Objectives Review of basic pathophysiology
Overview of treatment with focus on ED care Initial resuscitation Infection & source control Early goal directed therapy Ventilatory strategies Pharmacologic therapies
Epidemiology
Most common non-cardiac cause of death in ICU Disproportionately affects elderly, HIV, chemotherapy,
transplant, dialysis, diabetes, alcoholics
Accounts for 215,000 deaths/yr in US = MI deaths or 9.3% of all deaths in 1995
Annual cost in US $16.7 billion
Locally ~250 ICU admissions for sepsis per year
Systemic Inflammatory Response Syndrome
“a systemic inflammatory response to a variety of clinical insults.”
Diagnostic Criteria = 2 or more of T >38 or <36 HR > 90 RR > 20 or PCO2 < 32 WBC > 12 or < 4 or >10% bands
Problems Too simplistic & extremely non-specific
SIRS & Sepsis Infection
invasion of organ system(s) by microorganisms Sepsis
SIRS + infection Severe sepsis
Sepsis with organ dysfunction Lactic acidosis, oliguria, ALOC, etc.
Responsive to fluids Septic shock
Severe sepsis requiring vasopressors/inotropes to maintain normotension
Sepsis Spectrum & MortalityDiagnostic category Mortality (%)
SIRS criterianone 32 73 104 17
Sepsis 16Severe sepsis 20Septic shock 46
McCoy & Matthews. Drotrecogin Alfa (Recombinant Human Activated Protein C) for the treatment of severe sepsis. Clin Ther 2003; 25: 396-421
Sepsis Etiology > 90% bacterial
Gram negative ~42% Gram positive ~34% Anaerobes ~2-5% Mixed ~14%
Fungi ~5% Primarily Candida More common in ICU, immunocompromise,
steroids, diabetics
Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care Med. 2001; 27: S10-32Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001; 27: S33-48
Sources of Infection Specific sites:
Respiratory 36% Blood 20% Abdomen 19% Urinary tract 13% Wounds & Skin 7% Other 5%
Can be identified in ~92% of pts Extremely important in choosing Abx
Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001; 27: S33-48
Not all that is febrile & shocky is infectious…
Non-infectious causes of SIRS Tissue damage
Surgery, trauma, DVT, MI, PE, pancreatitis, etc Metabolic
Thyroid storm, adrenal insufficiency Malignancy
Tumor lysis syndrome, lymphoma CNS
SAH Iatrogenic
Transfusion rx, anesthetics, NMS, etc
Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care Med. 2001; 27: S10-32
International consensus guidelines
Provide guidance on Initial resuscitation Source control Drugs Fluid therapy Blood products Mechanical ventilation
Treatment of Septic Shock
InfectionControl
SupportiveCare
Immuno-modulatoryTherapies
Septic Shock
EGDT
Ventilation
Antibiotics
Surgical Management
Steroids
rhAPC
Case 1 76 F – from nursing home
Increasing confusion x 3 days Not eating Complaining of lower abdominal tenderness
O/E HR 105 RR 30 BP 95/62 Sats 91% T 38.1 CVS – Normal HS Chest – Decreased A/E to bases, no distress Abdo - soft, +BS, Moderate periumbilical and
suprapubic tenderness
Case 1 - Investigations ECG – sinus tach
CXR – cardiomegaly, hyperinflation, nil acute
Lab CBC
Hb 94; WBC 11 (bands 2); platelets 154 Lytes
Na 133 K 4.9 Cl 98 HCO3 18 LFT’s – normal Urine - +nitrites, + leuks, >30 WBC
Case 1 - continued
Diagnosis?
Does this patient have SIRS?
Sepsis?
Severe Sepsis?
Septic Shock?
Initial Management?
DBRCT, N=6997. 4% albumin vs crystalloid
Amount titrated to clinical status and response to fluids
Primary outcome: 28d mortality 18% patients had severe sepsis
Crystalloid vs Colloid Cochrane Systematic Reviews, 2005.
Albumin or plasma protein fraction. 19 Trials reported data on mortality N= 7576 RR from these trials was 1.02 (0.93, 1.11).
No evidence of meaningful benefit to colloids vs crystalloids
Normal Saline Cheap, available USE IT FIRST
How much are you going to give?
EGDT – Fluid Resuscitation EGDT
Step 1 – Fill the tank
Normal Saline 500ml bolus then 500ml q30min until CVP 8-12
How can you measure CVP in the ED?
What if the patient is intubated Target a CVP 12-15 to account for increased
intrathoracic pressure
Surviving Sepsis Guidelines - Fluids
No evidence for choosing colloid over crystalloids (Grade C)
Administer crystalloids as 500-1000 cc over 30 mins & repeat prn based on response (E)
Administer colloids at 300-500 cc over 30 mins & repeat prn based on response (E)
“resuscitation…should not be delayed pending ICU admission.”
Goals of resuscitation in 1st 6 hrs of recognition: (B) CVP: 8-12 mm Hg (12-15 if ventilated) MAP: > 65 mm Hg Urine output: > 0.5 ml/kg/hr SVO2 > 70% If unable to attain SVO2 >70% despite above then:
Transfuse to keep Hct > 30% Dobutamine
Dellinger et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32: 858-73
Surviving Sepsis Guidelines - Fluids
Back to Case 1 After 2500ml of NS CVP is ~10
You reassess the patient
O/E HR 100 RR 32 BP 80/50 Sats 91% T 38.4
What is their MAP?
What is your next move?
Vasopressors
Goals MAP >65 Improvement in indicators of end organ perfusion
Which vasopressor do you choose?
What is your starting dose?
Vasopressors Dopamine
Precursor of epi/norepi Release of norepi from
presynaptic terminals Dosing
Dopaminergic <5ug/kg/min Vasodilation coronary,
renal, mesenteric beds Beta - 5-10ug/kg/min
Increase contractility and HR
Alpha - >10ug/kg/min vasoconstriction
Norepinephrine Alpha agonist Increases BP by
vasoconstriction, little effect on HR or cardiac output
Dosing Start at 0.1 ug/kg/min Double every five minutes
to effect Maximum ~ 2ug/kg/min
Dopamine vs Norepinephrine Theoretical advantages to norepinephrine
Direct acting, works in catecholamine depleted patients Less tachycardias & dysrhythmias
Indirect evidence of benefit over dopamine in multiple small trials Improved hemodynamics Improved gastric pH Improved lactate
Single non-randomized trial showing mortality benefit
No RCT showing mortality benefit
Surviving Sepsis Guidelines - Vasopressors
Should be used when shock refractory to fluid resuscitation Life-threatening hypotension (E)
Dopamine or norepinephrine are 1st line agents (D)
‘Renal dose’ dopamine does not work & should not be used (B)
Invasive BP monitoring & central IV lines should be placed as soon as possible (E)
Vasopressin may be considered as a 2nd line agent in refractory shock (E)
Back to our case Our patient now on dopamine 10ug/kg/min
VS 120 RR 30 BP 95/65 Sats 92% T 38.1
You now have a few moments to think
You’re pretty sure this patient has Urosepsis?
What else would you like to do?
Antibiotics & Source Control
“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
Do Antibiotics make a difference? Animal models
increased mortality with each hour of delay to antibiotics
Few prospective RCT’s most outcome data based on retrospective analyses ARR 16 – 26% when initial Abx were appropriate
Virtually all studies in ICU setting Prospective cohort study of 406 pts w/ sepsis found
inadequate initial Abx Tx significantly increased risk of death in non-surgical sepsis (OR 8.15; 95%CI 1.98-33.5)
Adequate Tx dec’d risk of death in surgical sepsis (OR 0.37, 95%CI 0.18-0.77)
Garnacho-Montero et al. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003; 31: 2742-51
Community Acquired Pneumonia Ceftriaxone 2gm IV PLUS Azithromycin 500mg IV OR Levofloxacin 500mg IV
Intra-abdominal Infection Piperacillin/Tazobactam 3.375gm IV OR Ceftriaxone 2gm IV PLUS Flagyl 500mg IV OR Ampicillin 2gm IV PLUS Gentamicin 6mg/kg IV
PLUS Metronidazole 500mg IV
Urosepsis Gentamicin 6mg/kg IV OR Ceftriaxone 2gm IV
Meningitis Dexamethasone 10 mg IV at or before antibiotics
given Ceftriaxone 2 gm IV PLUS Vancomycin 1 gm IV
Cellulitis/Bone/Joint Cefazolin 2 gm IV OR Cloxacillin 1 gm IV
Fasciitis Clindamycin 600 mg IV PLUS Penicillin 4 MU IV
PLUS IVIG PLUS Surgery
Endocarditis Ensure Blood Culture x THREE are done Ceftriaxone 2gm IV ADD Vancomycin 1 gm IV if MRSA suspected
Infected Central Line Pull Line Vancomycin 1 gm IV
Neutropaenic Piperacillin/Tazobactam 3.375gm IV PLUS
Gentamycin 6 mg/kg IV
Sepsis Source Unknown Treat for MOST likely source Treat as per Intra-abdominal Infection
CHR Sepsis Protocol Recommendations
Blood cultures
Important to establish Dx for: Guiding antimicrobial Tx Guiding adjunctive Tx Microbiological epidemiological surveillance
Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care Med. 2001; 27: S10-32
Yield of cultures ranges from 9-64% Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001;
27: S33-48
Don’t forget to draw cultures before antibiotics!
Blood cultures
Limitations Colonization vs. infection Prior antimicrobial Tx Significance of
Rare or unfamiliar organisms Mixed culture results Organisms not usually associated with disease
Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care Med. 2001; 27: S10-32
Surviving Sepsis Guidelines-Antibiotics
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
Surviving Sepsis Guidelines - Source Control Get appropriate study to find the source (CT,
U/S, etc.)
Choose least invasive effective intervention eg. CT guided percutaneous drainage vs surgery
Source control ASAP after initial resuscitation
Remove any possible iatrogenic sources Central lines, foley catheters, etc.
Back to our case You started our patient on gentamicin
He’s still on dopamine 10ug/kg/min
VS 120 RR 30 BP 95/65 Sats 92% T 38.1
What would you like to do now?
Measurement of ScvO2 What is ScvO2?
Reflects oxygenation at tissue level
How are you going to measure ScvO2?
What is the difference between mixed venous and central venous SvO2? ScvO2
blood from SVC or right atrium SmvO2
blood from pulmonary artery Contains blood from IVC (lower extremity) and coronary sinus
ScvO2 and SmvO2 correlate well
ScvO2 What is a normal ScvO2
Normal ~75% Normal pO2 ~40
ScvO2 comes back ScvO2 = 64%
What does this result mean?
Repeat CBC Hb 81 Hct 0.25
What do you do Transfuse patient to Hct of 0.3
What is the physiological rationale for transfusion
O2 content = (1.34 x Hb x SaO2) + (0.0031 x PO2)
Transfusion in Sepsis 95% of ICU pts anemic by day 3 of ICU stay
Mechanisms Phlebotomy = average 65 ml/day Ongoing bleeding Fluid resuscitation Underproduction anemia
Blunted erythropoietin response secondary to inflammatory cytokine production
Abnormal iron metabolism due to immune activation Low iron levels & elevated ferritin
Corwin et al. Transfusion practice in the critically ill. Crit Care Med 2003; 31(S): S668-71
When should you transfuse? Surviving Sepsis Guidelines
Transfuse to keep Hb > 70 g/L unless extenuating circumstances (e.g. CAD) (B)
Based on TRICC trial
Rivers et al. 2001 Transfuse to keep hematocrit at least 30%
Multicenter RCT of 838 ICU pts w/ Hb <90 Randomized to
Liberal strategy Transfusion threshold 100 g/L – aim for 100 -120g/L
Restrictive strategy (study group) Transfusion threshold 70 g/L – aim for 70 – 90 g/L
Primary outcome All cause mortality at 30 days
TRICC Trial Results
No difference in 30 or 60 day mortality Lower in-hospital mortality in restrictive group
22.2% vs 28.1% (p=0.005) No difference in mortality in sepsis sub-group
But only 5% of patients had sepsis Less sick pts (APACHE II score <20) did better with
restrictive strategy ARR 7.4% (95%CI 1.0 – 13.6%)
Conclusion Restrictive strategy equivalent to, and possibly better
than keeping Hb > 100 g/L
Reconciling EGDT and TRICC EGDT
Hypovolemic patients Actual measurement of suboptimal O2 delivery Early resuscitation phase
TRICC Euvolemic pts enrolled within 72 hours of ICU Only 6% sepsis, only 27% had any infection
Bottom Line Use EGDT in acute resuscitation, use TRICC
afterwards when stabilized
Surviving Sepsis Guidelines - Transfusion
“Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as significant coronary artery disease, acute hemorrhage, or lactic acidosis (see recommendations for initial resuscitation), red blood cell transfusion should occur only when hemoglobin decreases to 70 to a target Hb of 70-90.”
Recommends EGDT in initial resuscitation
Back to our case You gave our patient one unit of blood Repeat CBC
Hb 91 Hct 0.31
What now?
Repeat ScvO2 ScvO2 = 68%
What now?
Inotropes Dobutamine
Beta adrenergic agonist B1 – increases contractility, minimal effect on HR B2 – vasodilation
Overall effect Increased stroke volume Increased HR Increased cardiac output = increased O2 delivery
NB – BP can go up or down
Survivng Sepsis Guidelines - Inotropes
“In patients with low cardiac output despite adequate fluid resuscitation, dobutamine may be used to increase cardiac output. If used in the presence of low blood pressure, it should be combined with vasopressor therapy.”
Rationale Time is survival: Goal is to achieve balance b/w O2 delivery & consumption
Standardized approaches to ED Tx have improved outcomes in other diseases (e.g. MI)
Traditional parameters to guide resus (vitals, mental status, urine output) appear to be too insensitive for ongoing tissue hypoxia
Early observational trials found survivors to have hemodynamic parameters that were both higher than non-survivors
Previous trials of goal directed therapy 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
No convincing benefit
Limitations NOT EARLY 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
Previous trials of goal directed therapy
Prospective RCT – N=263 Patients with SIRS and sBP<90 or lactate >4 Randomized to EGDT protocol or standard care
All had arterial & IJ central venous lines EGDT group had catheter capable of ScvO2 monitoring
EGDT discontinued once transferred to ICU
ICU staff blinded to patient assignments
Primary endpoint was mortality
EGDT - Results 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
EGDT - Results Differences in EGDT group
More fluid early (4.9 L vs. 3.5L) No difference in overall fluids at 72h (13 vs 13L)
More early transfusions (64.1% vs. 18.5%) More early inotropes (13.7% vs. 0.8%) Less use of pulmonary artery catheters
later in ICU stay (18% vs. 31.9%)
EGDT - Controversies Conflicts with earlier studies showing lack of
benefit from using hemodynamic goals all prior studies in ICU setting
Has never been replicated
A whole package of interventions Which one(s) actually matter?
Back to the case You start our patient on dobutamine at
10ug/kg/min
Repeat ScvO2 ScvO2 = 69%
Patient becoming more confused, no urine output
What now?
Intubating the Septic Patient What do you use for
Pretreatment Induction agent Paralytic agent
You successfully intubate the patient
RCT – N=861 (stopped early) Patients with strictly defined ARDS 27% of patients had sepsis
Used A/C ventilation mode Traditional ventilatory parameters
12cc/kg, plateau pressures <50
Intervention (=low Tv) 6cc/kg, plateau pressures <30 RR variable to achieve near normal pH
ARDS Network
Primary outcomes In hospital mortality Ventilator-free days in first 28 days
Secondary outcomes Organ failure Barotrauma Plasma IL-6 levels
ARDS Network - Results Low Vt group
Significantly decreased mortality 31.0% vs. 39.8% ARR 8.8% (95%CI 2.4-15.3%); NNT = 11
More ventilator free days More organ-failure free days More pts breathing w/o assistance at 28d Greater decreases and lower absolute levels of
IL-6 at day 3 No difference in barotrauma
Surviving Sepsis Guidelines – Ventilation Strategy Avoid high tidal volumes & high plateau pressures
(B) Target TV 6 ml/kg Target end-inspiratory plateau pressure < 30 cm H20
Small levels of PEEP should be used to prevent atelectasis (E)
Utilize permissive hypercapnea to help minimize TV & plateau pressures if necessary (C)
In absence of contraindications, position intubated & ventilated pts w/ HOB 45o to prevent VAP
The patient is transferred to the ICU
You are the ICU resident
What other therapies have proven mortality benefit in sepsis?
Steroids in Sepsis Initially proposed for anti-inflammatory effects
Large dose (methylprednisolone 30 mg/kg then 5 mg/kg) 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
Adrenal insufficiency Stress steroid response essential
Removing adrenals increases septic shock mortality in animal models -- 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 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 Hydrocortisone 50 mg q6h IV & fludrocortisone 50 ug PO
OD for 7 days Primary outcome
28d survival Secondary outcomes
28d survival in responders vs. nonresponders 28d, 1 yr, ICU, & hospital mortality Time to vasopressor Tx withdrawal Adverse events
Results Mortality
Overall No difference in 28 day mortality
Non-responders 28 day mortality - 53 vs 63%; ARR 10%, OR 0.54 (95%CI
0.31-0.97) NNT = 10
Reliance on vasopressors Overall
No difference Non-responders
Median time to withdrawal 7 vs 10 d, HR 1.91 (95%CI 1.29-2.84)
Criticisms
Possible inclusion of true adrenal insufficiency High mortality rate in placebo group
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 Change of entry criteria during study
No analysis of pts recruited before & after
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
Steroid Algorithm Draw baseline cortisol
and do ACTH stim test Give dexamethasone in
ED Does not interfere with
ACTH stim test
<414nmol/L 414-938 >938nmol/L
<250nmol/L >250nmol/L
Cooper & Stewart. Corticosteroid insufficiency in acutely ill patients. N Eng J Med. 2003; 348: 727-34
Surviving Sepsis Guidelines - Steroids
IV hydrocortisone 200-300 mg/day for 7 days should be given to adequately fluid-resuscitated pts in refractory shock (C)
Doses of > 300 mg/day should not be used (A)
Use dexamethasone in ED & consider use of ACTH stim test to identify pts in need of continued steroids (E)
Van den Berghe et al. Intensive insulin therapy in critically ill patients. N Eng J Med. 2001; 345: 1359-67
RCT N=1548 Mostly surgical patients
Randomized to Intensive insulin Tx
Continuous IV insulin initiated if glucose >6.1 mmol/L & adjusted to maintain glu b/w 4.4 – 6.1 mmol/L
Traditional Tx Continuous IV insulin initiated if glucose >11.9 mmol/L &
adjusted to maintain glu b/w 10-11.1 mmol/L
Primary outcomes All-cause ICU mortality
Intensive Insulin group Lower rate of developing septicemia
4.2% vs 7.8% (p=0.003) Lower requirement for prolonged antibiotics
11.2% vs 17.1% (p<0.001)
Patients with bacteremia had trend towards lower mortality with intensive insulin therapy 29.5% vs 12.5% (NS)
Intensive Insulin Therapy and Sepsis
Criticisms Generalizability
Mostly post-surgical patients Does this apply to septic or other medically sick patients? Does use of insulin to prevent sepsis translate into mortality
benefit when treating primary sepsis? Single center trial
Not blinded Is the benefit related to euglycemia or to insulin?
Van den Berghe et al. Intensive insulin therapy in critically ill patients. N Eng J Med. 2001; 345: 1359-67
Surviving Sepsis Guidelines – Glucose Control
IV infusions of insulin should be used to maintain serum glucose levels < 8.3 mmol/L (D)
RhAPC - Pharmacologic Actions Anti-thrombotic
Inhibits FVa & FVIIIa
Anti-fibrinolytic Inhibits PAI-1 & TAFI Decreases thrombin
production
Anti-apoptotic Induces Bcl-2 & inhibitor
of apoptosis-1 gene expression
Anti-inflammatory Inhibits TNF-α, IL-1, IL-
6 production Inhibits monocyte &
neutrophil migration Inhibits lipid A
activation of monocytes
Inhibits tissue factor activation
McCoy & Matthews. Drotrecogin Alfa (Recombinant Human Activated Protein C) for the treatment of severe sepsis. Clin Ther 2003; 25: 396-421
RhAPC Most septic pts have low levels of protein C
Associated with increased M & M
Pharmacologic properties Anti-inflammatory, anti-thrombotic, anti-fibrinolytic
Increased survival in primate model of septic shock
Improved outcomes suggested in non-randomized trial of meningococcemia
Administration associated w/ dec’d levels of proinflammatory mediators & D-dimer in humans
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
RCT – N=1690 Severe sepsis
Randomized to rhAPC infusion @ 24 ug/kg/h for 96 hrs Placebo
Primary outcome All-cause mortality at 28d
PROWESS Trial - Results
rhAPC significantly reduced 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
Post hoc analyses APACHE II scores <25 did worse with rhAPC
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
Dhainaut et al. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Int Care Med 2003; 29: 894 - 903
Dhainaut et al. Drotrecogin alfa (activated) in the treatment of severe
sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Int Care Med 2003; 29: 894 - 903
Prowess - Criticisms Face Validity
When multiple other trials of anti-cytokine or anti-thrombotic meds have not worked why does this one?
Validity of the results Entry criteria where changed ½ way through Cell line used to produce rhAPC was changed
½ way through Changes not mentioned anywhere in methods Changes coincided w/ significant difference in
observed efficacy
Criticisms External validity
Exclusion criteria extensive & included many pt groups relevant to increasing incidence of sepsis
What is mortality beyond 28d? What is status of survivors?
Other concerns Sponsored by Eli Lilly 3 authors are Eli Lilly employees, 2 are stockholders,
5 have served as consultants leaving only 3/11 primary authors as having no ties
Remaining questions What is the mortality benefit beyond 28d? What
about morbidity? What is the best method to identify pts most likely to
benefit from rhAPC? Can we use rhAPC in any of the pt populations
excluded from PROWESS? Would giving rhAPC earlier = greater efficacy? Would a longer Tx period = greater efficacy? How does rhAPC interact w/ other existing or novel
sepsis therapies?
Is it cost effective? CAD$335 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
Surviving Sepsis Guidelines - rhAPC
rhAPC should be given to severely ill pts: APACHE II score > 25 Sepsis-induced MOF Septic shock ARDS
In the absence of absolute or significant relative contraindications (B)
We can reduce mortality in sepsis in the ED
EGDT ARR 16.0% Steroids ARR 10.0% ARDS Net vent strategy ARR 8.8% rhAPC ARR 6.1% Insulin ARR 3.4% Dex in Meningitis ARR 8.0% Early appropriate Abx Source control
Surviving Sepsis – Summary Utilize
EGDT in 1st 6 hrs Cultures before Abx Source control Fluid resuscitation
Crystalloid = colloid Vasoactive medications
when fluid fails Dopamine = norepinephrine
Steroids replacement
rhAPC when appropriate Keep Hb 70-90 Ventilate with low TV and
peak pressures Euglycemia
Avoid Supranormal oxygenation Bicarbonate
q Pneumonia, emphysemaq Urinary tract infectionq Acute abdominal infectionq Meningitisq Skin/soft tissue infectionq Bone/joint infectionq Wound infectionq Bloodstream catheter infectionq Endocarditis (IVDA)q Implantable device infectionq No known source other than
clinical suspicion***q Other
Suspected or Proven Infection
Draw and send: q CBC with diff, electrolytes q Glucose, creatinine
q O2 saturation <90%n on Room Airq Hypotensive: systolic BP <90 or MAP <60q Oliguria – urine output <0.5ml/kg/hrq Mottledq Increased Creatinine >60 umol/l from baselineq Coagulation Abn: INR >1.5, PTT > 60secq Thrombocytopenia PLT <100q Hyperbilirubinemia: >70 mmol/lq Hyperlactatemia: >4 mmol/l
S.I.R.S. criteria:q Hyperthermia > 38 Cq Hypothermia < 36 Cq Tachycardia > 90 bpmq Tachypnea > 20 bpmq Acutely altered mental status (GCS < 15)q Leukocytosis (WBC count >12.0 x 10E9/L)q Leukopenia (WBC count <4.0 x 10E9/L)q Normal WBC with bands > 0q Hyperglycemia (plasma glucose > 7.7 mmol/L in
the absence of diabetes
Draw and send: q Bilirubin q Lactate
Does the patient have any evidence of new end organ dysfunction
· Ensure patient is in a monitored bed· Initiate Severe Sepsis Order Set and Algorithm
Does the patient have 2 or more S.I.R.S. criteria
Addressograph:
Complete:q Urinalysis, Chemstripq Order Old Charts
Complete the following
Complete the followingq Blood Cultures x2q PTT/INRYES
YES
PHYSICIAN SCREENING TOOL for SEVERE SEPSISPilot Form- Please retain on patient chart
YES
Time Severe Sepsis Diagnosed: _________
*** High Risk PatientsImmunocompromised
Substance AbuseChronic Disease
DiabeticSplenectomy
Elderly and neonatesPostoperative
CHR Sepsis Protocol
Severe Sepsis:
· S.I.R.S. associated with evidence of new end organ dysfunction
· O2 Saturation <90%· Oliguria (urine output <0.5 ml/kg/hr)· Mottled· Increased Creatinine > 60 umol/l from pt
known baseline· Coag Abn: INR >1.5, PTT >60 sec· Thrombocytopenia: PLT <100· Hyperbilirubinemia: > 70 mmmol/l· Hyperlactatemia: >4mmol/l
Septic Shock:
Acute circulatory failure due to suspected infection.
Hypotension: SBP <90 mmHg or MAP <60 mmHg
S.I.R.S:(Systemic Inflammatory Response Syndrome) 2 or more of the following:· Temp >38 or <36· Hr >90· RR >20· Altered Mental Status (GCS <15)· Hyperglycemia – Glucose > 7.7mmol/l
in the absence of diabetes· Abn CBC diff:
WBC > 12.0 x 10E9/L or WBC < 4.0 x 10E9/L ornormal WBC with bands >0
Severe Sepsis/Septic Shock Algorithm
ASSESSMENT
Continuous: · O2 Saturation· ECG Monitoring · Urine output
(Foley catheter)
Intermittently: · B/P, HR, RR
q15 mins· Temp q1h
O2 Sat < 90% on Room Air
q Supplement O2
q Maintain O2
Saturation >90%q Call for ABGs.
Consider Intubation
SBP <90 or MAP <65(manual BP)
MAP = DBP + (SBP – DBP) 3
2 large bore I.V.sFluid Resuscitation
Give:Crystalloid 500ml bolus q5-10min
Titrate to:SBP > 90HR <100
Do Not Exceed:40cc/kg to a maximum of 4 litres of crystalloid
Maintenance fluids:Crystalloid 150cc/hr
Draw appropriate labs and blood cultures as per the Severe Sepsis order set
**INITIATE ANTIBIOTIC**
Initiate Consult
q ICU (attending) and MTU (senior resident) on all severe sepsis/septic shock patients.
q If MTU senior resident not available or at RGH, call attending directly.
q Intubated patients consult ICU only.
Hospitalist: Palliative Patients Only
Advanced Goal Directed Therapy Central Line Required
CVP 8-12 mm Hg
MAP >65 mm Hg
SV02 >70% from central
line
Give Fluid bolus: Crystalloid 500mlMaintanience Fluids: 150 ml/hr
Start Norepinephrine infusion at 0.1ug/kg/min and titrate to effect or max 2.0ug/kg/min.
Start Dobutamine infusion at 2.5ug/kg/min. increase by 2.5 ug/kg/min q30 min to effect or max of 20 ug/kg/min.
ADMIT ICU
ADMIT ICU
Transfusion 1 unit PRBC
Hgb <100 g/l
YES
YES
YES
NO
YES
NO
NO
CHR Severe Sepsis Algorithm