Sepsis

Sepsis. Communicable Diseases report- Internal Medicine

1. DEFINITION OF TERMS • BACTEREMIA : bacteria in blood, evidence with (+) blood culture • SEPTICEMIA : presence of microbes or their toxins in blood • SIRS - ANY Two or more of the following: 1. Temperature 1.1.Fever → oral T >38ʼC 1.2.Hypothermia <36ʼ 2. Respiratory Rate 2.1.Tachypnea > 24cpm 3 . Tachycardia >90bpm 4. WBC 4.1.Leukocytosis >12,000/ uL 4.2.Leukopenia <4,000/ uL 4.3. >10%band cells 4.4. May have non-infectious etiology • SEPSIS : SIRS + proven microbial etiology Harrison’ s Internal Medicine 18 th edition 1 SEPSIS GROUP 1 Camacho, Hans Robert C. Francisco, Rimmon Pineda, Francis Ivan G. Yang, Sheryl Ray B. Zagada , Timothy M. SEPSIS

2. Sepsis • SEPSIS + severe distant organ dysfunction = SEVERE SEPSIS • SEVERE SEPSIS + Hypoperfusion /Hypotension = SEPTIC SHOCK • Sepsis often reversible • Septic shock usually succumb SEPTIC SHOCK >1hr not respond to fluid resuscitation or pressor administration = REFRACTORY SEPTIC SHOCK Dysfunction of more than one organ, requiring Intervention to maintain Homeostasis = MODS - according to National Institute of Health define as an illness in which the body has a severe response to microbial infections. Harrison’ s Internal Medicine 18 th edition 2

3. Severe sepsis can be a response to any class of microorganism Microbial invasion in the blood stream – not ESSENTIAL , since local inflammation can also illicit organ dysfunction and hypotension. ETIOLOGY Harrison’ s Internal Medicine 18 th edition 3

4. Blood cultures are positive : 20–40 % of Severe sepsis cases 40–70 % of septic shock cases Of cases with positive blood cultures, 40 % - gram-positive bacteria , 35 % t - gram-negative bacteria , 11 % - Polymicrobial 7 % - fungi <5% - classic pathogens (-) blood culture patients : the etiologic agent is often established by culture or microscopic examination of infected material from a local site ETIOLOGY Harrison’ s Internal Medicine 18 th edition 4

5. The septic response is a contributing factor in >200,000 deaths per year in the United States . The incidence of severe sepsis and septic shock has increased over the past 20 years T he annual number of cases is now >700,000 (~3 per 1000 population). Epidemiology of sepsis: an update. (2001) National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov/pubmed/11445744 EPIDEMIOLOGY 5

6. EPIDEMIOLOGY 6

7. EPIDEMIOLOGY 7

8. Patients hospitalized for septicemia or sepsis were more severely ill than patients hospitalized for another diagnosis . Patients hospitalized for septicemia or sepsis stayed longer than other inpatients . Patients hospitalized for septicemia or sepsis were more than eight times as likely to die during their hospitalization. 8

9. 11th National Convention on Statistics (NCS ), 2010 NEWBORN DEATHS IN THE PHILIPPINES Aurora T. Reolalas* and Ma. Goretti M. Novilla Chief, Vital Statistics Division National Statistics Office 9

10. Neonatal Sepsis in the Philippines Gram-negative organisms comprised the majority of the neonatal infections, with Pseudomonas and Burkholderia being the most prevalent. PIDSP Journal 2011 Vol 12 No.2 ETIOLOGY OF NEONATAL SEPSIS IN FIVE URBAN HOSPITALS IN THE PHILIPPINES Copyright ® 2011 10

11. LBP Bacteria LPS Phagocyte CD 14 Toxin Recognition by the Host 11

12. LBP Bacteria LPS Phagocyte CD 14 LPS MD-2 TLR-4 TLR4 – transmembrane protein, transmits the LPS recognition signal to the interior of the cell, where signal transduction and gene transcription pathways promote the production and/or secretion of numerous molecules that mediate the inflammatory response LPS MD-2 Extracellular protein which binds the lipid A moiety of LPS Toxin Recognition by the Host Signaling complex Mandell Principles of Infectious Disease 12

13. Inflammatory Mediators TNF alpha Potent mediator of the subsequent inflammatory response Stimulates muscle breakdown and cachexia, mediates coagulation activation, enhances expression of adhesion molecules, prostaglandin E2 & PAF IL-1 Released in response to inflammation Endogenous pyrogen IL-6 Increasingly expressed during stress as in septic shock. Promote intravascular coagulation Other Interleukins, Cytokines and Chemokines  increased capillary permeability and blood flow, infiltration of neutrophils, and pain. Schwartz Principles of Surgery Mandell Principles of Infectious Disease 13

14. Microbial killing The major inherited mechanisms for killing microbes in the blood are soluble molecules: the mannose-binding lectin & C -reactive protein (CRP) pathways for activating complement the alternative complement pathway antibacterial proteins (such as bactericidal permeability -increasing protein [BPI] ) natural IgM antibodies. Increased capillary permeability allows these molecules to diffuse into tissues where there is local inflammation. Mandell Principles of Infectious Disease 14

15. Control Mechanisms Local Control Mechanisms Intracellular factors (e.g., suppressor of cytokine signaling 3 and IL-1 receptor associated kinase 3) Molecules derived from essential polyunsaturated fatty acids ( lipoxins , resolvins , and protectins ) Enzymatic inactivation of microbial signal molecules (e.g., LPS )   Systemic Control Mechanisms LPS -binding protein Glucocorticoids Epinephrine   Prostaglandin E2   IL -10, and C-reactive protein     IL -1 receptor antagonist.   soluble TNF receptors protease inhibitors or antioxidants;   Hepcidin     Harrison’s Principle of IM 15

16. 16

17. CLINICAL MANIFESTATION Patients usually manifests symptoms and signs related to primary infection . Manifestations of Systemic Inflammatory Response Evidence of shock (-) fever : most common in neonates, elderly patients and in persons with uremia or alcoholism Harrison’ s Internal Medicine 18 th edition 17

18. Hyperventilation Encephalopathy Hypotension DIC , acrocyanosis , ischemic necros is of peripheral tissues (e.g., digits ) • Skin : hemorrhagic lesions, bullae, cellulitis . Skin lesions may suggest specific pathogens—e.g ., petechiae and purpura with Neisseria meningitidis , ecthyma gangrenosum with Pseudomonas aeruginosa . • Gastrointestinal • Hypoxemia CLINICAL MANIFESTATION Harrison’ s Internal Medicine 18 th edition 18

19. 1. Cardiopulmonary Complications Acute respiratory distress syndrome Hypotension Decrease Myocardial function II. Renal Complications Oliguira Azotemia Proteinuria Nonspecific casts MAJOR COMPLICATIONS 19

20. III. Coagulopathy • Thrombocytopenia in 10-30% • Platelet usually very low <50,000/ uL in px with DIC IV. Neurological Complications • DDX: Guillain-Barre syndrome , metabolic disturbance , toxin activity MAJOR COMPLICATIONS Harrison’ s Internal Medicine 18 th edition 20

21. LEUKOCYTOSIS with a left shift Thrombocytopenia Hyperbilirubinemia Proteinuria Neutrophils - may contain toxic granulations, D o hle bodies or cytoplasmic vacuoles Early sepsis: hyperventilation  respiratory alkalosis Respiratory muscle fatigue & accum . of lactate  metabolic acidosis ABG : hypoxemia (initially correctable with supplemental oxygen) LABORATORY FINDINGS Harrison’ s Internal Medicine 18 th edition 21

22. CXR : normal or may show evidence of underlying pneumonia, volume overload, or the diffuse infiltrates of ARDS ECG : sinus tachycardia & nonspecific ST-T wave abnormalities Diabetic patients : develops hyperglycemia Severe infection diabetic ketoacidosis (may exacerbate hypotension) Serum albumin - initially within normal range, declines as sepsis continues LABORATORY FINDINGS Harrison’ s Internal Medicine 18 th edition 22

23. NO specific diagnostic test Diagnostically sensitive findings: Fever or hypothermia Tachypnea Tachycardia Leukocytosis or leukopenia Acutely altered mental status Thrombocytopenia Elevated blood lactate level hypotension DIAGNOSIS 23

24. 36% normal temperature 40% normal respiratory rate 10% normal pulse rate 33% normal WBC count Systemic responses of uninfected patients with other conditions are similar to those characteristic of sepsis DIAGNOSIS Harrison’ s Internal Medicine 18 th edition 24

25. Definitive etiologic diagnosis requires isolation of the microorganism from blood or a local site of infection Culture: At least 2 blood samples (10mL each) should be obtained (from different venipuncture sites) Gram (-) bacteremia typically low grade (10 organism/mL of blood), prolonged incubation may be necessary S. aureus grows more rapidly – detectable in blood within 48 hours Harrison’ s Internal Medicine 18 th edition 25

26. Antimicrobial Agents Given after blood and other relevant sites have been cultured. major determinant of outcome: interval between hypotension and the administration antimicrobial chemotherapy a delay of 1 h is associated with lower survival rates. Harrison’ s Internal Medicine 18 th edition Treatment: 27

27. A Single antimicrobial agent for treatment of known pathogens is adequate. Combination antimicrobial therapy is NOT superior to monotherapy in treating Gram(-) bacteremia. EXCEPT in P.aeruginosa bacteremia where aminoglycoside monotherapy is less effective than combination of an aminoglycoside with an antipseudomonal -lactam agent. antimicrobial therapy-at least 1 week; Factors in duration of treatment: site of infection adequacy of surgical drainage, underlying diseases susceptibility of the bacterial isolate(s ) to antimicrobials. Harrison’ s Internal Medicine 18 th edition Antimicrobial Agents 28

28. Factors in duration of treatment: site of infection adequacy of surgical drainage, underlying diseases susceptibility of the bacterial isolate(s) to antimicrobials. Harrison’ s Internal Medicine 18 th edition Antimicrobial Agents 29

29. Clinical Condition Antimicrobial Regimens (Intravenous Therapy) Immunocompetent adult The many acceptable regimens include (1) ceftriaxone (2 g q24h) or  ticarcillin-clavulanate (3.1 g q4–6h) or  piperacillin-tazobactam (3.375 g q4–6h); (2) imipenem-cilastatin (0.5 g q6h) or  meropenem (1 g q8h) or  cefepime (2 g q12h). Gentamicin  or  tobramycin (5–7 mg/kg q24h) may be added to either regimen. If the patient is allergic to -lactam agents, use ciprofloxacin (400 mg q12h) or  levofloxacin (500–750 mg q12h) plus  clindamycin (600 mg q8h). If the institution or the community has a high prevalence of MRSA isolates, add vancomycin (15 mg/kg q12h) to each of the above regimens. Neutropenia a (<500 neutrophils/L)   Regimens include (1) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h) or  cefepime (2 g q8h); (2) ticarcillin-clavulanate (3.1 g q4h) or  piperacillin-tazobactam (3.375 g q4h) plus  tobramycin (5–7 mg/kg q24h). Vancomycin (15 mg/kg q12h) should be added if the patient has an infected vascular catheter, if staphylococci are suspected, if the patient has received quinolone prophylaxis, if the patient has received intensive chemotherapy that produces mucosal damage, if the institution has a high incidence of MRSA infections, or if there is a high prevalence of MRSA isolates in the community. Splenectomy Cefotaxime (2 g q6–8h) or  ceftriaxone (2 g q12h) should be used. If the local prevalence of cephalosporin-resistant pneumococci is high, add  vancomycin. If the patient is allergic to -lactam drugs, vancomycin (15 mg/kg q12h) plus  ciprofloxacin (400 mg q12h) or  levofloxacin (750 mg q12h) or  aztreonam (2 g q8h) should be used. IV drug user Nafcillin or oxacillin (2 g q8h) plus  gentamicin (5–7 mg/kg q24h). If the local prevalence of MRSA is high or if the patient is allergic to -lactam drugs, vancomycin (15 mg/kg q12h) with gentamicin should be used. AIDS Cefepime (2 g q8h), ticarcillin-clavulanate (3.1 g q4h), or  piperacillin-tazobactam (3.375 g q4h) plus  tobramycin (5–7 mg/kg q24h) should be used. If the patient is allergic to -lactam drugs, ciprofloxacin (400 mg q12h) or  levofloxacin (750 mg q12h) plus  vancomycin (15 mg/kg q12h) plus  tobramycin should be used. Initial Antimicrobial Therapy for Severe Sepsis with No Obvious Source in Adults with Normal Renal Function Harrison’ s Internal Medicine 18 th edition 30

30. Removal of the Source of Infection Indwelling IV cathethers should be removed and the tip should be rolled over an agar plate for culture. After antibiotic therapy, a new catheter should be replaced at a different site and Foley and drainage catherters should be replaced Consider paranasal sinusitis in patients who have undergone nasal intubation. In patients with abnormal CXR, a CT of the chest may identify parenchymal,mediastinal or pleural diseases. In neutropenic patients, sites of tenderness and erythema must be carefully sought. In sacral or ischial decubitus ulcers, exclude pelvic of soft tissue pus collections wit CT/MRI In severe sepsis from the urinary tract, rule out urethereal obstruction, pernephric abcess and renall abcess by sonography or CT. Harrison’ s Internal Medicine 18 th edition Treatment: 31

31. Hemodynamic, Respiratory, and Metabolic Support Primary goals restore adequate oxygen and substrate delivery to the tissues. improve tissue oxygen utilization and cellular metabolism . Initial management of hypotension Administration of IV fluids (1-2L of NSS over 1-2 h) Circulatory adequacy can be assessed by: clinical parameters (mentation, urine output, skin perfusion) measurements of oxygen delivery and consumption. Harrison’ s Internal Medicine 18 th edition Treatment: 32

32. "early goal-directed therapy" (EGDT) resuscitation based on maintenance of the SvO 2 at >70% was associated with significantly improved survival of patients The treatment algorithm rapid administration of fluids , antibiotics , and vasopressor support; erythrocyte transfusion (to maintain the hematocrit above 30 % ); and Dobutamine is administered if fluids, erythrocytes, and pressors did not result in an SvO 2 of >70%. Harrison’ s Internal Medicine 18 th edition Hemodynamic, Respiratory, and Metabolic Support 33

33. Vasopressin potent vasoconstrictor Useful in vasodilatory shock and relative resistance to other pressor hormones. Ventilator therapy For progressive hypoxemia, hypercapnia, neurologic deterioration, or respiratory muscle failure. Bicarbonates administered if severe metabolic acidosis <7.2ph FFP and platelet transfusion in DIC if complicated by major bleeding. In hypercatabolic patients and Acute renal failure, hemodialysis or hemofiltration is beneficial. Harrison’ s Internal Medicine 18 th edition 34

34. General Support Nutritional supplementation may reduce the impact of protein hypercatabolism in patients with prolonged sepsis. Prophylactic heparinization to prevent deep venous thrombosis for patients without active bleeding or coagulopathy. Maintenance of blood glucose improved survival rates among patients who have undergone major surgery and received IV glucose. Hypoglycemia was much more common in the intensive-insulin group. Harrison’ s Internal Medicine 18 th edition Treatment: 35

35. Other Measures Endotoxin-neutralizing proteins, inhibitors of COX or nitric oxide synthase, anticoagulants, polyclonal immunoglobulins, glucocorticoids, and antagonists to TNF-, IL-1, PAF, and bradykinin. Harrison’ s Internal Medicine 18 th edition Treatment: 36

36. Recombinant activated protein C (aPC) Treatment of patients with severe sepsis or septic shock. The FDA approved aPC for use in adults (>18 years of age) who meet the APACHE II criterion and have a low risk of hemorrhage-related side effects. aPC is administered as a constant IV infusion of 24 g/kg per hour for 96 h. Harrison’ s Internal Medicine 18 th edition 37

37. should not be given to patients platelet counts of <30,000/L dysfunction of one organ system and surgery within 30 days. Treatment with aPC should not be started >24 h after the onset of severe sepsis, nor should it be used in the patient subsets—e.g., patients with pancreatitis or AIDS—that were excluded from the clinical trial. Harrison’ s Internal Medicine 18 th edition 38

38. " bundling " of multiple therapeutic maneuvers as the standard of care for severe sepsis. The proposed resuscitation (6-h) bundle incorporates most of the elements discussed above for acute (EGDT) resuscitation. The management (24-h) bundle includes three measures of uncertain or marginal benefit: tight control of blood glucose, administration of low-dose hydrocortisone, and treatment with aPC. Harrison’ s Internal Medicine 18 th edition 39

39. Harrison’ s Internal Medicine 18 th edition Prevention Limit the use of indwelling vascular and bladder catheters Reduce the incidence and duration of profound neutropenia (<500 neutrophils/L ) Aggressively treating localized nosocomial infections Indiscriminate use of antimicrobial agents and glucocorticoids should be avoided, and optimal infection-control measures should be used 40