Results of severe sepsis treatment program using recombinant human activated protein C in Poland

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1 Med Sci Monit, 2006; 12(3): CR PMID: Clinical Research Received: Accepted: Published: Results of severe sepsis treatment program using recombinant human activated protein C in Poland CR Authors Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection Andrzej Kübler 1 ABDEF, Ewa Mayzner-Zawadzka 2 ABD, Grażyna Durek 1 BEF, Wojciech Gaszyński 3 BD, Ewa Karpel 4 BD, Małgorzata Mikaszewska-Sokolewicz 2 B, Paweł Majak 5 BC 1 Chair and Department of Anesthesiology and Intensive Care, Medical University of Wrocław, Wrocław, Poland 2 Chair and Department of Anesthesiology and Intensive Care, Medical University of Warsaw, Warsaw, Poland 3 Chair and Department of Anesthesiology and Intensive Care, Medical University of Łódź, Łódź, Poland 4 Chair and Department of Anesthesiology and Intensive Care, Medical University of Katowice, Katowice, Poland 5 District Hospital in Zgierz, Zgierz, Poland Source of support: Departmental sources Background: Material/Methods: Results: Conclusions: key words: Summary Recombinant human activated protein C (drotrecogin alfa [activated] DAA) demonstrated in Phase III controlled clinical studies significant reduction of mortality in patients with severe sepsis and high risk of death. The aim of the study was to assess the therapeutic efficacy of DAA in patients included in the National Severe Sepsis Register in Poland. The analysis included 3233 cases of severe sepsis reported between and patients (9.3%) were treated with DAA. The clinical course of the disease in DAA and non-daa treatment groups was compared. Logistic regression models for the effects of independent variables on the risk of death (dependent variable) were developed. In the patients treated with DAA, the relative risk of death was lower by 31% than in those who were not treated. In a multivariate logistic regression model, the use of DAA was, independently of the patient s age, severity of the clinical condition and type of organ dysfunction, the most significant mortality-reducing factor in severe sepsis. The use of DAA in the treatment of severe sepsis proved to be a very effective method of mortality reduction. Controlled nationwide surveillance program contributed to its effective utilization. The National Severe Sepsis Register proved to be a very useful instrument for assessment of the course of the disease and treatment efficacy. severe sepsis septic shock recombinant human activated protein C mortality intensive care unit Full-text PDF: Word count: 2429 Tables: 9 Figures: 2 References: 11 Author s address: Andrzej Kübler, Chair and Department of Anesthesiology and Intensive Care, Medical University of Wrocław, Chałubińskiego 1A, Wrocław, Poland Current Contents/Clinical Medicine SCI Expanded ISI Alerting System Index Medicus/MEDLINE EMBASE/Excerpta Medica Chemical Abstracts Index Copernicus CR107

2 Clinical Research Med Sci Monit, 2006; 12(3): CR BACKGROUND The diagnosis of severe sepsis is established when dysfunction of the most vital organs develops in the course of a generalized infection. The syndrome was described during the Consensus Conference of Medical Societies in 1991, which formulated the basic definitions of clinical conditions associated with infection and systemic inflammatory response. [1] These definitions provided the basis for the research programs allowing comparative assessment of the effectiveness of various severe sepsis treatment methods. The severe sepsis syndrome is currently perceived as a result of two essential processes: an invasion of pathogenic microorganisms associated with the effect of their toxic factors and the reaction of the host to that invasion, which, if the control is lost, may be threatening for the function of the organism. [2] Whereas the therapeutic measures directed against microorganisms are well-known and well-developed (chemotherapy, antibiotic therapy), the treatment aimed at the regulation of disturbed systemic reaction in the course of an infection creates an entirely new problem. During the last decade of the 20 th century, intensive experimental and clinical studies concerned with modulation of the host reaction to an infection were conducted. Most of these studies involved blocking of systemic inflammatory response mediators. Despite promising experimental results, none of the clinical studies of mediator inhibition demonstrated a significant decrease of mortality among severe sepsis patients. [3]. Another method of inflammatory response modification involved administering preparations of natural coagulation inhibitors, whose function is significantly impaired in the course of severe sepsis. Administration of recombinant tissue factor inhibitor [4], as well as high antithrombin doses [5] did not lead to significant reduction of mortality among patients with severe sepsis during 28-day observation period. In contrast, the use of recombinant human activated protein C (drotrecogin alfa [activated] DAA) in a prospective, controlled clinical study (PROWESS) resulted in a significant reduction of mortality associated with severe sepsis [6]. The DAA preparation was registered in 2002 in the USA as a drug with specific indication treatment of severe sepsis with high risk of death (Xigris Eli Lilly). During the next years, registration in the European Union and also in Poland was obtained. The term high risk of death resulted from the analysis of the PROWESS study, where the relative effectiveness of DAA increased in the cases of severe sepsis and septic shock with multiorgan dysfunction and poor general condition. Therefore, the presence of dysfunction of 2 or more organs is an indication for DAA in severe sepsis in Europe, and in the USA the Apache II score of 25 or higher. The use of DAA in clinical practice is not an easy task. In order to utilize the full potential of the drug, it could be administered as early as possible in the cases of severe sepsis with multiorgan dysfunction developing despite optimal stan dard treatments. A controlled study of clinical utility of DAA in patients with severe sepsis without increased risk of death, i.e. with a single-organ dysfunction or APACHE II score below 25, was discontinued after inclusion of 2640 patients because of ineffectiveness of the therapy. [7] Administration of DAA at an early stage of infection without multiorgan dysfunction was ineffective and carried a risk of hemorrhagic complications. The use of this drug must be therefore limited to the ICU s. Additionally, the physicians working there should be trained appropriately both in the diagnostics and standard treatment of severe sepsis and in practical use of DAA. Without such prerequisites, this valuable but also expensive drug can be used in inappropriate situations and clinical conditions, which may considerably limit its effectiveness. The program of severe sepsis treatment with DAA is implemented in Poland under the supervision and control of a specialist team National Anesthesiology and Intensive Care Surveillance and the Sepsis Group of the Polish Society of Anesthesiology and Intensive Care. The aims of the program are to optimize the therapeutic use of DAA as well as to realize the international action - Surviving Sepsis Campaign (SSC) in Poland. The preliminary, essential element of the program involved training of the personnel in about 90 ICU s located in all parts of Poland. The aim of that training, organized by the Sepsis Group, was to familiarize the medical staff with the definition, diagnostics and treatment of severe sepsis with special emphasis on DAA use. The units with trained personnel obtained the accreditation of the National Consultant in Anesthesiology and Intensive Care allowing them to use DAA within the framework of the program, which meant that the costs of treatment with DAA in these units were reimbursed by the National Health Fund. DAA was used under the supervision and consultation of the Regional Consultants in 16 provinces. MATERIAL AND METHOD Information concerning the cases of severe sepsis treated in Polish ICU s have been collected in the National Severe Sepsis Register initiated by the Sepsis Group in The register was organized because severe sepsis syndrome is not included in the International Classification of Diseases (ICD - 10) and there are no administrative instruments that could be used for assessment of its incidence and clinical course. For this reason, voluntary and anonymous registration of cases based on a uniform questionnaire posted at the website was introduced. The information provided by the register, concerning the pathogenesis, course and prognosis of severe sepsis cases, facilitates surveillance and implementation of new management strategies in this clinical syndrome [8]. Information concerning severe sepsis cases reported to the National Register between April 2003 and November 2005 was analyzed. The information included demographic data, type and site of infection, type and number of organ dysfunctions, assessment of severity of the condition, management methods and results of treatment. The analysed cases were divided into 2 groups: patients treated and not treated with DAA. Descriptive statistics was used for comparison between these 2 groups, whereas logistic regression was used for assessment of the effect of the treatment method on survival. All CR108

3 Med Sci Monit, 2006; 12(3): CR Kübler A et al Results of severe sepsis treatment program using recombinant Table 1. Basic information about the patients. potential death risk factors were analyzed using a univariate logistic regression model. Independent variables, affecting considerably the adjustment of univariate models, were included in a multivariate model used for identification of the most significant and independent predictors of death. The significance level µ=0.05 was adopted for all statistical tests. The statistical analysis was carried out using SPSS PC and STATISTICA software packages. RESULTS Total number of patients Mean age (years) 44.7± ±20.4 Sex M 52% F 48% M 60% F 40% Time of treatment in ICU (days) Mortality in ICU (%) Table 2. Organ dysfunction in patients with severe sepsis. Number of affected organs 1 organ 0.0% 3.8% 2 organs 6.6% 13.3% 3 organs 15.2% 21.4% 4 and more organs 78.2% 61.5% Table 3. Mean score assessments of the condition of patients with severe sepsis treated in the ICU. Score APACHE II (mean on admission) TISS-28 (mean from ICU hospitalization time) SOFA (mean after severe sepsis diagnosis) 25.3± ± ± ± ± ±2.4 During the analyzed period, information concerning 3233 severe sepsis cases was entered into the register. The patients mean age was 54.1 years, the population consisted of 59% men and 41% women. On the average, the patients were treated in ICU for 17.8 days. The mortality rate was 54.5%. Table 4. Type of disorder in patients with severe sepsis on admission to ICU. Disorder type Surgical 52.3% 54.2% Medical 33.8% 30.6% Trauma 3.3% 7.4% Others 10.6% 7.8% Table 5. Most common sites of infections leading to sepsis. Infection site Abdominal cavity 43.3% 45.7% Respiratory tract 24.8% 27.5% Blood 7.3% 8.2% Urinary tract 8.8% 7.7% Surgical wound 6.6% 4.6% Central nervous system 5.9% 3.2% Others 3.2% 3.1% In that population, 302 patients (9.3%) were treated with DAA (). The remaining 2931 patients received no DAA (). The basic information concerning both groups is presented in Table 1. As it follows from the table, the patients treated with DAA were younger, more frequently female, than in the other group. The use of DAA was associated with significantly reduced mortality. The reduction of relative mortality risk in the DAA-treated group was 31%. Respiratory failure was the most frequent organ dysfunction ( 95.7%, 92.9%), followed by circulatory failure ( 92.7%, 81.4%). Most patients had already dysfunction of a few organs at the moment of admission to the ICU (Table 2). The mean value of patient condition assessment scores is presented in Table 3. It includes the values of Apache II scores on admission to the ICU, as well as mean values of TISS-28 during treatment in the ICU and SOFA scores calculated after diagnosis of severe sepsis. In over 50% of patients with severe sepsis, the underlying disease was surgical (Table 4). Therefore, the abdominal cavity was most frequently the primary location of infections leading to severe sepsis (Table 5). The most frequent pathogens responsible for severe sepsis were G, then G+ bacteria and fungi (Table 6). Positive cultures were obtained in 45.4% of DAA-treated patients and 43.1% of the rema ining patient population. CR109 CR

4 Clinical Research Med Sci Monit, 2006; 12(3): CR Table 6. Types of pathogens potentially responsible for the development of severe sepsis (more than one can be involved). Pathogen type G- 51.0% 56.8% G+ 48.3% 44.5% Fungi 15.9% 18.7% Viruses 4.0% 1.1% Unknown 11.6% 9.1% Table 8. Results of DAA administration in 5 centers where it was used most frequently. Mean age of the patients (years) APACHE II score (on admission) SOFA score (mean from hospitalization) Mortality (%) Table 7. Methods of treatment of severe sepsis. Method of treatment Antibiotics 100.0% 100.0% Vasopressors 92.1% 86.2% 60% 50% 40% 30% Mechanical ventilation 88.4% 87.8% Heparin 81.8% 81.9% Steroids 76.8% 55.3% Renal replacement therapy 32.4% 18.6% Blood platelets 28.4% 9.9% 20% 10% 0% n=1043; Standard therapy n=2191; n=3233; Standard therapy + DAA Antibiotics were used in all patients with severe sepsis. The commonly used treatment methods included also the administration of vasopressors, mechanical ventilation, heparin and low doses of steroids. Some patients received renal replacement, and almost a half underwent a surgical procedure during the therapy. ( 52.3%; 46.2%) (Table 7). In the DAA-treated group, higher proportion of patients received vasopressors, steroids and blood platelets, there was also a higher proportion of patients ventilated mechanically and receiving renal replacement therapy. DAA was used in 302 patients in 74 ICU s in Poland, which gives a mean of 4 uses per ICU. In five university centers, there were over 10 DAA-treated cases per center. These centers carried out separate comparisons of DAA-treated patients with severe sepsis with those who did not receive the drug (Table 8). The results were very similar to those obtained in the overall population, the relative risk of death was reduced by 29%. The favorable effects of DAA use have been remaining stable since the introduction of the national program throughout the whole period of its function (Figure 1). A similar therapeutic effect was observed after the first, second and third thousand of severe sepsis cases. Therapeutic efficacy of DAA was assessed using a logistic regression model. Figure 1. The results of DAA therapy in different numbers of registered patients. In the univariate model analyzing the correlation of treatment methods with mortality, statistically significant correlations were obtained only for specific parameters (Table 9). Longer duration of vasopressor treatment, renal replacement therapy and surgical procedure during the treatment of severe sepsis significantly increased the risk of death, whereas low-molecule heparin and DAA significantly reduced that risk. The analysis of independent death risk factors by means of a multivariate logistic regression model demonstrated that DAA treatment was, irrespective of age, underlying disease, type of organ dysfunction and clinical course, the most significant factor reducing the risk of death (Figure 2). Adverse effects attributed to DAA were associated with increased predisposition for hemorrhages. Severe, life-threatening hemorrhages in patients treated with DAA were confirmed in 5 cases (1.7%). The incidence of these hemo rrhages was not significantly different from the frequency of hemorrhagic incidents observed in the other group of patients. Additionally, increased local bleeding (surgical wound, catheter insertion sites) was observed in over ten patients (6%) during DAA treatment, which was the reason for periodic discontinuation of the drug infusion. However, these symptoms were not associated with life-threatening complications. CR110

5 Med Sci Monit, 2006; 12(3): CR Kübler A et al Results of severe sepsis treatment program using recombinant Table 9. Association between methods of treatment of severe sepsis and deaths in univariate logistic regression model. Method OR 95% CI +95% CI p Duration of vasopressors use (days) Renal replacement therapy Surgical procedures Heparin DAA Low doses of steroids Gamma globulins AT III CR DISCUSSION Renal dysfunction Metabolic system dysfunction Liver dysfunction Respiratory system dysfunction Duration of vasopressors use (days) Treatment with DAA Age OR (95% CI) Decreased death risk Increased death risk Figure 2. Association between death risk factors in multivariate logistic regression model. The therapeutic efficacy of recombinant human activated protein C demonstrated in the PROWESS study, was manifested by reduction of the absolute mortality risk by 6.1%, and relative mortality risk by 19.4%. The value of NNT (number needed to treat) index was 16, which means that for each 16 patients treated with DAA, one more life was saved in comparison with the control group. The observational study of severe sepsis patients included in the Polish Severe Sepsis Register indicates even higher effectiveness of DAA than that demonstrated by phase III clinical studies. The reduction of absolute mortality risk reached 17.3%, of relative risk 31% and the NNT value was 6. Such a result might have been influenced by several different factors. One of them was poor condition of the analyzed patients, most of whom had multiorgan dysfunctions, high APACHE II and SOFA scores. In such subgroups in the PROWESS study, the effectiveness of DAA was also significantly higher than in the whole analyzed group. In the group with APACHE II scores exceeding 24, the absolute mortality risk was reduced by 13.0%, the relative risk by 31%, and NNT=7.7, whereas in the group with SOFA values higher than 11, the absolute mortality risk was reduced by 11.4%, the relative by 25%, NNT=9 [9]. Another important factor was appropriate training of physicians in the SSC guidelines for treatment of severe sepsis and principles of clinical use of DAA. Additionally, the surveillance and consultation system allowed to avoid errors associated with inappropriate selection of patients for treatment with DAA. High therapeutic efficacy obtained due to implementation of a uniform, controlled program of DAA utilization in severe sepsis remained at more or less stable level at ca. 1-year intervals after the registration of each consecutive thousand cases. The efficacy cannot be associated with the fact that DAA was used in 74 ICU s offering the highest level of medical services and information concerning all patients with severe sepsis was collected from 139 ICU s scattered all over the country. In the leading academic centers, where DAA was used over 10 times, the relative risk of death reduction rates were nearly identical (29%) with those noted for the whole material of patients (31%). The use of DAA in the treatment of severe sepsis significantly reduced mortality in the treated group. However, the treatment was used in 9.3% of all the patients, which cannot reduce significantly the overall mortality of patients with severe sepsis. The frequency of DAA administration should increase in the near future as the therapy implementation program develops. However, to reduce significantly the overall mortality among severe sepsis patients, other management strategies should also be implemented. One of them involves identification of severe sepsis patients at an early stage of development of the syndrome, and early institution of standard therapy. For this purpose, better conditions should be created for adoption of the strategy for early detection of vital functions disturbances by intensive care personnel in hospital wards and for appointment of outreach service teams. [10] Another direction of activity should be implementation of new treatment approach, so-called sepsis bundles, in the early therapy of severe sepsis. Compliance with sepsis bundles significantly reduced mortality in comparison with the control group in one of observational studies [11]. CR111

6 Clinical Research Med Sci Monit, 2006; 12(3): CR Combination of organizational and therapeutic measures, utilizing the latest advances in pharmacotherapy, i.e. DAA, can allow to reach the main objective of SSC, reduction of the overall severe sepsis-related mortality by 25% within 5 years. The nationwide surveillance system in the form of an online register collecting reports of severe sepsis cases is a useful instrument for assessment of the effect of newly adopted treatment strategies on the clinical outcome. CONCLUSIONS 1. The use of DAA in patients with severe sepsis included in the National Severe Sepsis Register was associated with significant reduction of absolute mortality risk by 17.3% and relative risk by 31%. 2. As demonstrated by logistic regression model analysis, the treatment with DAA was the most significant factor reducing mortality in severe sepsis irrespectively of age, clinical condition and course of the therapy. 3. One of the prerequisites for successful treatment of severe sepsis with DAA was implementation of a uniform and controlled nationwide program of drug use. 4. The course of treatment could be assessed effectively owing to continuous surveillance utilizing a common reporting system, registering all the cases of severe sepsis. REFERENCES: 1. Bone RC, Balk RA, Cerra FB et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest, 1992; 101: Cohen J: The immunopathogenesis of sepsis. Nature, 2002; 420: Vincent JL, Sun Q, Dubois MJ: Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin Infect Dis, 2002; 34: Abraham E, Reinhart K, Opal S et al: Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA, 2003; 290: Warren BL, Eid A, Singer P et al: High-dose antithrombin III in severe sepsis. A randomised, controlled trial. JAMA, 2001; 286: Bernard GL, Vincent Jl, Laterre PF et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 2001; 344: Abraham E, Laterre PF, Garg R et al: Drotrecogin alfa (activated) for adults with severe sepsis and low risk of death. N Engl J Med, 2005; 353: Kübler A, Durek G, Zamirowska A et al: Severe sepsis in Poland results of internet surveillance of 1043 cases. Med Sci Monit, 2004, 10(11), CR635 CR Ely EW, Laterre PF, Angus DC et al: Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med, 2003; 31: Hillman K: Critical care without walls. Curr Op Crit Care, 2002; 8: Gao F, Melody T, Daniels DF et al: The impact of compliance with 6 hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective, observational study. Crit Care, 2005; 9: R764 R770 CR112

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