SIRS & Sepsis
Represents a dysregulaton of the normal host response with a massive & uncontrolled release of pro-inflammatory mediators creating a chain of events leading to widespread tissue injury
Etiologies: infectious & noninfectious - (eg: pancreatitis, pulm. contussion)
Definitions
Systemic Inflammatory Response Syndrome (SIRS)
No infectious focus, evidence of systemic inflammation with two or more of the following:
- Temp >38.3 (100.5) or < 36 (96.8)
- HR > 90
- RR > 20 or PaCO2 < 32 or on vent support (respiratory alkalosis early sign of sepsis)
- WBC >12,000, <4,000 or >10% bands on diff
- Lactate elevation
Acute pancreatitis, vasculitis, burns, trauma, etc…
Overall mortality: 7%;
Sepsis
Presence of infectious focus and two of the following
- Temp >38.3 (100.5) or < 36 (96.8)
- HR > 90
- RR > 20 or PaCO2 < 32 or on vent support (respiratory alkalosis early sign of sepsis)
- WBC >12,000, <4,000 or >10% bands on diff
- Lactate elevation
16% Mortality; 17% + Blood Cx Rate;
Severe Sepsis
Sepsis with evidence of organ hypoperfusion/dysfunction
- Sepsis-induced hypotension
- Lactate above 3.9
- UOP < 0.5 mL/kg/hr for more than 2 hrs despite adequate fluid resuscitation
- acute lung injury with PaO2/FiO2 < 250 in the absence of PNA as infectious source
- acute lung injury with PaO2/FiO2 < 200 (ARDS) in the presence of PNA as infectious source
- Cr >2.0 mg/dL (176.8 umol/L)
- Bilirubin >2mg/dL (34.2 umol/L)
- Platelet Count < 100,000 uL
- Coagulopathy (INR > 1.5)
20% Mortality;
Septic Shock
Severe Sepsis with Hypotension (MAP < 65 or more than 40 under baseline HTN)
- unresponsive to initial fluid challenge (40-60 cc/kg) or serum lcatate > 4
- responsive to mild/moderate dose of vasopressors: NE or E < 0.25 mcg/kg/min, Dopamine < 15 mcg/kg/min
46% Mortality
69% + Blood Cx Rate
Refractory Septic Shock
Septic shock requiring NE or E > 0.25 mcg/kg/min or dopamine > 15 mcg/kg/min to maintain MAP >65 (80 in baseline hypertensive patients) after adequate fluid resuscitation
Adequate fluid resuscitation: 40-60 cc/kg crystalloid or PCWP > 11 for definition but should give fluids as long as patient responds
Multiple System Organ Failure (MSOF) aka Multiple Organ Dysfunction Syndrome (MODS)
Primary MODS
- Early, direct result of insult, eg. Renal Failure from Rhabdo
Secondary MODS
- Later injury resulting from excessive host response, eg. ARDS
Signs of disfunctional organs:
- Respiratory: PO2/FIO2 ratio < 250 without pneumonia, or < 200 with pneumonia
- Renal: Cr > 2.0
- Hematologic: Plts < 100,000
- CNS: GCS < 15
- Liver: Bili > 2
- Cardiac: varying definition
Epidemiology
~ 750,000 cases of SIRS/Sepsis per year in US
~ 225,000 deaths / year (20-50% mortality)
Trend toward more severe cases but better survival
Increased incidence with: winter season, black males, elderly patients, immunocompromised
Prognosis - 7% Mortality with SIRS, 46% with Septic Shock
MSOF:
- Single system - 21% mortality
- 2 system 44% mortality
- 3 system 65%
- 4 system 76%
Characteristics associated with worse outcome:
- Host response - absence of fever/hypothermia, leukopenia
- Age > 40
- Comorbidities: immunosuppression, liver failure, alcoholism, CA
- Malnutrition
- Site of infection
Acute Physiology And Chronic Health Evaluation (APACHE) Scoring
Sum of: Acute physiology score, GCS, Chronic Health Points
APACHE Scoring:
Rectal Temp, MAP, HR, RR, pH, PaO2 or A-a, Na, K, Cr, Hct, WBC
Chronic Health Conditions considered: Cirrhosis, class IV angina, Chronic respiratory failure, renal failure on dialysis, immunocompromise
Pathophysiology of SIRS/Sepsis
Pathophysiology
Malignant
- uncontrolled, unregulated, and self-sustaining
Intravascular
- blood-borne spread of what is usually a cell-to-cell interaction in interstitium
Inflammation
- All steps involve exaggerations of normal inflammatory response
Immunosuppression
Inflammatory Response
3 Major Components:
1 - Alterations in vascular caliber --> inc local blood flow
2 - Microvascular structural changes facilitating diapedesis and migration of plasma proteins and WBCs
3 - Activation of leukocytes with production of inflammatory mediators (TNF a, IL-1, etc.)
The Basic Pathophysiologies of SIRS
1 - Systemic vasodilation --> distributive shock
2 - 3rd spacing --> hypovolemia
3 - Excessive immune response --> cell death
Septic Shock MAP < 65 --> associated with worse outcomes
- Pathologic Vasodilation
- Relative & Absolute Hypovolemia
- Direct Myocardial Depression
- Microvascular Blood Flow Abnormalities
Pathophysiology of SIRS/Sepsis
Basic Mechanisms of Cell Damage/Death:
- Cytokine effects, bacterial factors, complement activation, direct cellular injury, apoptosis
Pathophysiology of SIRS/Sepsis
Cytokines:
- Pro-inflammatory: TNF a, IL-1
- Anti-inflammatory: IL-6, IL-10
Bacterial Factors:
- Endotoxin
- Other Cell Wall components (eg. peptidoglycans, lipotechoic acid, etc...)
- Exotoxins (Toxic shock syndrom toxin, pseudomonas exotoxin)
Pathophysiology of SIRS/Sepsis: The New Model
Acute and often severe inflammation with concurrent immunosuppression
1. Fulminant Sepsis & Early Death in the ICU
2. Recovery
3. PICS & Protracted Death in the L-TACH
PICS: Persistent Inflammation - Immunosuppression Catabolism Syndrome - Delayed death
Management of SIRS/Sepsis
Airway
- Avoid etomidate as it is associated with increased adrenal insufficiency
- Increased mortality observed after etomidate and subsequent steroids
- Can crump when intubating - fall off physiologic curve
Breathing
- Prophylactic lung protective ventilation - keep plateau pressures < 30
Circulation
- Aggressive fluid resuscitation to achieve SCVO2 > 70%
- Pulmonary artery catheters (swan-ganz) rarely needed in most they increase complications iwthout improving fluid management
- routine A-line in patients on vasopressors
Resuscitation from Septic Shock
First line: Crystalloid Fluids
Second line: Vasopressor support
Third line: Corticosteroids
MAP < 60 is associated c compromised coronary, renal, & CNS perfusion in animal models
Observational studies demonstrate association c MAP > 65 & better outcomes in sepsis
Increasing >65 significantly, an cause lungs
Tissue Oxygenation Variables
CaO2 = (1.34) (Hgb) (SaO2) + (0.003) (PaO2)
DO2 = (10) (CaO2) (CO)
VO2 = (10) (CaO2 – CvO2) (CO)
O2 Extraction Ratio
Normally 25% can increase up to ~ .50
Corresponds c SvO2 ~ 50%
Further imbalance between
DO2 & VO2 results in tissue hypoxia (SHOCK)
Basic Avoidance/Treatment of Shock
Increase DO2:
- Increase HgB, Increase SaO2, Increase CO
Decrease O2 Consumption/Facilitate O2 Offloading:
- Decrease physiologic stressors, selective role for hypothermic arrest in future?
- Avoid alkalosis, hypothermia, old blood
ICU Goal-Directed Therapy of Shock
Supraoxidazation
- No survival advantage
- ? Problem = Missing “Golden Hour”
- A period of global tissue hypoxia perpetuates:
1. Worsening inflammation
2. Endothelial activation
3. disruption of homeostasis between: vascular tone, vascular permeability and coagulation
MANNY RIVERS!!!
RIVERS, ET AL. NEJM 2001; 345: 1368-77
Prospective randomized trial March 1997 to March 2001
Inclusion criteria:
- SIRS & SBP <90 after fluids or lactate >3.9
Goals:
- CVP > 8-12, MAP > 65 mmHg, UOP > 0.5 mL/Kg/hr, (+ ScvO2 > 70% in goal directed group)
Achieved by crystalloid infusion, vasopressors, transfusion, dobutamine if needed
Mortality: Standard therapy 46% vs. early goal directed therapy 31%
Comments: both groups received similar amounts of fluids but goal directed group got these earlier, improved mortality and decreased vasopressor needs likely because these fluids were given early
Early (< 6hr) achievement of:
- ScvO2 > 70% in Septic Pts (associated c 20% reduced mortality 47% --> 31%)
Goal-directed Approach: (optimizing CVP, MAP, Hgb) achieved target ScvO2 in 95%, VRS 60% c standard therapy
Higher CVP (12-15) for patients mech ventilated, known decreased ventricular compliance, abdominal compartment syndrome, diastolic dysfunction, known pulmonary artery hypertension
EARLY GOAL DIRECTED THERAPY GOSPEL (PROTOCOL)
Supplemental O2 +/- endotracheal intubation and mechanical ventilation --> CVC and a-line --> sedation, paralysis prn -->
CVP: if < 8 mmHg give crystalloid (or colloid); if 8-12 mmHg move on to check MAP
MAP: if <65 mmHg or >90 mmHg use vasoactive agents; if >65 and <=90 check ScvO2
SvcO2: if <70% transfuse red cells until hematocrit >30; if SvcO2 remains < 70 consider inotropic agent dobutamine (though B2 can cause hypotension); once SvcO2 > 70 goals are achieved then admit to ICU
Lactate Data
Prognostic marker for mortality
< 2 low risk
2-4 intermediate risk
> 4 high risk
Lactate has been shown to be equivalent or better than ScvO2
348 septic patients, Lactate > 3, Addition of Lactate clearance goal of 20% every 2 hours in addition to ScvO2 >69% associated with 10% decreased absolute mortality rate
Metabolic Acidosis in Sepsis and bicarbonate
- do not use bicarbonate unless pH is <7.1
- the treatment is continued resusscitation
Local Sepsis Policies
Sepsis Alerts
Sepsis EGDT Order Sets - cannot replace a physician at the bedside
Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012; crit care med 2013; 41:580-638
Septic Shock - Treatment
To be completed within 3 hours:
1) Measure lactate level
2) Obtain blood cultures prior to administration of antibiotics
3) Administer broad spectrum antibiotics
4) Administer 30 mL/kg crystalloid for hypotension or lactate >= mmol/L
To be completed within 6 hours:
5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) >= 65 mmHg
6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate >=4 mmol/L (36 mg/dL)
- Measure central venous pressure (CVP)
- Measure central venous oxygen saturation (Scvo2)
7) Remeasure lactate if initial lactate was elevated
Target for quantitative resuscitation included in the guidelines are CVP or >=8 mmHg, Scvo2 of >=70 and normalization of lactate
Early Maximization of DO2
Aggressive Fluid Resuscitation start with 40cc/kg NS bolus
- So long as patient is improving --> keep giving fluids
- Increased CVP without improved MAP/UOP --> time to slow down and increase pressors PRN
- What fluid? - isotonic crystalloid (albumin is okay but usually not within 24 hours)
Colloid Advantage: Remains intravascular better - has not translated to improved clinical outcomes
Colloid Disadvantages:
Hetastarches – expense, coagulopathy potential, risk of AKI
Albumin – expense, older data c ? ARDS risk, now accepted as a "back up" resuscitation fluid
Blood – the “Good Colloid”
During initial resuscitative phase transfuse to goal of Hgb 101
Appropriate threshold with anemia after shock has resolved = Hgb 7-9
SSC Recs on Transfusion Therapy
1) Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxia, acute hemorrhage or ischemic heart disease, we recommend that red blood cell transfusion occur only when hemoglobin concentration decreases to < 70 g/dL to target a hemoglobin concentration 7-9 g/dL in adults
2) Erythropoieten not indicated aside from renal failure
3) Don't use fresh frozen plasma to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures (grade 2D - chambers uses FFP)
4) Don't use antithrombin to treat severe sepsis or septic shock
5) In patients with severe sepsis if plt count is:
<10,000 - prophylactic platelets for all patients
<20,000 - prophylactic platelets for patients with significant risk for bleeding
<50,000 - prophylactic platelets for patients that are actively bleeding, undergoing surgery or invasive procedures
Resuscitation from Septic Shock
Crystalloid Fluids
Vasopressor support
1) When adequate filling pressures have been achieved but MAP still < 60-65
2) While adequate filling pressures are being achieved in patients with severely low BP
MAP < 60 is associated c compromised coronary, renal, & CNS perfusion in animal models
Observational studies demonstrate association c MAP > 65 & better outcomes in sepsis (higher pressures can actually worsen outcomes)
Vasopressors in Septic Shock
Norepinephrine (Levophed) = Drug of choice
Prospective, randomized trial demonstrating significant difference in BP normalization (97 vs 31%) & survival (59 vs 17%) c NE as compared to Dopamine
Associated c increased survival compared to Dopamine & Epi in early SvO2 optimization trial2
“Renal Dose” Dopamine is a myth
Renal & Splanchnic Hypoperfusion not seen c NE if adequate fluid resuscitation given prior to or concurrent with it
Dobutamine useful in conjuction c NE with low cardiac output sepsis
Epinephrine recommended as 2nd line pressor
Vasopressin 0.03-0.04 units/min as a fixed dose may help in some cases c suboptimal response
Phenylephrine (pure alpha agonist) may be useful in pts with tachyarrhythmias (50-200 mcg/min)
2013 SSC Recs on Vasopressors
1) Target MAP 65
2) Norepi first choice
3) Epinephrine (added or substituted) when additional agent is needed
4) Vasopressin 0.03 units/minute can be added to raise MAP or decrease NE usage
5) Only use vasopressin as a fixed dose, either 0.03 or 0.04 units/minute
6) Rarely use dopamine - causes tachyarrhythmias so could use with absolute or relative bradycardias
7) Phenylephrine not recommended except if a) norepi is associated with serious arrhythmias, b) cardiac output is high and blood pressure persistently low, c) salvage therapy when combined inotrope/vasopresor drugs and low dose vasopressin have failed to achieve MAP (probably going to die)
8) Low-dose dopamine is a myth, don't use for renal protection
9) Use a CVC and a-line when using pressors
Inotropic Therapy in Sepsis
Dobutamine trial up to 20 micrograms/kg/min used in presence of a) myocardial dysfunction with elevated filling pressures and low output, or b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate MAP
Not using a strategy to increase cardiac index to predetermined supranormal levels
Management of SIRS/Sepsis
Identification & Source Control
Early Cxs then ASAP Abx administration
Once maximally stabilized to OR or IR as indicated
Antibiotic Therapy
Blood Cxs should be obtained prior to institution of Empiric Broad Spectrum Antibiotics
Minimum of 2 sets(at least one peripheral)
Cxs from all vascular access lines in for > 48 hr
Consider anti-fungals in possible intra-abd. sepsis
Other Cxs (sputum, urine, wound, CSF etc…) selectively prior to Abx
Abx should be in within 1 hour of presentation with severe sepsis (should not be delayed by obtaining of Cxs)
Delay in Abx in Septic Shock: Association with Mortality
Each hour of delay in septic shock = Increase in mortality of 8%
- 30 minutes --> 83% survival
- 1 hr --> 77%
- 6 hrs --> 42%
Rate of Abx given
- within 1 hr: 14.5%
- within 3 hr: 33%
- within 6 hr: 51%
Avoid Abx the patient has been on recently
De-escalate Abx in most instances after 3-5 days based on Cx data
Continue Abx for 7-10 days
Additional Therapies: Immunomodulators in SIRS/Sepsis
2 Basic Problems:
>30 cytokines involved
Decreasing inflammation can increase infectious complications
Benefits seen in lab models but not clinically in multiple studies in ’80-90s
Activated Protein C
Xigris (Drotrecogin)
Protein C --> factor Va&VIIIa --> coagulation
Protein C --> Inflammation
Mechanisms: decreased TNF alpha release, decreased E-selectin, decreased NO vasodilatory effect, decreased tissue ischemia, decreased IL 6 release, decreased WBC apoptosis
Protein C levels are decreased c severe sepsis - correlates with mortality risk
PROWESS Trial - post hock analysis, drug company sponsored
Xigris group 28 day mortality: 24.7%
Control group 28 day mortality: 30.8%
The Xigris Debacle - not indicated
Steroids in Septic Shock
2 trials:2 Consensus Statements
- 2002 JAMA Annane Study
- 2008 NEM CORTICUS study
2 consensus statements
- 2012 Surviving sepsis recommendations
- 2008 American College of Critical Care Medicine Recommendations
2002 JAMA Annane Study
French multi-center study with 299 patients 40 % surgical
Sepsis, SBP < 90 for > 1 hr despite fluids/pressors
Randomized to placebo or Hydrocortisone & Fluodrocortisone
time limit from onset to enrolement: 8 hours
All pts underwent ACTH stim-testing
Delta Cortisol < 9 --> + relative adrenal insufficiency
10% decreased 28 day mortality with RAI treatment with hydrocortisone, fluodrocortisone
Hydrocortisone 50 mg IV q6h, fludorocortisone 50 mcg po QD x 7 days
Complications in Annane Trial
- No difference between steroid & placebo group’s complication rates
Conclusions from Annane Trial
- Pts with RAI (CIRCI) & refractory septic shock benefit from a 7 day course of low dose hydrocortisone & fludrocortisone without increased incidence of complications
2008 CORTICUS Trial – Inclusion Criteria
Multicenter, randomized, double-blind, placebo-controlled study
52 European Centers
499 patients between March 2002 – Nov. 2005
Inclusion criteria:
- Sepsis
- SBP < 90 for > 1 hr despite fluids
Time limit from onset to enrollment: 72 hrs (problem with study)
- Hypoperfusion or Organ Dysfunction
Method
- Hydrocortisone 50 mg IV Q 6 hr x 5 days then Q 12 hr x 3 days then Q 24 hr x 3days
- No Fluodrocortisone
- 65% surgical patients
Results
- It's a wash, no statistically significant differences
Conclusion
- “Hydrocortisone did not improve survival or shock reversal in patients with septic shock”
- In patients who ultimately recovered, Hydrocortisone hastened the speed of their recovery from shock.
2002 Annane VS 2008 CORTICUS
Annane trial enrolled only septic patients requiring > 5 mcg/kg/min Dopamine or NE/E (ie: CORTICUS patients weren't as sick) probably more benefit when resistant/sicker
Annane trial utilized Fludrocortisone
Annane trial enrolled within 8 hr of shock (CORTICUS pts were treated later)
Less surgical patients in Annane trial
Shorter course of treatment (no weaning) in Annane trial
Conclusions:
- Reserve steroids for refractory septic shock
- Use them early
- Use with mineralocorticoid
- ? Less benefit c surgical patients ?
- ? Utility of stim testing - Chambers believes there is benefit based on Annane results that resistant patients show more benefit
- Do not use hydrocortisone if patient responds to other treatments - only use with refractory shock
- Taper may not be required
2008 ACCCM Recs
- Not a useful paper
- Call it CIRCI
- Best Dx is c stim test (delta cortisol < 9 or random cortisol < 10 mcg/dl)
- But don’t use stim test clinically (?/!)
- Consider hydrocortisone with septic shock
("especially" with poor initial response to fluids/pressors)
Hyperglycemia Management in Sepsis
- Protocolized approach - keep blood glucose between 110 and 180
- Monitor every 1-2 hrs
- POC glucose should be interpreted with caution
- Avoid insulin without caloric input
Nutrition in Sepsis
- oral/enteral better than fasting - but make sure pressors don't cause mesenteric ischemia
- low dose feedings
- IV glucose or enteral nutrition best for first 7 days, then start TPN
- Immunomodulating supplements don't help
- Permissive high gastric residuals - beware
- Overaggressive use of tpn - beware
- enteral feeds with pressors - beware
Surv. Sepsis Campaign: Guideline Adherence Outcomes
2005-08
15,022 septic pts
165 hospitals
Compliance: 10%, w/ education --> 36%
Mortality: 37%, w/ education --> 30%