Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan.

BACKGROUND: The updated Surviving Sepsis Campaign guidelines recommend a 1-hour window for completion of a sepsis care bundle; however, the effectiveness of the hour-1 bundle has not been fully evaluated. The present study aimed to evaluate the impact of hour-1 bundle completion on clinical outcomes in sepsis patients.
METHODS: This was a multicenter, prospective, observational study conducted in 17 intensive care units in tertiary hospitals in Japan. We included all adult patients who were diagnosed as having sepsis by Sepsis-3 and admitted to intensive care units from July 2019 to August 2020. Impacts of hour-1 bundle adherence and delay of adherence on risk-adjusted in-hospital mortality were estimated by multivariable logistic regression analyses.
RESULTS: The final study cohort included 178 patients with sepsis. Among them, 89 received bundle-adherent care. Completion rates of each component (measure lactate level, obtain blood cultures, administer broad-spectrum antibiotics, administer crystalloid, apply vasopressors) within 1 hour were 98.9%, 86.2%, 51.1%, 94.9%, and 69.1%, respectively. Completion rate of all components within 1 hour was 50%. In-hospital mortality was 18.0% in the patients with and 30.3% in the patients without bundle-adherent care (p = 0.054). The adjusted odds ratio of non-bundle-adherent versus bundle-adherent care for in-hospital mortality was 2.32 (95% CI 1.09-4.95) using propensity scoring. Non-adherence to obtaining blood cultures and administering broad-spectrum antibiotics within 1 hour was related to in-hospital mortality (2.65 [95% CI 1.25-5.62] and 4.81 [95% CI 1.38-16.72], respectively). The adjusted odds ratio for 1-hour delay in achieving hour-1 bundle components for in-hospital mortality was 1.28 (95% CI 1.04-1.57) by logistic regression analysis.
CONCLUSION: Completion of the hour-1 bundle was associated with lower in-hospital mortality. Obtaining blood cultures and administering antibiotics within 1 hour may have been the components most contributing to decreased in-hospital mortality.

Introduction

Sepsis is now defined “as life-threatening organ dysfunction caused by a dysregulated host response to infection” [1]. Although tremendous progress in medical management has been made over the past few decades, sepsis remains a leading cause of death and enormously impacts global health systems, with approximately 11 million sepsis-related deaths reported in 2017 [2].

Multidisciplinary intensive care has been mainly required as sepsis is a fatal disease, and no specific medicines have been developed to resolve it. The care bundle has recently become a key factor in multidisciplinary intensive care. In the Surviving Sepsis Campaign (SSC) guidelines, to improve awareness and outcomes of sepsis, time-dependent bundles such as time to antibiotic administration have become one of the key components [3-6]. The updated 2018 SSC guidelines recommend a 1-hour window for completion of a sepsis care bundle following the recognition of sepsis to be a reasonable approach instead of within 3 hours from triage or recognition of sepsis [7]. This update has been intensively debated and remains controversial [8].

The effectiveness of the hour-1 bundle has not been fully evaluated because fundamentally, initiation of earlier treatment does not negatively affect the disease. Several recent studies showed significant associations between bundle-adherent care completed within 3 hours and lower mortality. To date, however, little evidence has been provided of an association between completion of the hour-1 bundle components within 1 hour and lower mortality [9, 10]. In addition, a randomized controlled trial in the pre-hospital setting that assessed early antibiotic use in patients with suspected infection showed that it failed to reduce mortality [11]. Herein, we hypothesized that conventional bundle-adherent care within 3 hours would not be sufficiently effective to reduce the mortality of sepsis and septic shock, and adherence to the hour-1 bundle could play an important role in improving outcomes. Therefore, our aim was to prospectively evaluate adherence to the hour-1 care bundle. We also evaluated the association between completion of the hour-1 bundle and patient outcomes.

Materials and methods

Ethics approval and consent to participate

The study protocol was reviewed and approved by the ethics committee of all participating institutions in the Japanese Association for Acute Medicine (JAAM) study group. Osaka University, the representative for the JAAM Multicenter Assessment for Sepsis Treatment and Outcome (MAESTRO) study, was responsible for the overall approval (IRB number 18323). The board waived the requirement for informed consent because of the anonymous nature of the data and because no information on individual patients, hospitals, or treating physicians was obtained.

Design and setting

This multicenter, prospective, observational study, JAAM MAESTRO (UMIN000036349), was conducted in 17 intensive care units (ICUs) in Japan from July 2019 to August 2020.

Participants

Patients were eligible for this study if they met the following criteria: 1) were older than 16 years; 2) fulfilled the Sepsis-3 criteria [6], i.e., had a proven or suspected infection and an acute increase of 2 or more points in the Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score; and 3) were diagnosed as having only new-onset infection.

Exclusion criteria included 1) patients with cardiopulmonary arrest on hospital arrival; 2) patients with the limitation of sustained life care or post-cardiopulmonary arrest resuscitation status at the time of sepsis diagnosis; 3) patients deemed ineligible as study participants by a research director; and 4) patients transferred from other hospitals.

Data collection

Data were extracted from the MAESTRO database and compiled by the MAESTRO investigators. Collected variables included relevant patient information such as demographics, comorbidities, vital signs, laboratory data, and site of infection. We also obtained data on adherence to sepsis care bundles (specifically, the hour-1 bundle).

In-hospital mortality was identified as the primary outcome. Secondary outcomes were the number of ventilator-free days and ICU-free days, length of hospital stay, and condition at discharge.

Data collection was conducted as part of the clinical routine workup. The MAESTRO site investigators recorded all data throughout the patient’s hospital stay. In the case of missing data, the MAESTRO committee requested a reconfirmation of data extraction from the MAESTRO investigators.

Data definitions

Sepsis care bundles were defined according to SSC guidelines [12] as whether all bundle components were achieved within the appropriate time frame (i.e., 1 hour) and whether they adhered to the indications. Thus, if a component of the bundle was not applicable, we treated achievement of the other components as completion of the bundle (i.e., in cases where administration of crystalloid and application of vasopressor were not indicated), and adherence was defined when the other three components were completed. For all patients, bundle initiation time was defined as the time of sepsis recognition in the emergency department, ward, or ICU. Sepsis recognition was based on clinical judgement, by which the physician-in-charge suspected sepsis at the initial evaluation. The timestamp was recorded in the database by the physician-in-charge.

Analysis

In total, 100 participants were required in the present study for the bundle-adherent group to conduct multivariate regression analyses. In a previous study conducted in Japan, early administration of antibiotics (within 1 hour) was adhered to in approximately 33% of septic patients [13]. Therefore, a total sample size of 300 patients was assumed to be necessary to include 100 patients with bundle-adherent care.

We divided the patients into two groups, those receiving bundle-adherent care (bundle-adherent group) and those not receiving it (non-bundle adherent group). We performed univariate analyses of the characteristics of the patients in whom the hour-1 bundle was or was not completed within 1 hour. Continuous data are expressed as mean (SD) or median (interquartile range), depending on normality. Categorical variables are shown as proportions. We also evaluated the time to completion of each component of the hour-1 bundle.

The impact of non-adherence to the hour-1 bundle on risk-adjusted in-hospital mortality was estimated by logistic regression analyses adjusted by an inverse probability of treatment weighting analysis using propensity scoring. The propensity score for adherence to the hour-1 bundle was determined using a logistic regression with the following covariates as independent variables, which were specified a priori based on clinical experience and prior studies: patient age, sex, admission source (emergency department, ward, or in ICU), Charlson comorbidity index (CCI), mechanical ventilation use, and each organ score within the SOFA (S1 Table). In addition, after replacing time to completion of each component of the hour-1 bundle as a continuous variable, we performed a multivariable logistic regression analysis adjusted for clinically plausible and relevant confounders equal to the covariates to calculate the propensity score. We also fitted logistic regression models to evaluate the association between the increase in mortality and failure or delay in achieving the hour-1 bundle in subgroups with and without septic shock by including product terms between achieving the bundle and the presence of shock. No assumptions were made about these data because the amount of missing data was low.

Sensitivity analysis

Because two components (measure initial lactate level and begin rapid administration of crystalloid) in the hour-1 bundle were completed in almost all of the patients, we performed the same analyses excluding these two components. Two-tailed p values < 0.05 were considered to indicate significance. All statistical analyses were performed using STATA software version 15.0 (Stata Corp, College Station, TX, USA).

Results

Among the 180 patients, 178 individuals who met all eligibility criteria entered the final analyses. Of them, 89 patients received bundle-adherent care (Fig 1).

Fig 1

Patient flow diagram.

JAAM MAESTRO Japanese Association for Acute Medicine Multicenter Assessment for Sepsis Treatment and Outcome.

Baseline characteristics, vital signs, laboratory test results, and severity scores obtained at the time of sepsis recognition were similar between the two groups, with the exception of body temperature, white blood cell count, and mechanical ventilation use (Table 1).

Table 1

Patient characteristics.

	Non-bundle-adherent group	Bundle-adherent group	p Value
	n = 89	n = 89
Age	75 (67–84)	75 (69–82)	0.946
Sex, male	62 (70%)	58 (65%)	0.522
BMI (kg/m2)	21 (18–24)	22 (19–25)	0.327
Charlson comorbidity index	1 (1–4)	1 (0–2)	0.073
Site of infection			0.092
Lung	42 (47%)	40 (45%)
Abdomen	15 (17%)	18 (20%)
Urinary tract	12 (13%)	19 (21%)
Bone soft tissue	6 (7%)	6 (7%)
Cardiovascular	0 (0%)	2 (2%)
Other unidentified	14 (16%)	4 (4%)
Glasgow Coma Scale	13 (10–14)	13 (9–15)	0.509
Respiratory rate (/min)	22 (19–30)	20 (16–30)	0.144
Systolic blood pressure (mmHg)	96 (74–119)	92 (69–132)	0.776
Diastolic blood pressure (mmHg)	50 (41–70)	56 (42–72)	0.371
Mean blood pressure (mmHg)	65 (53–86)	69 (51–94)	0.687
Heart rate (bpm)	105 (87–122)	111 (91–129)	0.259
Body temperature (°C)	37.3 (36.3–38.5)	38.2 (36.9–39.1)	0.002
Lactate (mmol/L)	3.7 (2.1–5.6)	3.7 (1.8–5.3)	0.624
White blood cell count (×103/μL)	12.3 (7.7–17)	9.7 (5.6–14.3)	0.049
Platelet count (×104/μL)	18.3 (13.8–25.4)	16.3 (11.8–22.5)	0.137
Total bilirubin (mg/dL)	0.8 (0.6–1.2)	0.9 (0.6–1.5)	0.176
Creatinine (mg/dL)	2 (1–3.8)	1.4 (1.1–2.6)	0.178
Glucose (mg/dL)	141 (100–231)	154 (108–200)	0.976
CRP (mg/dL)	11.3 (5.3–22.2)	10.6 (2.9–21.9)	0.501
24-hour urine volume (mL)	945 (430–1700)	1220 (641–1703)	0.279
FDP (μg/mL)	13.4 (8.1–32.6)	12.3 (6.5–27.4)	0.233
D-dimer (μg/mL)	5.8 (2.9–12.3)	6.3 (2.4–11.6)	0.439
APACHE II score	24 (18–28)	24 (18–27)	0.587
SOFA score	8 (6–10)	8 (5–10)	0.357
Mechanical ventilation use	26 (29%)	44 (49%)	0.006

BMI body mass index, CRP C-reactive protein, FDP fibrin/fibrinogen degradation products, APACHE Acute Physiology and Chronic Health Evaluation, SOFA Sequential Organ Failure Assessment.

We show time to completion of each component of the hour-1 bundle in S2 Table. Two components (measure initial lactate level [98.9%] and begin rapid administration of crystalloid [94.9%]) were completed in 1 hour in almost all patients. The rate of completion of all components within 1 hour was 50%. In-hospital mortality was 18.0% in the bundle-adherent group and 30.3% in the non-bundle-adherent group (p = 0.054) (Table 2). The number of ventilator-free days and ICU-free days and length of hospital stay were not different between the two groups.

Table 2

Primary and secondary outcomes in the two groups.

	Non-bundle-adherent group	Bundle-adherent group	p Value
	n = 89	n = 89
In-hospital mortality	27 (30.3%)	16 (18.0%)	0.054
Ventilator-free days	19 (0–28)	21 (0–28)	0.696
Intensive care unit-free days	15 (0–22)	18 (0–23)	0.24
Length of hospitalization (days)	19 (10–42)	21 (10–46)	0.827

The adjusted odds ratio (OR) of the non-bundle-adherent group versus bundle-adherent group for in-hospital mortality was 2.32 (95% CI 1.09–4.95) using an inverse probability of treatment weighting analysis with propensity score (Fig 2).

Fig 2

Association between mortality and adherence to each bundle component within 1 hour.

Univariate and multivariate-adjusted ORs with 95% CIs for mortality risk are represented as forest plots. Inverse probability of treatment weighting analysis with propensity score was used as the adjustment method. OR odds ratio, CI confidence interval, PS propensity score.

In the subgroup analysis, adjusted and non-adjusted mortality risks in the patients with septic shock were more likely to increase due to failure or delay in achieving the hour-1 bundle compared to those in the patients without septic shock. However, the effect modification was not statistically significant (S1 Fig).

Among the components of the hour-1 bundle, non-adherence to obtaining blood cultures (OR 2.65 [95% CI 1.25–5.62]), administering broad spectrum antibiotics (OR 4.81 [95% CI 1.38–16.72]), and administering of crystalloid (OR 13.97 [95% CI 2.19–89.31]) within 1 hour were associated with increased in-hospital mortality among the patients with sepsis. In addition, the adjusted OR for 1-hour delay of achievement of the components of the hour-1 bundle for in-hospital mortality was 1.28 (95% CI 1.04–1.57) using a multivariable logistic regression analysis (Fig 3). The results were similar in a sensitivity analysis that excluded components with adherence rates that were too high (S2 Fig).

Fig 3

Association between the increase in mortality and 1-hour delay in the achievement of each bundle component.

Univariate and multivariate-adjusted ORs with 95% CIs for mortality risk are represented as forest plots. Regression analyses were adjusted by including several clinically plausible and relevant confounders as covariates. OR odds ratio, CI confidence interval.

Discussion

Our study showed that approximately one-half of the patients with sepsis received care that adhered to the hour-1 bundle, and their outcomes were significantly improved when the hour-1 bundle was completed within 1 hour. However, among the hour-1 bundle components, only obtaining blood cultures and administering antibiotics may have contributed to the decreased in-hospital mortality.

Since the original studies of care bundle effectiveness were published [14, 15], there have been mainly negative opinions about its implementation [8, 16, 17]. In fact, our previous descriptive study did not prove the effectiveness of the 3-hour bundle [13]. However, few studies have directly investigated its effectiveness. Sepsis is different from other emergent conditions such as acute coronary syndrome, stroke, or trauma in terms of disease onset, although appropriate and timely detection and treatment should be essential in improving the outcome of sepsis. A recent retrospective cohort study showed no association between completion of the hour-1 bundle components within 1 hour and lower mortality, whereas bundle completion within 3 hours was associated with lower mortality [9]. In that study, the hour-1 bundle was completed in only 8% of the patients, whereas it was completed in half of the patients in the present study. Facilities with high bundle adherence rates may have better outcomes because of the multidisciplinary nature of the treatment. A better understanding and implementation of the hour-1 bundle may be important for health care personnel to achieve an improvement in patient prognosis. For example, early goal-directed therapy (EGDT) has never been well recognized, and its effectiveness compared with usual care was only shown as it became better known. However, after most physicians came to understand it, the prognosis of sepsis treated with usual care based on EGDT knowledge and the SSC Guideline has been equal to or better than that for EGDT itself [18]. It is natural in health care research for results to change as education is disseminated. Thus, it may take some time until we see the effects of adherence to the hour-1 bundle.

Among the components of the hour-1 bundle, only obtaining blood cultures and administering antibiotics may have contributed to the decreased in-hospital mortality in the present study. These time-dependent factors were similarly significant whether they were dichotomized in 1 hour after diagnosis or as continuous variables every hour. Especially, early administration of antibiotics was adhered to in a considerably lower proportion of the study patients, and thus, this might strongly influence the study results. Early administration of antibiotics within 1 hour is sometimes difficult to achieve in a critical care setting. Actually, several previous studies reported similar or even lower proportions of patients receiving antibiotics within 1 hour [19, 20]. Multiple factors that might cause a delay in antibiotic administration include overcrowding, limited staffing, high patient load, blood culture testing, difficult intravenous line access, fluid resuscitation, and atypical presentation leading to delayed recognition of sepsis.

A systematic review of seven observational studies in the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 showed no significant difference in outcomes with administration of antibiotics within 1 hour versus sometime later [21]. Therefore, it was given a weak recommendation: initiation of antibiotics as early as possible, but not necessarily within 1 hour. However, we validated and agree with the importance of the hour-1 bundle as reported in previous studies [13, 14]. The study of a quality indicator such as time to antibiotic can influence the standardization of medical practice. However, education on sepsis care was not disseminated from previous studies that did not show an association with early antibiotic administration [17]. Actually, the results are more greatly influenced by strong clinical variables such as a certain treatment if clinically more important known or unknown (unmeasured) variables than a quality measurement such as time to antibiotic are assessed. It is most important that two groups with similar severity of illness receive similar treatments before looking at differences in time to antibiotic. Otherwise, patients receiving non-adherent care might experience worse outcomes because it may have been difficult to diagnose sepsis or its severity in these patients compared with patients receiving adherent care [22, 23]. The patients receiving non-adherent care had more unknown sources of infection, fewer fevers, and lower ventilator use. Thus, time to antibiotic might not have been a cause but a result of non-adherent care.

The resuscitation protocol of the hour-1 bundle such as maintenance of fluid volume and application of vasopressors will continue to be controversial. Adherence to the administration of crystalloid and lactate measurement were both very high in the present study. However, it is difficult to assess clinical effectiveness of a resuscitation protocol only from these results. Further study of fluid resuscitation and fluid balance is needed.

There are several potential approaches to reducing the delay in medical management and enhancing adherence to the hour-1 bundle in sepsis. First, greater education of hospital staff would improve their understanding and awareness of sepsis, leading to earlier diagnosis and treatment by first responders. Second, multidisciplinary collaboration that includes different health professionals could shorten the time to total medical contact and especially to antibiotic administration. As the optimal strategy to improve the quality of sepsis management might vary widely according to hospitals, regions, and countries, daily discussions among multidisciplinary professionals are important as a means of providing education to and enhancing the awareness of clinical staff participating in sepsis management.

Our study has several limitations. First, this study included convenience samples but not consecutive ones, which might have led to selection bias. Second, the adherence rate was very high. Regarding generalizability, as triage and the path to emergency care and intensive care are influenced by the health care system in each country, the current findings may not be applicable in different countries. Third, due to the nature of observational studies, the possibility remains that the prognosis was better for the patients who received bundle-adherent care within 1 hour than for those who could not receive it within this time. Fourth, the present study did not evaluate detailed reasons for the delay in or non-adherence to bundle care. Finally, the number of study patients was smaller than the pre-calculated sample size, which might have reduced the statistical power for detection of a true effect. Nevertheless, we reconfirmed that the time of antibiotic administration is a key component in the treatment of sepsis.

Conclusions

We showed an association between completion of the hour-1 bundle and lower in-hospital mortality. Especially, administering antibiotics might have contributed the most to the decrease of in-hospital mortality, and these findings would need to be confirmed in future further large-scale studies.

Association between the increase in mortality and failure or delay in achieving the hour-1 bundle in subgroups with and without septic shock.

Univariate and multivariate-adjusted ORs with 95% CIs for mortality risk are represented as forest plots. Covariate adjustment or propensity score adjustment was used in the regression analyses as appropriate, and the significance level (p value) for effect modification was calculated. OR odds ratio, CI confidence interval, PS propensity score.

(DOCX)

Click here for additional data file.

Association between the increase in mortality and failure or delay in achieving three relatively low-compliance bundle components: Blood culture, antibiotics, and vasopressors.

Univariate and multivariate-adjusted ORs with 95% CIs for mortality risk are represented as forest plots. Covariate adjustment or propensity score adjustment was used in the regression analyses as appropriate. OR odds ratio, CI confidence interval, PS propensity score.

(DOCX)

Click here for additional data file.

The 11 variables used to calculate propensity scores for adherence to the hour-1 bundle in the logistic regression models.

SOFA Sequential Organ Failure Assessment, ICU intensive care unit.

(DOCX)

Click here for additional data file.

Time to completion of each component of the hour-1 bundle.

Missing data: Obtain blood cultures = 4; Administration of crystalloid = 1; Apply vasopressors = 2; completion of all elements = 1.

(DOCX)

Click here for additional data file.

Time to completion of each component of the hour-1 bundle in the non-bundle-adherent group.

(DOCX)

Click here for additional data file.

9 Nov 2021

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Reviewer #1: Thank you for the opportunity to review this manuscript. This was a prospective, multi-center, observational study to validate the effectiveness of hour-1 bundle in Japanese patients with sepsis. They concluded that the adherence of hour-1 bundle was associated with decreased mortality risk, and the collection of blood culture and administration of antibiotics within 1 hour was independently associated with mortality risk in septic patients. I had several comments that the authors need to address:

1. The definition of hour-1 bundle adherence: the authors mentioned that "if a component of the bundle was not applicable, we treated achievement of the other components as completion of the bundle". I have concerns of that the authors mixed the non-shock and shock patients in this study (although the guideline did it so, and growing evidence suggested that these two groups should be treated differently). For example, 79 of 178 patients had no vasopressor administration (Table S1) and they were presumed to have low disease severity and mortality risk. What were the distribution of these non-shock patients in the adherence and non-adherence groups? They may significantly influence the study outcomes. I suggest the authors to perform subgroup analysis (shock: adherence vs.non-adherence, non-shock: adherence vs. non-adherence) in outcome analysis.

2. Since this study was conducted in multiple ICUs in Japanese hospitals, these patients were presumed to admit in ICUs,

but they had relative low proportion of vasopressor administration and mechanical ventilator use. They also had very

low CCI score.

3. Please clarify the origin of vital signs and laboratory results of each patient? from initial time of ICU admission? from

initial hospital admission? from the time of sepsis recognition?

4. It's surprising that the proportion of antibiotics administration within one hour was lower than vasopressor

administration (Table S1). Since the authors identifies the antibiotics administration as the independent factor associated with mortality risk, they may want to address more on this issue.

5. Similarly, the authors mentioned that they applied "multidisciplinary methods" to promote the adherence of hour-1

bundle in patients with sepsis. They should address more how they did it as the issue of quality improvement.

6. The recruitment period is different: in the design and setting "from July 2019 to August 2020." In the figure 1 "from July 2019 to December 2019" So the recruitment period is 13 or 6 months?

Reviewer #2: I read with interest the manuscript of Umemura et al. entitled “Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan”.

In the present study the authors aimed to evaluate the effect of hour-1 bundle completion on clinical outcomes in sepsis. They showed an association between completion of the hour-1 bundle and lower in-hospital mortality in an observational multicenter study of 178 prospectively enrolled patients with sepsis.

The study’s conclusions are presented in an appropriate fashion and are supported by the data. The studies sample size of 178 individuals appears low in order to draw the presented conclusions, especially considering that 17 centers were involved into the study. The article is presented in an intelligible fashion and is written in standard English. However, the following comments/questions need to be addressed by the authors:

1. Introduction: “A recent study did not show an association between completion of the hour-1 bundle components within 1 hour and lower mortality, whereas they did show an association between care completed within 3 hours and lower mortality [9].”

Reference (9) refers to patients with septic shock and not patients with sepsis. The authors need to clarify that in the introduction or reference appropriate other studies.

2. The authors should provide a clear hypothesis at the end of the introduction based on clinical adjudication or existing research in the field.

3. How was the sample size of n=178 determined? The authors should provide a power calculation in order to verify that the sample size of n=178 is appropriate to show the study’s results at sufficient statistical power.

4. The authors state that 178 patients were enrolled into the study. 89 of the patients received bundle-adherent care (50%). However, it is stated in the results section that “the rate of completion of all components within 1 hour was 50.3%”. This is confusing. How do the authors explain 50.3% in table S1, while it should be 50%? Are the numbers correct?

5. The authors should clarify, if and how the performed multivariate analysis adjusts for the differences between the two groups at baseline (blood temperature and mechanical ventilation use).

6. “A systematic review of seven observational studies in the Japanese clinical practice guidelines for management of sepsis and septic shock 2020 showed no significant difference in outcomes with administration of antibiotic within 1 hour compared to later. “

The authors need to provide a reference for this in the discussion section.

Reviewer #3: Please get a native English speaker to correct the language in the manuscript. The lanugage is not up to the standard.

It might be reasonable to include the following in the limitation: The study did not anayse the reasons for non adherence.

It would be better if a graph/ table could show the time time period taken to complete the bundle in the non adherent group.

**********

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3 Jan 2022

December 8, 2021

Ashham Mansur, MD, PhD

Academic Editor, PLOS ONE

Dear Prof. Mansur

Manuscript Number: PONE-D-21-31986

Article Title: Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan

We would like to thank all of the editors and reviewers for helping us improve our article. We revised our manuscript according to the comments and suggestions given by the reviewers. We also highlighted additional changes in the revised manuscript in red color with underline. Below are our point-by-point responses to the reviewers’ comments.

Additional Editor Comments:

The reviewers have raised major concerns regarding to the relatively small number of patients in relation to the number pf the involved centers. you need to adress this major issue adequately and make corrdctions to the conclusions respectively.

Reply: Thank you for your valuable suggestion. We have revised the entire manuscript to address the reviewers’ concerns regarding sample size. The conclusions were revised as indicated below;

Original sentence: “We showed an association between completion of the hour-1 bundle and lower in-hospital mortality. Among the components of the hour-1 bundle, obtaining blood cultures and administering antibiotics may have contributed the most to the decrease of in-hospital mortality.”

(Page 23, lines 3-6, in the CONCLUSIONS)

Revised sentence: “We showed an association between completion of the hour-1 bundle and lower in-hospital mortality. Especially, administering antibiotics might have contributed the most to the decrease of in-hospital mortality, and these findings would need to be confirmed in future further large-scale studies.”

Reviewer #1: Thank you for the opportunity to review this manuscript. This was a prospective, multi-center, observational study to validate the effectiveness of hour-1 bundle in Japanese patients with sepsis. They concluded that the adherence of hour-1 bundle was associated with decreased mortality risk, and the collection of blood culture and administration of antibiotics within 1 hour was independently associated with mortality risk in septic patients. I had several comments that the authors need to address:

1. The definition of hour-1 bundle adherence: the authors mentioned that "if a component of the bundle was not applicable, we treated achievement of the other components as completion of the bundle". I have concerns of that the authors mixed the non-shock and shock patients in this study (although the guideline did it so, and growing evidence suggested that these two groups should be treated differently). For example, 79 of 178 patients had no vasopressor administration (Table S1) and they were presumed to have low disease severity and mortality risk. What were the distribution of these non-shock patients in the adherence and non-adherence groups? They may significantly influence the study outcomes. I suggest the authors to perform subgroup analysis (shock: adherence vs.non-adherence, non-shock: adherence vs. non-adherence) in outcome analysis.

Reply: Thank you for your valuable comments and suggestions. We fully agree with your comment that the presence or absence of septic shock might influence the study results. Accordingly, we conducted a subgroup analysis and evaluated the associations between the increase in mortality and failure or delay in achieving hour-1 bundle in subgroups with and without septic shock. As a result, mortality in shock patients was more likely to increase by failure or delay in achieving the hour-1 bundle; however, effect modifications were not statistically significant. To address this information, we added a new supplemental Figure (Figure S2) and the following sentences.

(Page 13, lines 3-6, in the MATERIALS AND METHODS)

We added: “We also fitted logistic regression models to evaluate the association between the increase in mortality and failure or delay in achieving the hour-1 bundle in subgroups with and without septic shock, by including product terms between achieving the bundle and the presence of shock.”

(Page 17, lines 2-5, in the RESULTS)

We added: “In the subgroup analysis, adjusted and non-adjusted mortality risks in the patients with septic shock were more likely to increase due to failure or delay in achieving the hour-1 bundle compared to those in the patients without septic shock. However, the effect modification was not statistically significant (Fig S1 in the Supporting Information).”

Fig. S1. Association between the increase in mortality and failure or delay in achieving the hour-1 bundle in subgroups with and without septic shock. Univariate and multivariate-adjusted ORs with 95% CIs for mortality risk are represented as forest plots. Covariate adjustment or propensity score adjustment was used in the regression analyses as appropriate. The significance level (p value) for effect modification was calculated. OR odds ratio, CI confidence interval, PS propensity score

2. Since this study was conducted in multiple ICUs in Japanese hospitals, these patients were presumed to admit in ICUs, but they had relative low proportion of vasopressor administration and mechanical ventilator use. They also had very low CCI score.

Reply: Thank you for your valuable comments. As you mentioned, 44% of the study patients did not require vasopressor administration, and 61% did not require mechanical ventilation at the time of sepsis diagnosis. In Japan, septic patients diagnosed in emergency departments were typically admitted to ICUs, even when they did not require vasopressor administration or mechanical ventilation, to be monitored closely for progression of illness. Actually, a previous large-scale observational study* including septic patients in Japan a reported similar rate of vasopressor use. Also, 78.8% of the sepsis patients in the previous study had a CCI score of 2 points or less, which was equal to that of the present study. One possible reason for the low CCI score might be the lower prevalence of HIV/AIDS. The relatively higher rate of the population that receives a regular medical check-up in Japan might be another explanation for the low CCI score.

* Abe T, Ogura H, Shiraishi A, et al. Characteristics, management, and in-hospital mortality among patients with severe sepsis in intensive care units in Japan: the FORECAST study. Crit Care. 2018 Nov 22;22(1):322.

3. Please clarify the origin of vital signs and laboratory results of each patient? from initial time of ICU admission? From initial hospital admission? from the time of sepsis recognition?

Reply: Thank you for your valuable question. In the present study, we defined bundle initiation time as the time of sepsis recognition, and all presented vital signs and laboratory tests were recorded at that time. To address this point more clearly, we have revised the following sentence.

Original sentence: “Baseline characteristics and comorbidities were similar between the two groups, with the exception of body temperature and mechanical ventilation use (Table 1).”

(Page 14, lines 8-10, in the RESULTS)

Revised sentence: “Baseline characteristics, vital signs, laboratory test results, and severity scores obtained at the time of sepsis recognition were similar between the two groups, with the exception of body temperature, white blood cell count, and mechanical ventilation use (Table 1).”

4. It's surprising that the proportion of antibiotics administration within one hour was lower than vasopressor administration (Table S1). Since the authors identifies the antibiotics administration as the independent factor associated with mortality risk, they may want to address more on this issue.

Reply: Thank you for your valuable comments. We fully agree with your comment that the lower proportion (51.1%) of antibiotics administration within one hour in this study might be problematic. Unfortunately, however, several previous studies reported similar or even lower proportions of patients receiving antibiotics within 1 hour. A meta-analysis including 8 studies reported that only 3,335 (30.0%) among 11,017 patients with sepsis/septic shock received antibiotics within 1 hour after recognition of severe sepsis/shock. In the emergency department, there are several possible factors for the delay of antibiotics administration, including overcrowding, limited staffing, high patient load, blood culture testing, difficult intravenous line access, fluid resuscitation, and atypical presentation leading to delayed recognition of sepsis. We thus believe that early antibiotics administration, if successfully achieved, could decrease mortality risk in sepsis. To address these points more clearly, we have revised the manuscript and added two new references, as indicated below;

(Page 19, line 15 – page 20, line 6, in the DISCUSSION)

We added “Especially, early administration of antibiotics was adhered to in a considerably lower proportion of the study patients, and thus, this might strongly influence the study results. Early administration of antibiotics within 1 hour is sometimes difficult to achieve in a critical care setting. Actually, several previous studies reported similar or even lower proportions of patients receiving antibiotics within 1 hour [19, 20]. Multiple factors that might cause a delay in antibiotic administration include overcrowding, limited staffing, high patient load, blood culture testing, difficult intravenous line access, fluid resuscitation, and atypical presentation leading to delayed recognition of sepsis”

(Page 28, lines 7-12, in the References)

We added

“19. Sankar J, Garg M, Ghimire JJ, Sankar MJ, Lodha R, Kabra SK: Delayed administration of antibiotics beyond the first hour of recognition is associated with increased mortality rates in children with sepsis/severe sepsis and septic shock. J Pediatr 2021; 233:183–190.e3.

20. Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE: The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis. Crit Care Med 2015; 43:1907–1915.”

5. Similarly, the authors mentioned that they applied "multidisciplinary methods" to promote the adherence of hour-1 bundle in patients with sepsis. They should address more how they did it as the issue of quality improvement.

Reply: Thank you for your valuable comment and suggestion. Accordingly, we added several sentences to address how to improve the quality of sepsis management in regard to adherence to the hour-1 bundle and revised the manuscript as indicated below.

(Page 21, line 13 – page 22, line 5, in the DISCUSSION)

We added “There are several potential approaches to reducing the delay in medical management and enhancing adherence to the hour-1 bundle in sepsis. First, greater education of hospital staff would improve their understanding and awareness of sepsis, leading to earlier diagnosis and treatment by first responders. Second, multidisciplinary collaboration that includes different health professionals could shorten the time to total medical contact and especially to antibiotic administration. As the optimal strategy to improve the quality of sepsis management might vary widely according to hospitals, regions, and countries, daily discussions among multidisciplinary professionals are important as a means of providing education to and enhancing the awareness of clinical staff participating in sepsis management.”

6. The recruitment period is different: in the design and setting "from July 2019 to August 2020." In the figure 1 "from July 2019 to December 2019" So the recruitment period is 13 or 6 months?

Reply: Thank you for noticing this. “From July 2019 to August 2020” is the correct recruitment period in this study. We revised Figure 1 as indicated below.

Reviewer #2: I read with interest the manuscript of Umemura et al. entitled “Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan”.

In the present study the authors aimed to evaluate the effect of hour-1 bundle completion on clinical outcomes in sepsis. They showed an association between completion of the hour-1 bundle and lower in-hospital mortality in an observational multicenter study of 178 prospectively enrolled patients with sepsis.

The study’s conclusions are presented in an appropriate fashion and are supported by the data. The studies sample size of 178 individuals appears low in order to draw the presented conclusions, especially considering that 17 centers were involved into the study. The article is presented in an intelligible fashion and is written in standard English. However, the following comments/questions need to be addressed by the authors:

1. Introduction: “A recent study did not show an association between completion of the hour-1 bundle components within 1 hour and lower mortality, whereas they did show an association between care completed within 3 hours and lower mortality [9].”

Reference (9) refers to patients with septic shock and not patients with sepsis. The authors need to clarify that in the introduction or reference appropriate other studies.

Reply: Thank you for your valuable comment and suggestion. We added a reference article to present more detailed evidence on the association between bundle adherence and mortality in both sepsis and septic shock and revised the manuscript as indicated below.

Original sentence: “A recent study did not show an association between completion of the hour-1 bundle components within 1 hour and lower mortality, whereas they did show an association between care completed within 3 hours and lower mortality [9].”

(Page 7, line 15 – Page 8, line 2, in the INTRODUCTION)

Revised sentence: “Several recent studies showed significant associations between bundle-adherent care completed within 3 hours and lower mortality. To date, however, little evidence has been provided of an association between completion of the hour-1 bundle components within 1 hour and lower mortality [9, 10].”

(Page 27, lines 1-3, in the References)

We added “10. Baghdadi JD, Brook RH, Uslan DZ, et al: Association of a care bundle for early sepsis management with mortality among patients with hospital-onset or community-onset sepsis. JAMA Intern Med 2020; 180:707–716.

2. The authors should provide a clear hypothesis at the end of the introduction based on clinical adjudication or existing research in the field.

Reply: Thank you for your valuable suggestion. Accordingly, we added the following sentence to clearly state the study hypothesis.

(Page 8, lines 4-7, in the INTRODUCTION)

We added: “Herein, we hypothesized that conventional bundle-adherent care within 3 hours would not be sufficiently effective to reduce the mortality of sepsis and septic shock, and adherence to the hour-1 bundle could play an important role in improving outcomes.”

3. How was the sample size of n=178 determined? The authors should provide a power calculation in order to verify that the sample size of n=178 is appropriate to show the study’s results at sufficient statistical power.

Reply: Thank you for your important question and suggestion. According to your suggestion, we described the detailed method to determine sample size in the present study. A total sample size of 300 patients was assumed to be necessary to conduct the pre-analysis plan. Unfortunately, however, we included a smaller number in the present study than the pre-calculated sample size. We thus addressed this point as a major limitation possibly reducing the statistical power in this study and revised the manuscript as indicated below;

(Page 11, line 12 – page 12, line 2, in the MATERIALS AND METHODS)

We added: “In total, 100 participants were required in the present study for the bundle-adherent group to conduct multivariate regression analyses. In a previous study conducted in Japan, early administration of antibiotics (within 1 hour) was adhered to in approximately 33% of septic patients [13]. Therefore, a total sample size of 300 patients was assumed to be necessary to include 100 patients with bundle-adherent care.”

(Page 22, lines 13-15, in the DISCUSSION)

We added: “Finally, the number of study patients was smaller than the pre-calculated sample size, which might have reduced the statistical power for detection of a true effect.”

4. The authors state that 178 patients were enrolled into the study. 89 of the patients received bundle-adherent care (50%). However, it is stated in the results section that “the rate of completion of all components within 1 hour was 50.3%”. This is confusing. How do the authors explain 50.3% in table S1, while it should be 50%? Are the numbers correct?

Reply: Thank you for noticing this. Actually, 50% is correct. We are sorry about this and have revised the wording to “50%”.

5. The authors should clarify, if and how the performed multivariate analysis adjusts for the differences between the two groups at baseline (blood temperature and mechanical ventilation use).

Reply: Thank you for your valuable suggestion. In the present study, adjusted regression analyses using propensity scoring for adherence to the hour-1 bundle were performed. The propensity score was calculated using multivariate logistic regression including 11 clinically plausible and relevant variables. Also, we performed a multivariable logistic regression analysis to estimate the risk of death associated with every 1-hour delay in achieving the bundle, adjusted by including the equal covariates. To address these points more clearly, we added a supplemental table (Table S1) describing the covariables used to adjust the regression analyses, and we revised the manuscript as indicated below.

Original sentence: “The impact of non-adherence to the hour-1 bundle on risk-adjusted in-hospital mortality was estimated using an inverse probability of treatment weighting analysis with a propensity score.”

(Page 12, lines 9-11, in the MATERIALS AND METHODS)

Revised sentence: “The impact of non-adherence to the hour-1 bundle on risk-adjusted in-hospital mortality was estimated by logistic regression analyses adjusted by an inverse probability of treatment weighting analysis using propensity scoring.”

(Page 12, lines 15-16, in the MATERIALS AND METHODS)

We added: “(Table S1 in the Supporting Information)”

6. “A systematic review of seven observational studies in the Japanese clinical practice guidelines for management of sepsis and septic shock 2020 showed no significant difference in outcomes with administration of antibiotic within 1 hour compared to later. “

The authors need to provide a reference for this in the discussion section.

Reply: Thank you for your suggestion. Accordingly, we added a new reference as Reference 21.

(Page 28, lines 13-14, in the References)

We added: “Egi M, Ogura H, Yatabe T, et al: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020). Acute Med Surg 2021; 8:e659.”

Reviewer #3: Please get a native English speaker to correct the language in the manuscript. The lanugage is not up to the standard.

Reply: Thank you for your suggestion. We had our revised manuscript checked by an English language native speaker.

It might be reasonable to include the following in the limitation: The study did not anayse the reasons for non adherence.

Reply: Thank you for this valuable suggestion. We added the following sentence in the limitations paragraph.

(Page 22, lines 12-13, in the DISCUSSION)

We added: “Fourth, the present study did not evaluate detailed reasons for the delay in or non-adherence to bundle care.”

It would be better if a graph/ table could show the time time period taken to complete the bundle in the non adherent group.

Reply: Thank you for this valuable suggestion. Accordingly, we added the following new table as Table S3 in the supporting information to present the time period taken to achieve each component of bundle care in the non-adherent group.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

31 Jan 2022

Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan

PONE-D-21-31986R1

Dear Dr. Abe,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ashham Mansur, MD, PhD

Academic Editor

PLOS ONE

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: (No Response)

Reviewer #2: No

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Reviewer #2: Thank you for the provided point by point review. All mentioned concerns have been addressed sufficiently. I recommend to accept the manuscript in the current version.

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Reviewer #1: No

Reviewer #2: No

4 Feb 2022

PONE-D-21-31986R1

Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan

Dear Dr. Abe:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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