title: Early activation of the kynurenine pathway predicts early death and long-term outcome in patients resuscitated from out-of-hospital cardiac arrest.
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.
  
  
  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.
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (G.R., R.L., S.M., J.L., C.F., G.G., S.B., M.G.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ristagno
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (G.R., R.L., S.M., J.L., C.F., G.G., S.B., M.G.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Latini
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland (J.V., T.V., V.P., M.B.S.).
authors.forename: Jukka
authors.initials: J
authors.lastname: Vaahersalo
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (G.R., R.L., S.M., J.L., C.F., G.G., S.B., M.G.).
authors.forename: Serge
authors.initials: S
authors.lastname: Masson
authors.affiliation: Department of Intensive Care, Kuopio University Central Hospital, Kuopio, Finland (J.K.).
authors.forename: Jouni
authors.initials: J
authors.lastname: Kurola
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland (J.V., T.V., V.P., M.B.S.).
authors.forename: Tero
authors.initials: T
authors.lastname: Varpula
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (G.R., R.L., S.M., J.L., C.F., G.G., S.B., M.G.).
authors.forename: Jacopo
authors.initials: J
authors.lastname: Lucchetti
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (G.R., R.L., S.M., J.L., C.F., G.G., S.B., M.G.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Fracasso
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (G.R., R.L., S.M., J.L., C.F., G.G., S.B., M.G.).
authors.forename: Giovanna
authors.initials: G
authors.lastname: Guiso
authors.affiliation: Clinical Investigations Laboratory, Humanitas Clinical and Research Center, Milan, Italy (A.M.).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Montanelli
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (G.R., R.L., S.M., J.L., C.F., G.G., S.B., M.G.).
authors.forename: Simona
authors.initials: S
authors.lastname: Barlera
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy (G.R., R.L., S.M., J.L., C.F., G.G., S.B., M.G.).
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: Department of Neurology, Helsinki University Hospital, Helsinki, Finland (M.T.).
authors.forename: Marjaana
authors.initials: M
authors.lastname: Tiainen
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland (J.V., T.V., V.P., M.B.S.).
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland (J.V., T.V., V.P., M.B.S.).
authors.forename: Markus B
authors.initials: MB
authors.lastname: Skrifvars
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism; D000368:Aged; D062186:Arterial Pressure / Q000502:physiology; D016887:Cardiopulmonary Resuscitation; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D007736:Kynurenic Acid / Q000097:blood; D007737:Kynurenine / Q000097:blood*; D016015:Logistic Models; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D058687:Out-of-Hospital Cardiac Arrest / Q000097:blood / Q000401:mortality* / Q000628:therapy; D011379:Prognosis; D011446:Prospective Studies; D012770:Shock, Cardiogenic / Q000097:blood / Q000401:mortality* / Q000503:physiopathology; D014364:Tryptophan / Q000097:blood
chemical_list: D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D014364:Tryptophan; D007736:Kynurenic Acid
keywords: brain; cardiac arrest; kynurenine; shock; survival; tryptophan
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