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NES Evidence Search & Summary
Sepsis Evidence Base – Update of 2011 search
Author (Name, organisation, job title)
Siobhán O’Brien ([email protected])NESKnowledge Manager
Enquirer(Name, organisation, job title)
Prof. Kevin RooneyNHS GG&C
Date of Search August 2015Search Type Update
1. IntroductionThis report describes the evidence search request, the search methodology, the findings of the search and the associated reference list.
An evidence base for sepsis management was developed in 2011 (1), which informed the work of the Scottish Patient Safety Collaborative. This report is an updated version of this search in answer to two questions:
1. Have there been any changes in the evidence base for sepsis diagnosis and management since the last search in 2011?
2. Are there any new examples of implementation of improvement in sepsis in healthcare systems outside NHS Scotland, or any updates to the examples identified in the last search in 2011?
2. Search OverviewAn extensive search of the published literature was conducted in July 2015, based directly on the search terms and checklist used to facilitate the 2011 search as provided by NHS GG&C and HIS respectively. The details of the search conducted are included in the Appendix.
The following inclusion / exclusion criteria were applied.
Inclusion:
Adult population; Publication focus diagnosis, management and implementation of improvement
programmes;
Please note that the search does not explicitly investigate prevention measures, or indicators of increased risk.
The search was conducted and screened based on the inclusion criteria. The total of included studies followed a screening process. The outcome of the screening process was as follows:
Total: 229 DeDuplication: 203 Screened on Title / Abstract: 43 Final References Sent / Reviewed: 15
3. FindingsThe screened results found:
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The international guidelines for management severe sepsis and septic shock were updated in 2012 (2), based on review of the evidence base at that time;
The effectiveness of early goal directed therapy (EGDT) has been questioned, following the publication of three trials (3-5) and two meta-analyses (6, 7).
Four of the Cochrane Reviews included in the original search have been updated (8-11);
Two of the five sepsis improvement programmes identified in the original search have updated the bundles for management and implementation of sepsis implementation programmes (12, 13); and
Three new ongoing implementation projects were identified (14-16).
The following sections examine these updates in more detail.
3.1 Guidance and Research Evidence Update
3.1.1 GuidanceDellinger et al. (2) produced a guideline in 2012 to update the previous 2008 version on behalf of the Surviving Sepsis Campaign (SSC).
Martin-Loeches et al. (17) summarise the changes to the guideline and the grades of evidence in Table 1 of their paper as:
Antibiotics within 1 hour (Grade 1C) Central venous pressure (CVP) 8–12 mmHg (1C) and mean arterial pressure (MAP)
≥65 mmHg (Grade 1C) No corticosteroids in the absence of refractory shock (Grade 1D) Crystalloids as first choice (Grade 1B) and against hydroxyethyl starches (Grade 1B) Norephinephrine (NE) first choice (Grade 1B) with E added or substituted if not
adequate blood pressure (BP) (Grade 2B) Phenylephrine not recommended except arrhythmias, high cardiac output (CO) and
BP low or rescue (Grade 1C) Dobutamine if myocardial dysfunction (Grade 1C) not for supranormal (Grade 1B) Protocolized approach blood glucose >180 mg/dL and target an upper blood glucose
≤180 mg/dL (Grade 1A) Maintain inspiratory plateau pressure <30 cm H2O (Grade 1B).
Martin-Loeches et al. (17) provide an update on two topics identified as controversial by the authors. These topics are:
Glycemic control and the use of intensive insulin therapy to treat hyperglycemia. The updated evidence has resulted in a protocolised approach and should target an upper blood glucose level ≤ 180 mg/dL rather than an upper target blood glucose level ≤ 110 mg/dL.
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The use of corticosteroids. The most recent evidence suggests “the benefit of treatment with steroids seems to be limited to patients with vasopressor-dependent septic shock with adequate fluid resuscitation.”
3.1.2 Research Evidence – Early Goal-Directed TherapyThree trials on the topic of Early Goal-Directed Therapy (EGDT) have published results and Martin-Loeches et al. (17) note that the SSC are due to review their bundles on the subject of EGDT. These trials are the ARISE trial (3); the ProMISe trial (4) and the ProCESS trial (5).
Two recent meta-analyses have been published on the topic of EGDT as a strategy to decrease mortality in severe sepsis or septic shock when presenting at emergency departments. The Angus et al. review (6) takes into account the recent reporting of the ProMISe trial and the Zhang et al. review (7) was published before these results were made available.
The conclusion of these reviews found that EGDT was not associated with a survival benefit among patients with severe sepsis or septic shock (7) and was not superior to usual care for patients presenting at emergency departments with septic shock (6).
3.1.3 Research Evidence - Cochrane reviews and Health Technology Assessments
Four reviews included in the original search have since been updated. Below the relevant reviews are listed, with conclusion directly quoted from text, and full-text links are available in the Bibliography.
Alejandria et al., Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock, Cochrane Database of Systematic Reviews, 2013 (8)
“Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates with sepsis, there is sufficient evidence that standard polyclonal IVIG, as adjunctive therapy, does not reduce mortality based on the inclusion of the large polyclonal IVIG trial on neonates. For Ig-M enriched IVIG, the trials on neonates and adults were small and the totality of the evidence is still insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.”
Marti-Carvajal et al., Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients, Cochrane Database of Systematic Reviews, 2012 (9)
“This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all
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ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.”
Silva et al., De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock, Cochrane Database of Systematic Reviews, 2013 (11)
“There is no adequate, direct evidence as to whether de-escalation of antimicrobial agents is effective and safe for adults with sepsis, severe sepsis or septic shock. This uncertainty warrants further research via RCTs and the authors are awaiting the results of an ongoing RCT testing the de-escalation of empirical antimicrobial therapy for severe sepsis.”
Soares et al., An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis, Health technology assessment (Winchester, England), 2012 (10)
“Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research. Our recommendations for future research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct.”
3.2 Sepsis Bundle UpdatesThe Institute for Health Improvement (IHI) and the Surviving Sepsis Campaign (SSC) have introduced 3-hour bundles (12, 13) as a result of the guidance published in 2012 (2). The SSC bundle was last updated in April 2015, and the most recent update to the IHI bundle was in April 2013. The 3-hour bundles contain the following elements:
Measure Lactate Level Obtain Blood Cultures Prior to Administration of Antibiotics Administer Broad Spectrum Antibiotics Administer 30 mL/kg Crystalloid for Hypotension or Lactate ≥4 mmol/L.
Both the IHI and SSC have revised the 6 hour bundle as shown in Table 1.
The IHI note the Sepsis Management Bundle, which was part of the previous version of the Severe Sepsis Bundles, has been eliminated, and Other Supportive Therapies have been added to the documentation (12).
The SSC update (13) states that the bundles have been updated following three trials that “do not demonstrate superiority of required use of a central venous catheter to monitor
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central venous pressure and central venous oxygen saturation in all patients with septic shock who have received timely antibiotics and fluid resuscitation compared with controls or in all patients with lactate >4 mmol/L”.
Table 1: 6-Hour Bundle Updates
Bundle Intervention (Original)
(1)
Intervention (Updated)
(12, 13)
IHI Sepsis Resuscitation Bundle (within 6 Hours)
Surviving Sepsis Campaign (within 6 Hours)
Serum lactate measured Apply Vasopressors (for Hypotension That Does Not Respond to Initial Fluid Resuscitation to Maintain a Mean Arterial Pressure (MAP) ≥65 mm Hg)
Blood cultures obtained prior to antibiotic administration
In the Event of Persistent Arterial Hypotension Despite Volume Resuscitation (Septic Shock) or Initial Lactate ≥4 mmol/L (36 mg/dL):
a. Measure Central Venous Pressure (CVP)
b. Measure Central Venous Oxygen Saturation (ScvO2)
Improve time to broad-spectrum antibiotics
Remeasure Lactate If Initial Lactate Was Elevated
Treat hypotension and/or elevated lactate with fluids
Apply Vasopressors for ongoing hypotension
Maintain adequate central venous pressure
Maintain adequate central venous oxygen saturation
3.3 ImplementationThree new implementation programmes were identified during the search, in addition to those identified in 2011. The programme descriptions have been extracted directly from the project web pages.
Clinical Excellence Commission (16)
Status: In progress
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“The inpatient phase of the SEPSIS KILLS program started in 2014 and is focused on improving the recognition and management of sepsis in adults and children in the inpatient wards of public hospitals in NSW.”
Joint Commission Center for Transforming Healthcare (14)
Status: In progress.
“The five leading hospitals and health centers participating in this project will work with the Center to identify the root causes of barriers to identifying and treating sepsis, and find solutions that are unique to their organization’s specific causes. These solutions will be tested and validated, and then spread to other organizations.”
Northumbria H ealthcare NHS Foundation Trust . – funded by The Health Foundation (15)
Status: In progress
“Project aims:
Aims to understand what contributes to avoidable mortality in sepsis in an acute health care organisation, and to implement proven techniques.
Uses statistical process control (SPC) methods to analyse, display and feed back data to clinical teams.
Running from early 2014 to mid 2016. Full details available from here.
The project team will be working with local commissioners to develop a new care bundle, to include:
weekly measurement and reporting simplification of standard documentation on sepsis pathways development of a Sepsis Pathway for Community Hospitals, with interventions for
health care professionals to carry out before patients reach acute care introduction of outreach service introduction of sepsis trolleys in A&E and admissions units multidisciplinary education programme, using a range of media, targeted at clinical
and paramedical staff.
Each of the interventions will be piloted with team-led plan, do, study, act (PDSA) cycles, using the Institute for Healthcare Improvement model as the main improvement methodology.”
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4. Bibliography
(1) WILSON, S., 2011. Sepsis Literature Search. http://www.knowledge.scot.nhs.uk/media/CLT/ResourceUploads/4006514/20120105%20Sepsis%20package%20v2.0.pdf.
(2) DELLINGER, R.P., LEVY, M.M., RHODES, A., ANNANE, D., GERLACH, H., OPAL, S.M., SEVRANSKY, J.E., SPRUNG, C.L., DOUGLAS, I.S., JAESCHKE, R., OSBORN, T.M., NUNNALLY, M.E., TOWNSEND, S.R., REINHART, K., KLEINPELL, R.M.C.S., ANGUS, D.C., DEUTSCHMAN, C.S., MACHADO, F.R., RUBENFELD, G.D., WEBB, S.A., BEALE, R.J., VINCENT, J., MORENO, R. and AND THE SURVIVING SEPSIS CAMPAIGN GUIDELINES COMMITTEE INCLUDING THE PEDIATRIC SUBGROUP, 2013. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Critical Care Medicine, 41(2), pp. 580-637; http://ovidsp.ovid.com/athens/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&AN=00003246-201302000-00024&LSLINK=80&D=ovft.
(3) ARISE INVESTIGATORS AND THE ANZICS CLINICAL TRIALS GROUP, 2014. Goal-Directed Resuscitation for Patients with Early Septic Shock. N Engl J Med, 371(16), pp. 1496-1506; http://dx.doi.org/10.1056/NEJMoa1404380.
(4) MOUNCEY, P.R., OSBORN, T.M., POWER, G.S., HARRISON, D.A., SADIQUE, M.Z., GRIEVE, R.D., JAHAN, R., HARVEY, S.E., BELL, D., BION, J.F., COATS, T.J., SINGER, M., YOUNG, J.D. and ROWAN, K.M., 2015. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med, 372(14), pp. 1301-1311; http://dx.doi.org/10.1056/NEJMoa1500896.
(5) PROCESS INVESTIGATORS, 2014. A Randomized Trial of Protocol-Based Care for Early Septic Shock. N Engl J Med, 370(18), pp. 1683-1693; http://dx.doi.org/10.1056/NEJMoa1401602.
(6) ANGUS, D.C., BARNATO, A.E., BELL, D., BELLOMO, R., CHONG, C.-., COATS, T.J., DAVIES, A., DELANEY, A., HARRISON, D.A., HOLDGATE, A., HOWE, B., HUANG, D.T., IWASHYNA, T., KELLUM, J.A., PEAKE, S.L., PIKE, F., READE, M.C., ROWAN, K.M., SINGER, M., WEBB, S.A.R., WEISSFELD, L.A., YEALY, D.M. and YOUNG, J.D., 2015. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive care medicine, , pp. 1-12; http://dx.doi.org/10.1007/s00134-015-3822-1.
(7) ZHANG, L., ZHU, G., HAN, L. and FU, P., 2015. Early goal-directed therapy in the management of severe sepsis or septic shock in adults: a meta-analysis of randomized controlled trials. BMC Medicine, 13, pp. 71; http://www.biomedcentral.com/1741-7015/13/71.
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(8) ALEJANDRIA MM, LANSANG MA, DANS LF and MANTARING JB 3RD, 2013. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database of Systematic Reviews, 9, pp. 001090; http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001090.pub2/abstract.
(9) MARTI-CARVAJAL AJ, SOLA I, GLUUD C, LATHYRIS D and CARDONA AF, 2012. Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database of Systematic Reviews, 12, pp. 004388; http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004388.pub6/abstract.
(10) SOARES MO, WELTON NJ, HARRISON DA, PEURA P, SHANKAR- HARI M, HARVEY SE, MADAN JJ, ADES AE, PALMER SJ and ROWAN KM, 2012. An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis. Health technology assessment (Winchester, England), 16(7), pp. 1-186; http://dx.doi.org/10.3310/hta16070.
(11) SILVA BN, ANDRIOLO RB, ATALLAH AN and SALOMAO R, 2013. De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Database of Systematic Reviews, 3, pp. 007934; http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007934.pub3/abstract.
(12) INSTITUTE FOR HEALTHCARE IMPROVEMENT, 2013. Severe Sepsis Bundles. Institute for Healthcare Improvement; http://www.ihi.org/resources/Pages/Tools/SevereSepsisBundles.aspx.
(13) SSC EXECUTIVE COMMITTEE, 2015. Surviving Sepsis Bundles: Updated Bundles in Response to New Evidence. Surviving Sepsis Campaign; http://www.survivingsepsis.org/Bundles/Pages/default.aspx.
(14) JOINT COMMISSION CENTER FOR TRANSFORMING HEALTHCARE, 2015-last update, Reducing Sepsis Mortality. Available from: http://www.centerfortransforminghealthcare.org/projects/detail.aspx?Project=8 [08/06, 2015].
(15) THE HEALTH FOUNDATION, 2015-last update, Surviving sepsis: Making best care routine, at scale. Available from: http://www.health.org.uk/programmes/closing-gap-patient-safety/projects/surviving-sepsis-making-best-care-routine-scale [08/06, 2015].
(16) CLINICAL EXCELLENCE COMISSION, 2015-last update, Sepsis Kills program. Available from: http://www.cec.health.nsw.gov.au/programs/sepsis/program-elements#PhasedImplementation [08/06, 2015].
(17) MARTIN-LOECHES, I., LEVY, M.M. and ARTIGAS, A., 2015. Management of severe sepsis: advances, challenges, and current status. Drug design, development and therapy, 9, pp. 2079; http://dx.doi.org/10.2147/DDDT.S78757.
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5. Appendix: ChecklistTopic: Sepsis bundle (adults) – Update
Date of search: 31/7/2015 (original search 21/11/2011)
Searched by: Siobhán O’Brien
Key terms: Sepsis / blood infection / septic shock limit to systematic reviews
Note: Adapted from HIS Checklist 21.11.11 and NHS GG&C search terms November 2011.
Search Documentation
Comments / Search Issues
N/A
Inclusion / Exclusion Criteria
These criteria are applied to the search results to screen for relevance.
Inclusion criteria:
-Adult population
-Diagnosis, management and implementation of improvement programmes (note: exclude prevention)
Number of references (RefWorks)
Total: 229
DeDuplication: 203
Screened on Title and Abstract: 43
Final References Sent / Reviewed: 15
Filepath to search folder on server
J:\E Library\Business As Usual\KBP\ReferenceDesk\EvidenceSearching\
Filepath to RefWorks file (.txt)
J:\E Library\Business As Usual\KBP\ReferenceDesk\EvidenceSearching\
Record of files sent to requester
Report
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Bibliographic Databases
Resource Number of Hits
MEDLINE Filter: Systematic reviews; reviews (specificity)
98; 58
EMBASE Filter: Systematic reviews;
65
Secondary Evidence
Resource Number of Hits
CADTH 0
Cochrane Database of Systematic Reviews Filter: Cochrane reviews; Technology Assessments
*Note number of hits not limited by year, completed manually
87 ; 37
EVIP Net 47
Epistemonikos 48
TRIP Filter: Systematic reviews – DARE, Scottish Medcines Consortium, NHS Economic Evaluation Database
43; 11; 10
Topic Specific – As per 2011 Search
Resource Number of Hits
NOTE: Search Strategy combination of sepsis / infection / septic shock from 2012
Scottish Agencies/Organisations
Scottish Patient Safety Research Network 0
Scottish Patient Safety Alliance 0
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Patient Safety Research Group 0
Clinical governance: learning to improve Not Found
Patient safety board (RCS – Edinburgh) 0
National Agencies/Organisations (UK)
NPSA 0
MHRA 0
King’s Patient Safety and Service Quality Research Centre
0
The Joint Commission: Patient Safety 0 - 1 ongoing
Patient Safety Research Portfolio, University of Birmingham
0
RCN: patient safety 0
Lancaster patients safety research unit 0
Improvement Agencies
Institute for Healthcare Improvement 1 – updated 2012 / 13
The Health Foundation 0 – 2 ongoing
Institute for Innovation and Improvement N/A - closed
Healthcare quality improvement partnership
0
Regulation and quality improvement authority
0
International Organisations
AHRQ Patient Safety Network 1 (guidance document)
Institute of Medicine 0
WHO collaborating centre for Patient Safety Solutions
0
World Alliance for Patient Safety (WHO) 0
VA National Center for Patient Safety 0
National Patient Safety Foundation 0
13
National Coordinating Council for Medication Error Reporting and Correction
0
FDA 0
Australian Patient Safety Foundation 0
Australian Commission on Safety and Quality in Health Care
0 – one ongoing
Centre for Research Excellence in Patient Safety
N/A
Canadian Patient Safety Institute 0
Institute for safe medication practices 0
Web search
Other
UK Sepsis Group 0
Global Sepsis Alliance 0
Sepsis Alliance 0
Surviving Sepsis Campaign 0
Grey Literature
Resource Number of Hits
Not Applicable
14
Database search record
Database
e.g. OVIDSP/Medline
Search strategy (inc. limits and filters)
OvidSP/Medline 1 exp Sepsis/ 98204
2 exp Bacteremia/ 23042
3 exp Shock, Septic/ 19196
4 exp Systemic Inflammatory Response Syndrome/101358
5 (Pyoh?emia$ or py?emia$ septic?em$ or (blood adj poison$) or ((toxic or septic or endotoxic) adj2 shock)).mp.
27943
6 or/1-5 107734
7 limit 6 to (english language and humans and yr="2012 -Current" and "all adult (19 plus years)") 5796
8 or/1-3 98204
9 limit 8 to (english language and humans and yr="2012 -Current" and "all adult (19 plus years)") 5216
10 limit 7 to systematic reviews 98
11 limit 7 to "reviews (maximizes specificity)" 58
EMBASE 1 exp sepsis/ 185865
2 exp bacteremia/ 35777
3 exp septic shock/ 35159
4 exp systemic inflammatory response syndrome/ 190560
5 (Pyoh?emia$ or py?emia$ septic?em$ or (blood adj poison$) or ((toxic or septic or endotoxic) adj2 shock)).mp.
45585
6 or/1-5 198171
7 limit 6 to (english language and yr="2012 -Current" and
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(adult <18 to 64 years> or aged <65+ years>)) 16728
8 limit 7 to "systematic review" 65
9 limit 7 to randomized controlled trial 756
Cochrane Library #1 MeSH descriptor: [Sepsis] explode all trees
#2 MeSH descriptor: [Bacteremia] explode all trees
#3 MeSH descriptor: [Shock, Septic] explode all trees
#4 MeSH descriptor: [Systemic Inflammatory Response Syndrome] explode all trees
#5 Pyoh?emia$ or py?emia$ septic?em$ or (blood adj poison$)
#6 ((toxic or septic or endotoxic) adj2 shock)
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 diagnosis or management
#9 #7 and #8
Epistemonikos Sepsis or Bacteremia or "septic shock" or "Systemic Inflammatory Response Syndrome" or Pyoh?emia$ or "blood poison*" or septic?em$
Limit: Systematic Review, Interventions, 2012 - 2015
TRIP Database Sepsis or Bacteremia or "septic shock" or "Systemic Inflammatory Response Syndrome" from:2012
Limit:
Systematic Reviews
NHS Economic Evaluation Databases
Scottish Medicines Consortium
DARE
EVIP Net Sepsis or Bacteremia or "septic shock" or "Systemic Inflammatory Response Syndrome" or Pyoh?emia$ or "blood poison*" or septic?em$
Limit: Adult and systematic reviews
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