Severe and multiple hypoglycemic episodes are associated with increased risk of death in ICU patients

Pierre Kalfon, Yannick Le Manach, Carole Ichai, Nicolas Bréchot, Raphaël Cinotti, Pierre-François Dequin, Béatrice Riu-Poulenc, Philippe Montravers, Djilalli Annane, Hervé Dupont, Michel Sorine, Bruno Riou, CGAO-REA Study Group, Hervé Dupont, François Tinturier, Alexandre Ouattara, Catherine Fleureau, Hadrien Roze, David Osman, François Richard, Alexandre Avenel, Roland Amathieu, Anne-Sophie Le Floch, Jean-François Loriferne, Olivier Gontier, Teodora Cirilovic, Pierre Kalfon, Michel Hira, Patrick Blanchet, Alexandre Conia, Virginie Maxime, Djillali Annane, Maud Fiancette, Jean Reignier, Christophe Lenclud, Eric Barré, Emmanuel Cantais, Lionel Velly, Nicolas Bruder, Thomas Signouret, Xavier Capdevila, Jonathan Charbit, Karim Lakhal, Jean-Marc Delay, Samir Jaber, Gérald Chanques, Raphaël Cinotti, Bertrand Rozec, Jean-Christophe Rigal, Carole Ichai, Jean-Christophe Orban, Guillaume Dufour, Philippe Montravers, Mathieu Desmard, Bruno Mourvillier, Nicoals Brechot, Jean Chastre, Antoine Landivier, Julien Mayaux, Alexandre Duguet, Paul Bonneil, Jean-Noël Drault, William Picard, Eric Boulet, Jack Richecoeur, Gaëlle Demeilllers-Pfister, Philippe Gouin, Benoit Veber, Thierry De Lentdecker, Mathieu Debauchez, Richard Galliot, Anne-Gaëlle Si Larbi, Florent Perin-Dureau, Gaëlle Corno, Jacques Durand-Gassselin, Béatrice Riu-Poulenc, Michèle Genestal, Pierre Cougot, Hélène Gonzalez, Pierre-François Dequin, Stéphane Ehrmann, Denis Garrot, Emmanuelle Mercier, Mathieu Henri-Lagarrigue, Jean-Pierre Bedos, Bruno Riou, Pierre Kalfon, Djillali Annane, Jean Chastre, Pierre-François Dequin, Hervé Dupont, Bruno Giraudeau, Alexandre Guerrini, Carole Ichai, Philippe Montravers, Michel Sorine, Pierre Kalfon, Yannick Le Manach, Carole Ichai, Nicolas Bréchot, Raphaël Cinotti, Pierre-François Dequin, Béatrice Riu-Poulenc, Philippe Montravers, Djilalli Annane, Hervé Dupont, Michel Sorine, Bruno Riou, CGAO-REA Study Group, Hervé Dupont, François Tinturier, Alexandre Ouattara, Catherine Fleureau, Hadrien Roze, David Osman, François Richard, Alexandre Avenel, Roland Amathieu, Anne-Sophie Le Floch, Jean-François Loriferne, Olivier Gontier, Teodora Cirilovic, Pierre Kalfon, Michel Hira, Patrick Blanchet, Alexandre Conia, Virginie Maxime, Djillali Annane, Maud Fiancette, Jean Reignier, Christophe Lenclud, Eric Barré, Emmanuel Cantais, Lionel Velly, Nicolas Bruder, Thomas Signouret, Xavier Capdevila, Jonathan Charbit, Karim Lakhal, Jean-Marc Delay, Samir Jaber, Gérald Chanques, Raphaël Cinotti, Bertrand Rozec, Jean-Christophe Rigal, Carole Ichai, Jean-Christophe Orban, Guillaume Dufour, Philippe Montravers, Mathieu Desmard, Bruno Mourvillier, Nicoals Brechot, Jean Chastre, Antoine Landivier, Julien Mayaux, Alexandre Duguet, Paul Bonneil, Jean-Noël Drault, William Picard, Eric Boulet, Jack Richecoeur, Gaëlle Demeilllers-Pfister, Philippe Gouin, Benoit Veber, Thierry De Lentdecker, Mathieu Debauchez, Richard Galliot, Anne-Gaëlle Si Larbi, Florent Perin-Dureau, Gaëlle Corno, Jacques Durand-Gassselin, Béatrice Riu-Poulenc, Michèle Genestal, Pierre Cougot, Hélène Gonzalez, Pierre-François Dequin, Stéphane Ehrmann, Denis Garrot, Emmanuelle Mercier, Mathieu Henri-Lagarrigue, Jean-Pierre Bedos, Bruno Riou, Pierre Kalfon, Djillali Annane, Jean Chastre, Pierre-François Dequin, Hervé Dupont, Bruno Giraudeau, Alexandre Guerrini, Carole Ichai, Philippe Montravers, Michel Sorine

Abstract

Introduction: In a randomized controlled trial comparing tight glucose control with a computerized decision support system and conventional protocols (post hoc analysis), we tested the hypothesis that hypoglycemia is associated with a poor outcome, even when controlling for initial severity.

Methods: We looked for moderate (2.2 to 3.3 mmol/L) and severe (<2.2 mmol/L) hypoglycemia, multiple hypoglycemic events (n ≥3) and the other main components of glycemic control (mean blood glucose level and blood glucose coefficient of variation (CV)). The primary endpoint was 90-day mortality. We used both a multivariable analysis taking into account only variables observed at admission and a multivariable matching process (greedy matching algorithm; caliper width of 10(-5) digit with no replacement).

Results: A total of 2,601 patients were analyzed and divided into three groups: no hypoglycemia (n =1,474), moderate hypoglycemia (n =874, 34%) and severe hypoglycemia (n =253, 10%). Patients with moderate or severe hypoglycemia had a poorer prognosis, as shown by a higher mortality rate (36% and 54%, respectively, vs. 28%) and decreased number of treatment-free days. In the multivariable analysis, severe (odds ratio (OR), 1.50; 95% CI, 1.36 to 1.56; P =0.043) and multiple hypoglycemic events (OR, 1.76, 95% CI, 1.31 to 3.37; P <0.001) were significantly associated with mortality, whereas blood glucose CV was not. Using multivariable matching, patients with severe (53% vs. 35%; P <0.001), moderate (33% vs. 27%; P =0.029) and multiple hypoglycemic events (46% vs. 32%, P <0.001) had a higher 90-day mortality.

Conclusion: In a large cohort of ICU patients, severe hypoglycemia and multiple hypoglycemic events were associated with increased 90-day mortality.

Trial registration: Clinicaltrials.gov Identifier: NCT01002482 . Registered 26 October 2009.

Figures

Figure 1
Figure 1
Flowchart of the study.
Figure 2
Figure 2
Distribution of the number of hypoglycemic events per patient. (A) Severe (<2.2 mmol/L). (B) Moderate (2.2 to 3.3 mmol/L). (C) Any type (<3.3 mmol/L).
Figure 3
Figure 3
Subgroup analysis. Odds ratio (OR) and 95% confidence interval (CI) for death at 90 days associated with moderate (filled squares) or severe (filled circles) hypoglycemia or multiple (n ≥3) hypoglycemic (filled triangles) events in the total population and in matched subgroups according to treatment assignment (conventional vs. computerized decision support system (CDSS)) and diabetes status (diabetic vs. non-diabetic). Matching was performed using propensity score and a ratio of 2:1 for severe hypoglycemia and 1:1 for moderate hypoglycemia and multiple hypoglycemic events. The size of symbols is related to the number of patients (N) retained in the matching process.

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