Definitions for the Compliance with Sepsis Bundle

(1)

Supplemental Digital Content

Normothermia in Patients with Sepsis Who Present to Emergency Departments is Associated with Low Compliance with Sepsis Bundles and Increased In-

Hospital Mortality Rate

Sunghoon Park, Kyeongman Jeon, Dong Kyu Oh, Eun Young Choi, Gil Myeong

Seong, Jeongwon Heo, Youjin Chang, Won Gun Kwack, Byung Ju Kang, Won-Il

Choi, Kyung Chan Kim, So Young Park, Yoon Mi Shin, Heung Bum Lee, So Hee

Park, Seok Chan Kim, Sang Hyun Kwak, Jae Hwa Cho, Beongki Kim, Chae Man

Lim; Korean Sepsis Alliance (KSA) study group

(2)

(3)

(4)

(5)

(6)

(7)

Diagnostic Criteria for Sepsis and Septic Shock (the Sepsis-3)

1. Screening for Sepsis Patients in the Emergency Departments

¹

Quick Sequential Organ Failure Assessment (qSOFA) was used for screening sepsis patients. And, a 'positive qSOFA' was defined if patient satisfied two of the following conditions:

1) Systolic blood pressure ≤ 100 mm Hg 2) Respiratory rate ≥ 22/min

3) Altered mental status (i.e., Glasgow Coma Scale ≤ 14)

A positive qSOFA suggests high risk of poor outcome in patients with suspected infection. These patients were promptly assessed for evidence of organ dysfunctions (i.e., calculation of total SOFA score to confirm the diagnosis of sepsis).

2. Criteria for Sepsis

^1,2

A patient was diagnosed as having sepsis if the patient satisfied the following two conditions:

1) Probable or confirmed diagnosis of infection

2) Acute change in total SOFA score of ≥2 consequent to the infection: the baseline SOFA score was assumed to be zero in patients not known to have pre-existing organ dysfunction.

3. Criteria for Septic Shock

Septic shock was defined as persistent arterial hypotension requiring vasopressors to maintain a

mean arterial pressure of ≥65 mmHg and a serum lactate level of >2 mmol/L despite adequate

volume resuscitation.

(8)

1.Seymour CW, Liu VX, Iwashyna TJ, et al: Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:762-74

2. Singer M, Deutschman CS, Seymour CW et al: The Third International Consensus Definitions for

Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315: 801-810

(9)

Definitions for the Systemic Inflammatory Response Syndrome (SIRS)

¹

A ‘positive SIRS criteria’ was defined if patient satisfied two of the following conditions:

1) BT < 36

℃

or > 38

℃

2) Heart rate > 90 beats/min

3) Respiratory rate > 20/min or P

a

CO

2

< 32 mmHg

^a

4) White blood cell counts < 4,000 cells/mm

³

or > 12,000 cells/mm

³

or presence of greater than 10% immature neutrophils (band forms)

a

Because respiratory rate was not available in our study, P

a

CO

2

(< 32 mmHg) was used for tachypnea.

Reference

1. Kaukonen KM, Bailey M, Pilcher D, et al: Systemic Inflammatory Response Syndrome Criteria in

Defining Severe Sepsis. N Engl J Med 2015; 372:1629-1638.

(10)

Definitions for the Compliance with Sepsis Bundle

1. Time Zero

¹

‘Time zero’ was defined as the time of triage in the emergency departments in this study.

2. The hour-1 Bundle

¹

1)‘Compliance with the hour-1 bundle’ was defined as achievement of the bundle elements within 1 hour from the time zero.

2) Following six elements were evaluated for the 1-hour compliance (‘yes’ or ‘no’ answer).

① Measurement of lactate

② Blood culture prior to antibiotic administration

③ Administration of broad-spectrum antibiotics

④ Any bolus Infusion of crystalloid fluid

⑤ Application of vasopressors if patient is hypotensive during or after fluid resuscitation to

maintain mean arterial pressure ≥ 65 mmHg

⑥ Remeasurement of lactate level if initial lactate level > 2 mmol/L

3) For the three elements (i.e., measurement of lactate level, blood culture, and antibiotic administration), time interval from time zero to bundle completion was investigated.

3. Completion rate within 3 hours

²

1) ‘Completion rate within 3-hours’ was defined as the achievement of the bundle elements within 3 hours from the time zero.

2) Three elements, for which the time interval from time zero to bundle completion was collected, were evaluated for the 3-hour bundle compliance.

① Measurement of lactate

(11)

② Blood culture prior to antibiotic administration

③ Administration of broad-spectrum antibiotics

References

1. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive

Care Med 2018;44:925-928

2. Rhodes A, Evans LE, Alhazzani W et al: Surviving Sepsis Campaign: International Guidelines for

Management of Sepsis and Septic Shock: 2016. Crit Care Med 2017;45:486-552

(12)

Definitions for ICU events (Supplemental Table 8)

1. Ventilator-Associated Pneumonia (VAP)

¹

1) VAP is defined as a pneumonia occurring >48 hours after endotracheal intubation.

2) Pneumonia was defined as the presence of new lung infiltrate plus clinical evidence that the infiltrate is of an infectious origin, which includes the new onset of fever, purulent sputum, leukocytosis, and decline in oxygenation.

2. Central Line-Associated Blood Stream Infection (CLABSI)

²

1) CLABSI was defined as a laboratory-confirmed bloodstream infection, not related to an infection at another site, in a patient who had central line at the time of infection or within 48 hours before development of infection.

2) It was defined as recovery of a pathogen from a blood culture: a single blood culture for organisms not commonly present on the skin, and two or more blood cultures for organisms commonly present on the skin.

3. Cather-Associated Urinary Tract Infection (CA-UTI)

³

1) CA-UTI was defined in patients with indwelling urethral, indwelling suprapubic, or intermittent catheterization.

2) CA-UTI was defined by the presence of symptoms or signs compatible with UTI, with no other identified source of infection, along with ≥10

³

colony-forming units/mL of ≥1 bacterial species in a single catheter urine specimen.

4. Acute Respiratory Distress Syndrome (ARDS)

⁴

According to the 2012 Berlin definition, ARDS was defined when the following criteria were met:

①

Lung injury of acute onset, within 1 week of an apparent clinical insult and with progression of

respiratory symptoms

(13)

②

Bilateral opacities on chest imaging (chest radiograph or CT) not explained by other lung pathology such as effusion, lobar/lung collapse, and nodules

③

Respiratory failure not explained by heart failure or volume overload

④

Decreased PaO

2

/FiO

2

ratio < 300 mmHg

The definition requires a minimum positive end expiratory pressure (PEEP) of 5 cmH

2

O for consideration of the PaO

2

/FiO

2

ratio; this degree of PEEP may be delivered noninvasively with CPAP to diagnose mild ARDS.

5. Major Bleeding

⁵

Major bleeding complications indicate one of the followings:

1) Life-threatening bleeding.

2) Bleeding causing a fall in hemoglobin level of 2.0 g/dL.

3) Bleeding causing hemodynamic instability which requires transfusions of two or more units of packed RBCs or interventions.

References

1. Kalil AC, Metersky ML. Klompas M, et al: Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016;63: e61–e111

2. Wright MO, Decker SG, Allen-Bridson K, et al: Healthcare-associated infections studies project:

An American Journal of Infection Control and National Healthcare Safety Network data quality

collaboration: Location mapping. Am J Infect Control 2018;46::577-578

(14)

3. Hooton TM, Bradley SF, Cardenas DD, et al: Diagnosis, prevention, and treatment of catheter- associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010;50:625-663

4. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al: Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526-2533

5. Schulman S, Angerås U, Bergqvist D, et al: Definition of major bleeding in clinical investigations

of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010;8:202-204

(15)

Twenty-Seven Covariates (with a p < 0.10 in Univariable Analyses) Initially Included in the Multivariable Model for Risk Factor for In-Hospital Mortality (Table 3)

Age (p = 0.129), gender (p = 0.050), body mass index (p = 0.078), solid malignancy (p = 0.007), Charlson comorbidity index (CCI) (p = 0.004), systolic blood pressure (p = 0.007), diastolic blood pressure (p = 0.016), heart rate (p = 0.021), septic shock (p<0.001), body temperature groups (p

<0.001), SOFA score (p<0.001), urinary origin (p = 0.016),

MDR

(multidrug-resistant) organisms (p

= 0.067), hemoglobin (p = 0.001), lactate (p<0.001), blood urea nitrogen (p<0.001), creatinine (p<

0.001), AST (p = 0.055), albumin (p< 0.001), prothrombin time (INR, international normalized ratio)

(p = 0.001), pH (p = 0.001), HCO3

^-

(p = 0.003), anion gap (p = 0.001), c-reactive protein (p =

0.011), Tropoinin I (p = 0.084), mechanical ventilation (p< 0.001), and continuous renal replacement

therapy (CRRT) (p< 0.001).

(16)

Supplemental Table 1

Participating Institutions in The Study

Number Name of Institutions

1 Hallym University Sacred Heart Hospital

2 Samsung Medical Center, Sungkyunkwan University School of Medicine 3 Asan Medical Center, University of Ulsan College of Medicine

4 Yeungnam University Medical Center

5 Seoul St. Mary’s Hospital, Catholic University 6 Jeju National University School of Medicine 7 Kangwon National University Hospital 8 Inje University Sanggye Paik Hospital 9 Kyung Hee University Hospital

10 Ulsan University Hospital, University of Ulsan College of Medicine 11 Keimyung University Dongsan Medical Center

12 Daegu Catholic University Medical Center 13 Chungnam National University Hospital 14 Chonnam National University Hospital 15 Chungbuk National University Hospital 16 Chonbuk National University Medical School 17 Inje University Ilsan Paik Hospital

18 Gangnam Severance Hospital, College of Medicine, Yonsei University

19 Korea University Ansan Hospital

(17)

Characteristics And Outcomes of the Excluded Patients (n = 103)

Characteristics Enrolled Patients (n = 689)

Excluded Patients

(n = 103) p

Age, years 71.4 ± 13.3 73.1 ± 13.8 0.226

Gender (female/male) 298/391 43/60 0.774

BMI, kg/m² 22.5 ± 4.0 22.0± 4.1 0.320

Underlying comorbidities

Heart disease 172 (25.0%) 28 (27.2%) 0.628

Cerebrovascular disease 131 (19.0%) 19 (18.4) 0.891

Liver disease 78 (11.3%) 6 (5.8%) 0.091

Connective tissue disease 16 (2.3%) 1 (1.0%) 0.377

Hematologic disease 39 (5.7%) 4 (3.9%) 0.458

Chronic lung disease 121 (17.6%) 17 (16.5%) 0.792

Chronic kidney disease 117 (17.0%) 12 (11.7%) 0.362

Diabetes 203 (29.5%) 26 (25.2%) 0.378

Solid cancer 184 (26.7%) 31 (30.1%) 0.470

Immunocompromised 22 (3.2%) 8 (7.8%) 0.023

Charlson comorbidity index 5.4± 2.6 5.6 ± 2.8 0.394

Systolic blood pressure, mmHg 112.7± 32.8 119.5± 34.9 0.052

Diastolic blood pressure, mmHg 66.5± 20.3 69.9± 18.7 0.090

Heart rate, beats/min 105.4± 22.7 99.0± 29.5 0.037

Body temperature, ℃ 37.4± 1.2 37.6± 1.2 0.106

Hyper- /normo- /hypothermia 182/420/87 34/60/7^a 0.127

Infection origin

Pulmonary 432 (62.7%) 59 (57.3%) 0.327

Abdomen 117 (17.0%) 27 (26.2%) 0.023

Urinary 82 (11.9%) 11 (10.7%) 0.719

Skin and soft tissue 22 (3.3%) 1 (1.0%) 0.344

Catheter-associated 2 (2.0%) 0 (0.0%) 1.000

(18)

WBC,ⅹ10³/µL 11.9 (7.4 – 17.8) 10.9 (6.7 – 16.1) 0.361

Hemoglobin, g/dL 11.4 ± 2.5 11.6 ± 2.1 0.442

Platelet, ⅹ10³ /µL

152.0 (101.0 – 222.0) 184.5 (111.0 –

261.5) 0.104

BUN, mg/dL 24.8 (16.2 – 39.0) 27.0 (17.0 – 46.0) 0.105

Creatinine, mg/dL 1.3 (0.9 – 2.3) 1.3 (0.9 – 2.2) 0.945

Lactate, mmol/L 4.4 (1.1 – 8.9) 2.4 (1.5 – 4.2) ^b 0.255

pH 7.39 ± 0.12 7.37 ± 0.14 0.175

SOFA score at ED 5.6 ± 3.3 4.7 ± 2.7 0.002

LV dysfunction 54 (7.8%) 6 (5.8%) 0.472

Mechanical ventilation 135 (19.6%) 12 (11.7%) 0.053

CRRT 50 (7.3%) 5 (4.9%) 0.371

ICU admission 206 (29.9%) 19/97 (19.6%)^c 0.035

Hospital mortality 199 (28.9%) 19/97 (19.6%)^c 0.056

Data are presented as mean ± standard deviation or median (interquartile range) for continuous data, or as number (%) for categorical data.

BMI= body mass index, BUN = blood urea nitrogen, CRRT= continuous renal replacement therapy, ED = emergency department, ICU = intensive care unit, LV= left ventricle (LV dysfunction: ejection fraction <

40%), MDR= multidrug resistant, SOFA = sequential organ failure assessment.

a Data are not available for two patients

b Data are not available for ninety-five patients

c Data are not available for six patients

(19)

Supplemental Table 3

Laboratory Parameters of Enrolled Patients (n = 689)

Laboratory Parameters

Hyperthermia (n = 182)

Normothermia (n = 420)

Hypothermia

(n = 87) p

WBC, ⅹ10³/µL 9.9 (6.1 – 14.2) 11.2 (7.0 – 16.3) 11.6 (7.1 – 17.1) 0.022

Hemoglobin, g/dL 11.5 ± 2.4 11.4 ± 2.5 11.3 ± 2.6 0.825

Platelet, ⅹ10³ /µL 160.0 (109.8 – 247.3) 184.5 (108.3 – 262.8) 192.0 (138.0 – 303.8) 0.245 Lactate, mmol/L 2.4 (1.5 – 4.1) 2.3 (1.4 – 3.8) 3.6 (1.7 – 6.7) 0.519 BUN, mg/dL ^a,b,c 22.0 (16.3 – 36.5) 28.1 (17.0 – 47.0) 32.6 (23.6 – 62.3) 0.005 Creatinine, mg/dL 1.1 (0.9 – 1.8) 1.4 (0.8 - 2.4) 1.5 (1.1 – 2.6) 0.107 AST, IU/L 36.0 (24.0 – 78.0) 35.0 (23.0 – 59.0) 41.0 (28.0 – 79.0) 0.135 ALT, IU/L 26.0 (15.0 – 46.0) 21.0 (14.0 – 43.0) 24.0 (14.0 – 45.0) 0.026

Albumin, g/dL ^a,c 3.3 ± 0.6 2.9 ± 0.7 3.1 ± 0.7 <0.001

Glucose, mg/dL 145.0 (116.5 – 215.5) 142.5 (110.0 – 187.0) 144.5 (106.8 – 237.8) 0.073

Na⁺, mmol/L 136.0 ± 6.2 136.7 ± 8.5 134.6 ± 7.4 0.065

K⁺, mmol/L 4.2 (3.7 - 4.7) 4.2 (3.8 - 4.8) 4.6 (4.0 - 5.1) 0.466

Cl^-, mmol/L ^a,b 100.2 ± 9.2 102.0 ± 8.8 99.4 ± 8.6 0.015

PT (INR) 1.2 (1.1 – 1.3) 1.2 (1.1 – 1.4) 1.3 (1.1 – 1.5) 0.195

pH^a,b,c 7.4 ± 0.1 7.4 ± 0.1 7.3 ± 0.2 <0.001

PaCO2, mm Hg^b,c 32.7 ± 10.8 33.7 ± 10.4 38.5 ± 19.4^c 0.006

PaO2, mm Hg^b,c 73.5 ± 23.7 78.5 ± 35.3 89.3 ± 60.3 <0.001

HCO3-, mEq/L ^b,c 21.3 ± 4.8 20.8 ± 5.8 17.7 ± 6.7 <0.001

Anion gap ^b,c 18.8 ± 6.3 18.2 ± 6.4^a 22.2 ± 9.6 <0.001

CRP, mg/dL 10.2 (4.7 – 22.5) 12.3 (5.7 – 24.1) 11.8 (4.1 – 21.1) 0.110 Troponin I, pg/mL 0.04 (0.01 – 0.11) 0.04 (0.01 – 0.10) 0.05 (0.01 – 0.10) 0.692

LV dysfunction 18 (9.9%) 25 (6.0%) 11 (12.6%) 0.052

BUN = blood urea nitrogen, CRP = C-reactive protein, INR = international normalized ratio, LV = left ventricle (LV dysfunction: ejection fraction < 40%), PT = prothrombin time, WBC = white blood cell.

(20)

c p< 0.05 between hyperthermia vs. hypothermia (by correction for multiple comparison).

(21)

Supplemental Table 4

Comparisons of Initial SOFA Scores by Body Temperature Groups (n = 689)

Components of SOFA Score

Hyperthermia (n = 182)

Normothermia (n = 420)

Hypothermia

(n = 87)

p

Respiratory 2.0 (1.0 – 3.0) 2.0 (1.0 – 2.0) 2.0 (0.0 – 3.0) 0.959

1.7 ± 1.2 1.7 ± 1.3 1.7 ± 1.3 0.984

Coagulation 0.0 (0.0 – 1.0)

^c

0.0 (0.0 – 1.0) 0.0 (0.0 – 1.0)

^c

0.024

0.8 ± 1.0 0.7 ± 1.0 0.5 ± 0.9 0.087

Liver 0.0 (0.0 – 0.0) 0.0 (0.0 – 1.0) 0.0 (0.0 – 1.0) 0.549

0.5 ± 0.9 0.5 ± 0.9 0.5 ± 0.9 0.725

Heart 0.0 (0.0 – 1.0)

^c

0.0 (0.0 – 1.0)

^b

1.0 (0.0 – 3.0)

^b,c

0.001 0.9 ± 1.4

^c

1.0 ± 1.4

^b

1.6 ± 1.6

^b

<0.001 CNS 0.0 (0.0 – 1.0)

^c

0.0 (0.0 – 1.0) 0.0 (0.0 – 2.0)

^c

0.029

0.7 ± 1.2

^c

0.7 ± 1.2 1.1 ± 1.4

^c

0.046

Kidney 0.0 (0.0 – 1.0)

^a,c

1.0 (0.0 – 2.0)

^a

1.0 (0.0 – 2.0)

^c

0.003

0.9 ± 1.2

^c

1.1 ± 1.2 1.4 ± 1.4

^c

0.009

Total SOFA 4.5 (3.0 – 7.0)

^c

5.0 (3.0 – 7.0)

^b

6.0 (4.0 – 8.0)

^b,c

0.009

5.3 ± 3.2

^c

5.5 ± 3.3

^b

6.5 ± 3.5

^b,c

0.020

Data are presented as mean ± standard deviation or median (interquartile range).

CNS = central nervous system, SOFA = sequential organ failure assessment.

a p < 0.05 between hyperthermia vs. normothermia (by correction for multiple comparison).

b p< 0.05 between northermia vs. hypothermia (by correction for multiple comparison).

c p< 0.05 between hyperthermia vs. hypothermia (by correction for multiple comparison).

(22)

Supplemental Table 5

Microorganisms Identified in 264 patients

Microorganisms Number (%)

Escherichia coli 63(23.9%)

Staphylococcus spp. 48 (18.2%)

Coagulase-negative Staphylococcus spp. 7 (2.7%)

Klebsiella spp. 40 (15.2%)

Streptococcus spp. 29 (11.0%)

Pseudomonas spp. 16 (6.1%)

Enterobacter spp. 11 (4.2%)

Entercoccus spp. 13 (4.9%)

Acinetobacter spp. 4 (1.5%)

Clostridium spp. 4 (1.5%)

Proteus spp. 3 (1.1%)

Citrobacter spp. 3 (1.1%)

Morganella morganii 2 (0.8%)

Serratia marcescens 3 (1.1%)

Stenotrophomonas maltophilia 1 (0.4%)

Haemophilus influenzae 2 (0.8%)

Gemella spp. 1 (0.4%)

Moraxella catarrhalis 1 (0.4%)

Burkholderia cepacia 1 (0.4%)

Bacillus circulans 1 (0.4%)

Gram-negative bacilli 1 (0.4%)

Fungi 2 (0.8%)

Virus 2 (0.8%)

Other organisms ^a 7 (2.7%)

Data are presented as number (%).

aBacteroides spp. (n = 2); Corynebacterium pseudodiphteriticum (n=1); Fusobacterium nucleatum (n = 1);

Mcirococcus luteus (n = 1); and Mycobacterium tuberculosis (n = 2).

(23)

Supplemental Table 6

Time Intervals (Minutes) from ‘Time Zero’ to Completion of Sepsis Bundle Elements

Sepsis bundle Hyperthermia Normothermia Hypothermia p

Lactate measurement (n = 620)

24.0 (10.0 - 56.0) 23.0 (11.0 - 70.8) 20.0 (8.0 - 46.5) 0.177

63.0 ± 114.7 88.8 ± 175.6 78.1 ± 193.0 0.283

Blood culture (n = 663) 31.0 (15.0 - 56.0)â,b 52.5 (19.0 - 146.0)â 52.0 (16.8 - 130.5)^b <0.001 62.3 ± 140.3â,b 131.8 ± 211.7â 120.1 ± 200.1^b <0.001 Antibiotics (n = 665) 147.0 (83.0 - 220.0) 146.0 (86.0 - 269.0) 129.0 (73.0 - 195.0) 0.207

178.3 ± 157.2^a 224.4 ± 233.7^a 185.1 ± 191.9 0.033 Data are presented as mean ± standard deviation or median (interquartile range).

a p < 0.05 between hyperthermia vs. normothermia (by correction for multiple comparison).

b p< 0.05 between hyperthermia vs. hypothermia (by correction for multiple comparison).

(24)

Supplemental Table 7

Comparison of Resource Use between Body Temperature Groups (n = 689)

Resources Hyperthermia

(n = 182)

Normothermi a

(n = 420)

Hypothermia

(n = 87)

p

HFNC 8 (4.4%) 20 (4.8%) 8 (9.2%) 0.201

Mechanical ventilation

^a,b

28 (15.4%) 78 (18.6%) 29 (33.3%) 0.002

CRRT 16 (8.8%) 26 (6.2%) 8 (9.2%) 0.400

ECMO 4 (2.2%) 8 (1.9%) 0 (0.0%) 0.401

Hemoperfusion 5 (2.7%) 14 (3.3%) 1 (1.1%) 0.538

Resource use (total)

^a,b

33 (18.1%) 88 (21.0%) 31 (35.6%) 0.004 ICU admission

^a,b

49 (26.9%) 12.0 (28.6%) 37 (42.5%) 0.021

ICU = intensive care unit, HFNC= high flow nasal cannula, CRRT = continuous renal replacement therapy, ECMO = extracorporeal membrane oxygenation.

ap < 0.05 between normothermia vs. hypothermia (by correction for multiple comparison)

bp< 0.05 between hyperthermia vs. hypothermia (by correction for multiple comparison)

(25)

Supplemental Table 8

ICU Medical Events by Body Temperature Groups (n = 206)

ICU Medical Events Hyperthermia (n = 49)

Normothermia (n = 120)

Hypothermia

(n = 37)

p

SAPS3 at ICU admission 66.3 ± 16.4 68.7 ± 19.3 68.5 ± 15.8 0.742

VAP 4 (8.2%) 22 (18.3%) 6 (16.2%) 0.252

ARDS 4 (8.2%) 17 (14.2%) 6 (16.2%) 0.476

VAP and ARDS (combined) 6 (12.2%) 31 (25.8%) 12 (32.4%) 0.067

CLABSI 2 (4.1%) 4 (3.3%) 1 (2.7%) 0.939

Catheter-associated UTI 1 (2.0%) 2 (1.7%) 1 (2.7%) 0.922

Arrhythmia 6 (12.2%) 18 (15.0%) 5 (13.5%) 0.891

Bleeding 3 (6.1%) 4 (3.3%) 2 (5.4%) 0.683

CPR 7 (14.3%) 13 (10.8%) 8 (21.6%) 0.243

ICU death 13 (26.5%) 36 (30.0%) 19 (51.4%) 0.029

ARDS = acute respiratory distress syndrome, CLABSI= central line-associated blood stream

infection, CPR= cardiopulmonary resuscitation, ICU= intensive care unit, SAPS3 = simplified acute

physiology score 3, VAP= ventilator-associated pneumonia.

(26)

Comparisons of Parameters Between Survivors And Nonsurvivors Among Patients Without Do-Not-Resuscitate Order (n = 563)

Variables Survivors

(n = 459)

Nonsurvivors

(n = 104) p

Age, years 70.5 ± 13.3 72.7 ± 13.1 0.129

Gender (female/male) 194/265 55/49 0.049

BMI, kg/m² 22.7 ± 4.1 21.9 ± 3.9 0.078

Hyper-/normo-/hypothermia 140/274/45 13/71/20 <0.001

Underlying comorbidities

Heart disease 105 (22.9%) 27 (26.0%) 0.502

Cerebrovascular disease 85 (18.5%) 15 (14.4%) 0.324

Liver disease 56 (12.2%) 10 (9.6%) 0.459

Connective tissue disease 11 (2.4%) 3 (2.9%) 0.730

Hematologic disease 25 (5.4%) 7 (6.7%) 0.610

Chronic lung disease 87 (19.0%) 17 (16.3%) 0.536

Chronic kidney disease 83 (18.1%) 23 (22.1%) 0.343

Diabetes 139 (30.3%) 27 (26.0%) 0.383

Solid cancer 116 (25.3%) 40 (38.5%) 0.007

Immunocompromised 15 (3.3%) 5 (4.8%) 0.392

Charlson comorbidity index 5.3 ± 2.6 6.1 ± 2.7 0.003

Systolic blood pressure 116.1 ± 32.0 106.6 ± 30.2 0.007

Diastolic blood pressure 68.7 ± 19.9 63.5 ± 18.2 0.015

Heart rate 104.4 ± 22.3 107.8 ± 23.5 0.080

SOFA score 4.7 ± 2.6 6.8 ± 3.3 <0.001

SIRS criteria ≥ 2 325 (70.8%) 81 (77.9%) 0.146

Septic shock 127 (27.7%) 58 (55.8%) <0.001

Infection origin

Pulmonary 274 (59.7%) 69 (66.3%) 0.209

Abdomen 81 (17.6%) 22 (21.2%) 0.404

Urinary 69 (15.0%) 6 (5.8%) 0.012

Skin and soft tissue 16 (3.5%) 2 (1.9%) 0.549

Catheter-associated 2 (0.4%) 0 (0.0%) 1.000

(27)

Systemic infection without a

primary site 17 (3.7%) 5 (4.8%) 0.578

MDR organisms 64 (13.9%) 22 (21.2%) 0.065

White blood cells, ⅹ10³ /µL 10.9 (7.2 – 15.7) 10.5 (5.7 – 16.3) 0.303

Hemoglobin, g/dL 11.6 ± 2.4 10.6 ± 2.6 <0.001

Platelet, ⅹ10³ /µL 186.0 (117.0 – 276.0) 174.0 (99.5 – 259.8) 0.201

Lactate, mmol/L 2.1 (1.3 – 3.4) 3.2 (1.9 – 5.8) <0.001

Blood urea nitrogen, mg/dL 24.0 (16.0 – 37.5) 42.0 (21.2 – 66.1) <0.001

Creatinine, mg/dL 1.2 (0.8 – 1.9) 1.6 (0.9 – 3.0) 0.001

AST, IU/L 33.0 (23.0 – 56.3) 40.0 (24.0 – 78.0) 0.048

ALT, IU/L 22.0 (14.0 – 43.0) 21.0 (14.0 – 45.0) 0.798

Albumin, g/dL 3.2 ± 0.6 2.8 ± 0.7 <0.001

Glucose, mg/dL 141.0 (111.0 – 193.0) 136.0 (108.5 – 205.5) 0.612

Na⁺, mmol/L 136.1 ± 7.7 135.3± 6.7 0.389

K⁺, mmol/L 4.2 (3.7 - 4.7) 4.4 (3.8 - 4.9) 0.042

Cl^-, mmol/L 101.1 ± 8.2 99.7 ± 8.2 0.118

Prothrombin time (INR) 1.2 (1.1 – 1.3) 1.3 (1.1 – 1.5) <0.001

pH 7.40 ± 0.09 7.37 ± 0.15 0.014

PaCO2, mm Hg 34.5 ± 12.3 32.3 ± 10.7 0.104

PaO2, mm Hg 78.3 ± 34.9 81.8 ± 47.3 0.393

HCO3-, mEq/L 21.4 ± 5.3 19.3 ± 6.4 0.003

Anion gap 17.9 ± 6.1 20.7 ± 7.2 <0.001

C-reactive protein, mg/dL 10.2 (4.3 – 19.8) 13.9 (6.8 – 27.1) 0.005

Troponin I, pg/mL 0.03 (0.01 – 0.08) 0.05 (0.02 – 0.18) 0.002

LV dysfunction 27 (5.9%) 5 (4.8%) 0.669

Adequacy of antibiotics 337 (73.4%) 72 (69.2%) 0.677

Steroid therapy for septic shock 50 (10.9%) 16 (15.4%) 0.199

Mechanical ventilation 51 (11.1%) 37 (35.6%) <0.001

CRRT 14 (3.1%) 17 (16.3%) <0.001

(28)

BMI= body mass index, CRRT= continuous renal replacement therapy, INR = international normalized ratio, LV= left ventricle (LV dysfunction: ejection fraction < 40%), MDR= multidrug resistant, SIRS = systemic inflammatory response syndrome, SOFA = sequential organ failure assessment.

(29)

Supplemental Table 10

Comparison of Compliances With Sepsis Bundles Between Survivors And Nonsurvivors Among Patients Without Do-Not-Resuscitate Order (n = 563)

Sepsis Bundle Survivors

(n = 459)

Nonsurvivors

(n = 104) p

The hour-1 bundle

Lactate measurement 298 (64.9%) 64 (61.5%) 0.515

Antibiotic administration 62 (13.5%) 16 (15.4%) 0.617

Blood culture 258 (56.2%) 55 (52.9%) 0.538

Fluid bolus infusion ^a 101/208 (48.6%) 37/61 (60.7%) 0.096

Vasopressor ^b 93/127 (73.2%) 43/58 (74.1%) 0.897

Lactate re-measurement ^c 118/234 (50.4%) 50/78 (64.1%) 0.036

Three elements ^d 41 (8.9%) 7 (6.7%) 0.468

Total elements ^e 25 (5.4%) 6 (5.8%) 0.896

Time to completion of elements (min)

Antibiotic administration 155.0 (95.0 – 257.0) 139.0 (88.0 – 244.0) 0.231 Lactate measurement 22.0 (10.0 – 67.8) 21.0 (10.0 – 97.3) 0.921 Blood culture 44.0 (18.0 – 126.0) 47.0 (21.0 – 130.0) 0.703 Data are presented as median (interquartile range) or number (%).

a In patients with hypotension or lactate levels ≥ 4 mmol/L.

b In patients with septic shock.

c In patients with sepsis whose initial lactate levels were of > 2 mmol/L.

d Antibiotic administration plus lactate measurement plus blood culture.

e Indicates the six bundle elements (i.e., lactate measurement, antibiotic administration, blood culture, fluid bolus infusion, vasopressor, and lactate remeasurement)

(30)

Supplemental Table 11

Univariable and Multivariable Analyses for Hospital Death Among Patients With Positive SIRS Criteria (n = 406)

Variables

Univariable Analysis Multivariable Analysis ^a

ORs 95% CIs ORs 95% CIs

Age 1.011 0.991 – 1.030 1.034 1.000 – 1.070

Solid malignancy 2.109 1.271 – 3.501 4.283 1.752 – 10.469

SOFA 1.243 1.144 – 1.351 1.163 1.020 – 1.325

Lactate 1.197 1.108 – 1.294 1.135 1.004 – 1.283

Albumin 0.412 0.277 – 0.611 0.354 0.180 – 0.696

Prothrombin time (INR) 3.674 1.859 – 7.264 1.516 0.690 – 3.332

Mechanical ventilation 4.874 2.819 – 8.427 2.685 1.029 – 7.008

CRRT 5.928 2.653 – 13.248 3.319 0.849 – 12.977

Body temperature groups

Hyperthermia Reference Reference Reference Reference

Normothermia 3.413 1.776 – 6.558 2.862 1.038 – 7.892

Hypothermia 4.638 2.093 – 10.282 3.883 1.110 – 13.581

a Twenty-five variables (p < 0.10 by univariable analyses) were initially included into the

multivariable model: age (p = 0.277), gender (p = 0.021), septic shock (p < 0.001), diabetes mellitus (p = 0.041), solid malignancy (p = 0.004), Charlson comorbidity index (p = 0.025), SOFA (sequential organ failure assessment) score (p < 0.001), systolic blood pressure (p = 0.025), diastolic blood pressure (p = 0.047), lactate (p < 0.001), hemoglobin (p = 0.004), blood urea nitrogen (p < 0.001), creatinine (p = 0.003), AST (p = 0.054), albumin (p < 0.001), prothrombin time (INR, international normalized ratio) (p < 0.001), C-reactive protein (p = 0.034), pH (p = 0.002), HCO3- (p = 0.002), d- dimer (p = 0.027), urinary origin (p = 0.038), body temperature (p < 0.001), mechanical ventilation (p

< 0.001), continuous renal replacement therapy (CRRT) (p < 0.001), and anion gap (p = 0.008).

a Hosmer-Lemeshow test, chi-square = 14.692 and p = 0.065.

OR = odds ratio, CI = confidence interval.

(31)

(32)

Supplemental Fig. 1

Flowchart of Patient Enrollment

BT = body temperature, DNR = do not resuscitate

(33)

Supplemental Fig. 2

Time Intervals from "Time Zero" to Bundle Completion for Three Sepsis

Bundle Elements. Time to blood culture is significantly longer (i.e., delayed) in

the normothermia and hypothermia groups than in the hyperthermia group

(p<0.001 and p = 0.012, respectively)*.

(34)

Supplemental Fig. 3

Proportion of Hospital Death by Body Temperature Decile Groups (Total

number of patients = 563).

(35)

Supplemental Fig. 4

Odds Ratios and 95% Confidence Intervals of Normothermia and

Hypothermia Groups for Hospital Mortality after Stratification by Lactate

Levels