Scholarly article on topic 'Management and outcome of mechanically ventilated patients after cardiac arrest'

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Academic research paper on topic "Management and outcome of mechanically ventilated patients after cardiac arrest"

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Management and outcome of mechanically ventilated patients after cardiac arrest

Critical Care (2015) 19:215

doi:10.1186/s13054-015-0922-9

Yuda Sutherasan (sutherasan_yuda@yahoo.com) Oscar Peñuelas (openuelas@gmail.com) Alfonso Muriel (alfonso.muriel@hrc.es) Maria Vargas (vargas.maria82@gmail.com) Fernando Frutos-Vivar (ffrutos@ucigetafe.com)

Iole Brunetti (ibrunetti@tin.it) Konstantinos Raymondos (raymondos@ards.eu) Davide D'Antini (davide.dantini@hotmail.it) Niklas Nielsen (niklas.nielsen@med.lu.se) Niall D Ferguson (n.ferguson@utoronto.ca) Bernd W Böttiger (bernd.boettiger@uk-koeln.de)

Arnaud W Thille (aw.thille@gmail.com) Andrew R Davies (andrew.davies@monash.edu) Javier Hurtado (jhurtado@hc.edu.uy) Fernando Rios (fernandrios@gmail.com) Carlos Apezteguía (capez@intramed.net) Damian A Violi (damianalejandro.violi@gmail.com) Nahit Cakar (cakarn@istanbul.edu.tr) Marco González (mga@une.net.co)

Bin Du (dubin98@gmail.com) Michael A Kuiper (mi.kuiper@wxs.nl) Marco Antonio Soares (marcreis@uai.com.br) Younsuck Koh (yskoh@amc.seoul.kr) Rui P Moreno (r.moreno@mail.telepac.pt) Pravin Amin (pamin@vsnl.com) Vinko Tomicic (vtomicic@alemana.cl) Luis Soto (lusoro@ctcinternet.cl) Hans-Henrik Bülow (hhbulow@dadlnet.dk) Antonio Anzueto (anzueto@uthscsa.edu) Andrés Esteban (aesteban@ucigetafe.com) Paolo Pelosi (ppelosi@hotmail.com) For the VENTILA GROUP

Published online: 08 May 2015

ISSN 1364-8535

Article type Research

Submission date 4 February 2015

Acceptance date 13 April 2015

Article URL http://dx.doi.org/10.1186/s13054-015-0922-9

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© 2015 Sutherasan et al. ; licensee BioMed Central This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.orq/licenses/bv/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.orq/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Management and outcome of mechanically ventilated patients after cardiac arrest

Yuda Sutherasan1,2

Email: sutherasan_yuda@yahoo.com

Oscar Peñuelas3

Email: openuelas@gmail.com

Alfonso Muriel4

Email: alfonso.muriel@hrc.es

Maria Vargas5

Email: vargas.maria82@gmail.com

Fernando Frutos-Vivar6 Email: ffrutos@ucigetafe.com

Iole Brunetti2 Email: ibrunetti@tin.it

Konstantinos Raymondos7 Email: raymondos@ards.eu

Davide D'Antini8

Email: davide.dantini@hotmail.it

Niklas Nielsen9

Email: niklas.nielsen@med.lu.se

Niall D Ferguson10

Email: n.ferguson@utoronto.ca

Bernd W Böttiger11

Email: bernd.boettiger@uk-koeln.de

Arnaud W Thille12 Email: aw.thille@gmail.com

Andrew R Davies13

Email: andrew.davies@monash.edu

Javier Hurtado14 Email: jhurtado@hc.edu.uy

Fernando Rios15

Email: fernandrios@gmail.com

Carlos Apezteguía15 Email: capez@intramed.net

Damian A Violi16

Email: damianalejandro.violi@gmail.com Nahit Cakar17

Email: cakarn@istanbul.edu.tr

Marco González18 Email: mga@une.net.co

Bin Du19

Email: dubin98@gmail.com

Michael A Kuiper20 Email: mi.kuiper@wxs.nl

Marco Antonio Soares Email: marcreis@uai.com.br

Younsuck Koh22

Email: yskoh@amc.seoul.kr

Rui P Moreno23

Email: r.moreno@mail.telepac.pt

Pravin Amin24 Email: pamin@vsnl.com

Vinko Tomicic25

Email: vtomicic@alemana.cl

Luis Soto26

Email: lusoro@ctcinternet.cl

Hans-Henrik Bülow27 Email: hhbulow@dadlnet.dk

Antonio Anzueto

Email: anzueto@uthscsa.edu

Andrés Esteban6

Email: aesteban@ucigetafe.com

Paolo Pelosi2*

Corresponding author Email: ppelosi@hotmail.com

For the VENTILA GROUP

1 Ramathibodi hospital, Mahidol University, Bangkok, Thailand

2 Department of Surgical Sciences and Integrated Diagnostics IRCCS AOU San Martino-IST, Largo Rosanna Benzi 8, Genoa 16131, Italy

3 Critical Care Department, Hospital Universitario de Getafe, Madrid, Spain

4 Biostatistics Unit, Ramón y Cajal Hospital Ramón y Cajal Institute and Research Health, IRYCIS, CIBERESP, Madrid, Spain

5 Department of Neuroscience and Reproductive and Odontostomatological Sciences, University of Naples "Federico II, Naples, Italy

6 Hospital Universitario de Getafe and CIBER Enfermedades Respiratorias, Madrid, Spain

7 Anaesthesiology and Intensive Care Medicine, Medical School Hanover, Carl-Neuberg-Strasse 1, D-30625 Hanover, Germany

8 Dipartimento di Anestesia, Rianimazione e Terapia Intensiva, Universita' degli Studi di Foggia, Foggia, Italy

9 Department of Anesthesia and Intensive Care, Intensive Care Unit, Helsingborg Hospital, S Vallgatan 5, 251 87 Helsingborg, Sweden

10 Interdepartmental Division of Critical Care Medicine, Department of Medicine, University of Toronto, University Health Network and Mount Sinai Hospital, Toronto, ON, Canada

11 Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Kerpener Straße 62, 50937 Köln, Germany

12 Cenre Hospitalier Universitaire de Poitiers, Réanimation Médicale, INSERM CIC 1402, Université de Poitiers, Poitiers, France

13 ANZIC-RC, Monash University, Melbourne, Australia

14 Hospital de Clínicas de Montevideo, Montevideo, Uruguay

15 Hospital Nacional Alejandro Posadas, Buenos Aires, Argentina

16 Hospital Interzonal General de Agudos Dr. Luis Güemes, Haedo, Argentina

17 Istanbul Medical Faculty, Anesthesiology and Intensive Care, Capa/Istanbul, Istanbul, Turkey

18 Clínica Medellín & Universidad Pontificia Bolivariana, Medellín, Colombia

19 Peking Union Medical College Hospital, Beijing, People's Republic of China

20 Medical Center Leeuwarden, Leeuwarden, The Netherlands

21 Hospital Universitário Sao José, Belo Horizonte, Brazil

22 Asan Medical Center, University of Ulsan, Seoul, Republic of Korea

23 Unidade de Cuidados Intensivos Polivalente, Hospital de Sao José, Centro Hospitalar, de Lisboa Central, Rua José Antonio Serrano, 1150-199 Lisbon, Portugal

24 Bombay Hospital Institute of Medical Sciences, Mumbai, India

25 Clínica Las Lilas de Santiago, Santiago, Chile

26 Instituto Nacional del Tórax de Santiago, Santiago, Chile

27 Holbaek Hospital, Region Zealand University of Copenhagen, Copenhagen, Denmark

28 South Texas Veterans Health Care System and University of Texas Health Science Center, San Antonio, Texas

Abstract

Introduction

The aim of this study was to describe and compare the changes in ventilator management and complications over time as well as variables associated with 28-day hospital mortality in patients receiving mechanical ventilation (MV) after cardiac arrest.

Methods

Secondary analysis of three prospective, observational multicenter studies conducted in 1998, 2004 and 2010 in 927 intensive care units (ICUs) from 40 countries. We screened 18,302 patients receiving MV for longer than 12 hours during a one-month period. We included 812 patients receiving MV after cardiac arrest. We collected demographics, daily ventilator settings, complications during ventilation and outcomes. Multivariate logistic regression analysis was performed to calculate odds ratios determining that which variables within 24 hours of hospital admission were associated with 28-day hospital mortality and the occurrence of ARDS and pneumonia acquired during ICU stay at 48 hours after admission.

Results

Among 812 patients, 100 were included from 1998, 239 from 2004 and 473 from 2010. Ventilatory management changed over time with decreased tidal volumes (Vt) [from a mean 8.9 (standard deviation 2) ml/kg actual body weight (ABW) in 1998 to 6.7(2) ml/kg ABW in 2010 and from 9(2.3) ml/kg predicted body weight (PBW) in 2004 to 7.95(1.7) ml/kg PBW in 2010] and increased positive end-expiratory pressure (PEEP) [from 3.5(3) in 1998 to 6.5(3) in 2010] (p <0.001). Patients included in 2010 had more sepsis, cardiovascular

dysfunction and neurologic failure but 28-day hospital mortality was similar over the time (52% in 1998, 57% in 2004 and 52% in 2010). Variables independently associated with 28-day hospital mortality were: older age, PaO2 < 60 mmHg, cardiovascular dysfunction and less use of sedative agents. Higher VT, and plateau pressure with lower PEEP were associated with the occurrence of ARDS and pneumonia acquired during ICU stay.

Conclusions

Protective mechanical ventilation with lower VT and higher PEEP is more commonly used after cardiac arrest. The incidence of pulmonary complications decreased, while other non-respiratory organ failures increased with time. The application of protective mechanical ventilation and the prevention of single and multiple organ failure may be considered to improve outcome in patients after cardiac arrest.

Introduction

Many studies in patients after cardiac arrest with return of spontaneous circulation (ROSC) focus on how to improve survival and neurological outcomes. Despite several interventions such as targeted temperature management (TTM) [1-4], vasopressor drugs [5], control of seizures and blood sugar level [6], poor neurologic outcome and mortality are still as high as 50% [4,7,8].

However, not only neurological damage, but also other organ failures should be considered. Roberts et al. reported that the highest cardiovascular and respiratory specific sequential organ failure assessment score (SOFA) score are associated with higher in-hospital mortality in 203 post-cardiac arrest patients [9] suggesting the value of hemodynamic and respiratory optimization. A recent study demonstrated that the outcomes of mechanically ventilated patients have improved over time [10]. The characteristics and the influence of ventilator settings, i.e. tidal volume and positive end expiratory pressure (PEEP) on organ failure and outcome of patients after cardiac arrest have not been described previously.

The main aim of this study was to describe and compare the changes in ventilator management and complications over time. Secondary objectives were to investigate the potential risk factors associated with 28-day hospital mortality and development of pulmonary complications, namely acute respiratory distress syndrome (ARDS) and pneumonia acquired during intensive care unit (ICU) stay, in patients without pre-existing lung injury at ICU admission.

Material and methods

Study design

Secondary analysis of three prospective observational cohort studies conducted in 1998 [11], 2004 [12] and 2010 [10] including adult patients (>18 year-old) who received mechanical ventilation for more than 12 hours and performed in 927 ICUs in 40 countries. National coordinators recruited local investigators from eligible ICUs. An additional file shows this in more detail (see Additional file 1). In order to minimize practice changes in response to observation, only the investigator and research coordinators at each site were aware of the

exact purpose and timing of the study in order to minimize practice changes in response to observation. The research ethics board of each participating institution approved the protocol and waived the need for informed consent [10-12]. Please see Additional file 1 for detail of each participant institution.

Protocol and data collection

For the purpose of this analysis, among 18,302 patients enrolled, we included 812 patients (4.4%) who received mechanical ventilation after ROSC post-cardiac arrest. The eligible patients were those receiving mechanical ventilation (MV) caused by developing sudden cessation of cardio-pulmonary function.

We collected baseline characteristics, blood gas measurements at ICU admission, daily ventilator settings, clinical management, blood gas measurements, characteristics, and observed complications while patients were ventilated or up to day 28. Patients' data were collected accordingly; ICU, in-hospital and 28-day mortality and length of stay outcomes. Detailed descriptions of the variables collected along with their definitions have previously been published [10-12]. In brief, complications arising during the course of the mechanical ventilation namely ARDS, pneumonia, sepsis, and multiorgan failure [cardiovascular, respiratory, renal, hepatic, and hematologic] defined as a score higher than 2 points in the Sequential Organ Failure Assessment). Pneumonia acquired during ICU stay was defined by modifying Centers for Disease Control and Prevention criteria which require a new radiographic infiltrate persistent for 48 hours or more plus a body temperature more than 38.5°C or less than 35.0°C, a leukocyte count of more than 10000/^L or less than 3000/^L, purulent sputum or change in character of sputum, or isolation of pathogenic bacteria from an endotracheal aspirate [11]. In the 1998 cohort, data on height and Glasgow Coma Score (GCS) were not collected; therefore no data regarding tidal volume/kg predicted body weight (PBW) were available in that group. The use of neuromuscular blocking agents, sedative and analgesic drugs had been recorded daily for 28 days when the drugs were given for > 3 hours daily. The onset of weaning was the time point when physician considered the patients ready for spontaneous ventilation. Weaning was categorized as a trial of spontaneous breathing and gradual reduction in the level of ventilator support. We recorded date of extubation, date of any reintubation, and tracheostomy, if and when performed. Patients were prospectively followed until hospital discharge.

Statistical analysis

Data are expressed as mean (standard deviation), median (interquartile range), and absolute and relative frequencies, as appropriate. One-way ANOVA were used to compare continuous variables, and Chi-square tests were used for categorical variables. We rejected the null hypothesis of no difference among cohorts at a nominal significance level of 0.05.

Multivariate logistic regression analysis (Backward stepwise) was performed to calculate odds ratios determining that which variables within 24 hours of hospital admission were associated with 28-day hospital mortality. The variables with p-value less than 0.1 in univariate analysis were included in multivariate analysis. Variables considered for inclusion in multivariate analysis associated with 28-day mortality were age, PaO2, arterial pH (pHa), use of sedative agents, cardiovascular dysfunction and renal failure during the first 24 hours of MV.

For the purpose of the analysis, we categorized pHa and PaO2 as the following; pHa <7.35, pHa 7.35-7.45 and pHa >7.45 according to the normal pHa range which is 7.35-7.45, PaO2 < 60 mmHg, PaO2 of 60-300 mmHg and PaO2 > 300 mmHg, respectively according to recent publications which demonstrated that PaO2 < 60 mmHg and PaO2 > 300 mmHg were independently associated with in hospital mortality [13-15]. We did not include GCS in the multivariate analysis because during MV with sedation, the GCS is unreliable. In addition, in 1998, GCS was not collected. Odds ratios with 95% confidence intervals were calculated for statistically significant variables to determine independent predictors of mortality. These analyses were performed using SPSS version 16.0.

The development of pulmonary complications, namely acute respiratory distress syndrome (ARDS) and pneumonia acquired during ICU stay, in patients without pre-existing lung injury at ICU admission were collected and we also performed the multivariate logistic regression analysis to determine which variables within 24 hours of hospital admission were associated with the occurrence of ARDS and pneumonia acquired during intensive care unit (ICU) stay at 48 hours after admission. We excluded the patients with diagnosed ARDS at admission. The variables considered for inclusion in the analysis were age, pHa, plateau pressure, PaO2 and sepsis during the first 24 hours of hospital admission.

Results

Characteristics of included patients and management during mechanical ventilation

In Table 1, baseline characteristics between the three cohorts are shown. Baseline characteristics including age, body mass index, gender and SAPS were not different across the cohort time periods. At admission the most significant difference was the lower GCS in patients included in 2010 vs. patients included in 2004 (in 1998 this variable was not registered).

Table 1 Baseline characteristics and management during mechanical ventilation of included patients

Cohort 1998 (N = 100) Cohort 2004 (N = 239) Cohort 2010 (N = 473) P

Age, years, mean (SD) 66(14) 63(16) 63(16) 0.261

Female, n (%) 37(37) 90(38) 174(37) 0.966

Body mass index, kg/cm2, mean (SD) n.a. 27(8) 27(7) 0.754

SAPS II, points, mean (SD) 61(19) 56(20) 59(20) 0.060

Glasgow Coma Score at admission, median (IQR) n.a. 6(3,15) 3(3,8) <0.001

Arterial blood gases at admission

pHa, mean (SD) 7.17(0.09) 7.23(0.20) 7.23(0.18) 0.003

PaCO2, mmHg, mean (SD) 50 (13) 48 (22) 50(23) 0.733

Ratio PaO2 to FiO2, mmHg, mean (SD) 249 (78) 233 (116) 221(186) 0.367

Ventilatory settings during mechanical ventilation

Tidal volume, ml/kg ABW, mean (SD) 8.9 (2) 7.4 (2) 6.7 (2) <0.001

Tidal volume /kg PBW mean(SD) n.a. 9.04(2.3) 7.95(1.7) <0.001

Respiratory rate, bpm, mean (SD) 17 (4) 18(6) 19 (6) <0.001

PEEP, cmH2O, mean (SD) 3.5(3) 4.8 (4) 6.5 (3) <0.001

Peak pressure, cmH2O, mean (SD) 29.1 (7.5) 27.1 (7.9) 24.1 (7.9) <0.001

Plateau pressure, cmH2O, mean (SD) 22.7(3.7) 21.5(6.5) 19.5(6.3) <0.001

PaCO2, , mmHg, mean (SD) 37.3(7.4) 38.8(10.4) 39.8(11.7) <0.001

pHa, mean (SD) 7.41(0.08) 7.39(0.1) 7..39(0.1) <0.001

Ratio PaO2 to FiO2, mmHg, mean (SD) 238(95) 242(95) 252(114) <0.05

Sedation, n (%) 50 (50) 175 (73) 332 (70) <0.001

Analgesia, n (%) 20 (20) n.a. 272 (58) <0.001

Neuromuscular blocking, n (%) 8 (8) 29 (12) 99 (21) <0.001

Abbreviations; n.a.: no data available, ABW: actual body weight; APRV/BIPAP: Airway pressure release ventilation/Biphasic positive airway pressure; IQR, interquartile range; PCV: Pressure controlled ventilation; PEEP, Positive End-expiratory Pressure; PRVC: Pressure regulated volume control; SAPS, Simplified Acute Physiology Score; SD, standard deviation; SIMV, Synchronized intermittent mandatory ventilation; ICU: Intensive Care Unit.

As shown in Figure 1, the mode of MV, expressed as days of use per 1000 days of invasive mechanical ventilation, changed over time with a significant increase of pressure support ventilation (PSV) and pressure regulated volume control (PRVC) and a significant decrease of other considered modes. Among ventilation settings over the years, we found a significant reduction in tidal volume, peak and plateau pressure and a significant increase of respiratory rate, PEEP and PaCO2. Sedation, analgesia and neuromuscular blocking were frequently used in 2010 (Table 1). At 24 hours after ICU admission, in patients with ARDS compared to those without ARDS at ICU admission, tidal volume and respiratory rate were similar [7.3(standard deviation1.8) ml/kg actual body weight (ABW) vs. 7.5(2) ml/kg ABW, p = 0.613 and 18.1(5.9) rate/min vs. 17.7(5.5) rate/min p = 0.658, respectively], while applied PEEP was higher [7.3(4.5) cmH2O vs. 5.2(3.1) cmH2O, p = 0.000].

Figure 1 Mode of ventilation and days of use per 1000 days of invasive mechanical ventilation from 1998, 2004 to 2010 (excluding days during weaning from mechanical ventilation process) ([light gray square symbol] 1998, [Black square symbol] 2004, [dark gray square symbol] 2010)*. Abbreviations: SIMV, synchronized intermittent mandatory ventilation; SIMV_PS, synchronized intermittent mandatory ventilation with pressure support; PSV, pressure support ventilation; PCV, pressure control ventilation; PRVC, pressure regulated volume control ventilation; APRV, airway pressure release ventilation; BIPAP, biphasic positive airway pressure. * Among three years, days of use per 1000 days of invasive mechanical ventilation in each mode of ventilation are statistically significant difference (p < 0.001)._

Complications during mechanical ventilation

As shown in Table 2, the incidence of pneumonia acquired during ICU stay decreased from 13% in 1998 to 4% in 2010(p = 0.001). In the meantime, other non-respiratory organ failures like sepsis, cardiovascular dysfunction, neurological and hepatic failure significantly increased.

Table 2 Comparison of complications emerged over the course of mechanical ventilation

Cohort 1998 (N = 100) Cohort 2004 (N = 239) Cohort 2010 (N = 473) P

Acute respiratory distress syndrome, n (%) 4 (4) 7 (3) 31 (7) 0.102

Acquired intensive care unit pneumonia, n (%) 13 (13) 14 (6) 18 (4) 0.001

Sepsis, n (%) 3 (3) 6 (6.5) 89 (19) <0.001

Barotrauma, n (%) 2 (2) 6 (3) 7 (2) 0.62

Cardiovascular failure, n (%) 25 (25) 46 (19) 229 (48) <0.001

Renal failure, n (%) 20 (20) 60 (25) 140 (30) 0.104

Hepatic failure, n (%) 2 (2) 30 (13) 24 (5) <0.001

Hematological failure, n (%) 11 (11) 17 (7) 31 (7) 0.296

Neurologic failure3

Glasgow coma scale, median (IQR) n.a. 4 (3,10) 3 (3,6) <0.001

aLowest Glasgow Coma Scale during the ventilatory support.

Abbreviations: n.a.: no data available, SD: standard deviation; IQR: interquartile range.

Withdrawal from mechanical ventilation

Table 3 demonstrates the characteristics of variables related to weaning process across the three cohort time periods. The percentage of patients who were weaned and extubated was similar over time (47% in 1998, 44% in 2004 and 45% in 2010; p = 0.856). Among weaning methods, spontaneous breathing trial (SBT) was more commonly used than gradual reduction of ventilator support. PSV was mostly used among gradual reduction of support methods and tended to increase (12.5% (1998), 78% (2004) and 38% (2010)). In SBT group, the most common method was low level PSV. Tracheostomy was performed in 13.8 %, overall and did not change significantly over time.

Table 3 Comparison of variables related to weaning process

Cohort 1998 (N = 100) Cohort 2004 (N = 239) Cohort 2010 (N = 473) P

Accidental extubation, n (%)a 3 (3) 6 (3) 29 (6) 0.062

Reintubation, % 67 33 14 0.074

Patients weaned and scheduled extubated, n (%) 47 (47) 104 (44) 211 (45) 0.856

Method for first attempt

Spontaneous breathing trial, n (%) 33 / 47 (70) 71 / 104 (68) 154 /211(73) 0.675

T-piece, % 48.5 38 36 0.022

CPAP, % 6 34 24

Low level pressure support, % 42 27 40

Other, % 3 1 0

Gradual reduction of support, n (%) 14 / 47 (30) 33 / 104 (32) 57 / 211 (27) 0.675

Pressure support, % 14 61 89 <0.001

SIMV, % 29 6 0

SIMV-PS, % 50 18 9

Other, % 7 15 2

Failure first weaning attempt, no (%) 24 / 47 (51) 45 /104 (43) 95 / 211 (45) 0.667

Method for weaning

Spontaneous breathing trial, n (%) 21 (87.5) 10 (22) 59 (62) <0.001

T-piece, % 67 40 36 0.049

CPAP, % 5 20 34

Low level pressure support, % 24 40 30

Other, % 5 0 0

Gradual reduction of support, n (%) 3 (12.5) 35 (78) 36 (38) <0.001

Pressure support, % 0 66 94 <0.001

SIMV, % 0 6 0

SIMV-PS, % 100 14 3

Other, % 0 14 3

Reintubation after scheduled extubation, % 11 7 11 0.426

Tracheotomy, n (%)a 12 (12) 30 (13) 66 (14.5) 0.758

a Excluded patients with prior tracheostomy: 1 patient in 1998, 7 patients in 2004 and 18 patients in 2010.

Abbreviations: SIMV, synchronized intermittent mandatory ventilation; SIMV-PS, synchronized intermittent mandatory ventilation with pressure support; PSV, pressure support ventilation; CPAP, continuous positive airway pressure.

Outcomes

We observed significant differences in the duration of ventilatory support over time with a longer duration of mechanical ventilation in the most recent study of 2010 (Table 4). There were no differences in length of stay in the intensive care unit or in the hospital (Table 4).

Table 4 Comparison of outcomes

Cohort 1998 Cohort 2004 Cohort 2010 P

(N = 100) (N = 239) (N = 473)

Days of mechanical ventilation, median (IQR)a 4 (3,7) 5 (3, 9) 6 (4, 10) <0.001

Length of stay in the intensive care unit, days, median (IQR) 7 (3,11) 6 (4, 12) 6 (3, 12) 0.925

Length of stay in the Hospital, days, median (IQR) 14 (7,27) 13 (6, 24) 12 (6, 26) 0.934

Mortality in the intensive care unit, n (%) 44 (44) 115 (48) 223 (49) 0.785

Mortality at day 28, n (%) 52 (52) 137 (57) 246 (52) 0.384

Mortality in the hospital, n (%) 57 (57) 143 (60) 259 (55) 0.434

a Including time devoted to weaning from mechanical ventilation. Abbreviation: IQR: interquartile range.

There was no difference in 28-day hospital mortality over time (52% in 1998, 57% in 2004 and 52% in 2010 (Table 4).

Factors associated with 28-day hospital mortality

Table 5 shows the univariate and logistic regression analysis for 28-day hospital mortality of cardiac arrest patients.

Table 5 Univariate and logistic regression analysis for 28 days mortality of cardiac arrest patients

Variable Univariate analysis Odd ratio(95%CI) p Logistic regression Odd ratio(95%CI) p

Age,yearsa 1.02(1.01-1.03) 0.002 1.01(1.00-1.03) 0.010

SAPS II score, pointsa 1.03(1.02-1.03) <0.001

Glascow coma scale, point b 0.92(0.88-0.95) <0.001

PaO2 60-300 mmHg b 1 (reference) 1 (reference)

PaO2 < 60 mmHg 2.23(1.05-4.72) 0.036 2.71(1.06-6.95) 0.038

PaO2 > 300 mmHg 1.19(0.76-1.85) 0.444 0.89(0.54-1.46) 0.640

pHa 7.35-7.45 b 1 (reference) 1 (reference)

Acidosis(pHa < 7.35) 1.48(1.07-2.04) 0.017 1.40(0.98-2.02) 0.068

Alkalosis(pHa > 7.45) 1.07(0.67-1.71) 0.770 1.20(0.71-2.02) 0.491

PaCO2 35-45 mmHg b 1 (reference)

PaCO2 < 35 mmHg 1.20(0.86-1.68) 0.277

PaCO2 > 45 mmHg 0.94(0.70-1.41) 0.973

Tidal Volume/PBWml/kg b

Tidal Volume /PBW 6-8 ml/kg 1(reference)

Tidal Volume /PBW < 6 ml/kg 1.01(0.51-2.02) 0.975

Tidal Volume /PBW > 8 ml/kg 0.76( 0.55- 1.06) 0.111

PEEP cmH2O b

PEEP 6-8 cmH2O 1 (reference)

PEEP < 6 cmH2O 1.35(0.94-1.95) 0.100

PEEP > 8 cmH20 0.86(0.52-1.42) 0.556

Pplat cmH2O b

Pplat 28-30 cmH2O 1 (reference)

Pplat < 28 cmH2O 0.58(0.28-1.22) 0.149

Pplat > 30 cmH2O 0.64(0.22-1.89) 0.421

Use of sedative drugsb 0.61(0.46-0.81) 0.001 0.51(0.36-0.72) 0.000

Cardiovascular failure/shock (yes/no) b,c 1.53(1.15-2.03) <0.001 1.65(1.17-2.32) 0.004

ARDS (yes/no) b,c 3.14(1.41-6.97) 0.005

Renal failure (yes/no) b,c 1.35(0 .95- 1.91) 0.095 1.34(0.91-1.95) 0.135

Hepatic failure (yes/no) b,c 1.20(0.72-2.00) 0.483

Sepsis (yes/no) ,c 1.38(0.88-2.18) 0.163

Hematologic failure (yes/no) b,c 1.05(0.51-2.17) 0.885

Legend. Abbreviations: SAPS, Simplified Acute Physiology Score; PBW, predicted body weight; ml, milliliters; kg, kilograms PEEP, positive end expiratory pressure; Pplat, plateau pressure ; pHa, arterial pH; ARDS, acute respiratory distress syndrome; PaO2, partial pressure of oxygen in arterial blood; PaCO2, partial pressure of carbon dioxide in arterial blood; CI, confidence interval.

aAge and SAPS score were collected as baseline characteristics ,b indicate the values within 24 hours from admission , c the absence of organ failure as the reference value.

In the multivariate analysis, older age, PaO2 < 60 mmHg, less use of sedative drugs and the presence of cardiovascular dysfunction within 24 hours from hospital admission were found to be associated with 28-day hospital mortality [odds ratio (OR) 1.01; 95% confidence interval (CI) 1.00-1.03, OR 2.71; 95% CI 1.06-6.95 OR 0.51; 95% CI 0.36-0.72) and OR 1.65; 95% CI 1.17-2.32], respectively].

Factors associated to ARDS and ICU-acquired pneumonia

At multivariate analysis, in patients without lung injury at admission, the potential risk factors for the development of ARDS 48 hours after ICU stay was higher plateau pressure (OR 1.12; 95% CI 1.04-1.21) while those associated with ICU pneumonia acquired during ICU stay were higher tidal volume and lower applied PEEP levels (OR 1.003; 95% CI 1.0003-1.01, OR 0.89; 95% CI 0.80-0.99, respectively.

Discussion

In this large retrospective analysis of prospective observational cohort, we described evolution of ventilator management, pulmonary and other non-respiratory organ failures over time. Furthermore, we investigated variables associated with 28-day hospital mortality and the occurrence of ARDS and/or pneumonia acquired during ICU stay among cardiac arrest patients undergoing MV. We found that: 1) the use of protective and assisted MV increased from 1998 to 2010; 2) pulmonary complications decreased while cardiovascular, neurological complications and sepsis increased with years; 3) independent risk factors for 28-day hospital mortality were older age, PaO2 < 60 mmHg, the less use of sedative drugs and the presence of cardiovascular dysfunction at 24 hours after ICU admission; and 4) in patients without lung injury at ICU admission, higher tidal volume, higher plateau pressure and lower PEEP in the first 24 hours were independent potential risk factors for developing ARDS or pneumonia acquired during ICU stay.

To our knowledge, this is the first study describing the ventilator management in a large sample of patients after cardiac arrest undergoing MV in ICU. Our results show that protective MV is increasingly used among patients after cardiac arrest. The implementation of protective MV was associated with a progressive reduction in pneumonia acquired during ICU stay over time and a lower incidence of ARDS than that reported in mechanically ventilated patients [16,17]. Similar changes in ventilation pattern have been recently shown in a general population of critically ill patients, associated with a reduction of development of ARDS [10,18]. Protective ventilation with low tidal volume has been shown to be associated with a reduction in respiratory failure and mortality in non-ARDS lung patients [19,20] and postoperative complications after surgery [21,22]. In donors, protective MV increased the number of lungs eligible to be harvested compared to traditional MV [23]. The application of PEEP ranging from 5-8 cmH2O in non-hypoxemic patients decreased the incidence of ventilator-associated pneumonia [24]. Moreover, protocols aimed to prevent ventilator-associated pneumonia have been more widely implemented in recent years [25,26]. On the other hand, we observed an increased incidence of non-pulmonary organ failure, namely sepsis, cardiovascular dysfunction and neurological failure, over time which may increase the duration of mechanical ventilation. The increase in non-pulmonary complications may be explained by the implementation of targeted temperature management protocols or by higher incidence of aspiration and thus, sicker patients [7], which might predispose to infection and consequent multiple organ failure [27]. The significant differences in the duration of

ventilatory support over time with a longer duration in the most recent study of 2010 is probably because of the implementation of targeted temperature management protocols and thus longer sedation.

A previous study demonstrated that changes in MV practice were associated with a significant decrease in mortality [10]. In post cardiac arrest patients, despite the introduction of temperature management, percutaneous coronary intervention and standard operating procedures, we did not observe any change in mortality over the years, likely due to the balance between the decreased pulmonary but increased extra-pulmonary complication incidences. We also found that the main independent predictors of 28-day in-hospital mortality were older age, PaO2 < 60 mmHg, the use of sedative drugs, and cardiovascular dysfuntion within 24 hours from admission, in line with previous reports [14,15].

In the present study, the analysis by Logistic regression demonstrated that the PaO2 < 60 mmHg as a predictor of 28-day hospital mortality. This result is different from previous meta-analysis showing that not only hypoxemia but also hyperoxemia are associated with higher in-hospital mortality [28]. The effects of high oxygen tension to increase neuronal damage after cardiac arrest are conflicting [13,14,29-31]. We also found that higher or lower PaCO2 level had no detectable association with mortality. This was different from previous studies showing that hypocarbia defined by PaCO2 < 35 mmHg was associated with higher in-hospital mortality [28,32] while hypercapnia defined by PaCO2 > 45 mmHg with better outcome [33,34].

Use of sedative drugs was associated with 28-days mortality in this cohort. This finding is in contrast to other studies showing that sedation protocols did not affect mortality in a general population of critically ill patients [35]. We have no completed value of GCS in three cohort years. The lower GCS on admission in the most recent cohort would indicate more severe brain injury and thus lower need for sedation with higher risk of death. On the other hand, our data suggest that higher sedation in the early phase after cardiac arrest might promote less secondary brain injury and better implementation of protective mechanical ventilation. Furthermore, the use of sedative drungs may be related to the implementation of therapeutic hypothermia which was associated with the improvement of outcome in ROSC patients [7,8].

In Table 1, 26%(63/239) of the patients in the 2004 study had a GCS of 15, our population are the study population included patients who developed cardiac arrest and needed mechanical ventilation due to sudden and unexpected cessation of cardiopulmonary functions in any rhythms. This is not the population included in target temperature management studies therefore we expect a higher percentage of patients awake upon arrival in ICU. Our study is comparable with the study by Gold et al. [36] in patients with out of hospital cardiac arrest of any rhythm demonstrated that of the 185 survivors, 96 patients (50%) were sufficiently awake upon arrival to the intensive care unit so they did not meet the TTM protocol inclusion criteria but data of GCS were not reported.

In our study, we evaluated the potential independent risk factors for development of pulmonary complications in patients without pre-existing lung injury at ICU admission. We found that higher tidal volume, higher plateau pressure with lower PEEP were associated with occurrence of lung worsening during ICU stay. These findings are in line with those reported in patients without lung injury in the perioperative period [19-22] and in ICU [19] showing that protective ventilation by low tidal volume and plateau pressure < 20 cmH2O

resulted in a decreased incidence of pulmonary complications after initiation of mechanical ventilation [19-22,37].

We also found that tidal volume was similar, while PEEP was slightly higher in patients with ARDS compared to those without ARDS at ICU admission. This suggests that, protective ventilation should include lower tidal volume than actually used in daily clinical practice in cardiac arrest patients with ARDS.

The use of controlled MV decreased while pressure support increased with years. The use of assisted ventilation may be associated with potential advantages like the use of less sedative agents [38-40], better hemodynamic stability [39,40], less atrophy of respiratory muscles [41] and ventilator associated lung injury [42,43]. The rate of tracheostomy was 12-14.5 % higher than that reported in a general population of critically ill patients (11%) [12] and comparable to that reported in neurologic patients (13%) [44]. This might be explained by the possible occurrence of residual neurological deficits in cardiac arrest patients due brain hypoxia impairing cough, swallowing and secretion clearance [45].

Our study has some limitations. First, this was a post-hoc analysis of previously collected available data where the statistically significant predictors of mortality might have been influenced by undefined confounding factors, i.e. site, cause, and initial rhythm of the cardiac arrest. A statistical post-hoc analysis on 28-days hospital mortality has been performed to assess the power of mortality variation among the years and showed a power < 50%, so the variation of mortality over years should be interpreted with caution. Second, our study focused on the details related to mechanical ventilation. Thus we did not record possible implementation of targeted temperature management, including patients after cardiac arrest due to cardiac and non-cardiac causes [46]. However, a recent study showed that moderate hypothermia compared to mild hypothermia did not affect mortality [4]. Third, we did not include GCS in the multivariate analysis since the evaluation of GCS is not reliable within the first 72 hours during MV with sedation and data were not collected in 1998. The lower GCS on admission in the most recent cohort would indicate more severe brain injury and thus lower need for sedation and higher risk of death. Fourth, we also did not have access to cardiac arrest related variables like whether the arrest was witnessed or not, whether bystander cardiopulmonary resuscitation was performed, initial presenting rhythm, and the time of resuscitation commencement or return of spontaneous circulation. Fifth, in the multivariate logistic regression analysis defining risk factors associated with 28-days hospital mortality and the development of ARDS and/or pneumonia acquired in ICU, we used data collected within 24 hours after admission, therefore with very few missing data. Nevertheless, we used variables regardless of the different years which might have been affected by the change of clinical management and the number of patients with development of ARDS and/or pneumonia acquired in ICU is a small portion of the whole population (5 % of the total population). For this reason, the results of multivariate analysis should be interpreted with caution.

Conclusions

Protective mechanical ventilation with lower VT and higher PEEP is more commonly used after cardiac arrest. The incidence of pulmonary complications decreased, while other nonrespiratory organ failures increased with time. The application of protective mechanical ventilation and the prevention of single and multiple organ failure may be considered to improve outcome in patients after cardiac arrest.

Key messages

• The use of protective mechanical ventilation in patients after cardiac arrest increased from 1998 to 2010 and is associated with a decrease of pulmonary complications.

• Variables independently associated with 28-day hospital mortality were: older age, PaO2 < 60 mmHg, cardiovascular dysfunction and less use of sedative agents

• The application of protective mechanical ventilation and the prevention of single and multiple organ failures may be considered to improve outcome in patients after cardiac arrest.

Abbreviations

ABW, Actual body weight; ARDS, Acute respiratory distress syndrome; CI, Confidence interval; GCS, Glasgow Coma Score; GEE, Generalized estimating equation; ICUs, Intensive care unit; MV, Mechanical ventilation; OR, Odds ratio; PBW, Predicted body weight; PEEP, Positive end-expiratory pressure; PRVC, Pressure regulated volume control; PSV, Pressure support ventilation; ROSC, Return of spontaneous circulation; SAPS, Simplified acute physiology score; SOFA, Sequential organ failure assessment score; TTM, Targeted temperature management; VT, Tidal volumes.

Competing interests

Dr. Bernd W. Bottiger is a director of Science and Research of European Resuscitation Council. Dr. Niklas Nielsen received payment for lecture from BARD medical(not related to current article) Dr. Pravin Amin is the consultant of CIPLA, was the consultant of Boehringer Ingelheim and Smiths Medical and received payment for lecture from MSD, Fresenius Kabi and Aventis (not related to current article). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Authors' contributions

YS was responsible for conception and design, analysing and interpretation, manuscript writing and final approval of the manuscript. OP, FF and AE were responsible for conception and design, data interpretation, and final approval of the manuscript. AM was responsible for data analysis and interpretation. MV, IB and DD were responsible for data analysis and interpretation, and final approval of the manuscript. NN, NF, and BB were responsible for manuscript writing, review of the manuscript, study design, and analysis of the data. KR, AT, AD, JH, FR, CA, DV, NC, MG, BD, MK, AS, YK, RM, PA, VT, LS, HB, and AA were responsible for data acquisition and review of the manuscript. PP was responsible for conception and design, data interpretation, manuscript writing and final approval of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We are grateful to all investigators of the VENTILA study group for collecting data for this article (see Additional file 1).

The VENTILA study was supported by Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III. Madrid, Spain. Dr.Ferguson is supported by a Canadian Institutes of Health Research New Investigator Award (Ottawa, Canada). The funding organizations had no role in the design or conduct of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript.

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Addtional files provided with this submission:

Additional file 1. Participants in three international cohort studies on mechanical ventilation (1998, 2004 and 2010). National coordinators recruited local investigators from eligible intensive care units. The research ethics board of each participating institution approved the protocol and waived the need for informed consent (195kb) http://ccforum.com/content/supplementary/s13054-015-0922-9-s 1 .pdf