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Treatment of Patients with Severe Sepsis and Septic Shock: A Retrospective review of Practice Prior to the Publication of Sepsis

Jonathan S Davidow1,2 MD, FRCPC, Michael J Jacka2,3 MD, MSc, FRCPC, Peter G Brindley2 MD, FRCPC, and RT Noel Gibney2 MB, FRCPC 1. Department of Emergency Medicine, 2. Division of Critical Care Medicine, 3. Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta, Canada Correspondence to: Jonathan S Davidow MD Division of Critical Care Medicine 3C4 Walter C. MacKenzie Health Sciences Center University of Alberta Hospital 8440 112 Street, Edmonton, Alberta, Canada T6G 2R7 Email: Phone: c/o M. Jacka (780) 407-8861 Fax: c/o M. Jacka (780) 407-3200 No external financial support was provided for this study. However, it is unclear how quickly or comprehensively these are administered in everyday practice. We sought to determine the utilization of timely, evidence-based therapy among severely septic patients. Methods: A retrospective medical record review was undertaken of all patients that received rhAPC in the four intensive care units in the Capital Health Region


Introduction: Therapy for severe sepsis and septic shock includes: broad spectrum antibiotics, early goal-directed hemodynamic support, corticosteroids, tight glycemic control, and recombinant human activated protein C (rhAPC).

University of Alberta Health Sciences Journal • September 2007 • Volume 4 • Issue 1


Results: All patients had septic shock. because it is important to ensure that. a recombinant protein with antithrombotic. and only 6% (2/34) central venous oximetry within 6 hours. there needs to be a continuum of care involving both the ED and ICU. source elimination and general supportive measures. our sickest sepsis patients are receiving not just rhAPC. Areas for improvement include: faster recognition of sepsis. 45) MATERIALS AND METHODS The Capital Health Region administers health care for a referral population of 1. Overall. We chose to study this group. At the beginning of our study period. Until recently. we reviewed the records of all patients within the Capital Health hospitals who were prescribed rhAPC over a period of 14 months.5% (9/34). given cost considerations.3% (12/34). known as the Surviving Sepsis Guidelines [5]. faster fluid resuscitation. and that this occurs in a timely manner.4%) 17. Treatment cannot wait for ICU admission.5 hours. 12]. The use of rhAPC is indicated in patients with sepsis and an APACHE II (Acute Physiology and Chronic Health Evaluation) [14] score of ≥ 25 or multi-organ failure. an APACHE II ≥ 25 (mean 31. evidence-based therapy included early goal-directed therapy [3.of Northern Alberta over a 14 month period. Concerns that therapy was neither comprehensive nor timely led to a consensus statement. 82% (29/33) of patients received rhAPC within 24 hours of ICU admission. we institute these therapies in everyday practice. 9. few therapies existed beyond antibiotics. The most common underlying conditions were pneumonia 41.3) and all had at least 3 organ failures. and ended with the publication of the Surviving Sepsis guidelines. 38% (13/34) received central venous pressure (CVP) monitoring. To address this question. it was unclear how often or how rapidly these therapies were given.4) 31. 94% (32/34) of patients received fluid resuscitation within 6 hours of sepsis recognition.6 17 (50%) 17 (50%) 17 (50%) 16 (47%) 18 (53%) Value 57. As such.SE) APACHE II score (range) Sex: Male Female Patient Referral: Within Health Region Beyond Health Region Sepsis Source: Pulmonary Abdominal Other Mortality (28 day) ICU Length of stay (days) Initial Presentation to tertiary care 14 (41%) 9 (26%) 10 (29%) 11 (32. This study was intended to examine how appropriately Table 1: Characteristics of patients receiving rhAPC Characteristic Age (mean +/.3 (25. in real life practise. Furthermore. and earlier central venous saturation measurement. and recombinant human activated protein C (rhAPC. evidence now indicates “golden hours” during which early and aggressive treatment can prevent progression to intractable organ failure[3]. Furthermore. prior to its publication. patients receiving rhAPC are arguably the most severely ill. Intensive Care Unit (ICU) mortality was 35. early antibiotics [8. in 2 large teaching hospitals University of Alberta Health Sciences Journal • September 2007 • Volume 4 • Issue 1 . and profibrinolytic properties. ORIGINAL RESEARCH 6 INTRODUCTION Sepsis is a common presentation to the Emergency Department (ED). 10]. anti-inflammatory. Canada. it is also to be assumed that there is full commitment to ongoing aggressive therapy in those receiving rhAPC. Discussion: Mortality in this group of patients with septic shock was very similar to those in previous reports. and has pharmaceutical formulary control for this region. This period was chosen as it began with approval of formulary rhAPC. 32% (12/34) received antibiotics within 1 hour.2% (14/34) and intraabdominal sepsis 26. earlier antibiotics. However. We sought to determine the utilization of proven therapies for sepsis in the absence of published guidelines or local protocol.5 (18. tight glycemic control [13]. but all evidence-based therapies. and in the absence of contraindications as evidenced by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis Study Group (PROWESS) trial [6]. As such. However. low dose corticosteroids [11. this increasingly prevalent condition has an associated mortality rate of 28–50% at 28 days [1-4]. It remains to be seen if dissemination of the sepsis guidelines will further improve management or outcome. Its levels are decreased in septic patients) [6].7]. Mean time from event to ICU admission was 4.5 million people in northern Alberta. Patients with severe sepsis in this health region are admitted to one of four closed general systems intensive care units (GSICUs).

all patients receiving rhAPC were admitted to or were waiting for admission to one of the regional GSICUs. Our results show that while mortality was comparable to patients with an APACHE II score of 25 or greater in the PROWESS trial.3. The data extracted from each patient file included age.and 2 community general hospitals. and only 6% had central venous oxygen saturation measurement within the recommended time of 6 hours. 2004. either continuous renal replacement therapy or intermittent hemodialysis was required in 62% (21/34). Mean APACHE II score was 31. All interventions were at the discretion of the treating intensivist. In the case of admitted inpatients.7% of patients had appropriate cultures drawn prior to initiation of antibiotics. Low dose corticosteroids were given to 85% (29/34) of patients for a mean duration of 7 days. Renal replacement therapy. nt ib io C tic V P s m ea su re Sc m vO en 2 t m ea su re m en t Fl ui ds Figure 1 legend: Fluids .4%. No site specific guidelines for the treatment of severely septic patients existed.IV antibiotic administration within 1 hour. Only 35. ScvO2. and all patients had at least three organ failures. Recombinant human activated protein C was added to the regional formulary in mid-February 2003 with prescription restricted to intensivists. Average mortality was 32. diagnostic category. glycemic control. Approval of the University of Alberta Health Research Ethics Board was obtained. the results of this study suggest that concerted efforts are needed to decrease response times. over 85% of patients received low dose corticosteroids. preceded publication of the Surviving Sepsis Guidelines. Figure 1 shows the proportion of patients for whom the various therapies were initiated within the target times as recommended by the Surviving Sepsis Campaign Guidelines and the Institute for Healthcare Improvement [5. Tables 2a and 2b show the times to initiation and adherence to these therapies. Data is entered either by the ordering intensivist or clinical pharmacist. Consequently.14]. All charts were reviewed by a single reviewer. emergency and critical care physicians can have a major impact upon morbidity and mortality.Number of patients that received > 20 cc/kg fluids within 6 hours. location of admission. All GSICUs in this study had previous investigative experience with the indications and use of rhAPC. The Surviving Sepsis Campaign Guidelines are a key part of increasing awareness [5]. and APACHE II score and its components. The descriptive statistics are shown in Table 1. Norepinephrine was the initial vasopressor in 65% (22/34). As such. before rh A PC University of Alberta Health Sciences Journal • September 2007 • Volume 4 • Issue 1 7 . Mortality was less than predicted from APACHE II (76%). We performed a retrospective chart review of all patients prescribed rhAPC between February 18. Our results illustrate that. Approximately 91% of patients received greater than 20cc/kg intravenous fluid resuscitation within 6 hours from presentation. Antibiotics . As shown in table 2b. 2003 and April 30. initial central venous pressure measurement within 6hrs. Pasted version in 01-Davidow-Figure-Tables no good. similar to that of patients in the PROWESS study with APACHE II ≥25 (31%) [1]. by design. RESULTS Thirty-four (34) patients received rhAPC during the study period. and was A eventually used in 91% (31/34). sex. All patients receiving rhAPC are tracked by a regional pharmacy online order entry system interfaced to an Oracle database. type of organ failure. patients were not treated as rapidly as the evidence suggests they should be. Only 32% of patients received antibiotics within the recommended 1st hour. initial central venous oxygen saturation measurement within 6 hours. CVP. all with twenty-four hour coverage by fellowship-trained intensivists. DISCUSSION Early and aggressive treatment of severe sepsis and septic shock can prevent progression to intractable organ failure. ORIGINAL RESEARCH NOTE: Figure 1 chart needs to be resent. rhAPC – infusion of rhAPC initiated within 24 hours. time zero was defined as the time of ICU consultation. using a standardised data acquisition form. All patients received vasopressors. Time zero was defined as the moment the patient presented to the Emergency Department or ICU if transferred directly from an out of region hospital. Eighty eight percent of patients had rhAPC administered within 24 hours. adequate gastrointestinal ulcer and deep venous thrombosis prophylaxis. While this study period. Scarcely more than one third (35%) of patients had central venous hemodynamic monitoring.

Most patients in this study received prompt fluid resuscitation. suggest that along with any guidelines.5 (11. mortality is significantly increased by delays in definitive resuscitation [3]. Sadly. sepsis has not received similar attention and funding.Table 2a: Delivery of evidence based interventions Recommended time to intervention (hours) 6 1 6 6 n/a 24 ORIGINAL RESEARCH 8 their dissemination.3) 4. (%) 12 (35.9. The opportunity to improve begins with recognition that delays are unacceptable and can be surmounted.8 (1. Unfortunately.5 (0. this study emphasises that prior to release of the Surviving Sepsis Campaign Guidelines [5] exposure to the literature.9 (0-3. Recent studies have suggested a significant increase in mortality for each hour that appropriate antibiotics are delayed [8.4 (4. Again.3) 21. on its own. This educational gap is short-sighted. as there is a clear link between delay of appropriate therapy and decreased survival. We intend to subsequently study what effect the guidelines will have on therapeutic targets and outcomes. rhAPC was administered within the target 24-hour window in the great majority (82%) of patients. may be lacking. For example. educational funding to promote the use of equally efficacious.2) 32 (94. Furthermore.6) 0. Education is a key component in any effort to improve everyday therapy in sepsis. University of Alberta Health Sciences Journal • September 2007 • Volume 4 • Issue 1 .1) enough to significantly change this. less than one-in twenty received central venous oximetry within the recommended timeline. The delay in delivery is presumably multifactorial and offers a provocative area for research.10]. similar conditions previously existed with the treatment of acute coronary syndromes.7) 29 (85) 7 30 (88. Considerable product education is provided by pharmaceutical companies when products such as rhAPC are marketed. Similarly.7-30. or grand rounds were insufficient to translate into optimal patient care. However. Similar standards for physician training and attendance at common educational sessions for all our local intensivists. mortality and cost similar to acute coronary syndromes [18]. but a key feature of its effectiveness is timely initiation.-1. Conceptually. delays in other areas of treatment were concerning. This suggests the need to systematically address each step in order to decrease response time.5) Table 2b: Delivery of evidence based interventions (n = 34) Intervention Culture prior to Antibiotics Use of low dose corticosteroids Mean duration (d) Glucose control (maintained <8. but inexpensive therapies.7-21. this is similar to the ideas of “chain-of-survival”. “doorto-drug times” and “taking treatment to the patient” that were developed for coronary disease [17].8) 6. be Time to intervention (hours) Initial Fluid bolus (>20cc/kg) Initial antibiotics Central venous pressure monitoring Central venous saturation monitoring Intensive Care Unit admission rhAPC administration Median (IQR) 0. ED physicians have to triage and care for many patients concurrently. Given that published guidelines emphasize that treatment should not be delayed until ICU admission. two-thirds of patients did not have antibiotics administered or central venous pressure monitored within the recommended timelines. sepsis treatment was suboptimal. attention needs to be given to structural and process factors associated with the actual delivery of care. such as steroids or fluids.1) 32 (94. however. Early goal-directed therapy has been shown to be highly effective in improving survival in septic patients. close collaboration is required between ICU and ED staff in order to rapidly and comprehensively treat the patient.7) 14. As such. Therefore it is quite possible that the mere dissemination of the guidelines will not. journal clubs.1 (5. This comparison is appropriate given that severe sepsis and septic shock are associated with an incidence. it is necessary to expedite a continuum of care from the Emergency Department to the ICU. This problem was addressed by making the timely treatment of patients a priority. In contrast. Furthermore. regardless of where that patient is located.5-11. as well as increased costs [16].8-7.3mmol/L) Gastrointestinal ulcer prophylaxis within 24hours Deep venous thrombosis prophylaxis within 24hours No.

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