Feature Articles

Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study)*
Fabia n Jaimes, MD, MSc, PhD; Gisela De La Rosa, MD; Carlos Morales, MD, MSc; Fernando Fortich, MD; lvaro Mun Clara Arango, MD; Daniel Aguirre, MSc; A oz, PhD
Objective: The primary aims of this study were to determine the effects of heparin on length of stay and change from baseline multiple organ dysfunction (MOD) score. Secondary objectives were to estimate the effects of heparin on 28-day all-cause mortality, and to determine the possible effect modication on 28-day all-cause mortality, in subgroups dened by site of infection and baseline values of Acute Physiology and Chronic Health Evaluation II score, MOD score, and D-dimer. Design: Randomized, double-masked, placebo-controlled, single-center clinical trial, testing low dose continuous infusion of unfractioned heparin (UFH) as complementary treatment for sepsis. Setting: Five hundred fty bed University Hospital and referral center in Medelln, Columbia. Patients: Three hundred nineteen patients admitted at the emergency room with signs indicative of sepsis. Interventions: Patients were randomly assigned to receive placebo or UFH (500 units/hour for 7 days). Measurements and Main Results: The median length of stay in patients discharged alive in the placebo group was 12.5 days (interquartile range 8 20), and 12 days (interquartile range 8 19.5) in the heparin group (p 0.976). The MOD score improved equally in the two treatments arms with an average decline of 0.13 and 0.11 per day for the placebo and heparin groups (p 0.240), respectively. The overall 28-day mortality was 16% in the placebo group and 14% in the heparin group (p 0.652). Subgroup analyses did not show any statistically signicant reduction in 28-day mortality with UFH. There was only one serious adverse event on a patient who received heparin but it was fully resolved without complications. Conclusions: Our ndings suggested that UFH may be a feasible and safe intervention in sepsis. However, this study was not able to demonstrate a benecial effect on the chosen primary outcomes or in the 28-day mortality rate. (Crit Care Med 2009; 37: 11851196) KEY WORDS: sepsis; coagulation; heparin; clinical trial; organ dysfunction; longitudinal studies

everal investigators have documented the close relationship among infection, inammation, and coagulation in sepsis (13); and even though clinically overt disseminated intravascular coagulation may occur in only 30% to 50% of septic patients, the activation of coagulation

*See also p. 1486. From the Departments of Internal Medicine (FJ, GDLR, FF, CA), Surgery (CM), and Neurosciences Group (DA), School of Medicine, Universidad de Antioquia, Medelln, Colombia; and Department of Epidemiology (AM), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. This work was performed at the Hospital Universitario San Vicente de Pau l, Medelln, Colombia. Supported by Instituto Colombiano para el Desarollo de la Ciencia y la Tecnologa (COLCIENCIAS), Grant 410-2004 (11150416347) and by the Universidad de Antioquia, Comite para el Desarrollo de la Investigacio n (CODI, 2407-2005). The authors have not disclosed any potential conict of interests. For information regarding this article, E-mail: fjaimes@udea.edu.co Copyright 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e31819c06bc

cascade is an early and common response to the infectious challenge (1, 2, 4, 5). In turn, most of the molecules involved in the procoagulant state that characterizes sepsis (e.g., thrombin) are also powerful generators or ampliers of the inammatory response (6, 7). The rationale behind anticoagulant treatments is that certain factors (e.g., activated protein C, antithrombin, and tissue factor pathway inhibitor) are depleted, and the use of recombinant technology or plasma-puried derivatives may replenish them. In contrast, heparin (a naturally occurring proteoglycan) does not simply replenish what sepsis patients have depleted, it binds to and activates antithrombin. As a consequence of this activation, heparin dramatically reduces thrombin generation and brin formation (8, 9). Animal and human models have suggested that heparin, in addition to successfully inhibiting the coagulation cascade in sepsis, may also modulate a wide array of responses to infection (10 14). Furthermore, three clinical trials for recombinant anticoagulants allowed the

use of prophylactic treatment for venous thrombosis with a dose of heparin of up to 10,000 or 15,000 units subcutaneously per day (1517). Although heparin was not given based on a random allocation, when those who did receive heparin were compared with those who did not in the placebo arms of the clinical trials, all three studies showed a higher mortality in the subgroups that did not receive heparin. Therefore, this randomized clinical trial was designed to test the hypothesis that use of unfractioned heparin (UFH, low-dose continuous-infusion: 500 units/ hour during 7 days) is efcacious as a complementary treatment in patients with signs indicative of sepsis. Our primary aims were to determine the effects of heparin on length of stay (LOS) among those discharged alive and on change from baseline multiple organ dysfunction (MOD) score. Secondary objectives were to determine the effects of heparin on 28-day all-cause mortality, and to estimate the possible effect modication on 28-day all-cause mortality in subgroups
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dened by site of infection and baseline values of APACHE (Acute Physiology and Chronic Health Evaluation) II score, MOD score, and D-dimer.

MATERIALS AND METHODS Screening and Patient Selection

Patients were recruited through the emergency room at Hospital Universitario San Vicente de Paul (Medelln, Columbia). Patients aged 18 years or older hospitalized with a suspected or conrmed infection as the main diagnosis for admission, unexplained fever, unexplained altered mental status, or unexplained arterial hypotension (systolic blood pressure 90 mm Hg or a decrease 40 mm Hg) were considered potentially eligible for the trial. Inclusion criteria were as follows: patients had to have an infection dened by clinical and/or microbiological criteria in accordance with modied Centers for Disease Control definitions for nosocomial infections (18) (Appendix A); and they had to present with one or more of the general variables and one or more inammatory variables in the rst 24 hours after admission to the emergency room (Appendix B). These variables could not have been attributable to an underlying disease other than infection or because of the effects of concomitant therapy. Exclusion criteria include pregnancy, increased risk for bleeding, requirement of anticoagulation, transplantation, refusal to participate, or more than 24 hours of admission to the hospital (Appendix C).

treatment. The total dose for a 24-hour period in the heparin group was 12,000 international units and continued for 7 days or until discharge, death, or interruption, if these occur before 7 days. The general treatment for patients was left up to the medical team in charge of each patient and to clinical practice guidelines for infectious diseases available at the institution. The study was approved by the institutional review boards of the Universidad de Antioquia and Hospital Universitario San Vicente de Pau l, Medellin, COmbia (the site where the study was carried out), and of the Johns Hopkins Bloomberg School of Public Health as the study was the doctoral thesis of the rst author (F.J.). A signed consent form was obtained from the subjects after clear explanation of the purpose of study. For subjects who could not consent for themselves, a competent relative signed the consent form.

Data and Safety Monitoring Board comprising three members from academic centers other than University of Antioquia was responsible for the interim monitoring process. Stopping guidelines for efcacy monitoring were determined for the clinical end point of 28-day mortality according to the modied OBrien Fleming (19, 20) procedure in two interim analyses at 6 months and 18 months after study beginning. Stopping guidelines for safety were left at discretion of the Data and Safety Monitoring Board.

Evaluation of Patients
The primary outcome measures were LOS among those discharged alive, and change from baseline MOD score (21, 22). The secondary outcome measure was death from any cause occurring within the 28 days following randomization. Outcome measures were documented only by research assistants masked to both the subjects intervention group assignment and the aPTT values corresponding to specic days of the intervention period. Research assistants measured in a standardized way a modied version of the MOD score (21, 22) at baseline (0 day), and at days 1, 2, 3, 5, 7, 9, 12, and 15 or until discharge or death (Appendix D). For respiratory, renal, hepatic, and hematologic organ systems, which were evaluated using laboratory variables, two consecutive normal results conducted to a zero score in subsequent measures, unless clinical criteria indicated the realization of a new test. Severe sepsis was dened as a MOD score higher than 2 (23), and septic shock was dened as mean blood pressure equal to or less than 65 mm Hg (systolic pressure 2 diastolic pressure/3). The information about comorbidities (i.e., diabetes, chronic obstructive pulmonary disease, trauma or surgery within the last 30 days, use of corticosteroids or chemotherapy within the last 30 days, any type of cancer within the previous year, alcoholism or drug addiction, chronic heart failure, chronic kidney disease, or acquired immunodeciency syndrome), clinical and demographic data, basic laboratory, microbiology and therapy was abstracted from clinical records. APACHE II score (24) was determined by research assistants in a standardized way for all participants.

Precautionary Measures
1. Infusion was interrupted 2 hours before any percutaneous procedure or major surgery and was only resumed 1 hour after a percutaneous procedure or 12 hours after major surgery. In the presence of bleeding complications with any of these procedures, infusion was only resumed after normal results in coagulation tests, and no less than 24 hours after the procedure. Infusion was to be stopped if the activated partial thromboplastin time (aPTT, normal range: 25 40 seconds) was prolonged more than 60 seconds at any time during the intervention period (rst 7 days). The aPTT was tested daily within the rst 7 days. Infusion was to be stopped if there were new signs or symptoms of hemorrhage such as bleeding from gums, nosebleeds, extensive bruising, evidence of purplish skin areas, or gastrointestinal bleeding. Infusion was to be stopped if there was an otherwise unexplained drop of 50% or greater in platelet count between two samples, or an absolute platelet count below 30,000 cell per mm3 any time during the study.

2.

Study Design, Randomization, and Procedures

Randomized, double-masked, placebocontrolled, and single-center clinical trial. The allocation to UFH or placebo was dened by randomly permuted blocks of size 2, 4, and 6 generated by a random number generator (ralloc program, Stata 8.2, College Station, TX), and this randomization scheme remained in a condential le in the data coordinating center. Once the assignment was known, the study statisticianwho was the only person for whom the link between the sequential ID and the drug was available instructed a research assistant to adhere the label with the ID to the appropriate ampoules containing UFH or placebo. Complete treatments (four ampoules for each patient) were available in the emergency rooms pharmacy center. The placebo was packed identically to the heparin sodium injection, and had the same color and volume. Procedures for administration were identical, and were performed by nurses in charge of each patients

3.

4.

These precautionary measures were decided by independent medical safety monitors with responsibilities in the clinical follow-up of the patients. The medical monitors were also the only personnel involved in the study who have daily access to the aPTT values. The clinicians in charge for the day-to-day management of the patients also were aware of the aPTT values, but they have full access to the clinical records and laboratory data by an independent procedure in the electronic system. In addition, to protect blinding, they were not aware of the primary outcomes of the study. A

Statistical Analysis
For sample size calculation, LOS was considered a time-to-event end point with patient discharge alive as the outcome. With a type I error of 0.05 and a type II error of 0.2, the estimated number of patients required to detect a relative hazard of being discharged alive of 1.4 was 272. This number of events was expected to be achieved with a total sample

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1401 assessed for eligibility 429 did not meet inclusion criteria 653 met exclusion criteria: -Consent refusal (223) -Increased risk for bleeding or requirement of full anticoagulation (140) -Contacted later than 24 hours from admission (125) -Other reasons (165) 319 randomized

160 assigned to placebo 135 received at least three days of treatment

159 assigned to heparin 98 received at least three days of treatment

size of 320 patients, assuming an overall hospital mortality rate of 15%. Overall study efcacy was established using the intention-to-treat principle. LOS were compared using only total inpatients days corresponding to patients discharged alive in the UFH and placebo groups with a log-rank test (25), and also using the cumulative frequency function and the cause-specic hazard of being discharged alive in presence of the competing event of death in the same two groups (26). MOD scores and aPTT values were compared with the application of a random-effects model for longitudinal data (27). Both a mixed linear model with the total daily score as the outcome and a mixed logistic model with 1, if MOD 0 and 0 otherwise, were performed to compare the trajectories of the two treatment arms. The mortality rates were compared with the chi-square test, and the relative mortality was presented as odds ratios with exact 95% condence interval. Subgroups analyses were performed using interaction terms in a logistic model, and their statistical signicance was evaluated with a likelihood ratio test comparing nested and full models.

RESULTS
Study Population. Between June 2005 and June 2007, 1401 patients were screened and assessed for eligibility. Within this eligible population, 429 patients did not meet inclusion criteria and 653 patients had at least one exclusion criteria (Fig. 1). Thus, the study population was made up of 319 patients randomly assigned to placebo (n 160) or UFH (n 159) groups. The study population had a median age of 56 years (interquartile range, IQR 40 71) and 51.4% (n 164) were males. Among study participants, 167 (52.3%) were free from any comorbidity, with diabetes and chronic obstructive pulmonary disease being the most frequent diseases with percentages of 19% (n 61) and 11% (n 34), respectively. The median MOD score at baseline was 2 (IQR 1 4) and the median APACHE II score was 10 (IQR 6 13). Table 1 shows the general characteristics at randomization for each of the two arms of the study. There were no clinically significant differences between the UFH and placebo groups. Effect of UFH on LOS. There were 278 patients discharged alive from the hospital, 86% (n 138) in the placebo group and 88% (n 140) in the heparin group. The median LOS in patients discharged alive was 12.5 days (IQR 8 20) and 12 days (IQR 8 19.5) in the placebo group
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Causes of <three days (n=25) Consent withdrawal (1) Physician refusal (5) Requirement of full anticoagulation (4) Problems in drug supply (0) Discharge (6) aPTT > 60 sec (4) Nosebleeds (1) Major surgery (1) Tracheal bleeding (1) Gastrointestinal bleeding (0) Hematuria (0) Death (2) Unknown (0)

Causes of < three days (n=61) Consent withdrawal (7) Physician refusal (0) Requirement of full anticoagulation (0) Problem in drug supply (1) Discharge (6) aPTT > 60 sec (36) Nosebleeds (1) Major surgery (0) Tracheal bleeding (0) Gastrointestinal bleeding (1) * Hematuria (1) Death (7) Unknown (1)

160 analyzed by ITT 160 main end points (LOS and organ dysfunction) 28-day mortality status unavailable in 1 participant

159 analyzed by ITT 159 main end points (LOS and organ dysfunction) 28-day mortality status unavailable in 1 participant

Figure 1. Trial prole. *The only serious adverse event. aPTT, activated partial thromboplastin time; ITT, intent to treat; LOS, length of stay.

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Table 1. General characteristics at randomizationa Placebo (n 160) Age Male sex Transferred from another institution Comorbidities None Diabetes Chronic obstructive pulmonary disease Trauma/surgery Corticosteroids/chemotherapy Cancer Drugs/alcohol Heart failure Kidney disease Acquired immunodeciency syndrome Clinical data Duration of symptoms before admission (hours) Heart rate (bpm) Respiratory rate Temperature (C) Systolic blood pressure Diastolic blood pressure Acute Physiology and Chronic Health Evaluation II score Multiple organ dysfunction score Severe sepsis without shockb Septic shockc Admission to intensive care unit Prophylactic low-molecularweight heparin Time from admission to randomization (hours) Basic laboratory data Leucocytes count (109/L) C-reactive protein (mg/dL) D-dimer (ng/mL) Source of infection Lung Skin/soft tissues Urinary tract Intra-abdominal Surgical Others Microbiology and therapy Positive blood culture Any positive culture Adequate initial antibiotic according to blood culturesd Time to antibiotics from clinical diagnosis (hours)
a

Heparin (n 159) 57 (3970) 88 (55%) 30 (21%), n 141 81 (49%) 31 (20%) 18 (11%) 15 (9%) 7 (4%) 9 (6%) 5 (3%) 5 (3%) 1 (1%) 1 (1%) 72 (24136), n 141 100 (91115) 24 (2030), n 158 37 (36.538.3) 118 (100137) 70 (6080) 9 (713) 2 (14) 54 (39%) 16 (10%) 28 (18%) 114 (72%), n 158 18.3 (13.722.5)

55 (4072) 76 (48%) 31 (22%), n 142 86 (51%) 30 (19%) 16 (10%) 13 (8%) 7 (4%) 5 (3%) 6 (4%) 4 (3%) 3 (2%) 2 (1%) 72 (24168), n 142 100 (90115) 24 (2028) 37 (36.538.4) 117.5 (100132.5) 70 (6080) 10 (614) 2 (14) 60 (38%) 16 (10%) 25 (16%) 115 (72%) 18.2 (13.521.7)

15.0 (11.919.9) 18 (1027) 950 (4871685) 53 (33%) 33 (21%) 31 (19%) 17 (11%) 14 (9%) 12 (7%) 26 (22%), n 119 64 (43%), n 149 19 (73%) 3 (16), n 142

15.1 (1119.7) 17 (1027) 1028 (5651643) 49 (31%) 31 (19%) 31 (19%) 25 (16%) 11 (7%) 12 (8%) 27 (23%), n 116 61 (42%), n 146 22 (81%) 4 (17), n 141

Data are median (interquartile range) for continuous variables and n (%) for categorical variables. Sample sizes (n) are reported in case of missing or not available data (for positive cultures, they correspond to total requested). bSevere sepsis dened as multiple organ dysfunction score 3. cSeptic shock dened as mean blood pressure 65 mm Hg. dAn antibiotic was considered adequate if the isolated bacterial strain was sensitive in the antibiogram.

and the heparin group, respectively. Among those who were discharged alive, the proportions of individuals who did so before day t were practically identical in the two treatment groups (p 0.976 using the log-rank test). The median time to death at the hospital was 9.5 days (IQR 6 20) in the
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placebo group and 8 days (IQR 119) in the heparin group. The cumulative frequency function of being discharge alive by groups of treatment, estimated in presence of the competing event of death in the hospital, is shown in Figure 2. A Cox regression on the cause-specic hazard being discharged alive was tted with

a dummy variable for treatment (1 UHF, 0 placebo), resulting in a relative hazard of 1.04 (95% condence interval CI 0.821.32). Effect of UFH on MOD Score. Figure 3 depicts the percentage of patients who achieved a 0 value in the MOD score (i.e., no organ dysfunction) by day and group of treatment. According to the linear mixed model, a patient in the placebo group had a signicant average decline of MOD score at a rate of 0.13 per day (95% CI 0.159 to 0.105), and a patient in the heparin group had a signicant decline of the MOD score at a rate of 0.11 per day (95% CI 0.137 to 0.080), but the difference between them was not statistically signicant (p 0.240). The analysis with a logistic mixed model conrms the general trend of improvement along the hospitalization stay, as a patient in the placebo group increased the odds of getting a MOD score equal to zero by 29% per day (OR 1.29, 95% CI 0.90 186), and a patient in the heparin group increased the odds in 31% per day (OR 1.31, 95% CI 0.92 1.86). Consistent with the mixed linear model, the difference between odds ratios per day in the two treatment arms was not statistically signicant (p 0.965). Effect of UFH on Mortality. Table 2 shows the effect of the intervention on all-cause mortality rates according to the intention-to-treat principle and in previously dened subgroups. Table 3 presents mortality rates in other subgroups that were not prespecied but represent actual exposure to treatments, co-interventions, gender, and severity of sepsis. Adherence, Safety, and Adverse Events. In the study population, 119 (74%) and 84 (53%) participants from the placebo and heparin group, respectively, completed the full treatment (i.e., 7 days of low-dose continuous-infusion UFH). According to precautionary measures, an aPTT prolonged more than 60 seconds was an indication for stopping the infusion, and this was the main reason for suspension in the heparin group (51%, n 38) accounting for the group unbalance of the total suspensions in the rst 3 days (Fig. 1 and Table 3). The daily values of aPTT by treatment groups are presented in Table 4 (p 0.192). Two episodes of minor bleeding were detected in each group: nosebleeds (1) and tracheal bleeding (1) in the placebo group, and nosebleeds (1) and hematuria (1) in the heparin group. We observed only one episode of serious bleeding in the total
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Deceased .8 In hospital .6

Discharged .4

study population, corresponding to a diabetic woman hospitalized with soft tissue infection and who presented a gastrointestinal bleeding that required blood transfusion. This case was controlled without complications and the patient was discharged alive. There were no deaths related to the intervention (i.e., there were not deaths associated with bleeding episodes) nor suspensions by thrombocytopenia.
60 Heparin 80

.2

20

40 Length of stay (days) Placebo

DISCUSSION
Our study was unable to identify any effect of UFH on the primary outcome measures LOS and rate of change in the MOD score. Furthermore, there were no differences neither in the 28-day mortality rate in the overall population nor within subgroups. However, given the exploratory purpose of our investigationas it was necessary to determine the feasibility and safety of the proposed interventionmortality was not considered a primary outcome and the study was intentionally underpowered to detect small differences, either overall or within subgroups, in mortality. The use of anticoagulant and antithrombotic therapies for sepsis have raised considerable attention during the last years (1517), highlighted by the recent approval of drotrecogin alfa (activated) (16). The use of this treatment, however, have not been exempted from controversy, because there are concerns about the specic type of patients who can actually obtain a clear advantage, and there is no agreement about the exact drugs risk/benet ratio (28 31). In this context, the search for an efcacious compound has pointed heparin as a potentially useful, safe, and inexpensive alternative for the complementary treatment of patients with sepsis (9, 32, 33). Only three trials have explored in very different settings the clinical use of heparin in patients with sepsis (34 36). Ai et al (34) investigated the therapeutic effect of low-molecular weight heparin (LMWH) in 40 patients with sepsis at the intensive care unit. They reported differences in the following outcomes: APACHE II score at day 7 (13 5.43 vs. 8.39 5.39), time of stay in intensive care unit (12.85 9.14 days vs. 9.92 6.81 days) and 28-day mortality rates (50% vs. 40.9%) for the routine and the LMWH groups, respectively. These results, contrary to our ndings, may be explained by differences in the type of
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Figure 2. Discharged alive with competing risk of death.

Figure 3. Patients with multiple organ dysfunction (MOD) 0. Table 2. All cause mortality rates in pre-specied groupsa Placebo Hospital mortality 28-day mortality 28-day mortality rates by selected variables APACHE II score 10 10 MOD score 0 or 1 2 D-dimer (ng/ml) 500 500 Pneumonia No Yes 22 (14%, n 160) 25 (16%, n 159) Heparin 19 (12%, n 159) 22 (14%, n 158) OR (95% CI) 0.85 (0.42;1.93) 0.87 (0.44;1.69) p Value 0.631b 0.652b

8 (11%, n 76) 17 (20%, n 83) 4(6%, n 62) 21 (22%, n 97) 1 (2%, n 42) 24 (21%, n 117) 15 (14%, n 106) 10 (19%, n 53)

4 (5%, n 82) 18 (24%, n 76) 3 (5%, n 65) 19 (20%, n 93) 2 (6%, n 35) 20 (16%, n 123) 13 (12%, n 109) 9 (18%, n 49)

0.169c 0.43 (0.09;1.72) 1.20 (0.53;2.74) 0.745c 0.70 (0.10;4.35) 0.92 (0.43;1.98) 0.355c 2.48 (0.12; 150) 0.75 (0.37;1.53) 0.666c 0.82 (0.34;1.97) 0.97 (0.31;2.96)

APACHE, Acute Physiologic and Chronic Health Evaluation; MOD, multiple organ dysfunction; OR, odds ratio, CI, condence interval. a Data are number of events (%, sample size). bchi square test; clikelihood ratio test for a model with the interaction term.

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Table 3. All causes 28-day mortality rates in non prespecied groups Placebo Days on treatment 3 days 3 days Suspension by aPTT Yes No Prophylactic LMWH Yes No Sex Males Females Severe sepsis or septic shock Yes No 8 (33%, n 24) 17 (13%, n 135) 1 (25%, n 4) 24 (15%, n 155) 22 (19%, n 114) 3 (7%, n 45) 6 (8%, n 75) 19 (23%, n 84) 20 (27%, n 75) 5 (6%, n 84) Heparin 16 (27%, n 60) 6 (6%, n 98) 6 (16%, n 38) 16 (13%, n 120) 15 (13%, n 114) 7 (16%, n 43) 10 (11%, n 87) 12 (17%, n 71) 17 (24%, n 70) 5 (6%, n 88) OR (95% CI) p Valuea 0.510 0.73 (0.24; 2.37) 0.45 (0.14; 1.27) 0.616 0.56 (0.04; 34.4) 0.84 (0.39; 1.75) 0.209 0.63 (0.29; 1.37) 2.72 (0.56; 17.3) 0.261 1.49 (0.46; 5.26) 0.69 (0.28; 1.66) 0.276 0.88 (0.39; 1.99) 0.95 (0.21; 4.31)

OR, odds ratio; 95% CI, exact 95% condence interval; aPTT, activated partial thromboplastin time; LMWH, low molecular weight heparin. a Likelihood ratio test for a model with the interaction term. Severe Sepsis dened as MOD score 2. Septic Shock dened as mean blood pressure 65. Data are number of events (%, sample size).

Table 4. Activated partial thromboplastin time values by days and treatment groupsa Day 1 Placebo 33.5 (3039) 1674 n 158 38 (3252) 22176 n 155 Day 2 33 (2837) 1176 n 151 34 (3041) 21146 n 122 Day 3 32 (2837) 1763 n 140 34 (2940) 21141 n 105 Day 4 32 (2836) 1587 n 131 32 (2937) 2073 n 95 Day 5 32 (2835) 1655 n 127 34 (29.538.5) 22232 n 88 Day 6 31 (2835) 1859 n 122 33.5 (3038) 2259 n 88 Day 7 31 (2837) 1264 n 119 32 (3038) 2061 n 84

Heparin

Data are medians (interquartile range) minimum and maximum values and sample size. p 0.192 by a random-effects model.
a

heparin and the severity of the patients included in the trial. Zhang and Ma (35) randomly assigned 22 patients with severe sepsis to very low doses of UFH (3 4 unitskg1hr1) or to routine treatment. Despite a faster improvement of the coagulation function in the UFH group, they did not detect signicant differences in hospital LOS or 28-day survival rates between the two groups. The Xigris and Prophylactic Heparin Evaluation in Severe Sepsis trial was designed to evaluate whether heparin interfered with the efcacy of drotrecogin alfa (activated) in adult patients with severe sepsis and high risk of death (36). Patients were assigned in a 1:1:2 randomization scheme to UFH (5000 units subcutaneously twice per day), LMWH (enoxaparin 40 mg subcutaneously once per day), or placebo, respectively. Unexpectedly, an absolute 3.6% lower 28-day mortality was observed in the combined heparin group compared with placebo group (28.3% vs. 31.9%, p 0.08), and this difference increased if
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considering only the LMWH subgroup (27.3% vs. 31.9%, p 0.07). Although all the patients were treated with drotrecogin alfa (activated), these results warrant further research regarding the potential use of heparin in sepsis. Noticeably, the overall mortality rate in drotrecogin alfa (activated)-treated patients in this trial was overly similar to that reported in the placebo group of the pivotal trial (31.9% vs. 30.8%) despite an equivalent mean APACHE II score (24 7.4 vs. 25 7.8), underlying the importance of further clinical trials to conrm the benets and reinforcing the opinions favoring a conrmatory trial for this drug (3739). At least three limitations should be discussed to understand our ndings: the study population, the outcome measures, and the characteristics of the intervention. The Study Population. We proposed a set of inclusion criteria that allowed a population with a wide spectrum of the syndrome. This was reected in the fact

that less than 50% of the participants were admitted to the hospital with signs indicative of severe sepsis or septic shock. Furthermore, the average severity measured by the median MOD score at baseline ( 2) and the median APACHE II score ( 10), was lower than that commonly reported in sepsis trials (1517, 36), which have focused only on patients with severe sepsis and/or septic shock. Notwithstanding the low severity of our study population, the overall 28-day mortality rate in the placebo group was comparable with that reported in the placebo group of the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis study (40) (16% vs. 17%, respectively), which was designed to evaluate the efcacy and safety of drotrecogin alfa (activated) in adult patients with severe sepsis and a low risk of death. In addition, some particularly different characteristics of our hospitalized patients with bacterial infectious diseases have been also noticed in our previous investigations (41, 42). First of all, more than 50% of the patients were healthy before suffering the infection, as we did not detect any major comorbidity. Similarly, their median age of 56 years is well below the ones reported on epidemiologic studies of sepsis worldwide, although it was a common nding in several small studies from Latin America (43). Thus, our study population provides a clear example of casemix with strong components in both patients characteristics and hospital care. Such a less severely ill but heterogeneous population could be an unfavorable setting to detect the effect of any therapeutic measure or experimental intervention. The Outcome Measures. Our results showed a signicant improvement in organ function with time, but this change was not modied by the intervention. These ndings are not surprising because demonstration of improved morbidity in patients with severe sepsis or septic shock has been difcult. An exception was the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis trial, in which signicant improvements in both cardiovascular and respiratory organ function were seen in patients treated with drotrecogin alfa (activated) (44). However, this morbidity benet was also accompanied by a signicant mortality benet and no signicant difference in morbidity was found between drotrecogin alfa (activated)-treated and placebotreated 28-day survivors. In general, up to now, organ dysfunction scales do not
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seem to be more sensitive than mortality measures in detecting the aggregate effects of intervention (45). Furthermore, the mean MOD score at baseline in our study population was 2.6 (SD, 2.39), and such a low value in itself hinders the possibility of detecting any signicant rate of change. Thus, although organ dysfunction scales may provide strong supportive evidence of the efcacy of interventions in sepsis, they are unlikely to obviate the need for demonstration of unequivocal important benet inpatientcentered outcomes such as mortality. The Intervention. We considered the use of low-dose continuous infusion of UFH, equivalent to the dose widely used as prophylactic treatment for patients considered at risk for venous thrombosis, as it has been recommended by some authors for the treatment of overt disseminated intravascular coagulation (46, 47). This low dosage, however, was enough to prolong the aPTT more than 60 seconds and it was an indication to stop the infusion. This measure reduced the time of exposure to UFH in 24% (n 38) of the participants, and most of these suspensions (n 36) occurred within the rst 3 days of the intended intervention. In addition, because the bioavailability of UFH is reduced in the presence of high levels of acute phase proteins (48), our study population with a mean C-reactive protein of 18.7 mg/dL (SD, 10.4) could have had an irregular exposure to the treatment. Although it has not been tested enough in animal or human models of infection, LMWH might have a similar or even a better prole than UFH because of their superior bioavailability and sustained pharmacodynamic effects (49). In fact, the Xigris and Prophylactic Heparin Evaluation in Severe Sepsis trial showed a larger reduction in mortality in the LMWH group compared with the UFH group, which further suggests that heparin may modulate effectively the pathogenesis and clinical course of sepsis.

group analysis of placebo patients suggested that use of low-dose heparin might be benecial in sepsis (1517). Our ndings do not support these analyses and suggest that other variables (e.g., differences in severity of disease) may have accounted for apparent differences in survival between these subgroups.

11.

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ACKNOWLEDGMENTS
We are grateful to the nurses, the residents, the physicians, and all the staff in the Hospital Universitario San Vicente de Pau l (Medelln, Columbia); the Data Coordinating Center: Daniel Aguirre and Julieth Wiedemann; the Medical Safety Monitors: Alejandro Arbela ez, Jaime Ramrez, and John Nieto; the Research Assistants: Eliana Garca, Marly Molina, Nirvana Ortiz, Susana Osorno, Adriana Henao, Luz Zapata, and Oscar Rueda; and the Data Safety and Monitoring Board: Francisco Molina, Jorge Donado, and Juan Salazar.
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Appendix A Modied Centers for Disease Control denitions of infections for inclusion criteria at the emergency room Pneumonia must meet the following criterion: At least one chest radiograph with at least one of the following: A. New or progressive and persistent inltrate B. Consolidation C. Cavitation And At least one of the following: A. Fever 38C with no other recognized cause B. Leukopenia (4,000 WBC/mm3) or leukocytosis (12,000 WBC/mm3) C. For adults 70 years old, altered mental status with no other recognized cause And At least two of the following: A. New onset of purulent sputum, or change in character of sputum, or increased respiratory secretions B. New onset or worsening cough, or dyspnea, or tachypnea C. Rales or bronchial breath sounds D. Worsening gas exchange (e.g., O2 desaturation or increased oxygen requirements) Laboratory-conrmed bloodstream infection must meet at least one of the following criteria: Criterion 1: Patient has a recognized pathogen cultured from one or more blood cultures And Organism cultured from blood is not related to an infection at another site Criterion 2: Patient has at least one of the following signs or symptoms: fever (38C), chills, or hypotension And At least one of the following: A. Common skin contaminant (e.g., diphtheroids, Bacillus sp., Propionibacterium sp., coagulase-negative staphylococci, or micrococci) is cultured from two or more blood cultures drawn on separate occasions B. Common skin contaminant (e.g., diphtheroids, Bacillus sp., Propionibacterium sp., coagulase-negative staphylococci, or micrococci) is cultured from at least one blood culture from a patient with an intravascular line, and the physician institutes appropriate antimicrobial therapy Clinical sepsis must meet the following criterion: Patient has at least one of the following clinical signs or symptoms with no other recognized cause: fever (38C), hypotension (systolic pressure 90 mm), or oliguria (20 cm3/hr) And Blood culture not done or no organisms or antigen detected in blood And No apparent infection at another site And Physician institutes treatment for sepsis Symptomatic urinary tract infection must meet at least one of the following criteria: Criterion 1: Patient has at least one of the following signs or symptoms with no other recognized cause: fever (38C), urgency, frequency, dysuria, or suprapubic tenderness And Patient has a positive urine culture, that is, 105 microorganisms per cm3 or urine with no more than two species of microorganisms Criterion 2: Patient has at least two of the following signs or symptoms with no other recognized cause: fever (38C), urgency, frequency, dysuria, or suprapubic tenderness And at least one of the following: A. Positive dipstick for leukocyte esterase and/or nitrate B. Pyuria (urine specimen with 10 WBC/mm3 or 3 WBC/high power eld of unspun urine) C. Organisms seen on Gram stain of unspun urine D. At least two urine cultures with repeated isolation of the same uropathogen (gram-negative bacteria or S. saprophyticus) with 102 colonies/ml in nonvoided specimens E. 105 colonies/ml of a single uropathogen (gram-negative bacteria or S. saprophyticus) in a patient being treated with an effective antimicrobial agent for a urinary tract infection F. physician diagnosis of a urinary tract infection G. physician institutes appropriate therapy for a urinary tract infection Other infections of the urinary tract must meet at least one of the following criteria: Criterion 1: Patient has organisms isolated from culture of uid (other than urine) or tissue from affected site Criterion 2: Patient has an abscess or other evidence of infection seen on direct examination, during a surgical operation, or during a histopathologic examination Criterion 3: Patient has at least two of the following signs or symptoms with no other recognized cause: fever (38C), localized pain, or localized tenderness at the involved site And At least one of the following: A. Purulent drainage from affected site B. Organisms cultured from blood that are compatible with suspected site of infection C. Radiographic evidence of infection, e.g., abnormal ultrasound, computed tomography scan, magnetic resonance imaging, or radiolabel scan (gallium, technetium) D. Physician diagnosis of infection of the kidney, ureter, bladder, urethra, or tissues surrounding the retroperitoneal or perinephric space E. Physician institutes appropriate therapy for an infection of the kidney, ureter, bladder, urethra, or tissues surrounding the retroperitoneal or perinephric space

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Appendix A Continued Intraabdominal infections must meet at least one of the following criteria: Criterion 1: Patient has organisms cultured from purulent material from intraabdominal space obtained during a surgical operation or needle aspiration Criterion 2: Patient has abscess or other evidence of intraabdominal infection seen during a surgical operation or histopathologic examination Criterion 3: Patient has at least two of the following signs or symptoms with no other recognized cause: fever (38C), nausea, vomiting, abdominal pain, or jaundice And At least one of the following: A. Organisms cultured from drainage from surgically placed drain (e.g., closed suction drainage system, open drain, T-tube drain) B. Organisms seen on Gram stain of drainage or tissue obtained during surgical operation or needle aspiration C. Organisms cultured from blood and radiographic evidence of infection, e.g., abnormal ndings on ultrasound, computed tomography scan, magnetic resonance imaging, or radiolabel scans (e.g., gallium, technetium) or on abdominal x-ray Skin infections must meet at least one of the following criteria: Criterion 1: Patient has purulent drainage, pustules, vesicles, or boils Criterion 2: Patient has at least two of the following signs or symptoms with no other recognized cause: pain or tenderness, localized swelling, redness, or heat And At least one of the following: A. Organisms cultured from aspirate or drainage from affected site; if organisms are normal skin ora (e.g., coagulase negative staphylococci, micrococci, diphtheroids) they must be a pure culture B. Organisms cultured from blood Soft tissue infections must meet at least one of the following criteria: Criterion 1: Patient has organisms cultured from tissue or drainage from affected site Criterion 2: Patient has purulent drainage at affected site Criterion 3: Patient has an abscess or other evidence of infection seen during a surgical operation or histopathologic examination Criterion 4: Patient has at least two of the following signs of symptoms at the affected site with no other recognized cause: localized pain or tenderness, redness, swelling, or heat And At least one of the following: A Organisms cultured from blood B. Positive antigen test performed on blood or urine (e.g., H. inuenzae, S. pneumoniae, n. meningitidis, group B Streptococcus, Candida sp.) Supercial SSI must meet the following criterion: Infection occurs within 30 days after the operative procedure And Involves only skin and subcutaneous tissue of the incision And Patient has at least one of the following: A. Purulent draining from the supercial incision B. Organisms isolated from an aseptically obtained culture of uid or tissue from the supercial incision C. At least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat, and supercial incision is deliberately opened by surgeon, unless incision is culture-negative D. Diagnosis of supercial incisional SSI by the surgeon or attending physician Deep SSI must meet the following criterion: Infection occurs within 30 days after the operative procedure if no implant is left in place or within one year if implant is in place and the infection appears to be related to the operative procedure And Involves deep soft tissues or spaces at or beneath fascial layers And Patient has at least one of the following: A. Purulent drainage from the deep incision or from the organ/space component of the surgical site B. A deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient has at least one of the following signs or symptoms: fever (38C), or localized pain or tenderness, unless incision is culture-negative C. An abscess or other evidence of infection is found on direct examination, during reoperation, or by histopathologic or radiologic examination D. Diagnosis of a deep SSI by a surgeon or attending physician Joint or bursa infections must meet at least one of the following criteria: Criterion 1: Patient has organisms cultured from joint uid or synovial biopsy Criterion 2: Patient has evidence of joint or bursa infection seen during a surgical operation or histopathologic examination Criterion 3: Patient has at least two of the following signs or symptoms with no other recognized cause: joint pain, swelling, tenderness, heat, evidence of effusion or limitation of motion And At least one of the following: A. Organisms and white blood cells seen on Gram stain of joint uid B. Positive antigen test on blood, urine, or joint uid C. Cellular prole and chemistries of joint uid compatible with infection and not explained by an underlying rheumatologic disorder WBC, white blood cell; SSI, surgical site infection.

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Appendix B Inclusion criteria Modied Centers for Disease Control Denitions for Infection 1) Pneumonia

General Variables 1) Temperature (oral or axillary) 38C or 36C 2) Heart rate 90 beats/min 3) Respiratory rate 20 breaths/min 4) Altered mental status determined by Glasgow Coma Scale 15 5) Systolic blood pressure 90 mm Hg or a decrease 40 mm Hg

Inammatory Variables 1) White blood cells 12,000 L1 or 4,000 L1 or with 10% immature forms 2) Plasma C-reactive protein 5 mg/dL

2) Bloodstream infection 3) Clinical sepsis 4) Symptomatic urinary tract infection and other infections of urinary tract 5) Intra-abdominal infections 6) Skin infections 7) Soft tissue infections 8) Supercial and deep surgical site infections 9) Joint or bursa infections Appendix C Exclusion criteria

Pregnant or breastfeeding. Platelet count 60,000/mm3 Increased risk for bleeding: a) Any patient who had undergone major surgery, dened as surgery that required general or spinal anesthesia, performed within the 12-hour period immediately preceding admission to the hospital; any postoperative patient who demonstrated evidence of active bleeding; or any patient with planned or anticipated major surgery during the rst 12 hours after admission to the hospital b) History of: severe head trauma that required hospitalization, intracranial surgery, or stroke within 3 months of study entry; or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion c) History of congenital bleeding diatheses, such as hemophilia d) Gastrointestinal bleeding within 6 weeks of study entry that required medical intervention unless denitive surgery has been performed e) Trauma patients at increased risk of bleeding, for example: ail chest; signicant contusion to lung, liver, or spleen; retroperitoneal bleed; pelvic fracture; or compartment syndrome - Patients with a known hypercoagulable condition including activated Protein C resistance; a hereditary deciency of Protein C, Protein S, or antithrombin; presence of anticardiolipin antibody, antiphospholipid syndrome, lupus anticoagulant or homocysteinemia; or patients with a recently documented (within 3 months of study entry) or highly suspected deep venous thrombosis or pulmonary embolism - Patients taking or requiring the following medications: a) Therapeutic heparin, dened as unfractionated heparin dosed to treat an active thrombotic or embolic event within the 12 hours prior to study entry, or low-molecular-weight heparin used at any dose higher or more frequent than the recommended dose on the product label for prophylaxis within the 12 hours prior to study entry b) Warfarin, if used within 7 days of study entry c) Thrombolytic treatment within 3 days of study entry (for example, streptokinase, rtPA, and urokinase) d) Glycoprotein IIb/IIIa antagonists within 7 days of study entry - Patients with known esophageal varices, chronic jaundice, cirrhosis, or chronic ascites - Presence of an advance directive to withhold life-sustaining treatment - Patients not expected to survive 28 days given their preexisting, uncorrectable medical condition. This criterion includes patients with, or suspected to have, poorly controlled neoplasms or other end-stage processes, such as end-stage cardiac disease, prior cardiac arrest, end-stage lung disease, or end-stage liver disease - Patients with chronic renal failure on either hemodialysis or peritoneal dialysis - Human immunodeency virus positive patients with most recent CD4 count 200/mm3 - Patients who have undergone bone marrow, liver, lung, kidney or pancreas transplantation - Inability or unwillingness of patients or legal representative to give written informed consent - Patients with more than 24 hours of admission to the hospital before the rst evaluation for eligibility to the trial

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Appendix D Modied multiple organ dysfunction score Organ System Respiratory (PaO2/FIo2 ratio) Renal (serum creatinine mg/mL) Hepatic (serum bilirrubin, mg/dL) Hematologic (platelet count, cells/mm3) Cardiovascular (heart rate, inotropes, lactate) Neurologic (Glasgow Coma Scale) 0 300 1.13 1.17 120,000 120 15 1 226300 1.142.26 1.183.50 81,000120,000 120140 1314 2 151225 2.273.96 3.517.00 51,00080,000 140 1012 3 76150 3.975.66 7.0114.0 21,00050,000 Inotropes 79 4 75 5.66 14 20,000 Lactate 5 or more than one inotrope 6

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