Usefulness of the Degree of Blood–brain Barrier Disruption to Predict Neurological Prognosis in Cardiac Arrest Survivors who Wnderwent Target Temperature Management: A Retrospective Study

Usefulness of the Degree of Blood–brain Barrier Disruption to Predict Neurological Prognosis in Cardiac Arrest Survivors who Wnderwent Target Temperature Management: A Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Usefulness of the Degree of Blood–brain Barrier Disruption to Predict Neurological Prognosis in Cardiac Arrest Survivors who Wnderwent Target Temperature Management: A Retrospective Study Ga Ram Jeon, Hong Joon Ahn, Jung Soo Park, Insool Yoo, Yeonho You, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-61579/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: This study aimed to compare the day-specific association of blood–brain barrier (BBB) disruption with neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors treated with target temperature management (TTM). Methods: This retrospective single-center study included 68 OHCA survivors, who underwent TTM between April 2018 and December 2019. The albumin quotient (Q A ) was calculated as [albumin CSF ] / [albumin serum ] immediately (day 1), and at 24 h (day 2), 48 h (day 3), and 72 h (day 4) after return of spontaneous circulation (ROSC). The degree of BBB disruption was weighted using the following scoring system: 0.07 ≥ Q A (normal), 0.01 ≥ Q A > 0.007 (mild), 0.02 ≥ Q A > 0.01 (moderate), and Q A > 0.02 (severe). This system gave it 0 (normal), 1 (mild), 4 (moderate), and 9 (severe) points. Poor neurological outcome was determined at six months after ROSC and was defined as cerebral performance categories 3–5. Results: We enrolled 68 patients (males, 48; 71%); 37 (54%) of them had a poor neurological outcome. The distributions of this outcome at six months in patients with moderate and severe BBB disruption versus the other groups were 19/22 (80%) vs. 18/46 (50%) on day 1, 31/37 (79%) vs. 6/31 (32%) on day 2, 32/37 (81%) vs. 5/31 (30%) on day 3, and 32/39 (85%) vs. 5/29 (30%) on day 4 ( P 0.009 (sensitivity 56.8%, specificity 87.1%); day 2, > 0.012 (sensitivity 81.1%, specificity 87.1%); day 3, > 0.013 (sensitivity 83.8%, specificity 87.1%); day 4, > 0.013 (sensitivity 86.5%, specificity 87.1%); sum of all time points, > 0.039 (sensitivity 89.5%, specificity 79.4%); and scoring system, > 9 (sensitivity 91.9%, specificity 87.1%). Conclusions: Our results suggested that Q A is a useful tool for predicting neurological outcomes in OHCA survivors treated with TTM. However, the prediction of poor neurological outcome using Q A showed low sensitivity at 100% specificity. Thus, it could be used as part of a multimodal approach than as a single prognostic prediction tool. Critical Care & Emergency Medicine Out-of-hospital cardiac arrest Blood–brain barrier Prognosis Edema Figures Figure 1 Figure 2 Figure 3 Figure 4 Background The blood–brain barrier (BBB) is composed of cerebral microvascular endothelial cells, a capillary base membrane, pericytes, and astrocyte end-feet. It regulates the movement of plasma constituents into the brain parenchyma [ 1 – 3 ]. The junctional complexes between endothelial cells comprise tight junctions and adherens junctions [ 1 ]. An ischemic/reperfusion injury, such as ischemic stroke and cardiac arrest (CA), increases the permeability of the BBB tight junctions due to microvascular damage induced through oxidative stress, resulting in BBB disruption [ 1 , 4 ]. With cytotoxic edema that does not produce BBB disruption, the total tissue brain mass will initially remain unchanged. However, vasogenic edema resulting in BBB disruption is compounded through the addition of water from the vascular space, which leads to tissue swelling, tissue movement, and eventually to an increase in intracranial pressure (ICP) [ 5 ]. Brain edema and ICP are associated with poor neurological outcome and death in patients who have survived a CA. The relationship between BBB disruption after CA and neurological prognosis is rare in clinical studies and mostly reported in animal studies. Our previous study was the first clinical study, where we reported that severe BBB disruption and its onset timing were strongly associated with poor neurological outcomes in the out-of-hospital cardiac arrest (OHCA) survivors who had undergone target temperature management (TTM) [ 6 ]. However, that study had several limitations. First, it was limited in its generalizability, as it comprised only a small number of patients (n = 21). Second, it did not reveal any relationship between the neurological outcome and the degree of BBB disruption. Third, the study could not predict poor neurological outcome of BBB disruption. We hypothesized that the degree of BBB disruption was associated with the neurological status in OHCA survivors. Therefore, we investigated the association between the degree of BBB disruption for three days and the neurological status six months after the return of spontaneous circulation (ROSC) in patients with OHCA who had been treated with TTM. Methods Study design and patients In this retrospective observational study, we used prospectively collected data derived from adult comatose OHCA survivors treated with TTM at Chungnam National University Hospital in Daejeon, Republic of Korea, between April 2018 and December 2019. The Institutional Review Board of Chungnam National University Hospital approved this study (CNUH-2020-04-103). This study included 14 patients from our previous studies on severe BBB disruption [6]. We included adult (≥ 18 years) OHCA survivors, who were unconscious (Glasgow Coma Scale score, ≤ 8) after ROSC. They had been treated with TTM using an Arctic Sun ® system (Energy Transfer Pads™; Medivance Corp, Louisville, CO, USA). We excluded patients (1) who had experienced a traumatic CA or an interrupted TTM owing to transfer or death, (2) who were ineligible for lumbar puncture (LP), (3) who were receiving extracorporeal membrane oxygenation, (4) who had no next of kin to provide consent for an LP procedure, and (5) whose next of kin did not consent to further treatment. The ineligibility for LP was determined if the brain computed tomography showed severe cerebral edema, obliteration of the basal cisterns, an occult intracranial mass lesion, or coagulopathy with a platelet count 1.5. Targeted temperature management Comatose OHCA survivors underwent TTM in accordance with our previously published TTM protocols [7]. A target temperature of 33°C was maintained for 24 h using an Arctic Sun ® feedback-controlled surface cooling device. Upon completion of the TTM maintenance period, the patients were rewarmed to 37°C at a rate of 0.25°C/h, and the temperature was monitored using a bladder temperature probe. All patients received sedatives, and a neuromuscular blocking agent was used during TTM. Midazolam (0.05 mg/kg intravenous bolus, followed by a titrated intravenous continuous infusion between 0.05 and 0.2 mg/kg/h) and cisatracurium (0.15 mg/kg intravenous bolus, followed by an infusion up to 5 μg/kg/min) were administered to sedate the patient and to control shivering, respectively. Anesthetic depth was monitored using ADMS™ (Anesthetic Depth Monitor for Sedation, Unimedics Co., Ltd., Seoul, Republic of Korea). An electroencephalography was performed if persistent deterioration in a patient’s consciousness level, involuntary movements, or seizures were observed. In case of evidence of electrographic seizures or clinical diagnosis of seizures, we administered an antiepileptic medication, namely, levetiracetam (loading dose, 2 g bolus, intravenously; maintenance dose, 1 g bolus, twice daily, intravenously). All other aspects of patient management involved standard intensive care processes, carried out in accordance with our institutional intensive care unit protocol. Data collection We obtained data on the following parameters from hospital records: age, sex, medical history (hypertension, coronary artery disease, diabetes mellitus), witnessed collapse, bystander cardiopulmonary resuscitation (CPR), first monitored rhythm, etiology of CA, time from collapse to CPR (no flow time), time from CPR to ROSC (low flow time), time from ROSC to obtaining ICP via LP (ICP time), and sequential organ failure assessment (SOFA) score within the first 24 h after admission. We assessed the neurological outcomes at three months after OHCA via phone interview, using the cerebral performance category (CPC) scale, as follows: CPC 1, good performance; CPC 2, moderate disability; CPC 3, severe disability; CPC 4, vegetative state; or CPC 5, brain death or death [8, 9]. Measurement of albumin quotient and scoring system A lumbar catheter insertion was performed using the Hermetic TM lumbar catheter accessory kit (Integra Neurosciences, Plainsboro, NJ, USA) with the patient lying in a lateral decubitus position with hips and knees flexed. CSF albumin and serum albumin samples were obtained at the same time immediately (day 1), and at 24 h (day 2), 48 h (day 3), and 72 h (day 4) after ROSC. The albumin quotient (Q A ) was calculated using the following formula: albumin quotient (Q A ) = [albumin CSF ] / [albumin serum ] The degree of BBB disruption was defined as follows: 0.07 ≥ Q A (normal), 0.01 ≥ Q A > 0.007 (mild), 0.02 ≥ Q A > 0.01 (moderate), and Q A > 0.02 (severe). Based on our previous studies, the scoring system weighted the degree of BBB disruption and gave it 0 (normal), 1 (mild), 4 (moderate), and 9 (severe) points. For example, if normal disruption occurred on day 1, mild disruption on day 2, moderate disruption on day 3, and severe disruption on day 4, then the weighted score would be 0 + 1 + 4 + 9 = 14 points. Statistical analysis We described categorical variables as frequencies and percentages and continuous variables as median values with interquartile ranges. We compared categorical variables between groups using the χ 2 test with continuity correction in 2 × 2 tables. We compared continuous variables between groups using the Mann–Whitney U test, since all continuous variables showed non-normal distribution. At each time point, the receiver operating characteristic (ROC) curves were plotted and corresponding areas under the curve (AUC) were determined to evaluate the predictive performance of BBB disruption on poor neurological outcome (CPC 3–5). The cutoff value for predicting poor neurological outcomes after six months post-OHCA was determined using the Youden index. Data were analyzed using SPSS software version 18 (SPSS Inc., Chicago, IL, USA). The ROC curves were calculated using MedCalc version 15.2.2 (MedCalc Software, Mariakerke, Belgium). The significance level was set to P < 0.05. Results Clinical characteristics of the patients In total, 81 adult comatose OHCA survivors had been treated with TTM during the study period. Of these, 68 patients were enrolled in the study. At six months after ROSC, 31 (45.6%) patients were in the good neurological outcome group, whereas 37 (54.4%) were in the poor neurological outcome group (Fig. 1). Table 1 displays the demographic and OHCA characteristics, stratified according to the neurological outcome at six months. There were no significant differences between the two groups in terms of median age, sex, pre-existing illness, and LP time. Patients with good neurological outcome had a higher incidence of witness arrest and bystander CPR, were more likely to have a shockable rhythm and a cardiac etiology, had shorter no- and low flow times, and had lower SOFA scores. Table 1 Baseline demographics and clinical characteristics Characteristics Total (n=68) Good neurological outcome (n=31) Poor neurological outcome (n=37) P-value Age, years, median (IQR) 55.9 (52.1 – 59.8) 54.7 (48.8 – 60.6) 57.1 (51.8 – 62.5) 0.53 Male, n (%) 53 (73.6) 28 (82.4) 25 (65.8) 0.18 Preexisting illness, n (%) DM 25 (34.7) 11 (32.4) 14 (36.8) 0.81 HTN 26 (36.1) 14 (41.2) 12 (31.6) 0.47 Coronary artery disease 11 (15.4) 6 (17.6) 5 (13.2) 0.75 Cardiac arrest Witness, n (%), 49 (68.1) 28 (82.4) 21(55.3) 0.02 Bystander CPR, n (%) 49 (68.1) 30 (88.2) 19 (50.0) < 0.001 Shockable rhythm, n (%) 19 (26.4) 18 (52.9) 1 (2.6) < 0.001 Cardiac aetiology, n (%) 29 (40.3) 20 (58.8) 9 (23.7) 0.04 No flow time, min, median (IQR) 2.0 (0.0 – 18.5) 0.5 (0.0 – 4.25) 10.5 (1.0 – 31.3) < 0.001 Low flow time, min, median (IQR) 19.0 (9.0–30.0) 12.0 (5.8 – 20.0) 28.0 (15.0 – 43.0) < 0.001 LP time, hour, median (IQR) 4.7 (3.3 – 6.1) 4.3 (3.0 – 5.6) 4.8 (4.3 – 6.4) 0.1 SOFA score 10.0 (7.0–12.0) 8.0 (7.0 – 11.0) 11.0 (8.0 – 12.0) 0.04 IQR, interquartile range; DM, diabetes mellitus; HTN, hypertension; CPR, cardiopulmonary resuscitation; ROSC, restoration of spontaneous circulation; LP, lumbar puncture; SOFA, sequential organ failure assessment Serial comparison of Q A levels between good and poor neurological outcome groups The Q A levels were significantly lower in the good neurological outcome group compared with that in the poor neurological outcome group at each time point ( P < 0.001). On days 1–4, the Q A values between the good and poor neurological outcome groups were 0.006 (0.003–0.009) vs. 0.011 (0.007–0.018); 0.007 (0.004–0.009) vs. 0.027 (0.015–0.131); 0.007 (0.004–0.009) vs. 0.032 (0.017–0.151); and 0.006 (0.004–0.010) vs. 0.044 (0.017–0.226) (Fig. 2). Serial comparison of the degree of BBB disruption and neurological outcome Fig. 3 shows that the proportion of poor neurological outcomes was higher than that of good neurological outcomes, when there was a moderate or severe BBB disruption at all time point. Of the 68 patients, moderate and severe BBB disruption was determined for 22 (32.4%) patients on day 1, 37 (54.4%) on day 2, 37 (54.4%) on day 3, and 39 (57.3%) on day 4, with the highest number of patients on day 4. The distributions of poor neurological outcome at six months in the moderate and severe BBB disruption group and other groups were 19/22 (80%) vs. 18/46 (50%) on day 1, 31/37 (79%) vs. 6/31 (32%) on day 2, 32/37 (81%) vs. 5/31 (30%) on day 3, and 32/39 (85%) vs. 5/29 (30%) on day 4, respectively, with P 0.009 (sensitivity 56.8%, specificity 87.1%; P 0.012 (sensitivity 81.1%, specificity 87.1%; P 0.013 (sensitivity 83.8%, specificity 87.1%; P 0.013 (sensitivity 86.5%, specificity 87.1%; P 0.039 (sensitivity 89.5%, specificity 79.4%; P 9 (sensitivity 91.9%, specificity 87.1%; P < 0.001) (Fig. 4). Comparison of ROC curves revealed that predictive value of Q A on day 1 was significantly lower compared with that on other days, sum of all time points, and scoring system (Table 2). Numerically, the largest area under the curve was of the scoring system, followed by sum of all time points and day 4 (Fig. 4). Table 2 Comparison of ROC curves for day-specific Q A prediction of poor neurological outcome at 6-month. ROC Difference AUC 95% Confidence interval P Day 1 – Day 2 0.118 0.007– 0.228 0.037 Day 1 – Day 3 0.122 0.004– 0.240 0.043 Day 1 – Day 4 0.142 0.033 – 0.250 0.011 Day 1 – Sum, 0.156 0.068– 0.244 <0.001 Day 1 – Score 0.168 0.075 – 0.260 <0.001 Day 2 – Day 3 0.004 -0.069– 0.078 0.907 Day 2 – Day 4 0.024 -0.041– 0.089 0.467 Day 2 – Sum 0.038 -0.023– 0.098 0.219 Day 2 – Score 0.050 -0.004 – 0.104 0.070 Day 3 – Day 4 0.020 -0.039 – 0.079 0.514 Day 3 – Sum 0.034 -0.021 – 0.089 0.232 Day 3 – Score 0.046 -0.007– 0.098 0.087 Day 4 – Sum 0.014 -0.035– 0.062 0.572 Day 4 – Score 0.026 -0.013– 0.065 0.188 Sum – Score 0.012 -0.011 – 0.036 0.303. ROC, receiver operating characteristic; Q A , albumin quotient Specific Q A levels associated with poor neurological outcomes on the different days of measurement: Q A level > 0.061 on day 1 with 100% specificity and 5.4% sensitivity; Q A level > 0.056 on day 2 with 100% specificity and 34.2% sensitivity; Q A level > 0.167 on day 3 with 100% specificity and 24.3% sensitivity; and Q A level > 0.062 on day 4 with 100% specificity and 40.5% sensitivity. The sum of all time points Q A level > 0.26 was associated with poor neurological outcomes with 100% specificity and 44.7% sensitivity; and scoring system > 27 points was associated with poor neurological outcomes with 100% specificity and 48.7% sensitivity. Discussion In this study, we determined that the degrees of BBB disruption measured during the 72 h after ROSC in OHCA survivors significantly associated with the 6-month poor neurological outcomes. However, the major result of our study was that the association of BBB disruption with neurological outcomes significantly differed depending on the degree and day of measurement. Moderate and severe BBB disruption (Q A > 0.01) was associated with poor neurological outcomes, and 72 h after ROSC had the highest predictive prognostic performance. Several clinical studies have reported that BBB disruption occurs in people with severe traumatic brain injury and contributes to poor neurological outcomes [10, 11]. However, the relationship between BBB disruption and neurological outcomes in post-CA has primarily been reported in animal studies, except our previous study [12, 13]. Li et al. [12] reported that post-CA global cerebral ischemia resulted in BBB disruption at 24 h after ROSC in a swine model, and attenuation of the BBB disruption was achieved through mild hypothermia (33°C). Miclescu et al. [13] reported that the BBB disruption and neurologic injury increased 30 min after ROSC, the early stage in reperfusion after CA in a piglet model study, and that methylene blue could attenuate the BBB disruption. In our previous study [6], we reported that the Q A levels measured 24 h after ROSC would have poor prognosis if severe BBB disruption was observed; however, we did not provide an accurate cutoff value and time to predict the poor neurological outcomes. In this study, we determined the degree of BBB disruption, cutoff value, and time associated with poor neurological outcomes. The distributions of poor neurological outcome at six months in the moderate and severe BBB disruption group and other groups were 80% vs. 50% on day 1, 79% vs. 32% on day 2, 81% vs. 30% on day 3, and 85% vs. 30% on day 4. The moderate and severe BBB disruption group exhibited poorer neurological prognosis than the normal and mild BBB disruption group with the greatest difference on day 4. Although the Q A levels on all individual days of measurement predicted six months poor neurological outcomes, our results indicated that association with outcomes varied depending on the Q A measurement time. The Q A levels measured on day 1 offered significantly weaker association compared with the other days, sum of all time points, and scoring system. Numerically, the largest area under the curve was of the scoring system, followed by sum of all time points. Unfortunately, the prediction of poor neurological outcomes using BBB disruption displayed low sensitivity at 100% specificity; thus, it could be used as part of the multimodal approach than as a single prognostic prediction tool. It is important to determine the timing of BBB disruption in OHCA survivors for timely treatment and better prognosis [14]. International guidelines for the treatment of OHCA survivors do not recommend any special medication, except for TTM to reduce ICP [15]. From a clinical perspective, hyperosmolar therapy is performed to reduce ICP occurring in brain edema; it reduces edema by draining fluid from the brain. When the BBB is disrupted, osmotic active particles can accumulate in the brain and potentiate edema [16]. However, the use of hyperosmolar therapy in treating cerebral edema due to CA requires further investigations. Heradstveit et al. [17] conducted a comparative study of 19 CA survivors using 7.2% hypertonic saline with 6% poly starch solution (HH) therapy or standard fluid therapy (Ringer’s acetate and normal saline) for 24 h after ROSC. The authors reported that the effects of both forms of fluid therapy on brain edema were similar, as magnetic resonance imaging (MRI) showed no differentiation between the two therapies. However, of the 10 patients who underwent MRI in their study, nine were scanned immediately at ROSC. The authors reported that MRI did not reveal vasogenic cerebral edema, such as BBB disruption, in any of these patients. They explained that this absence of vasogenic edema may have been due to CA, that the arrests were witnessed, and the short time before CPR initiation. However, in our study, the number of patients with BBB disruption was 41/68 (60%) on day 1, 49/68 (72%) on day 2, 44/68 (65%) on day 3, and 46/68 (68%) on day 4. We assume that the study by Heradstveit et al. involved CA survivors without BBB disruption, and that there was selection bias in their comparison of cerebral edema deterioration between HH and standard fluid therapies. However, although some animal studies have shown that hyperosmolar therapy had an anti-edema effect [18, 19], Kaufmann and Cardoso [20] reported that repeated mannitol infusion of cold-induced cerebral edema in cat models worsened the vasogenic cerebral edema, possibly due to the accumulation of osmotic active particles in the interstitial space due to BBB disruption. Therefore, we consider that hyperosmolar therapy to reduce cerebral edema for OHCA survivors remains an under-researched area, and that determining whether BBB disruption has occurred in such patients is important. This study had several limitations. First, this was a retrospective and single-centered study; however, it comprised the largest number of patients with BBB disruption among patients with OHCA, published to date. Future studies with larger sample sizes and prospective multicenter designs are warranted. Second, of the 81 patients who had undergone TTM during the study, 13 (16%) were excluded because their lumbar drainage had not been undertaken. This might have caused selection bias and could limit the generalizability of our findings. Third, lumbar drainage is rare in clinical practice and is very complex to apply; hence, the general use of this procedure is unlikely. Conclusions Our results suggest that the degree of BBB disruption is a useful tool for predicting 6-month neurological outcome in OHCA survivors treated with TTM. The highest associations of BBB disruption with poor neurological outcomes were observed on scoring system, followed by sum of all time points and on day 4 after ROSC. However, the prediction of poor neurological outcomes using BBB disruption displayed low sensitivity at 100% specificity; thus, it could be used as part of a multimodal approach than as a single prognostic prediction tool. List Of Abbreviations BBB, blood-brain barrier; CA, cardiac arrest; ICP, intracranial pressure; OHCA, out-of hospital cardiac arrest; TTM, target temperature management; ROSC, return of spontaneous circulation; LP, lumbar puncture; CPR, cardiopulmonary resuscitation; SOFA, sequential organ failure assessment; CPC, cerebral performance category; Q A , albumin quotient; ROC, receiver operating characteristic; AUC, areas under the curve; HH, 7.2% hypertonic saline with 6% poly starch solution; MRI, magnetic resonance imaging Declarations Ethics approval and consent to participate The study design and plan were approved by the institutional review boards (IRB) of Chungnam National University Hospital (Approval No. CNUH-2020-04-103). Written informed consent was waived by the IRB. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding Y.You received a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1F1A1041024). Authors' Contributions JS Park and BK Lee contributed to study conception and design. YC Choi, W Jeong, C Kang, I Yoo, and JH Min contributed to data acquisition. GR Jeon, HJ Ahn and JS Park contributed to data analysis and interpretation. Y You and HJ Ahn contributed to statistical analysis and revision. Y You contributed to acquisition of funding. HR Jeon, I Yoo, HJ Ahn, BK Lee and JS Park contributed to the drafting of the manuscript and its critical revision for important intellectual content. All authors have read and approved the final version of the manuscript. Acknowledgements None References Obermeier B, Daneman R, Ransohoff RM: Development, Maintenance and Disruption of the Blood-Brain Barrier. Nat Med. 2013; 19:1584–96. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ: Structure and function of the blood-brain barrier. Neurobiol Dis 2010; 37:13-25. Ballabh P, Braun A, Nedergaard M: The blood-brain barrier : an overview: structure, regulation, and clinical implications. Neurobiol Dis 2004; 16:1-13. Gursoy-Ozdemir Y, Yemisci M, Dalkara T: Microvascular protection is essential for successful neuroprotection in stroke. J Neurochem. 2012; 123 Suppl 2:2-11. Keijzer HM, Hedemaekers CWE, Meijer FJA, Tonino BAR, Klijn CJM, Hofmeijer J: Brain Imaging in Comatose Survivors of Cardiac Arrest: Pathophysiological Correlates and Prognostic Properties. Resuscitation 2018; 133:124–36. Park JS, You Y, Min JH, Yoo I, Jeong W, Cho Y, Ryu S, Lee J, Kim SW, Cho SU, et al.: Study on the timing of severe blood-brain barrier disruption using cerebrospinal fluid-serum albumin quotient in post cardiac arrest patients treated with targeted temperature management. Resuscitation 2019; 135:118–23. You Y, Park J, Min J, Yoo I, Jeong W, Cho Y, Ryu S, Lee J, Kim S, Cho S, et al: Relationship between time related serum albumin concentration, optic nerve sheath diameter, cerebrospinal fluid pressure, and neurological prognosis in cardiac arrest survivors. Resuscitation 2018; 131:42–7. Longstreth Jr. WT, Nichol G, Van Ottingham L, Hallstrom AP: Two simple questions to assess neurologic outcomes at 3 months after outofhospital cardiac arrest: experience from the public access defibrillation trial. Resuscitation 2010; 81:530–3. Booth CM, Boone RH, Tomlinson G, Detsky AS: Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA 2004; 291:870–879. Saw MM, Chamberlain J, Barr M, Morgan MPG, Burnett JR, Ho KM: Differential Disruption of Blood-Brain Barrier in Severe Traumatic Brain Injury. Neurocrit Care. 2014; 20:209-16. Jeffcote T, Ho KM: Associations between cerebrospinal fluid concentrations, serum albumin concentrations and intracranial pressure in neurotrauma and intracranial haemorrhage. Anaesth Intensive Care. 2010;38:274–9. Li J, Li C, Yuan W, Wu J, Li J, Li Z, Zhao Y: Mild Hypothermia Alleviates Brain Edema and Blood-Brain Barrier Disruption by Attenuating Tight Junction and Adherens Junction Breakdown in a Swine Model of Cardiopulmonary Resuscitation. PLoS One 2017; 12: e0174596. Miclescu A, Sharma HS, Martijn C, Wiklund L: Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions. Crit Care Med 2010; 38:2199–206. Blyth BJ, Farhavar A, Gee C, Hawthorn B, He H, Nayak A, Stöcklein V, Bazarian JJ: Validation of serum markers for blood-brain barrier disruption in traumatic brain injury. J Neurotrauma 2009; 26:1497–507. Nolan JP, Soar J, Cariou A, Cronberg T, Moulaert VR, Deakin CD, Bottiger BW, Friberg H, Sunde K, Sandroni C.: European Resuscitation Council and European Society of Intensive Care Medicine guidelines for post-resuscitation care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015. Resuscitation 2015; 95:202–22. Hayman EG, Patel AP, Kimberly WT, Sheth KN, Simard JM.: Cerebral Edema After Cardiopulmonary Resuscitation: A Therapeutic Target Following Cardiac Arrest? Neurocrit Care 2018; 28:276–87. Heradstveit BE, Guttormsen AB, Langørgen J, Hammersborg SM, Wentzel-Larsen T, Fanebust R, Larsson EM, Heltne JK.: Capillary leakage in post-cardiac arrest survivors during therapeutic hypothermia: a prospective, randomised study. Scand J Trauma Resusc Emerg Med. 2010; 18:29. Nakayama S, Migliati E, Amiry-Moghaddam M, Ottersen OP, Bhardwaj A.: Osmotherapy with hypertonic saline attenuates global cerebral edema following experimental cardiac arrest via perivascular pool of aquaporin-4. Crit Care Med.2016;44:e702–10. Miclescu A, Sharma HS, Wiklund L: Crystalloid vs. hypertonic crystalloid-colloid solutions for induction of mild therapeutic hypothermia after experimental cardiac arrest. Resuscitation 2013; 84:256–62. Kaufmann AM, Cardoso ER: Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg. 1992; 77:584-9. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-61579","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":1637363,"identity":"6f006087-98c1-477e-b3dd-c7b66f47cf15","order_by":0,"name":"Ga Ram Jeon","email":"","orcid":"","institution":"Chungnam National University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ga","middleName":"Ram","lastName":"Jeon","suffix":""},{"id":1637364,"identity":"ca63d8ca-9916-4b81-9fd0-e517dd9de4b8","order_by":1,"name":"Hong Joon Ahn","email":"","orcid":"","institution":"Chungnam National University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hong","middleName":"Joon","lastName":"Ahn","suffix":""},{"id":1637365,"identity":"eca3b528-9d54-43f1-a058-ab8e72f2eed3","order_by":2,"name":"Jung Soo Park","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAoElEQVRIiWNgGAWjYLCCD1CasYFYHYwzSNbCzEOSFv7Zzc8+29TcSWxgP/yAceYeIrRI3DlmPDvn2LPEBp40A8YNz4jQYiCRw8yc23A4sYEhh4HxwQFitViCtPC/IUULI0iLBNCWDcRoAfmFsefYYeM2iWcGB2cQowUYYo8ZftQclu3nT374sIcYLQwSUJoNiInSgNAyCkbBKBgFowAnAABeuzScA33s1gAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4283-5423","institution":"Chungnam National University School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jung","middleName":"Soo","lastName":"Park","suffix":""},{"id":1637366,"identity":"492bcd8d-d190-46ab-8751-87b1cf0eadc8","order_by":3,"name":"Insool Yoo","email":"","orcid":"","institution":"Chungnam National University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Insool","middleName":"","lastName":"Yoo","suffix":""},{"id":1637367,"identity":"c4912e74-a88c-4aee-865a-930470173278","order_by":4,"name":"Yeonho You","email":"","orcid":"","institution":"Chungnam National University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yeonho","middleName":"","lastName":"You","suffix":""},{"id":1637368,"identity":"187b9ef4-c762-41bf-9234-aa2b7b3dfe89","order_by":5,"name":"Jin Hong Min","email":"","orcid":"","institution":"Chungnam National University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jin","middleName":"Hong","lastName":"Min","suffix":""},{"id":1637369,"identity":"fb0a7145-2571-46b3-b662-b7da49d9e1c6","order_by":6,"name":"Wonjoon Jeong","email":"","orcid":"","institution":"Chungnam National University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wonjoon","middleName":"","lastName":"Jeong","suffix":""},{"id":1637370,"identity":"557aec44-f69b-4af3-9b4b-50c97e03a07f","order_by":7,"name":"Yong Chul Cho","email":"","orcid":"","institution":"Chungnam National University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yong","middleName":"Chul","lastName":"Cho","suffix":""},{"id":1637371,"identity":"35d66bf4-1b55-41d1-880b-fedfa951e970","order_by":8,"name":"Changshin Kang","email":"","orcid":"","institution":"Chungnam National University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Changshin","middleName":"","lastName":"Kang","suffix":""},{"id":1637372,"identity":"7ac17ca9-0da3-47f2-90ee-ebb4d369936d","order_by":9,"name":"Byung KooK Lee","email":"","orcid":"","institution":"Chonnam National University Medical School","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Byung","middleName":"KooK","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2020-08-18 10:45:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-61579/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-61579/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":2064728,"identity":"cf28acc9-6589-49a3-97d4-c2dd8df77294","added_by":"auto","created_at":"2020-08-25 11:42:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56480,"visible":true,"origin":"","legend":"Flow diagram for patient inclusion","description":"","filename":"OnlineFigure1.Png","url":"https://assets-eu.researchsquare.com/files/rs-61579/v1/OnlineFigure1.Png"},{"id":2064729,"identity":"8ef4fa33-8f90-4b09-a77f-5be0052b9afd","added_by":"auto","created_at":"2020-08-25 11:42:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30130,"visible":true,"origin":"","legend":"Comparison of the albumin quotient levels (QA) for different neurological outcomes at each time point. Poor neurological outcome group had significantly higher QA levels (median with interquartile range) than good neurological outcome group at all time point. *P \u003c 0.001","description":"","filename":"OnlineFigure2...Png","url":"https://assets-eu.researchsquare.com/files/rs-61579/v1/OnlineFigure2...Png"},{"id":2064730,"identity":"f612039c-33e2-4062-b301-48754637131c","added_by":"auto","created_at":"2020-08-25 11:42:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":61850,"visible":true,"origin":"","legend":"Comparison of neurological outcomes after six months of return of spontaneous circulation according to the degree of blood–brain barrier disruption at each time point. In the moderate and severe blood–brain barrier disruption group, the distribution of poor neurological outcome was significantly higher than hat in the normal and moderate blood–brain barrier disruption groups (P \u003c 0.001)","description":"","filename":"OnlineFigure3.Png","url":"https://assets-eu.researchsquare.com/files/rs-61579/v1/OnlineFigure3.Png"},{"id":2064731,"identity":"5720c2ed-da28-4150-ab29-57113be7e0f9","added_by":"auto","created_at":"2020-08-25 11:42:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":84510,"visible":true,"origin":"","legend":"Association of albumin quotient (QA) with poor neurological outcomes. (A) Receiver operating characteristic (ROC) curve for QA levels on day 1. (B) ROC curve for QA levels on day 2. (C) ROC curve for QA levels on day 3. (D) ROC curve for QA levels on day 4. E ROC curve for QA levels at sum of all time points. (F) ROC curve for QA levels at scoring system","description":"","filename":"OnlineFigure4.Png","url":"https://assets-eu.researchsquare.com/files/rs-61579/v1/OnlineFigure4.Png"},{"id":13585765,"identity":"b2683a22-7abc-4de3-80a0-9cb71aed3c42","added_by":"auto","created_at":"2021-09-17 04:44:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1046093,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-61579/v1/2c158372-04ca-4fad-9771-b88b3b78db3e.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eUsefulness of the Degree of Blood–brain Barrier Disruption to Predict Neurological Prognosis in Cardiac Arrest Survivors who Wnderwent Target Temperature Management: A Retrospective Study\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eThe blood\u0026ndash;brain barrier (BBB) is composed of cerebral microvascular endothelial cells, a capillary base membrane, pericytes, and astrocyte end-feet. It regulates the movement of plasma constituents into the brain parenchyma [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The junctional complexes between endothelial cells comprise tight junctions and adherens junctions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. An ischemic/reperfusion injury, such as ischemic stroke and cardiac arrest (CA), increases the permeability of the BBB tight junctions due to microvascular damage induced through oxidative stress, resulting in BBB disruption [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. With cytotoxic edema that does not produce BBB disruption, the total tissue brain mass will initially remain unchanged. However, vasogenic edema resulting in BBB disruption is compounded through the addition of water from the vascular space, which leads to tissue swelling, tissue movement, and eventually to an increase in intracranial pressure (ICP) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Brain edema and ICP are associated with poor neurological outcome and death in patients who have survived a CA.\u003c/p\u003e \u003cp\u003eThe relationship between BBB disruption after CA and neurological prognosis is rare in clinical studies and mostly reported in animal studies. Our previous study was the first clinical study, where we reported that severe BBB disruption and its onset timing were strongly associated with poor neurological outcomes in the out-of-hospital cardiac arrest (OHCA) survivors who had undergone target temperature management (TTM) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, that study had several limitations. First, it was limited in its generalizability, as it comprised only a small number of patients (n\u0026thinsp;=\u0026thinsp;21). Second, it did not reveal any relationship between the neurological outcome and the degree of BBB disruption. Third, the study could not predict poor neurological outcome of BBB disruption.\u003c/p\u003e \u003cp\u003eWe hypothesized that the degree of BBB disruption was associated with the neurological status in OHCA survivors. Therefore, we investigated the association between the degree of BBB disruption for three days and the neurological status six months after the return of spontaneous circulation (ROSC) in patients with OHCA who had been treated with TTM.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003eStudy design and patients\u003c/h2\u003e\n\u003cp\u003eIn this retrospective observational study, we used prospectively collected data derived from adult comatose OHCA survivors treated with TTM at Chungnam National University Hospital in Daejeon, Republic of Korea, between April 2018 and December 2019. The Institutional Review Board of Chungnam National University Hospital approved this study (CNUH-2020-04-103). This study included 14 patients from our previous studies on severe BBB disruption [6].\u003c/p\u003e\n\u003cp\u003eWe included adult (\u0026ge;\u0026nbsp;18 years) OHCA survivors, who were unconscious (Glasgow Coma Scale score, \u0026le;\u0026nbsp;8) after ROSC. They had been treated with TTM using an Arctic Sun\u003csup\u003e\u0026reg;\u003c/sup\u003e system (Energy Transfer Pads\u0026trade;; Medivance Corp, Louisville, CO, USA). We excluded patients (1) who had experienced a traumatic CA or an interrupted TTM owing to transfer or death, (2) who were ineligible for lumbar puncture (LP), (3) who were receiving extracorporeal membrane oxygenation, (4) who had no next of kin to provide consent for an LP procedure, and (5) whose next of kin did not consent to further treatment. The ineligibility for LP was determined if the brain computed tomography showed severe cerebral edema, obliteration of the basal cisterns, an occult intracranial mass lesion, or coagulopathy with a platelet count\u0026nbsp;\u0026lt;\u0026nbsp;40\u0026nbsp;\u0026times;\u0026nbsp;10\u003csup\u003e3\u003c/sup\u003e/mL or international normalized ratio\u0026nbsp;\u0026gt;\u0026nbsp;1.5.\u003c/p\u003e\n\u003ch2\u003eTargeted temperature management\u003c/h2\u003e\n\u003cp\u003eComatose OHCA survivors underwent TTM in accordance with our previously published TTM protocols [7]. A target temperature of 33\u0026deg;C was maintained for 24 h using an Arctic Sun\u003csup\u003e\u0026reg; \u003c/sup\u003efeedback-controlled surface cooling device. Upon completion of the TTM maintenance period, the patients were rewarmed to 37\u0026deg;C at a rate of 0.25\u0026deg;C/h, and the temperature was monitored using a bladder temperature probe.\u003c/p\u003e\n\u003cp\u003eAll patients received sedatives, and a neuromuscular blocking agent was used during TTM. Midazolam (0.05 mg/kg intravenous bolus, followed by a titrated intravenous continuous infusion between 0.05 and 0.2 mg/kg/h) and cisatracurium (0.15 mg/kg intravenous bolus, followed by an infusion up to 5 \u0026mu;g/kg/min) were administered to sedate the patient and to control shivering, respectively. Anesthetic depth was monitored using ADMS\u0026trade; (Anesthetic Depth Monitor for Sedation, Unimedics Co., Ltd., Seoul, Republic of Korea). An electroencephalography was performed if persistent deterioration in a patient\u0026rsquo;s consciousness level, involuntary movements, or seizures were observed. In case of evidence of electrographic seizures or clinical diagnosis of seizures, we administered an antiepileptic medication, namely, levetiracetam (loading dose, 2 g bolus, intravenously; maintenance dose, 1 g bolus, twice daily, intravenously). All other aspects of patient management involved standard intensive care processes, carried out in accordance with our institutional intensive care unit protocol.\u003c/p\u003e\n\u003ch2\u003eData collection\u003c/h2\u003e\n\u003cp\u003eWe obtained data on the following parameters from hospital records: age, sex, medical history (hypertension, coronary artery disease, diabetes mellitus), witnessed collapse, bystander cardiopulmonary resuscitation (CPR), first monitored rhythm, etiology of CA, time from collapse to CPR (no flow time), time from CPR to ROSC (low flow time), time from ROSC to obtaining ICP via LP (ICP time), and sequential organ failure assessment (SOFA) score within the first 24 h after admission. We assessed the neurological outcomes at three months after OHCA via phone interview, using the cerebral performance category (CPC) scale, as follows: CPC 1, good performance; CPC 2, moderate disability; CPC 3, severe disability; CPC 4, vegetative state; or CPC 5, brain death or death [8, 9].\u003c/p\u003e\n\u003ch2\u003eMeasurement of albumin quotient and scoring system\u003c/h2\u003e\n\u003cp\u003eA lumbar catheter insertion was performed using the Hermetic\u003csup\u003eTM\u003c/sup\u003e lumbar catheter accessory kit (Integra Neurosciences, Plainsboro, NJ, USA) with the patient lying in a lateral decubitus position with hips and knees flexed. CSF albumin and serum albumin samples were obtained at the same time immediately (day 1), and at 24 h (day 2), 48 h (day 3), and 72 h (day 4) after ROSC. The albumin quotient (Q\u003csub\u003eA\u003c/sub\u003e) was calculated using the following formula:\u003c/p\u003e\n\u003cp\u003ealbumin quotient (Q\u003csub\u003eA\u003c/sub\u003e)\u0026nbsp;=\u0026nbsp;[albumin\u003csub\u003eCSF\u003c/sub\u003e] / [albumin\u003csub\u003eserum\u003c/sub\u003e]\u003c/p\u003e\n\u003cp\u003eThe degree of BBB disruption was defined as follows: 0.07\u0026nbsp;\u0026ge;\u0026nbsp;Q\u003csub\u003eA \u003c/sub\u003e(normal), 0.01\u0026nbsp;\u0026ge;\u0026nbsp;Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;\u0026gt;\u0026nbsp;0.007 (mild), 0.02\u0026nbsp;\u0026ge;\u0026nbsp;Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;\u0026gt;\u0026nbsp;0.01 (moderate), and Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;\u0026gt;\u0026nbsp;0.02 (severe). Based on our previous studies, the scoring system weighted the degree of BBB disruption and gave it 0 (normal), 1 (mild), 4 (moderate), and 9 (severe) points. For example, if normal disruption occurred on day 1, mild disruption on day 2, moderate disruption on day 3, and severe disruption on day 4, then the weighted score would be 0\u0026nbsp;+\u0026nbsp;1\u0026nbsp;+\u0026nbsp;4\u0026nbsp;+\u0026nbsp;9\u0026nbsp;=\u0026nbsp;14 points.\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eWe described categorical variables as frequencies and percentages and continuous variables as median values with interquartile ranges. We compared categorical variables between groups using the \u0026chi;\u003csup\u003e2\u003c/sup\u003e test with continuity correction in 2 \u0026times; 2 tables. We compared continuous variables between groups using the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test, since all continuous variables showed non-normal distribution. At each time point, the receiver operating characteristic (ROC) curves were plotted and corresponding areas under the curve (AUC) were determined to evaluate the predictive performance of BBB disruption on poor neurological outcome (CPC 3\u0026ndash;5). The cutoff value for predicting poor neurological outcomes after six months post-OHCA was determined using the Youden index. Data were analyzed using SPSS software version 18 (SPSS Inc., Chicago, IL, USA). The ROC curves were calculated using MedCalc version 15.2.2 (MedCalc Software, Mariakerke, Belgium). The significance level was set to \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eClinical characteristics of the patients\u003c/h2\u003e\n\u003cp\u003eIn total, 81 adult comatose OHCA survivors had been treated with TTM during the study period. Of these, 68 patients were enrolled in the study. At six months after ROSC, 31 (45.6%) patients were in the good neurological outcome group, whereas 37 (54.4%) were in the poor neurological outcome group (Fig. 1). Table 1 displays the demographic and OHCA characteristics, stratified according to the neurological outcome at six months. There were no significant differences between the two groups in terms of median age, sex, pre-existing illness, and LP time. Patients with good neurological outcome had a higher incidence of witness arrest and bystander CPR, were more likely to have a shockable rhythm and a cardiac etiology, had shorter no- and low flow times, and had lower SOFA scores.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline demographics and clinical characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003eTotal (n=68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003eGood neurological outcome (n=31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003ePoor neurological outcome (n=37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003eAge, years, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e55.9 (52.1 \u0026ndash; 59.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e54.7 (48.8 \u0026ndash; 60.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e57.1 (51.8 \u0026ndash; 62.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.53\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003eMale, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e53 (73.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e28 (82.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e25 (65.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003ePreexisting illness, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;DM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e25 (34.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e11 (32.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e14 (36.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;HTN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e26 (36.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e14 (41.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e12 (31.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;Coronary artery disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e11 (15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e6 (17.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e5 (13.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.75\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003eCardiac arrest\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;Witness, n (%),\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e49 (68.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e28 (82.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e21(55.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.02\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;Bystander CPR, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e49 (68.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e30 (88.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e19 (50.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;Shockable rhythm, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e19 (26.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e18 (52.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e1 (2.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;Cardiac aetiology, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e29 (40.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e20 (58.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e9 (23.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;No flow time, min, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e2.0 (0.0 \u0026ndash; 18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e0.5 (0.0 \u0026ndash; 4.25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e10.5 (1.0 \u0026ndash; 31.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003e\u0026nbsp;Low flow time, min, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e19.0 (9.0\u0026ndash;30.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e12.0 (5.8 \u0026ndash; 20.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e28.0 (15.0 \u0026ndash; 43.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003eLP time, hour, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e4.7 (3.3 \u0026ndash; 6.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e4.3 (3.0 \u0026ndash; 5.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e4.8 (4.3 \u0026ndash; 6.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"227\"\u003e\n\u003cp\u003eSOFA score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e10.0 (7.0\u0026ndash;12.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e8.0 (7.0 \u0026ndash; 11.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e11.0 (8.0 \u0026ndash; 12.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" width=\"227\"\u003eIQR, interquartile range; DM, diabetes mellitus; HTN, hypertension; CPR, cardiopulmonary resuscitation; ROSC, restoration of spontaneous circulation; LP, lumbar puncture; SOFA, sequential organ failure assessment\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003e\u0026nbsp;Serial comparison of Q\u003csub\u003eA\u003c/sub\u003e levels between good and poor neurological outcome groups\u003c/h2\u003e\n\u003cp\u003eThe Q\u003csub\u003eA\u003c/sub\u003e levels were significantly lower in the good neurological outcome group compared with that in the poor neurological outcome group at each time point (\u003cem\u003eP\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001). On days 1\u0026ndash;4, the Q\u003csub\u003eA\u003c/sub\u003e values between the good and poor neurological outcome groups were 0.006 (0.003\u0026ndash;0.009) vs. 0.011 (0.007\u0026ndash;0.018); 0.007 (0.004\u0026ndash;0.009) vs. 0.027 (0.015\u0026ndash;0.131); 0.007 (0.004\u0026ndash;0.009) vs. 0.032 (0.017\u0026ndash;0.151); and 0.006 (0.004\u0026ndash;0.010) vs. 0.044 (0.017\u0026ndash;0.226) (Fig. 2).\u003c/p\u003e\n\u003ch2\u003eSerial comparison of the degree of BBB disruption and neurological outcome\u003c/h2\u003e\n\u003cp\u003eFig. 3 shows that the proportion of poor neurological outcomes was higher than that of good neurological outcomes, when there was a moderate or severe BBB disruption at all time point. Of the 68 patients, moderate and severe BBB disruption was determined for 22 (32.4%) patients on day 1, 37 (54.4%) on day 2, 37 (54.4%) on day 3, and 39 (57.3%) on day 4, with the highest number of patients on day 4. The distributions of poor neurological outcome at six months in the moderate and severe BBB disruption group and other groups were 19/22 (80%) vs. 18/46 (50%) on day 1, 31/37 (79%) vs. 6/31 (32%) on day 2, 32/37 (81%) vs. 5/31 (30%) on day 3, and 32/39 (85%) vs. 5/29 (30%) on day 4, respectively, with \u003cem\u003eP\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001.\u003c/p\u003e\n\u003ch2\u003eQ\u003csub\u003eA \u003c/sub\u003eand 6-month neurological outcome\u003c/h2\u003e\n\u003cp\u003eUsing ROC analyses, optimal cutoff values of Q\u003csub\u003eA\u003c/sub\u003e levels for prediction of poor neurological outcomes at six months were determined as: day 1, \u0026gt;\u0026nbsp;0.009 (sensitivity 56.8%, specificity 87.1%;\u003cem\u003e P\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001); day 2, \u0026gt;\u0026nbsp;0.012 (sensitivity 81.1%, specificity 87.1%;\u003cem\u003e P\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001); day 3, \u0026gt;\u0026nbsp;0.013 (sensitivity 83.8%, specificity 87.1%;\u003cem\u003e P\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001); day 4, \u0026gt;\u0026nbsp;0.013 (sensitivity 86.5%, specificity 87.1%;\u003cem\u003e P\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001); sum of all time points, \u0026gt;\u0026nbsp;0.039 (sensitivity 89.5%, specificity 79.4%;\u003cem\u003e P\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001); and scoring system, \u0026gt;\u0026nbsp;9 (sensitivity 91.9%, specificity 87.1%;\u003cem\u003e P\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001) (Fig. 4). Comparison of ROC curves revealed that predictive value of Q\u003csub\u003eA\u003c/sub\u003e on day 1 was significantly lower compared with that on other days, sum of all time points, and scoring system (Table 2). Numerically, the largest area under the curve was of the scoring system, followed by sum of all time points and day 4 (Fig. 4).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eComparison of ROC curves for day-specific Q\u003csub\u003eA\u003c/sub\u003e prediction of poor neurological outcome at 6-month.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eROC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDifference AUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e95% Confidence interval\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 1 \u0026ndash; Day 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.118\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e0.007\u0026ndash; 0.228\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.037\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 1 \u0026ndash; Day 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.122\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e0.004\u0026ndash; 0.240\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.043\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 1 \u0026ndash; Day 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.142\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e0.033 \u0026ndash; 0.250\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.011\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 1 \u0026ndash; Sum,\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.156\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e0.068\u0026ndash; 0.244\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 1 \u0026ndash; Score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.168\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e0.075 \u0026ndash; 0.260\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 2 \u0026ndash; Day 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.069\u0026ndash; 0.078\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.907\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 2 \u0026ndash; Day 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.024\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.041\u0026ndash; 0.089\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.467\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 2 \u0026ndash; Sum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.038\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.023\u0026ndash; 0.098\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.219\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 2 \u0026ndash; Score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.050\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.004 \u0026ndash; 0.104\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.070\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 3 \u0026ndash; Day 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.020\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.039 \u0026ndash; 0.079\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.514\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 3 \u0026ndash; Sum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.034\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.021 \u0026ndash; 0.089\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.232\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 3 \u0026ndash; Score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.046\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.007\u0026ndash; 0.098\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.087\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 4 \u0026ndash; Sum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.014\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.035\u0026ndash; 0.062\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.572\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eDay 4 \u0026ndash; Score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.026\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.013\u0026ndash; 0.065\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.188\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eSum \u0026ndash; Score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003e0.012\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e-0.011 \u0026ndash; 0.036\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"73\"\u003e\n\u003cp\u003e0.303.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" width=\"189\"\u003eROC,\u0026nbsp; receiver operating characteristic; Q\u003csub\u003eA\u003c/sub\u003e, albumin quotient\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSpecific Q\u003csub\u003eA\u003c/sub\u003e levels associated with poor neurological outcomes on the different days of measurement: Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;level\u0026nbsp;\u0026gt;\u0026nbsp;0.061 on day 1 with 100% specificity and 5.4% sensitivity; Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;level\u0026nbsp;\u0026gt;\u0026nbsp;0.056 on day 2 with 100% specificity and 34.2% sensitivity; Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;level\u0026nbsp;\u0026gt;\u0026nbsp;0.167 on day 3 with 100% specificity and 24.3% sensitivity; and Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;level\u0026nbsp;\u0026gt;\u0026nbsp;0.062 on day 4 with 100% specificity and 40.5% sensitivity. The sum of all time points Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;level\u0026nbsp;\u0026gt;\u0026nbsp;0.26 was associated with poor neurological outcomes with 100% specificity and 44.7% sensitivity; and scoring system \u0026gt; 27 points was associated with poor neurological outcomes with 100% specificity and 48.7% sensitivity.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we determined that the degrees of BBB disruption measured during the 72 h after ROSC in OHCA survivors significantly associated with the 6-month poor neurological outcomes. However, the major result of our study was that the association of BBB disruption with neurological outcomes significantly differed depending on the degree and day of measurement. Moderate and severe BBB disruption (Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;\u0026gt;\u0026nbsp;0.01) was associated with poor neurological outcomes, and 72 h after ROSC had the highest predictive prognostic performance.\u003c/p\u003e\n\u003cp\u003eSeveral clinical studies have reported that BBB disruption occurs in people with severe traumatic brain injury and contributes to poor neurological outcomes [10, 11]. However, the relationship between BBB disruption and neurological outcomes in post-CA has primarily been reported in animal studies, except our previous study [12, 13]. Li et al. [12] reported that post-CA global cerebral ischemia resulted in BBB disruption at 24 h after ROSC in a swine model, and attenuation of the BBB disruption was achieved through mild hypothermia (33\u0026deg;C). Miclescu et al. [13] reported that the BBB disruption and neurologic injury increased 30 min after ROSC, the early stage in reperfusion after CA in a piglet model study, and that methylene blue could attenuate the BBB disruption.\u003c/p\u003e\n\u003cp\u003eIn our previous study [6], we reported that the Q\u003csub\u003eA\u003c/sub\u003e levels measured 24 h after ROSC would have poor prognosis if severe BBB disruption was observed; however, we did not provide an accurate cutoff value and time to predict the poor neurological outcomes. In this study, we determined the degree of BBB disruption, cutoff value, and time associated with poor neurological outcomes. The distributions of poor neurological outcome at six months in the moderate and severe BBB disruption group and other groups were 80% vs. 50% on day 1, 79% vs. 32% on day 2, 81% vs. 30% on day 3, and 85% vs. 30% on day 4. The moderate and severe BBB disruption group exhibited poorer neurological prognosis than the normal and mild BBB disruption group with the greatest difference on day 4. Although the Q\u003csub\u003eA\u003c/sub\u003e levels on all individual days of measurement predicted six months poor neurological outcomes, our results indicated that association with outcomes varied depending on the Q\u003csub\u003eA\u003c/sub\u003e measurement time. The Q\u003csub\u003eA\u003c/sub\u003e levels measured on day 1 offered significantly weaker association compared with the other days, sum of all time points, and scoring system. Numerically, the largest area under the curve was of the scoring system, followed by sum of all time points. Unfortunately, the prediction of poor neurological outcomes using BBB disruption displayed low sensitivity at 100% specificity; thus, it could be used as part of the multimodal approach than as a single prognostic prediction tool.\u003c/p\u003e\n\u003cp\u003eIt is important to determine the timing of BBB disruption in OHCA survivors for timely treatment and better prognosis [14]. International guidelines for the treatment of OHCA survivors do not recommend any special medication, except for TTM to reduce ICP [15]. From a clinical perspective, hyperosmolar therapy is performed to reduce ICP occurring in brain edema; it reduces edema by draining fluid from the brain. When the BBB is disrupted, osmotic active particles can accumulate in the brain and potentiate edema [16]. However, the use of hyperosmolar therapy in treating cerebral edema due to CA requires further investigations. Heradstveit et al. [17] conducted a comparative study of 19 CA survivors using 7.2% hypertonic saline with 6% poly starch solution (HH) therapy or standard fluid therapy (Ringer\u0026rsquo;s acetate and normal saline) for 24 h after ROSC. The authors reported that the effects of both forms of fluid therapy on brain edema were similar, as magnetic resonance imaging (MRI) showed no differentiation between the two therapies. However, of the 10 patients who underwent MRI in their study, nine were scanned immediately at ROSC. The authors reported that MRI did not reveal vasogenic cerebral edema, such as BBB disruption, in any of these patients. They explained that this absence of vasogenic edema may have been due to CA, that the arrests were witnessed, and the short time before CPR initiation. However, in our study, the number of patients with BBB disruption was 41/68 (60%) on day 1, 49/68 (72%) on day 2, 44/68 (65%) on day 3, and 46/68 (68%) on day 4. We assume that the study by Heradstveit et al. involved CA survivors without BBB disruption, and that there was selection bias in their comparison of cerebral edema deterioration between HH and standard fluid therapies. However, although some animal studies have shown that hyperosmolar therapy had an anti-edema effect [18, 19], Kaufmann and Cardoso [20] reported that repeated mannitol infusion of cold-induced cerebral edema in cat models worsened the vasogenic cerebral edema, possibly due to the accumulation of osmotic active particles in the interstitial space due to BBB disruption. Therefore, we consider that hyperosmolar therapy to reduce cerebral edema for OHCA survivors remains an under-researched area, and that determining whether BBB disruption has occurred in such patients is important.\u003c/p\u003e\n\u003cp\u003eThis study had several limitations. First, this was a retrospective and single-centered study; however, it comprised the largest number of patients with BBB disruption among patients with OHCA, published to date. Future studies with larger sample sizes and prospective multicenter designs are warranted. Second, of the 81 patients who had undergone TTM during the study, 13 (16%) were excluded because their lumbar drainage had not been undertaken. This might have caused selection bias and could limit the generalizability of our findings. Third, lumbar drainage is rare in clinical practice and is very complex to apply; hence, the general use of this procedure is unlikely.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur results suggest that the degree of BBB disruption is a useful tool for predicting 6-month neurological outcome in OHCA survivors treated with TTM. The highest associations of BBB disruption with poor neurological outcomes were observed on scoring system, followed by sum of all time points and on day 4 after ROSC. However, the prediction of poor neurological outcomes using BBB disruption displayed low sensitivity at 100% specificity; thus, it could be used as part of a multimodal approach than as a single prognostic prediction tool.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003eBBB, blood-brain barrier; CA, cardiac arrest; ICP, intracranial pressure; OHCA, out-of hospital cardiac arrest; TTM, target temperature management; ROSC, return of spontaneous circulation; LP, lumbar puncture; CPR, cardiopulmonary resuscitation; SOFA, sequential organ failure assessment; CPC, cerebral performance category; Q\u003csub\u003eA\u003c/sub\u003e, albumin quotient; ROC, receiver operating characteristic; AUC, areas under the curve; HH, 7.2% hypertonic saline with 6% poly starch solution; MRI, magnetic resonance imaging\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThe study design and plan were approved by the institutional review boards (IRB) of Chungnam National University Hospital (Approval No. CNUH-2020-04-103). Written informed consent was waived by the IRB.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eY.You received a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1F1A1041024).\u003c/p\u003e\n\u003ch2\u003eAuthors' Contributions\u003c/h2\u003e\n\u003cp\u003eJS Park and BK Lee contributed to study conception and design. YC Choi, W Jeong, C Kang, I Yoo, and JH Min contributed to data acquisition. GR Jeon, HJ Ahn and JS Park contributed to data analysis and interpretation. Y You and HJ Ahn contributed to statistical analysis and revision. Y You contributed to acquisition of funding. HR Jeon, I Yoo, HJ Ahn, BK Lee and JS Park contributed to the drafting of the manuscript and its critical revision for important intellectual content. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eObermeier B, Daneman R, Ransohoff RM: Development, Maintenance and Disruption of the Blood-Brain Barrier. Nat Med. 2013; 19:1584\u0026ndash;96.\u003c/li\u003e\n\u003cli\u003eAbbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ: Structure and function of the blood-brain barrier. Neurobiol Dis 2010; 37:13-25.\u003c/li\u003e\n\u003cli\u003eBallabh P, Braun A, Nedergaard M: The blood-brain barrier : an overview: structure, regulation, and clinical implications. Neurobiol Dis 2004; 16:1-13.\u003c/li\u003e\n\u003cli\u003eGursoy-Ozdemir Y, Yemisci M, Dalkara T: Microvascular protection is essential for successful neuroprotection in stroke. J Neurochem. 2012; 123 Suppl 2:2-11.\u003c/li\u003e\n\u003cli\u003eKeijzer HM, Hedemaekers CWE, Meijer FJA, Tonino BAR, Klijn CJM, Hofmeijer J: Brain Imaging in Comatose Survivors of Cardiac Arrest: Pathophysiological Correlates and Prognostic Properties. Resuscitation 2018; 133:124\u0026ndash;36.\u003c/li\u003e\n\u003cli\u003ePark JS, You Y, Min JH, Yoo I, Jeong W, Cho Y, Ryu S, Lee J, Kim SW, Cho SU, et al.: Study on the timing of severe blood-brain barrier disruption using cerebrospinal fluid-serum albumin quotient in post cardiac arrest patients treated with targeted temperature management. Resuscitation 2019; 135:118\u0026ndash;23.\u003c/li\u003e\n\u003cli\u003eYou Y, Park J, Min J, Yoo I, Jeong W, Cho Y, Ryu S, Lee J, Kim S, Cho S, et al: Relationship between time related serum albumin concentration, optic nerve sheath diameter, cerebrospinal fluid pressure, and neurological prognosis in cardiac arrest survivors. Resuscitation 2018; 131:42\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eLongstreth Jr. WT, Nichol G, Van Ottingham L, Hallstrom AP: Two simple questions to assess neurologic outcomes at 3 months after outofhospital cardiac arrest: experience from the public access defibrillation trial. Resuscitation 2010; 81:530\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eBooth CM, Boone RH, Tomlinson G, Detsky AS: Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA 2004; 291:870\u0026ndash;879.\u003c/li\u003e\n\u003cli\u003eSaw MM, Chamberlain J, Barr M, Morgan MPG, Burnett JR, Ho KM: Differential Disruption of Blood-Brain Barrier in Severe Traumatic Brain Injury. Neurocrit Care. 2014; 20:209-16.\u003c/li\u003e\n\u003cli\u003eJeffcote T, Ho KM: Associations between cerebrospinal fluid concentrations, serum albumin concentrations and intracranial pressure in neurotrauma and intracranial haemorrhage. Anaesth Intensive Care. 2010;38:274\u0026ndash;9.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"12\"\u003e\n\u003cli\u003eLi J, Li C, Yuan W, Wu J, Li J, Li Z, Zhao Y: Mild Hypothermia Alleviates Brain Edema and Blood-Brain Barrier Disruption by Attenuating Tight Junction and Adherens Junction Breakdown in a Swine Model of Cardiopulmonary Resuscitation. PLoS One 2017; 12: e0174596.\u003c/li\u003e\n\u003cli\u003eMiclescu A, Sharma HS, Martijn C, Wiklund L: Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions. Crit Care Med 2010; 38:2199\u0026ndash;206.\u003c/li\u003e\n\u003cli\u003eBlyth BJ, Farhavar A, Gee C, Hawthorn B, He H, Nayak A, St\u0026ouml;cklein V, Bazarian JJ: Validation of serum markers for blood-brain barrier disruption in traumatic brain injury. J Neurotrauma 2009; 26:1497\u0026ndash;507.\u003c/li\u003e\n\u003cli\u003eNolan JP, Soar J, Cariou A, Cronberg T, Moulaert VR, Deakin CD, Bottiger BW, Friberg H, Sunde K, Sandroni C.: European Resuscitation Council and European Society of Intensive Care Medicine guidelines for post-resuscitation care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015. Resuscitation 2015; 95:202\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eHayman EG, Patel AP, Kimberly WT, Sheth KN, Simard JM.: Cerebral Edema After Cardiopulmonary Resuscitation: A Therapeutic Target Following Cardiac Arrest? Neurocrit Care 2018; 28:276\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eHeradstveit BE, Guttormsen AB, Lang\u0026oslash;rgen J, Hammersborg SM, Wentzel-Larsen T, Fanebust R, Larsson EM, Heltne JK.: Capillary leakage in post-cardiac arrest survivors during therapeutic hypothermia: a prospective, randomised study. Scand J Trauma Resusc Emerg Med. 2010; 18:29.\u003c/li\u003e\n\u003cli\u003eNakayama S, Migliati E, Amiry-Moghaddam M, Ottersen OP, Bhardwaj A.: Osmotherapy with hypertonic saline attenuates global cerebral edema following experimental cardiac arrest via perivascular pool of aquaporin-4. Crit Care Med.2016;44:e702\u0026ndash;10.\u003c/li\u003e\n\u003cli\u003eMiclescu A, Sharma HS, Wiklund L: Crystalloid vs. hypertonic crystalloid-colloid solutions for induction of mild therapeutic hypothermia after experimental cardiac arrest. Resuscitation 2013; 84:256\u0026ndash;62.\u003c/li\u003e\n\u003cli\u003eKaufmann AM, Cardoso ER: Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg. 1992; 77:584-9.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Out-of-hospital cardiac arrest, Blood–brain barrier, Prognosis, Edema","lastPublishedDoi":"10.21203/rs.3.rs-61579/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-61579/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThis study aimed to compare the day-specific association of blood–brain barrier (BBB) disruption with neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors treated with target temperature management (TTM).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This retrospective single-center study included 68 OHCA survivors, who underwent TTM between April 2018 and December 2019. The albumin quotient (Q\u003csub\u003eA\u003c/sub\u003e) was calculated as [albumin\u003csub\u003eCSF\u003c/sub\u003e]\u0026nbsp;/\u0026nbsp;[albumin\u003csub\u003eserum\u003c/sub\u003e] immediately (day 1), and at 24 h (day 2), 48 h (day 3), and 72 h (day 4) after return of spontaneous circulation (ROSC). The degree of BBB disruption was weighted using the following scoring system: 0.07\u0026nbsp;≥\u0026nbsp;Q\u003csub\u003eA \u003c/sub\u003e(normal), 0.01\u0026nbsp;≥\u0026nbsp;Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;\u0026gt;\u0026nbsp;0.007 (mild), 0.02\u0026nbsp;≥\u0026nbsp;Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;\u0026gt;\u0026nbsp;0.01 (moderate), and Q\u003csub\u003eA\u003c/sub\u003e\u0026nbsp;\u0026gt;\u0026nbsp;0.02 (severe). This system gave it 0 (normal), 1 (mild), 4 (moderate), and 9 (severe) points. Poor neurological outcome was determined at six months after ROSC and was defined as cerebral performance categories 3–5.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e We enrolled 68 patients (males, 48; 71%); 37 (54%) of them had a poor neurological outcome. The distributions of this outcome at six months in patients with moderate and severe BBB disruption versus the other groups were 19/22 (80%) vs. 18/46 (50%) on day 1, 31/37 (79%) vs. 6/31 (32%) on day 2, 32/37 (81%) vs. 5/31 (30%) on day 3, and 32/39 (85%) vs. 5/29 (30%) on day 4 (\u003cem\u003eP\u003c/em\u003e\u0026nbsp;\u0026lt;\u0026nbsp;0.001). Using ROC analyses, the optimal cutoff values of Q\u003csub\u003eA\u003c/sub\u003e levels for prediction of neurological outcomes were determined as: day 1, \u0026gt;\u0026nbsp;0.009 (sensitivity 56.8%, specificity 87.1%); day 2, \u0026gt;\u0026nbsp;0.012 (sensitivity 81.1%, specificity 87.1%); day 3, \u0026gt;\u0026nbsp;0.013 (sensitivity 83.8%, specificity 87.1%); day 4, \u0026gt;\u0026nbsp;0.013 (sensitivity 86.5%, specificity 87.1%); sum of all time points, \u0026gt;\u0026nbsp;0.039 (sensitivity 89.5%, specificity 79.4%); and scoring system, \u0026gt;\u0026nbsp;9 (sensitivity 91.9%, specificity 87.1%). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Our results suggested that Q\u003csub\u003eA\u003c/sub\u003e is a useful tool for predicting neurological outcomes in OHCA survivors treated with TTM. However, the prediction of poor neurological outcome using Q\u003csub\u003eA\u003c/sub\u003e showed low sensitivity at 100% specificity. Thus, it could be used as part of a multimodal approach than as a single prognostic prediction tool.\u003c/p\u003e","manuscriptTitle":"Usefulness of the Degree of Blood–brain Barrier Disruption to Predict Neurological Prognosis in Cardiac Arrest Survivors who Wnderwent Target Temperature Management: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-08-25 11:42:44","doi":"10.21203/rs.3.rs-61579/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"df7f398e-0a0b-4fe9-8f3a-6f50acac016a","owner":[],"postedDate":"August 25th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":357016,"name":"Critical Care \u0026 Emergency Medicine"}],"tags":[],"updatedAt":"2020-08-25T11:42:44+00:00","versionOfRecord":[],"versionCreatedAt":"2020-08-25 11:42:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-61579","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-61579","identity":"rs-61579","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}