Approach of Infected patient in Critical Care Unit Mazen Kherallah, MD, FCCP Consultant, Infectious Disease & Critical Care Chairman, Critical Care Department King Faisal Specialist Hospital & Research Center

1. What Sepsis Syndrome are we Dealing with? Infection Sepsis Severe sepsis Septic shock Multi-organ system failure

ACCP/SCCM Consensus Definitions Infection Inflammatory response to microorganisms, or Invasion of normally sterile tissues Systemic Inflammatory Response Syndrome (SIRS) Systemic response to a variety of processes Sepsis Infection plus 2 SIRS criteria Severe Sepsis Sepsis Organ dysfunction Septic shock Hypotension despite fluid resuscitation Multiple Organ Dysfunction Syndrome (MODS) Altered organ function in an acutely ill patient Homeostasis cannot be maintained without intervention The American College of Chest Physicians (ACCP) and Society of Critical Care Medicine (SCCM) held a consensus conference in August 1991 to agree on a set of definitions that could be applied to patients with sepsis and organ dysfunction. The consensus panel also recommended the use of severity scoring methods to characterize the disease and develop a comprehensive model for the syndrome. This slide provides a brief definition of the various components of the sepsis syndrome. Notably, this is a non-linear process rather than a continuum and the presence of organ dysfunction identifies a population with a significant risk of mortality. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:1644-55. Bone RC et al. Chest. 1992;101:1644-55.

SIRS: More Than Just a Systemic Inflammatory Response SIRS: A clinical response arising from a nonspecific insult manifested by 2 of the following: Temperature 38°C or 36°C HR 90 beats/min Respirations 20/min WBC count 12,000/mL or 4,000/mL or >10% immature neutrophils Recent evidence indicates that hemostatic changes are also involved The systemic inflammatory response syndrome (SIRS) is a clinical response arising from a nonspecific insult manifested by two or more of the following: Fever or hypothermia Tachycardia Tachypnea Leukocytosis, leukopenia, or a left-shift (increase in immature neutrophilic leukocytes in the blood) Recent evidence indicates that hemostatic changes play a significant role in many SIRS-linked disorders. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:1644-55. Opal SM, Thijs L, Cavaillon JM, et al. Relationships between coagulation and inflammatory processes. Crit Care Med. 2000; 28:S81-2. Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Opal SM et al. Crit Care Med. 2000;28:S81-2.

Severe Sepsis: Acute Organ Dysfunction and Disordered Hemostasis Severe Sepsis: Sepsis with signs of organ dysfunction in 1 of the following systems: Cardiovascular Renal Respiratory Hepatic Hemostasis CNS Unexplained metabolic acidosis Severe sepsis is sepsis plus signs and symptoms of acute organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. As shown on the next slide, organ dysfunction may involve any of the following alone or in combination: Cardiovascular system Kidney Respiratory system Liver Hematologic (blood, coagulation) Central nervous system Presence of an otherwise unexplained metabolic acidosis Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:1644-55. Adapted from: Bone RC et al. Chest. 1992;101:1644-55.

Infection Sepsis Severe Sepsis Septic Shock Sepsis Syndromes Infection Sepsis Severe Sepsis Septic Shock Microbiological Phenomenon Infection + SIRS Sepsis + End-Organ Damage Severe Sepsis + Refractory Hypotension

Sepsis Parameters: Leukocytosis with left shift Bandemia Toxic granulation Elevated sed. Rate C- reactive protein Acute phase reactant: fibrinogen, haptoglobin,.. IL1, IL6, IL8

2. Organ Localization of infection Skin Soft tissue CNS Upper airway Lower airway Head and neck Mediastinal GI Liver Biliary tract Intra-abdominal Bones and joints Urinary tract Genital tract Blood stream infection Systemic

3. Tissue Localization of Infection Skin and soft tissue: Superficial epidermal layers (impetigo) Deeper epidermal layers (Icthyma) Superficial subcutaneous: Erysipelas Deeper subcut.: cellulitis Folliculitis Hydradenitis Fascia: Fasciitis Fat: panuculitis Lower respiratory tract: Alveolar: consolidative pneumonia Interstitial: atypical pneumonia Pleural: empyema

4. Suspected Microbiology of Infection Host factors Immunosuppression Age Gender Previous antibiotics Co-morbidity: SSD DM CGD Environmental Community: contacts Travel Animals Hospital: Location Nursing homes

4. Suspected Microbiology of Infection Community acquired pneumonia: Lobar pneumonia Streptococcus Pn. H. flu Moraxella catarrhalis Staphylococcal Klebsiella Community acquired pneumonia: interstitial: Mycoplasma Pn. Legionella Viral

4. Suspected Microbiology of Infection Intra-abdominal infection E. coli Klebsiella B. fragilis Enterococcus Candida Urinary tract infection E. coli Proteus Enterococcus

4. Suspected Microbiology of Infection Meningitis: <1 month: Group B strep 49% E. Coli 18% Listeria 7% Gram neg. 10% Meningitis: 1 mo-50 yrs: S. pneumoniae Meningococci H. flu (very rare)

5. Surgical Indication: Foreign body: central line infection Prosthesis: PVE, Prosthetic infection Sequestration: chronic osteomyelitis Gangrene: wet gangrene Obstructed normal draining procedure: cholecystitis No penetration for antibiotics: empyema, abscess

5. Empiric Treatment Appropriate coverage Adequate dose: MIC, MBC Appropriate route Absorption Penetration Tissue level Cellular level

4. Suspected Microbiology of Infection Meningitis: <1 month: Group B strep 49% E. Coli 18% Listeria 7% Gram neg. 10% Ampicillin+Cefotaxime Meningitis: 1 mo-50 yrs: S. pneumoniae Meningococci H. flu (very rare) Vancomycin+Ceftriaxone or cefotaxime

Empiric Treatment: Intra-abdominal Infection E. coli, Klebsiella Amp/sulbactam Piperacillin/tazobactam Ticarcillin/clavaulinate Aztreonam Imipenem Cefazolin Cefuroxime Ceftriaxone Ciprofloxacin B. Fragilis Amp/sulbactam Piperacillin/tazobactam Ticarcillin/clavaulinate Imipenem Cefoxitin Clindamycin Metronidazole Chloramphonicole

Introduction Fever Work-Up Automatic set order Repeated several times within 24 hours Time consuming Costly Disruptive and patient’s discomfort Considerable blood loss Unneeded radiation

Practice Parameters Goals Rational consumption of resources Efficient evaluation

The Search for the Underlying Cause of Fever? What temperature should elicit an evaluation? When are blood cultures warranted When should intravascular catheters be cultured or removed When are cultures of respiratory secretions, urine, stool, or CSF warranted When are radiological studies warranted

Initiating Fever Evaluation Definition of Fever Arbitrary: core temperature >38.0°C, or two consecutive elevation of > 38.3°C The lower the temperature that is used to define fever, the more sensitive and less specific the indicator is for detecting an infectious etiology

Initiating Fever Evaluation Normal Body Temperature Normal body temperature is 37.0°C Varies by 0.5°C to 1°C according to circadian rhythm and menstrual cycle Exercise can increase temperature by 2°C to 3°C

Initiating Fever Evaluation Variation of Temperature in ICU Specialized mattresses Hot lights Air conditioning Cardiopulmonary bypass Peritoneal lavage Dialysis and continuous hemofiltration Drugs altering thermoregulatory mechanisms

Initiating Fever Evaluation Non-infectious Causes of Fever can be Life-threatening Adrenal insufficiency Thyroid storm Malignant hyperthermia Heat stroke

Initiating Fever Evaluation Infected Patient but Afebrile Elderly Open abdominal wounds Large burns Extracorporeal membrane oxygenation Patients taking anti-inflammatory or anti-pyretic drugs

Initiating Fever Evaluation Temperature Measurement Most accurately measured using intravascular or bladder thermistor Mouth, rectal or external auditory measurements using electronic probes is acceptable in appropriate patients Axillary measurements should not be used

Initiating Fever Evaluation Clinical Evaluation A new onset of temperature to or above 38.3C is reasonable trigger for a clinical assessment but not necessarily a laboratory or radiological evaluation Clinical assessment may reveal a purulent wound or phlebitic leg, then diagnosis and therapy for that infectious process should commence

Bacterial Synergistic Gangrene

Anaerobic Cellulitis

Initiating Fever Evaluation Obtaining Blood Cultures Skin Preperation The site of venipunture should be cleaned with either 10% povidone iodine or 1-2% tincture of iodine. If the patient is allergic to iodine alcohol 70% swabs should be used The access to intravascular device and to the stopper on the culture bottle should be cleaned with 70% alcohol Iodophors must be allowed to dry to provide maximal antiseptic activity

Initiating Fever Evaluation Obtaining Blood Cultures Blood Volume One blood culture is defined as a sample of blood drawn at a single time at a single site One milliliter of blood is needed per five milliliter of media 5 ml of blood is injected into each of two or three bottles for routine blood culture 10-15 ml per one set of blood cultre

Initiating Fever Evaluation Obtaining Blood Cultures Number of Cultures & Sites Two cultures 10 minutes apart after the onset of fever. Culture should not be repeated till 24 hours passed Each culture should be drawn by separate venipuncture One culture can be obtained from the most recently inserted catheter in case venipuncture is difficult (the second B/C from a venipuncture site)

Initiating Fever Evaluation CXR & Sputum Chest x-ray in an erect sitting position during deep inspiration The absence of infiltrates, masses or effusion does not exclude pneumonia, abscess or empyema Respiratory secretion obtained by suctioned or expectorated sputum is adequate for initial evaluation

Initiating Fever Evaluation Urinalysis and Urine Culture Obtain urine for culture and for determination of the presence of pyuria Patients who have Foley catheter in place should have urine collected from the urine port of the catheter and not from the drainage bag Urine should be transported to the laboratory rapidly to avoid bacterial multiplication, otherwise should be refrigerated

Initiating Fever Evaluation Stool Examination Mandatory when more than 2 stools per day conform to the container in which they are placed in a patient at risk for C-difficile Stool should be sent for WBC or lactoferrin latex agglutination test Stool should be sent for c-diff assay for at least 2 times in 24 hours Stool should not be sent for other enteric pathogens unless the patient is HIV or present to the hospital with diarrhea

Infectious Causes of Fever Catheter-related Infections ICU acquired Pneumonia Urinary Tract Infection Pseudomembraneous colitis Wound Infection Sinusitis Acaculous cholecystitis

Vascular Devices & fever Localized infection Exit site infection Tunnel infection Systemic infection Allergic reaction

Relative Risks of CR-BSI Duration of catheter in place Anatomic site of insertion Type of the device: Catheter composition A-Line, Central line, Hickman’s catheter Regular vs antibiotic-impregnated catheter Patient population Techniques used in insertion and maintenance Frequency of manipulation

Duration of Catheter Use Optimal Time for Catheter Removal? The incidence of CR-BSI is directly proportional to the length of time the catheter is used The risk that any catheter may cause CR-BSI is low if the catheter is removed within 3 days The optimal time for catheter removal is unknown

Anatomic Site of Insertion Incidence of Catheter Colonization: Kemp and associates Femoral line: 36% Internal jugular: 17% Subclavian: 5%

Type of the Device Risk of CR-BSI Short-term noncuffed central venous catheters: 5-10 cases per 1000 catheter days Peripheral IV catheter: less than 0.2 cases per 1000 catheter days Permanent surgically implanted central device: 2 bacteremias per 1000 catheter days

Catheter Related Infections Definitions Colonized Catheter Positive culture from the catheter tip or intracutaneous segment without evidence of systemic infection Semiquantitative culture of 15 or more CFU is used to consider culture as positive Values of less than 15 CFU are regarded as negative culture, contaminant, or insignificant infection requiring no therapy

Catheter Related Infections Definitions Catheter-Related Bloodstream Infection A positive catheter culture 15 CFU with concomitant positive blood culture A quantitative blood culture drawn from the catheter shows marked step-up in concentration of organisms (ten-fold or greater) as compared with peripherally drawn quantitative blood culture No other identifiable source of infection

Catheter Related Infections Definitions Infusate-Related Bloodstream Infection Isolation of the same organism from the infusate and from separate percutaneous peripheral blood culture No other identifiable source of infection

Catheter Related Infections Definitions Local Catheter-Related Infection Growth of 15 or more CFU from a catheter specimen by semiquantitative culture Local signs of inflammation: erythema, swelling, tenderness, purulent material Negative peripheral blood culture

When the Catheter Should be Removed in a Febrile Patient When the Catheter Should be Removed in a Febrile Patient? No other identifiable Source For stable patients with fever, there is no necessity to remove or change all indwelling catheters unless CR-BSI or Local infection is documented If patients are in shock, manifest peripheral embolization, DIC or ARDS, removal of all intravascular catheters and reinsertion at new sites is indicated.

Pulmonary Infections & Fever Diagnostic Strategies Empirical strategy based only on clinical evaluation Invasive strategy based on fiberoptic bronchoscopy and quantitative cultures of distal uncontaminated pulmonary secretions Intermediate strategy based on quantitative culture of nonbronchoscopic sample

Diagnostic Strategy based on Clinical Evaluation only Fever, cough, sputum production, new pulmonary infiltrate and elevated leukocyte count. May not be present in the hospitalized patients with nosocomial pneumonia May be present but may not be caused by pneumonia: CHF, ARDS, atelectasis

Diagnostic Strategy based on Clinical Evaluation only Andrews et al, chest 1981;80:254-258

Diagnostic Strategy based on Clinical Evaluation only Autopsy Results Andrews et al, chest 1981;80:254-258

Chastre et al. Evaluation of bronchoscopic techniques for the diagnosis of nosocomial pneumonia. Am J Respir Crit Care Med 1995; 152:231-240

Diagnostic Strategy based on Invasive Evaluation Bronchoalveolar Lavage

Chastre et al. Evaluation of bronchoscopic techniques for the diagnosis of nosocomial pneumonia. Am J Respir Crit Care Med 1995; 152:231-240

Diagnostic Strategy based on Invasive Evaluation Protected Brush Specimen

Diagnostic Strategy based on Invasive Evaluation Protected Brush Specimen Drawbacks: False Negative Results Bronchoscopy performed at an early stage of infection with bacterial burden below the concentration necessary to reach diagnostic significance Specimens obtained from unaffected segments Specimens incorrectly processed Specimens obtained after initiation of a new antimicrobial therapy

Quantitative Cultures of Nonbronchoscopic Distal Intermediate Strategy Based on Quantitative Culture of Nonbronchoscopic Samples Quantitative Cultures of Nonbronchoscopic Distal Protected Specimen Represents a good alternative in patients with very unstable conditions and in patients for whom it is not possible to delay the initiation of antimicrobial treatment while awaiting bronchoscopy Diagnosis can be missed, especially in the case of upper lobes or left lung infection

Jourdain et al. Role of quantitative cultures of Endotracheal aspirates for the diagnosis of nosocomial pneumonia. Am J Resp Crit Care Med 1995; 152:241-246 68% VS 84%

Intermediate Strategy Based on Quantitative Culture of Nonbronchoscopic Samples Quantitative Cultures of Endotracheal aspirates

Diarrhea & Fever in ICU Diarrhea is caused by enteral feeding or drugs The only common enteric cause of fever in the ICU is Clostridium difficile C. difficile accounts for about 25% of all cases of antibiotic-related diarrhea

Pseudomembraneous Colitis

Methylene Blue Stain

Cytotoxin Effect on Baby Hamster kidney Cells

UTI & Fever in ICU The presence of pyuria can help establish the importance of urinary bacteria Leukocyte esterase dipstick test is easy and simple Gram stain of a centrifuged urine sediment may provide clues to the type of microorganisms present

Other Causes of Fever in ICU Respiratory Tracheobronchitis Empyema Lung abscess Sinusitis

Other Causes of Fever in ICU Wound & Soft Tissue Wound infection Decubitus ulcers Cellulitis Deep-seated abscess: sub-diaphragmatic

Other Causes of Fever in ICU Gastrointestinal Ischemic colitis Acalculous cholecystitis Cholangitis Transfusion-related hepatitis: CMV, hepatitis C, and hepatitis B Intraabdominal abscess Diverticulitis

Other Causes of Fever in ICU Prosthetic Devices Cardiac valve/pacemaker Joint replacement prosthesis Peritoneal dialysis catheter CNS intraventricular shunt

Non-Infectious Source of Fever in ICU Drugs Antibiotics: B-lactam agents Anti-epileptic drugs: phenytoin Antiarrythmics: quinidine and procainamide Antihypertensive: methyldopa

Non-Infectious Source of Fever in ICU Post-operative Up till 72 hours postoperative Atelectasis Post-pericardiotomy syndrome

Non-Infectious Source of Fever in ICU Vascular Conditions Deep venous thrombophlebitis Pulmonary embolism and infarction Bowel ischemia Hemorrhage into CNS, retroperitonium, joint, lung, and adrenals Myocardial infarction and Dressler’s syndrome

Non-Infectious Source of Fever in ICU Inflammatory Conditions Reaction to blood products Proliferative phase of ARDS Infusion of interleukin-2, granulocyte macrophage colony stimulating factor, and granulocyte colony stimulating factor Postpericardiotomy syndrome Pancreatitis Vasculitis

Non-Infectious Source of Fever in ICU Metabolic Conditions Heat stroke Malignant hyperthermia Neuroleptic malignant syndrome Adrenal insufficiency Alcohol withdrawal Seizures Hyperthyroidism

Non-Infectious Source of Fever in ICU Neoplasms Lymphoma Renal cell carcinoma Hepatoma Malignant metastatic to the liver Colon carcinoma