What’s new in Clinical Practice Guidelines (CPG)
in Critical Care
Kuwait, April 11, 2013
What is new in CPG in Critical Care
Past, Present, Future
1. Process of CPG development (GRADE)
2. Examples of new and / or controversial recommendations
3. Future tasks
4. Allow you to use those guidelines with more satisfaction
New developments in communism
The evolution of power in medicine
• Clinical Experience and pathophysiological knowledge
• RCTs
• Meta-analyses, decision analyses, economic analyses
• Above with recommendation  Practice guidelines
In the beginning...
• Early 2000
– CPG increasing in importance
– Chaos all over the place, especially for ‘generalists’
– Need to create order out of chaos
GRADE: Guideline development process
– What is the question?
• Step two
– Find and summarize best evidence
• Step three
– Apply judgments (quality of evidence, strength of
recommendations)
rade
• Step one
G
GRADE defining feature
• Evidence: high or low quality?
• quality of evidence: the likelihood that our estimates
of effects are true and adequate to support given
recommendation
• Recommendation: weak or strong?
• confidence that following the recommendation will
cause more good than harm
Recommendations: Weak or strong?
strong methods
AND
benefits clearly outweigh downsides
weak recommendations
weak methods
OR
balance of benefits and downsides unclear or close
ecommendation
strong recommendations
R
Formulate
question
Select
outcomes
Rate
importance
of outcomes
Systematic Review
(outcomes across studies)
Evidence Profile
(GRADEpro)
1
2
Pooled estimate of effect for each outcome
Quality of evidence for each outcome
PICO
Critical
Outcome2
Critical
Outcome3
Important
Outcome4
Not
start
RCT
observational
rate down
action
Outcome1
1.
2.
3.
4.
5.
rate up
High
 Moderate
High
| Moderate |Low
Low| Very
Very low
low
1. large effect
2. dose-response
3. antagonistic bias
risk of bias
inconsistency
indirectness
imprecision
publication bias
systematic review of evidence
Formulate recommendations
 For or against an action
 Strong or weak (strength)
Strong or weak:
 Quality of evidence
 Balance benefits/downsides
 Values and preferences
 Resource use (cost)
recommendation
Guideline panel
Rate overall quality of evidence
across outcomes
Wording
 “We recommend…” | “Clinicians should…”
 “We suggest…” | “Clinicians might…”



unambiguous
clear implications for action
transparent (values & preferences statement)
high
low
Strength of recommendation
degree of confidence that desirable effects of
adhering to recommendation outweigh the
undesirable effects.
Desirable effects
•health benefits
•less burden
•savings
Undesirable effects
•harms
•more burden
•costs
Strong or Weak Recommendation?
• Quality of the evidence
• Balance between desirable and undesirable
effects
• Values and preferences
• Costs (resource allocation, feasibility)
Strenght of Recommendations
• strong recommendation
• authors confident that following the
recommendation will cause more good than harm
• weak recommendation (suggestion)
• authors believe that following the
recommendation will cause more good than harm,
but are less confident
Why Grade Recommendations?
Implications
• strong recommendation
– one size fits all
– expect uniform clinician behavior
– use as performance indicator
• weaker recommendation
– expect action to vary
Strenght of Recommendations
• do it or don’t do it
–strong recommendation
• probably do it, or probably don’t
–weaker recommendation
How to present grades?
• words only
– recommendations versus suggestions
– quality high, moderate, low, very low
• numbers and letters
– recommendation 1 and 2
– quality A, B, C, D
   
GRADE pragmatic approach
•
•
•
•
•
If question appropriate, look for meta-analysis (MA)
If no published MA, identify main studies
If possible, do your own MA
If no MA, describe main studies and their results
Be explicit about the way you identified and summarized
the evidence
• Make sure there is explicit link between recommendation
and evidence
Surviving Sepsis Campaign
• New or controversial
recommendations
•
•
•
•
•
•
68 international authors
30 international organizations
19 reviewers
Attention to COI
GRADE system
Emphasis on meta-analyses (636 references)
– If you can't dazzle them with brilliance, baffle
them with bs
Formulate
question
Select
outcomes
Rate
importance
of outcomes
Systematic Review
(outcomes across studies)
Evidence Profile
(GRADEpro)
1
2
Pooled estimate of effect for each outcome
Quality of evidence for each outcome
PICO
Critical
Outcome2
Critical
Outcome3
Important
Outcome4
Not
start
RCT
observational
rate down
action
Outcome1
1.
2.
3.
4.
5.
rate up
High
 Moderate
High
| Moderate |Low
Low| Very
Very low
low
1. large effect
2. dose-response
3. antagonistic bias
risk of bias
inconsistency
indirectness
imprecision
publication bias
systematic review of evidence
Formulate recommendations
 For or against an action
 Strong or weak (strength)
Strong or weak:
 Quality of evidence
 Balance benefits/downsides
 Values and preferences
 Resource use (cost)
recommendation
Guideline panel
Rate overall quality of evidence
across outcomes
Wording
 “We recommend…” | “Clinicians should…”
 “We suggest…” | “Clinicians might…”



unambiguous
clear implications for action
transparent (values & preferences statement)
high
low
Importance of team work!
Controversies and changes – team work
• Sepsis management requires a multidisciplinary team
(physicians, nurses, pharmacy, respiratory, dieticians,
and administration) and multispecialty collaboration
(medicine, surgery, and emergency medicine) to
maximize the chance for success.
Calibrating the level of your enthusiasm
• There will be one week of extra paid vacation
for all attending this conference
• Kuwait and UAE meet in the opening match
of the World Cup in Qatar 2022
• New personal income tax is introduced to
pay the football team players for winning
more games
Controversies and changes (plus some
gossiping)
• The administration of effective intravenous
antimicrobials within the first hour of recognition of
septic shock (grade 1B) and severe sepsis without septic
shock (grade 1C) should be the goal of therapy.
• Remark: Although the weight of the evidence supports
prompt administration of antibiotics following the
recognition of severe sepsis and septic shock, the
feasibility with which clinicians may achieve this ideal
state has not been scientifically evaluated.
Controversies and changes (plus some
gossiping)
• The administration of effective intravenous
antimicrobials within the first hour of recognition of
septic shock (grade 1B) and severe sepsis without septic
shock (grade 1C) should be the goal of therapy.
• Remark: Although the weight of the evidence supports
prompt administration of antibiotics following the
recognition of severe sepsis and septic shock, the
feasibility with which clinicians may achieve this ideal
state has not been scientifically evaluated.
surviving
patients
[%]
time from onset of hypotension [hours]
Importance of team work!
Controversies and changes (plus some
gossiping)
• The administration of effective intravenous
antimicrobials within the first hour of recognition of
septic shock (grade 1B) and severe sepsis without septic
shock (grade 1C) should be the goal of therapy.
• Remark: Although the weight of the evidence supports
prompt administration of antibiotics following the
recognition of severe sepsis and septic shock, the
feasibility with which clinicians may achieve this ideal
state has not been scientifically evaluated.
Controversies and changes – protocolized
care
• EGDT (targets BP, CVP, UO, Scvo2) with the use of
fluids, pressors, transfusion, dobutamine (1C)
– CVP too low (high PEEP)
– one protocol versus another
– Transfusion and dobutamine
Another protocol
JAMA Feb 24, 2010
(Jan 2007-Jan 2009)
17% mortality
23% mortality
Controversies and changes – new protocol
• We suggest targeting resuscitation to normalize lactate
in patients with elevated lactate levels as a marker of
tissue hypoperfusion (grade 2C)
• Text: If Scvo2 is not available, lactate normalization
may be a feasible option in the patient with severe
sepsis-induced tissue hypoperfusion. Scvo2 and lactate
normalization may also be used as a combined
endpoint when both are available.
Controversies and changes – new
diagnostic possibilities (plus gossiping)
• We suggest the use of low procalcitonin levels or similar
biomarkers to assist the clinician in the discontinuation
of empiric antibiotics in patients who appeared septic,
but have no subsequent evidence of infection (grade 2C).
Vasopressors and inotrops – positive thinking
Controversies and changes - vasopressors
• We recommend norepinephrine as the first-choice
vasopressor (grade 1B).
• We suggest epinephrine (added to and potentially
substituted for norepinephrine) when an additional agent is
needed to maintain adequate blood pressure (grade 2B).
• We suggest dopamine as an alternative vasopressor agent to
norepinephrine only in highly selected patients (eg, patients
with low risk of tachyarrhythmias and absolute or relative
bradycardia) (grade 2C).
• A trial of dobutamine infusion up to 20 mcg/kg/min be
administered or added to vasopressor (if in use) in the
presence of (a) myocardial dysfunction as suggested by
elevated cardiac filling pressures and low cardiac output, or
(b) ongoing signs of hypoperfusion, despite achieving
adequate intravascular volume and adequate MAP (grade 1C)
Low dose long term glucocorticosteroids for severe sepsis and septic shock
Outcomes
Illustrative comparative risks
(95% CI)
Assumed risk Corresponding
risk
Placebo
Low dose long
term
glucocorticost
eroids
Mortality
432 per 1000 394 per 1000
Follow-up: mean 28
(329 to 467)
days
Mortality in higher 612 per 1000
baseline mortality
studies
Follow-up: mean 28
days
Mortality in lower 317 per 1000
baseline mortality
studies
Follow-up: mean 28
days
471 per 1000
(343 to 642)
336 per 1000
(270 to 425)
Relativ No of
Quality of Comments
e effect Participa the
(95% nts
evidence
CI)
(studies) (GRADE)
RR
0.91
(0.76 to
1.08)
RR
0.77
(0.56 to
1.05)
968
⊕⊕⊝⊝
(6
low1,2
studies)
381
⊕⊕⊕⊝
(3
moderate3,
studies) 4
RR
587
⊕⊕⊕⊝
1.06
(3
moderate5
(0.85 to studies)
1.34)
Controversies and changes
2008: We suggest that intravenous hydrocortisone be
given only to adult septic shock patients after it has
been confirmed that their blood pressure is poorly
responsive to fluid resuscitation and vasopressor
therapy (grade 2C)
2012: We suggest not using intravenous hydrocortisone as
a treatment of adult septic shock patients if adequate
fluid resuscitation and vasopressor therapy are able to
restore hemodynamic stability. If this is not achievable,
we suggest intravenous hydrocortisone alone at a dose
of 200 mg per day (grade 2C)
ARDS
Controversies and changes - ARDS
• We recommend target a tidal volume of 6 mL/kg predicted
body weight in patients with sepsis-induced ARDS (grade 1A
vs. 12 mL/kg).
• We suggest strategies based on higher rather than lower
levels of PEEP for patients with sepsis-induced moderate to
severe ARDS (grade 2C).
• We suggest recruitment maneuvers in sepsis patients with
severe refractory hypoxemia due to ARDS (grade 2C).
• We suggest a short course of NMBA of not greater than 48
hours for patients with early sepsis-induced ARDS and a
Pao2/Fio2 < 150 mm Hg (grade 2C).
• We suggest prone positioning be used in sepsis-induced
ARDS patients with a Pao2/Fio2 ratio ≤ 100 mm Hg in
facilities that have experience with such practices (grade 2B).
Sedation
Controversies and changes – less sedation
• We recommend that either continuous or
intermittent sedation be minimized in mechanically
ventilated sepsis patients, targeting specific titration
endpoints (grade 1B).
Stress ulcer prophylaxis
Controversies and changes
• 2008: We recommend that stress ulcer prophylaxis
using H2 blocker (grade 1A) or proton pump inhibitor
(grade 1B) be given to patients with severe sepsis to
prevent upper gastrointestinal (GI) bleed.
• 2012: We recommend that stress ulcer prophylaxis using
H2 blocker or proton pump inhibitor be given to
patients with severe sepsis/septic shock who have
bleeding risk factors (grade 1B).
• When stress ulcer prophylaxis is used, we suggest the
use of proton pump inhibitors rather than H2 receptor
antagonists (H2RA) (grade 2C).
• We suggest that patients without risk factors should
not receive prophylaxis (grade 2B).
Stress ulcer prophylaxis
• The balance of benefits and risks may thus
depend on the individual patient’s
characteristics (including the presence of
enteral feeding) as well as on the local
epidemiology of VAP and C. difficile
infections.
Controversies and changes – DVT
2008:
• We recommend that patients
with severe sepsis receive DVT
prophylaxis with either a) low
dose UFH administered twice
or three times per day; or b)
daily LMWH unless there are
contraindications (grade 1A).
• We suggest that in patients at
very high risk, LMWH be used
rather than UFH as LMWH is
proven superior in other highrisk patients (grade 2C).
• We recommend that patients
with severe sepsis receive daily
pharmacoprophylaxis against
VTE (grade 1B).
• We recommend that this be
accomplished with daily
subcutaneous LMWH (grade 1B
versus UFH twice daily and
grade 2C versus UFH given
thrice daily).
Sweet is good!
Controversies and changes – sweet is good!
• 2008
We suggest use of a validated
protocol for insulin dose
adjustments and targeting
glucose levels to the 150
mg/dL range (grade 2C).
• A protocolized approach
to blood glucose
management in ICU
patients with severe sepsis
commencing insulin
dosing when 2 consecutive
blood glucose levels are
>180 mg/dL.
• This protocolized
approach should target an
upper blood glucose ≤180
mg/dL rather than an
upper target blood glucose
≤ 110 mg/dL (grade 1A).
Controversies and changes - platelets
• 2012: In patients with severe
sepsis, we suggest that
platelets be administered
prophylactically when counts
are ≤ 10,000/ mm3 (10 ×
109/L) in the absence of
apparent bleeding, as well
when counts are ≤
20,000/mm3 (20 × 109/L) if
the patient has a significant
risk of bleeding. Higher
platelet counts (≥
50,000/mm3 [50 × 109/L])
are advised for active
bleeding, surgery, or invasive
procedures (grade 2D).
• 2008: In patients with severe
sepsis, we suggest that
platelets be administered
when counts are 5000/mm3
(5x109/L) regardless of
apparent bleeding.
• Platelet transfusion may be
considered when counts are
5000–30,000/mm3 (5–30
109/L) and there is a
significant risk of bleeding.
Higher platelet counts
(50,000/mm3 [50 109/L]) are
typically required for surgery
or invasive procedures (grade
2D).
Nutrition
Controversies and changes – don’t push
calories...
• 1. We suggest administering oral or enteral (if necessary) feedings, as
tolerated, rather than either complete fasting or provision of only
intravenous glucose within the first 48 hrs after a diagnosis of severe
sepsis/septic shock (grade 2C).
• 2. We suggest avoiding mandatory full caloric feeding in the first week,
but rather suggest low-dose feeding (eg, up to 500 kcal per day),
advancing only as tolerated (grade 2B).
• 3. We suggest using intravenous glucose and enteral nutrition rather
than total parenteral nutrition (TPN) alone or parenteral nutrition in
conjunction with enteral feeding in the first 7 days after a diagnosis of
severe sepsis/septic shock (grade 2B).
• 4. We suggest using nutrition with no specific immunomodulating
supplementation in patients with severe sepsis (grade 2C).
• Translation: Atempt feeding as patient tolerates, don’t push full caloric
intake for its own sake, underfeeding (2/3) / trophic feeding (up to 500
kcal) is OK/even better (but may increase it if fast recovery), don’t use
TPN early, do not use supplements (all 2C)
Controversies and changes - Communication
2008
Consideration for Limitation
of Support
2012
Setting Goals of Care
• 1. We recommend that advance
care planning, including the
communication of likely
outcomes and realistic goals of
treatment, be discussed with
patients and families (grade
1D).
• 1. We recommend that goals of
care and prognosis be discussed
with patients and families
(grade 1B).
• 2. We recommend that the goals
of care be incorporated into
treatment and end-of-life care
planning, utilizing palliative
care principles where
appropriate (grade 1B).
• 3. We suggest that goals of care
be addressed as early as feasible,
but no later than within 72 hrs
of ICU admission (grade 2C).
Sepsis bundles: Converting guidelines
into meaningful change in behavior
Controversies and changes - Fluids
2008 We recommend fluid resuscitation with either natural/artificial colloids
or crystalloids (1B)
2011 We recommend not using ‘200 starch’ (Grade 1A) and suggest not using
130 starches (2B)
Albumin versus other fluids for sepsis
Patient or population: Patients with sepsis
Settings: Intensive care unit
Intervention: Albumin versus other fluids.
Outcomes
Illustrative comparative risks
(95% CI)
Assumed risk
Corresponding
risk
Other fluids
(may be
crystalloid or
colloid)
Albumin
Relative effect
(95% CI)
No of
Participants
(studies)
Quality of the
evidence
(GRADE)
Short term
mortality
Study population
342 per 1000
287 per 1000
(249 to 332)
RR 0.84
(0.73 to 0.97)
1683
(11 studies)
⊕⊕⊕⊝
moderate
Short term
mortality
(albumin vs
crystalloids)
444 per 1000
377 per 1000
(324 t o440)
RR 0.85
(0.73 to 0.98)
1402
(4 studies)
⊕⊕⊕⊝
moderate1
342 per 1000
Short term
mortality
(albumin vs
other colloids)
195 per 1000
(249 to 396)
RR 0.81
(0.57 to 1.16)
281
(7 studies)
⊕⊕⊕⊝
moderate1
Comments
*The assumed risk is the control group risk across studies. The corresponding risk (and its 95% confidence interval) is
based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio
Grade reduced for imprecision.
Controversies and changes fluids
2011 We suggest to include some albumin over crystalloids
alone in the initial fluid resuscitation regimen(2B) and
recommend albumin be combined with crystalloids in the
initial fluid resuscitation regimen when serum albumin
concentration is known to be low (1B)
In the initial volume management of septic patients we suggest
crystalloids with supplemental discretionary use of albumin
over other management strategies (2B)
Controversies and changes - fluids
2012 We recommend crystalloids be used as the initial
fluid of choice in the resuscitation (1B)
2012 We recommend against the use of hydroxyethyl
starches (HES) for fluid resuscitation (grade 1B).
2012 We suggest the use of albumin in the fluid
resuscitation of severe sepsis and septic shock when
patients require substantial amounts of crystalloids
(grade 2C)
Controversies and changes - fluids
2013 administration of saline should be limited in septic shock
(2C) (proposal)
PAD guideliens
PAD guidelines
PAD guideliness
• Process
– 20 people
– 6 year long work
– Developing questions, review/evaluate/sumarize
evidence
– Develop descriptive statements and actionable
recomendation
– Evaluated and compared pain, agitation/sedation
and delirium measurement tools
PAD guideliness
• Differences from previous 2002 guidelines:
– Use of GRADE (connecting evidence with
recommendations)
– Use of professional librarian (19,000 papers, 472 references)
– Scope (Pain, Agitation, Sedation, Delirium)
– Anonymous pooling of opinions and assessments
– Multidisciplinary approach (MD (9), RN (6), pharmacy (2),
geriatrics)
PAD guidelines
Descriptive statement
Actionable recommendation
• Adult medical, surgical,
and trauma ICU patients
routinely experience pain,
both at rest and with
routine ICU care (B)
• We recommend that pain be
routinely monitored in all adult
ICU patients (+1B)
• Pre-procedural analgesia
used in about 20% (B)
• All available IV opioids,
when titrated to similar
pain intensity endpoints,
are equally effective (C).
• We recommend that IV opioids be
considered as the first-line drug
class of choice to treat nonneuropathic pain in critically ill
patients (+1C)
• We suggest that analgesia-first
sedation be used in mechanically
ventilated adult ICU patients (+2B)
Pain
PAD guidelines - Pain
• Pain frequent (especially in cardiac surgery, especially
in women) (B)
• All opioids, when titrated, are equally effective (C)
• Preemptive analgesis prior to chest tube removal (1C)
• Opioids first class of drugs (1C)
• The Behavioral Pain Scale (BPS) and the Critical-Care
Pain Observation Tool (CPOT) are the most valid and
reliable behavioral pain scales (B).
PAD guidelines - Pain
Goal – 5 or less; 6 or more not acceptable
PAD guidelines – Agitation and Sedation
• Maintaining light levels of sedation :
– is associated with shorter duration of MV and a shorter ICU LOS [B)
– increases the physiologic stress response, but not myocardial ischemia (B)
– its association with psychological stress remains unclear (C).
• We recommend that sedative medications be titrated to maintain
a light rather than a deep level of sedation in adult ICU patients,
unless clinically contraindicated (+1B).
– RASS and SAS (Richmond Sedation Agitation Scale and Reiker SAS) are
valid sedation assesment tools (B)
PAD guidelines – Agitation and Sedation
PAD guidelines – Agitation and sedation
• Prompt identification and treatment of possible
underlying causes of agitation, such as pain, delirium,
hypoxemia, hypoglycemia, hypotension, or withdrawal
from alcohol and other drugs, are important
• Maintenance of patient comfort, provision of adequate
analgesia, frequent reorientation, and optimization of
the environment to maintain normal sleep patterns,
should be attempted before administering sedatives
PAD guidelines – Agitation and Sedation
• We suggest that sedation strategies using nonbenzodiazepine
sedatives (either propofol or dexmedetomidine) may be preferred
over sedation with benzodiazepines (either midazolam or
lorazepam) to improve clinical outcomes in mechanically
ventilated adult ICU patients (+2B).
PAD guidelines – Agitation and Sedation
Delirium
PAD guidelines – Delirium
• Delirium:
– syndrome of acute onset of cerebral dysfunction with
change or fluctuation in baseline mental status
– disorganized thinking or an altered level of consciousness
– inattention, inability to sustain or shift attention
– reduced awareness of the environment
– perceptual disturbance (i.e., hallucinations, delusions) are
frequent but neither required for diagnosis
– Other symptoms : sleep disturbances, emotional
disturbances (i.e., fear, anxiety, anger, depression, apathy,
euphoria)
– may be agitated (hyperactive delirium), calm or lethargic
(hypoactive delirium), or may fluctuate between the two
subtypes.
PAD guidelines – Delirium
Delirium is associated with:
– increased mortality (A)
– prolonged LOS (A)
– development of post-ICU cognitive impairment (B)
– Risk factors (baseline): dementia, hypertension,
alkoholism, severity of ilness (B)
– Risk factors (later): coma, benzodiazepine use (in
comparison to dex) (B)
– Confusion Assesment Method (CAM-ICU) and
Intensive Care Delirium Screening Checklist most
valid for monitoring (A)
– We recommend routine monitoring for delirium in
adult ICU patients (+1B)
PAD guidelines – Delirium
• Delirium prevention:
– early mobilization (1B)
• Delirium treatment:
– No evidence to support haloperidol (0)
– Atypical may reduce duration (in comparison to placebo (all
patients on haloperidol) (C)
– Against ryvastigmine (1B)
– Early mobilization (+1B)
– If sedation required (and no benzos or alkohol withdrawal),
suggest dexmedetomidine vs. benzos (2B)
– No magic bullet drug, more in way of delivering care
PAD guidelines – Management Strategies
• Strategies for management:
– Measure PAD
– Analgesia first sedation (2B)
– Daily sedation interruption OR light target sedation (with
sedation only if required and goal to allow responsiveness
and awarness) (1B)
– Promoting and protecting sleep cycles (1C)
– We recommend using an interdisciplinary ICU team
approach that includes provider education, preprinted
and/or computerized protocols and order forms, and
quality ICU rounds checklists to facilitate the use of pain,
agitation, and delirium management guidelines or
protocols in adult ICUs (+1B)
Future challenges for method center
• training of GRADE resource individuals;
• training of content area experts in GRADE
methodology (rise and usefulness of webinars);
• planning for the future updates and reiterations
(succession plans);
• continuous struggle to link the recommendation
to evidence;
Proton Pump Inhibitors Versus Histamine 2 Receptor
Antagonists for Stress Ulcer Prophylaxis in Critically Ill
Patients: A Systematic Review and Meta-Analysis.
Waleed Alhazzani, Farhan Alenezi, et al
Neuromuscular blocking agents in acute respiratory
distress syndrome: a systematic review and metaanalysis of randomized controlled trials.
Alhazzani W, Alshahrani M, et al
The Effect of Selenium Therapy on Mortality in
Patients With Sepsis Syndrome: A Systematic Review
and Meta-Analysis of Randomized Controlled Trials.
Waleed Alhazzani, et al
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