Surviving Sepsis Campaign: International Guidelines

67 Pages·2017·0.5 MB·English

Surviving Sepsis Campaign: International
Guidelines for Management of Sepsis and Septic
Shock: 2016
Andrew Rhodes, MB BS, MD(Res) (Co-chair)1; Laura E. Evans, MD, MSc, FCCM (Co-chair)2;
Waleed Alhazzani, MD, MSc, FRCPC (methodology chair)3; Mitchell M. Levy, MD, MCCM4;
Massimo Antonelli, MD5; Ricard Ferrer, MD, PhD6; Anand Kumar, MD, FCCM7;
Jonathan E. Sevransky, MD, FCCM8; Charles L. Sprung, MD, JD, MCCM9; Mark E. Nunnally, MD, FCCM2;
Bram Rochwerg, MD, MSc (Epi)3; Gordon D. Rubenfeld, MD (conflict of interest chair)10;
Derek C. Angus, MD, MPH, MCCM11; Djillali Annane, MD12; Richard J. Beale, MD, MB BS13;
Geoffrey J. Bellinghan, MRCP14; Gordon R. Bernard, MD15; Jean-Daniel Chiche, MD16;
Craig Coopersmith, MD, FACS, FCCM8; Daniel P. De Backer, MD, PhD17; Craig J. French, MB BS18;
Seitaro Fujishima, MD19; Herwig Gerlach, MBA, MD, PhD20; Jorge Luis Hidalgo, MD, MACP, MCCM21;
Steven M. Hollenberg, MD, FCCM22; Alan E. Jones, MD23; Dilip R. Karnad, MD, FACP24;
Ruth M. Kleinpell, PhD, RN-CS, FCCM25; Younsuk Koh, MD, PhD, FCCM26; Thiago Costa Lisboa, MD27;
Flavia R. Machado, MD, PhD28; John J. Marini, MD29; John C. Marshall, MD, FRCSC30;
John E. Mazuski, MD, PhD, FCCM31; Lauralyn A. McIntyre, MD, MSc, FRCPC32;
Anthony S. McLean, MB ChB, MD, FRACP, FJFICM33; Sangeeta Mehta, MD34; Rui P. Moreno, MD, PhD35;
John Myburgh, MB ChB, MD, PhD, FANZCA, FCICM, FAICD36; Paolo Navalesi, MD37;
Osamu Nishida, MD, PhD38; Tiffany M. Osborn, MD, MPH, FCCM31; Anders Perner, MD39;
Colleen M. Plunkett25; Marco Ranieri, MD40; Christa A. Schorr, MSN, RN, FCCM22;
Maureen A. Seckel, CCRN, CNS, MSN, FCCM41; Christopher W. Seymour, MD42; Lisa Shieh, MD, PhD43;
Khalid A. Shukri, MD44; Steven Q. Simpson, MD45; Mervyn Singer, MD46; B. Taylor Thompson, MD47;
Sean R. Townsend, MD48; Thomas Van der Poll, MD49; Jean-Louis Vincent, MD, PhD, FCCM50;
W. Joost Wiersinga, MD, PhD51, Janice L. Zimmerman, MD, MACP, MCCM52;
R. Phillip Dellinger, MD, MCCM22
1St. George’s Hospital London, England, United Kingdom. 9Hadassah Hebrew University Medical Center Jerusalem, Israel.
2New York University School of Medicine New York, NY. 10Sunnybrook Health Sciences Centre Toronto, Ontario, Canada.
3McMaster University Hamilton, Ontario, Canada. 11 University of Pittsburgh Critical Care Medicine CRISMA Laboratory
4Brown University School of Medicine Providence, RI. Pittsburgh, PA.
5Instituto di Anestesiologia e Rianimazione, Università Cattolica del Sacro 12Hospital Raymond Poincare Garches, France.
Cuore, Rome, Italy. 13Saint Thomas Hospital London, England, United Kingdom.
6Vall d’Hebron University Hospital Barcelona, Spain. 14University College London Hospitals London, England, United Kingdom.
7University of Manitoba Winnipeg, Manitoba, Canada. 15Vanderbilt University Medical Center Nashville, TN.
8Emory University Hospital Atlanta, GA. 16Service de Reanimation Medicale Paris, France.
Copyright © 2017 by the Society of Critical Care Medicine and the 17CHIREC Hospitals Braine L’Alleud, Belgium.
European Society of Intensive Care Medicine 18Western Hospital Victoria, Australia.
DOI: 10.1097/CCM.0000000000002255 19Keio University School of Medicine, Tokyo, Japan.
Critical Care Medicine www.ccmjournal.org 1
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Rhodes et al
20Vivantes-Klinikum Neukölln, Berlin, Germany. Society of Paediatric and Neonatal Intensive Care, European Society for
21 Karl Heusner Memorial Hospital Belize Healthcare Partners Belize City, Emergency Medicine, Federación Panamericana e Ibérica de Medicina
Crítica y Terapia Intensiva, Sociedad Peruana de Medicina Intensiva, Shock
Belize.
Society, Sociedad Argentina de Terapia Intensiva, World Federation of
22Cooper Health System Camden, NJ. Pediatric Intensive and Critical Care Societies.
23University of Mississippi Medical Center Jackson, MS. Dr. Rhodes is a past-president of the European Society of Intensive Care
24Jupiter Hospital Thane, India. Medicine. Dr. Levy received consulting fees from ImmuneExpress.
25Rush University Medical Center Chicago, IL. Dr. Antonelli received funding from Pfizer, MSD, Cubist, Maquet, Drager,
Toray, and Baxter; he participates in ESA and SIAARTI. Dr. Kumar received
26 ASAN Medical Center University of Ulsan College of Medicine Seoul, scientific consulting fees from Baxter, Isomark, and Opsonix on diagnostic
South Korea. technologies; he received grant funding from GSK in the area of influenza.
27Hospital de Clinicas de Porto Alegre Porto Alegre, Brazil. Dr. Ferrer Roca received funding from Estor, MSD, Astra-Zeneca, and Grifols
28Federal University of Sao Paulo Sao Paulo, Brazil. and participates in ESICM and SEMICYUC. Dr. Sevransky is an Associate
Editor of Critical Care Medicine. Dr. Sprung received funding from Asahi
29Regions Hospital St. Paul, MN.
Kasei Pharma America Corporation (consultant, Data Safety and Monitoring
30Saint Michael’s Hospital Toronto, Ontario, Canada. Committee) and LeukoDx Ltd. (consultant; PI, research study on biomarkers
31Washington University School of Medicine St. Louis, MO. of sepsis). He participates in International Sepsis Forum (board member). Dr.
Angus received funding Ferring Inc (consulting fees for serving on the Trial
32Ottawa Hospital Ottawa, Ontario, Canada.
Steering Committee of a Phase 2/3 trial of selepressin for septic shock), and
33 Nepean Hospital, University of Sydney Penrith, New South Wales, Aus- from Ibis and Genmark (both for consulting fees regarding diagnostic strate-
tralia. gies in sepsis). He is a contributing editor for JAMA, has conducted commit-
34Mount Sinai Hospital Toronto, Ontario, Canada. tee membership work for the American Thoracic Society, and has contributed
to an IOM workshop on regulatory science. Dr. Angus provided expert testi-
35UCINC, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.
mony in medical malpractice cases. Dr. Beale’s institution received funding
36University of New South Wales, Sydney, New South Wales, Australia. from Roche (consulting regarding sepsis diagnostics); he received funding
37Università dellla Magna Graecia Catanzaro, Italy. from Quintiles (consulting on routes to license for a potential ARDS therapy);
he participates in the UK National Institute for Clinical and Healthcare Excel-
38Fujita Health University School of Medicine, Toyoake, Aich, Japan.
lence Sepsis Guideline Development Group; he has served as an expert
39Rigshospitalet Copenhagen, Denmark. witness, disclosing that he is approached from time to time regarding expert
40Università Sapienza, Rome, Italy. witness testimony for ICU cases, which may involve patients who have sep-
sis and the testimony relates to generally accepted current standards of care,
41Christiana Care Health Services Newark, DE.
and formal guidance, as it currently pertains within the UK. Dr. Bellingan
42University of Pittsburgh School of Medicine Pittsburgh, PA. received funding from Faron (research into interferon in lung injury) and
43Stanford University School of Medicine Stanford, CA. Athersys (stem cells in lung injury). Dr. Chiche received funding for consult-
ing activities and honoraria for lectures from GE Healthcare, monitoring and
44Kaust Medical Services Thuwal, Saudi Arabia.
IT solutions; he received funding from Nestlé Healthsciences (consulting
45University of Kansas Medical Center Kansas City, KS. activities and honorarium), and from Abbott diagnostics (consulting activi-
46 Wolfson Institute of Biomedical Research London, England, United ties). Dr. Coopersmith is on the fellowship committee of Surgical Infection
Kingdom. Society. Dr. De Backer received funding from Edwards Healthcare, Frese-
nius Kabi, and Grifols. Dr. Dellinger provided expert testimony for alleged
47Massachusetts General Hospital Boston, MA.
malpractice in critical care. Dr. French participates in Australian and New
48California Pacific Medical Center San Francisco, CA. Zealand Intensive Care Society Clinical Trials Group (chair). Dr. Fujishima
49University of Amsterdam Amsterdam, Netherlands. participates in the Japanese Association for Acute Medicine (board member,
Japanese Guidelines for the management of sepsis) and Japanese Respira-
50Erasmé University Hospital Brussels, Belgium.
tory Society (board member, Japanese Guidelines for the management of
51University of Amsterdam, Amsterdam, Netherlands. ARDS); he received funding from Asahi Kasei Co (lecture). Dr. Hollenberg
52Houston Methodist Hospital, Houston, TX. participates in the ACC/AHA PCI and Heart Failure guidelines, CHEST edi-
torial board, ACCP-SEEK, and CHEST CV Network chair. Dr. Jones partici-
Corresponding author: Andrew Rhodes, St. George’s Hospital,
pates in ACEP and SAEM, and has served as an expert witness on various
London, United Kingdom. Email: [email protected]
cases. Dr. Karnad received funding from Quintiles Cardiac Safety Services
Supplemental digital content is available for this article. Direct URL cita- (consultant) and from Bharat Serum and Vaccines Ltd (consultant). He par-
tions appear in the printed text and are provided in the HTML and PDF ticipates in the Indian Society of Critical Care Medicine and the Association
versions of this on the journal’s Web site of Physicians of India. Dr. Kleinpell participates in Critical Care Medicine
This article is being simultaneously published in Critical Care Medicine American Board of Internal Medicine (board member), Institute of Medicine
and Intensive Care Medicine. of Chicago (board member), and the Commission on Collegiate Nursing
Education (board member). Dr. Koh participates in The Korean Society of
The following sponsoring organizations (with formal liaison appointees)
Critical Care Medicine, The European Society of Intensive Care Medicine,
endorse this guideline: American College of Chest Physicians, American
and The Korean Society of Medical Ethics. Dr. Lisboa participates in ILAS,
College of Emergency Physicians, American Thoracic Society, Asia Pacific
AMIB, and ESICM. Dr. Machado participates in the Latin America Sepsis
Association of Critical Care Medicine, Associação de Medicina Intensiva
Institution (CEO). Dr. Marshall received funding from Member Data Safety
Brasileira, Australian and New Zealand Intensive Care Society, Consorcio
Monitoring Committee AKPA Pharma; he participates in International Forum
Centroamericano y del Caribe de Terapia Intensiva, European Society of
for Acute Care Trialists (Chair) and World Federation of Societies of Inten-
Clinical Microbiology and Infectious Diseases, German Sepsis Society,
sive and Critical Care Medicine (Secretary-General). Dr. Mazuski received
Indian Society of Critical Care Medicine, International Pan Arab Critical
funding from Actavis (Allergan) (consultant), Astra-Zeneca (consultant),
Care Medicine Society, Japanese Association for Acute Medicine, Japa-
Bayer (consultant), and from Cubist (now part of Merck) (consultant); he
nese Society of Intensive Care Medicine, Latin American Sepsis Institute,
received research grant funding from Astra-Zeneca, Bayer, and from Merck;
Scandinavian Critical Care Trials Group, Society for Academic Emergency
and participates in Surgical Infection Society (President-elect and Chair of
Medicine, Society of Hospital Medicine, Surgical Infection Society, World
Task Force on Guidelines for the Management of Intra-abdominal Infection)
Federation of Critical Care Nurses, World Federation of Societies of Inten-
and in the American College of Surgeons (speaker at Annual Congress,
sive and Critical Care Medicine.
member of Trusted Medical Information Commission). Dr. Mehta participates
The following non-sponsoring organizations (without formal liaison appoin- in ATS activities. Dr. Moreno participates in the Portuguese and Brasilian
tees) endorse this guideline: Academy of Medical Royal Colleges, Chinese Societies of Intensive Care Medicine. Dr. Myburgh’s institution received
Society of Critical Care Medicine, Asociación Colombiana de Medicina unrestricted grant funding, logistical support and reimbursement from Frese-
Crítica y Cuidado Intensivo, Emirates Intensive Care Society, European nius Kabi for travel expenses to conduct a randomized controlled trial of fluid
2 www.ccmjournal.org March 2017 • Volume 45 • Number 3
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Guidelines
resuscitation (CHEST study): 2008–2012: A$7600000 (US$ 5000000); Objective: To provide an update to “Surviving Sepsis Campaign
an unrestricted grant for partial funding from Baxter Healthcare of an interna-
Guidelines for Management of Sepsis and Septic Shock: 2012.”
tional observational study of patterns of fluid resuscitation (FLUID TRIPS
Design: A consensus committee of 55 international experts rep-
study) in 2014: A$70,000 (US$ 50,000); honoraria and travel reimburse-
ments from Baxter Healthcare for participation in Advisory Board meetings in resenting 25 international organizations was convened. Nominal
Sydney (2013), Paris (2014) and China (2014); and an unrestricted grant
groups were assembled at key international meetings (for those
for partial funding from CSL Bioplasma for an international observational
committee members attending the conference). A formal conflict-
study of patterns of fluid resuscitation (FLUID TRIPS study) in 2014:
A$10,000 (US$ 7,500); he also participates as a council member in the of-interest (COI) policy was developed at the onset of the process
World Federation of Societies of Intensive and Critical Care Medicine. Dr. and enforced throughout. A stand-alone meeting was held for all
Navalesi participates in the European Respiratory Society (Head of Assem-
panel members in December 2015. Teleconferences and elec-
bly Respiratory Intensive Care), is a member of ESICM (European Society of
Intensive Care Medicine) and ESA (European Society of Anaesthesiology), tronic-based discussion among subgroups and among the entire
and is in the Scientific Committee of SIAARTI (the Italian Association of committee served as an integral part of the development.
Anesthesia and Intensive Care). Dr. Nishida participates in The Japanese
Methods: The panel consisted of five sections: hemodynamics,
Society of Intensive Care Medicine (vice chairman of the executive boards),
the Japanese Guidelines for the Management of Sepsis and Septic Shock infection, adjunctive therapies, metabolic, and ventilation. Popula-
2016 (chairman), The Japanese Guidelines for Nutrition Support Therapy in tion, intervention, comparison, and outcomes (PICO) questions
the Adult and Pediatric Critically Ill Patients (board), The Japanese Guide-
were reviewed and updated as needed, and evidence profiles
lines for the Management of Acute Kidney Injury 2016 (board), The Expert
Consensus of the Early Rehabilitation in Critical Care (board), The sepsis were generated. Each subgroup generated a list of questions,
registry organization in Japan (member). Dr. Osborn received funding from searched for best available evidence, and then followed the prin-
Cheetah (speaker related to fluid resuscitation and use of NICOM); she par-
ciples of the Grading of Recommendations Assessment, Devel-
ticipates in American College of Emergency Physicians (Representative to
SCC), consultant for national database development, CDC sepsis task opment, and Evaluation (GRADE) system to assess the quality of
force, IHI consultant. Dr. Perner is the editor of ICM; his department received evidence from high to very low, and to formulate recommendations
research funding from CSL Behring and Fresenius Kabi. Dr. Ranieri partici-
as strong or weak, or best practice statement when applicable.
pates in ESICM. Dr. Seckel received funding from American Association of
Critical-Care Nurses (AACN) (honorarium for speaker at 2016 annual con- Results: The Surviving Sepsis Guideline panel provided 93 state-
ference; AACN Online Web based Essentials of Critical Care Orientation); ments on early management and resuscitation of patients with
she participates as a volunteer for AACN, and served as AACN liaison to the
sepsis or septic shock. Overall, 32 were strong recommenda-
ATS/ESICM/SCCM CPG: Mechanical Ventilation in Adult Patients with
ARDS. Dr. Shieh participates in Society of Hospital Medicine Faculty for tions, 39 were weak recommendations, and 18 were best-practice
Sepsis Workshop, SHM-SCCM Moore Foundation collaborative faculty. Dr. statements. No recommendation was provided for four questions.
Shukri participates in the International Pan Arab Critical Care Society educa-
Conclusions: Substantial agreement exists among a large cohort of
tional activities. Dr. Simpson participates in CHEST Regent at Large (board
of directors), and is an ATS member. Dr. Singer received funding from Deltex international experts regarding many strong recommendations for
Medical, Bayer, Biotest, and MSD; he participates in the UK Intensive Care the best care of patients with sepsis. Although a significant num-
Society research and Meeting committees; he has provided expert testi-
ber of aspects of care have relatively weak support, evidence-based
mony, disclosing: I do medicolegal work (6 cases/year) as an independent
expert, 80% on behalf of the defendant. Dr. Thompson received funding from recommendations regarding the acute management of sepsis and
serving on DSMBs trials sponsored by Ferring Pharmaceuticals, Farron septic shock are the foundation of improved outcomes for these crit-
Labs, and Roche Genentec; also received funding from Asahi Kasei Pharma
ically ill patients with high mortality. (Crit Care Med 2017; 3:00–00)
America (consulting), UpToDate (wrote two chapters on pulmonary embo-
lism diagnosis), and was a pro bono consultant for BioAegis; participates as Key Words: evidence-based medicine; Grading of
a member of the American Thoracic Society committee to develop the ATS/ Recommendations Assessment, Development, and Evaluation
ESICM/SCCM Clinical Practice Guideline: Mechanical Ventilation in Adult
criteria; guidelines; infection; sepsis; sepsis bundles; sepsis
Patients with Acute Respiratory Distress Syndrome. Dr. Vincent participates
in World Federation of Societies of Intensive and Critical Care Societies syndrome; septic shock; Surviving Sepsis Campaign
(president) and Critical Care Foundation (president). Dr. Wiersinga is trea-
surer of both the ESCMID Study Group for Bloodstream Infections and Sep-
sis (ESGBIS) and the Dutch Working Party on Antibiotic Policy (SWAB),
Academic Medical Center, University of Amsterdam (all non-profit). Dr. Zim-
merman participates in ACCP, ACP, WFSICCM, and PAIF; she has pro- INTRODUCTION
vided expert testimony on loss of digits due to DIC, mesenteric ischemia. Dr.
Sepsis is life-threatening organ dysfunction caused by a dysreg-
Nunnally participates in SOCCA (board), ASA (committee), NYSSA, IARS,
and AUA. Dr. Rochwerg participates as a methodologist for ATS, ESCIM, ulated host response to infection (1–3). Sepsis and septic shock
and Canadian Blood services. The remaining authors have disclosed that are major healthcare problems, affecting millions of people
they do not have any potential conflicts of interest.
around the world each year, and killing as many as one in four
Governance of Surviving Sepsis Campaign Guidelines Committee
(and often more) (4–6). Similar to polytrauma, acute myocar-
SSC Executive and Steering Committees
dial infarction, or stroke, early identification and appropriate
http://www.survivingsepsis.org/About-SSC/Pages/Leadership.aspx
management in the initial hours after sepsis develops improves
SSC Guidelines Committee Oversight Group
outcomes.
Andrew Rhodes, Laura Evans, Mitchell M. Levy
The recommendations in this document are intended to
SSC Guidelines Committee Group Heads
provide guidance for the clinician caring for adult patients with
Massimo Antonelli (Hemodynamics), Ricard Ferrer (Adjunctive therapies),
sepsis or septic shock. Recommendations from these guide-
Anand Kumar (Infection), Jonathan E. Sevransky (Ventilation), Charles L.
Sprung (Metabolic) lines cannot replace the clinician’s decision-making capability
GRADE Methodology Group when presented with a patient’s unique set of clinical variables.
Waleed Alhazzani (chair), Mark E. Nunnally, Bram Rochwerg These guidelines are appropriate for the sepsis patient in a hos-
For additional information regarding this article, email [email protected] pital setting. These guidelines are intended to be best practice
Critical Care Medicine www.ccmjournal.org 3
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Rhodes et al
(the committee considers this a goal for clinical practice) and were the internal work structure of the guidelines commit-
not created to represent standard of care. tee. Topic selection was the responsibility of the co-chairs
and group heads, with input from the guideline panel in each
group. Prioritization of the topics was completed by discussion
METHODOLOGY
through e-mails, teleconferences, and face-to-face meetings.
Below is a summary of the important methodologic consider-
All guideline questions were structured in PICO format, which
ations for developing these guidelines.
described the population, intervention, control, and outcomes.
Questions from the last version of the SSC guidelines were
Definitions
reviewed; those that were considered important and clinically
As these guidelines were being developed, new definitions for
relevant were retained. Questions that were considered less
sepsis and septic shock (Sepsis-3) were published. Sepsis is now
important or of low priority to clinicians were omitted, and new
defined as life-threatening organ dysfunction caused by a dys-
questions that were considered high priority were added. The
regulated host response to infection. Septic shock is a subset of
decision regarding question inclusion was reached by discussion
sepsis with circulatory and cellular/metabolic dysfunction asso-
and consensus among the guideline panel leaders with input
ciated with a higher risk of mortality (3). The Sepsis-3 definition
from panel members and the methodology team in each group.
also proposed clinical criteria to operationalize the new defini-
GRADE methodology was applied in selecting only out-
tions; however, in the studies used to establish the evidence for
comes that were considered critical from a patient’s perspec-
these guidelines, patient populations were primarily character-
tive (13). All PICO questions with supporting evidence are
ized by the previous definition of sepsis, severe sepsis, and septic
presented in Supplemental Digital Content 1 (http://links.
shock stated in the 1991 and 2001 consensus documents (7).
lww.com/CCM/C322).
History of the Guidelines
Search Strategy
These clinical practice guidelines are a revision of the 2012 Sur-
With the assistance of professional librarians, an independent
viving Sepsis Campaign (SSC) guidelines for the management
literature search was performed for each defined question. The
of severe sepsis and septic shock (8, 9). The initial SSC guide-
panel members worked with group heads, methodologists, and
lines were first published in 2004 (10), and revised in 2008 (11,
librarians to identify pertinent search terms that included, at a
12) and 2012 (8, 9). The current iteration is based on updated
minimum, sepsis, severe sepsis, septic shock, sepsis syndrome, and
literature searches incorporated into the evolving manuscript
critical illness, combined with appropriate key words specific to
through July 2016. A summary of the 2016 guidelines appears in
the question posed.
Appendix 1. A comparison of recommendations from 2012 to
For questions addressed in the 2012 SSC guidelines, the
2016 appears in Appendix 2. Unlike previous editions, the SSC
search strategy was updated from the date of the last litera-
pediatric guidelines will appear in a separate document, also to
ture search. For each of the new questions, an electronic search
be published by the Society of Critical Care Medicine (SCCM)
was conducted of a minimum of two major databases (e.g.,
and the European Society of Intensive Care Medicine (ESICM).
Cochrane Registry, MEDLINE, or EMBASE) to identify rele-
vant systematic reviews and randomized clinical trials (RCTs).
Sponsorship
Funding for the development of these guidelines was provided
Grading of Recommendations
by SCCM and ESICM. In addition, sponsoring organizations
Grading of Recommendations Assessment, Development, and
provided support for their members’ involvement.
Evaluation (GRADE) system principles guided assessment of
quality of evidence from high to very low and were used to
Selection and Organization of Committee Members
determine the strength of recommendations (Tables 1 and 2)
The selection of committee members was based on expertise in
(14). The GRADE methodology is based on assessment of evi-
specific aspects of sepsis. Co-chairs were appointed by the SCCM
dence according to six categories: 1) risk of bias, 2) inconsis-
and ESICM governing bodies. Each sponsoring organization
tency, 3) indirectness, 4) imprecision, 5) publication bias, and
appointed a representative who had sepsis expertise. Additional
6) other criteria, followed by assessment of the balance between
committee members were appointed by the co-chairs and the
benefit and harm, patients’ values and preferences, cost and
SSC Guidelines Committee Oversight Group to balance conti-
resources, and feasibility and acceptability of the interven-
nuity and provide new perspectives with the previous commit-
tion. The final recommendations formulated by the guideline
tees’ membership as well as to address content needs. A patient
panel are based on the assessment of these factors. The GRADE
representative was appointed by the co-chairs. Methodologic
assessment of the quality of evidence is presented in Table 1.
expertise was provided by the GRADE Methodology Group.
RCTs begin as high-quality evidence that could be down-
graded due to limitations in any of the aforementioned cat-
Question Development
egories. While observational (nonrandomized) studies begin
The scope of this guideline focused on early management of
as low-quality evidence, the quality level could be upgraded
patients with sepsis or septic shock. The guideline panel was
on the basis of a large magnitude of effect or other factors. The
divided into five sections (hemodynamics, infection, adjunctive
GRADE methodology classifies recommendations as strong
therapies, metabolic, and ventilation). The group designations
4 www.ccmjournal.org March 2017 • Volume 45 • Number 3
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Guidelines
TABLE 1. Determination of the Quality of recommendation will clearly outweigh the undesirable effects.
Evidence A weak recommendation in favor of an intervention indicates
the judgment that the desirable effects of adherence to a rec-
Underlying methodology ommendation probably will outweigh the undesirable effects,
1. High: RCTs but the panel is not confident about these trade-offs—either
because some of the evidence is low quality (and thus uncer-
2. Moderate: Downgraded RCTs or upgraded observational
tainty remains regarding the benefits and risks) or the benefits
studies
and downsides are closely balanced. A strong recommendation
3. Low: Well-done observational studies with RCTs
is worded as “we recommend” and a weak recommendation as
4. Very Low: Downgraded controlled studies or expert opinion “we suggest.” An alphanumeric scheme was used in previous
or other evidence editions of the SSC guidelines. Table 3 provides a comparison
to the current grading system.
Factors that may decrease the strength of evidence
The implications of calling a recommendation strong are
1. Methodologic features of available RCTs suggesting high
that most patients would accept that intervention and that
likelihood of bias
most clinicians should use it in most situations. Circumstances
2. Inconsistency of results, including problems with subgroup may exist in which a strong recommendation cannot or should
analyses
not be followed for an individual because of that patient’s pref-
3. Indirectness of evidence (differing population, intervention, erences or clinical characteristics that make the recommenda-
control, outcomes, comparison) tion less applicable. These are described in Table 4. A strong
4. Imprecision of results recommendation does not imply standard of care.
A number of best practice statements (BPSs) appear through-
5. High likelihood of reporting bias
out the document; these statements represent ungraded strong
Main factors that may increase the strength of recommendations and are used under strict criteria. A BPS would
evidence
be appropriate, for example, when the benefit or harm is unequiv-
1. Large magnitude of effect (direct evidence, relative risk ocal, but the evidence is hard to summarize or assess using GRADE
> 2 with no plausible confounders) methodology. The criteria suggested by the GRADE Working
2. Very large magnitude of effect with relative risk > 5 and no Group in Table 5 were applied in issuing BPSs (15).
threats to validity (by two levels)
Voting Process
3. Dose-response gradient
Following formulation of statements through discussion in
RCT = randomized clinical trial
each group and deliberation among all panel members dur-
ing face-to-face meetings at which the groups presented their
or weak. The factors influencing this determination are pre- draft statements, all panel members received links to polls
sented in Table 2. The guideline committee assessed whether created using SurveyMonkey, Inc. (Palo Alto, CA) to indicate
the desirable effects of adherence would outweigh the undesir- agreement or disagreement with the statement, or abstention.
able effects, and the strength of a recommendation reflects the Acceptance of a statement required votes from 75% of the panel
group’s degree of confidence in that balance assessment. Thus, members with an 80% agreement threshold. Voters could pro-
a strong recommendation in favor of an intervention reflects vide feedback for consideration in revising statements that did
the panel’s opinion that the desirable effects of adherence to a not receive consensus in up to three rounds of voting.
TABLE 2. Factors Determining Strong vs. Weak Recommendation
What Should Be Considered Recommended Process
High or moderate evidence The higher the quality of evidence, the more likely a strong recommendation
(Is there high- or moderate-quality
evidence?)
Certainty about the balance of benefits vs. The larger the difference between the desirable and undesirable consequences
harms and burdens and the certainty around that difference, the more likely a strong recommendation.
The smaller the net benefit and the lower the certainty for that benefit, the more
(Is there certainty?)
likely a weak recommendation.
Certainty in, or similar, values The more certainty or similarity in values and preferences, the more likely a strong
recommendation.
(Is there certainty or similarity?)
Resource implications The lower the cost of an intervention compared to the alternative and other costs
related to the decision (i.e., fewer resources consumed), the more likely a strong
(Are resources worth expected benefits?)
recommendation.
Critical Care Medicine www.ccmjournal.org 5
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Rhodes et al
TABLE 3. Comparison of 2016 Grading judged as having conflicts that were managed through reassign-
Terminology with Previous Alphanumeric ment to another group as well as the described restrictions on
voting on recommendations in areas of potential COI. One indi-
Descriptors
vidual was asked to step down from the committee. All panel-
2016 2012 ists with COI were required to work within their group with full
Descriptor Descriptor disclosure when a topic for which they had relevant COI was
discussed, and they were not allowed to serve as group head. At
Strength Strong 1
the time of final approval of the document, an update of the COI
Weak 2
statement was required. No additional COI issues were reported
Quality High A that required further adjudication.
A summary of all statements determined by the guidelines
Moderate B
panel appears in Appendix 1. All evidence summaries and
Low C evidence profiles that informed the recommendations and
Very Low D statements appear in Supplemental Digital Content 2 (http://
links.lww.com/CCM/C323). Links to specific tables and figures
Ungraded strong Best Practice Ungraded
appear within the relevant text.
recommendation Statement
A. INITIAL RESUSCITATION
Conflict-of-Interest Policy
No industry input into guidelines development occurred, and 1. Sepsis and septic shock are medical emergencies, and
no industry representatives were present at any of the meet- we recommend that treatment and resuscitation begin
ings. No member of the guidelines committee received hono- immediately (BPS).
raria for any role in the guidelines process. 2. We recommend that, in the resuscitation from sepsis-
The process relied solely on personal disclosure, and no induced hypoperfusion, at least 30 mL/kg of IV crystalloid
attempt was made by the group to seek additional confirma- fluid be given within the first 3 hours (strong recommen-
tion. The co-chairs, COI chair, and group heads adjudicated dation, low quality of evidence).
this to the best of their abilities. 3. We recommend that, following initial fluid resuscitation,
On initial review, 31 financial COI disclosures and five non- additional fluids be guided by frequent reassessment of
financial disclosures were submitted by committee members; hemodynamic status (BPS).
others reported no COI. Panelists could have both financial and
Remarks: Reassessment should include a thorough clinical
nonfinancial COI. Declared COI disclosures from 11 members
examination and evaluation of available physiologic variables
were determined by the COI subcommittee to be not relevant
(heart rate, blood pressure, arterial oxygen saturation, respira-
to the guidelines content process. Fifteen who were determined
tory rate, temperature, urine output, and others, as available) as
to have COI (financial and nonfinancial) were adjudicated by a
well as other noninvasive or invasive monitoring, as available.
management plan that required adherence to SSC COI policy
limiting discussion or voting at any committee meetings during 4. We recommend further hemodynamic assessment (such
which content germane to their COI was discussed. Five were as assessing cardiac function) to determine the type of
TABLE 4. Implications of the Strength of Recommendation
Strong Recommendation Weak Recommendation
For patients Most individuals in this situation would want the The majority of individuals in this situation would
recommended course of action, and only a small want the suggested course of action, but many
proportion would not. would not.
For clinicians Most individuals should receive the Different choices are likely to be appropriate
recommended course of action. Adherence to for different patients, and therapy should be
this recommendation according to the guideline tailored to the individual patient’s circumstances.
could be used as a quality criterion or performance These circumstances may include the patient’s
indicator. Formal decision aids are not likely to or family’s values and preferences.
be needed to help individuals make decisions
consistent with their values and preferences.
For policy makers The recommendation can be adapted as policy in Policy-making will require substantial debates
most situations, including for use as performance and involvement of many stakeholders. Policies
indicators. are also more likely to vary between regions.
Performance indicators would have to focus on
the fact that adequate deliberation about the
management options has taken place.
6 www.ccmjournal.org March 2017 • Volume 45 • Number 3
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Guidelines
TABLE 5. Criteria for Best Practice the patient and while awaiting more precise measurements of
Statements hemodynamic status. Although little literature includes con-
trolled data to support this volume of fluid, recent interven-
Criteria for Best Practice Statements tional studies have described this as usual practice in the early
stages of resuscitation, and observational evidence supports the
1 Is the statement clear and actionable?
practice (20, 21). The average volume of fluid pre-randomiza-
2 Is the message necessary? tion given in the PROCESS and ARISE trials was approximately
3 Is the net benefit (or harm) unequivocal? 30mL/kg, and approximately 2 liters in the PROMISE trial (17–
19). Many patients will require more fluid than this, and for
4 Is the evidence difficult to collect and summarize?
this group we advocate that further fluid be given in accordance
5 Is the rationale explicit? with functional hemodynamic measurements.
6 Is this better to be formally GRADEd? One of the most important principles to understand in the
management of these complex patients is the need for a detailed
GRADE = Grading of Recommendations Assessment, Development, and
Evaluation initial assessment and ongoing reevaluation of the response to
Modified from Guyatt et al (15). treatment. This evaluation should start with a thorough clinical
examination and evaluation of available physiologic variables
shock if the clinical examination does not lead to a clear
that can describe the patient’s clinical state (heart rate, blood
diagnosis (BPS).
pressure, arterial oxygen saturation, respiratory rate, tempera-
5. We suggest that dynamic over static variables be used to
ture, urine output, and others as available). Echocardiography
predict fluid responsiveness, where available (weak rec-
in recent years has become available to many bedside clinicians
ommendation, low quality of evidence).
and enables a more detailed assessment of the causes of the
6. We recommend an initial target mean arterial pressure
hemodynamic issues (22).
(MAP) of 65 mm Hg in patients with septic shock requir-
The use of CVP alone to guide fluid resuscitation can no
ing vasopressors (strong recommendation, moderate
longer be justified (22) because the ability to predict a response
quality of evidence).
to a fluid challenge when the CVP is within a relatively nor-
7. We suggest guiding resuscitation to normalize lactate in
mal range (8–12 mm Hg) is limited (23). The same holds true
patients with elevated lactate levels as a marker of tissue
for other static measurements of right or left heart pressures
hypoperfusion (weak recommendation, low quality of
or volumes. Dynamic measures of assessing whether a patient
evidence).
requires additional fluid have been proposed in an effort to
Rationale. Early effective fluid resuscitation is crucial for sta- improve fluid management and have demonstrated better
bilization of sepsis-induced tissue hypoperfusion or septic diagnostic accuracy at predicting those patients who are likely
shock. Sepsis-induced hypoperfusion may be manifested by to respond to a fluid challenge by increasing stroke volume.
acute organ dysfunction and/or ± decreased blood pressure These techniques encompass passive leg raises, fluid challenges
and increased serum lactate. Previous iterations of these guide- against stroke volume measurements, or the variations in sys-
lines have recommended a protocolized quantitative resuscita- tolic pressure, pulse pressure, or stroke volume to changes in
tion, otherwise known as early goal-directed therapy (EGDT), intrathoracic pressure induced by mechanical ventilation (24).
which was based on the protocol published by Rivers (16). This Our review of five studies of the use of pulse pressure varia-
recommendation described the use of a series of “goals” that tion to predict fluid responsiveness in patients with sepsis or
included central venous pressure (CVP) and central venous septic shock demonstrated a sensitivity of 0.72 (95% CI, 0.61–
oxygen saturation (Scvo . This approach has now been chal- 0.81) and a specificity of 0.91 (95% CI, 0.83–0.95); the qual-
2)
lenged following the failure to show a mortality reduction in ity of evidence was low due to imprecision and risk of bias
three subsequent large multicenter RCTs (17–19). No harm was (Supplemental Digital Content 3, http://links.lww.com/CCM/
associated with the interventional strategies; thus, the use of the C324) (24). A recent multicenter study demonstrated limited
previous targets is still safe and may be considered. Of note, the use of cardiac function monitors during fluid administration
more recent trials included less severely ill patients (lower base- in the ICUs. Even though data on the use of these monitors in
line lactate levels, Scvo at or above the target value on admis- the emergency department are lacking, the availability of the
2
sion, and lower mortality in the control group). Although this devices and applicability of the parameters to all situations may
protocol cannot now be recommended from its evidence base, influence the routine use of dynamic indices (22, 25).
bedside clinicians still need guidance as to how to approach this MAP is the driving pressure of tissue perfusion. While
group of patients who have significant mortality and morbid- perfusion of critical organs such as the brain or kidney may
ity. We recommend, therefore, that these patients be viewed as be protected from systemic hypotension by autoregulation
having a medical emergency that necessitates urgent assessment of regional perfusion, below a threshold MAP, tissue per-
and treatment. As part of this, we recommend that initial fluid fusion becomes linearly dependent on arterial pressure. In
resuscitation begin with 30 mL/kg of crystalloid within the first a single-center trial (26), dose titration of norepinephrine
3 hours. This fixed volume of fluid enables clinicians to initiate from 65 to 75 and 85 mm Hg raised cardiac index (from
resuscitation while obtaining more specific information about 4.7 ± 0.5 to 5.5 ± 0.6 L/min/m2) but did not change urinary
Critical Care Medicine www.ccmjournal.org 7
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Rhodes et al
flow, arterial lactate levels, oxygen delivery and consumption, B.SCREENING FOR SEPSIS AND
gastric mucosal Pco, RBC velocity, or skin capillary flow. PERFORMANCE IMPROVEMENT
2
Another single-center (27) trial compared, in norepineph-
1. We recommend that hospitals and hospital systems have a
rine-treated septic shock, dose titration to maintain MAP at
performance improvement program for sepsis, including
65 mm Hg versus achieving 85 mm Hg. In this trial, targeting
sepsis screening for acutely ill, high-risk patients (BPS).
high MAP increased cardiac index from 4.8 (3.8–6.0) to 5.8
(4.3–6.9) L/min/m2 but did not change renal function, arte- Rationale: Performance improvement efforts for sepsis are
rial lactate levels, or oxygen consumption. A third single-cen- associated with improved patient outcomes (40). Sepsis per-
ter trial (28) found improved microcirculation, as assessed by formance improvement programs should optimally have
sublingual vessel density and the ascending slope of thenar multiprofessional representation (physicians, nurses, affili-
oxygen saturation after an occlusion test, by titrating norepi- ate providers, pharmacists, respiratory therapists, dietitians,
nephrine to a MAP of 85 mm Hg compared to 65 mm Hg. administrators) with stakeholders from all key disciplines rep-
Only one multicenter trial that compared norepinephrine resented in their development and implementation. Successful
dose titration to achieve a MAP of 65 mm Hg versus 85 mm programs should include protocol development and imple-
Hg had mortality as a primary outcome (29). There was no mentation, targeted metrics to be evaluated, data collection,
significant difference in mortality at 28 days (36.6% in the and ongoing feedback to facilitate continuous performance
high-target group and 34.0% in the low-target group) or 90 improvement (41). In addition to traditional continuing edu-
days (43.8% in the high-target group and 42.3% in the low- cation efforts to introduce guidelines into clinical practice,
target group). Targeting a MAP of 85 mm Hg resulted in a knowledge translation efforts can be valuable in promoting the
significantly higher risk of arrhythmias, but the subgroup of use of high-quality evidence in changing behavior (42).
patients with previously diagnosed chronic hypertension had Sepsis performance improvement programs can be aimed
a reduced need for renal replacement therapy (RRT) at this at earlier recognition of sepsis via a formal screening effort
higher MAP. A recent pilot trial of 118 septic shock patients and improved management of patients once they are identi-
(30) suggested that, in the subgroup of patients older than fied as being septic. Because lack of recognition prevents timely
75 years, mortality was reduced when targeting a MAP of therapy, sepsis screening is associated with earlier treatment
60–65 mm Hg versus 75–80 mm Hg. The quality of evidence (43, 44). Notably, sepsis screening has been associated with
was moderate (Supplemental Digital Content 4, http://links. decreased mortality in several studies (20, 45). The implemen-
lww.com/CCM/C325) due to imprecise estimates (wide con- tation of a core set of recommendations (“bundle”) has been
fidence intervals). As a result, the desirable consequences of a cornerstone of sepsis performance improvement programs
targeting MAP of 65 mm Hg (lower risk of atrial fibrillation, aimed at improving management (46). Note that the SSC
lower doses of vasopressors, and similar mortality) led to a bundles have been developed separately from the guidelines in
strong recommendation favoring an initial MAP target of conjunction with an educational and improvement partner-
65 mm Hg over higher MAP targets. When a better under- ship with the Institute for Healthcare Improvement (46). The
standing of any patient’s condition is obtained, this target SSC bundles that are based on previous guidelines have been
should be individualized to the pertaining circumstances. adopted by the U.S.-based National Quality Forum and have
Serum lactate is not a direct measure of tissue perfusion (31). also been adapted by the U.S. healthcare system’s regulatory
Increases in the serum lactate level may represent tissue agencies for public reporting. To align with emerging evidence
hypoxia, accelerated aerobic glycolysis driven by excess beta- and U.S. national efforts, the SSC bundles were revised in 2015.
adrenergic stimulation, or other causes (e.g., liver failure). While specifics vary widely among different programs, a
Regardless of the source, increased lactate levels are associated common theme is the drive toward improvement in compli-
with worse outcomes (32). Because lactate is a standard labo- ance with sepsis bundles and practice guidelines such as SSC (8).
ratory test with prescribed techniques for its measurement, it A meta-analysis of 50 observational studies demonstrated that
may serve as a more objective surrogate for tissue perfusion performance improvement programs were associated with a
as compared with physical examination or urine output. Five significant increase in compliance with the SSC bundles and a
randomized controlled trials (647 patients) have evaluated lac- reduction in mortality (OR 0.66; 95% CI, 0.61–0.72) (47). The
tate-guided resuscitation of patients with septic shock (33–37). largest study to date examined the relationship between com-
A significant reduction in mortality was seen in lactate-guided pliance with the SSC bundles (based on the 2004 guidelines)
resuscitation compared to resuscitation without lactate moni- and mortality. A total of 29,470 patients in 218 hospitals in the
toring (RR 0.67; 95% CI, 0.53–0.84; low quality). There was United States, Europe, and South America were examined over a
no evidence for difference in ICU length of stay (LOS) (mean 7.5-year period (21). Lower mortality was observed in hospitals
difference –1.51 days; 95% CI, –3.65 to 0.62; low quality). Two with higher compliance. Overall hospital mortality decreased
other meta-analyses of the 647 patients who were enrolled in 0.7% for every 3 months a hospital participated in the SSC, asso-
these trials demonstrate moderate evidence for reduction in ciated with a 4% decreased LOS for every 10% improvement
mortality when an early lactate clearance strategy was used, in compliance with bundles. This benefit has also been shown
compared with either usual care (nonspecified) or with a Scvo across a wide geographic spectrum. A study of 1,794 patients
2
normalization strategy (38, 39). from 62 countries with severe sepsis (now termed “sepsis”
8 www.ccmjournal.org March 2017 • Volume 45 • Number 3
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Guidelines
after the Sepsis-3 definition (1) or septic shock demonstrated clinical examination clearly indicates a specific anatomic site of
a 36%–40% reduction of the odds of dying in the hospital with infection, cultures of other sites (apart from blood) are gener-
compliance with either the 3- or 6-hour SSC bundles (48). This ally unnecessary. We suggest 45 minutes as an example of what
recommendation met the prespecified criteria for a BPS. The may be considered to be no substantial delay in the initiation
specifics of performance improvement methods varied mark- of antimicrobial therapy while cultures are being obtained.
edly between studies; thus, no single approach to performance Two or more sets (aerobic and anaerobic) of blood cultures
improvement could be recommended (Supplemental Digital are recommended before initiation of any new antimicrobial
Content 5, http://links.lww.com/CCM/C326). in all patients with suspected sepsis (59). All necessary blood
cultures may be drawn together on the same occasion. Blood
culture yield has not been shown to be improved with sequen-
C. DIAGNOSIS
tial draws or timing to temperature spikes (60, 61). Details
1. We recommend that appropriate routine microbiologic on appropriate methods to draw and transport blood culture
cultures (including blood) be obtained before starting samples are enumerated in other guidelines (61, 62).
antimicrobial therapy in patients with suspected sepsis or In potentially septic patients with an intravascular catheter
septic shock if doing so results in no substantial delay in (in place > 48 hours) in whom a site of infection is not clini-
the start of antimicrobials (BPS). cally apparent or a suspicion of intravascular catheter-associ-
ated infection exists, at least one blood culture set should be
Remarks: Appropriate routine microbiologic cultures always
obtained from the catheter (along with simultaneous periph-
include at least two sets of blood cultures (aerobic and
eral blood cultures). This is done to assist in the diagnosis of
anaerobic).
a potential catheter-related bloodstream infection. Data are
Rationale: Sterilization of cultures can occur within minutes to inconsistent regarding the utility of differential time to blood
hours after the first dose of an appropriate antimicrobial (49, 50). culture positivity (i.e., equivalent volume blood culture from
Obtaining cultures prior to the administration of antimicrobials the vascular access device positive more than 2 hours before
significantly increases the yield of cultures, making identification the peripheral blood culture) in suggesting that the vascular
of a pathogen more likely. Isolation of an infecting organism(s) access device is the source of the infection (63–65). It is impor-
allows for de-escalation of antimicrobial therapy first at the tant to note that drawing blood cultures from an intravascu-
point of identification and then again when susceptibilities are lar catheter in case of possible infection of the device does not
obtained. De-escalation of antimicrobial therapy is a mainstay eliminate the option of removing the catheter (particular non-
of antibiotic stewardship programs and is associated with less tunneled catheters) immediately afterward.
resistant microorganisms, fewer side effects, and lower costs (51). In patients without a suspicion of catheter-associated infec-
Several retrospective studies have suggested that obtaining cul- tion and in whom another clinical infection site is suspected, at
tures prior to antimicrobial therapy is associated with improved least one blood culture (of the two or more that are required)
outcome (52, 53). Similarly, de-escalation has also been associ- should be obtained peripherally. However, no recommenda-
ated with improved survival in several observational studies tion can be made as to where additional blood cultures should
(54, 55). The desire to obtain cultures prior to initiating anti- be drawn. Options include: a) all cultures drawn peripherally
microbial therapy must be balanced against the mortality risk via venipuncture, b) cultures drawn through each separate
of delaying a key therapy in critically ill patients with suspected intravascular device but not through multiple lumens of the
sepsis or septic shock who are at significant risk of death (56, 57). same intravascular catheter, or c) cultures drawn through mul-
We recommend that blood cultures be obtained prior to tiple lumens in an intravascular device (66–70).
initiating antimicrobial therapy if cultures can be obtained in In the near future, molecular diagnostic methods may offer
a timely manner. However, the risk/benefit ratio favors rapid the potential to diagnose infections more quickly and more
administration of antimicrobials if it is not logistically pos- accurately than current techniques. However, varying tech-
sible to obtain cultures promptly. Therefore, in patients with nologies have been described, clinical experience remains lim-
suspected sepsis or septic shock, appropriate routine microbi- ited, and additional validation is needed before recommending
ologic cultures should be obtained before initiation of antimi- these methods as an adjunct to or replacement for standard
crobial therapy from all sites considered to be potential sources blood culture techniques (71–73). In addition, susceptibility
of infection if it results in no substantial delay in the start of testing is likely to require isolation and direct testing of viable
antimicrobials. This may include blood, cerebrospinal fluid, pathogens for the foreseeable future.
urine, wounds, respiratory secretions, and other body fluids,
but does not normally include samples that require an invasive
D. ANTIMICROBIAL THERAPY
procedure such as bronchoscopy or open surgery. The decision
regarding which sites to culture requires careful consideration 1. We recommend that administration of IV antimicrobi-
from the treatment team. “Pan culture” of all sites that could als be initiated as soon as possible after recognition and
potentially be cultured should be discouraged (unless the within one hour for both sepsis and septic shock (strong
source of sepsis is not clinically apparent), because this practice recommendation, moderate quality of evidence; grade
can lead to inappropriate antimicrobial use (58). If history or applies to both conditions).
Critical Care Medicine www.ccmjournal.org 9
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Rhodes et al
Rationale: The rapidity of administration is central to the cannot be mixed and delivered promptly from the pharmacy,
beneficial effect of appropriate antimicrobials. In the presence establishing a supply of premixed drugs for urgent situations
of sepsis or septic shock, each hour delay in administration is an appropriate strategy for ensuring prompt administration.
of appropriate antimicrobials is associated with a measurable Many antimicrobials will not remain stable if premixed in a
increase in mortality (57, 74). Further, several studies show an solution. This issue must be taken into consideration in insti-
adverse effect on secondary end points (e.g., LOS (75), acute tutions that rely on premixed solutions for rapid antimicrobial
kidney injury (76), acute lung injury (77), and organ injury availability. In choosing the antimicrobial regimen, clini-
assessed by Sepsis-Related Organ Assessment score (78) with cians should be aware that some antimicrobial agents (nota-
increasing delays. Despite a meta-analysis of mostly poor-qual- bly β-lactams) have the advantage of being able to be safely
ity studies that failed to demonstrate a benefit of rapid antimi- administered as a bolus or rapid infusion, while others require
crobial therapy, the largest and highest-quality studies support a lengthy infusion. If vascular access is limited and many dif-
giving appropriate antimicrobials as soon as possible in patients ferent agents must be infused, drugs that can be administered
with sepsis with or without septic shock (57, 74, 79–81). The as a bolus or rapid infusion may offer an advantage for rapid
majority of studies within the meta-analysis were of low qual- achievement of therapeutic levels for the initial dose.
ity due to a number of deficiencies, including small study size, While establishing vascular access and initiating aggressive
using an initial index time of an arbitrary time point such as fluid resuscitation are very important when managing patients
emergency department arrival, and indexing of outcome to with sepsis or septic shock, prompt IV infusion of antimicro-
delay in time to the first antimicrobial (regardless of activity bial agents is also a priority. This may require additional vas-
against the putative pathogen) (82, 83). Other negative studies cular access ports. Intraosseous access, which can be quickly
not included in this meta-analysis are compromised by equating and reliably established (even in adults), can be used to rapidly
bacteremia with sepsis (as currently defined to include organ administer the initial doses of any antimicrobial (90, 91). In
failure) and septic shock (84–87). Many of these studies are also addition, intramuscular preparations are approved and avail-
compromised by indexing delays to easily accessible but non- able for several first-line β-lactams, including imipenem/cilas-
physiologic variables such as time of initial blood culture draw tatin, cefepime, ceftriaxone, and ertapenem. Several additional
(an event likely to be highly variable in timing occurrence). first-line β-lactams can also be effectively administered intra-
While available data suggest that the earliest possible muscularly in emergency situations if vascular and intraosseous
administration of appropriate IV antimicrobials following access is unavailable, although regulatory approval for intra-
recognition of sepsis or septic shock yields optimal outcomes, muscular administration for these drugs is lacking (92–94).
one hour is recommended as a reasonable minimal target. The Intramuscular absorption and distribution of some of these
feasibility of achieving this target consistently, however, has not agents in severe illness has not been studied; intramuscular
been adequately assessed. Practical considerations, for exam- administration should be considered only if timely establish-
ple, challenges with clinicians’ early identification of patients ment of vascular access is not possible.
or operational complexities in the drug delivery chain, rep-
2. We recommend empiric broad-spectrum therapy with
resent poorly studied variables that may affect achieving this
one or more antimicrobials for patients presenting with
goal. A number of patient and organizational factors appear to
sepsis or septic shock to cover all likely pathogens (includ-
influence antimicrobial delays (88).
ing bacterial and potentially fungal or viral coverage)
Accelerating appropriate antimicrobial delivery institu-
(strong recommendation, moderate quality of evidence).
tionally starts with an assessment of causes of delays (89).
3. We recommend that empiric antimicrobial therapy be
These can include an unacceptably high frequency of failure
narrowed once pathogen identification and sensitivities
to recognize the potential existence of sepsis or septic shock
are established and/or adequate clinical improvement is
and of inappropriate empiric antimicrobial initiation (e.g.,
noted (BPS).
as a consequence of lack of appreciation of the potential for
microbial resistance or recent previous antimicrobial use in a Rationale: The initiation of appropriate antimicrobial therapy
given patient). In addition, unrecognized or underappreciated (i.e., with activity against the causative pathogen or pathogens)
administrative or logistic factors (often easily remedied) may is one of the most important facets of effective management
be found. Possible solutions to delays in antimicrobial initia- of life-threatening infections causing sepsis and septic shock.
tion include use of “stat” orders or including a minimal time Failure to initiate appropriate empiric therapy in patients with
element in antimicrobial orders, addressing delays in obtain- sepsis and septic shock is associated with a substantial increase
ing blood and site cultures pending antimicrobial adminis- in morbidity and mortality (79, 95–97). In addition, the prob-
tration, and sequencing antimicrobial delivery optimally or ability of progression from gram-negative bacteremic infection
using simultaneous delivery of key antimicrobials, as well as to septic shock is increased (98). Accordingly, the initial selec-
improving supply chain deficiencies. Improving communica- tion of antimicrobial therapy must be broad enough to cover all
tion among medical, pharmacy, and nursing staff can also be likely pathogens. The choice of empiric antimicrobial therapy
highly beneficial. depends on complex issues related to the patient’s history, clini-
Most issues can be addressed by quality improvement ini- cal status, and local epidemiologic factors. Key patient factors
tiatives, including defined order sets. If antimicrobial agents include the nature of the clinical syndrome/site of infection,
10 www.ccmjournal.org March 2017 • Volume 45 • Number 3
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