Comparative analysis of survival between elderly and non-elderly severe sepsis and septic shock resuscitated patients

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1 IGINAL ARTICLE Comarative analysis of survival between elderly and non-elderly severe sesis and setic shock resuscitated atients Análise comarativa da sobrevida de idosos e não idosos com sese grave ou choque sético ressuscitados Henrique Palomba 1, Thiago Domingos Corrêa 1, Eliézer Silva 1, Andreia Pardini 1, Murillo Santucci Cesar de Assuncao 1 ABSTRACT Objective: To comare outcomes between elderly ( 65 years old) and non-elderly (<65 years old) resuscitated severe sesis and setic shock atients and determine redictors of death among elderly atients. Methods: Retrosective cohort study including 848 severe sesis and setic shock atients admitted to the intensive care unit between January 2006 and March Results: Elderly atients accounted for 62.6% (531/848) and non-elderly atients for 37.4% (317/848). Elderly atients had a higher APACHE II score [22 (18-28) versus 19 (15-24); <0.001], comared to non-elderly atients, although the number of organ dysfunctions did not differ between the grous. No significant differences were found in 28-day and in-hosital mortality rates between elderly and non-elderly atients. The length of hosital stay was higher in elderly comared to non-elderly atients admitted with severe sesis and setic shock [18 (10-41) versus 14 (8-29) days, resectively; =0.0001]. Predictors of death among elderly atients included age, site of diagnosis, APACHE II score, need for mechanical ventilation and vasoressors. Conclusion: In this study oulation early resuscitation of elderly atients was not associated with increased inhosital mortality. Prosective studies addressing the long-term imact on functional status and quality of life are necessary. Keywords: Aged; Sesis; Shock, setic; Shock; Resuscitation; Multile organ failure; Fluid theray; Vasoconstrictor agents RESUMO Objetivo: Comarar os resultados obtidos com a ressuscitação de idosos ( 65 anos) e não idosos (<65 anos) com sese grave ou choque sético e determinar os reditores de óbito em acientes idosos. Métodos: Estudo de coorte retrosectivo com 848 acientes com sese grave ou choque sético admitidos na unidade de teraia intensiva entre janeiro de 2006 e março de Resultados: Pacientes idosos reresentaram 62,6% (531/848) e não idosos 37,4% (317/848) dos acientes. Pacientes idosos aresentaram maior escore APACHE II [22 (18-28) versus 19 (15-24); <0,001] em comaração com acientes não idosos, embora o número de disfunções orgânicas não tenha sido diferente entre os gruos. Não se observaram diferenças significativas na mortalidade hositalar e em 28 dias entre acientes idosos e não idosos, embora o temo de internação hositalar tenha sido suerior nos acientes idosos, em comaração com não idosos [18 (10-41) versus 14 (8-29) dias, resectivamente; =0,0001]. Foram reditores de óbito entre acientes idosos a idade, o local do diagnóstico, o escore APACHE II e a necessidade de ventilação mecânica e vasoressores. Conclusão: A ressuscitação de acientes idosos com sese grave ou choque sético não associou-se ao aumento de mortalidade hositalar. Estudos rosectivos são necessários ara avaliação do imacto a longo razo no estado funcional e qualidade de vida dos acientes idosos ressuscitados. Descritores: Idoso; Sese; Choque sético; Choque; Ressuscitação; Insuficiência de múltilos órgãos; Hidratação; Vasoconstritores INTRODUCTION Severe sesis and setic shock are major reasons for intensive care unit (ICU) admission worldwide and they are associated with high morbidity and mortality rates, desite intense efforts towards early diagnosis and treatment. (1-3) Rivers et al. (4) roosed the concet of early goaldirected theray for the treatment of severe sesis and setic shock atients in This rincile has been incororated in the Surviving Sesis Camaign International Guidelines for Management of Severe Sesis and Setic Shock. (5) Accordingly, early identification, broad sectrum antibiotic administration and hemodynamic stabilization have been the cornerstone of severe sesis and setic shock management. (6) 1 Hosital Israelita Albert Einstein, São Paulo, SP, Brazil. Corresonding author: Murillo Santucci Cesar de Assuncao Avenida Albert Einstein, 627/701, 5th floor Morumbi Zi code: São Paulo, SP, Brazil Phone: (55 11) murillo.assuncao@.br Received on: Dec 24, Acceted on: May 21, 2015 Conflict of interest: none. DOI: /S AO3313

2 2 Palomba H, Corrêa TD, Silva E, Pardini A, Assuncao MS The number of elderly atients (age 65 years old according to the World Health Organization) with severe sesis and setic shock has been increasing steadily. (7) This oulation of elderly atients is characterized by an increased revalence of chronic illness, comorbidities, frailty and functional imairment. (8,9) Nevertheless, while recent evidence has demonstrated that elderly atients submitted to comlex theraeutic interventions during hositalization showed benefits in long-term survival, (10) observational studies have shown that increased age is an indeendent redictor of death among setic and non-setic atients. (11-13) We ostulated that elderly atients with severe sesis or setic shock resuscitated following the Surviving Sesis Camaign Guidelines have similar short-term mortality rates when comared to non-elderly atients with severe sesis or setic shock. OBJECTIVE To erform a retrosective, single-center cohort study to comare the outcomes between elderly ( 65 years) and non-elderly (<65 years) severe sesis and setic shock resuscitated atients and to determine the main redictors of death among elderly atients. METHODS This study was aroved and the informed consent waived by the Hosital Israelita Albert Einstein Institutional Review Board (rotocol 716,880 and CAAE: ). This study was conducted in a 41-bed medical-surgical ICU of a tertiary care at a rivate hosital in São Paulo, Brazil. Patients According to the institutional rotocol for severe sesis and setic shock resuscitation, all atients admitted to the emergency deartment or those in hosital who had been seen by the raid resonse team and fulfilled the criteria for severe sesis and setic shock were admitted to the ICU. All adult atients with severe sesis or setic shock admitted to the ICU between January 2006 and December 2012 were included in this study. A case manager followed these atients until hosital discharge and their data were recorded. The criteria for admission to hosital floor, intermediary care and ICU for atients with no diagnosis of severe sesis and setic shock was based on the clinical judgment of the attending hysician. However, severe sesis and setic shock atients coming from the emergency deartment, or those who had been screened by the raid resonse team were necessarily admitted to the ICU. Definitions The American College of Chest Physicians/Society of Critical Care Medicine definitions were used and sesis was defined as infection lus two or more systemic inflammatory resonse syndrome (SIRS) criteria: temerature >38 C or <36 C, heart rate >90/minute, resiratory rate >20/minute or PaCO 2 <32mmHg, white blood cell count >12,000cells/mL or <4,000cells/mL (or >10% band forms). (14) Severe sesis was defined as sesis associated with organ dysfunction, including mental status changes, systolic blood ressure <90mmHg or mean arterial ressure (MAP) <65mmHg, serum creatinine >2.0mg/dL or diuresis <0.5mL/kg/h, total bilirubin >2.0mg/dL, latelet count <100,000 cells/mm 3, arterial lactate >1.5 time the normal, INR >1.5 or TTPa >60 seconds and relationshi between arterial oxygen artial ressure and fraction of insired oxygen (PaO 2 /FiO 2 ) <300. Setic shock was defined as sesis-induced hyotension (systolic blood ressure <90mmHg or mean arterial blood ressure <65mmHg or a dro of >40mmHg in the absence of another cause of hyotension) desite adequate fluid resuscitation. Elderly atients were defined according to the World Health Organization as those aged 65 years. Early goal-directed theray All atients were resuscitated following the institutional rotocol for severe sesis and setic shock. The onset of treatment was defined as the time of severe sesis and setic shock diagnosis. Once a atient was diagnosed with severe sesis or setic shock, the 6-hour resuscitation bundle was initiated. This included blood samling with measurement of arterial lactate level, collection of blood cultures before antibiotics administration, broadsectrum antibiotics administration within 1 hour of the onset and a fluid load with crystalloids (20mL/kg) or equivalent doses of colloids. (5) The early goal-directed theray was alied to atients with severe sesis associated with arterial lactate levels 4.0mmol/L or those who remained hyotensive (systolic blood ressure <90mmHg or MAP <65mmHg) desite fluid resuscitation with crystalloids (20mL/kg) or equivalent doses of colloids. After the diagnosis of severe sesis or setic shock, the following

3 Comarative analysis of survival between elderly and non-elderly severe sesis and setic shock resuscitated atients 3 theraeutic goals were targeted during the first 6-hours of resuscitation: central venous ressure between 8 and 12mmHg (12 to 15mmHg in mechanically ventilated atients), MAP 65mmHg, central venous oxygen saturation (SvcO 2 ) or mixed venous (SvO 2 ) 70% and 65%, and diuresis 0.5mL/kg/h. Variables collected Demograhic data, number of comorbidities, location before ICU admission, number of new organ dysfunctions at severe sesis and setic shock diagnosis, source of infection, Acute Physiology and Chronic Health Evaluation II (APACHE) score, (15) need for vasoressors, invasive mechanical ventilation, amount of fluids administered, in-hosital and ICU length of stay, inhosital and mortality at day 28 were collected. Statistical analysis Categorical variables were resented as absolute and relative frequencies. Continuous variables were resented as mean and standard deviation (SD) when normally distributed and as median and interquartile range (IQR) when not normally distributed (tested by the Kolmogorov-Smirnov test). Patients were divided into two grous according to the age: elderly atients ( 65 years) and non-elderly atients (<65 years). Categorical data were comared between elderly and non-elderly atients with the χ 2 test or Fisher s exact test when aroriate. Continuous data were comared with the indeendent t test when normally distributed and with the Mann-Whitney U test in the case of non-normal distribution. A univariate logistic regression analysis was first erformed to identify which factors or redictors were associated with in-hosital mortality in all study atients and then only among the elderly atients. Predictors that showed a 0.20 in the univariate analysis were entered into the multivariate analysis. A multivariate logistic regression analysis with a backward elimination rocedure was undertaken to obtain an adjusted odds ratio () along with 95% confidence interval () and define which variables were indeendently associated with inhosital mortality between all study atients and then only among the elderly atients. Statistical tests were 2-sided and <0.05 was considered statistically significant. Statistical analyses were erformed using IBM Statistical Package for the Social Science (SPSS ) version 20.0 for Windows. RESULTS Patients This analysis included 848 atients admitted to the ICU with severe sesis or setic shock. Elderly atients accounted for 62.6% (531/848) of atients and nonelderly atients for 37.4% (317/848) of atients (Table 1). The median (IQR) age was, resectively, for elderly and nonelderly atients, 80 years (73-86) and 51 years (40-59), with < Table 1. Baseline characteristics of study articiants Characteristic <65 years 317 (37.4%) n (%) 65 years 531 (62.6%) n (%) Male sex 178 (56.2) 310 (58.4) Underlying disease Systemic hyertension 89 (28.1) 280 (52.9) <0.001 Diabetes mellitus 69 (21.8) 173 (32.7) Neolasms 73 (23.0) 146 (27.6) Congestive heart failure 12 (3.8) 73 (13.8) <0.001 Coronary insufficiency 18 (5.7) 72 (13.6) <0.001 COPD 7 (2.2) 67 (12.7) <0.001 Chronic renal failure 10 (3.2) 44 (8.3) Chronic renal failure RRT 12 (3.8) 30 (5.7) Liver cirrhosis 60 (18.9) 20 (3.8) <0.001 Solid organ translantation 66 (20.8) 14 (2.6) <0.001 HIV 3 (0.9) 1 (0.2) Number of comorbid conditions < (26.8) 75 (14.1) (34.4) 161 (30.3) 2 80 (25.2) 168 (31.7) 3 43 (13.6) 127 (23.9) Source of infection Resiratory tract 144 (45.4) 307 (57.8) <0.001 Urinary tract 51 (16.1) 85 (16.0) Abdominal 84 (26.5) 77 (14.5) <0.001 Skin and soft tissue 9 (2.8) 25 (4.7) Others 12 (3.8) 20 (3.8) Bloodstream 13 (4.1) 10 (1.9) Unknown 4 (1.3) 7 (1.3) Site of diagnosis, n (%) Emergency deartment 155 (48.9) 270 (50.8) Hosital floor 107 (33.8) 104 (19.6) <0.001 Intermediary care 18 (5.7) 93 (17.5) <0.001 Intensive care unit 33 (10.4) 61 (11.5) Other 4 (1.3) 3 (0.6) s are given by χ 2 test or Fisher s exact test for binary variables and Unaired test for continuous variables. COPD: chronic obstructive ulmonary disease; HIV: human immunodeficiency virus; RRT: renal relacement theray. Elderly atients were more likely to have systemic hyertension (52.9% versus 28.1%; <0.001), diabetes (32.7% versus 21.8%; =0.001), ischemic heart disease (13.6% versus 5.7%; <0.001), congestive heart failure (13.8% versus 3.8%; <0.001), chronic renal failure (8.3% versus 3.2%; =0.003) and chronic obstructive

4 4 Palomba H, Corrêa TD, Silva E, Pardini A, Assuncao MS ulmonary disease (12.7% versus 2.2%; <0.001) when comared to non-elderly atients. Solid organ translantation (20.8% versus 2.6%; <0.001) and liver cirrhosis (18.9% versus 3.8%; <0.001) were more frequent in non-elderly atients comared to elderly atients (Table 1). The main source of infection in elderly and nonelderly atients was the resiratory tract (57.8% versus 45.4%, for elderly and non-elderly atients; <0.001) while intra-abdominal infections were more common in non-elderly atients. Site of diagnosis The most common atient location at severe sesis and setic shock diagnosis was the emergency deartment, with no difference between elderly and non-elderly atients (50.8% versus 48.9%; =0.619) (Table 1). A large roortion of non-elderly atients were diagnosed on the hosital floor (33.8% versus 19.6%, for non-elderly and elderly atients; <0.001), while intermediary care was the most frequent site of diagnosis for elderly atients in comarison to nonelderly atients (17.5% versus 5.7%; <0.001) (Table 1). Clinical resentation The frequency of severe sesis (43.3% versus 44.5%, for elderly and non-elderly atients; =0.783) and setic shock (56.7% versus 55.5%, for elderly and nonelderly atients; =0.783) did not differ between the grous (Table 2). Elderly atients had a higher median Table 2. Clinical resentation of study atients Characteristic <65 years 65 years 317 (37.4%) 531 (62.6%) APACHE II score, median [IQR] 19 [15-24] 22 [18-28] <0.001 Arterial lactate (mmol/l), median [IQR] 2.4 [ ] 2.2 [ ] Severe sesis, n (%) 141 (44.5) 230 (43.3) Setic shock, n (%) 176 (55.5) 301 (56.7) Clinical resentation, n (%) Hyotension 229 (72.2) 384 (72.3) Lactate 4.0mmol/L 86 (27.7) 101 (19.7) Number of organ dysfunctions, median [IQR] 2 [2-4] 3 [2-3] Organ dysfunction, n (%) Circulatory 230 (72.6) 361 (68.0) Resiratory 181 (57.1) 325 (61.2) Renal 136 (42.9) 205 (38.6) CNS 92 (29.0) 181 (34.1) Heatic 19 (6.0) 17 (3.2) Metabolic 106 (33.4) 177 (33.3) Hematologic 93 (29.3) 130 (24.5) s are given by χ 2 test for binary variables and Mann-Whitney U test for continuous variables; APACHE II: Acute Physiology and Chronic Health Evaluation II (the score can range from zero to 71, with higher scores indicating more severe illness); IQR: interquartile range; CNS: central nervous system. (IQR) APACHE II score [22 (18-28) versus 19 (15-24); <0.001] comared to non-elderly atients, although the median number of new organ dysfunctions did not differ between the grous (=0.829). Administered treatments Comliance with the institutional rotocol for severe sesis and setic shock resuscitation has been ublished elsewhere. (3) The elderly atients received less fluid [median (IQR)] during the initial 6-hours of resuscitation than the non-elderly atients [1.8 (1.0 to 2.5) versus 2.0 (1.4 to 3.0) liters, for elderly and non-elderly atients; =0.001]. The need for vasoressors (58.8% versus 58.7, for elderly and non-elderly atients; =0.981) and mechanical ventilation (38.4% versus 38.2%, for elderly and non-elderly atients; =0.943) did not differ between the grous. Outcomes In-hosital mortality and mortality at day 28 did not differ between elderly and non-elderly severe sesis and setic shock atients (Table 3). The median (IQR) length of hosital stay was higher in elderly comared to non-elderly atients admitted with severe sesis [15 (8-34) versus 12 (6-24) days; =0.027] or setic shock [21 (11-47) versus 18 (9-36) days; =0.016]. The median length of ICU stay did not differ between elderly and non-elderly severe sesis and setic shock atients. Table 3. Mortality rates and length of intensive care unit and hosital stay Outcomes <65 years 317 (37.4%) 65 years 531 (62.6%) Severe sesis Mortality day 28, n (%) 13/135 (9.6) 33/217 (15.2) In-hosital mortality, n (%) 20/141 (14.2) 47/230 (20.4) Length of ICU stay (days), median [IQR] 3 [2-7] 3 [1-9] Length of hosital stay (days), median [IQR] 12 [6-24] 15 [8-34] Setic shock Mortality day 28, nº (%) 63/166 (38.0) 101/290 (34.8) In-hosital mortality, nº (%) 70/176 (39.8) 134/301(44.5) Length of ICU stay (days), median [IQR] 5 [2-12] 6 [3-13] Length of hosital stay (days), median [IQR] 18 [9-36] 21 [11-47] Severe sesis and setic shock Mortality day 28, n (%) 76/301 (25.2) 134/507 (26.4) In-hosital mortality, n (%) 90/317 (28.4) 181/531 (34.1) Length of ICU stay (days), median [IQR] 4 [2-10] 5 [2-11] Length of hosital stay (days), median [IQR] 14 [8-29] 18 [10-41] s are given by χ 2 test for binary variables and Mann-Whitney U test for continuous variables. ICU: intensive care unit; IQR: interquartile range. Predictors of death The univariate and multivariate logistic regression analysis addressing the redictors of death in all setic

5 Comarative analysis of survival between elderly and non-elderly severe sesis and setic shock resuscitated atients 5 atients and only among the elderly atients are resented in tables 4 and 5, resectively. Table 4. Univariate and multivariate logistic regression analysis addressing the main risk factors for in-hosital mortality including 848 severe sesis and setic shock atients Univariate analysis Multivariate analysis Characteristics Male sex Site of diagnosis Emergency deartment 1.00 Hosital floor < <0.001 Intermediary care < <0.001 Intensive care unit < <0.001 Liver cirrhosis < Urinary tract infection < APACHE II score < <0.001 Arterial lactate < <0.001 Number of organ dysfunction < Mechanical ventilation < APACHE II: Acute Physiology and Chronic Health Evaluation II (the score can range from zero to 71, with higher scores indicating more severe illness). : odds ratio; : 95% confidence interval. Table 5. Univariate and multivariate logistic regression analysis addressing the main risk factors for in-hosital mortality among the 531 elderly ( 65 years) atients Univariate analysis Multivariate analysis Characteristics Age, years < Male sex Site of diagnosis Emergency deartment 1.00 Hosital floor < Intermediary care < <0.001 Intensive care unit < Systemic hyertension Diabetes mellitus Abdominal infection APACHE II score < <0.001 Mechanical ventilation < Vasoressor administration < APACHE II: Acute Physiology and Chronic Health Evaluation II (the score can range from zero to 71, with higher scores indicating more severe illness). : odds ratio; : 95% confidence interval. The site of diagnosis, the resence of liver cirrhosis, APACHE II score, the arterial blood lactate level, the number of organ dysfunction and the need for mechanical ventilation were indeendently associated with increased risk of in-hosital death among severe sesis and setic shock atients. Increased age, the site of diagnosis, APACHE II score, the need for mechanical ventilation and vasoressor administration were indeendently associated with increased risk of inhosital death among elderly atients. DISCUSSION This study demonstrated that in-hosital and 28-day mortality rates were not different between elderly and non-elderly atients submitted to early goal-directed theray for the treatment of severe sesis and setic shock. However, increased age was an indeendent redictor of in-hosital death among elderly atients. Theraeutic goals included in the first 6 hours of resuscitation from the initial diagnosis of severe sesis and setic shock were achieved similarly in both grous. Nevertheless, less fluid for hemodynamic stabilization was administered to the elderly atients. Traditionally, elderly atients receive less intensive treatment comared to non-elderly atients, robably due to the ossibility of deleterious effects of an aggressive theray and fear of fluid overload. (16) Recently, increased accetance of comlex ICU interventions in older atients was associated with greater intensity of treatment and imroved survival. (10) This is erhas the result of increased exerience with the care of elderly atients over the years and technical imrovements such as rotocols associated with hemodynamic monitoring tools and continuous renal relacement theray, reresenting a true evolution in ractice throughout the times. Our results confirm these findings, as the roortion of elderly atients receiving mechanical ventilation and vasoressors was not different from that in younger atients. Our findings confirm the tolerance of elderly atients to an early goal-directed theray algorithm for severe sesis and setic shock resuscitation, with no differences in mortality comared to non-elderly atients. These results have imortant clinical imlications, since there is an increasing demand for ICU admission of elderly atients, which is often associated with high costs and limited availability of ICU beds worldwide. (7,17,18) Our results suort the concet that ICU admission and early goal-directed theray imlementation should not be denied to elderly atients showing severe sesis and setic shock. The imact of age itself on higher mortality rates due to sesis is not uniformly observed in eidemiological investigations. (11,19,20) Other retrosective analysis demonstrated that age was associated with a significantly increased risk of death in elderly atients with severe sesis or setic shock. (11,18) Nonetheless, these studies rely on administrative databases for sesis diagnosis, which may be inaccurate and lacking imortant asects such as adherence to the roosed treatment. Similarly, in our study, after adjustments for baseline atient s characteristics in a multivariable logistic regression

6 6 Palomba H, Corrêa TD, Silva E, Pardini A, Assuncao MS model, age was indeendently associated with increased risk of in-hosital mortality in elderly atients with severe sesis or setic shock. Most studies addressing mortality in setic atients have focused on short-term endoints. (4,12) Few observational studies have addressed the long-term rognosis of elderly severe sesis and setic shock atients submitted to early goal-directed theray. Lemay et al. reorted a 1-year mortality rate of 31% in elderly atients with severe sesis. (20) Nevertheless, adherence to secific theraeutic goals besides antibiotics administration was not reorted and the study relied on administrative database for sesis diagnosis. Similarly, Wang et al. described a 1-year mortality rate of 23% in a oulation of adults aged 45 or older, with sesis defined as hositalization or treatment in the emergency deartment for a serious infection with the resence of two or more systemic inflammatory resonse criteria, with no mention of ICU atients with severe sesis or setic shock. (21) Recently, it was shown that long-term survival in elderly atients with circulatory failure (including sesis) is oor, with mortality rates of 92 and 97% after 6 and 12 months, resectively. (13) These findings suort the hyothesis that excess longterm mortality ersists among those suffering from sesis, robably because sesis triggers an indeendent athohysiological rocess leading to early death. Resiratory infections accounted for the most sesis cases in elderly atients, whereas abdominal infections were the most common cause in younger atients, a finding which has not been confirmed by other authors, where resiratory infection was the major source of infection in both elderly and non-elderly atients. (11) A ossible exlanation for this interesting finding is the greater incidence of liver cirrhosis and solid organ translantation in younger atients, robably reflecting a high roortion of atients with sontaneous bacterial eritonitis. Our study has limitations. First, we were unable to evaluate the functional status before and after ICU discharge. Functional status has been related to re-existing underlying factors, and it lays a greater role than chronological age in the outcome of elderly atients with severe sesis and setic shock. (22) Second, this was a single center and retrosective study, which otentially limits the generalizability of our findings. Lastly, we used 65 as the cut-off age following the definition of elderly by World Health Organization. However, as ointed out earlier, the chronological age is not always reresentative of the functional condition of the atients. CONCLUSION In this study oulation of severe sesis and setic shock atients, early resuscitation of elderly atients was not associated with increase in mortality. Elderly atients with severe sesis or setic shock may benefit from aggressive resuscitation and advanced treatment modalities. However, rosective studies are warranted to address long-term imact of resuscitation maneuvers on functional status and quality of life. ACKNOWLEDGEMENTS We thank Débora Raquel de Melo for her assistance during the data acquisition and to Helena Salic for roof-reading this manuscrit. REFERENCES 1. Vincent JL, Marshall JC, Namendys-Silva SA, François B, Martin-Loeches I, Liman J, Reinhart K, Antonelli M, Pickkers P, Njimi H, Jimenez E, Sakr Y; ICON investigators. 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