Trials in Critical Care:
evidence you should know
Dr. N.S. MacCallum MB BS PhD MRCP FRCA EDIC DICM
Consultant in Intensive Care Medicine
University College Hospital
NS MacCallum 2010
Outline
•  introduction
•  sepsis
•  ARDS
NS MacCallum 2010
Efficacy versus effectiveness
Efficacy
•  result obtained in
expert hands
•  ... under their
conditions
•  ... with their
enthusiasm
Effectiveness
•  result obtained in
general use
 how well it works under
“real-world” conditions
Don’t worry.
I had the same thing
and they cured me!
how well something works
in an ideal or controlled
setting
NS MacCallum 2010
Sepsis
•  definition
•  epidemiology
•  Early goal directed
therapy
•  corticosteroids
•  activated protein C
•  cathecholamines
•  vasopressin
NS MacCallum 2010
What is sepsis?
A clinical syndrome that we all recognise…
…but difficult to define.
NS MacCallum 2010
ACCP/SCCM definitions
Systemic
Inflammatory Response Syndrome (SIRS)
temperature
•
•
SIRS defines an inflammatory response independent of its cause.
>38°Cconditions:
or <36°C
The response is manifested by two or more of the following
temperature >38°C or <36°C
heart
rate
heart rate
>90 beats/min




respiratory rate >20 breaths/min or PaCO2 <4.3kPa
white blood cell count >12,000 cells/mm3, <4,000 cells/mm3, or >10% immature
(band) forms
>90 beats/min
respiratory rate
Sepsis
•
>20
breaths/min
The systemic response to infection; i.e. SIRS as
a result
of infection.
Severe sepsis
•
Sepsis
associated
organ
dysfunction, hypoperfusion, or hypotension.
white
bloodwith
cell
count
Septic Shock
•
or
PaCO2 <4.3kPa
>12,000 cells/mm3
Sepsis with hypotension, despite adequate fluid resuscitation, along with the
presence of perfusion abnormalities.
<4,000 cells/mm3
Bone Chest 1992 101:1644
NS MacCallum 2010
Clinically useful definitions
Sepsis - exaggerated inflammatory response to infection
•
The systemic response to infection; i.e. SIRS as a result of infection.
Severe sepsis - sepsis + organ dysfunction
•
Sepsis associated with organ dysfunction, hypoperfusion, or hypotension.
Septic Shock - severe sepsis + fluid-unresponsive low BP
•
Sepsis with hypotension, despite adequate fluid resuscitation, along with the
presence of perfusion abnormalities.
NS MacCallum 2010
Sepsis: a continuum of clinical and
pathological severity
Severe
sepsis
A clinical response
precipitated by a
non-specific insult
SIRS + confirmed infection
(later modified to
suspected infection)
Sepsis + organ dysfunction
Highly sensitive definition,
incidence dependent on aetiology
Bone Chest 1992 101:1644
Septic
shock
Sepsis induced hypotension:
•  SBP <90mmHg or
•  ↓ >40mmHg (baseline)
Severe sepsis
+ fluid
unresponsive
hypotension
NS MacCallum 2010
The nature of the clinical problem
•  SIRS, sepsis, and MODS, together constitute the principle
cause of death in adult intensive care units (ICU), with an
associated mortality reaching 60%.
•  Sepsis recently ranked 7th ‘greatest killer’ in the US…on a
par with AMI…but rising.
•  Disproportionate utilisation of resources:
  47% of ICU bed days
  33% hospital bed days
  Hospital length of stay has decreased, but is paralleled by an
increase in discharge to longer term care facilities.
•  Economic burden - $16.7 billion in the USA alone.
Angus CCM 2001 29:1303; Padkin CCM 2003 31:2332; Martin NEJM 2003 16:1546
NS MacCallum 2010
Comparison with other major diseases
Mortality of Severe Sepsis
Cases/100,000
Incidence of Severe Sepsis
AIDS* Colon Breast CHF† Severe
Cancer§ Cancer§
Sepsis‡
AIDS*
Breast AMI†
Cancer§
‡Angus CCM 2001 29:1303; †Nat Center for Health Stat 2001; §Am Cancer Soc 2001; *AHA 2000
Severe
Sepsis‡
NS MacCallum 2010
Epidemiology
•  Incidence and number of
sepsis-related deaths are
increasing in spite of an
apparent decline in sepsis
mortality.
•  Incidence of the sepsis
syndromes ranges from 51 –
300 per 100,000 population
per year
Respiratory
40 - 70%
Genitourinary
10%
Abdominal
10%
Bacteraemia
10-20%
•  15-27% ICU admissions fulfil
diagnostic criteria for severe
sepsis in the first 24 hours
Angus CCM 2001 29:1303; Brun-Buisson ICM 2004 30:580; Vincent CCM 2006 34:344
Padkin CCM 2003 31:2332; Martin NEJM 2003 16:1546
NS MacCallum 2010
Mortality
•  Sepsis
•  Severe sepsis
•  Septic shock
18 – 24%
29 – 47%
40 – 60%
•  Almost two-thirds of cases of severe sepsis are
non-surgical.
•  The syndromes also have a significant impact on
long term outcome, with an estimated 50%
reduction in 5 year life expectancy.
Alberti AJRCCM 2003 168:77; Brun-Buisson ICM 2000 26:S64; Angus CCM 2001 29:1303;
Brun-Buisson ICM 2004 30:580; Padkin CCM 2003 31:2332; Martin NEJM 2003 16:1546;
Vincent CCM 2006 34:344; Sundaraajan CCM 2005 33:71; Finfer ICM 2004 30:589
NS MacCallum 2010
Management
•  Source identification and control
•  Early antibiotics
•  Supportive therapy
•  Adjunctive therapy
•  Surviving Sepsis Guidelines 2008
NS MacCallum 2010
Source identification and control
Identification
•  establish specific anatomic site of infection as rapidly as possible
•  evaluate if amenable to source control measures (e.g. drainage)
Imaging
•  to confirm and sample any source of infection
Control
•  implement source control ASAP
•  exception - infected pancreatic necrosis, where surgery best
delayed
•  use intervention with least physiologic insult e.g. percutaneous
rather than surgical drainage of abcess
•  remove intravascular access devices if potentially infected
Early antibiotics
Crit Care Med 2006; 34:1589–1596
•  retrospective cohort; n=2731 with septic
shock
•  survival to hospital discharge
Anand Kumar et al.
CCM 2006;34(6):1589-1596
•  each hour of delay in antimicrobial administration over
the ensuing 6 hours was associated with an average
decrease in survival of 7.6%
•  despite a progressive increase in mortality with
increasing delays, only 50% septic shock patients
receive effective antimicrobial therapy within 6 hours of
documents hypotension
•  Administration of an antimicrobial effective for isolated or
suspected pathogens within the first hour of documented
hypotension was associated with a survival rate of
79.9%
Anand Kumar et al.
CCM 2006;34(6):1589-1596
Early antibiotics: key points
•  begin iv antibiotics early and always within the first hour
of recognizing septic shock and severe sepsis
**mortality rises by 8% / hour delay**
•  broad spectrum, active against likely pathogens, good
penetration into presumed source
•  combination therapy for pseudomonas and neutropenic
patients
•  reassess daily
•  de-escalate to the most appropriate single therapy when
susceptibility profile known
•  duration typically 7-10 days
Supportive therapy I:
Early goal directed therapy
N Engl J Med. 2001 Nov 8;345(19):1368-77
•  initiated treatment & resuscitation in the ED
•  263 pts – treated for 6hrs
•  500ml CSL every 30mins – CVP 8-12
•  if Scv02 < 70% - RBC to Hct >30%
•  dobutamine
Rivers – EGDT
N Engl J Med. 2001 Nov 8;345(19):1368-77
Rivers – EGDT
N Engl J Med. 2001 Nov 8;345(19):1368-77
NNT = 6
Rivers EGDT:
Why did it work? Are there concerns?
•  short interval between
admission and treatment
•  less patients developed
CVS failure
•  standard group (0–7hrs)
–
–
–
–
less time in ED
less fluid 3.5 v 5L
less blood 18.5 v 64.1%
more sudden CVS death
•  treatment bias (?)
•  single centre
Rivers EGDT: Key messages
•  standard tools for recognition of adequate
resuscitation are ‘poor’
•  early optimisation makes a difference - mainly
fluid
**begin protocolised resuscitation immediately if
hypotension or lactate ≥ 4mmol/L**
•  new trials
–  ProCESS (NIH-funded trial)
–  ProMISE (NIHR)
–  ARISE (ANZICS)
Supportive therapy II:
Fluids / blood
•  no evidence base to support one type of
fluid over another
•  albumin debate
•  hydroxyethyl starch debate
•  haemoglobin debate
Albumin
N Engl J Med. 2004 May 27;350(22):2247-56
•
•
•
•
RCT: 6,997 Australasian ICU pts
saline vs. albumin
albumin safe / equally effective as crystalloid
small ns benefit from albumin in severe sepsis
Albumin: SAFE study
N Engl J Med. 2004 May 27;350(22):2247-56
Hydroxyethylstarch: VISEP trial
N Engl J Med. 2008 Jan 10;358(2):125-39
VISEP trial
•  RCT; n=537, severe sepsis / septic shock
•  Ringer’s lactate vs. 10% HES (200/0.5)
•  stopped after first interim analysis
•  significantly more HES pts. developed ARF
–  dose dependant
–  doubled days requiring RRT
•  increased coagulopathy
•  mortality
–  no difference in early mortality (Days 1-28)
–  27% increase in late mortality (Days 29-90) in HES group (ns)
VISEP trial
N Engl J Med. 2008 Jan 10;358(2):125-39
Hydroxyethyl starch
•  “Although the administration of hydroxyethyl
starch may increase the risk of acute renal
failure in patients with sepsis, variable findings
preclude definitive recommendations”
•  maybe newer HES preparations (e.g. 6% HES
130/0.4) safer but currently little evidence to
support their use in severe sepsis
When to transfuse?
N Engl J Med. 1999;340:409-17
Haemoglobin: TRICC study
Tx at Hb <7
Tx at Hb <10
N Engl J Med. 1999;340:409-17
Key messages: Fluids
•  clear fluid - uncertainty continues
•  blood
–  do TRICC results hold true for leukodepleted
transfusions?
–  early (e.g. Hct 30% in Rivers’) vs. late (7-9g/
dl) Hb?
–  what Hb in severe cardiorespiratory disease?
Adjunctive therapy: steroids
JAMA 2002;288:862-87
Effect of Treatment With Low Doses of Hydrocortisone and
Fludrocortisone on Mortality in Patients With Septic Shock
JAMA 2002;288:862-87
•  RCT; n=300
•  short synacthen test
•  randomly assigned to receive either
hydrocortisone and fludrocortisone (n = 151) or
placebos (n = 149) for 7 days
•  1° outcome: 28 - day survival in patients with
relative adrenal insufficiency (non-responders to
the corticotropin test)
Patients with relative adrenal insufficiency (non-responders) n=229
Hospital †: 61% vs 72% (p=0.04)
Patients without relative adrenal insufficiency (responders) n=70
Hospital †: 69% vs 59% (p=0.75)
Effect of Treatment With Low Doses of Hydrocortisone and
Fludrocortisone on Mortality in Patients With Septic Shock
JAMA 2002;288:862-87
•  all patients, 28 day mortality, 63 % v 53%
RR = 0.83; p = 0.04
•  28 day vasopressor withdrawal 40%
placebo vs 57% treatment group in nonresponders ACTH; p = 0.001
Adjunctive therapy: steroids…
NEJM 2008;358:111-24
Hydrocortisone Therapy for Patients with Septic
Shock: Corticus trial
NEJM 2008;358:111-24
•  RCT ~500pts
•  50 mg of intravenous hydrocortisone or placebo every 6
hours for 5 days; the dose was then tapered during a 6day period.
•  Primary outcome was 28 day mortality among patients
who did not have a response to a corticotropin test.
Hydrocortisone Therapy for Patients with
Septic Shock: Corticus trial
NEJM 2008;358:111-24
No difference between any study groups
Annane vs. CORTICUS
•  Annane study, the patients had higher SAPS II scores at baseline,
and there was a much higher rate of death at 28 days in the placebo
group (61%, as compared with 32% in Corticus study).
•  enrollment in the Annane study was allowed only within 8 hours
after fulfilling entry criteria, as compared with a 72-hour window in
Corticus study.
•  CORTICUS enrolled both steroid responsive andunresponsiev
patients
•  fludrocortisone was not given to patients in Corticus study, since 200
mg of hydrocortisone should provide adequate mineralocorticoid
activity.
COITTS (Annane)
Corticosteroid Treatment and Intensive Insulin Therapy
for Septic Shock in Adults
JAMA Vol. 303 No. 4, January 27, 2010
•  To test the efficacy of intensive insulin therapy in patients
whose septic shock was treated with hydrocortisone and
to assess, as a secondary objective, the benefit of
fludrocortisone
•  509 adults with septic shock who presented with multiple
organ dysfunction and who had received hydrocortisone
treatment was conducted in 11 intensive care units in
France.
•  Compared with conventional insulin therapy, intensive
insulin therapy did not improve in-hospital mortality
among patients who were treated with hydrocortisone for
septic shock. The addition of oral fludrocortisone did not
result in a statistically significant improvement in inhospital mortality
Steroids: Key message
•  The short corticotropin test does not appear to be useful
for determining the advisability of corticosteroid
treatment in patients with septic shock
•  Studies have described the poor relationship between
total and free cortisol levels and other issues concerning
the dose, timing, and type of corticotropin.
Current recommendation
•  Low dose hydrocortisone for severe septic shock
unresponsive to vasopressors
•  No indication for ACTH test
Adjunctive therapy:
activated protein C
NEJM 2001;344:699-709
Adjunctive therapy:
Activated Protein C
Anti-inflammatory
↓ cytokines
↓ selectin mediated
adhesion
Anticoagulant
Inactivates Va and VIIIa
Pro-Fibrinolytic
Inhibits PAI-1
↓ Thrombin Activatable
Fibrinolysis Inhibitor
activation
28 day mortality rate was 30.8 % vs. 24.7%
p=0.005.
NNT = 16
But….
aPC: Key message
•  early promise not subsequently fulfilled
•  EMA mandated a new placebo-controlled trial
–  PROWESS-SHOCK trial
•  more sophisticated use (eg targeting protein C
levels)
•  efficacy vs. side effects
aPC: NICE Guidelines
•  Drotrecogin alfa (activated) is recommended for use in
adult patients who have severe sepsis that has resulted
in multiple organ failure (that is, two or more major
organs have failed) and who are being provided with
optimum intensive care support.
•  The use of drotrecogin alfa (activated) should only be
initiated and supervised by a specialist consultant with
intensive care skills and experience in the care of
patients with sepsis.
Adjunctive therapy: insulin
NEJM 2001; 345: 1359-67
Intensive Insulin Therapy in Critically Ill Patients
(2001)
•  RCT; n=1548 SICU
•  intensive therapy targeted glucose between 80-110 mg/
dl (4.4-6.1 mmol/l) vs. the conventional range was
180-200 mg/dl (10.0 – 11.1 mmol/l)
•  primary outcome: death in ICU
•  Mortality 4.6% in the Intensive Glucose control group vs.
8.0% in Conventional glucose control group (p<0.04)
(42% relative risk reduction)
van den Berghe G. Intensive insulin therapy in the critically ill patients.
N Engl J Med 2001; 345(19): 1359-67.
NEJM 2001; 345: 1359-67
Intensive Insulin Therapy in the Medical ICU
(2006)
•  RCT; n=1200
•  same authors and same conventional and intensive
parameters as the first study
•  primary outcome was death in hospital which was 37.3%
in the intensive group versus 40% in the conventional
group (p=ns)
•  some benefit in subgroup requiring critical care for 3 or
more days
Van den Berghe G.Intensive insulin therapy in the medical ICU.
N Engl J Med 2006; 354(5): 449-61.
Intensive versus Conventional
Glucose Control in Critically Ill
Patients
The NICE-SUGAR Study
Investigators
N Engl J Med 2009;360:1283-97
March 26 2009
NICE-SUGAR study
•  >6000pts
•  Intensive 4.5 - 6.0 mmol/l
•  Conventional < 10.0 mmol/l
•  Stratified
–  Type of admission – surgical or non surgical
–  Region – Australia and New Zealand or North
America
•  Staff were aware of allocation post randomization
2.6% difference
@ 90days
NNTH = 38
Acute lung injury / ARDS
•  protective lung ventilation
•  PEEP
•  fluid strategy
ARDS: low TV ventilation
ARDS: low TV volume
ARDS: low TV ventilation
6 ml/kg
12 ml/kg
ARDSnet: low TV key points
•  Trial stopped early - 861pts
•  reduced mortality in 6ml/kg group
•  31.0 % vs 39.8 %, P=0.007
•  increased ventilator free days
•  mean [±SD], 12±11 vs 10±11; P=0.007
Summary: Sepsis
•
•
•
•
•
•
•
prompt recognition
early and appropriate antibiotic therapy
± surgical/radiological eradication of focus
early and appropriate fluid resuscitation
restoration of an adequate circulation
restoration of an adequate BP
adjunctive therapy
Summary: ARDS
•  avoid ‘baro-volutrauma’
•  ensure early adequate fluid resuscitation &
oxygen delivery
•  ... thereafter try to avoid excess positive
fluid balance
•  optimise PEEP to the individual patient may change daily
Surviving Sepsis Campaign 2008
New guidelines for management of
severe sepsis and septic shock
Consensus of international experts
Crit Care Med 2008: 36; 296-327