Oxygen, biomarkers, and the injured brain

Aims: The purpose of this study was 1) to investigate the prevalence of high PaO2 and its association with long- term functional outcomes in critically ill patients after CA and several types of brain injuries as well as investigate the association of oxygen and outcome with low blood pressure; 2) to determine the course of oxidative stress and the effect of arterial oxygen tensions on oxidative tissue injury after OHCA with biomarkers expressing lipid peroxidation; and 3) to determine the severity of hypoxic- ischaemic brain injury and functional outcomes after OHCA with glial fibrillary acidic protein (GFAp) and tau protein, two biomarkers specific to neuronal injury, as well as the biomarkers’ association with arterial oxygen tension. Materials and methods: This study consists of four substudies (Studies I-IV). Studies I and II are retrospective epidemiological studies using data from the Finnish Intensive Care Consortium (FICC) database. Study I includes adult patients on mechanical ventilation admitted to intensive care units (ICUs) of five university hospitals in Finland between 2003 and 2013 with several types of brain injuries (traumatic brain injury, hypoxic-ischaemic brain injury, and haemorrhagic and ischemic stroke). We defined oxygen exposure based on the PaO2 value recorded in connection with the lowest PaO2/fraction of inspired oxygen (FiO2) ratio and the patient haemodynamic condition based on the worst recorded mean arterial pressure (MAP) within the first 24h in the ICU. The study endpoint was one-year mortality. Study II consists of a sub-cohort from Study I, including all the CA patients treated in the ICUs of Helsinki University Hospital between 2005 and 2013. We determined severe hyperoxaemia as >40 kPa and moderate hyperoxaemia as 16– 40 kPa based on the first PaO2 sample obtained within two hours after the return of spontaneous circulation (ROSC). The study endpoint was one-year functional outcome defined according to the Cerebral Performance Category (CPC). We defined CPC scores of 3–5 as unfavourable, corresponding to severe cerebral disability or death. Studies III and IV utilized blood samples collected during the Carbon Dioxide, Oxygen, and Mean arterial pressure After Cardiac Arrest (COMACARE) – pilot trial (NCT02698917). This trial randomized comatose OHCA patients to different targets of arterial oxygen (PaO2 10–15 kPa vs 20– 25 kPa) during the first 36h in the ICU. In Study III, we determined the concentrations of four lipid peroxidation biomarkers (isoprostanes, isofurans, neuroprostanes, and neurofurans) and in Study IV, the concentrations of GFAp and tau protein on ICU admission (0h), and at 24 h, 48 h, and 72 h thereafter. The lipid peroxidation biomarker concentrations were compared with oxygen exposure prior to hospital admission (according to the first pre-hospital PaO2 sample obtained after ROSC) and between the PaO2 treatment target groups. We determined the ability of GFAp and tau to predict six- month functional outcome after OHCA (unfavourable outcomes defined as CPC 3–5). Main results: Study I included 8,290 patients of whom 3912 (47%) were dead at one year. The threshold for hyperoxaemia was >18.3 kPa according to the highest 10th percentile, and we grouped patients by worst MAP in equal-sized tertiles (68 mmHg). PaO2 was not associated with one- year mortality at any MAP level, however, higher MAP levels were associated with lower one-year mortality compared to MAP 68 mmHg it was 0.80 [ 0.69–0.92]). Study II included 1,110 patients after CA, of whom 11% were exposed to severe and 37% to moderate hyperoxaemia soon after ROSC. Of the study population in Study II 585 (53%) patients had unfavourable functional outcomes, but severe hyperoxaemia exposure was not associated with outcome. Studies III and IV included 112 patients after OHCA, of whom 39 (35%) had unfavourable functional outcome at six months. We found no associations between lipid peroxidation biomarker concentrations and PaO2 exposure prior to hospital admission or between the PaO2 treatment target groups. Both GFAp and tau predicted six-month functional outcome well 48h after OHCA with areas under the receiving operating characteristics curve (AUROCs) of 0.91 (95% confidence interval 0.85– 0.97) for GFAp and 0.93 (0.86 –0.99) for tau. Conclusions: About 10% of the study’s CA population were exposed to early hyperoxaemia after ROSC. We did not find an association between early post-arrest hyperoxaemia and unfavourable one-year outcome. Our study showed no benefit of hyperoxemia exposure in patients with hypotension after several types of brain injuries. The levels of lipid peroxidation biomarkers were similar, irrespective of PaO2 levels in the pre-hospital setting and during the initial ICU care, suggesting that moderate differences in PaO2 tension do not influence the burden of oxidative stress after OHCA. GFAp and tau demonstrated good accuracy in predicting functional outcome after OHCA.Sydänpysähdyksen aikana elimistön verenkierto sekä hapensaanti pysähtyvät. Elimistön hapenpuute johtaa nopeasti elinvaurioihin. Erityisen vahingollista hapenpuute on aivoille, lisähapen anto onkin elvytystilanteessa tärkeää. Kudoksissa ylimääräiset happimolekyylit muodostavat solun rakenteita vaurioittavia happiradikaaleja ja liiallinenkin hapensaanti voi olla haitallista. Happiradikaaleja muodostuu runsaasti hapen palatessa hapenpuutteesta kärsineeseen kudokseen. Onnistuneen elvytyksen jälkeen palautuva verenkierto (reperfuusio) laajentaakin hapenpuutteen aikana muodostunutta kudosvauriota. Kirjallisuudessa on viitteitä, että lisähappea antamalla saavutettu korkea valtimoveren happiosapaine onnistuneen elvytyksen jälkeen hankaloittaa syntyvää reperfuusiovauriota ja huonontaa potilaan toipumisennustetta, mutta tutkimusnäyttö on ristiriitaista. Selvitimme valtimoveren korkean happiosapaineen ilmenemistä teho-osastolla hoidetuilla potilailla varhaisessa vaiheessa sydänpysähdyksen ja onnistuneen elvytyksen jälkeen sekä korkean valtimoveren happiosapaineen ja potilaan huonon toipumisen välistä yhteyttä. Lisäksi määritimme happiradikaalien aiheuttamaa soluvauriota kuvaavien kudosmerkkiaineiden pitoisuuksia elvytetyillä potilailla kolmen ensimmäisen tehohoitovuorokauden aikana ja tutkimme näiden merkkiaineiden ja valtimoveren happiosapaineen välistä yhteyttä. Lopuksi tutkimme sydänpysähdyksen jälkeisen aivovaurion laajuutta kahden eri verestä mitattavan hermokudosvauriota kuvaavan kudosmerkkiaineen avulla ja määritimme, kuinka näiden merkkiaineiden pitoisuudet ennustavat sydänpysähdyspotilaan pitkäaikaista toipumista. Tutkimus pohjautui kahteen eri Suomen Tehohoitokonsortion potilasaineistoon sekä verinäytteisiin, jotka olivat kerätty kliinisen satunnaistetun tutkimukseen aikana. Satunnaistettu kliininen tutkimus sisälsi sairaalan ulkopuolella sydänpysähdyksen saaneita onnistuneesti elvytettyjä tehohoitopotilaita, jotka olivat 36 ensimmäisen tehohoitotunnin ajan satunnaistettu kahteen eri ryhmään valtimoveren happiosapaineen suhteen (normaali 10–15 kPa ja lievästi korkea 20–25 kPa). Rekisteriaineistossa hyvin korkean valtimoveren happiosapaineen ilmaantuvuus pian elvytyksen jälkeen oli noin 10 %. Huono toipuminen todettiin noin 50 %:lla potilaista tarkoittaen lievimmillään kyvyttömyyttä selviytyä itsenäisesti arjen toimista tai vakavimmillaan kuolemaa. Korkea valtimoveren happiosapaine ei ollut yhteydessä huonomman pitkäaikaistoipumisen kanssa. Happiradikaalien aiheuttamaa soluvauriota kuvaavilla kudosmerkkiaineilla suurimmat pitoisuudet ilmenivät noin 24 tuntia sydänpysähdyksen jälkeen ja valtimoveren happiosapaine ei ollut yhteydessä kudosmerkkiaineiden pitoisuuksiin. Hermokudoksen vauriota kuvaavien kudosmerkkiaineiden pitoisuudet ennustivat sydänpysähdyspotilaan pitkäaikaista toipumista hyvin. Rekisteriaineistossamme korkean valtimoveren happiosapaineen ilmaantuvuus oli jokseenkin matalampi verrattuna aiemmin esitettyyn, kuitenkin kirjallisuudessa ilmaantuvuus vaihtelee suuresti mittaushetkestä ja potilasaineistosta riippuen. Löydöstemme perusteella päättelimme, että lyhytkestoisella korkealla tai pitkäkestoisemmalla lievästi kohonneella valtimoveren happiosapaineella ei ole vahvaa yhteyttä potilaan pitkäaikaistoipumisen kanssa. Hermokudoksen vauriota kuvaavien kudosmerkkiaineiden pitoisuudet korreloivat vahvasti potilaan pitkäaikaisen toipumisennusteen kanssa, joten näiden kudosmerkkiaineiden pitoisuudet kuvastavat sydänpysähdyksen jälkeisen aivovaurion laajuutta ja voivat olla apuna elvytetyn potilaan toipumisen ennustamisessa

Positiiviset ennusteelliset tekijät lapsuusiän allogeenisissa kantasolusiirroissa

Tutkimus käsittelee HYKS:n lastenklinikalla vuosina 1980-2010 tehtyjä lapsuusiän allogeenisia hematopoieettisia kantasolunsiirtoja. Tutkimus tehtiin retrospektiivisenä rekisteritutkimuksena HUS:n lapsuusiän syöpärekisterin (ProLapsi) tietojen pohjalta. Aineisto kerättiin rekisteristä käsin ja analysoitiin SPSS-ohjelmistoa apuna käyttäen. Tutkimuksen tavoitteena oli rekisteritietojen pohjalta tutkia kantasolusiirtojen onnistumista ja kartoittaa eri tekijöiden vaikutusta siirron lopputulokseen sekä peilata tuloksia kirjallisuudesta löytyviin aikaisempiin tutkimustuloksiin. Siirron onnistumisen kannalta haluttiin tarkastella siirteen hyljinnän ja taudin relapsin todennäköisyyttä sekä potilaiden parantumista sairaudestaan ja kuolleisuutta ensimmäisenä vuotena siirron jälkeen. Vertailuparametreinä käytettiin muun muassa HLA-yhteensopivuutta, luovuttajan ja vastaanottajan ikää sekä luovuttajan ja vastaanottajan veriryhmää. Tulokset toimivat apuna verrattaessa Lastenklinikalla tehtyjen kantasolusiirtojen lopputulosta muualla tehtyihin siirtoihin sekä auttavat havaitsemaan riskejä ja vahvuuksia klinikan toiminnassa. Tutkimustuloksissa ei tullut esiin Lastenklinikan siirtotoimintaan liittyviä riskitekijöitä. Saadut tutkimustulokset olivat pääosin linjassa aiheesta aiemmin tehtyjen tutkimusten kanssa. Tulokset, jotka olivat ristiriidassa aiempien havaintojen kanssa, eivät saavuttaneet tilastollista merkittävyyttä. Merkittävimpänä tutkimustuloksena havaittiin viitettä siitä, että luovuttajavalinnassa sekä ABO-veriryhmätekijöiden lisäksi myös Rh- veriryhmätekijät tulisi ottaa huomioon

Response to "Pay Attention to Blood Pressure and Oxygen Supply for Neurocritically Ill Patients : Each Pathology Deserves a Specific Treatment"

Correction: Volume35, Issue1 Page281-281 DOI10.1007/s12028-021-01268-3 Published AUG 2021 https://doi.org/10.1007/s12028-021-01213-4 WOS: 000651323400001Non peer reviewe

Brain Injury Biomarkers for Predicting Outcome After Cardiac Arrest

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2022. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2022. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link. springer.com/bookseries/8901.Peer reviewe

Early hyperoxemia is not associated with cardiac arrest outcome

Aim: Studies suggest that hyperoxemia increases short-term mortality after cardiopulmonary resuscitation (CPR), but the effect of hyperoxemia on long-term outcomes is unclear. We determined the prevalence of early hyperoxemia after CPR and its association with long-term neurological outcome and mortality. Methods: We analysed data from adult cardiac arrest patients treated after CPR in tertiary ICUs during 2005-2013. We retrieved data from the resuscitation and the first arterial blood sample collected after return of spontaneous circulation (ROSC) (severe hyperoxemia defined as PaO2 > 40 kPa and moderate as PaO2 16-40 kPa). We inspected two outcomes, neurological performance at one year after resuscitation according to the Cerebral Performance Category and one-year mortality. We used logistic regression to test associations between hyperoxemia and the outcome and interaction analyses to test the effect of hyperoxemia exposure on the outcomes in smaller subgroups. Results: Of 1110 patients 11% had severe hyperoxemia, prevalence was 10% for out-of-hospital arrests, 13% for in-hospital arrests and 9% for in-ICU arrests. In total 585(53%) patients had an unfavourable neurological outcome. Compared to normoxemia, severe (Odds ratio [OR] 0.81, 95% confidence interval [CI] 0.50-1.30) and moderate hyperoxemia (OR 0.94 95%CI 0.69-1.27) did not associate with neurological outcome. Additionally, hyperoxemia had no association with mortality. In subgroup analyses there were no significant associations between severe hyperoxemia and outcomes regardless of cardiac arrest location, initial rhythm or time-to-ROSC. Conclusion: We found no association between early post-arrest hyperoxemia and unfavourable outcome, Subgroup analysis found no differential effect depending on arrest location, initial rhythm or time-to-ROSC.Peer reviewe

The Association Between Arterial Oxygen Level and Outcome in Neurocritically Ill Patients is not Affected by Blood Pressure

Background In neurocritically ill patients, one early mechanism behind secondary brain injury is low systemic blood pressure resulting in inadequate cerebral perfusion and consequent hypoxia. Intuitively, higher partial pressures of arterial oxygen (PaO2) could be protective in case of inadequate cerebral circulation related to hemodynamic instability. Study purpose We examined whether the association between PaO2 and mortality is different in patients with low compared to normal and high mean arterial pressure (MAP) in patients after various types of brain injury. Methods We screened the Finnish Intensive Care Consortium database for mechanically ventilated adult (>= 18) brain injury patients treated in several tertiary intensive care units (ICUs) between 2003 and 2013. Admission diagnoses included traumatic brain injury, cardiac arrest, subarachnoid and intracranial hemorrhage, and acute ischemic stroke. The primary exposures of interest were PaO2 (recorded in connection with the lowest measured PaO2/fraction of inspired oxygen ratio) and the lowest MAP, recorded during the first 24 h in the ICU. PaO2 was grouped as follows: hypoxemia ( 18.3 kPa, the highest 10th percentile), and MAP was divided into equally sized tertiles ( 68 mmHg). The primary outcome was 1-year mortality. We tested the association between hyperoxemia, MAP, and mortality with a multivariable logistic regression model, including the PaO2, MAP, and interaction of PaO2*MAP, adjusting for age, admission diagnosis, premorbid physical performance, vasoactive use, intracranial pressure monitoring use, and disease severity. The relationship between predicted 1-year mortality and PaO2 was visualized with locally weighted scatterplot smoothing curves (Loess) for different MAP levels. Results From a total of 8290 patients, 3912 (47%) were dead at 1 year. PaO2 was not an independent predictor of mortality: the odds ratio (OR) for hyperoxemia was 1.16 (95% CI 0.85-1.59) and for hypoxemia 1.24 (95% CI 0.96-1.61) compared to normoxemia. Higher MAP predicted lower mortality: OR for MAP 60-68 mmHg was 0.73 (95% CI 0.64-0.84) and for MAP > 68 mmHg 0.80 (95% CI 0.69-0.92) compared to MAP <60 mmHg. The interaction term PaO2*MAP was nonsignificant. In Loess visualization, the relationship between PaO2 and predicted mortality appeared similar in all MAP tertiles. Conclusions During the first 24 h of ICU treatment in mechanically ventilated brain injured patients, the association between PaO2 and mortality was not different in patients with low compared to normal MAP.Peer reviewe

High Oxygen Does Not Increase Reperfusion Injury Assessed with Lipid Peroxidation Biomarkers after Cardiac Arrest: A Post Hoc Analysis of the COMACARE Trial

The products of polyunsaturated fatty acid peroxidation are considered reliable biomarkers of oxidative injury in vivo. We investigated ischemia-reperfusion-related oxidative injury by determining the levels of lipid peroxidation biomarkers (isoprostane, isofuran, neuroprostane, and neurofuran) after cardiac arrest and tested the associations between the biomarkers and different arterial oxygen tensions (PaO2). We utilized blood samples collected during the COMACARE trial (NCT02698917). In the trial, 123 patients resuscitated from out-of-hospital cardiac arrest were treated with a 10–15 kPa or 20–25 kPa PaO2 target during the initial 36 h in the intensive care unit. We measured the biomarker levels at admission, and 24, 48, and 72 h thereafter. We compared biomarker levels in the intervention groups and in groups that differed in oxygen exposure prior to randomization. Blood samples for biomarker determination were available for 112 patients. All four biomarker levels peaked at 24 h; the increase appeared greater in younger patients and in patients without bystander-initiated life support. No association between the lipid peroxidation biomarkers and oxygen exposure either before or after randomization was found. Increases in the biomarker levels during the first 24 h in intensive care suggest continuing oxidative stress, but the clinical relevance of this remains unresolved

High Oxygen Does Not Increase Reperfusion Injury Assessed with Lipid Peroxidation Biomarkers after Cardiac Arrest: A Post Hoc Analysis of the COMACARE Trial

The products of polyunsaturated fatty acid peroxidation are considered reliable biomarkers of oxidative injury in vivo. We investigated ischemia-reperfusion-related oxidative injury by determining the levels of lipid peroxidation biomarkers (isoprostane, isofuran, neuroprostane, and neurofuran) after cardiac arrest and tested the associations between the biomarkers and different arterial oxygen tensions (PaO2). We utilized blood samples collected during the COMACARE trial (NCT02698917). In the trial, 123 patients resuscitated from out-of-hospital cardiac arrest were treated with a 10–15 kPa or 20–25 kPa PaO2 target during the initial 36 h in the intensive care unit. We measured the biomarker levels at admission, and 24, 48, and 72 h thereafter. We compared biomarker levels in the intervention groups and in groups that differed in oxygen exposure prior to randomization. Blood samples for biomarker determination were available for 112 patients. All four biomarker levels peaked at 24 h; the increase appeared greater in younger patients and in patients without bystander-initiated life support. No association between the lipid peroxidation biomarkers and oxygen exposure either before or after randomization was found. Increases in the biomarker levels during the first 24 h in intensive care suggest continuing oxidative stress, but the clinical relevance of this remains unresolved

GFAp and tau protein as predictors of neurological outcome after out-of-hospital cardiac arrest: A post hoc analysis of the COMACARE trial

Aim: To determine the ability of serum glial fibrillary acidic protein (GFAp) and tau protein to predict neurological outcome after out-of-hospital cardiac arrest (OHCA). Methods: We measured plasma concentrations of GFAp and tau of patients included in the previously published COMACARE trial (NCT02698917) on intensive care unit admission and at 24, 48, and 72 h after OHCA, and compared them to neuron specific enolase (NSE). NSE concentrations were determined already during the original trial. We defined unfavourable outcome as a cerebral performance category (CPC) score of 3-5 six months after OHCA. We determined the prognostic accuracy of GFAp and tau using the receiver operating characteristic curve and area under the curve (AUROC). Results: Overall, 39/112 (35%) patients had unfavourable outcomes. Over time, both markers were evidently higher in the unfavourable outcome group (p < 0.001). At 48 h, the median (interquartile range) GFAp concentration was 1514 (886-4995) in the unfavourable versus 238 (135-463) pg/ ml in the favourable outcome group (p < 0.001). The corresponding tau concentrations were 99.6 (14.5-352) and 3.0 (2.2-4.8) pg/ml (p < 0.001). AUROCs at 48 and 72 h were 0.91 (95% confidence interval 0.85-0.97) and 0.91 (0.85-0.96) for GFAp and 0.93 (0.86-0.99) and 0.95 (0.89-1.00) for tau. Corresponding AUROCs for NSE were 0.86 (0.79-0.94) and 0.90 (0.82-0.97). The difference between the prognostic accuracies of GFAp or tau and NSE were not statistically significant. Conclusions: At 48 and 72 h, serum both GFAp and tau demonstrated excellent accuracy in predicting outcomes after OHCA but were not superior to NSE. Clinical trial registration: NCT02698917 (https://www.clinicaltrials.gov/ct2/show/NCT02698917).Peer reviewe

High Oxygen Does Not Increase Reperfusion Injury Assessed with Lipid Peroxidation Biomarkers after Cardiac Arrest: A Post Hoc Analysis of the COMACARE Trial

The products of polyunsaturated fatty acid peroxidation are considered reliable biomarkers of oxidative injury in vivo. We investigated ischemia-reperfusion-related oxidative injury by determining the levels of lipid peroxidation biomarkers (isoprostane, isofuran, neuroprostane, and neurofuran) after cardiac arrest and tested the associations between the biomarkers and different arterial oxygen tensions (PaO2). We utilized blood samples collected during the COMACARE trial (NCT02698917). In the trial, 123 patients resuscitated from out-of-hospital cardiac arrest were treated with a 10–15 kPa or 20–25 kPa PaO2 target during the initial 36 h in the intensive care unit. We measured the biomarker levels at admission, and 24, 48, and 72 h thereafter. We compared biomarker levels in the intervention groups and in groups that differed in oxygen exposure prior to randomization. Blood samples for biomarker determination were available for 112 patients. All four biomarker levels peaked at 24 h; the increase appeared greater in younger patients and in patients without bystander-initiated life support. No association between the lipid peroxidation biomarkers and oxygen exposure either before or after randomization was found. Increases in the biomarker levels during the first 24 h in intensive care suggest continuing oxidative stress, but the clinical relevance of this remains unresolved