Sepsis 9-2015 an approach

2. Objectives & Outcomes
2
R E D U C E M O R B I D I T Y a n d M O R TA L I T Y R AT E S
P ro v i d i n g p ro t o c o l i z e d re s u s c i t a t i o n b u n d l e s
S E C U R E A D E Q U AT E F U N D I N G
I M P R O V E S TA N D A R D S O F C A R E
D E C R E A S E I C U A N D H O S P I TA L S TAY

3. 3
Severe Sepsis
• Major cause of morbidity and mortality worldwide.
• Leading cause of death in non coronary ICU.
• 10th leading cause of death overall.
• Sepsis consumes significant healthcare resources.
• In a study of Patients who contract nosocomial infections,
develop sepsis and survive:
• ICU stay prolonged an additional 8 days.
• Additional costs incurred were $ 40,890/ patient.
 Mortality rate depends on severity of illness
• Range 15% (sepsis) to 70% (septic shock and multi‐organ failure)
• In-hospital mortality associated with severe sepsis and septic shock is around
25%
• Incidence increases 13 % annually 2015
Why Sepsis is Important?

4. 40,000
148,300
203,500
1,100,000
751,000
0
100,000
200,000
300,000
400,000
500,000
600,000
700,000
800,000
900,000
1,000,000
1,100,000
Incidence of Severe Sepsis: Comparison
With Other Major Diseases
Cases/Year
AIDS1 Colon
Cancer2
Breast
Cancer2
Acute
MI3
Severe
Sepsis4
1.Centers for Disease Control and Prevention. National Center for HIV, STD and TB Prevention.
HIV/AIDs Surveillance Report, 2002; 2. American Cancer Society. Cancer Facts & Figures,
2002:1-44; 3. National Institutes of Health. Morbidity & Mortality: 2000 Chart Book on Cardiovascular, Lung,
and Blood Diseases; 4. Angus DC, et al. Crit Care Med. 2001;29:1303-1310. 4

5. Mortality of Severe Sepsis
14,370
42,290
192,811
215,000
0
50,000
100,000
150,000
200,000
250,000
Deaths/Year
AIDS1 Breast
Cancer1
Acute
MI1
Severe
Sepsis2
1. Minino AM, Smith BL. National Vital Statistics Reports. 2001;49:1-40.
2. Angus DC, et al. Crit Care Med. 2001;29:1303-1310. 5

6. Severe Sepsis Mortality Over Time

7. Sepsis:
A clinical response arising
from a nonspecific insult,
with  2 of the following:
• Temperature 38oC or 36oC
• HR 90 beats/min
• Respirations 20/min
• WBC 12,000 or 4,000/mm3
or >10% immature
neutrophils
SIRS with a
presumed or
confirmed
infectious
process
SepsisSIRS
Infection
/Trauma Severe Sepsis
Adapted from: Bone RC, et al. Chest 1992;101:1644
Opal SM, et al. Crit Care Med 2000;28:S81
Sepsis is a systemic inflammatory host response to infection which ( if not treated )
• Leads to severe sepsis (acute organ dysfunction secondary to infection) and
• septic shock (severe sepsis plus hypotension not reversed with fluid resuscitation).
Sepsis with at least one
organ system failing
Cardiovascular
(refractory hypotension)
Renal
Respiratory
Hepatic
Hematologic
CNS
Metabolic acidosis
Shock
7

8. Infection
Inflammatory
Mediators
Endothelial
Cell injury
Vasodilation
Hypotension Low preload &Edema
Maldistribution of Microvascular Blood Flow
Organ Dysfunction
Microvascular Plugging
Ischemia
proinflammatory and procoagulant
state,
8

9. 9
General Variables
 Fever (> 38.3°C)
 Hypothermia (< 36°C)
 Heart rate > 90/min–1 or more
than two SD above the normal
value for age
 Tachypnea
 Altered mental status
 Significant edema or +ve fluid
balance (> 20 mL/kg /24 hr)
 Hyperglycemia (plasma glucose
> 140 mg/dL or 7.7 mmol/L) in the
absence of diabetes Crit Care Med 2013;41(2):580-637
Inflammatory Variables
 Leukocytosis (WBC
count > 12,000 µL–1)
 Leukopenia (WBC
count < 4000 µL–1)
 Normal WBC count
with greater than 10%
immature forms
 Plasma C-reactive
protein more than
two SD above the
normal value
 Plasma procalcitonin
more than two SD
above the normal value
Hemodynamic Variables
 Arterial hypotension (SBP
< 90 mm Hg, MAP < 70 mm
Hg, or an SBP decrease >
40 mm Hg in adults or less
than two SD below normal
for age)
Tissue perfusion
Variables
 Hyperlactatemia ( > 1
mmol/l)
 Decreased capillary
refill or mottling
Diagnostic Criteria for Sepsis

10. A clinician, armed with the sepsis bundles, attacks the three heads of severe sepsis—hypotension, hypoperfusion, and organ
dysfunction. Crit Care Med. 2004;320(Suppl):S595-S597.
MANAGEMENT
10
“Hercules Kills Cerberus,” by Renato Pettinato, 2001

11. • MN is a 65 year‐old female presented to the emergency
department with hospital‐acquired pneumonia
• Labs and vitals
Temp 100.9°F (38.3°C)
HR 105 beats/min
RR 31 breaths/min
BP 80/55 (mean 63 mm Hg)
Lactate 5.5 mmol/L
• Intubated and placed on mechanical ventilation
Would you recommend placement of a central
line and initiation of resuscitation protocol to
target CVP and ScvO2?
Yes
No

12. 12
Initial
Resuscitation
Goals during the first 3 hours of presentation
A. Measure serum lactate concentration
B. Obtain blood cultures before administration of antibiotics
C. Administer broad-spectrum antibiotics
D. Administer crystalloid 30 mL/kg for hypotension or lactate ≥ 4 mmol/L
Goals during the first six hours of resuscitation
• Central venous pressure (CVP) 8‐12 mm Hg
• Goal 12‐15 mm Hg in mechanically ventilated patients
• MAP ≥ 65 mm Hg
• Urine output (UOP) ≥ 0.5 mL/kg/hr
• Central venous oxygen saturation (ScvO2) ≥ 70%
or mixed venous oxygen saturation (SvO2) ≥ 65%
Dellinger RP CCM 2013;41:580‐637

13. Important differences between the 2008 and 2012 SSC
guideline recommendations

16. 16
The Importance of Early Goal-Directed
Therapy for Sepsis-induced Hypo perfusion

17. ProCESS
ARISE
ProMISe
May 2014
October 2014
March 2015
2001 Rivers Study  Mortality
47  31%
Process study 201560 day Mortality
18.2 – 18.9 – 21.0%

18. PROCESS – Outcomes

19. So we have 4 main weapons
Fluid
Therapy
Vasopress
ors and
Inotropes
Antibiotic
therapy &
source
control
Corticoster
oids

20. A. clarithromycin plus linezolid.
B. Piperacillin/tazobactam.
C. Ceftriaxone plus linezolid .
D. Cefepime plus tobramycin plus vancomycin .
The team wishes to initiate antimicrobial therapy for MN
as soon as possible. Which regimen would u recommend?
Antimicrobial Therapy

21. Antimicrobial Therapy and Source Control
21
 1. Effective antimicrobials within the first hour of recognition (grade 1B)
and severe sepsis without septic shock (grade 1C)
 2a. Initial empiric anti-infective therapy of one or more drugs that have
activity against all likely pathogens
(grade 1B)
 2b. Antimicrobial regimen should be reassessed daily for potential
deescalation
(grade 1B)
 3. Duration of therapy typically 7–10 days; longer courses may be
appropriate in some patients
(grade 2C)
 4.Antiviral therapy initiated as early as possible in patients with severe
sepsis or septic shock of viral origin
(grade 2C)
Never forget withdrawing
blood cultures before
antibiotics initiation

22. Antibiotics therapy
Anand Kumar, MD; Daniel Roberts, MD; Kenneth E. Wood, DO; Bruce Light, MD; Joseph E. Parrillo, MD; Satendra Sharma, MD; Robert Suppes,
BSc; Daniel Feinstein, MD; Sergio Zanotti, MD; Leo Taiberg, MD; David Gurka, MD; Aseem Kumar, PhD; Mary Cheang, MSc. Duration of
hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care
Med 2006 ;34:1589-1596. 22

23. Antibiotics therapy
Matthew R.Morrell, MD, Scott T.Micek, PharmD,Marin H. Kollef, MD. The Management of Severe Sepsis and
Septic Shock. Infect Dis Clin N Am 2009;23:485–501. 23
severe sepsis and septic
shock can significantly
affect the probability of
attaining the antimicrobial
PK/PD target

24. 24
Source Control
Source Control
*the drainage of infected fluids.
*Removal of infected devices.
*Debridement of infected soft
tissues.
*Matthew R.Morrell, MD, Scott T.Micek, PharmD,Marin H. Kollef, MD. The Management of Severe Sepsis and Septic Shock.
Infect Dis Clin N Am 2009;23:485–501.
*Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis Campaign: International guidelines for management of severe
sepsis and septic shock: 2008. Crit Care Med 2008; 36:296–327.

26. Case, continued
• The medical team inserted a central venous catheter in the right
internal jugular vein
• Pertinent data
• HR 115 beats/min in sinus rhythm
• MAP 59 mm Hg
• UOP 0.3 mL/kg/hr
• CVP 3 mm Hg
• A venous blood gas was sent from the catheter
• ScvO2 59%
• Lactate 6.3 mmol/L
Which of the following is the recommended initial fluid choice
for a patient with severe sepsis or septic shock?
 Hydroxyethyl starch
 5% albumin
 Lactate Ringer’s solution
 Normal saline

27. Fluid Therapy of Severe Sepsis
 1. Crystalloids as the initial fluid of choice in the resuscitation
(grade 1B)
 2. Initial fluid challenge to achieve a minimum of 30 mL/kg of crystalloids
 3. Against the use of hydroxyethyl starches
(grade 1B)
(Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of Hydroxyethyl Starch Administration with Mortality and Acute Kidney Injury in
Critically Ill Patients Requiring Volume Resuscitation. JAMA 2013;309:678-88; Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl Starch
130/0.42 Versus Ringer’s Acetate in Severe Sepsis. N Engl J Med 2012;367:124-34; U.S. Food and Drug Administration (FDA) boxed warning is
available at www. fda.gov/biologicsbloodvaccines/safetyavailability/ucm358271.htm. Accessed November 29, 2014).
 4. Albumin in the fluid resuscitation when patients require substantial amounts
of crystalloids (grade 2C)
 5.More rapid administration and greater amounts of fluid may be needed in
some patients (grade 1C)
 6. Recommendation for RBCs transfusion only when hemoglobin
concentration decreases to <7.0 g/dL to target a hemoglobin
concentration of 7.0 –9.0 g/dL in adults (grade 1B). 27

28. 28
 Colloids vs Crystalloids??
Fluid Therapy
Emanuel P. Rivers, Anja Kathrin Jaehne, Laura Eichhorn-Wharry, Samantha Brown and David Amponsah.
Fluid therapy in septic shock. Current Opinion in Critical Care 2010;16:001–012.

29. Raghunathan K. CCM 2014;42:1585‐91
IV Crystalloids and Mortality

30. Should Chloride be Avoided?

31. ALBIOS: Study Design
Outcomes
Albumn gp

32.  Evaluation of the safety and efficacy of HES for fluid
resuscitation
 Modeled after the SAFE study
 7000 patients in ICU randomized to HES or normal saline
 No significant difference in 90 day mortality
 More patients receiving HES were treated with renal-
replacement therapy (P=0.04)
N Engl J Med 2012;367:1901-11 32

33. HES in ICU patients and Severe Sepsis
FDA Safety Communication: Boxed Warning on
increased mortality and severe renal injury, and
additional warning on risk of bleeding, for use of
hydroxyethyl starch solutions in some settings
Public Workshop – Risks and Benefits of Hydroxyethyl Starch Solutions
http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm313370.htm

34. Case, continued
• The patient was given a total of 4 liters of Ringer’s Lactate
over 3 hours
• Updated patient data
• MAP 65 mm Hg
• UOP 0.4 mL/kg/hr
• CVP 12 mm Hg
• Lactate 5.9 mmol/L
• ScvO2 52%
• Hgb=7.7 g/dl
Would you recommend giving PRBC to optimize oxygen
delivery?
Yes
No

35. Surviving Sepsis Campaign
Maintain Hct ≥30%
Hb ≤7g/dL
Level 1B Rec
Transfuse to maintain Hct 30% in presence of hypoperfusion in 1st six hours,
Transfusion threshold is Hb ≤7g/dL with goal of maintaining Hb between 7 –
9g/dL

36. Does a Liberal Transfusion Strategy
Improve Mortality in Sepsis?
Liberal
Transfusion
Hb ≤9g/dL
Restrictive
Transfusion
Hb ≤7g/dL

37. No 90 Day Mortality Difference

38. TRISS Study

39. Patient Case (continued)
• Initiated on norepinephrine at 5 mcg/min, titrated quickly up to 12 mcg/min
• MAP = 57 mm Hg
• CVP = 12
• ScVO2 = 72%
• Urine output = 20 to 30 mL/hr
• Lactate = 5.3
• HR = 110 bpm
• ICU team is looking to initiate a second vasoactive agent due to low
MAPs
What is your recommendation for a second vasoactive agent
and MAP goal?
 dopamine for MAP > 65 mm Hg
 Epinephrine for MAP > 85 mm Hg
 Vasopressin for MAP > 65 mm Hg
 Dobutamine for MAP > 85 mm Hg

40. 40
Vasopressors and inotropes therapy
Vasopressors therapy
•Maintain MAP 65 mm Hg.
•NE is the initial vasopressor of choice (1C)
•Use epinephrine if blood pressure is poorly responsive to norepinephrine or
dopamine.
•Do not use low-dose dopamine for renal protection.
Inotropes therapy
•Dobutamine is the first choice inotrope for patients low cardiac output in adequate
left ventricular filling pressure and adequate mean arterial pressure.
*Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis Campaign: International guidelines for
management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296–327.
*Matthew R.Morrell, MD, Scott T.Micek, PharmD,Marin H. Kollef, MD. The Management of Severe
Sepsis and Septic Shock. Infect Dis Clin N Am 2009;23:485–501.

41. Vasoactive Agents
Dellinger RP, et al. Crit Care Med 2013;41(2):580‐637
Dellinger RP, et al. Crit Care Med 2008;36(1):296‐327

43. 29 Centers in France
with 776 Patients

44. Difference
NO
Difference
28 or 90 Day
Mortality
28 Day Survival
w/o Organ Support
More
Atrial
Fibrillation
Longer
Pressor
Duration &
Dose

45. Corticosteroids
45

46. 46
CORTICOIDS
 Consider intravenous hydrocortisone for adult septic shock when hypotension responds poorly to adequate
fluid resuscitation and vasopressors.
 we suggest intravenous hydrocortisone alone at a dose of 200 mg per day (grade 2C)
 ACTH stimulation test is not recommended. (grade 2B)
 Hydrocortisone is preferred to dexamethasone.
 To assess whether low doses of corticosteroids improve 28-day
survival in patients with septic shock and relative adrenal insufficiency
(50 mg hydrocortisone q 6 hours x 5 days vs. placebo) in 499 patients
 Primary endpoint: 28-day mortality
 No significant difference in overall 28 day mortality
 No significant difference in rates of shock reversal
 Increased hyperglycemia, hypernatremia, superinfections with steroids
Additional TherapiesCorticus Study

47. Days to Shock Reversal with LD CS
Annane D, et al. JAMA 2002;288:862‐871
Sprung CL, et al. N Engl J Med
2008;358:111‐124
Sprung CL, et al. N Engl J Med
2008;358:111‐124
CORTICUS 2008 – Mortality

48. 48
Recommendations: Other Supportive Therapy of
Severe Sepsis
Immunoglobulins
Selenium
Mechanical ventilation of sepsis-induced acute respiratory distress syndrome (ARDS)
Sedation, analgesia, and neuromuscular blockade in sepsis
Glucose control
Renal replacement therapy
Bicarbonate therapy
Deep vein thrombosis prophylaxis
Stress ulcer prophylaxis
Nutrition
Crit Care Med 2013;41(2):580-637

49. 49
Finally
• At early stages diagnosis is difficult ,management is easy
While at later it`s easy to diagnose but difficult to manage
• Systemic vasodilation , nitric oxide and neutrophilic activation are the principle
hemodynamic problems
• Acute sepsis bundles must be completed within 6hrs of diagnosis
• Blood cultures and antibiotics therapy :as early as possible survivance dec by
7.6 /hr
• Rapid intravascular volume restoration and maintaining MAP and ScVo2
• Flexibility in management
• Steroids the risk and the benefit
• Antioxidant therapy ( glutathione and vitamin E)
• Intensive follow up and monitoring

50. Keep Working together
If you want to achieve Better Outcomes
50