The J-SSCG 2020 was created through the three following processes: 1) planning a clinical question (CQ); 2) searching, collecting, and integrating evidence through a systematic review and evaluating its certainty; and 3) formulating a recommendation. Relevant information for a recommendation based on GRADE and expert consensus were available at https://www.jsicm.org/pdf/J-SSCG2020_supplementary_appendix01.pdf.

1) Planning a CQ

Clinical practice guidelines should cover the basic knowledge of clinical practice and contribute to the construction of a standard clinical practice system. For this reason, important CQs were extracted from each domain regardless of presence or absence of evidences, and important CQs taken up in previous guidelines were adopted in this guideline. Based on the rules of planning a CQ, committee members and working group members collaborated to create a draft CQ in their area of responsibility, an opinion extracted from mutual peer review by committee members was reflected, and a CQ list was created by the Guideline Creation Committee. Public comments were solicited online for these CQs. The CQs were then revised using these public comments received, and a total of 118 CQs were ultimately decided by the committee.

2) CQ classifications

CQs include background questions (BQs) and foreground questions. BQs indicate CQs that inquire about what is well known as general knowledge, such as diseases, diagnoses, and treatment. Meanwhile, foreground questions are CQs that inquire about information specialized to various situations in clinical settings and can influence decision-making in clinical practice (Table 1).

Table 1. CQ classifications CQ classifications Background questions (BQ) CQs which inquire about what is general knowledge, such as diseases, diagnoses, and treatment

Standard knowledge is presented.

Systematic review is not needed.

No recommendations are given.

Foreground questions (FQ) CQs which inquire about information specialized to various situations in clinical settings. For example, whether a particular treatment is effective for a patient with a specific illness. This can influence decisions in clinical settings.

Treatment options are presented.

Systematic review is required for FQs other than GPS.

Recommendations on treatment selection are given.

Recommendation classifications for FQs Good practice statement (GPS) Recommendations on topics that are so common that they cannot become a research theme and of which all medical personnel should be made aware GRADE-based recommendation (GRADE) Recommendations presented in accordance with the principles of the GRADE system. A systematic review is conducted, four factors (certainty of evidence, balance of benefits and harms, values and preferences, costs and resource utilization) based on the obtained evidence are taken into consideration, and recommendations are made in consultation with the committee. Expert consensus-based recommendation (unGRADE) Consensus made by experts for CQs for which a systematic review was conducted but had no target articles. Three factors (balance of expected benefits and harms, values and preferences, costs and resource utilization) are taken into consideration and recommendations are made in consultation with the committee. 3) Formulating answers to BQs

BQs aim to present information that summarizes general knowledge such as illnesses, diagnoses, and treatment. Each area group prepared draft recommendations for the CQs, which were amended and revised repeatedly until the approval rate in the committee exceeded 95% for consensus.

4) Formulating answers to foreground questions

Foreground questions include (1) GPS, which are CQs that are extremely common and of which all medical personnel should be aware, and (2) CQs that are subject to systematic review and for which recommendations are formulated. The latter CQ was given a recommendation based on GRADE or on expert consensus depending on whether target articles were present or absent, respectively.

4-1) Formulating GPS

GPS was displayed for CQs, which handled themes that were extremely common and for which randomized controlled trials were theoretically impossible. These were amended and revised repeatedly until the approval rate in the committee exceeded 95% for consensus.

4-2) Searching, collecting, and integrating evidence through systematic review

A comprehensive literature review was conducted for each CQ in the foreground questions except for GPS, from which randomized controlled trials (RCTs) were extracted. As a general rule, the methodology was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Step 1: Literature review

Literature reviews were conducted using the search engines of CENTRAL, PubMed, and Ichushi-Web.

The search equations were created by two or more independent reviewers using Medical Subject Headings (MeSH) terms and free search terms. Searches on PubMed used the sensitive-maximizing version of search strategies created by Cochrane as a general ruler for research design filters that specified RCTs. The publication date of the subject articles was not restricted. The languages of the manuscript were limited to Japanese and English. After confirming that the key RCTs specified in advance were included, the literature review equations underwent a final decision, and the literature review date and number of articles found in each search engine were recorded.

Step 2: Primary screening

All the titles and abstracts specified in Step 1 were downloaded. The automatic duplicate deletion function of the literature management software EndNote (Clarivate Analytics, USA) or Mendeley (Mendeley Ltd., UK) were used to remove duplicates, with duplicate articles further deleted manually. Article screening was conducted online using Rayyan (https://rayyan.qcri.org/welcome). Two independent reviewers reviewed the titles and abstracts of the literature and excluded research methods and PICO criteria, which were clearly not within the target. If there was any possibility that it was a target article, it was not excluded.

Step 3: Secondary screening

The full text of the remaining articles from Step 2 were ordered, and two reviewers selected articles whose research design and PICO criteria conformed to the CQ, and they confirmed them as target articles. Articles for which the opinions of the two reviewers did not match were sent to a third reviewer and discussed among the three reviewers. Articles excluded at this stage were provided a reason for exclusion. The process from literature review to target article selection is summarized in the PRISMA flow diagram.

Step 4: Evaluation of the certainty of evidence for CQs where evidence existed

Risk evaluations were conducted for the certainty of evidence (A-D) of the CQ undergoing systematic review for which each group was responsible. The definitions for the certainty of evidence as set by the GRADE system adopted in this guideline are as follows.

Definition of the certainty of evidence High: Highly confident in the estimated value of effects Medium: Moderate confidence in the estimated value of effects Low: Limited confidence in the estimated value of effects Very low: Almost no confidence in the estimated value of effects

Step 5: Data extraction, bias risk evaluation

Data extraction was performed by two independent reviewers, and a standardized data extraction form was used. In cases where insufficient information was recorded in the reference, this was stated as such, and the authors were not contacted.

Step 6: Meta-analysis and evaluation of the certainty of evidence

Qualitative and quantitative evaluations of the references to be adopted were performed. The qualitative evaluations used RevMan 5 whenever possible to conduct meta-analyses. This was summarized so that each area group could create evaluations of the certainty of evidence.

Handling of CQs with network meta-analysis

Indirect and network estimate values were calculated using a frequency-based analysis method for CQs with network meta-analyses (Confidence in Network Meta-Analysis [CINeMA] from R package netmeta used). The surface under the cumulative ranking curve (SUCRA) was used for rankings (calculated as Stata mvmeta command). The quality of evidence was evaluated based on the GRADE working group methods (ref). Network meta-analyses were conducted on CQ9-2 and CQ9-6 of this guideline.

Handling of CQs with qualitative research as evidence

The GRADE-Confidence in the Evidence from Reviews of Qualitative research (CERQual) approach was adopted as an evidence extraction method for CQs, where qualitative research was thought to be an appropriate research method. This was used in CQ20-3, “Should physical binding (restraints) be avoid during intensive care?”, in this guideline.

4-3) Formulation of proposed recommendations The committee members and working group collaborated to create an evidence to decision (EtD) table in advance of deciding the recommendations. They then considered four factors (certainty of evidence, balance of effects, values, and cost/resource utilization) and formulated recommendations in consultation with the committee. The strengths of the recommendations shown in the GRADE system are classified as recommended, suggested, not suggested, and not recommended. =Description methods for the strength of recommendations= Strength of recommendation “1”: recommended. Strength of recommendation “2”: suggested.

Committee members and the working group collaborated to create an EtD table for foreground question type CQs, for which insufficient evidence was obtained through comprehensive literature reviews conforming to the PICO criteria and formed an expert consensus based on this EtD. Recommendations in this EtD took into consideration the expert-proposed factors of the balance between the desired and undesired effects of each intervention, values, and costs/resource utilization, conducted in consultation with the committee. Recommendations with these expert consensuses were “suggestions”, and “(expert consensus: insufficient evidence)” was added at the end of the text so that this could be distinguished from the above-mentioned recommendations based on GRADE.

4-4) Consensus building in CQs in accordance with GRADE and CQs showing expert consensus

The modified Delphi method was used for consensus building among committee members.

Step 1: Voting

Each committee member anonymously voted online in an independent manner using a point system ranging from 1 to 9 (1: disagree, 9: agree). The median, interpercentile range (IPR), interpercentile range adjusted for symmetry (IPRAS), and disagreement index (DI) of the obtained scores were calculated.

Step 2: Panel meeting Panel meetings were conducted based on the aggregated results as shown below to reach a consensus. When median <7.5 and DI ≥0.2 Discussions were held within the committee, after which amendments were made to the EtD and recommended text, and a second vote was held. When median ≥7.5 or DI <0.2 When a serious opinion was present during voting for a comment or recommendation presented by committee member Discussions were held within the committee, and a consensus was reached. CQs for which a consensus was not reached within the committee resulted in amendments to the EtD and recommended text, after which a second vote was held. When no serious opinions were present during voting for a comment or recommendation presented by a committee member. The voting results were confirmed among the committee members, and a consensus was reached. Quick reference list of CQ&As CQ1: Definition and diagnosis of sepsis

CQ1-1: Definition of sepsis

Summary: According to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection.” Septic shock is defined as a subset of sepsis in which the underlying circulatory and cellular/metabolic abnormalities profoundly increase the risk of mortality.

CQ1-2: Diagnosis of sepsis and septic shock

Summary: A diagnosis of sepsis is confirmed when the Sequential Organ Failure Assessment (SOFA) score of 2 points or more acutely increase in the presence of a clear infection or suspected infection. Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain mBP ≥ 65 mmHg and having a serum lactate level >2 mmol/L (18 mg/dL) despite adequate volume resuscitation. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as more likely to have poor outcomes typical of sepsis if they have at least two of the following clinical criteria that together constitute the quick SOFA (qSOFA) score: a respiratory rate of 22 breaths/min or higher, altered consciousness, and a systolic blood pressure of ≤100 mmHg. The qSOFA criteria can be used to prompt clinicians to further investigate organ dysfunction, initiate or escalate therapy as appropriate, and to consider referral for critical care. Ultimately, an acutely increased SOFA score of 2 or more points confirms the diagnosis of sepsis. Daily routine screening for sepsis is recommended to support the early diagnosis and treatment of sepsis.

CQ2: Diagnosis of infection

CQ2-1: When should a blood culture be taken?

Answer: Take two or more sets before administering the antibacterial drug (Good Practice Statement).

CQ2-2: When should culture specimens other than blood be collected?

Answer: Each cultured specimen other than blood should be collected as needed prior to the administration of antibacterial drugs (Good Practice Statement).

CQ2-3: Is Gram staining useful in the selection of antimicrobial agents before obtaining culture results?

Answer: We suggest referencing Gram staining findings of the culture specimen when selecting an antibacterial drug to use for empirical treatment (expert consensus: insufficient evidence).

CQ2-4-1: What are the positions of C-reactive protein (CRP), procalcitonin (PCT), presepsin (P-SEP), and interleukin 6 (IL-6) as biomarker tests for sepsis diagnosis in general ward and emergency rooms (ER)?

Answer: Sensitivity and specificity in biomarker tests when sepsis was suspected in general ward and ER visits were as follows: CRP, 59%, 79%; PCT, 74, 81%; P-SEP, 75%, 74%; IL-6, 78%, 78%. As such, sepsis diagnosis with biomarkers alone is generally thought to be difficult, and its use should be seen as supplemental to any observations of general conditions (Provision of information for background question).

CQ2-4-2: What are the positions of C-reactive protein (CRP), procalcitonin (PCT), presepsin (P-SEP), and interleukin-6 (IL-6) as biomarker tests for sepsis diagnosis in the intensive care unit?

Answer: Sensitivity and specificity in biomarker tests when sepsis was suspected in the intensive care unit were as follows: CRP, 74%, 70%; P-SEP, 82%, 73%; IL-6, 72%, 76%. As such, sepsis diagnosis with biomarkers alone is generally thought to be difficult, and its use should be supplemental to any observations of general conditions (Provision of information for background question).

CQ3: Source control

CQ3-1: Should imaging tests be conducted in patients suspected of sepsis in order to search for the source of infection?

Answer: Imaging tests should be conducted when the source of infection is unclear in order to search for the source of infection (Good Practice Statement).

CQ3-2: Should whole-body contrast-enhanced CT tests be conducted at an early stage for sepsis patients with unknown source of infection?

Answer: We suggest conducting whole-body contrast-enhanced CT tests as soon as possible for sepsis patients with unknown source of infection (expert consensus: insufficient evidence).

CQ3-3: Should the source of infection be controlled by surgery/invasive drainage in patients with sepsis due to intraperitoneal infection?

Answer: We suggest controlling the source of infection as soon as possible with surgery/invasive drainage (including abscess drainage, biliary tract/gallbladder drainage) for patients with sepsis due to intraperitoneal infection (expert consensus: insufficient evidence).

CQ3-4-1: Should the source of infection be controlled with invasive interventional therapy during the early period of infectious pancreatic necrosis?

Answer: We suggest against controlling the source of infection with invasive interventional therapy during the early period of infectious pancreatic necrosis (GRADE 2C: certainty of evidence = "low").

CQ3-4-2: Should the source of infection be controlled with low-invasive interventional therapy for infectious pancreatic necrosis?

Answer: We recommend controlling the source of infection with less invasive interventional therapy for patients with sepsis caused by infectious pancreatic necrosis (GRADE 2B: certainty of evidence = "moderate").

CQ3-5: Should the source of infection be controlled with invasive drainage for patients with sepsis due to acute pyelonephritis caused by ureteral obstruction?

Answer: We suggest controlling the source of infection as soon as possible with transurethral ureteral stent implantation or percutaneous nephrostomy in patients with sepsis due to acute pyelonephritis caused by ureteral obstruction (expert consensus: insufficient evidence).

CQ3-6: Should source control be achieved by means of surgical debridement for sepsis patients due to necrotic soft tissue infection?

Answer: We suggest controlling the source of infection as soon as possible by means of surgical debridement for sepsis patients due to necrotic soft tissue infection (expert consensus: insufficient evidence).

CQ3-7: Should the source of infection be controlled with catheter removal in patients with sepsis where catheter-related bloodstream infections are suspected?

Answer: We suggest controlling the source of infection as soon as possible with catheter removal in patients with sepsis where catheter-related bloodstream infections are suspected (expert consensus: insufficient evidence).

CQ3-8: Should the source of infection be controlled through invasive drainage in patients with sepsis due to empyema?

Answer: We suggest controlling the source of infection as soon as possible with percutaneous thoracic drainage or surgical intervention in patients with sepsis due to empyema (expert consensus: insufficient evidence).

CQ4: Antimicrobial therapy

CQ4-1: How should empirical antimicrobial therapy be selected?

Answer: Antimicrobials can be selected by estimating the causative microorganism based on suspected infectious foci, patient background, epidemiology and rapid microbial diagnostic tests, and by considering the tissue penetration properties of drugs and the probabilities of resistant bacteria (see Table 11 for reference). (Provision of information for background question).

Table 10. Diseases that require control of the source of infection and imaging tests Region Main tests expected Simple X-ray Ultrasonography CT scan MRI scan Head and neck Brain abscess/meningoencephalitis ○(contrast-enhanced imaging) ○(contrast-enhanced imaging), contrast enhanced fluid-attenuated inversion recovery (FLAIR) (for encephalitis) Cervical abscess (descending mediastinitis) ○ ○(contrast-enhanced imaging) Chest Empyema ○ ○ ○(contrast-enhanced imaging) Infective endocarditis ○* ○(contrast-enhanced imaging) Abdomen Intestinal perforation/peritonitis ○ ○ ○(contrast-enhanced imaging) Cholecystitis/cholangitis ○ ○(contrast-enhanced imaging) ○ (MRI/MRCP) Obstructive urinary tract infection ○ ○ ○ Other Necrotic soft tissue infections ○(contrast-enhanced imaging) * Transesophageal echocardiography other than the transthoracic wall variant is more accurate in diagnosing infective endocarditis.

CQ4-2: Under what circumstances should carbapenems be used in empirical antimicrobial therapy?

Answer: Carbapenems can be included in the empirical antimicrobial regimen when the use of carbapenem is considered to be particularly effective; ESBL-producing Enterobacteriaceae or Pseudomonas aeruginosa or Acinetobacter species with limited susceptibility for carbapenems (Provision of information for background question).

CQ4-3: Under what circumstances should empirical antimicrobial therapy be selected for MRSA and non-bacterial pathogens (e.g., Candida, Viruses, Legionella, Rickettsia, or Clostridioides difficile)?

Answer: Each microorganism can be covered by empirical antimicrobial regimen if highly suspected by suspected infectious foci, patient background and culture results (Provision of information for background question).

CQ4-4: Should empirical antimicrobial therapy be suspended if culture results were negative?

Answer: We suggest stopping any empiric antimicrobials where sepsis is excluded by negative culture results and after careful consideration of clinical progress (expert consensus: insufficient evidence).

CQ4-5: Under what circumstances should an infectious disease specialist or antimicrobial stewardship team be consulted?

Answer: An infectious disease specialist and/or antimicrobial stewardship team can be consulted when 1) the cause of sepsis is unknown, 2) involvement of extensively drug-resistant bacteria is suspected, 3) emerging, re-emerging, or imported infectious diseases are suspected, or 4) in cases of Staphylococcus aureus bacteremia or candidemia (Provision of information for background question).

CQ4-6: Should empirical antibacterial drugs for sepsis begin within 1 h upon identification of sepsis?

Answer: We suggest that antibacterial drugs be administered as soon as possible upon identification of sepsis or septic shock, but we suggest against using the target time of less than 1 h (GRADE 2C: certainty of evidence = "low").

CQ4-7: Should continuous or extended infusion of β-lactam antibiotics be used for sepsis?

Answer: We suggest using continuous or extended infusion of β-lactam antimicrobials (GRADE 2B: certainty of evidence = "moderate").

CQ4-8: Should de-escalation antimicrobial therapy be used for sepsis?

Answer: We suggest applying de-escalation antimicrobial therapy for sepsis (GRADE 2D, certainty of evidence = "very low").

CQ4-9: Should procalcitonin be used as an indicator for stopping antimicrobial therapy for sepsis?

Answer: We suggest using procalcitonin as an indicator for stopping antimicrobial therapy for sepsis (GRADE 2B, certainty of evidence = "moderate").

CQ4-10: Should relatively short-term (i.e. within 7 days) antimicrobial therapy be applied for sepsis?

Answer: We suggest applying relatively short-term (i.e. within 7 days) antimicrobial therapy for sepsis (GRADE 2D: certainty of evidence = "very low").

CQ4-11: What should be used as a reference for adjusting the dose for renal-excretion antimicrobial drugs?

Answer: Changes in bodily fluid volume and the presence of renal replacement therapy and other extracorporeal circulation therapies in addition to renal function test values (e.g., serum Cr level, eGFR level) measured at multiple time points are informative (Provision of information for background question).

CQ5: Intravenous immunoglobulin therapy

CQ5-1: Should intravenous immunoglobulin (IVIG) be administered to adult patients with sepsis?

Answer: We suggest against administering IVIG to patients with sepsis (GRADE 2B: certainty of evidence = "moderate").

CQ5-2-1: Should IVIG be administered to patients with streptococcal toxic shock syndrome (STSS)?

Answer: We suggest administering IVIG to patients with STSS (GRADE 2D: certainty of evidence = "very low").

CQ5-2-2: Should IVIG be administered to patients with staphylococcal toxic shock syndrome (staphylococcal TSS)?

Answer: We suggest against administering IVG to patients with staphylococcal TSS (expert consensus: insufficient evidence).

CQ6: Initial resuscitation/inotropes

CQ6-1: Should echocardiography be conducted in patients with sepsis?

Answer: We suggest, following initial fluid resuscitation, conducting cardiac function and hemodynamics assessments with echocardiography in patients with sepsis/septic shock (GRADE 2D: certainty of evidence = "very low").

CQ6-2: Is EGDT recommended for initial resuscitation in patients with sepsis?

Answer: We suggest against conducting EGDT as initial resuscitation in patients with sepsis/septic shock (GRADE 2C: certainty of evidence = "low").

CQ6-3: Should vasopressors be used simultaneously or in the early stage (within 3 h) of initial fluid resuscitation in adult patients with sepsis?

Answer: We suggest administering vasopressors simultaneously or in the early stages (within 3 h) of initial fluid resuscitation in patients with sepsis/septic shock who have difficult maintaining hemodynamics (GRADE 2C: certainty of evidence = "low").

CQ6-4: Should lactate levels be used as an indicator for initial resuscitation in adult patients with sepsis?

Answer: We suggest using lactate levels as an indicator of tissue hypoperfusion during initial resuscitation in patients with sepsis/septic shock (GRADE 2C: certainty of evidence = "low").

CQ6-5: What is the initial fluid infusion rate and volume in adult patients with sepsis?

Answer: There is an opinion that the initial fluid resuscitation in patients with reduced intravascular volume due to sepsis should be administered over 30 mL/kg of crystalloid solution within 3 h, aiming to optimize the circulating blood volume. It is important during initial fluid resuscitation to carefully observe vital signs and to avoid excessive fluid loads by using lactate clearance and echocardiography while conducting tissue oxygen metabolism and hemodynamics assessments (Provision of information for background question).

CQ6-6: How should fluid responsiveness be assessed in adult patients with sepsis?

Answer: Fluid responsiveness is significant increase in stroke volume (SV) after fluid infusion, and multiple parameters, including static and dynamic parameters, should be used to predict fluid responsiveness. Static parameters, including central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP), are measured at a point. Dynamic parameters include changes in cardiac output by passive leg raising (PLR) and fluid challenge, pulse pressure variation (PPV) and stroke volume variation (SVV) during mechanical ventilation (Provision of information for background question).

CQ6-7: Should albumin solution be used for initial resuscitation in adult patients with sepsis?

Answer: We suggest against administering albumin solution as a standard treatment at the beginning of initial fluid resuscitation in patients with sepsis (GRADE 2C: certainty of evidence = "low"). Albumin solution can be used in patients with sepsis when patients do not respond to standard treatment and require substantial amounts of crystalloids (expert consensus: insufficient evidence).

CQ6-8: Should artificial colloids be used for initial resuscitation in adult patients with sepsis?

Answer: We suggest against administering artificial colloids in patients with sepsis/septic shock (GRADE 2D: certainty of evidence = "very low").

CQ6-9-1: Should noradrenaline, dopamine, or phenylephrine be used as a first-line vasopressor in adult patients with sepsis? noradrenaline vs. dopamine

Answer: Between noradrenaline and dopamine, we suggest administering noradrenaline as a first-line vasopressor in adult patients with sepsis (GRADE 2D: certainty of evidence = "very low").

CQ6-9-2: Should noradrenaline, dopamine, or phenylephrine be used as a first-line vasopressor in adult patients with sepsis? noradrenaline vs. phenylephrine

Answer: Between noradrenaline and phenylephrine, we suggest administering noradrenaline as a first-line vasopressor in adult patients with sepsis (GRADE 2D: certainty of evidence = "very low").

CQ6-10-1: Should adrenaline be used as a second-line vasopressor in adult patients with sepsis?

Answer: We suggest against using adrenaline as a second-line vasopressor in patients with sepsis/septic shock (GRADE 2D: certainty of evidence = "very low").

CQ6-10-2: Should vasopressin be used as a second-line vasopressor in adult patients with sepsis?

Answer: We suggest using vasopressin as a second-line vasopressor in patients with sepsis/septic shock (GRADE 2D: certainty of evidence = "very low").

CQ6-11: Should inotropes be used in adult patients with sepsis accompanied by cardiogenic shock?

Answer: We suggest administering inotropes (adrenaline, dobutamine) in adult patients with septic shock accompanied by cardiac dysfunction (expert consensus: insufficient evidence).

CQ6-12: Should β-blockers be used in adult patients with sepsis?

Answer: We suggest administering short-acting β1-adrenoceptor antagonists in patients with sepsis/septic shock while being monitored with the objectives of managing tachycardia which cannot be controlled with standard therapy like initial fluid resuscitation (GRADE 2D: certainty of evidence = "very low"). Administering short-acting β1-adrenoceptor antagonists can induce hemodynamic fluctuations, so they should be administered under the supervision of a physician with expertise in cardiovascular management in the intensive care unit (expert consensus: insufficient evidence).

CQ6-13: What are the indications of assisted circulation in adult patients with septic shock?

Answer: There is insufficient evidence for the effects of assisted circulation such as veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and intra-aortic balloon pump (IABP) for cardiac dysfunction in septic shock, and its applications are still under investigation (Provision of information for background question).

CQ7: Corticosteroid therapy

CQ7-1: Should low-dose corticosteroids (hydrocortisone) be administered to adult patients with septic shock who do not respond to initial fluid resuscitation and vasopressors?

Answer: We suggest administering low-dose corticosteroids (hydrocortisone) to adult patients with septic shock who do not respond to initial fluid resuscitation and vasopressors for the purpose of withdrawing from shock (GRADE 2D: certainty of evidence = "very low").

CQ7-2: Should hydrocortisone and fludrocortisone be administered to patients with septic shock who do not respond to initial fluid resuscitation and vasopressors?

Answer: We suggest concomitant administration of hydrocortisone and fludrocortisone to adult patients with septic shock who do not respond to initial fluid resuscitation and vasopressors (GRADE 2C: certainty of evidence = "low").

CQ7-3: Should corticosteroids (hydrocortisone) be administered to patients with sepsis without shock?

Answer: We suggest against administering hydrocortisone to patients with sepsis without shock (GRADE 2D: certainty of evidence = "very low").

CQ8: Blood transfusion therapy

CQ8-1: How should blood transfusion be conducted during the initial resuscitation of septic shock?

Answer: We suggest starting blood transfusion at a hemoglobin level of less than 7 g/dL during initial resuscitation for patients with septic shock (GRADE 2C: certainty of evidence = "low").

CQ8-2: How should blood transfusion be conducted during hemodynamically stable sepsis?

Answer: We suggest starting blood transfusion at a hemoglobin level of less than 7 g/dL in patients with hemodynamically stable sepsis (expert consensus: insufficient evidence).

CQ8-3: How should fresh frozen plasma be administered in patients with sepsis?

Answer: We suggest administering fresh frozen plasma in patients with sepsis when hemorrhaging tendencies are observed. If surgical/invasive interventions are required, we suggest administering when PT/APTT is extended (PT is over INR 2.0 or activity level of less than 30%; APTT is over two times the upper limit of standards at each medical institution or activity level less than 25%) or when fibrinogen levels are less than 150 mg/dL (expert consensus: insufficient evidence).

CQ8-4: How should platelet transfusion be conducted for patients with sepsis?

Answer: We suggest conducting platelet transfusion in patients with sepsis and platelet counts of less than 10,000/μL, or less than 50,000/μL when accompanied by hemorrhaging symptoms (expert consensus: insufficient evidence). We suggest conducting platelet transfusion so as to maintain a platelet count of over 50,000/μL when active hemorrhaging is observed or when surgical/invasive procedures are needed (expert consensus: insufficient evidence).

CQ9: Respiratory management

CQ9-1: What is the SPO2 range for respiratory management in adult patients with sepsis?

Answer: We suggest against setting a high target SPO2 (98-100%) during respiratory management in adult patients with sepsis (GRADE 2B: certainty of evidence = "moderate").

Remarks: This does not apply in cases where there is the possibility of a disruption in the oxygen supply/demand balance due to severe anemia or increased metabolism due to infection in cases where hemodynamics are unstable.

CQ9-2: Should non-invasive ventilation (NIV) or nasal high-flow therapy (NHFT) be conducted for early respiratory failure in adult patients with sepsis?

Answer: We suggest conducting non-invasive ventilation (NIV) or nasal high-flow therapy (NHFT) for early respiratory failure in adult patients with sepsis (GRADE 2A: certainty of evidence = "high").

CQ9-3: Should protective ventilation strategies be implemented for ventilation management in adult patients with sepsis?

Answer: We suggest implementing protective ventilation strategies for ventilation management in adult patients with sepsis (GRADE 2B: certainty of evidence = "moderate").

CQ9-4: Should high PEEP settings be utilized for ventilation management in adult patients with sepsis?

Answer: We suggest against utilizing high PEEP settings (PEEP over 12 cm H2O) for the initial stage of ventilation management in adult patients with sepsis (GRADE 2B: certainty of evidence = "very low").

CQ9-5: Should spontaneous breathing trials (SBT) be conducted prior to extubation in adult patients with sepsis placed under ventilation management?

Answer: We suggest utilizing weaning protocols from ventilators, including spontaneous breathing trials (SBTs) prior to extubation in adult patients with sepsis placed under ventilation management (GRADE 2D: certainty of evidence = "very low").

CQ9-6: Should preventative non-invasive ventilation (NIV) or nasal high-flow therapy (NHFT) be conducted after extubation for adult patients with sepsis placed under ventilation management?

Answer: We suggest conducting preventative non-invasive ventilation (NIV) or nasal high-flow therapy (NHFT) over standard oxygen therapy following extubation for adult patients with sepsis placed under ventilation management (GRADE 2B: certainty of evidence = "moderate").

CQ10: Management of pain, agitation, and delirium

CQ10-1: Should management based on analgesia-first sedation protocol be used for adult patients with sepsis on mechanical ventilation?

Answer: We suggest using management based on analgesia-first sedation protocol in adult patients with sepsis on mechanical ventilation (GRADE 2C: certainty of evidence = "low").

CQ10-2: Should propofol or dexmedetomidine be prioritized over benzodiazepines as sedatives for adult patients with sepsis on mechanical ventilation?

Answer: We suggest using propofol or dexmedetomidine over benzodiazepines as sedatives for patients with sepsis on mechanical ventilation (GRADE 2D: certainty of evidence = "very low").

CQ10-3: Should light sedation through the interruption of sedatives once a day or sedative adjustments based on protocol be used for adult patients with sepsis on mechanical ventilation?

Answer: We suggest using light sedation through the interruption of sedatives once a day or sedative adjustments based on protocol for patients with sepsis on mechanical ventilation (GRADE 2C: certainty of evidence = "low").

CQ10-4: Should drug therapy be used to prevent delirium in adult patients with sepsis?

Answer: We suggest administering dexmedetomidine for delirium prevention in adult patients with sepsis (GRADE 2C: certainty of evidence = "low"). We suggest against the administration of haloperidol (GRADE 2B: certainty of evidence = "moderate"). We suggest against the administration of atypical antipsychotics (GRADE 2C: certainty of evidence = "low"). We suggest against the administration of statins (GRADE 2D: certainty of evidence = "very low").

Remarks: We recommend against the routine administration of dexmedetomidine to patients who do not require sedation. Furthermore, dexmedetomidine administration can cause hemodynamic fluctuations, so this should ideally be administered under the supervision of a physician who is experienced with systematic management in an intensive care unit (expert consensus).

CQ10-5: Should drug therapy be used to treat delirium in adult patients with sepsis?

Answer: We suggest against administering dexmedetomidine for delirium treatment in adult patients with sepsis (GRADE 2D: certainty of evidence = "very low"). We suggest against administering haloperidol (GRADE 2C: certainty of evidence = "low"). We suggest against administering atypical antipsychotics (GRADE 2B: certainty of evidence = "moderate").

Remarks: The use of dexmedetomidine, haloperidol, or atypical antipsychotics should not be prevented when the patient's life or body is at risk due to hyperactive delirium.

CQ10-6: Should non-drug therapy be used to prevent delirium in adult patients with sepsis?

Answer: We suggest using non-drug therapy to prevent delirium in adult patients with sepsis (GRADE 2C: certainty of evidence = "low").

CQ11: Acute kidney injury/blood purification

CQ11-1: Should furosemide be used to prevent or treat septic AKI?

Answer: We suggest against using furosemide for preventing or treating septic AKI (GRADE 2C, certainty of evidence = "low").

CQ11-2: Should atrial natriuretic peptide (ANP) be used to prevent or treat septic AKI?

Answer: We suggest against using ANP for preventing or treating septic AKI (GRADE 2D, certainty of evidence = "very low").

CQ11-3: Should dopamine be used to prevent or treat septic AKI?

Answer: We suggest against using dopamine for preventing or treating septic AKI (GRADE 2C, certainty of evidence = "low").

CQ11-4: Should continuous renal replacement therapy (RRT) rather than intermittent RRT be used for the management of septic AKI?

Answer: Either continuous or intermittent RRT can be selected for septic AKI (GRADE 2C, certainty of evidence = "low"). Continuous RRT should be used for hemodynamically unstable patients (Good Practice Statement).

CQ11-5-1: Should RRT be initiated early for septic AKI (Stage 2 vs. Stage 3 or absolute indications)?

Answer: We make no recommendation on whether RRT should be initiated early at Stage 2 for patients with septic AKI.

CQ11-5-2: Should RRT be initiated early for septic AKI (Stage 3 vs. absolute indications)?

Answer: We suggest against initiating RRT at Stage 3 for patients with septic AKI rather than absolute indication (GRADE 2D, certainty of evidence = "very low").

CQ11-6: Should a large RRT dose be delivered for septic AKI?

Answer: We suggest against increasing a RRT dose beyond the standard dose for patients with septic AKI (GRADE 2C, certainty of evidence = "low").

CQ11-7: Should PMX-DHP be used for patients with septic shock?

Answer: We suggest against using PMX-DHP for patients with septic shock (GRADE 2B, certainty of evidence = "moderate").

CQ12: Nutrition support therapy

CQ12-1: Should either enteral nutrition or parenteral nutrition be given for nutrition administration in septic patients?

Answer: We suggest enteral nutrition be administered for septic patients. (GRADE 2D: certainty of evidence = "very low").

CQ12-2: Should hemodynamically unstable septic shock patients receive enteral nutrition?

Answer: We suggest against administering enteral nutrition in hemodynamically unstable septic shock patients (GRADE 2D: certainty of evidence = "very low").

CQ12-3: When should enteral nutrition be initiated in septic patients?

Answer: We suggest initiating enteral nutrition at an early period of acute phase (within 24-48 h following the start of treatment to critical illness) for septic patients (GRADE 2D: the certainty of evidence = "very low").

CQ12-4: Should the septic patients receive enteral nutrition less than their energy expenditure in the acute phase?

Answer: We suggest the septic patients receive enteral nutrition less than their energy expenditure in the acute phase. (GRADE 2B: certainty of evidence = "moderate").

CQ12-5: Should parenteral nutrition be combined with enteral nutrition in septic patients?

Answer: We suggest supplemental parenteral nutrition be combined in septic patients receiving insufficient amount of enteral nutrition (GRADE 2D: certainty of evidence = "very low").

CQ12-6: What is the optimal protein dose in the acute phase for septic patients?

Answer: We suggest providing less than 1g/kg/day of protein (peptides, amino acids) to septic patients in the acute phase (GRADE 2D: certainty of evidence = "very low").

CQ12-7-1: Should vitamin C be actively provided to septic patients in the acute phase?

Answer: We suggest providing vitamin C to septic patients (GRADE 2D: certainty of evidence = "very low").

CQ12-7-2: Should vitamin D be actively provided to septic patients in the acute phase?

Answer: We suggest against providing vitamin D in s