Download Shock - Calgary Emergency Medicine

Shock
Moritz Haager, PGY-4
Dr. Lisa Campfens
July 29, 2004
Objectives
 Develop

an approach to the shock patient
Are there any novel diagnostic tools?
 Review
the DDx of shock
 Discuss specific controversies and new
therapies for specific shock states


Primary focus on Hypovolemic & septic shock
Other shock etiologies covered elsewhere
The common thread

Shock is not a disease but a symptom of
numerous possible underlying etiologies
 Best defined as a state where supply of oxygen
& nutrients is inadequate for metabolic demand
resulting in tissue ischemia
 Time is money


The longer the time spent in the shock state the more
irreversible the damage
Combined mortality tends to be >20%
Initial Approach
 Triage

to resus bay
O2, monitors, IV’s x2, help
 ABC’s

Intubate these pts early
• Be prepared for their BP to crash


Paralyze to decrease metabolic demands
Fluid resuscitation
• Which fluid? How fast? How much?
• Choice of fluid, rate, and amount will depend on
your DDx for underlying cause
Initial Approach
D – Disability & Neuro
 E – Environment, Exposure, Every vital sign



There are 6 vitals – don’t forget Temp & C/S
F – Find an underlying cause

How to get a good Hx
• EMS, CPS, Bystanders, Family, Roommates, Medical
records – the earlier the better

Actively look for possible causes on your DDx
• Focused physical including DRE
• ABG, ECG, CXR
• Echo, ED U/S for AAA, free fluid, tamponade
DDx: Mechanistic Approach
SHOCK
Vasculature
Pump
Decreased vascular tone:
•Neurogenic shock
•Septic shock
•Endocrine shock
Cardiogenic:
•MI / ischemia
•Arrhythmias
•Cardiomyopathies
•Myocarditis
•Trauma
•Wall rupture
•Drug (BB, CCB, TCA) OD
Increased Permeability:
•Anaphylaxis
•Sepsis & SIRS
Obstructive:
•PE
•Tamponade
•Valves
(Stenosis, thrombosis, rupture)
•PTX
•Congenital defects
(Coarctation & other
ductus-dependant lesions)
Volume
Hypovolemia:
GI losses
Hemorrhage
Third spacing / inflammation
Anaphylaxis
Burns
Insensible losses
Metabolic
Endocrinological Causes:
•Addison's
•CAH
•Adrenal infarct
•Chronic steroids
Cellular Poisons:
•Carbon monoxide
•Methemoglobinemia
•Hydrogen sulfide
•Cyanide
DDx: Empiric Approach






S - septic
S - spinal (neurogenic)
H - hypovolemic
H - hemorrhagic
O - obstructive (PE, PTX, HTX, Tamponade)
C - cardiogenic (rate, contractility,
obstruction, valve)
 C - cellular toxins (CN, CO, HS, ASA, Fe)
 K - anaphylaCTic
 E - endocrine/adrenal crisis
Having a good DDx in the back of you head is absolutely
KEY to providing appropriate subsequent care
Pediatric Shock:









S S H H O C C
K
E
-
septic
spinal (neurogenic)
hypovolemic: gastro, abdo surgical
emergency, DKA
hemorrhagic
obstructive (PE, pthrx, hthrx, ct)
cardiogenic (rate- SVT, contractility,
obstruction, valve, congenital heart dz)
cellular toxins (CN, CO, HS, ASA, Fe)
anaphylaCTic
endocrine: adrenal crisis (CAH)
/hypoglcemia/metabolic defects
Why is the DDx so important?
 After
primary survey & initial resus optimal
further Tx can be radically different
depending on etiology


E.g. fluid resus in sepsis vs. penetrating
trauma
Epi for anaphylactic vs. cardiogenic shock
 Re-emphasizes
point that shock is a
symptom – not the disease
Empiric Criteria for Diagnosis of
Circulatory Shock
 Need






any 4 of:
Ill appearance or altered mental status
Heart rate > 100 beats/min
RR > 22 breaths/min or PaCO2 < 32 mm Hg
Arterial base deficit < –5 mEq/L or lactate > 4
mM
Urine output < 0.5 ml/kg/hr
Arterial hypotension > 20 minutes duration
• From Rosens Textbook of Emergency Medicine
Diagnosing Shock

The dilemma
The more advanced the shock state, the easier it is to
identify
but
 Significant tissue hypoxia appears to exist prior to
development of significant signs & symptoms

• Normal BP in face of hypovolemia means some organs are
hypoperfused to maintain systemic BP
• Evidence suggests we are frequently underestimating
disease severity in pts w/ early shock (see Rivers study)

Early reversal of shock is key determinant of
preventing MODS
Diagnostic Adjuncts

Base deficit


Shock index


Serial [lactate] should decrease by 50% 1 hour w/ resus
Urine output


[lactate] > 4.0 mM predicts MOF
Lactate clearance index


HR/systolic BP; should be less than 0.8 (more sensitive than either
alone)
Lactate


= amount of strong base required to be added to a liter of blood to
normalize the pH; should > –2 mEq/L; < -4 mEq/L predicts MOF
Should be > 0.5 ml/kg/h; requires Foley & 30 min to be accurate
SvO2 (mixed venous O2 sat)

Should be >70%; limits of physiologic compensation at 50%
Future Adjuncts?

NIRS (Near-Infrared Spectroscopy)


Same basic principle as SpO2 monitors except
measures tissue O2
Sublingual Tonometry
• Uses sublingual vascular bed as marker for splanchnic
perfusion

Thoracic bioimpedance


Similar to ECG; uses multiple electrodes to measure
impedance across thorax as estimate of CO
None in common use yet; no outcome studies
evaluating their utility
Case 1

39 M stabbed
multiple times by
jealous lover
 O/E: 355, 140, 80/p,
22, 90% RA
 What do you do for
him?
ATLS Classification of
Hemorrhagic Shock
Blood Products ASAP
Tx of Hypovolemic Shock
 ABC’s
 Direct

Estimated 20% of combat deaths in Vietnam
could have been prevented w/ pressure or
tourniquet
 Up

pressure on any bleeder
to 2 L of fluid – then blood…right?
Depends on underlying etiology
• Trauma: Blunt vs. penetrating
• Dehydration etc
Fluid Resus in Hemorrhagic Shock
 Multiple

Which fluid?
•
•
•
•
•

Controversies
Crystalloids: NS, Ringers lactate (RL)
Colloids: Albumin, Starches, Dextrans, Gelatins
Hypertonic saline +/- dextran
Oxygen carrier substitutes
Blood products
How much fluid? How fast?
• Blunt vs. penetrating trauma

What end-points should be used?
Historical Overview
Moore FA, McKinley BA, Moore EE. The next generation in shock resuscitation. Lancet 2004; 363: 1988–96
Crystalloids or Colloids?
Theoretical Pro’s & Con’s

Crystalloids





Resuscitate both intra- &
extravascular compartment
Improve organ function
Minimal risk of
anaphylactoid reactions
Inexpensive
Reduce colloid oncotic
pressure -- may predispose
to pulmonary and
peripheral edema
• Decrease gas exchange
• Delayed wound healing

Colloids






Require less volume
Work faster
Improve organ function
Risk of anaphylaxis
Risk of infection
Risk of coagulopathy
• Dextrans > starches >
gelatins

Expensive
Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief
Overview of the Current Debate. J Trauma. 2003;54:S82–S88.
Crystalloids or Colloids?
What is the Evidence?



Meta-analysis of 16 RCT’s of isotonic crystalloids vs.
colloids
Primary outcomes of mortality & pulmonary edema
Results:


No statistically significant differences found for mortality,
pulmonary edema, or LOS
Subgroup Analyses
• Trend in favor of crystalloids (RR 0.64, 95% CI: 0.17 to 2.42) for
decreasing pulmonary edema in trials with well-described
randomization methods
• Trend to decreased mortality w/ crystalloids in trauma pts (RR 0.39,
95% CI: 0.17 to 0.89)


Analysis underpowered to detect small but imp differences
Concluded:

Results equivocal; unable to argue for or against either fluid due
to lack of power & study heterogeneity
Choi PTL, et al. Crystalloids vs. colloids in fluid resuscitation: A systematic review.
Crit Care Med. 1999; 27: 200-10
Crystalloids or Colloids?
What is the Evidence?



Meta-analysis of 18 RCT’s
Primary outcome: all cause mortality
Results





Albumin or plasma protein fraction: 7 RCTs RR1.52 (1.08 to
2.13).
Hydroxyethylstarch: 7 RCTs RR 1.16 (0.68 to 1.96).
Modified gelatin: 4 RCTs RR 0.50 (0.08 to 3.03).
Dextran: 8 RCTs RR 1.24 (0.94 to 1.65).
Colloids in hypertonic crystalloid compared to isotonic crystalloid:
• albumin and hypertonic saline vs. isotonic crystalloid: 1 RCT RR of
death 0.50 (0.06 to 4.33)
• dextran in hypertonic crystalloid vs. isotonic crystalloid: 8 RCTs RR
0.88 (0.74 to 1.05)

Conclusions:

No benefit for colloids; should not be used
Alderson, P; Schierhout, G; Roberts, I; Bunn, F. Colloids versus crystalloids for
fluid resuscitation in critically ill patients . 2004; 2. The Cochrane Database of Systematic Reviews
Crystalloids or Colloids?
What is the Evidence?
 Analyzing




the meta-analyses
6 meta-analyses to date on crystalloids vs.
colloids
All fail to show statistical difference
All indicate trend towards increased mortality
w/ colloids in trauma pts
Many limitations in primary studies
Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief
Overview of the Current Debate. J Trauma. 2003;54:S82–S88.
Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief
Overview of the Current Debate. J Trauma. 2003;54:S82–S88.
Rizoli. 2003 cont’d

Concluded



“The first limitation of a meta-analysis is that it can
only be as good as the quality of the individual RCTs
it includes”
“meta-analysis should be interpreted cautiously and
…viewed as hypothesis generating given the
limitations in both study design and limitations of the
primary RCTs”
Large well done trial is needed but evidence suggests
trauma pts should continue to be resuscitated w/
crystalloids
Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief
Overview of the Current Debate. J Trauma. 2003;54:S82–S88.
Crystalloids or Colloids?
 Conclusion



No real conclusive data to firmly support one
over the other but trend towards harm w/
colloids in trauma
Lots of limitations in primary studies limits
utility of meta-analyses
Given cost, ease of use, and familiarity
crystalloids should continue to be our primary
fluid in the ED
Hypertonic Saline
Hypertonic Saline


HTS = 7.5% saline +/- 6% dextran (HTS-D)
Dose: 4 ml/kg or 250 cc as initial bolus over 5-10
min
 MOA:

shifts water 1st out of RBCs & endothelium into
plasma, & then out of interstitium & tissue cell
• a rapid but transient improvement in intravascular volume &
hemodynamics
• hemodilution and endothelial cell shrinkage  decreased
capillary hydraulic pressure  improved perfusion.
Hypertonic Saline

Advantages

Improves hemodynamics,
lowers subsequent fluid and
blood requirements, and
improves DO2

Disadvantages

• Rare to non-existent reports
in literature
• Primarily related to
hypernatremia, rapid volume
expansion, & dextran
• Many animal studies and
clinical trials demonstrate this

Decreased inflammatory
response
• may limit ischemia /
reperfusion injury and thus
decrease MOF


May be neuroprotective
Small fluid volume required
Primarily theoretical:


Central pontine myelinolysis
Worsened bleeding
• Shown in animals but not
observed in human trials


Interference w/ X-matching
Anaphylactoid reactions
(dextran)
Orlinsky, M. Current controversies in shock
and resuscitation.Surg Clin North Am 2001;
81(6): 1217-62
Cochrane Review

Methods



Results:




Systematic review of mortality in17 studies of HTS or
HTS-D vs. isotonic crystalloids in trauma, burn, &
surgical pts
Only 6 were adequate methodology (5/6 trauma trials)
Trauma: RR for death w/ HTS 0.84 (0.61-1.16)
Burns: RR for death w/ HTS 1.49 (0.56-3.95)
Surgery: RR for death w/ HTS 0.62 (0.08-4.57)
Conclusions:


Data too limited to exclude or prove benefit from HTS
Need more & larger trials to narrow CI’s
• Bunn, F et al. Hypertonic versus isotonic crystalloid for fluid
resuscitation in critically ill patients. Cochrane Database of
Systematic Reviews. 2004
Is dextran confounding?

Meta-analysis of 12 RCT’s


Analyzed HTS & HTS-D separately in hypotensive trauma pts
Results


4/6 HTS trials “positive” but non-significant pooled OR 0.98 (0.71
- 1.36)
7/8 HTS-D trials “positive” but non-significant pooled OR 1.20
(0.94 - 1.57)
• Only 1/8 trials reached statistical significance

Concluded

HTS-D appears better than HTS, and both may be better than
isotonic crystalloids (but fails to reach significance)
• Wade, CE et al. Efficacy of hypertonic 7.5% saline and 6%
dextran-70 in treating trauma: A meta-analysis of controlled clinical
studies. Surgery 1997;122:609-16.
HTS: Conclusion
 Looks
promising, lots of theoretical
benefits, but so far no convincing evidence
its better (or worse) than isotonic
crystalloids
 Data limited




Small studies
Heterogeneous populations
Different solutions used
Virtually all adult studies – unable to
extrapolate to peds
Oxygen-carriers

3 basic types

Hemoglobin-based
• Surface-modified hemoglobins
• Intramolecular cross-linked hemoglobins
• Polymerized hemoglobins




PolyHeme – promising; in Phase III trials
Hemopure – approved in S. Africa; trials ongoing
Hemolink – promising; trials ongoing
Perfluorocarbons
• Work by allowing large amts of O2 to dissolve in them but studies
disappointing to date

Liposome-encapsulated Hemoglobin
• Costly, potential RES overload

Jury is still out on these but they are coming
Delayed vs. Early Fluid
Resuscitation
The Golden Hour
 Perspective



Hypotension occurs after ~1/3 loss of blood
volume (~1.5 L in 70 kg adult)
Death occurs after ~50% loss of blood volume
Rate of bleeding determines “golden hour”
• 25 cc/min – hypotensive at 1 hr; dead at 2 hrs e.g.
liver laceration
• 100 cc/min – hypotensive at 15 min, dead at 30
min e.g. vascular injury
Delayed vs. Early Fluid Resus
Pro’s and Con’s

Delayed


Bleeding from injured
vessels will decrease
due to clot formation,
vasoconstriction etc
Fluid resus may
increase hemorrhage:
• Raises BP increasing
hydraulic pressure
• Vasodilate
• Dilute clotting factors

Early


Fluid resus increases
perfusion & DO2 to
end organs
Prolonged
hypoperfusion leads to
MODS
• = main cause of posttraumatic death after
immediate
exsanguination or head
injury
Historical Background

Early 1900’s fluid resus was frowned upon


50’s -60’s: Popularity of fluid resus


Canon in 1910 pointed out that increasing BP prior to achieving
hemostasis could “pop the clot”
based on animal data where rapid reversal of shock induced by
controlled blood loss (e.g. through phlebotomy) w/ IV fluids
improved survival
Subsequent studies of uncontrolled blood loss (e.g. razor
wire into aorta) found decreased survival w/ aggressive
fluid resus


Raising BP caused more bleeding
Limited resus targeting lower BP’s improved survival the most
Bickell, WH et al. Immediate versus Delayed Fluid
Resuscitation for Hypotensive Patients with Penetrating
Torso Injuries. NEJM 1994; 331: 1105-09

RCT of 598 pts >16 yo w/ penetrating torso
trauma in urban setting
 Odd/even day randomization into early
(prehospital ATLS protocol) or delayed (no fluids
until in OR) fluid resuscitation
 Results


Sig increased survival in delayed group (70% vs.
62%, P = 0.04)
Significantly prolonged PT/PTT in immediate resus
group -- ?clinical significance
Criticisms

Odd / even day randomization
 Rapid transport times (12-13mins)


Not analyzed in Intention-to-treat fashion


How does this change in rural setting?
ITT analysis of data failed to show sig benefit
Relatively small volumes of fluids used
 High mortality rates in both groups
 Most of the benefit appeared to occur in pts w/
tamponade
Cochrane Review
 Systematic


review of RCT’s looking at
Early vs. delayed fluid resus
Large vs. small volume fluid resus
4487 potential papers – only 6 met
the inclusion criteria
 Unable to combine the results
quantitatively due to heterogeneity
 Found
Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with
bleeding. (Cochrane Review). In: The Cochrane Library, Vol 2; 2004
Cochrane Review

Early versus delayed fluids:

Bickel 1994:
• 598 hypotensive penetrating torso trauma pts
• Mortality 116/309 (38%) vs. 86/289 (30%)
• RR for death w/ early fluids was 1.26 (95% CI 1.00-1.58)

Blair 1986:
• 50 hypotensive pts w/ UGIB
• Mortality 2/24 (8%) vs. 0/26 (0%)
• RR for death w/ early blood transfusion was 5.4 (95% CI 0.3107.1)

Turner 2000:
• 1309 trauma pts
• Mortality 73/699 (10.4%) vs. 60/610 (9.8%)
• RR for death with early fluids was 1.06 (95% CI 0.77-1.47).
Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with
bleeding. (Cochrane Review). In: The Cochrane Library, Vol 2; 2004
Cochrane Review

Large vs. small volume fluid resus

Dunham 1992:
• 36 hypotensive trauma pts.
• Mortality 5/20 (25%) vs. 5/16 (31%)
• RR for death for large volume was 0.80 (95% CI 0.28-2.29)

Dutton 2002:
• 110 hypotensive blunt & penetrating trauma pts
• Mortality 4/55 (7.3%) vs. 4/55 (7.3%)
• The RR for death w/ large volume was 1.00 (95% CI 0.263.81).

Fortune 1987
• 25 pts; No mortality data
Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with
bleeding. (Cochrane Review). In: The Cochrane Library, Vol 2; 2004
Cochrane Review
 “This
review found insufficient evidence for
or against the use of early or larger
volume fluid resuscitation in the treatment
of uncontrolled haemorrhage. While
vigorous fluid resuscitation may be lifesaving in some patients, results from
clinical trials are inconclusive.”
Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with
bleeding. (Cochrane Review). In: The Cochrane Library, Vol 2; 2004
So give fluids…Don’t give fluids?

Best study to date (Bickel 1994)


Tons of variables & unanswered questions






Suggests we should limit pre-OR fluid resus in penetrating
trauma
At what time point does reversal of benefit occur? i.e. when does
the wait become too long?
How does this apply to blunt trauma?
In pigs there appears to be a middle ground – is there an ideal
SBP at which we should maintain pts?
Different etiologies of shock likely need different approaches
How does choice of resus fluid figure in all of this?
Limiting resus to attain SBP ~90 mm Hg

makes intuitive sense, and is recommended by some authorities
BUT at this point has not been adequately studied
Experimental Treatments in
Hemorrhagic Shock
 Vasopressin

Promising in porcine models
 Oxygen

No large clinical trials yet
 FVIIa

carriers
concentrate
No conclusive evidence yet – stops bleeding
but also appears to cause thrombotic
complications
Case 2
 65
M presents w/ fever & AMS
 PMHx: DM, HTN,
 O/E: 392, 122, 100/45, 24, 90% RA,
GCS14
 CXR: bilateral pulm infiltrates
 What do you want to do for him?
Septic Shock
Epidemiology

Incidence variable but on the rise



~ 1/1000 – 260/1000 pts days
Larger # of elderly, HIV, chemotherapy, organ
transplant, and dialysis pts in addition to diabetics,
alcoholics etc
Mortality ranges from 3% for pts w/ no SIRS
criteria to 46% for septic shock
 Locally ~250 ICU admissions for sepsis per year
Latest ACCP/SCCM Consensus
Definitions
 Infection
= invasion of organ system(s) by
microorganisms
 Sepsis = systemic host response to
infection requiring > 1 signs & symptoms
of sepsis
 Severe sepsis = sepsis w/ organ failure
 Septic shock = severe sepsis w/
cardiovascular failure requiring vasoactive
medications
• Vincent & Jacobs. Curr Opin Infect Dis 16: 309-13. 2003
Vincent & Jacobs. Curr Opin
Infect Dis 16: 309-13. 2003
Classifications reflect disease
severity
Diagnostic category
SIRS criteria
none
2
3
4
Sepsis
Severe sepsis
Septic shock
•
Mortality (%)
3
7
10
17
16
20
46
McCoy & Matthews. Drotrecogin Alfa (Recombinant Human
Activated Protein C) for the treatment of severe sepsis. Clin
Ther 2003; 25: 396-421
INFLAMMATION
PATHOGENS
TNF-α, IL-1, IL-6, IL-7,
Proteases, Leukotrienes,
Prostaglandins
Bradykinin, Platelet activating
factors
Free oxygen radicals
Endotoxins, Exotoxins
Direct endothelial invasion
SEPSIS
TF EXPOSURE
ENDOTHELIAL INJURY
ANTI-COAGULANT
SYSTEM INHIBITON
↓ AT III, ↓ aPC, ↓ pS
↓ thrombomodulin
ACTIVATION
OF CLOTTING
CASCADE
FIBRINOLYTIC
SYSTEM INHIBITION
↑ PAI-1
PRO-COAGULANT EFFECT
MICROVASCULAR THROMBOSIS
MULTI ORGAN DYSFUNTION SYNDROME
SCCM Guidelines for Treatment
of Septic Shock
 Utilize
st 6 hrs
 EGDT in 1
 Cultures before Abx
 Source control
 Aggressive rehydration
with colloid or crystalloid
 Use dopamine or
norepinephrine for
refractory shock
 Give stress dose steroids




Give rhAPC when
appropriate
Keep Hb 70-90
Use low TV’s & minimal
peak pressure & PEEP
vent strategy
Use insulin therapy
 Avoid
 Supranormal oxygenation
 Bicarb
•
Dellinger et al. Surviving sepsis
campaign guidelines for management of
severe sepsis and septic shock. Crit
Care Med. 2004; 32: 858-73
Early Goal Directed
Therapy
Rationale behind EGDT

Time is survival:


Goal is to achieve balance b/w O2 delivery &
consumption
Standardized approaches to ED Tx have
improved outcomes in other Dz (e.g. MI)
 Traditional parameters of perfusion appear to be
too insensitive for ongoing tissue hypoxia
 Early observational trials found survivors to have
supranormal hemodynamic parameters
Earlier Trials
 No
consistent benefit from using goaldirected therapy to optimize oxygen delivery
in ICU patients






Gattinoni et al. A trial of goal-directed hemodynamic therapy in
critically ill patients. N Eng J Med 1995; 333: 1025-32
Hayes et al. Elevation of systemic oxygen delivery in the treatment
of critically ill patients. N Eng J Med 1994; 330: 1717-22
Yu et al. Effect of maximizing oxygen delivery on morbidity and
mortality rates in critically ill patients: a prospective randomized
controlled study. Crit Care Med. 1993; 21: 830-8
Boyd et al. A randomized clinical trial of the effect of deliberate
perioperative increase of oxygen delivery on mortality in high-risk
surgical patients. JAMA. 1993; 270: 2699-707
Tuchschmidt et al. Elevation of cardiac output and oxygen delivery
improves outcome in septic shock. Chest 1992; 102: 216-20
Shoemaker et al. prospective trial of supranormal values of survivors
as therapeutic goals in high-risk surgical patients. Chest 1988; 94:
1176-86
Earlier Trials
 Limitations:





Heterogeneous study populations
Small sample sizes & wide CI’s
Enrollment after ICU admission
Tended to focus on one intervention in
isolation
Most used PA catheters
Rivers et al. Early goal-directed therapy in the
treatment of severe sepsis and septic shock. N
Eng J Med. 2001; 345: 1368-77
 Prospective RCT of 263 adult pts with sepsis
treated either with traditional care or a
standardized resuscitation protocol in the ED
 All had arterial & central venous lines placed –
the EGDT group got a catheter capable of
continuous O2 sat measurement
 EGDT discontinued once transferred to ICU – all
ICU staff blinded to pts assignments
 Primary endpoint was mortality
EGDT Protocol
Edwards PreSep Central
Venous Oximetry Catheter
Rivers et al. 2001 (cont’d)

Found that EGDT did significantly better




In-hospital mortality 30.5% vs. 46.5%,
ARR 16%, NNT = 6; OR 0.58 (95%CI 0.38 – 0.87)
60d mortality 44.3% vs. 56.9%
• Primarily explained by reduction in sudden CVS collapse
deaths (10.3% vs. 21.0%)
Various secondary outcomes (labs & severity
scores) significantly better in EGDT group



EGDT pts spent longer time in the ED
EGDT survivors spent less time in hospital than standard
Tx survivors (14.6 d vs. 18.4 d)
Baseline SVO2 was 48% despite only 50% ventilated
Rivers et al. 2001 (cont’d)
 Differences




in EGDT group
More fluid early (4.9 L vs. 3.5L)
More transfusions (64.1% vs. 18.5%)
More inotropic support (13.7% vs. 0.8%)
Less use of pulmonary artery catheters
later in ICU stay (18% vs. 31.9%)
Controversies

Above average mortality in both Tx arms
 Liberal use of transfusion
 Use of SvO2 never thoroughly studied as resus
end point – is it equivalent to SmO2?
 Conflicts with earlier studies showing lack of
benefit from using hemodynamic goals
•
•


Hayes et al. N Eng J Med 1995; 330: 1717-22
Gattinoni et al. N Eng J Med 1995; 333: 1025-32
Different time points – all prior studies in ICU setting
More heterogeneous patient populations
Controversies
 Transfusion
practice
 How does this fit with the TRICC trial?
 Need for IJ or SC lines
 Which part of protocol accounts for benefit?
 How will this affect department flow?
 Does this protocol have any applicability to
other shock etiologies?
Why the TRICC trial does not
contradict Rivers et al
 Different



patient population
Euvolemic pts
Enrolled within 72 hrs of ICU admission
Only 6% had Dx of sepsis, and only 26.5%
had any infection at all
Supporting data
 Success
of hemodynamic optimization
appears time-dependent



Meta-analysis of ICU pts
Studies instituting PAC goal-directed therapy
later than 12 hrs or after onset of organ failure
failed to show benefit
Studies that intervened early found to result in
significant mortality reduction of 23% (95%CI
16-30)
• Kern et al. Meta-analysis of hemodynamic optimization in
high-risk patients. Crit Care Med 2002; 30: 1686-92
Fluids in Sepsis
How much fluid?
 Till
they froth at the mouth!!
 These pts need a ton of fluid – average of
6L in Rivers study

Note difference compared to approach to
penetrating trauma
Vasopressors
Just need a little squeeze..
Vasopressors:

Dopamine:

Dose:
• 1-5 ug/kg/min: 10ly
dopaminergic effect
• 5-10 ug/kg/min :10ly
beta effect
• 10-20 ug/kg/min : 10ly
alpha effect

Levophed:

Dose:
• 0.01 – 3 ug/kg/min

MOA:
• 10ly potent alpha
agonist
• Some beta effect

Controversies
• Used to be thought that
it worsened tissue
perfusion
• More recent studies
contradict this
Norepinephrine or Dopamine
in septic shock?

Tons of animal data; very few clinical studies


Decreased mortality w/ norepinephrine vs. dopamine
in one NON-randomized trial
Theoretical benefits w/ norepinephrine
•
•
•
•
•
Less tachycardia
No effect on HPA or cerebral perfusion pressure
Increased GFR
Decreased lactate levels
Improved splanchnic blood flow
•


st
1
Vincent & de Backer. Crit Care 2003; 7: 6-8
On the other hand dopamine is quickly available and
familiar
Bottom line = either will do as an initial pressor
Antibiotics
SCCM Guidelines





Draw appropriate cultures first
Give antibiotics within 1 hr of recognition of
septic syndrome
Antibiotics should be broad-spectrum & chosen
to cover most likely organisms based on
presentation & local resistance patterns
Arrange for further diagnostic studies to rule out
surgically correctable foci of infection once
appropriate
Remove lines & tubes if appropriate
GIVE ABX EARLY

“Autopsy studies in persons
who died in the intensive
care unit show that failure
to diagnose and
appropriately treat
infections with antibiotics or
surgical drainage is the
most common avoidable
error”
•
Hotchkiss & Karl. The
pathophysiology and treatment of
sepsis. N Eng J Med. 2003; 348:
138-50
Local ID recommendations:
Quick reference guide

Undifferentiated febrile
shocky pt w/ no focus



Ceftriaxone

Gentamicin or quinolone
Meningitis


Ceftriaxone + macrolide or
resp quinolone
Urinary tract

Intraabdominal

Respiratory



Ceftriaxone +/- vancomycin
+/- ampicillin


Ancef + flagyl + gentamicin
(24 hr dosing)
Ceftriaxone + flagyl
Pip-tazo
Carbapenem
Necrotizing fasciitis

IVIG + penicillin +
clindamycin + surgery

Dr. Dan Gregson personal
communication
A Plea from Dr. Kortbeek

When inserting
central lines, chest
tubes etc




Wear a sterile gown
Wear a mask
Prep & drape a huge
area
Communicate potential
‘dirty’ lines to admitting
service
Ventilatory Strategies
Background
 Traditional


vent parameters
TV 10 – 15 ml/kg, minimal PEEP to maintain
normal PCO2, PO2 & pH
ARDS mortality as high as 90% in the 70’s
(currently 30-40%)
• Gattinoni et al. Physiologic rationale for ventilator setting in
acute lung injury / acute respiratory distress syndrome
patients. Crit Care Med. 2003; 31(S): S300-04
ARDS-Net trial


Multicenter RCT of 861 adults with ARDS
Randomized within 36 hrs of intubation to:
 Control group
• Vt 12 ml/kg predicted body wt on AC mode
• Adjusted Vt to keep plateau pressure b/w 45-50 cm
H2O

Low Vt group
• Vt 6-8 ml/kg predicted body wt on AC mode
• Adjusted Vt to keep plateau pressure b/w 25-30 cm
H20

Followed for 180 days

Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal
volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome
. N Eng J Med. 2000; 342: 1301-8
ARDS-Net trial (cont’d)
 Primary


outcomes
In hospital mortality
Ventilator-free days in first 28 days
 Secondary



outcomes
Organ failure
Barotrauma
Plasma IL-6 levels
ARDS-Net trial (cont’d)
 Results:

Low Vt group had
Sig decreased mortality
• 31.0% vs. 39.8%
• ARR 8.8% (95%CI 2.4-15.3%); NNT = 11

Numerous improved secondary outcomes
Conclusions

General consensus in the literature that ARDS
trial results are valid, and that
• VT should be 6-8 ml/kg
• Plateau pressures should be kept to < 30 cm H2O
• PEEP should be used to minimize alveolar collapse
at pressures as low as possible (start 5-10 cm H2O)
Steroids
Background

Anti-inflammatory effects


Basis for large dose (primarily methylprednisolone 30
mg/kg followed by 5 mg/kg }steroid trials in 80’s
2 large RCT’s failed to show benefit
•
•

Veterans administration. Effect of high-dose glucocorticoid
therapy on mortality in patients wit clinical signs of systemic
sepsis. N Eng J Med. 1987; 317: 659-65
Bone et al. A controlled clinical trial of high dose
methylprednisolone in the treatment of severe sepsis and
septic shock. N Eng j Med. 1987; 317: 653-58
Meta-analysis of 9 RCT’s found no benefit, and
possibly increased mortality w/ large dose steroids RR
1.13, 95%CI 0.99 – 1.29
•
Cronin et al. Corticosteroid treatment for sepsis: A critical
appraisal and meta-analysis of the literature. Crit Care Med.
1995; 23: 1430-39
Background

Concept of adrenal insufficiency

Stress steroid response essential
• Taking out adrenals increases septic & hemorrhagic
shock mortality in animals -- reversible with exogenous
steroids
• Bilateral adrenal necrosis or infarction noted in ~30% of
septic pts at autopsy
• Multiple factors affect HPA axis during stress
• Studies of sepsis pts have shown that up to 42% have
adrenal or HPA dysfunction which correlates w/
increased mortality
• Multiple studies document improved catecholamine
response in steroid-treated septic shock
•
Prigent et al. Clinical review: Corticotherapy in sepsis. Crit Care
2004; 8: 122-29
Annane et al. Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in
patients with septic shock. JAMA 2002; 288: 862-71

Multicenter DBRCT of 300 adult septic shock pts
tested with short corticotropin test & randomized
to

Placebo
or


Hydrocortisone 50 mg q6h IV & fludrocortisone 50 ug
PO OD for 7 days
Primary outcome

28d survival
Annane et al cont’d
 Results


No significant difference in mortality for all pts
Non-responders treated w/ steroids had
decreased 28d mortality


Less reliance on vasopressors



53 vs. 63%; ARR 10%, OR 0.54 (95%CI 0.31-0.97) NNT = 10
Non-responders: Median time to withdrawal 7 vs. 10 d; HR
1.91 (95%CI 1.29-2.84)
All pts: Median time to withdrawal 7 vs. 9 d; HR 1.54 (95%CI
1.10-2.16)
No significant differences in adverse events
Criticisms

Possible inclusion of true adrenal insufficiency


Use of fludrocortisone in addition to
hydrocortisone



Not widely practiced
CORTICUS trial ongoing to evaluate hydrocortisone
alone in septic shock
Underpowered to detect harm in responders



High mortality rate in placebo group
Trend towards harm in responders needs clarification
Avoid steroids for all approach
Change of entry criteria during study

No analysis of pts recruited before & after
DX of adrenal insufficiency

What is a normal serum cortisol during stress?


Most controversial area -- Nobody knows
No clear cut normal range:
• Serum cortisol levels variable & poorly reflective of biologic action
during stress
• Elevated and depressed cortisol levels are both associated w/
increased morbidity & mortality

Current approach to Dx based on consensus opinion & limited
literature
•

Cooper & Stewart. Corticosteroid insufficiency in acutely ill patients. N
Eng J Med. 2003; 348: 727-34
Serum free cortisol measurements appear to be more predictive
& may become new standard
•
Harnrahian et al. Measurement of serum free cortisol in critically ill
patients. N Eng J Med 2004; 350: 1629-38
Suggested diagnostic approach

Draw a random cortisol level
 Perform a ACTH stim test



Administer 250 ug of cosyntropin IV
Draw serum cortisol levels at 0, 30, and 60 min
Give dexamethasone 2-4 mg in ED


Does not interfere w/ ACTH stim test
Treatment should be stopped if test negative
• Serum cortisol levels >1242 nmol/L have been found to
be associated w/ significantly greater mortality
• Suggests that exogenous steroids could be harmful
•
Sam et al. Cortisol levels and mortality in severe sepsis. Clin
Endo. 2004; 60: 29-35
Interpreting results

Random cortisol




< 414 nmol/L (15 ug/dL) – suggestive of adrenal
insufficiency – start steroids
>938 nmol/L (34 ug/dL) – suggestive of steroid
resistance – replacement unlikely to help
414 – 938 nmol/L – base decision on ACTH stim test
result
ACTH stim test


>250 nmol/L (9 ug/dL) change  adrenal insufficiency
unlikely
<250 nmol/L (9 ug/dL) change  suggestive of
adrenal insufficiency – start steroids
•
Cooper & Stewart. Corticosteroid insufficiency in acutely ill
patients. N Eng J Med. 2003; 348: 727-34
Steroid conclusions
 Think
of steroids in pts w/ apparent septic
shock refractory to standard treatment
 Draw baseline cortisol levels & do ACTH
stim test
 Use dexamethasone in the ED
 Do NOT give steroids card blanche
 Await trials on use of free cortisol
Recombinant Human
Activated Protein C
(rhAPC = Drotrecogin alfa = Xigiris®
aka superdrug)
Background

No pharmacologic agent shown to reduce in
sepsis mortality in phase III trials….











Ibuprofen
NAC
Anti-TNF-α mAb vs. placebo (NORASEPT II)
IL-1 receptor antagonist vs. placebo
PAF receptor antagonist vs. placebo
High dose steroids
Bradykinin antagonist (Deltibant)
Tissue factor pathway inhibitor
AT III vs. placebo (KYBERSEPT)
Etc, etc
…until now (maybe)
PROWESS Trial: Bernard et al. Efficacy and safety
of recombinant human activated protein C for severe
sepsis. N Eng J Med 2001; 344: 699-709
 Multicenter
DBRCT of 1690 adult pts w/
severe sepsis
 Randomized to


rhAPC infusion @ 24 ug/kg/h for 96 hrs
Placebo
 Primary

outcome
All-cause mortality at 28d
Bernard et al. cont’d
 Results

rhAPC significantly reduced mortality
• 28d mortality 24.7% APC vs. 30.8% placebo
• ARR 6.1% (95% CI 1.9-10.4); NNT = 16

rhAPC had non-significant increase in risk of
serious bleeding
• 3.5% vs. 2.0% (p=0.06), NNH = 67
Sounds great, but don’t forget to
read the fine print…
Post hoc analyses
 Pts
w/ APACHE II scores <25 did worse w/
rhAPC than w/ placebo
 Benefit dec’d w/ less organ dysfunction


ARR single organ system 1.7%
ARR multi-organ failure 7.4%
 More
benefit in pts w/ septic shock rather
than sepsis
 Pts not in DIC did worse w/ rhAPC than w/
placebo
Cost

$335 Cdn per 5 mg vial


0.024 mg x 70g kg x 96 hrs = ~161 mg or 32 vials =
$10, 800 Cdn per treatment
Is it cost-effective? Yes, if used selectively.

Cost per life-year gained
• APACHE II <25 $19, 723 USD
• APACHE II >25 $575,054 USD

Total cost to our system
• CHR ICU pharmacy budget 2001: $1.6 million USD
• Cost if rhAPC was used in pts w/ APACHE II > 25:
$482,800 USD
•
Manns et al. An economic evaluation of activated protein C for
severe sepsis. N Eng J Med. 2002; 347: 993-1000
The Future
 ADDRESS

Trial
Placebo-controlled trial of rhAPC in lower-risk
pts w/ severe sepsis
 Trials
in pediatric populations
 Trials examining use of heparin in
conjunction w/ rhAPC
 Development of more defined criteria for
selecting pts likely to benefit from rhAPC
Septic Shock Summary
 Mortality








reduction strategies:
EGDT:
ARDSNet vent strategy
Steroids
rhAPC
Insulin
Dex in Meningitis
Early appropriate Abx
Source control
ARR 16.0%
ARR 8.8%
ARR 10.0%
ARR 6.1%
ARR 3.4%
ARR 8.0%
Case 3
 56F
w/ SOB & pleuritic CP & syncope
 PMHx: Breast CA, Hx of DVT
 O/E: 370, 110, 80/40, 86% RA, big fat red
leg




ECG: deep S in I, Q in III, inverted T in III, RV
strain pattern
CXR: Hampton’s hump, Westermark sign
Echo: high right-sided pressures, RV dilation
D-dimer: 7.0
Are you going to
thrombolyse her?
Obstructive Shock: PE

25% mortality for shock 2o to PE
2/3 of pts w/ fatal PE die within 1 hr of presentation
BUT
 Only a few pts w/ “massive” PE exhibit shock – many
more exhibit RV dysfunction but never deteriorate into
shock


Indications for thrombolysis


Very controversial
Shock is the one indication most experts agree on
• Based only on hemodynamic improvements
• No good mortality data
• Wood. The presence of shock defines the threshold to
initiate thrombolytic therapy in patients with pulmonary
embolism. Crit Care Med. 2002. 28:1537–1546
PE + Shock: Thrombolyze?

Meta-analysis



9 RCT’s of 461 pts: lytics vs. heparin
Only 1 study (n=8) demonstrated mortality benefit (all
pts in shock)
No statistically sig benefit for 10 outcomes:

Pooled RR for death w/ lytics: 0.63 (0.32-1.23)
• No sig difference in shock subset analysis


Pooled RR for recurrence : 0.59 (0.30 – 1.18)
Statistically sig increase in serious bleeds

RR 1.76 (1.04 – 2.98), NNH = 17
• Thabut et al. Thrombolytic Therapy of Pulmonary
Embolism: A Meta-Analysis J Am Coll Cardiol 2002;40:1660
–7
Conclusion:
 No
good literature support for thrombolysis
in PE but




Small studies (underpowered)
No good studies looking at shock exclusively
Good physiologic and observational data to
support use in PE + shock
Most experts agree it should be given in
shock
OK, So what is the dose?
 Standard

regimen:
Alteplase:
• 10 mg IV bolus, then 90 mg over 2 hours
 Rapid

regimen:
Alteplase:
• 0.6 mg/kg over 15 min
Case 4
 48
yo Male w/ crushing RSCP radiating to L
arm & jaw while shoveling snow





PMHx: DM, HTN, Chol, Smoker, Obese
FHx: 3 brothers, 6 sisters, 2 fathers, 2 mothers
all w/ MI’s in their 40’s
Pale, diaphoretic, vomiting, GCS 8, SOB
373, 120, 75/palp, 22, 89% RA
ECG: tombstones in V2-4 w/ reciprocal
changes
 What
do you want to do with him?
Approach to Cardiogenic Shock


ABC’s
Consider DDx & identify etiology


MI, myocarditis, dissection, arrhythmia, LV wall
rupture, cardiomyopathy, PE, valve, tamponade,
OD’s, etc
Your Tx plan is CRRRAP






C – Contractility (inotropes, IABP)
R – Rate control
R -- Rhythm control
R – Reperfusion strategies (PTCA, lytics)
A – Afterload reduction
P – Preload (fluids)
Management
Are you going to cath him? Lyse
him? Anything else?
Reperfusion Strategies
 PTCA or


Lytics? – The SHOCK Trial
RCT of 302 pts w/ AMI & shock randomized to
surgical (PTCA or CABG) vs. medical (lysis) Tx
No significant mortality difference at 30d
• ARR 9.3% (20.5 to -1.9%)

Sig dec in mortality at 6 mo in surgical group
• ARR 12.8% (23.2 – 0.9%)

Benefit sustained at 1 year
Important Considerations
 PTCA appears
to be slightly better than
thrombolysis for all comers
• Keeley et al. Primary angioplasty versus intravenous
thrombolytic therapy for acute myocardial infarction:
a quantitative review of 23 randomised trials. Lancet
2003; 361: 13–20
 No
trial has ever shown benefit of
reperfusion alone in shock pts – IABP
appears to be essential
Case 5
 49
F w/ fever, AMS, N&V, abd pain
 PMHx: HTN, Asthma, RA
 O/E: 384, 125, 85/30, 24, 87% RA
 CXR: RLL pneumonia
 Fluids, Abx, pressors – still hypotensive
 What is going on?
Don’t forget about meds
 Pt
is on prednisone 50 mg PO OD for last
20 years!!!!
Etiology of Adrenal Crisis
Pre-existing or
New Adrenal
Insufficiency





Acute Precipitant
•Surgery
•Anesthesia
•Procedures
•Infection
•MI/CVA/PE
•Alcohol/drugs
•Hypothermia
Addisons
Chronic steroids
Sepsis
Adrenal infarcts
/ hemorrhage
Pituitary infarct /
hemorrhage
Adrenal
Crisis
Tx: As for sepsis…

Draw a random cortisol level
 Perform a ACTH stim test



Administer 250 ug of cosyntropin IV
Draw serum cortisol levels at 0, 30, and 60 min
Give dexamethasone 2-4 mg in ED


Does not interfere w/ ACTH stim test
Treatment should be stopped if test negative
• Serum cortisol levels >1242 nmol/L have been found to
be associated w/ significantly greater mortality
• Suggests that exogenous steroids could be harmful
•
Sam et al. Cortisol levels and mortality in severe sepsis. Clin
Endo. 2004; 60: 29-35
Case 6
yo M mountain biking – goes over
handlebars & lands on his head
 PMHx: none
 O/E: 370, 45, 80/60, 12, 95% RA, GCS 15
 Tx?
 Why is he bradycardic?
 Why is he hypotensive?
 32
Neurogenic Shock
 Differentiate

b/w:
Spinal shock:
• Loss of all cord function below level of injury
occuring in first 24 hrs (occ several days)

Neurogenic hypotension:
• Part of spinal shock – get disruption of sympathetic
innervation & unopposed vagal tone

No reflex tachycardia (>T4) & peripheral vasodilation
(>T6)
• Dx of exclusion in trauma

areflexia, flaccid paralysis, vasodilation, bradycardia
Neurogenic Shock: Tx
R/O other causes of shock 1st
 Tends to respond to




Trendelenburg
Fluids
May require

Atropine 0.5 – 1.0 mg IV
• NB: Pre-Tx prior to intubation to avoid unopposed vagal
stimulation  bradyarrest


Pressors: dopamine
Generally should not require aggressive Tx:
consider other causes
Key Points
 Shock


is a symptom, not a disease
General approach (ABC’s), then
DDx is KEY!!
• SSHHOCCKE mnemonic or mechanistic approach

Empiric investigations & treatment is indicated