Goal Directed Therapy For Sepsis

1. Sepsis Update 2009
Troy Pennington DO

2. The First Physician c. 2980 BC
Ancient Egyptians founded
medical schools; Imhotep was the
first known physician to receive
a medical degree.

3. Early Scientific Papers
2735 BC
Chinese Emperor Shen Nung
wrote a treatise on the use
of ch’ang shan in fever.

4. The Code of Hammurabi 1800 BC

5. The first Contagion c. 100 BC
“small creatures invisible
to the eye, fill the
atmosphere, and
breathed through the
nose cause dangerous
diseases.”
– Marcus Terentius Varro, De re rustica
libri III

6. Case One
36 year old female with URI symptoms
resolving after 5 days followed by high
fever, body aches, cough, nausea,
vomiting and diarrhea.
BP 90/50 responds to fluids
K3.1, serum CO2 14

7. Case Two
71 year old male with acute altered
mental status, fever and cough
CXR-multilobar pneumonia
BP 80/40, Pulse 136, no change in blood
pressure after 3 liters of fluid
Central line CVP is 5cm H2O

8. Case Three
69 year old female from a convalscent
home BIB EMS intubated, febrile, Bp
94/56, RR 30.
Labs: UA WBC TNTC, CBC 25K with
48% bands, Creatine 5, Glucose 328,
Lactate 1.4mmol, Coags nl, CXR
Negative

9. Severe Sepsis
• Approximately 950,000 cases per year
• Over 200,000 deaths per year
• Costs for sepsis and related diseases over
$25 billion/year (Angus Crit Care Med 2003)

10. The Numbers
• Sepsis & Septic Shock account for about 2.9%
of hospital admits and 10% of ICU admissions
• Estimated 50% came from the ED
• Early Goal Directed Therapy focused on the
initial 6 hours of patient care
• The Surviving Sepsis Campaign incorporated
EM as a key component

11. Sepsis…How does it Stack up
Trauma Cardiac Arrest
150,000
Deaths
AMI
SEPSIS 250,000
Stroke 700,000 yr. 950,000yr deaths
140,000 deaths yr.
200,000
deaths

12. Changing Paradigms
Fighting the old paradigm
it doesn’t make a difference
intensivist’s job
way too complicated
Goals
show outcomes differences
early intervention is essential
Keep it simple

13. Epidemiology
The Most Common sites of sepsis are:
1. Lungs 45%
2. Abdomen 17%
3. Urinary Tract 10%
4. Undetermined 20-30%
The Incidence of Fungal Sepsis has tripled due to
transplant patients and those on immunosuppresive
therapy.
(Accounts for only 5% of all cases of sepsis)
N Engl J Med 340 (3):207

14. Epidemiology
Gm-positive sepsis has overtaken
Gram-negative sepsis
Common gram-positive bacteria include:
Staphylococcus aureus, coagulase-negative
staphylococci, enterococci, and streptococci;
Most common gram-negative pathogens are
Escherichia coli, Klebsiella, and Pseudomonas;

15. The Sepsis Continuum
INSULT SIRS SEPSIS SEVERE SEPSIS
A clinical response arising Refractory
from a nonspecific insult, SIRS with a Hypotension
including > or = 2 of the &
following Presumed Septic Shock
or
• Temperature <36c or >38c
• HR>90 beats per minute confirmed
• Respirations > 20 BPM or infectious process
PaCO2 <32
• WBC Count <4,000 or
>12,000or >10% bands
Bone et al. Chest. 1992:101.1644.

16. Sepsis…defined
Sepsis
SIRS with
Documented or Presumed
infection

17. Severe Sepsis
Sepsis and organ
dysfuntion
May include but not
limitied to lactic acidosis,
oliguria, AMS

18. Septic Shock
Sepsis induced
hypotension SBP <90
May include >40mmhg
drop from baseline blood
pressure not relieved with
fluids

20. Global Tissue Hypoxia
• “Early hemodynamic assessment on the
basis of physical findings, vital signs,
central venous pressure, and urinary
output fails to detect persistent global
tissue hypoxia.” Rivers NEJM Nov. 8, 2001

21. Early Lab Clues
• Glucose > 120 mg/dl
• Creatinine Increase > 0.5mg/dl
• INR >1.5 or aPTT 60s
• Thromobocytopenia <100,000
• Hyperbilirubinemia >4mg/dl
• Lactate Level > 1mmol
• Balk RA -DIS Mon - 01-APR-2004; 50(4): 168-213

22. The Sepsis Cascade

23. Systemic Inflammatory
Response Syndrome (SIRS)
• Can be self limited or progress to severe
sepsis & shock
– Circulatory abnormalities
• Intravascular volume depletion
• Peripheral vasodilatation
• Myocardial depression
• Increased metabolism
• Lead to an imbalance between systemic
oxygen delivery & demand…resulting in
global tissue hypoxia or shock

25. Global Tissue Hypoxia
• A key development & indicator preceding
multiorgan failure and death.
• The transition to serious illness often
occurs in the “Golden hours” when early
recognition and treatment in the
emergency department provide maximal
benefit in terms of outcome

26. Goal Directed Therapy
• Goal Oriented manipulation of
– Cardiac Preload
– Cardiac Afterload & Contractility
• To achieve a balance between systemic
oxygen delivery and oxygen demand
• End points of Resuscitation
– Normalized values for mixed venous oxygen
saturation, arterial lactate concentration, base
deficit, and pH Rivers NEJM Nov. 8, 2001

27. Early Goal Directed Therapy
• A prospective randomized study looking at adult
patients who presented to a Detroit emergency
department over a 3 year period.
• Criteria for inclusion included at least 2 SIRS
criteria and a systolic blood pressure of no
higher than 90mm Hg (after a crystalloid –fluid
challenge of 20-30cc/kg of body weight over a
30 minute period or a blood lactate
concentration of 4 mmol per liter or more.

28. Early Goal Directed Therapy
• The researchers enrolled 263 patients
• 130 to Early GDT
• 133 to Standard Therapy
• Detroit investigators examined whether early
goal-directed therapy, instituted immediately in
the emergency department (ED), reduced
mortality in septic patients

29. Early Goal Directed Therapy
• In the GDT group, a protocol outlined a sequence
of interventions (including fluids, vasoactive and
inotropic drugs, and transfusions)
• Targeted central venous pressure was
8 to 12 mm Hg
• Goal mean arterial pressure of 65 to 90 mm Hg
• Central venous oxygen saturation of 70 percent
or higher
• Urine Output of >0.5cc/kg/hr

32. Early Goal Directed Therapy
• Results:
– Early Goal-Directed Therapy
associated with significantly
lower in-hospital mortality
(47 percent vs. 31 percent of patients)
(p=.009)
60-day mortality (57 percent vs. 44 percent)

33. Early Goal Directed Therapy
• Results:
– After admission the patients that had received
Early Goal Directed therapy had:
• A higher mean central venous oxygen
saturation
• A lower lactate concentration
• A lower base deficit
• And a higher PH

34. Early Goal Directed Therapy
What were the differences?
GDT vs. Standard Therapy
• More fluids…500cc q 30minutes over the 1st 6 hours,
an average of 5 liters vs 3.5
• Increased transfusion rate in GDT to goal HCT of at
least 30
• More inotropic support
• Similar use of mechanical ventilation & vasopressors

35. Antibiotics-GO BIG or GO HOME!
Choose the appropriate antibotic.
Early empiric antibiotic coverage
In a series of patients with gram negative sepsis those
treated with appropriate antibiotics had an 18% mortality
compared to the inappropriate group 34%
Bochud PY - Crit Care Med -010NOV-2004;32(11suppl): S495-512

36. Antibiotics
Choose Wisely
•Empiric Choices
•Sources
•Lung
•Bloodstream
•Urine
•Abd / pelvis
•Soft tissue
•Most Commonly Encountered Bugs
I
•E-coli, klebisella, pseudomonas
•Staph aureus, coagulase-negative staphylococci,
enterococci, and streptococci
•Don’t Forget Fungal………….. (5%)

37. Fluids
• No superiority of colloids
over crystalloids
regarding; pulmonary
edema, length of stay or
survival
• Serial crystalloid bolus of
500cc or serial colloid
bolus of 300cc
Balk RA - DIS Mon -01-APR-2004; 50(4):168-213

38. Pressors
• Appears that the jury is still out
• In most studies the initial drug of choice is
still Dopamine
• Norepinephrine is supported by many
– Has better alpha activity
– Less associated tachycardia

39. Blood
• Lack of significant
outcome benefit to raising
hemoglobin above 10g/dl
in non-bleeding critically ill
patients without active
coronary / cerebral
ischemia.
Balk RA - DIS Mon -01-APR-2004; 50(4):168-213

40. Vasoactive Agents
• Consider Ionotropic therapy: Patients with
persistent SCVO2< 70% with MABP>65 mm
HG and CVP within the 8-12 range.
• Dobutamine titrated 2.5mcg/kg/min every
20-30 minutes to a SCVO2 >70%
• Consider a phosphodiesterase inhibitor,
Milrinone, in tachycardiac patients
Rivers EP- CMAJ -25-OCT-2005; 173 (9): 1054-65

41. Lower Blood Glucose
• A surprising result emerged from a randomized study of
1548 patients in a surgical ICU, most of whom had
undergone cardiac surgery.
• Although most of the patients were not diabetic, they
received either intravenous insulin (to keep blood
glucose between 80 and 110 mg/dL) or conventional
treatment (insulin infusion started if blood glucose
exceeded 215 mg/dL).
• In-hospital mortality was significantly lower in the
intensive-insulin group (7.2 percent vs. 10.9 percent);
this difference was attributable to fewer deaths from
multiple organ failure with proven infection.
(JW Dec 15, p. 191, accession number 011116001, and N Engl J Med Nov 8; 345:1359).

42. • In a meta-analysis
published in 1992, NIH
researchers reported that
steroid use was not
Steroids
beneficial
• Now, the latest meta-
analysis indicates that
steroids are useful but only
when started later and
delivered in lower doses
over a longer period
• The analysis also confirmed
that a delayed, low-dose
five- to seven-day steroid
regimen followed by steroid
taper for an equal period is
effective regardless of
response to corticotropin
stimulation test

43. Lower Tidal Volume Ventilation
Patients with acute lung injury and the acute respiratory
distress syndrome were enrolled in a multicenter,
randomized trial.
• Traditional ventilation treatment… initial TV of 12 ml per kg
of predicted body weight
VS
• Lower tidal volume, of 6 ml per kilogram of predicted body
weight
• The first primary outcome was death before a patient was
discharged home and was breathing without assistance.
• The second primary outcome was the number of days
without ventilator use from day 1 to day 28.
NEJM Vol.342:1302-1308 May 4, 2000 Number 18

44. Lower Tidal Volume Ventilation
Results:
• The trial was stopped after the
enrollment of 861 patients
because mortality was lower in
the group treated with lower
tidal volumes than in the group
treated with traditional tidal
volumes (31.0 percent vs. 39.8)
(P=0.007)

45. Xigris
• Xigris is the first FDA-approved therapy with a proven ability to increase survival
in adult patients with high-risk severe sepsis
• A recent randomized, double blinded, placebo-controlled trial of 164 centers in
11 countries, demonstrated statistically significant reduction in mortality with
one life saved for every 16 patients treated
• Endorsed by the Surviving Sepsis Campaign Guidelines

46. Case One
36 year old female with URI symptoms resolving
after 5 days followed by high fever, body aches,
cough, nausea, vomiting and diarrhea.
BP 90/50 responds to fluids
K3.1, serum CO2 14

47. Case One
Consideration For:
Early antibiotic therapy
Placement of a central venous catheter
Early Goal Directed Therapy
ICU Admission and monitoring

48. Case Two
71 year old male with acute altered mental status,
fever and cough
CXR-multilobar pneumonia
BP 80/40, Pulse 136, no change in blood pressure
after 3 liters of fluid
Central line CVP is 5cm H2O

49. Case Two
Consideration For:
Serial crystalloid boluses
If CVP 8-12mmHG and pt. hypotensive initiate
vasopressor therapy to reach goal of MAP >
65mmHG
If MAP goal attained & lactate remains
elevated or increasing or SCVO< 70% the add
Dobutamine or Milrinone to improve cardiac
output

50. Case Three
69 year old female from a convalscent home BIB
EMS intubated, febrile, Bp 94/56, RR 30.
Labs: UA WBC TNTC, CBC 25K with 48%
bands, Creatine 5, Glucose 328, Lactate 1.4mmol,
Coags nl, CXR Negative

51. Case Three
Consideration For:
Central line placement for monitoring
purposes
Insulin drip for tight glycemic control
Activated protein C administration

52. Conclusions
– Other things to consider
• Xigris or activated protein C reduces mortality in a
subset of patients with severe sepsis and septic
shock
• Use Dexamethasone at or 15-20 minutes prior to
I
antibotics in cases of bacterial menigitis
• Use a pressor you are comfortable with
• Transfuse to keep your HCT 30 or above
• Use inotropes early
• In GAS consider the use of IVIG in addition to your
antibotics

53. Conclusions
• In sepsis
– Early Goal Directed therapy reduces morbidity
and mortality of patients with sepsis and
septic shock
– Be aggressive with your fluids & early
antibiotic administration
I
– Use low tidal volumes on ventilator patients
– Consider optimization of blood glucose
– Low dose (physiologic steroids) show some
benefit