unit when Hb lt7
• Exceptions
• Ischaemic
• MI
• Early intervention DO2 optimization.
• Future
• Long term QOL studies

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Restrictive Transfusion
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Restrictive Ventilation

• 861 patients, ALI/ARDS
• Control
• 12ml/kg TV, Pplat lt50cmH2O
• Mim TV 4ml/kg (Pp gt50 if pHlt7.15)
• Intervention
• 6ml/kg TV, Pplat lt30cmH2O
• Min TV 4ml/kg (Ppgt30 if pHlt7.15)
• Bicarbonate for severe acidosis

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Results

• Marked reduction in hospital mortality NNT 11
• With restrictive policy
• Lower TVs and Pp
• Higher FiO2 Peep (until day 7)
• Higher pCO2 (pO2 similar)
• Lower pH
• Increased ventilator-free days
• Decreased other organ failure

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But.

• Difficult to do?
• Pressure control ventilation?
• What do you do?
• Surely bigger is better?

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What do I do?

• Beat by head against the wall!!
• Use APRV

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Restrictive Ventilation
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• 128 ventilated patients, sedated by infusion
• Control
• Sedation stopped at discretion of clinicians
• Intervention
• Sedation stopped daily, until patient awake
• Both groups sub-divide into propofol / morphine
  or midazolam / morphine

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Results

• Duration of ventilation reduced by 2.4 days
• ICU stay reduced by 3.5 days
• No difference in adverse events
• No difference between propofol and midazolam

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What do I do?

• Encourage daily sedation vacation
• Then.Switch off sedation myself
• Use less propofo and more MM
• Use less noradrenaline
• Use less steroids
• Need to reassure that not torturing patients
• Need to communicate and be on hand

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Daily interruption of Sedation
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SSC

• What about combined strategies?

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Resuscitation Bundle

• As soon as possible (but within 6 hours)
• Measure lactate
• BCs prior to antibiotics
• Broad spectrum Abs within 1-3 hours
• If hypotension and/or lactate gt4mmol/l
• 20ml/kg fluid challenge
• Norad. If no response to fluid (MAPgt65)
• If persistant hypotension and/or lactate
• CVP gt8mmHg
• CVsat gt70

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Management Bundle

• As soon as possible (but within 24hrs)
• Low-dose steroids as per unit policy
• aPC as per unit policy
• Glucose control
• Protective ventilation if appropriate

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• NNT 4 for 6 hr bundle
• But
• Bundles different
• Numbers small

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Out-of-hospital cardiac arrest
Hypothermia post out-of-hospital cardiac arrest
improves outcome
The hypothermia After Cardiac Arrest Study Group
(2002). Mild Therapeutic Hypothermia To Improve
Neurologic Outcome After Cardiac Arrest. NEJM
3468549-56
Bernard SA, TW Gray, MD Buist, BM Jones, W
Silvester, G Gutteridge, K Smith.  Treatment of
Comatose Survivors of out-of-hospital Cardiac
Arrest with Induced Hypothermia NEJM 2002
3468557-63
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..cooling

• Target 32-34C
• Aim to reach target within 4 hours
• Cool for 24 hrs (external)
• Passive rewarming over 8 hrs
• All patients sedated, paralysed, ventilated

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.. Results..
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also

• Fear of creating poor outcome survivors has not
  materialized

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But.

• Select group of patients
• Small of Cardiac arrests
• Not necessarily a bad thing
• Aftercare varies hugely

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What do I do?

• If they come to ICU then they get cooled

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SSC
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SSC survivors?
Too hard?
Harm?
Too hard?
Harm?
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SSC survivors?
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The Fabulous 5?
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sicsebm.org.uk