Hiilidioksidin, hapen ja verenpaineen merkitys äkillisen sydänpysähdyksen ja elvytyksen jälkeen

Väittelijä Pekka Jakkula ; Helsingin yliopist

Hiilidioksidi-, happi- ja verenpainetasojen merkitys sydänpysähdyksestä elvytetyn potilaan tehohoidossa

Aims The objective of this study was to determine the feasibility of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2), normoxia or moderate hyperoxia, and low-normal or high-normal mean arterial pressure (MAP) in comatose patients after out-of-hospital cardiac arrest (OHCA) and successful resuscitation. In addition, we assessed the effects of the two different levels of PaCO2, arterial oxygen tension (PaO2) and MAP on markers of neurological and myocardial injury, cerebral oxygenation, and epileptic activity. Moreover, we investigated the association between cerebral oxygenation and the extent of cerebral injury as assessed with markers of brain injury and neurological outcome. Materials and methods In the Carbon dioxide, Oxygen and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial with 23 factorial design, 123 patients resuscitated from OHCA with a shockable initial rhythm were randomly assigned to targeting low-normal (4.5–4.7 kPa) or high-normal (5.8–6.0 kPa) PaCO2, normoxia (PaO2 10–15 kPa) or moderate hyperoxia (PaO2 20–25 kPa), and low-normal (65-75 mmHg) or high-normal (80-100 mmHg) MAP during the first 36 h in the intensive care unit. The primary outcome was the serum concentration of neuron-specific enolase (NSE) at 48 h after cardiac arrest (CA). Secondary endpoints included NSE concentrations at 24 and 72 h after CA; S100 calcium-binding protein B (S100B) and cardiac troponin T (TnT) concentrations at 24, 48, and 72 h after CA; clinically significant changes in continuous electroencephalography (EEG), results of frontal regional oxygen saturation (rSO2) measured with near-infrared spectroscopy (NIRS) during the first 48 h of intensive care; and neurologic outcome at 6 months (Studies II-III). In a post hoc analysis, we evaluated the association between frontal rSO2 and NSE concentration at 48 h, and the association between frontal rSO2 and good (Cerebral Performance Category [CPC] 1-2) and poor (CPC 3-5) neurological outcome (Study IV). In another post hoc analysis, we combined data from a subgroup of patients with acute myocardial infarction (AMI) and vasopressor dependent hypotension with data from a comparable subgroup of another trial (Neuroprotect) to evaluate the association between MAP and myocardial injury assessed with the area under the 72-hour TnT curve (Study V). Main results We observed a clear separation between the study groups in PaCO2, PaO2, and MAP during the 36-hour intervention period. However, there was no difference in serum NSE concentrations between the intervention groups at any of the studied time points. S100B and TnT concentrations, EEG findings, and neurological outcome at 6 months were comparable between the groups. High-normal PaCO2 and moderate hyperoxia significantly increased frontal rSO2, but MAP level did not. No significant association between frontal rSO2 and NSE or neurological outcome was observed. In a subgroup of patients with AMI and vasopressor dependent hypotension, combined from the two trials (COMACARE and Neuroprotect), myocardial injury was significantly lower in patients assigned to the higher MAP group. The risk of new-onset CA or arrhythmias was not increased despite significantly higher doses of noradrenaline and dobutamine in the higher MAP group. Conclusions Targeting low-normal or high-normal PaCO2, normoxia or moderate hyperoxia, and low-normal or high-normal MAP was feasible in comatose patients after OHCA and successful resuscitation. None of the studied interventions affected the extent of the developing brain damage as measured with biomarkers of neurological injury. High-normal PaCO2 and moderate hyperoxia resulted in increased cerebral oxygenation, but this was not associated with the extent of brain injury. In patients with AMI and vasopressor dependent hypotension, targeting a MAP between 80/85-100 mmHg was associated with smaller myocardial injury without clinically significant side effects.Väitöskirjatutkimuksen tarkoituksena oli selvittää, voidaanko sairaalan ulkopuolella äkillisen sydänpysähdyksen saaneiden potilaiden valtimoveren hiilidioksidi- ja happiosapaineita sekä verenpainetasoa säädellä luotettavasti tuloksekkaan elvytyksen jälkeen. Lisäksi tutkimme, miten erilaiset hiilidioksidi-, happi- ja verenpainetasot vaikuttavat aivovaurion ja sydänlihasvaurion laajuutta kuvaavien merkkiaineiden pitoisuuksiin, aivojen happeutumiseen ja epileptiseen aktiviteettiin. Selvitimme myös, liittyykö elvytyksen jälkeinen aivojen happisaturaatio aivovaurion laajuuteen tai potilaiden neurologiseen ennusteeseen. 120 sairaalan ulkopuolella kammiovärinästä elvytettyä, tajutonta ja hengityskonehoitoa tarvitsevaa potilasta satunnaistettiin samanaikaisesti kolmen eri muuttujan suhteen joko matalampaan tai korkeampaan tavoitearvoon 36 h ajaksi teho-osastolle saapumisesta lukien. Tavoitteet olivat valtimoveren hiilidioksidiosapaine 4.5-4.7 tai 5.8-6.0 kPa, valtimoveren happiosapaine 10-15 tai 20-25 kPa ja keskiverenpaine 65-75 tai 80-100 mmHg. Aivo- ja sydänlihasvaurioiden laajuutta kuvaavien merkkiaineiden pitoisuudet määritettiin verinäytteistä 24, 48 ja 72 h sydänpysähdyksen jälkeen. Kaikilta potilailta mitattiin aivojen happisaturaatiota sekä 4-kanavaista aivosähkökäyrää kahden ensimmäisen tehohoitovuorokauden ajan. Neurologinen toipuminen selvitettiin 6 kk tapahtuman jälkeen. Jälkikäteen suunnitellussa lisäanalyysissä selvitettiin, liittyikö verenpainetaso sydänlihasvaurion laajuuteen niillä elvytetyillä potilailla, joilla sydänpysähdyksen syy oli akuutti sydäninfarkti. Tätä varten yhdistimme oman tutkimuksemme tulokset toisen verenpainetason vaikutusta sydänpysähdyspotilaiden neurologiseen toipumiseen selvittäneen tutkimuksen tuloksiin. Elvytettyjen sydänpysähdyspotilaiden valtimoveren hiilidioksidi- ja happiosapaineen sekä verenpainetason tarkka säätely onnistui erinomaisesti. Mikään tutkituista interventioista ei kuitenkaan vaikuttanut aivo- tai sydänlihasvaurion laajuutta kuvaavien merkkiaineiden pitoisuuksiin tehohoidon aikana. Korkeampi happi- ja hiilidioksiditaso johti korkeampaan aivojen happisaturaatioon, mutta sillä ei ollut yhteyttä aivovaurion laajuuteen tai potilaiden neurologiseen ennusteeseen. Aivojen epileptisessä aktiivisuudessa tai potilaiden neurologisessa toipumisessa ei todettu tilastollisesti merkitseviä eroja ryhmien välillä. Kammiovärinästä elvytetyillä akuutista sydäninfarktista kärsivillä potilailla korkeampi keskiverenpainetaso liittyi pienempään sydänlihasvaurioon ilman merkittäviä haittavaikutuksia

NSE concentrations and haemolysis after cardiac arrest

Non peer reviewe

Serum fibroblast growth factor 21 levels after out of hospital cardiac arrest are associated with neurological outcome

Fibroblast growth factor (FGF) 21 is a marker associated with mitochondrial and cellular stress. Cardiac arrest causes mitochondrial stress, and we tested if FGF 21 would reflect the severity of hypoxia-reperfusion injury after cardiac arrest. We measured serum concentrations of FGF 21 in 112 patients on ICU admission and 24, 48 and 72 h after out-of-hospital cardiac arrest with shockable initial rhythm included in the COMACARE study (NCT02698917). All patients received targeted temperature management for 24 h. We defined 6-month cerebral performance category 1-2 as good and 3-5 as poor neurological outcome. We used samples from 40 non-critically ill emergency room patients as controls. We assessed group differences with the Mann Whitney U test and temporal differences with linear modeling with restricted maximum likelihood estimation. We used multivariate logistic regression to assess the independent predictive value of FGF 21 concentration for neurologic outcome. The median (inter-quartile range, IQR) FGF 21 concentration was 0.25 (0.094-0.91) ng/ml in controls, 0.79 (0.37-1.6) ng/ml in patients at ICU admission (PPeer reviewe

Cerebrovascular autoregulation following cardiac arrest : Protocol for a post hoc analysis of the randomised COMACARE pilot trial

Background Approximately two-thirds of the mortality following out of hospital cardiac arrest is related to devastating neurological injury. Previous small cohort studies have reported an impaired cerebrovascular autoregulation following cardiac arrest, but no studies have assessed the impact of differences in oxygen and carbon dioxide tensions in addition to mean arterial pressure management. Methods This is a protocol and statistical analysis plan to assess the correlation between changes in cerebral tissue oxygenation and arterial pressure as measure of cerebrovascular autoregulation, the tissue oxygenation index, in patients following out of hospital cardiac arrest and in healthy volunteers. The COMACARE study included 120 comatose survivors of out of hospital cardiac arrest admitted to ICU and managed with low-normal or high-normal targets for mean arterial pressure, arterial oxygen and carbon dioxide partial pressures. In addition, 102 healthy volunteers have been investigated as a reference group for the tissue oxygenation index. In both cohorts, the cerebral tissue oxygenation was measured by near infrared spectroscopy. Conclusions Cerebrovascular autoregulation is critical to maintain homoeostatic brain perfusion. This study of changes in autoregulation following out of hospital cardiac arrest over the first 48 hours, as compared to data from healthy volunteers, will generate important physiological information that may guide the rationale and design of interventional studies.Peer reviewe

Near-infrared spectroscopy after out-of-hospital cardiac arrest

BackgroundCerebral hypoperfusion may aggravate neurological damage after cardiac arrest. Near-infrared spectroscopy (NIRS) provides information on cerebral oxygenation but its relevance during post-resuscitation care is undefined. We investigated whether cerebral oxygen saturation (rSO(2)) measured with NIRS correlates with the serum concentration of neuron-specific enolase (NSE), a marker of neurological injury, and with clinical outcome in out-of-hospital cardiac arrest (OHCA) patients.MethodsWe performed a post hoc analysis of a randomised clinical trial (COMACARE, NCT02698917) comparing two different levels of carbon dioxide, oxygen and arterial pressure after resuscitation from OHCA with ventricular fibrillation as the initial rhythm. We measured rSO(2) in 118 OHCA patients with NIRS during the first 36h of intensive care. We determined the NSE concentrations from serum samples at 48h after cardiac arrest and assessed neurological outcome with the Cerebral Performance Category (CPC) scale at 6months. We evaluated the association between rSO(2) and serum NSE concentrations and the association between rSO(2) and good (CPC 1-2) and poor (CPC 3-5) neurological outcome.ResultsThe median (inter-quartile range (IQR)) NSE concentration at 48h was 17.5 (13.4-25.0) g/l in patients with good neurological outcome and 35.2 (22.6-95.8) g/l in those with poor outcome, pPeer reviewe

Near-infrared spectroscopy after out-of-hospital cardiac arrest

BackgroundCerebral hypoperfusion may aggravate neurological damage after cardiac arrest. Near-infrared spectroscopy (NIRS) provides information on cerebral oxygenation but its relevance during post-resuscitation care is undefined. We investigated whether cerebral oxygen saturation (rSO(2)) measured with NIRS correlates with the serum concentration of neuron-specific enolase (NSE), a marker of neurological injury, and with clinical outcome in out-of-hospital cardiac arrest (OHCA) patients.MethodsWe performed a post hoc analysis of a randomised clinical trial (COMACARE, NCT02698917) comparing two different levels of carbon dioxide, oxygen and arterial pressure after resuscitation from OHCA with ventricular fibrillation as the initial rhythm. We measured rSO(2) in 118 OHCA patients with NIRS during the first 36h of intensive care. We determined the NSE concentrations from serum samples at 48h after cardiac arrest and assessed neurological outcome with the Cerebral Performance Category (CPC) scale at 6months. We evaluated the association between rSO(2) and serum NSE concentrations and the association between rSO(2) and good (CPC 1-2) and poor (CPC 3-5) neurological outcome.ResultsThe median (inter-quartile range (IQR)) NSE concentration at 48h was 17.5 (13.4-25.0) g/l in patients with good neurological outcome and 35.2 (22.6-95.8) g/l in those with poor outcome, pPeer reviewe

Neurofilament light as an outcome predictor after cardiac arrest : a post hoc analysis of the COMACARE trial

Purpose Neurofilament light (NfL) is a biomarker reflecting neurodegeneration and acute neuronal injury, and an increase is found following hypoxic brain damage. We assessed the ability of plasma NfL to predict outcome in comatose patients after out-of-hospital cardiac arrest (OHCA). We also compared plasma NfL concentrations between patients treated with two different targets of arterial carbon dioxide tension (PaCO2), arterial oxygen tension (PaO2), and mean arterial pressure (MAP). Methods We measured NfL concentrations in plasma obtained at intensive care unit admission and at 24, 48, and 72 h after OHCA. We assessed neurological outcome at 6 months and defined a good outcome as Cerebral Performance Category (CPC) 1-2 and poor outcome as CPC 3-5. Results Six-month outcome was good in 73/112 (65%) patients. Forty-eight hours after OHCA, the median NfL concentration was 19 (interquartile range [IQR] 11-31) pg/ml in patients with good outcome and 2343 (587-5829) pg/ml in those with poor outcome,p <0.001. NfL predicted poor outcome with an area under the receiver operating characteristic curve (AUROC) of 0.98 (95% confidence interval [CI] 0.97-1.00) at 24 h, 0.98 (0.97-1.00) at 48 h, and 0.98 (0.95-1.00) at 72 h. NfL concentrations were lower in the higher MAP (80-100 mmHg) group than in the lower MAP (65-75 mmHg) group at 48 h (median, 23 vs. 43 pg/ml,p = 0.04). PaCO(2)and PaO(2)targets did not associate with NfL levels. Conclusions NfL demonstrated excellent prognostic accuracy after OHCA. Higher MAP was associated with lower NfL concentrations.Peer reviewe

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