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Abstract

  1. Top of page
  2. AbstractResumen
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

Objectives

Progressive organ dysfunction is the leading cause of sepsis-associated mortality; however, its incidence and management are incompletely understood. Sepsis patients with moderately impaired perfusion (serum lactate 2.0 to 3.9 mmol/L) who are not in hemodynamic shock (“preshock” sepsis patients) may be at increased risk for progressive organ dysfunction and increased mortality. The objectives of this study were to: 1) quantify the occurrence of progressive organ dysfunction among preshock sepsis patients, 2) examine if there were baseline differences in demographic and physiologic parameters between preshock sepsis patients who experienced progressive organ dysfunction and those who did not, and 3) examine if intravenous (IV) fluid administered in the emergency department (ED) differed between these two groups of patients.

Methods

This was a prospective, observational study in four urban EDs targeting the preshock sepsis population, defined as adults (18 years or older) with suspected infection, serum lactate between 2.0 and 3.9 mmol/L, and without hypotension (systolic blood pressure [sBP] < 90 mm Hg or mean arterial pressure [MAP] < 70 mm Hg) or requiring mechanical ventilation at ED presentation. The primary composite outcome was progressive organ dysfunction, defined as a rise in the Sequential Organ Failure Assessment (SOFA) score of ≥1, vasopressor use, mechanical ventilation use within 72 hours after ED presentation, or in-hospital death. The secondary outcomes were any intensive care unit (ICU) admission, and total ICU and hospital lengths of stay (LOS).

Results

Among 94 preshock sepsis patients, the primary composite outcome occurred in 24 of 94 (26%). In patients with the primary outcome, 22 of 24 (92%) experienced a rise in SOFA score of ≥1, five of 24 (21%) received vasopressor agents, and seven of 24 (30%) required mechanical ventilation. There were no baseline demographic or physiologic parameter differences between patients who met the primary outcome versus those who did not, while patients with the primary outcome had a higher average SOFA score at admission (2.4 vs. 1.3, p = 0.011) and at all subsequent time points. Median IV fluid volume administered to all preshock sepsis patients during their ED stay was 1,225 mL (interquartile range [IQR] = 712 to 2,000 mL) and did not differ significantly between patients with (1,150 mL, IQR = 469 to 2,000 mL) or without (1,250 mL, IQR = 750 to 2,000 mL) the primary outcome (p = 0.73). Patients with progressive organ dysfunction or death were more likely to be admitted to an ICU (50% vs. 20%, p < 0.01) and have an increased median hospital LOS (6 days vs. 3 days, p = 0.005), compared to those without progressive organ dysfunction.

Conclusions

Over one-quarter of preshock sepsis patients developed progressive organ dysfunction with associated increased resource use. Demographic and physiologic parameters were unable to differentiate patients with progressive organ dysfunction, while the initial SOFA score was increased in patients meeting the outcome. Overall, these patients received relatively little IV fluid therapy during their ED stays. Further research to determine if more aggressive therapy can prevent progressive organ dysfunction in this population is warranted.

Resumen

Estudio Observacional Multicéntrico del Desarrollo de la Disfunción Orgánica Progresiva y las Intervenciones Terapéuticas en los Pacientes con Sepsis Normotensiva en el Servicio de Urgencias

Objetivos

La disfunción orgánica progresiva es la principal causa de mortalidad asociada a la sepsis; sin embargo, su incidencia y manejo son completamente desconocidos. Los pacientes con sepsis con deterioro de la perfusión moderada (lactato sérico de 2,0 a 3,9 mmol/L) que no están en shock hemodinámico (pacientes con sepsis “preshock”) pueden tener un riesgo aumentado de disfunción orgánica progresiva e incremento de la mortalidad. Los objetivos de este estudio fueron: 1) cuantificar la aparición de disfunción orgánica progresiva en los pacientes con sepsis preshock, 2) examinar si hubo diferencias basales en los parámetros demográficos y fisiológicos entre los pacientes con sepsis preshock que experimentaron disfunción orgánica progresiva frente a aquéllos que no, y 3) examinar si la administración de fluidos intravenosos (IV) en el servicio de urgencias (SU) difirió entre estos dos grupos de pacientes.

Metodología

Estudio observacional prospectivo en cuatro SU urbanos que seleccionaron la población con sepsis preshock, definida como adultos (18 años o más) con sospecha de infección, lactato sérico entre 2,0 y 3,9 mmol/L, y sin hipotensión (presión arterial sistólica < 90 mmHg o presión arterial media < 70 mmHg) y sin necesidad de ventilación mecánica a la llegada al SU. El resultado principal compuesto fue la disfunción orgánica progresiva, definida como un aumento en la escala Sequential Organ Failure Assessment (SOFA) de ≥1, uso de vasopresor, uso de ventilación mecánica en las primeras 72 horas tras la llegada al SU o muerte intrahospitalaria. El resultado secundario fue cualquier ingreso en la unidad de cuidados intensivos (UCI) y los tiempos de estancia (TDE) en la UCI y total en el hospital.

Resultados

De los 94 pacientes con sepsis preshock, el resultado principal compuesto ocurrió en 24 de los 94 (26%). En pacientes con el resultado primario, 22 de 24 (92%) experimentaron un incremento en la puntuación del SOFA ≥ 1;5 de 24 (21%) recibieron agentes vasopresores, y 7 de 24 (30%) requirieron ventilación mecánica. No hubo diferencias demográficas o en los parámetros fisiológicos basales entre los pacientes que tuvieron el resultado principal frente a los que no, mientras que los pacientes con el resultado principal tuvieron una mayor media de puntuación de SOFA al ingreso (2,4 vs. 1,3; p = 0,011) y en todos los momentos posteriores. La mediana de volumen de fluido IV administrado a todos los pacientes con sepsis preshock durante su estancia en el SU fue 1.225 mL (RIC 712 a 2.000 mL) y no difirió significativamente entre los pacientes con o sin el resultado principal (grupo resultado 1.150 mL (RIC 469 a 2.000 mL) frente grupo sin resultado principal 1.250 mL (RIC 750 a 2.000 mL); p = 0,73). Los pacientes con disfunción orgánica progresiva o muerte tuvieron mayor probabilidad de ser ingresados en una UCI (50% vs 20%; p < 0,01) y tuvieron una mayor mediana de TDE hospitalaria (6 vs. 3 días, p = 0,005), comparados con aquéllos sin disfunción orgánica progresiva.

Conclusiones

Algo más de un cuarto de los pacientes con sepsis preshock desarrollaron disfunción orgánica progresiva y se asociaron a un incremento en el consumo de recursos. Los parámetros demográficos y fisiológicos no fueron capaces de diferenciar a los pacientes con disfunción orgánica progresiva, mientras que la puntación inicial del SOFA estaba aumentada en los pacientes que alcanzaron el resultado. En general, esta población recibió relativamente menos tratamiento con fluidos IV durante su estancia en SU. Futuras investigaciones determinaran si está justificada una terapia más agresiva que pueda prevenir la disfunción orgánica progresiva en esta población.

Progressive organ dysfunction resulting from systemic inflammation is the final common pathway in sepsis pathophysiology and often leads to death.[1, 2] Although current treatment efforts such as “early goal-directed therapy”[3] focus on patients with overt hypoperfusion, little research in the resuscitation sciences exists in targeting treatment for patients before they develop shock.

Recent evidence from a multicenter study demonstrated that patients with sepsis who developed shock 48 hours after hospital admission experienced a higher mortality rate than those noted to be in shock at their initial emergency department (ED) presentations (69% vs. 48%, p < 0.05).[4] This study highlighted the need to better anticipate disease progression in normotensive sepsis patients to prevent delayed deterioration. We have named this population the “preshock” sepsis cohort, an important population of sepsis patients in a presumed preshock state. We defined this group as patients with suspected infection, moderately elevated serum lactate levels (2.0 mmol/L to 3.9 mmol/L), without hypotension (systolic blood pressure [sBP] < 90 mm Hg or mean arterial pressure [MAP] < 70 mm Hg), and not requiring mechanical ventilation. These patients have a reported in-hospital mortality of 16%, which is significantly worse than sepsis patients with serum lactate less than 2.0 mmol/L (in-hospital mortality of 9%, p < 0.024).[5] Moreover, although organ system dysfunction is directly linked to mortality among patients with sepsis,[2, 6] there are no published recommendations on how to intervene until overt hemodynamic failure is apparent.

Current guidelines for the management of severe sepsis and septic shock recommend expeditious intravenous (IV) fluid resuscitation for patients with hypotension (sBP < 90 mm Hg) or elevated serum lactate > 4.0 mmol/L7 and the early initiation of vasopressor therapy for hypotension refractory to IV fluids. However, there is no widely accepted standard of care or treatment protocols to treat preshock patients. Accordingly, targeting this at-risk sepsis population to prevent subsequent progressive organ dysfunction is a novel therapeutic approach. By identifying the subset of preshock patients who develop progressive organ dysfunction and comparing them to those who do not develop organ dysfunction, we may identify those most likely to benefit from future investigational trials and novel interventions.

The objectives of this study were to: 1) quantify the occurrence of progressive organ dysfunction among preshock sepsis patients, 2) examine if there were baseline differences in demographic and physiologic parameters between those who experienced progressive organ dysfunction and those who did not, and 3) and to examine if IV fluids administered in the ED differed between these two groups of patients.

Methods

  1. Top of page
  2. AbstractResumen
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

Study Design

This was a prospective, multicenter, observational study of a convenience population of adult preshock sepsis patients. Each participant or the legally authorized next of kin provided written informed consent prior to collection of data. The protocol was reviewed and approved by each local institutional review board.

Study Setting and Population

The study was conducted within the Emergency Medicine Shock Research Network (EM Shock Net). EM Shock Net is composed of four urban university EDs: Beth Israel Deaconess Medical Center, Boston, MA; Carolinas Medical Center, Charlotte, NC; Cooper University Hospital, Camden, NJ; and Detroit Receiving Hospital, Detroit, MI.

Over a 6-month period (March 2010 to August 2010), we enrolled adult preshock sepsis patients presenting to the EM Shock Net EDs for medical care. Inclusion criteria were adults (at least 18 years old) admitted to the hospital from the ED with sepsis in a preshock state. We defined this as having a suspected infection, having a serum lactate level of 2.0 to 3.9 mmol/L, not being hypotensive (with hypotension defined as sBP < 90 mm Hg sustained for 60 minutes while in the ED), not receiving vasopressors, and not undergoing mechanical ventilation at ED enrollment. These parameters are in the context of current consensus guidelines that define septic shock as sBP < 90 mm Hg or MAP < 70 mm Hg, despite adequate volume resuscitation.[8]

Study Protocol

Research staff and study investigators prospectively collected the data elements using a standardized data abstraction form. Study investigators were not blinded to the study hypotheses. The primary clinical team, including physicians from emergency medicine, critical care medicine, and internal medicine, guided all therapeutic and diagnostic decisions made in the care of each patient without regard to their study participation. Data collected included patient demographic characteristics; suspected source of infection; and physiologic parameters, including heart rate, blood pressure, shock index (ratio of heart rate/sBP[9]), initial and any repeat serum lactate concentrations, and the occurrence of hypotension (sBP < 90 mm Hg) while in the ED. The timing and amount of IV fluids administered in the ED and over the succeeding 24 hours was recorded for each participant. Laboratory values for each participant obtained during standard care were used to assess organ function using the Acute Physiology and Chronic Health Evaluation (APACHE) II[10] score over the first 24 hours, and the Sequential Organ Failure Assessment (SOFA)[11] score calculated on admission and every 24 hours after admission up to 72 hours postenrollment. The APACHE II score, a disease severity classification system using previous health status, age, and physiologic measurements, is a standard prognostic severity index designed to evaluate the risk of death starting at initial evaluation. We also collected resource use data for participants in regards to the occurrence of intensive care unit (ICU) admissions and their total hospital and ICU lengths of stay (LOS).

Outcomes

The primary outcome was a composite outcome of progressive organ dysfunction, defined as a rise in the SOFA score ≥ 1, vasopressor use or mechanical ventilation use within 72 hours of enrollment, or any in-hospital mortality. Progressive organ dysfunction was calculated irrespective of initial organ dysfunction present at enrollment (i.e., a worsening of organ dysfunction during the 72 hours after initial ED assessment was the outcome of interest). The secondary outcome measure focused on resource utilization, specifically any transfer to the ICU after an ED admission to a general medical floor, and quantified the total ICU and hospital LOS.

To determine the occurrence of progressive organ dysfunction, SOFA scores were calculated at enrollment and then every 24 hours up to 72 hours after ED presentation[6] for a maximum of four SOFA scores for each participant. The SOFA score is composed of a quantitative assessment of the degree of dysfunction within six individual organ systems, allowing for an individualized daily assessment of each organ. The SOFA score was determined for each patient using the worst value for each parameter of the five organ systems at ED enrollment and over the prior 24-hour period. We used a previously described modified SOFA score, which removes the neurologic component of the score[12] (Figure 1), due to the low interrater reliability of the Glasgow Coma Scale, which is a component of the unmodified SOFA score.[13] The respiratory component of the SOFA score was calculated using data from the medical record to define the highest amount of supplemental oxygen (FiO2) delivered, and the corresponding pulse oximeter saturation (SpO2), to enable the calculation of the SpO2/FiO2 ratio. The SpO2/FiO2 has been validated as a replacement for the PaO2/FiO2 when arterial blood gases are not available,[14] which is a standard occurrence in this patient population. The change in SOFA score (ΔSOFA) was defined as the difference between the current and previous SOFA score over a 24-hour period. As the primary outcome of this study, progressive organ dysfunction was defined a priori as a ΔSOFA ≥ 1 at any point up to 72 hours after enrollment.[2] Missing data (e.g., unmeasured values) for each component of the score were presumed to be normal (i.e., score of 0) if never measured. The score component was presumed to be unchanged from the previous value if its measurement was not repeated, and the prior score for that organ system carried forward, as previously described.[6] Participants also were followed throughout their hospitalizations for the occurrence of vasopressor administration, initiation of mechanical ventilation, and all-cause in-hospital mortality. To evaluate IV fluid administration practices and their association with the occurrence of the primary outcome, we collected data on the total IV fluid administered within the ED and over the succeeding 24 hours to those with and without the primary outcome.

image

Figure 1. SOFA score. Organ system components and scores associated with increasing perturbations from normal are summarized. This score is modified from its original description through the omission of the neurologic component of the score due to poor inter-rater reliability and an amendment of the respiratory component of the score utilizing SpO2 in place of PaO2 when arterial blood gases are not available. SOFA = Sequential Organ Failure Assessment; SpO2 = oxygen saturation; FiO2 = supplemental oxygen delivered; MAP = mean arterial pressure; Epi =epinephrine; Norepi = norepinephrine.

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Data Analysis

Summary statistics were performed to describe the demographic and clinical characteristics of the study cohort, as well as to describe the occurrence of the primary outcome. We analyzed the difference in physiologic and demographic parameters between patients with and without the primary outcome using the Student's t-test, Mann-Whitney test, chi-square, or Fisher's exact test and the two-sample test of binomial proportions, as appropriate, and with the associated 95% confidence intervals (CIs) and p-values. To examine if IV fluid administered in the ED differed between those with and without the primary outcome, we compared the mean and median volume of IV fluids administered within 24 hours after ED enrollment. To test for a relationship between IV fluid administration and elevated lactate or hypotension exposure, simple linear regression analyses were used to assess the ability of initial lactate level and lowest sBP to predict the amount of fluid administration. We used SigmaStat (v. 3.5, Systat, Chicago, IL) for all analyses, and p-values of <0.05 were considered significant.

Results

  1. Top of page
  2. AbstractResumen
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

Study Population Characteristics

Ninety-four sepsis patients meeting preshock criteria were enrolled (Table 1). The mean age of the cohort was 58 years (SD ± 15 years) and 45% were women. The most common infection was pneumonia (40%), followed by skin or soft tissue (18%) and genitourinary tract (13%) infections. The mean (±SD) initial lactate level was 2.7 (±0.6) mmol/L.

Table 1. Characteristics of the Study Cohort (N = 94)
Characteristic
  1. Each comorbidity was defined by its presence as documented in the medical record. Specific components of their presence were defined by the following criteria: malignancy = presence of any active solid organ or hematologic cancer and does not include history of previous malignancies in remission; end-stage renal disease = history of renal disease requiring hemodialysis; stroke = history of previous cerebral vascular ischemic event; liver disease = history of chronic liver disease including hepatitis B or C, cirrhosis, and liver failure.

  2. COPD = chronic obstructive pulmonary disease.

Mean (±SD) age, yr58 (±15)
Sex, female, n (%)42 (45)
Comorbidities, n (%)
Hypertension56 (60)
Diabetes35 (37)
COPD9 (10)
Heart failure7 (8)
Malignancy7 (8)
End-stage renal disease6 (6)
Stroke6 (6)
Liver disease4 (4)
Nursing home residence4 (4)
IV drug abuse3 (3)
Suspected source of infection in ED, n (%)
Pneumonia38 (40)
Skin or soft tissue17 (18)
Urinary tract12 (13)
Other/viral (presumed)12 (13)
Intraabdominal10 (11)
Unknown6 (6)
Endocarditis2 (2)
Line/device1 (1)

Primary and Secondary Outcomes

The primary outcome of progressive organ dysfunction occurred in 24 of 94 subjects (26%). Among these 24 patients, 15 (65%) had the primary outcome within 24 hours, five (22%) within 48 hours, and two (9%) within 72 hours. Individual components identifying progressive organ dysfunction occurred as follows: 22 (92%) experienced increased SOFA scores of ≥1, five (21%) required vasopressor utilization, seven (30%) required mechanical ventilation within 72 hours, and three (13%) suffered in-hospital death. Patients with the primary outcome had higher average SOFA scores at all time points assessed than those without the primary outcome (initial—2.4 vs. 1.3, p = 0.011; 24 hours—3.4 vs. 0.8, p < 0.001; 48 hours—3.3 vs. 0.7, p < 0.001; and 72 hours—3.0 vs. 0.7, p < 0.001; Figure 2). Among the 66 patients who had SOFA scores > 0 during the 72-hour study period, 48 (73%) had their highest SOFA scores at the time of enrollment, 11 (17%) by 24 hours, four (6%) by 48 hours, and three (5%) within 72 hours. Of patients meeting the primary outcome, seven (29%) met more than one component of the composite outcome: in addition to an increased SOFA score, one patient (4%) required vasopressors, three patients (13%) required mechanical ventilation, and four patients (17%) required both vasopressors and mechanical ventilation. There were no baseline demographic or physiologic parameter differences between patients who met the primary outcome versus those who did not (Table 2). There was no statistically significant difference between the populations in their average APACHE II scores (13.3 vs. 10.6, p < 0.09).

Table 2. Characteristics of Primary Outcome Occurrence: Progression of Organ Failurea
VariableTotal (N = 94)Progression (n = 24)Nonprogression (n = 70)p-value
  1. APACHE = Acute Physiology and Chronic Health Evaluation; HR = heart rate; ICU = intensive care unit; LOS = length of stay; MAP = mean arterial pressure; sBP = systolic blood pressure; SOFA = Sequential Organ Failure Assessment.

  2. Values are mean (±SD) or median (IQR) unless otherwise noted

  3. a

    Subjects who met the composite outcome of progressive organ dysfunction [progression] (SOFA score ≥ 1, any vasopressor use, mechanical ventilation within 72 hours, or in-hospital death), compared to those who did not [nonprogression].

Age, yr61 (±15)61 (±15)57 (±14)0.239
Sex, female, n (%)12 (50)12 (50)30 (43)0.721
Physiologic parameters
HR, beats/min99 (±17)99 (±17)96 (±19)0.495
sBP, mm Hg119 (±27)119 (±27)117 (±27)0.755
MAP, mm Hg84 (±15)84 (±15)85 (±17)0.799
Shock index (HR/sBP)0.87 (±0.23)0.87 (±0.23)0.86 (±0.26)0.868
sBP < 90 mm Hg in ED, n (%)29 (31)7 (29)22 (31)0.942
Lactate, mmol/L, initial2.67 (±0.56)2.71 (±0.56)2.66 (±0.57)0.710
Lactate > 3, n (%)24 (26)7 (29)17 (24) 
Lactate > 3.5, n (%)13 (13)3 (13)10 (14) 
IV fluid resuscitation, mL
At ED presentation1,638 (±1,460)1,548 (±1,557)1,668 (±1,437)0.730
At 24 hours1,840 (±2,088)2,510 (±2,643)1,610 (±1,828)06.80
Organ dysfunction, SOFA score
ED presentation2.0 (±2.0)2.4 (±2.3)1.3 (±1.5)0.009
24 hours1.5 (±2.1)3.4 (±2.8)0.8 (±1.3)<0.001
48 hours1.3 (±2.2)3.3 (±3.1)0.7 (±1.2)<0.001
72 hours1.3 (±2.1)3.0 (±3.0)0.7 (±1.2)<0.001
ΔSOFA 0–24 hours–0.1 (±1.3)00.1 (±2.0)–0.5 (±0.7)<0.001
ΔSOFA 24–48 hours–0.1 (±1.0)–0.1 (±–0.1)–0.2 (±0.4)0.729
ΔSOFA 48–72 hours–0.1 (±0.8)–0.3 (±1.6)0.0 (±0.2)0.247
APACHE score at 24 hrs11.3 (±6.8)13.3 (±7.8)3.8 (±1.6)0.610
Resource use
ICU admission, n (%)26 (28)12 (50)14 (20)0.010
ICU LOS, days0 (0–1)0 (0–3)0 (0–0)0.028
Hospital LOS, days4 (2–7)6 (3–15)3 (2–5)0.005
image

Figure 2. Serial SOFA scores over 72 hours. Comparison of mean (±SD) serial SOFA scores over 72 hours in patients with and without the primary outcome. SOFA scores differed by group at all time points assessed. Initial—2.4 (±2.3) vs. 1.3 (±1.5), difference of 1.1, (p = 0.011); 24 hours—3.4 (±2.8) vs. 0.8 (±1.3), difference of 2.6, (p < 0.001); 48 hours—3.3 (±3.1) vs. 0.7 (±1.2), difference of 2.6, (p < 0.001); and 72 hours—3.0 (±3.0) vs. 0.7 (±1.2), difference of 2.3, (p < 0.001). SOFA = Sequential Organ Failure Assessment.

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In regard to the secondary outcome measure, there were 26 ICU admissions (28%). Patients who experienced the primary outcome compared to those who did not were more likely to have ICU admissions (50% vs. 20%, p < 0.01) and longer median hospital LOS (6 days, interquartile range [IQR] = 3 to 15 days vs. 3 days, IQR = 2 to 5 days; p < 0.005).

IV Fluid Resuscitation

Figure 3 is a histogram of the volume of IV fluids delivered during each patient's ED stay (includes fluids administered before and after study enrollment). The median volume of IV fluids administered in the ED was 1,225 mL (IQR = 712 to 2,000 mL), with a range of 0 to 7,000 mL, and 1,286 mL by 24 hours (IQR = 0 to 2,360 mL) postenrollment. Patients who experienced the outcome received a median of 1,150 mL (IQR = 469 to 2,000 mL) of IV fluids in the ED compared to patients without the outcome, who received 1,250 mL (IQR = 750 to 2,000 mL) (p < 0.73), the majority of which was delivered in the first 2 hours (Figure 3). In assessing the relationship of the volume of IV fluid administration to serum lactate or hypotension, the linear regression analysis revealed no relationship between the volumes of IV fluid administered and the lowest recorded sBP in the ED (slope = −0.005, R2 = 0.08) or initial lactate (slope = −0.00004, R2 = 0.008).

image

Figure 3. Frequency histogram of IV fluid. Summary of the cumulative volume of fluid delivered over the initial ED study period.

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Discussion

  1. Top of page
  2. AbstractResumen
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

In this multicenter sample of ED patients with preshock sepsis, we found that 26% experienced progressive organ dysfunction or death during their hospital courses. We also found increased ICU use and prolonged hospital LOS in the subjects with progressive organ dysfunction.

The primary outcome of this study focused on progressive organ dysfunction and was based on the previous observation of increased mortality associated with worsening organ failure.[6] The higher ICU admission rate and longer hospital LOS support the clinical validity of the primary outcome used in this study. The inability of age, comorbidities, and physiologic parameters, including lactate levels, to differentiate patients who will develop progressive organ failure identifies the challenge inherent to disease trajectory prediction in sepsis. Among patients who experienced the primary outcome of progressive organ dysfunction, the initial SOFA scores were higher (2.4 vs. 1.3) relative to patients not experiencing the outcome, which indicates an early signal of impending decline. These results are similar to those of a recent study by Song et al.[15] showing that initial SOFA scores predicted the progression to septic shock or serum lactate ≥ 4 within 72 hours. However, organ failure quantification is not currently a standard practice in clinical care, and its adoption is challenged by the relatively complicated scoring systems.

It is not completely clear why sepsis patients within the preshock population deteriorate and progress to a shock state or even death. This deterioration may be due to a clinical underestimation of the importance of an abnormal serum lactate. The lactate cutoff of 4.0 mmol/L currently used to define the need for an aggressive, invasive, quantitative resuscitation protocol[7] is based on a previous study in which that threshold appears to have been arbitrarily selected.[3] There is growing evidence that a linear relationship exists between increasing lactate levels and mortality rates in the context of advanced age, critical illness, and sepsis.[5, 16-18] In our study, only 14 of 94 patients (15%) had lactate levels measured again within 24 hours despite evidence that a decreasing lactate on serial measurements is associated with improved outcomes in sepsis.[19] The results from our investigation add to the body of literature defining the increased risk of progressive organ dysfunction and clinical deterioration associated with moderately elevated lactate levels between 2.0–3.9 mmol/L, particularly in the absence of overt hypotension.[20-22]

Mikkelsen et al.[5] described a 28-day mortality rate of 16% in nonshock sepsis and severe sepsis patients with intermediate lactate levels (2.0–3.9 mmol/L), consistent with previous studies showing high mortality in this population (9% to 25%).[21, 22] Additionally, within that cohort, nonsurvivors had significantly higher lactates than survivors (3.4 mmol/L vs. 2.6 mmol/L, p < 0.001).[5] Other authors have reported a rate of disease progression in normotensive sepsis patients to septic shock of 17.8% within 72 hours and a 30-day mortality of 4.9%.[23] Each of these studies defined shock by the presence of hypotension after fluid resuscitation, as per consensus guidelines. Using this strict, parameter-based definition fails to define the common clinical practice of utilizing IV fluid resuscitation to stabilize a transient hypotensive episode that does not require vasopressor support. We were interested in the occurrence of shock within the preshock population, which we captured in the primary outcome as any vasopressor requirement. This definition of shock required vasopressor administration and was not defined by a blood pressure threshold, regardless of IV fluid therapy. This was done to focus the definition on a clinically meaningful and patient-centered outcome. We believe that this is a more rigorous definition for shock as it accounts for the physician's interpretation of the significance of a low blood pressure in the context of that patient's overall condition.

Our purpose in evaluating the amount of IV fluids administered to preshock sepsis patients was based on our observations that IV fluid resuscitation in sepsis is often guided by the occurrence of hypotension or an elevated lactate and associated with large volumes (> 4 L) of IV crystalloid administration in the ED.[24] In fact, greater IV fluid administration (3,500 mL vs. 5,000 mL) was one variable associated with improved outcomes in an interventional trial of sepsis patients.[3] The timing and quantity of IV fluid resuscitation were widely variable in our study, ranging from 0 to 7,000 mL, with 50% of patients receiving < 20 mL/kg over the initial ED resuscitation. This amount stands in contrast to sepsis patients with lactate ≥ 4.0 mmol/L or refractory hypotension, who receive 4,000 to 5,600 mL of IV fluids in the ED setting.[25-27]

Limitations

  1. Top of page
  2. AbstractResumen
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

First, this study was performed within a four-center research network in which early identification and a quantitative resuscitation protocol are part of an aggressive approach to the management of ED patients with sepsis, and as such the findings might not be applicable to other settings. Second, our population represents a convenience sample, and as such may be prone to some degree of selection bias that may have affected the occurrence of the primary outcome. Third, we used a modified SOFA score for this study by omitting the GCS component of the assessment. While it has been previously described that the GCS score has low inter-rater variability, it is unclear what effect this omission could have on the results as presented, and this could not be assessed in this study. Fourth, a “time to event” analysis could not be performed because of the frequency that the data points were collected, which could have added an additional depth of understanding to this topic. Finally, we did not collect data regarding the timing, spectrum, or adequacy of antibiotic therapy. Antibiotic administration occurred in all patients, either prior to enrollment or subsequently while in the ED. It is possible that the timing of antibiotic administration could have affected the outcomes of this study; however, antibiotic timing in sepsis does not seem to be predictive of outcome.[28]

Conclusions

  1. Top of page
  2. AbstractResumen
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References

Within this multicenter prospective study, one-quarter of preshock sepsis patients with moderately elevated lactate levels in the ED developed progressive organ dysfunction associated with longer lengths of stay and greater resource utilization. Demographic and physiologic parameters were unable to differentiate patients with progressive organ dysfunction, while the initial SOFA score was increased in patients meeting the primary outcome. This highlights the utility of an objective assessment of organ function at ED presentation. This sepsis cohort with a high risk for progressive organ dysfunction received relatively low volumes of IV fluids. Further research is necessary to determine if more aggressive therapy can prevent progressive organ dysfunction in this population.

The authors thank the Randall Scholarship Fund and Pepperdine University for support of the research internship students who assisted with this study.

References

  1. Top of page
  2. AbstractResumen
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. References
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