Sepsis 2020

CLINICAL PRACTICE GUIDELINES FOR
SEPSIS AND SEPTIC SHOCK IN ADULTS

IN THE PHILIPPINES
2020
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Table of Contents
Participating Professional Medical Societies..............................................................................................3
Clinical Practice Guidelines for Sepsis and Septic Shock Task Force 2020....................................4
Abbreviations ...................................................................................................................................................... 13
Introduction......................................................................................................................................................... 15
Objectives of the Clinical Practice Guideline ........................................................................................... 18
Scope and Target Population......................................................................................................................... 18
Target Audience and Users ............................................................................................................................ 18
Methodology ........................................................................................................................................................ 18
Health Questions Covered by this Guideline ........................................................................................... 23
SEPSIS DEFINITION AND CRITERIA FOR DIAGNOSIS.................................................................... 26
DIAGNOSTIC TESTS...................................................................................................................................... 37
FLUID THERAPY............................................................................................................................................ 41
VASOACTIVE AGENTS................................................................................................................................. 58
HEMODYNAMIC MONITORING................................................................................................................ 62
ANTIMICROBIAL THERAPY ...................................................................................................................... 70
SOURCE CONTROL........................................................................................................................................ 93
CORTICOSTEROIDS...................................................................................................................................... 96
GLYCEMIC CONTROL.................................................................................................................................100
ACUTE RESPIRATORY FAILURE............................................................................................................102
ACUTE KIDNEY INJURY ............................................................................................................................117
BLOOD PURIFICATION..............................................................................................................................125
BLOOD TRANSFUSION..............................................................................................................................127
IMMUNOGLOBULINS.................................................................................................................................133
ANTICOAGULANT THERAPY..................................................................................................................134
VENOUS THROMBOPROPHYLAXIS......................................................................................................135
STRESS ULCER PROPHYLAXIS...............................................................................................................138
FEEDING AND NUTRITION......................................................................................................................141
SEDATION AND ANALGESIA...................................................................................................................156
Clinical Practice Guideline for Sepsis and Septic Shock in Adults in the Philippines 2020
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Participating Professional Medical Societies
Philippine Society for Microbiology and Infectious Diseases

(PSMID) Philippine Academy of Family Physicians (PAFP)
Philippine College of Emergency Medicine, Inc. (PCEM)
Philippine College of Physicians (PCP)
Philippine College of Surgeons (PCS)
Philippine College of Chest Physicians (PCCP)
Philippine Heart Association (PHA)
Philippine Medical Association (PMA)
Philippine Neurological Association (PNA)
Philippine Nurses Association (PNA)
Philippine Society of Critical Care Medicine (PSCCM)
Philippine Society of Endocrinology, Diabetes & Metabolism
(PSEDM) Philippine Society of Gastroenterology (PSG)
Philippine Society of General Internal Medicine (PSGIM)
Philippine Society of Hematology & Blood Transfusion (PSHBT)
Philippine College of Hematology & Transfusion Medicine
(PCHTM) Philippine Society of Nephrology (PSN)
Philippine Society for Parenteral & Enteral Nutrition (PhilSPEN)
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Clinical Practice Guidelines for Sepsis and Septic

Shock Task Force 2020
STEERING COMMITTEE
Chairpersons: Mari Rose A. De los Reyes, MD, FPCP, FPSMID

Internal Medicine (IM)– Infectious Diseases
Research Institute of Tropical Medicine
Asian Hospital and Medical Center
Marissa M. Alejandria, MD, FPCP, FPSMID

IM– Infectious Diseases
University of the Philippines – Philippine General Hospital
The Medical City
Members: Jubert P. Benedicto, MD, FPCP, FPCCP

IM – Pulmonary Medicine
Lung Center of the Philippines
Pauline F. Convocar, MD, MCHM, FPCEM, DPCOM

Emergency Medicine
Southern Philippines Medical Center
Corazon Locsin Montelibano Memorial Regional Hospital
Manila Doctors Hospital
Jose Emmanuel T. Palo, MD, FCCM, FPSCCM

IM - Critical Care
The Medical City
TECHNICAL WORKING GROUP
Chair: Joseph Adrian L. Buensalido, MD, FPCP, FPSMID IM–

Infectious Diseases
Makati Medical Center
Co-Chair: Anna Flor Gaboy Malundo, MD, FPCP

IM– Infectious Diseases
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Members: CARDIOLOGY
Jaime Alfonso M. Aherrera, MD, FPCP, FPCC

De La Salle University Medical Center
Jose Donato A. Magno, MD,FPCP, FPCC, FPSE, FASE

Angeles University Foundation Medical Center
Marie Kirk Patrich A. Maramara, MD, FPCP

Felix Eduardo R. Punzalan, MD,FPCP, FPCC

Medical Center Manila
CLINICAL EPIDEMIOLOGY (Technical Writer)
Maria Teresa F. Sanchez-Tolosa, MD, D Clin Epi, FPDS

University of the Philippines – Department of Clinical
Epidemiology St. Luke’s Medical Center
University of the East Ramon Magsaysay Memorial Medical Center
CRITICAL CARE MEDICINE
Gerardo M. Briones, Jr, MD, FPCP, FPSCCM

The Medical City
Aaron Mark R. Hernandez, MD, FPCP, FPSCCM

The Medical City
Anthony F. Pantaleon, MD, FPCP

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Joanne B. Robles, MD, FPCP, FPNA, FPSCCM

The Medical City
EMERGENCY MEDICINE
Faith Joan M. Gaerlan, MD, FPCEM

University of the Philippines – Philippine General
Hospital Southern Philippines Medical Center
St. Luke’s Medical Center – Quezon City
Christopher G. Manalo, MD, DPCEM

Hospital ENDOCRINOLOGY
Paulette D. Nacpil-Dominguez, MD, FPCP, FPSEDM

Hospital Delos Santos Medical Center
Cardinal Santos Medical Center
Diliman Doctors Hospital, Inc.
Hannah C. Urbanozo-Corpuz, MD, FPCP, FPSEDM

Ilocos Training and Regional Medical Center
Lorma Medical Center
GASTROENTEROLOGY AND NUTRITION
Joyce B. Bernardino, MD, FPCP, DPBCN

De La Salle Medical and Health Sciences Institute
Rona Marie A. Lawenko, MD, FPSG, FPSDE

De La Salle Medical and Health Sciences Institute
Elvie Victonette B. Razon-Gonzalez, MD, FPCP, FPSG,

FPSDE Medicus Medical Center
West Visayas State University Medical Center
Iloilo Mission Hospital
Iloilo Doctors Hospital
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HEMATOLOGY
Teresita E. Dumagay, MD, FPCP, FPSHBT, FPCHTM

Hospital National Kidney and Transplant Institute
Manila Medical Center
Josephine Anne C. Lucero, MD, FPCP

Anne Kristine H. Quero, MD, FPCP

Maria Clariza M. Santos, MD, FPCP, FPSHBT,

FPCHTM University of the Philippines – Philippine
General Hospital Makati Medical Center
INFECTIOUS DISEASES
Cybele Lara R. Abad, MD, FPCP

Hospital The Medical City
National Kidney and Transplant Institute
Karl Evans R. Henson, MD, FPCP, FPSMID

Hospital The Medical City
Honey Jane B. Limos, MD

Hospital Eastern Visayas Regional Medical Center
Monica Pia R. Montecillo, MD, FPCP

Westlake Medical Center
Unihealth Southwoods Hospital and Medical
Center Calamba Medical Center
The Medical City – South Luzon
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Leonell Albert L. Quitos, MD, FPCP

Adventist Medical Center – Iligan
Iligan Medical Center and Hospital
Dr. Uy Hospital, Inc.
Mercy Community Hospital
St. Mary’s Maternity and Children’s Hospital, Inc.
Sebar S. Sala, MD, FPCP

Zamboanga City Medical Center
Zamboanga Peninsula Medical Center
West Metro Medical Center
Ciudad Medical Zamboanga
Universidad de Zamboanga Medical Center
Brent Hospital
Maria Sonia S. Salamat, MD, FPCP, FPSMID

Hospital Manila Doctors Hospital
Joanne Carmela M. Sandejas, MD

Hospital INTERNAL MEDICINE
Krishja T. Dela Torre, MD

Pamantasan ng Lungsod ng Maynila – Ospital ng
Maynila San Beda University – College of Medicine
Metropolitan Medical Center College of Arts and Sciences
College of Medicine
Bryan Paul G. Ramirez, MD

De La Salle Medical and Health Sciences
Institute NEPHROLOGY
Isabelle Dominique V. Tomacruz, MD, FPCP

Anthony Russell T. Villanueva, MD, FPCP, FPSN

Hospital
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PULMONARY MEDICINE
Albert B. Albay, Jr., MD, FPCP, FPCCP, FPSCCM

Hospital Lung Center of the Philippines
Manila Medical Center
Gene Phillip Louie C. Ambrocio, MD, FPCP, FPCCP

Hospital Manila Doctors Hospital
Blake Warren C. Ang, MD

Carla Emille D. Barbon, MD-MBA

Jamie R. Chua, MD, FPCP

Anjuli Mae P. Jaen, MD, FPCP

West Visayas State University Medical Center
Jonray R. Magallanes, MD, FPCP, FPCCP

St. Luke’s Medical Center – Global City
Irene Rosellen P. Tan, MD, FPCP

Mithi Kalayaan S. Zamora, MD

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CONSENSUS PANEL
PHILIPPINE ACADEMY OF FAMILY PHYSICIANS (PAFP)
Josephine A. Chikiamco-Dizon, MD
Raquel P. Evangelista-Lopez, MD, DFM

San Lazaro Hospital
PHILIPPINE COLLEGE OF CHEST PHYSICIANS (PCCP)
George Paul T. Habacon, MD, FPCP, FPCCP

Manila East Medical Center
Philippine Heart Center
Rodolfo Roman T. Bigornia, MD, FPCP, FPCCP

Cebu Institute of Medicine
PHILIPPINE COLLEGE OF EMERGENCY MEDICINE (PCEM)
Nannede C. Mercado, MD, FPCEM

DOH-TRC Las Pinas
Dave C. Gamboa, MD, FPCEM

The Medical City
Unihealth Paranaque
PHILIPPINE COLLEGE OF PHYSICIANS (PCP)
Diana R. Tamondong-Lachica, MD, FPCP

University of the Philippines – College of Medicine
Nemencio A. Nicodemus, Jr. MD, FPCP, FPSEDM

PHILIPPINE COLLEGE OF SURGERY (PCS)
Esther A. Saguil, MD, FPCS

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George Robert L. Uyquiengco, MD, FPCS

San Lazaro Hospital
Victor R. Potenciano Medical Center
PHILIPPINE HEART ASSOCIATION (PHA)
Jude Erric L. Cinco, MD, FPCP, FPCC, FPSCCM

The Medical City
Vincent V. Valencia, MD, FPCP, FPCC

St. Luke’s Medical Center
PHILIPPINE SOCIETY FOR PARENTERAL & ENTERAL NUTRITION (PHILSPEN)
Maricar M. Esculto, MD
Makati Medical Center
PHILIPPINE MEDICAL ASSOCIATION (PMA)
Ramon C. Severino, MD
East Avenue Medical Center
Ma. Lorena D. Lorenzo, MD, FPAFP, DPAAB

Healthway Medical Clinics
Our Lady of Fatima University, Fatima University Medical
Center PHILIPPINE NURSES ASSOCIATION (PNA)
Maria Liza Peraren, RN, MAN
PHILIPPINE SOCIETY OF GASTROENTEROLOGY (PSG)
Dulcinea Keiko A. Balce Santos, MD, FPCP, FPSDE

Paranaque Doctors Hospital
Anne Marie Geraldine J. Javier, MD, FPCP, FPSDE

University of the East Ramon Magsaysay Memorial Medical
Center Our Lady of Lourdes Hospital
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PHILIPPINE SOCIETY OF ENDOCRINOLOGY, DIABETES, AND METABOLISM

(PSEDM)
Michael L. Villa, MD, FPCP, FPSEDM

Oliver Alan C. Dampil, MD, FPCP, FPSEDM

St. Luke’s Medical Center – Quezon City
Elaine C. Cunanan, MD, MHPed

University of Santo Tomas
PHILIPPINE SOCIETY FOR GENERAL INTERNAL MEDICINE (PSGIM)
Diana R. Tamondong-Lachica, MD, FPCP

Roberto Razo II, MD, FPCP

De La Salle University Medical Center
PHILIPPINE SOCIETY OF HEMATOLOGY & BLOOD TRANSFUSION (PSHBT) /

PHILIPPINE COLLEGE OF HEMATOLOGY & TRANSFUSION MEDICINE (PCHTM)
Rico Paolo G. Tee, MD, FPCP, DPSHBT, DPCHTM

Ateneo School of Medicine and Public Health
Dr. Jose R. Reyes Memorial Medical Center
Las Pinas General Hospital and Satellite Trauma Center
Las Pinas Doctors Hospital
Medical Center Muntinlupa
PHILIPPINE SOCIETY FOR MICROBIOLOGY AND INFECTIOUS DISEASES (PSMID)
Mario M. Panaligan, MD, FPCP, FPSMID

St. Luke’s Medical Center
Center Jose R. Reyes Memorial Medical Center
Minette Claire O. Rosario, MD, FPCP, FPSMID

Center St. Luke’s Medical Center – Quezon City
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Abbreviations
ACCP American College of Chest Physicians
ACTH Adrenocorticotropic hormone
AKI Acute Kidney Injury
ARDS Acute Respiratory Distress Syndrome
ATS American Thoracic Society
AUC Area Under the Curve
AUROC Area Under the Receiver Operating Characteristic
AVP Arginine vasopressin
CDC Centers for Disease Control and Prevention
CI Confidence Interval
CIRCI Critical illness-related corticosteroid insufficiency
CIV Continuous intravenous infusion
CO2 Carbon dioxide
COI Conflict of Interest
CPG Clinical Practice Guideline
CRT Capillary Refill Time
CVP Central Venous Pressure
CO Cardiac Output
CRRT Continuous Renal Replacement Therapy
DOH Department of Health
ED Emergency Department
EEO End-expiratory occlusion
EGDT Early Goal-Directed Therapy
EN Enteral Nutrition
ESA Erythropoiesis Stimulating Agent
ESICM European Society of Intensive Care Medicine
GRADE Grades of Recommendation, Assessment, Development and Evaluation
GRV Gastric residual volume
HAP Hospital-acquired pneumonia
H2R Histamine 2 Receptor
HES Hydroxyethyl Starch
Hgb Hemoglobin
HPA Hypothalamic-Pituitary-Adrenal
ICU Intensive Care Unit
IDSA Infectious Diseases Society of America
IHD Intermittent Hemodialysis
IIV Intermittent intravenous infusion
LGT Lactate-guided Therapy
LMWH Low-molecular weight heparin
MAP Mean Arterial Pressure
MD Mean Difference
MRSA Methicillin-resistant Staphylococcus aureus
MSSA Methicillin-susceptible Staphylococcus aureus
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NLR Negative likelihood ratio

NNT Number needed to treat
OR Odds Ratio
PA Pulmonary Artery
PAC Pulmonary Artery Catheter
PCT Procalcitonin
PD Peritoneal Dialysis
PEEP Positive end-expiratory pressure PICO
Population, Intervention, Control, Outcome PK/PD
Pharmacokinetic/Pharmacodynamic PLR plain
Lactated Ringer’s solution
PLR Positive likelihood ratio
PLR Passive Leg Raise
PN Parenteral Nutrition
POCL Point-of-care Lactate
PPI Proton pump inhibitor
PPV Pulse pressure variation
qSOFA Quick Sequential Organ Failure Assessment
RCT Randomized controlled trial
RR Risk Ratio / Relative Risk
RRT Renal Replacement Therapy
SCCM Society of Critical Care Medicine SCVO2
Central venous oxygen saturation SIRS Systemic
inflammatory response syndrome SIS Surgical
Infection Society
Sn Sensitivity
SOFA Sequential Organ Failure Assessment
Sp Specificity
SSC Surviving Sepsis Campaign
SVV Stroke volume variation
TTE Transthoracic Echocardiogram
TWG Technical Working Group
UFH Unfractionated Heparin
VAP Ventilator-associated pneumonia
VILI Ventilator-induced Lung Injury
VTE Venous Thromboembolism
VTI Velocity time index
WBC White blood cell
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Introduction
This Clinical Practice Guideline (CPG) is intended for the use of practicing clinicians
in the Philippines who are involved in the care of adult patients with sepsis and septic
shock. This document may be used by government and private practicing physicians, as
well as trainors and trainees with respect to medical education, training, and mentoring.
This Philippine CPG for Sepsis and Septic Shock was developed because of (1) the
significant burden of disease, (2) the confusion over the definitions, (3) the significant
variability in clinical practice, (4) the availability of new evidence, and (5) the feasibility
issues concerning cost, availability, and access to resources in the Philippines.
Disease Burden
While the World Health Organization (WHO) states that “the global epidemiological
burden of sepsis is difficult to ascertain,” the disease is thought to affect over 30 million
individuals all over the world annually, and puts at risk of death some six million of these
people.1 The incidence of sepsis throughout the world had been reported to be 22 to 240
cases per 100,000 persons using the old sepsis definition. 2 On the other hand, the incidence
of septic shock was estimated at 11 per 100,000. It is one of the leading causes of death
among hospitalized patients with case fatality rate of 30% for sepsis, and as high as 80% for
septic shock.
Sepsis and Septic Shock Definitions
The Sepsis-3 definitions drastically changed the paradigm for sepsis with its
publication in the Journal of the American Medical Association (JAMA) in February 2016. 3
Old Definition
Before the Sepsis-3 publication, sepsis was known as a syndrome resulting from the
host response to infection. Its definition was based on the systemic inflammatory response
syndrome (SIRS) developing from documented or suspected infection. 2 The SIRS criteria
needed to have at least two (2) of the following:
• Temperature >38°C or <36°C
• heart rate >90 beats per minute
• respiratory rate >20 breaths per minute or PaCO2 <32 mmHg
• white blood cell (WBC) count >12,000 cells/mm3 or <4,000 cells/mm3, or >10%
immature (band) forms
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Severe sepsis was defined as sepsis with organ dysfunction, hypotension or signs of
hypoperfusion, while septic shock was identified as sepsis occurring with acute circulatory
failure, presenting with persistent hypotension even after adequate fluid resuscitation, and
requiring vasopressor treatment.2
New Definition
The Third International Consensus now defines “sepsis” as a life-threatening organ

dysfunction caused by a dysregulated host response to infection. 3 In this new definition,
sepsis is now upgraded to what we previously knew as “severe sepsis.” This new definition
excludes a number of patients who were previously thought would be “septic.” On the other
hand, septic shock is now defined as a subset of sepsis with circulatory and
cellular/metabolic dysfunction associated with a higher risk of mortality.
Issues on Sepsis Definition
The updates were appreciated but certain quarters raised concerns about the new
definitions, including the lack of prospective validation in a "generalizable population," the
fact that data were almost exclusively derived from high-income countries and adults, and
the possibility of delayed diagnosis and treatment due to the focus on organ dysfunction.
These concerns regarding validity and applicability, led to incomplete uptake of the
definitions. A study conducted in a private tertiary teaching hospital in the Philippines
showed that only 30% are using the Sepsis-3 criteria, with a large fraction (63%) still using
the SIRS-based criteria.4 The remaining number of respondents did not provide a definite
response. Further assessment showed that three years after Sepsis-3 publication, only 26%
of physician-respondents correctly defined sepsis, and less than 7% correctly defined septic
shock.4
On the other hand, the SIRS criteria were also criticized because they were very non
specific, and bordering on unhelpful, inaccurate sepsis identification. 5 SIRS criteria was
panned for being too focused on inflammation which may be present in many hospitalized
patients, including those who never develop infection and never incur adverse outcomes.
Variations in Care
In reference to the multidisciplinary issues in sepsis and the slow catch-up in terms
of medical practice, this guideline now aims to resolve the confusion that arose from the
Sepsis-3 Consensus and to assist health care practitioners in the diagnosis and management
of sepsis to reduce variations in practice. As an example, there is evidence that around 14%
of 175 physicians surveyed in a private tertiary hospital admit to continue using
hydroxyethylstarch (HES) even after the international Surviving Sepsis Campaign
Guidelines recommended against its use.4 A third of physicians do not even consider giving
steroids to septic shock patients.
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In another study conducted in a tertiary teaching public hospital in the Philippines,

compliance with the 2016 Surviving Sepsis Campaign (SSC) Guidelines was assessed in 224
patients admitted for sepsis and septic shock in 2017. 6 Of these, only 36% (81/224) were
given initial bolus of intravenous fluid for resuscitation and only 52 of 81 (64%) were given
the prescribed 30ml/kg volume. Less than a fourth (24%) of patients received empiric
antibiotics within an hour of sepsis recognition.
New Evidence
In the recent years, there has been a rapid turnover of evidence for sepsis relating to
the type of fluid for resuscitation, the volume of fluid for resuscitation, assessment of fluid
responsiveness using dynamic parameters, the pharmacokinetic and pharmacodynamic
optimization of antibiotic dosing, corticosteroids in septic shock, different strategies to
address acute respiratory failure, and blood purification techniques, to name a few. The
emergence of new information called for thorough review of new data for validity and
applicability in our setting.
Feasibility Issues
With the advent of the Universal Health Care Law, it is important to establish local
guidelines that would set the standard of sepsis care in the Philippines. It is not only
important that old and new evidence be considered but cost, availability and access to
resources in different settings as well.
Potential impact of the guideline
There is great possibility to reduce the baseline case-fatality rates for sepsis and
septic shock with implementation of evidence-based recommendations. However, the wide
variation in the current diagnosis and treatment of sepsis and septic shock poses a
challenge to the attainment of these reductions. The inconsistency of therapeutic
maneuvers, while largely supported by prior evidence, documentation and clinical
experience, results in a wide range of outcomes and events. This 2020 clinical practice
guideline for sepsis and septic shock reviewed and consolidated current best evidence for
specific issues of concern in practice, towards the improvement of patient care and the
constancy of management in sepsis and septic shock.
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Objectives of the Clinical Practice Guideline
1. To establish the definition and clinical criteria to be used to diagnose sepsis and septic
shock in the Philippines
2. To present evidence-based recommendations with regard to screening, diagnosis,
treatment, and prognostication of sepsis and septic shock in immunocompetent adults 3. To
reduce practice variability among healthcare practitioners and improve clinical outcomes
in patients with sepsis and septic shock
Scope and Target Population
This clinical practice guideline will cover sepsis in non-pregnant, immunocompetent adults.
Target Audience and Users

In line with its purpose, this clinical practice guideline is intended for use among physicians
of various disciplines, medical practitioners, mentors and trainees, to include the following:
1. Primary care physicians (general practitioners, general internists, family

medicine practitioners)
2. Emergency medicine physicians
3. Intensivists
4. Relevant subspecialty physicians
5. Medical educators and mentors
6. Medical interns and students
Methodology
Selection and Organization of Committee Members
The preparation of the guidelines began with the formation of the Steering
Committee that consisted of two co-chairpersons, both specialists in infectious diseases.
Additional members in the committee included one Emergency Medicine physician, one
Internal Medicine-Pulmonary Medicine specialist, and one Critical Care specialist. The
Steering Committee examined the existing guidelines, identified problems which should be
addressed in the current guidelines, projected the required budget and looked for funding
sources, and
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selected the members of the Technical Working Group (TWG)/Evidence Review Experts
and the Consensus Panel.
Formulation of Clinical Questions
Some of the questions from the 2016 SSC guidelines were selected for updating
based on knowledge of new research data and publications. Controversial topics, and
questions on diagnostic and therapeutic interventions which were considered challenging
in terms of resource availability were also selected.
The TWG assisted the Steering Committee in the formulation of the guideline
questions structured in PICO format (population, intervention, control, and outcome). A
complete list of the guideline questions in PICO format is presented in Supplementary
Material 1.
Search Strategy and Data Synthesis
A multidisciplinary TWG was formed to collect and synthesize data. The TWG
divided the questions into several sections with at least two persons designated to work on
each question. An independent literature search was performed for each guideline
question. Electronic search was conducted in at least two databases such as Cochrane
Database, MEDLINE, HERDIN, and clinical trial registries using the search terms sepsis,
severe sepsis, and septic shock, combined with pertinent keywords based on the question
(Supplementary Material 2). Related articles were also examined. Unpublished data were
sourced, especially from local researches. Assistance from librarians, clinical
epidemiologists, and statisticians was sought.
It should be noted that for this guideline, the GRADE (Grades of Recommendation,
Assessment, Development and Evaluation) Framework/Approach was used to determine
the quality of evidence (Table 1). This approach enabled the TWG to identify the strengths
and limitations of the body of evidence, and prepare the evidence summaries that were
presented to the Steering Committee and the Consensus Panel.
The synthesized data and initial draft of the recommendations were presented at the
49th Annual Convention of the Philippine Society for Microbiology and Infectious Diseases
on November 14, 2019 at the SMX Convention Center to solicit public reaction, opinion and
recommendations. The event was attended by Infectious Diseases specialists, internists,
general practitioners, nurses, medical technologists, and other allied medical professionals.
Consensus Development
A multidisciplinary Consensus Panel was created to vote on each recommendation

and the strength of recommendations, taking into consideration (1) the quality of the
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evidence, (2) the value of the outcome, (3) the balance between benefit and harm, and (4)
the cost and resource availability. Again, the GRADE Approach was used to guide the
strength of recommendations (Table 2).
Table 1. Quality of Evidence using Grades of Recommendation, Assessment, Development

and Evaluation (GRADE) Framework
QUALITY OF EVIDENCE STUDY DESIGN LOWER IF: HIGHER IF:
High Further research is Randomized Study quality: Stronger association:

very unlikely to controlled studies Poor quality of Large magnitude
change (RCTs) implementation of RCT effect, no plausible
confidence in the confounders
estimate of effect Inconsistency of
results: Very large magnitude
Moderate Further research is Downgraded RCTs Indirectness: of effect, no major
likely to have impact or upgraded Different population, threats to validity
in confidence in the observational studies intervention,
estimate of effect outcomes Dose response gradient
Low Further research is Observational studies Imprecise results:

very likely to have an
High probability of
important impact on
reporting bias
the confidence in the
estimate of effect
Very low Any estimate of effect Case series or

is very uncertain expert opinion
Reference: Guyatt GH, OXman AD, Vist GE et al. GRADE: am emerging consensus on rating quality of evidence and
strength of recommendations. BMJ, 2008;336:924-926.
Table 2. Implications of Strength of Recommendations to Patients, Clinicians and Policy

Makers using GRADE Approach
STRENGTH OF RECOMMENDATION IMPLICATIONS OF THE RECOMMENDATIONS
TO PATIENTS TO CLINICIANS TO POLICY MAKERS
Strong The benefits outweighed Most people in the Most patients The
the harm. There are no situation would want should receive the recommendation
cost or access issues for the recommended recommended can be adopted as
the general population. course of action and course of action a policy in most
only very few would situations
not; request for
discussion if the
intervention is not offered
Weak Best available evidence Most people in the Different choices Policy making will
is very low to low situation would want are appropriate for require substantial
quality; the recommended different patients, debate and
Magnitude of benefits or course of action, but and clinician must involvement of
risks is uncertain or closely many would not help any
balanced for the general patients arrive at a stakeholders
population and applicable management
to a specific group, decision consistent
population or setting; with
Benefits may not warrant patient's values
the cost or resource and preferences
requirements in all settings
Reference: Guyatt GH et al. Going from evidence to recommendations. BMJ. 2008 May 10;336(7652):1049-1051.
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Representatives from relevant groups and societies participated in a two-day

meeting held on November 23 and 30, 2019 in order to discuss controversial topics and
questions with new recommendations. A copy of the evidence summaries and draft
recommendations were sent through email at least a week before the meetings. The voting
process was conducted manually using flags to indicate agreement, disagreement, or
abstention. Consensus required at least 75% of votes. Each participating society or group
was entitled to one vote, even if it had two or more representatives. If consensus was not
reached, voters were allowed to share their perspective and provide feedback for a chance
to revise the statement or ask for clarification. The voting process was repeated until a
maximum of three rounds, at which unresolved questions were deliberated via Modified
Delphi Technique.
The rest of the guideline questions, together with unresolved ones were sent for
voting via the Modified Delphi Technique. A copy of the evidence summaries and draft
recommendations were sent through email and voting was accomplished using Google
forms. A tally of the votes was generated and downloaded to an excel spreadsheet.
Consensus for this part was agreement of at least 75%.
Guideline Dissemination
The final recommendations are to be presented in scientific fora (including the

annual conventions in 2020 of the Philippine College of Physicians and Philippine College
of Emergency Medicine) to target the expected end-users of the guidelines. Printed copies
of the guidelines will be distributed to medical societies and posted online for wider
coverage.
Guideline Monitoring and Updating
The impact of this Clinical Practice Guideline will be assessed by monitoring

adherence to the recommendations, and more importantly, evaluate clinical outcomes such
as reduction in mortality. In order to achieve this, PSMID will continue to spearhead the
process and collaborate with societies, institutions, and hospitals in the country, and will
use a modified version of the Center for Disease Control and Prevention (CDC)’s March
2018 “Hospital Toolkit for Adult Sepsis Surveillance.” 9 The Steering Committee plans to
update the guideline after five (5) years, or earlier, considering new evidence, availability
of resources and interventions, and the results of the monitoring.
Sponsorship and Funding
The development of this guideline was funded by the Philippine Department of

Health (DOH) and the Philippine Society for Microbiology and Infectious Diseases (PSMID).
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Management of Conflicts of Interest (COI)
All members of the Steering Committee, Technical Working Group, and the
Consensus Panel were asked to disclose all potential conflicts of interest (COIs), including
financial. Identified COIs were adjudicated by theSteering Committee, and the TWG chair
and co-chair. COIs were managed by limiting the discussion and voting ability of panel
members with relevant COI to a particular question or topic. Likewise, TWG members with
relevant COI to a particular topic were re-assigned to work on another question.
References
1. World Health Organization. (2018, April 19). Sepsis. Retrieved from https://www.who.int/news room/fact-
sheets/detail/sepsis
2. Buensalido JAL & MacArthur RD. Sepsis, severe sepsis, and septic shock (Book Chapter). Clinical Infectious
Disease (Cambridge University Press); edited by David Schlossberg, 2015
3. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD,
Coopersmith CM, Hotchkiss RS. The third international consensus definitions for sepsis and septic shock
(Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10.
4. Grecia GP & Buensalido JAL (2016). Assessment of the knowledge, attitudes and preception of physicians on
sepsis & septic shock, the recent Third International Consensus Definitions (Sepsis-3), and the 2016 Surviving
Sepsis Campaign Guidelines. Unpublished manuscript
5. Sartelli M, Kluger Y, et al. Raising concerns about the Sepsis-3 definitions. World Journal of Emergency Surgery.
13, Article number: 6 (2018).
6. Reyes RB, Uy CF, & Alejandria MM (2017). Compliance rates and barriers to compliance to the Surviving Sepsis
Campaign Guidelines in the management of sepsis and septic shock in a government university hospital.
Unpublished manuscript
7. Guyatt GH, OXman AD, Vist GE et al. GRADE: an emerging consensus on rating quality of evidence and strength of
recommendations. BMJ, 2008;336:924-926.
8. Guyatt GH et al. Going from evidence to recommendations. BMJ. 2008 May 10; 336 (7652): 1049-1051.
9. Centers for Disease Control and Prevention. (2018, March). Sepsis Screening and Assessment Tools. Retrieved
from http://www.cdc.gov/sepsis/pdfs/Sepsis-Surveillance-Toolkit-Mar-2018_508.pdf
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23
Health Questions Covered by this Guideline
A complete list of PICO – formatted questions is included in Supplementary Material 1.
1. Should we use the Sepsis-3 definition over the old sepsis definition?
2. Should we use the quick Sequential Organ Failure Assessment (qSOFA) over the Systemic
Inflammatory Response Syndrome (SIRS) as clinical criteria to identify patients with sepsis? 3.
Should the Sequential Organ Failure Assessment (SOFA) scoring-based clinical criteria be used
instead of SIRS-based criteria in the diagnosis of sepsis in the Intensive Care Unit (ICU)? 4.
Should we use the Sepsis-3 definition and clinical criteria to diagnose patients with septic
shock?
5. Should we routinely request blood cultures from patients suspected with sepsis or septic
shock?
6. Should we use procalcitonin to diagnose adult patients with sepsis?
7. In patients with sepsis or septic shock, should we use crystalloids for initial fluid resuscitation
versus colloid solutions?
8. In patients with sepsis or septic shock, should we use balanced crystalloids for initial fluid
resuscitation versus normal saline solution?
9. In patients with sepsis or septic shock, should we use crystalloids supplemented with
albumin for initial fluid resuscitation versus crystalloids alone?
10. In patients with sepsis or septic shock, should we initiate fluid resuscitation within an hour
of sepsis recognition?
11. In patients with sepsis or septic shock, should we give 30ml/kg intravenous fluid bolus for
initial fluid resuscitation?
12. In patients with sepsis or septic shock, should we limit the volume of intravenous fluids? 13.
In patients with sepsis or septic shock, should deresuscitation be performed after
hemodynamic stabilization?
14. In patients with sepsis and septic shock, should we use dynamic parameters versus static
parameters to predict fluid responsiveness?
15. In patients with septic shock requiring vasopressors, should we use norepinephrine over
other agents?
16. In patients with septic shock requiring a second vasopressor, which agent should be added
to norepinephrine?
17. In patients with septic shock and persistent hypoperfusion, should we use dobutamine? 18.
In patients with septic shock requiring vasopressors, should we target a mean arterial pressure
(MAP) of at least 65mmHg versus higher MAP?
19. Should we aim for normalization of lactate levels during resuscitation of patients with
sepsis? 20. Can we use base excess (as surrogate) to diagnose hyperlactatemia?
21. Should we use base excess to monitor fluid resuscitation?
22. In patients with sepsis, should low venoarterial CO2 gap be used as a goal for resuscitation?
23. In patients with sepsis, should we use a pulmonary artery catheter (PAC)? 24. In patients
with sepsis, should we use empiric broad-spectrum antibiotic(s)? 25. In patients with sepsis,
should we use empiric combination antimicrobial therapy versus monotherapy?
24
26. In patients with sepsis or septic shock, should we empirically start antibiotics for methicillin
resistant Staphylococcus aureus (MRSA)?
27. In patients with sepsis or septic shock, should empiric antibiotics be administered within the
first hour of sepsis recognition?
28. In patients with sepsis, should we implement pharmacokinetic dosing optimization for each
antimicrobial?
29. In patients with sepsis or septic shock who are receiving antimicrobial agents, should we de
escalate antimicrobial therapy once culture sensitivities are determined? 30. In patients with
sepsis or septic shock, should we recommend longer versus shorter duration of antibiotic
therapy?
31. In patients with sepsis or septic shock, should we use procalcitonin to support
discontinuation or de-escalation of antibiotic therapy?
32. In patients with sepsis or septic shock, should we attempt early source control? 33. In adult
patients with septic shock, should we use intravenous corticosteroids? 34. In adult patients with
septic shock, should we use intermittent (bolus) versus continuous intravenous
corticosteroids?
35. In patients with sepsis, should we aim for intensive glycemic control? 36. In patients with
sepsis- induced acquired respiratory distress syndrome (ARDS), should we use lung protective
ventilation strategy?
36.1. In patients with sepsis-induced ARDS, should we use low tidal volume ventilation?
36.2. In patients with sepsis- induced ARDS on mechanical ventilation (MV), should we use
high- versus low- positive end-expiratory pressure (PEEP) strategy?
36.3. In patients with sepsis-induced ARDS who are mechanically ventilated, should we use
plateau pressures less than 30 mmHg?
37. In sepsis patients who are mechanically ventilated but without ARDS, should we use lung
protective ventilation strategies?
38. In patients with sepsis-induced ARDS, should we use conservative fluid strategy? 39. In
patients with sepsis-induced ARDS on MV, should we do recruitment maneuvers? 40. In patients
with sepsis-induced ARDS on MV should we use prone positioning? 41. In patients with sepsis-
induced ARDS on MV should we use neuromuscular blocking agents? 42. In patients with sepsis-
induced ARDS, should we use extracorporeal membrane oxygenation (ECMO) treatment?
43. In patients with sepsis induced ARDS, should we use high frequency oscillatory ventilation
(HFOV)?
44. In patients with sepsis-induced ARDS, should we use non-invasive positive pressure
ventilation?
45. In patients with sepsis and hypoxic respiratory failure, should we use non-invasive
ventilation (NIV)?
46. In patients with sepsis and indication for renal replacement therapy, should we use
hemodialysis versus peritoneal dialysis?
47. In patients with sepsis and indication for renal replacement therapy, should we use
continuous renal replacement therapy (CRRT) versus intermittent hemodialysis? 48. In patients
with sepsis and acute kidney injury, should we initiate renal replacement therapy early (versus
delayed renal replacement therapy)?
49. In patients with sepsis and septic shock and hypoperfusion-induced lactic acidosis, should
we use sodium bicarbonate therapy?
25
50. In adult patients with sepsis, should we use hemoperfusion or other blood purification
techniques?
51. In adult patients with sepsis, should we use restrictive transfusion strategy versus liberal
transfusion?
52. In adult patients with sepsis, should we use erythropoiesis-stimulating agent (ESA) to treat
anemia?
53. In nonbleeding patients with sepsis and coagulation abnormalities, should we use
prophylactic fresh frozen plasma (FFP)?
54. In nonbleeding patients with sepsis and thrombocytopenia, should we use prophylactic
platelet transfusion based on specific platelet levels?
55. In adult patients with sepsis or septic shock, should we use intravenous immunoglobulins?
56. In adult patients with sepsis or septic shock, should we use anticoagulants as adjunctive
treatment?
57. In adult patients with sepsis, should we use pharmacologic venous thromboembolism (VTE)
prophylaxis?
58. In patients with sepsis, should we use low molecular weight heparin (LMWH) versus
unfractionated heparin (UFH) for VTE prophylaxis?
59. In adult patients with sepsis, should we use stress ulcer prophylaxis? 60. In adult patients
with sepsis, should we use proton pump inhibitor (PPI) versus histamine 2 (H2) receptor
antagonist for stress ulcer prophylaxis?
61. In adult patients with sepsis or septic shock who can be fed enterally, should we use enteral
feeding versus early total parenteral nutrition (TPN)?
62. In adult patients with sepsis or septic shock who can be fed enterally, should we give early
enteral feeding (versus delayed enteral feeding)?
63. In adult patients with sepsis or septic shock who can be fed enterally, should we give
supplemental parenteral nutrition on top of enteral feeding?
64. In adult patients with sepsis who are fed enterally, should we give prokinetic agents to
prevent feeding intolerance?
65. In adult patients with sepsis or septic shock who are fed enterally, should we give prokinetic
agents to manage/treat feeding intolerance?
66. In adult patients with sepsis who have enteral tubes, should we use post-pyloric tube
feeding versus gastric tube feeding?
67. In adult patients with sepsis, should we follow a standard feeding protocol? 68. In
mechanically-ventilated patients with sepsis or septic shock who require sedation, should we
use continuous versus intermittent sedation?
69. In patients with sepsis or septic shock, should we give nonbenzodiazepines (versus other
agents) for sedation?
70. In patients with sepsis or septic shock who are in pain, should we give opioids (versus other
agents) for analgesia?
26
SEPSIS DEFINITION AND CRITERIA FOR DIAGNOSIS
Question 1. Should we use the Sepsis-3 definition over the old sepsis definition?
Recommendation
We recommend adoption of the Sepsis-3 definition of sepsis ("life-threatening organ

dysfunction caused by a dysregulated host response to infection") (strong recommendation,
moderate quality of evidence).
Summary of Evidence
Before the Sepsis-3 definitions of sepsis and septic shock were published, the old
definition of sepsis consisted of at least two criteria of the systemic inflammatory response
syndrome (SIRS) plus infection, whether suspected or proven. The term "severe sepsis" was
previously defined as sepsis that was complicated by organ dysfunction, hypotension
responsive to fluids, or signs of hypoperfusion. Similarly, the term septic shock used to refer
to sepsis with acute circulatory failure, particularly with a persistence of hypotension that
was unresponsive to adequate fluid resuscitation, and needing vasopressor treatment. 1
The 2016 Sepsis-3 consensus revised the definition of sepsis to "a life-threatening
organ dysfunction caused by a dysregulated host response to infection," which was actually
equivalent to the severe sepsis of old. The new definition makes the condition more specific,
as it removes those infections that are not life-threatening and present with at least two
SIRS criteria, which could actually be just a normal host response to infection. 2
The new sepsis definition has led to the formulation of new clinical criteria for
sepsis, again by the 2016 Sepsis-3 Consensus. Because there is no gold standard for it,
patient cases with infection but were "really sick" were used as the proxy for "septic"
patients, as recently defined. In the study of Seymour, twenty-one (21) variables that were
clinically relevant and assessible, tested for association with in-hospital mortality, were
statistically analyzed by multivariable logistic regression. 3 This led to the new criteria for
sepsis outside of the intensive care unit (ICU) and was called the quick sequential organ
failure assessment (qSOFA) score, which consisted of: (1) respiratory rate > 22 breaths per
minute, (2) altered mentation, and (3) systolic blood pressure < 100 mmHg. Outside the
ICU, the presence of two or more qSOFA points would be a reasonable prompt to consider
sepsis. On the other hand, the SOFA score was much better in the ICU, particularly a change
of > 2 from the baseline SOFA score. These criteria would prompt one to consider sepsis in
ICU patients.
It is important to note that because sepsis has no gold standard diagnostic test,
Question 1 was answered by testing the sensitivity and specificity of the clinical criteria that
represented the new sepsis definition, particularly the components of the qSOFA or the
SOFA in those patients with suspected or proven infection. Simply put, the summaries of
evidence for Questions 2 and 3 were used to support the recommendation for Question 1.
27
References
1. Buensalido JAL & MacArthur RD. Sepsis, severe sepsis, and septic shock (Book Chapter). Clinical Infectious
Disease (Cambridge University Press); edited by David Schlossberg, 2015
2. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD,
Coopersmith CM, Hotchkiss RS. The third international consensus definitions for sepsis and septic shock
(Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10.
3. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, Rubenfeld G, Kahn JM, Shankar-Hari M,
Singer M, Deutschman CS. Assessment of clinical criteria for sepsis: for the Third International Consensus
Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):762-74.
Question 2. Should we use the quick Sequential Organ Failure Assessment (qSOFA) over the
Systemic Inflammatory Response Syndrome (SIRS) as clinical criteria to identify patients with
sepsis?
Recommendations
We recommend that qSOFA-based clinical criteria (at least two criteria in a patient
suspected/proven infection) be used to identify patients with sepsis (strong recommendation,
moderate quality evidence).
We recommend that those with at least two (2) SIRS criteria plus suspected/proven infection
but not meeting qSOFA>2, be observed for progression to sepsis (strong recommendation,
moderate quality evidence.)
Summary of Evidence
Sepsis definition of a life-threatening infection prompted search for studies that

looked into the ability of qSOFA and SIRS to predict mortality among patients suspected of
infection. A meta-analysis that included 38 studies demonstrated qSOFA sensitivity of
51.2% outside the ICU, and 46.7% in the emergency department (ED). 1 On the other hand,
specificity was 79.6% outside the ICU, and 81.3% in the ED. In contrast, SIRS had a
sensitivity of 82.2% outside the ICU, and 83.6% in the ED. The specificity of SIRS criteria
though was only 34.2% outside the ICU, and 30.6% in the ED. The above evidence shows
that SIRS is more sensitive but less specific in predicting mortality compared to qSOFA.
This means that the use of the SIRS criteria for sepsis screening identifies a significant
number of cases that were not at high risk of mortality, and were probably infections
exhibiting appropriate inflammatory response.
The same meta-analysis also looked into more clinically useful positive and negative
likelihood ratios. The positive likelihood ratio (PLR) for mortality was 2.50 outside the ICU
and 2.49 in the ED, when using qSOFA. This is much higher compared to PLR values 1.25
28
and 1.20 outside the ICU and in the ED, respectively using the SIRS criteria. A higher PLR
means that the probability of dying is higher for patients with qSOFA score ≥2 compared to
patients who satisfy at least two SIRS criteria. On the other hand, the negative likelihood
ratio (NLR) for mortality using qSOFA was 0.61 outside the ICU, and 0.66 in the ED. The
NLR of SIRS criteria was lower at 0.52 outside the ICU, and 0.54 in the ED. This means that
the probability of dying is lower for patients who do not meet at least two of the SIRS
criteria compared to those whose qSOFA scores are <2.
Another meta-analysis of ten studies which included a total of 229,480 patients

showed similar results.2 The sensitivity in predicting mortality ranged from 19.9%
(n=184,875) to 97.4% (n=214) for SIRS, and 22.8% (n=184,875) to 90.0% (n=152) for
qSOFA, in favor of SIRS. Then again, specificity ranged from 2.3% (n=214) to 90.2%
(n=184,875) for SIRS, and 27.4% (n=214) to 91.3% (n=8,871) for qSOFA, in favor of qSOFA.
In terms of predicting risk for organ dysfunction, several studies showed

sensitivities ranging from 71% to 91% for SIRS, and 28% to 66% for qSOFA. 3-7 Conversely,
specificities were only 29% to 69% for SIRS, and 88% to 97% for qSOFA. This only shows
that qSOFA more reliably predicts organ dysfunction compared to SIRS.
For sepsis diagnosis, a systematic review by Serafim and colleagues investigated the
diagnostic accuracy of both SIRS and qSOFA using a combination of clinical, laboratory and
microbiologic criteria as gold standard. 2 Included studies reported sensitivities of 39.5%
(n=152) to 88.3% (n=30,677) for SIRS, and 10.2% (n=8,871) to 54.4% for qSOFA, again
favoring the old SIRS criteria. Only one study that included 152 patients reported specificity
at 84.4% for SIRS and 97.3% for qSOFA, in favor of the new Sepsis-3 clinical criteria.
A study conducted in a tertiary teaching private hospital in the Philippines also

looked into the diagnostic accuracy of both SIRS and qSOFA for predicting mortality and
diagnosing sepsis in 295 subjects. SIRS was found to be more sensitive in diagnosing sepsis
at 73.7% versus 46.3%, while qSOFA was more specific at 95.5% versus 60%. 8
Foreign and local studies consistently demonstrate higher sensitivity of SIRS, but
better specificity of qSOFA in terms of (1) predicting mortality, (2) predicting organ
dysfunction, and (3) diagnosing sepsis. 1-13 For either SIRS or qSOFA, mortality increase
progressively with each criterion satisfied or point increased. 3,14 The use of qSOFA appears
to be attractive in terms of diagnosing true, life-threatening infections – as the third
International Consensus defined Sepsis. But the sensitivity of SIRS is difficult to ignore,
given the fact that clinicians would not want to miss even a small number of cases at high
risk of mortality.
To reconcile this, qSOFA and SIRS were included in the clinical algorithm for the
diagnosis of patients suspected of sepsis (Figure 1) The panel agreed to recommend the
more specific qSOFA criteria to diagnose sepsis. Using qSOFA as a primary clinical tool will
allow clinicians to easily identify patients at high risk of mortality using only four clinical
variables. But in recognition of SIRS’ higher sensitivity, those with <2 qSOFA score should
29
still be evaluated using the SIRS criteria. Patients who satisfy at least two SIRS criteria (but
have qSOFA <2), should be monitored for progression to sepsis.
Figure 1. Identification of patients with sepsis
References
1. Fernando SM, Tran A, Taljaard M et al., Prognostic Accuracy of the Quick Sequential Organ Failure Assesment for
Mortality in Patients With Suspected Infection. A Systematic Review and Meta-analysis. Annals of Internal
Medicine, 2018; 168(4): 266-275.
2. Serafim R, Gomes JA, Salluh J, Pó voa P. A comparison of the quick-SOFA and systemic inflammatory response
syndrome criteria for the diagnosis of sepsis and prediction of mortality: a systematic review and meta-
analysis. Chest. 2018 Mar 1;153(3):646-55.
3. Giamarellos-Bourboulis EJ, Tsaganos T, Tsangaris I et al. Validation of the new Sepsis-3 definitions: proposal for
improvement in early risk identification. Clinical Microbiology and Infection 2017;23:104- 109;
4. Khwannimit B, Bhurayanontachai R, Vattanavit V. Comparison of the performance of SOFA, qSOFA and SIRS for
predicting mortality and organ failure among sepsis patients admitted to the intensive care unit in a middle-
income country. Journal of Critical Care 2018;44:156-160;
5. Park HK, Kim WY, Kim MC et al. Quick sequential organ failure assessment compared to systemic inflammatory
response syndrome for predicting sepsis in emergency department. Journal of Critical Care 2017;42:12-17;
6. Song JU, Sin CK, Park HK et al. Performance of the quick Sequential (sepsis-related) Organ Failure Assessment
score as a prognostic tool in infected patients outside the intensive care unit: a systematic review and meta-
analysis. Critical Care 2018;22:28;
7. Williams JM, Greenslade JH, McKenzie JV et al. SIRS, qSOFA and organ dysfunction: insights from a prospective
database of emergency department patients with infection. Chest 2016, doi:10.1016/j.chest.2016.10.057.
30
8. Ang SRC, Ubaldo OGV, Tayzon MFR, Abad CLR, Henson KER, Gueco IP, Cinco JEL. A Prospective Cohort Study of
the Quick Sequential Organ Failure Assessment (qSOFA) Score versus the Systemic Inflammatory Response
Sydnrome (SIRS) Criteria in the Determination and Prognostication of Sepsis in a Philippine Tertiary Hospital.
Unpublished as of 2018.
9. Askim A, Moser F, Gustad LT et al. Poor performance of quick-SOFA (qSOFA) score in predicting severe sepsis
and mortality - a prospective study of patients admitted with infection to the emergency department.
Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2017;25:56. DOI 10.1186/s13049-
017-0399-4
10. Finkelsztein EJ, Jones DS, Ma KC et al. Comparison of qSOFA and SIRS for predicting adverse outcomes of
patients with suspicion of sepsis outside the intensive care unit. Critical Care 2017;21:73.
11. Freund Y, Lemachatti N, Krastinova E et al. Prognostic Accuracy of Sepsis-3 Criteria for In-hospital Mortality
Among Patients With Suspected Infection Presenting to the Emergency Department. JAMA 2017;317(3):301-
308. doi:10.1001/JAMA.2016.20329
12. Szakmany T, Pugh R, Kopczynska M, Lundin RM, Sharif B, Morgan P, Ellis G, Abreu J, Kulikouskaya S, Bashir K,
Galloway L. Defining sepsis on the wards: results of a multi-centre point-prevalence study comparing two
sepsis definitions. Anaesthesia. 2018 Feb;73(2):195-204.
13. April MD, Aguirre J, Tannenbaum LI et al. Sepsis Clinical Criteria in Emergency Department Patients Admitted
to an Intensive Care Unit: An External Validation Study of Quick Sequential Organ Failure Assessment.The
Journal of Emergency Medicine; http://dx.doi.org/10.1016/j-jemermed.2016.10.012
14. Churpek MM, Snyder A, Han X et al. Quick Sepsis-related Organ Failure Assessment, Systemic Inflammatory
Response Syndrome, and Early Warning Scores for Detecting Clinical Deterioration in Infected Patients outside
the Intensive Care Unit. American Journal of Respiratory and Critical Care Medicine 2017;195(7):906-911
Question 3. Should the Sequential Organ Failure Assessment (SOFA) scoring-based clinical
criteria be used instead of SIRS-based criteria in the diagnosis of sepsis in the Intensive Care Unit
(ICU)?
Recommendation
We recommend the use of SOFA scoring-based clinical criteria instead of SIRS-based criteria in
diagnosing sepsis in the ICU (strong recommendation, high quality of evidence).
Summary of Evidence
The Sequential Organ Failure Assessment (SOFA) is a mortality prediction score that
is based on the degree of dysfunction of six organ systems. The SOFA score can be used to
determine the level of organ dysfunction and mortality risk in ICU patients. The scores can
be used in several ways, including (1) as individual scores for each organ to determine the
progression of organ dysfunction, (2) as a sum of scores on a single intensive care unit (ICU)
day, or (3) as a sum of the worst scores during the ICU stay.1
31
The SOFA variables were selected by a working group of the European Society of
Intensive Care Medicine in the 1990s. 1 In the initial validation study, 1449 patients from 40
ICUs in 16 countries were enrolled over a period of one month. The study found that the
SOFA score had a good correlation to organ dysfunction/failure in critically-ill patients. 2
In a retrospective cohort analysis done in 182 Australian and New Zealand ICUs,
SOFA score demonstrated significantly greater discrimination (crude AUROC 0.753 [99& CI
0.750- 0.757]) for in-hospital mortality than SIRS (crude AUROC 0.589 [99% CI 0.585-
0.593]) criteria, and even qSOFA (crude AUROC 0.607 [99% CI 0.603-0.611]). 3 It also
outperformed SIRS and qSOFA in terms of the composite secondary outcome of in-hospital
mortality or ICU length of stay of three days or longer. Findings were consistent for both
outcomes in multiple sensitivity analyses. These findings suggest that compared to SOFA,
SIRS criteria and qSOFA have inferior utility for predicting mortality in an ICU setting.
It is important to note that the meta-analysis of 38 studies showed that when qSOFA
was used in the ICU, its sensitivity for mortality was 87.2%, better than when it was used
outside the ICU, where its sensitivity was only 51.2%. 4 Conversely, the specificity of qSOFA
for mortality in the ICU was inferior at only 33.3% compared to outside the ICU, where it
was 81.3%. Similarly, the sensitivity of the SIRS criteria for mortality was 93.9% in the ICU,
which was slightly better than the 82.2% when it was used outside the ICU. The specificity
of SIRS criteria for mortality though was only 13% in the ICU, and was much better at
34.2% outside the ICU.
A ten-year retrospective cohort study conducted in a teaching hospital in Thailand
involved 2350 mixed sepsis patients, and it compared the performance of SOFA, qSOFA and
SIRS for predicting mortality and organ failure.5 The SOFA score presented the best
discrimination with an AUROC of 0.839. The AUC of SOFA score for hospital mortality was
significantly higher than qSOFA (AUC 0.814, p=0.003) and SIRS (AUC 0.587, p<0.0001). It
was shown that SOFA is a superior prognostic tool for predicting mortality and organ
failure than qSOFA and SIRS criteria among sepsis patients admitted to the ICU.
Seymour et al., on the other hand, conducted a retrospective study to assess the
clinical criteria for sepsis for the Third International Consensus Definitions for Sepsis and
Septic Shock (Sepsis-3).6 This involved 148,907 electronic health records encounters with
suspected infection from January 2010 to December 2012 at 12 hospitals in southwestern
Pennsylvania. Their findings showed that among ICU encounters with suspected infection,
the predictive validity for in-hospital mortality of SOFA was statistically greater than SIRS
and qSOFA, supporting its use in clinical criteria for sepsis.
All of the above demonstrate why SOFA scoring is preferred over qSOFA in the
identification of sepsis inside the ICU. Both qSOFA and SIRS can be used while waiting for
the test results necessary to finalize the SOFA score. However, when used in this setting, the
limitations of qSOFA and/or SIRS should be taken into consideration. Figure 1 shows the
clinical algorithm for the identification of patients with sepsis incorporating the use of the
different clinical criteria discussed.
32
References
1. Vincent, J.L., Moreno, R., Takala, J., Willatts, S., De Mendonça, A., Bruining, H., Reinhart, C.K., Suter, P. and Thijs,
L.G., The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On
behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
Intensive Care Med. 1996 Jul;22(7):707-10
2. Vincent JL1, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S. Use of
the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a
multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of
Intensive Care Medicine. Crit Care Med. 1998 Nov;26(11):1793-800.
3. Eamon P. Raith, MBBS, MACCP; Andrew A. Udy, MBChB, PhD, FCICM; Michael Bailey, PhD; et al. Prognostic
Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortalityv Among Adults with
Suspected Infection Admitted to the Intensive Care Unit. JAMA. 2017;317(3):290-300.
doi:10.1001/JAMA.2016.20328
4. Fernando SM, Tran A, Taljaard M et al. Prognostic Accuracy of the Quick Sequential Organ Failure Assesment for
Mortality in Patients With Suspected Infection. A Systematic Review and Meta-analysis. Annals of Internal
Medicine, 2018; 168(4): 266-275.
5. Khwannimit B, Bhurayanontachai R, Vattanavit V. Comparison of the performance of SOFA, qSOFA and SIRS for
predicting mortality and organ failure among sepsis patients admitted to the intensive care unit in a middle-
income country. Journal of Critical Care 2018;44:156-160.
6. Seymour CW, Liu VX, Iwashyna TJ et al. Assessment of Clinical Criteria for Sepsis. For the third International
Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:762-774.
Question 4. Should we use the Sepsis-3 definition and clinical criteria to diagnose patients with
septic shock?
Recommendations
We recommend the adoption of the Sepsis-3 definition of septic shock - "a subset of sepsis with
underlying circulatory, cellular and metabolic abnormalities that are profound enough to
substantially increase mortality than sepsis alone" (strong recommendation, moderate quality
of evidence)
When serum lactate is available, we recommend that the Sepsis-3 clinical criteria of (1)
hypotension requiring vasopressor to maintain MAP ≥65mmHg, and (2) a serum lactate level
>2mmol/L (18mg/dl) after adequate fluid resuscitation be used to identify patients with septic
shock (strong recommendation, moderate quality of evidence)
Remark: A high lactate level further stratifies septic patients at higher risk of mortality.
33
When serum lactate is not available, we recommend that the previous clinical criteria of (1)
hypotension that does not improve after adequate fluid resuscitation, and (2) needing
vasopressor to maintain MAP of ≥65mmHg, be used at the minimum to identify patients with
septic shock (strong recommendation, moderate quality of evidence).
Summary of Evidence
In the 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions

Conference, septic shock was described as “a state of acute circulatory failure” or
hypotension (SBP <90 mmHg) after fluid resuscitation or the initiation of vasopressor
infusion.1 The Sepsis-3 defines septic shock as "a subset of sepsis in which underlying
circulatory and cellular metabolism abnormalities are profound enough to substantially
increase mortality.”2 In Sepsis-3, the operational criteria for septic shock include (1)
persisting hypotension requiring vasopressors to maintain a mean arterial pressure (MAP)
of ≥65mmHg, and (2) serum lactate level >2 mmol/L (18mg/dL) despite adequate volume
resuscitation. The task force agreed that septic shock is not cardiovascular dysfunction
alone, and recognized the importance of cellular abnormalities. The clinical criteria for
septic shock combined hypotension and hyperlactatemia, representing both cardiovascular
compromise and cellular dysfunction, since both have been uniformly associated with a
significantly higher risk of mortality and organ dysfunction .3-6 The addition of
hyperlactatemia of > 2 mmol/liter to hypotension was seen to increase hospital mortality
from 30.1% to 42.3%, which signifies that a serum lactate of that level is clinically relevant. 7
Nonetheless, patients who met only the old definition still demonstrated significant organ
failure and mortality.4-6
Hyperlactatemia has been a reasonable marker of illness severity in patients with

sepsis reflecting cellular dysfunction. Some may argue that lactate may rise with other
conditions, but studies have shown that higher lactate levels predict mortality. A
prospective observational study that included 985 patients with sepsis show high
predictive value for clinical deterioration with lactate values greater than 4mmol/L
(Sensitivity [Sn] 27.4%, 95% confidence interval [CI] 18.2, 38.2; Specificity [Sp] 97.5%,
95%CI 96.2, 98.4).8 In this study, clinical deterioration was a composite of death,
endotracheal intubation, vasoactive medication administration for a minimum of 1 hour,
noninvasive positive pressure ventilation for a minimum of 1 hour, or ICU admission for a
minimum of 24 hours. Other studies which analyzed large datasets from statewide
(n=12,349) and international reporting systems (n=28,150) that prospectively collected
data from participating sites show similar results, with elevated lactate levels found to be
strongly associated with mortality. 9,10 Lactate values greater than 4mmol/L, with or
without hypotension, were associated with higher mortality than intermediate levels (2-3
and 3-4mmol/L).
34
The addition of lactate to the existing clinical criteria of septic shock was found to be
associated with consistently higher mortalities, that is 42%, 54%, and 35% in three large
databases.2 These databases include the SSC multicenter registry (n=28,150), the University
of Pittsburgh Medical Center with 12 participating hospitals (n=5,984), and the Kaiser
Permanente Northern California with 20 participating hospitals (n=54,135). Exclusion of
lactate revealed varying mortality rates from as high as 30% to as low as 8%. Indeed,
lactate is a useful marker that discriminates the subset of patients that have higher
mortality than sepsis alone.
Several studies further support the ability of the Sepsis-3 septic shock criteria in
discriminating patients at higher risk of mortality. A secondary analysis of two clinical trials
that included 470 patients showed higher SOFA score (9 versus 5; p < 0.001) and mortality
(29% vs 14%; p < 0.001) of patients labeled as septic shock by the Sepsis-3 compared to the
old definition.4 In a prospective multicenter study in Korea (n=1,028), those who met the
Sepsis-3 septic shock criteria demonstrated higher morbidity (83.1% vs. 75.3%), SOFA
scores (6.5±3.1 vs. 5.0±2.9), acute physiology scores (9.3±3.8 vs. 6.6±3.4) and chronic
health evaluation II scores ( 20.0 [15.0–26.0] vs. 15.0 [10.0–20.3]) compared to when the
old criteria was used.11 Furthermore, mortality rates in the hospital, at 28 days, and at 90
days were also higher at 26.8% vs. 17.1%, 25.1% vs. 16.5%, and 32.1% vs. 23.3%,
respectively. A third study by Driessen and colleagues prospectively collected data from a
cohort of 632 septic patients in the ICU, 482 (76.3%) of which had septic shock according
to Sepsis-2 and 300 patients (48.4%) according to Sepsis-3 definition. 6 Patients meeting
Sepsis-3 definition had a higher mortality than patients meeting Sepsis-2 definition (38.9
vs. 34.0%).
Current evidence strongly supports the inclusion of hyperlactatemia, hence the

adoption of the Sepsis-3 criteria for diagnosis of septic shock. However, the panel
recognizes the potential limitation in terms of availability, accessibility and cost of serum
lactate testing. Thus, the old criteria was recommended at a minimum for diagnosis of
septic shock – though at the expense of lower prognostic accuracy.
Figure 2 shows the clinical algorithm for the identification of patients with sepsis
induced hypoperfusion based on serum lactate level, while Figure 3 shows the algorithm in
the diagnosis and initial management of septic shock.
-remainder of page left blank-
35
Figure 2. Initial Management of Patients with Sepsis and Identification of Patients with
Sepsis-induced hypoperfusion
Figure 3. Initial Management of Patients with Sepsis-induced hypoperfusion and

Identification of Patients with Septic Shock
36
References
1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. 2001
sccm/esicm/accp/ats/sis international sepsis definitions conference. Intensive care medicine. 2003 Apr
1;29(4):530-8.
2. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche
JD, Coopersmith CM, Hotchkiss RS. The third international consensus definitions for sepsis and septic
shock (Sepsis-3). Jama. 2016 Feb 23;315(8):801-10.
3. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of
innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of
Chest Physicians/Society of Critical Care Medicine. Chest. 1992; 101(6):1644655.
4. Sterling SA, Puskarich MA, Glass AF, Guirgis F, Jones AE. The impact of the Sepsis-3 septic shock definition on
previously defined septic shock patients. Critical care medicine. 2017 Sep;45(9):1436.
5. Henning DJ, Puskarich MA, Self WH, Howell MD, Donnino MW, Yealy DM, Jones AE, Shapiro NI. An emergency
department validation of the SEP-3 sepsis and septic shock definitions and comparison with 1992 consensus
definitions. Annals of emergency medicine. 2017 Oct 1;70(4):544-52.
6. Driessen RG, van de Poll MC, Mol MF, van Mook WN, Schnabel RM. The influence of a change in septic shock
definitions on intensive care epidemiology and outcome: comparison of sepsis-2 and sepsis-3 definitions.
Infectious Diseases. 2018 Mar 4;50(3):207-13.
7. Shankar-Hari M, Phillips G, Levy M, Seymour C, Liu V, Deutschman C et al. Developing a New Definition and
Assessing New Clinical Criteria for Septic Shock. JAMA. 2016;315(8):775.
8. Fernando SM, Barnaby DP, Herry CL, Gallagher EJ, Shapiro NI, Seely AJ. Helpful only when elevated: initial serum
lactate in stable emergency department patients with sepsis is specific, but not sensitive for future
deterioration. The Journal of emergency medicine. 2018 Jun 1;54(6):766-73.
9. Shetty AL, Thompson K, Byth K, Macaskill P, Green M, Fullick M, Lander H, Iredell J. Serum lactate cut-offs as a
risk stratification tool for in-hospital adverse outcomes in emergency department patients screened for
suspected sepsis. BMJ open. 2018 Jan 1;8(1):e015492.
10. Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, Reinhart K, Selvakumar N, Levy MM.
Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign
database. Critical care medicine. 2015 Mar 1;43(3):567-73.
11. Ryoo SM, Kang GH, Shin TG, Hwang SY, Kim K, Jo YH, Park YS, Choi SH, Yoon YH, Kwon WY, Suh GJ. Clinical
outcome comparison of patients with septic shock defined by the new sepsis-3 criteria and by previous
criteria. Journal of thoracic disease. 2018 Feb;10(2):845.
37
DIAGNOSTIC TESTS
Question 5. Should we routinely request blood cultures from patients suspected with sepsis or
septic shock?
Recommendations
Blood cultures should be obtained before administering antibiotics to patients suspected of

sepsis or septic shock, if doing so will not result in substantial delay in the initiation of
antibiotics (strong recommendation, low quality of evidence).
Note: Antibiotics should be administered within an hour of sepsis recognition. The reader is directed to Question 27 for
further information.
Blood cultures should be complemented by appropriate cultures taken from the suspected
focus of infection (strong recommendation, low quality of evidence ).
Summary of Evidence
The diagnosis of sepsis remains a challenge due to lack of unambiguous clinical

criteria or laboratory features that would clearly identify patients with sepsis. Most
physicians rely on their clinical skills and experience to diagnose sepsis, and both clinical
and microbiologic criteria are often used as reference standard in diagnostic studies. In
some scenarios, bacterial cultures are still considered as reference standard for detection
of infection. However, the low pathogen yield, as well as the waiting time for results
continue to be a stumbling block in the efficient and accurate diagnosis of sepsis. A review
by Coburn and colleagues revealed that blood culture positivity varied depending on the
clinical context.1 Microbiological yield is low among patients with cellulitis (2%),
community acquired pneumonia (7%), community-onset fever (13%), and ambulatory
patients (2%), and high among those with acute bacterial meningitis (53%), severe sepsis
(38%), and septic shock (69%). A trend showing greater probability of bacteremia with
increasing illness severity was also observed in a prospective observational study that
included 2,527 patients presenting with SIRS. 2 Microbiologic yield was 25.4% among
patients with severe sepsis, and 69.1% among those with septic shock.
Culture positivity or bacteremia among patients with sepsis was found to be

associated with increased mortality in various prospective cohort studies. Two large
prospective, multicenter cohort studies that included 3,147 and 11,828 patients showed
increased odds of mortality among bacteremic patients with sepsis, Odds Ratios (OR) 1.7
(95% CI 1.2, 2.4) and 1.7 (95% CI 1.1, 2.8), respectively. 3,4 This finding was also observed in
a cohort of 3,588 patients with either community- or hospital-acquired infections, with
mortalities of 48.5% (vs 40.3%) and 43% (vs 36.9%), respectively.
38
Despite the limitations of blood culture, it has been consistently recommended in

various sepsis clinical practice guidelines such as the Surviving Sepsis Campaign and the
Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock. 5,6
Blood cultures do not only allow proper identification of the causative microorganism and
targeted antimicrobial therapy but also support de-escalation of antibiotics to prevent
unnecessary use of broad-spectrum antimicrobials. De-escalation is associated with less
risk of developing resistant microorganisms, fewer antibiotic-related side effects, and
lower costs.
Blood cultures obtained after initiation of antibiotics demonstrated reduction in

microbiologic yield, from 31.4% pre- to 19.4% post-antibiotic administration. 7 On the
average, cultures obtained after antibiotics took longer to grow organisms. The rational
desire to obtain cultures should be balanced against the risk of delaying antimicrobials. A
study by Kumar and colleagues showed that every hour of delay in administration of
antimicrobials increases the risk of mortality among patients with sepsis and septic shock. 8
Therefore, the need for blood cultures must not delay initiation of antibiotics beyond the
first hour of sepsis recognition.
The addition of specimen for culture from other potential sites of infection increased
the sensitivity of the test to 68%. 7 Positivity rate was also higher with paired blood culture
compared to single blood culture.9 Unless there is clinically apparent focus of infection,
culture from other sites apart from the suspected site(s) of infection should be discouraged
as it could lead to inappropriate use of antibiotics.
Consensus Panel Issues. The panel would like to emphasize the importance of
timely administration of antibiotics in improving the survival of patients with sepsis and
septic shock. If blood cultures cannot be obtained within an hour, administration of
antibiotics should be prioritized. Nonetheless, every effort to immediately obtain blood
cultures should be sought to assist clinicians in making decisions related to optimal
antimicrobial therapy.
Targeted focused investigation is the key to treatment, complemented by the proper
manner of specimen collection.
References
1. Coburn B, Morris AM, Tomlinson G, Detsky AS. Does this adult patient with suspected bacteremia require blood
cultures?. JAMA. 2012 Aug 1;308(5):502-11.
2. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic
inflammatory response syndrome (SIRS): a prospective study. JAMA. 1995 Jan 11;273(2):117-23.
3. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D. Sepsis in
European intensive care units: results of the SOAP study. Critical care medicine. 2006 Feb 1;34(2):344-53.
4. Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, Mercier JC, Offenstadt G, Ré gnier B.
Incidence, risk factors, and outcome of severe sepsis and septic shock in adults: a multicenter prospective
study in intensive care units. JAMA. 1995 Sep 27;274(12):968-74.
39
5. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally
ME, Rochwerg B. Surviving sepsis campaign: international guidelines for management of sepsis and septic
shock: 2016. Intensive care medicine. 2017 Mar 1;43(3):304-77.
6. Nishida O, Ogura H, Egi M, Fujishima S, Hayashi Y, Iba T, Imaizumi H, Inoue S, Kakihana Y, Kotani J, Kushimoto S.
The Japanese clinical practice guidelines for management of sepsis and septic shock 2016 (J SSCG 2016).
Journal of intensive care. 2018 Dec;6(1):7.
7. Cheng MP, Stenstrom R, Paquette K, Stabler SN, Akhter M, Davidson AC, Gavric M, Lawandi A, Jinah R, Saeed Z,
Demir K. Blood culture results before and after antimicrobial administration in patients with severe
manifestations of sepsis: A diagnostic study. Annals of internal medicine. 2019 Sep 17.
8. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, MD; Suppes R, Feinstein D, Zanotti S, Taiberg L,
Gurka D, Kumar A, Cheang M. Duration of hypotension before initiation of effective antimicrobial therapy is the
critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589–1596
9. Tarai B, Jain D, Das P, Budhiraja S. Paired blood cultures increase the sensitivity for detecting pathogens in both
inpatients and outpatients. European Journal of Clinical Microbiology & Infectious Diseases. 2018 Mar
1;37(3):435-41.
Question 6. Should we use procalcitonin to diagnose adult patients with sepsis?
Recommendation
When there is uncertainty, procalcitonin may be used as an adjunct to support the diagnosis of
sepsis in adults (weak recommendation, low quality of evidence).
Note: Procalcitonin does not reliably rule out sepsis and should not be used solely to decide whether or not to start
antibiotics.
Summary of Evidence
A meta-analysis by Kondo and colleagues that included 1,377 patients showed

moderate sensitivity (0.80, 95%CI 0.75, 0.84) and specificity (0.75, 95% CI 0.67, 0.81) of
procalcitonin (PCT) in diagnosing patients with sepsis and septic shock. 1 Significant
heterogeneity was observed across studies (Sn I 2=81.72, Sp I2=87.13), and this was
attributed to differences in the PCT cutoff values and the prevalence of sepsis. Sensitivity
analysis showed results to be significantly different between studies having high and low
risk of bias (Sn 0.79, 95%CI 0.72-0.86 vs 0.79, 95%CI 0.59-0.99; Sp 0.79, 95%CI 0.69-0.89 vs
0.74, 95%CI 0.38-1.00), as well as those conducted before and after 2015 (Sn 0.75, 95%CI
0.65-0.86 vs 0.82, 95%CI 0.74-0.90; Sp 0.72, 95%CI 0.57-0.87 vs 0.83, 95%CI 0.73-0.94).
Additional information from observational studies also showed that PCT values
varied depending on sepsis severity, the causative organism, and the site of infection. 2,3 PCT
concentration increased with greater sepsis severity as shown in Figure Q6.3
(Supplementary Material 2).2 Patients with gram-negative bacteremia had distinctly higher
PCT values (26ng/ml, 95%CI 7.7, 63.1), compared to those with gram-positive bacteremia
40
(7.1ng/ml, 95%CI 2.0, 23.3) and candidemia (4.7ng/ml, 95%CI 1.9, 13.7). The area under
the curve (AUC) was 0.69 (95%CI 0.67–0.72) for the differentiation of Gram-negative
bacteremia from Gram-positive bacteremia or candidemia, and 0.72 (95% CI 0.71–0.74) for
the prediction of Gram-negative bacteremia compared to all other blood culture results,
including those read as negative. 3 AUC is a reflection of how good the test is in
distinguishing between patients with the condition and those without. In general, the
closer the AUC is to 1, the better overall diagnostic performance of the test. In this case, PCT
had moderate diagnostic accuracy in predicting gram-negative infection compared to those
caused by other organisms.
A systematic review and meta-analysis of 58 studies that included 16,514 patients

studied the diagnostic accuracy of PCT in predicting bacteremia. 4 Similar to sepsis studies,
the sensitivity and specificity of PCT for bacteremia was only moderate at 0.76 (95% CI:
0.72 to 0.80) and 0.69 (95% CI: 0.64 to 0.72), respectively. A PCT value of less than
0.5ng/ml had low positive predictive value (17% to 28%) but high negative predictive
value for bacteremia (95 to 98%) across different clinical settings: in the ED, ICU, or wards.
In another prospective observational study that included 106 patients with sepsis, PCT
values >4.68ng/ml were found to have high positive predictive value for bacteremia
(97%).2
Current evidence show that among numerous biological markers which have been
examined to date, PCT had the best diagnostic value in predicting sepsis. The rapid rise of
plasma PCT concentration within 6 to 12 hours of infection, as well as its short plasma half
life of approximately 24 hours, make it very attractive in terms of diagnosis and monitoring.
Although low PCT concentrations make bacteremia less likely, it does not reliably rule out
sepsis or infection, hence should not be used to support clinical decisions to withhold
antibiotics and other interventions to a patient suspected of sepsis. On the other hand, an
elevated PCT value especially in patients whom diagnosis is uncertain, supports initiation of
sepsis management while further diagnostic evaluation is being pursued.
Consensus Panel Issues. Although the panel agreed to the adjunctive use of
procalcitonin for patients whose diagnosis is uncertain, we would like to emphasize that
PCT is not essential for sepsis diagnosis.
References
1. Kondo Y, Umemura Y, Hayashida K, Hara Y, Aihara M, Yamakawa K. Diagnostic value of procalcitonin and
presepsin for sepsis in critically ill adult patients: a systematic review and meta-analysis. Journal of intensive
care. 2019 Dec;7(1):22.
2. Mustafić S, Brkić S, Prnjavorac B, Sinanović A, Porobić Jahić H, Salkić S. Diagnostic and prognostic value of
procalcitonin in patients with sepsis. Med Glas (Zenica). 2018 Aug 1;15(2):93-100.
3. Thomas-Rü ddel DO, Poidinger B, Kott M, Weiss M, Reinhart K, Bloos F. Influence of pathogen and focus of
infection on procalcitonin values in sepsis patients with bacteremia or candidemia. Critical Care. 2018
Dec;22(1):128.
41
4. Hoeboer SH, van der Geest PJ, Nieboer D, Groeneveld AJ. The diagnostic accuracy of procalcitonin for
bacteraemia: a systematic review and meta-analysis. Clinical Microbiology and Infection. 2015 May
1;21(5):474-81.
FLUID THERAPY
Sepsis and septic shock are life-threatening conditions which require emergent
interventions. Among these interventions, fluid resuscitation is crucial to improve tissue
perfusion and has been recommended as first line strategy in patients with sepsis and
septic shock.1
In 2001, Rivers and colleagues introduced a protocolized resuscitation strategy for
septic patients which we now know as the early goal-directed therapy (EGDT). 2 It included
central venous pressure (CVP), mean arterial pressure (MAP), and central venous oxygen
saturation (SCVO2) “goals” for the first six hours of therapy. Patients assigned to EGDT had
significantly lower mortalities (30.5% vs 46.5%) compared to those assigned to standard
care. They noted that the former group of patients received significantly more intravenous
fluids (5L vs 3.5L), more frequent red-cell transfusion (64% vs 18.5%), and inotropic
support (13.7% vs 0.8%) during the six-hour period. Their methodology was later adopted
in the earlier recommendations of the Surviving Sepsis Campaign as a sepsis resuscitation
“bundle” and influenced the widespread practice of administering large volume of fluids to
patients with sepsis and septic shock. 3 However, recent observational studies have
questioned the safety of the “liberal approach” with findings that large fluid volumes were
associated with greater mortality compared to a more fluid-restrictive approach. 4,5 In the
same way, other components of the sepsis bundle were questioned including the usefulness
of targeting CVP of 8-12mmHg and obtaining SCVO2 measurements.6
In recent years, there has been rapid turnover of evidence related to various
components of fluid therapy in sepsis including the type of fluid for resuscitation, the timing
of fluid administration, the optimal amount of fluid to be used, as well as the assessment of
fluid responsiveness. There is also an evolving concept in fluid therapy that recognizes four
phases or stages of fluid resuscitation among patients with sepsis and septic shock. 7 These
include: Rescue, Optimization, Stabilization, and De-escalation or De-resuscitation. The
Rescue phase anticipates an immediate escalation of fluid therapy for resuscitation of
patients, such as in cases of sepsis-induced hypoperfusion or shock. Optimization occurs
when the patient is no longer at imminent risk of death, but at a state of compensated
shock, such that additional fluids are titrated to optimize perfusion and mitigate organ
dysfunction. Stabilization is a steady state where there is absence of shock or imminent risk
of shock, and that fluids are only used for ongoing maintenance. And finally, de-escalation
or de resuscitation phase pertains to active removal of fluid in order to promote a negative
fluid balance.
42
Taken altogether, the abundance of new data and the concept of resuscitation by
different phases only show that fluid therapy in patients with sepsis and septic shock is not
actually straightforward. There is a need to validate new data and assess its applicability in
our setting.
References
2. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early goal directed
therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine. 2001 Nov
8;345(19):1368-77.
3. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker
MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM, Surviving Sepsis Campaign Management Guidelines
Committee. Crit Care Med. 2004 Mar; 32(3):858-73.
4. Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic
shock, patterns and outcomes: an analysis of a large national database. Intensive care medicine. 2017 May
1;43(5):625-32.
5. Sadaka F, Juarez M, Naydenov S, O’brien J. Fluid resuscitation in septic shock: the effect of increasing fluid
balance on mortality. Journal of intensive care medicine. 2014 Jul;29(4):213-7.
6. Barochia AV, Cui X, Eichacker PQ. The Surviving Sepsis Campaign’s revised sepsis bundles. Current infectious
disease reports. 2013 Oct 1;15(5):385-93.
7. Hoste EA, Maitland K, Brudney CS, Mehta R, Vincent JL, Yates D, Kellum JA, Mythen MG, Shaw AD. Four phases of
intravenous fluid therapy: a conceptual model. British journal of anaesthesia. 2014 Sep 9;113(5):740-7.
Question 7. In patients with sepsis or septic shock, should we use crystalloids for initial fluid
resuscitation versus colloid solutions?
Recommendations
We recommend the use of crystalloids for initial fluid resuscitation of patients with sepsis or
septic shock (strong recommendation, moderate quality of evidence).
We recommend against the use of hydroxyethylstarch (HES) for fluid resuscitation due to safety
concerns (strong recommendation, high quality of evidence).
43
Summary of Evidence
Current evidence show that crystalloids have the highest benefit-to-risk ratio among
intravenous fluids for patients with sepsis or septic shock. Two meta-analyses by Rochwerg
in 2014 and 2015 analyzed 18,916 (14 RCTs) and 6,664 (10 RCTs) patients with sepsis,
respectively.1,2 The first meta-analysis looked into mortality, while the second focused on
renal replacement therapy. Results showed no difference in mortality but lower risk for
renal replacement therapy in favor of crystalloids over colloid solutions. Further analysis of
colloids showed that this risk was associated with the use of hydroxyethyl starch (HES).
This finding was also supported by a meta-analysis that focused on comparisons of
crystalloids and HES. It included a total of 4,624 patients (10 RCTs), with results showing
no differences in short- and long-term mortality but greater risk of acute kidney injury (RR
1.24, 95% CI 1.13 to 1.36) and renal replacement therapy (RRT) (Relative Risk [RR] 1.36,
95% CI 1.17 to 1.57) with the use of HES. 3 This effect was seen not only in patients with
sepsis but critically ill patients in general.4,5
Aside from the apparent advantage of using crystalloids as above, crystalloids are
almost always available in health facilities and are economical compared to colloids, and
hence are strongly recommended.
References
1. Rochwerg B, Alhazzani W,Sindi A,Heels-Ansdell D,Thabane L,Fox-Robichaud A,Mbuagbaw L,Szczeklik
W,Alshamsi F,Altayyar S,Ip WC. Fluid resuscitation in sepsis: a systematic review and network meta
analysis. Annals of internal medicine; 2014 Sep 2.
2. Rochwerg B, Alhazzani W,Gibson A,Ribic CM,Sindi A,Heels-Ansdell D,Thabane L,Fox-Robichaud A,Mbuagbaw
L,Szczeklik W,Alshamsi F. Fluid type and the use of renal replacement therapy in sepsis: a systematic review
and network meta-analysis. Intensive care medicine; 2015 Sep 1.
3. Neto AS, Veelo DP,Peireira VG,de Assunçã o MS,Manetta JA,Espó sito DC,Schultz MJ. Fluid resuscitation with
hydroxyethyl starches in patients with sepsis is associated with an increased incidence of acute kidney
injury and use of renal replacement therapy: a systematic review and meta-analysis of the literature.
Journal of critical care; 2014 Feb 1.
4. Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, Wetterslev J. Hydroxyethyl starch
130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta analysis
and trial sequential analysis. BMJ. 2013 Feb 15;346:f839.
5. Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, Fergusson DA. Association of
hydroxyethyl starch administration with mortality and acute kidney injury in critically-ill patients requiring
volume resuscitation: a systematic review and meta-analysis. JAMA. 2013 Feb 20;309(7):678-88.
44
Question 8. In patients with sepsis or septic shock, should we use balanced crystalloids for initial
fluid resuscitation versus normal saline solution?
Recommendation
We recommend the use of either balanced crystalloids or normal saline solution for initial
resuscitation of patients with sepsis or septic shock (strong recommendation, moderate quality
of evidence).
Summary of Evidence
There were two cluster-randomized crossover trials that included critically-ill

patients randomized to either balanced crystalloid or normal saline solution. Both trials
analyzed a subgroup of patients with sepsis.1,2 The SMART trial included 1,641 sepsis
patients from a total of 15,802 critically-ill patients enrolled in the study. 1 The SPLIT trial
included 84 sepsis patients from a total of 2,093 critically-ill patients enrolled. 2 Data on
mortality and renal replacement therapy were extracted. We performed a meta-analysis on
the risk of acute kidney injury between balanced crystalloids and normal saline solution as
initial fluid for resuscitation of patients with sepsis or septic shock.
Studies showed marginal 30-day mortality benefit with the use of balanced crystalloids
compared to saline solution among patients with sepsis (OR 0.74, 95%CI: 0.59, 0.93), 1 but
no difference in the 90-day mortality (OR 0.98, 95%CI: 0.28, 3.42). 2 There was a trend
toward benefit in terms of prevention of renal replacement therapy (OR 0.71, 95%CI: 0.48,
1.0) and acute kidney injury (OR 0.82, 95%: 0.66, 1.01) in favor of balanced crystalloids
versus normal saline solution.
Consensus Panel Issues. The risk of bias related to secondary analysis of a subgroup of
patients with sepsis, as well as imprecision, emphasizes the need for more studies to
definitely assess whether one treatment has an advantage over the other. At this time, there
are three ongoing randomized clinical trials comparing balanced crystalloids and normal
saline solution.3-5 As we wait for the results of these trials, the consensus panel deems
reasonable that either balanced crystalloids or normal saline solution be used for initial
fluid resuscitation in patients with sepsis or septic shock. We found no issues related to
cost and resource availability for both fluids for resuscitation.
References
1. Brown RM, Wang L, Coston TD, Krishnan NI, Casey JD, Wanderer JP, Ehrenfeld JM, Byrne DW, Stollings JL, Siew
ED, Bernard GR. Balanced Crystalloids Versus Saline in Sepsis: A Secondary Analysis of the SMART Trial.
American journal of respiratory and critical care medicine. 2019 Aug 27(ja).
45
2. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides
A, Reddy S. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the
intensive care unit: the SPLIT randomized clinical trial. JAMA. 2015 Oct 27;314(16):1701-10.
3. ZhiYong Peng. Comparison of Balanced Crystalloids and Normal Saline in Septic Patients. 2018 September 26.
ClinicalTrials.gov NCT03685214.
4. Hammond NE, Bellomo R, Gallagher M, Gattas D, Glass P, Mackle D, Micallef S, Myburgh J, Saxena M, Taylor C,
Young P. The Plasma-Lyte 148 v Saline (PLUS) study protocol: A multicentre, randomised controlled trial of
the effect of intensive care fl uid therapy on mortality. Critical Care and Resuscitation. 2017 Oct;19(3):239.
5. Zampieri FG, Azevedo LC, Corrê a TD, Falavigna M, Machado FR, de Assunçã o MS, Lobo S, Dourado LK,
Berwanger O, Kellum JA, Brandã o N. Study protocol for the Balanced Solution versus Saline in Intensive Care
Study (BaSICS): a factorial randomised trial. Critical Care and Resuscitation. 2017 Jun;19(2):175.
ClinicalTrials.gov NCT02875873.
6. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The
Cochrane Collaboration, 2014.
Question 9. In patients with sepsis or septic shock, should we use crystalloids supplemented with
albumin for initial fluid resuscitation versus crystalloids alone?
Recommendation
Addition of albumin to crystalloids may be considered in septic shock patients who are
unresponsive to standard volume and vasopressor therapy or if with other indications (weak
recommendation, moderate quality of evidence).
Summary of Evidence
A meta-analysis by Xu and colleagues compared the effect of albumin

supplementation versus crystalloids alone in the mortality of 3,658 patients with sepsis
(former “severe sepsis”) and 2,180 patients with septic shock. 1 An updated meta-analysis
by Zou and colleagues in 2018 focused on the mortality of 3,088 patients with septic shock. 2
In both studies there was a trend towards survival with the addition of albumin to
crystalloids in patients with sepsis or septic shock. Use of hyperoncotic (20%) albumin
solution resulted to lower mortality among septic shock patients (OR 0.88, 95%CI 0.79,
0.99).1 With regard to adverse events, a meta-analysis that included 2,771 patients who
received either albumin or crystalloid solution found no increased risk for renal
replacement therapy (RRT) with the use of albumin.3
Two registered trials on the use of albumin in septic shock patients already
completed enrolment, and their results are awaited. One study, the Fluid Resuscitation in
Early Septic Shock (PRECISE)4 was funded by the Ottawa Hospital Research Institute and
aimed to
46
compare 5% albumin with normal saline solution. The other study, the Early Albumin
Resuscitation During Septic Shock5 trial was funded by Laboratoire Français de
Fractionnement et de Biotechnologies and compared 20% albumin with normal saline
solution. The result of these trials will hopefully provide further guidance on the optimal
resuscitation fluid for patients with sepsis and septic shock. At the moment, given the
significant cost of albumin, we suggest that its use be considered only in septic shock
patients who present with indications for its use and are unresponsive to standard volume
therapy.
Consensus Panel Issues. It is important that fluid responsiveness be assessed prior
to the infusion of additional intravenous fluids, including albumin. The use of albumin for
patients with sepsis is to maintain intravascular oncotic pressure and maintain perfusion,
which is a step forward towards resuscitation. Although beyond the scope of this guidelines,
note that albumin may be given for other indications in patients with sepsis or septic shock.
References
1. Xu JY, Chen QH,Xie JF,Pan C,Liu SQ,Huang LW,Yang CS,Liu L,Huang YZ,Guo FM,Yang Y. Comparison of the effects
of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis
of randomized clinical trials. Critical Care; 2014 Dec.
2. Zou Y, Ma K,Xiong JB,Xi CH,Deng XJ. Comparison of the effects of albumin and crystalloid on mortality among
patients with septic shock: systematic review with meta-analysis and trial sequential analysis. Sao Paulo
Medical Journal; 2018 Oct.
3. Rochwerg B, Alhazzani W,Gibson A,Ribic CM,Sindi A,Heels-Ansdell D,Thabane L,Fox-Robichaud A,Mbuagbaw
L,Szczeklik W,Alshamsi F. Fluid type and the use of renal replacement therapy in sepsis: a systematic review
and network meta-analysis. Intensive care medicine; 2015 Sep 1.
4. McIntyre L. Fluid Resuscitation in Early Septic Shock (PRECISE). 9 January 2009. ClinicalTrials.gov
NCT00819416.
5. Mira JP. Early Albumin Resuscitation During Septic Shock. 18 May 2006. . ClinicalTrials.gov
NCT00327704.
47
Question 10. In patients with sepsis or septic shock, should we initiate fluid resuscitation within
an hour of sepsis recognition?
Recommendation
We recommend that fluid resuscitation be initiated immediately upon the recognition of sepsis
or septic shock (strong recommendation, moderate quality of evidence).
Summary of Evidence
Review of literature revealed that most studies bundle the pre-specified timing of
fluid administration together with other interventions (i.e. amount and type of fluid, timing
of antibiotics, and lactate-guided resuscitation), such that available studies on single or
component therapy were assessed to be of low to moderate quality.
Of the ten studies retrieved, the best evidence came from a large prospective cohort
study that included 11,182 adult patients with sepsis and septic shock. 1 This study analyzed
patients who received crystalloids within 30 minutes, 31-120 minutes, and more than 120
minutes from sepsis recognition. Fluid resuscitation initiated within 30 minutes was
associated with reduced odds of mortality (OR 0.76, 95%CI 0.69, 0.84), decreased need for
mechanical ventilation (OR 0.62, 95%CI 0.57, 0.68), lower need for vasopressor therapy
(OR 0.77, 95%CI 0.71, 0.85), decreased refractory hypotension (OR 0.77, 95%CI 0.69, 0.87),
and decreased ICU admission (OR 0.76, 95%CI 0.70, 0.82). 1 Further analysis showed that
risk reduction was similar even when a cut-off of 120 minutes was used. When assessed as
a continuous variable, time to crystalloid initiation was associated with 1.09 times greater
odds of mortality (95%CI 1.03, 1.16) per hour of delay. With these results, it may be difficult
to ascertain whether the appropriate timing of fluid resuscitation is bound by a critical
window period or a dose-response effect, and this limitation and other possible biases were
cited in the article. “Sicker patients” may have received fluids earlier, as observed in the
positive effect modification among hypotensive patients and those presenting at the
emergency department. On the other hand, more patients with risk for fluid congestion
(heart failure and renal failure) received fluids at a later time, though statistical analysis
revealed no significant interaction effect in this subset of patients.
The Surviving Sepsis Campaign published in 2016 and updated in 2018 recommend
immediate fluid resuscitation in patients with sepsis and septic shock. Like the SSC, the task
force recognizes sepsis and septic shock as life-threatening conditions, hence the strength
of our recommendation. Fluid resuscitation is crucial to improve tissue perfusion while
pursuing source control and diagnostic evaluation. We make no recommendation regarding
the timing of fluid resuscitation so as not to misconstrue that fluid loading may be delayed
until a particular cut-off period. Doing so would impose serious risks especially among
48
patients with hypotension and signs of hypoperfusion. Until better evidence on a window
period or threshold for fluid initiation is available, the dose-response effect will serve as the
basis for recommending immediate fluid resuscitation in patients with sepsis and septic
shock.
References
2. Leisman D, Wie B, Doerfler M, Bianculli A, Ward MF, Akerman M, D’angelo JK, D’amore JA. Association of fluid
resuscitation initiation within 30 minutes of severe sepsis and septic shock recognition with reduced
mortality and length of stay. Annals of emergency medicine. 2016 Sep 1;68(3):298-311
3. Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Intensive care medicine.
2018 Jun 1;44(6):925-8.
Question 11. In patients with sepsis or septic shock, should we give 30ml/kg intravenous fluid
bolus for initial fluid resuscitation?
Recommendation
We suggest initial resuscitation of 30ml/kg of intravenous fluids to patients with sepsis-induced

hypoperfusion (conditional recommendation, low quality of evidence).
Remark: Patients with sepsis-induced hypoperfusion include those who are hypotensive or have lactate levels of
>4mmol/L.
Summary of Evidence
The 2016 Surviving Sepsis Campaign (SSC) Guidelines and its 2018 update continue
to recommend administration of at least 30ml/kg of intravenous crystalloids to patients
with sepsis-induced hypoperfusion despite absence of moderate to high quality evidence. 1,2
The SSC recommendation was based on a large prospective observational study (n=
29,470) showing lower mortality (OR 0.79, 95%CI 0.73, 0.85) with compliance to a sepsis
resuscitation bundle that included the 30ml/kg intravenous fluid bolus. 3 Additional data
from 17 observational studies (n=15,662) also revealed similar reductions in mortality (OR
0.78, 95%CI 0.71, 0.85) with compliance to a sepsis resuscitation bundle. 4 In these studies,
however, several confounders were identified including early antibiotic administration and
use of adjunctive aids in the intervention group. They were unable to adjust survival
49
estimates based on these factors; hence the overall quality of evidence was deemed to be
low.
Apart from the evidence cited above, there are no studies that looked into the
volume element of the sepsis resuscitation bundle. Furthermore, there is also limited
evidence on the efficacy of giving intravenous fluid bolus to those who do not have sepsis-
induced hypoperfusion. Patients with sepsis-induced hypoperfusion include those
presenting with hypotension or lactate ≥4mmol/L.
The SSC recommendation of 30ml/kg intravenous fluid bolus for initial resuscitation
was adopted in our recommendation in recognition of its established precedence, in the
context of the sepsis bundle, and in improving mortality among patients with sepsis and
septic shock. Notwithstanding this, the absence of high- or even moderate-quality evidence
supporting this fluid volume acknowledges the clinician’s judgment and decision of the risk
and benefit per individual patient. Figure 3 shows the clinical algorithm for the
identification and initial fluid management of patients with sepsis-induced hypoperfusion
incorporating the 30ml/kg intravenous bolus of crystalloid.
References
ME, Rochwerg B. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock:
2016. Intensive care medicine. 2017 Mar 1;43(3):304-77.
2. Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Intensive care medicine. 2018
Jun 1;44(6):925-8.
3. Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R, Osborn T, Lemeshow S, Chiche JD, Artigas A,
Dellinger RP. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year
study. Intensive care medicine. 2014 Nov 1;40(11):1623-33.
4. Pepper DJ, Jaswal D, Sun J, Welsh J, Natanson C, Eichacker PQ. Evidence underpinning the centers for Medicare &
Medicaid services' severe sepsis and septic shock management bundle (sep-1): a systematic review. Annals of
internal medicine. 2018 Apr 17;168(8):558-68.
50
Question 12. In patients with sepsis or septic shock, should we limit the volume of intravenous
fluids?
Recommendation
We suggest not exceeding five (5) liters of total intravenous fluid volume in the first 24 hours of
resuscitation (conditional recommendation, moderate quality evidence).
Remark: Further fluid administration should be guided by hemodynamic targets, lactate levels, and repeated assessments of
fluid responsiveness. Nonetheless, other measures to improve targets should be sought if total fluid volumes approach five (5)
liters given the incremental increase in mortality associated per liter of fluid beyond five (5).
Summary of Evidence
Studies on fluid volumes are limited and often do not define a specific amount or cut
off of fluid for initial resuscitation. The best available evidence comes from a large
retrospective study which included 23,513 patients. Results showed incremental increase
in mortality of 2.3% per liter of fluid in excess of 5 liters given within the first day of
admission even after adjusting for illness severity (Supplementary Material 2, Figure
sQ12.1).1 On the other hand, low volume resuscitation (1 to 4.99L) exhibited small
reduction in mortality of 0.7% per liter (-1.0 to -0.4). Patients who were mechanically
ventilated had over
resuscitation signal for harm, while those with shock but not mechanically ventilated had
harm signals for both under- and over-resuscitation (Supplementary Material 2, Figure
sQ12.2).
This recommendation is in consideration of the harm associated with

overyhydration especially in patients who are mechanically ventilated. Clinicians should be
guided by repeated assessment of fluid responsiveness before additional fluids are
administered. Early vasopressor therapy should be considered for fluid unresponsive
patients.
Reference
1. Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic
shock, patterns and outcomes: an analysis of a large national database. Intensive care medicine. 2017 May
1;43(5):625-32.
51
Question 13. In patients with sepsis or septic shock, should deresuscitation be performed after
hemodynamic stabilization?
Recommendation
We recommend deresuscitation by preventing positive cumulative fluid balance after

stabilization of patients with sepsis or septic shock (strong recommendation, moderate quality
evidence).
Remarks: Fluid administration to improve end-organ perfusion is still recommended using hemodynamic targets. Limiting fluid
administration to prevent positive fluid balance and attempting to achieve negative fluid balance once the patient is stabilized
prevents adverse events and improves patient outcomes.
Summary of Evidence
An international, multicenter, observational cohort that included 1,808 patients with

sepsis demonstrated increased mortality with greater cumulative fluid balance at day 3
after adjustment for possible confounders (Supplementary Material 2, Figure sQ13.1). 2 The
investigators noted that the cumulative fluid intake was similar at 24 hours, 3 days, and 7
days, and that the lower cumulative fluid balance observed among survivors was due to
greater fluid output. Given the retrospective nature of the analysis, they were not able to
determine whether limiting fluids or enforcing diuresis would be the most appropriate
approach to achieve a lower cumulative fluid balance.
In a meta-analysis that included 2,051 patients with acute respiratory distress

syndrome (ARDS), sepsis and SIRS in the post-resuscitation phase of critical illness, a trend
toward lower mortality (OR 0.86, 95%CI 0.62, 1.17) and renal replacement therapy (OR
0.88, 95%CI 0.64, 1.22) was observed with conservative and deresuscitative fluid strategy. 3
Conservative and deresuscitative strategy also resulted to greater ventilator-free days
(mean difference [MD] 1.82 days higher, 95%CI 0.53 to 3.1 days higher), shorter ICU stay
(MD 1.88 days lower , 95%CI 0.12 to 3.64 lower), and better post-ICU cognitive function
(MD 10.71 points higher, 95%CI 5.22 to 16.22 point higher QLQ-C30 cognitive domain).
References
1. Hoste EA, Maitland K, Brudney CS, Mehta R, Vincent JL, Yates D, Kellum JA, Mythen MG, Shaw AD. Four phases of
intravenous fluid therapy: a conceptual model. British journal of anaesthesia. 2014 Sep 9;113(5):740-7.
2. Sakr Y, Rubatto Birri PN, Kotfis K, Nanchal R, Shah B, Kluge S, Schroeder ME, Marshall JC, Vincent JL. Higher fluid
balance increases the risk of death from sepsis: results from a large international audit. Critical care medicine.
2017 Mar 1;45(3):386-94.
52
3. Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, Blackwood B, Fan E. Conservative fluid
management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the
resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive care medicine. 2017
Feb 1;43(2):155-70.
Question 14. In patients with sepsis and septic shock, should we use dynamic parameters versus
static parameters to predict fluid responsiveness?
Recommendations
Following initial fluid resuscitation, we suggest assessment of fluid responsiveness using
dynamic variables over static variables before administration of additional fluids (weak
recommendation, moderate quality of evidence).
We suggest against the use of central venous pressure (CVP) to assess fluid responsiveness
(conditional recommendation, moderate quality of evidence).
We recommend the use of non-invasive cardiac output monitor such as ultrasound or

echocardiogram coupled with passive leg raise for assessing fluid responsiveness whenever
possible (weak recommendation, moderate quality of evidence).
We recommend an individualized approach to the integration of various modalities and

maneuvers to assess fluid responsiveness (best practice statement).
Summary of Evidence
For patients who remain hypotensive despite initial fluid resuscitation, the decision
to give additional fluids is not always easy. Only about half of hemodynamically unstable
patients respond to further fluid administration. 1 In some cases, overzealous hydration can
lead to pulmonary edema, worsen heart failure and increase the risk of death. Thus, it is
crucial to identify patients who will likely benefit from fluid administration.
For years, static measurements of preload have been relied on to predict fluid
responsiveness. Static variables take “snapshot” estimations of preload, with measurements
of central venous pressure (CVP) being the most common. A systematic review and meta
analysis that included 23 studies and 1148 patient data sets showed that the predictive
value of CVP was similar across different cut-off values.2 CVP is an invasive method of
assessing preload and should not be used in predicting responsiveness to fluid loading
when more accurate indices of fluid responsiveness are available.
53
Dynamic variables are proven to be accurate predictors of fluid responsiveness. In

order to assess fluid responsiveness, maneuvers that increase preload are combined with
measurements of variation in cardiac output. Commonly utilized indices of cardiac output
are stroke volume and pulse pressure, and their variations with certain maneuvers and
situations. Stroke volume variation (SVV) is the natural stroke volume increase during
inspiration and decrease during expiration, induced by changes in the intrathoracic
pressure resulting from mechanical ventilation. Pulse pressure is the difference between
systolic and diastolic blood pressure. Pulse pressure variation (PPV) is the calculated
difference between pulse pressures during the respiratory cycle. A systematic review of 29
diagnostic accuracy studies (n=685) show high diagnostic accuracies for both SVV
(Sensitivity 0.82, 95% CI 0.75 to 0.98, Specificity 0.86, 95% CI: 0.77 to 0.92) and PPV
(Sensitivity 0.89, 95%CI 0.82 to 0.94, Specificity 0.88, 95% CI 0.81 to 0.92). The diagnostic
threshold for both SVV and PPV is ≥12%. 3 PPV values between 9% and 13% are considered
by some to be “gray zone values” and may be less conclusive. 4 Beyond this range, PPV more
accurately delineates between fluid responsiveness and unresponsiveness with an AUROC
>0.90. PPV and SVV can be measured using peripheral arterial pressure waveforms or
pulse contour analysis that are obtained through an arterial catheter or calibrated
noninvasive cardiac output monitoring devices. Alternatively, SVV can be measured
centrally by echocardiography.
Given the physiologic basis of SVV and PPV measurements, they are deemed
unreliable in spontaneously breathing patients, ventilated patients with low tidal volume,
and patients with cardiac arrhythmias. However, certain maneuvers that increase preload
have been shown to override these limitations, allowing their use in conjunction with SVV,
PPV, and other measures of cardiac output. These maneuvers include passive leg raise
(PLR), mini- fluid challenge, end-expiratory occlusive test, and tidal volume challenge. The
evidence is more extensive for PLR, while evidence for the rest came from small
observational studies.
Passive leg raise coupled with monitoring of change in flow or pressure variables
have high sensitivity and specificity for predicting fluid responsiveness. A meta-analysis
that included 23 studies with 1,013 critically-ill patients demonstrated PLR sensitivity and
specificity for predicting fluid responsiveness of 0.86 (95% CI 0.79, 0.92) and 0.92 (95% CI
0.88, 0.96), respectively.5 Majority of the patients included were diagnosed with sepsis and
septic shock. The heterogeneity (I2=50.2%) observed was attributed to differences in the
technique utilized for measuring cardiac output. PLR-induced changes in pulse pressure (Sn
0.58%, 95% CI, 0.44 to 0.71, Sp 0.83, 95% CI 0.68 to 0.92) exhibited lower diagnostic
performance compared to PLR-induced changes in flow variables (Sn 0.85, 95% CI 0.78 to
0.90, Sp 0.92, 95% CI 0.87 to 0.94). 5 PPV is said to poorly reflect stroke volume during
sepsis because of increased arterial compliance. 6 Stimulation of arterial baroreceptors -
through pain, for instance - can also increase pulse pressure, thus inaccurately reflecting
stroke volume. Different techniques used to measure flow variables exhibit comparable
sensitivities and specificities, as shown in Table Q12.1. Subgroup analysis showed similar
54
diagnostic performance when PLR was used in both spontaneously- breathing and
mechanically-ventilated patient scenarios (p 0.10), with starting position of supine versus
semi-recumbent (p 0.33), and use of either crystalloid or colloid (p 0.36).
Table Q14.1. Diagnostic Accuracy of Passive Leg Raise combined with different Primary
Measurement Techniques measuring Flow Variables.

From Cherpanath TG, Hirsch A, Geerts BF, Lagrand WK, Leeflang MM, Schultz MJ, Groeneveld AB. Predicting fluid
responsiveness by passive leg raising: a systematic review and meta-analysis of 23 clinical trials. Critical care
medicine. 2016 May 1;44(5):981-91.
PLR is performed by elevating the lower limbs to 45 degrees for two minutes, while
placing the patient in the supine position to mobilize blood from the lower body and create
sufficient venous return to increase preload. Measurements of cardiac output are taken at
baseline and after PLR. The use of hospital beds equipped with the ability to raise the legs
are preferred since manual stimulation may result to increased sympathetic tone and result
to false readings. The thorax should be kept in the horizontal position, and not lower, to
prevent gastric fluid aspiration. Of the primary measurement techniques used to measure
cardiac output, ultrasound is a readily-accessible, and the least invasive, tool to the clinician
in various settings (ED, ICU, ward). The limitation lies in that ultrasonography is operator
dependent, requires some level of technical training, and may be limited by poor acoustic
window brought about by obesity, high positive end-expiratory pressure (PEEP), high tidal
volume, and others. Nonetheless, technique is very important when using ultrasound, and
pressure transducers should be kept at heart level during the PLR maneuver.
PLR has limitations and cannot be implemented in every clinical setting. It may be
difficult, painful, dangerous or impossible in some situations such as in patients with hip or
extensive lower leg surgery, amputated patients, patients in the prone position, some
patients who underwent gynecologic or urologic operations, and patients with increased
intracranial pressure.7,8 In such instances, other maneuvers or techniques may be more
applicable.
55
Small prospective observational studies have demonstrated the feasibility of mini

fluid challenge when assessing fluid responsiveness. Mini-fluid challenge involves rapid
infusion of 100ml of fluid with estimation of cardiac output before and after. A study that
included 49 patients with circulatory shock, mostly septic (94%), and on low tidal volume
ventilation revealed sensitivity of 0.86 (95% CI: 0.65 to 0.97) and specificity of 0.89 (95%
CI: 0.71 to 0.98) for SVV, and sensitivity 0.86 (95% CI: 0.64 to 0.96) and specificity of 0.85
(95% CI: 0.65 to 0.95) for PPV. 9 Accuracy was highest using a cutoff of 2% for both SVV and
PPV. Another study which included 39 patients measured subaortic velocity time index
(VTI) after mini-fluid challenge.10 Transthoracic echocardiography (TTE) provided a
noninvasive assessment of VTI by pulse-waved Doppler on a 5-chamber apical view. An
increase of ≥10% in VTI has a sensitivity of 0.95 (95% CI: 0.87 to 0.99) and specificity of
0.78 (95% CI: 0.59 to 0.97) in predicting fluid responsiveness. The best cut off was 3% but
was found to be inferior to 10% in terms of interobserver variability.
In patients who are mechanically ventilated, an end-expiratory occlusion (EEO)

prevents the cyclic decrease in cardiac preload and acts as a fluid challenge. A study that
included 34 patients, 32 of whom had sepsis, assessed the diagnostic accuracy of EEO
combined with measurements of PPV and change in cardiac index. 11 Investigators employed
a 15-second EEO using the automatic device of the ventilator for measuring positive end
expiratory pressure. Measurements of cardiac output were taken before and at the last five
seconds of the EEO. Fluid responsiveness was predicted by a ≥5% increase in PPV,
demonstrating a sensitivity of 0.87 (95% CI: 0.66 to 0.97) and specificity of 1.00 (95% CI:
0.71 to 1.00), and by a ≥5% increase in cardiac index with a sensitivity of 0.91 (95% CI: 0.72
to 0.99) and specificity of 1.00 (95% CI: 0.72 to 1.00). Another study which included 50
patients - 20 of them with septic shock - evaluated the diagnostic accuracy of EEO with the
aid of echocardiography.12 An increase of >9% in subaortic VTI induced by EEO showed a
sensitivity of 0.93 (95% CI: 0.68 to 1.00), and specificity of 1.00 (95% CI: 0.78 to 1.00). An
increase of >4% in continuous pulse contour cardiac index had a sensitivity of 0.93 (95% CI:
0.68 to 1.00) and specificity of 1.00 (95% CI: 0.78 to 1.00) in predicting fluid
responsiveness.12 In this study, a 12-second EEO was employed.
The evidence on tidal volume challenge was from a single study that included 20
mechanically-ventilated patients on low tidal volume ventilation. Increasing the tidal
volume for one minute from 6 ml/kg to 8 ml/kg of predicted body weight demonstrated a
sensitivity of 94% and specificity of 100% for PPV, and sensitivity of 88% and specificity of
100% for SVV. The best cut off values for PPV and SVV were 3.5% and 2.5%, respectively. 13
In summary, the use of dynamic variables for assessing fluid responsiveness involve
maneuvers that increase preload, interpreted with concommitantly-measured variations in
cardiac output. Each maneuver has its limitations and may be more applicable to certain
patients than others. Therefore, an individualized approach to the integration of modalities
and maneuvers to assess fluid responsiveness is recommended to guide fluid resuscitation
56
in patients with sepsis. Current recommendations were similar to the Surviving Sepsis
Campaign published in 2016.14 We provided a clinical algorithm (Figure 4) to guide
clinicians on the techniques, modalities and threshold used in assessing fluid
responsiveness.7,8,15
Figure 4. Clinical Algorithm for the Assessment of Fluid Responsiveness
References
1. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable
patient respond to a bolus of intravenous fluids?. JAMA. 2016 Sep 27;316(12):1298-309.
2. Eskesen TG, Wetterslev M, Perner A. Systematic review including re-analyses of 1148 individual data sets of
central venous pressure as a predictor of fluid responsiveness. Intensive care medicine. 2016 Mar
1;42(3):324-32.
3. Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in arterial waveform derived variables and fluid
responsiveness in mechanically ventilated patients: a systematic review of the literature. Critical care
medicine. 2009 Sep 1;37(9):2642-7.
4. Cannesson M, Le Manach Y, Hofer CK, Goarin JP, Lehot JJ, Vallet B, Tavernier B. Assessing the Diagnostic Accuracy
of Pulse Pressure Variations for the Prediction of Fluid ResponsivenessA “Gray Zone” Approach. Anesthesiology:
The Journal of the American Society of Anesthesiologists. 2011 Aug 1;115(2):231-41.
57
5. Cherpanath TG, Hirsch A, Geerts BF, Lagrand WK, Leeflang MM, Schultz MJ, Groeneveld AB. Predicting fluid
responsiveness by passive leg raising: a systematic review and meta-analysis of 23 clinical trials. Critical
care medicine. 2016 May 1;44(5):981-91.
6. Monge García MI, Guijo Gonzá lez P, Gracia Romero M, et al.: Effects of fluid administration on arterial load in
septic shock patients. Intensive Care Med 2015; 41:1247–1255
7. Monnet X, Marik PE, Teboul JL. Prediction of fluid responsiveness: an update. Annals of intensive care. 2016
Dec 1;6(1):111.
8. Jalil BA, Cavallazzi R. Predicting fluid responsiveness: a review of literature and a guide for the clinician. The
American journal of emergency medicine. 2018 Nov 1;36(11):2093-102.
9. Mallat J, Meddour M, Durville E, Lemyze M, Pepy F, Temime J, Vangrunderbeeck N, Tronchon L, Thevenin D,
Tavernier B. Decrease in pulse pressure and stroke volume variations after mini-fluid challenge accurately
predicts fluid responsiveness. British journal of anaesthesia. 2015 Jul 6;115(3):449-56.
10. Muller L, Toumi M, Bousquet PJ, Riu-Poulenc B, Louart G, Candela D, et al. An increase in aortic blood flow after
an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study.
Anesthesiology. 2011;115:541–7
11. Monnet X, Osman D, Ridel C, Lamia B, Richard C, Teboul JL. Predicting volume responsiveness by using the
end-expiratory occlusion in mechanically ventilated intensive care unit patients. Critical care medicine.
2009 Mar 1;37(3):951-6.
12. Jozwiak M, Depret F, Teboul JL, Alphonsine JE, Lai C, Richard C, Monnet X. Predicting fluid responsiveness in
critically-ill patients by using combined end-expiratory and end-inspiratory occlusions with
echocardiography. Critical care medicine. 2017 Nov 1;45(11):e1131-8.
13. Myatra SN, Prabu NR, Divatia JV, Monnet X, Kulkarni AP, Teboul JL. The changes in pulse pressure variation or
stroke volume variation after a “tidal volume challenge” reliably predict fluid responsiveness during low tidal
volume ventilation. Critical care medicine. 2017 Mar 1;45(3):415-21.
15. Monnet X, Teboul JL. Assessment of fluid responsiveness: recent advances. Current opinion in critical care.
2018 Jun 1;24(3):190-5.4. Georges D, de Courson H, Lanchon R, Sesay M, Nouette-Gaulain K, Biais M. End-
expiratory occlusion maneuver to predict fluid responsiveness in the intensive care unit: an
echocardiographic study. Critical Care. 2018 Dec;22(1):32.
58
VASOACTIVE AGENTS
Question 15. In patients with septic shock requiring vasopressors, should we use norepinephrine
over other agents?
Recommendation
We recommend norepinephrine as a first–line agent in septic shock requiring vasopressors

(strong recommendation, high quality of evidence).
Summary of Evidence
In septic shock, when initial fluid resuscitation is insufficient to maintain a mean

arterial pressure (MAP) ≥ 65mmHg, vasopressor therapy is indicated. Norepinephrine is
recommended as the first-line vasopressor agent. The highest quality of evidence is given
by the systematic review done by Avni and colleagues which reviewed 32 studies, including
14 randomized controlled trials involving 3544 patients. 1 Results showed a relative risk of
0.89 (95% CI 0.81-0.98) corresponding to an absolute risk reduction of 11% and a number
needed-to-treat (NNT) of nine (9) to prevent one mortality. This supports an early report
by Vasu et al., where authors reviewed six randomized controlled trials involving 2043
participants. They compared norepinephrine with dopamine as first line agent in septic
shock unresponsive to initial fluid resuscitation. The study reported a pooled relative risk
of 0.91 (95% CI 0.83-0.99), with benefit favoring norepinephrine. 2
The use of epinephrine, vasopressin, or terlipressin in patients with septic shock did
not show improvement in 28-day mortality. Meta-analysis of randomized controlled trials
showed no significant mortality benefit with the use of epinephrine (RR 0.97, 95% CI 0.77-
1.21, I2=0%), vasopressin (RR 1.04, 95% CI 0.70-1.53, I2 = 0%), or terlipressin (RR 0.98,
95% CI 0.83-1.15) compared to norepinephrine as first-line vasopressor agent. 3 In terms of
major adverse events, epinephrine (RR 0.88, 95% CI 0.60-1.30, I2=38%) and vasopressin
(RR 0.47, 95% CI 0.18-1.18) showed no significant difference with norepinephrine as well.
Major adverse events for epinephrine and vasopressin included arrhythmias, acute
coronary events, acute mesenteric and limb ischemia, and acute cerebrovascular events.
Compared with terlipressin, norepinephrine showed significantly decreased adverse
events (RR 0.43, 95% CI 0.31-0.60, I 2 = 0%). Most commonly observed adverse events in
the use of terlipressin when as a first-line vasopressor included acute mesenteric and
digital ischemia.4
References
1. Anvi T, Lador A, Lev S, Leibovici L, Paul M, Grossman A. Vasopressor for the treatment of septic shock: Systematic
review and meta-analysis. PLoS One. 2015;10(8):e0129305.
2. Vasu T, Cavallazzi R, Hirani A, Kaplan G, Leibby B, Marik PE. Norepinephrine or dopamine for septic shock.
59
J Intensive Care Med. 2011;27(3):172-178.

3. Cheng L, Yan J, Han S, Chen Q, Chen M, Jiang H et al. Comparative efficacy of vasoactive medications in patients
with septic shock: A network meta-analysis of randomized controlled trials. Critical Care. 2019;23:168.
4. Liu ZM, Chen J, Kou Q, Lin Q, Huang X, Tang Z et al. Terlipressin versus norepinephrine as infusion in patients
with septic shock: A multicenter, randomized, double-blinded trial. Intensive Care Med. 2018;44(11):1816-
1825.
Question 16. In patients with septic shock requiring a second vasopressor, which agent should
be added to norepinephrine?
Recommendation
We recommend the use of vasopressin (titrated up to 0.03 U/min) as the second vasopressor of
choice on top of norepinephrine in patients with septic shock, with the intent of raising mean
arterial pressure to target or decreasing norepinephrine dosage (conditional recommendation,
low quality of evidence).
Summary of Evidence
Several studies have investigated the value of adding a second vasopressor to

norepinephrine for patients with septic shock. Three options can be considered:
vasopressin, terlipressin and dobutamine. Among these three vasopressors, we only found
literature that studied vasopressin and terlipressin as add-on to norepinephrine.
Norepinephrine plus vasopressin
A recent meta-analysis of 23 trials investigating the benefit of a second vasopressor

to norepinephrine failed to demonstrate the mortality benefit of vasopressin after filtering
out studies with high risk of bias. 1 Despite an overall RR estimate of 0.89 (95% CI, 0.82 to
0.97; RD, -0.04 [95% CI, -0.07 to 0.00]), mortality benefit was not observed when limited to
trials with low risk of bias, where the RR estimate was 0.96 (95% CI, 0.84 to 1.11). This
analysis is consistent with other trials and meta-analyses that have demonstrated no
mortality benefit from vasopressin in patients with septic shock. 2-5
In terms of the prespecified primary outcome of atrial fibrillation, the addition of

vasopressin resulted in lower rates of atrial fibrillation (RR 0.77, 95% CI 0.67-0.88). 1
However, the benefit was not observed for the secondary outcomes of requirement for
renal replacement therapy, rate of myocardial injury, stroke, ventricular arrhythmias, or
length of hospital stay.
60
Aside from mortality and arrhythmia mitigation, the reduction of pre-existing

norepinephrine dose is another outcome worthy of consideration when contemplating a
second vasopressor. The TERLIVAP trial in 2009 by Morelli and colleagues , however, failed
to demonstrate a reduction in norepinephrine doses despite the addition of vasopressin. 6
They surmise that the lack of reduction in norepinephrine requirements may potentially be
explained by the low dose infused in their present study (0.03 U/min). This theory seems to
be corroborated by Luckner and colleagues who reported that 0.067 U/min is more
effective in hemodynamic support and catecholamine reduction than 0.033 U/min. 7 And
although previous studies suggest that AVP infusion in septic shock should not exceed 0.04
U/min because of the potential risk of adverse effects, the observations noted above raise
the issue of effectiveness of 0.03 U/min vasopressin.8,9
Norepinephrine plus terlipressin

For patients with distributive shock from sepsis who are already on norepinephrine,
there was only one study that compared stand-alone norepinephrine versus
norepinephrine plus terlipressin.10 In addition to the fact that the study had a very small
sample size of 45, there was no benefit, but rather harm, seen with add-on terlipressin [RR
of 2.83, CI 1.12 to 7.18], on the seven-day survival rates or mortality outcomes.
Norepinephrine plus dobutamine
There were no studies comparing stand-alone norepinephrine and norepinephrine

plus dobutamine with respect to mortality benefit, as well as other clinical end points.
In essence, there is a lack of evidence to support the use of an add-on vasopressor to

norepinephrine with respect to mortality benefit. In real world practice, the decision to add
a second vasopressor to norepinephrine for adult patients with septic shock will have to
depend on mechanistic evidence in the absence of established mortality benefit based on
clinical trials. Despite lack of mortality benefit, the potential of add-on vasopressin to
improve mean arterial pressure and reduce norepinephrine requirement still makes it a
viable option in selected clinical situations, taking into consideration its availability and
accessibility in the local setting.
References
1. McIntyre WF., et al. Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone
With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta analysis. JAMA
2018;319: 1889
2. Nagendran M., et al. Comparative safety and efficacy of vasopressors for mortality in septic shock: A
network meta-analysis. J Intensive Care Soc 2016; 17:136.
3. Gamper G., et al. Vasopressors for hypotensive shock. Cochrane Database Syst Review 2016; 2:CD003709.
4. Nagendran M., et al. Vasopressin in septic shock: an individual patient data meta-analysis of randomised
controlled trials. Intensive Care Med 2019; 45:844.
61
5. Delmas, A, Marc Leone, et al. Clinical review: Vasopressin and terlipressin in septic shock patients:
Critical care 2004
6. Morelli A, Ertmer C, Rehberg S, et al. Continuous terlipressin versus vasopressin infusion in septic shock
(TERLIVAP): a randomized controlled ilot study. Critical Care 2009
7. Luckner G, Mayr V, Jochberger S et al. Comparison of two dose regimens of arginine vasopressin in
advanced vasodilatory shock. Crit Care Med 2007 Oct;35(10):2280-5.
8. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign:
international guidelines for management of severe sepsis and septic shock: 2008. Critical Care
Medicine 2008;36(1):296-327.
9. Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe
septic shock. Anesthesiology 2002;96:576-82.
10. Xiao X, Zhang J, Wang Y, Zhou J, Zhu Y, Jiang D, Liu L, Li T. Effects of terlipressin on patients with sepsis via
improving tissue blood flow. J Surg Res. 2016 Jan;200(1):274-82. doi: 10.1016/j.jss.2015.07.016. Epub 2015
Jul 14. PubMed PMID: 26253455.
11. Mü llner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors for shock. Cochrane
Database Syst Rev.
Question 17. In patients with septic shock and persistent hypoperfusion, should we use
dobutamine?
Recommendation
We suggest using dobutamine in patients with persistent hypoperfusion and low cardiac index
despite adequate fluid administration and the use of vasopressors (weak recommendation, low
quality of evidence).
Summary of Evidence
Current evidence supporting the use of dobutamine in septic shock was mainly
physiologic in nature characterized by improved hemodynamics and perfusion indices.
Importantly, inotropic therapy in septic shock is aimed at increasing oxygen delivery and
improved tissue perfusion. In this case, dobutamine is considered as the inotrope-of-choice
for patients with measured low cardiac index despite optimal left ventricular filling
pressure and adequate mean arterial pressure. 1 A randomized controlled trial comparing
dobutamine and epinephrine as add-on agent among patients with septic shock and
myocardial dysfunction showed that the 28-day mortality was similar between treatment
groups with a relative risk of 0.94 (95% CI 0.57-1.53). Complication rates were also
comparable with a relative risk of 0.70 (95% CI 0.31-1.59). The adverse events included in
the study were acute coronary syndrome, arrhythmia, cerebral stroke, and limb ischemia.
In terms of physiologic and hemodynamic standpoints, dobutamine infusion also resulted
in significantly better arterial pH and lower serum lactate compared to epinephrine. 2 To
date, no randomized
62
controlled trials had investigated the effects of dobutamine versus placebo in this
population.
References
1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International
guidelines for management of sepsis and septic shock. Intensive Care Med. 2017;43(3):304- 377.
2. Mahmoud K and Ammar A. Norepinephrine supplemented with dobutamine or epinephrine for the
cardiovascular support of patients with septic shock. Indian J Crit Care Med. 2012;16(2):75-80.
HEMODYNAMIC MONITORING
Question 18: In patients with septic shock requiring vasopressors, should we target a mean
arterial pressure (MAP) of at least 65mmHg versus higher MAP?
Recommendations
We recommend a target MAP of at least 65 mmHg in patients with septic shock (strong
recommendation, moderate quality of evidence ).
We suggest targeting a higher MAP of 75mmHg to 85mmHg for patients with septic shock and
preexisting hypertension (weak recommendation, low quality of evidence).
Summary of Evidence
Septic shock is often associated with multiple organ failure, mainly respiratory and
renal in nature. Early and adequate hemodynamic support is crucial to prevent further
worsening of organ dysfunction. As the severity of each of these disorders is variable from
patient to patient, it is important to assess the degree of each component of the
hemodynamic failure in order to select the appropriate therapeutic measures. 1
The blood pressure level that should be targeted during the management of septic
shock is an important clinical issue. The mean arterial pressure (MAP) is one of the first
variables that is monitored in these patients. The Surviving Sepsis Guidelines recommend
that vasopressor therapy initially target a MAP of 65 mmHg (grade 1C recommendation),
but the actual value should be individualized. 2 The study of Asfar et al. showed that
targeting a MAP of 80 to 85 mmHg, as compared to 65 to 70 mmHg, in patients with shock
undergoing resuscitation, did not result in significant differences in mortality at either 28
or 90 days.3
63
However, targeting higher blood pressure may increase mortality in patients who have
been treated with vasopressors for more than six hours.4
Cecconi et al. suggest a higher MAP in septic patients with history of hypertension
and in patients who show clinical improvement with higher blood pressure. 5 A cohort study
by Lee and colleagues in 2019 showed that in patients with previously known high blood
pressure trends, targeting a MAP of 75-85mmHg improved survival, however, the mortality
risk starts to increase at MAP >85mmHg.6
References
1. Hamzaoui, O and Teboul, Jean – Louis. How do I Integrate Hemodynamic Variables when managing Septic
1Shock?. Korean J Crit Care Med 2016 (4): 265-275. Doi: org/10.4266/kjccm. 2016.00927.
2. Leone, M., Asfar, P., et al., Optimizing mean arterial pressure in Septic Shock: a critical reappraisal of the
literature. Critical Care (2015) 19:101. Doi 10.1186/s13054-015-0794-z.
3. Asfar, P., Meziani, F., et al., High vesus Low Blood – Pressure Target in Patients with Septic Shock. The New
England Journal of Medicine 2014; 370: 1583-93.
4. Lamontagne, F., Day, A., et al., Pooled analysis of higher versus lower blood pressure targets for vasopressor
therapy septic and vasodilatory shock. Intensive Care Med (2017). DOI: 10.1007/s00134- 017-5016-5.
5. Cecconi, M, Back, D et al., Consensus in Circulatory Shock and Hemodynamic Monitoring. Task Force of the
European Society of Intensive Care Medicine. 2014,. 40:1795 – 1815.
6. Lee SM, An WS. New clinical criteria for septic shock: serum lactate level as new emerging vital sign. J
Thoracic Dis 2016; 8(7): 1388-1390. Doi: 10.21037/jtd.2016.05.55.
Question 19. Should we aim for normalization of lactate levels during resuscitation of patients
with sepsis?
Recommendation
We suggest the use of lactate as guide to hemodynamic resuscitation, with the goal of
normalizing serum lactate levels (weak recommendation, moderate quality of evidence)
Summary of evidence
The Surviving Sepsis Campaign proposes to guide hemodynamic resuscitation by

measuring blood lactate levels, considering the strong relationship between
hyperlactatemia, lactate kinetics, and mortality.1-3 However, persistent hyperlactatemia
may be related to causes other than tissue hypoperfusion. 4 Moreover, lactate kinetics is
relatively slow even in survivors,3,5 and measurements of lactate levels are not universally
64
available, especially in resource-poor areas. Despite this, lactate-guided therapy (LGT) is

recommended since high lactate levels among septic patients are associated with higher
risk of organ failure and mortality.2
In a recent systematic review comprised of seven randomized controlled trials (n=

1,301 patients), the effects of LGT versus ScvO2-guided therapy on in-hospital mortality
among septic patients was evaluated.6 LGT was found to produce significantly better in
hospital survival rates (RR 0.68, 95% CI 0.56 to 0.82; P < .00001; fixed- effect model) with
no significant heterogeneity between studies (x 2 = 2.87, degrees of freedom [df] = 7, P = .90,
I2 = 0%). Lactate guidance also resulted to shorter ICU stay (mean difference [MD]-1.64
days, 95% CI -3.23 to -0.05), shorter mechanical ventilation time (MD -10.22 hours, 95% CI
-15.94 to -4.5), and lower APACHE II scores (MD -4.47, 95% CI -7.25 to -1.69), but no
difference in total length of hospital stay and SOFA scores. In another meta-analysis that
included six randomized controlled trials (n=917 patients), the effectiveness of LGT was
compared to early goal-directed therapy (EGDT). 7 In these RCTs there was no
heterogeneity, and EGDT was shown to be associated with higher mortality (RR 1.42,
95%CI 1.19 to 1.70). Use of red-cell transfusion, vasopressor infusion, dobutamine
infusion, and mechanical ventilation did not differ between LGT and EGDT. The optimal or
desired rate of lactate clearance is still open to debate, with most studies aiming for
normalization of lactate levels or a decline of at least 10% in six hours. To achieve this goal,
hemodynamic resuscitation using intravenous fluids, vasopressors and inodilators were
usually employed.
In a systematic review of eight observational studies (n= 3,063 patients), the

effectiveness of point-of-care lactate (POCL) was investigated. 8 Six studies focused on
patients with sepsis or septic shock. Four studies evaluated mortality, and found a pooled
odds ratio of 0.419 (95 CI, 0.268-0.654). 9-12 Turn-around time was also shortened with the
use of POCL compared to laboratory lactate testing, from a median of 122 minutes to 34
minutes.11 Time to treatment was also reduced with POCL testing. Time to receive
intravenous fluids was reduced from a median time of 71 minutes to 55 minutes. 13 More
patients (25% versus 15%) also received antibiotics within an hour of admission. 14 As these
studies were observational, the utility of POCL testing should be investigated further in
controlled clinical trials.
In the Philippines, not all centers have access to lactate determination. Interestingly,
a recently concluded multicenter randomized controlled trial (The ANDROMEDA-SHOCK
trial) that included 424 patients compared resuscitation strategies targeting normalization
of capillary refill time (CRT) versus normalization of serum lactate levels among patients
with septic shock.15 In the study, CRT was measured by applying firm pressure to the
ventral surface of the right index finger distal phalanx with a glass microscope slide. The
pressure was increased until the skin was blank, and then maintained for 10 seconds. The
time for return of the normal skin color was registered with a chronometer, and a refill
time greater than three (3) seconds was defined as abnormal. Mortality at 28 and 90 days
did not differ between the two resuscitation strategies with hazard ratio of 0.75 (95% CI
0.55, 1.02) and 0.82 (95% CI 0.61, 1.09), respectively. There was a trend towards benefit
with normalization of peripheral perfusion targets. At 72 hours, patients in the peripheral
perfusion group had less organ dysfunction with mean difference in SOFA score of -1.00
(95%CI -1.97 to -0.02).
65
There were no differences in mechanical ventilator-free days, renal replacement-free days,

vasopressor-free days, ICU length of stay, and hospital length of stay. This is the first study
that looked into peripheral perfusion targets and further trials should be conducted to
affirm the usefulness of CRT as a viable goal for hemodynamic monitoring. In centers
without access to lactate tests, targeting normal CRT provides a feasible and inexpensive
alternative to lactate monitoring.
References
1. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a
multicenter, open-label, randomized controlled trial. American journal of respiratory and critical care medicine
2010; 182(6): 752-61.
2. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 Update. Critical care medicine 2018;
46(6): 997-1000.
3. Vincent JL, Quintairos ESA, Couto L, Jr., Taccone FS. The value of blood lactate kinetics in critically-ill patients: a
systematic review. Critical care (London, England) 2016; 20(1): 257.
4. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Critical care (London, England) 2014;
18(5): 503.
5. Hernandez G, Luengo C, Bruhn A, et al. When to stop septic shock resuscitation: clues from a dynamic perfusion
monitoring. Annals of intensive care 2014; 4: 30.
6. Pan J, Peng M, Liao C, Hu X, Wang A, Li X. Relative efficacy and safety of early lactate clearance-guided therapy
resuscitation in patients with sepsis: A meta-analysis. Medicine 2019; 98(8): e14453.
7. Ding XF, Yang ZY, Xu ZT, Li LF, Yuan B, Guo LN, Wang LX, Zhu X, Sun TW. Early goal-directed and lactate guided
therapy in adult patients with severe sepsis and septic shock: a meta-analysis of randomized controlled trials.
Journal of translational medicine. 2018 Dec;16(1):331.
8. Morris E, McCartney D, Lasserson D, Van den Bruel A, Fisher R, Hayward G. Point-of-care lactate testing for sepsis
at presentation to health care: a systematic review of patient outcomes. The British journal of general practice :
the journal of the Royal College of General Practitioners 2017; 67(665): e859-e70.
9. Larsen GY, Mecham N, Greenberg R. An emergency department septic shock protocol and care guideline for
children initiated at triage. Pediatrics 2011; 127(6): e1585-92.
10. Mullen M, Cerri G, Murray R, et al. Use of point-of-care lactate in the prehospital aeromedical environment.
Prehospital and disaster medicine 2014; 29(2): 200-3.
11. Singer AJ, Taylor M, LeBlanc D, Williams J, Thode HC, Jr. ED bedside point-of-care lactate in patients with
suspected sepsis is associated with reduced time to iv fluids and mortality. The American journal of emergency
medicine 2014; 32(9): 1120-4.
12. Varpula M, Karlsson S, Parviainen I, Ruokonen E, Pettila V. Community-acquired septic shock: early
management and outcome in a nationwide study in Finland. Acta anaesthesiologica Scandinavica 2007;
51(10): 1320-6.
13. Smith S, Russi CS, Kashyap R, et al. Point-of-care lactate measurement in an emergency department is
associated with expedited early goal-directed management of severe sepsis and septic shock. [Conference
abstract]. Am J Respir Crit Care Med 2010; 181: A6141. http://www.atsjournals.org/
doi/pdf/10.1164/ajrccm-conference.2010.181.1_MeetingAbstracts.A6141
14. Maung LH, Ng XH, Ong ZY, See KC. Early lactate measurement triggers early treatment and improves outcomes
in critically-ill patients. [Conference abstract]. Ann Acad Med Singapore 2014; 1: S327.
http://www.annals.edu.sg/ pdf/43VolNo9Sep2014/SHBC2014_Final.pdf
66
15. Herná ndez G, Ospina-Tascó n GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegría L,
Teboul JL, Cecconi M. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate
levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical
trial. JAMA. 2019 Feb 19;321(7):654-64.
Question 20. Can we use base excess (as surrogate) to diagnose hyperlactatemia?
Recommendation
An initial base excess value <(-3) is moderately predictive of hyperlactatemia (>4mmol/L), and
should prompt immediate fluid resuscitation (weak recommendation, low quality of evidence).
Summary of Evidence
Lactate has been used a biomarker of the shock state, which entails immediate fluid
resuscitation. Since serum lactate tests are not readily available in all centers in the
Philippines, options to estimate lactate levels have been explored. According to Pogmanee
and Vattanavanit, lactate and anion gap showed a strong correlation with each other. 1
Lactate and base excess showed a moderate correlation, and each may possibly be used
interchangeably to help determine septic shock severity in patients. This is supported by a
study by Montassier and colleagues, which showed that base excess levels may predict
elevated lactate levels among septic patients in the emergency department. 2 This suggests
the availability of a quick marker in assessing the severity of hypoperfusion.
References
1. Pongmanee, W.,et al. Can base excess and anion gap predict lactate level in diagnosis of septic shock? . Open
Access Emergency Medicine; 2018.
2. Montassier E, Batard E,et. al.. Base excess is an accurate predictor of elevated lactate in ED septic patients.
American Journal of Emergency Medicine; 2012.
3. Chawla, L.S.,Shih,S.,Davison,D.L.,Junker,C.D.,& Seneff,M.G.. Anion gap, anion gap corrected for albumin, base
deficit and unmeasured anions in critically-ill patients: implications on the assessment of metabolic acidosis
and the diagnosis of hyperlactatemia. BMC Emergency Medicine; 2008.
67
Question 21. Should we use base excess to monitor fluid resuscitation?
Recommendation
Base excess may be used to monitor fluid resuscitation by targeting an improvement or

increase from baseline (weak recommendation, low quality of evidence).
Summary of Evidence
There is existing evidence - though from small studies - regarding the value of
targeting improvement in base excess levels. These studies report a trend towards survival
among patients with sepsis and septic shock. Single center studies by Palma and colleagues
as well as Park and colleagues showed that targeting improvement in base excess from
baseline measurements revealed lower mortality rates compared to septic patients who
were noted to have further decreases in base excess levels. 1,2 This same observation was
noted by Smith and colleagues in another single center but with a larger sample size. 3 It was
noted that 15 of 85 patients died after an increase in base excess levels from admission
while 36 of 63 patients died after having lower base excess levels compared to baseline.
References
1. Palma, L.,Ferreira,G.,Amaral,A.,Brauer,L.,Azevedo,L.,& Park,M.. Acidosis and mortality in severe sepsis and septic
shock evaluated by base excess variation. . Critical Care; 2003.
2. Park M, Noritomi D,Maciel,A,Azevedo LC,Pizzo V,& Cruz-Neto,L.. Partitioning evolutive standard base excess
determinants in septic shock patients. . Revista Brasileira De Terapia Intensiva; 2007.
3. Smith I, Kumar P,Molloy S,Rhodes A,Newman P,Grounds R,& Bennett,E.. Base excess and lactate as
prognostic indicators for patients admitted to intensive care. . Intensive care medicine; 2001.
4. Min Ho Seo, Minhong Choa,Je Sung You,Hye Sun Lee,Jung Hwa Hong,Yoo Seok Park,Sung Phil Chung,and
Incheol Park. Hypoalbuminemia, Low Base Excess Values, and Tachypnea Predict 28-Day Mortality in Severe
Sepsis and Septic Shock Patients in the Emergency Department. Yonsei Med J; 2016.
5. Noritomi DT, Soriano FG,et. al.. Metabolic acidosis in patients with severe sepsis and septic shock: A
longitudinal quantitative study. Crit Care Med; 2009.
6. Diao MY, Wang T,Cui Y,Lin Z. Prognostic value of arterial lactate content combined with base excess in
patients with sepsis: a retrospective study. Chin Crit Care Med; 2013
68
Question 22: In patients with sepsis or septic shock, should low venoarterial CO2 gap be used as
a goal for resuscitation?
Recommendation
We suggest using venoarterial carbon dioxide gap as adjunct to serum lactate to monitor
response to fluid resuscitation (weak recommendation, low quality of evidence).
Remarks: In order to measure venoarterial carbon dioxide gap, arterial and central venou s blood gas samples should be
taken. We do not recommend insertion of central venous catheters for the sole purpose of obtaining central venous
blood gas.
Summary of Evidence
The central venous-to-arterial tension difference is the gradient between the PCO 2 in
central venous blood and PCO2 in arterial blood. It has been directly linked to CO 2
production and inversely linked to cardiac output. 1 In the study of Mallat et al., it was
suggested that it can be used as a marker to identify under-resuscitated patients. 1 The
results of the study by Vallee et al. suggest that a gap or difference of > 6 mmHg has been
suggested to reflect insufficient blood flow to the tissues, even when the central venous
oxygenation (ScvO2) is greater than 70%.2
Multiple small studies, mostly from single centers, have consistently proposed that a
low CO2 gap was associated with a higher cardiac index, and a lower lactate level. These
studies have noted that patients with lower CO 2 gap levels – less than or equal to 6 mmHg –
from the consensus statement on circulatory shock and hemodynamic monitoring from the
European Society of Intensive Care Medicine - had higher survival rates compared to those
with higher CO2 gap levels.3
References
1. Mallat J, Lemyze M, Tronchon L, Vallet B, Thevenin D. (2016) Use of venous-to-arterial carbon dioxide
tension difference to guide resuscitation therapy in septic shock.
2. Vallee F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, Samii K, Fourcade O, Genestal M (2008) Central
venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock?
Intensive Care Med 34:2218–2225
3. Cecconi M, De Backer D, Antonelli M, et. al. (2014) Consensus on circulatory shock and hemodynamic
monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 40: 1795 -
1815
69
Question 23. In patients with sepsis or septic shock, should we use a pulmonary artery catheter
(PAC)?
Recommendation
The routine use of a pulmonary artery catheter alone for hemodynamic monitoring in patients
with sepsis and septic shock is not recommended (strong recommendation, moderate quality of
evidence).
The use of a pulmonary artery catheter may be reserved for the management of severe
multifactorial shock conditions, and to be used with other hemodynamic monitoring
parameters (weak recommendation, low quality of evidence).
Summary of Evidence
Sepsis is known to cause various presentations of mixed shock states that require
targeted hemodynamic monitoring. Hemodynamic monitoring allows for assessment of
important variables and the identification of the causes of hemodynamic instability - which
can then be targeted, treated and tracked.1
Among different available tools and equipment, the pulmonary artery catheter has
been used to manage patients with underlying cardiac conditions such as acute heart failure
and cardiogenic shock, and for monitoring during major cardiac surgeries. 2 It has also been
used for hemodynamic monitoring in the ICU especially for sepsis patients, who are at risk
of developing myocardial dysfunction as one of its severe complications. 1
Due to numerous large trials that have shown lack of mortality benefit with the use
of the PA catheter, its indications for use have been put to question. A meta-analysis
comparing the use versus non-use of a PA catheter among ICU patients revealed that there
was no significant difference in mortality between the group managed with a PA catheter
versus the group without PA catheter use. 2 As a result, the general use of PA catheter
declined. This was seen in the study of Koo and colleagues that included 15,006 patients,
showing more than 50% decrease in the use of the PA catheter over a five-year period. 3 The
extent and efficiency of PA catheter employment is affected by illness severity and greatly
by the skill of the intensive care unit and attending physician utilizing it as a monitoring
device.
It is worthy to note, however, that using the PA catheter with other tools or methods
of hemodynamic monitoring may provide benefit in patients with high-severity illness, such
as when blood volume analysis and PA catheter monitoring are performed together versus
PA catheter monitoring alone.4
The 2016 Surviving Sepsis Campaign Guidelines have strongly recommended against
the routine use of the pulmonary artery catheter for patients with sepsis-induced acute
respiratory distress syndrome (ARDS).5 There was no explicit recommendation on its use
70
as a means for hemodynamic monitoring, whether as a static or dynamic measure of

response to therapy.
References
1. Velissaris D., et. al. (2016). The Use of Pulmonary Artery Catheter in Sepsis Patients: Literature Review. J Clin
Med Res. 2016; 8(11): 769-776
2. Rajaram SS, Desai NK, Kalra A, Gajera M, Cavanaugh SK, Brampton W, Young D, Harvey S, Rowan K. (2013)
Pulmonary artery catheters for adult patients in intensive care. Cochrane Database Syst Rev. 2013 Feb 28;
(2):CD003408
3. Koo KKY, Sun JCJ, et. al. (2011) Pulmonary artery catheters: Evolving rates and reasons. Crit Care Med 2011;
39:1613–1618
4. Yu, M., et. al. (2011). A Prospective Randomized Trial Using Blood Volume Analysis in Addition to Pulmonary
Artery Catheter, Compared With Pulmonary Artery Catheter Alone, to Guide Shock Resuscitation in Critically Ill
Surgical Patients. Shock, 35(3), 220–228.
5. Rhodes A , Evans LE , Alhazzani W , Levy MM , Antonelli M , Ferrer R , Kumar A , Sevransky JE , Sprung CL ,
Nunnally ME ,et al. . Surviving Sepsis campaign: international guidelines for management of Sepsis and Septic
shock: 2016. Intensive Care Med 2017;43:304–77
ANTIMICROBIAL THERAPY
Question 24. In patients with sepsis or septic shock, should we use empiric broad-spectrum
antibiotic(s)?
Recommendation:
We recommend broad-spectrum antimicrobial therapy targeted to the site of infection based

on existing recommendations (strong recommendation, moderate quality of evidence).
Remark: The reader is directed to Question 25 and the accompanying table for the updated recommendations for
empiric antimicrobial therapy for the most common infections.
Summary of Evidence
On first recognition of sepsis or septic shock, a decision must be made regarding

empiric antimicrobial therapy. Because of the pervasive problem of rising antimicrobial
resistance, the need for empiric broad-spectrum antimicrobial therapy must always be
balanced with the need for antimicrobial stewardship. The choice of what antimicrobial
regimen to start on a septic patient has become increasingly difficult. In considering this
question about empirical therapy, we included studies on appropriate versus inappropriate
71
empiric therapy as a surrogate to answer the question of how broad an antimicrobial

regimen must be. There are two systematic reviews which synthesized the evidence and
were considered by the Consensus Panel for this recommendation.
The systematic review and meta-analysis of Paul et al. 1 provides the most robust
evidence in favor of giving broad-spectrum antimicrobials at the onset of treatment for
sepsis or septic shock. The review included 69 prospective cohort studies from 1965 to
2008, providing data from 21,338 adult patients with various infections. It is important to
note that not all patients in the individual studies have actual sepsis or septic shock and it
was not possible to extract data specific only to the septic patients. Despite this
heterogeneity in the pooled study population (I 2 = 79.7%), the adjusted multivariable
analysis of risk factors showed a two-fold increase in 30-day all-cause mortality when
inappropriate empiric therapy was given, compared to appropriate empiric therapy (OR
2.05, 95% CI 1.69-2.49, p<0.001). In maneuvers to explain the heterogeneity, the authors
further showed that none of the other clinical variables affected the results of the study
(study year and setting, patient’s age, bacteremia, source of infection, neutropenia, and
causative bacteria) except for septic shock, which resulted in higher ORs.
The systematic review and meta-analysis of Marquet et al. 2 investigated the
outcomes of inappropriate empiric antibiotics on hospital mortality, reviewing studies
published between 2004 to 2014. The review included data from 27 studies, covering
15,306 patients with “severe infections.” The meta-analysis showed that risk ratios for 30-
day mortality and in-hospital mortality were 0.71 (95% confidence interval 0.62 to 0.82)
and 0.67 (95% confidence interval 0.56 to 0.80), respectively. Heterogeneity was high in
this review as well (I2 = 86.6% for in-hospital mortality). Notably, the Marquet review
included the study by Kumar et al., 3 perhaps the largest single study on outcomes of
inappropriate empiric antibiotics in septic shock patients. The study was a multicenter,
multi-country, retrospective review of 5715 patients with septic shock from 1996-2005. It
demonstrated a 5-fold reduction in survival of patients who received inappropriate empiric
antibiotics (Survivalappropriate = 52%, Survivalinappropriate = 10.3%; adjusted OR 8.99, 95% CI
6.6-12.23, p<0.0001).
A question that arises from the data presented above is how “broad” broad-spectrum
regimens should be. The answer to this has important implications for antimicrobial
stewardship and the development of antimicrobial resistance. Certainly, a knowledge of the
most common pathogens associated with the suspected infection site plays the greatest role
in determining the best empiric regimen. Other factors to consider include whether the
infection is community-acquired or nosocomial in origin, the presence of shock, the
presence of devices, as well as patient age and other patient-related factors. Knowledge of
local antimicrobial susceptibility rates and whether multidrug-resistant organisms must be
considered are also important. If in doubt, an infectious disease specialist, in localities and
situations when one is available, should be consulted. In some centers where algorithms are
employed for managing patients with sepsis, an infectious disease consultation is
mandatory.
72
References
1. Paul, M. et al. (2010) ‘Systematic Review and Meta-Analysis of the Efficacy of Appropriate Empiric Antibiotic
Therapy for Sepsis▿ †’, Antimicrobial Agents and Chemotherapy, 54(11), pp. 4851–4863. doi:
10.1128/aac.00627-10 .
2. Marquet, K. et al.(2015) ‘Incidence and outcome of inappropriate in-hospital empiric antibiotics for severe
infection: a systematic review and meta-analysis’, Critical Care, 19(1), p. 63. doi: 10.1186/s13054-015- 0795-y
3. Kumar, Anand et al. (2009) ‘Initiation of Inappropriate Antimicrobial Therapy Results in a Fivefold Reduction of
Survival in Human Septic Shock’, Chest, 136(5), pp. 1237–1248. doi: 10.1378/chest.09-0087.
Question 25. In patients with sepsis or septic shock, should we use empiric combination
antimicrobial therapy versus monotherapy?
Recommendation
Among adults with septic shock, empiric combination therapy (i.e. the use of two antibiotics
from different mechanistic classes) is suggested over monotherapy (weak recommendation,
low quality of evidence).
Summary of Evidence
The prompt use of empiric antimicrobial therapy in patients with sepsis and septic
shock is a critical determinant of survival in this type of population. 1 The 2016 Surviving
Sepsis Campaign (SSC) guidelines on the management of sepsis and septic shock
recommended the use of empiric broad-spectrum therapy with one or more antimicrobials
(combination therapy) of different classes and mechanisms of action. 2 Multidrug therapy
tends to broaden the spectrum of therapy or potentially accelerate pathogen clearance. 2
Combination therapy, which is a form of multidrug therapy, tends to accelerate pathogen
clearance rather than broaden the antimicrobial coverage. Combination therapy also
inhibits bacterial toxin production and conveys assurance that the pathogen is sensitive to
at least one of the antibiotics given, in the face of the prevalent problem of microbial
resistance.2,3 The initiation of appropriate antimicrobial therapy - defined as having in-vitro
activity appropriate to the isolated pathogenic organisms or, if a pathogen was not isolated,
appropriate for the underlying clinical syndrome - has been associated with increased
survival in patients with septic shock.4 This has been the primary cornerstone of
recommending initial empiric combination therapy in serious life-threating infections. 5
However, several studies showed conflicting results regarding the use of empiric
combination therapy over monotherapy in septic patients. This unresolved issue is one of
the top six identified research priorities by the Surviving Sepsis Research Committee. 3
73
A retrospective, propensity-matched, multi-center, cohort study was done by Kumar

et al., which involved 4,662 adult ICU patients with culture-positive bacterial septic shock. 6
Combination therapy was associated with decreased 28-day mortality and significant
reductions in mortality in the ICU and in the hospital, compared to patients on
monotherapy. The authors also noted more ventilator-free days, more pressor-free days
and shorter length of hospital stay among patients given early empiric combination
therapy.
In contrast, other reports have shown no benefits in the use of combination therapy.
Paul et al. did a systematic review of 69 randomized and quasi-RCTs on β-lactam antibiotic
monotherapy vs β-lactam–aminoglycoside antibiotic combination therapy for sepsis. 7 All
cause mortality was similar among both monotherapy and combination therapy groups. A
subgroup analyses showed no difference in all-cause mortality. There was also no
difference in the treatment failure and adverse events, except for nephrotoxicity, between
both groups. Nephrotoxicity was found to be more common in the combination arm in
nearly all studies, with a highly significant combined risk ratio in favor of monotherapy (RR
0.30, 95% CI 0.23-
0.29). It is important to note that this study used β-lactam–aminoglycoside combination
and this adverse effect cannot be generalized in other combination antimicrobials with less
nephrotoxic risks. Hence a recommendation on the adverse events cannot be derived.
The conflicting results on the benefits of combination therapy in sepsis might be

explained by the heterogeneous nature and structural bias of the different studies. There is
also variation in the site and severity of infection and antibiotic treatment. It is important to
note at this point that most randomized studies are designed to assess noninferiority. Also,
these studies often do not compare the same antibiotic in monotherapy and in combination
with a second agent. Thus, synergy is difficult to assess rigorously in many individual
studies.5 More prospective, randomized studies are needed to evaluate the benefits of
empiric combination therapy in sepsis as suggested by the Surviving Sepsis Research
Committee.
In general, the decision to give empiric combination antibiotic therapy or

monotherapy should be individualized and based on the suspected site of infection, disease
severity, likely pathogen, renal function, and local/institutional microbiological and
resistance patterns.8,9 Current local and international guidelines provide the recommended
empiric combination therapy for a specific given focus of infection (Table Q25.1).
74
Table Q25.1. Recommended initial empiric antibiotic therapy for patients with sepsis and/or
septic shock.
Site of Guideline Recommendation
infection
Community (ATS/IDSA 2019) Without risk for MRSA or Pseudomonas aeruginosa:
acquired Diagnosis and Ampicillin + Sulbactam 1.5g-3g IV q6 OR Cefotaxime 1-2g IV q8
pneumonia, Treatment of OR Ceftriaxone 1-2g IV q24
severe Adults with
Community PLUS
Acquired Azithromycin dihydrate 500mg IV q24 OR Clarithromycin 500mg PO bid
Pneumonia10 OR Levofloxacin 750mg IV q24 OR Moxifloxacin 400mg IV q24
With risk for Pseudomonas aeruginosa:

Piperacillin-Tazobactam 4.5g IV q6 OR Cefepime 2g IV q8
OR Ceftazidime 2g IV q8 OR Aztreonam 2g IV q8
OR Meropenem 1g IV q8 OR Imipenem 500mg IV q6
PLUS
Azithromycin dihydrate 500mg IV q24 OR Clarithromycin 500mg PO bid
OR Levofloxacin 750mg IV q24 OR Moxifloxacin 400mg IV q24
With risk for MRSA, add:

Vancomycin 15mg/kg IV q12 OR Linezolid 600mg IV q12
All doses should be adjusted based on the patient’s renal function.
Risk factor for Pseudomonas infection: 11

1. History of chronic or prolonged (>7 days within the past month) use of broad
spectrum antibiotic therapy
2. With severe underlying bronchopulmonary disease
3. Malnutrition
4. Chronic use of steroid therapy >7.5mg/day
Hospital (ATS/IDSA 2016) Not at high risk of mortality but with factors increasing the likelihood of MRSA:
acquired Management of Ceftazidime or Cefepime 2g IV q8 OR Piperacillin-Tazobactam 4.5g IV q6
pneumonia Adults with OR Levofloxacin 750mg IV q24 OR Ciprofloxacin 400mg IV q8
Hospital- OR Aztreonam 2g IV q8 OR Imipenem 500mg IV q6 OR Meropenem 1g IV
acquired and q8
Ventilator
associated PLUS
Pneumonia: Vancomycin 15mg/kg IV q8-12 (consider a loading dose of 25-30mg/kg for
2016 Clinical severe illness) OR Linezolid 600mg IV q12
Practice
Guideline by the High risk of mortality or receipt of IV antibiotics during the prior 90 days:
Infectious Two of the following but avoid 2 β-lactams:
Disease Society Ceftazidime or Cefepime 2g IV q8 OR Piperacillin-Tazobactam 4.5g IV q6
of America and OR Levofloxacin 750mg IV q24 OR Ciprofloxacin 400mg IV q8
the American OR Aztreonam 2g IV q8 OR Imipenem 500mg IV q6
Thoracic OR Meropenem 1g IV q8 OR Amikacin 15-20mg/kg IV q24
Society12 OR Gentamicin 5-7mg/kg IV q24 OR Tobramycin 5-7mg/kg IV q24
PLUS
Vancomycin 15mg/kg IV q8-12 (consider a loading dose of 25-30mg/kg for
severe illness) OR Linezolid 600mg IV q12
75
High risk for mortality include need for ventilatory support due to pneumonia and septic
shock.
Ventilator (IDSA/ATS 2016) VAP in units where empiric MRSA coverage and double antipseudomonal/ gram
associated Management of negative coverage are appropriate:
pneumonia Adults with Vancomycin 15mg/kg IV q8-12 (consider a loading dose of 25-30mg/kg for
Hospital- severe illness) OR Linezolid 600mg IV q12
acquired and
Ventilator PLUS
associated Piperacillin-Tazobactam 4.5g IV q6 OR Cefepime or Ceftazidime 2g IV q8-12
Pneumonia: OR Imipenem 500mg IV q6 OR Meropenem 1g IV q8 OR Aztreonam 2g IV q8
2016 Clinical
Practice PLUS
Guideline by the Levofloxacin 750mg IV q24 OR Ciprofloxacin 400mg IV q8
Infectious OR Amikacin 15-20mg/kg IV q24 OR Gentamicin 5-7mg/kg IV q24
Disease Society OR Tobramycin 5-7mg/kg IV q24 (OR Colistin 5mg/kg IV loading dose
of America and followed by 2.5mg x (1.5 x CrCl + 30) IV q12 OR Polymyxin B 2.5-
the American 3mg/kg/day divided in 2 daily doses, after consulting an ID specialist)
Thoracic
Society12 All doses should be adjusted based on the patient’s renal function.
Intraabdomin Asian Severe community-acquired complicated intraabdominal infection: (Cefazolin

al infections Consensus OR Cefuroxime OR Ceftriaxone OR Ceftazidime OR Cefepime OR
Taskforce on Cefotaxime) PLUS Metronidazole
Complicated
Intra Abdominal OR
Infections Piperacillin-Tazobactam 4.5g IV q6
(ACT-cIAI) 201413
OR
(Levofloxacin OR Ciprofloxacin) PLUS Metronidazole
Severe healthcare-associated complicated intraabdominal infection:

(Meropenem OR Imipenem/Cilastatin OR Doripenem) with or without
Vancomycin OR Linezolid
OR
Tigecycline PLUS (Aztreonam OR Ciprofloxacin OR Levofloxacin)
OR
Carbapenem PLUS (Tigecycline OR Polymyxin B OR Colistin, after
consulting an ID specialist)
Severe skin (IDSA 2014) Severe Purulent SSTI

and soft Practice Vancomycin OR Linezolid
tissue Guidelines for
infection the Diagnosis Severe Nonpurulent SSTI (Necrotizing Infection/Cellulitis/Erysipelas)
and Management Vancomycin OR Linezolid
of Skin and Soft
Tissue Infections: PLUS
2014 Update by (Ceftriaxone PLUS Metronidazole) OR Piperacillin-Tazobactam
the Infectious OR Meropenem OR Imipenem
Diseases Society
of Severe purulent SSTI: patients who have failed incision and drainage plus oral
America14 antibiotics with signs of SIRS or those who are immunocompromised.
76
Severe nonpurulent SSTI: patients who have failed oral antibiotic treatment or those
with signs of SIRS, or those who are immunocompromised, or those with clinical signs
of deeper infection such as bullae, skin sloughing, hypotension, or evidence of organ
dysfunction.
Clindamycin should be administered as soon as possible to patients with necrotizing
fasciitis. 15
Sepsis/Septic National Piperacillin-Tazobactam 4.5g IV q 6 OR Meropenem 1g IV q8

shock, source Antibiotic
is unclear Guidelines PLUS
201716 Vancomycin 25-30mg/kg IV loading dose then 1g IV q8, if with substantial risk for
MRSA infection (The reader is directed to Question 23 on when to add MRSA
coverage).
References
1. Abad CL, Kumar A, Safdar N. Antimicrobial therapy of sepsis and septic shock – when are two drugs better than
one? Crit Care Clin 27 (2011) e1–e27. doi:10.1016/j.ccc.2010.12.001
2. Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock:
2016. Intensive Care Med (2017) 43:304–377. DOI 10.1007/s00134-017-4683-6
3. Coopersmith CM, et al. Surviving sepsis campaign: research priorities for sepsis and septic shock. Intensive Care
Med (2018) 44:1400–1426. https://doi.org/10.1007/s00134-018-5175-z
4. Kumar A, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in
human septic shock. CHEST 2009; 136:1237–1248
5. Vasquez-Grande G, Kumar A. Optimizing antimicrobial therapy of sepsis and septic shock: focus on antibiotic
combination therapy. Semin Respir Crit Care Med 2015;36:154–166. DOI 10.1055/s-0034- 1398742
6. Kumar A, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in
septic shock: a propensity-matched analysis. Crit Care Med 2010 Vol. 38, No. 9. DOI:
10.1097/CCM.0b013e3181eb3ccd
7. Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy vs beta lactam –
aminoglycoside antibiotic combination therapy for sepsis (Cochrane review). Cochrane Database of Systematic
Reviews 2014, Issue 1. Art. No.: CD003344. DOI: 10.1002/14651858.CD003344.pub3
8. Vincent JL, et al. Advances in antibiotic therapy in the critically ill. Vincent et al. Critical Care (2016) 20:133. DOI:
10.1186/s13054-016-1285-6
9. Buckman SA, et al. Empiric Antibiotics for Sepsis. Surg Infect (Larchmt). 2018 Feb/Mar;19(2):147-154. DOI:
10.1089/sur.2017.282
10. Metlay JP, Waterer GW, at al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An
Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America.
Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67. DOI: 10.1164/rccm.201908-1581ST
11. Philippine Clinical Practice Guidelines in the Diagnosis, Empiric Management, and Prevention of Community-
acquired Pneumonia (CAP) in Immunocompromised Adults, 2010 Update. Joint Statement of PSMID, PCCP,
PAFP, PCR.
77
12. Kalil AC, et al. Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia: 2016
Clinical Practice Guideline by the Infectious Disease Society of America and the American Thoracic Society.
Clinical Infectious Diseases 2016; 63(5):361-111 DOI: 1093/cid/ciw353
13. Kurup A, et al. Antibiotic management of complicated intra-abdominal infections in adults: The Asian
perspective. Annals of Medicine and Surgery 3 (2014) 85-91. DOI: 10.1016/j.amsu.2014.06.005
14. Stevens DL, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014
Update by the Infectious Diseases Society of America. Clinical Infectious Diseases 2014; 59(2):e10- 52 DOI:
10.1093/cid/ciu296
15. Andreoni F, et al. Clindamycin Affects Group A Streptococcus Virulence Factors and Improves Clinical Outcome.
Journal of Infectious Diseases 2017; 215:269-77 DOI: 10.1093/infdis/jiw229
16. National Antibiotic Guidelines Committee. National Antibiotic Guidelines 2017. http://ritm.gov.ph/national-
antibiotic-guidelines-2017/
Question 26. In patients with sepsis or septic shock, should we empirically start antibiotics for
methicillin-resistant Staphylococcus aureus (MRSA)?
Recommendations
We recommend empiric MRSA coverage on septic shock patients who have invasive vascular
catheters, previous intravenous antibiotics in the past 90 days, and previous MRSA infection or
colonization. We do not recommend routine use of empiric MRSA coverage for all patients with
sepsis and septic shock (strong recommendation, low quality of evidence)
We suggest infectious diseases referral for septic patients with MRSA risk factors (best practice
statement).
Summary of Evidence
The Philippine Antimicrobial Resistance Surveillance Program of 2018 reported that

the local cumulative rate of MRSA is 53% (n= 3,794). 1 Many of these isolates were from
cutaneous (43%) and blood (21%) culture isolates. Majority (63%) were presumptively
community-acquired. Invasive MRSA infections are associated with mortality that is as high
as 30-40%. Compared to methicillin-sensitive strains, bacteremia caused by MRSA is
associated with a worse prognosis such as increased hospital stay, morbidity, and mortality.
After thorough search, no studies were found directly answering when empiric MRSA
coverage is indicated for septic patients. Search terms used include methicillin-resistant
Staphylococcus aureus, MRSA, sepsis, septic shock, and empiric antibiotic. In lieu of this,
there are several published observational reports which identified the risk factors
predisposing patients to have MRSA infections. Based on the presence of identified risk
factors and high clinical suspicion that MRSA is the possible cause of the sepsis, prompt
empiric antibiotics to cover for MRSA must be given to optimize patient outcome.
78
A retrospective paired case-control study was conducted in 41 intensive care units in

Colombia with the aim of determining risk factors associated with the emergence of MRSA
bacteremia.2 It included 372 subjects, of which 186 cases had MRSA bacteremia and 186
had methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. The multivariate
analysis demonstrated an association between the presence of MRSA and history of use of
vascular catheters (OR=1.986; 95% CI: 1.038-3.801) and of urinary catheters prior to
hospitalization (OR=2.559; 95% CI: 1.170-5.596). The increased risk of MRSA infection can
be explained by factors such as bacterial colonization of devices, greater exposure to
manipulation and therefore to cross-transmission, and increased exposure to the use of
prophylactic antimicrobials which could have a selective effect on the microorganism. The
previous use of intravenous antibiotics emerged as the main risk factor for the presence of
MRSA as a causal agent of bacteremia. A gradient related to the number of antibiotic
families used was found in the study population: one family (OR=4.565, 95% CI: 2.541-
8.203), two families (OR=12.405, 95% CI: 5.286-29.111) and three or more families
(OR=31.742, 95% CI: 8.967-112.367). The effect of carbapenems on the emergence of
MRSA was greater than that of quinolone, beta-lactams, aminoglycosides and vancomycin. 2
The presence of these histories should serve as an alert to identify at-risk populations so as
to anticipate and prevent the negative consequences of MRSA infection.
Another case control study by Carnicer-Pont in Wales, United Kingdom included 132
patients for whom risk factors for hospital-acquired MRSA bacteremia were identified. 3
Forty two cases had MRSA bacteremia and 90 patients who stayed in the hospital for more
than two days were selected as controls. After adjusting for all factors, having a central line
[adjusted OR (aOR) 35.3, 95% CI 3.8–325.5] or a urinary catheter (aOR 37.1, 95% CI 7.1–
193.2) inserted during the stay, and suffering from a surgical site infection (aOR 4.3, 95% CI
1.2–14.6) remained independent risk factors for hospital-acquired MRSA bacteraemia.
Patients with end-stage renal disease have a 100-fold higher risk of MRSA infection
compared to the general population. To estimate the prevalence of MRSA colonization in
dialysis patients and long-term risk of subsequent infections, a meta-analysis of 38 studies
including 5596 patients was published by Zacharioudakis. It revealed that 6.2% of dialysis
patients are MRSA-colonized, and that patients on hemodialysis were more frequently
colonized than those who are on peritoneal dialysis (p=0.01). 4 The risk of developing MRSA
infections increased among colonized hemodialysis patients compared to noncolonized
patients (RR, 11.5 [95%CI, 4.7 to 28.0]).
In a case control study by Torre-Cisneros, clinical predictors of MRSA nosocomial or

healthcare-associated pneumonia were identified to define a high-risk population in whom
coverage against MRSA may be needed. The variables associated with the risk of MRSA
pneumonia were respiratory infection/colonization caused by MRSA in the previous year,
hospitalization in the previous 90 days and age (sensitivity 74.5%, specificity 63.3, positive
predictive value 52.5%, and a negative predictive value 82.0%). 5
Several studies have been done to identify factors associated with mortality among
patients with MRSA bacteremia. Previous hospitalization in the past three months,
residence in a long-term care facility, previous admission in the ICU, and complicated,
severe or critical
79
initial presentation (endocarditis, septic shock, altered mental status) may be used as a
guide for empirical MRSA therapy and application of infection control measures in older
adults with suspected S. aureus bacteremia.6
Table Q26.1 Risk Factors Associated with MRSA Infection
Study Design Risk Factor Odds Ratio 95%
Confidence Interval
Zacharioudakis, 2014 Meta-analysis MRSA colonization 11.5 4.7-28.0

(n=5596)
Arias-Ortiz, 2016 Retrospective Intravascular device 1.986 1.038-3.801

paired case
control study Urinary device 2.559 1.170-5.596
(n=372)
Number of antibiotic families 4.565 2.541-8.203
One 12.405 5.286-29.11
Two 31.742 8.967-112.367
Three or more
Carnicer-Pont, 2006 Case control Intravascular line 35.3 3.8-325.5

(n=132)
Urinary catheter 37.1 7.1-193.2
Surgical Site Infection 4.3 1.2-14.6
Torres-Cisneros, Case-control Respiratory infection or 14.81 4.13-53.13

2017 (n=320) colonization with MRSA in the
previous year
Hospitalization in the previous 2.41 1.21-4.81

90 days
Age 1.02 1.001-1.05
Bader, 2006 Retrospective Previous hospitalization in the 2.6 1.1-5.9

cohort past 3 months
(n=209)
Residence in a long-term 4.5 1.7-12.3
care facility
Altered mental status at the 2.5 1.5-5.16

onset of S. aureus
In summary, the identified risk factors that are most common and most highly
associated with MRSA infections based on high odds ratio are septic shock, previous
extensive intravenous antibiotic use in the past 90 days, previous MRSA colonization or
infection, and presence of intravascular devices. The presence of urinary catheter was not
included as a risk factor because prevalence of MRSA, especially as a pathogen, in the
urinary tract is low.
References
1. Department of Health, Research Institute for Tropical Medicine. 2018. Antimicrobial Resistance
Surveillance Program: 2018 Annual Report.
2. Arias-Otiz PM, Calderon LdP, Castillo JS, et.al. 2016. Risk factors for methicillin-resistant Staphylococcus aureus
bacteremia: a multicenter matched case-control study. Biomedica: 36: 612-8. doi:
http://dx.doi.org/10.7705/biomedica.v36i4.3193
3. Carnicer-Pont D, Bailey KA, Mason BW, et. al. 2006. Risk factors for hospital-acquired methicillin resistant
Staphylococcus aureus bacteremia: a case-control study. Epidemiol Infect, 134, 1167-1173.
doi:10.1017/S0950268806006327
80
4. Zacharioudakis IM, Fainareti NZ, Ziakas PD, et. al. 2014. Meta-analysis of Methicillin-Resistant Staphylococcus
aureus colonization and risk of infection in dialysis patients. Journal of American Society of Nephrology. 25:
2131-2141,
5. Torre-Cisneros J, Natera C, Mesa F, et. al. 2017. Clinical predictors of methicillin-resistant Staphylococcus aureus
in nosocomial and healthcare-associated pneumonia: a multicenter, matched case–control study. Eur J Clin
Microbiol Infect Dis. DOI 10.1007/s10096-017-3100-y
6. Bader MS. 2006. Staphylococcus aureus Bacteremia in Older Adults: Predictors of 7-Day Mortality and Infection
with a Methicillin-Resistant Strain. Infection Control and Hospital Epidemiology, Vol. 27, No. 11 pp. 1219-
1225. http://www.jstor.org/stable/10.1086/507924
Question 27. In patients with sepsis or septic shock, should empiric antibiotics be administered
within the first hour of sepsis recognition?
Recommendation
We recommend that empiric antimicrobials be given within an hour after recognition of sepsis
or septic shock (strong recommendation, moderate quality of evidence).
Summary of Evidence
The Surviving Sepsis Campaign Bundle: 2018 Update recommends the

administration of antibiotics within the first hour of recognition of sepsis, as initial studies
showed mortality benefit on patients who received the antibiotics within the first hour. 1 An
hourly delay of effective antimicrobial therapy was associated with mean decrease in
survival of 7.6%, as shown in the study done by Kumar et al. 2 The latter focused on the
timely administration of appropriate antibiotics, based on antibiogram and culture
sensitivity results. With a total of 2,154 septic shock patients (78.9% total) who received
effective antimicrobial therapy after the onset of hypotension, delay in effective
antimicrobial initiation was shown to be associated with in-hospital mortality (adjusted
odds ratio 1.119 [per hour delay], 95% CI, 1.103 to 1.136, p <.0001). Furthermore, a
survival rate of 79.9% was seen with administration of effective antimicrobial for isolated
or suspected pathogens within the first hour of hypotension.
In a systematic review done by Sterling et al., the association between the timing of
antibiotics and mortality in septic and septic shock patients was assessed. In 11 studies that
included a total of 11,017 patients from the emergency department and ICU, patients were
divided into two groups: those who received antibiotics more than three hours after triage,
and those who received the antibiotics at least one hour after recognition of severe sepsis
and septic shock. In the first group, the pooled OR for mortality was 1.16 (0.92 to 1.46,
p=0.21), in the second group the pooled OR was 1.46 (0.89 to 2.40, p=0.13). 3 The study
showed no significant difference in mortality whether antibiotics were started at least an
hour, or after three hours. We performed a meta-analysis on the subgroup of patients with
septic shock patients. Figure sQ27.1 showed a trend favoring the administration of

Sepsis 2020

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CLINICAL PRACTICE GUIDELINES FOR

SEPSIS AND SEPTIC SHOCK IN ADULTS

Participating Professional Medical Societies

Philippine Society for Microbiology and Infectious Diseases

Clinical Practice Guidelines for Sepsis and Septic

Chairpersons: Mari Rose A. De los Reyes, MD, FPCP, FPSMID

Marissa M. Alejandria, MD, FPCP, FPSMID

Members: Jubert P. Benedicto, MD, FPCP, FPCCP

Pauline F. Convocar, MD, MCHM, FPCEM, DPCOM

Jose Emmanuel T. Palo, MD, FCCM, FPSCCM

TECHNICAL WORKING GROUP

Chair: Joseph Adrian L. Buensalido, MD, FPCP, FPSMID IM–

Co-Chair: Anna Flor Gaboy Malundo, MD, FPCP

Jaime Alfonso M. Aherrera, MD, FPCP, FPCC

Jose Donato A. Magno, MD,FPCP, FPCC, FPSE, FASE

Marie Kirk Patrich A. Maramara, MD, FPCP

Felix Eduardo R. Punzalan, MD,FPCP, FPCC

CLINICAL EPIDEMIOLOGY (Technical Writer)

Maria Teresa F. Sanchez-Tolosa, MD, D Clin Epi, FPDS

CRITICAL CARE MEDICINE

Gerardo M. Briones, Jr, MD, FPCP, FPSCCM

Aaron Mark R. Hernandez, MD, FPCP, FPSCCM

Anthony F. Pantaleon, MD, FPCP

Joanne B. Robles, MD, FPCP, FPNA, FPSCCM

Faith Joan M. Gaerlan, MD, FPCEM

Christopher G. Manalo, MD, DPCEM

Paulette D. Nacpil-Dominguez, MD, FPCP, FPSEDM

Hannah C. Urbanozo-Corpuz, MD, FPCP, FPSEDM

GASTROENTEROLOGY AND NUTRITION

Joyce B. Bernardino, MD, FPCP, DPBCN

Rona Marie A. Lawenko, MD, FPSG, FPSDE

Elvie Victonette B. Razon-Gonzalez, MD, FPCP, FPSG,

Teresita E. Dumagay, MD, FPCP, FPSHBT, FPCHTM

Josephine Anne C. Lucero, MD, FPCP

Anne Kristine H. Quero, MD, FPCP

Maria Clariza M. Santos, MD, FPCP, FPSHBT,

Cybele Lara R. Abad, MD, FPCP

Karl Evans R. Henson, MD, FPCP, FPSMID

Honey Jane B. Limos, MD

Monica Pia R. Montecillo, MD, FPCP

Leonell Albert L. Quitos, MD, FPCP

Sebar S. Sala, MD, FPCP

Maria Sonia S. Salamat, MD, FPCP, FPSMID

Joanne Carmela M. Sandejas, MD

Hospital INTERNAL MEDICINE

Krishja T. Dela Torre, MD

Bryan Paul G. Ramirez, MD

Isabelle Dominique V. Tomacruz, MD, FPCP

Anthony Russell T. Villanueva, MD, FPCP, FPSN

National Kidney and Transplant Institute

Albert B. Albay, Jr., MD, FPCP, FPCCP, FPSCCM

Gene Phillip Louie C. Ambrocio, MD, FPCP, FPCCP

Blake Warren C. Ang, MD

Carla Emille D. Barbon, MD-MBA

Jamie R. Chua, MD, FPCP

Anjuli Mae P. Jaen, MD, FPCP

Jonray R. Magallanes, MD, FPCP, FPCCP

Irene Rosellen P. Tan, MD, FPCP

Mithi Kalayaan S. Zamora, MD

PHILIPPINE ACADEMY OF FAMILY PHYSICIANS (PAFP)