Giuseppe
Emeritus
[Source: JAMA, full page: (LINK). Abstract, edited.]
Online First
Original Investigation | October 08, 2013 Caring for the Critically Ill Patient
Induced Hypothermia in Severe Bacterial Meningitis: A Randomized Clinical Trial
FREE ONLINE FIRST
Bruno Mourvillier, MD<SUP>1</SUP>; Florence Tubach, MD<SUP>2</SUP>; Diederik van de Beek, MD<SUP>3</SUP>; Denis Garot, MD<SUP>4</SUP>; Nicolas Pichon, MD<SUP>5</SUP>; Hugues Georges, MD<SUP>6</SUP>; Laurent Martin Lefevre, MD<SUP>7</SUP>; Pierre-Edouard Bollaert, MD<SUP>8</SUP>; Thierry Boulain, MD<SUP>9</SUP>; David Luis, MD<SUP>10</SUP>; Alain Cariou, MD<SUP>11</SUP>; Patrick Girardie, MD<SUP>12</SUP>; Riad Chelha, MD<SUP>13</SUP>; Bruno Megarbane, MD<SUP>14</SUP>; Arnaud Delahaye, MD<SUP>15</SUP>; Ludivine Chalumeau-Lemoine, MD<SUP>16 </SUP>; St?phane Legriel, MD<SUP>17</SUP>; Pascal Beuret, MD<SUP>18 </SUP>; Fran?ois Brivet, MD<SUP>19</SUP>; C?dric Bruel, MD<SUP>20</SUP>; Fabrice Camou, MD<SUP>21</SUP>; Delphine Chatellier, MD<SUP>22</SUP>; Patrick Chillet, MD<SUP>23</SUP>; Bernard Clair, MD<SUP>24</SUP>; Jean-Michel Constantin, MD<SUP>25</SUP>; Alexandre Duguet, MD<SUP>26</SUP>; Richard Galliot, MD<SUP>27</SUP>; Fr?d?rique Bayle, MD<SUP>28</SUP>; Herv? Hyvernat, MD<SUP>29</SUP>; Kader Ouchenir, MD<SUP>30</SUP>; Gaetan Plantefeve, MD<SUP>31</SUP>; Jean-Pierre Quenot, MD<SUP>32</SUP>; Jack Richecoeur, MD<SUP>33</SUP>; Carole Schwebel, MD<SUP>34</SUP>; Michel Sirodot, MD<SUP>35</SUP>; Marina Esposito-Far?se, PhD<SUP>2</SUP>; Yves Le Tulzo, MD<SUP>36</SUP>; Michel Wolff, MD<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: <SUP>1</SUP>R?animation M?dicale et Infectieuse, Assistance Publique-H?pitaux de Paris, Groupe Hospitalier Bichat-Claude Bernard, Universit? Paris Diderot, Sorbonne Paris Cit?, Paris, France <SUP>2</SUP>D?partement d?Epid?miologie et Recherche Clinique, Assistance Publique-H?pitaux de Paris Hopital Bichat, INSERM, CIE 801, Universit? Paris Diderot, Sorbonne Paris Cit?, Paris, France <SUP>3</SUP>Department of Neurology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands <SUP>4</SUP>Service de R?animation M?dicale, Centre Hospitalier Universitaire de Tours?H?pital Bretonneau, Tours, France <SUP>5</SUP>R?animation Medico-Chirurgicale, Centre Hospitalier Universitaire Dupuytren, Limoges Cedex, Cedex, France <SUP>6</SUP>R?animation Polyvalente et Maladies Infectieuses, Centre Hospitalier Universitaire de Tourcoing, Tourcoing, France <SUP>7</SUP>Centre Hospitalier Departemental Les Oudaries, Service de R?animation Polyvalente, La Roche-sur-Yon, France <SUP>8</SUP>Centre Hospitalier Universitaire de Nancy, Hopital Central, Service de R?animation M?dicale, Nancy, France <SUP>9</SUP>Service de R?animation Polyvalente, Centre Hospitalier Regional Orl?ans, Orl?ans, France <SUP>10</SUP>Service de R?animation M?dico-Chirurgicale, Centre Hospitalier Universitaire Jean Verdier, Assistance Publique-H?pitaux de Paris, Bondy, France <SUP>11</SUP>Service de R?animation M?dicale, Paris, France, Centre Hospitalier Universitaire Cochin-Saint-Vincent de Paul-Site Cochin, Assistance Publique-H?pitaux de Paris, Paris, France <SUP>12</SUP>Service de R?animation Polyvalente, Centre Hospitalier Regional Universitaire de Lille-H?pital Roger Salengro, Lille, France <SUP>13</SUP>Service de R?animation Polyvalente, Centre Hospitalier Intercommunal Andr? Gr?goire Montreuil, Montreuil, France <SUP>14</SUP>Service de R?animation M?dicale et Toxicologique, Centre Hospitalier Universitaire Lariboisi?re Assistance Publique-H?pitaux, Paris, France <SUP>15</SUP>Service de R?animation Polyvalente, Centre Hospitalier, Rodez, France <SUP>16 </SUP>Service de R?animation M?dico-Chirurgicale, Assistance Publique-H?pitaux de Paris, Centre Hospitalier Universitaire Tenon, Paris, France <SUP>17</SUP>Service de R?animation, Centre Hospitalier de Versailles, Le Chesnay, France <SUP>18 </SUP>Service de R?animation M?dico-Chirurgicale, Centre Hospitalier, Roanne, Fance <SUP>19</SUP>R?animation M?dicale Centre Hospitalier Universitaire Antoine Becl?re, Assistance Publique-H?pitaux de Paris, Clamart, France <SUP>20</SUP>Service de R?animation Polyvalente, Groupe Hospitalier Paris Saint-Joseph, Paris, France <SUP>21</SUP>R?animation M?dicale, H?pital Saint Andr?, Centre Hospitalier Universitaire, Bordeaux, France <SUP>22</SUP>Service de R?animation Medicale, Centre Hospitalier Universitaire , Poitiers, France <SUP>23</SUP>Service de R?animation Polyvalente, Centre Hospitalier, Ch?lons-en-Champagne, France <SUP>24</SUP>Service de R?animation M?dico-Chirurgicale, Assistance Publique-H?pitaux de Paris, Garches, France <SUP>25</SUP>Service de R?animation Adultes and USC, Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France <SUP>26</SUP>Service de Pneumologie et R?animation M?dicale, Centre Hospitalier Universitaire La Piti?-Salp?tri?re Assistance Publique-H?pitaux de Paris, Paris, France <SUP>27</SUP>R?animation Polyvalente, H?pital Foch, Suresnes, France <SUP>28</SUP>Service de R?animation M?dicale et Respiratoire, Centre Hospitalier Universitaire H?pital de la Croix Rousse, Lyon, France <SUP>29</SUP>Service de R?animation M?dicale, H?pital de l?Archet, Nice, France <SUP>30</SUP>R?animation Polyvalente, Les H?pitaux de Chartres, Chartres, France <SUP>31</SUP>Service de R?animation Polyvalente, Centre Hospitalier, d'Argenteuil, France <SUP>32</SUP>Service de R?animation M?dicale, Centre Hospitalier Universitaire, Dijon, France <SUP>33</SUP>Service de R?animation M?dico-Chirurgicale, CH Ren? Dubos, Pontoise, France <SUP>34</SUP>Service de R?animation M?dicale, Centre Hospitalier Universitaire H?pital A. Michallon, La Tronche, France <SUP>35</SUP>Service de R?animation Polyvalente, Centre Hospitalier de la R?gion d?Annecy, Pringy, France <SUP>36</SUP>Service de R?animation M?dicale et Infectieuse, Centre Hospitalier Universitaire H?pital Pontchaillou, Rennes, France
JAMA. Published online October 08, 2013. doi:10.1001/jama.2013.280506
ABSTRACT
Importance
Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia.
Objective
To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis.
Design, Setting, and Patients
An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009?November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized.
Interventions
Hypothermia group received a loading dose of 4?C cold saline and were cooled to 32?C to 34?C for 48 hours. The rewarming phase was passive. Controls received standard care.
Main Outcomes and Measures
Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients.
Results
After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3?C (0.9?C) and 37.0?C (0.9?C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977).
Conclusions and Relevance
Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke.
Trial Registration clinicaltrials.gov Identifier: NCT00774631
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------
Online First
Original Investigation | October 08, 2013 Caring for the Critically Ill Patient
Induced Hypothermia in Severe Bacterial Meningitis: A Randomized Clinical Trial
FREE ONLINE FIRST
Bruno Mourvillier, MD<SUP>1</SUP>; Florence Tubach, MD<SUP>2</SUP>; Diederik van de Beek, MD<SUP>3</SUP>; Denis Garot, MD<SUP>4</SUP>; Nicolas Pichon, MD<SUP>5</SUP>; Hugues Georges, MD<SUP>6</SUP>; Laurent Martin Lefevre, MD<SUP>7</SUP>; Pierre-Edouard Bollaert, MD<SUP>8</SUP>; Thierry Boulain, MD<SUP>9</SUP>; David Luis, MD<SUP>10</SUP>; Alain Cariou, MD<SUP>11</SUP>; Patrick Girardie, MD<SUP>12</SUP>; Riad Chelha, MD<SUP>13</SUP>; Bruno Megarbane, MD<SUP>14</SUP>; Arnaud Delahaye, MD<SUP>15</SUP>; Ludivine Chalumeau-Lemoine, MD<SUP>16 </SUP>; St?phane Legriel, MD<SUP>17</SUP>; Pascal Beuret, MD<SUP>18 </SUP>; Fran?ois Brivet, MD<SUP>19</SUP>; C?dric Bruel, MD<SUP>20</SUP>; Fabrice Camou, MD<SUP>21</SUP>; Delphine Chatellier, MD<SUP>22</SUP>; Patrick Chillet, MD<SUP>23</SUP>; Bernard Clair, MD<SUP>24</SUP>; Jean-Michel Constantin, MD<SUP>25</SUP>; Alexandre Duguet, MD<SUP>26</SUP>; Richard Galliot, MD<SUP>27</SUP>; Fr?d?rique Bayle, MD<SUP>28</SUP>; Herv? Hyvernat, MD<SUP>29</SUP>; Kader Ouchenir, MD<SUP>30</SUP>; Gaetan Plantefeve, MD<SUP>31</SUP>; Jean-Pierre Quenot, MD<SUP>32</SUP>; Jack Richecoeur, MD<SUP>33</SUP>; Carole Schwebel, MD<SUP>34</SUP>; Michel Sirodot, MD<SUP>35</SUP>; Marina Esposito-Far?se, PhD<SUP>2</SUP>; Yves Le Tulzo, MD<SUP>36</SUP>; Michel Wolff, MD<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: <SUP>1</SUP>R?animation M?dicale et Infectieuse, Assistance Publique-H?pitaux de Paris, Groupe Hospitalier Bichat-Claude Bernard, Universit? Paris Diderot, Sorbonne Paris Cit?, Paris, France <SUP>2</SUP>D?partement d?Epid?miologie et Recherche Clinique, Assistance Publique-H?pitaux de Paris Hopital Bichat, INSERM, CIE 801, Universit? Paris Diderot, Sorbonne Paris Cit?, Paris, France <SUP>3</SUP>Department of Neurology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands <SUP>4</SUP>Service de R?animation M?dicale, Centre Hospitalier Universitaire de Tours?H?pital Bretonneau, Tours, France <SUP>5</SUP>R?animation Medico-Chirurgicale, Centre Hospitalier Universitaire Dupuytren, Limoges Cedex, Cedex, France <SUP>6</SUP>R?animation Polyvalente et Maladies Infectieuses, Centre Hospitalier Universitaire de Tourcoing, Tourcoing, France <SUP>7</SUP>Centre Hospitalier Departemental Les Oudaries, Service de R?animation Polyvalente, La Roche-sur-Yon, France <SUP>8</SUP>Centre Hospitalier Universitaire de Nancy, Hopital Central, Service de R?animation M?dicale, Nancy, France <SUP>9</SUP>Service de R?animation Polyvalente, Centre Hospitalier Regional Orl?ans, Orl?ans, France <SUP>10</SUP>Service de R?animation M?dico-Chirurgicale, Centre Hospitalier Universitaire Jean Verdier, Assistance Publique-H?pitaux de Paris, Bondy, France <SUP>11</SUP>Service de R?animation M?dicale, Paris, France, Centre Hospitalier Universitaire Cochin-Saint-Vincent de Paul-Site Cochin, Assistance Publique-H?pitaux de Paris, Paris, France <SUP>12</SUP>Service de R?animation Polyvalente, Centre Hospitalier Regional Universitaire de Lille-H?pital Roger Salengro, Lille, France <SUP>13</SUP>Service de R?animation Polyvalente, Centre Hospitalier Intercommunal Andr? Gr?goire Montreuil, Montreuil, France <SUP>14</SUP>Service de R?animation M?dicale et Toxicologique, Centre Hospitalier Universitaire Lariboisi?re Assistance Publique-H?pitaux, Paris, France <SUP>15</SUP>Service de R?animation Polyvalente, Centre Hospitalier, Rodez, France <SUP>16 </SUP>Service de R?animation M?dico-Chirurgicale, Assistance Publique-H?pitaux de Paris, Centre Hospitalier Universitaire Tenon, Paris, France <SUP>17</SUP>Service de R?animation, Centre Hospitalier de Versailles, Le Chesnay, France <SUP>18 </SUP>Service de R?animation M?dico-Chirurgicale, Centre Hospitalier, Roanne, Fance <SUP>19</SUP>R?animation M?dicale Centre Hospitalier Universitaire Antoine Becl?re, Assistance Publique-H?pitaux de Paris, Clamart, France <SUP>20</SUP>Service de R?animation Polyvalente, Groupe Hospitalier Paris Saint-Joseph, Paris, France <SUP>21</SUP>R?animation M?dicale, H?pital Saint Andr?, Centre Hospitalier Universitaire, Bordeaux, France <SUP>22</SUP>Service de R?animation Medicale, Centre Hospitalier Universitaire , Poitiers, France <SUP>23</SUP>Service de R?animation Polyvalente, Centre Hospitalier, Ch?lons-en-Champagne, France <SUP>24</SUP>Service de R?animation M?dico-Chirurgicale, Assistance Publique-H?pitaux de Paris, Garches, France <SUP>25</SUP>Service de R?animation Adultes and USC, Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France <SUP>26</SUP>Service de Pneumologie et R?animation M?dicale, Centre Hospitalier Universitaire La Piti?-Salp?tri?re Assistance Publique-H?pitaux de Paris, Paris, France <SUP>27</SUP>R?animation Polyvalente, H?pital Foch, Suresnes, France <SUP>28</SUP>Service de R?animation M?dicale et Respiratoire, Centre Hospitalier Universitaire H?pital de la Croix Rousse, Lyon, France <SUP>29</SUP>Service de R?animation M?dicale, H?pital de l?Archet, Nice, France <SUP>30</SUP>R?animation Polyvalente, Les H?pitaux de Chartres, Chartres, France <SUP>31</SUP>Service de R?animation Polyvalente, Centre Hospitalier, d'Argenteuil, France <SUP>32</SUP>Service de R?animation M?dicale, Centre Hospitalier Universitaire, Dijon, France <SUP>33</SUP>Service de R?animation M?dico-Chirurgicale, CH Ren? Dubos, Pontoise, France <SUP>34</SUP>Service de R?animation M?dicale, Centre Hospitalier Universitaire H?pital A. Michallon, La Tronche, France <SUP>35</SUP>Service de R?animation Polyvalente, Centre Hospitalier de la R?gion d?Annecy, Pringy, France <SUP>36</SUP>Service de R?animation M?dicale et Infectieuse, Centre Hospitalier Universitaire H?pital Pontchaillou, Rennes, France
JAMA. Published online October 08, 2013. doi:10.1001/jama.2013.280506
ABSTRACT
Importance
Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia.
Objective
To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis.
Design, Setting, and Patients
An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009?November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized.
Interventions
Hypothermia group received a loading dose of 4?C cold saline and were cooled to 32?C to 34?C for 48 hours. The rewarming phase was passive. Controls received standard care.
Main Outcomes and Measures
Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients.
Results
After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3?C (0.9?C) and 37.0?C (0.9?C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977).
Conclusions and Relevance
Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke.
Trial Registration clinicaltrials.gov Identifier: NCT00774631
-
------