1. Dr. M. A. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin Septic shock

2. What is shock? Shock is a state of acute disruption of circulatory function, resulting in insufficiency of tissue utilization and cellular energy production. “Sepsis is a clinical syndrome characterized by systemic inflammation due to infection. There is a continuum of severity ranging from sepsis to severe sepsis and septic shock” Septic shock refers to sepsis with cardiovascular dysfunction (i.e., hypotension, reliance on administration of vasoactive drug to maintain a normal blood pressure, or two of the following: “prolonged capillary refill, oliguria, metabolic acidosis, or elevated arterial lactate) that persists despite the administration of ≥40 mL/kg of isotonic fluid in one hour.”

3.  Systemic Inflammatory Response Syndrome (SIRS)  Temp > 38 or < 36  HR > 90  RR > 20 or PaCO2 < 32  WBC > 12 or 10%  Sepsis  The systemic inflammatory response to infection.  Severe Sepsis  Organ dysfunction secondary to Sepsis.  e.g. hypoperfusion, hypotension, acute lung injury, encephalopathy, acute kidney injury, coagulopathy.  Septic Shock  Hypotension secondary to Sepsis that is resistant to adequate fluid administration and associated with hypoperfusion. Two out of four criteria acute change from baseline Terminology

5. The incidence of sepsis syndrome is between 51 – 95 cases per 100,000 in several countries Over 1,665,000 cases of sepsis occur in the United States each year, with a mortality rate up to 50 percent. Even with optimal treatment, mortality due to severe sepsis or septic shock is approximately 40 percent and can exceed 50 percent in the sickest patients Comparable global Epidemiology

6. SIRS  SIRS – systemic inflammatory response syndrome  Must have at least 2 of the following:  Temperature >38.5ºC or <36ºC  Heart rate >90 beats/min  Respiratory rate >20 breaths/min or PaCO2 <32 mmHg  WBC >12,000 cells/mm3, 10 % immature (band) forms  SIRS is the body’s response to infection, inflammation, stress.

7. Sepsis and Severe Sepsis Sepsis – SIRS + suspected or confirmed infection (documented via cultures or visualized via physical exam/imaging) Severe Sepsis – Sepsis + at least one sign of organ hypo-perfusion or dysfunction Areas of mottled skinDisseminated intravascular coagulation Capillary refill > 3 secsAKI UOP < 0.5cc/kg /hrARDS or acute lung injury (ALI) Lactate > 2mmol /LCardiac dysfunction on echo Altered mental statusPlt < 100 Abnormal EEGTroponin Leak

8. Septic Shock Septic Shock - Severe sepsis plus one of the following conditions:  MAP <60 mm Hg (<80 mm Hg if previous hypertension) after adequate fluid resuscitation  Need for vasopressors to maintain BP after fluid resuscitation  Adequate fluid resuscitation = 40 to 60 mL/kg saline solution (NS 5L-10L)  Lactate > 4mmol /L

9. Detrimental host responses to infection occupy a continuum that ranges from sepsis to severe sepsis to septic shock and multiple organ dysfunction syndrome (MODS). The specific clinical features depend on where the patient falls on that continuum. Signs and symptoms of sepsis are often nonspecific and include the following: Fever, chills, or rigors Confusion Anxiety Difficulty breathing Fatigue, malaise Nausea and vomiting Alternatively, typical symptoms of systemic inflammation may be absent in severe sepsis, especially in elderly individuals. Septic shock: Signs and symptoms

10. Identify any potential source of infection. Localizing signs and symptoms referable to organ systems include: Head and neck infections – Severe headache, neck stiffness, altered mental status Chest and pulmonary infections – Cough (especially if productive), pleuritic chest pain, dyspnea, dullness on percussion, bronchial breath sounds, localized rales, any evidence of consolidation Cardiac infections – Any new murmur, especially in patients with a history of injection or IV drug use GIT infections – Diarrhea, abdominal pain, abdominal distention, guarding or rebound tenderness, rectal tenderness or swelling Pelvic and GU infections – Pelvic or flank pain, adnexal tenderness or masses, vaginal or urethral discharge, dysuria, frequency, urgency Bone and soft-tissue infections – Localized limb pain or tenderness, focal erythema, edema, swollen joint, crepitus in necrotizing infections, joint effusions Skin infections – Petechiae, purpura, erythema, ulceration, bullous formation, fluctuance Septic shock: Signs and symptoms

11. Organ dysfunction at time of severe sepsis recognition

12. Where is infection?

13. Noninfectious mimics of sepsis Acute myocardial infarction Overzealous diuresis Acute pulmonary embolusTransfusion reactions Acute pancreatitisAdverse drug reactions Fat emboli syndrome Procedure-related transient bacteremia Acute adrenal insufficiency Amniotic fluid embolism Acute gastrointestinal hemorrhage

14. Unbalanced Immune Reaction Tissue Factor Procoagulant State Microvascular Thrombosis Mediators of Inflammation ROS Vasodilation CapillaryLeak An incompletely understood pathogenesis: hallmarks are microvascular thrombosis, vasodilation, free radical damage, Capillary Leak Sepsis Pathogenesis

15.  Shock is as inadequate circulating blood volume producing decreased peripheral vascular perfusion and cellular metabolic derangements.  Microcirculatory hypo- perfusion is the common all types of shock.  Caused by an immunologic reaction characterized by a hyperdynamic state, which produces increased cardiac output and decreased peripheral resistance  This reaction is secondary to endotoxin-antibody complement complexing and leukocyte lysis that results in the production of histamine, serotonin, super-radicals, lysosomal enzymes, and kinins.  These substances induce a marked capillary permeability and a third space loss, leading to hypovolemia.  This is the hypodynamic state of septic shock, which is characterized by decreased cardiac output and increased peripheral resistance. Pathophysiology septic shock:

17. Shock is identified by hypotension & inadequate organ perfusion, which may be caused by either low cardiac output or low systemic vascular resistance. Circulatory shock can be subdivided into 4 distinct classes : Hypovolemic shock results from the loss of blood volume caused by GI bleeding, extravasation of plasma, major surgery, trauma Obstructive shock from an intrinsic or extrinsic obstruction of circulation. PE embolism and pericardial tamponade. Distributive shock is caused by excessive vasodilation and impaired distribution of blood flow. Patients have hyperdynamic shock with high cardiac output, hypotension. Cardiogenic shock is caused by primary myocardial dysfunction. The patients have cool clammy extremities, Shock Classification, Terminology, and Staging

18. Clinical Manifestations. Staging of Septic Shock: I.Compensated / Pre-shock / Hyperdynamic II. Decompensated / Organ hypoperfusion III. End organ failure / Irreversible

19. Clinical Manifestations. Recognition of Septic Shock: Early compensated, hyperdynamiic state Clinical signs – Warm extremities – Bounding pulses – Tachycardia Warm shock – tachypnoea – confusion – flushed skin – Decreased systemic vascular resistance

20. Clinical Manifestations. Hypotension – Cold and clammy skin – Mottling – Tachycardia – CyanosisCold shock – Narrow pulse pressure – Hypoxemia – Acidosis.

21. Investigations Sepsis work up:  CBC, ABG, Lactate  PCT, CRP  Metabolic panel/Electrolytes  Coagulation profile  Urine, Sputum, Blood, Stools, Throat swab cultures  Viral cultures  Gastric aspirate/ET aspirate  CIE/Latex agglutination Imaging: CXR, CT, MRI, PET Scan, Echo. Ultrasound

22.  Start adequate antibiotic therapy (proper dosage and spectrum) as early as possible  Resuscitate the patient, using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation (hypoperfusion)  Identify the source of infection, and treat with antimicrobial therapy, surgery, or both (source control)  Maintain adequate organ system function, guided by cardiovascular monitoring, and interrupt the progression to multiple organ dysfunction syndrome(MODS) Goals and principles of treatment

23. Management principles for septic shock include: Early recognition Early and adequate antibiotic therapy Source control Early hemodynamic resuscitation and continued support Proper ventilator management with low tidal volume in patients with acute respiratory distress syndrome (ARDS) Pharmacotherapy The medications used in the management of septic shock: Alpha-/beta-adrenergic agonists (eg, dopamine, dobutamine, epinephrine) Isotonic crystalloids Volume expanders Antibiotics (eg, cefotaxime, piperacillin-tazobactam, ceftriaxone, ciprofloxacin, levofloxacin, vancomycin) Corticosteroids (eg, hydrocortisone, dexamethasone) Goals and principles of treatment

24. Two means of death: 1.Shock. 2.Multi organ failure. Aims of treatment: 1.Assure perfusion of critical vascular beds. ( cerebral, coronary, renal) 2.Rx underlying cause. Prevent / correct hypoxemia: Supplement oxygen 95-100%. 3.IV access: peripheral vein. 4.If IV access fails: Interosseous line. 5.Fluid resuscitation: 20mL/Kg NS or RL as bolus, repeat up to 60 mL/Kg. End point : Improved perfusion. Management.

25. Central Line Access (Fluid hydration +/- pressor) 1 st line therapy – fluids, fluids, fluids! Crystalloid equivalent to colloid Initial 1-2 Liters (20mg /kg) crystalloid or 500 ml colloid Careful in CHF patients !! Establish a 2nd IV line for Dopamine infusion (Draw blood for culture) Administer IV antibiotics  Ampicillin + gentamicin or  Ampicillin+ Ceftriaxone/Cefataxime  Ceftriaxone or Cefotaxime alone or  Ampicillin + Chloramphenicol Management Steps

26. Correct metabolic derangement:  Metabolic acidosis.  Hyperglycemia  hypoglycemia (always correct hypoglycemia) DIC:Restoration of normovolemia: Reverses abnormal activation. ‘Component replacement’ (Goal - Normal PT, PTT, fibrinogen, PC = 40,000 to 100000 /cu mm.) a. FFP - most beneficial in early stages. b. Cryo- consider 1 unit/3 units of FFP transfused. c. Platelet concentrate Management Steps

27. Recognize and manage organ failure: Cardiovascular support: Rate & rhythm- correct 02, acidosis, Ca, Mg, K variations Stroke volume - fluid correction & replace losses Inotrope support. Respiratory support: Supplement 02, Early intubation and PPV (PEEP) Gastrointestinal: Antacids, sucralfate, early enteral nutrition Renal: Volume replacement Low dose dopamine ?diuretic with volume expansion Indications for dialysis:  Hyperkalemia  Refractory metabolic acidosis  Anuria despite diuresis  BUN>100mg% Management Steps

28. Antibiotics Cultures / Antibiotics / Labs  Cultures PRIOR to Antibiotics ( 2 Sets, one peripheral and one from any line older than 48hrs)  IV Abx within 3 hrs in the ED, within 1 hr in the ICU  Broad Spectrum, combination therapy for neutropenic and patients with pseudomonas risk factors  Vancomycin PLUS Zosyn (Piperacillin and tazobactam) Consider need for Source Control !  Drainage of abscess or cholangitis, removal of infected catheters, debridement or amputation of osteomyelitis

29. AgentTypical intravenous dose range Dopamine6 – 25 µg/Kg/min Epinephrine1 – 10 µg/min Norepinephrine1 – 30 µg/min Phenylpherine40 – 180 µg/min Vasopressin0.01 – 0.04 units/min Vasopressor agents used in septic shock

30. Use in Septic Shock, if NO response to vasopressors and fluids – HYDROCORTISONE 200mg -300mg / day Divided doses (Q6hrs) Initial Dose 100mg IV x1 Consider for patients who received etomidate No need for cosyntropin stimulation test Wean Steroids QUICKLY once off vasopressors Corticosteroids

31. Organ systemParameter Respiratory systemPaO2/FiO2 ratio Renal system Urine output and serum creatinine Hematologic systemPlatelet count Central nervous systemGlasgow coma score Hepatobiliary system Serum bilirubin and liver enzymes Cardiovascular systemBlood pressure, arterial lactate Gastrointestinal system Gastric intramucosal pH (pHi), ileus, blood in nasogastric aspirate Parameters for monitoring organ system function in patients with sepsis

32. Therapeutic priorities include securing the airway, correcting hypoxemia, and administering fluids and antibiotics. Intubation and mechanical ventilation are required in some patients  Common signs of hypoperfusion include warm, vasodilated skin in early sepsis that progresses to cool, vaso-constricted skin in late sepsis, tachycardia >90 per min, obtundation or restlessness, oliguria or anuria, and lactic acidosis.  For initial fluid replacement use a crystalloid solution rather than albumin-containing solution SUMMARY AND RECOMMENDATIONS

33.  Those who remain hypotensive following intravascular volume repletion, use vasopressors  Prompt identification and treatment of the site of infection are essential.  Sputum and urine should be collected for Gram stain and culture. Intra-abdominal fluid collections should be percutaneously sampled.  Blood should be taken from 2 distinct venipuncture sites and from indwelling vascular access devices and cultured aerobically and anaerobically. SUMMARY AND RECOMMENDATIONS

34. SUMMARY AND RECOMMENDATION  Antibiotics should be administered within six hours of presentation, preferably after appropriate cultures have been obtained.  Empiric broad spectrum antibiotics when a definite source of infection can not be identified  Glucocorticoid therapy, nutritional support, glucose control, and investigational therapies are additional considerations in the management of patients with severe sepsis or septic shock

35. Management- summary. Five important points 1. ABC, supplement 02 always. 2. IV or IO access and fluid resuscitation up to 60 mL/Kg. 3. Early dopamine infusion @10µg/Kg/min 4. Empirical antibiotic. 5. Frequent monitoring.