Sepsis Severe Sepsis Septic Shock Meral SNMEZOLU Assoc

Sepsis, Severe Sepsis & Septic Shock Meral SÖNMEZOĞLU, Assoc Prof Yeditepe University Hospital Infectious Diseases Department 1

Overview • Differentiation between Septic Shock in relation to other conditions in current code, Sepsis, and Severe Sepsis • Disease Epidemiology, Incidence and Mortality • Inadequacy of Current Diagnostic Codes • Proposed Modifications and Clarification • Discussion 2

Systemic Inflammatory Response • At least 2 of 4 ( abnormal temp or leukocytes count is a must) —Core temp >38. 5 or <36 —Tachycardia: HR >2 sd above Normal for age or bradycardia <10% for age —Tachypnea: RR >2 sd for age or mechanical ventilation for acute process —Leukocyte elevated or depressed for age or >10% immature neutrophils 3

Definitions • Infection: Suspected or proven caused by any pathogen Or clinical syndrome associated with high probability of infection • Sepsis: SIRS in the presence of or as a result of suspected of proven infection 4

Definitions • Severe Sepsis: sepsis + one —Cardiovascular dysfunction —ARDS —OR 2 or more other organ dysfunctions • Septic shock —Sepsis and cardiovascular organ dysfunction 5

Sepsis: Defining a Disease Continuum Infection/ Trauma SIRS A clinical response arising from a nonspecific insult, including 2 of the following: • • Temperature 38 o. C or 36 o. C HR 90 beats/min Respirations 20/min WBC count 12, 000/mm 3 or 4, 000/mm 3 or >10% immature neutrophils Sepsis Severe Sepsis 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: S 81 6

Sepsis: Defining a Disease Continuum Infection/ Trauma SIRS Sepsis Severe 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 Engl J Med 1999; 340: 207 7

Relationship Of Infection, SIRS, Sepsis Severe Sepsis and Septic Shock SEPSIS PANCREATITIS SEVERE SEPSIS INFECTION SEPTIC SHOCK SIRS BURNS TRAUMA OTHER 8 Bone et al. Chest 1992; 101: 1644

Inflamatory Cascade Chemotaxis Gramnegative Bacteria/ Endotoxin Complement System Neutrophils Superoxide Radicals Lysosomal Enzymes Neutrophil Accumulation Capillary Leak Adhesion Molecules Monocytic Cells Cytokines TNF-a, IL-1, IL-6, IL-8, etc. Lipid Mediators Nitric Oxide Endothelial Cells Fever Metabolic Changes Hormonal Changes* Hypotension, ARDS, DIC, Multiple Organ Failure, Death Vasodilation Clotting Abnormalities Bradykinin Tissue Factor * = inhibited by r. BPI in vivo or in vitro = not investigated Coagulation System 9

SEPSIS MEDIATORS Russell J. N Engl J Med 2006; 355: 1699 -1713 10

Mortality Increases in Septic Shock Patients Incidence Mortality Sepsis 400, 000 7 -17% Severe Sepsis 300, 000 Approximately 200, 000 Septic patients including 70, 000 Shock Medicare patients have septic shock annually Balk, R. A. Crit Care Clin 2000; 337: 52 20 -53% 53 -63% 11

Septic Shock is Unique within 785. 59 785. 5 Unspecified Shock 7% 10, 100 785. 59 Other Shock 62% 785. 59 Details Population Mortality Length Of Stay 45, 200 88, 600 785. 51 Cardiogenic Shock 31% Cost With infection * 70, 900 51% 17. 1 $30, 300 Without infection 17, 700 52% 8. 9 $17, 400 * Represents Septic Shock Patients ICD-9 -CM code 785. 5 X Population Septic Shock patients have a longer length of stay and a higher cost than other patients within 785. 59 12

Severe Sepsis: A Significant Healthcare Challenge 1 Major cause of morbidity and mortality worldwide Leading cause of death in noncoronary ICU (US)* 11 th leading cause of death overall (US) †§ 2 3 About 1, 000 cases of severe sepsis in US annually‡ In the US, about 600 -1000 patients die of severe sepsis daily *Sands KE et al. JAMA. 1997; 278: 234 -40; †Based on data for septicemia. §Murphy SL. National Vital Statistics *Sands KE et al. JAMA. 1997; 278: 234 -40; Reports. ‡Angus DC et al. Crit Care Med. 2001 (In Press); reflects hospital-wide cases of severe sepsis as defined by infection in www. themegallery. com the presence of organ failure.

Sepsis Epidemiology: Effect of the Aging Population www. themegallery. com

Severe Sepsis: Comparison With Other Major Diseases Mortality of Severe Sepsis Deaths/Year Cases/100, 000 Incidence of Severe Sepsis AIDS* Colon Breast Cancer§ CHF† Severe Sepsis‡ AIDS* Breast Cancer§ AMI† Severe Sepsis‡ †National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med. 2001 www. themegallery. com

Proportion of Patients with Sepsis Who Died Mortality of Sepsis over Time 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 www. themegallery. com

Economics of Sepsis • Severe Sepsis Ø $22, 000 per case Ø US annual cost $16. 7 Billion • Nosocomial Sepsis Ø increased LOS - ICU 8 days, Hosp 24 days Ø $40, 890 per case Angus CCM, 2001 Pittet JAMA, 1994 www. themegallery. com

Time Sensitive Interventions AMI “Door to PCI” Focus on the timely return of blood flow to the affected areas of the heart. (percutanous coronary intervention) Stroke Trauma “Time is Brain” The sooner that treatment begins, the better are one’s chances of survival without disability. “The Golden Hour” Requires immediate response and medical care “on the scene. ” Patients typically transferred to a qualified trauma center for care. www. themegallery. com

Trauma vs. Sepsis Patient Care Where we spend our efforts www. themegallery. com

Severe Sepsis vs. Current Care Priorities U. S. Incidence # of Deaths Mortality Rate AMI (1) 900, 000 225, 000 25% Stroke (2) 700, 000 163, 500 23% Trauma (3) 2. 9 million (Motor Vehicle) (injuries) 42, 643 1. 5% Severe Sepsis (4) 751, 000 215, 000 29% Source: (1) Ryan TJ, et al. ACC/AHA Guidelines for management of patients with AMI. JACC. 1996; 28: 1328 -1428. (2) American Heart Association. Heart Disease and Stroke Statistics – 2005 Update. Available at: www. americanheart. org. (3) National Highway Traffic Safety Administration. Traffic Safety Facts 2003: A Compilation of Motor Vehicle Crash Data from the Fatality Analysis Reporting System and the General Estimates System. Available at http: //www. nhtsa. dot. gov/. (4) Angus DC et al. Crit Care Med 2001; 29(7): 1303 -1310. www. themegallery. com

The Surviving Sepsis Campaign 25% Reduction In Sepsis Mortality within next 5 yrs v = ~ 50, 000 people in the United States each year. v = ~ 1, 100, 000 individuals worldwide each year. Angus DC, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Critical Care Medicine. Jul 2001; 29(7): 1303 -1310. www. themegallery. com

Cardiovascular Dysfunction • Despite administration of isotonic intravenous fluid • bolus ≥ 40 m. L/kg in 1 hr — Hypotension: BP <5 th % or <2 sd OR — Need for vasoactive drug to maintain BP (dopamine >5 mcg/kg/min or dob, epi, or norepi at any dose) OR — Two of the following § § § Unexplained metabolic acidosis: Base deficit >5. 0 m. Eq/L Arterial lactate: >2 times upper limit of normal Oliguria: Urine output <0. 5 m. L/kg/hr Capillary refill: >5 secs Core to peripheral temperature gap >3°C 22

Respiratory Dysfunction • Pa. O 2 /Fio 2 <300 in absence of cyanotic heart • disease or preexisting lung disease OR • Pa. Co 2 >65 or 20 mm Hg over baseline Paco 2 OR • Need or >50% Fio 2 to maintain saturation ≥ 92% OR • Need for non-elective invasive or non-invasive • mechanical ventilation 23

Neurologic Dysfunction • Glasgow Coma Score ≤ 11 OR • Acute change in mental status with a decrease in Glasgow Coma Score ≥ 3 points from abnormal baseline 24

Hematologic Dysfunction • Platelet count <80, 000/mm or a decline of 50% in platelet count from highest value recorded over the past 3 days • INR >2 25

Renal Dysfunction • Serum creatinine ≥ 2 times upper limit of • normal for age or • 2 -fold increase in baseline creatinine 26

Hepatic Dysfunction • Total bilirubin ≥ 4 mg/d. L (not applicable for • newborn) OR • ALT 2 times upper limit of normal for age 27

Mortality and SIRS 28

Mortality

Mortality

Conclusion • Septic shock has distinct characteristics that support the creation of a unique code (785. 52) • Septic shock should be linked to severe sepsis • Modification of current SIRS coding will better represent the clinical presentation of the sepsis syndrome — 995. 51, sepsis — Modification to “code also” list in 995. 92 31

Deficiencies of 1991 Consensus Conference • Limitations inherent in these definitions: —Incomplete agreement as to what defines “Systemic Response" § Inflammation only? —Organ/System failures not defined § Except hypotension (SBP <90 mm. Hg or >40 mm. Hg decline from baseline; need for vasopressor support) "Dear SIRS, I do not like you" Jean Louis Vincent

2001 Sepsis Definitions Conference • Current definitions will remain unchanged • However, will accept the uncertainty of definitions • SIRS expanded to signs and symptoms — Chills — Alteration in temperature — Tachypnea — Change in mental status — Tachycardia — Altered WBC, Bandemia — Thrombocytopenia — Decreased perfusion: mottling, poor capillary refill — Increased blood sugar — Petichiae/Purpura 33

2001 Sepsis Definitions Conference • PIRO staging system proposed —Predisposition: Genetics, Chronic illness —Insult: Infection, Injury, Ischemia —Response: Physiologic, Mediators, Markers —Organ Dysfunction: Outcome, Organ dysfunction To be published 2002 (Verbal communication Mitchell Levy, SCCM 2002) 34

Inflammatory Responses to Sepsis Russell J. N Engl J Med 2006; 355: 1699 -1713 35

Procoagulant Response in Sepsis Russell J. N Engl J Med 2006; 355: 1699 -1713 36

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Treatment

Severe Sepsis/Septic Shock Goals CVP 8 – 12 mm. Hg MAP 65 mm. Hg SBP > 90 mm. Hg Sa. O 2 93% Sc. VO 2 > 70%

Sepsis Resuscitation Emergency Department and Intensive Care Unit

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 — within 1 hour for non-ED ICU admissions • In the event of hypotension and/or lactate > 4 mmol/L (36 mg/dl): — Deliver an initial minimum of 20 -30 ml/kg of crystalloid (or colloid equivalent) — Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP > 65 mm. Hg • 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 (Scv. O 2) of > 70% Information taken from Institute for Healthcare Improvement, Sepsis Module: http: //www. ihi. org/IHI/Topics/Critical. Care/Sepsis/

SOP

Bundle Completion and Outcome A 2 -year Implementation Experience Total Patients = 330 patients from Oct 2003 – Sept 2005 Bundle Not Completed = 253; Bundle Completed = 77 Mortality (p=0. 003) Hospital LOS (p=0. 22) Nguyen, Ann Emerg Med, 2005 - ACEP Annual Meeting; and Crit Care Med, 2005 - Critical Care Congress www. themegallery. com

Serum Lactate • Hyperlactatemia is typically present in patients with severe sepsis or septic shock and may be secondary to anaerobic metabolism due to hypoperfusion. • The prognostic value of raised blood lactate levels has been well established in septic shock patients, particularly if the high levels persist (that’s why we trend them). • Obtaining serum lactate is essential to identifying tissue hypoperfusion in patients who are not yet hypotensive but who are at risk for septic shock. Information taken from Institute for Healthcare Improvement, Sepsis Module: http: //www. ihi. org/IHI/Topics/Critical. Care/Sepsis/

Blood cultures • The incidence of sepsis and bacteremia in critically ill patients has been increasing in the past two decades. — 30 - 50% of patients presenting with a clinical syndrome of severe sepsis or shock have positive blood cultures. — Therefore, blood should be obtained for culture in any critically ill septic patient. • Collecting blood cultures prior to antibiotic administration offers the best hope of identifying the organism that caused severe sepsis in an individual patient. — Failure to check blood cultures prior to antibiotic infusion will perhaps affect the growth of any blood borne bacteria and prevent a culture from becoming positive later. Information taken from Institute for Healthcare Improvement, Sepsis Module: http: //www. ihi. org/IHI/Topics/Critical. Care/Sepsis/

Broad Spectrum Antibiotics • The balance of evidence unwaveringly suggests that early administration of appropriate antibiotics reduces mortality in patients with Gram-positive and Gram-negative bacteremias. — Some of the evidence supporting early administration is based upon the assumption that patients who fail to receive appropriate antibiotics essentially represent a set of patients for whom delay has occurred in antibiotic delivery. — Several studies have confirmed the mortality benefit associated with appropriate antimicrobials in patients with severe infections due to Gramnegative and Gram-positive bacteria. — All patients should receive a full loading dose of each antimicrobial. § However, patients with sepsis or septic shock often have abnormal renal or hepatic function and may have abnormal volumes of distribution due to aggressive fluid resuscitation. The ICU pharmacist should be consulted to ensure that serum concentrations are attained that maximize efficacy and minimize toxicity Information taken from Institute for Healthcare Improvement, Sepsis Module: http: //www. ihi. org/IHI/Topics/Critical. Care/Sepsis/

Antibiotics and Mortality p = 0. 006 p = 0. 01 • In addition, the major sources of infection in severe sepsis or shock are pneumonia and intraabdominal infections and other sources generally account for < 5 percent of cases. — The prevalence of pneumonia as a cause of sepsis lends support to the case for treating severe sepsis with early antibiotic administration. — In a recent study of ventilator acquired pneumonia, patients with significant organ dysfunction who received antibiotics later had far greater ICU mortality: 37 percent vs. 7 percent, P=0. 006; hospital mortality: 44 percent vs. 15 percent, P=0. 01. Information taken from Institute for Healthcare Improvement, Sepsis Module: http: //www. ihi. org/IHI/Topics/Critical. Care/Sepsis/

Fluid Resuscitation • The Severe Sepsis Resuscitation Bundle calls for an initial administration of 20 – 30 ml/kg of crystalloid as a fluid challenge in cases of suspected hypovolemia or actual cases of serum lactate greater than 4 mmol/L (36 g/dl). — A colloid equivalent is an acceptable alternative to crystalloid, and an equivalent dose generally ranges from 0. 2 g/kg to 0. 3 g/kg depending upon the colloid. • Fluid resuscitation should be commenced as early as possible in the course of septic shock (even before intensive care unit admission). Requirements for fluid infusion are not easily determined so that repeated fluid challenges should be performed. • The bundle does not restrict the amount and extent of an initial fluid challenge, but rather defines a minimum challenge. Subsequent actions in the bundle are undertaken only for hypotension not responding to fluid challenge or for an elevated lactate level as above. Information taken from Institute for Healthcare Improvement, Sepsis Module: http: //www. ihi. org/IHI/Topics/Critical. Care/Sepsis/

Vasopressor Support • Adequate fluid resuscitation is a prerequisite for the successful and appropriate use of vasopressors in patients with septic shock. — In general, the end points of fluid resuscitation are the same as those for the use of pharmacologic hemodynamic support, i. e. MAP > 65 mm. Hg. Sometimes, fluid resuscitation alone may suffice. — When an appropriate fluid challenge fails to restore an adequate arterial pressure and organ perfusion, therapy with vasopressor agents should be started. Vasopressor therapy may also be required transiently to sustain life and maintain perfusion in the face of life-threatening hypotension, even when hypovolemia has not been resolved or when a fluid challenge is in progress • Either norepinephrine or dopamine (through a central catheter as soon as placement is possible) is the first-choice vasopressor agent to correct hypotension in septic shock. Information taken from Institute for Healthcare Improvement, Sepsis Module: http: //www. ihi. org/IHI/Topics/Critical. Care/Sepsis/

Maintaining Hemodynamics • Goal-directed therapy represents an attempt to predefine resuscitation end-points to help clinicians at the bedside to resuscitate patients in septic shock. — The end-points used vary according to the clinical study but attempt to adjust cardiac preload, contractility, and afterload to balance systemic oxygen delivery with demand. • Two essential features of early goal directed therapy include: — maintaining an adequate central venous pressure (CVP) to carryout other hemodynamic adjustments — maximizing mixed or central venous oxygen saturation (Sc. VO 2) • Special patients: — In mechanically ventilated patients, a higher target central venous pressure of 12– 15 mm. Hg is recommended to account for the presence of positive end expiratory pressure and increases in intrathoracic pressure. — Similar consideration to the above may be warranted in circumstances of increased abdominal pressure. Information taken from Institute for Healthcare Improvement, Sepsis Module: http: //www. ihi. org/IHI/Topics/Critical. Care/Sepsis/

Sepsis Management Intensive Care Unit

Early Goal-directed therapy in the treatment of severe sepsis and septic shock Rivers et al; NEJM 2001; 345: 1368

Early Recognition of Adult Patients with Severe Sepsis/Septic Shock Two or more of the following: NO Re. Assess Suspected Infection YES 1) Temp >38. 3 C(100. 9 F) or <36. 0 C(96. 8 F) 2) Heart Rate >90 3) Resp Rate >20 or Pa. CO 2 <32 mm. Hg 4) WBC >12 K, <4 K or >10% Bands NO Re. Assess YES Obtain Appropriate Cultures SBP < 90 after Bolus NO YES Septic Shock Check Lactate > 4 mmol/L or NO Multi-Organ Dysfunction YES Severe Sepsis High Risk Lactate > 2 mmol/L NO or Organ Dysfunction Sepsis Antibiotics & IVF Re-Assess YES Severe Sepsis Low Risk Antibiotics & IVF Re-check Lactate Early Intervention to Resolve Organ Hypoperfusion www. themegallery. com

Sepsis Management Bundle • Low-dose steroids administered for septic shock • Glucose control maintained: 80 - 150 mg/dl • Inspiratory plateau pressures maintained < 30 cm H 2 O for mechanically ventilated patients • Drotrecogin alfa (Xigris) administered in accordance with a standardized ICU policy Information taken from Institute for Healthcare Improvement, Sepsis Module:

Corticosteroid use • Intravenous corticosteroids are recommended in patients with septic shock who despite adequate fluid replacement require vasopressor therapy to maintain adequate blood pressure. —Hydrocortisone 200– 300 mg/day in three or four divided doses for 7 days § § § Hydrocortisone 50 mg IV q 6 h Hydrocortisone 100 mg IV q 8 h Doses > 300 mg per day are associated with increased mortality Information taken from Institute for Healthcare Improvement, Sepsis Module:

Glucose control • Following initial stabilization of patients with severe sepsis, blood glucose should be maintained 80 – 150 mg/d. L. — Studies supporting the role of glycemic control have used continuous infusion of insulin and glucose. — With this protocol, glucose should be monitored frequently after initiation of the protocol (every 60 minutes) and on a regular basis (every 4 hours) once the blood glucose concentration has stabilized. • Hyperglycemia, caused by insulin resistance in the liver and muscle, is a common finding in intensive care unit (ICU) patients. — It can be considered an adaptive response, providing glucose for the brain, red cells, and wound healing, and is generally only treated when blood glucose increases to > 215 mg/d. L (>12 mmol/L). — Conventional wisdom in the ICU has been that hyperglycemia is beneficial and that hypoglycemia is dangerous and should be avoided. This concept has been challenged recently, and controlling blood glucose levels by intensive insulin therapy decreased mortality and morbidity in surgical critically ill patients. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Plateau Pressures • Patients with sepsis are at increased risk for developing acute respiratory failure, and most patients with severe sepsis and septic shock will require endotracheal intubation and mechanical ventilation. — Nearly 50% of patients with severe sepsis will develop acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). • High tidal volumes that are coupled with high plateau pressures should be avoided in ALI/ARDS. — Clinicians should use as a starting point a reduction in tidal volumes over 1 to 2 hours to a “low” tidal volume (6 m. L/kg lean body weight) as a goal in conjunction with the goal of maintaining end-inspiratory plateau pressures of < 30 cm H 2 O. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Drotrecogin alfa • Drotrecogin Alfa (Activated), a. k. a. recombinant activated protein C (rh. APC), is recommended in patients at high risk of death (APACHE II of > 25, sepsisinduced multiple organ failure, septic shock, or sepsis-induced acute respiratory distress syndrome) and no absolute contraindication related to bleeding risk or relative contraindication that outweighs the potential benefit of rh. APC. • The inflammatory response in severe sepsis is integrally linked to pro-coagulant activity and endothelial activation. The inflammatory response in sepsis is procoagulant in the early stages. In a large, multicenter, randomized, controlled trial, the PROWESS trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) rh. APC, an endogenous anticoagulant with antiinflammatory properties, has been shown to improve survival in patients with sepsis-induced organ dysfunction. • At present, risk assessment is best determined by bedside clinical evaluation and judgment. The use of a standardized policy in intensive care units for the administration of rh. APC is essential to avoid capricious and unscientific decision-making about applying rh. APC. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Therapies

Vasopressors • Norepinephrine and Dopamine —First line therapy —Central line preferred • Vasopressin —Give at doses of 0. 04 units/minute in addition to norepinephrine or dopamine —Not titrated • Phenylephrine/Epinephrine —Not used as first line due to risk of ischemia —In septic patients, it is added in shock refractory to norepinephrine or dopamine

Dobutamine • When it’s used: after fluid resuscitation, it is considered (in conjunction with hematocrit evaluation) to increase Sc. VO 2 > 70%. • How it works: Dobutamine directly stimulates ß 1 receptors of the heart to increase myocardial contractility and stroke volume, resulting in increased cardiac output. • Dosing: — Increase by 2 mcg/kg/minute with each Sc. VO 2 reading that is < 70% • Monitoring: — Monitor for hypotension, arrhythmia

Blood products • When it’s used: if the Sc. VO 2 remains < 70% despite adequate fluid resuscitation, consider transfusion to a hematocrit of 30%. • How it works: Increases blood carrying capacity to the tissues. • Dosing: — Patient specific (however, 1 unit of PRBCs should increase the hematocrit by ~3%) • Monitoring: — Per routine

Fluids • Crystalloids: —Another name for IV fluids —Isotonic crystalloid solutions should be used for resuscitation § NSS or LR § § § Use caution with LR in patients with renal disease or electrolyte abnormalities (contains Na, K, Ca, Cl, and lactate) Lactate content has not been shown to affect serum lacate levels NOT: D 5 W, D 5 W/½NSS, etc. • Colloids: —Solutions like albumin and blood § Also, hespan/hextend

Initial Resussitation • Begin as soon as the sepsis syndrome is recognized 66

Initial Fluid Resuscitation • Central venous pressure: 8– 12 mm Hg • Mean arterial pressure ≥ 65 mm Hg (adult) • Urine output ≥ 0. 5 m. L·kg− 1 ·hr− 1 • Central venous (superior vena cava) or mixed venous oxygen saturation ≥ 70% Grade B 67

Initial Fluid Resuscitation • s. VO 2 >70% is not achieved with CVP 8– 12 mm Hg, then transfuse PRBC to achieve a hematocrit of 30% and/or • Dobutamine infusion (up to a maximum of 20 mcg/kg/min) Grade B 68

Diagnosis • Appropriate cultures should always be obtained before antimicrobial therapy is initiated • at least 2 B/C should be obtained at least one drawn percutaneously and one drawn through each vascular access device. • Cultures of other sites such as urine, CSF, wounds, respiratory secretions, or other body fluids should be obtained before antibiotic therapy 69

Antibiotic Therapy • Started within the first hour of recognition of severe sepsis after cultures (Grade E) • One or more drugs with activity against the likely pathogens • Penetrate into the presumed source of sepsis • Guided by the susceptibility patterns of mo. s in the community and in the hospital (Grade D) • Reassess after 48– 72 hrs, aim for narrow spectrum antibiotic • Duration 7– 10 days and guided by clinical response. (Grade E) 70

Novel Therapies • Steroids JAMA. 2002 Aug 21; 288(7): 862 -71 § § § Many (>50%) septic patients have relative adrenocortical insufficiency. Physiological hydrocortisone improves mortality in this group (63% → 53%, p=0. 02 in this study, n=229) Antiinflammatory 71

Novel Therapies • Activated Protein C (Drotrecogin α) N Engl J Med. 2001 Mar 8; 344(10): 699 -709 § § § Antithrombotic, antiinflammatory, profibrinolytic 1690 patients, Mortality 30. 8% → 24. 7% p<0. 01 Increased bleeding 2% → 3. 5% p=0. 06 § § § Caution in meningococcal sepsis / trauma / ICH / pregnant! $17181 / patient Consensus in NZ is restricted last resort use in selected ICU patients 72

Novel Therapies • Tight glucose control with insulin N Engl J Med. 2001 Nov 8; 345(19): 1359 -67. § § Mortality reduction 8→ 4. 6% (p<0. 04) all icu patients Biggest reductions in severe sepsis / long stayers Also reduced bacteraemic episodes / icu neuropathy Aim 4. 4 -6. 1 mmol/L 73

Novel Therapies • r. Bacteriocidal/Permeability-increasing protein — In neutrophil granules — Binds to and inactivates endotoxin Lancet. 2000 Sep 16; 356(9234): 961 -7. § § 393 Children with clinical meningococcaemia Mortality 9. 9% → 7. 4% p=0. 48 Amputations 7. 4% → 3. 6%, p=0. 067 Better functional outcome 66. 3% → 77. 3% p=0. 019 74

Novel Therapies • NAC Crit. Care. Med. 2003 31 (11) 2574 -78 —Nuclear factor-κB controls expression inflammatory mediators —NAC inhibits NFKB in vitro —Pilot trial § § 20 patients, randomised 72 hrs NAC or placebo IL-8 suppressed (may be implicated in lung injury) Recommend larger human trials 75

Summary • • • Sepsis may be obvious or subtle early There is a high mortality and morbidity Have a high index of suspicion Know local organisms / susceptibilities Take appropriate cultures Treat early and aggressively Investigate early and aggressively Refer early and aggressively Be aware of new developments 76

TUS 2012 77

TUS 2012 78

TUS 2012 79

TUS 2012 80

TUS 2012 81

TUS 2012 • Tanısı radyolojik olarak da doğrulanmış bir nekrotizan pankreatit olgusunda vücut sıcaklığı 39°C, kalp atım hızı: 104/dak ve beyaz küre sayısı: 5000/mm 3 bulunuyor. Peripankreatik sıvıdan alınan örnekte iltihap olduğu ve oligüri geliştiği görülüyor. • Arteryal kan basıncı sıvı resusitasyonuna cevap veren bu hastada en olası tanı aşağıdakilerden hangisidir? • • • A) Sistemik inflamatuvar yanıt sendromu B) Bakteriyemi C) Sepsis D) Ciddi sepsis E) Septik şok 82

TUS 2012 • Tanısı radyolojik olarak da doğrulanmış bir nekrotizan pankreatit olgusunda vücut sıcaklığı 39°C, kalp atım hızı: 104/dak ve beyaz küre sayısı: 5000/mm 3 bulunuyor. Peripankreatik sıvıdan alınan örnekte iltihap olduğu ve oligüri geliştiği görülüyor. • Arteryal kan basıncı sıvı resusitasyonuna cevap veren bu hastada en olası tanı aşağıdakilerden hangisidir? • • • A) Sistemik inflamatuvar yanıt sendromu B) Bakteriyemi C) Sepsis D) Ciddi sepsis E) Septik şok 83