Time to Treatment and Mortality during Mandated Emergency ...・sepsisに誘発された低灌流は最初の3時間以内に少なくとも30 ml/kgの晶質液の投与が推奨される

慈恵ICU勉強会2017年7⽉25⽇研修医河津圭佑

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med nejm.org 1

From the Departments of Critical Care Medicine and Emergency Medicine, Uni-versity of Pittsburgh School of Medicine, and the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center — both in Pittsburgh (C.W.S.); the New York State Department of Health, Albany (F.G., M.E.F.), and IPRO, Lake Success (G.S.P., K.M.T.) — both in New York; the University of Mich-igan and the Veterans Affairs Center for Clinical Management Research — both in Ann Arbor (H.C.P., T.J.I.); the Division of Biostatistics, Ohio State University College of Public Health, Columbus (S.L.); Washington University, St. Louis (T.O.); and the Warren Alpert Medical School at Brown University, Providence, RI (M.M.L.). Address reprint requests to Dr. Seymour at the Departments of Criti-cal Care Medicine and Emergency Medi-cine, University of Pittsburgh School of Medicine, 3550 Terrace St., Scaife Hall, Rm. 639, Pittsburgh, PA 15261, or at seymourcw@ upmc . edu.

This article was published on May 21, 2017, at NEJM.org.

DOI: 10.1056/NEJMoa1703058Copyright © 2017 Massachusetts Medical Society.

BACKGROUNDIn 2013, New York began requiring hospitals to follow protocols for the early iden-tification and treatment of sepsis. However, there is controversy about whether more rapid treatment of sepsis improves outcomes in patients.

METHODSWe studied data from patients with sepsis and septic shock that were reported to the New York State Department of Health from April 1, 2014, to June 30, 2016. Pa-tients had a sepsis protocol initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care for patients with sepsis (i.e., blood cultures, broad-spectrum antibiotic agents, and lactate measurement) completed within 12 hours. Multilevel models were used to assess the associations between the time until completion of the 3-hour bundle and risk-adjusted mortal-ity. We also examined the times to the administration of antibiotics and to the comple-tion of an initial bolus of intravenous fluid.

RESULTSAmong 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3-hour bundle com-pleted within 3 hours. The median time to completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P<0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P = 0.21).

CONCLUSIONSMore rapid completion of a 3-hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk-adjusted in-hospital mortality. (Funded by the Na-tional Institutes of Health and others.)

A BS TR AC T

Time to Treatment and Mortality during Mandated Emergency Care for Sepsis

Christopher W. Seymour, M.D., Foster Gesten, M.D., Hallie C. Prescott, M.D., Marcus E. Friedrich, M.D., Theodore J. Iwashyna, M.D., Ph.D.,

Gary S. Phillips, M.A.S., Stanley Lemeshow, Ph.D., Tiffany Osborn, M.D., M.P.H., Kathleen M. Terry, Ph.D., and Mitchell M. Levy, M.D.

Original Article

The New England Journal of Medicine Downloaded from nejm.org by Takahisa Kaneko on May 22, 2017. For personal use only. No other uses without permission.

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

Introduction

・毎年150万件以上のsepsis患者がアメリカで発⽣している.

CritCareMed2013;41:1167-74.

・sepsisやsepticshockはmedicalemergencyであり，すぐに治療や蘇⽣をすることが推奨されている.

IntensiveCareMed2017;43:304-77.

・sepsisに誘発された低灌流は最初の3時間以内に少なくとも30ml/kgの晶質液の投与が推奨される.

・可能な限り早期に1時間以内に抗菌薬を投与することが推奨される.

・empiricな広域抗菌薬の投与が推奨される.IntensiveCareMed2017;43:304-77.

Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Critical Care Medicine www.ccmjournal.org 1907

Objectives: We sought to systematically review and meta-analyze the available data on the association between timing of antibiotic administration and mortality in severe sepsis and septic shock.Data Sources: A comprehensive search criteria was performed using a predefined protocol.Study Selection: Inclusion criteria: adult patients with severe sep-sis or septic shock, reported time to antibiotic administration in relation to emergency department triage and/or shock recogni-tion, and mortality. Exclusion criteria: immunosuppressed popula-tions, review article, editorial, or nonhuman studies.Data Extraction: Two reviewers screened abstracts with a third reviewer arbitrating. The effect of time to antibiotic administration on mortality was based on current guideline recommendations: 1) administration within 3 hours of emergency department triage and 2) administration within 1 hour of severe sepsis/septic shock recognition. Odds ratios were calculated using a random effect model. The primary outcome was mortality.Data Synthesis: A total of 1,123 publications were identified and 11 were included in the analysis. Among the 11 included studies, 16,178 patients were evaluable for antibiotic administration from emergency department triage. Patients who received antibiotics more than 3 hours after emergency department triage (< 3 hr ref-erence) had a pooled odds ratio for mortality of 1.16 (0.92–1.46; p = 0.21). A total of 11,017 patients were evaluable for antibi-otic administration from severe sepsis/septic shock recognition. Patients who received antibiotics more than 1 hour after severe

sepsis/shock recognition (< 1 hr reference) had a pooled odds ratio for mortality of 1.46 (0.89–2.40; p = 0.13). There was no increased mortality in the pooled odds ratios for each hourly delay from less than 1 to more than 5 hours in antibiotic administration from severe sepsis/shock recognition.Conclusion: Using the available pooled data, we found no signifi-cant mortality benefit of administering antibiotics within 3 hours of emergency department triage or within 1 hour of shock recogni-tion in severe sepsis and septic shock. These results suggest that currently recommended timing metrics as measures of quality of care are not supported by the available evidence. (Crit Care Med 2015; 43:1907–1915)Key Words: antibacterial agents; antibiotics; septic shock; severe sepsis; shock recognition; timing of antibiotics

Severe sepsis and septic shock remain a major cause of emergency department (ED) visits and ICU admissions and are associated with significant morbidity, mortality,

and healthcare costs (1, 2). Previous studies have suggested improved outcomes with the implementation of a structured resuscitation, focusing largely on IV fluid resuscitation, timely broad-spectrum antibiotics, and vasopressor therapy (3–7). Although some authors have suggested the primacy of timely antibiotics administration for improved mortality in severe sepsis and septic shock (8, 9), previously published research evaluating the association of the time to antibiotic administra-tion on outcomes has produced disparate results.

In 2006, Kumar et al (10) reported a 7.6% increase in mortal-ity in patients with sepsis for each hourly delay after the onset of shock. Although subsequent studies have failed to demonstrate such substantial results, several studies have reported increased mortality associated with delays in antibiotic administration either from shock recognition or time from ED triage (8–10). Other studies have not demonstrated any increase in mortality with delay of antibiotic administration based on triage time (11, 12).

The most recent Surviving Sepsis Campaign (SSC) guide-lines include specific recommendations regarding the timing

Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.DOI: 10.1097/CCM.0000000000001142

*See also p. 2030.All authors: Department of Emergency Medicine, University of Mississippi School of Medicine, Jackson, MS.Dr. Sterling received support for article research from the National Institutes of Health (NIH). Her institution received grant support from the NIH (T32 training grant). Dr. Puskarich’s institution received grant support from the Emergency Medicine Foundation (Career Development Award) and National Institute of General Medical Sciences (K23 GM113041-01). Dr. Jones’ institution received grant support from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest.For information regarding this article, E-mail: [email protected]

The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis*

Sarah A. Sterling, MD; W. Ryan Miller, MD; Jason Pryor, MD; Michael A. Puskarich, MD; Alan E. Jones, MD

CCM2015;43:1907–1915)

⽬的:sepsis,septicshockに対して抗菌薬の早期投与は死亡率を改善するかを評価

⽅法:メタアナリシス対象:sepsis,septicshockにおける抗菌薬

投与時期と死亡率の関連についての11研究

結果:


Sterling et al

1912 www.ccmjournal.org

and more than 5 hours for further assessment of the effect of hourly delays to antibiotic administration from severe sepsis/shock recognition. The groups contained 848 deaths of 2,318 patients in the less than 1-hour group, 471 deaths of 1,298 patients in the 1- to 2-hour group, 323 deaths of 853 patients in the 2- to 3-hour group, 245 deaths of 615 patients in the 3- to 4-hour group, 193 deaths of 453 patients in the 4- to 5-hour group, and 1,537 deaths of 2,386 patients in the more than 5-hour group. We observed no statistical significant increased

mortality in the pooled ORs for each hourly incremental delay in antibiotic administra-tion from severe sepsis/shock recognition (Table 5).

DISCUSSIONThe SSC international guide-lines for the management of severe sepsis and septic shock recommend administer-ing antibiotics within 1 hour of recognition and within 3 hours of ED triage (13). Using the available published data, our results indicate that in patients with severe sepsis and septic shock, antibiotic administration within 3 hours of ED triage and/or within 1 hour of shock recognition is not associated with significant improvement in mortality. Our findings do not support the SSC guideline recommen-dations on timing of antibi-otic administration and raise concern about the use of time to antibiotic administration as currently recommended as a specific metric of treatment quality in sepsis care (13).

The recognition and treat-ment of severe sepsis and septic shock remain a complex and challenging burden for clini-cians with a persistently high mortality rate (1, 2, 12). In the past 15 years, research has sug-gested that an early structured approach to recognition and treatment of sepsis improves outcomes likely due to a com-bination of factors includ-ing heightened recognition or awareness, early reversal of microcirculatory or endothe-

lial dysfunction, reversal of hypoperfusion, and/or eradication of infectious nidus (3–5, 7). However, the results of studies focusing on the impact of timing of antibiotic administration have been inconsistent (8, 9, 11, 14, 19).

While it is recognized that failure to administer effective antimicrobial therapy will at some time point be detrimental to patient outcomes, the exact time frame when this shift begins to occur remains unknown. Furthermore, no randomized clin-ical trials examine the impact of the timing of antibiotics on

Figure 2. Summary of forest plots. A, Pooled odds ratios for mortality and time to antibiotics in less than or more than 3 hr from triage time. B, Pooled odds ratios for mortality and time to antibiotics in less than or more than 1 hr from severe sepsis/shock recognition.


Sterling et al

1912 www.ccmjournal.org

and more than 5 hours for further assessment of the effect of hourly delays to antibiotic administration from severe sepsis/shock recognition. The groups contained 848 deaths of 2,318 patients in the less than 1-hour group, 471 deaths of 1,298 patients in the 1- to 2-hour group, 323 deaths of 853 patients in the 2- to 3-hour group, 245 deaths of 615 patients in the 3- to 4-hour group, 193 deaths of 453 patients in the 4- to 5-hour group, and 1,537 deaths of 2,386 patients in the more than 5-hour group. We observed no statistical significant increased

mortality in the pooled ORs for each hourly incremental delay in antibiotic administra-tion from severe sepsis/shock recognition (Table 5).

DISCUSSIONThe SSC international guide-lines for the management of severe sepsis and septic shock recommend administer-ing antibiotics within 1 hour of recognition and within 3 hours of ED triage (13). Using the available published data, our results indicate that in patients with severe sepsis and septic shock, antibiotic administration within 3 hours of ED triage and/or within 1 hour of shock recognition is not associated with significant improvement in mortality. Our findings do not support the SSC guideline recommen-dations on timing of antibi-otic administration and raise concern about the use of time to antibiotic administration as currently recommended as a specific metric of treatment quality in sepsis care (13).

The recognition and treat-ment of severe sepsis and septic shock remain a complex and challenging burden for clini-cians with a persistently high mortality rate (1, 2, 12). In the past 15 years, research has sug-gested that an early structured approach to recognition and treatment of sepsis improves outcomes likely due to a com-bination of factors includ-ing heightened recognition or awareness, early reversal of microcirculatory or endothe-

lial dysfunction, reversal of hypoperfusion, and/or eradication of infectious nidus (3–5, 7). However, the results of studies focusing on the impact of timing of antibiotic administration have been inconsistent (8, 9, 11, 14, 19).

While it is recognized that failure to administer effective antimicrobial therapy will at some time point be detrimental to patient outcomes, the exact time frame when this shift begins to occur remains unknown. Furthermore, no randomized clin-ical trials examine the impact of the timing of antibiotics on

Figure 2. Summary of forest plots. A, Pooled odds ratios for mortality and time to antibiotics in less than or more than 3 hr from triage time. B, Pooled odds ratios for mortality and time to antibiotics in less than or more than 1 hr from severe sepsis/shock recognition.A:3時間以内に投与されたか

オッズ⽐1.16（0.92-1.46;p=0.21）B:1時間以内に投与されたか

オッズ⽐1.46（0.89-2.40;p=0.13）有意差なし

Feature Articles


consulted for Hill Rom, and lectured for Pulsion. His institution received grant support from Pulsion. The remaining authors have disclosed that they do not have any potential conflicts of interest.For information regarding this article, E-mail: [email protected]

Objectives: Compelling evidence has shown that aggressive resuscitation bundles, adequate source control, appropriate anti-biotic therapy, and organ support are cornerstone for the success in the treatment of patients with sepsis. Delay in the initiation of appropriate antibiotic therapy has been recognized as a risk factor for mortality. To perform a retrospective analysis on the Surviving Sepsis Campaign database to evaluate the relationship between timing of antibiotic administration and mortality.Design: Retrospective analysis of a large dataset collected pro-spectively for the Surviving Sepsis Campaign.Setting: One hundred sixty-five ICUs in Europe, the United States, and South America.Patients: A total of 28,150 patients with severe sepsis and septic shock, from January 2005 through February 2010, were evaluated.Interventions: Antibiotic administration and hospital mortality.Measurements and Main Results: A total of 17,990 patients received antibiotics after sepsis identification and were included in the analysis. In-hospital mortality was 29.7% for the cohort as a whole. There was a statically significant increase in the probability of death associated with the number of hours of delay for first antibiotic administration. Hospital mortality adjusted for severity (sepsis severity score), ICU admission source (emergency depart-ment, ward, vs ICU), and geographic region increased steadily after 1 hour of time to antibiotic administration. Results were simi-lar in patients with severe sepsis and septic shock, regardless of the number of organ failure.Conclusions: The results of the analysis of this large population of patients with severe sepsis and septic shock demonstrate that delay in first antibiotic administration was associated with increased in-hospital mortality. In addition, there was a linear

*See also p. 1931.1Department of Intensive Care, Mútua Terrassa University Hospital, CIBER Enfermedades Respiratorias, Barcelona, Spain.

2Critical Care Center, Sabadell Hospital, CIBER Enfermedades Respi-ratorias, Corporacion Sanitaria Universitaria Parc Tauli, Autonomous University of Barcelona, Sabadell, Spain.

3The Ohio State University Center for Biostatistics, Columbus, OH.4Department of Surgery and Emergency Medicine, Division of Acute Care Surgery, Surgical/Trauma Critical Care, Barnes Jewish Hospital, Wash-ington University, St. Louis, MO.

5California Pacific Medical Center, San Francisco, CA.6Brown University/Rhode Island Hospital, Providence, RI.7Cooper University Hospital, Camden, NJ.Dr. Levy had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Supplemental digital content is available for this article. Direct URL cita-tions appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).Initial funding for the Surviving Sepsis Campaign (from 2002 to 2006) was through unrestricted educational grants from Eli Lilly, Edwards Lifesciences, Phillips Medical Systems, and the Coalition for Critical Care Excellence (Society of Critical Care Medicine). There was no involvement by the spon-sors in the development, data analysis, or manuscript preparation of the current study. No additional funding has been received since that time or during the analysis and development of the current study and manuscript.Dr. Ferrer served as board member for Laboratorios Ferrer and lectured for Merck, Sharp and Dohme, and Pfizer. His institution received grant support from Instituto de Salud Carlos III. Mr. Phillips received support for participation in review activities from the Rhode Island Hospital, a Lifespan Partner. His institution received grant support from the National Institutes of Health Grant and Murdoch Children’s Research Institution. Dr. Osborn consulted for Institute of Healthcare Improvement (sepsis consultant on quality initiative); and received support for travel from American College of Emergency Physicians (Scientific Assembly 2011, 2012, 2013. Dr. Townsend received support for article research from the Gordon and Betty Moore Foundation. Dr. Dellinger received support for travel for the meeting of Surviving Sepsis Campaign (SSC) steer-ing committee. Dr. Artigas served as board member for Ferrer Farma, Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & WilkinsDOI: 10.1097/CCM.0000000000000330

Empiric Antibiotic Treatment Reduces Mortality in Severe Sepsis and Septic Shock From the First Hour: Results From a Guideline-Based Performance Improvement Program*

Ricard Ferrer, MD, PhD1; Ignacio Martin-Loeches, MD, PhD2; Gary Phillips, MAS3; Tiffany M. Osborn, MD, MPH4; Sean Townsend, MD5; R. Phillip Dellinger, MD, FCCP, FCCM6; Antonio Artigas, MD, PhD2; Christa Schorr, RN, MSN6; Mitchell M. Levy, MD, FCCP, FCCM7

CritCareMed2014Aug;42(8):1749-55.

⽬的:抗菌薬投与時期と死亡率の関係を評価

対象:ヨーロッパ,南アメリカ,アメリカ合衆国にある165のICUに⼊室したseveresepsis,septicshockの患者 28150例

⽅法:後ろ向き観察研究，多施設

結果:

Feature Articles


regression model uses the same seven time periods as shown in Table 1. Figure 2 illustrates the trend in hospital mortality over timing to first antibiotic, relative to suspicion of sepsis. Table 2 shows that the adjusted hospital mortality odds ratios steadily

increase from 1.00 to 1.52 as time to antibiotic administration increases from 0 to greater than 6 hours where 0–1 hour is the referent group. The probability of mortality increases from 24.6% to 33.1% and is based on a subject having the following characteristics: from the United States, admission source is the ED, and the SSS is 52 (median of all observations).

DISCUSSIONThe results of this study confirm, in the largest population of patients with severe sepsis and septic shock reported to date, that delay in antibiotic administration was associated with increased in-hospital mortality. In addition, we confirm the increasing risk associated with delay—there was a linear increase in the risk of mortality for each hour delay in anti-biotic administration from the first through the sixth hour after patient identification This relationship between delay in antibiotic administration and mortality has been demon-strated before by Kumar et al (5). However, the population in that study was patients with septic shock, and the delay was from the onset of hypotension. Our study findings are distinct and unique in the population studied and the location of these patients in the hospital: similar results were found in patients with either severe sepsis or septic shock, and consistent results were also seen when patients were stratified by severity (num-ber of organ failure) and whether sepsis was identified in the ED, on the wards, or in the ICU. This study demonstrates, for

Number of acute organ dysfunction

1 1,898 (40.1) 2,078 (45.2) 1,363 (45.1) 777 (44.8) 458 (44.2) 275 (43.0) 942 (42.1)

< 0.001

2 1,653 (35.0) 1,587 (34.5) 1,060 (35.1) 608 (35.1) 358 (34.5) 227 (35.5) 732 (32.7)

3 847 (17.9) 681 (14.8) 436 (14.4) 268 (15.5) 154 (14.9) 99 (15.5) 387 (17.3)

4 265 (5.6) 207 (4.5) 131 (4.3) 68 (3.9) 51 (4.9) 31 (4.8) 134 (6.0)

5 65 (1.4) 42 (0.9) 30 (1.0) 13 (0.8) 16 (1.5) 8 (1.3) 41 (1.8)

Cardiovascular

No cardiovascular dysfunction

376 (7.9) 379 (8.3) 265 (8.8) 168 (9.7) 115 (11.1) 57 (8.9) 349 (15.6)

< 0.001

Cardiovascular dysfunction no hypertension

803 (17.0) 1,004 (21.8) 659 (21.8) 402 (23.2) 174 (16.8) 116 (18.1) 403 (18.0)

Total shock 3,549 (75.1) 3,212 (69.9) 2,096 (69.4) 1,164 (67.2) 748 (72.1) 467 (73.0) 1,484 (66.4)

Lactate > 4 260 (5.5) 332 (7.2) 249 (8.3) 117 (6.8) 64 (6.2) 26 (4.1) 114 (5.1)

Vasopressors only

2,273 (48.1) 1,938 (42.2) 1,309 (43.3) 769 (44.4) 522 (50.3) 346 (54.1) 1,126 (50.4)

Lactate > 4 and vasopressors

1,016 (21.5) 942 (20.5) 538 (17.8) 278 (16.0) 162 (15.6) 95 (14.8) 244 (10.9)

IQR = interquartile range, LOS = length of stay, ED = emergency department.ap value based on Pearson chi-square test for categorical variables and Wilcox rank-sum test for continuous variables.

TABLE 1. (Continued). Patient Characteristics by Timing in Hours to the First Antibiotic

Patient Characteristic, n (%)

Antibiotic Timing (Hr)

pa0.0–1.0 1.0–2.0 2.0–3.0 3.0–4.0 4.0–5.0 5.0–6.0 > 6.0

Figure 2. Predicted hospital mortality and the associated 95% CIs for time to first antibiotic administration. The results are adjusted by the sepsis severity score (SSS), ICU admission source (emergency department [ED], ward, vs ICU), and geographic region (Europe, United States, and South America). Probability of hospital mortality is based on the subject having the following specific characteristics: the patient is from the United States, admission source is the ED, and the SSS is 52 (median of all observations).

コホート全体の死亡率は29.7%で初回抗菌薬投与の遅延は死亡率を有意に増加させた.

The timing of early antibiotics and hospital mortality in sepsis

Am J Respir Crit Care Med 2017; Epub ahead of print

⽬的：Sepsis患者への抗菌薬投与タイミングと死亡率の関連の検討対象：2010-2013年にカリフォルニア北部の21の救急部に搬送された患者のうちsepsisと診断された中から無作為に選択された35000⼈⽅法：多施設後ろ向き観察研究

結果:

抗菌薬投与の遅れと院内死亡オッズに相関が認められた

Early Lactate-Guided Therapy in Intensive CareUnit PatientsA Multicenter, Open-Label, Randomized Controlled Trial

Tim C. Jansen1, Jasper van Bommel1, F. Jeanette Schoonderbeek3, Steven J. Sleeswijk Visser4,Johan M. van der Klooster5, Alex P. Lima1, Sten P. Willemsen2, and Jan Bakker1, for the LACTATE study group*

1Department of Intensive Care, Erasmus MC University Medical Centre, Rotterdam, The Netherlands; 2Department of Biostatistics, UniversityMedical Centre Rotterdam, Rotterdam, The Netherlands; 3Department of Intensive Care, Ikazia Hospital, Rotterdam, The Netherlands; 4Departmentof Intensive Care, Reinier de Graaf Hospital, Delft, The Netherlands; and 5Department of Intensive Care, St. Franciscus Gasthuis, Rotterdam,The Netherlands

Rationale: It is unknown whether lactate monitoring aimed to de-crease levels during initial treatment in critically ill patients improvesoutcome.Objectives: To assess the effect of lactate monitoring and resuscita-tion directed at decreasing lactate levels in intensive care unit (ICU)patients admitted with a lactate level of greater than or equal to 3.0mEq/L.Methods: Patients were randomly allocated to two groups. In thelactate group, treatment was guided by lactate levels with theobjective to decrease lactate by 20% or more per 2 hours forthe initial 8 hours of ICU stay. In the control group, the treatmentteam had no knowledge of lactate levels (except for the admissionvalue) during this period. The primary outcome measure washospital mortality.Measurements and Main Results: The lactate group received morefluids and vasodilators. However, there were no significant differ-ences in lactate levels between the groups. In the intention-to-treatpopulation (348 patients), hospital mortality in the control groupwas 43.5% (77/177) compared with 33.9% (58/171) in the lactategroup (P 5 0.067). When adjusted for predefined risk factors,hospital mortality was lower in the lactate group (hazard ratio,0.61; 95% confidence interval, 0.43–0.87; P 5 0.006). In the lactategroup, Sequential Organ Failure Assessment scores were lowerbetween 9 and 72 hours, inotropes could be stopped earlier, andpatients could be weaned from mechanical ventilation and dis-charged from the ICU earlier.Conclusions: In patients with hyperlactatemia on ICU admission,lactate-guided therapy significantly reduced hospital mortalitywhen adjusting for predefined risk factors. As this was consistentwith important secondary endpoints, this study suggests that initiallactate monitoring has clinical benefit.Clinical trial registered with www.clinicaltrials.gov (NCT00270673).

Keywords: lactate; shock; central venous oxygenation; early goaldirected therapy; oxygen delivery

Increased blood lactate levels have been associated withsignificant morbidity and mortality ever since their first de-scription in 1843 by Scherer (1). Many studies have emphasizedthe prognostic importance of either a single lactate level (2) orlimited lactate reduction during treatment (3–5). Interestingly,the prognostic value of lactate levels seems to be independentfrom the underlying critical illness (6) or the presence of shockor organ failure (7).

Despite this strong and already long-lasting predictive powerof lactate levels, little evidence exists on what interventionswould benefit patients with increased lactate levels or a failureto reduce lactate (8). Earlier studies have shown that improvinglactate metabolism by the administration of dichloroacetatedecreases lactate levels but does not result in improved outcomein critically ill patients (9, 10). This could indicate that thedetrimental outcome associated with increased lactate levels ordelayed reduction is more likely related to the underlying causethan to the hyperlactatemia itself.

Both experimental (11) and clinical studies (12, 13) haveemphasized tissue hypoxia, characterized by supply-dependentoxygen consumption, as a cause of increased lactate levels.These findings would support therapy aimed at improving thebalance between the demand for oxygen by the tissues and thedelivery of oxygen to the tissues, by increasing oxygen deliveryand/or decreasing oxygen demand, in patients with increasedlactate levels or a failure to reduce lactate. However, as otherprocesses, not related to anaerobic metabolism, can also resultin increased blood lactate levels (14, 15), the efficacy of thelatter approach could be limited. In the literature, the efficacy of

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Increased blood lactate levels have been associated withsignificant morbidity and mortality. Nevertheless, it isunknown whether monitoring of lactate aimed to decreaselevels during initial treatment in critically ill patientsimproves outcome.

What This Study Adds to the Field

In patients with hyperlactatemia on ICU admission, lactatemonitoring followed by targeted treatment significantlyreduced ICU length of stay. In addition, ICU and hospitalmortality were reduced when adjusting for predefined riskfactors. This study suggests that initial treatment aimed atreducing lactate levels has clinical benefit.

(Received in original form December 23, 2010; accepted in final form May 11, 2010)

Supported by Pulsion Medical Systems AG (Munich, Germany), which providedthe CeVOX central venous oximetry monitors and catheters, and by RocheDiagnostics (Mannheim, Germany), which provided Accutrend hand-held lactateanalyzers. Sponsors have not been involved in the design of the study and havehad no access to the data, nor were they involved in the analysis of the data orcontent of this article.

* A complete list of members may be found at the end of the article.

Correspondence and requests for reprints should be addressed to Jan BakkerM.D., Ph.D., Department of Intensive Care, Erasmus MC University MedicalCentre, PO Box 2040 – Room Hs 324, 3000 CA Rotterdam, The Netherlands.E-mail: [email protected]

This article has an online supplement, which is accessible from this issue’s table ofcontents at www.atsjournals.org

Am J Respir Crit Care Med Vol 182. pp 752–761, 2010Originally Published in Press as DOI: 10.1164/rccm.200912-1918OC on May 12, 2010Internet address: www.atsjournals.org

Am J Respir Crit Care Med 2010;182: 752-61.

⽬的：⾎清乳酸値⾼値を認めた患者の乳酸濃度の低下させるための乳酸モニタリングによる死亡率を評価する.

対象：2006年2⽉から2008年3⽉までにオランダにあるICUに⼊室した患者で⾎清乳酸値3.0mEq/L以上の患者⽅法：多施設,open-label,RCT

treatment

therapy aimed at decreasing lactate levels is only indirectlysupported by observational studies (16–18) and studies evalu-ating goal-directed therapy aimed at optimizing oxygen delivery(19, 20). The landmark study in the latter respect by Rivers andcolleagues showed that early goal-directed therapy, aimed atimproving hemodynamics and oxygen delivery improved out-come in patients with severe sepsis and increased lactate levels(19). Only one randomized controlled single-center study hasspecifically studied the effects of a resuscitation strategy aimedat normalizing lactate levels (21). Although this study showeda decrease in morbidity associated with this therapeutic ap-proach, the findings cannot easily be extrapolated to the generalintensive care population, as only postcardiac surgery patientswere included.

Therefore, the primary objective of this multicenter studywas to test whether patients with elevated lactate levels (> 3.0mEq/L) on intensive care unit (ICU) admission would benefitfrom serial lactate monitoring, aimed to reduce these levels by20% per 2 hours, when compared with patients in whom seriallactate monitoring was not available. Secondary objectives werethe effects of lactate monitoring on the development of organfailure; the duration of mechanical ventilation; the use of ino-tropes, vasopressors, and renal replacement therapy; and thelength of ICU stay.

Some of the results of this study have been previously re-ported in the form of an abstract (22).

METHODS

Study Population

Patients were recruited from four Dutch mixed ICUs (one universityhospital and three university-affiliated hospitals) between February2006 and March 2008. All consecutive patients with a blood lactatelevel at or above 3.0 mEq/L on ICU admission were eligible forinclusion. We excluded patients with liver failure (prothrombin time .15 s or international normalized ratio equal to or greater than 1.5 andany hepatic encephalopathy [23]), after liver surgery, age less than18 years, a contraindication for central venous catheterization, epilepticseizures (grand mal, shortly before or during admission), an evidentaerobic cause of hyperlactatemia (at the discretion of the treatingphysician), or a do-not-resuscitate status.

Study Design

This was a multicenter, open-label randomized controlled study, con-ducted under supervision of an independent Data Safety MonitoringBoard (DSMB). The ethics committees of all participating centersapproved the study protocol. Because of the emergency nature andseverity of disease in the target population, patients were enrolledunder deferred consent: study procedures were temporarily allowed

Figure 1. (A) Treatment algorithm, controlgroup and lactate group. The goal for centralvenous pressure (CVP) was 12 to 15 mm Hg inmechanically ventilated patients. Besides thestatic CVP goals, CVP was used as a dynamicsafety limit during fluid challenges (27). Bothcrystalloids and colloids could be used at thediscretion of the clinician. Albumin was not astandard resuscitation fluid in the participat-ing centers. The goal for hemoglobin was10 g/dl in patients with cardiac ischemia.(Hemoglobin [Hb] 7.0 g/dl 5 4.3 mmol/L,10 g/dl 5 6.2 mmol/L). (B) Additional treat-ment algorithm, lactate group. If the lactatelevel became less than or equal to 2.0 mEq/L,a further decrease was no longer required. Fluidresponsiveness was assessed by a fluid challengeof 200 ml crystalloids or colloids. The goal wasan increase in blood pressure, ScvO2

, or strokevolume, or a decrease in heart rate. CVP wasused as a dynamic safety limit (27): if CVPincreased less than or equal to 2 mm Hg, fluidadministration was continued; if CVP increasedmore than 2 and less than or equal to 5 mm Hg,the fluid challenge was repeated after waitingfor 10 minutes; if CVP increased greater than orequal to 5 mm Hg, fluid administration wasstopped. Before administration of vasodilators,fluid responsiveness was assessed and fluids wereinfused if necessary. The recommended dose fornitroglycerin was 2 mg in 1/2 hour followed by2 mg per hour. Hb 7.0 g/dl 5 4.3 mmol/L,10 g/dl 5 6.2 mmol/L. MAP 5 mean arterialpressure; NTG 5 nitroglycerin; RBCs 5 redblood cell transfusions; SaO2 5 arterial oxygensaturation; ScvO2

5 central venous oxygensaturation; T 5 time; UP 5 urine production.

Jansen, van Bommel, Schoonderbeek, et al.: Early Lactate-Guided Therapy 753

treatment

without consent and, as soon as possible, written consent from thepatient or legal representative was obtained. The Dutch central com-mittee on research involving human subjects approved the use of alldata if the research procedures were finished or if the patient had diedbefore consent could be obtained (24).

The start of the study was defined as the time of the first availablelactate level immediately after ICU admission. For the next 8 hours(treatment period), patients were randomly allocated to either treat-ment aimed to decrease lactate levels by at least 20% per 2 hours or tostandard therapy, wherein the treatment team was blinded for theresults of lactate level measurements (except for the admission value).Thereafter, patients were followed up until discharge from the hospitalor death, whichever came first (observation period). The randomiza-tion, using a block size of eight, was stratified according to participatingcenter and the presence or absence of sepsis as defined by standardcriteria (25). Randomization was done with the use of opaque, sealedenvelopes. The statistician of the DSMB generated the random allo-cation sequence with the use of a computer program. Physicians en-rolled the patients and opened the envelope with the lowest availableregistration number within the appropriate stratum. By immediatelyfilling out name and date on the randomization form the connectionbetween the patient and the outcome of the randomization wassafeguarded. Physicians were unaware of the randomization block size.

Treatment assignment was not recorded in the medical chart orelectronic patient data monitoring system and clinicians on generalwards, who cared for the patients after ICU discharge, were not awareof the treatment assignment.

Treatment

Patients were treated according to their randomization group byqualified intensivists available 7 3 24 hours in a closed-format setting.In both groups the treating clinicians, and not the (principle) inves-

tigator(s), were primarily responsible for the treatment of the includedpatients. Duration of the 8-hour treatment period was based on thestudy of Polonen and colleagues (21). Thereafter, both groups receivedstandard treatment, during which lactate levels could be obtained in allpatients at the discretion of the treating physician.

In the control group, hemodynamic support was aimed at standardresuscitation endpoints, adapted from recently published guidelines(26) (Figure 1A): heart rate less than 100 beats/min, mean arterialpressure (MAP) at or above 60 mm Hg, central venous pressure (CVP)8–12 mm Hg (12–15 in mechanically ventilated patients) with the use ofCVP as a dynamic safety limit during fluid challenges (27), urinaryoutput more than 0.5 ml/kg/h, arterial oxygen saturation (SaO2

) at orabove 92%, and hemoglobin level at or above 7.0 g/dl (>10.0 g/dl incase of cardiac ischemia) (28). The use of central venous oxygensaturation (ScvO2

) and clinical assessment of peripheral perfusion (e.g.,by touching the skin or measuring capillary refill time [29]) was allowedat the discretion of the attending clinician. Most important, in thecontrol group lactate levels were not available for the treatment teamand patient during the treatment period.

In the lactate group, blood lactate levels were measured every2 hours. The therapeutic endpoints were identical to those in the con-trol group (Figure 1A). However, in addition, the therapeutic inter-ventions had to result in a decrease in the lactate level of at least 20%every 2 hours (cut-off level based on findings of two studies [3, 30]).This endpoint was to be achieved by a resuscitation strategy as outlinedin Figure 1B. ScvO2

was measured continuously with a fiberoptic probe(CeVOX; Pulsion Medical Systems AG, Munich, Germany), which wasinserted through a lumen of the central venous catheter. The centralvenous oxygenation parameter was used to balance oxygen deliverywith demand as suggested by Pinsky and Vincent (31). This probe wasremoved at the end of the treatment period. When ScvO2

was at orabove 70%, but lactate levels did not decrease by at least 20% during

Figure 1. (continued).

754 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 182 2010

P 5 0.91), therapeutic hypothermia (10% vs. 6%, P 5 0.20), anda percutaneous coronary intervention (1% vs. 1%, P 5 0.96).

During the observation period, more patients assigned to thelactate group received vasodilators when compared with thecontrol group (Table 3). During the observation period a trendtoward less use of fluids was observed in the lactate group whencompared with control group.

Mortality

In the control group 43.5% (77/177) of the patients did not sur-vive to hospital discharge, whereas in the lactate group 33.9%(58/171) died during their hospital stay (P 5 0.067, Table 4,Figure 2). When adjusted for the predefined risk factors atbaseline, the treatment protocol to decrease lactate levels re-sulted in a significant reduction in the risk of hospital death(hazard ratio [HR], 0.61; confidence interval [CI], 0.43–0.87;Table 4, Table E5).

Organ Failure, Inotropes, Vasopressors, Renal ReplacementTherapy, and Length of Stay

Patients assigned to the lactate group had reduced organ failure(SOFA score) in the observation period (Table 5). Patients inthe lactate group were faster weaned from mechanical ventila-tion (HR, 0.72; 95% CI, 0.54–0.98; Figure 3A) and inotropes(HR, 0.65; 95% CI, 0.42–1.00; Figure 3B) than patients in thecontrol group. More importantly, patients in the lactate groupcould be discharged from the ICU earlier (HR, 0.65; 95% CI,0.50–0.85; Figure 4).

There were no significant differences in the time to stopvasopressors (HR, 0.84; 95% CI, 0.61–1.15; Figure 3C) or renalreplacement therapy (HR, 0.56; 95% CI, 0.22–1.43; Figure 3D)between both groups.

Subgroup and Exploratory Analyses

Prespecified and post hoc specified subgroup analyses areshown in Figure 5. In addition, two post hoc exploratoryanalyses were performed to investigate the difference instatistical significance between the unadjusted and the ad-justed primary outcome. First, when adding interaction termsfor age and APACHE II score to the predefined multivariable

model for hospital mortality, effect modification could not bedemonstrated (age 3 randomization group [P 5 0.74] andAPACHE II score 3 randomization group [P 5 0.85]).Second, when excluding six patients with missing data oncovariates (APACHE II and SOFA scores at 0 h), effect sizeand P value remained similar (data not shown).

DISCUSSION

In this multicenter, open-label randomized controlled study,lactate monitoring during the first 8 hours of ICU admission,aimed at reducing lactate levels by at least 20% per 2 hours,significantly reduced ICU length of stay and also ICU andhospital mortality when adjusting for predefined and commonlyaccepted risk factors.

There was a discrepancy in statistical significance betweenthe adjusted and unadjusted analysis of the study’s primaryoutcome measure. This could not be explained by different datasets being used due to missing data or by a heterogeneous effectof the randomization therapy in some end of the spectrum ofage or APACHE II score. Instead, this difference might prob-

Figure 2. Kaplan-Meier survival curve. Survival was fol-lowed up until hospital discharge. The longest duration ofhospital stay was 196 days.

TABLE 5. DISEASE SEVERITY AND ORGAN FAILURE

Hours after Start of Therapy Control Group Lactate Group P Value

APACHE II scoreBaseline (0 h) 15.6 (14.4–16.8) 16.3 (15.1–17.5) 0.288 13.4 (12.2–14.7) 13.0 (11.8–14.3) 0.520–8 14.5 (13.4–15.7) 14.7 (13.5–15.8) 0.789–72 10.5 (9.3–11.6) 9.9 (8.7–11.0) 0.17SOFA scoreBaseline (0 h) 6.4 (5.6–7.1) 6.4 (5.6–7.1) 0.898 7.2 (6.5–7.9) 6.9 (6.2–7.6) 0.270–8 6.8 (6.0–7.5) 6.8 (6.0–7.5) 0.589–72 7.0 (6.3–7.7) 6.4 (5.7–7.2) 0.009

Definition of abbreviations: APACHE 5 Acute Physiology and Chronic HealthEvaluation; CI 5 confidence interval; SOFA 5 Sequential Organ Failure Assess-ment.

The adjusted mean values (95% CI) were obtained from mixed model analysis.APACHE II and SOFA scores were calculated at the various time points (0, 8, 24,48, and 72 h after study entry).

Jansen, van Bommel, Schoonderbeek, et al.: Early Lactate-Guided Therapy 757

結果:

乳酸値モニタリングを⾏なった⽅がリスク調整院内死亡率が低かった.

・早期の抗菌薬投与はした⽅が良さそう. ・乳酸値も測った⽅が良さそう

・しかしどのくらい早く測定, 投与すればいいのかはコンセンサスが得られていない状況.

今回NewYorkでのsepsis,septicshockについて治療のタイミングとリスク調整死亡率との関連性を検討した.

Methods

Design

【setting】多施設後ろ向き研究

【患者】2014年4⽉1⽇から2016年6⽉30⽇までにNewYorkStateDepartmentofHealth(NYSDOH)のデータベースに登録された185施設のsepsis, septicshockの患者

Inclusioncriteria

・Sepsis2により定義されるseveresepsis，septicshockの患者で17歳以上の患者.

・病院到着後６時間以内に救急部でsepsisprotocolが開始されたもの.

SepsisprotocoluNYSDOHが2013年に定めた医療施設が作成すべきプロトコル

の要件

1. Sepsis,septicshockの早期診断のための⼿順2. プロトコルを適⽤すべきか否かの判断基準の明

⽰3. ⾎⾏動態補助の明確な⽬標(⾎圧やバイオマー

カー等)の設定およびモニタリング⽅法の設定4. 感染部位特定のための⼿順、および抗菌薬投与

までの⽬標時間の設定5. 侵襲的治療および⾎管作動薬の導⼊の基準

これらを満たせば施設ごとに作成が可能だが、この他に3hourbundleおよび6hourbundleを盛り込むことが求められた

bundle 適応内容

3hour Sepsis,septicshock

広域抗菌薬の投与

抗菌薬使⽤前の⾎液培養の採取

⾎清乳酸値の測定

6hour

sBP<90mmHg,⾎清乳酸値≥4.0

30ml/kgの輸液ボーラス

難治性の低⾎圧に対する昇圧剤の使⽤6時間以内の⾎清乳酸値の再測定

exclusioncriteria

・3hour bundleが完了するのに１２時間以上かかったもの

・bundle care が禁忌であるもの・治療制限があるのもの・他の臨床試験に参加しているもの・介⼊を拒否したもの・敗⾎症症例が50例以下の施設

Primaryoutcome

院内調整死亡率

【リスク調整モデル】

年齢，⺠族，収⼊など⼈⼝統計的要因，感染源，保険，ショック，⾎清乳酸値，⾎⼩板値，⼈⼯呼吸器装着の有無を変数とした⽤いたロジスティック回帰モデルを作成を⾏った.

Analyses

【解析】３時間以内に3-hour bundleを完了した群とそうでない群について⼆変量解析を⾏った.

【Software】Statasoftware,version14.2

Results

Populationofpatients

6

Figure S1. Patient accrual.

All cases, 185 hospitalsN=111,816

Eligible cases, 149 hospitalsN= 90,770

Duplicate encounters N=9,171Age<18 years N=1,105Clinically contraindicated N=3,763Advanced directive present N=2,840Declined participation N=1,013Enrolled in concomitant trial N=1Transferred from another hospital N=2,566Hospital with fewer than 50 cases N=587

Protocol initiated outside of ED N=32,665Protocol initiated > 6 hrs after ED arrival N=3,6483-hour bundle not completed within 12 hrs N=4,759Discharged within 12 hrs of protocol initiated N=367

Study population, 149 hospitalsN=49,331

3-hr bundle completed N=40,696

3-hr bundle not completed in 3 hrsN=8,635

Excluded

Excluded

Populationofpatients

6

Figure S1. Patient accrual.

All cases, 185 hospitalsN=111,816

Eligible cases, 149 hospitalsN= 90,770

Duplicate encounters N=9,171Age<18 years N=1,105Clinically contraindicated N=3,763Advanced directive present N=2,840Declined participation N=1,013Enrolled in concomitant trial N=1Transferred from another hospital N=2,566Hospital with fewer than 50 cases N=587

Protocol initiated outside of ED N=32,665Protocol initiated > 6 hrs after ED arrival N=3,6483-hour bundle not completed within 12 hrs N=4,759Discharged within 12 hrs of protocol initiated N=367

Study population, 149 hospitalsN=49,331

3-hr bundle completed N=40,696

3-hr bundle not completed in 3 hrsN=8,635

Excluded

Excluded

Characteristics

男⼥⽐はほぼ等しい.

年齢の中央値が73歳と⾼齢.

Septic shockは45％程度


Time to Treatment and Mortality in Emergency Sepsis Care

of in-hospital death than patients in whom all three items in the 3-hour bundle were completed in 3 hours (odds ratio, 1.14; 95% CI, 1.07 to 1.21; P<0.001). The association between the time to the administration of antibiotics and in-hospital

mortality was similar (odds ratio of death until antibiotics were administered, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) (Fig. S3 in the Supplementary Appendix). Patients who received antibiotics in hours 3 through 12 had 14% higher

CharacteristicAll Patients (N = 49,331) 3-Hr Bundle Completed in 3 Hr P Value*

Yes (N = 40,696)

No (N = 8635)

Percentage of patients 100.0 82.5 17.5 —

Age at admission — yr <0.001

Median 73 73 71

Interquartile range 60–83 61–84 59–82

Female sex — no. (%) 23,634 (47.9) 19,157 (47.1) 4477 (51.8) <0.001

Race — no. (%)† <0.001

White 33,075 (67.0) 27,605 (67.8) 5470 (63.3)

Black 8,269 (16.8) 6,487 (15.9) 1782 (20.6)

Asian 2,167 (4.4) 1,774 (4.4) 393 (4.6)

Other 5,820 (11.8) 4,830 (11.9) 990 (11.5)

Hispanic ethnic group — no. (%)† 4,851 (9.8) 4,022 (9.9) 829 (9.6) 0.39

Coexisting condition — no. (%)

Chronic respiratory failure 5,738 (11.6) 4,656 (11.4) 1082 (12.5) 0.004

Congestive heart failure 10,092 (20.5) 8,311 (20.4) 1781 (20.6) 0.67

End-stage renal disease 5,207 (10.6) 4,109 (10.1) 1098 (12.7) <0.001

Admission source — no. (%) <0.001

Home 33,464 (67.8) 27,306 (67.1) 6158 (71.3)

Skilled nursing facility 13,233 (26.8) 11,247 (27.6) 1986 (23.0)

Other‡ 2,634 (5.3) 2,143 (5.3) 491 (5.7)

Site of infection — no. (%) <0.001

Urinary 13,439 (27.2) 10,963 (26.9) 2476 (28.7)

Respiratory 19,839 (40.2) 16,806 (41.3) 3033 (35.1)

Gastrointestinal 4,649 (9.4) 3,580 (8.8) 1069 (12.4)

Other§ 11,404 (23.1) 9,347 (23.0) 2057 (23.8)

Positive blood cultures — no. (%) 14,574 (29.5) 12,322 (30.3) 2252 (26.1) <0.001

Serum lactate — mmol/liter <0.001

Median 2.7 2.8 2.5

Interquartile range 1.7–4.4 1.8–4.4 1.6–4.1

Septic shock — no. (%) 22,336 (45.3) 18,393 (45.2) 3943 (45.7) 0.43

Teaching facility — no. (%) 40,257 (81.6) 7,739 (19.0) 7300 (84.5) <0.001

In-hospital death — no. (%) 11,251 (22.8) 9,213 (22.6) 2038 (23.6) 0.05

* P values are based on Pearson’s chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous variables.

† Race and ethnic group were determined from medical records.‡ Other locations include clinic or unknown.§ Other site of infection includes skin, central nervous system, and unknown.

Table 1. Characteristics of the Patients.





of in-hospital death than patients in whom all three items in the 3-hour bundle were completed in 3 hours (odds ratio, 1.14; 95% CI, 1.07 to 1.21; P<0.001). The association between the time to the administration of antibiotics and in-hospital

mortality was similar (odds ratio of death until antibiotics were administered, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) (Fig. S3 in the Supplementary Appendix). Patients who received antibiotics in hours 3 through 12 had 14% higher

CharacteristicAll Patients (N = 49,331) 3-Hr Bundle Completed in 3 Hr P Value*

Yes (N = 40,696)

No (N = 8635)

Percentage of patients 100.0 82.5 17.5 —

Age at admission — yr <0.001

Median 73 73 71

Interquartile range 60–83 61–84 59–82

Female sex — no. (%) 23,634 (47.9) 19,157 (47.1) 4477 (51.8) <0.001

Race — no. (%)† <0.001

White 33,075 (67.0) 27,605 (67.8) 5470 (63.3)

Black 8,269 (16.8) 6,487 (15.9) 1782 (20.6)

Asian 2,167 (4.4) 1,774 (4.4) 393 (4.6)

Other 5,820 (11.8) 4,830 (11.9) 990 (11.5)

Hispanic ethnic group — no. (%)† 4,851 (9.8) 4,022 (9.9) 829 (9.6) 0.39

Coexisting condition — no. (%)

Chronic respiratory failure 5,738 (11.6) 4,656 (11.4) 1082 (12.5) 0.004

Congestive heart failure 10,092 (20.5) 8,311 (20.4) 1781 (20.6) 0.67

End-stage renal disease 5,207 (10.6) 4,109 (10.1) 1098 (12.7) <0.001

Admission source — no. (%) <0.001

Home 33,464 (67.8) 27,306 (67.1) 6158 (71.3)

Skilled nursing facility 13,233 (26.8) 11,247 (27.6) 1986 (23.0)

Other‡ 2,634 (5.3) 2,143 (5.3) 491 (5.7)

Site of infection — no. (%) <0.001

Urinary 13,439 (27.2) 10,963 (26.9) 2476 (28.7)

Respiratory 19,839 (40.2) 16,806 (41.3) 3033 (35.1)

Gastrointestinal 4,649 (9.4) 3,580 (8.8) 1069 (12.4)

Other§ 11,404 (23.1) 9,347 (23.0) 2057 (23.8)

Positive blood cultures — no. (%) 14,574 (29.5) 12,322 (30.3) 2252 (26.1) <0.001

Serum lactate — mmol/liter <0.001

Median 2.7 2.8 2.5

Interquartile range 1.7–4.4 1.8–4.4 1.6–4.1

Septic shock — no. (%) 22,336 (45.3) 18,393 (45.2) 3943 (45.7) 0.43

Teaching facility — no. (%) 40,257 (81.6) 7,739 (19.0) 7300 (84.5) <0.001

In-hospital death — no. (%) 11,251 (22.8) 9,213 (22.6) 2038 (23.6) 0.05

* P values are based on Pearson’s chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous variables.

† Race and ethnic group were determined from medical records.‡ Other locations include clinic or unknown.§ Other site of infection includes skin, central nervous system, and unknown.

Table 1. Characteristics of the Patients.



Characteristics

感染源としては肺が最も多く、ついで泌尿器，消化器の順であった.

17

Table S4. Additional patient characteristics

3-hour bundle completed in 3 hours

All patients Yes No P value†

No. 49,331 (100.0) 40,696 (82.5) 8,635 (17.5)

Site of infection, no. (%) Urinary 13,439 (27.2) 10,963 (26.9) 2,476 (28.7) <0.001

Respiratory 19,839 (40.2) 16,806 (41.3) 3,033 (35.1)

Gastrointestinal 4,649 (9.4) 3,580 (8.8) 1,069 (12.4)

Skin 3,480 (7.1) 2,921 (7.2) 559 (6.5)

Central Nervous System 239 (0.5) 201 (0.5) 38 (0.4)

Other 3,770 (7.6) 3,073 (7.6) 697 (8.1)

Unknown 3,915 (7.9) 3,152 (7.8) 763 (8.8)

Positive blood cultures, no. (%) <0.001

Gram positive 7,178 (14.5) 6,078 (14.9) 1,100 (12.7)

Gram negative 6,431 (13.0) 5,455 (13.4) 976 (11.3)

Other ^ 965 (2.0) 789 (1.9) 176 (2.0)

None 34,757 (70.5) 28,374 (69.2) 6,383 (73.9) First serum lactate > 4.0 mmol/L, no. (%) 14,143 (28.7) 11,941 (29.3) 2,205 (25.5) < 0.001

Persistent hypotension, no. (%) 19,469 (39.5) 15,915 (39.1) 3,554 (41.2) < 0.001

† p-values based on Pearson chi-square for categorical variables and the Wilcoxon rank-sum test for continuous variables ^ Other includes anaerobic, mixed, viral, fungal, and yeast cultures

Characteristics

21

Table S7. Hospital characteristics stratified by quartile of reliability-adjusted rate of completing

the 3-hr bundle within 3 hours.

Characteristic Quartiles of the probability of completing the 3-hour bundle

in 3 hours 1st 2nd 3rd 4th

Lowest Below median

Above median Highest

No. of hospitals 38 41 35 35 No. of patients 12,647 12,048 12,891 11,745 Serum lactate, median [IQR], mmol/L 2.8 [1.8 - 4.5] 2.7 [1.7 - 4.3] 2.7 [1.7 - 4.4] 2.7 [1.7 - 4.3]

Area, no. (%) * Metro 37 (97.4) 32 (78.1) 30 (85.7) 31 (88.6) Rural 1 (2.65) 9 (21.9) 5 (14.3) 4 (11.4)

Teaching facility, no. (%) ~ No 8 (21.0) 14 (34.1) 10 (28.6) 16 (45.7) Yes 30 (79.0) 27 (65.9) 25 (71.4) 19 (54.3)

Number of hospital beds, median (IQR) 312 (223-464) 265 (130-362) 312 (192-514) 228 (171-375)

*Teaching hospital defined by NYSDOH using graduate medical education codes on Medicaid

clams, verified by the Office of Primary Care and Health Systems Management and the

Department of Education

~Hospital rurality is defined by rural-urban commuting codes, where rural corresponds to non-

metropolitan / urban population

3-hour bundleの遵守率はNot teaching facilityの割合が⾼く、teaching facilityでは遵守率が低かった.

Timetotreatment



dow. Continuous data are expressed as means with standard deviations or as medians with in-terquartile ranges, depending on normality. Cat-egorical variables are shown as proportions. The range and variability in the times to treatments are shown with the use of histograms and cumu-lative proportions.

Multivariable modeling of the association between the time to treatment and in-hospital mortality was performed with the use of logistic regression, with adjustment for covariates. Binary variables were modeled as indicator covariates, and continuous variables were included as linear covariates, after assessment for nonlinear rela-tionships with the use of fractional polynomials (P>0.05 for all models).14 We used multilevel re-gression with a random effect of hospital to ac-count for hospital-level clustering. Each exposure (i.e., time to completion of the 3-hour bundle, time to the administration of broad-spectrum antibiotics, and time to completion of initial bolus of intravenous fluids) was evaluated separately. The risk of in-hospital death across the range of time to treatment was generated for the “typical” patient with the use of predictive margins that were adjusted for an average of the independent variables, as appropriate. We show adjusted risk estimates that are derived from the nonlinear mod-els in order to show changes in risk over time.14

We used empirical Bayesian methods to de-termine the hospital-level rate of completion of the 3-hour bundle within 3 hours, administration of antibiotics within 3 hours, and completion of the initial bolus of intravenous fluids within 6 hours.9 We show the ranked order of adjusted rates across hospitals in caterpillar plots. All the analyses were performed with the use of Stata software, version 14.2 (StataCorp).

R esult s

Population of Patients and Time to TreatmentOf 111,816 patients at 185 hospitals, we excluded 21,046 patients (18.8%) who were ineligible, 32,665 (29.2%) who had protocols initiated outside the emergency department, 3648 (3.3%) who had pro-tocols initiated after 6 hours, and 5126 (4.6%) who did not have the 3-hour bundle completed within 12 hours (Fig. S1 and Table S3 in the Supplemen-tary Appendix). Of the remaining 49,331 eligible patients in the emergency department at 149 hos-pitals, most (40,696 patients [82.5%]) had the 3-hour bundle completed within 3 hours.

The median time to the completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administra-tion of broad-spectrum antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the me-dian time to the completion of the initial bolus of intravenous fluids was 2.56 hours (interquar-tile range, 1.33 to 4.20) (Fig. 1). The characteris-tics of the patients who had the 3-hour bundle completed within 3 hours were similar to those who had the bundle completed during hours 3 through 12 (Table 1, and Table S4 in the Supple-mentary Appendix).

Primary AnalysesIn a multivariable model, each hour of time to the completion of the 3-hour bundle was associated with higher mortality (odds ratio of death until completion of 3-hour bundle, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P<0.001) (Fig. 2, and Table S5 in the Supplementary Ap-pendix). Patients who had the bundle completed during hours 3 through 12 had 14% higher odds

Figure 1. Cumulative Probability of Completion of the 3-Hour Bundle, Administration of Broad-Spectrum Antibiotics, and Completion of the Initial Intravenous-Fluid Bolus after the Time That the Sepsis Protocol Was Initiated.

The 3-hour bundle for the care of patients with sepsis or septic shock had to include receipt of the following care within 3 hours: obtaining of a blood culture before the administration of antibiotics, measurement of the serum lactate level, and the administration of broad-spectrum antibiotics; however, protocols could be tai-lored by each hospital. We also assessed the time to the administration of broad-spectrum antibiotics and the time to the completion of an initial bolus of intra-venous fluids.

Cum

ulat

ive

Prob

abili

ty

1.0

0.6

0.8

0.4

0.2

0.01 2 3 4 5 6 7 8 9 10 11 12

Time after Protocol Initiation (hr)

3-Hr bundle completed

Broad-spectrum antibiotics administered

Initial intravenous-fluid bolus completed



49,331⼈の内３時間以内に3 hour bundleを完了した患者は40,696 ⼈(82.5%)であった.

3 hour bundle完了までの中央値；1.3時間広域抗⽣剤投与までの中央値；0.95時間静脈内ボーラス投与までの中央値；2.56時間

Primaryanalyses



odds of in-hospital death than those who received antibiotics within 3 hours (odds ratio, 1.14; 95% CI, 1.06 to 1.22; P = 0.001). These associations ap-peared to be stronger among patients receiving vasopressors than among those who were not receiving vasopressors (Fig. 2, and Fig. S3 in the Supplementary Appendix). Figure 3 shows the crude and predicted risks of in-hospital death across a range of times to treatment in typical patients who presented to the emergency depart-ment. On average, the completion of the 3-hour bundle at 6 hours was associated with mortality that was approximately 3 percentage points high-er than the mortality associated with completion of the bundle within the first hour.

Among the 26,978 patients who were eligible for and had the bolus of intravenous fluids com-pleted within 12 hours, the time to completion of the fluid bolus was not associated with in-hospital mortality (odds ratio of death until fluid bolus was completed, 1.01 per hour; 95% CI, 0.99

to 1.02; P = 0.21) (Fig. S4 in the Supplementary Ap-pendix). Patients who had the initial fluid bolus completed during hours 6 through 12 had an odds of in-hospital death that was similar to that among patients who had the initial fluid bolus completed within 6 hours (odds ratio of death for >6 hours to complete intravenous-fluid bolus, 1.02; 95% CI, 0.92 to 1.14; P = 0.65). We found no interaction between time to the administration of antibiotics and time to completion of the ini-tial bolus of intravenous fluids (P = 0.88).

Additional AnalysesA sensitivity analysis that used the earliest time of arrival in the emergency department to mea-sure the time to treatment showed an association that was similar to that in the primary analyses. The results were unchanged when hospice dis-charges were reclassified as in-hospital deaths or when we excluded patients who had treatments completed before protocol initiation. When the

Figure 2. Risk-Adjusted Odds Ratios of In-Hospital Death in the Primary Model and Prespecified Subgroups.

Shown are odds ratios, with 95% confidence intervals, for in-hospital death for each hour that it took to complete the 3-hour bundle. Other site of infection includes gastrointestinal, skin, central nervous system, and unknown.

All patientsSex

MaleFemale

Vasopressor useYesNo

Admission sourceHomeOther

Coexisting conditionCongestive heart failureHemodialysisChronic respiratory failure

Site of infectionRespiratoryUrinaryOther

BacteremiaGram positiveGram negativeOtherNone

No. of Patients Odds Ratio (95% CI)Subgroup

49,331

25,68923,634

16,72132,610

33,46415,867

10,0925,2075,738

19,83913,43916,053

7,1756,431

96534,757

1.0 1.1 1.3

In-Hospital DeathMore Likely

In-Hospital DeathLess Likely

1.04 (1.02–1.05)

1.04 (1.02–1.05)1.03 (1.02–1.05)

1.05 (1.03–1.07)1.02 (1.00–1.03)

1.04 (1.02–1.05)1.04 (1.02–1.06)

1.06 (1.04–1.09)1.06 (1.03–1.09)1.06 (1.03–1.09)

1.03 (1.01–1.06)1.03 (1.01–1.06)1.04 (1.02–1.06)

1.01 (0.98–1.05)1.05 (1.01–1.09)1.15 (1.07–1.24)1.03 (1.02–1.05)











All patientsSex

MaleFemale







49,331

25,68923,634

16,72132,610

33,46415,867

10,0925,2075,738

19,83913,43916,053

7,1756,431

96534,757

1.0 1.1 1.3



1.04 (1.02–1.05)

1.04 (1.02–1.05)1.03 (1.02–1.05)

1.05 (1.03–1.07)1.02 (1.00–1.03)

1.04 (1.02–1.05)1.04 (1.02–1.06)

1.06 (1.04–1.09)1.06 (1.03–1.09)1.06 (1.03–1.09)

1.03 (1.01–1.06)1.03 (1.01–1.06)1.04 (1.02–1.06)

1.01 (0.98–1.05)1.05 (1.01–1.09)1.15 (1.07–1.24)1.03 (1.02–1.05)



1時間抗菌薬投与が遅れるごとに死亡率が上昇する（オッズ⽐1.04/hour）

Subgroupanalyses









All patientsSex

MaleFemale







49,331

25,68923,634

16,72132,610

33,46415,867

10,0925,2075,738

19,83913,43916,053

7,1756,431

96534,757

1.0 1.1 1.3



1.04 (1.02–1.05)

1.04 (1.02–1.05)1.03 (1.02–1.05)

1.05 (1.03–1.07)1.02 (1.00–1.03)

1.04 (1.02–1.05)1.04 (1.02–1.06)

1.06 (1.04–1.09)1.06 (1.03–1.09)1.06 (1.03–1.09)

1.03 (1.01–1.06)1.03 (1.01–1.06)1.04 (1.02–1.06)

1.01 (0.98–1.05)1.05 (1.01–1.09)1.15 (1.07–1.24)1.03 (1.02–1.05)











All patientsSex

MaleFemale







49,331

25,68923,634

16,72132,610

33,46415,867

10,0925,2075,738

19,83913,43916,053

7,1756,431

96534,757

1.0 1.1 1.3



1.04 (1.02–1.05)

1.04 (1.02–1.05)1.03 (1.02–1.05)

1.05 (1.03–1.07)1.02 (1.00–1.03)

1.04 (1.02–1.05)1.04 (1.02–1.06)

1.06 (1.04–1.09)1.06 (1.03–1.09)1.06 (1.03–1.09)

1.03 (1.01–1.06)1.03 (1.01–1.06)1.04 (1.02–1.06)

1.01 (0.98–1.05)1.05 (1.01–1.09)1.15 (1.07–1.24)1.03 (1.02–1.05)



Subgroupanalyses



time window for protocol initiation or comple-tion of the 3-hour bundle was relaxed to 24 hours, the association between completion of the bolus of intravenous fluids and mortality became sig-nificant, albeit of very small magnitude (odds ratio 1.001; 95% CI, 1.000 to 1.002; P = 0.03). Details are provided in Table S6 in the Supplementary Appendix.

In supporting analyses, we found that the time to obtaining a blood culture was associated with mortality (odds ratio, 1.04 per hour; 95% confidence interval, 1.02 to 1.06; P<0.001). Similar findings were observed for each hour until se-rum lactate measurement (Figs. S5 and S6 in the Supplementary Appendix). The quantitative bias analysis indicated that our results would be ro-bust unless an unmeasured confounder was at least twice as prevalent among patients who had the 3-hour bundle completed later as among those who had it completed 1 hour earlier and unless the unmeasured confounder increased the odds of in-hospital death by more than 1.35 times (Fig. S7 in the Supplementary Appendix).

The risk-adjusted and reliability-adjusted rates of completing the 3-hour bundle ranged from 53 to 97% (median, 83%; interquartile range, 75 to 88) (Fig. 4, and Fig. S8 in the Supplementary Ap-pendix). After we ranked hospitals from the low-est to greatest likelihood of completing the 3-hour bundle, the hospitals in the highest decile, despite similar illness severity among their patients, were 1.5 times as likely to complete the 3-hour bundle as hospitals in the lowest decile (94.3% vs. 64.1%). Hospitals that had a higher rate of bundle com-pletion within 3 hours were somewhat smaller and less likely to be teaching hospitals than those that took longer than 3 hours to complete the bundle (Table S7 in the Supplementary Appendix).

Discussion

Our findings support an association between time to treatment and outcome among patients with sepsis or septic shock treated in the emer-gency department during a statewide initiative mandating protocolized care. We found that a longer time to completion of a 3-hour bundle of care for patients with sepsis and the administra-tion of broad-spectrum antibiotics were each associated with higher risk-adjusted in-hospital mortality. In our primary analysis, we did not find an association between the time to completion

Figure 3. Crude In-Hospital Mortality and Predicted Risks of In-Hospital Death.

Shown are the crude in-hospital mortality and predict-ed risks of in-hospital death, with adjustment for co-variates across a range of time after protocol initiation, for the completion of the 3-hour bundle of sepsis care (Panel A), the administration of broad-spectrum anti-biotics (Panel B), and the completion of the initial bo-lus of intravenous fluids (Panel C) in a typical patient. I bars represent 95% confidence intervals.

In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12

Time to Completion of 3-Hr Bundle (hr)

Crude

Risk adjusted

5

A 3-Hr Bundle

In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12

Time to Administration of Antibiotics (hr)

Crude

Risk adjusted

5

B Administration of Antibiotics

In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12

Time to Completion of Bolus (hr)

Crude

Risk adjusted

5

C Initial Bolus of Intravenous Fluids



6時間で3-hourbundleの完了した群は、最初の1時間で完了した群に⽐べリスク調整死亡率約3％⾼かった

Subgroupanalyses






Discussion




In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12


Crude

Risk adjusted

5

A 3-Hr Bundle

In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12


Crude

Risk adjusted

5


In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12


Crude

Risk adjusted

5




抗菌薬投与に関しても同様の傾向が⾒られた

Subgroupanalyses






Discussion




In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12


Crude

Risk adjusted

5

A 3-Hr Bundle

In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12


Crude

Risk adjusted

5


In-H

ospi

tal M

orta

lity

(%)

35

25

30

20

00 1 2 3 4 5 6 7 8 9 10 11 12


Crude

Risk adjusted

5




12時間以内に静脈内ボーラスが完了した患者26,978⼈のうち、ボーラス投与の完了までの時間は、病院内死亡率と関連していなかった。

Additionalanalyses

20

Table S6. Sensitivity analyses

Model No. of encounters in the model

OR (95%CI) for one hour change in completing the 3-hr bundle

OR (95%CI) for hour change in administration of antibiotics

OR (95%CI) for hour change in completing the initial IV fluid bolus

Primary cohort 49,331 1.036

(1.023 – 1.048) p < 0.001

1.046 (1.030 – 1.061)

p < 0.001

1.009 (0.995 – 1.022)

p = 0.215

Includes protocol initiated within 24 hours after ED arrival

51,573 1.035

(1.023 – 1.047) p < 0.001

1.044 (1.029 – 1.059)

p < 0.001

1.001 (1.000 – 1.002)

p = 0.029

All encounters with 3-hour bundle completed up to 24 hours after protocol initiated

49,921 1.023

(1.015 – 1.030) p < 0.001

1.034 (1.028 – 1.045)

p < 0.001

1.001 (1.000 – 1.003)

p = 0.012

Up to 24 hours for protocol initiated and up to 24 hours to complete the 3 hour bundle

52,902 1.025

(1.018 – 1.033) p < 0.001

1.037 (1.027 – 1.048)

p < 0.001

1.001 (1.000 – 1.002)

p = 0.019

ED arrival as “time zero”

49,331 1.032

(1.023 – 1.048) p < 0.001

1.037 (1.023 – 1.051)

p < 0.001

1.009 (0.995 – 1.024)

p = 0.198

Including hospice discharges as in-hospital deaths

49,331 1.034

(1.021 – 1.046) p < 0.001

1.044 (1.039 – 1.059)

p < 0.001

1.009 (0.995 – 1.023)

p = 0.226

Excluding bundle elements that occur prior to protocol initiation

30,782 1.036

(1.022 – 1.047) p < 0.001

1.043 (1.027 – 1.059)

p < 0.001

1.012 (0.996 – 1.027)

p = 0.139

Exclusionされたものを含めても結果を変わらなかった

Discussion

• 3 hour-bundle完了までの時間および広域抗菌薬投与までの時間には死亡率との関連が認められた

• ⼀⽅で輸液の初期ボーラス(30ml/kg)の完了までの時間と死亡率には関連が認められなかった

• 3つの⼤規模RCT(ARISE,ProCESS,ProMISe)の患者レベルでのメタ解析

• EGDTが通常の治療に⽐べ、死亡率を改善させるかを検討

NEnglJMed 2017DOI:10.1056/NEJMoa1701380.

【結果】EGDT群が1857⼈通常治療群が1880⼈

90⽇死亡率、院内死亡率いずれにおいても有意差なし1年間⽣存率にも有意差認めず

2017/5/30慈恵ICU勉強会より改変

• EGDTについての3つの⼤規模RCTのメタ解析(PRISM trial)では対象となった患者の75%以上が3 hour bundleの構成要素をランダム化以前に受けていた※ただし⾎液培養検体の採取時間ついては3つのRCT,PRISM

のどちらにも記載がない

輸液ボーラス投与完了までの時間• 初期の輸液ボーラス投与完了までの時間と

死亡率には関連が認められなかったが,初期の輸液負荷を否定するものではない.

• 重症の患者ほど早期に輸液負荷を受け,死亡率が⾼い傾向にあるというバイアスを含む可能性を否定できない.

• 急速な多量の輸液が肺⽔腫などの有害事象を引き起こす可能性があるため,輸液ボーラスの是⾮についてのランダム化試験が求められる.

3hourbundle達成までの時間と死亡率が関連した理由として• 抗菌薬投与を早期投与することで効果が⾼まり,そ

の後の臓器不全が減少した.

• 原因不明のショックに遭遇した際に早期に乳酸を測定する医師が,予後改善効果が⽰唆されている,乳酸値を指標とした治療を⾏う傾向にあった.

• プロトコルによってsepsisの早期診断,早期介⼊が可能であった．

Limitation

• ランダム化研究ではないためにバイアスの存在を否定できない.

• 広域スペクトラム抗菌薬の選択が適切であったかのデータがない.

• 単⼀の州での研究であるため他の地域と疫学的な特性が異なる可能性がある.

• 測定の開始時間の正確性が担保されていない.

私⾒

• Sepsisに対してできるだけ早期に抗菌薬の投与の必要性を感じた.• しかしそもそもsepsisを疑う患者への抗

菌薬投与, ⾎液検体採取や, ついでの乳酸値の測定をためらう理由が存在するのか.• 重症な患者はより早期に輸液投与を受け

る可能性があるとしているが, 抗菌薬投与や乳酸値の測定についても同様のことが⾔えるのではないか.

Documents

Time to Treatment and Mortality during Mandated Emergency ...・sepsisに誘発された低灌流は最初の3時間 以内に少なくとも30 ml/kgの晶質液の投与が 推奨される

Time to Treatment and Mortality during Mandated Emergency ...・sepsisに誘発された低灌流は最初の3時間以内に少なくとも30 ml/kgの晶質液の投与が推奨される