- Email: [email protected]
Fluid resuscitation in pre-hospital management of septic shock
YAJEM-57286; No of Pages 5 American Journal of Emergency Medicine xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Fluid resuscitation in pre-hospital management of septic shock Romain Jouffroy, M.D. ⁎,1, Anastasia Saade, M.D., Ph.D. 1, Alexandre Muret, M.D., Pascal Philippe, M.D., Maud Michaloux, M.D., Pierre Carli, M.D., Ph.D., Benoit Vivien, M.D., Ph.D. Department of Anesthesia & Intensive Care Unit, SAMU, Hôpital Necker Enfants Malades, 149 rue de Sèvres, 75015 Paris, France
1. Introduction The estimated incidence of sepsis is approximately 300 per 100,000 inhabitants [1,2], making sepsis a major public health problem, with a mortality rate reaching 30% at day 28 (D28) [1,3-5]. The outcome of septic patients relies on the early identification and rapid implementation of appropriate treatments, including hemodynamic optimization and antibiotics administration [3,6]. Hemodynamic failure is frequently encountered in most severe forms of sepsis and often has to be initially managed in a pre-hospital setting. Hypotension and its consequences, i.e. neurological failure and/or weakness, are the most common symptoms for people to call emergency services. In France, out-of-hospital emergencies are managed by the Service d'Aide Médicale d'Urgence (SAMU) [7]. For medical assistance, the SAMU can be reached dialling the number 15. The SAMU hospital-based team is composed of switchboard operators and physicians. Over the phone, the SAMU determine the appropriate level of care to dispatch to the scene, based on patient's symptoms communicated by the patient itself, by a relative or any witness. For life-threatening emergencies, the “Service Mobile d'Urgence et de Réanimation” (SMUR), a mobile intensive care unit (MICU), is dispatched to the scene. The MICU is composed of a driver, a nurse and an emergency physician [7]. MICU is equipped with medical devices and drugs allowing initial management of main organs deficiency (neurological, respiratory and cardiovascular). The first step in hemodynamic resuscitation relies on early fluid expansion that has to be administered within the first hour [8]. In a lot of situations, fluid resuscitation is initiated in a pre-hospital setting. The benefit of early fluid expansion is described in the management of trauma [9,10] as in septic shock and associated with a hospital mortality decrease [11]. The aim of this study was to describe qualitative and quantitative fluid resuscitation in patients with septic shock managed by MICU in a pre-hospital setting and its adequacy with recommendations [8] to evaluate its impact on mortality at D28. 2. Methods 2.1. Study population All consecutive patients admitted to the intensive care unit (ICU) of Necker Hospital for septic shock, between January 2012 and January ⁎ Corresponding author. E-mail address: [email protected] (R. Jouffroy). 1 Contribute equally to the manuscript.
2014, who received pre-hospital medical care by MICU, were retrospectively analysed. Septic shock was defined according to the surviving sepsis campaign criteria [8]. The primary outcome was mortality at day 28. Institutional review board (Comité de Protection des Personnes Paris-Ile de France 2 - Number ID-RCB: 2012-A01289-34) approved the study with a waiver of signed informed consent. 2.2. Data collection Data were extracted from medicals reports (pre-hospital and ICU). Variables were defined prior to data collection and included: patients' demographic characteristics (age, weight, size, and gender), immunosuppression status, initial pre-hospital vital signs (mean blood pressure, diastolic and systolic blood pressure, heart rate, pulse oximetry, respiratory rate, and temperature), duration of pre-hospital care, and length of stay in the ICU. Immunosuppression was defined by the presence of one or more elements between: diabetes mellitus, chronic renal insufficiency, corticosteroids or another immunosuppressive treatment, infection by human immunodeficiency virus and/or C hepatitis viral. 2.3. Statistical analysis Qualitative and quantitative characteristics of fluid resuscitation administered in the pre-hospital setting were analysed. Fluid expansion indexed on body weight (BW) and ideal body weight (IBW) was estimated using Lorentz formula. The “grey zone” concept was applied and 3 categories of patients were defined according to quantitative fluid resuscitation [12,13]. “Low fluid expansion” corresponded to b10 ml/kg IBW, “optimal fluid expansion” to N20 ml/ kg IBW and the ‘grey zone’ was defined as fluid expansion between 10 and 20 ml/kg IBW. The ‘optimal fluid expansion’ volume was defined according to the Surviving Sepsis Campaign guidelines, describing the association between fluid volume expansion and mortality [8]. Predictive performances of pre-hospital fluid volume expansion for mortality was evaluated using adjusted average receiver operating characteristic (ROC) curves obtained by averaging 10,000 bootstrapped samples (sampling with replacement). The aim of this method is to limit the impact of outliers and to allow the provision of more robust presentations [12]. Thereafter, univariate and multivariate analyses were conducted to evaluate the relationship between all covariables and mortality at D28. Variables included in multivariate analysis were chosen considering
https://doi.org/10.1016/j.ajem.2018.01.078 0735-6757/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
2
R. Jouffroy et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
their potential impact on outcome on one side and on their availability in pre-hospital medicals reports. Results are expressed as mean with standard deviation for quantitative parameters with normal distribution, or median with interquartile range (25–75) for non-normal distribution and, as absolute value and percentage for qualitative parameters. Results are given as Odds Ratio (OR) with 95% confidence interval (95% CI). All analyses were performed using R 3.4.2 (http://www.R-project. org; the R Foundation for Statistical Computing, Vienna, Austria). 3. Results
Table 2 Origin of sepsis of patients with septic shock initially managed in a pre-hospital setting. Data are expressed as absolute value with percentage. Site of infection
n (%)
Pulmonary Urinary Digestive Cutaneous Invasive medical device Meningeal Dental Undefined
65 (68%) 15 (16%) 8 (8%) 2 (2%) 2 (2%) 1 (1%) 1 (2%) 2 (2%)
3.1. Study characteristics Ninety-five patients initially managed in a pre-hospital setting for septic shock prior to their admission in the ICU were included in this study. Populations' demographic and clinical characteristics are summarized in Table 1. Fifty-six patients (59%) were male with a mean age of 70 ± 15 years. Septic shock was mainly associated with pulmonary (68%), urinary (16%) or abdominal (8%) infections (Table 2). The median length of stay in the ICU was of 6 (2−13) days (Table 1). Mortality reached 34% at D28. 3.2. Main measurements No significant difference was observed in the duration of pre-hospital medical care between alive and deceased patients (101 ± 34 min vs 93 ± 34 min respectively, p = 0.29; Table 1). Pre-hospital fluid expansion was performed using crystalloids, e.g. serum saline in 98% of the cases. Mean pre-hospital fluid expansion was 1158 ± 559 ml in the overall population and reached 1287 ± 553 ml vs 906 ± 487 ml in alive and deceased patients respectively (p = 0.001) (Table 1).
Table 1 Demographic, clinical and biological characteristics of patients with septic shock managed by pre-hospital mobile intensive care units. Quantitative variables are expressed as mean ± standard deviation, apart for “length of stay in the ICU” which has no normal distribution. Qualitative variables are expressed as absolute value and percentage.
Age (years) Weight (kg) Size (cm) Male gender Immunosuppression Mean blood pressure (mm Hg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Pulse oximetry (%) Respiratory rate (moves/min) Duration of pre-hospital care (min) Length of stay in the ICU (days) Fluid volume expansion (ml) Fluid volume expansion indexed on BW (ml/kg) Fluid volume expansion indexed on IBW (ml/kg) Fluid volume expansion indexed on IBW b 10 ml/kg Fluid volume expansion indexed on 10 b IBW b 20 ml/kg Fluid volume expansion indexed on IBW N 20 ml/kg
Alive at D28 (n = 63)
Deceased at D28 (n = 32)
Overall population (n = 95)
68 ± 15 69 ± 14 171 ± 8 40 (63%) 35 (56%) 65 ± 21 90 ± 27 55 ± 21 120 ± 28 89 ± 10 30 ± 8 101 ± 34 5 (3–14) 1287 ± 553 20 ± 10
73 ± 14 65 ± 15 168 ± 7 16 (50%) 14 (44%) 69 ± 24 58 ± 19 58 ± 19 109 ± 27 87 ± 12 33 ± 7 93 ± 34 6 (2−10) 906 ± 488 16 ± 12
70 ± 15 67 ± 15 170 ± 8 56 (59%) 49 (52%) 72 ± 20 99 ± 24 60 ± 19 121 ± 24 83 ± 11 30 ± 9 99 ± 34 6 (2–13) 1158 ± 559 18 ± 11
20 ± 9
15 ± 8
18 ± 9
11 (42%)
15 (58%)
26 (27.4%)
17 (65%)
9 (35%)
26 (27.4%)
35 (81%)
8 (19%)
43 (45.2%)
Mean pre-hospital fluid expansion indexed on BW was 18 ± 11 ml/ kg in the overall population and 20 ± 10 ml/kg vs 16 ± 12 ml/kg in alive and deceased patients respectively (p = 0.09) (Table 1). Mean pre-hospital fluid expansion indexed on IBW was 18 ± 9 ml/ kg in the overall population, 20 ± 9 ml/kg in alive and 15 ± 8 ml/kg in deceased patients (p = 0.005) (Table 1). The area under the average ROC curve [95% CI] (Fig. 1) for pre-hospital fluid expansion and pre-hospital fluid expansion indexed on IBW were respectively of 0.70 [0.58–0.81] and 0.67 [0.55–0.78]. Visual subjective analysis of pre-specified categories (b10, 10–20 and 20 ml/kg fluid expansion indexed on IBW) showed an inversed linear association between fluid expansion indexed on IBW and mortality (Fig. 2). Absolute values (A) and proportion (B) of patients in the predefined categories of pre-hospital fluid volume expansion indexed on ideal body weight. Black plot represents deceased patients and white plot alive patients. In univariate analysis, mortality was significantly association with fluid expansion: p = 0.002, OR [95% CI] = 0.998 [0.997–0.999], fluid expansion indexed on IBW: p = 0.007, OR [95% CI] = 0.93 [0.88–0.97], fluid expansion indexed on IBW b 10 p = 0.003, OR [95% CI] = 4.17 [1.89–9.43] and fluid expansion indexed on IBW N 20: p = 0.006, OR [95% CI] = 0.27 [0.12–0.57] (Table 3). No significant association was observed between mortality and fluid expansion indexed on IBM between 10 and 20 ml/kg: p = 0,91, OR [95% CI] = 1.06 [0.47–2.33] (Table 3). Using logistic regression model, including age, immunosuppression, pre-hospital duration as covariables, association with mortality only remained significant for fluid expansion indexed on IBW: p = 0.02, ORa [95% CI] = 0.93 [0.89–0.98], fluid expansion indexed on IBW b 10 p = 0.005, OR [95% CI] = 4.03 [1.78–9.41] and fluid expansion indexed on IBW N 20: p = 0.01, OR [95% CI] = 0.30 [0.13–0.66] (Table 4). 4. Discussion Among 95 patients with septic shock initially managed by pre-hospital medical teams and admitted to the ICU, fluid resuscitation was mainly performed using crystalloids. Interestingly, quantitative prehospital fluid expansion indexed on ideal body weight was lower than recommended within the first hour. An inversed association between mortality and fluid expansion indexed on ideal body weight was observed. In other words, fluid volume expansion indexed on ideal body weight lower than 10 ml/kg was associated with increased mortality whereas fluid volume expansion indexed on ideal body weight N20 ml/kg was associated with decreased mortality. Sepsis is characterized by relative and absolute hypovolemia, due to vasodilatation. The body compensate with increased heart rate and blood vessels constriction to maintain blood pressure and organ perfusion. Decompensation results in hypotension with hypoperfusion of peripheral organ leading to organ failure associated with poor prognosis [14]. One major prognosis factor is the early initiation of treatments [15,16]. Bundle of care including early identification of sepsis and early instauration of treatments proved their efficacy in the reduction
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
R. Jouffroy et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
3
Fig. 1. Pre-hospital fluid volume expansion average ROC curves for prediction of mortality at day 28 (A). Pre-hospital fluid volume expansion indexed on ideal body weight, average ROC curves for prediction of mortality at D28 (B). The dotted line represents to the non-discrimination curve.
of mortality [15,17-21], despite controversial results when each element of bundle is taken apart [22,23]. This debate could be explained by the difficulty to diagnose severe sepsis and septic shock, especially in patients with normal blood pressure and/or without obvious source of infection [22,24]. Fluid volume expansion is the first step in hemodynamic resuscitation and should be performed within the first hour when septic shock is suspected [8]. Crystalloid is recommended for intravenous fluid therapy [8].
4.1. Strengths and limitations Our study is retrospective, monocentric and small sample sized. A sorting bias might exist as data were retrospectively collected from pre-hospital and ICU medical reports. The study was not designed to determine the optimal threshold for fluid volume expansion indexed on IBW. In our work, we report a relationship between mortality and fluid volume expansion indexed on IBW. However, our study does not provide adequate evidence that a
Fig. 2. Deceased and alive patients at day 28 in the predefined categories of fluid volume expansion. Absolute values (A) and proportion (B) of patients in the predefined categories of prehospital fluid volume expansion indexed on ideal body weight. Black plot represents deceased patients and white plot alive patients.
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
4
R. Jouffroy et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
Table 3 Univariate analysis of factors associated with mortality at Day 28 of patients with septic shock managed in a pre-hospital setting prior to ICU admission. Data are presented as p values and Odds Ratio (OR) with a 95% confidence interval [95% CI]. Variables
Age (years) Weight (kg) Height (cm) Male Immunosuppression Mean blood pressure (mm Hg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Pulse oximetry (%) Respiratory rate (moves/min) Duration of pre-hospital care (min) Length of stay into ICU (days) Fluid volume expansion (ml) Fluid volume expansion indexed on body weight (ml/kg) Fluid volume expansion indexed on ideal body weight (ml/kg) Fluid volume expansion indexed on ideal body weight b 10 ml/kg Fluid volume expansion indexed on ideal body 10 b weight b 20 ml/kg Fluid volume expansion indexed on ideal body weight N 20 ml/kg
Univariate analysis OR [95% CI]
p value
1.02 [0.99–1.05] 0.98 [0.91–1.01] 0.95 [0.91–1.01] 1.74 [0.84–3.61] 0.62 [0.30–1.27] 1.01 [0.99–1.02] 1.01 [0.99–1.02] 1.01 [0.99–1.02] 0.98 [0.97–1.01] 0.98 [0.95–1.01] 1.04 [0.99–1.09] 0.99 [0.98–1.01] 0.97 [0.92–1.01] 0.998 [0.997–0.999] 0.98 [0.96–1.01]
0.14 0.20 0.11 0.21 0.28 0.48 0.39 0.57 0.06 0.28 0.15 0.29 0.25 0.002 0.20
0.93 [0.88–0.97]
0.007
4.17 [1.89–9.43]
0.003
1.06 [0.47–2.33]
0.91
0.27 [0.12–0.57]
0.006
causal link between mortality and fluid volume expansion exists in a pre-hospital setting. As previously described by others [12,13], we also report the ‘grey zone’ which reinforces the need for further studies designed to precisely define accurate guideline for pre-hospital management of fluid resuscitation in sepsis. Actually, pre-hospital fluid expansion is mostly studied for trauma patients [9,10]. Yet, studies concerning the management of septic shock in pre-hospital setting remain scarce [11]. 5. Conclusion In this study, we observed that fluid resuscitation in septic shock managed by pre-hospital medical care teams, is mainly performed using crystalloids with lower fluid volume expansion than recommended. There is an association between low fluid expansion and mortality underling the importance of optimal initial management in prehospital settings.
Table 4 Multivariate analysis of factors associated with mortality at Day 28 of patients with septic shock managed in a pre-hospital setting prior to ICU admission. Data are presented as p value and Odds Ratio adjusted (ORa) with a 95% confidence interval [95% CI]. Variables
Age (years) Immunosuppression Duration of pre-hospital care (min) Fluid volume expansion indexed on ideal body weight (ml/kg) Fluid volume expansion indexed on ideal body weight b 10 ml/kg Fluid volume expansion indexed on ideal body weight N 20 ml/kg
Multivariate analysis ORa [95% CI]
p value
1.02 [0.99–1.05] 0.77 [0.35–1.70] 0.99 [0.98–1.01] 0.93 [0.89–0.98]
0.28 0.59 0.63 0.02
4.03 [1.78–9.41]
0.005
0.30 [0.13–0.66]
0.01
Authors contribution − − − − −
Study concept and design: Jouffroy. Acquisition of data: Muret, Jouffroy. Analysis and interpretation of data: Jouffroy. Drafting of the manuscript: Jouffroy, Saade. Critical revision of the manuscript for important intellectual content: Philippe, Michaloux, Carli, Vivien.
Funding/support None. Conflict of interest The authors declare no competing interests 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 Mai 2013;41(5):1167–74. [2] Jawad I, Lukšić I, Rafnsson SB. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J Glob Health Juin 2012; 2(1):10404. [3] The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med Mai 2014;370(18):1683–93. [4] ARISE, ANZICS APD Management Committee. The outcome of patients with sepsis and septic shock presenting to emergency departments in Australia and New Zealand. Crit Care Resusc Mars 2007;9(1):8–18. [5] Annane D, Aegerter P, Jars-Guincestre MC, Guidet B, CUB-Réa Network. Current epidemiology of septic shock: the CUB-Réa Network. Am J Respir Crit Care Med 15 Juill 2003;168(2):165–72. [6] Delaney AP, Peake SL, Bellomo R, Cameron P, Holdgate A, Howe B, et al. The Australasian Resuscitation in Sepsis Evaluation (ARISE) trial statistical analysis plan. Crit Care Resusc sept 2013;15(3):162–71. [7] Adnet F, Lapostolle F. International EMS systems: France. Resuscitation Oct 2004;63 (1):7–9. [8] Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med Févr 2013;39(2):165–228. [9] Bulger EM, May S, Brasel KJ, Schreiber M, Kerby JD, Tisherman SA, et al. Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. JAMA 6 Oct 2010;304(13):1455–64. [10] Bulger EM, May S, Kerby JD, Emerson S, Stiell IG, Schreiber MA, et al. Out-of-hospital hypertonic resuscitation after traumatic hypovolemic shock: a randomized, placebo controlled trial. Ann Surg Mars 2011;253(3):431–41. [11] Seymour CW, Cooke CR, Heckbert SR, Spertus JA, Callaway CW, Martin-Gill C, et al. Pre-hospital intravenous access and fluid resuscitation in severe sepsis: an observational cohort study. Crit Care 27 Sept 2014;18(5):533. [12] Cannesson M, Le Manach Y, Hofer CK, Goarin JP, Lehot J-J, Vallet B, et al. Assessing the diagnostic accuracy of pulse pressure variations for the prediction of fluid responsiveness: a “gray zone” approach. Anesthesiology Août 2011;115(2):231–41. [13] Biais M, Ehrmann S, Mari A, Conte B, Mahjoub Y, Desebbe O, et al. Clinical relevance of pulse pressure variations for predicting fluid responsiveness in mechanically ventilated intensive care unit patients: the grey zone approach. Crit Care [Internet] 2014;18(6) Disponible sur: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240833/. [cité 16 nov 2017]. [14] Brun-Buisson C, Meshaka P, Pinton P, Vallet B, EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med Avr 2004;30(4):580–8. [15] Leisman DE, Doerfler ME, Ward MF, Masick KD, Wie BJ, Gribben JL, et al. Survival benefit and cost savings from compliance with a simplified 3-hour sepsis bundle in a series of prospective, multisite, observational cohorts. Crit Care Med Mars 2017;45(3):395–406. [16] Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 08 2017;376(23):2235–44. [17] 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 8 Nov 2001;345(19):1368–77. [18] Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De Backer D, et al. The surviving sepsis campaign bundles and outcome: results from the international multicentre prevalence study on sepsis (the IMPreSS study). Intensive Care Med Sept 2015;41 (9):1620–8. [19] Kalil AC, Sweeney DA. Should we manage all septic patients based on a single definition? An alternative approach. Crit Care Med Feb 2018;46(2):177–80. [20] Prasad PA, Shea ER, Shiboski S, Sullivan MC, Gonzales R, Shimabukuro D. Relationship between a sepsis intervention bundle and in-hospital mortality among hospitalized patients: a retrospective analysis of real-world data. Anesth Analg Août 2017;125(2):507–13.
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
R. Jouffroy et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx [21] Damiani E, Donati A, Serafini G, Rinaldi L, Adrario E, Pelaia P, et al. Effect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies. PLoS One 2015;10 (5):e0125827. [22] Peltan ID, Mitchell KH, Rudd KE, Mann BA, Carlbom DJ, Hough CL, et al. Physician variation in time to antimicrobial treatment for septic patients presenting to the emergency department. Crit Care Med Juin 2017;45(6):1011–8.
5
[23] Alam N, Oskam E, Stassen PM, van Exter P, van de Ven PM, Haak HR, et al. Pre-hospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med 2017;28. [24] Vincent J-L. Antibiotic administration in the ambulance? Lancet Respir Med Jan 2018;6(1):5–6.
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Fluid resuscitation in pre-hospital management of septic shock Romain Jouffroy, M.D. ⁎,1, Anastasia Saade, M.D., Ph.D. 1, Alexandre Muret, M.D., Pascal Philippe, M.D., Maud Michaloux, M.D., Pierre Carli, M.D., Ph.D., Benoit Vivien, M.D., Ph.D. Department of Anesthesia & Intensive Care Unit, SAMU, Hôpital Necker Enfants Malades, 149 rue de Sèvres, 75015 Paris, France
1. Introduction The estimated incidence of sepsis is approximately 300 per 100,000 inhabitants [1,2], making sepsis a major public health problem, with a mortality rate reaching 30% at day 28 (D28) [1,3-5]. The outcome of septic patients relies on the early identification and rapid implementation of appropriate treatments, including hemodynamic optimization and antibiotics administration [3,6]. Hemodynamic failure is frequently encountered in most severe forms of sepsis and often has to be initially managed in a pre-hospital setting. Hypotension and its consequences, i.e. neurological failure and/or weakness, are the most common symptoms for people to call emergency services. In France, out-of-hospital emergencies are managed by the Service d'Aide Médicale d'Urgence (SAMU) [7]. For medical assistance, the SAMU can be reached dialling the number 15. The SAMU hospital-based team is composed of switchboard operators and physicians. Over the phone, the SAMU determine the appropriate level of care to dispatch to the scene, based on patient's symptoms communicated by the patient itself, by a relative or any witness. For life-threatening emergencies, the “Service Mobile d'Urgence et de Réanimation” (SMUR), a mobile intensive care unit (MICU), is dispatched to the scene. The MICU is composed of a driver, a nurse and an emergency physician [7]. MICU is equipped with medical devices and drugs allowing initial management of main organs deficiency (neurological, respiratory and cardiovascular). The first step in hemodynamic resuscitation relies on early fluid expansion that has to be administered within the first hour [8]. In a lot of situations, fluid resuscitation is initiated in a pre-hospital setting. The benefit of early fluid expansion is described in the management of trauma [9,10] as in septic shock and associated with a hospital mortality decrease [11]. The aim of this study was to describe qualitative and quantitative fluid resuscitation in patients with septic shock managed by MICU in a pre-hospital setting and its adequacy with recommendations [8] to evaluate its impact on mortality at D28. 2. Methods 2.1. Study population All consecutive patients admitted to the intensive care unit (ICU) of Necker Hospital for septic shock, between January 2012 and January ⁎ Corresponding author. E-mail address: [email protected] (R. Jouffroy). 1 Contribute equally to the manuscript.
2014, who received pre-hospital medical care by MICU, were retrospectively analysed. Septic shock was defined according to the surviving sepsis campaign criteria [8]. The primary outcome was mortality at day 28. Institutional review board (Comité de Protection des Personnes Paris-Ile de France 2 - Number ID-RCB: 2012-A01289-34) approved the study with a waiver of signed informed consent. 2.2. Data collection Data were extracted from medicals reports (pre-hospital and ICU). Variables were defined prior to data collection and included: patients' demographic characteristics (age, weight, size, and gender), immunosuppression status, initial pre-hospital vital signs (mean blood pressure, diastolic and systolic blood pressure, heart rate, pulse oximetry, respiratory rate, and temperature), duration of pre-hospital care, and length of stay in the ICU. Immunosuppression was defined by the presence of one or more elements between: diabetes mellitus, chronic renal insufficiency, corticosteroids or another immunosuppressive treatment, infection by human immunodeficiency virus and/or C hepatitis viral. 2.3. Statistical analysis Qualitative and quantitative characteristics of fluid resuscitation administered in the pre-hospital setting were analysed. Fluid expansion indexed on body weight (BW) and ideal body weight (IBW) was estimated using Lorentz formula. The “grey zone” concept was applied and 3 categories of patients were defined according to quantitative fluid resuscitation [12,13]. “Low fluid expansion” corresponded to b10 ml/kg IBW, “optimal fluid expansion” to N20 ml/ kg IBW and the ‘grey zone’ was defined as fluid expansion between 10 and 20 ml/kg IBW. The ‘optimal fluid expansion’ volume was defined according to the Surviving Sepsis Campaign guidelines, describing the association between fluid volume expansion and mortality [8]. Predictive performances of pre-hospital fluid volume expansion for mortality was evaluated using adjusted average receiver operating characteristic (ROC) curves obtained by averaging 10,000 bootstrapped samples (sampling with replacement). The aim of this method is to limit the impact of outliers and to allow the provision of more robust presentations [12]. Thereafter, univariate and multivariate analyses were conducted to evaluate the relationship between all covariables and mortality at D28. Variables included in multivariate analysis were chosen considering
https://doi.org/10.1016/j.ajem.2018.01.078 0735-6757/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
2
R. Jouffroy et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
their potential impact on outcome on one side and on their availability in pre-hospital medicals reports. Results are expressed as mean with standard deviation for quantitative parameters with normal distribution, or median with interquartile range (25–75) for non-normal distribution and, as absolute value and percentage for qualitative parameters. Results are given as Odds Ratio (OR) with 95% confidence interval (95% CI). All analyses were performed using R 3.4.2 (http://www.R-project. org; the R Foundation for Statistical Computing, Vienna, Austria). 3. Results
Table 2 Origin of sepsis of patients with septic shock initially managed in a pre-hospital setting. Data are expressed as absolute value with percentage. Site of infection
n (%)
Pulmonary Urinary Digestive Cutaneous Invasive medical device Meningeal Dental Undefined
65 (68%) 15 (16%) 8 (8%) 2 (2%) 2 (2%) 1 (1%) 1 (2%) 2 (2%)
3.1. Study characteristics Ninety-five patients initially managed in a pre-hospital setting for septic shock prior to their admission in the ICU were included in this study. Populations' demographic and clinical characteristics are summarized in Table 1. Fifty-six patients (59%) were male with a mean age of 70 ± 15 years. Septic shock was mainly associated with pulmonary (68%), urinary (16%) or abdominal (8%) infections (Table 2). The median length of stay in the ICU was of 6 (2−13) days (Table 1). Mortality reached 34% at D28. 3.2. Main measurements No significant difference was observed in the duration of pre-hospital medical care between alive and deceased patients (101 ± 34 min vs 93 ± 34 min respectively, p = 0.29; Table 1). Pre-hospital fluid expansion was performed using crystalloids, e.g. serum saline in 98% of the cases. Mean pre-hospital fluid expansion was 1158 ± 559 ml in the overall population and reached 1287 ± 553 ml vs 906 ± 487 ml in alive and deceased patients respectively (p = 0.001) (Table 1).
Table 1 Demographic, clinical and biological characteristics of patients with septic shock managed by pre-hospital mobile intensive care units. Quantitative variables are expressed as mean ± standard deviation, apart for “length of stay in the ICU” which has no normal distribution. Qualitative variables are expressed as absolute value and percentage.
Age (years) Weight (kg) Size (cm) Male gender Immunosuppression Mean blood pressure (mm Hg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Pulse oximetry (%) Respiratory rate (moves/min) Duration of pre-hospital care (min) Length of stay in the ICU (days) Fluid volume expansion (ml) Fluid volume expansion indexed on BW (ml/kg) Fluid volume expansion indexed on IBW (ml/kg) Fluid volume expansion indexed on IBW b 10 ml/kg Fluid volume expansion indexed on 10 b IBW b 20 ml/kg Fluid volume expansion indexed on IBW N 20 ml/kg
Alive at D28 (n = 63)
Deceased at D28 (n = 32)
Overall population (n = 95)
68 ± 15 69 ± 14 171 ± 8 40 (63%) 35 (56%) 65 ± 21 90 ± 27 55 ± 21 120 ± 28 89 ± 10 30 ± 8 101 ± 34 5 (3–14) 1287 ± 553 20 ± 10
73 ± 14 65 ± 15 168 ± 7 16 (50%) 14 (44%) 69 ± 24 58 ± 19 58 ± 19 109 ± 27 87 ± 12 33 ± 7 93 ± 34 6 (2−10) 906 ± 488 16 ± 12
70 ± 15 67 ± 15 170 ± 8 56 (59%) 49 (52%) 72 ± 20 99 ± 24 60 ± 19 121 ± 24 83 ± 11 30 ± 9 99 ± 34 6 (2–13) 1158 ± 559 18 ± 11
20 ± 9
15 ± 8
18 ± 9
11 (42%)
15 (58%)
26 (27.4%)
17 (65%)
9 (35%)
26 (27.4%)
35 (81%)
8 (19%)
43 (45.2%)
Mean pre-hospital fluid expansion indexed on BW was 18 ± 11 ml/ kg in the overall population and 20 ± 10 ml/kg vs 16 ± 12 ml/kg in alive and deceased patients respectively (p = 0.09) (Table 1). Mean pre-hospital fluid expansion indexed on IBW was 18 ± 9 ml/ kg in the overall population, 20 ± 9 ml/kg in alive and 15 ± 8 ml/kg in deceased patients (p = 0.005) (Table 1). The area under the average ROC curve [95% CI] (Fig. 1) for pre-hospital fluid expansion and pre-hospital fluid expansion indexed on IBW were respectively of 0.70 [0.58–0.81] and 0.67 [0.55–0.78]. Visual subjective analysis of pre-specified categories (b10, 10–20 and 20 ml/kg fluid expansion indexed on IBW) showed an inversed linear association between fluid expansion indexed on IBW and mortality (Fig. 2). Absolute values (A) and proportion (B) of patients in the predefined categories of pre-hospital fluid volume expansion indexed on ideal body weight. Black plot represents deceased patients and white plot alive patients. In univariate analysis, mortality was significantly association with fluid expansion: p = 0.002, OR [95% CI] = 0.998 [0.997–0.999], fluid expansion indexed on IBW: p = 0.007, OR [95% CI] = 0.93 [0.88–0.97], fluid expansion indexed on IBW b 10 p = 0.003, OR [95% CI] = 4.17 [1.89–9.43] and fluid expansion indexed on IBW N 20: p = 0.006, OR [95% CI] = 0.27 [0.12–0.57] (Table 3). No significant association was observed between mortality and fluid expansion indexed on IBM between 10 and 20 ml/kg: p = 0,91, OR [95% CI] = 1.06 [0.47–2.33] (Table 3). Using logistic regression model, including age, immunosuppression, pre-hospital duration as covariables, association with mortality only remained significant for fluid expansion indexed on IBW: p = 0.02, ORa [95% CI] = 0.93 [0.89–0.98], fluid expansion indexed on IBW b 10 p = 0.005, OR [95% CI] = 4.03 [1.78–9.41] and fluid expansion indexed on IBW N 20: p = 0.01, OR [95% CI] = 0.30 [0.13–0.66] (Table 4). 4. Discussion Among 95 patients with septic shock initially managed by pre-hospital medical teams and admitted to the ICU, fluid resuscitation was mainly performed using crystalloids. Interestingly, quantitative prehospital fluid expansion indexed on ideal body weight was lower than recommended within the first hour. An inversed association between mortality and fluid expansion indexed on ideal body weight was observed. In other words, fluid volume expansion indexed on ideal body weight lower than 10 ml/kg was associated with increased mortality whereas fluid volume expansion indexed on ideal body weight N20 ml/kg was associated with decreased mortality. Sepsis is characterized by relative and absolute hypovolemia, due to vasodilatation. The body compensate with increased heart rate and blood vessels constriction to maintain blood pressure and organ perfusion. Decompensation results in hypotension with hypoperfusion of peripheral organ leading to organ failure associated with poor prognosis [14]. One major prognosis factor is the early initiation of treatments [15,16]. Bundle of care including early identification of sepsis and early instauration of treatments proved their efficacy in the reduction
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
R. Jouffroy et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
3
Fig. 1. Pre-hospital fluid volume expansion average ROC curves for prediction of mortality at day 28 (A). Pre-hospital fluid volume expansion indexed on ideal body weight, average ROC curves for prediction of mortality at D28 (B). The dotted line represents to the non-discrimination curve.
of mortality [15,17-21], despite controversial results when each element of bundle is taken apart [22,23]. This debate could be explained by the difficulty to diagnose severe sepsis and septic shock, especially in patients with normal blood pressure and/or without obvious source of infection [22,24]. Fluid volume expansion is the first step in hemodynamic resuscitation and should be performed within the first hour when septic shock is suspected [8]. Crystalloid is recommended for intravenous fluid therapy [8].
4.1. Strengths and limitations Our study is retrospective, monocentric and small sample sized. A sorting bias might exist as data were retrospectively collected from pre-hospital and ICU medical reports. The study was not designed to determine the optimal threshold for fluid volume expansion indexed on IBW. In our work, we report a relationship between mortality and fluid volume expansion indexed on IBW. However, our study does not provide adequate evidence that a
Fig. 2. Deceased and alive patients at day 28 in the predefined categories of fluid volume expansion. Absolute values (A) and proportion (B) of patients in the predefined categories of prehospital fluid volume expansion indexed on ideal body weight. Black plot represents deceased patients and white plot alive patients.
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
4
R. Jouffroy et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx
Table 3 Univariate analysis of factors associated with mortality at Day 28 of patients with septic shock managed in a pre-hospital setting prior to ICU admission. Data are presented as p values and Odds Ratio (OR) with a 95% confidence interval [95% CI]. Variables
Age (years) Weight (kg) Height (cm) Male Immunosuppression Mean blood pressure (mm Hg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Pulse oximetry (%) Respiratory rate (moves/min) Duration of pre-hospital care (min) Length of stay into ICU (days) Fluid volume expansion (ml) Fluid volume expansion indexed on body weight (ml/kg) Fluid volume expansion indexed on ideal body weight (ml/kg) Fluid volume expansion indexed on ideal body weight b 10 ml/kg Fluid volume expansion indexed on ideal body 10 b weight b 20 ml/kg Fluid volume expansion indexed on ideal body weight N 20 ml/kg
Univariate analysis OR [95% CI]
p value
1.02 [0.99–1.05] 0.98 [0.91–1.01] 0.95 [0.91–1.01] 1.74 [0.84–3.61] 0.62 [0.30–1.27] 1.01 [0.99–1.02] 1.01 [0.99–1.02] 1.01 [0.99–1.02] 0.98 [0.97–1.01] 0.98 [0.95–1.01] 1.04 [0.99–1.09] 0.99 [0.98–1.01] 0.97 [0.92–1.01] 0.998 [0.997–0.999] 0.98 [0.96–1.01]
0.14 0.20 0.11 0.21 0.28 0.48 0.39 0.57 0.06 0.28 0.15 0.29 0.25 0.002 0.20
0.93 [0.88–0.97]
0.007
4.17 [1.89–9.43]
0.003
1.06 [0.47–2.33]
0.91
0.27 [0.12–0.57]
0.006
causal link between mortality and fluid volume expansion exists in a pre-hospital setting. As previously described by others [12,13], we also report the ‘grey zone’ which reinforces the need for further studies designed to precisely define accurate guideline for pre-hospital management of fluid resuscitation in sepsis. Actually, pre-hospital fluid expansion is mostly studied for trauma patients [9,10]. Yet, studies concerning the management of septic shock in pre-hospital setting remain scarce [11]. 5. Conclusion In this study, we observed that fluid resuscitation in septic shock managed by pre-hospital medical care teams, is mainly performed using crystalloids with lower fluid volume expansion than recommended. There is an association between low fluid expansion and mortality underling the importance of optimal initial management in prehospital settings.
Table 4 Multivariate analysis of factors associated with mortality at Day 28 of patients with septic shock managed in a pre-hospital setting prior to ICU admission. Data are presented as p value and Odds Ratio adjusted (ORa) with a 95% confidence interval [95% CI]. Variables
Age (years) Immunosuppression Duration of pre-hospital care (min) Fluid volume expansion indexed on ideal body weight (ml/kg) Fluid volume expansion indexed on ideal body weight b 10 ml/kg Fluid volume expansion indexed on ideal body weight N 20 ml/kg
Multivariate analysis ORa [95% CI]
p value
1.02 [0.99–1.05] 0.77 [0.35–1.70] 0.99 [0.98–1.01] 0.93 [0.89–0.98]
0.28 0.59 0.63 0.02
4.03 [1.78–9.41]
0.005
0.30 [0.13–0.66]
0.01
Authors contribution − − − − −
Study concept and design: Jouffroy. Acquisition of data: Muret, Jouffroy. Analysis and interpretation of data: Jouffroy. Drafting of the manuscript: Jouffroy, Saade. Critical revision of the manuscript for important intellectual content: Philippe, Michaloux, Carli, Vivien.
Funding/support None. Conflict of interest The authors declare no competing interests 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 Mai 2013;41(5):1167–74. [2] Jawad I, Lukšić I, Rafnsson SB. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J Glob Health Juin 2012; 2(1):10404. [3] The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med Mai 2014;370(18):1683–93. [4] ARISE, ANZICS APD Management Committee. The outcome of patients with sepsis and septic shock presenting to emergency departments in Australia and New Zealand. Crit Care Resusc Mars 2007;9(1):8–18. [5] Annane D, Aegerter P, Jars-Guincestre MC, Guidet B, CUB-Réa Network. Current epidemiology of septic shock: the CUB-Réa Network. Am J Respir Crit Care Med 15 Juill 2003;168(2):165–72. [6] Delaney AP, Peake SL, Bellomo R, Cameron P, Holdgate A, Howe B, et al. The Australasian Resuscitation in Sepsis Evaluation (ARISE) trial statistical analysis plan. Crit Care Resusc sept 2013;15(3):162–71. [7] Adnet F, Lapostolle F. International EMS systems: France. Resuscitation Oct 2004;63 (1):7–9. [8] Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med Févr 2013;39(2):165–228. [9] Bulger EM, May S, Brasel KJ, Schreiber M, Kerby JD, Tisherman SA, et al. Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. JAMA 6 Oct 2010;304(13):1455–64. [10] Bulger EM, May S, Kerby JD, Emerson S, Stiell IG, Schreiber MA, et al. Out-of-hospital hypertonic resuscitation after traumatic hypovolemic shock: a randomized, placebo controlled trial. Ann Surg Mars 2011;253(3):431–41. [11] Seymour CW, Cooke CR, Heckbert SR, Spertus JA, Callaway CW, Martin-Gill C, et al. Pre-hospital intravenous access and fluid resuscitation in severe sepsis: an observational cohort study. Crit Care 27 Sept 2014;18(5):533. [12] Cannesson M, Le Manach Y, Hofer CK, Goarin JP, Lehot J-J, Vallet B, et al. Assessing the diagnostic accuracy of pulse pressure variations for the prediction of fluid responsiveness: a “gray zone” approach. Anesthesiology Août 2011;115(2):231–41. [13] Biais M, Ehrmann S, Mari A, Conte B, Mahjoub Y, Desebbe O, et al. Clinical relevance of pulse pressure variations for predicting fluid responsiveness in mechanically ventilated intensive care unit patients: the grey zone approach. Crit Care [Internet] 2014;18(6) Disponible sur: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240833/. [cité 16 nov 2017]. [14] Brun-Buisson C, Meshaka P, Pinton P, Vallet B, EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med Avr 2004;30(4):580–8. [15] Leisman DE, Doerfler ME, Ward MF, Masick KD, Wie BJ, Gribben JL, et al. Survival benefit and cost savings from compliance with a simplified 3-hour sepsis bundle in a series of prospective, multisite, observational cohorts. Crit Care Med Mars 2017;45(3):395–406. [16] Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 08 2017;376(23):2235–44. [17] 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 8 Nov 2001;345(19):1368–77. [18] Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De Backer D, et al. The surviving sepsis campaign bundles and outcome: results from the international multicentre prevalence study on sepsis (the IMPreSS study). Intensive Care Med Sept 2015;41 (9):1620–8. [19] Kalil AC, Sweeney DA. Should we manage all septic patients based on a single definition? An alternative approach. Crit Care Med Feb 2018;46(2):177–80. [20] Prasad PA, Shea ER, Shiboski S, Sullivan MC, Gonzales R, Shimabukuro D. Relationship between a sepsis intervention bundle and in-hospital mortality among hospitalized patients: a retrospective analysis of real-world data. Anesth Analg Août 2017;125(2):507–13.
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078
R. Jouffroy et al. / American Journal of Emergency Medicine xxx (2018) xxx–xxx [21] Damiani E, Donati A, Serafini G, Rinaldi L, Adrario E, Pelaia P, et al. Effect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies. PLoS One 2015;10 (5):e0125827. [22] Peltan ID, Mitchell KH, Rudd KE, Mann BA, Carlbom DJ, Hough CL, et al. Physician variation in time to antimicrobial treatment for septic patients presenting to the emergency department. Crit Care Med Juin 2017;45(6):1011–8.
5
[23] Alam N, Oskam E, Stassen PM, van Exter P, van de Ven PM, Haak HR, et al. Pre-hospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med 2017;28. [24] Vincent J-L. Antibiotic administration in the ambulance? Lancet Respir Med Jan 2018;6(1):5–6.
Please cite this article as: Jouffroy R, et al, Fluid resuscitation in pre-hospital management of septic shock, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.01.078