Gram Negative Sepsis

gram negative sepsis dr shabeel pn www.hi-dentfinishingschool.blogspot.com

Objectives
Understand the current nomenclature
Know the local organisms
Understand the spectrum of presenting illness
Get a handle on the basic treatment
Introduce novel treatments

The Increasing Importance of the Intensive Care Unit 356 358 360 362 364 366 368 370 372 374 1988 1989 1990 1991 1992 1993 1994 1995 Mean no of hospital beds 36 38 40 42 44 46 48 50 Mean no of ICU beds Clin Infect Dis 1997;24:211-215 Seminars in Respiratory and critical care med 2003,24(1):3-22, Though ICUs account for only 8% of hospital beds, 45% of infections in a hospital originate in an ICU

Distribution of major sites of infection in medical ICU’s 5% 5% 6% 30% 30% 16% 3% 3% CVS GI LRI PN UTI BSI SST EENT Ref. : Seminars in Respiratory and critical care med 24(1):3-22,2003

Nosocomial troika ……..
S.aureus
E.coli
Pseudomonas aeruginosa
extended
K.Pneumoniae
Enterobacteriaceae
Citrobacter fruendii

Eight most common pathogens associated with nosocomial infection in an ICU, NNIS January 1989 - July 1998 Clinics in Chest Medicine 1999; Vol 20: No: 2,JAC 2003; 51, Suppl S2, 115-117 13.7 12.6 1.6 16.8 10.7 11.4 S. aureus 3.5 3.5 6.1 6.5 2.9 4.7 Klebsiella Pneumoniae 4.3 4.8 15.3 4.0 4.9 6.6 Candida Albicans 4.0 8.1 18.2 4.4 2.9 7.0 E. coli 6.8 8.8 5.7 10.7 4.2 7.3 Citrobacter spp. 5.9 14.5 13.8 1.9 10.3 8.1 Enterococci spp. 8.7 9.2 10.6 16.1 3.0 9.9 P. aeruginosa 15.4 13.5 3.1 2.5 39.3 14.3 Coagulase negative staphylococci Others n=52,066 SSI n=22,043 UTI n=47,502 PNEU n=64,056 BSI n=50,091 All sites n=235,758

High Risk Patients
For Sepsis
Post op / post procedure / post trauma
Post splenectomy (encapsulated organisms)
Cancer
Transplant / immune supressed
Alcoholic / Malnourished
For Dying
Genetic predisposition (e.g. meningococcus)
Delayed appropriate antibiotics
Yeasts and Enterococcus
Site
For Both
Cultural or religious impediment to treatment

Sepsis: Defining a Disease Continuum
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
SIRS = Systemic Inflammatory Response Syndrome SIRS with a presumed or confirmed infectious process Sepsis SIRS Infection/ Trauma Severe Sepsis Chest 1992;101:1644, Crit Care Med 2000;28:S81

Sepsis: Defining a Disease Continuum 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
Metabolic acidosis
Shock

Definitions
Sepsis = SIRS + Infection
SIRS = 2/4 of
Temp >38 or <36
HR >90
Respiratory Rate >20 or P a CO 2 <32 (4.3kPa)
WCC >12 or <4 or >10% bands
Infection = either
Bacteraemia (or viraemia/fungaemia/protozoan)
Septic focus (abscess / cavity / tissue mass)

Definitions Cont.
Severe sepsis = Sepsis + Organ Dysfunction
Organ Dysfunction = Any of
SBP <90 or 40 <usual or inotrope to get MAP 90
BE <-5mmol/L
Lactate >2mmol/L
Oliguria <30ml/hr for 1 hour
Creatinine >0.16mmol/L
Toxic confusional state
FIO 2 >0.4 and PEEP >5 for oxygenation

Definitions Cont.
Septic Shock = Severe sepsis + Hypotension
Hypotension = either
SBP <90 or 40<usual
Inotrope to get MAP >90

Sepsis the systemic response to infection Pathophysiology : a continuum A disorder due to uncontrolled inflammation or due to failure of the immune system? Clinical presentation of sepsis A disorder due to uncontrolled inflammation ? Or due to failure of the immune system? LIR Local infection SIRS SEPSIS SIRS altered organ perfusion SEVERE SEPSIS Lung failure Cardio vascular failure ARDS SEPTIC SHOCK Renal failure Liver failure CNS failure Heme failure MOFS D E A T H D E A T H bacteria fungi, viruses parasites focus When microorganisms invade, multiply in a sterile site Site of infection TUMOR NODES METASTASES D E A T H Death Characteristics of the particular pathogen GENETIC POLYMORPHISMS

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

Dear SIRS I don’t like you...

Definitions Cont.

Differential Diagnosis
Pancreatitis
Ischeamic Gut
Hypovolaemic shock
GI bleed / AAA rupture / ectopic / dehydration
Cardiogenic shock
AMI / Myocarditis / Tamponade
PE
Toxic Shock Syndromes
Staph Aureus
Group A Strep
Addisonian crisis (note relative adrenocorticoid insufficiency in many septic patients)
Thyroid Storm
Toxidromes
Anticholinergic / serotoninergic

Investigations
Basic
WBC
Platelets
Coags
Renal function
Glucose
Albumin
LFT
ABG
Specific ?Source
Urine
CxR
Blood Cultures x 2
LP
Aspirate
Biopsy
May all be normal early on!

Clinical progression and laboratory results
Patient’s fever persists to hospital Day 7 and he develops new pulmonary infiltrates
Blood pressure remains stable
Peripheral WBC count increases to 18.2 x 10 9 /L (18 200/µL) with 50% mature polymorphonuclear leukocytes and 30% bands

measured severity OUTCOME Physiologic Reserve genetic environmental factors that contribute to Stressor Event Disease process Massive hemorrhage Trauma Burns Major operations Infections Proactive Adjunctive Reactive Supportive THERAPY Errors Complications Comorbid disease and immunosuppression-chronological vs biological age-population health: * socio economic factors cultural influences environmental influences diet, exercise, employment alcohol, smoking Inappropriate statistical methods, poor selection of patients Assessment of specific therapy: antibiotics, timely surgery, thrombolytics, insulin Assessment of supportive management: hemodynamics, ventilation, dialysis Variability in supportive management Cardiovascular reserve Immune state Inflammatory response Nutrition Potential links between Cardiovascular reserve and Inflammatory response OUTCOME Which? Inappropriate use of mortality End point for both supportive and specific therapy RISK OF CRITICAL ILLNESS FAILURE TO SHOW CONVINCINGLY COMPARABILITY BETWEEN PATIENTS CRITICAL CARE STUDIES: REDEFINING THE RULES
Cell injury
Dysoxia
diagnosis

Key learning points
It is important to select appropriate antibiotics
Administer antibiotics at the right dose for the appropriate duration
Cultures should be obtained to confirm the microbiological diagnosis — nosocomial pathogens not previously encountered may cause infections

THE EARLIEST , THE BETTER

Candida endophtalmitis Urinary tract infection Candiduria with leukocyturia >10 5 mL Pancreas pancreatitis liver Candida in the blood Peritoneal infection Candida in peritoneal cavity +drainage cultures HIGH RISK PATIENT >3 risk factors and symptoms 2 or more Candida positive foci spleen Tipical Ct scan findings Prophylaxis therapy Signs and symptoms of infection and organ dysfunction Certain infection Suspected infection Definite therapy Early pre-emptive/empiric therapy Cultures of Pleural fluid Pericardial fluid, BAL, Tracheal aspirate >10 4 BAL >10 3 PBS abnormal chest radiograph

“ MORE IS MISSED BY NOT LOOKING THAN BY NOT KNOWING” Anonymous Patient examination in the Intensive Care Unit

THE INITIAL EXAMINATION
THE PHYSICAL EXAMINATION
Neurological
Airway
Breathing
Cardiovascular system
Gastrointestinal system
Renal system and fluids
Limbs
A airway
B breathing
C circulation
D disability – GCS and focal neurology
E electrolytes – results
F fluids – are they appropriate?
G gut- examine (IAP) and nutritional assessment
H ematology
I infection – microbiology and WC count, procalcitonin , CRP
L lines – are the sites clean ? How long have they been in ?
M medications- review and interactions
R relatives – what is the common message ?
S skin
Guidelines for daily recording of patient’s clinical status

MOST COMMON SIGNS OF SEPSIS
Fever (sometimes hypothermia), chills
Increased serum concentration of C reactive protein (CRP) and procalcitonin (PCT), altered white blood cell count, increased interleukin 6 (IL-6), IL-8……
Increased heart rate, increased cardiac output, low systemic vascular resistance, increased oxygen consumption, low oxygen extraction ratio (OER)
Tachypnea, low PaO 2 /FiO 2
Altered skin perfusion, reduced urine output
alterations in coagulation parameters, increases D-dimers, low protein C , low antithrombin, increased prothrombin time/activated partial thromboplastin time
Increased insulin requirements
unexplained alterations in mental status
Increased urea and creatinine, low platelet count or other coagulation abnormalities, hyperbilirubinemia
Vincent JL: “Sepsis definitions” Lancet Infect Dis 2002, 2:135

Cytokines Kinetics

Dispersal of biofilm with ventilation Pooled secretions in airway Endotracheal tube cuff Subglottic secretions Endotracheal tube biofilm Wean/semirecumbent/condensate removal/avoid gastric overdistension Avoid sedation/Infection control Oral care/oral intubation BIPAP/HME Kinetic rx CASS increasing costs and resource utilization decreasing evidence or acceptance
Kinetic rx= kinetic therapy
CASS= Coninuous aspiration subglottic space

Treatment
Specific
Antibiotics
Empiric based on source
Know local pathogens
Use the RMO guidelines / pharmacy handbook for best guess treatment
Ideal to get cultures 1 st but do not delay antibiotics
Surgery
Get the pus out! All of it!
Early definitive care will improve survival

Treatment
Supportive
Oxygenate / Ventilate (6ml/kg)
Volume
Will need more than ‘maintenance’ + replace losses with like fluid
Colloid v Chrystalloid (SAFE trial awaited – know the results!)
Inotropes
Noradrenalin is inotrope of choice, dopamine next
Early ICU referral

Treatment
Supportive
Electrolyte homeostasis
THAM for pH <7.2 1-2mL / kg over 20min
Address co-morbidities
ß-Blocker & reduced inotropy
DM / COAD
Alcoholism / malnutrition / steroids
Stop nephrotoxins (NSAIDs)
Early ICU referral

ANTIBIOTICS IN SEPSIS 1
Retrospective studies have shown that early administration of appropriate antibiotics reduces the mortality in patients with bloodstream infections caused by Gram-negative bacteria
Antifungal therapy is recommended for patients with candidemia. Whether early treatment is associated with better outcome is unknown, and additional studies are needed to evaluate this question

ANTIBIOTICS IN SEPSIS 2 Monotherapy with carbapenem antibiotics = β-lactam and an aminoglycoside (Netspan) Extended spectrum carboxypenicillins or ureidopenicillins combined with beta lactamase inhibitors (Tazact) have been shown to be effective for the treatment of suspected infections in febrile , neutropenic cancer patients and in patients with peritonitis or nosocomial pneumonia. Monotherapy with aztreonam appears to be as effective as combination of a beta lactam and an aminoglycoside (Netspan) for the treatment of patients with documented Gram negative sepsis

TREATMENT OPTIONS FOR INFECTIONS DUE TO EXTENDED –SPECTRUM β-LACTAMASE (ESBL) PRODUCING ORGANISMS ? Cefepime (in very high dose) MEROPENEM Post-neurosurgical meningitis Quinolone CARBAPENEM Intra-abdominal infection Quinolone CARBAPENEM (imipenem or meropenem) Bacteremia Quinolone CARBAPENEM / betalactam-beta-lactamase inhibitor combination (TAZACT ) Ventilator-associated pneumonia Amoxycillin/clavulanate QUINOLONE Urinary tract infection SECOND CHOICE FIRST CHOICE

Possible empiric antibiotic choice in severe sepsis Nosocomial severe sepsis and septic shock without a clear site of infection: Beta lactam + vancomycin + aminoglycoside or quinolone Ureidopenicillin + aminoglycoside or Ceftazidime monotherapy Neutropenic Ureidopenicillin + aminoglycoside Biliary tract Cefotaxime + metronidazole or Ureidopenicillin + aminoglycoside or Carbapenem (monotherapy), quinolone Intra-abdominal Benzyl-penicillin + nafcillin (flucloxacillin) Cefotaxime + nafcillin or Cefotaxime + vancomycin Skin and soft tissue Community acquired Hospital acquired Quinolone Amoxicillin + clavulanic acid (co-amoxiclav) Ceftazidime alone or Ureidopenicillin + aminoglycoside Urinary trait Community acquired Hospital acquired Cefotaxime + erythromicin Cefotaxime/ceftazidime alone or Ureidopenicillin + aminoglycoside Carbapenem , quinolone Pneumonia Community acquired Hospital acquired VAP antibiotic Suspected site of infection

CONCENTRATION DEPENDENT vs INDEPENDENT BEHAVIOR OF ANTIBIOTICS
CONCENTRATION DEPENDENT (TIME INDEPENDENT)
The rate and extent of bacterial kill and the PAE all increase as the antibiotic concentration increase
A) aminoglycosides
B) fluoroquinolones
C) metronidazole
CONCENTRATION INDEPENDENT (TIME DEPENDENT)
Once a threshold concentration of these antibiotics is achieved , further increases in antibiotic concentration do not result in an appreciably increased rate or extent of bacterial kill or an extension of the PAE
A) β-lactam antibiotics
B) vancomycin
C) Monobactam (aztreonam) ?
D) Carbapenem (imipenem) ?

Site of infection Extracellular fluid cells Cellular compartment Intracellular penetration Environmental factors
Oxygen tension
Ion concentration
pH
Y Y Y Y Y Y Immune function CENTRAL COMPARTMENT (plasma) I.V. P.O. Altered absorption I.M. Tissue perfusion Drug distribution Protein binding hypermetabolic elimination hypometabolic elimination
Bacterial pathogen
Inoculum
Growth phase
Glycocalyx
Intra/extracellular
In vivo host, pathogen and antibiotic factors that may influence the antimicrobial effect at the site of infection

Biofilm , Antimicrobial Resistance and Infections Stimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes The ability of catecholamine inotropic drugs to stimulate bacterial proliferation and biofilm formation may be an aetiological factor in the development of intravascular catheter colonisation and catheter related infection. The removal of iron from trasferrin for subsequent use by S. epidermidis is a possible mechanism by which catecholamine inotropes stimulate bacterial growth as biofilms Lancet 2003; 361:130-135 Singh PK, Parsek MR, Greenberg EP, Welsh MJ A component of innate immunity prevents bacterial biofilm development . Nature 2002; 417:552-5 Drenkard E, Ausubel FM Psedomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature 2002; 416:740-3 Planktonic growth Pili Flagella Antibiotic susceptibility QS QS QS QS Quorum Sensors (homoserine lactones) Transcriptional activators LasR RhIR Proteases Hemolysins ExotoxinA Pyocyanin Superoxide dismutase Catalase ANTIBIOTIC RESISTANCE

Mortality with and without appropriate antibiotics Pierre Yves Bochem Intensive Care Med (2001) 27

Hospital mortality and rates of inadequate antimicrobial treatment according to the most common pathogens associated with bloodstrem infections. OSSA= oxacillin sensitive S aureus; CNS= coagulase negative staphylococci; VRE= vancomycin resistant enterococci Chest 2000; 118:146-155

Infection: certain or suspected Microbiological monitoring
DEFINITIVE ANTIBIOTIC
TREATMENT **
Antibiogram
MIC
Antibiotic serum concentration
(peak and through)
AUC 24 /MIC 18 >125%
SUCCESS FAILURE EMPIRIC ANTIBIOTIC THERAPY EARLY ADEQUATE APPROPRIATE Way of treatment Bacterical and fungine epidemiology of that specific ICU Primary cofactor Early start of chemotherapy (no more than 6hrs from the admittance) Inadequate 52.5% Adequate 47.5% Failure 5.7% Failure 23.3% OPTIMAL ANTIBIOTIC THERAPY IN ICU appropriate inappropriate ** high doses endovenous bolus high peak concentration polychemotherapy rotation therapy 3 days and reassess Prophylactic therapy Pre-emptive therapy PRECAUTIONARY THERAPY

Immunocompromised Host + Infection septicaemia Inadequate antibiotic therapy (e.g. penicillin binding protein (PBP)-2 and 3 specific) PBP3 PBP2 Induction of filamentous bacterial forms Conversion of bacilli to round, spheroidal cells High bacterial mass High endotoxin release SEPTIC SHOCK Other factors Aztreonam Piperacillin Mezlocillin and at lower concentration Cefuroxime Ceftazidime Cefotaxime Imipenem Meropenem Mecillinam Cefepime Intermediate endotoxin release Low endotoxin release Tobramycin,Amikacin Gentamicin,Polymyxins Teicoplanim,Vancomycin Ciprofloxacin,Moxifloxacin

SCREEN * Hemocultures *Colonization index *Signs and symptoms of sepsis SICK NOT SICK NOT SICK SICK + - SEPTIC OK Removal of catheters To treat? =To treat Removal of catheters Antifungal therapy Know the fungal species and antibiogram (MIC) Fluconazole or Ambisome or Caspofungin or both Prophylaxis with high dose fluconazole SEPTIC Surveillance: Hemocultures plus Colonization index >2 sites or clinical or sterile site positive. Sepsis in spite of antibiotics Treat like candida NOT SEPTIC bacterical sepsis plus 2 sites probably treatment PROPHYLAXIS In high risk patient *oral nasogastric Nystatin Fluconazole *Yoghurt Positive Fungal hemocultures Negative Fungal hemocultures Assess clinical scenario

TO PRESERVE VITAL ORGAN PERFUSION AND TO MAINTAIN TISSUE OXYGENATION
SUPPORTIVE THERAPY
- Haemodynamic support
Early goal directed therapy
- Respiratory support
Protective ventilation strategy
MANAGEMENT OF COAGULOPATHY

Supplemental oxygen +/- Endotracheal intubation and Mechanical ventilation Central venous and Arterial catheterization Sedation,paralysis (if intubated) Or both CVP MAP ScvO2 Goals achieved ICU admission crystalloid colloid 8-12 mmHg Vasoactive agents >65 and<90mmHg <65mmHg >90mmHg Transfusion of red cells Until hematocrit>30% >70% <70% Inotropic agents <70% >70% NO YES Rivers E et al “ EGDT in the treatment of severe sepsis and septic shock” N Engl J Med 2001, 345:1368-1377

Clinical diagnosis of ALI If 150 > PaO2/FiO2 >100 If PaO2/FiO2 < 100 Colloids and diuresis Colloids and CVVH Colloids and CVVH

THE KIDNEY IN SEPSIS
Renal failure developing in the ICU carries a poor prognosis while combined renal and respiratory failure carries a considerably worse prognosis than respiratory failure alone
In the absence of disease modifying therapies, it is impossible to measure the impact on mortality for preventing acute renal failure
Renal salvage with furosemide, while having some theoretical benefits on reducing tubular cell energy consumption and flushing of debris out of tubules and ducts, has never been shown convincingly to improve either renal function or survival
Similarly , the use of dopamine to increase renal flow is probably not advantageous and may be detrimental
De Mendoca A,Vincent JL,Suter PM et al (2000) Acute renal failure in the ICU:risk factors and outcome evaluated by the SOFA score. Intensive Care Med 26:915-921
Sweet SJ, Glenney CU, Fitzgibbons JP, Friedman P, Teres D (1981) Synergistic effect of acute renal failure and respiratory failure in the surgical intensive care unit. Am J Surg 141:492-496
Brezis M, Agmon Y, Epstein FH (1994) Determinants of intrarenal oxygenation. I. Effects of diuretics. Am J Physiol 267: F1059-F1062
Bellomo R, Chapman M, Finfer S, Hicking K, Myburgh J (2000) Low dose dopamine in pazienta with early renal dysfunction: a placebo controlled randomized trial. Australian and New Zealand Intensive Care Society (ANZIC) Clinical Trial Group. Lancet 356:2139-2143
Galley HF (2000) Renal dose dopamine: will the message now get through? Lancet 356:2112-2113

Administration of low dose dopamine by continuous intravenous infusion (2 μg/Kg/min/) to critically ill patients at risk of renal failure does not confer clinically significant protection from renal dysfunction Low dose dopamine in patients with early renal dysfunction: A placebo controlled randomized trial (ANZICS clinical trials group) Lancet 2000; 356:2139-43 low dose of dopamine is thought to be harmless. That is not true. DOPAMINE: * suppress respiratory drive * increase cardiac output * increase myocardial VO2 * trigger myocardial ischaemia, arrhytmias * induce hypokalaemia, hypophosphataemia * predispose to gut ischaemia * disrupt metabolic, immunological homoeostasis (action on T cells function) There is no justification for using “renal dose” dopamine in the critically ill

Normal nonstressed function of the hypothalamic- pituitary-adrenal axis Normal function of the hypothalamic-pituitary- adrenal axis during illness Corticosteroid insufficiency during acute illness Binding of cortisol to corticosteroid binding globulin Increased cortisol and decreased corticosteroid binding globulin Decreased cortisol and Decreased corticosteroid Binding globulin Normal action in tissue Increased action in tissue Decreased action in tissue Hypothalamus Reduced feedback Pitutary Adrenal CTRH + ACTH + - - Stress cytokines CTRH++ ACTH++ + Cytokines,local corticosteroid activation + - CTRH+ ACTH+ Cytokines Glucocorticoid resistance - Central nervous system disease, corticosteroids Pituitary apoplexy, corticosteroids Cytokines, anesthetics antiinfective agents corticosteroids hemorrage, infection - - - - - A B C Activity of the Hypothalamic-Pitutary-Adrenal Axis under Normal Conditions (A), during an Appropriate Response to Stress (B) and during an Inappropriate Response to Critical Illness ( C )

Potential effetcs of corticosteroids during septic shock Activation of IKB-  Inhibition of NFk-  Correction of a relative adrenocortical deficiency Reversal of adrenergic receptor desensitization deficiency Inhibition of inducible iNOS Hemodynamic improvement Decrease in the dosage of catecholamines Decreased trascription for proinflammatory cytokines, Cox-2, ICAM-1, VCAM-1. Increased transcription for IL-1-RA

Nonresolving acute respiratory distress syndrome Initiate pharmacologic glucocorticoid therapy Critical illness (especially if features of corticosteroids insufficiecy are present Randomly, timed measurement of cortisol level <15 μg/dl 15-34 μg/dl >34 μg/dl Increase in response to corticotropin test <9 μg/dl > 9 μg/dl Hypoadrenalism likely Functional hypoadrenalism unlikely Consider physiologic Corticosteroid replacement Corticosteroid therapy Unlikely to be helpful Investigation of adrenal corticosteroid function in critically ill patients on the basis of cortisol levels and response to the corticotropin stimulation test. It must be borne in mind that no cutoff value will be entirely reliable THE SCHEME HAS BEEN EVALUATED FOR PATIENTS WITH SEPTIC SHOCK Annane et al. JAMA 2000 283:1038-1045 Annane et al JAMA 2002 288:862-871

Mild illness or condition (nonfebrile cough or cold Dental extraction with Local anesthetic) Moderate illness or condition(fever, minor trauma,minor surgery) Severe illness or condition (major surgery, trauma, critical illness Septic shock (cathecolamine dependency, poor response to ACTH) Increase dose to 15mg of prednisolone/day or equivalent Increase dose to 50mg of Hydrocortisone IM or IV every 6 hr 50 mg of Hydrocortisone IV Every 6 hr with or without 50 μg of Fludrocortisone/ day Return to normal dose 24 hr after resolution Taper dose to normal by decreasing by 50% per day Treat for 7 days No change Suggested corticosteroid replacement doses during intercurrent and acute illness in patients with proven or suspected adrenal insufficiency, including those receiving corticosteroid therapy

OTHER SUPPORTIVE THERAPY IN SEPSIS 1
Deep Vein Thrombosis (DVT) in septic patients and the high percentage of sepsis /infected patients included in studies that have demonstrated efficacy of DVT prophylaxis in general, septic patients should be treated with DVT prophylaxis. Even though there is not a randomized study that establishes the impact of DVT prophylaxis on morbidity and mortality specifically in septic patients, the significant number of septic patients included in the populations of patients enrolled in other prospective randomized trials supports that the use of DVT prophylaxis reduces morbidity and mortality in septic patients.

Glycolysis Proteinolysis Lipolysis Lactate pyruvate Gluconeogenesis Glycolysis Glycerol Amino acids Glucose Lactate Glycogen Glucose Pyruvate Alanine Glucose Pyruvate Alanine Lactate Alanine COUNTER REGULATORY HORMONES CYTOKINES STRESS glycogen LIVER

INFECTION symptoms Specific care Supportive care SEPSIS SEVERE SEPSIS SEPTIC SHOCK MODS BP Oxygenation BP Oxygenation Oliguria Fever Tachycardia Tachypnea Empiric antibiotic therapy Source control *Fluids *oxygen therapy * vasopressors *mechanical *EGDT *pressure support * inotropes ventilation ventilation * moderate *low TV *NIV corticosteroids *recruitment * vasopressin manovreus *prone position *CVVH etc Drotecogin α (activated) Cultures, source control , antibiotics, intensive insulin therapy ? High risk patient APACHE II > 25

Conceptual models of multiple organ dysfunction syndrome Metabolic,endocrine dysfunction Hyperglicemia,relative adrenal insufficiency, hypothyroidism Strict control of glycemia, coticosteroids in stress doses in septic shock Selective digestive tract decontamination, enteral feeding, immunenutrition, reconditioning of the gut flora Increased infection with gut organisms (translocation?) endotoxemia, Kupffer cell activation, spill over Gut liver axis Caspase inhibition Anti-oxidants Increased epithelial and lymphoid apoptosis (gut and spleen), decreased neutrophil apoptosis Dysregulated apoptosis Augmentation of anticoagulant mechanisms (APC-Prowess trial !, AT-Kybersept trial ? TFPI ?) Increased procoagulant activity, decreased anticoagulant activity, increased von Willebrand factor, soluble thrombomodulin; increased capillary permeability Microvascular coagulopathy and endothelial activation Augmentation of DO 2 (early optimization of DO 2 and SvO 2 ) Increased lactate Tissue hypoxia G-CSF, interferon gamma Nosocomial infection, increased anti-inflammatory cytokine levels (IL-10), decreased HLA-DR expression Immune paralysis Neutralization of specific cytokines (IL-1, TNF, PAF) or of activational pathways (afelimomab when IL-6 ) Cytokinemia (particularly IL-6,IL-8,TNF), leukocytosis, increased capillary permeability: edema Systemic inflammation (SIRS) Aggressive (?!) use of antibiotics and source control measure Persistent infection, nosocomial ICU acquired infection, endotoxemia Uncontrolled infection, occult poorly controlled infections (pneumonia, peritonitis) Therapeutic Implications Manifestations of MODS Pathologic process

Novel Therapies Summary
Reducing mortality in sepsis: new directions
This is highly recommended reading, concise reviews of
Low tidal volume ventilation
Early goal directed therapy
Drotrecogin alfa (activated)
Moderate dose corticosteroids
Tight control of blood sugar
Critical Care 2002, 6 (Suppl 3) : S1-S18 (http://ccforum.com/content/6/S3/S1 )

Novel Therapies
NAC Crit. Care. Med. 2003 31 (11) 2574-78
Nuclear factor- κ B 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

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

Gram Negative Sepsis

by shabeel pn

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