Statins do not improve short-term survival in an oriental population with sepsis

American Journal of Emergency Medicine (2007) 25, 494 – 501

www.elsevier.com/locate/ajem

Original Contribution

Statins do not improve short-term survival in an oriental population with sepsis Kai-Chien Yang MD, MMSa, Jung-Yien Chien MDb, Wei-Kung Tseng MDa, Po-Ren Hsueh MDb, Chong-Jen Yu MD, PhDb, Chau-Chung Wu MD, PhDa,b,* a

Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

b

Received 8 August 2006; revised 4 September 2006; accepted 5 September 2006

Abstract Objectives: The aim of this study was to define the effect of statin on 30-day mortality in an oriental population with sepsis. Design: We conducted a retrospective study on patients with sepsis at National Taiwan University Hospital from 2001 to 2002. The effects of statins on 30-day mortality were evaluated based on clinical settings. Log-rank test and Cox regression analysis were performed using the proportional hazards assumption. Results: A total of 763 episodes of sepsis were reviewed; 454 consecutive patients were considered eligible. Among them, 104 (22.9%) took a statin at least 30 days before admission and during sepsis course, whereas the other 350 control (77.1%) did not. There was no significant difference of 30-day sepsis-related mortality between groups (19.2% vs 18.9%, P = .952). Statin treatment was not associated with decreased mortality at 30 days ( P = .853; risk ratio, 0.95; 95% confidence interval, 0.53-1.68). Conclusion: Short-term, sepsis-related mortality in a septic Taiwanese population was not reduced with statin treatment in our study. We concluded that statin therapy may have little effect on the survival of sepsis in oriental people, particularly in Taiwanese. D 2007 Elsevier Inc. All rights reserved.

1. Introduction Sepsis is a complex syndrome associated with a high mortality rate of 30% to 50% and significant morbidity despite advances in current medical care [1]. The generalized inflammatory and procoagulant response conferred by

* Corresponding author. Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Tel.: +886 2 23123456x5408; fax: +886 2 23966013. E-mail address: [email protected] (C.-C. Wu). 0735-6757/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2006.09.011

sepsis results in diffuse endothelial dysfunction [2], endovascular injury, and ultimately, multiorgan dysfunction. The balance between the effects of microorganisms and triggered immunologic defense mechanisms determines the outcome of sepsis. Several attempts have been made to intervene in the complex process of sepsis, including various anti- or proinflammatory mediators. However, only a few have been shown to be effective in improving survival from sepsis and its related complications [3]. The statins, inhibitors of 3-hydroxy-3-methylglutaryl– coenzyme A reductase, exert not only a lipid-lowering effect via regulation of the biosynthesis of cholesterol but also via

Statins do not benefit oriental patient with sepsis the anti-inflammatory effect through several mechanisms. Statins have been shown to modulate the immune response by inhibiting the activation of inflammatory cellular components such as macrophages [4] and T cells [5]. Statin treatment can also reduce expression and production of proinflammatory cytokines, such as tumor necrosis factor a, interleukin 6 [6] and acute phase proteins like C-reactive protein (CRP) [7]. Statins restore the endothelial function in patients with diabetes [8] and dyslipidemia [9] as well. Statin therapy decreases the interaction among endothelium, antigen-presenting cells, and leukocytes [4] and can attenuate the inflammatory reactions in vessel walls [10,11]. Based on these anti-inflammatory properties, statins have been proposed as playing a potential role in modulating the exaggerated inflammatory response of sepsis [12]. This hypothesis has been tested in a murine model with the use of simvastatin, which significantly improves the survival of mice rendered septic by cecal ligation and perforation [13]. A retrospective study has also suggested an association between statin therapy and a reduction in mortality in patients with bacteremia [14]. In a recent study on a prospective cohort of patients with pneumonia, urinary tract infection, or cellulitis, prior therapy with statins was shown to be associated with a reduced rate of severe sepsis Table 1

495 and ICU admission [15]. However, all the clinical studies designed to evaluate the effect of statin on sepsis were conducted in Western countries. There is scant information with regard to the role of statin in oriental septic population. To elucidate whether statins produce properties of protection against sepsis at usual doses prescribed for dyslipidemia in oriental septic patients, we conducted a retrospective review of the clinical outcomes of hospitalized patients with sepsis at a medical center in Taiwan. The overall 30-day mortality, mortality due to the index episode of sepsis, and clinical parameters among the patients who took statins were compared with those of the patients who did not take statins at the time of sepsis. Factors that potentially influence the effect of statin therapy, including treatment duration, severity of sepsis, and underlying illness, were analyzed with regard to the short-term survival from sepsis.

2. Materials and methods 2.1. Study patients and design We reviewed the medical records of adult patients with a clinical diagnosis of sepsis and at least 1 positive blood

Demographic characteristics and laboratory data of hospitalized patients with sepsis at the time of bacteremia

Characteristics and laboratory data

Statin group (n = 104)

Nonstatin group (n = 350)

Age (y) Male sex (no. [%]) Creatinine (mg/dL) BUN (mg/dL) Body temperature (8C) Heart rate (beats per min) CRP (mg/dL) AST (U/L) T-bilirubin (mg/dL) Albumin (g/dL) Glucose (mg/dL) Hemoglobin (g/dL) White blood cell count (1000 cells/lL) Platelet count (1000 platelets/lL) Lipid profiles (mg/dL) Total cholesterol LDL-C High-density lipoprotein cholesterol Triglycerides ICU admission (no. [%]) APACHE II score Shock (no. [%]) Severe sepsis (no. [%]) No. of dysfunctional systems (no. [%]) 1 2 3 z4

65 F 14 46 (44.2) 2.05 F 2.06 37.6 F 37.2 38.2 F 1.1 101.2 F 19.5 5.64 F 4.93 60.5 F 106.6 1.76 F 3.97 3.12 F 0.75 229.2 F 152.7 10.5 F 2.1 12.13 F 7.20 177.6 F 99.9

64 F 18 202 (57.7) 1.78 F 1.75 34.9 F 37.1 38.1 F 1.2 100.8 F 20.6 10.33 F 6.01 80.6 F 126.2 3.16 F 7.01 3.22 F 2.62 197.9 F 123.0 10.9 F 2.1 12.68 F 9.61 161.3 F 103.7

.897 .086 .711 .571 .626 .842 .002 .021 .040 .335 .360 .595 .966 .286

238.7 F 188.3 106.6 F 33.3 38.1 F 15.5 284.3 F 449.1 28 (26.9) 13.7 F 1.7 14 (13.5) 52 (50.0)

151.0 F 62.8 77.2 F 44.1 28.6 F 14.6 155.1 F 98.3 104 (29.7) 15.9 F 0.9 53 (15.1) 174 (49.7)

b.001 .001 .016 .064 .697 .192 .671 .971 .058*

34 12 4 2

(32.7) (11.5) (3.85) (1.9)

70 36 40 28

Values are mean F SD. * P value for v 2 test for overall comparison of number of dysfunctional systems between groups.

(20.0) (10.3) (11.4) (8.0)

P

496

K.-C. Yang et al. Evaluation in Severe Sepsis (PROWESS) investigators [3]. The typical treatment of patients with sepsis during the study period was primarily based on guidelines developed for the management of specific infections recommended by Infectious Disease Society of America or American Thoracic Society. Hemodynamic management of patients with sepsis was mainly guided by the recommendation issued by the American Society of Critical Care Medicine [17]. Prehospital antibiotics and antibiotics use after admission were reviewed by an independent infectious disease specialist to determine adherence to guidelines and the sensitivity of blood culture isolates. Overall mortality and mortality attributable to the index episode of sepsis within 30 days of bacteremia were assessed. Subgroup analyses for septic patients with different durations of prior statin treatment, different underlying diseases, and different severity of sepsis were performed with regard to the effect of statins on the mortality of sepsis.

culture at National Taiwan University Hospital for 2 years (January 2001 through December 2002). The clinical diagnosis of sepsis was defined according to the criteria proposed by the American College of Chest Physicians and the Society of Critical Care Medicine [16]. Potential skin contaminants such as coagulase-negative staphylococci and diphtheroids were excluded from the study. To avoid the possible confounding effect of statin use and lipid levels influencing the outcome of sepsis, only those with a complete lipid profile at the time of septicemia were considered eligible in the subsequent analyses. Patients who took a statin at least 30 days before the sepsis episode and continued to receive statin therapy during the hospital course were included in the statin treatment group. Other eligible patients were included as the control group. The clinical parameters including age, sex, underlying medical conditions, concurrent medications, isolates of pathogen, initial disposition of the patients (at general ward or intensive care unit), vital signs, and laboratory data at time of bacteremia were collected. Nosocomial blood stream infections were defined as positive blood cultures yielding more than 48 hours after admission. Patients with severe sepsis and sepsis-induced organ dysfunction at the time of septicemia were determined as such according to the criteria defined by the Protein C Worldwide

Table 2

2.2. Statistical analysis Data are presented as means F SD or as numbers and percentages. Categorical variables were compared between groups using the v 2 test or Fisher exact test, where appropriate. Continuous variables were compared with the

Baseline medical conditions of hospitalized patients with sepsis at the time of bacteremia

Diagnosis

All patients (n = 454)

Statin group (n = 104)

Nonstatin group (n = 350)

P

(23.8) (14.1) (19.8) (44.1) (48.5) (7.0) (21.1) (7.0) (12.8) (14.1) (4.8) (11.0) (14.1) (4.8)

44 28 20 54 58 10 18 4 22 12 4 16 10 5

(42.3) (27.5) (19.2) (51.9) (55.8) (9.6) (17.3) (3.9) (21.2) (11.5) (3.8) (15.4) (9.6) (4.8)

64 36 70 146 162 22 78 28 36 52 18 34 54 17

(18.4) (10.3) (20.1) (42.0) (46.6) (6.3) (22.4) (8.1) (10.3) (14.9) (5.1) (9.8) (15.7) (4.9)

.001 .004 .889 .204 .243 .417 .430 .314 .052 .537 .589 .257 .273 .984

58 (12.8) 76 (16.7) 158 (34.8) 44 (9.7) 88(19.4) 46 (10.1) 14 (3.1) 74 (16.3) 84(18.5) 124 (27.3) 30 (6.6)

22 28 62 20 26 14 2 24 30 14 10

(21.1) (26.9) (59.6) (19.2) (25.0) (13.5) (1.9) (23.1) (28.9) (13.7) (9.6)

36 48 96 24 62 32 12 50 54 110 20

(10.3) (13.7) (27.4) (6.9) (17.8) (9.1) (3.4) (14.3) (15.4) (31.4) (5.7)

.039 .025 .012 .008 .251 .365 .581 .132 .029 .011 .249

No. (%) Coronary artery disease Any myocardial Infarction Cerebral vascular disease Diabetes mellitus Hypertension ESRD or hemodialysis Malignancy Neutropenia Congestive heart failure Arrhythmia HIV or AIDS Chronic lung disease Chronic liver disease Seizure disorder Concurrent medication ACEI/ARB Aspirin Any antiplatelet agenta h-Blockers Calcium-channel blockers Digoxin Antiarrhythmic drugs Insulin Diuretics Inotropic agents Steroid use

108 64 90 200 220 32 96 32 58 64 22 50 64 22

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ESRD, end-stage renal disease. a Including aspirin, ticlopidine, clopidogrel, and dipyridamole.

Statins do not benefit oriental patient with sepsis use of the Mann-Whitney U test. Log-rank test and Cox regression analysis were applied to identify risk factors for 30-day mortality using the proportional hazards assumption. The proportional hazards assumption was tested using the scaled Schoenfeld residuals against time to provide relatively precise information about the time dependence of the covariate effects [18]. Observed survival curves were calculated using the Kaplan-Meyer technique. Two-tailed P values of less than .05 were considered statistically significant. Statistical calculations were performed using Stata software version 8.0 (Stata Corp, College Station, TX, 2003).

3. Results A total of 763 episodes of septicemia were selected initially, and 309 of them were excluded because of inadequate statin treatment (b30 days before sepsis episode or did not continue statin use during sepsis), lack of lipid profile at the time of bacteremia, or missing of essential data. The eligible study population consisted of 454 Taiwanese Table 3

497 patients (248 men and 206 women) with a mean age of 64 F 17 years (range, 18-101 years); 104 patients (22.9%) were taking a statin, and 350 (77.1%) were not. Among the statin treatment group, simvastatin was the most commonly used (52 cases, 50% of the statin group, dose range, 10-40 mg/d). The others included atorvastatin (20 cases, 19.2%; dose range, 10-30 mg/d), pravastatin (18 cases, 17.3%; dose range, 10-30 mg/d), fluvastatin (10 cases, 9.6%; dose range, 20-40 mg/d), and lovastatin (4 cases, 3.8%; dose range, 2040 mg/d). The duration of prior statin treatment ranged from 35 to 796 days before the sepsis episode (median duration, 78 days). The demographic characteristics and laboratory data at the time of bacteremia are summarized in Table 1. The statin group had a higher mean total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol level. The mean serum level of CRP at the time of bacteremia was significantly lower in the statin group (5.64 F 4.93 vs 10.33 F 6.01 mg/dL, P = .002). Except for an increased serum level of liver enzyme and borderline increased serum total bilirubin level among patients who did not take statins, the 2 groups were similar with regard to

Sites and etiology of infection in hospitalized patients with sepsis

Sites and types of infection

All patients (%) (n = 454)

Statin group (n = 104)

Nonstatin group (n = 350)

P

No. (%) Site of infection Pulmonary Urinary tract Catheter-related infection Soft tissue/skin Peritoneal Biliary/gastrointestinal tract Bone/joint Endocarditis Central nervous system infection Unknown Etiology of blood stream infections Nosocomial Infection Gram-positive bacteria S aureus Streptococcus pneumoniae Other Streptococcus spp Enterococcus spp Othersa Gram-negative bacteria Escherichia coli Klebsiella spp Enterobacter spp Acinetobacter spp Pseudomonas spp Othersb Fungemia Polymicrobial

128 88 50 12 10 68 10 4 2 78

(28.2) (19.4) (11.0) (2.6) (2.2) (15.0) (2.2) (0.9) (0.4) (17.2)

36 16 18 2 3 10 2 2 0 22

(34.6) (15.4) (17.3) (1.9) (2.8) (7.7) (1.9) (1.9) (0) (21.2)

92 72 32 10 7 58 8 2 2 56

(26.4) (20.7) (9.2) (2.8) (2.0) (17.2) (2.3) (0.6) (0.6) (16.1)

.241 .406 .099 .602 .589 .081 .825 .195 .440 .221

204 150 52 6 24 30 38 302 102 60 20 30 20 70 30 50

(44.9) (33.0) (11.5) (1.3) (5.3) (6.6) (8.4) (66.5) (11.5) (13.2) (4.4) (6.6) (4.4) (15.4) (6.6) (11.0)

54 40 20 1 4 8 7 64 20 12 4 8 4 16 6 11

(51.9) (38.5) (19.2) (0.9) (3.6) (7.7) (6.7) (61.5) (19.2) (11.5) (3.8) (7.7) (3.8) (15.4) (5.8) (10.6)

150 110 32 5 20 22 31 238 82 48 16 22 16 54 24 39

(42.9) (31.4) (9.1) (1.4) (5.7) (6.3) (8.9) (68.0) (23.4) (13.7) (4.6) (6.3) (4.6) (15.4) (6.86) (11.1)

.103 .181

.220

0.695 0.871

Patients could have more than 1 pathogen cultured. a Including Peptostreptococcus spp, Corynebacterium spp, and Micrococcus spp. b Including Salmonella spp, Stenotrophomonas spp, Bacteroides spp, Aeromonas spp, Burkhoderia spp, Cryseobacterium spp, and Agrobacterium spp.

498 other clinical parameters at the time of bacteremia. The statin group had more coronary artery disease (CAD) and previous myocardial infarctions (Table 2); otherwise, the 2 groups did not differ with regard to their underlying medical conditions. Table 3 summarizes the sources and etiology of blood stream infections (Gram-positive, Gram-negative, fungal, and polymicrobial infection) in both groups. Pulmonary and urinary tract infection accounted for half of the identifiable sources of bacteremia for all patients; one fifth of the patients came along with unknown foci of sepsis in both groups. The sources of infection were similar between groups. The statin group had more nosocomial blood stream infections and less polymicrobial infection. Both groups had similar proportions of Grampositive bacteremia, Gram-negative bacteremia, and fungemia. Retrospectively reviewing the rate of appropriateness of empirical antibiotic use assessed by adherence to guidelines showed that the rates were not significantly different between groups (84.6% vs 85.1%, P = .925). The rate of appropriate antibiotic therapy according to the sensitivity of blood culture isolates were also similar (86.5% vs 86.9%, P = .952). The incidence of ICU admission was similar between groups. The acute physiology and chronic health evaluation II (APACHE II) scores were insignificantly higher in the statin group ( P = .092). The incidence of severe sepsis, according to the criteria defined by the PROWESS investigators, were 50.0% and 49.7% in the statin and nonstatin groups ( P = .971), respectively. Although there were no differences in the incidence of severe sepsis between groups, there was a trend of more dysfunctional organs of the patients in the nonstatin group ( P = .058) (Table 1). Moreover, patients who did not take statins had a higher incidence of shock at the time of septicemia (32.6% vs 13.7%, P = .009). A higher proportion of patients in the nonstatin group needed an inotropic agent at the time of sepsis (31.4% vs 13.7%, P = .011). The statin group had more patients who were taking angiotensinconverting enzyme inhibitors, antiplatelet agents (including aspirin), b-blockers, and diuretics. There were no significant differences between both groups with regard to the use of nitrate, digoxin, antiarrhythmia drugs, calcium-channel blockers, and insulin. The proportion of long-term steroid use between groups was similar as well ( P = .249).

K.-C. Yang et al. Table 4 Overall 30-day mortality rates between statin and nonstatin group and subgroup analysis of 30-day mortality with regard to type of infection and underlying medical conditions Clinical status

Statin group n/N (%)

Nonstatin group P

a

Overall 30-day 20/104 (19.2) 66/350 (18.9) mortality Type of infection Nosocomial 18/64 (28.1) 52/150 (34.7) infection ICU admission 8/28 (28.6) 40/104 (38.5) Gram-positive 14/42 (33.3) 30/108 (27.8) bacteremia Gram-negative 6/58 (10.3) 40/244 (16.4) bacteremia Fungemia 1/6 (16.7) 8/24 (33.3) Mixed pathogens 1/2 (50.0) 20/48 (41.7) Underlying conditions With CAD 10/44 (22.7) 18/64 (28.1) Without CAD 10/60 (16.7) 46/286 (16.1) Old myocardial 8/28 (28.6) 8/36 (22.2) infarction Total CholesterolN200 6/44 (13.6) 54/274 (19.7)

.952

.350 .334 .502 .249 .426 .815

.529 .911 .681 .769

a

N indicates total case number; n denotes case number with mortality by 30 days.

The overall 30-day survival among the 104 patients who took statins was similar to that among the 350 controls without statin treatment (Fig. 1, P = .888). The subgroup analyses of the mortality rates related to nosocomial bacteremia, ICU admission, types of bacteremia, and the presence of CAD revealed no significant differences between groups (Table 4). Univariate and multivariate predictors of 30-day mortality are summarized in Table 5. As expected, ICU admission, nosocomial bacteremia, underlying malignancy, shock, fungal infection, neutropenia, and severe sepsis were associated with a higher incidence of mortality. Statin treatment was not associated with decreased mortality at 30 days ( P = .853; risk ratio, 0.95; 95% confidence interval Table 5 Predictors of 30-day mortality among hospitalized patients with sepsis Variable

Fig. 1 Kaplan-Meier curves showing the percentage of patients surviving in the statin group (dashed line) and the nonstatin group (solid line).

Univariate predictors Statin Treatment ICU admission Malignancy Shock Nosocomial infection Fungal infection Severe sepsis Neutropenia Multivariate predictors Severe sepsis

Risk ratio (95% CI)

P

0.95 3.70 3.28 4.84 3.75 3.52 6.21 2.88

(0.53-1.68) (2.02-6.76) (2.01-5.35) (2.99-7.86) (2.18-6.45) (1.84-6.72) (2.91-13.26) (1.43-5.83)

.853 b.001 b.001 b.001 b.001 b.001 b.001 .003

4.43 (1.83-10.73)

.001

Statins do not benefit oriental patient with sepsis [CI], 0.53-1.68). In the multivariate analysis model of age, sex, underlying medical conditions, lipid profiles, concurrent medications, source of infection, causative pathogen, and ICU admission, shock and laboratory data showed that severe sepsis was the only independent predictor of 30-day mortality related to sepsis ( P = .001; risk ratio, 4.43; 95% CI, 1.83-10.73). No concurrent medications were predictive for the 30-day survival in the multivariate analysis.

4. Discussion In this retrospective study, we analyzed the demographic characteristics and clinical parameters of Taiwanese patients with culture-proven sepsis, evaluating the clinical outcomes between the 2 groups of patients with and without concurrent statin therapy. We found that at usual doses for dyslipidemia, statin treatment failed to improve the 30-day survival related to sepsis in this Taiwanese septic population. We included only septic patients with a complete lipid profile at the time of bacteremia. This was based on the rationale that phospholipid and lipoprotein levels might affect the outcome of critically ill patients with sepsis [19,20]. Because the use of statins could alter the lipid profiles significantly, evaluating the lipid levels concurrently was necessary to avoid possible confounding interaction between statin use and lipid levels on the mortality of septicemia. At baseline, the nonstatin controls more frequently had shock ( P = .009), inotropic treatment ( P = .011), multiorgan dysfunction ( P = .058), and a higher APACHE II score ( P = .092). These indicated that the nonstatin group had a sicker septic process. In contrast, the statin group had more CAD and previous myocardial infarctions ( P = .001 and .004). They had less overall severity of sepsis but had more severe atherosclerosis. The outcomes in terms of mortality were thus comparable. The serum levels of CRP were significantly lower in the statin group than in the control group (5.64 F 4.93 vs 10.33 F 6.01 mg/dL, P = .002) at the time of sepsis. Possible explanations to this observation include the following: first, the baseline characteristics of the statin group were not as severely septic as those of the nonstatin group, which might have been reflected in the levels of CRP. Second, lipids might attenuate the intensity of inflammatory response [19]. As lipid levels were significantly higher in the statin group, the CRP levels could have thus decreased because of the inflammation-attenuating effect of the lipids. Finally, statin use resulted in a reduction of blood CRP levels in otherwise healthy patients [7,21]. The effect of statins on lowering blood CRP levels might be preserved under such circumstances of systemic inflammatory response related to sepsis. The effect of anti-inflammatory agents during sepsis depends on risk. Activated protein C, for example, is the only immunomodulatory agent other than steroids that improves survival in septic patients [3]. However, activated protein C confers its benefit mostly on high-risk septic

499 patients; rather, it may be harmful in low-risk patients [22]. Interestingly, statin therapy made the mortality rate of our lower-risk septic patients in the statin group equal to that of the sicker septic nonstatin controls. This finding suggests that statins might not be beneficial; rather, it could be slightly harmful in lower-risk septic patients. The doses of anti-inflammatory agents during sepsis also play an important role in the outcomes of septic patients. In a meta-analysis which examined the effect of steroids on survival during sepsis by reviewing 5 randomized, controlled trials evaluating the effect of steroids on sepsis, steroids were found to be beneficial at lower doses, becoming harmful as the dose increased [23]. It is possible that statins had relatively no impact on sepsis because improper doses were used in our population. On the other hand, the statin group had a significantly higher level of total cholesterol and LDL-C, which might reflect relative underdosing of statins in this population with higher cardiovascular risks. We could not exclude the possibility that, at higher doses, statins could still benefit this population. Another possibility is that increased atherosclerotic burden, as reflected in a higher incidence of CAD and myocardial infarctions in the statin group, had a significant impact that we could not determine at the present time. Currently, we do not have enough data to explain how sepsis, CAD, and anti-inflammatory therapies interact with the therapies against atherosclerosis. Interestingly, there appeared to be a lower rate of mortality in patients without CAD than that in CAD patients (Table 4). However, the study was underpowered to allow a clear answer to this group of patients with such a high mortality. There was a discernable trend of lower mortality related to Gram-negative sepsis in the statin group (Table 4, 10.3% vs 16.4%, P = .249). This is compatible with some animal and human studies discussing about the role of statin treatment against Gram-negative sepsis. Ando et al [24] reported that mice receiving cerivastatin before lipopolysaccharide injection had significantly reduced serum levels of tissue necrosis factor a and interleukin 1-b at 2 hours ( P b .05). These changes turned into a survival benefit, with 7-day survival rates significantly improved in treated mice (26.7% vs 73.3%, P = .016). Another study using a high dose of simvastatin (20 mg/kg) demonstrated that statin treatment offered a significant protection against lipopolysaccharide-induced pulmonary vascular leaks ( P b .05) and inflammation in a murine inflammatory model of acute lung injury [25]. In human beings, Liappis et al [14] retrospectively reviewed 388 patients with Staphylococcus aureus and Gram-negative bacteremia, which demonstrated significant reduction in both overall (6% vs 28%, P = .002) and attributable (3% vs 20%, P = .01) mortality in patients receiving statin treatment before admission. Finally, genetic and environmental factors may not only influence the development and progression of diseases but also the response to medication. The result of our study may reflect that, in an oriental septic population, particularly in Taiwanese people, statins prescribed at the doses for

500

K.-C. Yang et al.

hypercholesterolemia do not change the mortality related to sepsis. We could not exclude the possibility that differences of underlying racial response to statins may contribute to the differential result. There are 2 major limitations of this retrospective study. First, the population selected was confounded by several baseline differences, including the severity of sepsis, lipid levels, and the underlying atherosclerotic burdens, making results difficult to interpret. Second, the eligible patient number is relatively small in this study, owing to the restrictive inclusion criteria of septicemia and a complete lipid profile. The treatment effects are relatively small in previous sepsis trials of mediator-specific, anti-inflammatory agents (such as anti–tumor necrosis factor antibodies), particularly in low-risk patients. This retrospective study might be underpowered because it took 6000 to 7000 patients to find effects in such a low-risk septic population for death [23]. Nonetheless, this study is helpful in providing information with regard to the effectiveness of regular-dose statin therapy among oriental patients with septicemia of different risks. In conclusion, there is abundant evidence supporting the effect of statins against inflammatory responses, yet there are still uncertainties with regard to how important race or ethnicity is in determining statins’ protective effect against sepsis. The result of this retrospective study demonstrates no marked beneficial or harmful effect of statin during sepsis in terms of 30-day survival rates of blood stream infection in an oriental population. We could not exclude, at these doses in this lowrisk septic oriental patients, that statins have a slightly harmful effect. At different doses or in selected septic patients at higher risk of death, statins could still be beneficial.

Appendix A Modified systemic inflammatory response syndrome criteria [3] Patients had to meet z3 of the following criteria: 1. 2.

3.

4.

Core temperature of N388C (100.48F) or b368C (96.88F) Heart rate of N90 beats per minute, except in patients with a medical condition known to increase the heart rate or those receiving treatment that would prevent tachycardia Respiratory rate of N20 breaths per minute or a partial pressure of arterial carbon dioxide (Paco2) of b32 mm Hg or the use of mechanical ventilation for an acute respiratory process White cell count of N12 000 or b4000/mm or a differential count showing N10% immature neutrophils

Criteria for dysfunctional organs or systems [3] 1.

Cardiovascular: systolic blood pressure Q90 mm Hg or mean arterial blood pressure Q70 mm Hg for at

least 1 hour despite adequate fluid resuscitation, adequate intravascular volume status, or the use of vasopressors to keep blood pressure higher than the criteria described above 2. Kidney: urine output b0.5 mL/kg per hour for 1 hour, despite adequate fluid resuscitation 3. Respiratory: Pao2/Fio2 Q250 in the presence of other dysfunctional organs or Q200 if the lung was the only dysfunctional organ 4. Hematology: platelets b80 000 or drop by 50% in 3 days preceding enrollment 5. Metabolic: unexplained metabolic acidosis, pH Q7.30 or the base deficit z5.0 in association with a plasma lactate level N1.5 times the upper limit of the normal value

References [1] 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 - 23. [2] Faust SN, Levin M, Harrison OB, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001;345:408 - 16. [3] Gordon Bernard R, Jean-Louis V, Pierre-Francois L, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699 - 709. [4] Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399 - 402. [5] Fehr T, Kahlert C, Fierz W, et al. Statin-induced immunomodulatory effects on human T cells in vivo. Atherosclerosis 2004;175:83 - 90. [6] Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet 1998;353:983 - 4. [7] Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933 - 5. [8] Economides PA, Caselli A, Tiani E, et al. The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes. J Clin Endocrinol Metab 2004;89:740 - 7. [9] Dupuis J, Tardif JC, Cernacek P, et al. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial. Circulation 1999;99:3227 - 33. [10] Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000;47:648 - 57. [11] Bellosta S, Bernini F, Ferri N, et al. Direct vascular effects of HMGCoA reductase inhibitors. Atherosclerosis 1998;137(Suppl):S101 - 9. [12] Almog Y. Statins, inflammation, and sepsis: hypothesis. Chest 2003; 124:740 - 3. [13] Merx MW, Liehn EA, Janssens U, et al. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation 2004;109:2560 - 5. [14] Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 2001;33:1352 - 7. [15] Yaniv A, Alexander S, Victor N, et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 2004;110:880 - 5. [16] American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864 - 87. [17] Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine. Crit Care Med 1999;27:639 - 60.

Statins do not benefit oriental patient with sepsis [18] Schoenfeld DA. Partial residuals for the proportional hazards regression model. Biometrika 1982;69:239 - 41. [19] Iribarren C, Jacobs Jr DR, Sidney S, et al. Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases. Epidemiol Infect 1998;121:335 - 47. [20] Gordon BR, Parker TS, Levine DM, et al. Relationship of hypolipidemia to cytokine concentrations and outcomes in critically ill surgical patients. Crit Care Med 2001;29:1536 - 68. [21] Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230 - 5.

501 [22] Xigris. Drotrecogin alfa (activated) [Package insert]. Indianapolis (IN)7 Eli Lilly; 2002. [23] Peter CM, Katherine JD, Steven MB, et al. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47 - 56. [24] Ando H, Takamura T, Ota T, et al. Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther 2000;294:1043 - 6. [25] Jacobson JR, Barnard JW, Grigoryev DN, et al. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 2005;288:L1026 - 32.