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. 2020 Mar 11;15(3):e0229919. doi: 10.1371/journal.pone.0229919

Impact of blood glucose abnormalities on outcomes and disease severity in patients with severe sepsis: An analysis from a multicenter, prospective survey of severe sepsis

Shigeki Kushimoto 1,*, Toshikazu Abe 2,3, Hiroshi Ogura 4, Atsushi Shiraishi 5, Daizoh Saitoh 6, Seitaro Fujishima 7, Toshihiko Mayumi 8, Toru Hifumi 9, Yasukazu Shiino 10, Taka-aki Nakada 11, Takehiko Tarui 12, Yasuhiro Otomo 13, Kohji Okamoto 14, Yutaka Umemura 4, Joji Kotani 15, Yuichiro Sakamoto 16, Junichi Sasaki 17, Shin-ichiro Shiraishi 18, Kiyotsugu Takuma 19, Ryosuke Tsuruta 20, Akiyoshi Hagiwara 21, Kazuma Yamakawa 22, Tomohiko Masuno 23, Naoshi Takeyama 24, Norio Yamashita 25, Hiroto Ikeda 26, Masashi Ueyama 27, Satoshi Fujimi 22, Satoshi Gando 28,29; on behalf of JAAM FORECAST group
Editor: Robert Ehrman30
PMCID: PMC7065801  PMID: 32160234

Abstract

Background

Dysglycemia is frequently observed in patients with sepsis. However, the relationship between dysglycemia and outcome is inconsistent. We evaluate the clinical characteristics, glycemic abnormalities, and the relationship between the initial glucose level and mortality in patients with sepsis.

Methods

This is a retrospective sub-analysis of a multicenter, prospective cohort study. Adult patients with severe sepsis (Sepsis-2) were divided into groups based on blood glucose categories (<70 (hypoglycemia), 70–139, 140–179, and ≥180 mg/dL), according to the admission values. In-hospital mortality and the relationship between pre-existing diabetes and septic shock were evaluated.

Results

Of 1158 patients, 69, 543, 233, and 313 patients were categorized as glucose levels <70, 70–139, 140–179, ≥180 mg/dL, respectively. Both the Acute Physiological and Chronic Health Evaluation II and Sequential Organ Failure Assessment (SOFA) scores on the day of enrollment were higher in the hypoglycemic patients than in those with 70–179 mg/dL. The hepatic SOFA scores were also higher in hypoglycemic patients. In-hospital mortality rates were higher in hypoglycemic patients than in those with 70–139 mg/dL (26/68, 38.2% vs 43/221, 19.5%). A significant relationship between mortality and hypoglycemia was demonstrated only in patients without known diabetes. Mortality in patients with both hypoglycemia and septic shock was 2.5-times higher than that in patients without hypoglycemia and septic shock.

Conclusions

Hypoglycemia may be related to increased severity and high mortality in patients with severe sepsis. These relationships were evident only in patients without known diabetes. Patients with both hypoglycemia and septic shock had an associated increased mortality rate.

Introduction

Glycemic abnormalities are frequently observed in patients with sepsis. While it is well accepted that hyperglycemia is one of the physiological responses related to acute stress [13], a hypoglycemic response may indicate a non-physiological, or pathological, response. Inflammatory mediators and stress hormone-induced glucose utilization is usually associated with increased glucose production. Hypoglycemia develops when the latter fails to respond to the former, secondary to cytokine-induced inhibition of gluconeogenesis in the setting of glycogen depletion [4, 5]. Previous reports have shown that mortality rates are higher in patients with hypoglycemic responses to sepsis [68]. However, this relationship is inconsistent and may vary individually based on the presence of diabetes, the severity and etiology of the septic condition [1, 911]. Further, the majority of previous studies have evaluated general intensive care unit (ICU) patients [3, 8, 12, 13] and performed analyses on databases consisting of various infectious diseases, in addition to severe sepsis. Additionally, the majority of these previous works was conducted prior to the publication of the Surviving Sepsis Campaign Guidelines 2012 [14]. This includes revisions of the 6 hour resuscitation bundle and the 24 hour management bundle to the 3-hour/6-hour severe sepsis bundles.

The objective of this study was to evaluate the clinical characteristics, associated glycemic abnormalities, and the relationship between the initial blood glucose level and mortality rates in patients with severe sepsis.

Materials and methods

Ethical approval

The study protocol was reviewed and approved by the ethics committee of all participant institutes in the Japanese Association for Acute Medicine (JAAM) study group, Japan. (IRB number 014–0306 on Hokkaido University, the representative for FORECAST). The data collection was performed as a part of routine clinical workup without any interventions, and data management and statistical analyses were processed anonymously. For these reasons, the need for informed consent was waived by the ethics committee/institutional review board.

Design and setting

The Focused Outcome Research on Emergency Care for Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) study described the incidence, clinical characteristics, and evolving management of sepsis in Japan [15]. This study is a sub-analysis performed using a cohort of patients with severe sepsis from the FORECAST study. It is comprised of a multicenter, prospective cohort of acutely ill patients; including those with acute respiratory distress syndrome, sepsis, and trauma. The FORECAST study used consecutive patients’ data from 59 ICUs in Japan and was conducted from January 2016 to March 2017. Design and reporting of the study adheres to Strengthening the Reporting of Observational Studies in Epidemiology statement [16].

Participants

The Japanese Association for Acute Medicine Sepsis Registry study group investigated the epidemiology of severe sepsis in patients admitted to 15 ICUs in Japan in 2011, subsequently reporting their findings in 2014 [17]. This registry was implemented with the Surviving Sepsis Campaign Registry, in which Sepsis-2 was used as an inclusion criterion. Since the FORECAST study was planned before the publication of the Sepsis-3 definition, and the purpose of the study includes examining larger comprehensive follow-up reports on the incidence, clinical characteristics, and evolving management of sepsis in Japan, we used the Sepsis-2 definition as the inclusion criterion.

The FORECAST study included adult patients (aged ≥16 years) with severe sepsis based on the Sepsis-2 criteria in 2003 [18]. All patients were admitted to ICUs. Inclusion criteria were: diagnosis of or suspected new onset of infection by the history of present illness; ≥2 systemic inflammatory response syndrome (SIRS) criteria [19]; and presence of at least one organ dysfunction. Sepsis-2 criteria also included: a systolic blood pressure <90 mmHg, mean arterial pressure (MAP) <65 mmHg or a decrease in blood pressure of >40 mmHg, serum creatinine level >2.0 mg/dL or diuresis of <0.5 mL/kg/h, total bilirubin >2.0 mg/dL, platelet count <100,000 cells/mm3, arterial lactate level >2 mmol/L, international normalized ratio >1.5, and the presence of arterial hypoxemia (PaO2/FIO2 <200 with pneumonia or PaO2/FIO2 <250 without pneumonia) [18]. Exclusion criteria included limitations of sustained life-care or post-cardiopulmonary arrest resuscitation status at the time of the diagnosis of sepsis. This sub-study selected all patients registered in the FORECAST sepsis study and in the sub-analysis. Patients without a value for initial glucose level were excluded.

Data collection

Data were obtained from the FORECAST database, which was compiled by the FORECAST investigators. Patient data included such information as patient demographics, admission source, comorbidities, suspected site(s) of infection, organ dysfunction(s), and sepsis-related severity scores. The Sequential Organ Failure Assessment (SOFA) score was calculated using physiological and laboratory values during the initial evaluation. We also obtained data on compliance with established sepsis care protocols, such as serum lactate levels obtained within three hours. Data collection was performed as a part of the routine clinical workup.

Blood glucose levels were measured using a blood gas analyzer (and not a glucometer) as recommend by Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012 [14]. All glucose levels were measured prior to the administration of corticosteroids (if required).

In-hospital mortality, 28-day mortality, disposition after discharge, and number of ICU-free and ventilator-free days (VFDs) were used as outcome measures.

Data definitions

Based on the initial blood glucose value, patients were divided into four groups: <70 (defined as hypoglycemia), 70–139, 140–179, ≥180 mg/dL. Although there is no universally agreed upon definition of hypoglycemia, a blood glucose level of 70 mg/dL or less is widely accepted as the definition of hypoglycemia [20]. As such, it is the classification defined as “hypoglycemia” in this study. We defined all glucose categories a priori based on previously published studies, regardless of the presence or absence of diabetes [21]. Although inpatient management was performed based on the Surviving Sepsis Campaign Guidelines 2012, no uniform protocol to control blood glucose level was used in this study.

Septic shock was defined by the Sepsis-2 criteria [18]. In the evaluation of organ dysfunction, hypotension was defined as a systolic blood pressure <90 mmHg, MAP<65 mmHg, or a decrease in blood pressure >40 mmHg. Acute lung injury included arterial hypoxemia; that is, PaO2/FIO2 <200 mmHg with pneumonia or PaO2/FIO2 <250 mmHg without pneumonia. The results of the Charlson comorbidity index were classified into four previously defined grades of severity: 0 (none), 1–2 (low), 3–4 (moderate), and ≥5 points (high) [22]. We also measured the compliance with the bundles proposed in the Surviving Sepsis Campaign Guidelines (SSCG) 2012 [14]. We defined compliance as evidence that all bundle elements were adhered to within the established time-frame (i.e., 3 h or 6 h) and to the respective indications (i.e., septic shock or lactate >4 mmol/L). In addition, VFDs were defined as the number of days on which a patient was able to breathe without a ventilator during the initial 28 days after enrollment. The number of VFDs of patients who died during the study period was assigned as 0. The number of ICU-free days was calculated in this same manner.

Hepatic disease/dysfunction, glycemic abnormalities, Sepsis-3, and outcomes

To evaluate the relationship between hepatic impairment and glycemic abnormalities, the presence of moderate to severe hepatic disease as a comorbidity and hepatic SOFA score were compared among groups. In addition, to assess the influence of hepatic impairment on the outcome of hypoglycemia, the presence of moderate to severe hepatic disease and hepatic SOFA score >0 were compared between hypoglycemia and non-hypoglycemia patients. Severe, moderate, and mild liver disease as comorbidities were defined as follows: severe; cirrhosis and portal hypertension with variceal bleeding history; moderate, cirrhosis and portal hypertension but no variceal bleeding history; and mild, chronic hepatitis (or cirrhosis without portal hypertension) [23].

To identify patients who were diagnosed with sepsis according to the Sepsis-3 criteria [24], we calculated an acute increase in SOFA scores of ≥2 as follows: a baseline SOFA score of 0 was assumed in patients without a diagnosis of any chronic disease, as defined per APACHE II scores. If a chronic disease was present, a baseline SOFA score of 2 was assigned (as previously reported [25]).

Analysis

Descriptive statistics included proportions for categorical and median (interquartile range) for continuous variables, as not all variables had a normal distribution. Since the amount of missing data was low (with the exception of bundle data), no assumptions were made for missing data.

Categorical variables were summarized using proportions and compared using Fisher’s exact test or chi-square tests. Kruskal-Wallis one-way analysis of variance was used to compare results among multiple groups. Odds ratios are reported relative to a reference range of blood glucose. Kaplan–Meier curves for patient survival was used to assess the duration of survival, and compared by using a log-rank test.

We assessed the relationships between hospital mortality and the various independent variables by a Cox regression model. Mortality was used as the criterion variable (death = 1; survival = 0), while age ≤75 years or not, Charlson comorbidity index, SOFA and Acute Physiological and Chronic Health Evaluation II (APACHE II) scores, and blood glucose level <70 mg/dL or not were used as explanatory variables. Before the multivariate analysis, the variance inflation factor for each explanatory variable was calculated. For all explanatory variables, the variance inflation factor was less than five. After an initial review of the data demonstrated a significant association between blood glucose (<70 mg/dL or not) and survival duration, we performed a sensitivity analysis that changed the Charlson comorbidity index, SOFA score, and age >75 years with the APACHE II score. We defined statistical significance as P<0.05 for single comparisons and P<0.00833 for multiple comparisons (after Bonferroni correction). Statistical analyses were performed using SPSS software, version 25.0 (IBM, Armonk, NY, USA).

Results

Baseline characteristics

A total of 1,184 patients with severe sepsis were included in the sepsis cohort of the FORECAST study. Of those, 26 patients with missing data on blood glucose at the time of admission were excluded from this analysis. The patients were divided into four groups based on the initial blood glucose value (Fig 1).

Fig 1. Flow chart of subject selection and blood glucose categories.

Fig 1

Patient characteristics at enrollment are shown in Tables 1 and S1. The median age was 73 years, and the majority of the infections were of pulmonary (31.0%), intra-abdominal (26.2%), and urinary (18.7%) origin. Positive blood culture was observed in 58.8% of patients, and 62.8% of patients were diagnosed with septic shock.

Table 1. Characteristics and blood glucose levels (mg/dL) on admission among patients with severe sepsis in 59 intensive care units in Japan (n = 1158).

Characteristics All patients (n = 1158) <70 mg/dL (n = 69) 70–139 mg/dL (n = 543) 140–179 mg/dL (n = 233) ≥180 mg/dL (n = 313) P value
Age 73 (64–81) 73 (66–79.5) 72 (62–82) 74 (64–81.5) 74 (64.5–81) 0.292
Male sex (n, %) 696, 60.1% 34, 49.3%**,# 313, 57.6% 149, 63.9% 200, 63.9% 0.045
BMI 21.8 (19.0–24.7) 21.3 (19.1–24.8) 21.3 (18.8–24.2) 21.9 (19.5–25.1) 22.4 (19.1–25.4) 0.076
Pre-existing diabetes mellitus (n, %) 270, 23.3% 13, 18.6%# 69, 12.7%# 45, 19.3%# 143, 45.7% <0.001
Coexisting conditions (n, %)
 Myocardial infarction 57, 4.9% 1, 1.4% 26, 4.8% 10, 4.3% 20, 6.4% 0.329
 Congestive heart failure 124, 10.7% 5, 7.2% 52, 9.6% 36, 15.5% 31, 9.9% 0.063
 Cerebrovascular disease 136, 11.7% 5, 4.2% 42, 13.3% 26, 11.2% 33, 10.5% 0.382
 COPD 81, 7.0% 4, 5.8% 38, 7.0% 19, 8.2% 20, 6.4% 0.847
 Connective tissue disease 83, 7.2% 6, 8.7% 48, 8.8% 13, 5.6% 16, 5.1% 0.145
 Peptic ulcer disease 32, 2.8% 1, 1.4% 15, 2.8% 5, 2.1% 11, 3.5% 0.698
 Diabetes mellitus without organ damage 196, 16.9% 6, 8.7%**,# 46, 8.5%**,# 37, 15.9% 101, 34.2% <0.001
 Diabetes mellitus with organ damage 74, 6.4% 7, 10.1%*,** 23, 4.2%# 8, 3.4%# 36, 11.5% <0.001
 Chronic kidney disease 83, 7.2% 4, 5.8% 40, 7.4% 20, 8.6% 19, 6.1% 0.683
 Malignancy (solid) 159, 13.7% 8, 11.5% 69, 12.7% 42, 18.0% 40, 12.8% 0.202
 Moderate to severe liver disease 26, 2.2% 8, 11.6%*,**,# 9, 1.7% 2, 0.9% 7, 2.2% <0.001
CCI 1(0–2) 1(0–2) 1(0–2) 1(0–2) 1(0–3) 0.293
ADL: Inactive (n, %) 282, 24.4% 10, 14.5% 139, 25.6% 60, 25.8% 73, 23.3% 0.003
Suspected site of infection (n, %) 0.001
 Lung 359, 31.0% 20, 29.0% 140, 25.8% 82, 35.2% 117, 37.4%
 Abdomen 303, 26.2% 17, 24.6% 159, 29.3% 62, 26.6% 65, 20.8%
 Urinary tract 216, 18.7% 15, 23.2% 107, 19.7% 43, 18.5% 50, 16.0%
 Soft tissue 115, 9.9% 5, 7.2% 66, 12.2% 14, 6.0% 30, 9.6%
Positivity of blood cultures (n, %) 681, 58.8% 43, 62.3% 338, 62.2% 117, 50.2% 183, 58.5% 0.072
Septic shock (n, %) 727, 62.8% 57, 82.6%*,**,# 351, 64.6% 132, 56.7% 187, 59.7% 0.001
Lactate level (mmol/L) 3.00 (1.80–5.30) 5.50 (3.05–9.75) 2.70 (1.60–5.10) 2.80 (1.78–4.93) 3.25 (2.18–5.60) <0.001
qSOFA score 2 (1–2) 2 (1–2) 2 (1–2) 2 (1–2) 1 (1–2) 0.003
APACHE II score 23 (17–29) 29(21.75–36) *,** 22 (16–29) 22 (15–28) 23(17–30) 0.013
SIRS score 3 (2–4) 3 (2–3.75) 3 (2–3.5) 3 (2–4) 3 (3–4) 0.032
SOFA score 9 (6–11.25) 11.5 (9–14) *,** 8(6–11) 8(5–11) 9 (6–11) <0.001
Compliance with all applicable elements of sepsis 3-h bundle (n, %)
Entire 3-h resuscitation bundle 535, 64.5% 47, 75.8% 240, 62.5% 109, 69.9% 139, 61.2% 0.067
B1. Serum lactate obtained 1125, 97.2% 68, 98.6% 529, 97.4% 222, 95.3% 306, 97.8% 0.261
B2. Broad-spectrum antibiotic given 970, 83.8% 59, 85.5% 452, 83.2% 192, 82.4% 267, 85.6% 0.721
B3. Blood cultures obtained before broad-spectrum antibiotic administration 1064, 92.0% 66, 95.7% 498, 91.9% 213, 91.4% 287, 92.0% 0.712
B4. 30 mg/kg crystalloid fluid bolus delivered (yes/cases with indication) 636, 76.6% 51, 82.3% 295, 76.6% 126, 80.8% 164, 72.3% 0.170
Number of patients with corticosteroid requirement within 6 h (n, %) 191, 16.5% 30, 43.5%*,**,# 90, 16.6% 24, 10.3% 47, 15.0% <0.001

Reported counts (proportions) for categorical and median (interquartile range) for continuous variables.

†septic shock or lactate >4 mmol/L.

Missing data: BMI = 20, Admission source = 2, ADL = 1, blood culture = 6, qSOFA = 24, APACHE II = 124, SIRS = 0, SOFA = 153

ICU = intensive care unit, BMI = body mass index, ED = emergency department, CCI = Charlson Comorbidity Index, COPD = chronic obstructive pulmonary disease; AIDS = acquired immune deficiency syndrome, ADL = activities of daily living, IV = intravenous, qSOFA = quick sepsis organ failure assessment, APACHE = acute physiology and chronic health evaluation, SIRS = systemic inflammatory response syndrome, SOFA = sequential organ failure assessment, INR = international normalized ratio.

*, <0.00833 vs. 70–139 mg/dL.

**, <0.00833 vs. 140–179 mg/dL.

#, <0.00833 vs. ≥180 mg/dL.

Of 1,158 enrolled patients, 69, 543, 233, and 313 patients were categorized as having glucose levels <70, 70–139, 140–179, ≥180 mg/dL, respectively. Hypoglycemia was observed in 6.0% of all patients. The incidence of moderate to severe liver disease and the prevalence of septic shock were significantly higher in patients with blood glucose level <70 mg/dL than in all other groups.

Blood glucose and outcomes

Although the number of ICU-free days and VFDs were not significantly different between the groups, the in-hospital and 28-day mortality rates were significantly higher in patients with blood glucose level <70 mg/dL than in patients of all other groups (Table 2).

Table 2. Clinical outcomes and blood glucose on admission.

Outcomes All patients (n = 1158) <70 mg/dL (n = 69) 70–139 mg/dL (n = 543) 140–179 mg/dL (n = 233) ≥180 mg/dL (n = 313)
In-hospital mortality 266/1127, 23.6% 26/68, 38.2%*,** 123/533, 23.1% 43/221, 19.5% 54/301, 24.6% 0.002
28-day mortality 213/1116, 19.1% 24/68, 35.3%*,** 99/529, 18.7% 36/218, 16.5% 54/301, 24.6% 0.002
Survivor dispositions (n = 861) (n = 42) (n = 410) (n = 178) (n = 231) 0.025
Home (n, %) 317, 36.8% 8, 19.0% 158, 38.5% 72, 40.4% 79, 34.2%
Transfer (n, %) 544, 63.2% 34, 81.0% 252, 61.5% 106, 59.6% 152, 65.8%
ICU-free days 19 (11–24) 16.5 (8.5–22) 22 (12–24) 20 (10–24) 18 (9–23) 0.048
Ventilator-free days 21 (0–28) 14 (0–25) 22 (0–28) 21 (0.75–28) 19 (0–26) 0.051
Length of hospital stay 24 (12–46) 23.5 (7.25–43.5) 23 (11–45.5) 25 (14–39) 24 (13–51) 0.925

Reported counts (proportions) for categorical and median (interquartile range) for continuous variables.

Missing data: in-hospital mortality = 31, 28-day mortality = 42, ICU-free days = 255, Ventilator-free days = 42, Length of hospital stay = 31.

ICU = intensive care unit.

*, <0.00833 vs. 140–179 mg/dL.

**, <0.00833 vs. ≥180 mg/dL.

Outcome data for patients with sepsis according to the Sepsis-3 criteria (S2 Table) and patients divided according to quartiles of glucose level (S3 Table) and the odds ratios for in-hospital mortality (relative to patients with blood glucose levels of 70–139 mg/dL) (S4 Table) are shown as supplementary tables.

Kaplan–Meier curves analyzing patient survival demonstrated a significant difference between patients with glucose level <70 mg/dL and all other groups (S1 Fig).

Influence of hepatic disease/dysfunction on mortality

The hepatic SOFA scores in the patients who were categorized according to their glucose levels of <70, 70–139, 140–179, and >180 mg/dL were 1 (0–1), 0 (0–1), 0 (0–1), and 0 (0–1), respectively (p<0.001). The score was significantly higher in the blood glucose level <70 mg/dL group than in the other groups (Table 1).

In contrast, the presence of "moderate to severe liver disease" as a comorbidity was not different between hypoglycemia and non-hypoglycemia patients (8/69, 151/1089, p = 0.719). Furthermore, hepatic SOFA score on admission was not higher in survivors than in non-survivors (p = 0.232). Odds ratios of hepatic SOFA score of ≥1 for in-hospital mortality and 28-day mortality were 1.18 (0.89–1.57) and 1.22 (0.90–1.66), respectively.

Blood glucose level and clinical outcomes in patients with known diabetes and septic shock

The in-hospital mortality rates with each group with or without a diabetes diagnosis were compared. Although a significantly higher in-hospital mortality rate was observed in patients with blood glucose levels <70 mg/dL than in those with blood glucose levels of 140–179 mg/dL among patients without known diabetes, this difference was not evident in patients with known diabetes (Table 3).

Table 3. In-hospital mortality and body glucose category on admission.

Glucose categories Mortality (n, %)
Patients with known diabetes mellitus
<70 mg/dL 6/13, 46.2%
70–139 mg/dL 22/66, 33.3%
140–179 mg/dL 12/42, 28.6%
≥180 mg/dL 32/140, 22.9%
Patients without known diabetes mellitus
<70 mg/dL 20/55, 36.4%*
70–139 mg/dL 101/467, 21.6%
140–179 mg/dL 31/179, 17.3%
≥180 mg/dL 42/165, 25.5%
Patients with septic shock
<70 mg/dL 22/56, 39.3%
70–139 mg/dL 94/343, 27.4%
140–179 mg/dL 26/123, 21.1%
≥180 mg/dL 55/182, 30.2%
Patients without septic shock
<70 mg/dL 4/12, 33.3%
70–139 mg/dL 29/190, 15.3%
140–179 mg/dL 17/98, 17.3%
≥180 mg/dL 19/123, 15.4%

*, <0.00833 vs. 140–179 mg/dL

Odds ratio for the in-hospital mortality ratio with each group with or without a diabetes diagnosis were also analyzed, relative to the group with a normal glycemic reference range (70–139 mg/dL) (S4 Table, middle portion). The relationship between mortality and blood glucose level was only significant in patients without known diabetes and blood glucose level <70 mg/dL (odds ratio, 2.07, 95% confidence interval, 1.15–3.72). Significant relationships were not demonstrated in patients with or without septic shock (Tables 3 and S4, lower part).

Mortality in patients with both hypoglycemia and septic shock was 2.5-times higher than that in patients without hypoglycemia and septic shock (15.8% vs. 39.3%) (Table 4), and the unadjusted odds ratio for the in-hospital mortality rate in patients with presence of both blood glucose level <70 mg/dL and septic shock was 3.44 (95% confidence interval, 1.90–6.24) when compared to non-hypoglycemic patients (blood glucose ≥70 mg/dL) without septic shock (S5 Table).

Table 4. In-hospital mortality in patients with or without hypoglycemia (<70 mg/dL) and septic shock.

Mortality (n, %)
Glucose <70 mg/dL with Septic shock 22/56, 39.3%*
Glucose <70 mg/dL without Septic shock 4/12, 33.3%
Glucose ≥70 mg/dL with Septic shock 175/648, 27.0%
Glucose ≥70 mg/dL without Septic shock 65/411, 15.8%

*, <0.00833 vs. Glucose >70 mg/dL without Septic shock

Evaluation utilizing the Cox regression model demonstrated that in-hospital mortality rates and blood glucose levels <70 mg/dL on admission were independently associated with a survival duration. Sensitivity analysis also demonstrated this same association (Table 5).

Table 5. Cox regression analysis for the duration of survival (forced entry model).

Hazard ratio 95.0% CI P value
Glucose level <70 mg/dL 1.38 1.03 2.18 0.044
Charlson Comorbidity Index 1.15 1.08 1.23 < 0.001
SOFA score 1.13 1.00 1.70 0.051
Age >75 years 1.30 0.58 0.94 < 0.001
Sensitivity analysis
Glucose level <jl70 mg/dL 1.38 1.02 2.22 0.048
APACHE II score 1.08 1.06 1.09 < 0.001

Independent variable = Duration of Survival

Explanatory variables = hypoglycemia (defined as <70 mg/dL), Age >75 years, Charlson Comorbidity Index, APACHE II score, SOFA score

Discussion

Our findings clearly indicate that severe sepsis patients with hypoglycemia, defined as blood glucose levels <70 mg/dL, have substantial divergent characteristics and clinical outcomes when compared to those with normal blood glucose levels. Although some patients with hypoglycemia had an associated increase in mortality, this relationship was only evident in patients without known diabetes mellitus. In addition, patients with both hypoglycemia and septic shock had an associated increase in mortality rate. This study was conducted using a dataset consisting of patients with severe sepsis, specifically to address the recent advances in the management of the most serious septic cases.

Dysglycemia in patients with sepsis

Several studies have suggested that patients with stress-induced hyperglycemia and no previous diagnosis of diabetes face more dire consequences at a given severity of hyperglycemia than in those with pre-existing diabetes. A retrospective review that stratified patients as having normoglycemia, pre-existing diabetes, or newly diagnosed hyperglycemia demonstrated that mortality was 18.3 times higher in patients with newly diagnosed hyperglycemia [26]. Furthermore, there is a high mortality rate in hyperglycemic patients without known diabetes and an absence of a relationship between hyperglycemia and mortality rates in patients with diabetes in different conditions [9, 10]. Recently, it has been reported that septic ICU patients with insulin-treated diabetes have lower adjusted hospital mortality rates and higher peak blood glucose levels when compared to non-insulin-treated patients. This suggests that septic patients with a pre-existing diagnosis of diabetes present with an altered relationship between hospital mortality and elevated glucose levels [27]. Although the findings are inconsistent, we suggest hyperglycemia may have different clinical implications in patients with or without pre-existing diabetes.

Hypoglycemia has been suggested to be associated with an increased mortality rate in critically ill patients [68]. There is a J- or U-shaped relationship between glucose levels and mortality, such that hyper- and hypoglycemic patients have higher mortality rates than normoglycemic patients [28, 29]. The NICE-SUGAR study reported a relationship between hypoglycemia and the risk of death [6]. The mortality rates in patients who did not have hypoglycemia, moderate hypoglycemia, and severe hypoglycemia were 23.5%, 28.5%, and 35.4%, respectively. The adjusted hazard ratio for mortality among patients with severe hypoglycemia was 2.10. In other studies, hypoglycemia has been independently associated with an increased mortality rate [7, 8].

Although different associations between the effects of hyperglycemia and elevated mortality risk in pre-existing diabetes have been suggested [21, 30], we did not observe this association in this study. This may have been a result of the glucose categories used in this study or a lack of a standardized inpatient glucose control protocol. However, patients with hypoglycemia had an associated increase in mortality rate in this study, which is consistent with findings of the majority of previous studies. Interestingly, this relationship was only evident in patients without known diabetes mellitus, which is a novel finding implicating an association between dysglycemia and sepsis only in patients without a preexisting diabetes diagnosis.

The liver plays an important role in glucose metabolism, and hypoglycemia may occur due to impaired ability of the liver to increase plasma glucose through gluconeogenesis [31]. Hypoglycemia has also been reported as a common manifestation of sepsis patients in cirrhosis [32]. Although the hepatic SOFA score in hypoglycemic patients was significantly higher than those in other groups, the presence of "moderate to severe liver disease" as a comorbidity was not different between hypoglycemia and non-hypoglycemia patients in this study. In addition, hepatic SOFA score on admission in survivors was not higher than that in non-survivors, and the odds ratios of hepatic SOFA scores of ≥1 for in-hospital mortality and 28-day mortality were 1.18 (0.89–1.57) and 1.22 (0.90–1.66), respectively. Hypoglycemia may be related to hepatic impairment accompanied by corticosteroid insufficiency, and further study including a larger number of patients is required to elucidate the impact of the relationship between hypoglycemia and hepatic impairment on the outcome of patients with sepsis.

Hypoglycemia in patients with sepsis—biologic plausibility

Sepsis has been observed to be commonly associated with hypoglycemia [33]. Although spontaneous hypoglycemia is strongly associated with mortality [34], a causal relationship may also be plausible as hypoglycemia can have substantial and varied biological effects in critically ill patients. These effects include an increased systemic inflammatory response, induced neuroglycopenia, inhibition of the corticosteroid response to stress, impairments in the responsiveness and exhaustion of the sympathetic nervous system, and induction of hypotension, vasodilatation, and nitric oxide release [6]. These critical pathological responses suggest hypoglycemia is an epiphenomenon of severe organ dysfunction that can precede death. Although the mechanisms and relationships between hypoglycemia and disease severity in septic patients has not been clarified, inflammatory cytokines, which both increase glucose utilization and inhibit gluconeogenesis [4], may be implicated. That is, hypoglycemia may be a part of a phenotype reflecting a pathological acute stress response.

Hypoglycemia and hypotension are well demonstrated symptoms of adrenal insufficiency. These symptoms in patients with sepsis can be related to Critical Illness-Related Corticosteroid Insufficiency (CIRCI). As such, patients with hypoglycemia may be treated with systemic corticosteroid administration. In this study, the rate of septic shock in hypoglycemic patients was significantly higher, and administration of corticosteroids was more frequent in the hypoglycemic patients. Moreover, the unadjusted odds ratio for in-hospital mortality in patients with both blood glucose <70 mg/dL and presence of septic shock was 3.444 (95% confidence interval, 1.904–6.236) compared to that in patients with blood glucose ≥70 mg/dL without septic shock. Although the prevalence of CIRCI was not evaluated in this study, these relationships may contribute to a poor outcome in patients with hypoglycemia, and the efficacy of corticosteroid administration in patients with hypoglycemia, with or without CIRCI, will need further clarification.

This study involved analyses of databases restricted to patients with severe sepsis only, and after the publication of the Surviving Sepsis Campaign Guidelines 2012 [14]. This is different from most other previous studies, which included patients with less severe conditions in their analyses [3, 8, 12, 13]. There are some limitations of our study. First, we may have underestimated the number of patients with diabetes because of our patient inclusion procedure. Previous studies have shown that diabetes is often unrecognized in hospitalized patients [29], and we defined pre-existing diabetes based on the hospital records for Charlson comorbidity indexing. Both the presence of preexisting diabetes and preadmission glucose control status have important implications for patient health and outocome. However, glucose control status, i.e. HgbA1c levels, was not included in this prospective study. This may be a significant limitation in demonstrating a relationship between glycemic abnormalities and the relevant clinical outcomes of patients with sepsis. Second, although we evaluated the relationships between the initial blood glucose levels and mortality rates in patients with severe sepsis, we acknowledge that glucose management may influence patient outcomes substantially. The effect of glucose management was not included in the current analysis, and as such was not considered as a prognostic factor. Third, although we used the blood glucose levels measured during initial evaluation and management, the time between measurement and the diagnosis of severe sepsis or septic shock was not defined in this registry. These measurement related issues may have influenced the results.

Conclusions

Hypoglycemia may be related to increased disease severity and a higher mortality rate in patients with sepsis and an independently associated predictor of poor clinical outcome. These relationships were evident only in patients without known diabetes. Patients with both hypoglycemia and septic shock had an associated increase in mortality rates. Although hypoglycemia may be related to hepatic impairment, further studies are needed to examine this relationship with regard to the outcomes of patients with sepsis.

Supporting information

S1 Table. Characteristics and blood glucose levels (mg/dL) on admission among patients with severe sepsis in 59 intensive care units in Japan (n = 1158).

(DOCX)

S2 Table. Clinical outcomes and blood glucose levels at admission in patients diagnosed with sepsis according to the Sepsis-3 criteria.

(DOCX)

S3 Table. Clinical outcomes according to the quartiles of patient’s blood glucose levels at admission.

(DOCX)

S4 Table. In-hospital mortality and body glucose category on admission.

(DOCX)

S5 Table. In-hospital mortality in patients with or without hypoglycemia (<70 mg/dL) and septic shock.

(DOCX)

S6 Table. List of the names of all of the ethics committees that reviewed and approved this study.

(DOCX)

S1 Fig

(TIF)

Acknowledgments

We thank the JAAM FORECAST Study Group for contribution to this study.

Investigators of the JAAM FORECAST Study Group:

Nagasaki University Hospital (Osamu Tasaki); Osaka City University Hospital (Yasumitsu Mizobata); Tokyobay Urayasu Ichikawa Medical Center (Hiraku Funakoshi); Aso Iizuka Hospital (Toshiro Okuyama); Tomei Atsugi Hospital (Iwao Yamashita); Hiratsuka City Hospital (Toshio Kanai); National Hospital Organization Sendai Medical Center (Yasuo Yamada); Ehime University Hospital (Mayuki Aibiki); Okayama University Hospital (Keiji Sato); Tokuyama Central Hospital (Susumu Yamashita); Fukuyama City Hospital (Susumu Yamashita); JA Hiroshima General Hospital (Kenichi Yoshida); Kumamoto University Hospital (Shunji Kasaoka); Hachinohe City Hospital (Akihide Kon); Osaka City General Hospital (Hiroshi Rinka); National Hospital Organization Disaster Medical Center (Hiroshi Kato); University of Toyama (Hiroshi Okudera); Sapporo Medical University (Eichi Narimatsu); Okayama Saiseikai General Hospital (Toshifumi Fujiwara); Juntendo University Nerima Hospital (Manabu Sugita); National Hospital Organization Hokkaido Medical Center (Yasuo Shichinohe); Akita University Hospital (Hajime Nakae); Japanese Red Cross Society Kyoto Daini Hospital (Ryouji Iiduka); Maebashi Red Cross Hospital (Mitsunobu Nakamura); Sendai City Hospital (Yuji Murata); Subaru Health Insurance Society Ota Memorial Hospital (Yoshitake Sato); Fukuoka University Hospital (Hiroyasu Ishikura); Ishikawa Prefectural Central Hospital (Yasuhiro Myojo); Shiga University of Medical Science (Yasuyuki Tsujita); Nihon University School of Medicine (Kosaku Kinoshita); Seirei Yokohama General Hospital (Hiroyuki Yamaguchi); National Hospital Organization Kumamoto Medical Center (Toshihiro Sakurai); Saiseikai Utsunomiya Hospital (Satoru Miyatake); National Hospital Organization Higashi-Ohmi General Medical Center (Takao Saotome); National Hospital Organization Mito Medical Center (Susumu Yasuda); Tsukuba Medical Center Hospital (Toshikazu Abe); Osaka University Graduate School of Medicine (Hiroshi Ogura, Yutaka Umemura); Kameda Medical Center (Atsushi Shiraishi); Tohoku University Graduate School of Medicine (Shigeki Kushimoto); National Defense Medical College (Daizoh Saitoh); Keio University School of Medicine (Seitaro Fujishima, Junichi Sasaki); University of Occupational and Environmental Health (Toshihiko Mayumi); Kawasaki Medical School (Yasukazu Shiino); Chiba University Graduate School of Medicine (Taka-aki Nakada); Kyorin University School of Medicine (Takehiko Tarui); Kagawa University Hospital (Toru Hifumi); Tokyo Medical and Dental University (Yasuhiro Otomo); Hyogo College of Medicine (Joji Kotani); Saga University Hospital (Yuichiro Sakamoto); Aizu Chuo Hospital (Shin-ichiro Shiraishi); Kawasaki Municipal Kawasaki Hospital (Kiyotsugu Takuma); Yamaguchi University Hospital (Ryosuke Tsuruta); Center Hospital of the National Center for Global Health and Medicine (Akiyoshi Hagiwara); Osaka General Medical Center (Kazuma Yamakawa); Aichi Medical University Hospital (Naoshi Takeyama); Kurume University Hospital (Norio Yamashita); Teikyo University School of Medicine (Hiroto Ikeda); Rinku General Medical Center (Yasuaki Mizushima); Hokkaido University Graduate School of Medicine (Satoshi Gando).

Abbreviations

ADL

Activities of daily living

APACHE II

Acute Physiologic Assessment and Chronic Health Evaluation II

BMI

Body mass index

CCI

Charlson comorbidity index

CVP

Central venous pressure

ED

Emergency department

EGDT

Early goal direct therapy

FIO2

Fraction of inspired oxygen

FORECAST

Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma

ICU

Intensive care unit

IQR

Interquartile range

LOS

Length of hospital stay

MAP

Mean arterial pressure

PaO2

Partial pressure of arterial oxygen

ScvO2

Central venous oxygen saturation

SIRS

Systemic inflammatory response syndrome

SOFA

Sepsis-related Organ Failure Assessment

SSC

Surviving Sepsis Campaign

SSCG

Surviving Sepsis Campaign Guidelines

UMIN-CTR

University Hospital Medical Information Network Clinical Trials Registry

VFDs

Ventilator-free days

Data Availability

Data cannot be shared publicly because the collected data contain potentially sensitive information. The data that support the findings of this study are available from the corresponding author upon reasonable request through the Japanese Association for Acute Medicine for researchers who meet the criteria for access to confidential data. Alternatively, data are available from the Japanese Association for Acute Medicine Ethics Committee with the following contact information: E-mail: jaam-6@bz04.plala.or.jp, name of dataset: JAAM FORECAST-Sepsis.

Funding Statement

This study was supported by the Japanese Association for Acute Medicine (2014–01).

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Decision Letter 0

Robert Ehrman

13 Sep 2019

PONE-D-19-25111

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

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PLoS One. 2020 Mar 11;15(3):e0229919. doi: 10.1371/journal.pone.0229919.r002

Author response to Decision Letter 0


17 Sep 2019

Response to the Editor’s comments

We thank the Editor for the favorable comments and acknowledgment of our work. We have revised our manuscript accordingly.

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Decision Letter 1

Robert Ehrman

23 Dec 2019

PONE-D-19-25111R1

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

PLOS ONE

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Reviewer #1: Summary

Thank you for the opportunity to review this paper. This is a very interesting study that aims to elucidate the predictive role of hypoglycemia in septic patients. The authors utilize a large prospective cohort study to answer the question of whether initial hypoglycemia is predictive of outcome. The results are interesting, but I have issues with how the data was analyzed and presented. Hepatic failure needs to be accounted for specifically in the analyses. As it is currently presented, I think this study is at risk of making the assumption that hypoglycemia is predictive of death, when it is actually just associated with severe disease.

Major points

The study objective to elucidate dysglycemia in a sepsis population is clinically relevant

The authors state “initial blood glucose” level but do not provide timing of this initial glucose or how this was obtained. Was this from finger stick measurements, blood chemistries, etc? Also what was the mean time to measurement of this value from enrollment into the study? It is important to know where in the course of their disease the hypoglycemia occurred.

Even though the parent study (FORECAST) was designed prior to Sepsis-3, they should still report the proportion of patients meeting Sepsis-3 definitions. This should not be difficult given that the authors have SOFA score data available and will make the study more directly comparable to more recent studies.

The authors provide data to support for their choice of blood glucose groups. It would be important to know what they learned from their own data, rather than to utilize prior categorizations of blood glucose from other work. Separating the blood glucose measurements of their patients by quartiles (or similar) and looking at outcomes based on this would be informative.

How did the authors handle censored data for SOFA score in patients who died early?

A larger proportion of patients in the hypoglycemia group had glucose mod to severe liver disease. It is not surprising that those patients are more prone to hypoglycemia. Also, the SOFA scores of the hypoglycemia patients are significantly higher. It is important to know what the Hepatic SOFA scores are for the patients with hypoglycemia. The predictive ability of hypoglycemia could be confounded by liver disease or acute liver failure.

Given the potential interaction between liver disease/failure above it is important to add lactate levels (initial and repeat) to Table 1 and compare across groups.

Corticosteroid requirement is much higher in hypoglycemia group. Is there any data on whether the glucose levels were obtained prior to administration of corticosteroids or if these are post-steroid measures?

The presentation of the data is confusing. The authors mention Kaplan-Meier curves for survival, but then use a Cox regression. But they also report unadjusted odds ratios. If the outcome of interest is the association with mortality, I don’t think a Cox regression is needed as the time to death is not really that relevant. I also do not think unadjusted odds ratios should be presented, and should only be added as supplementary material. The Cox regression shows a higher hazard ratio for glucose < 70, which was robust to sensitivity analysis I think components of SOFA, specifically liver failure should be evaluated in the model as well as Charlson score for mod to severe liver disease. I think we are at risk of finding that hypoglycemia is associated with severely ill patients at risk of mortality, rather than predictive of itself.

Why are unadjusted odds ratios displayed in Table 3 and 4, rather than adjusted?

Minor

Would prefer to see the tables separately and not in the body of the text, which makes it harder to read

Also the authors should indicate units appropriately in tables (N, %) in the first column

Odds ratios should only be reported to 1 or 2 places after the decimal

Reviewer #2: An interesting subgroup analysis highlighting the association between hypoglycemia on admission and mortality in severe sepsis patients from a previously performed multicenter prospective cohort. Highlighting an association between hypoglycemia in non-diabetic sepsis patients and increased mortality is a relevant finding.

Appropriate statistics used for the most part and findings correctly described as an association only in need of further study to determine causation.

The fact that the cohort is a mixed ICU population including medical and trauma patients may confound some of the data a bit. Would be interesting to see if the association still stands in both the trauma and medical ICU subgroups or if it would change.

Abstract still has a few errors and needs some rewording to aid in understanding for readers.

**********

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Reviewer #1: No

Reviewer #2: No

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Attachment

Submitted filename: Plos One dysglycemia.docx

PLoS One. 2020 Mar 11;15(3):e0229919. doi: 10.1371/journal.pone.0229919.r004

Author response to Decision Letter 1


17 Jan 2020

Reviewer #1:

Summary

Thank you for the opportunity to review this paper. This is a very interesting study that aims to elucidate the predictive role of hypoglycemia in septic patients. The authors utilize a large prospective cohort study to answer the question of whether initial hypoglycemia is predictive of outcome. The results are interesting, but I have issues with how the data was analyzed and presented. Hepatic failure needs to be accounted for specifically in the analyses. As it is currently presented, I think this study is at risk of making the assumption that hypoglycemia is predictive of death, when it is actually just associated with severe disease.

(Response)

We thank the Reviewer for the favorable comments and acknowledgment of our work. Accordingly, we have revised our manuscript. To facilitate the review process, the revised sentences are shown in red in the revised manuscript.

Major points

The study objective to elucidate dysglycemia in a sepsis population is clinically relevant

The authors state “initial blood glucose” level but do not provide timing of this initial glucose or how this was obtained. Was this from finger stick measurements, blood chemistries, etc? Also what was the mean time to measurement of this value from enrollment into the study? It is important to know where in the course of their disease the hypoglycemia occurred.

(Response)

Thank you for your comments. Accordingly, we have added the following information in the methods and limitations section:

Methods: Blood glucose levels were measured using a blood gas analyzer (and not a glucometer) as recommend by Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012 (14). All glucose levels were measured prior to the administration of corticosteroids (if required).

Limitations: Third, although we used the blood glucose levels measured during initial evaluation and management, the time between measurement and the diagnosis of severe sepsis or septic shock was not defined in this registry. These measurement related issues may have influenced the results.

Even though the parent study (FORECAST) was designed prior to Sepsis-3, they should still report the proportion of patients meeting Sepsis-3 definitions. This should not be difficult given that the authors have SOFA score data available and will make the study more directly comparable to more recent studies.

(Response)

Thank you for your comments. We have added the outcome data for patients diagnosed with sepsis by the Sepsis-3 definition in Supplementary Table 2. For defining an acute increase in SOFA scores of ≥2, a baseline SOFA score of 0 was assumed in patients without a diagnosis of any chronic disease, as defined per APACHE II scores. If a chronic disease was present, a baseline SOFA score of 2 was assigned, similar to methods used in a previous study (JAMA. 2016;317:290–300).

The authors provide data to support for their choice of blood glucose groups. It would be important to know what they learned from their own data, rather than to utilize prior categorizations of blood glucose from other work. Separating the blood glucose measurements of their patients by quartiles (or similar) and looking at outcomes based on this would be informative.

(Response)

Thank you for your comments. Although we performed our analysis based on pre-defined categorization of blood glucose levels to recognize the importance of hypoglycemia (70 mg/dL or less), it is important to know the findings obtained from our own data. As such, we have presented all outcomes according to quartiles of patient glucose levels in Supplementary Table 3.

How did the authors handle censored data for SOFA score in patients who died early?

(Response)

Thank you for your comments. The SOFA score was calculated using physiological and laboratory values determined during the initial evaluation. Therefore, we did not handle censored data for SOFA scores.

We have added the following information in the methods section:

The Sequential Organ Failure Assessment (SOFA) score was calculated using physiological and laboratory values during the initial evaluation.

A larger proportion of patients in the hypoglycemia group had glucose mod to severe liver disease. It is not surprising that those patients are more prone to hypoglycemia. Also, the SOFA scores of the hypoglycemia patients are significantly higher. It is important to know what the Hepatic SOFA scores are for the patients with hypoglycemia. The predictive ability of hypoglycemia could be confounded by liver disease or acute liver failure.

Given the potential interaction between liver disease/failure above it is important to add lactate levels (initial and repeat) to Table 1 and compare across groups.

(Response)

Thank you for your comments. We have added lactate levels in Table 1 and the hepatic SOFA scores in the main text according to the reviewer’s comments. However, we have no repeated values of lactate levels in this dataset.

Added data and information:

Lactate levels in Table 1: 3.00 (1.80-5.30), 5.50 (3.05- 9.75), 2.70 (1.60- 5.10), 2.80 (1.78- 4.93), 3.25 (2.18-5.60), respectively.

Hepatic SOFA scores in the main text (Results section): The hepatic SOFA scores in the categories with glucose levels of <70, 70-139, 140-179, and >180 mg/dL were 1 (0-1), 0 (0-1), 0 (0-1), and 0 (0-1), respectively (p<0.001).

We have also added the following comments:

This score was significantly higher in the group with patients with blood glucose levels <70 mg/dL than in the other groups.

Corticosteroid requirement is much higher in hypoglycemia group. Is there any data on whether the glucose levels were obtained prior to administration of corticosteroids or if these are post-steroid measures?

(Response)

Thank you for your comments. We have added the following information in the methods section:

All glucose levels were measured prior to the administration of corticosteroids (if required).

The authors mention Kaplan-Meier curves for survival, but then use a Cox regression. But they also report unadjusted odds ratios. If the outcome of interest is the association with mortality, I don’t think a Cox regression is needed as the time to death is not really that relevant. I also do not think unadjusted odds ratios should be presented, and should only be added as supplementary material. The Cox regression shows a higher hazard ratio for glucose < 70, which was robust to sensitivity analysis I think components of SOFA, specifically liver failure should be evaluated in the model as well as Charlson score for mod to severe liver disease. I think we are at risk of finding that hypoglycemia is associated with severely ill patients at risk of mortality, rather than predictive of itself.

Why are unadjusted odds ratios displayed in Table 3 and 4, rather than adjusted? These should not be displayed though they can be presented in the body of the manuscript, briefly.

(Response)

Thank you for your comments. The Kaplan-Meier curves for survival were deleted from the main body of the manuscript and presented as supplementary content. Tables 3 and 4 are presented without the unadjusted odds ratios in the main body of the manuscript, and odds ratios are presented in Supplementary Tables 4 and 5.

The reviewer has highlighted the significance of the coexistence of moderate-to-severe liver disease. Although these comments were reasonable, coexisting moderate-to-severe liver disease was only present in 26 patients showing significantly higher mortality and prevalence of hypoglycemia (Mortality: 255/1132, 22.5% vs. 11/26, 42.3%, p=0.011; Hypoglycemia: 61/1132, 5.4% vs 8/26, 30.8%, p<0.001). Based on these interactions, we did not evaluate the coexistence of moderate-to-severe liver disease as an explanatory variable in this study.

In addition, the outcome of interest was not only mortality but also the duration of survival, as demonstrated in the Kaplan-Meier survival curves. Therefore, we evaluated the significance of hypoglycemia using Cox regression analysis.

Minor

Would prefer to see the tables separately and not in the body of the text, which makes it harder to read

(Response)

We have revised the manuscript as per your suggestion.

Also the authors should indicate units appropriately in tables (N, %) in the first column

(Response)

We add the (N, %) in the tables as per your suggestion.

Odds ratios should only be reported to 1 or 2 places after the decimal

(Response)

We have revised the description of odds ratios and hazard ratios as per your suggestion.

Reviewer #2: An interesting subgroup analysis highlighting the association between hypoglycemia on admission and mortality in severe sepsis patients from a previously performed multicenter prospective cohort. Highlighting an association between hypoglycemia in non-diabetic sepsis patients and increased mortality is a relevant finding.

Appropriate statistics used for the most part and findings correctly described as an association only in need of further study to determine causation.

(Response)

We thank the Reviewer for the favorable comments and acknowledgment of our work. Accordingly, we have revised our manuscript. To facilitate the review process, the revised sentences are shown in red in the revised manuscript.

The fact that the cohort is a mixed ICU population including medical and trauma patients may confound some of the data a bit. Would be interesting to see if the association still stands in both the trauma and medical ICU subgroups or if it would change.

(Response)

Thank you for your comments. We agree with the Reviewer’s comments. However, the dataset of the FORECAST Sepsis cohort has no information on trauma and medical ICU subgroups.

Abstract still has a few errors and needs some rewording to aid in understanding for readers.

(Response)

Thank you for your comments. We revised the abstract as you kindly suggested. In addition, we revised some sentences according to the changes made in the main manuscript.

Attachment

Submitted filename: 20MQVO284779_Plos One dysglycemia_200102.docx

Decision Letter 2

Robert Ehrman

4 Feb 2020

PONE-D-19-25111R2

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

PLOS ONE

Dear Prof. Kushimoto,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Thank you for your time and effort revising the manuscript, which has been substantially improved. I am in agreement with the reviewer about the potential confounding effect of liver disease--are the poor outcomes related to hypoglycemia itself, or is this simply a manifestation of liver disease? With only 26 patients in this category, I think it would be difficult to make any firm conclusions about which factor drove the outcome (ie, an analysis comparing liver disease with vs without hypoglycemia would be under-powered).

However, I do think it is worth addressing, most substantively in the discussion, as well mentioning this in the abstract. Can you also include in the methods what criteria were used to classify patients as "moderate to severe liver disease"? I think this would also be informative to readers.

Also, I think the first line of the abstract should read "Dysglycemia is..." not "Dysglycemia are..."

==============================

We would appreciate receiving your revised manuscript by Mar 20 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

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.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

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Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall the authors have addressed most of my concerns. However, now that they have identified the significant influence of hepatic disease (elevated hepatic SOFA) in the subgroup with glucose < 70, the reader needs to be sure that hepatic failure isn't driving most of the difference seen in this group. I am not sure based on reviewing their regression models that liver failure was fully accounted for here. It is not explicitly stated nor made clear in the methods. This point may require a statistical review. Moreover, I believe the finding of significantly elevated hepatic SOFA should be mentioned in the abstract, discussion and conclusion.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Mar 11;15(3):e0229919. doi: 10.1371/journal.pone.0229919.r006

Author response to Decision Letter 2


14 Feb 2020

Editor’s comments

Thank you for your time and effort revising the manuscript, which has been substantially improved. I am in agreement with the reviewer about the potential confounding effect of liver disease--are the poor outcomes related to hypoglycemia itself, or is this simply a manifestation of liver disease? With only 26 patients in this category, I think it would be difficult to make any firm conclusions about which factor drove the outcome (ie, an analysis comparing liver disease with vs without hypoglycemia would be under-powered). However, I do think it is worth addressing, most substantively in the discussion, as well mentioning this in the abstract.

(Response)

We thank the Editor for the favorable comments and acknowledgment of our work. Accordingly, we have revised our manuscript. To facilitate the review process, the revised sentences are shown in red in the revised manuscript. According to the Editor’s comments, we revised the manuscript as follows.

We have added the following comments to the discussion section:

The liver plays an important role in glucose metabolism, and hypoglycemia may occur due to impaired ability of the liver to increase plasma glucose through gluconeogenesis (31). Hypoglycemia has also been reported as a common manifestation of sepsis patients in cirrhosis (32). Although the hepatic SOFA score in hypoglycemic patients was significantly higher than those in other groups, the presence of "moderate to severe liver disease" as a comorbidity was not different between hypoglycemia and non-hypoglycemia patients in this study. In addition, hepatic SOFA score on admission in survivors was not higher than that in non-survivors, and the odds ratios of hepatic SOFA scores of ≥1 for in-hospital mortality and 28-day mortality were 1.18 (0.89–1.57) and 1.22 (0.90–1.66), respectively. Hypoglycemia may be related to hepatic impairment accompanied by corticosteroid insufficiency, and further study including a larger number of patients is required to elucidate the impact of the relationship between hypoglycemia and hepatic impairment on the outcome of patients with sepsis.

We have also added the following comments in results section of the abstract:

Of 1158 patients, 69, 543, 233, and 313 patients were categorized as glucose levels <70 (hypoglycemia), 70-139, 140-179, >180 mg/dL, respectively. Both the Acute Physiological and Chronic Health Evaluation II and Sequential Organ Failure Assessment (SOFA) scores on the day of enrollment were higher in the hypoglycemia patients than non-hypoglycemic patients than in those with 70-179 mg/dL. The hepatic SOFA scores were also higher in hypoglycemia patients.

Can you also include in the methods what criteria were used to classify patients as "moderate to severe liver disease"? I think this would also be informative to readers.

(Response)

We have provided the following definitions in the methods section: Severe, moderate, and mild liver disease as comorbidities were defined as follows: severe; cirrhosis and portal hypertension with variceal bleeding history; moderate, cirrhosis and portal hypertension but no variceal bleeding history; and mild, chronic hepatitis (or cirrhosis without portal hypertension) (23).

Also, I think the first line of the abstract should read "Dysglycemia is..." not "Dysglycemia are..."

➠ We have revised as per your suggestion.

Reviewer #1:

Overall the authors have addressed most of my concerns.

However, now that they have identified the significant influence of hepatic disease (elevated hepatic SOFA) in the subgroup with glucose < 70, the reader needs to be sure that hepatic failure isn't driving most of the difference seen in this group. I am not sure based on reviewing their regression models that liver failure was fully accounted for here. It is not explicitly stated nor made clear in the methods. This point may require a statistical review.

(Response)

We thank the Reviewer for the favorable comments and acknowledgment of our work. Accordingly, we have revised our manuscript. To facilitate the review process, the revised sentences are shown in red in the revised manuscript.

We have added the following comments in the methods and results sections:

Methods:

Hepatic disease/dysfunction, glycemic abnormalities, Sepsis-3, and outcomes

To evaluate the relationship between hepatic impairment and glycemic abnormalities, the presence of moderate to severe hepatic disease as a comorbidity and hepatic SOFA score were compared among groups. In addition, to assess the influence of hepatic impairment on the outcome of hypoglycemia, the presence of moderate to severe hepatic disease and hepatic SOFA score >0 were compared between hypoglycemia and non-hypoglycemia patients. Severe, moderate, and mild liver disease as comorbidities were defined as follows: severe; cirrhosis and portal hypertension with variceal bleeding history; moderate, cirrhosis and portal hypertension but no variceal bleeding history; and mild, chronic hepatitis (or cirrhosis without portal hypertension).

Results:

Influence of hepatic disease/dysfunction on mortality

The hepatic SOFA scores in the patients who were categorized according to their glucose levels of <70, 70-139, 140-179, and >180 mg/dL were 1 (0-1), 0 (0-1), 0 (0-1), and 0 (0-1), respectively (p<0.001). The score was significantly higher in the blood glucose level <70 mg/dL group than in the other groups (Table 1).

In contrast, the presence of "moderate to severe liver disease" as a comorbidity was not different between hypoglycemic and non-hypoglycemic patients (8/69, 151/1089, p =0.719). Also, hepatic SOFA on admission in survivors was not higher than that of non-survivors (p=0.232). Odds ratios of hepatic SOFA score of 1 or more for in-hospital mortality and 28-day mortality were 1.18 (0.89–1.57) and 1.22 (0.90–1.66), respectively.

Moreover, I believe the finding of significantly elevated hepatic SOFA should be mentioned in the abstract, discussion and conclusion.

(Response)

We have added the following comments in the abstract, discussion, and conclusion sections of the revised manuscript:

Results section of the abstract:

The hepatic SOFA scores were also higher in hypoglycemia patients.

Discussion:

The liver plays an important role in glucose metabolism, and hypoglycemia may occur due to impaired ability of the liver to increase plasma glucose through gluconeogenesis (31). Hypoglycemia has also been reported as a common manifestation of sepsis patients in cirrhosis (32). Although the hepatic SOFA score in hypoglycemic patients was significantly higher than those in other groups, the presence of "moderate to severe liver disease" as a comorbidity was not different between hypoglycemia and non-hypoglycemia patients in this study. In addition, hepatic SOFA score on admission in survivors was not higher than that in non-survivors, and the odds ratios of hepatic SOFA scores of ≥1 for in-hospital mortality and 28-day mortality were 1.18 (0.89–1.57) and 1.22 (0.90–1.66), respectively. Hypoglycemia may be related to hepatic impairment accompanied by corticosteroid insufficiency, and further study including a larger number of patients is required to elucidate the impact of the relationship between hypoglycemia and hepatic impairment on the outcome of patients with sepsis.

Conclusions

Hypoglycemia may be related to increased disease severity and a higher mortality rate in patients with sepsis, and moreover, was an independent predictor of poor clinical outcome. These relationships were evident only in patients without diabetes. Patients with both hypoglycemia and septic shock had increase mortality rates. Although hypoglycemia may be related to hepatic impairment, further studies are needed to explicate the relationship with respect to the outcomes of patients with sepsis.

Attachment

Submitted filename: PONE-D-19-25111R2.200213.docx

Decision Letter 3

Robert Ehrman

19 Feb 2020

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

PONE-D-19-25111R3

Dear Dr. Kushimoto,

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

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Robert Ehrman, MD, MS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Robert Ehrman

26 Feb 2020

PONE-D-19-25111R3

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

Dear Dr. Kushimoto:

I am 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.

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on behalf of

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PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Characteristics and blood glucose levels (mg/dL) on admission among patients with severe sepsis in 59 intensive care units in Japan (n = 1158).

    (DOCX)

    S2 Table. Clinical outcomes and blood glucose levels at admission in patients diagnosed with sepsis according to the Sepsis-3 criteria.

    (DOCX)

    S3 Table. Clinical outcomes according to the quartiles of patient’s blood glucose levels at admission.

    (DOCX)

    S4 Table. In-hospital mortality and body glucose category on admission.

    (DOCX)

    S5 Table. In-hospital mortality in patients with or without hypoglycemia (<70 mg/dL) and septic shock.

    (DOCX)

    S6 Table. List of the names of all of the ethics committees that reviewed and approved this study.

    (DOCX)

    S1 Fig

    (TIF)

    Attachment

    Submitted filename: Plos One dysglycemia.docx

    Attachment

    Submitted filename: 20MQVO284779_Plos One dysglycemia_200102.docx

    Attachment

    Submitted filename: PONE-D-19-25111R2.200213.docx

    Data Availability Statement

    Data cannot be shared publicly because the collected data contain potentially sensitive information. The data that support the findings of this study are available from the corresponding author upon reasonable request through the Japanese Association for Acute Medicine for researchers who meet the criteria for access to confidential data. Alternatively, data are available from the Japanese Association for Acute Medicine Ethics Committee with the following contact information: E-mail: jaam-6@bz04.plala.or.jp, name of dataset: JAAM FORECAST-Sepsis.


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