Infectious Diseases

Sepsis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has sepsis? What should you expect to find?

Definition

  • Sepsis is defined as a life-threatening organ dysfunction caused by an abnormal host response to infection. A subset of patients with sepsis will show signs of circulatory and metabolic abnormalities that can significantly increase mortality; these patients are considered to have septic shock.

  • For a patient to be classified as having systemic inflammatory response syndrome (SIRS), he or she must have more than one of the following clinical findings:

    • body temperature greater than 38 degrees Celsius or less than 36 degrees Celsius

    • heart rate greater than 90 beats per minute

    • respiratory rate greater than 20 breaths per minute or a carbon dioxide blood gas level greater than 32mm Hg

    • white blood cell count greater than 12,000 cells per liter or less than 4,000 cells per liter

  • Previously, severe sepsis was defined as sepsis with evidence of organ dysfunction, hypoperfusion, or hypotension. Based on recent recommendations, the term severse sepsis is no longer being recommended for use due to redundancy.

Newer tools, such as the Sequential Sepsis-Related Organ Failure Assessment (SOFA), are available to identify patients with sepsis induced organ dysfunction.

Symptoms and signs

  • Symptoms are wide-ranging and can vary from patient to patient. They include, but are not limited to:

    • altered mental status (confusion, agitation, somnolence, etc.)

    • chest pain

    • cough

    • dysuria

    • diarrhea

    • abnormal bleeding

  • Physical findings can vary as well. Most patients with sepsis can have:

    • tachycardia (heart rate >100 beats per minute)

    • alterations in body temperature (fever or hypothermia)

    • altered blood pressure (hypertension or hypotension)

    • cellulitis

    • infected catheters

    • changes in mental status (obtundation, stupor, or coma)

    • petechiae

  • Indications of decreased tissue perfusion include, but are not limited to:

    • oliguria

    • altered mentation

    • delayed capillary refill

    • cool skin

    • clammy extremities

How did the patient develop sepsis? What was the primary source from which the infection spread?

  • Obtain a thorough history from the patient and/or family and caregivers. Look for recent surgeries or prosthetic device placements, as well as intravenous catheters (e.g., hemodialysis lines).

  • Infectious sources associated with sepsis are summarized in Table I.

Table I

Infectious etiologies associated with sepsis.

Which individuals are of greater risk of developing sepsis?

Individuals who are at greater risk of developing sepsis are:

  • neonates and infants (aged <1 year)

  • elderly patients (age >65 years)

  • patients with human immunodeficiency virus infection/acquired immunodeficiency syndrome

  • patients with diabetes mellitus, renal failure, and hepatic failure

  • nursing home or long-term care facility residents

  • patients with recent exposure to antibiotics

  • burn or multiple-trauma victims

  • intravenous drug abusers

  • postoperative patients

  • patients with malignancies

  • patients receiving chemotherapy

Beware: there are other diseases that can mimic sepsis:

Differential diagnosis:

  • acute stroke

  • acute myocardial infarction

  • acute pulmonary embolism

  • acute hemorrhage

  • adrenal insufficiency

  • anaphylaxis

  • aspiration

  • central fever (patients with head trauma and/or neurologic dysfunction)

  • deep venous thrombosis

  • diabetic ketoacidosis

  • diuretic-induced hypovolemia

  • drug fever

  • pancreatitis

  • systemic lupus erythematosus flare

  • spinal cord injury

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Peripheral complete blood count: leukopenia or leukocytosis; low platelets; anemia

  • Liver tests: elevation of aspartate aminotransferase and/or alanine aminotransferase; low albumin; elevated bilirubin; elevated lactate

  • Coagulation factors: prolonged prothrombin or partial thromboplastin time; low fibrinogen

  • Basic metabolic panel: elevated blood urea nitrogen and/or creatinine; hyperglycemia

  • Urinalysis showing urinary tract infection

  • Arterial blood gas: low oxygen levels; metabolic (lactic) acidosis; respiratory alkalosis

  • Serum lactate: elevation can result from tissue hypoxia

Results that confirm the diagnosis

  • Blood cultures: positive organism (positive in approximately 30% of cases)

  • Ascitic fluid culture: positive organism (for patients with hepatic failure and/or underlying cirrhosis)

  • Catheter and/or indwelling device tip culture: positive organism

  • Urine Gram stain or urine culture: positive organism

What imaging studies will be helpful in making or excluding the diagnosis of sepsis?

  • The benefits of obtaining dedicated imaging scans need to be weighed against the risks of transporting potentially unstable patients with severe sepsis or septic shock.

  • Chest X-rays are useful to evaluate for pneumonia and can be ordered as portable in some hospitals.

  • Computed tomography scans can show abscesses, indwelling infections, or organ perforation.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

  • The Sequential (Sepsis-Related) Organ Failure Assessment Score can help identify patients developing organ dysfunction.

  • Infectious disease services can be helpful in elucidating sources of infection or in management of goal-directed therapy for resistant organisms.

  • Surgery can be helpful for sepsis caused by an abscess, necrosis, or device.

  • Nephrology can be helpful in cases of dialysis.

  • Rapid response teams can be helpful to facilitate transfer of patients to higher care settings.

If you decide the patient has sepsis, what therapies should you initiate immediately?

Key principles of therapy

  • Start broad spectrum antimicrobial treatment immediately.

  • Resuscitate with intravenous fluid.

  • If, despite adequate intravenous fluid, the patient remains hypotensive or hypoperfusing, start vasopressor support and/or steroid supplementation

  • Utilize the Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) scoring system to determine which patients are at a higher risk for mortality and may benefit from transfer to an intensive care setting.

  • Insert a Foley catheter (urinary catheter) if the patient does not have one already in order to adequately monitor urine output.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Antibiotic guidelines

  • Broad spectrum antimicrobial treatment is defined as a combination of antibiotics that act against a wide range of pathogens. This is especially important as most of the time, the infecting organism is not known. Most studies indicate starting antibiotics within the first hour of suspicion improves morbidity and mortality. This is particularly important in the preintensive care unit setting, such as emergency departments. Some suggest that for every additional hour before effective antibiotic therapy is instituted following initial hypotension, the survival rate decreases by 7.6% per hour on average. Empiric broad spectrum coverage may decrease risk of bacterial resistance and reduce the probability of antibiotic failure.

  • Obtain blood cultures, preferably from two different sites, prior to initiating antibiotics. One or more blood cultures should be percutaneous and, if the patient has vascular access device, then one blood culture should be obtained from that site.

  • Use antibiotics with broad spectrums of coverage, based on clinical presentation, probable source of infection, the patient's immune status, and underlying risk factors, as well as local epidemiologic factors, such as organism-resistance patterns. It is important to note whether a patient was previously exposed to antibiotics or previous culture results. Using inappropriate antibiotics increases risk of death in intensive care unit (ICU) bacteremia from 30 to 60% and from 70 to 100% in cases of gram-negative shock.

  • Many ICUs with a high frequency of multiresistant organisms are using two-drug empiric therapy for serious gram-negative infections until microbiological speciation and susceptibility data are available.

    • Reassess antimicrobial therapy daily.

    • Begin narrowing coverage as soon as pathogens are identified or with resolution of shock, usually within 48 to 72 hours. Experts suggest that there is no benefit to prolonged broad-spectrum coverage; in fact, this may actually increase chances of antibiotic resistance. Combination therapy should be continued for 3 to 5 days, with total duration of antibiotics between 7 to 10 days. Currently, there are no randomized controlled trials on de-escalation of therapy in patients with sepsis or septic shock.

    • Stop antimicrobial therapy if the cause of sepsis or shock is found to be noninfectious.

    • Begin source control as soon as possible after successful initial resuscitation.

    • Use patient allergy profiles to any antimicrobials to guide antibiotic choice (e.g., allergy to penicillins or sulfa drugs).

Specific recommendations

  • Pneumonia as source: add a fluoroquinolone.

  • Patients with splenectomies: be sure to cover for encapsulated organisms.

  • Neutropenic patients: cover for Pseudomonas and other resistant gram-negatives.

  • Resistant organisms in nosocomial setting:

    • increasing presence of methicillin-resistant Staphylococcus aureus: treat with vancomycin.

    • vancomycin-resistant Enterococcus (VRE): treat with linezolid, tigecycline, daptomycin, or quinupristin-dalfopristin.

Treatment options are summarized in Table II.

Table II:

Treatment options for sepsis.
  • Aminoglycosides: Pharmacokinetic monitoring may be appropriate to prevent toxicity. Daily dosing is recommended.

  • Beta-lactams: More frequent dosing or continuous infusion is preferred. For example, piperacillin-tazobactam 3.375g every 6 hours should be given instead of 4.5g every 8 hours.

  • Amingoglycosides, fluoroquinolones, metronidazole, and amphotericin B are some anti-infective agents that have dose-dependent microbicidal efficacy. Conversely, beta-lactams and vancomycin work in a time-dependent mechanism to kill organisms.

2. Next list other key therapeutic modalities.

What other therapies are helpful for reducing complications?

  • Initial fluid resuscitation over the first 6 hours, with titration to goals of central venous pressure (CVP) 8 to 12mm Hg (or 12-15mm Hg in mechanically ventilated patients or patients with pre-existing decreased ventricular compliance), mean arterial pressure (MAP) 65 to 90mm Hg, urine output greater than or equal to 0.5mL/kg/hour, or mixed venous oxygenation greater than or equal to 65%. Crystalloids or colloids can be used. Some newer studies are suggesting that a positive fluid balance over 4 days (measured with CVP >12mm Hg) may actually increase mortality.

  • Start with a fluid challenge of greater than or equal to 1,000mL of crystalloids or 300 to 500mL of colloids over 30 minutes.

  • Three recently published large multi-national studies have suggested no significant difference in mortality outcomes with early goal-directed therapy (ARISE 2014, ProCESS 2014, Mouncey et al 2015).

  • Vasopressor therapy and inotropes can be used alongside fluid to achieve MAP greater than or equal to 65mm Hg, in order to maintain perfusion. See next section on vasopressors.

  • Intravenous hydrocortisone can be initiated in adult patients with septic shock, though recent data is suggesting that intravenous steroids may not be better than placebo in terms of morbidity or mortality. Usual starting dose is 100mg every 8 hours. Steroids should be weaned when vasopressors are no longer required. Avoid dexamethasone if hydrocortisone is available, as this can lead to immediate and prolonged suppression of the hypothalamic-pituitary-adrenal axis. Hydrocortisone may not be feasible in many developing countries.

  • Transfuse red cells when hemoglobin is less than 7.0g/dL to a goal hemoglobin of 7.0 to 9.0g/dL. This increases oxygen delivery and has been shown to improve mortality in some cases.

Controversial or evolving therapies

  • Recombinant human activated protein C (rhAPC) has been shown to reduce mortality in patients with APACHE II scores greater than or equal to 25 or with multiorgan failure in two large randomized controlled trials. Activated protein C is a soluble, vitamin-K dependent anticoagulant that works by inactivating cofactors Va and VIIIa in the coagulation cascade, as well as plasminogen-activator inhibitor 1. It also has antiapoptotic activity, blocks productions of cytokines by monocytes, and blocks cell adhesion. Overall, it works by decreasing inflammation.

  • It is the only anticoagulant that has proved effective in patients with severe sepsis. One of the major adverse effects of activated protein C is an increased risk of significant, life-threatening hemorrhage. One study showed a 2.5 to 3% increased risk of hemorrhage, especially intracranial hemorrhage. Activated protein C should be avoided in patients with an international normalized ratio greater than 3, platelet counts of less than 30,000 per cubic millimeter, intracranial or intraspinal surgery within the last 2 months, severe head trauma, patients with epidural catheters, and intracranial neoplasm or mass lesion or evidence of cerebral herniation.

  • Measuring venous saturation of oxygen can be an indicator in evaluating cardiac function. If less than 2.5L/min/m2, consider starting dobutamine to increase cardiac output. This may not be feasible in many institutions.

  • Keep in mind that drug metabolism and pharmacokinetics may be altered in the intensive care setting. Patients with poor perfusion to the gut may have bowel edema and/or ileus, which would decrease absorption of oral antibiotics. In patients with volume overload, drugs that normally distribute to extracellular spaces may have lower than normal concentrations due to the presence of increased extracellular fluid. In these patients, maximal recommended dosing of antibiotics should be used in sepsis and septic shock.

  • Shock states can lower the glomerular filtration rate, and subsequently the clearance of certain anti-infective agents. Also, patients with increased cardiac output and low serum albumin may have increased drug clearance. On the other hand, burn victims and patients with sepsis alone can have an increased glomerular filtration rate. Infusion of albumin was not shown to reduce all-cause mortality in a randomized control trial, though this study may have been underpowered (Caironi et al 2014).

  • Measure antibiotic levels in ICU patients, when there is a low therapeutic index, and when there is a direct relationship between serum levels and efficacy or toxicity. Certain antibiotics have levels that can be followed, such as vancomycin and tobramycin.

  • Clinicians much watch for a response to antibiotics. Patients with chronic vascular insufficiency may need more penetrant drugs, such as fluoroquinolones, clindamycin, rifampicin, or metronidazole, or even revascularization procedures.

  • Abscesses often require surgical debridement. Smaller abscesses, such as anaerobic lung abscesses or small brain abscesses can be treated with prolonged antibiotics.

  • Controversy arises in terms of antibiotic antagonism, where some suggest that using a single agent with broad therapy may have better outcome than using multiple agents.

  • Source control to improve morbidity. This consists of using all measures to control the source of infection. Source control should be a balance between maximum efficacy and minimal physiologic changes. Source control in sepsis is summarized in Table III.

  • A randomized trial of rosuvastatin in patients with sepsis-associated acute respiratory distress syndrome did not show any significant reduction in in-hospital mortality (ARDS Clinical Trials Network 2014).

Table III.

Source control in sepsis.
Drainage Debridement Device removal Definitive control
Abscess Necrotizing fasciitis Infected intravascular catheter Surgical resection of necrotic organ or perforated viscus
Thoracic empyema Pyelonephritis Urinary catheter Sigmoid resection for diverticulitis
Septic arthritis Cholangitis Infected intrauterine device Cholecystectomy for gangrenous cholecystitis
Mesenteric ischemia Infected pacemaker Clostridial myonecrosis
Mediastinitis

Vasopressors

  • Goal is to maintain the MAP between 65mm Hg and 90mm Hg in order to maintain adequate tissue perfusion. MAP is considered the driving force for perfusion of most vital organs. The exact blood pressure goal to target in septic shock is uncertain. For example, patients with diastolic dysfunction, decreased ventricular compliance, elevated intra-abdominal pressures, and pulmonary hypertension can have different perfusion end points.

  • Remember to assess regional and global perfusion while on vasopressors. Variables to use to assess tissue perfusion include serum lactate levels, CVP, base deficit (as an indirect measure of lactic acidosis), and venous oxygen saturation.

  • Vasopressors can be used emergently to maintain perfusion, although fluid resuscitation is first and foremost. Remember to continue aggressive fluid resuscitation and wean vasopressors when appropriate.

  • Arterial cannula should be placed as soon as possible after vasopressor is started. This allows for more accurate blood pressure recordings, compared with using a blood pressure cuff.

  • There is ongoing debate as to which vasopressor agent is most effective. Generally, norepinephrine and dopamine are the first choice to correct hypotension in septic shock. Side effects overall include limb ischemia and necrosis.

Dopamine

  • Dose-dependent pharmacologic effects

  • Doses less than 5μg/hg/min: activates dopaminergic receptors, causing vasodilation of the renal and mesenteric circulation. However, current data suggests low-dose dopamine should not be used for renal protection in severe sepsis.

  • Doses between 5 to 10μg/kg/min: activates β-1 receptors, leading to cardiac contractility and causing increasing heart rate (subsequently perfusion).

  • Doses greater than 10μg/kg/min: activates α-1 adrenergic receptors, causing arterial vasoconstriction, which leads to elevated blood pressure.

  • Major side effects include tachycardia and arrhythmias.

Norepinephrine

  • α-adrenergic agonist, some β-adrenergic agonist effects

  • Dose is 0.01 to 3.3μg/kg/min

  • In studies where patients remained hypovolemic, norepinephrine was associated with renal ischemia

Phenylephrine

  • Selective α-1-adrenergic agonist

  • Rapid onset and short duration

  • Significant increase in urine output without change in serum creatinine

Epinephrine

  • α-adrenergic and β-adrenergic agent; also increases oxygen delivery

  • Potential to decrease splanchnic blood flow. This can increase serum lactate concentrations

  • Side effects include tachycardia, tachyarrhythmias, ischemia, and hypoglycemia

Vasopressin

  • Constricts vascular smooth muscle

  • Dose is 0.01 to 0.04 units per minute

  • Usually second line, though some studies are suggesting earlier initiation of vasopressin may improve outcomes

  • Side effects include coronary artery constriction leading to myocardial ischemia or infarction; especially in patients with severe coronary atherosclerosis

What complications could arise as a consequence of sepsis?

  • myopathy

  • acute respiratory distress syndrome

  • organ failure

  • respiratory failure

  • seeding of prosthetic valves or joints

  • prolonged hospitalization and/or rehabilitation

  • death

What should you tell the family about the patient's prognosis?

  • Sepsis has a high mortality rate, ranging from 19 to 56%.

  • Risk factors for poor outcomes include elderly and/or immunosuppressed patients. Mortality rates have been shown to increase from 10% in children to 38.4% in patients aged greater than 85 years.

What-if scenarios:

  • If you suspect a central intravenous-line infection as a source of sepsis, then remove the line as soon as possible and send the catheter tip for culture.

How do you contract sepsis and how frequent is this disease?

Epidemiology

  • The occurrence of sepsis ranges from 2% to 11% in ICUs in the United States.

  • The incidence is estimated to increase approximately 1.5% each year, with 76 to 110 cases per year per 100,000 population.

  • In the United States, incidence is higher in men than in women and in the non-white population compared with the white population.

  • It is estimated that there are 750,000 cases of severe sepsis yearly in the United States, with lower rates suggested in European countries.

  • There is an increasing emergence of multidrug resistant gram-positive and gram-negative pathogens.

Cost of care

  • Average cost per case has ranged from $9,000 to $22,100. Surgical patients cost approximately $30,800. Intensive care patients cost more than patients with sepsis managed on the floors; they cost $29,900.

  • Total national hospital associated with care of patients with severe sepsis was $16.7 to $20 billion in the United States.

How do these pathogens cause sepsis?

Sepsis is thought to be the result of a complex combination of exaggerated inflammatory response to infection, but also has features suggestive of immunosuppression.

  • Tissue hypoxia causes a heightened inflammatory response and release of cytokines such as interleukin 1, interleukin 6, and tumor necrosis factor α. Hypoxia also causes mitochondrial and endothelial dysfunction. These cytokines then lead to myocardial dysfunction, which causes decreased cardiac output and further tissue hypoperfusion. Decreased blood flow to kidneys leads to acute kidney injury.

  • Diffuse epithelial injury leads to tissue edema by capillary leak.

  • Activation of inflammatory cascade leads to excess production of clotting factors and subsequent microvascular thrombosis.

  • Neutrophil recruitment leads to multiple tissue death.

  • Loss of delayed hypersensitivity.

What other additional laboratory findings may be ordered?

  • Cerebrospinal fluid can show meningitis.

  • Urine antigens to Streptococcus pneumoniae and Legionella pneumophila type 1 may be found in patients with pneumonia as a source of sepsis.

  • Studies are looking at methods of measuring oxygen desaturation in the hepatic vein; these studies are suggesting that the splenic circulation is susceptible to ischemia and may drive organ failure.

How can sepsis be prevented?

  • Early identification of sepsis and initiating treatment immediately can decrease chance of progression to septic shock, as well as instituting correct antimicrobial regimens. Despite widespread use of the SIRS criteria, one out of eight patients may still have severe sepsis that may be missed by just SIRS criteria alone.

  • The SOFA score, previously known as the Sepsis-related Organ Failure Assessment, has been shown to predict patients at a higher risk for mortality and can be used to triage patients to a higher level of care (see Table IV). Recent large-scale studies have shown that patients with an acute SOFA score change of 2 or more as a result of infection reflects an overall mortality risk of approximately 10%. The quick SOFA (qSOFA) tool combines a respiratory rate ≥ 22/min, altered mentation, and a systolic blood pressure ≤ 100 mm Hg as a simple bedside criteria to identify adult patients with suspected infection who have higher morbidity.

  • Unfractionated or low-molecular weight heparin for deep venous thrombosis prophylaxis, unless there are contraindications such as severe coagulopathy, active or recent bleeding, or thrombocytopenia. If anticoagulation cannot be given for deep venous thrombosis prophylaxis, then institute graduated compression stockings or intermittent compression devices unless contraindicated.

  • Encourage primary prevention in outpatient settings, such as obtaining influenza or pneumococcal vaccines, routine health care, etc.

Table IV:

Sequential [Sepsis-Related] Organ Failure Assessment Score

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Dellinger, RP, Levy, MM, Carlet, JM. "Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008". Crit Care Med. vol. 36. 2008. pp. 296-327.

(Update on Surviving Sepsis Campaign from 2004 using Grades of Recommendation, Assessment, Development, and Evaluation via a consensus conference of experts. Categories include goal-directed therapy, broad-spectrum antimicrobials, culture data, source control, and adjunctive measures—including corticosteroids, vasopressors, activated protein C, and stress-dosed steroids.)

Machado, FR, Mazza, BF. "Improving mortality in sepsis: analysis of clinical trials". Shock. vol. 34. 2010. pp. 54-8.

(Analysis of studies implementing Surviving Sepsis Campaign bundles (or protocols) and effect on ICU cost. Presents Latin American Sepsis Institute data for mortality related to sepsis as well as short reduction in mortality rate after implementation of Surviving Sepsis Campaign bundles.)

Levy, MM, Fink, MP, Marshall, JC. "2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. 2001". Crit Care Med. vol. 31. 2003. pp. 1250-6.

(Signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters that are associated with sepsis as defined by group of leading experts in a joint conference.)

Angus, DC, Wax, RS.. "Epidemiology of sepsis: an update". Crit Care Med. vol. 29. 2001. pp. S109-16.

(Literature review of occurrence and hospital mortality of sepsis. Noted to show few population-based prospective cohort studies existed at this time to accurately determine risks and outcomes of sepsis. Reviews markers of inflammation and genetic predisposition that may be related to sepsis.)

Angus, DC, Linde-Zwirble, WT, Lidicker, J, Clermont, G, Carcillo, J, Pinsky, MR.. "Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care". Crit Care Med. vol. 29. 2001. pp. 1303-10.

(Observational study compiling data from seven hospitals in 2005; study showing frequency of mortality in patients with severe sepsis as well as cost anlaysis.)

Burchardi, H, Schneider, H.. "Economic aspects of severe sepsis: a review of intensive care unit costs, cost of illness and cost effectiveness of therapy". Pharmacoeconomics. vol. 22. 2004. pp. 793-813.

(Analysis of cost of ICU care of patients with severe sepsis as reported by multiple studies. Further discusses possibilities for cost containment in ICUs, including avoiding complications and introducing protocols.)

Siddiqui, S, Razzak, J.. "Early versus late preintensive care unit admission broad spectrum antibiotics for severe sepsis in adults". Cochrane Database of Systematic Reviews. 2010. pp. CD007081.

(Review article comparing early administration (<1 hour) of antibiotics versus late administration in patients with severe sepsis. However, despite broad search parameters, no randomized control studies were found that matched inclusion criteria.)

Robson, WP, Daniels, R.. "The Sepsis Six: helping patients to survive sepsis". Br J Nurs. vol. 17. 2008. pp. 16-21.

(Discussion of early detection, education of nurses and junior physicians, and six major categories of early goal-directed therapy (including blood cultures, oxygen delivery, administration of intravenous fluids and antibiotics, checking lactate, and monitoring urine output). Also briefly analyzes cost of sepsis in United Kingdom hospital.)

Claessens, YE, Dhainaut, JF.. "Diagnosis and treatment of severe sepsis". Crit Care. vol. 11. 2007. pp. S2.

(Discusses Surviving Sepsis Guidelines in terms of early goal-directed therapy and focuses on limitations in implementation, including delayed diagnosis and/or treatment.)

Hollenberg, SM.. "Vasopressor support in septic shock". Chest. vol. 132. 2007. pp. 1678-87.

(Review of the various vasopressors used in septic shock, including their mechanisms of action, doses, and complications.)

da Silva Ramos, FJ, Azevedo, LCP.. "Hemodynamic and perfusion end points for volemic resuscitation in sepsis". Shock. vol. 34. 2010. pp. 34-9.

(Review evaluating utility of mean arterial pressure, central venous pressure, pulse pressure variation, serum lactate, base deficit, and venous oxygen saturation. Briefly reviews pathophysiology.)

Boyd, JH, Forbes, J, Nakada, TA, Walley, KR, Russell, JA.. "Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality". Crit Care Med. vol. 39. 2011. pp. 259-65.

(Retrospective review of vasopressin in septic shock trial (VASST) patients who received intravenous fluids in the first four days showing increased mortality in patients with a cumulative positive fluid balance in 4 days.)

Zubert, S, Funk, DJ, Kumar, A.. "Antibiotics in sepsis and septic shock: like everything else in life, timing is everything". Crit Care Med. vol. 38. 2010. pp. 1211-12.

(Discussion of previous studies that looked at early goal-directed therapy in patients with sepsis, reviewing limitations, and ultimately focusing on importance of early administration of therapy to decrease morbidity and mortality of severe sepsis and septic shock.)

Sprung, CL, Brezis, M, Goodman, S, Weiss, YG.. "Corticosteroid therapy for patients in septic shock: some progress in a difficult decision". Crit Care Med. vol. 39. 2011. pp. 571-4.

(This study was a laboratory experiment using adrenal fasciculata-reticularis cells of rats and administering lipopolysaccharide with subsequent challenge with adrenocorticotropic hormone (ACTH). Study showed impaired production of steroids by cells pretreated with steroids as well as decreased response to ACTH stimulation in rats exposed to steroids; this suggests adrenal tolerance to steroids as a cause of adrenal insufficiency during sepsis.)

Barlow, G, Nathwani, D.. "Is antibiotic resistance a problem? A practical guide for hospital clinicians". Postgrad Med J. vol. 81. 2005. pp. 680-92.

(Identifies risk factors with resistant organisms, including methicillin-resistant S. aureus colonization. Reviews resistant patterns of Clostridium difficile, community acquired pneumonia, skin and soft tissue infection, and urinary tract infections in the United Kingdom by review of literature.

Murdoch, DR.. "Microbiological patterns in sepsis: what happened in the last 20 years?". Int J Antimicrob Agents. vol. 34. 2009. pp. S5-8.

(Review of microbial causes of sepsis, change in microbial patterns locally and globally, and effect of rise in prevalence of human immunodeficiency virus over the last 20 years.)

Sharma, S, Kumar, A.. "Antimicrobial management of sepsis and septic shock". Clin Chest Med. vol. 29. 2008. pp. 677-87.

(After brief review of pathophysiology, discusses pharmacodynamics and rationale for broad-spectrum antimicrobials. Also focuses on drug-level monitoring, failure of antibiotics, and de-escalation of therapy.)

Gomes Silva, BN, Andriolo, RB, Atallah, AN, Salomão, R.. "De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock". Cochrane Database Syst Rev. 2010. pp. CD007934.

(Intervention review using varying search engines, comparing randomized controlled trials where antimicrobial regimen was de-escalated based on culture results to studies with standard therapy for patients with sepsis, severe sepsis, or septic shock. Primary outcome was mortality at 28 days; no direct evidence available for de-escalation was found.)

Nguyen, HB, Rivers, EP, Knoblich, BP, Jacobsen, G, Muzzin, A, Ressler, JA, Tomlanovich, MC.. "Early lactate clearance is associated with improved outcome in severe sepsis and septic shock". Crit Care Med. vol. 32. 2004. pp. 1637-42.

(Prospective case series examining lactate clearance in patients with severe sepsis after 6 hours of emergency room intervention. Patients with early lactate clearance had decreased mortality rate.)

Gaieski, DF, Mikkelsen, ME, Band, RA. "Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department". Crit Care Med. vol. 38. 2010. pp. 1045-53.

(Single center study analyzing association of early goal-directed therapy in 261 patients with severe sepsis or septic shock when therapy started in emergency room. Antibiotics administered within 1 hour of qualification had lower mortality rate.)

Bozza, FA, Carnevale, R, Japiassú, AM, Castro-Faria-Neto, HC, Angus, DC, Salluh, JI.. "Early fluid resuscitation in sepsis: evidence and perspectives". Shock. vol. 34. 2010. pp. 40-3.

(Review of single randomized control-trial of early goal directed therapy for sepsis with a historical review of fluid resuscitation as well as potential mechanisms of improved clinical outcome with early fluid resuscitation. Briefly examines future studies pending.)

Spanos, A, Jhanji, S, Vivian-Smith, A, Harris, T, Pearse, RP.. "Early microvascular changes in sepsis and severe sepsis". Shock. vol. 33. 2010. pp. 387-91.

(Single-center trial comparing perfusion parameters in patients admitted with sepsis and severe sepsis compared with healthy individuals. Patients with more severe disease had a lower proportion of perfused vessels, lower microvascular flow index, and lower perfused vessel density.)

Kumar, A, Safdar, N, Kethireddy, S, Chateua, D.. "A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study". Crit Care Med. vol. 38. 2010. pp. 1651-64.

(Meta-analysis of randomized or observational studies in which high-risk patients were treated with combination antimicrobial agents versus low-risk patients as well as studies where monotherapy was administered. Of the 50 studies examined in the study, analysis suggested lower mortality in high-risk patients treated with combination antimicrobial therapy but higher mortality in low-risk patients treated with combination therapy.)

Rivers, E, Nguyen, B, Havstad, S. "Early goal-directed therapy in the treatment of severe sepsis and septic shock". N Engl J Med. vol. 345. 2001. pp. 1368-77.

(Study randomizing patients with severe sepsis and septic shock to either early goal-directed therapy (within 6 hours) or standard therapy with examination of primary endpoint of in-hospital mortality. Patients in the early goal-directed group had 30% mortality compared with 46% in the control group.)

Kollef, MH, Sherman, G, Ward, S, Fraser, VJ.. "Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients". Chest. vol. 115. 1999. pp. 462-74.

(A prospective, single-center cohort study examining the risk of inadequate antimicrobial treatment of community-acquired and nosocomial infections with hospital mortality rate. Patients at higher risk of receiving inadequate antibiotics included those with blood-stream infections, older age, increasing APACHE II scores, and previous administration of antibiotics.)

Hotchkiss, RS, Karl, IE.. "The pathophysiology and treatment of sepsis". N Engl J Med. vol. 348. 2003. pp. 138-50.

(Review article analyzing current knowledge regarding immune system function and cytokines. Autopsy studies in patients who died of sepsis indicate decreased immune cells, which was further demonstrated in this study. Also briefly highlights therapies in sepsis—including glycemic control, activated protein C, corticosteroids, and volume resuscitation.)

Toussaint, S, Gerlach, H.. "Activated protein C for sepsis". N Engl J Med. vol. 361. 2009. pp. 2646-52.

(Case followed by discussion of pathophysiology of sepsis, focusing on formation of procoagulant state, and pathophysiology of recombinant human activated protein C. Reviews current literature and studies using protein C and current guidelines.)

Wafaisade, A, Lefering, R, Bouillon, B. "Epidemiology and risk factors of sepsis after multiple trauma: an analysis of 29,829 patients from the Trauma Registry of the German Society for Trauma Surgery". Crit Care Med. vol. 39. 2011. pp. 621-8.

(Retrospective cohort study examining incidence of sepsis in trauma patients; patients were collected from Trauma Registry of the German Society for Trauma Surgery and incidence of sepsis was noted to decrease over the study period. However, while the overall mortality of trauma patients decreased, patients with sepsis complicating trauma did not change. This suggests greater need for early detection of sepsis in trauma patients.)

Gustot, T.. "Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response". Curr Opin Crit Care. vol. 17. 2011. pp. 153-9.

(Review article addressing current understanding of pathophysiology of systemic inflammatory response, sepsis, and severe sepsis. Includes review of inflammatory pathway and cytokines. Also discusses prognosis of sepsis and determinants of outcome of patients with sepsis.)

Callahan, LA, Supinski, GS.. "Sepsis-induced myopathy". Crit Care Med. vol. 37. 2009. pp. S354-67.

(Review of current evidence of incidence of myopathy in ICU patients, with specific reviews of studies showing alterations in skeletal muscles and subcellular changes along with possible pathophysiologic mechanisms of such changes in septic patients. Clinical implications are addressed.)

Vincent, JL, Nelson, DR, Williams, MD.. "Is worsening multiple organ failure the cause of death in patients with severe sepsis?". Crit Care Med. vol. 39. 2011. pp. 1-6.

(Retrospective analysis of multicenter database analyzing incidence of multiorgan failure, refractory shock, and respiratory failure as three leading causes of death in patients with severe sepsis.)

Russell, JA.. "Management of sepsis". N Engl J Med. vol. 355. 2006. pp. 1699-713.

(Review article of pathophysiology of sepsis and therapies for early and late stages of sepsis.)

Vincent, JL, Baron, JF, Reinhart, K. "Anemia and blood transfusion in critically ill patients". JAMA. vol. 288. 2002. pp. 1499-507.

(Multicenter prospective study examining frequency of blood draws, anemia, and transfusions in ICU patients with mortality. It was noted that patients who received transfusions had higher mortality and worsening organ function.)

Warren, HS, Suffredini, AF, Eichacker, PQ, Munford, RS.. "Risks and benefits of activated protein C treatment for severe sepsis". N Engl J Med. vol. 347. 2002. pp. 1027-30.

(Brief review of activated protein C with detailed discussion of two major trials in use of protein C in sepsis. Reviews indications for protein C as well as risks of hemorrhage.)

Sprung, CL, Annane, D, Keh, D. "Hydrocortisone therapy for patients with septic shock". N Engl J Med. vol. 358. 2008. pp. 111-24.

(Multicenter, randomized, placebo-controlled trial enrolling 499 patients with septic shock who were randomized to hydrocortisone 50mg every every 6 hours for 5 days versus placebo showed no signficant difference in mortality at 28 days.)

Mason, PE, Al-Khafaji, A, Milbrandt, EB, Suffoletto, BP, Huang, DT.. "CORTICUS: the end of unconditional love for steroid use?". Crit Care. vol. 13. 2009. pp. 309.

(Comparison of the two large studies examining steroid use in ICU patients. Recommendations including reserving steroid use for septic patients with hypotension unresponsive to fluid resuscitation and vasopressors.)

Chelazzi, C, Villa, G, De Gaudio, AR.. "Cardiorenal syndromes and sepsis". Int J Nephrol. vol. 2011. 2011. pp. 652967.

(Review of five types of cardiorenal syndrome, with focus on type 5, as associated with severe sepsis. This then reviews epidemiology, suspected pathophysiology, and treatment.)

Pea, F, Viale, P.. "Bench-to-bedside review: appropriate antibiotic therapy in severe sepsis and septic shock—does the dose matter?". Crit Care. vol. 13. 2009. pp. 1-13.

(Review of basic principles of antimicrobial management, such as minimum inhibitory concentration. Further delineates common dosing of antimicrobials and renal dosing.)

De Waele, JJ.. "Early source control in sepsis". Langenbecks Arch Surg. vol. 395. 2010. pp. 489-94.

(Review of rationale of early source control, specifically drainage, debridement and device removal, decompression, and restoration of anatomy, particularly for intra-abdominal infections. Calls for levels of urgency for source control.)

Micek, ST, Welch, EC, Khan, J, Pervez, M, Doherty, JA, Reichley, RM, Kollef, MH.. "Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to gram-negative bacteria: a retrospective analysis". Antimicrob Agents Chemother. vol. 54. 2010. pp. 1742-8.

(Retrospective cohort study in patients receiving appropriate versus inappropriate initial antimicrobial therapy showed increased incidence of healthcare-associated nosocomial infections. These patients were also more likely to have kidney disease, diabetes, and prior antibiotic exposure in subgroup analysis.)

Wong, F, Bernardi, M, Balk, R. "Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club". Gut. vol. 54. 2005. pp. 718-25.

(Review of current knowledge of sepsis, including definitions, epidemiology, pathophysiology, with a focus on how sepsis presents in patients with cirrhosis. Discusses gut translocation, spontaneous bacterial peritonitis, and recommendations on antibiotic prophylaxis.)

Sheu, CC, Gong, MN, Zhai, R. "Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS". Chest. vol. 138. 2010. pp. 559-67.

(Prospective cohort study comparing patients with sepsis-related acute respiratory distress syndrome (ARDS) and nonsepsis related ARDS in terms of disease severity, time to extubation, and overall mortality rate. It was suggested that patients with sepsis-related ARDS had poorer outcomes and higher disease severity.)

Kampmeier, TG, Rehberg, S, Westphal, M, Lange, M.. "Vasopressin in sepsis and septic shock". Minerva Anestesiol. vol. 76. 2010. pp. 844-50.

(This article reviews the experiments and summaries of vasopressin use in sepsis and septic shock, including discussion of pathophysiology.)

Wilson, PG, Manji, M, Neoptolemos, JP.. "Acute pancreatitis as a model of sepsis". J Antimicrob Chemother. vol. 41. 1998. pp. 51-63.

(Reviews details of pathophysiology of systemic inflammatory response syndrome and how pancreatitis presents as a form of SIRS and can mimic sepsis.)

Barton, JR, Sibai, BM.. "Severe sepsis and septic shock in pregnancy". Obstret Gynecol. vol. 120. 2012. pp. 689-706.

(Review and case series of pregnant patients with severe sepsis and septic shock. Includes incidence, common causes, as well as management.)

Singer, M, Deutschman, CS, Warren Seymour, C, Shankar-Hari, M. "The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)". JAMA. vol. 315. 2016. pp. 801-810.

(Most recent update to guidelines for definitions of sepsis.)

Vincent, J-L, Moreno, R, Takala, J, Willats, S. "The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure". Intensive Care Med.. vol. 22. 1999. pp. 707-710.

(One of the original studies describing the SOFA tool and showing increased mortality with progressively higher SOFA scores).

Antonelli, M, DeBacker, D, Dorman, T, Kleinpell, R, Levy, M, Rhodes, A.. "Surviving Sepsis Campaign Responds to Sepsis-3.2016". pp. 1-2.

Kaukonen, K-M, Baily, M, Pilcher, D, Jamie Cooper, D, Bellomo, R.. "Systemic inflammatory response syndrome criteria in defining severe sepsis". N Engl J Med. vol. 372. 2015. pp. 1629-38.

(A retrospective review of patients with SIRS criteria enrolled in the ANZICS Adult Patient Database that compared outcome measures in terms of morbidity and mortality. It showed that that mortality increased with increasing SIRS criteria and that SIRS criteria missed one out of eight patients with severe sepsis.)

Mouncey, PR, Osborn, TM, Power, GS, Harrison, DA, Sadique, Z, Grieve, RD. "Trial of Early, Goal-Directed Resuscitation for Septic Shock". N Engl J Med. vol. 372. 2015. pp. 1301-11.

(A randomized, open, multicenter, parallel-group trial based in England. Patients were randomized 1:1 to early goal directed therapy or usual care. Ninety day mortality was not significantly different between the two groups).

"Goal-Directed Resuscitation for Patients with Early Septic Shock. The ARISE Investigators and the ANZICS Clinical Trials Group". N Engl J Med. vol. 371. 2014. pp. 1496-506.

(A multicenter, prospective, randomized, parallel-group trial comparing early-goal directed therapy of protocol resuscitation versus standard of care of 1600 patients. Patients in the early-goal directed therapy group received more fluids in the first 6 hours and often received more blood transfusions and vasopressors. There were no significant differences in all-cause mortality at 90 days. There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay.)

"A Randomized Trial of Protocol-Based Care for Early Septic Shock. The ProCESS investigators". N Engl J Med.. vol. 370. 2014. pp. 1683-93.

(A multicenter, randomized trial in which patients were randomized 1:1:1 to either protocol-based early goal directed therapy, protocol-based standard therapy, or usual care. In-hospital mortality did not significantly differ between any of the groups.)

"Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome. The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network". N Engl J Med. vol. 370. 2014. pp. 2191-200.

(A multicenter trial with patients requiring mechanical ventilation and pulmonary infiltrates with systemic inflammatory response syndrome who were randomized to receive 40 mg enteral rosuvastatin loading dose followed by 20 mg daily or placebo. There was no significant difference in in-hospital mortality at 60 days between the two groups.)

Caironi, P, Tognoni, G, Masson, S, Fumagalli, R. "Albumin Replacement in Patients with Severe Sepsis or Septic Shock". N Engl J Med.. vol. 370. 2014. pp. 1412-21.

(A multicenter, randomized, controlled trial conducted by the Albumin Italian Outcome Sepsis (ALBIOS) study group where patients in Italy were randomly assigned to receive 20% albumin and crystalloid solution or crystalloid solution alone from start of study until day 28 or discharge from the intensive care unit. Daily albumin was infusion for goal serum albumin of 30 grams per liter or more. There was no significant difference in all-cause mortality at day 28 or day 90. However, the study may have been underpowered and the majority of patients were enrolled during later stages of sepsis.)

DRG CODES and expected length of stay

  • 995.91 Sepsis

  • 995.92 Severe sepsis

  • 995.93 Systemic inflammatory response syndrome due to noninfectious process without acute organ dysfunction

  • 995.94 Systemic inflammatory response syndrome due to noninfectious process with acute organ dysfunction

ICD 10 Codes: (Singer et al 2016)

  • R65.20 Sepsis

  • R65.21 Septic shock

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