Journal of Critical Care 30 (2015) 261–263
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
Sepsis
The effect of early quantitative resuscitation on organ function in survivors of septic shock Sarah A. Sterling, MD, Michael A. Puskarich, MD, Richard L. Summers, MD, Alan E. Jones, MD ⁎ Department of Emergency Medicine, University of Mississippi Medical Center School of Medicine, 2500 N State St, Jackson, MS 39216, USA
a r t i c l e
i n f o
Keywords: Septic shock Resuscitation Organ dysfunction Organ failure Sepsis
a b s t r a c t Objective: The objective of this study is to determine if early quantitative resuscitation (QR) attenuates organ dysfunction in survivors of septic shock. Methods: This is a secondary analysis of a completed implementation study. Inclusion criteria are suspected infection, greater than or equal to 2 systemic inflammatory response syndrome criteria and either systolic blood pressure less than 90 mm Hg after a fluid bolus or lactate more than 4 mmol/L and survival to hospital discharge. Data were prospectively collected on eligible patients for 1 year before and 3 years after implementation of early QR. Patients in the before phase received nonprotocolized care (NPC) at physician discretion. Survivors who received QR were compared with survivors who received NPC. The primary outcome was the worst sequential organ failure assessment (SOFA) score during hospitalization. Results: Two hundred sixty patients in the QR group and 41 patients in the NPC group were included. There were no significant differences in demographics between the 2 groups. The initial SOFA score in the QR group was 6 and in the NPC group was 6 (P = .17). There was no significant difference in the worst SOFA score during hospitalization between the QR and NPC groups (6 vs 6, respectively; P = .16). Conclusions: In survivors of septic shock, we found no difference in maximal organ dysfunction during hospitalization between patients who received QR vs NPC. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Over the past decade, improvements in the mortality rates of patients with severe sepsis and septic shock have been reported [1]. Although the extent of this effect has varied due to multiple factors, increased emphasis on the identification and early recognition of sepsis in addition to treatment changes using early, quantitative resuscitation (QR) protocols have reportedly largely impacted this trend [1-4]. Many studies have suggested the beneficial effects of a protocolized resuscitation on mortality in sepsis [5-8]. A meta-analysis of randomized control trials evaluating the influence of a QR on mortality in septic shock showed that, before the implementation of a resuscitation with specific hemodynamic end points, mortality rates ranged from 27% to 72% (mean, 57%) compared with 13% to 74% (mean, 47%) after implementation of QR [9]. Despite the effects on mortality seen with the implementation of QR protocols, little is known about what impact it has on those patients who survive septic shock. Although the importance of improving mortality is obvious, there is increasing emphasis on the importance of patient-centered outcomes and quality of life during and after acute ⁎ Corresponding author at: Department of Emergency Medicine, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. Tel.: +1 601 984 5572; fax: +1 601 984 5583. E-mail addresses: [email protected] (S.A. Sterling), [email protected] (M.A. Puskarich), [email protected] (R.L. Summers), [email protected] (A.E. Jones). http://dx.doi.org/10.1016/j.jcrc.2014.10.029 0883-9441/© 2014 Elsevier Inc. All rights reserved.
illness. Previous research has suggested that physical and social functioning and general health are worse in survivors of critical illness compared with the general population [10]. In addition to improving patients' quality of life, improving morbidity could result in a positive public health impact by potentially decreasing the need for invasive procedures (ie, hemodialysis), decreasing intensive care unit (ICU) and hospital length of stay (LOS), and ultimately decreasing total health care costs. To our knowledge, no previous study has examined the effect of an early QR on clinical outcomes in septic shock survivors. The goal of this study was to evaluate if an early QR attenuates organ dysfunction in survivors of septic shock. 2. Methods 2.1. Study design We conducted a secondary analysis of a completed prospective before-and-after study evaluating the clinical effectiveness of early QR protocol in severe sepsis [6]. The methodology has been previously published. Briefly, a before-and-after study was conducted upon the implementation of a QR protocol. The study took place from August 2004 to October 2006 in the emergency department (ED) of an academic hospital with more than 100 000 patient visits, of which approximately 80 000 were adults. The study was approved by the institutional review board.
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S.A. Sterling et al. / Journal of Critical Care 30 (2015) 261–263
Patients were eligible for inclusion if they had suspected or confirmed infection, 2 or more systemic inflammatory response syndrome criteria [11] and either (1) a systolic blood pressure less than 90 mm Hg or mean arterial pressure less than 65 mm Hg after a 20 mL/kg fluid bolus or (2) anticipated need for ICU care and a serum lactate concentration greater than or equal to 4.0 mmol/L. Patients were excluded if they were younger than 18 years old, had a need for immediate surgery, or had an absolute contraindication for a chest central venous catheter placement. In the before phase, data were prospectively collected on eligible patients using a standardized data collection form for 1 year. The study institution did not have a protocol for the treatment of severe sepsis or septic shock during this time, and ED physicians were not aware of plans for implementation of a treatment protocol. Upon completion of the before phase, a 1-month training period and washout phase occurred before the enactment of the treatment protocol. In the after phase, a resuscitation protocol based upon the protocol described by Rivers et al [7] was implemented. The results of the implementation study demonstrated the clinical effectiveness of a protocolized resuscitation in septic shock with a 9% absolute mortality difference and 33% relative morality difference between the before and after groups, and these results have been published previously [6]. The initial published study data were collected for 1 year after protocol implementation; however, data on additional QR patients were collected for 2 added years after publication of the original study (3 years total from protocol implementation). 2.2. Data analysis and outcomes For the current study, we conducted a secondary analysis of only the survivors from the nonprotocolized care (NPC) group and the QR group in the trial. The primary outcome was maximal organ dysfunction, defined as the highest composite sequential organ failure assessment (SOFA) score documented during the patient's ICU stay. Sequential organ failure assessment score was calculated on ED arrival and every 24 hours while in the ICU. Given the primary outcome, patients were excluded if they did not have both initial and worst SOFA score documented; therefore, the initial ED SOFA score alone was not counted as worst SOFA score for this analysis. Secondary outcomes included ICU and hospital LOS in addition to change (Δ) in SOFA score (worst SOFA − initial SOFA score). Patient demographics and baseline clinical characteristics between the 2 groups were compared using χ 2, Fisher exact, and MannWhitney U tests as appropriate. Primary and secondary outcomes were compared using Mann-Whitney U tests. All statistical tests were 2 sided with P b .05 considered significant. Data were analyzed using StatsDirect statistical software (StatsDirect 2.7.7; Cheshire, England). 3. Results Mortality was 21 (27%) of 79 in the NPC group, leaving 58 survivors for potential analysis. After excluding patients for incomplete SOFA score data, 41 patients were left in the NPC group. Mortality in the QR group was 73 (22%) of 333, which left 260 survivors for further analysis. All of the patients in the QR group had complete SOFA score data and were included in the final analysis, which left a total of 301 patients, with 41 (14%) in NPC group and 260 (86%) in the QR group. Patient demographics and characteristics are noted in Table. No significant differences were noted between the 2 groups in terms of either demographics or baseline clinical characteristics (Table). Of note, initial SOFA score was not significantly different between the 2 groups. The primary outcome (worst SOFA score) did not differ significantly between the NPC group (6 points; interquartile range (IQR) 3, 8) and QR group (6 points; IQR 4, 9; P = .16) (Table 1). Likewise, no significant difference was noted in ΔSOFA score or overall hospital LOS, although ICU LOS was slightly longer in the NPC (3 days; IQR 1.5, 5) as compared with the QR groups (2 days; IQR 0, 3.5; P = .0004) (Table).
Table Patient demographics, clinical characteristics, and study outcomes Variable
NPC group (n = 41)
Age (IQR)a Sex (%) Male Female Race (%) Caucasian Black American Comorbidities (%) DM HIV COPD Suspected source of infection (%) Pneumonia Urinary tract Intraabdominal Skin/soft tissue Unknown Disease severitya Initial SOFA scoreb ΔSOFA score Worst SOFA scorec LOSa ICU Hospital
58 (46,74)
EQR group (n = 260) 58 (45,70)
P .77
22 (54) 19 (46)
131 (50) 129 (50)
.82
22 (54) 19 (46)
134 (52) 104 (40)
.89
14 (34) 2 (5) 8 (20)
72 (28) 26 (9) 45 (17)
.51 .31 .91
9 (22) 15 (37) 8 (20) 7 (17) 6 (15)
101 (39) 75 (29) 45 (18) 26 (10) 14 (5)
.06 .41 .90 .20 .05
6 (3,7) 0 (−1,1) 6 (3,8)
6 (4,8) 0 (−1,2) 6 (4,9)
.17 .85 .16
2 (0,3.5) 8 (5,14)
3 (1.5,5) 8 (5,14)
.0004 .995
EQR indicates early quantitative resuscitation; DM, diabetes mellitus; HIV, human immunodeficiency virus; COPD, chronic obstructive pulmonary disease. a Median (IQR). b Calculated at the time of enrollment. c Primary study end point.
To better assess the worst SOFA score and ΔSOFA score, we could be reasonably confident of detecting given our predefined sample size from this secondary analysis; we conducted a post hoc sample size calculation assuming the 0.16 controls per case we observed, using an observed SD of worst SOFA scores of 3.5. Given an α of .05, we would be 80% likely to detect a significant difference of 1.7 between groups. For ΔSOFA score, with an α of .05 and an observed SD of 2, we would expect to be able to detect a difference between means of 0.95 with 80% power.
4. Discussion The aim of this study was to evaluate the effect of a QR on organ dysfunction in survivors of septic shock. Our results suggest that, in patients who survive septic shock, neither maximal organ dysfunction nor change in organ dysfunction, as measured by SOFA score, is significantly affected by early QR. It may appear surprising that organ dysfunction in survivors is not significantly affected by the same protocols that have reported repeatedly to improve mortality in patients with septic shock. There are several potential explanations for these data. The number of survivors in the NPC group is relatively small, which may have impacted our ability to measure a significant treatment effect. To better estimate the likely power of our study to detect a true difference between groups, we conducted a post hoc sample size calculation based on our predefined sample size due to study methodology. At 80% power, we feel confident that we would have been able to detect a difference in worst SOFA score of 2 and ΔSOFA of 1 between groups. Although our study may therefore been unpowered to detect a difference in worst SOFA score of less than 2 and ΔSOFA of less than 1, the clinical significance of such a small difference is questionable, and we believe this study demonstrates adequate power to detect clinically meaningful differences in organ failure. In addition, the lack of significant improvement in maximal organ dysfunction may in fact be directly related to the effectiveness of QR protocols to reduce overall mortality in septic shock.
S.A. Sterling et al. / Journal of Critical Care 30 (2015) 261–263
It is likely that, in reducing mortality, a number of patients who would have otherwise died instead survived and were therefore included in the QR group. It is quite possible that this group of patients, who would have otherwise died, actually survived with significantly more organ dysfunction while hospitalized. Therefore, it is conceivable that there truly is a treatment effect on organ dysfunction that we were simply unable to detect due to more critically ill survivors, although this is merely a hypothesis. Considering this potential effect, it is important to note that, although we did not detect an improvement in organ dysfunction after the implementation of a QR, it also did not worsen. One may argue that excluding patients who died and focusing on those who survived may represent the introduction of selection bias; however, given that focusing on survivors was the a priori aim of the study, we feel that it does not represent a selection bias but correctly identifies the population of interest. We did find a significant decrease in ICU LOS, suggesting that an early protocolized resuscitation may have an impact on organ failure that we did not detect using our primary outcome. Some considerations limit this interpretation of our findings. First, hospital LOS did not change, so whatever improvement that was found in ICU LOS did not translate into an overall decreased length of hospital stay. Second, given the before and after methodology used by this study, it is possible that this difference could be attributed purely to changes in practice patterns or improvements in QR implementation rather than improvements in organ failure. Third, as attending physicians had the discretion to include patients based on their perceived need for ICU level care, we have no data on the outcomes of patients not admitted to the ICU or the possibility that these criteria introduce bias into the study. However, as all patients requiring intubation and vasopressor were admitted to the ICU, we expect that the population not admitted to the ICU would likely have represented a group of patients who were relatively less ill, and therefore, it is unlikely to have affected the results of this analysis. In addition, a portion of the patients in the NPC group was excluded based on lack of worst SOFA score information. Although it is possible that these patients could have had worse SOFA scores and their exclusion could lead to selection bias, analysis found that the excluded patients in the NPC group had a significantly shorter ICU and hospital LOS than patients in the NPC group who were included in this analysis.
263
Finally, we performed a secondary analysis, and thus, our findings are subject to the inherent shortcomings of such a methodology. 5. Conclusion In survivors of septic shock treated with a QR vs NPC, we found no difference in maximal organ dysfunction or change in organ dysfunction during hospitalization. Presently, there are no clear data that QR attenuates organ dysfunction in survivors of septic shock. References [1] Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 2013;41(5):1167–74. [2] Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, Holanda MS, Ortiz F, Llorca J, et al. Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasiexperimental study. Crit Care Med 2010;38(4):1036–43. [3] Ferrer R, Artigas A, Levy MM, Blanco J, Gonzalez-Diaz G, Garnacho-Montero J, et al. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA 2008;299(19):2294–303. [4] Puskarich MA, Marchick MR, Kline JA, Steuerwald MT, Jones AE. One year mortality of patients treated with an emergency department based early goal directed therapy protocol for severe sepsis and septic shock: a before and after study. Crit Care 2009; 13(5):R167–74. [5] Gao F, Melody T, Daniels DF, Giles S, Fox S. The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study. Crit Care 2005;9(6):R764–70. [6] Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest 2007;132(2):425–32. [7] Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345 (19):1368–77. [8] Kortgen A, Niederprum P, Bauer M. Implementation of an evidence-based "standard operating procedure" and outcome in septic shock. Crit Care Med 2006;34(4):943–9. [9] Jones AE, Brown MD, Trzeciak S, Shapiro NI, Garrett JS, Heffner AC, et al. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a metaanalysis. Crit Care Med 2008;36(10):2734–9. [10] Hofhuis JG, Spronk PE, van Stel HF, Schrijvers GJ, Rommes JH, Bakker J. The impact of critical illness on perceived health-related quality of life during ICU treatment, hospital stay, and after hospital discharge: a long-term follow-up study. Chest 2008;133(2):377–85. [11] Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101(6):1644–55.
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
Sepsis
The effect of early quantitative resuscitation on organ function in survivors of septic shock Sarah A. Sterling, MD, Michael A. Puskarich, MD, Richard L. Summers, MD, Alan E. Jones, MD ⁎ Department of Emergency Medicine, University of Mississippi Medical Center School of Medicine, 2500 N State St, Jackson, MS 39216, USA
a r t i c l e
i n f o
Keywords: Septic shock Resuscitation Organ dysfunction Organ failure Sepsis
a b s t r a c t Objective: The objective of this study is to determine if early quantitative resuscitation (QR) attenuates organ dysfunction in survivors of septic shock. Methods: This is a secondary analysis of a completed implementation study. Inclusion criteria are suspected infection, greater than or equal to 2 systemic inflammatory response syndrome criteria and either systolic blood pressure less than 90 mm Hg after a fluid bolus or lactate more than 4 mmol/L and survival to hospital discharge. Data were prospectively collected on eligible patients for 1 year before and 3 years after implementation of early QR. Patients in the before phase received nonprotocolized care (NPC) at physician discretion. Survivors who received QR were compared with survivors who received NPC. The primary outcome was the worst sequential organ failure assessment (SOFA) score during hospitalization. Results: Two hundred sixty patients in the QR group and 41 patients in the NPC group were included. There were no significant differences in demographics between the 2 groups. The initial SOFA score in the QR group was 6 and in the NPC group was 6 (P = .17). There was no significant difference in the worst SOFA score during hospitalization between the QR and NPC groups (6 vs 6, respectively; P = .16). Conclusions: In survivors of septic shock, we found no difference in maximal organ dysfunction during hospitalization between patients who received QR vs NPC. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Over the past decade, improvements in the mortality rates of patients with severe sepsis and septic shock have been reported [1]. Although the extent of this effect has varied due to multiple factors, increased emphasis on the identification and early recognition of sepsis in addition to treatment changes using early, quantitative resuscitation (QR) protocols have reportedly largely impacted this trend [1-4]. Many studies have suggested the beneficial effects of a protocolized resuscitation on mortality in sepsis [5-8]. A meta-analysis of randomized control trials evaluating the influence of a QR on mortality in septic shock showed that, before the implementation of a resuscitation with specific hemodynamic end points, mortality rates ranged from 27% to 72% (mean, 57%) compared with 13% to 74% (mean, 47%) after implementation of QR [9]. Despite the effects on mortality seen with the implementation of QR protocols, little is known about what impact it has on those patients who survive septic shock. Although the importance of improving mortality is obvious, there is increasing emphasis on the importance of patient-centered outcomes and quality of life during and after acute ⁎ Corresponding author at: Department of Emergency Medicine, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. Tel.: +1 601 984 5572; fax: +1 601 984 5583. E-mail addresses: [email protected] (S.A. Sterling), [email protected] (M.A. Puskarich), [email protected] (R.L. Summers), [email protected] (A.E. Jones). http://dx.doi.org/10.1016/j.jcrc.2014.10.029 0883-9441/© 2014 Elsevier Inc. All rights reserved.
illness. Previous research has suggested that physical and social functioning and general health are worse in survivors of critical illness compared with the general population [10]. In addition to improving patients' quality of life, improving morbidity could result in a positive public health impact by potentially decreasing the need for invasive procedures (ie, hemodialysis), decreasing intensive care unit (ICU) and hospital length of stay (LOS), and ultimately decreasing total health care costs. To our knowledge, no previous study has examined the effect of an early QR on clinical outcomes in septic shock survivors. The goal of this study was to evaluate if an early QR attenuates organ dysfunction in survivors of septic shock. 2. Methods 2.1. Study design We conducted a secondary analysis of a completed prospective before-and-after study evaluating the clinical effectiveness of early QR protocol in severe sepsis [6]. The methodology has been previously published. Briefly, a before-and-after study was conducted upon the implementation of a QR protocol. The study took place from August 2004 to October 2006 in the emergency department (ED) of an academic hospital with more than 100 000 patient visits, of which approximately 80 000 were adults. The study was approved by the institutional review board.
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S.A. Sterling et al. / Journal of Critical Care 30 (2015) 261–263
Patients were eligible for inclusion if they had suspected or confirmed infection, 2 or more systemic inflammatory response syndrome criteria [11] and either (1) a systolic blood pressure less than 90 mm Hg or mean arterial pressure less than 65 mm Hg after a 20 mL/kg fluid bolus or (2) anticipated need for ICU care and a serum lactate concentration greater than or equal to 4.0 mmol/L. Patients were excluded if they were younger than 18 years old, had a need for immediate surgery, or had an absolute contraindication for a chest central venous catheter placement. In the before phase, data were prospectively collected on eligible patients using a standardized data collection form for 1 year. The study institution did not have a protocol for the treatment of severe sepsis or septic shock during this time, and ED physicians were not aware of plans for implementation of a treatment protocol. Upon completion of the before phase, a 1-month training period and washout phase occurred before the enactment of the treatment protocol. In the after phase, a resuscitation protocol based upon the protocol described by Rivers et al [7] was implemented. The results of the implementation study demonstrated the clinical effectiveness of a protocolized resuscitation in septic shock with a 9% absolute mortality difference and 33% relative morality difference between the before and after groups, and these results have been published previously [6]. The initial published study data were collected for 1 year after protocol implementation; however, data on additional QR patients were collected for 2 added years after publication of the original study (3 years total from protocol implementation). 2.2. Data analysis and outcomes For the current study, we conducted a secondary analysis of only the survivors from the nonprotocolized care (NPC) group and the QR group in the trial. The primary outcome was maximal organ dysfunction, defined as the highest composite sequential organ failure assessment (SOFA) score documented during the patient's ICU stay. Sequential organ failure assessment score was calculated on ED arrival and every 24 hours while in the ICU. Given the primary outcome, patients were excluded if they did not have both initial and worst SOFA score documented; therefore, the initial ED SOFA score alone was not counted as worst SOFA score for this analysis. Secondary outcomes included ICU and hospital LOS in addition to change (Δ) in SOFA score (worst SOFA − initial SOFA score). Patient demographics and baseline clinical characteristics between the 2 groups were compared using χ 2, Fisher exact, and MannWhitney U tests as appropriate. Primary and secondary outcomes were compared using Mann-Whitney U tests. All statistical tests were 2 sided with P b .05 considered significant. Data were analyzed using StatsDirect statistical software (StatsDirect 2.7.7; Cheshire, England). 3. Results Mortality was 21 (27%) of 79 in the NPC group, leaving 58 survivors for potential analysis. After excluding patients for incomplete SOFA score data, 41 patients were left in the NPC group. Mortality in the QR group was 73 (22%) of 333, which left 260 survivors for further analysis. All of the patients in the QR group had complete SOFA score data and were included in the final analysis, which left a total of 301 patients, with 41 (14%) in NPC group and 260 (86%) in the QR group. Patient demographics and characteristics are noted in Table. No significant differences were noted between the 2 groups in terms of either demographics or baseline clinical characteristics (Table). Of note, initial SOFA score was not significantly different between the 2 groups. The primary outcome (worst SOFA score) did not differ significantly between the NPC group (6 points; interquartile range (IQR) 3, 8) and QR group (6 points; IQR 4, 9; P = .16) (Table 1). Likewise, no significant difference was noted in ΔSOFA score or overall hospital LOS, although ICU LOS was slightly longer in the NPC (3 days; IQR 1.5, 5) as compared with the QR groups (2 days; IQR 0, 3.5; P = .0004) (Table).
Table Patient demographics, clinical characteristics, and study outcomes Variable
NPC group (n = 41)
Age (IQR)a Sex (%) Male Female Race (%) Caucasian Black American Comorbidities (%) DM HIV COPD Suspected source of infection (%) Pneumonia Urinary tract Intraabdominal Skin/soft tissue Unknown Disease severitya Initial SOFA scoreb ΔSOFA score Worst SOFA scorec LOSa ICU Hospital
58 (46,74)
EQR group (n = 260) 58 (45,70)
P .77
22 (54) 19 (46)
131 (50) 129 (50)
.82
22 (54) 19 (46)
134 (52) 104 (40)
.89
14 (34) 2 (5) 8 (20)
72 (28) 26 (9) 45 (17)
.51 .31 .91
9 (22) 15 (37) 8 (20) 7 (17) 6 (15)
101 (39) 75 (29) 45 (18) 26 (10) 14 (5)
.06 .41 .90 .20 .05
6 (3,7) 0 (−1,1) 6 (3,8)
6 (4,8) 0 (−1,2) 6 (4,9)
.17 .85 .16
2 (0,3.5) 8 (5,14)
3 (1.5,5) 8 (5,14)
.0004 .995
EQR indicates early quantitative resuscitation; DM, diabetes mellitus; HIV, human immunodeficiency virus; COPD, chronic obstructive pulmonary disease. a Median (IQR). b Calculated at the time of enrollment. c Primary study end point.
To better assess the worst SOFA score and ΔSOFA score, we could be reasonably confident of detecting given our predefined sample size from this secondary analysis; we conducted a post hoc sample size calculation assuming the 0.16 controls per case we observed, using an observed SD of worst SOFA scores of 3.5. Given an α of .05, we would be 80% likely to detect a significant difference of 1.7 between groups. For ΔSOFA score, with an α of .05 and an observed SD of 2, we would expect to be able to detect a difference between means of 0.95 with 80% power.
4. Discussion The aim of this study was to evaluate the effect of a QR on organ dysfunction in survivors of septic shock. Our results suggest that, in patients who survive septic shock, neither maximal organ dysfunction nor change in organ dysfunction, as measured by SOFA score, is significantly affected by early QR. It may appear surprising that organ dysfunction in survivors is not significantly affected by the same protocols that have reported repeatedly to improve mortality in patients with septic shock. There are several potential explanations for these data. The number of survivors in the NPC group is relatively small, which may have impacted our ability to measure a significant treatment effect. To better estimate the likely power of our study to detect a true difference between groups, we conducted a post hoc sample size calculation based on our predefined sample size due to study methodology. At 80% power, we feel confident that we would have been able to detect a difference in worst SOFA score of 2 and ΔSOFA of 1 between groups. Although our study may therefore been unpowered to detect a difference in worst SOFA score of less than 2 and ΔSOFA of less than 1, the clinical significance of such a small difference is questionable, and we believe this study demonstrates adequate power to detect clinically meaningful differences in organ failure. In addition, the lack of significant improvement in maximal organ dysfunction may in fact be directly related to the effectiveness of QR protocols to reduce overall mortality in septic shock.
S.A. Sterling et al. / Journal of Critical Care 30 (2015) 261–263
It is likely that, in reducing mortality, a number of patients who would have otherwise died instead survived and were therefore included in the QR group. It is quite possible that this group of patients, who would have otherwise died, actually survived with significantly more organ dysfunction while hospitalized. Therefore, it is conceivable that there truly is a treatment effect on organ dysfunction that we were simply unable to detect due to more critically ill survivors, although this is merely a hypothesis. Considering this potential effect, it is important to note that, although we did not detect an improvement in organ dysfunction after the implementation of a QR, it also did not worsen. One may argue that excluding patients who died and focusing on those who survived may represent the introduction of selection bias; however, given that focusing on survivors was the a priori aim of the study, we feel that it does not represent a selection bias but correctly identifies the population of interest. We did find a significant decrease in ICU LOS, suggesting that an early protocolized resuscitation may have an impact on organ failure that we did not detect using our primary outcome. Some considerations limit this interpretation of our findings. First, hospital LOS did not change, so whatever improvement that was found in ICU LOS did not translate into an overall decreased length of hospital stay. Second, given the before and after methodology used by this study, it is possible that this difference could be attributed purely to changes in practice patterns or improvements in QR implementation rather than improvements in organ failure. Third, as attending physicians had the discretion to include patients based on their perceived need for ICU level care, we have no data on the outcomes of patients not admitted to the ICU or the possibility that these criteria introduce bias into the study. However, as all patients requiring intubation and vasopressor were admitted to the ICU, we expect that the population not admitted to the ICU would likely have represented a group of patients who were relatively less ill, and therefore, it is unlikely to have affected the results of this analysis. In addition, a portion of the patients in the NPC group was excluded based on lack of worst SOFA score information. Although it is possible that these patients could have had worse SOFA scores and their exclusion could lead to selection bias, analysis found that the excluded patients in the NPC group had a significantly shorter ICU and hospital LOS than patients in the NPC group who were included in this analysis.
263
Finally, we performed a secondary analysis, and thus, our findings are subject to the inherent shortcomings of such a methodology. 5. Conclusion In survivors of septic shock treated with a QR vs NPC, we found no difference in maximal organ dysfunction or change in organ dysfunction during hospitalization. Presently, there are no clear data that QR attenuates organ dysfunction in survivors of septic shock. References [1] Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 2013;41(5):1167–74. [2] Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, Holanda MS, Ortiz F, Llorca J, et al. Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasiexperimental study. Crit Care Med 2010;38(4):1036–43. [3] Ferrer R, Artigas A, Levy MM, Blanco J, Gonzalez-Diaz G, Garnacho-Montero J, et al. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA 2008;299(19):2294–303. [4] Puskarich MA, Marchick MR, Kline JA, Steuerwald MT, Jones AE. One year mortality of patients treated with an emergency department based early goal directed therapy protocol for severe sepsis and septic shock: a before and after study. Crit Care 2009; 13(5):R167–74. [5] Gao F, Melody T, Daniels DF, Giles S, Fox S. The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study. Crit Care 2005;9(6):R764–70. [6] Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest 2007;132(2):425–32. [7] Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345 (19):1368–77. [8] Kortgen A, Niederprum P, Bauer M. Implementation of an evidence-based "standard operating procedure" and outcome in septic shock. Crit Care Med 2006;34(4):943–9. [9] Jones AE, Brown MD, Trzeciak S, Shapiro NI, Garrett JS, Heffner AC, et al. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a metaanalysis. Crit Care Med 2008;36(10):2734–9. [10] Hofhuis JG, Spronk PE, van Stel HF, Schrijvers GJ, Rommes JH, Bakker J. The impact of critical illness on perceived health-related quality of life during ICU treatment, hospital stay, and after hospital discharge: a long-term follow-up study. Chest 2008;133(2):377–85. [11] Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101(6):1644–55.
