SEPSIS ,SEVERE SEPSIS

AND SEPTIC SHOCK

2008 UPDATE

J.TAVARES,MD,FCCP,FAASM
 Protocol for Early Goal-Directed Therapy

Rivers E et al. N Engl J Med 2001;345:1368-1377

• SEPSIS RESUSCITATION BUNDLE:
• 1-Serum Lactate
• 2-Blood Cultures
• 3-Antibiotics within 3 hours/1 hr
• 4-IVF
• 5-CVP 8-12 or 12-15mmHg
• 6-Scv02>70%
LACTIC ACID

• High Lactate levels due to liver

failure.
• Cutoff value still 4mmol/L .
• Rapid turnaround time (ABG
analyzer).
• SEPSIS RESUSCITATION BUNDLE:
• 1-Serum Lactate
• 2-Blood Cultures
• 3-Antibiotics within 3 hours/1 hr
• 4-IVF
• 5-CVP 8-12 or 12-15mmHg
• 6-Scv02>70%
FLUID MANAGEMENT

• 1-Crystalloids comparable to
Colloids(SAFE Trial:NEJM,2004)
• 2-May use Albumin in
individuals with Albumin less
than 4.
• 3- ?Hydroxyethyl starch(HES )
PENTASTARCH

• NEJM(358;2; jan 10/08)

• Ringer’s Lactate vs Pentastarch
• Mortality: no diference at 28
days(24.1% vs 26.7%) ; higher in
the Pentastarch group at 90
days(33.9% vs 41.0%; P=0.09)
PENTASTARCH

• MORBIDITY:

• Higher rate of acute renal

failure(22.8% vs 34.9%)
• Lower platelets count
• More PRBC transfusions
Kaplan-Meier Curves for Overall Survival

Brunkhorst F et al. N Engl J Med 2008;358:125-139

• SEPSIS RESUSCITATION BUNDLE:
• 1-Serum Lactate
• 2-Blood Cultures
• 3-Antibiotics within 3 hours/1 hr
• 4-IVF
• 5-CVP 8-12 or 12-15mmHg
• 6-Scv02>70%
CVP 8-12:?for how long
• Comparison of 2 fluid mngt
strategies in ALI(nejm;354,2006
• 1000 Pts(500 conservative fluid
mangt;497 liberal)

• No difference in 60 day
mortality,but less lung injury,
faster weaning and fewer days in
ICU for conservative.
 Protocol for Early Goal-Directed Therapy

Rivers E et al. N Engl J Med 2001;345:1368-1377

RBC Transfusion

• Controversies in RBC transfusion

in the critically
ill(chest/131/5/may,2007)
• TRICC trial(NEJM 1999;340)
• Lack of benefit of RBC
transfusions:1-immune
suppression(leukocytes);2-
prolonged RBC storage
RBC TransfusionClinical
Recommendations)
• 1-general critically ill:Hb=7g/dl
• 2-critically ill with septic shock(<6h):8-
10
• 3-critically ill with septic
shock(>6h):7g/dl
• 4-critically ill with chronic cardiac
disease:7g/dl
• 5-critically ill with acute cardiac
disease:8-10g/dl
Sepsis management
bundle
• 1-Tight blood sugar control

• 2-Low dose steroids

• 3-Drotrecogin alfa

• 4-Plateau pressures<30cm H2O

• 5-Extubation readiness.
Intensive insulin therapy
in the ICU
• Leuven study(nejm;nov2001)
• 1-BG<110
2-mortality reduced from 8% to
4.6%
• 3-Severe hypoglycemia(<40): 0.8%
in the conventional group and 5.1%
in the intensive treatment group.
• 4-Surgical ICU patients.
Kaplan-Meier Curves Showing Cumulative Survival of Patients Who Received Intensive Insulin
Treatment or Conventional Treatment in the Intensive Care Unit (ICU)

Van den Berghe G et al. N Engl J Med 2001;345:1359-1367

IIT in the ICU
• Leuven 2(nejm 2006;354)
• 1-Blood glucose 80-110
• 2- patients staying in ICU for 3 or
more days: mortality decreased
from 52.3% to 43%
• 3-Severe hypoglycemia(<40): 3.1%
in the conventional group and
18.7% in the treatment group.
• 4-medical IICU patients.
IIT in the ICU
• VISEP studies and Glucocontrol studies
both in Europe(stopped because of
increased risk of hypoglycemia).

• Both criticized for not having enough

number of patients.
• Ongoing clinical trial by NIH(NICE-SUGAR)
trial may have sufficient statistical power
to address the above issues.
Kaplan-Meier Curves for Overall Survival

Brunkhorst F et al. N Engl J Med 2008;358:125-139

ITT in the ICU

• Glycemic control needs to be done

safely.

• Use of computerized systems:

• Glucommander(can be loaded in a
bedside computer,hanheld computer
or nursing station computer
Glucommander
• 5 parameters:
• 1-low end of target range for blood
glucose
• 2-high end of target range for glucose
• 3-the initial multiplier(adjusted for
insulin sensitivity)
• 4-the maximum time interval between
measurements
• 5-the insulin concentration
Sepsis management
bundle
• 1-Tight blood sugar control

• 2-Low dose steroids

• 3-Drotrecogin alfa

• 4-Plateau pressures<30cm H2O

• 5-Extubation readiness.
Adrenal Insufficiency

• 2002:Annane et al(JAMA;288):299
patients-76% of nonresponders to
cosyntropin stimulation test,on
ventilator were randomized to
hydrocortisone plus fludrocortisone
for 7 days:13% reduction in mortality
for those treated
Adrenal Insufficiency
• The CORTICUS trial(double-
blinded,randomized,placebo-
controlled multicenter European
trial)( Goal:800 patients):

• Comparing hydrocortisone(50mg IV
q6h for 5 days,taper to 50mg IV q12h
for 3 days,then 50mg daily for 3
days)with placebo in septic shock.
Adrenal Insufficiency
• The retrospective Corticus cohort
study(Critical Care Medicine:Volume
35(4) April 2007pp 1012-1018)

• Total of 562 patients(after

exclusion:477pts were left)
 Enrollment and Outcomes

Sprung C et al. N Engl J Med 2008;358:111-124

CORTICUS

• 1-Hydrocortisone did not

improve survival or reversal of
shock even in patients who did
not respond to Cosyntropin test

• 2- Hydrocortisone hastened
reversal of shock.
Sepsis management
bundle
• 1-Tight blood sugar control

• 2-Low dose steroids

• 3-Drotrecogin alpha

• 4-Plateau pressures<30cm H2O

• 5-Extubation readiness.
Proposed Actions of Activated Protein C in Modulating the Systemic Inflammatory,
Procoagulant, and Fibrinolytic Host Responses to Infection

Bernard G et al. N Engl J Med 2001;344:699-709

Drotrecogin Alfa
• 1-PROWESS trial:NEJM 2001;344:699-709.

• 2-ADDRESS trial:(APACHE<25 or only one

organ dysfunction at baseline)-NEJM
2005;353:1332-1341.:no significant
reduction in 28-day mortality.

• 3-ADDRESS one year follow-up(critical care

medicine 2007;35:1457-1463):no increased
risk of death or evidence of harm at 1 year.
Kaplan-Meier Estimates of Survival among 850 Patients with Severe Sepsis in the Drotrecogin
Alfa Activated Group and 840 Patients with Severe Sepsis in the Placebo Group

Bernard G et al. N Engl J Med 2001;344:699-709

 Incidence of Serious Adverse Events

Bernard G et al. N Engl J Med 2001;344:699-709

How do I do
it(Resuscitation Phase)
• Septic shock:
• 1-IVF (up to 20cc/kg bolus to keep
MAP>=65
• 2-if unable to achieve above,place
central line for CVP monitoring:keep
CVP 8-12mmHg(12-15 if PPV).
• 3-If CVP goal achieved but
MAP<65,start vasopressors
How do I do
it(Resuscitation Phase)
• 4-NE,DA,PE,Vasopressin
• 5-follow serial lactate levels
6-If MAP>65,check ScVo2(goal
is ScVo2>70%).
7-If ScVo2<70% and
Ht<30%,transfuse PRBC
How do I do
it(Resuscitation Phase)
• 9-If Ht>30% and ScVo2 still
<70%,start Dobutamine.

If ScVo2>70%,goal achieved
FLUIDS

• Normal Saline:500 cc boluses

• Albumin:25g iv x 3 doses

• Avoid Hespan
Vasopressin

• 0.01-0.04 units/mn IV

• Do not titrate.
How do I do
it(Management Phase)
• STEROIDS
• 1-No need for baseline cortisol
level or Cosyntropin test: If BP
is not responding to IVF and
Vasopressors after 1 to 2
hours,start HYDROCORTISONE
at 50mg IV every 6 hours for 5
days(do not taper)
How do I do
it(Management)
• ACTIVATED PROTEIN C

• 2-APACHE>25 or at least two organs

failure,start drotrecogin alpha.

• 3-If APACHE<25 or only one organ

failure,may consider drotrecogin.
How do I do
it(management)
• BLOOD GLUCOSE
• 4-Tight Blood Sugar control: use
hospital protocol). Acceptable
to keep blood sugar less than
150.
How do I do
it(Management)
• Mechanical ventilation

• 5-keep plateau pressure below

30 cmH20
• 6-Spontaneous Awakening
Trials
• 7-Spontaneous Breathing Trials
Antibiotics

• USE HOSPITAL PROTOCOL

Goal for 2009

• DECREASE SEPSIS MORTALITY

BY 25%
Material for Research

• 1-Procalcitonin

• 2-C Reactive Protein

• 3-Statins