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Tri-Service General Hospital, National Defense Medical Center Slide 2: Crit Care Med 1992; 20:864 ACCP/SCCM Consensus Conference Definitions : ACCP/SCCM Consensus Conference Definitions 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 = the presence of viable bacteria in the blood. Crit Care Med 1992; 20:864 Systemic inflammatory response syndrome (SIRS) : Systemic inflammatory response syndrome (SIRS) The systemic inflammatory response to a variety of severe clinical insults. The response is manifested by two or more of the followings: Temperature >38°C or <36°C Heart rate >90 beats/min Respiratory rate >20 breaths/min or PaCO2 <32 mmHg WBC >12,000 cells/mm3, <4000cells/mm3, or >10 % immature (band) forms Crit Care Med 1992; 20:864 Sepsis vs Severe Sepsis : Sepsis vs Severe Sepsis Sepsis = the systemic response to infection. That is, SIRS with definitive evidence of infection. Severe sepsis = Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. The manifestations of hypoperfusion may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Crit Care Med 1992; 20:864 Septic Shock : Septic Shock Septic shock = sepsis induced hypotension despite adequate fluid resuscitation along with perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured. Hypotension = systolic BP of <90 mmHg or a reduction of ?40 mmHg from baseline in the absence of other causes for the fall in blood pressure. * 1 L/hour x 2 hours Crit Care Med 1992; 20:864 Definition : Definition Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207. Sepsis SIRS Infection/Trauma Severe Sepsis Sepsis with =1 sign of organ failure Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic CNS Unexplained metabolic acidosis Multiple Organ Dysfunction Syndrome (MODS/MOF) : Multiple Organ Dysfunction Syndrome (MODS/MOF) MODS/MOF = the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. Primary MODS = a well-defined insult, occurs early and can be directly attributable to the insult itself (eg, renal failure due to rhabdomyolysis). Secondary MODS = not in direct response to the insult itself, but as a consequence of a host response. MODS represents the more severe end of severity of illness characterized by SIRS/sepsis. Crit Care Med 1992; 20:864 Homeostasis Is Unbalanced in Severe Sepsis : Homeostasis Is Unbalanced in Severe Sepsis Carvalho AC, Freeman NJ. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-8; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44. Slide 10: Crit Care Med 2000 28(4):N3-N12 Cytokine Storm ? : Cytokine Storm ? High viral load Genetic predisposition to immune hyperstimulation Good side remove virus Bad side ARDS MODS Corticosteroid Incomplete Rx or relapse ??? Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis : Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis Tachycardia Hypotension ? CVP ? PAOP Jaundice ? Enzymes ? Albumin ? PT Altered Consciousness Confusion Psychosis Tachypnea PaO2 <70 mm Hg SaO2 <90% PaO2/FiO2 ?300 Oliguria Anuria ? Creatinine ? Platelets ? PT/APTT ? Protein C ? D-dimer Slide 14: Crit Care Med 2000, 28(4):N105-N113 with modification Infection Immune Response Sepsis Uncontrolled Pro-inflammatory Mechanisms Dysregulated anti-inflammatory Mechanisms SIRS MODS/MOF Severe Sepsis: The Final Common Pathway : Severe Sepsis: The Final Common Pathway Endothelial Dysfunction and Microvascular Thrombosis Hypoperfusion/Ischemia Acute Organ Dysfunction (Severe Sepsis) Death Cytokine storm Dysoxia : Dysoxia Pressure ? Perfusion ? Oxygenation (Vessel) (Tissue) (Cell) Hypovolemic Hypoxemic Cytopathic hypoxia hypoxia hypoxia Mechanism of regional tissue dysoxia (Cytopathic hypoxia) : Mechanism of regional tissue dysoxia (Cytopathic hypoxia) BP drop CO drop SVR drop Lact up PaO2 drop VO2 drop Tissue pO2 up ATP turnover Global hypoperfusion Microcirculatory shunting Mitochondrial failure Crit Care Med 1995; 23: 1217 Lancet 2002; 360: 219 Surviving Sepsis : Surviving Sepsis A global program to: Reduce mortality rates in severe sepsis The Surviving Sepsis Campaign was initiated in 2002 by the European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine with the intent to reduce mortality rates in severe sepsis by 25% in 5 years Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 : Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 R. Phillip Dellinger, MD; Mitchell M. Levy, MD; Jean M. Carlet, MD; Julian Bion, MD; Margaret M. Parker, MD; Roman Jaeschke, MD; Konrad Reinhart, MD; Derek C. Angus, MD, MPH; Christian Brun-Buisson, MD; Richard Beale, MD; Thierry Calandra, MD, PhD; Jean-Francois Dhainaut, MD; Herwig Gerlach, MD; Maurene Harvey, RN; John J. Marini, MD; John Marshall, MD; Marco Ranieri, MD; Graham Ramsay, MD; Jonathan Sevransky, MD; B. Taylor Thompson, MD; Sean Townsend, MD; Jeffrey S. Vender, MD; Janice L. Zimmerman, MD; Jean-Louis Vincent, MD, PhD; for the International Surviving Sepsis Campaign Guidelines Committee Crit Care Med 2008;36:296-327 available online at www.springerlink.com www.sccm.org www.sepsisforum.com Slide 21: 1 2 Guidelines for Management of Severe Sepsis and Septic Shock : Guidelines for Management of Severe Sepsis and Septic Shock I. MANAGEMENT OF SEVERE SEPSIS Initial Resuscitation Diagnosis Antibiotics Therapy Source Control Fluid therapy Vasopressors Inotropic Therapy Corticosteroid Recombinant Human Activated Protein C (rhAPC) Blood Product Administration II. SUPPORTIVE THERAPY OF SEVERE SEPSIS Mechanical Ventilation of Sepsis-induced ALI/ARDS Sedation, Analgesia, and N-M Blockade in Sepsis Glucose Control Renal Replacement Bicarbonate Therapy DVT Prophylaxis Stress Ulcer Prophylaxis Selective Digestive Tract Decontamination (SDD) Consideration for Limitation of Support III. Pediatric Consideration Slide 24: MANAGEMENT OF SEVERE SEPSIS Slide 25: Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31:946-955. Initial Resuscitation Early Goal-Directed Therapy : Early Goal-Directed Therapy 1000 ml of crystalloid or 300-500 ml bolus of colloid q 30 min to keep CVP 8-12 mmHg Vasoactive agents (MAP: ? 65 mmHg) Vasopressors if MAP < 65 mmHg Vasodilator if MAP > 90 mmHg Transfusion (? Hct > 30%) and Dobutamine if ScvO2 < 70% or mixed venous < 65% Keep urine output: ? 0.5 ml.kg-1.hr-1 In hospital mortality was 30.5% vs. 46.5% in control group River et al. N Engl J Med, 2001 EGDT first 6 hours in ER : EGDT first 6 hours in ER 500ml bolus of colloid every 30min Dobutamin started at 2.5 ug/kg/min, increase by 2.5ug/kg/min every 30 min, or until maximal dose 20ug/kg/min given Decrease dobutamin dose if MAP >65mmHg or HR> 120bpm Initial Resuscitation (2008) : Initial Resuscitation (2008) Initial resuscitation (first 6 hrs) Begin resuscitation immediately in patients with hypotension or elevated serum lactate 4 mmol/L; do not delay pending ICU admission (1C) Resuscitation goals (1C) CVP 8–12 mm Hg a Mean arterial pressure 65 mm Hg Urine output 0.5 mL/kg/hr Central venous (superior vena cava) oxygen saturation 70% or mixed venous 65% If venous oxygen saturation target is not achieved (2C) Consider further fluid Transfuse packed red blood cells if required to hematocrit of 30% and/or Start dobutamine infusion, maximum 20 µg/kg/min Diagnosis (2008) : Diagnosis (2008) Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration (1C) Obtain two or more BCs One or more BCs should be percutaneous One BC from each vascular access device in place 48 hrs Culture other sites as clinically indicated Perform imaging studies promptly to confirm and sample any source of infection, if safe to do so (1C), (ex. Sonography suitable, transport outside unit may be dangerous) Role of Infection Control : Role of Infection Control Right Drugs for Right patients at Right time De-Escalation Therapy (For severe infection in ICU) Why How Outcomes Resistance Controversial Clinical Definitions : Controversial Clinical Definitions Appropriate The etiologic organism is sensitive to the therapeutic agent Adequate Correct antibiotic Optimal dose-All patients should receive a full loading dose of each antimicrobial. Correct route of administration to ensure penetration at the site of infection Use of combination therapy if necessary ATS/IDSA. Am J Respir Crit Care Med 2005; 171: 388-416 Need for adequate antibiotic coverage : Need for adequate antibiotic coverage Major concerns is nosocomial infections Pseudomonas aeruginosa ESBL Acinetobacter spp MRSA VRE (in certain countries) Candidas fungus Antibiotic Therapy (2008) : Antibiotic Therapy (2008) Begin intravenous antibiotics as early as possible and always within the first hour of recognizing severe sepsis (1D) and septic shock (1B) In the presence of septic shock, each hour delay in achieving administration of effective antibiotics is associated with a measurable increase in mortality Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration into presumed source (1B) Watch out MRSA in some communities and healthcare settings Antibiotic Therapy (2008) : Antibiotic Therapy (2008) Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs (1C) Consider combination therapy in Pseudomonas infections (2D) Consider combination empiric therapy in neutropenic patients (2D) Antibiotic Therapy (2008) : Antibiotic Therapy (2008) Combination therapy 3–5 days and de-escalation following susceptibilities (To single therapy) (2D) Duration of therapy typically limited to 7–10 days; longer if response is slow or there are undrainable foci of infection or immunologic deficiencies (1D) Stop antimicrobial therapy if cause is found to be noninfectious (1D) Source identification and control (2008) : Source identification and control (2008) A specific anatomic site of infection should be established as rapidly as possible (1C) and within first 6 hrs of presentation (1D) E.g., necrotizing fascitis, diffuse peritonitis, cholangitis, intestinal infarction) Formally evaluate patient for a focus of infection amenable to source control measures (e.g. abscess drainage, tissue debridement, removal of a potentially infected device, or the definitive control of a source of ongoing microbial contamination) (1C) Source identification and control (2008) : Source identification and control (2008) Implement source control measures as soon as possible following successful initial resuscitation (1C) (exception: infected pancreatic necrosis, where surgical intervention is best delayed) (2B) Choose source control measure with maximum efficacy and minimal physiologic upset (1D) e.g., percutaneous rather than surgical drainage of an abscess Remove intravascular access devices if potentially infected (1C) Prompt remove after other vascular access had been established Fluid Therapy (2008) : Fluid Therapy (2008) Fluid resuscitation may consist of natural or artificial colloids or crystalloids (1B) Slide 40: Figure 2, page 206, reproduced with permission from Choi PT, Yip G, Quinonez L, Cook DJ. Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med 1999; 27:200–210 Fluid Therapy (2008) : Fluid Therapy (2008) Resuscitation initially target a central venous pressure of 8 mm Hg (12 mm Hg in mechanically ventilated patients) (1C) A fluid challenge technique be applied wherein fluid administration is continued as long as the hemodynamic improvement (e.g., arterial pressure, heart rate, urine output) continues (1D) Fluid Therapy (2008) : Fluid Therapy (2008) Fluid challenge over 30 min ?1000 ml crystalloid 300–500 ml colloid More rapid administration and greater amounts of fluid may be needed in patients with sepsis-induced tissue hypoperfusion (1D) Fluid Therapy (2008) : Fluid Therapy (2008) The rate of fluid administration be reduced when:cardiac filling pressures (central venous pressure or pulmonary artery balloon-occluded pressure) increase without concurrent hemodynamic improvement (1D) Slide 44: Effects of Dopamine, Norepinephrine,and Epinephrine on the SplanchnicCirculation in Septic Shock Figure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best? Crit Care Med 2003; 31:1659-1667 Vasopressors (2008) : Vasopressors (2008) Mean arterial pressure (MAP) be maintained 65 mm Hg (? 65) (1C) Sustain life and maintain perfusion in the face of life-threatening hypotension Either NOREPI or DOPA administered through a central catheter is the initial vasopressor of choice (1C) Epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock (2C). Vasopressin 0.03 units/min may be subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone Vasopressors (2008) : Vasopressors (2008) Epinephrine be the first chosen alternative agent in septic shock that is poorly responsive to norepinephrine or dopamine (2B) Do not use low-dose dopamine for renal perfusion (1A) Bellomo et al. Lancet 2000 In patients requiring vasopressors, place an arterial catheter as soon as possible.(1D) Relative vasopressin deficiency : Relative vasopressin deficiency Low doses of vasopressin may be effective in raising blood pressure in patients refractory to other vasopressors and may have other potential physiologic benefits Higher doses of vasopressin have been associated with cardiac, digital, and splanchnic ischemia and should be reserved for situations where alternative vasopressors have failed (96). Cardiac output measurement to allow maintenance of a normal or elevated flow is desirable when these pure vasopressors are instituted. 2008 surviving sepsis campaign : Grade 1D Vasopressors (2004) : Vasopressors (2004) Norepinephrine Less tachycardia Increased cardiac index No deleterious effect on cerebral perfusion pressure No effect on the hypothalamic-pituitary axis More effective and better outcome as compared with dopamine Amelioration of splanchnic hypoperfusion Increased glomerular filtration pressure Decreased serum lactate concentration Slide 49: Vasopressin and Septic Shock (2004) Versus cardiogenic shock Decreases or eliminates requirements of traditional pressors As a pure vasopressor expected to decrease cardiac output Slide 50: Vasopressors (2004) Vasopressin Not a replacement for norepinephrine or dopamine as a first-line agent Consider in refractory shock despite high-dose conventional vasopressors If used, administer at 0.01-0.04 units/minute in adults Grade E Slide 51: During Septic Shock Images used with permission from Joseph E. Parrillo, MD Inotropic Therapy (2008) : Inotropic Therapy (2008) Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output (1C) (check cardiac output) Do not increase cardiac index to predetermined supranormal levels (1B) (Yu et al. Crit Care Med, 1993) (Hayes et al. NEJM, 1994) Gattinoni et al. NEJM, 1995) Slide 53: Figure 2A, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862-871 Steroid Therapy Slide 54: Annane, Bollaert and Briegel Different doses, routes of administration and stopping/tapering rules Annane Required hypotension despite therapeutic intervention Bollaert and Briegel Required vasopressor support only Use of corticosteroid therapy in patients with sepsis and septic shock: An evidence-based review : Use of corticosteroid therapy in patients with sepsis and septic shock: An evidence-based review Keh et al. Crit Care Med 2004 Vol. 32, No. 11 (Suppl.) Corticosteroid in Septic Shock : Corticosteroid in Septic Shock High doses of corticosteroids do not improve survival and may worsen outcomes by increasing the frequency of secondary infections Low-dose (?physiologic?) steroids may be beneficial because of relative adrenal insufficiency Treat patients who still require vasopressors despite fluid replacement with hydrocortisone 200-300 mg/day, for 7 days in three or four divided doses or by continuous infusion Bone, et al. NEJM 1987; 317-658 VA Systemic Sepsis Cooperative Study Group. NEJM 1987; 317:659-665 Hydrocortisone Therapy for Patients with Septic Shock : Hydrocortisone Therapy for Patients with Septic Shock In the multicenter, randomized, double-blind, placebo-controlled trial 251 patients: 50 mg hydrocortisone iv q6h for 5 days, the dose was then tapered during a 6-day period 248 patients iv placebo 28-day mortality, 86/251 (34.3%) in the hydrocortisone group vs 78/248 (31.5%) in the placebo group (P=0.51) In the hydrocortisone group, shock was reversed more quickly than in the placebo group However, there were more episodes of superinfection, including new sepsis and septic shock. Sprung et al. NEJM 358(2): 111, 2008 Corticosteroid in ARDS : Corticosteroid in ARDS These results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death. Anonymous et al. NEJM 354(16): 1671, 2006 Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature : Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature To compare the design and results of randomized trials investigating prolonged glucocorticoid treatment (= 7 days) in patients with ALI-ARDS Trials were retrieved from the Cochrane Central Register of Controlled Trials (CENTRAL) Five selected trials ( n = 518) consistently reported significant improvement in gas exchange, reduction in markers of inflammation, and decreased duration of mechanical ventilation and intensive care unit stay (all p < 0.05) Three larger trials did not reproduce the marked reductions observed in the earlier trials (RR = 0.84; 95% CI 0.68-1.03; p = 0.09, I 2 = 9.1%), but achieved a distinct reduction in the RR of death in the larger subgroup of patients ( n = 400) treated before day 14 of ARDS [82/214 (38%) vs. 98/186 (52.5%), RR = 0.78; 95% CI 0.64-0.96; p = 0.02 A distinct survival benefit when initiated before day 14 of ARDS Meduri et al, Intensive Care Medicine, 2008 Corticosteroid (2008) : Corticosteroid (2008) Consider intravenous hydrocortisone for adult septic shock when hypotension responds poorly to adequate fluid resuscitation and vasopressors (2C) ACTH stimulation test is not recommended to identify the subset of adults with septic shock who should receive hydrocortisone (2B) Hydrocortisone is preferred to dexamethasone (2B) Corticosteroid (2008) : Corticosteroid (2008) Fludrocortisone (50 g orally once a day) may be included if an alternative to hydrocortisone is being used that lacks significant mineralocorticoid activity. Fludrocortisone if optional if hydrocortisone is used (2C) Steroid therapy may be weaned once vasopressors are no longer required (2D) Hydrocortisone dose should be 300 mg/day (1A) Do not use corticosteroids to treat sepsis in the absence of shock unless the patient’s endocrine or corticosteroid history warrants it (1D) Slide 62: Human Activated Protein CEndogenous Regulator of Coagulation Human Activated Protein C in Septic Shock : Human Activated Protein C in Septic Shock Activated protein C had anti-thrombotic, anti-inflammatory and pro-fibrinolytic properties Drotrecogin Alfa is the first anti-inflammatory agent that proved effective in the treatment of sepsis From Recombinant human activated protein c worldwide evaluation in severe sepsis (PROWESS) study group Bernard et al. NEJM, 2001 Slide 64: Results: 28-Day All-Cause Mortality Primary analysis results 2-sided p-value 0.005 Adjusted relative risk reduction 19.4% Increase in odds of survival 38.1% Adapted from Table 4, page 704, with permission from Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699-709 Slide 65: Mortality and APACHE II Quartile Adapted from Figure 2, page S90, with permission from Bernard GR. Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003; 31[Suppl.]:S85-S90 Slide 66: Mortality and Numbers of Organs Failing Adapted from Figure 4, page S91, with permission from Bernard GR. Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003; 31[Suppl.]:S85-S90 FDA labelingRecombinant human activated protein C (rhAPC) : FDA labelingRecombinant human activated protein C (rhAPC) Patients who have severe sepsis and with a high risk of death Such as with an APACHE II score of at least 25 Evidence of end-organ dysfunction Shock, acidosis, oliguria, or hypoxemia Be given within 24 hours of the first organ failure Not be given to mild-to-moderate sepsis who do not have evidence of end-organ injury Bernard et al. Crit Care Med, 2003 rhAPC (2004) : rhAPC (2004) High risk of death APACHE II ? 25 Sepsis-induced multiple organ failure Septic shock Sepsis induced ARDS No absolute contraindications Weigh relative contraindications Grade B Human Activated Protein C(2008) : Human Activated Protein C(2008) Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical assessment of high risk of death (typically APACHE II >25 or multiple organ failure) if there are no contraindications (2B, 2C for postoperative patients within 30 days). Adult patients with severe sepsis and low risk of death (typically, APACHE II < 20 or one organ failure) should not receive rhAPC (1A) Contraindications to Use of Recombinant Human Activated Protein C (rhAPC) : Contraindications to Use of Recombinant Human Activated Protein C (rhAPC) Active internal bleeding Recent (within 3 months) hemorrhagic stroke Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma Trauma with an increased risk of life threatening bleeding Presence of an epidural catheter Intracranial neoplasm or mass lesion or evidence of cerebral herniation Known hypersensitivity to rhAPC or any component of the product Slide 71: Transfusion Strategyin the Critically Ill Figure 2A, page 414, reproduced with permission from Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340:409-417 Blood Product Administration(2008) Red Blood Cells : Blood Product Administration(2008) Red Blood Cells Give red blood cells when hemoglobin decreases to 7.0 g/dL (70 g/L) to target a hemoglobin of 7.0–9.0 g/dL in adults (1B). A higher hemoglobin level may be required in special circumstances (e.g., myocardial ischaemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease, or lactic acidosis) Blood Product Administration (2008) : Blood Product Administration (2008) Do not use erythropoietin to treat sepsis-related anemia. Erythropoietin may be used for other accepted reasons (chronic renal failure). (1B) Do not use fresh frozen plasma to correct laboratory clotting abnormalities unless there is bleeding or planned invasive procedures (2D) Do not use antithrombin therapy (1B) Blood Product Administration (2008) : Blood Product Administration (2008) Administer platelets when (2D) Counts are 5000/mm3 (5x 109/L) regardless of bleeding Counts are 5000–30,000/mm3 (5–30x109/L) and there is significant bleeding risk Higher platelet counts (50,000/mm3 [50x 109/L]) are required for surgery or invasive procedures Mechanical Ventilation of Sepsis-Induced ALI/ARDS (2008) : Mechanical Ventilation of Sepsis-Induced ALI/ARDS (2008) Slide 76: % Mortality ARDSnet Mechanical Ventilation Protocol Results: Mortality Adapted from Figure 1, page 1306, with permission from The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-1378 Mechanical Ventilation ofSepsis-Induced ALI/ARDS : Mechanical Ventilation ofSepsis-Induced ALI/ARDS Target a tidal volume of 6 mL/kg (predicted) body weight in patients with ALI/ARDS (1B) Target an initial upper limit plateau pressure 30 cm H2O. Consider chest wall compliance when assessing plateau pressure (1C) If plateau pressure remain > 30 after reduction of tidal volume to 6 ml/kg PBW, tidal volume should be reduced further to as low as 4 ml/kg Slide 79: Allow PaCO2 to increase above normal, if needed, to minimize plateau pressures and tidal volumes (1C) Permissive hypercapnia Be limited in patients with preexisting metabolic acidosis and contraindicated in patients with increased initracranial pressure. Set PEEP to avoid extensive lung collapse at end-expiration (1C) Titrate PEEP based on Bedside measurement of thoracopulmonary compliance Guided by the FiO2 required to maintain adequate oxygenation PEEP > 5 cm H20 to avoid lung collapse Slide 82: The Role of Prone Positioning in ARDS 70% of prone patients improved oxygenation 70% of response within 1 hour 10-day mortality rate in quartile with lowest PaO2:FIO2 ratio (?88) Prone — 23.1% Supine – 47.2% Gattinoni L, et al. N Engl J Med 2001;345:568-73; Slutsky AS. N Engl J Med 2001;345:610-2. The Role of Prone Positioning in ARDS : The Role of Prone Positioning in ARDS Consider prone positioning in ARDS when: Potentially injurious levels of F1O2 or plateau pressure exist Not at high risk from positional changes (2C) Mechanical Ventilationof Severe Sepsis : Mechanical Ventilationof Severe Sepsis Maintain mechanically ventilated patients in a semirecumbent position (head of the bed raised to 45°) unless contraindicated (to limit aspiration risk and to prevent the development of VAP) (1B), between 30° and 45° (2C) Drakulovic et al. Lancet 1999; 354:1851-1858 Slide 85: Noninvasive mask ventilation (NIV) only be considered in that minority of ALI/ARDS patients with mild-moderate hypoxemic respiratory failure with stable hemodynamics who can be made comfortable and are easliy arousable Able to protect the airway and spontaneously clear the airway of secretions expected to recover rapidly 2B Mechanical Ventilationof Septic Patients : Mechanical Ventilationof Septic Patients Use a weaning protocol and an SBT regularly to evaluate the potential for discontinuing mechanical ventilation (1A) Ely, et al. NEJM 1996; 335:1864-1869 Esteban, et al. AJRCCM 1997; 156:459-465 Esteban, et al. AJRCCM 1999; 159:512-518 Prior to SBT, patients should : Prior to SBT, patients should a) Arousable b) Hemodynamically stable (without vasopressor agents) c) No new potentially serious conditions d) Low ventilatory and end-expiratory pressure requirements Requiring levels of FIO2 that could be safely delivered with a face mask or nasal cannula Slide 88: Mechanical Ventilation of Septic Patients SBT options Low level of pressure support (7) with continuous positive airway pressure 5 cm H2O T-piece Slide 90: Routine use of the pulmonary artery catheter for patient with ALI/ARDS is not recommanded. Potential benefits may be confounded by Differences in interpretation of results Lack of correlation of PAOP with clinical response Absence of a proven strategy to use catheter results to improve patient outcomes Grade 1A Slide 91: Conservative fluid strategy for patients with established acute lung injury who do not have evidence of tissue hypoperfusion Less weight gain, and fluid-conservative strategy based on either a CVP or a pulmonary artery catheter along with clinical variables ? led to fewer days of mechanical ventilation Only used in patients with established ALI Grade 1C Sedation and Analgesia in Sepsis (2008) : Sedation and Analgesia in Sepsis (2008) Use sedation protocols with a sedation goal for critically ill mechanically ventilated patients (1B) Ramsay score: daytime: 2-3, night time: 4-5 Use either intermittent bolus sedation or continuous infusion sedation to predetermined end points (sedation scales), with daily interruption/ lightening to produce awakening. Re-titrate if necessary (1B) Kollef, et al. Chest 1998; 114:541-548 Brook, et al. CCM 1999; 27:2609-2615 Kress, et al. NEJM 2000; 342:1471-1477 Neuromuscular Blockers : Neuromuscular Blockers Avoid neuromuscular blockers where possible Risk of prolonged neuromuscular blockade following discontinuation Monitor depth of block with train-of-four when using continuous infusions (1B) Slide 94: The Role of IntensiveInsulin Therapy in the Critically Ill At 12 months, intensive insulin therapy reduced mortality by 3.4% (P<0.04) Adapted from Figure 1B, page 1363, with permission from van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67 Glucose Control : Glucose Control After initial stabilization Glucose be maintained <150 mg/dl Continuous infusion insulin and glucose or feeding (enteral preferred) Monitoring Initially: q30-60 mins After stabilizaiton: q4h Van den Berghe et al. NEJM, 2001 Finney et al. JAMA, 2003 Krinsley. Mayo Clin Proc. 2004 Slide 96: Use intravenous insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU (1B) Aim to keep blood glucose < 150mg/dL (8.3 mmol/L) using a validated protocol for insulin dose adjustment (2C) Provide a glucose calorie source and monitor blood glucose values every 1-2 hrs (4 hrs when stable) in patients receiving intravenous insulin (1C) Interpret with caution low glucose levels obtained with point of care testing of capillary blood, as these techniques may overestimate arterial blood or plasma glucose values (1B) Renal Replacement : Renal Replacement Absence of hemodynamic instability Intermittent hemodialysis and continuous venovenous filtration equal (CVVH) Hemodynamic instability CVVH preferred --- to facilitate management of fluid balance in septic patients, no improved in regional perfusion and survival benefit Grade 2B Grade 2D 2008 update Renal Replacement : Renal Replacement Whether the dose of continuous renal replacement affects outcomes in patients with acute renal failure ? Increased the rate of ultrafiltration can improved mortality Limitation – not specifically in sepsis Two very large multicenter randomized trials will be available in 2008 --- greatly inform practive 2008 update Slide 99: Bicarbonate therapy not recommended to improve hemodynamics in patients with hypoperfusion-induced lactic acidemia pH >7.15 Will increase Na, fluid overload, increase lactate and PCO2 Grade 1B Cooper, et al. Ann Intern Med 1990; 112:492-498 Mathieu, et al. CCM 1991; 19:1352-1356 Bicarbonate Therapy Changing pH Has Limited Value : Changing pH Has Limited Value Treatment Before After NaHCO3 (2 mEq/kg) pH 7.22 7.36 PAOP 15 17 Cardiac output 6.7 7.5 0.9% NaCl pH 7.24 7.23 PAOP 14 17 Cardiac output 6.6 7.3 Cooper DJ, et al. Ann Intern Med 1990; 112:492-498 Deep Vein Thrombosis Prophylaxis : Deep Vein Thrombosis Prophylaxis Heparin (either UFH 2-3times perday or LMWH once daily) was recommended in patients with severe sepsis unless contraindications (1A) If contraindication for heparin, use mechanical prophylactic device (1A) Mechanical device (unless contraindicated) such as graduated compression stockings or intermittent compression devices Deep Vein Thrombosis Prophylaxis : Deep Vein Thrombosis Prophylaxis High risk patients (severe sepsis and history of DVT, trauma, or orthopedic surgery) Combination pharmacologic and mechanical In patient at very high risk, LMWH be used rather than UFH Grade 2C Grade 2C 2008 update Primary Stress Ulcer Risk Factors Frequently Present in Severe Sepsis : Primary Stress Ulcer Risk Factors Frequently Present in Severe Sepsis Mechanical ventilation Coagulopathy Hypotension Stress Ulcer prophylaxis : Stress Ulcer prophylaxis H2 blocker Proton pump inhibitor The benefit of prevention of upper GI bleed must be weighed against the potential effect of an increased stomach pH on development of ventilator-associated pneumonia 2008 update Grade 1A Grade 1B Intensive Care Med 2006;32:1151-1158 Selective Digestive Tract Decontamination (SDD) : Selective Digestive Tract Decontamination (SDD) SDD (enteral nonabsorbable antimicrobials and short-course intravenous antibiotics) --- reduces infections, mainly pneumonia, and mortality in general population of critically ill and trauma patients 2008 update New Issue Selective Digestive Tract Decontamination (SDD) : Selective Digestive Tract Decontamination (SDD) As the main effect of SDD is in preventing ventilator-associated pneumonia, studies comparing SDD with nonantimicrobial interventions are needed Vancomycin --- a safe and effective regimen concerns persist about the potential for emergence of resistant Gram(+) infection 2008 update New Issue Consideration forLimitation of Support : Consideration forLimitation of Support Advance care planning, including the communication of likely outcomes and realistic goals of treatment, should be discussed with patients and families. Decisions for less aggressive support or withdrawal of support may be in the patient’s best interest. Grade 1D Summary: gain in mortality in sepsis : Summary: gain in mortality in sepsis Activated protein C 31% vs 25% (-6%) Bernard et al. NEJM 2001; 344: 699-709 Early goal 47% vs 30% (-17%) River et al. NEJM 2001; 345: 1368-73 Hydrocortisone 63% vs 53% (-10%) Annane et al. JAMA 2002; 288: 862-871 Adequate antibiotics therapy 63% vs 31% (-32%) Valles J et al. Chest 2003; 123: 1615-1624 Sepsis BundlesSevere Sepsis/Septic Shock Bundles : Sepsis BundlesSevere Sepsis/Septic Shock Bundles 6 hours (Sepsis Resuscitation Bundles) 24 hours (Sepsis Management Bundles) STOP: Strategies to Timely Obviate the Progression of Sepsis H. Bryant Nguyen, MD, MS For the STOP Sepsis Working Group Loma Linda University Medical Center, Loma Linda, California MUST: Multiple Urgent Sepsis Therapies BEST: Better and Early Sepsis Treatment MOST: Multiple Organ Success Therapy Sepsis Resuscitation Bundle : Sepsis Resuscitation Bundle Serum lactate measured Blood cultures obtained prior to antibiotic administration From the time of presentation, broad-spectrum antibiotics administered within 3 hours for ED admissions and 1 hour for non-ED ICU admissions Sepsis Resuscitation Bundle : Sepsis Resuscitation Bundle In the event of hypotension and/or lactate >4 mmol/L (36 mg/dl): Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent*) Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) ?65 mm Hg *See the individual chart measurement tool for an equivalency chart. Perfusion and Pressure : Perfusion and Pressure Sepsis Resuscitation Bundle : Sepsis Resuscitation Bundle In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L (36 mg/dl): Achieve central venous pressure (CVP) of 8 mm Hg Achieve central venous oxygen saturation (ScvO2) of ? 70%** **Achieving a mixed venous oxygen saturation (SvO2) of 65% is an acceptable alternative. Sepsis Management Bundle : Sepsis Management Bundle Low-dose steroids* administered for septic shock in accordance with a standardized ICU policy Drotrecogin alfa (activated) administered in accordance with a standardized ICU policy *See the individual chart measurement tool for an equivalency chart. Sepsis Management Bundle : Sepsis Management Bundle Glucose control maintained ? lower limit of normal, but < 150 mg/dl (8.3 mmol/L) Inspiratory plateau pressures maintained < 30 cm H2O for mechanically ventilated patients. 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 : 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 7-3 RuleAnalg Anesth 1979; 38: 124-132 : 7-3 RuleAnalg Anesth 1979; 38: 124-132 Initial PCWP <10?200ml x 10 min 10-15?100ml >15?50ml Response in PCWP >7?Stop 3-7?wait 10min <3?Continue PAC-Guided Treatment Protocol : PAC-Guided Treatment Protocol Adapted from Pinsky & Vincent. Crit care Med 33: 1119-22, 2005 Pathways and Mediators of Sepsis, Potential Treatments, and Results of Randomized, Controlled Trials (RCTs) : Pathways and Mediators of Sepsis, Potential Treatments, and Results of Randomized, Controlled Trials (RCTs) Russell, NEJM 355(16): 1699, 2006 Pathways and Mediators of Sepsis, Potential Treatments, and Results of Randomized, Controlled Trials (RCTs) : Pathways and Mediators of Sepsis, Potential Treatments, and Results of Randomized, Controlled Trials (RCTs) Thanks for your attention : Thanks for your attention You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.