In recent years it has become clear that septic shock is caused by a combination of infectious, hemodynamic, coagulopathic, and inflammatory processes.¹ It is initiated by infection and can progress to hypoperfusion and organ failure.² The incidence and mortality of sepsis both rise exponentially with age and comorbidity, with mortality ranging from 20 to 60 percent.^2-6

Patients with sepsis have increased levels of several inflammatory cytokines, such as tumor necrosis factor a , interleukin-1b , and interleukin-6^7,8 ; these are associated with and may contribute to the systemic inflammatory response syndrome (SIRS).² Numerous trials over the last several decades have studied agents directed at components of the bacterial wall or secondary mediators of inflammation. Although some initial trials were promising, no treatments based on these strategies have stood the test of time. A review of 131 studies of septic shock published over a 40 year period showed persistently high mortality rates, despite a slight decrease over time.⁹

More recently, a new hypothesis regarding the pathobiology of sepsis has emerged that implicates endothelial damage and a hypercoagulable state. Three new agents attempt to treat sepsis by blocking the coagulation cascade: Anti-Thrombin III (ATIII), Tissue Factor Pathway Inhibitor (TFPI) and Activated Protein C (APC). All have recently been evaluated in clinical trials for sepsis. Both ATIII and TFPI failed to decrease mortality. However, the trial of APC demonstrated a significant reduction in mortality in patients with severe sepsis.

 
Septic shock mortality rate. Adapted from Friedman et al, 1998.⁹

The biological rationale for Protein C therapy: Endothelial damage with intravascular coagulation (DIC) and deficiencies of the anti-coagulant system are often present in severe sepsis.^10-11 Activated Protein C, as shown in the figure, inhibits coagulation via inhibition of the activated forms of factors V and VIII, which serve as cofactors in the clotting cascade.¹² Preliminary studies documented decreased levels of Protein C and other anticoagulant factors in patients with septic shock,^10,13 and Protein C levels are inversely associated with mortality.¹⁴ Studies in a baboon model of sepsis prompted the development of a recombinant form of Activated Protein C¹⁵ that in turn led to the large clinical trial of Activated Protein C described by the following graphic.

Adapted from ref. 12

Clinical trial outcome data5

A report in The New England Journal of Medicine in March 2001 described the results of a randomized placebo-controlled trial of a new treatment for sepsis: recombinant human Activated Protein C, also known as Xigris, or drotrecogin alfa (activated).5 The study included 1,690 patients with severe sepsis, defined as a combination of known or suspected infection, 3 out of 4 clinical criteria (tachycardia, tachypnea, abnormal temperature, abnormal WBC), and acute organ dysfunction. The trial excluded patients with: thrombocytopenia, recent surgery or trauma, HIV with low CD4 count, history of transplant, end-stage renal disease, liver disease, or pancreatitis. The study was terminated early because of the mortality benefit seen in the treatment group, with an absolute mortality reduction of 6.1 percentage points. The major adverse event was bleeding, with an excess risk of serious bleeding of 1.5 percentage points in the treated group. A summary of all aspects of the trial is posted on the FDA website: http://www.fda.gov/ohrms/dockets/ac/01/briefing /3787b1.htm.

Selecting the right patients for treatment: In this trial, the mortality benefit from activated Protein C was concentrated almost entirely in the 50% of patients who were most ill, as reflected in the number of organ failures and in APACHE II scores ≥25. The APACHE II score combines data from several measures of acute and chronic function; an on-line program to calculate it can be found at http://www.sfar.org/scores2/apache22.html. Analysis of the complete data presented to the FDA Advisory Panel indicates that patients in the half of the study sample who were less ill appeared to derive little benefit from APC, although they were exposed to the same level of bleeding risk.¹⁶

Benefit occurred primarily in sicker patients, as defined by APACHE II score or organ failure:

APC causes a significant increase in bleeding events: Patients at increased risk of bleeding were excluded from the efficacy trial.5 It is likely that use of APC in such patients would have resulted in higher rates of serious bleeding than those reported. Indeed, since the initial published study, 13 (2.5%) of 520 patients treated with APC in an open label study have developed intracranial hemorrhage; 8 (1.5%) of these events developed during APC infusion.17 Because of the product's limited efficacy in patients with lower risk of death and lower APACHE II scores and its risk of major bleeding complications, patients must be selected with great care. Estimated cost: The manufacturer has priced this product at $5,000 - $8,000 per four-day course of therapy for each patient prescribed APC.

Guidelines for APC use

The potential toxicity of APC is substantial, and may well exceed its benefit in patients who do not have severe sepsis. Specific decisions on its use must be based on a given patient's clinical situation, and on local guidelines. The following general recommendations are based on a review of the most current available information and represent areas of general agreement in interpretation of available data. Eligibility criteria may undergo further refinement as additional data become available

Patients treated with APC should have acute life-threatening infection manifested by:

1) systemic inflammatory response syndrome (SIRS), defined as abnormalities in 3 of the following 4 areas:

temperature, heart rate, respiratory status, and white blood cell count; and

2) acute organ failure, present for less than 24 hours, involving one or more of the following systems:

cardiovascular, pulmonary, renal, hematologic, and/or metabolic.

In addition, there should be a commitment to treat the patient aggressively.

These are minimal criteria for use. Other patient characteristics indicating an increased mortality risk, such as presence of shock and multiple organ failure, of APACHE II score>25, may be used in determining the potential benefit of treatment as compared to the risk of intracranial or other serious bleeding.

APC should NOT be administered to patients with the following contraindications:

• concurrent use of anticoagulants or recent use of thrombolytics
• thrombocytopenia
• active bleeding or coagulopathy
• recent major surgery or anticipated surgery
• recent hemorrhagic stroke
• cirrhosis (esophageal varicies, portal hypertension, etc.)
• recent cranial procedure, spinal procedure, or head trauma
• intracranial mass or neoplasm
• trauma with increased risk of bleeding
• epidural catheter
• age less than 18 years (patients with meningococcemia with purpura fulminans may be considered on a case-by-case basis).

APC should in general not be used in patients with an advance directive to withhold life-sustaining treatment or with other reason to avoid aggressive management (e.g., another terminal illness).

Monitoring APC Use

● If surgery or a percutaneous procedure is to be performed or an epidural catheter placed, APC should be stopped 2 hours prior to the procedure.

● APC can be restarted 1 hour after a percutaneous procedure and 12 hours after a surgical procedure or epidural catheter, if adequate hemostasis has been achieved.

● If evidence of gastrointestinal bleeding occurs, APC should be stopped, and endoscopy considered to detect a stomach or bowel lesion.

● Patients receiving APC should be given a gastroprotective agent such as sucralfate, a histamine-2 antagonist, or a proton-pump inhibitor.

● If a patient requires full-dose therapeutic heparin for the treatment of a thrombotic event, the APC infusion should be stopped.

● If a patient requires hemodialysis, consider using APC alone as the sole anticoagulant; if clotting occurs, use the lowest dose of heparin necessary to maintain the patency of the dialysis filter.

Note: This material will be available shortly in the Partners Handbook.

References:

1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and multiple organ failure, and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864-874.
2. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA 1995; 273:117-123.
3. Linde-Zwirble WT, Angus DC, Carcillo J, et al. Age-specific incidence and outcome of sepsis in the US. Crit Care Med 1999; 27:33A.
4. Sands KE, Bates DW, Lanken p, et al. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 1997; 278:234-240.
5. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.
6. Astiz ME, Rackow EC. Septic shock. Lancet 1998; 351:1501-1505.
7. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997; 112:235-243.
8. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997; 25:1095-1100.
9. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time? Crit Care Med 1998; 26:2078-2086.
10. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Chest 1992; 101:816-823.
11. Levi M, ten Cate H, van der Poll T, et al. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993; 270:975-979.
12. Adapted from: Leung LLK. Hemostasis and its regulation. in Scientific American Medicine Online, Dec 1999.
13. Kidokoro A, Iba T, Fukunaga M, et al. Alterations in coagulation and fibrinolysis during sepsis. Shock 1996; 5:223-228.
14. Hartman DL, Helterbrand JD, Bernard GR, et al. Protein C (PC) levels in sepsis: association with mortality. Am J Respir Crit Care Med 1997; 155:A708.
15. Hartman DL, Bernard GR, Helterbrand JD, et al. Recombinant activated protein C (rhAPC) improves coagulation abnormalities associated with severe sepsis. Intensive Care Med 1998b; 24:S77.
16. Food and Drug Administration. Drotrecogin Alfa briefing information. Available at: http://www.fda.gov/ohrms/dockets/ac/01 /briefing /3787b1.htm
17. Eli Lilly. Biologics license application: recombinant human activated protein C. Testimony to FDA Anti-Infective Advisory Committee October 16,2001.