1. MANAGEMENT OF SEVERE SEPSIS
Virginia Chung, MD
Director, MICU
Jacobi Medical Center

2. INTRODUCTION
Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic inflammation and widespread tissue injury.
Tissues remote from the original insult display signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation.
Tissue injury due to activation of the inflammatory system may also complicate noninfectious disorders such as acute pancreatitis or trauma.

3. TERMINOLOGY
In 1992, the ACCP/SCCM consensus panel defined the following terms:
Infection – microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms.
Bacteremia – presence of viable bacteria in the blood
SIRS (Systemic Inflammatory Response Syndrome) – is a widespread inflammatory response to a variety of severe clinical insults, manifested by 2 or more of the following:

4. TERMINOLOGY
SIRS
Temperature > 38ºC or < 36ºC
Heart rate > 90 beats/min
Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg
WBC count > 12,000/mm3, <4,000/mm3, or > 10% immature forms
Sepsis – is the systemic response to an infection, i.e., SIRS + infection.
Severe Sepsis – sepsis associated with organ dysfunction, hypoperfusion, or hypotension.

5. TERMINOLOGY Organ Dysfunction Criteria:
Cardiovascular – SBP <= 90 mmHg or MAP <= 70 mmHg for at least 1 hour despite adequate volume resuscitation, or the use of vasopressors to achieve the same goals.
Renal – urine output < 0.5 ml/kg of body weight for 1 hour despite adequate volume resuscitation.
Pulmonary – PaO2/FiO2 <= 250 if other organ dysfunction present or <= 200 if the lung is the only dysfunctional organ.
Hematologic – platelet count < 80,000/mm3 or decreased by 50% over 3 days.
Metabolic – pH<= 7.30 or base deficit > 5.0 mmol/l AND plasma lactate > 1.5 x upper limit of normal.
CNS – acute alteration in mental status

6. TERMINOLOGY Septic Shock –
a subset of severe sepsis with hypotension despite adequate fluid resuscitation combined with perfusion abnormalities.
patients requiring inotropic or vasopressor agents may no longer be hypotensive by the time they exhibit organ dysfunction, but are nonetheless considered to be in septic shock.
form of vasodilatory or distributive shock resulting from a marked reduction in systemic vascular resistance; it is often associated with an increased cardiac output but some patients can present with decreased cardiac output due to sepsis-induced cardiac dysfunction.

7. SIRS = Systemic Inflammatory Response Syndrome
SIRS & SEPSIS
Infection/ Trauma
SIRS
Sepsis
Severe Sepsis
A clinical response arising from a nonspecific insult, including  2 of the following:
Temperature 38oC or 36oC
HR 90 beats/min
Respirations 20/min
WBC count 12,000/mm3 or 4,000/mm3 or >10% immature neutrophils
SIRS with a presumed or confirmed infectious process
SIRS = Systemic Inflammatory Response Syndrome
Adapted from: Bone RC, et al. Chest 1992;101:1644
Opal SM, et al. Crit Care Med 2000;28:S81

8. SEVERE SEPSIS SIRS Sepsis Severe Sepsis Shock Infection/ Trauma
Sepsis with 1 sign of organ failure
Cardiovascular (refractory hypotension)
Renal
Respiratory
Hepatic
Hematologic
CNS
Metabolic acidosis
Shock
Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N England J Med 1999;340:207

9. WORLDWIDE Incidence of severe sepsis is 3.0 cases / 1,000
18 million cases of severe sepsis annually.
Kills approximately 1,400 people each day.
Leading cause of death in non-coronary ICUs
Number of cases of severe sepsis is growing at the rate of 1.5% per year.
This translates to an additional 1 million cases per year in the USA alone by 2020.

10. RISK FACTORS
Factors potentially responsible for the growing incidence of severe sepsis and septic shock:
Increased awareness and sensitivity for the diagnosis.
Increased number of immunocompromised individuals:
HIV/AIDS
Increased use of cytotoxic and immunosuppressant agents
Malnutrition
Alcoholism
Diabetes Mellitus

11. RISK FACTORS
Increased number of transplant recipients and transplantation procedures.
Increased use of aggressive invasive procedures in patient management and diagnosis.
Increased number of resistant microorganisms.
Increased number of elderly patients.
Increased number of institutionalized individuals.

12. MORTALITY Incidence Mortality 7-17% Sepsis 400,000 20-53%
Severe Sepsis
300,000
Septic Shock
53-63%
Approximately 200,000 patients including 70,000 Medicare patients have septic shock annually
Balk, R.A. Crit Care Clin 2000;337:52

14. WHAT CAN WE DO AS HEALTHCARE PROVIDERS TO IMPROVE THESE MORTALITY STATISTICS ?

15. IHI / SSC
To expedite Quality Improvement (QI) in health care, the Institute for Healthcare Improvement (IHI) launched the 100,000 Lives Campaign in December 2004.
This is a national initiative with a goal of saving 100,000 lives among patients in hospitals through improvements in the safety and effectiveness of health care by June 18, 2006.
A “life saved” is defined as a patient successfully discharged from a hospital who, absent the changes achieved through the campaign, would not have survived.
All 5,759 hospitals in the U.S. have been invited to join this campaign. The Health and Hospitals Corporation (HHC) with its 11 acute care hospitals (incl. Jacobi and NCB) are participants

16. IHI / SSC IHI Campaign Interventions:
Deploy Rapid Response Teams (RRT/MET)
Deliver Reliable Evidence-Based Care for Acute MI
Prevent Adverse Drug Events Through Medication Reconciliation.
Prevent Central Line Infections.
Prevent Surgical Site Infections.
Prevent Ventilator-Associated Pneumonia

17. IHI / SSC
At the same time, the Critical Care community formed a working group, launched the Surviving Sepsis Campaign (SSC), and published their “Guidelines for Management of Severe Sepsis and Septic Shock” in the March 2004 issue of Critical Care Medicine. (Recently updated Jan 2008)
IHI and the SSC working group have since teamed up to “wage war” on sepsis; their goal is to “achieve a 25% reduction in sepsis mortality by 2009”.
To implement these evidence-based guidelines, 3 core strategies are recommended:
Model for improvement : Plan-Do-Study-Act (PDSA) cycles
Using “Bundles” to simplify the complex process of caring for patients with severe sepsis by grouping specific management elements together.
Enhancing reliability of the bundled elements.

18. SEVERE SEPSIS BUNDLES
A “bundle” is a group of interventions related to a specific disease process that, when executed together, result in better outcomes than when implemented individually. The elements of the bundle are based upon evidence-based practice and should be considered generally accepted practice.
There are 2 different Severe Sepsis Bundles. Each bundle articulates objectives to be accomplished within specific timeframes:
Severe Sepsis Resuscitation Bundle
Severe Sepsis Management Bundle

19. Resuscitation Bundle
Describes 7 tasks that should begin immediately, but must be accomplished within the first 6 hours of presentation for patients with severe sepsis, septic shock, or a lactate > 4 mmol/l.
1. Measure serum lactate – hyperlactatemia is typically present and may be secondary to anaerobic metabolism due to hyperperfusion; obtaining a level is essential to identifying tissue hypoperfusion in patients who are not yet hypotensive, but who are at risk for septic shock.

20. Resuscitation Bundle
2. Blood Cultures Obtained Prior to Antibiotic Administration – 30-50% of these patients will have positive blood cultures; best hope of identifying the organism causing severe sepsis. Two or more blood cultures are recommended.
In patients with suspected catheter-related infection, blood cultures should be drawn simultaneously through the catheter hub and from a peripheral site. If the same organism is recovered and the culture drawn from the line is positive much earlier than the peripheral culture, then it is likely that the catheter is the source of infection.

21. Resuscitation Bundle
3. Improve Time to Broad-Spectrum Antibiotics – early administration of appropriate antibiotics reduces mortality in patients with Gram(+) and Gram(-) bacteremias. Therefore, broad-spectrum antibiotics should be given within 3 hours from time of presentation to the E.D. or within 1 hour for ward patients transferred to the ICU. 2008: 1 hour.
Major sources of infection in severe sepsis or septic shock are pneumonia and intra-abdominal infections; other sources accounting for < 5% of cases.
Choice of antibiotics should be guided by the susceptibility patterns of likely pathogens in the community or hospital as well as any specific knowledge about the patient. The regimen should cover all likely pathogens since there is little margin for error in critically ill patients. Re-evaluate at hours.

22. Resuscitation Bundle
4. Treat Hypotension and/or Elevated Lactate with fluids – patients may experience ineffective arterial circulation due to vasodilatation or impaired cardiac output; poorly perfused tissue beds result in global tissue hypoxia leading to an elevated serum lactate level.
Lactate > 4 mmol/l or 36 g/dl is correlated with increased severity of illness and poorer outcomes even if hypotension is not yet present.
Initial administration of at least of 20 ml/kg of crystalloid as a fluid challenge/bolus should be given ASAP to these patients; boluses should be repeated as necessary.

23. Resuscitation Bundle
Fluid Challenge – describes the initial volume expansion period in which the patient response is closely monitored; 4 componenets are:
1. Fluid type – crystalloid vs. colloid
2. Infusion rate – 500-1,000 ml over minutes
3. End points – MAP > 65 or 70 mmHg, hr < 110 beats/min
4. Safety limits – pulmonary edema
Crystalloid vs. Colloid – the volume of distribution for crystalloids is much larger than for colloids, hence a larger volume of crystalloids will be required to achieve the same goals and could result in more edema.

24. The SAFE (Saline versus Albumin Fluid Evaluation) Study Investigators
A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit
The SAFE (Saline versus Albumin Fluid Evaluation) Study Investigators
NEJM 2004; 350:

25. SAFE STUDY
Multicenter, randomized, double-blind trial comparing the effect of fluid resuscitation with 4% albumin versus normal saline on 28-day mortality in the 16 ICUs in Australia & New Zealand.
7,000 patients age 18 or older were randomized.
3 were mistakenly randomized twice, leaving 6,997 patients in the study; 3,497 received 4% albumin and 3,500 received NS.
Results: 726 deaths in the albumin group and 729 in NS group (relative risk of death 0.99; p=0.87); additionally, there was no significant differences in ICU days, hospital days, mechanical ventilation days, renal-replacement therapy days, or development of new single or multiorgan failures.

26. Resuscitation Bundle
End Points of Fluid Resuscitation – for refractory hypotension not responding to fluids or lactate > 4 mmol/l, patients should now enter the Early Goal Directed Therapy (EGDT) phase of the Resuscitation Bundle where central venous pressure (CVP) >= 8-12 mmHg and central venous saturation (ScvO2) >=70% are the goals.
Rivers, et al., demonstrated a 34% reduction in hospital mortality for the patients in the EGDT group versus those in the standard therapy group.
The degree of intravascular volume deficit in septic patients varies; with venodilation and ongoing capillary leak, most patients require aggressive fluid resuscitation during the first 24 hours of management.

27. Resuscitation Bundle
5. Apply Vasopressors for Ongoing Hypotension (Shock) – when an appropriate fluid challenge fails to restore an adequate arterial pressure and organ perfusion, therapy with vasopressors should be started; vasopressors may be required transiently to sustain life even when hypovolemia has not been corrected or when a fluid challenge is in progress.
MAP (mean arterial pressure) >= 65 mmHg
Place arterial catheter for continuous blood pressure measurements; ABGs, lactates readily available

28. Resuscitation Bundle
Choice of Vasopressors: either norepinephrine or dopamine is the first-choice vasopressor agent to correct hypotension in septic shock; epinephrine and phenylephrine should not be used as first-line vasopressors because they decrease splanchnic blood flow significantly
Vasopressin can be added when patients are still in shock despite adequate fluid resuscitation and high-dose conventional vasopressors.

29. Vasopressors
Dopamine – natural precursor of NE and Epi and possesses several dose-dependent pharmacologic effects.
Low doses (< 5 mcg/kg/min) – stimulates dopaminergic DA1 receptors in the renal, mesenteric, and coronary beds, resulting in vasodilation.
Intermediate doses (5-10 mcg/kg/min) – β-adrenergic effects predominate, resulting in an increase in cardiac contractility and heart rate
High doses (>10 mcg/kg/min) – α-adrenergic effects predominate, leading to arterial vasoconstriction and an increase in blood pressure.
Systemic hemodynamic effects of dopamine in septic patients : increases MAP primarily by increasing cardiac index with minimal effects on SVR; SV increases more than heart rate.
Very high doses (>20 mcg/kg/min) – increases heart rate and right heart pressures; consider alternative agent.

30. Vasopressors
Norepinephrine (NE) – is a potent α-adrenergic agonist with some β-adrenergic agonist effects; increases MAP due to vasoconstrictive effects, with little change in heart rate or cardiac output, leading to increased SVR.
In open label trials, NE was shown to increase MAP in hypo-tensive patients resistant to fluid resuscitation and dopamine.
In the past, there was concern that NE may have negative effects on splanchnic and renal blood flow leading to regional ischemia; however, recent experience does not support this.
In hyperdynamic septic shock, NE markedly improves MAP and glomerular filtration; after restoration of systemic hemodynamics urine output increases and renal function improves in most patients.

31. Russell, JA, MD, et. al., for the VASST Investigators
Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock
Russell, JA, MD, et. al., for the VASST Investigators
NEJM, 2008, 358:

32. VASST
Multicenter, randomized, double-blind trial, comparing the use of NE alone to NE plus vasopressin at 0.03units/min. on 28 day mortality.
27 centers in Canada, Australia, and USA participated between July 2001 and April 2006.
Inclusion criteria: age>16 with septic shock – hypotension despite fluid resuscitation requiring >= 5 mcg/min NE.
Less severe septic shock : NE 5-14 mcg/min
More severe septic shock : NE >=15 mcg/min
Of 6229 screened, 802 were randomized :
396 NE ; 406 vasopressin
Pts were very ill with mean APACHE II scores of 27 and > 3 organ dysfunction

33. VASST
Results: No significant difference in the primary outcome – rate of death from any cause, 28 days after start of the infusions- between the VP and the NE group (35.4 vs 39.3%, p=0.26)
Similarly, there was no difference in 90-day mortality either (43.9 vs 49.6%, p=0.11)
Sub-group analysis: less severe septic shock pts who received VP had lower mortality at 28-days (26.5 vs 35.7%, p=0.05) and at 90-days (35.8 vs 46.1%, p=0.04)
Investigators had hypothesized that beneficial effects of VA would be more pronounced in the more severe septic shock group

34. Resuscitation Bundle
6. Maintain Adequate Central Venous Pressure – in the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l (36 mg/dl) achieve CVP >= 8-12 mmHg.
Patients should receive the initial minimum of 20 ml/kg fluid challenge prior to placement of a Central Venous Catheter (CVC) and attempts to optimize CVP.
For patients who are hypovolemic and anemic with a Hct < 30, consider transfusing packed RBCs; blood is a better volume expander and increases oxygen carrying capacity.
In mechanically ventilated patients, a higher target CVP > 12 mmHg is recommended because positive pressure ventilation causes increases in intrathoracic pressures and decreases venous return.

35. Resuscitation Bundle
7. Maintain Adequate Central Venous Oxygen Saturation (ScvO2) – in the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l (36 g/dl) achieve a ScvO2 > 70% OR a mixed venous oxygen saturation (SvO2) via PA catheter > 65%.
Strategies to achieve target ScvO2:
If the CVP > 8 mmHg and Hct < 30, transfuse PRBCs to increase oxygen carrying capacity and hence oxygen delivery to the tissues.
If the patient has underlying cardiac dysfunction or has developed sepsis-induced cardiac dysfunction, then add an inotrope (dobutamine) provided the patient has been fluid resuscitated and transfused (if indicated). Increasing cardiac output increases oxygen delivery to the tissues.
2008 : option of transfusing first or go directly to inotropes

36. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock
Rivers, E., M.D., M.P.H., Nguyen, B., M.D., et. al., for the Early Goal-Directed Therapy Collaborative Group; NEJM, 2001, 345:

37. EGDT
Randomized, controlled, predominantly blinded study in an E.D. of an 850-bed tertiary referral center (Henry Ford Hospital, Detroit, MI) over a 3-yr period (3/1997-3/2000).
Enrollment criteria: 2 of 4 SIRS criteria with a SBP < 90 mmHg after a ml/kg fluid challenge or a blood lactate level > 4 mmol/l (36 g/dl).
Patients either received 6 hours of standard therapy or 6 hours of goal-directed therapy before admission to the ICU; clinicians subsequently involved in the care of the study patients were blinded to the treatment arm of the study.
Control group followed an existing protocol for hemodynamic support: CVP 8-12 mmHg, MAP > 65 mmHg, urine output > 0.5 ml/kg/hr; 500 ml fluid boluses and vasopressors were used.

38. EGDT
Treatment group had the same aims as the control group PLUS they had to achieve a central venous oxygen saturation (ScvO2) > 70%:
If the ScvO2 < 70 % and
Hct < 30, transfuse PRBCs
MAP > 90 mmHg, give vasodilators until MAP <= 90 mmHg
If CVP, Hct, and MAP were in the optimal range and ScvO2 still < 70%, start dobutamine 2.5 mcg/kg/min (inotrope) and titrate it up by 2.5 mcg/kg/min every 30 min until ScvO2 > 70% or a maximum dose of 20 mcg/kg/min is reached. The dose was decreased or d/c’ed if MAP < 65 mmHg or hr > 120 beats/min
Finally, to decrease O2 demand, sedate and mechanically ventilate the patient.

39. EGDT
Results: 263 patients randomized – 133 received standard therapy and 130 received EGDT; Temp, hr, urine output, BP, CVP were measured cont. for 6 hours, then q 12h for 72 hrs.
During the initial 6 hours, the EGDT group received more IV fluids, red cell transfusions, and inotropic therapy than the control group.
During the subsequent 66 hours, the control group received more transfusions, more vasopressors, and had a greater requirement for mechanical ventilation and PA catheterization.
This showed that the control group was relatively under-resuscitated initially.
In-hospital mortality was significantly higher in the control group than in the EGDT group – 46.5 % versus 30.5% (p=0.009).

40. Resuscitation Bundle
To summarize, for patients presenting with severe sepsis, septic shock, or lactate > 4 mmol/l, the following 7 tasks need to be accomplished within the first 6 hours of presentation:
1. Measure serum lactate.
2. Obtain blood cultures prior to antibiotic administration.
3. Improve time to broad-spectrum antibiotics (< 3(1) hrs).
4. Treat hypotension and/or elevated lactate with fluids.
5. Apply vasopressors for ongoing hypotension.
6. Maintain adequate CVP (>= 8 mmHg).
7. Maintain adequate ScvO2 (>= 70%).

41. Management Bundle
Describes 4 tasks that must be completed within 24 hours of presentation for patients with severe sepsis, septic shock, and/or lactate >4 mmol/l.
1. Administer Low-Dose Steroids by a Standard Policy – IV corticosteroids (hydrocortisone mg/day, for 7 days in 3-4 divided doses) are recommended in patients with septic shock who despite adequate fluid replacement require vasopressor therapy to maintain adequate blood pressure.
The use of fludrocortisone in addition to low-dose hydrocortisone is considered optional. Absolute primary adrenal insufficiency is rare in septic shock (0-3%).

42. Management Bundle
In refractory septic shock, the prevalence of Relative Adrenal Insufficiency (RAI) may be as high as 50-75%. RAI is present when the increase in serum cortisol level is < 9 mcg/dl, min after a 250- mcg ACTH stimulation.
Low dose CorticoSteroids (CS)promote shock reversal. Their effects on vascular tone were recognized well before their anti-inflammatory properties. In patients with septic shock, low dose CS significantly reduces nitrite/nitrate plasma concentrations, indicating inhibition of NO formation.
Median time to cessation of vasopressors in one study decr. from 13 to 4 days and 7 to 3 days in another. Another study showed that MAP and SVR increased and HR, CI, and NE requirement decreased with the use of low-dose CS.

43. Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock
Annane, D., Sebille, V., Charpentier, C., et al., JAMA, 2002; 288:

44. Low Dose CS
Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 ICUs in France from
1326 pts were assessed for eligibility; 1026 were ineligible; 300 randomized to receive either hydrocortisone 50 mg IV q6h and fludrocortisone 50 mcg po qd or matching placebos for 7 days.
Corticotropin test was performed in all patients; RAI was defined as a response of 9 mcg/dl or less. RAI pts were deemed Nonresponders while those who had a >9 mcg/dl increase were Responders.

45. Low Dose CS Mortality rates:
All patients – there was no significant effect of CS on 28-day, ICU, hospital, and 1-year mortality rates.
Responders (>9 mcg/dl incr.) – there was no significant effect of CS on 28-day, ICU, hospital, and 1-year mortality rates.
Nonresponders (<= 9 mcg/dl incr.) –
28 days : placebo 73 (63%) CS (53%) deaths p=.04
ICU: placebo 81 (70%) CS (58%) deaths p=.02
Hospital: placebo (72%) CS (61%) deaths p=.04
1-year: placebo (77%) CS (68%) deaths p=.07

46. Low Dose CS Median Time-to-Vasopressor-Therapy Withdrawal –
All patients – 9 days (placebo) , 7 days (CS) , p=.01
Responders – 7 days (placebo) , 9 days (CS) , p=.49
Nonresponders – 10 days (placebo) , 7 days (CS) , p=.001
No significant differences between the 2 groups in the rates of adverse events related to CS (infection, GI bleed, psychiatric d/o).
Conclusion: in pressor-dependent septic shock, administer low dose CS and fludrocortisone for 7 days in those with RAI.

47. Hydrocortisone Therapy for Patients with Septic Shock
Sprung, CL, MD, Annane, D, MD, et. al., for the CORTICUS Study Group
NEJM, 2008, 358:

48. CORTICUS
Multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of low-dose hydrocortisone (HC) therapy in septic shock.
52 European and Israeli ICUs took part between March 2002 and November 2005.
Inclusion criteria: age >=18 with onset of septic shock within the previous 72 hrs and hypoperfusion or organ dysfunction due to sepsis.
Exclusion criteria: underlying disease with poor prognosis, moribund (life expect < 24hrs), immunosuppression, Rx with long-term CS within 6 months, or short-term CS within 4 weeks.

49. CORTICUS
Protocol: 50 mg IVP q6h x 5days, then q12h x 3 days, and then q24h x 3 days (both HC and placebo)
Primary end-point was rate of death at 28-days in pts who DID NOT have a response to ACTH
Secondary end-points: 28-day mortality in pts who HAD a response to ACTH, and in all pts, ICU-mortality, 1 year mortality, reversal of organ failure and shock, ICU LOS, Hospital LOS.
500 pts enrolled: 252 (HC) and 248 (placebo)
233 (46.7%) did not respond to ACTH – 125(HC), 108(plac)
254 (50.9%) DID respond to ACTH – 118(HC), 136(plac)

50. CORTICUS
Results: No significant difference between the 2 study grps in the primary outcome – 28 day mortality in ACTH non-responders.
HC grp: 49/125 (39.2%) died
Placebo grp: 39/108 (36.1%) died; p=0.69
Likewise, there was no significant difference in 28 day mortality in the ACTH responders
HC grp: 34/118 (28.8%) died
Placebo grp: 39/136 (28.7%) died; p=1.00
Overall, there were 86/252 (34.3%) deaths in HC grp and 78/248 (31.5%) deaths in Placebo grp ; p=0.51
Of those patients who had reversal of their shock, those who rec’d HC took less days to do so ( 3.3 vs 5.8 days)

51. CORTICUS
Results (cont): ACTH non-responders had a higher 28-day mortality (38%) than ACTH responders (29%)
Adverse events:
HC grp: increased incidence of superinfections: new episodes of sepsis/septic shock (OR 1.37), increased incidence of hyperglycemia and hypernatremia
Conclusion:
HC cannot be recommended as general adjuvant therapy for septic shock (vasopressor responsive) nor can ACTH testing be recommended to determine which pt should receive HC.
HC may have a role among pts who are treated early after the onset of septic shock who remain hypotensive despite the administration of high-dose vasopressors (vasopressor unresponsive)

52. Management Bundle
2. Administer Drotrecogin Alfa (Activated) by a Standard Policy – the inflammatory response in severe sepsis is integrally linked to procoagulant activity and endothelial activation. In a large, multicenter RCT, recombinant human Activated Protein C (rhAPC) – an endogenous profibrinolytic anticoagulant with anti-inflammatory properties- improved survival in patients with sepsis-induced organ dysfunction.

53. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis
Bernard, G., Vincent, J., Laterre, P., et al., for the PROWESS study group, NEJM, 2001; 344:

54. PROWESS
Randomized, double-blind, placebo-controlled trial conducted at 164 centers in 11 countries from 7/1998 through 6/2000 evaluating rhAPC (24 mcg/kg/hr for 96 hours) in patients with severe sepsis.
Inclusion criteria: known or suspected infection PLUS 3 of 4 SIRS criteria PLUS at least one organ dysfunction (cardiac, renal, respiratory, hematologic) or presence of lactic acidosis.
Exclusion criteria: pregnancy, breast-feeding, age<18, weight>135 kg, platelet < 30,000, increased risk of bleeding, known hypercoagulable condition, AIDS witth CD4<50, moribund state with imminent death, CRF on HD/PD, liver failure, acute pancreatitis w/o infection, very recent use of anticoagulants or thrombolytics, high dose ASA.

55. PROWESS
Primary efficacy end point was death from any cause and was assessed 28 days after the initiation of the infusion; Powered to detect a 15% reduction in the RR of 28-day all-cause mortality.
Trial was suspended at the time of the 2nd interim analysis after 1,520 patients had been enrolled. There were 259 (30.8%) deaths in the placebo group versus 210 (24.7%) deaths in the rhAPC group yielding an absolute 6.1% mortality reduction and 19.4% reduction in RR of death.
16 patients would need to be treated to save one (1) life in this study population.

56. PROWESS
When subgroup analysis was performed, those patients with APACHE II scores > 25 (quartile 3 & 4), there was an absolute mortality reduction of 13% (44 vs 31) and RR reduction of 29.5%.
8 patients would need to be treated to save one (1) life.
Adverse events: serious bleeding events (ICH, life-threatening bleed, transfusion of 3 units prbc/day for 2 days, or assessed as serious by the investigator) occurred in 20 (2.4%) of the rhAPC group versus 8 (1.0%) in the placebo group.

57. PROWESS
In November 2001, the US FDA narrowly approved rhAPC for sepsis-induced organ dysfunction associated with high risk of death, such as APACHE II score > 25. (APACHE II = Acute Physiology and Chronic Health Evaluation)
In Europe, the European Agency for the Evaluation of Medicinal Products, approved rhAPC for the treatment of adult patients with >= 2 organ dysfunction.
Very expensive drug, costing approximately US $7,000 per 96 hour infusion.

58. Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death
Abraham, E., Laterre, P., Garg, R., et al., for the ADDRESS study group, NEJM, 2005; 353:

59. ADDRESS
After approving rhAPC, the FDA required a study to evaluate the efficacy of rhAPC in adults with severe sepsis and low risk of death, i.e., APACHE II < 25 or single organ dysfunction.
516 centers in 34 countries participated. The study began in 9/02 and was terminated early in 2/04 because it was clear a significant reduction in 28-day mortality would not be shown.
Mortality: rhAPC 18.5% vs. Placebo 17.0% p=.34
Serious Bleeding: rhAPC 2.4% vs. Placebo 1.2% p=.02
Patients who had recent surgery (< 30 days) and single organ dysfunction and received rhAPC had a higher mortality rate than those who received placebo, although it did not achieve significance.

60. Management Bundle
3. Maintain Adequate Glycemic Control – following initial stabilization of patients with severe sepsis, blood glucose should be maintained < 150 mg/dl. Continuous infusions of insulin and glucose are given. Glucose should be monitored frequently after initiating the protocol (q min) and on a regular basis (q4h) once blood glucose concentration has stabilized.

61. Intensive Insulin Therapy in Critically Ill Patients
Van den Berghe, G., Wouters, P., Weekers, F., et al., NEJM, 2001, 345:

62. I I T
Prospective, randomized, controlled study involving adults admitted to the SICU (Leuven, Belgium) requiring mechanical ventilation between 2/2/00 and 1/18/01.
1548 patients were enrolled. 63% were cardiothoracic patients.
783 received conventional treatment where the insulin drip was started only if the blood glucose level > 215 mg/dl; subsequent blood sugars were maintained between 180 and 200 mg/dl.
765 received intensive insulin therapy where the insulin drip was started for blood glucose > 110 mg/dl; blood sugars were then maintained between mg/dl.

63. I I T
Patients received IV glucose for the first 24 hrs in the SICU, then were enterally and/or parenterally fed thereafter.
39.2% of pts. in the conventional group was started on an insulin drip versus 98.7% in the intensive group (only 10 pts did not get IIT)
Morning blood sugars:
Conventional – 153 mg/dl (all); 173 mg/dl (insulin)
Intensive Rx – 103 mg/dl (all, insulin)

64. I I T Mortality: convent intense p-value
ICU 63(8.0%) 35(4.6%) <0.04
ICU<=5 d. 14(1.8%) 13(1.7%) 0.9
ICU> 5 d. 49(20.2%) 22(10.6%)
Hosp(all) 85(10.9%) 55(7.2%)
Hosp+ICU>5d. 64(26.3) 35(16.8%)
Cause/death:
MOF + Sepsis
MOF w/o Sepsis

65. I I T
IIT also reduced bloodstream infections by 46%, ARF requiring HD by 41%, median # of RBC transfusion by 50%, and critical illness polyneuropathy by 44%; required less days in the SICU and less mechanical ventilation days.
Hypoglycemia (< 40 mg/dl) occurred in 39 pts in IIT group vs. 6 in conventional group. 2/39 were symptomatic with sweating and agitation.
Post-hoc analysis confirmed best results with blood glucose mg/dl, but blood glucose < 150 mg/dl was also beneficial (less risk for hypoglycemia).

66. Intensive Insulin Therapy in the Medical ICU
Van den Berghe, G., Wilmer, A., Hermans, G., et al., NEJM, 2006; 354:

67. I I T (MICU)
Prospective, randomized, controlled study of adult MICU patients who would likely need intensive care for at least 3 days.
Intention to treat analysis of 1200 pts. enrolled between 3/02 and 5/05.
605 received conventional traetment: insulin drip for blood glucose > 215 mg/dl; then kept mg/dl.
595 received IIT: insulin drip started for blood glucose > 110 mg/dl; then kept mg/dl.

68. I I T (MICU)
Morbidity was significantly reduced in the IIT group: less days of mechanical ventilation, fewer MICU days, fewer hospital days, fewer instances of ARF.
Mortality: no difference in the intention-to-treat group (26.8% vs. 24.2%, p=0.31); for those who did stay in the MICU for 3 or more days, the IIT group had better outcomes (31.3% vs. 38.1%, p=0.05)
These differences held for in-hospital and 90-day mortality as well.
IIT will benefit those MICU patients who remain in the MICU for at least 3 days (cannot be predicted reliably upon admission).

69. I I T
2008: 2 large Mc-RCTs of IIT underway (sepsis, MSICU) failed to show mortality improvement and were stopped early due to high rates of hypoglycemia and adverse events in the IIT groups.

70. Management Bundle
4. Prevent Excessive Inspiratory Plateau Pressures – inspiratory plateau pressures should be maintained < 30 cm H2O for mechanically ventilated patients.
Most patients with severe sepsis and septic shock will require intubation and mechanical ventilation
Nearly 50% of these patients will develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS)
Bilateral patchy infiltrates on CXR
Low PaO2/FiO2 ratios (ALI < 300, ARDS < 200)
PCWP < 18 mmHg

71. Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for ALI and ARDS
The Acute Respiratory Distress Syndrome Network, NEJM, 2000; 342:

72. ARDS
Largest trial of a volume- and pressure-limited strategy that showed a 9% decrease of all-cause mortality in patients ventilated with tidal volumes of 6 ml/kg of estimated LBW (as opposed to 12 ml/kg) while aiming for a plateau pressure of < 30 cm H2O.
Hypercapnia is well tolerated in patients with ALI/ARDS if necessary to minimize plateau pressures and tidal volumes. A pH is reasonable, but this has not been studied prospectively.
Positive end-expiratory pressure (PEEP) prevents alveoli from collapsing at end-expiration; “recruits” or opens atelectatic areas to participate in gas exchange.

73. Management Bundle
To summarize: 4 elements that must be addressed or completed within the first 24 hours of presentation; can run concurrently with the resuscitation bundle.
1. Consider Administering low dose CS for vasopressor unresponsive shock .
2. Administer DroAA (rhAPC) by a standard policy.
3. Maintain Adequate Glycemic Control (<150).
4. Prevent Excessive Inspiratory Plateau Pressures.

74. Conclusions
Severe sepsis and septic shock have mortality rates between 30-50%.
To have any chance of reducing this significantly, we must apply best practices as stipulated in the literature.
By “bundling” the elements together, we will be more successful in accomplishing the many necessary tasks in treating these critically ill patients.

75. APACHE II
Age in years under Points Points Points Points over Points
History of severe organ insufficiency or immunocompromised? Yes, and non-operative or emergency post-operative patient Points Yes, and elective post-operative patient----2 Points No Points
Rectal Temperature over Points Points Points Points Points Points Points below Points

76. Heart rate over Points Points Points Points Points Points below Points
Respiratory Rate over Points Points Points Points Points Points below Points
Arterial pH over Points Points Points Points Points Points below Points
Mean arterial pressure over Points Points Points Points Points below Points

77. Hematocrit over 59. 9-------------------4 Points 50-59
Hematocrit over Points Points Points Points Points below Points
White blood count over Points Points  Points  Points  Points  below Points
Serum sodium over Points  Points Points Points Points Points Points below Points
Serum Creatinine over 3.4 & acute renal fail---8 Points & acute renal fail----6 Points over 3.4 & chronic renal fail-4 Points & acute renal fail----4 Points and chronic Points and chronic Points Points below Points

78. Oxygenation (use PaO2 if FiO2 < 50%, otherwise use A-a gradient) A-a gradient over Points A-a gradient Points A-a gradient Points A-a below 200 (if FiO2 over 49%) or pO2 more than 70 (if FiO2 less than 50%) Points pO2 = Points pO2 = Points pO2 below Points
Serum potassium over Points Points Points Points Points Points below Points

79. Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death
NEJM Vol. 353;13: September 29, 2005
Edward Abraham, M.D., Pierre-François Laterre, M.D., Rekha Garg, M.D., Howard Levy, M.D., Ph.D., Deepak Talwar, M.D., Benjamin L. Trzaskoma, M.S., Bruno François, M.D., Jeffrey S. Guy, M.D., Martina Brückmann, M.D., Álvaro Rea-Neto, M.D., Rolf Rossaint, M.D., Dominique Perrotin, M.D., Armin Sablotzki, M.D., Ph.D., Nancy Arkins, R.N., Barbara G. Utterback, M.S., M.B.A., William L. Macias, M.D., for the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group

80. 10% of ICU admissions worldwide
PROWEESS trial showed 6.1% reduction in 28 day mortality from severe sepsis in patients treated with Activated Protein C

81. METHODS
Randomized, double blind, placebo controlled and multicenter trial
2640 patients with severe sepsis and a low risk of death defined by APACHE II with score <25 or single organ dysfunction were enrolled in 516 centers in 34 countries
They were randomized to receive 96 hour of placebo(0.9NS) or DrotAA
Treatment with the study drug was started within 48 hours of documentation of first organ dysfunction

82. EXCLUSION CRITERIA Patients with multiorgan failure in Europe
Patients with APACHE score of 25 or more in US
If they had an increased risk of bleeding
If they were in moribund state
Or were not expected to survive for 28 days
If patients condition worsened