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

Guidelines
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: jdavidow@ualberta.ca Phone: c/o M. Jacka (780) 407-8861 Fax: c/o M. Jacka (780) 407-3200 No external nancial 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

ORIGINAL RESEARCH

ABSTRACT
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).

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of Northern Alberta over a 14 month period. Results: All patients had septic shock, an APACHE II 25 (mean 31.3) and all had at least 3 organ failures. The most common underlying conditions were pneumonia 41.2% (14/34) and intraabdominal sepsis 26.5% (9/34). Intensive Care Unit (ICU) mortality was 35.3% (12/34). Overall, 94% (32/34) of patients received fluid resuscitation within 6 hours of sepsis recognition, 32% (12/34) received antibiotics within 1 hour, 38% (13/34) received central venous pressure (CVP) monitoring, and only 6% (2/34) central venous oximetry within 6 hours. 82% (29/33) of patients received rhAPC within 24 hours of ICU admission. Mean time from event to ICU admission was 4.5 hours. Discussion: Mortality in this group of patients with septic shock was very similar to those in previous reports. Areas for improvement include: faster recognition of sepsis, earlier antibiotics, faster fluid resuscitation, and earlier

central venous saturation measurement. It remains to be seen if dissemination of the sepsis guidelines will further improve management or outcome.

we institute these therapies in everyday practice. At the beginning of our study period, evidence-based therapy included early goal-directed therapy [3,7], early antibiotics [8, 9, 10], low dose corticosteroids [11, 12], tight glycemic control [13], and recombinant human activated protein C (rhAPC, a recombinant protein with antithrombotic, anti-inflammatory, and profibrinolytic properties. Its levels are decreased in septic patients) [6]. 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, 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, patients receiving rhAPC are arguably the most severely ill. Furthermore, given cost considerations, it is also to be assumed that there is full commitment to ongoing aggressive therapy in those receiving rhAPC. We chose to study this group, because it is important to ensure that, in real life practise, our sickest sepsis patients are receiving not just rhAPC, but all evidence-based therapies, and that this occurs in a timely manner. To address this question, we reviewed the records of all patients within the Capital Health hospitals who were prescribed rhAPC over a period of 14 months. This period was chosen as it began with approval of formulary rhAPC, and ended with the publication of the Surviving Sepsis guidelines. We sought to determine the utilization of proven therapies for sepsis in the absence of published guidelines or local protocol.

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INTRODUCTION
Sepsis is a common presentation to the Emergency Department (ED). Furthermore, this increasingly prevalent condition has an associated mortality rate of 2850% at 28 days [1-4]. Until recently, few therapies existed beyond antibiotics, source elimination and general supportive measures. However, evidence now indicates golden hours during which early and aggressive treatment can prevent progression to intractable organ failure[3]. As such, there needs to be a continuum of care involving both the ED and ICU. Treatment cannot wait for ICU admission. Concerns that therapy was neither comprehensive nor timely led to a consensus statement, known as the Surviving Sepsis Guidelines [5]. However, prior to its publication, it was unclear how often or how rapidly these therapies were given. This study was intended to examine how appropriately

Table 1: Characteristics of patients receiving rhAPC

Characteristic Age (mean +/- 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 (32.4%) 17.6 17 (50%) 17 (50%) 17 (50%) 16 (47%) 18 (53%) Value 57.5 (18.4) 31.3 (25, 45)

MATERIALS AND METHODS

The Capital Health Region administers health care for a referral population of 1.5 million people in northern Alberta, Canada, and has pharmaceutical formulary control for this region. Patients with severe sepsis in this health region are admitted to one of four closed general systems intensive care units (GSICUs), in 2 large teaching hospitals

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and 2 community general hospitals, all with twenty-four hour coverage by fellowship-trained intensivists. Recombinant human activated protein C was added to the regional formulary in mid-February 2003 with prescription restricted to intensivists. Consequently, all patients receiving rhAPC were admitted to or were waiting for admission to one of the regional GSICUs. All GSICUs in this study had previous investigative experience with the indications and use of rhAPC. All patients receiving rhAPC are tracked by a regional pharmacy online order entry system interfaced to an Oracle database. Data is entered either by the ordering intensivist or clinical pharmacist. We performed a retrospective chart review of all patients prescribed rhAPC between February 18, 2003 and April 30, 2004. Approval of the University of Alberta Health Research Ethics Board was obtained. All interventions were at the discretion of the treating intensivist. No site specific guidelines for the treatment of severely septic patients existed. 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, In the case of admitted inpatients, time zero was defined as the time of ICU consultation. All charts were reviewed by a single reviewer, using a standardised data acquisition form. The data extracted from each patient file included age, sex, diagnostic category, location of admission, type of organ failure, and APACHE II score and its components.

ORIGINAL RESEARCH

NOTE: Figure 1 chart needs to be resent. Pasted version in 01-Davidow-Figure-Tables no good.

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 - Number of patients that received > 20 cc/kg fluids within 6 hours. Antibiotics - IV antibiotic administration within 1 hour. CVP; initial central venous pressure measurement within 6hrs. ScvO2; initial central venous oxygen saturation measurement within 6 hours. rhAPC infusion of rhAPC initiated within 24 hours.

RESULTS
Thirty-four (34) patients received rhAPC during the study period. The descriptive statistics are shown in Table 1. Mean APACHE II score was 31.3, and all patients had at least three organ failures. Average mortality was 32.4%, similar to that of patients in the PROWESS study with APACHE II 25 (31%) [1]. Mortality was less than predicted from APACHE II (76%). 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 [5,14]. Tables 2a and 2b show the times to initiation and adherence to these therapies. Approximately 91% of patients received greater than 20cc/kg intravenous fluid resuscitation within 6 hours from presentation. Only 32% of patients received antibiotics within the recommended 1st hour. Scarcely more than one third (35%) of patients had central venous hemodynamic monitoring, and only 6% had central venous oxygen saturation measurement within the recommended time of 6 hours. Eighty eight percent of patients had rhAPC administered within 24 hours. As shown in table 2b, over 85% of patients received low dose corticosteroids, glycemic control, adequate gastrointestinal ulcer and deep venous thrombosis prophylaxis. Only 35.7% of patients had appropriate cultures drawn prior to initiation of antibiotics. All patients received vasopressors. Norepinephrine was the initial vasopressor in 65% (22/34), and was

eventually used in 91% (31/34). Renal replacement therapy, either continuous renal replacement therapy or intermittent hemodialysis was required in 62% (21/34). Low dose corticosteroids were given to 85% (29/34) of patients for a mean duration of 7 days.

DISCUSSION
Early and aggressive treatment of severe sepsis and septic shock can prevent progression to intractable organ failure. As such, emergency and critical care physicians can have a major impact upon morbidity and mortality. Our results show that while mortality was comparable to patients with an APACHE II score of 25 or greater in the PROWESS trial, patients were not treated as rapidly as the evidence suggests they should be. While this study period, by design, preceded publication of the Surviving Sepsis Guidelines, the results of this study suggest that concerted efforts are needed to decrease response times. The Surviving Sepsis Campaign Guidelines are a key part of increasing awareness [5]. Our results illustrate that, before

rh

PC

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Table 2a: Delivery of evidence based interventions

Recommended time to intervention (hours) 6 1 6 6 n/a 24

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their dissemination, sepsis treatment was suboptimal. We intend to subsequently study what effect the guidelines will have on therapeutic targets and outcomes. Most patients in this study received prompt fluid resuscitation. However, delays in other areas of treatment were concerning. For example, two-thirds of patients did not have antibiotics administered or central venous pressure monitored within the recommended timelines. Furthermore, less than one-in twenty received central venous oximetry within the recommended timeline. This suggests the need to systematically address each step in order to decrease response time. In contrast, rhAPC was administered within the target 24-hour window in the great majority (82%) of patients. Early goal-directed therapy has been shown to be highly effective in improving survival in septic patients, but a key feature of its effectiveness is timely initiation. Recent studies have suggested a significant increase in mortality for each hour that appropriate antibiotics are delayed [8,9,10]. Similarly, mortality is significantly increased by delays in definitive resuscitation [3]. Education is a key component in any effort to improve everyday therapy in sepsis. Considerable product education is provided by pharmaceutical companies when products such as rhAPC are marketed. Unfortunately, educational funding to promote the use of equally efficacious, but inexpensive therapies, such as steroids or fluids, may be lacking. This educational gap is short-sighted, as there is a clear link between delay of appropriate therapy and decreased survival, as well as increased costs [16]. Furthermore, this study emphasises that prior to release of the Surviving Sepsis Campaign Guidelines [5] exposure to the literature, journal clubs, or grand rounds were insufficient to translate into optimal patient care. Therefore it is quite possible that the mere dissemination of the guidelines will not, on its own, 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) 0.5 (0.-1.6) 0.9 (0-3.8) 6.4 (4.5-11.7) 14.5 (11.7-21.3) 4.8 (1.8-7.3) 21.1 (5.7-30.5)

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 <8.3mmol/L) Gastrointestinal ulcer prophylaxis within 24hours Deep venous thrombosis prophylaxis within 24hours No. (%) 12 (35.7) 29 (85) 7 30 (88.2) 32 (94.1) 32 (94.1)

enough to significantly change this. The delay in delivery is presumably multifactorial and offers a provocative area for research. Similar standards for physician training and attendance at common educational sessions for all our local intensivists, suggest that along with any guidelines, attention needs to be given to structural and process factors associated with the actual delivery of care. ED physicians have to triage and care for many patients concurrently. As such, close collaboration is required between ICU and ED staff in order to rapidly and comprehensively treat the patient, regardless of where that patient is located. Given that published guidelines emphasize that treatment should not be delayed until ICU admission, it is

necessary to expedite a continuum of care from the Emergency Department to the ICU. Conceptually, 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]. This comparison is appropriate given that severe sepsis and septic shock are associated with an incidence, mortality and cost similar to acute coronary syndromes [18]. Sadly, however, sepsis has not received similar attention and funding. The opportunity to improve begins with recognition that delays are unacceptable and can be surmounted. Again, similar conditions previously existed with the treatment of acute coronary syndromes. This problem was addressed by making the timely treatment of patients a priority,

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ORIGINAL RESEARCH

REFERENCES
regardless of whether the patient was pre-hospital, in the emergency room or in the coronary care unit. Similarly, delivery of time-sensitive treatments for sepsis must be expedited regardless of whether that patient is on the ward, in the emergency department, in the critical care unit, or at the referring hospital.
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LIMITATIONS
This study has significant limitations, which include its small sample size, a highly selected patient group, the lack of a cohort comparison and the information bias that is inherent in a retrospective chart review. However, even rudimentary data on how we treat our sickest patients is an essential step towards improving care for all patients with this increasingly common disease.

CONCLUSIONS
This study illustrates that, prior to the publication of the Surviving Sepsis Campaign Guidelines, a clear opportunity existed for improvement. Furthermore, patients that received rhAPC were not receiving all evidencebased therapies in a timely manner. The greatest opportunity to deliver these time dependent interventions occurs in the Emergency Department regardless of whether therapy is given by the emergency or critical care teams. It is clear that there is room for improvement. Our challenge now is to convert guidelines into meaningful clinical practice change [17]. Abbreviations: rhAPC: recombinant human activated protein C. APACHE II: Acute Physiology and Chronic Health Evaluation II. CVP: central venous pressure. ScvO2: central venous oxygen saturation. GSICU: general systems intensive care unit. ICU: intensive care unit.

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