Attending Version
created by Dr. Dana Davis
Objectives:
1. Define and differentiate bacteremia and the clinical spectrum of SIRS, sepsis, severe sepsis, and septic shock.
2. Identify typical choices for empirical antibiotics for patients with sepsis.
3. Identify patient groups with increased risk for the development of sepsis, increased morbidity or mortality, or uncommon etiologic organisms.
4. Describe the indications, contraindications and side effects of therapeutic agents including fluids, vasopressors, antibiotics, steroids, and activated protein C in the treatment of sepsis.
References:
1. Lorente JA, et al, Time course of hemostatic abnormalities in sepsis and its relation to outcome., Chest, 1993, May, 103(1536-42)
2. McGill, Endothelial cells: role in infection and inflammation. World J Surg - 01-FEB-
1998; 22(2): 171-8
3. Levi M, Disseminated intravascular coagulation.
N Engl J Med - 19-AUG-1999;
341(8): 586-92
(antibiotics)
4. Bernard GR . Efficacy and safety of recombinant human activated protein C for severe sepsis.
N Engl J Med - 8-MAR-2001; 344(10): 699-709
5. O’Brien JM. New approaches to the treatment of sepsis. Clinics in Chest Medicine.
Volume 24 • Number 4 • December 2003
6. The International Sepsis Forum. Guidelines for the management of severe sepsis and septic shock. Intensive Care Med 2001;27(Suppl. 1):S1–134.
7. Simon D, Trenholme G. Antibiotic selection for patients with septic shock. Crit Care
Clin. 2000;16:215–230.
8. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288(7):862-71.
9. Briegel J , Forst H , Haller M , et al: Stress doses of hydrocortisone reverse hyperdynamic septic shock : A prospective, randomized, double-blind, single-center study . Crit Care Med 1999 ; 27 : 723–732
10. 14th European Congress of Clinical Microbiology and Infectious Diseases, May 1–4,
2004
11. Kumar A, Roberts D, Wood KE, et al. Delays in antimicrobial therapy for sepsis. Crit
Care Med. 2004;32:A11.
12. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32:85.

CASE
History:
33 y/o F presents with Fever, non-productive cough, sore throat and head ache. URI sxs
X 5 days. Came in b/c feeling tired and a little SOB. Not eating or drinking much. . 2 kids at home both of whom have had recent URI/sore throat about 2 weeks ago.
PMH
MVA

spleenectomy at age 9
Immunization status unknown
No medications
G2 P2
NKDA
ROS
Neg. except as reported in HPI
T 35.8 P 98 R 20 (PaCO2 will be 30) BP 100/56, O2 sat 91% RA
A&O X 4. Skin is dry.
HEENT – pharynx injected. Neck supple. No adenopathy
CV – no murmurs
Lungs – L posterior crackles
Abdomen – benign
Skin – no rash
Lymph – no adenopathy
Normal genital/rectal exams
No muscle or joint swelling.
WBC 24.5 (85 PMN - automated(15 Bands, 70 Segs), 5 lymphs, 10 monos), H/H
13.6/40, Plt 166 K
Chem 10 Na 148, K 4.6, Cl 105, Bicarb 24, BUN 22, Cr 1.2 , Ca 9.4, PO4 5, Mg 2.0
CXR – Possible LLL pneumonia
Hospital course:
Patient admitted to the hospital with suspected pneumonia in an asplenic patient. Initial blood cultures were taken, as were sputum and urine cultures. Antibiotics were ordered in the Emergency Room, but were delayed for approximately 2 hours. Initially she was started on cefotaxime and doxycycline.
She was started on IV fluids, bolused with lL of NS and infused with 1/2 NS at 150 cc per hour.
At the time that the antibiotics were being administered it was noted that her pulse was now 110 to 124 and her blood pressure was 98/46. The patient was complaining of worsening headache and photophobia. The remainder of her vitals were unchanged.
Suspecting meningitis a CT was performed which was normal.

An LP was performed.
Gram stain showed Gram positive diplococci. WBC count was 1500 with 200 RBC.
Glucose 44 and protein 88. At that time a call from the lab was received that the patient was noted to have Gram + diplococci on her peripheral blood smear.
Vancomycin was added to her antibiotics and she was switched from cefotaxime to ceftriaxone and was given a single dose of dexamethasone.
Two hours later the patient began to complain of bilateral leg numbness and weakness.
She was noted to have diminished strength in both lower extremities, as well as decreased pinprick sensation and reduced sphincter tone. The exam was also significant for a pulse of 138, BP of 86/42, she appeared mottled with multiple bruises where she had been stuck for lab draws and IVs, and she was oriented to person only.
Repeat labs were ordered:
Chem 10 – Na 144, K – 4.9, Cl – 98, Bicarb – 20, BUN – 32, Cr – 1.6, PO4 – 2.2, Mg –
1.7
CBC - WBC 12.5 (15 Bands, 55 Segs, 5 metamyelocytes, 12 Monos, 13 Lymphs), H/H
– 11/33, Plt - 70
PT – 28 (INR 9.2), PTT – 65
LFTs – AST 108, ALT 114, Alk. Phos 88, Total Bili. 5.2, Direct Bili. 1.1, Albumin 3.6,
Total Protein 8.6
MRI of L / S spine showed hematoma present in lumbar spinal cord.
The patient was transferred to the MICU and dopamine was instituted. Shortly after transfer the patient became hypoxic and required mechanical ventilation. A repeat CXR showed diffuse “white out” consistent with severe ARDS.
The following day the patient developed unrelenting seizures. Once the seizures were controlled with lorazepam and fosphenytoin a repeat CT scan was done which showed intracerebral hemorrhage. The patient also had bilateral dilated pupils and lacked brainstem reflexes.
After discussions with her family life support was withdrawn and the patient died shortly thereafter. Autopsy was performed. The blood cultures and spinal fluid grew out pneumococcus which was sensitive to ceftriaxone. The official cause of death was determined to be pneumococcal sepsis resulting in coagulopathy and subsequent intracerebral hemorrhage.
Discuss management of this patient including use of fluids, antibiotics, pressors, steroids as well as significance of results from lab/diagnostic tests.

Outline and discussion
Definitions:
1) Bacteremia – presence of viable bacteria in circulating blood
2) SIRS - is a widespread inflammatory response to a variety of severe clinical insults.
This syndrome is clinically recognized by the presence of two or more of the following:
Temperature >38ºC or <36ºC
Heart rate >90 beats/min
Respiratory rate >20 breaths/min or PaCO2 <32 mmHg
WBC >12,000 cells/mm3, <4000 cells/mm3, or with >10 percent immature
(band) forms
Tissue injury secondary to activation of the inflammatory system may complicate noninfectious disorders (eg, acute pancreatitis or pulmonary contusion). The term systemic inflammatory response syndrome (SIRS) is used in this setting to refer to the consequences of a dysregulated host inflammatory response which may or may not be associated with infection. Infections cause approximately 26% of cases of SIRS.
Non-infectious causes of SIRS
Trauma / burns (34 %)
CVA (6%)
GI bleeding (5%)
Pancreatitis, vaginal delivery, CHF, TTP, malignancies, acute coronary syndrome, thromboembolism, and DKA.
SIRS + infection = Sepsis

Severe Sepsis

Septic Shock
3) Sepsis - This is a systemic inflammatory response to a documented infection. The manifestations of sepsis are the same as those previously defined for SIRS.
4) Severe Sepsis - This is sepsis and SIRS associated with 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.
With severe sepsis, at least 1 of the following manifestations of inadequate organ function/perfusion also must be included:
Alteration in mental state
Hypoxemia (PaO
2
<72 mm Hg at FiO
2
[fraction of inspired oxygen] 0.21; overt pulmonary disease not the direct cause of hypoxemia)
Elevated plasma lactate level
Oliguria (urine output <30 mL or 0.5 mL/kg for at least 1 h)
5) Septic Shock A subset of people with severe sepsis develop hypotension despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving

inotropic or vasopressor agents may not be hypotensive by the time that they manifest hypoperfusion abnormalities or organ dysfunction.
6 ) MODS (multiple organ dysfunction syndrome) This is the presence of altered organ function in a patient who is acutely ill and in whom homeostasis cannot be maintained without intervention.
Epidemiology:
Patient characteristics which increase risk of sepsis:
Extremes of age (<10 y and >70 y)
Cirrhosis
Alcoholism
Diabetes mellitus
Cardiopulmonary diseases
Solid malignancy
Hematologic malignancy
Immunosuppression
Neutropenia
Immunosuppressive therapy
Corticosteroid therapy
Intravenous drug abuse
Compliment deficiencies
Asplenia
Major surgery, trauma, burns
Invasive procedures
Catheters
Intravascular devices
Prosthetic devices
Hemodialysis and peritoneal dialysis catheters
Endotracheal tubes
Prior antibiotic treatment
Prolonged hospitalization
Other factors - Childbirth, abortion, and malnutrition
Infections which lead to sepsis can originate in any tissue. Most commonly the infection arises from lungs (>25% of cases of sepsis), the urinary tract (25% of cases of sepsis), followed by abdominal (15%) and skin infections (15%). 6 – 15% of the time there are multiple sites of infection.
Microorganisms: Prior to the introduction of antibiotics in clinical practice, gram-positive bacteria were the principal organisms causing sepsis. More recently, gram-negative bacteria and fungal infections have become key pathogens causing severe sepsis and septic shock .

Pathophysiology
SIRS results from a dysregulated inflammatory response.
Typically, with localized infection or inflammatory response to a non-infectious stimulant cytokine release is instrumental in maintaining localization of the infection and activating the host response of macrophages, monocytes and neutrophils. However, if this response is systemic it can lead to host cell damage and hypoperfusion.
Tumor necrosis factor (TNF), interleukin (IL)-1 are most often cited as factors contributing to the normal as well as exaggerated response. Other factors which seem to be implicated are IL-6, IL-8, monocyte chemoatractant protein-1, IL-10, interferongamma, IL-12, macrophage migration inhibition factor, granulocyte colony-stimulating factor (GCSF) and gransulocyte macrophage colony-stimulating factor(GM-CSF).
Activation of the complement system leads to generation of bradykinin and nitric oxide which have been implicated in the induction of hypotension and hyperdynamic shock.
Abnormalities of coagulation and fibrinolysis homeostasis in sepsis
An imbalance of homeostatic mechanisms lead to subclinical coagulopathy and occasionally disseminated intravascular coagulopathy (DIC) and microvascular thrombosis causing organ dysfunction and death. Inflammatory mediators instigate direct injury to the vascular endothelium; the endothelial cells release tissue factor (TF), triggering the extrinsic coagulation cascade and accelerating production of thrombin.
Furthermore, the levels of protein C and endogenous activated protein C also are decreased in sepsis. Endogenous activated protein C is an important proteolytic inhibitor of coagulation cofactors Va and VIIa. Thrombin via thrombomodulin activates protein C that functions as an antithrombotic in the microvasculature. Endogenous activated protein
C also enhances fibrinolysis by neutralizing PAI-1 and by accelerating t-PA–dependent clot lysis.
The imbalance among inflammation, coagulation, and fibrinolysis results in widespread coagulopathy and microvascular thrombosis and suppressed fibrinolysis, ultimately leading to multiple organ dysfunction and death.
Circulatory pathophysiology of septic shock
The predominant hemodynamic feature of septic shock is arterial vasodilation.
Diminished peripheral arterial vascular tone may result in hypotension and shock if insufficiently compensated by a rise in cardiac output. Early in septic shock, the rise in cardiac output often is limited by hypovolemia.
Peripheral circulation during septic shock
An elevation of cardiac output occurs; however, the arterial-mixed venous oxygen difference usually is narrow, and the blood lactate level is elevated. This is a result of maldistribution of blood flow and oxygen delivery/extraction.
The peripheral blood flow abnormalities result from the balance between local regulation of arterial tone and the activity of central mechanisms (eg, autonomic nervous system).
The regional regulation, release of vasodilating substances (eg, nitric oxide, prostacyclin), and vasoconstricting substances (eg, endothelin) affect the regional blood flow.
Development of increased systemic microvascular permeability also occurs, remote from

the infectious focus, contributing to edema of various organs, particularly the lung microcirculation and development of acute respiratory distress syndrome (ARDS).
Maldistribution of blood flow, disturbances in the microcirculation, and, consequently, peripheral shunting of oxygen are responsible for diminished oxygen extraction and uptake, pathological supply dependency of oxygen, and lactate acidemia in patients experiencing septic shock.
Diagnostic Tests
CBC – Evaluate for anemia which may further impair oxygen delivery.
Abnormal WBC count with immature forms is part of diagnostic criteria.
Platelet count may be decreased suggesting DIC.
Chemistry - Sodium and chloride to evaluate fluid status.
Bicarbonate and anion gap to evaluate for acidosis.
BUN/Cr to assess renal function.
Liver tests to assess for MODS, or suggest biliary origin, pancreatitis, or hepatitis.
Lactate
Coagulation studies – May indicate DIC.
Blood and Urine cultures, preferably prior to initiation of antibiotics.
Chest x-ray
Abdominal films, possibly including CT if unable to localize site of infection, especially if the patient has abdominal complaints.
Lumbar puncture if the patient has meningeal signs or altered mental status.
Treatment
General supportive care : Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion.
The hemodynamic support in septic shock is provided by restoring the adequate circulating blood volume, and, if needed, optimizing the perfusion pressure and cardiac function with vasoactive and inotropic support to improve tissue oxygenation.
Shock refers to a state of inability to maintain adequate tissue perfusion and oxygenation
Hemodynamic support of septic shock
Evidence of inadequate tissue perfusion and oxygenation:
MAP < 60 mmHg, or a decrease in MAP of greater than 40 mm Hg.
Elevated blood lactate.
Mixed venous saturation of less than 65%.
Evidence of end-organ damage – acute coronary syndrome, renal dysfunction (decrease urine output or increase in creatinine), decreased level of consciousness, elevated transaminases, ileus or malabsorption.
The hemodynamic support in septic shock is provided by restoring the adequate circulating blood volume, and, if needed, optimizing the perfusion pressure and cardiac function with vasoactive and inotropic support to improve tissue oxygenation.

Intravascular volume resuscitation
Hypovolemia is an important factor contributing to shock and tissue hypoxia; therefore, all patients with sepsis require supplemental fluids. The amount and rate of infusion are guided by an assessment of the patient's volume and cardiovascular status. Monitor patients for signs of volume overload, such as dyspnea, elevated jugular venous pressure, crackles on auscultation, and pulmonary edema on the chest radiograph. Improvement in the patient's mental status, heart rate, MAP, capillary refill, and urine output indicate adequate volume resuscitation.
Large volumes of fluid (efficacy of crystalloids(NS, LR) and colloids (albumin, dextrans) is equivalent) infusions are required as initial therapy in patients with septic shock – possibly up to 10 liter in the first six hours. Administer fluid therapy with predetermined boluses (500 mL- 1L or 10 - 20 mL/kg each, and reassess frequently) titrated to the clinical end points of heart rate, central venous pressure (8 – 12 mmHg), mixed venous oxygen saturation (> 70%),urine output (>0.5 mL/kg/hr), and blood pressure (MAP > 65 mmHg) or the pulmonary capillary wedge pressure exceeds 18 mm Hg.
Vasopressor supportive therapy
When proper fluid resuscitation fails to restore hemodynamic stability and tissue perfusion, initiate therapy with vasopressor agents. Typical agents are: dopamine, norepinephrine, epinephrine, and phenylephrine.
The mean blood pressure required for adequate splanchnic and renal perfusion (MAP of
60 or 65 mm Hg) is based on clinical indices of organ function. Dopamine is the most commonly used agent for this purpose. Treatment usually begins at a rate of 5-10 mcg/kg/min IV, and the infusion is adjusted according to the blood pressure and other hemodynamic parameters.
If the patient remains hypotensive despite volume infusion and moderate doses of dopamine, a direct vasoconstrictor (eg, norepinephrine) should be started at a dose of 0.5 mcg/kg/min and titrated to maintain a MAP of 60 mm Hg. While potent vasoconstrictors
(eg, norepinephrine) traditionally have been avoided because of their adverse effects on cardiac output and renal perfusion, data from animal and human studies reveal that norepinephrine can reverse septic shock in patients unresponsive to volume and dopamine. Vasopressors may cause more harm than good if administered to patients whose inadequate intravascular volume is not restored (ie, a patient "whose tank is not filled").
Empirical antimicrobial therapy
Initiate this therapy early (prior to cultures if obtaining cultures would result in a delay in administering antibiotics) in patients experiencing septic shock as appropriate antibiotic therapy has been shown to have a survival benefit when compared to delayed, inadequate or inappropriate antibiotic therapy, though antibiotics have little effect on the clinical outcome for at least 24 hours. The selection of appropriate agents is based on the patient's underlying host defenses, the potential sources of infection, and the most likely culprit organisms.
Respiratory and urinary tract infections account for more than 50% of episodes of sepsis related to infections. The role of anaerobes in sepsis has been decreasing in recent years while fungal infections and polymicrobial infections have increased.

Initially, broad spectrum, cidal antibiotics are preferred. They should be chosen with consideration of the most likely site of infection as well as consideration of the patient’s risk for having acquired an infection with pseudomonas or resistant organisms (e.g. hospitalized patients).
In general, a regimen should include a broad spectrum beta-lactam, or quinolone for patients with penicillin allergy, along with clindamycin or metronidazole for anaerobic coverage. Burn patients or those who are hospitalized have an increased likelihood of resistant organisms as well as pseudomonas. First line antibiotics for these patients should include an anti-pseudomonal beta-lactam (pipercillin, ticarcillin, ceftazidime) or quinolone as well as an aminoglycoside and vancomycin. A list of typical (though not exhaustive) empirical antibiotic regimens for patients with suspected sepsis:
1.
Community acquired pneumonia Macrolide and third-generation cephalosporin or Levofloxacin
2.
Nosocomial pneumonia: Cefipime, pipercillin-tazobactam or Imipenemcilastatin and an aminoglycoside.
3.
Abdominal infection: Imipenem-cilastatin or Pipercillin-tazobactam and aminoglycoside.
4.
Nosocomial abdominal infection: Imipenem-cilastatin and aminoglycoside or Pipercillin-tazobactam and Amphotericin B.
5.
Skin/soft tissue: Vancomycin and Imipenem-cilastatin or Piperacillintazobactam
6.
Nosocomial skin/soft tissue: Vancomycin and Cefipime
7.
Urinary tract infection: Ciprofloxacin and aminoglycoside
8.
Nosocomial urinary tract infection: Vancomycin and Cefipime
9.
CNS infection: Vancomycin and third generation cephalosporin or
Meropenem
10.
Nosocomial CNS infection: Meropenem and Vancomycin
Surgery may be required for patients with localized foci of infections (abscesses) or intraabdominal infections.
Recombinant human activated protein C
The inflammatory mediators are known to cause activation of coagulation inhibitors of fibrinolysis, thereby causing diffuse endovascular injury, multiorgan dysfunction, and death. Activated protein C is an endogenous protein that not only promotes fibrinolysis and inhibits thrombosis and inflammation but also may modulate the coagulation and inflammation of severe sepsis. Sepsis reduces the level of protein C and inhibits conversion of protein C to activated protein C. Administration of recombinant activated protein C inhibits thrombosis and inflammation, promotes fibrinolysis, and modulates coagulation and inflammation. It is contraindicated in patients who have had recent major surgery, AVMs, recent stroke, cerebral aneurysm or mass.
A recent publication by the Recombinant Human Activated Protein C Worldwide
Evaluation in Severe Sepsis (PROWESS) study group demonstrated that the administration of recombinant human activated protein C (drotrecogin-alfa, activated)

resulted in lower mortality rates (24.7% versus 30.8%) in the treated group compared to placebo. Treatment with drotrecogin-alfa, was associated with reduction in the relative risk of death by 19.4% (95% CI, 6.6-30.5) and an absolute reduction in risk of death by
6.1%, ( P =.005).
High-dose glucocorticoids : While theoretical and experimental animal evidence exists for the use of large doses of corticosteroids in those with severe sepsis and septic shock, all randomized human studies (except 1 from 1976) found that corticosteroids did not prevent the development of shock, reverse the shock state, or improve the 14-day mortality rate. However, a study reported in JAMA in 2002 showed that 75% of patients in the study who remained hypotensive despite adequate fluid resuscitation and vasopressor therapy were adrenally insufficient and did benefit from hydrocortisone and fludrocortisone.
Stress-dose glucocorticoids : Recent trials demonstrated positive results of stress-dose administration of corticosteroids in patients with severe and refractory shock.

Review Question
A 71 year old man with a history of hypertension and chronic bronchitis who continues to smoke presents with a complaint of increasing shortness of breath. He has felt feverish and has had an increase in his usual cough, which is now productive of green, blood tinged sputum. His medications prior to admission were an Albuterol inhaler PRN,
Atrovent inhaler every six hours, and he had increased his prednisone from his usual 5 mg per day to 40 mg per day this morning because, “That’s what his doctor usually does when he has an exacerbation.” On exam the patient is pale, diaphoretic and appears anxious. Vitals: P 122, BP 92/42, Temp. 38.2, Resp. 24, O2 Sat. 90% on RA. He responds appropriately to questions, but is oriented only to person. He has no retractions and has good air movement. Crackles are heard in the left posterior lung fields.
What intervention will have the most immediate impact on this patient’s mortality?
A) Initiate empirical antibiotics for community acquired pneumonia with a macrolide and a third generation cephalosporin.
B) Obtain sputum and blood cultures prior to initiation of antibiotics.
C)
Obtain a CXR to affirm the cause of the patient’s symptoms are due to pneumonia rather than an exacerbation of CHF prior to any intervention.
D) Bolus with 1 L of NS immediately, then repeat boluses with 250 to 500 cc of crystalloid solution until the patient is clinically volume repleted.
E) Administer norepineprhine, initial dose 0.5 mcg/kg/min, titrate to MAP of 60.
The correct answer is D
The history of fever, shortness of breath, productive cough is consistent with pneumonia, as is the exam. CHF does not cause cough productive of purulent sputum, fever, or focal findings on lung exam. This patient meets clinical criteria for SIRS (Pulse > 90, respirations > 20, Temp. > 38) as well as evidence of infection (cough productive of purulent sputum, fever) meeting criteria for sepsis. He has an altered mental status suggesting severe sepsis. Though data indicates that each 1 hour delay in initiation of appropriate empirical antibiotics in the setting of sepsis results in a 5 to 10% increased mortality risk, choice and administration of antibiotics does not have significant immediate impact on survival. Sputum and blood cultures will not alter the initial choice of empirical antibiotics, which should be based on the site of the infection and whether or not the infection is likely community or hospital acquired. Though SIRS can rarely result from CHF, this patient has signs and symptoms of pneumonia. His initial survey (A, B,
C’s) indicates significant circulatory impairment with a pulse of 122, MAP < 60, altered mental status. Immediate survival is dependent on reestablishing adequate tissue perfusion. This is accomplished first through fluid resuscitation. If fluid resuscitation does not restore adequate perfusion based on specific clinical parameters (e.g. MAP, heart rate, capillary refill, urine output, mental status) then administration of vasopressors is indicated. Vasopressors administered prior to fluid resuscitation may worsen regional perfusion to vital organs.

Post Module Evaluation
Please place completed evaluation in an interdepartmental mail envelope and address to
Dr. Wendy Gerstein, Department of Medicine, VAMC (111).
1) Topic of module:__________________________
2) On a scale of 1-5, how effective was this module for learning this topic? _________
(1= not effective at all, 5 = extremely effective)
3) Were there any obvious errors, confusing data, or omissions? Please list/comment below:
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
4) Was the attending involved in the teaching of this module? Yes/no (please circle).
5) Please provide any further comments/feedback about this module, or the inpatient curriculum in general:
________________________________________________________________________
________________________________________________________________________
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6) Please circle one:
Attending Resident (R2/R3) Intern Medical student