Early activation of the kynurenine pathway predicts early death and long-term outcome in patients resuscitated from out-of-hospital cardiac arrest

Giuseppe Ristagno, Roberto Latini, Jukka Vaahersalo, Serge Masson, Jouni Kurola, Tero Varpula, Jacopo Lucchetti, Claudia Fracasso, Giovanna Guiso, Alessandro Montanelli, Simona Barlera, Marco Gobbi, Marjaana Tiainen, Ville Pettilä, Markus B. Skrifvars, Vesa Lund, Päivi Tuominen, Satu Johansson, Pauliina Perkola, Elina KumpulainenMarkku Suvela, Sari Hirvonen, Sirpa Kauppinen, Raili Laru-Sompa, Mikko Reilama, Heikki Laine, Pekka Kettunen, Iina Smolander, Matti Reinikainen, Tero Surakka, Kari Saarinen, Pauliina Lähdeaho, Johanna Soini, Seppo Hovilehto, Simo Pekka Koivisto, Raku Hautamäki, Ari Alaspää, Tarja Heikkilä, Outi Kiviniemi, Esa Lintula, Tadeusz Kaminski, Jane Roiko, Seija Alila, Jussi Pentti, Reija Koskinen, Jorma Heikkinen, Tuomas Oksanen, Anne Eronen, Teemu Hult, Taina Nieminen, Tom Bäcklund, Leevi Kauhanen, Kirsi Maija Kaukonen, Ville Pettilä, Leena Pettilä, Sari Sutinen, Sanna Hoppu, Jyrki Tenhunen, Sari Karlsson, Atte Kukkurainen, Simo Varila, Samuli Kortelainen, Minna Liisa Peltola, Pamela Hiltunen, Jouni Kurola, Esko Ruokonen, Elina Halonen, Saija Rissanen, Sari Rahikainen, Risto Ahola, Tero Ala-Kokko, Sinikka Sälkiö

Research output: Contribution to journalArticlepeer-review

Abstract

Background-The kynurenine pathway (KP) is the major route of tryptophan (TRP) catabolism and is activated by inflammation and after cardiac arrest in animals. We hypothesized that the KP activation level correlates with severity of post-cardiac arrest shock, early death, and long-term outcome. Methods and Results-Plasma was obtained from 245 patients enrolled in a prospective multicenter observational study in 21 intensive care units in Finland. Time to return of spontaneous circulation, lowest systolic arterial pressure, and bicarbonate during the first 24 hours were collected. A cerebral performance category of 3 to 5 defined 12-month poor outcome. Plasma TRP and KP metabolites, kynurenine (KYN), kynurenic acid, 3-hydroxyanthranilic acid, and the ratio of KYN to TRP were measured by liquid chromatography and mass spectrometry. All KP metabolites at intensive care unit admission were significantly higher in cardiac arrest patients with a nonshockable rhythm compared to those with a shockable rhythm, and kynurenic acid and 3-hydroxyanthranilic acid correlated with time to return of spontaneous circulation. Patients with higher levels of KYN, KYN to TRP, kynurenic acid, and 3-hydroxyanthranilic acid had lower 24-hour systolic arterial pressure and bicarbonate. All KP metabolites and the ratio of KYN to TRP, but not TRP, were significantly higher in patients who died in the intensive care unit in comparison to those who survived. Multivariable logistic regression showed that high kynurenic acid (odds ratio: 1.004; 95% confidence interval: 1.001 to 1.008; P=0.014), and 3-hydroxyanthranilic acid (odds ratio: 1.011; 95% confidence interval: 1.001 to 1.022; P=0.03) were independently associated with 12-month poor outcome and significantly improved risk reclassification. Conclusions-KP is activated early after cardiac arrest and is associated with severity of post-cardiac arrest shock, early death, and poor long-term outcome.

Original languageEnglish
Article numbere001094
JournalJournal of the American Heart Association
Volume3
Issue number4
DOIs
Publication statusPublished - 2014

Keywords

  • Brain
  • Cardiac arrest
  • Kynurenine
  • Shock
  • Survival
  • Tryptophan

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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