Journal of Critical Care 30 (2015) 78–84

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Epidemiology and outcomes in patients with severe sepsis admitted to the hospital wards☆,☆☆ Stacey-Ann Whittaker, MD a, Barry D. Fuchs, MD b, David F. Gaieski, MD c, Jason D. Christie, MD, MS b, d, Munish Goyal, MD e, Nuala J. Meyer, MD b, Craig Kean, MS f, Dylan S. Small, PhD g, Scarlett L. Bellamy, ScD c, Mark E. Mikkelsen, MD, MS a, c,⁎ a

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA c Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA d Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania e Department of Emergency Medicine, Medstar Washington Hospital Center, Georgetown University School of Medicine, Washington, DC f University of Pennsylvania Health System, Philadelphia, PA g The Wharton School, University of Pennsylvania, Philadelphia, PA b

a r t i c l e

i n f o

Keywords: Severe sepsis Infection Outcomes ICU transfer Mortality

a b s t r a c t Purpose: The purpose of this study was to detail the trajectory and outcomes of patients with severe sepsis admitted from the emergency department to a non–intensive care unit (ICU) setting and identify risk factors associated with adverse outcomes. Material and methods: This was a single-center retrospective cohort study conducted at a tertiary, academic hospital in the United States between 2005 and 2009. The primary outcome was a composite outcome of ICU transfer within 48 hours of admission and/or 28-day mortality. Results: Of 1853 patients admitted with severe sepsis, 841 (45%) were admitted to a non-ICU setting, the rate increased over time (P b .001), and 12.5% of these patients were transferred to the ICU within 48 hours and/or died within 28 days. In multivariable models, age (P b .001), an oncology diagnosis (P b .001), and illness severity as measured by Acute Physiologic and Chronic Health Evaluation II (P = .04) and high (≥ 4 mmol/L) initial serum lactate levels (P = .005) were associated with the primary outcome. Conclusions: Patients presenting to the emergency department with severe sepsis were frequently admitted to a non-ICU setting, and the rate increased over time. Of 8 patients admitted to the hospital ward, one was transferred to the ICU within 48 hours and/or died within 28 days of admission. Factors present at admission were identified that were associated with adverse outcomes. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Severe sepsis is common, costly, and frequently, life altering [1–7]. Severe sepsis afflicts as many as 3 000 000 adults in the United States annually and results in an estimated 750 000 deaths [4]. It is estimated that most patients with severe sepsis are admitted through the emergency department (ED) [2–4]. As a leading cause of morbidity and mortality internationally, epidemiological studies of severe sepsis

☆ Funding: The study was supported in part by National Institutes of Health, National Heart, Lung and Blood Institute Loan Repayment Program, Bethesda, MD. ☆☆ Disclosures: For each of the above authors, no financial or other potential conflicts of interest exists related to the work. Presented as an abstract, in part, at the Society of Critical Care Medicine Congress in San Diego, CA, in 2011. ⁎ Corresponding author. Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Gates 05.042, 3400 Spruce St, Philadelphia, PA 19104. Tel.: +1 215 615 5416. E-mail address: [email protected] (M.E. Mikkelsen). http://dx.doi.org/10.1016/j.jcrc.2014.07.012 0883-9441/© 2014 Elsevier Inc. All rights reserved.

have focused on those patients admitted to the intensive care unit (ICU) [8–10]. Because there is a wide spectrum of disease severity at presentation, ranging from single organ dysfunction to multisystem organ dysfunction that results in death, many patients with severe sepsis will be admitted to a non-ICU setting [1,7]. Although it is known that patients transferred from the hospital ward to the ICU are more likely to die than patients admitted directly to the ICU from the ED [11], and the sepsis population appears to be especially vulnerable [12,13], little is known about the epidemiology and outcomes of patients admitted to the wards with severe sepsis. We conducted an observational cohort study to examine the epidemiology of this understudied patient population. We describe the trajectory of care and the frequency of adverse outcomes in severe sepsis cases admitted to the hospital ward at a single center over 5 years. We hypothesized that admission to a non-ICU setting would increase over time and that we could identify clinical factors present at presentation associated with adverse outcomes, including death.

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2. Materials and methods This retrospective observational cohort study was reviewed by the Institutional Review Board at the University of Pennsylvania. The study was approved with an exemption for obtaining informed consent. 2.1. Study population We examined hospital admissions to the Hospital of the University of Pennsylvania who met consensus criteria for severe sepsis in the ED between 2005 and 2009. We have previously described the validated selection strategy to identify severe sepsis cases in the ED using the ED electronic medical record (EMR) [14–18]. First, we examined the charts of all patients with an ED serum lactate measurement or physician documentation that suggested suspected infection (eg, “sepsis” and “severe sepsis”) to identify sepsis cases [19,20]. In 2004, we had instituted a severe sepsis protocol that recommended serum lactate measurement be drawn during initial venous sampling in patients with suspected infection to identify patients eligible for quantitative resuscitation [21]. The protocol includes the suggestion that patients receiving quantitative resuscitation be admitted to an ICU [16], although the final decision was at the discretion of the ED provider team. We used antibiotic administration in the ED to satisfy the suspected infection criteria and the EMR to satisfy the systemic inflammatory response syndrome criteria [19]. Next, we applied consensus conference criteria to identify cases of severe sepsis [20]. We excluded trauma patients, patients not admitted to the hospital, patients not fulfilling severe sepsis criteria, and repeat patient visit(s). 2.2. Data collection Trained investigators used the case abstraction form to collect demographic and clinical data from the EMR and medical record to permit calculation of the Charlson Comorbidity Index with age score adjustment [22]. We identified the etiology of sepsis based on the EMR and medical record, recorded therapies administered in the ED, including central venous catheterization (CVC) and protocol-directed resuscitation defined as resuscitation guided by CVC-derived end points [15,21], and documented care-limiting orders (eg, do not resuscitate) from the EMR. We calculated an ED Acute Physiology and Chronic Health Evaluation (APACHE) II score [14–18,23]. Abstraction forms were examined for accuracy and completeness by a separate investigator at the time of data entry. We categorized hospital admission as admission to the hospital ward or ICU. Patients were categorized as admitted to the ICU if they were admitted to any of the following ICU or intermediate (step down) care locations: medical ICU, intermediate medical care unit, coronary care unit, coronary intermediate care unit, or a surgical ICU. We also abstracted whether patients received care in an ICU during the hospitalization and discharge disposition. We validated the admission locale, ICU admission status, and discharge disposition through the use of Horizon Performance Manager (McKesson Information Solutions, Alpharetta, GA), a hospital administrative database. We determined mortality status using the hospital record and the Social Security Death Index. Our primary outcome was a composite measure of 28-day mortality and/or ICU transfer within 48 hours of admission (“adverse outcome”). We a priori selected the 48-hour threshold, given our focus on clinical factors present at presentation and precedent [24], and our observed data validated this selected definition. We identified the cause of ICU transfer within 48 hours of admission, categorized as related to respiratory failure, hemodynamic instability, change in mental status, or other when not captured by one of the aforementioned categories. We focused on 28-day mortality, rather than in-hospital mortality, to capture patients transitioned to inpatient or outpatient hospice during the index hospitalization, a frequent occurrence at our institution, and to

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avoid capturing patients who died at the end of a lengthy hospitalization for reasons potentially unrelated to the severe sepsis presentation. Secondary outcomes included in-hospital mortality, 60-day mortality, ICU transfer at any time during the hospitalization, and disposition status, categorized as home, skilled care facility, and hospice. We a priori hypothesized risk factors that would be associated with adverse outcomes during the hospitalization. To minimize the potential for a type I error, we limited our hypothesized clinical risk factors to age, comorbidities, severity of illness as measured by initial ED serum lactate levels and ED Acute Physiologic and Chronic Health Evaluation II (APACHE II) score, and etiology of sepsis [14,15,22–25]. We considered year of admission [17], ED occupancy [26], and do-notresuscitate order at presentation as potential confounders [27,28]. 2.3. Statistical analysis We used the χ 2 statistic or Fisher exact test to compare groups. We compared groups using the Student t test for normally distributed continuous variables and the Wilcoxon rank sum test for nonnormally distributed continuous variables. We used the nonparametric test for trend to test whether ICU admission and ED process of care measures decreased over time [29]. We used multivariable logistic regression to adjust for potential confounding and specifically to determine whether candidate risk factors were independently associated with the primary outcome (adverse outcomes, defined as ICU transfer within 48 hours and/or 28day mortality) in patients admitted to the hospital ward. We included candidate risk factors associated with the primary outcome in univariate analyses at a significance level of P b .05. We adjusted for potential covariates associated with adverse outcomes in univariate analyses at a significance level of P b .20 one at a time into the multivariable models and maintained the covariate if its inclusion altered the odds ratio (OR) for a potential risk factor by more than 10% [30]. We assessed multicollinearity using variance inflation factors [31]. We found collinearity between age, Charlson Comorbidity Index, and APACHE II. We deconstructed these scores to identify the clinical variables associated with adverse outcomes. After removing the age and oncology adjustment for the comorbidity index score, there was no association between the modified score and outcomes (P = .58). Although attenuated, APACHE II without age adjustment remained associated with adverse outcomes. As such, we included the following candidate risk factors in multivariable risk factor models: age, initial serum lactate levels, oncology diagnosis, and nonage adjusted ED APACHE II scores. Given the nonnormal distribution of initial serum lactate measures, we stratified measures as low (0-1.9 mmol/L), intermediate (2.0-3.9), and high (≥4.0) in multivariable models, in accord with prior studies [14,32]. We conducted multiple secondary analyses. First, we performed 2 separate multivariable models, where we used the individual components of the composite outcome as the dependent variable to determine if the risk factors identified in the primary analyses were independently associated with ICU transfer within 48 hours and 28-day mortality [33]. In addition, we altered the definition of our primary outcome to include 28-day mortality and/or ICU transfer at any time during the hospitalization, and we repeated the primary analyses after excluding patients presenting with a do-not-resuscitate order. As the risk factors associated with ICU transfer within 48 hours differed from the other models, we repeated the univariate analyses to further examine which factors were associated with ICU transfer within 48 hours. Last, to examine the ability of APACHE II and initial serum lactate levels to predict an adverse outcome, we used a logistic regression model and calculated the area under the receiver operating curve (AUC) to assess model discrimination and conducted the Hosmer-Lemeshow test to assess model calibration. We used Stata 12.0 software (Stata Datacorp, College Station, TX) to perform statistical analyses [30]. We considered 2-sided P ≤ .05 to be significant.

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Fig. 1. Flow diagram of triage and disposition status of the cohort of patients admitted from the ED with severe sepsis. ⁎Discharged home group included 181 subjects discharged home with home health care and 6 subjects who left against medical advice. †Discharged to skilled care facility group included subjects discharged to acute rehabilitation facilities (n = 16), skilled nursing facilities (n = 100), and other facilities (n = 27).

3. Results 3.1. Baseline characteristics for ICU and hospital ward admissions Of 1853 patients with severe sepsis admitted through the ED, 841 (45.4%; 95% confidence interval [CI], 43.1, 47.7) were admitted to the hospital ward (Fig. 1). As shown in Table 1, compared with patients admitted to an ICU setting, patients admitted to a non-ICU setting were younger (P b .001), less severely ill (P b .001), had fewer comorbidities (P b .001), were more likely to present with a genitourinary (P b .001) or soft tissue source of infection (P = .002), were less likely to present with a respiratory source of infection (P b .001), and were less likely to receive CVC or protocol-directed resuscitation in the ED (P b .001). Of the 841 subjects admitted to the hospital ward, 217 (25.8%) experienced transient hypotension in the ED, 29 (3.5%) experienced sustained hypotension (ie, shock) in the ED, and 86 (10.2%) presented with an initial serum lactate of 4 or higher. Admission to an ICU setting decreased over time (64.1% in 2005 to 48.6% in 2009, P b .001) overall and, specifically, among patients eligible for protocol-directed resuscitation (91.2% in 2005 to a nadir of 76.4% in 2008, P = .001). In parallel, CVC in the ED decreased over time (28.9% in 2005 to 17.0% in 2009, P b .001) as did initiation of protocol-directed resuscitation among eligible patients (59.3% in 2005 to 37.8% in 2009, P b .001). Of 841 patients admitted directly to the hospital ward from the ED, 87 (10.3%; 95% CI, 8.4, 12.6) were transferred to the ICU during their hospital stay (Table 2). The median time to ICU transfer was 2 days after admission, with interquartile range of 1 to 5 days and range from 2 hours to 43 days (Fig. 2). The most common cause for ICU transfer within 48 hours was progressive hemodynamic instability, followed by respiratory failure (Table 3), and 8 of the 47 patients (17.0%) transferred within 48 hours of hospital admission were intubated before or upon arrival to the ICU. In-hospital, 28-, and 60-day mortality rates were 5%, 8%, and 11%, respectively, for the 841 patients admitted to the hospital ward. In total, 130 patients (15.5%; 95% CI, 13.1, 18.1) initially admitted to the hospital ward were transferred to the ICU during their hospitalization and/or died within 28 days of admission. In general, severe sepsis survivors admitted to the hospital

ward had a favorable disposition, with 78% of survivors being discharged to home (Fig. 1). However, many survivors required assistance, as 23% required home health care, 18% were discharged to a skilled care facility, and 4% were transitioned to hospice at discharge. Despite being younger and less severely ill at hospital admission compared with patients directly admitted to the ICU, as measured by initial serum lactate levels and APACHE II scores, the 28-day mortality rate for patients transferred to the ICU within 48 hours was 27.7% (13/47) and for patients transferred to the ICU during the hospitalization was 32.2% (23/87), similar to that experienced by patients admitted directly to the ICU (Table 2). After adjusting for APACHE II and initial serum lactate levels, compared with those directly admitted to the ICU, 28-day mortality was higher in those transferred within 48 hours (OR, 1.59; 95% CI, 0.80, 3.14; P = .19) or during the hospitalization (OR, 2.11; 95% CI, 1.28, 3.49; P = .004), achieving statistical significance in the latter. An adverse outcome occurred in 105 patients (12.5%; 95% CI, 10.3, 14.9) admitted to the hospital ward, defined as being transferred to the ICU within 48 hours and/or dying within 28 days of admission. Compared with ward admissions who did not experience an adverse outcomes, those who experienced an adverse outcome were significantly older (P b .001), more likely to have a higher burden of comorbid conditions (P b .001), an oncology diagnosis in particular (P b .001), a do-not-resuscitate order at admission (P b .001), and were more severely ill, as measured by initial serum lactate levels (P = .01), eligibility for protocol-directed resuscitation (P = .01), and baseline APACHE II levels (P b .001). There was no association between an adverse outcome and year of admission (P = .20), ED occupancy (P = .23), or site of infection (Table 4). In analyses using ICU transfer within 48 hours as the outcome, we confirmed that each of the illness severity measures were associated (Table 5). In multivariable models adjusted for potential confounders, age (P b .001), an oncology diagnosis (P b .001), and illness severity at presentation, as measured by APACHE II (P = .04) and high (≥4 mmol/L) initial serum lactate levels (P = .005) were independently associated with an adverse outcome in severe sepsis patients admitted to the hospital ward (Table 6). Illness severity, as measured by APACHE II, discriminated those who experienced an adverse

S-A. Whittaker et al. / Journal of Critical Care 30 (2015) 78–84 Table 1 Patient-level factors associated with admission to a hospital ward or ICU

Clinical factors at presentation Age, y Female sex (n, %) Race (n, %) White Black Other ED SIRS criteria Maximal temperature, °F Maximal heart rate/min Maximal respiratory rate/min White blood cell count Comorbidities (n, %) CAD CHF Chronic liver disease Chronic renal disease COPD Diabetes mellitus ESRD HIV Hypertension Oncology Transplant Charlson Comorbidity Index Do-not-resuscitate order at admission (n, %) Illness severity at presentation Initial serum lactate (mmol/L) Hyperlactatemia (≥4 mmol/L) Lowest systolic blood pressure, mm Hg Hypotension (n, %)a Acute kidney injury (n, %)a APACHE II ED processes of care (n, %) ED CVC Protocol-directed resuscitation initiated in EDa,b Site of infection (n, %) Bacteremia Respiratory Genitourinary Gastrointestinal Soft tissue

Table 2 Outcomes by admission location in patients with severe sepsis

Hospital ward admissions (n = 841)

ICU admissions (n = 1012)

P

53 ± 18 399 (47.4)

59 ± 17 451 (44.6)

b.001 .22

280 (39.8) 381 (54.2) 42 (6.0)

368 (42.2) 462 (53.0) 41 (4.7)

.40

100.8 ± 2.1 115 ± 18 23 ± 6

99.6 ± 3.1 120 ± 24 28 ± 9

b.001 b.001 b.001

12.1 (7.3-16.6)

13.0 (8-18.5)

80 (9.6) 71 (8.5) 26 (3.1) 107 (12.7) 48 (5.7) 168 (20.0) 67 (8.0) 29 (3.4) 347 (41.3) 297 (35.3) 85 (10.1) 4 (2-6) 30 (3.6)

112 (11.2) 127 (12.7) 69 (6.8) 153 (15.1) 81 (8.0) 207 (20.5) 81 (8.0) 45 (4.4) 464 (45.8) 301 (29.7) 115 (11.4) 5 (3-7) 46 (4.6)

.26 .004 b.001 .14 .05 .79 .97 .27 .05 .01 .38 b.001 .29

2.4 (1.7-3.1) 86 (10.2) 106 ± 22

3.6 (2.3-5.6) 455 (45.0) 94 ± 24

b.001 b.001 b.001

217 (25.8) 124 (14.7) 14 ± 5

525 (51.9) 311 (30.7) 19 ± 7

b.001 b.001 b.001

14 (1.7) 11 (1.3)

401 (39.6) 367 (36.3)

b.001 b.001

104 191 213 104 105

136 (13.4) 318 (31.4) 209 (20.6) 141 (13.9) 82 (8.1)

.49 b.001 b.001 .32 .002

(12.4) (22.7) (25.3) (12.4) (12.5)

81

Hospital ward admissions (n = 841)

.001

SIRS indicates systemic inflammatory response criteria; CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; HIV, human immunodeficiency virus. Categorical variables are reported as a percentage; continuous variables are reported as mean and SD or as median and interquartile range. Missing data were infrequent for each variable listed, except for race (b5% for each variable). a Hypotension defined as systolic blood pressure less than or equal to 90 mm Hg. Acute kidney injury defined as serum creatinine at presentation of at least 2 mg/dL. Protocol-directed resuscitation defined as resuscitation guided to CVC-derived end points [15,20]. b Among eligible patients (serum lactate ≥4 mmol/L or septic shock), protocoldirected resuscitation was initiated more often in patients admitted to an ICU (347/619 [56.1%] vs 9/113 [8.0%]; P b .001).

outcome with an AUC of 0.62 (95% CI, 0.57, 0.67) and was well calibrated (P = .57), whereas serum lactate did not significantly predict an adverse outcome (AUC, 0.56; 95% CI, 0.47, 0.64). In multivariable models using 28-day mortality as the dependent variable, we confirmed that age (P b .001), an oncology diagnosis (P b .001), and high initial serum lactate levels (P b .001) were associated with 28-day mortality after adjusting for potential confounders (Table 7). In models using ICU transfer within 48 hours as the dependent variable, we found that illness severity as measured by baseline APACHE

ICU admissions (n = 1012)

Outcomes Mortality In-hospital mortality (n, %) 44 (5.2) 228 (22.5) 28-day mortality (n, %) 71 (8.4) 276 (27.3) 60-day mortality (n, %) 91 (10.8) 311 (30.7) ICU transfer ICU transfer within 48 h 47 (5.6) – ICU transfer during 87 (10.3) – hospitalization Adverse outcome (ICU transfer within 48 h and/or 28-day mortality) Composite outcome 105 (12.5) –

P

b.001 b.001 b.001 – –

–

Categorical variables are reported as a percentage; continuous variables are reported as mean and SD or as median and interquartile range.

II (P = .005) and high initial serum lactate levels (P = .046) were associated with ICU transfer within 48 hours of admission (Table 8). Furthermore, patients transferred to the ICU within 48 hours who died within 28 days were significantly more likely to be oncology patients (P = .001) and were more severely ill at presentation, as measured by APACHE II scores (P = .02) and higher initial serum lactate levels (P = .03) (Table 9). Finally, when we altered the definition of the primary composite outcome to incorporate ICU transfer during the hospitalization, rather than limiting to ICU transfer within 48 hours or excluded patients with a do-not-resuscitate order at presentation in our primary analyses, with the exception that baseline APACHE II was attenuated to the null, the results were materially unchanged. 4. Discussion In this retrospective cohort study conducted over 5 years, we found that patients presenting to the hospital through the ED with severe sepsis were frequently admitted to a non-ICU setting, and the rate increased over time. Once admitted to a non-ICU setting, adverse outcomes, defined as transfer to the ICU within 48 hours and/or 28day mortality, occurred in 1 of 8 patients. Factors associated with adverse outcomes included patient age, oncologic diagnosis, and illness severity upon presentation to the ED, with measures of illness severity being associated with ICU transfer within 48 hours and 28day mortality.

Fig. 2. Timing of ICU transfer during hospital stay in patients with severe sepsis admitted from the ED to the hospital ward.

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Table 3 Cause for ICU transfer within 48 hours after admission to the hospital ward

Table 5 Patient-level factors associated with ICU transfer within 48 hours of hospital ward admission in patients with severe sepsis

Cause

n (%)

Hemodynamic instabilitya Respiratory failure Mental status change Otherb

28 (59.6) 9 (19.2) 4 (8.5) 6 (12.8) Total: n = 47

a Hemodynamic instability cases included 22 cases of shock, 3 cases of cardiac arrest, and 3 cases of arrhythmia. b Other cases included management of hypothermia (n = 1), acute kidney injury (n = 1), and resuscitation for hyperlactatemia (n = 1), gastrointestinal bleeding (n = 1), and preoperatively (n = 2).

Table 4 Patient-level factors associated with adverse outcomes in severe sepsis hospital ward admissions No adverse outcome Adverse outcome P (n = 736) (n = 105) Clinical factors at presentation Age, y Female sex (n, %) Race (n, %) White Black Other ED SIRS criteria Maximal temperature, °F Maximal heart rate/min Maximal respiratory rate/min White blood cell count Comorbidities (n, %) CAD CHF Chronic liver disease Chronic renal disease COPD Diabetes mellitus ESRD HIV Hypertension Oncology Transplant Charlson Comorbidity Index Do-not-resuscitate order at admission (n, %) Illness severity at presentation Initial serum lactate (mmol/L) Hyperlactatemia (≥4 mmol/L)a Lowest systolic blood pressure, mm Hg Hypotension (n, %)a Eligible for protocol-directed resuscitationa Acute kidney injury (n, %)a APACHE II Site of infection (n, %) Bacteremia Respiratory Genitourinary Gastrointestinal Soft tissue

54 ± 18 346 (47.0)

63 ± 17 53 (50.5)

b.001 .51

240 (38.8) 340 (55.0) 38 (6.1)

40 (47.1) 41 (48.2) 4 (4.7)

.38

100.9 ± 2.0 115 ± 18 23 ± 6

99.7 ± 2.7 114 ± 19 24 ± 6

b.001 .65 .13

12 (7.2-16.5)

12.7 (8.2-19.8)

72 (9.9) 63 (8.6) 22 (3.0) 93 (12.6) 41 (5.6) 145 (19.7) 57 (7.7) 25 (3.4) 305 (41.4) 239 (32.5) 79 (10.7) 4 (2-6) 16 (2.2)

8 (7.7) 8 (7.7) 4 (3.8) 14 (13.3) 7 (6.7) 23 (21.9) 10 (9.5) 4 (3.8) 42 (40.0) 58 (55.2) 6 (5.7) 6 (4-9) 14 (13.3)

2.3 (1.6-3.1) 67 (9.1) 106 ± 22

2.5 (2.0-3.5) 19 (18.1) 105 ± 21

.01 .004 .64

189 (25.7) 90 (12.2)

28 (26.7) 23 (21.9)

.83 .01

105 (14.3) 13 ± 5

19 (18.1) 16 ± 5

.30 b.001

86 (11.7) 165 (22.4) 186 (25.3) 89 (12.1) 95 (12.9)

18 (17.1) 26 (24.8) 27 (25.7) 15 (14.3) 10 (9.5)

.11 .59 .92 .52 .33

.08 .45 .75 .65 .84 .65 .60 .53 .78 .78 b.001 .11 b.001 b.001

Categorical variables are reported as a percentage; continuous variables are reported as mean and SD or as median and interquartile range. Missing data were infrequent for each variable listed, except for race (b5% for each variable). a Hypotension defined as systolic blood pressure less than or equal to 90 mm Hg and protocol-directed resuscitation eligibility defined as serum lactate at least 4 mmol/L or fluid-refractory hypotension.

No transfer (n = 794) Clinical factors at presentation Age, y 55 ± 18 Female sex (%) 368 (46.4) Race (%) White 262 (33.0) Black 362 (45.6) Other 170 (21.4) ED SIRS criteria Maximal temperature, °F 100.8 ± 2.0 Maximal heart rate/min 115 ± 18 Maximal respiratory rate/min 23 ± 6 White blood cell count 12.1 (7.2-16.5) Comorbidities (%) CAD 76 (9.7) CHF 67 (8.5) Chronic liver disease 23 (2.9) Chronic renal disease 98 (12.3) COPD 45 (5.7) Diabetes mellitus 158 (19.9) ESRD 60 (7.6) HIV 26 (3.3) Hypertension 327 (41.2) Oncology 282 (35.5) Transplant 83 (10.4) Charlson Comorbidity Index 4 (2-6) Do-not-resuscitate order at 28 (3.5) admission (n, %) Severity of illness measure Initial serum lactate (mmol/L) 2.4 (1.7-3.1) Hyperlactatemia (≥4 mmol/L) 77 (9.7) Lowest systolic blood pressure, mm Hg 106 ± 22 Hypotension (%)a 203 (25.6) Eligible for protocol-directed 102 (12.8) a resuscitation APACHE II 14 ± 5 Site of infection Bacteremia 94 (11.8) Respiratory 184 (23.2) Genitourinary 200 (25.2) Gastrointestinal 97 (12.2) Soft tissue 99 (12.5)

ICU transfer (n = 47)

P

55 ± 19 31 (66.0)

.91 .01

18 (38.3) 19 (40.4) 10 (21.3)

.72

100.0 ± 3.1 115 ± 19 24 ± 6 12.9 (9.7-21.8)

.01 .98 .22 .06

4 (8.5) 4 (8.7) 3 (6.4) 9 (19.2) 3 (6.4) 10 (21.3) 7 (14.9) 3 (6.4) 20 (42.6) 15 (31.9) 2 (4.3) 5 (2-7) 2 (4.3)

1.00 1.00 .17 .18 .75 .85 .09 .22 .88 .75 .22 .15 .79

2.5 (1.9-3.7) 9 (19.2) 104 ± 22 14 (29.8) 11 (23.4)

.19 .04 .53 .52 .04

16 ± 5

.01

10 (21.3) 7 (14.9) 13 (27.7) 7 (14.9) 6 (12.7)

.07 .21 .73 .65 1.00

Categorical variables are reported as a percentage; continuous variables are reported as mean and SD or as median and interquartile range. a Hypotension defined as systolic blood pressure less than or equal to 90 mm Hg and protocol-directed resuscitation eligibility defined as serum lactate at least 4 mmol/L or fluid-refractory hypotension.

We found that nearly half of patients with severe sepsis admitted through the ED were admitted to a non-ICU setting, consistent with prior work [1,7,34]. Over the study period, the proportion of patients Table 6 Association between clinical risk factors and adverse outcomes in severe sepsis hospital ward admissions using multivariable logistic regression Independent variablea

Adjusted OR (95% CI)

P

Age (y)a Oncology APACHE II (baseline)a,b Initial serum lactate strata Low (0-1.9) Intermediate (2.0-3.9) High (≥4.0)

1.02 (1.01-1.04) 2.22 (1.44-3.42) 1.05 (1.00-1.09)

b.001 b.001 .04

Reference 1.42 (0.85-2.37) 2.68 (1.35-5.32)

Reference .18 .005

a Odds ratio for each 1-U increase in age and baseline APACHE II score. An adjusted OR of greater than 1 is indicative of increased odds of developing an adverse outcome. Inclusion of potential confounders (ie, do-not-resuscitation order at admission) did not alter the OR estimates significantly. b The APACHE II calculation included in the model was not age adjusted given collinearity.

S-A. Whittaker et al. / Journal of Critical Care 30 (2015) 78–84 Table 7 Association between clinical risk factors and 28-day mortality in severe sepsis hospital ward admissions using multivariable logistic regression Independent variable

Adjusted OR (95% CI)

P

Age (years)a Oncology APACHE II (baseline)a,b Initial serum lactate strata Low (0-1.9) Intermediate (2.0-3.9) High (≥4.0) Year of admission

1.05 (1.03-1.07) 6.02 (3.34-10.87) 1.04 (0.98-1.09)

b.001 b.001 .16

Reference 1.90 (0.96-3.76) 4.86 (2.04-11.53) 0.77 (0.63-0.94)

Reference .06 b.001 .01

a Odds ratio for each 1-U increase in age and baseline APACHE II score. An adjusted OR of greater than 1 is indicative of increased odds of 28-day mortality. Inclusion of the potential confounder variable “do-not-resuscitate order at admission” did not alter the OR estimates significantly. Year of admission altered the OR estimates significantly and remained associated with 28-day mortality. Emergency department occupancy (P = .44) was not associated with 28-day mortality. b The APACHE II calculation included in the model was not age adjusted.

admitted to a non-ICU setting increased significantly. This admission pattern coincided with less frequent ED CVCs and less frequent initiation of protocol-directed resuscitation in eligible patients over time. In the recently completed randomized trial of protocol-based care for early septic shock, protocol-based early goal-directed therapy in the ED, which involved CVC in 94% of cases, did not result in improved outcomes [35]. Consistent with the 2 non–early goaldirected therapy arms of Protocolized Care for Early Septic Shock (ProCESS) trial [35], we found that 15% of patients eligible for protocol-directed resuscitation were admitted to a non-ICU setting, initiation of quantitative resuscitation was rare in these patients, and admission to a non-ICU setting increased over time in these patients. Because the results of ProCESS support a less (ie, lactate clearance [36]) invasive approach in many patients eligible for quantitative resuscitation initially, it will be important to examine triage decisions and the effects of these decisions in future studies. We found that 16% of severe sepsis patients admitted to the hospital ward were transferred to the ICU during the hospitalization and/or died within 28 day. As such, 84% of severe sepsis patients admitted to a nonICU setting were managed effectively to the degree that they were discharged alive from the hospital without requiring ICU-level care. However, 10% of ward admissions required ICU transfer at some point during their hospitalization, half of these occurring within the first 48 hours and 3-quarters occurring within the first 5 days (Fig. 2). For those transferred within the first 48 hours, hemodynamic instability was the most common event prompting transfer, followed by management of respiratory failure, and nearly 1 of 5 patients required intubation proximate to the time of transfer. Whether the deterioration could have been prevented had the triage decision or care provisions been different remains unclear and warrants further investigation. Table 8 Association between clinical risk factors and ICU transfer within 48 hours of hospital ward admission in patients with severe sepsis Independent variable

Adjusted OR (95% CI)

P

Age (y)a Oncology APACHE II (baseline)a,b Initial serum lactate strata Low (0-1.9) Intermediate (2.0-3.9) High (≥4.0)

1.00 (0.98-1.02) 0.72 (0.38-1.38) 1.08 (1.02-1.15)

.95 .32 .005

Reference 1.16 (0.58-2.35) 2.53 (1.02-6.29)

Reference .68 .046

a Odds ratio for each 1-U increase in age and baseline APACHE II score. An adjusted OR of greater than 1 is indicative of increased odds of being transferred to an ICU within 48 hours of admission. None of the potential confounders (year of admission [P = .55], ED occupancy [P = .40], and do-not-resuscitation order at admission [P = .79]) was associated with ICU transfer within 48 hours. b The APACHE II calculation included in the model was not age adjusted.

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Table 9 Patient-level factors associated with 28-day mortality in severe sepsis patients transferred to the ICU within 48 hours of hospital ward admission Clinical factors at ED presentation

28-Day survivors (n = 34)

Nonsurvivors (n = 13)

P

Age, y Oncology (n, %) Illness severity at presentation Initial serum lactate (mmol/L) Hyperlactatemia, ≥4 mmol/L (n, %) Eligible for protocol-directed resuscitation (n, %)a APACHE II (baseline)

53 ± 19 6 (17.6)

61 ± 17 9 (69.2)

.23 .001

2.3 (1.8-3.0) 4 (11.8) 6 (17.7)

3.7 (2.1-4.1) 5 (38.5) 5 (38.5)

.03 .04 .25

14 ± 5

18 ± 4

.02

Categorical variables are reported as a percentage; continuous variables are reported as mean and SD or as median and interquartile range. a Protocol-directed resuscitation eligibility defined as serum lactate at least 4 mmol/L or fluid-refractory hypotension.

Although the overall mortality rates for patients admitted to the hospital ward were significantly less than those patients admitted directly to the ICU, the observed mortality rates for ward admissions are at least 2-fold higher than the average hospitalization [37]. Furthermore, despite significantly lower illness severity at hospital admission, the 28-day mortality incurred by those requiring ICU transfer was similar to the mortality rate for those directly admitted to the ICU. Because the adjusted analyses suggest that outcomes may differ by triage decision, increased attention to those at increased risk is justified. Whether the observed mortality rate would have been less had those who required ICU transfer been directly admitted to an ICU remains unclear and requires further investigation. To estimate the causal effects of these critical triage decisions on patient-centered outcomes using observational data will require robust analyses to balance observed and unobserved covariates, such as instrumental variables or matching methods [38,39]. We found that patient age, comorbid conditions (oncology patients), and illness severity were associated with adverse outcomes. High initial serum lactate levels, a marker of illness severity and an established criterion to initiate quantitative resuscitation [14,15,21], along with higher APACHE II scores, were associated with the composite outcome of ICU transfer within 48 hours and/or 28-day hospital mortality as well as the individual components. These observations suggest that elevated serum lactate levels, previously demonstrated to be associated with morbidity and mortality in sepsis in general [14,18,32,40], also appear to effectively risk stratify patients with severe sepsis admitted to the hospital ward. Although plausible, whether outcomes would have been better for these patients had care [21,35,41] or triage decisions (ie, ICU care from time of admission) differed remains unclear and warrants further investigation. In addition, these findings have important implications for early warning systems aimed to identify at risk ward patients, given the potential utility of a strategy designed to augment a physiologic scoring system [42] with additional clinical data to permit improved risk stratification and precision regarding the target population. Survivors of severe sepsis admitted to the hospital ward, in general, were able to return home. And yet, 23% of survivors required home health care, 18% required placement in a skilled care facility, and 4% transitioned to hospice. In 2010, Iwashyna et al [5] revealed that severe sepsis was associated with new and clinically meaningful cognitive and physical impairments in elderly survivors. Odden et al [43] recently demonstrated that functional disability after severe sepsis is not confined to the most severely ill, as physical impairment and increased care needs were common in patients admitted to the medical ward. Our work supports and extends these observations by detailing the frequent care needs of the broader population of hospital ward admissions and the urgent need to identify strategies, such as early physical therapy [44], to mitigate these impairments.

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There are potential limitations to our study. First, our observational study design limits our ability to detail why patients were admitted to a non-ICU setting and whether outcomes would have differed had patients been triaged and managed differently. Future studies, designed to prospectively examine clinical decision making related to triage and care delivery, are warranted. Second, important, unobserved covariates may have influenced our results. For example, although we examined ED occupancy because delayed transfer of care is known to adversely affect outcomes [45], further study is required to examine how ICU occupancy impacts triage decisions, trajectory, and outcomes of patients admitted with severe sepsis. Related, as a single-center study with high ICU occupancy [46] and a robust oncology service, our results may not generalize to other hospitals. Third, although we designed our study to examine patient-specific risk factors, additional study is required to consider structural (eg, time of admission and day of admission) and process of care factors (eg, time to antibiotics [16] and management by a rapid response team on the ward) and to develop prediction scoring models to aid in triage decisions. Fourth, we did not include a penalty for multiple comparisons in our risk factor analyses. However, to account for this potential limitation, we limited our a priori hypotheses and conducted multiple sensitivity analyses. Furthermore, had we applied a Bonferroni correction and defined significance as a P = .01 based on the number of candidate risk factors, each of the risk factors identified in the primary analysis would have remained significant, save for baseline APACHE II. In conclusion, many patients presenting to an ED with severe sepsis were admitted to a non-ICU setting, and the rate appears to be increasing. 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