Individualized Autoregulation-Derived Cerebral Perfusion Targets in Aneurysmal Subarachnoid Hemorrhage: A New Therapeutic Avenue?

Background: Cerebral perfusion pressure (CPP) is an important target in aneurysmal subarachnoid hemorrhage (aSAH), but it does not take into account autoregulatory disturbances. The pressure reactivity index (PRx) and the CPP with the optimal PRx (CPPopt) are new variables that may capture these pathomechanisms. In this study, we investigated the effect on the outcome of certain combinations of CPP or ΔCPPopt (actual CPP-CPPopt) with the concurrent autoregulatory status (PRx) after aSAH. Methods: This observational study included 432 aSAH patients, treated in the neurointensive care unit, at Uppsala University Hospital, Sweden. Functional outcome (GOS-E) was assessed 1-year postictus. Heatmaps of the percentage of good monitoring time (%GMT) of PRx/CPP and PRx/ΔCPPopt combinations in relation to GOS-E were created to visualize the association between these variables and outcome. Results: In the heatmap of the %GMT of PRx/CPP, the combination of lower CPP with higher PRx values was more strongly associated with lower GOS-E. The tolerance for lower CPP values increased with lower PRx values until a threshold of -0.50. However, for decreasing PRx below -0.50, there was a gradual reduction in the tolerance for lower CPP. In the heatmap of the %GMT of PRx/ΔCPPopt, the combination of negative ΔCPPopt with higher PRx values was strongly associated with lower GOS-E. In particular, negative ΔCPPopt together with PRx above +0.50 correlated with worse outcomes. In addition, there was a transition toward an unfavorable outcome when PRx went below -0.50, particularly if ΔCPPopt was negative. Conclusions: The PRx levels influenced the association between CPP/ΔCPPopt and outcome. Thus, this variable could be used to individualize a safe CPP-/ΔCPPopt-range.

Trends in incidence and treatments of spontaneous subarachnoid hemorrhage- a 10 year hospital based study.

BACKGROUND: Improved endovascular methods make it possible to treat complex ruptured aneurysms, but surgery is still needed in certain cases. We evaluated the effects on the clinical results of the changes in aneurysm treatment. METHODS: The study cohort was 837 patients with spontaneous subarachnoid hemorrhage (SAH) and one or multiple aneurysms, admitted to Dept of Neurosurgery, Uppsala University Hospital from 2012 to 2021. Demography, location and treatment of aneurysms, neurologic condition at admission and discharge, mortality and last tier treatment of high intracranial pressure (ICP) was evaluated. Functional outcome was measured using the Extended Glasgow Outcome Scale (GOSE) Data concerning national incidences of stroke diseases was collected from open Swedish databases. RESULTS: Endovascular methods were used in 666 cases (79.6%). In 111 (13.3%) with stents. Surgery was performed in 115 cases (13.7%) and 56 patients (6.7%) had no aneurysm treatment. The indications for surgery were a hematoma (51 cases, 44.3%), endovascular treatment not considered safe (47 cases, 40.9%), or had been attempted without success (13 cases, 11.3%). Treatment with stent devices increased, and with surgery decreased over time. There was a trend in decrease in hemicraniectomias over time. Both the patient group admitted awake (n = 681) and unconscious (n = 156) improved significantly in consciousness between admission and discharge. Favorable outcome (GOSE 5-8) was seen in 69% for patients admitted in Hunt & Hess I-II and 25% for Hunt & Hess III-V. Mortality at one year was 10.9% and 42.7% for those admitted awake and unconscious, respectively.The number of cases decreased during the study period, which was in line with Swedish national data. CONCLUSIONS: The incidence of patients with SAH gradually decreased in our material, in line with national data. The treatment policy in our unit has been shifting to more use of endovascular methods. During the study period the use of hemicraniectomies decreased.

Diagnosis of external ventricular drainage related infections with real-time 16S PCR and third-generation 16S sequencing.

OBJECTIVE: Investigate the performance of real-time 16S PCR and third-generation 16S sequencing in the diagnosis of external ventricular drain related infections (EVDRI). METHODS: Subjects with suspected EVDRI were prospectively included at Uppsala University Hospital. Subjects were included into three groups: subjects with negative CSF culture with and without antibiotic treatment and subjects with positive CSF culture, respectively. CSF was analysed with real-time 16S PCR and third-generation 16S sequencing. Real-time 16S PCR positivity/negativity and number of 16S sequence reads were compared between groups. For culture positive subjects, species identification in third-generation sequencing and routine culture was compared. RESULTS: 84 subjects were included. There were 18, 44 and 22 subjects in the three groups. Real-time PCR was positive in 17 of 22 subjects in the culture positive group and negative in 61 of the 62 subjects in the two culture negative groups. The sensitivity and specificity for real-time 16S PCR compared to culture was estimated to 77% and 98%, respectively. Species identification in 16S sequencing and culture was concordant in 20 of 22 subjects. The number of 16S sequence reads were significantly higher in the culture positive group than in both culture negative groups (p < 0.001). There was no significant difference in number of 16S sequences between the two culture negative groups. CONCLUSIONS: Real-time 16S PCR predict culture results with sufficient reliability. Third-generation 16S sequencing could enhance sensitivity and species identification in diagnostics of EVD-related infections. False negative culture results appear to be uncommon in patients with suspected EVDRI.

Adverse events during endovascular treatment of ruptured aneurysms: A prospective nationwide study on subarachnoid hemorrhage in Sweden.

Introduction: A range of adverse events (AEs) may occur in patients with subarachnoid hemorrhage (SAH). Endovascular treatment is commonly used to prevent aneurysm re-rupture. Research question: The aim of this study was to identify AEs related to endovascular treatment, analyze risk factors for AEs and how AEs affect patient outcome. Material and methods: Patients with aneurysmal SAH admitted to all neurosurgical centers in Sweden during a 3.5-year period (2014-2018) were prospectively registered. AEs related to endovascular aneurysm treatment were thromboembolic events, aneurysm re-rupture, vessel dissection and puncture site hematoma. Potential risk factors for the AEs were analyzed using multivariate logistic regression. Functional outcome was assessed at one year using the extended Glasgow outcome scale. Results: In total, 1037 patients were treated for ruptured aneurysms. Of which, 715 patients were treated with endovascular occlusion. There were 115 AEs reported in 113 patients (16%). Thromboembolic events were noted in 78 patients (11%). Aneurysm re-rupture occurred in 28 (4%), vessel dissection in 4 (0.6%) and puncture site hematoma in 5 (0.7%). Blister type aneurysm, aneurysm smaller than 5 mm and endovascular techniques other than coiling were risk factors for treatment-related AEs. At follow-up, 230 (32%) of the patients had unfavorable outcome. Patients suffering intraprocedural aneurysm re-rupture were more likely to have unfavorable outcome (OR 6.9, 95% CI 2.3-20.9). Discussion and conclusion: Adverse events related to endovascular occlusion of a ruptured aneurysm were seen in 16% of patients. Aneurysm re-rupture during endovascular treatment was associated with increased risk of unfavorable functional outcome.

Thiopental and decompressive craniectomy as last-tier ICP-treatments in aneurysmal subarachnoid hemorrhage: is functional recovery within reach?

The study aimed to investigate the indication and functional outcome after barbiturates and decompressive craniectomy (DC) as last-tier treatments for elevated intracranial pressure (ICP) in aneurysmal subarachnoid hemorrhage (aSAH). This observational study included 891 aSAH patients treated at a single center between 2008 and 2018. Data on demography, admission status, radiology, ICP, clinical course, and outcome 1-year post-ictus were collected. Patients treated with thiopental (barbiturate) and DC were the main target group.Thirty-nine patients (4%) were treated with thiopental alone and 52 (6%) with DC. These patients were younger and had a worse neurological status than those who did not require these treatments. Before thiopental, the median midline shift was 0 mm, whereas basal cisterns were compressed/obliterated in 66%. The median percentage of monitoring time with ICP > 20 mmHg immediately before treatment was 38%, which did not improve after 6 h of infusion. Before DC, the median midline shift was 10 mm, and the median percentage of monitoring time with ICP > 20 mmHg before DC was 56%, which both significantly improved postoperatively. At follow-up, 52% of the patients not given thiopental or operated with DC reached favorable outcome, whereas this occurred in 10% of the thiopental and DC patients.In summary, 10% of the aSAH cohort required thiopental, DC, or both. Thiopental and DC are important integrated last-tier treatment options, but careful patient selection is needed due to the risk of saving many patients into a state of suffering.

Inflammatory biomarkers differentiate the stage of maturation in chronic subdural hematomas.

OBJECTIVE: Inflammation is a major pathophysiological driver of the development of chronic subdural hematomas (CSDH), but there is still limited knowledge on the key molecular processes and corresponding biomarkers involved in this disease. In this study, the aim was to study a subset of inflammatory biomarkers and their relation to the clinical status of the patient and the radiological characteristics of the CSDH. METHODS: In this observational study, 58 patients who were operated on with CSDH evacuation, at the Department of Neurosurgery, Uppsala, Sweden, between 2019 and 2021, were prospectively included. The CSDH fluid was collected peri-operatively and was later analyzed with proximity extension assay (PEA) technique (Olink) for a panel of 92 inflammatory biomarkers. Demographic, neurological (Markwalder), radiological (general (Nakaguchi classification) and focal (septa below the burr holes)), and outcome variables were collected. RESULTS: In 84 of the 92 inflammatory biomarkers, the concentration was above the detection limit in >50% of the patients. There was a significant difference in GDNF, NT-3, and IL-8 depending on the Nakaguchi class, with higher values in the trabeculated CSDH subtype. In addition, those with septa at the focal area of CSDH collection, had higher levels of GDNF, MCP-3, NT-3, CXCL1, CXCL5, IL8, and OSM. There was no association between Markwalder grade and the inflammatory biomarkers. CONCLUSIONS: Our findings support the presence of local inflammation in the CSDH, a shift in biomarker pattern as the CSDH matures towards the trabeculated state, potentially differences in biomarker patterns within the CSDH depending on the focal environment with presence of septa, and that the brain might develop protective mechanisms (GDNF and NT-3) in case of mature and long-standing CSDHs.

Lumbar puncture-verified subarachnoid hemorrhage: bleeding sources, need of radiological examination, and functional recovery.

BACKGROUND: The primary aim was to determine the diagnostic yield of vascular work-up, the clinical course during neurointensive care (NIC), and rate of functional recovery for patients with computed tomography (CT)-negative, lumbar puncture (LP)-verified SAH. METHODS: In this retrospective study, 1280 patients with spontaneous SAH, treated at our NIC unit, Uppsala University Hospital, Sweden, between 2008 and 2018, were included. Demography, admission status, radiological examinations (CT angiography (CTA) and digital subtraction angiography (DSA)), treatments, and functional outcome (GOS-E) at 12 months were evaluated. RESULTS: Eighty (6%) out of 1280 SAH patients were computed tomography (CT)-negative, LP-verified cases. Time between ictus and diagnosis was longer for the LP-verified SAH cohort in comparison to the CT-positive patients (median 3 vs 0 days, p < 0.001). One fifth of the LP-verified SAH patients exhibited an underlying vascular pathology (aneurysm/AVM), which was significantly less common than for the CT-verified SAH cohort (19% vs. 76%, p < 0.001). The CTA- and DSA-findings were consistent in all of the LP-verified cases. The LP-verified SAH patients exhibited a lower rate of delayed ischemic neurological deficits, but no difference in rebleeding rate, compared to the CT-verified cohort. At 1-year post-ictus, 89% of the LP-verified SAH patients had recovered favorably, but 45% of the cases did not reach good recovery. Having an underlying vascular pathology and an external ventricular drainage were associated with worse functional recovery (p = 0.02) in this cohort. CONCLUSIONS: LP-verified SAH constituted a small proportion of the entire SAH population. Having an underlying vascular pathology was less frequent in this cohort, but still occurred in one out of five patients. Despite the small initial bleeding in the LP-verified cohort, many of these patients did not reach good recovery at 1 year, this calls for more attentive follow-up and rehabilitation in this cohort.

Intracranial Pressure Variability: A New Potential Metric of Cerebral Ischemia and Energy Metabolic Dysfunction in Aneurysmal Subarachnoid Hemorrhage?

BACKGROUND: It was recently reported that lower intracranial pressure variability (ICPV) is associated with delayed ischemic neurological deficits and unfavorable outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). In this study, we aimed to determine whether lower ICPV also correlated with worse cerebral energy metabolism after aSAH. METHODS: A total of 75 aSAH patients treated in the neurointensive care unit at Uppsala University Hospital, Sweden between 2008 and 2018 and with both intracranial pressure and cerebral microdialysis (MD) monitoring during the first 10 days after ictus were included in this retrospective study. ICPV was calculated with a bandpass filter limited to intracranial pressure slow waves with a wavelength of 55 to 15 seconds. Cerebral energy metabolites were measured hourly with MD. The monitoring period was divided into 3 phases; early (days 1 to 3), early vasospasm (days 4 to 6.5), and late vasospasm (days 6.5 to 10). RESULTS: Lower ICPV was associated with lower MD-glucose in the late vasospasm phase, lower MD-pyruvate in the early vasospasm phases, and higher MD-lactate-pyruvate ratio (LPR) in the early and late vasospasm phases. Lower ICPV was associated with poor cerebral substrate supply (LPR >25 and pyruvate <120 µM) rather than mitochondrial failure (LPR >25 and pyruvate >120 µM). There was no association between ICPV and delayed ischemic neurological deficit, but lower ICPV in both vasospasm phases correlated with unfavorable outcomes. CONCLUSION: Lower ICPV was associated with an increased risk for disturbed cerebral energy metabolism and worse clinical outcomes in aSAH patients, possibly explained by a vasospasm-related decrease in cerebral blood volume dynamics and cerebral ischemia.

Adverse events associated with microsurgial treatment for ruptured intracerebral aneurysms: a prospective nationwide study on subarachnoid haemorrhage in Sweden.

BACKGROUND: Adverse events (AEs) or complications may arise secondary to the treatment of aneurysmal subarachnoid haemorrhage (SAH). The aim of this study was to identify AEs associated with microsurgical occlusion of ruptured aneurysms, as well as to analyse their risk factors and impact on functional outcome. METHODS: Patients with aneurysmal SAH admitted to the neurosurgical centres in Sweden were prospectively registered during a 3.5-year period (2014-2018). AEs were categorised as intraoperative or postoperative. A range of variables from patient history and SAH characteristics were explored as potential risk factors for an AE. Functional outcome was assessed approximately 1 year after the bleeding using the extended Glasgow Outcome Scale. RESULTS: In total, 1037 patients were treated for ruptured aneurysms, of which, 322 patients were treated with microsurgery. There were 105 surgical AEs in 97 patients (30%); 94 were intraoperative AEs in 79 patients (25%). Aneurysm rerupture occurred in 43 patients (13%), temporary occlusion of the parent artery >5 min in 26 patients (8%) and adjacent vessel injury in 25 patients (8%). High Fisher grade and brain oedema on CT were related to increased risk of AEs. At follow-up, 38% of patients had unfavourable outcome. Patients suffering AEs were more likely to have unfavourable outcome (OR 2.3, 95% CI 1.10 to 4.69). CONCLUSION: Intraoperative AEs occurred in 25% of patients treated with microsurgery for ruptured intracerebral aneurysm in this nationwide survey. Although most operated patients had favourable outcome, AEs were associated with increased risk of unfavourable outcome.

Temperature Changes in Poor-Grade Aneurysmal Subarachnoid Hemorrhage: Relation to Injury Pattern, Intracranial Pressure Dynamics, Cerebral Energy Metabolism, and Clinical Outcome.

BACKGROUND: The aim was to study the course of body temperature in the acute phase of poor-grade aneurysmal subarachnoid hemorrhage (aSAH) in relation to the primary brain injury, cerebral physiology, and clinical outcome. METHODS: In this observational study, 166 patients with aSAH treated at the neurosurgery department at Uppsala University Hospital in Sweden between 2008 and2018 with temperature, intracranial pressure (ICP), and microdialysis (MD) monitoring were included. The first 10 days were divided into the early phase (days 1-3) and the vasospasm phase (days 4-10). RESULTS: Normothermia (temperature = 36-38 °C) was most prevalent in the early phase. A lower mean temperature at this stage was univariately associated with a worse primary brain injury, with higher Fisher grade and higher MD glycerol concentration, as well as a worse neurological recovery at 1 year. There was otherwise no association between temperature and cerebral physiological variables in the early phase. There was a transition toward an increased burden of hyperthermia (temperature > 38 °C) in the vasospasm phase. This was associated with concurrent infections but not with neurological or radiological injury severity at admission. Elevated temperature was associated with higher MD pyruvate concentration, lower rate of an MD pattern indicative of ischemia, and higher rate of poor neurological recovery at 1 year. There was otherwise no association between temperature and cerebral physiological variables in the vasospasm phase. The associations between temperature and clinical outcome did not hold true in multiple logistic regression analyses. CONCLUSIONS: Spontaneously low temperature in the early phase reflected a worse primary brain injury and indicated a worse outcome prognosis. Hyperthermia was common in the vasospasm phase and was more related to infections than primary injury severity but also with a more favorable energy metabolic pattern with better substrate supply, possibly related to hyperemia.

Antithrombotic agent usage before ictus in aneurysmal subarachnoid hemorrhage: relation to hemorrhage severity, clinical course, and outcome.

BACKGROUND: The number of patients with aneurysmal subarachnoid hemorrhage (aSAH) who are on antithrombotic agents before ictus is rising. However, their effect on early brain injury and disease development remains unclear. The primary aim of this study was to determine if antithrombotic agents (antiplatelets and anticoagulants) were associated with a worse initial hemorrhage severity, rebleeding rate, clinical course, and functional recovery after aSAH. METHODS: In this observational study, those 888 patients with aSAH, treated at the neurosurgical department, Uppsala University Hospital, between 2008 and 2018 were included. Demographic, clinical, radiological (Fisher and Hijdra score), and outcome (Extended Glasgow Outcome Scale one year post-ictus) variables were assessed. RESULTS: Out of 888 aSAH patients, 14% were treated with antithrombotic agents before ictus. Seventy-five percent of these were on single therapy of antiplatelets, 23% on single therapy of anticoagulants, and 3% on a combination of antithrombotic agents. Those with antithrombotic agents pre-ictus were significantly older and exhibited more co-morbidities and a worse coagulation status according to lab tests. Antithrombotic agents, both as one group and as subtypes (antiplatelets and anticoagulants), were not associated with hemorrhage severity (Hijdra score/Fisher) nor rebleeding rate. The clinical course did not differ in terms of delayed ischemic neurological deficits or last-tier treatment with thiopental and decompressive craniectomy. These patients experienced a higher mortality and lower rate of favorable outcome in univariate analyses, but this did not hold true in multiple logistic regression analyses after adjustment for age and co-morbidities. CONCLUSIONS: After adjustment for age and co-morbidities, antithrombotic agents before aSAH ictus were not associated with worse hemorrhage severity, rebleeding rate, clinical course, or long-term functional recovery.

Elevated levels of several chemokines in the cerebrospinal fluid of patients with subarachnoid hemorrhage are associated with worse clinical outcome.

BACKGROUND: Chemokines are small cytokines that exert chemotactic actions on immune cells and are involved in many inflammatory processes. The present study aims to provide insight in the role of this relatively unexplored family of proteins in the inflammatory pathophysiology of subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: Cerebrospinal fluid of 29 patients (17 female; mean age 57 years) was collected at days 1, 4 and 10 after SAH, centrifuged and frozen at -70°C. Analysis of 92 inflammation-related proteins was performed using Target 96 Inflammation ® assay (Olink Proteomics, Uppsala, Sweden) based on Proximity Extension Assay technology. The panel included 20 chemokines (CCL2 (or MCP-1), CCL3, CCL4, CCL7 (or MCP-3), CCL8 (or MCP-2), CCL11 (or Eotaxin), CCL13 (or MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CXCL1, CXCL5, CXCL6, CXCL8 (or IL-8), CXCL9, CXCL10, CXCL11 and CX3CL1 (or Fractalkine)) that were analyzed for their temporal patterns of expression and compared in dichotomized clinical groups based on World Federation of Neurosurgical Societies (WFNS) admission score and amount of blood on admission CT based on Fisher scale; presence of delayed cerebral ischemia(DCI)/delayed ischemic neurological deficit (DIND); and clinical outcome based on Glasgow Outcome Scale. Protein expression levels were provided in output unit Normalized Protein Expression (NPX). ANOVA models were used for statistical analyses. RESULTS: Four temporal patterns of expression were observed (i.e., early, middle, late peak and no peak). Significantly higher day 10 mean NPX values were observed in patients with poor outcome (GOS 1-3) for chemokines CCL2, CCL4, CCL7, CCL11, CCL13, CCL19, CCL20, CXCL1, CXCL5, CXCL6 and CXCL8. In the WFNS 4-5 group, CCL11 showed significantly higher day 4 and day 10 mean NPX values and CCL25 significantly higher day 4 values. In patients with SAH Fisher 4, CCL11 showed significantly higher mean NPX values on days 1, 4 and 10. Finally, patients with DCI/DIND had significantly higher day 4 mean NPX values of CXCL5. CONCLUSION: Higher levels of multiple chemokines at the late stage of SAH seemed to correlate with worse clinical outcome. A few chemokines correlated with WFNS score, Fisher score and occurrence of DCI/DIND. Chemokines may be useful as biomarkers for describing the pathophysiology and prognosis of SAH. Further studies are needed to better understand their exact mechanism of action in the inflammatory cascade.

The impact of previous health on the mortality after aneurysmal subarachnoid hemorrhage: analysis of a prospective Swedish multicenter study.

PURPOSE: There is an an increasing awareness of the importance of health and lifestyle for stroke diseases like spontaneous subarachnoid hemorrhage (SAH). However, the importance of pre-existing medical conditions for clinical course and mortality after SAH has not been studied. The aim of the present study was to identify pre-existing conditions contributing to mortality after SAH. METHODS: Data were extracted from a Swedish national prospective study on patients with SAH. Variables were defined for age, sex, body mass index (BMI), clinical condition at admission, and for 10 pre-existing medical conditions. Models predicting mortality in three time intervals with all possible subsets of these variables were generated, compared and selected using Akaike's information criterion. RESULTS: 1155 patients with ruptured aneurysms were included. The mortality within 1 week was 7.6%, 1 month 14.3%, and 1 year 18.7%. The most common pre-existing medical conditions were smoking (57.6%) and hypertension (38.7%). The model's best predicting mortality within 1 week and from 1 week to 1 month included only the level of consciousness at admission and age, and these two variables were present in all the models among the top 200 in Akaike score for each time period. The most predictive model for mortality between 1 month and 1 year added previous stroke, diabetes, psychiatric disease, and BMI as predictors. CONCLUSION: Mortality within the first month was best predicted simply by initial level of consciousness and age, while mortality within from 1 month to 1 year was significantly influenced by pre-existing medical conditions.

Higher intracranial pressure variability is associated with lower cerebrovascular resistance in aneurysmal subarachnoid hemorrhage.

Higher intracranial pressure variability (ICPV) has been associated with a more favorable cerebral energy metabolism, lower rate of delayed ischemic neurologic deficits, and more favorable outcome in aneurysmal subarachnoid hemorrhage (aSAH). We have hypothesized that higher ICPV partly reflects more compliant and active cerebral vessels. In this study, the aim was to further test this by investigating if higher ICPV was associated with lower cerebrovascular resistance (CVR) and higher cerebral blood flow (CBF) after aSAH. In this observational study, 147 aSAH patients were included, all of whom had been treated in the Neurointensive Care (NIC) Unit, Uppsala, Sweden, 2012-2020. They were required to have had ICP monitoring and at least one xenon-enhanced computed tomography (Xe-CT) scan to study cortical CBF within the first 2 weeks post-ictus. CVR was defined as the cerebral perfusion pressure in association with the Xe-CT scan divided by the concurrent CBF. ICPV was defined over three intervals: subminute (ICPV-1m), 30-min (ICPV-30m), and 4 h (ICPV-4h). The first 14 days were divided into early (days 1-3) and vasospasm phase (days 4-14). In the vasospasm phase, but not in the early phase, higher ICPV-4h (ß = - 0.19, p < 0.05) was independently associated with a lower CVR in a multiple linear regression analysis and with a higher global cortical CBF (r = 0.19, p < 0.05) in a univariate analysis. ICPV-1m and ICPV-30m were not associated with CVR or CBF in any phase. This study corroborates the hypothesis that higher ICPV, at least in the 4-h interval, is favorable and may reflect more compliant and possibly more active cerebral vessels.

ICP, CPP, and PRx in traumatic brain injury and aneurysmal subarachnoid hemorrhage: association of insult intensity and duration with clinical outcome.

OBJECTIVE: The primary aim of this study was to determine the combined effect of insult intensity and duration of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and pressure reactivity index (PRx) on outcome measured with the Glasgow Outcome Scale-Extended (GOS-E) in patients with traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (aSAH). METHODS: This observational study included all TBI and aSAH patients treated in the neurointensive care unit in Uppsala, Sweden, 2008-2018, with at least 24 hours of ICP monitoring during the first 10 days following injury and available long-term clinical outcome data. ICP, CPP, and PRx insults were visualized as 2D plots to highlight the effects of both insult intensity and duration on patient outcome. RESULTS: Of 950 included patients, 436 were TBI and 514 aSAH patients. The TBI patients were younger, more often male, and exhibited worse neurological status at admission, but recovered more favorably than the aSAH patients. There was a transition from good to poor outcome with ICP above 15-20 mm Hg in both TBI and aSAH. The two diagnoses had opposite CPP patterns. In TBI patients, CPP episodes at or below 80 mm Hg were generally favorable, whereas CPP episodes above 80 mm Hg were favorable in the aSAH patients. In the TBI patients there was a transition from good to poor outcome when PRx exceeded zero, but no evident transition was found in the aSAH cohort. CONCLUSIONS: The insult intensity and duration plots formulated in this study illustrate the similarities and differences between TBI and aSAH patients. In particular, aSAH patients may benefit from much higher CPP targets than TBI patients.

Cerebral Microdialysis Monitoring of Energy Metabolism: Relation to Cerebral Blood Flow and Oxygen Delivery in Aneurysmal Subarachnoid Hemorrhage.

INTRODUCTION: In this study, we investigated the roles of cerebral blood flow (CBF) and cerebral oxygen delivery (CDO 2 ) in relation to cerebral energy metabolism after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Fifty-seven adult aSAH patients treated on the neurointensive care unit at Uppsala, Sweden between 2012 and 2020, with at least 1 xenon-enhanced computed tomography (Xe-CT) scan in the first 14 days after ictus and concurrent microdialysis (MD) monitoring, were included in this retrospective study. CBF was measured globally and focally (around the MD catheter) with Xe-CT, and CDO 2 calculated. Cerebral energy metabolites were measured using MD. RESULTS: Focal ischemia (CBF <20 mL/100 g/min around the MD catheter was associated with lower median [interquartile range]) MD-glucose (1.2 [0.7 to 2.2] mM vs. 2.3 [1.3 to 3.5] mM; P =0.05) and higher MD-lactate-pyruvate (LPR) ratio (34 [29 to 66] vs. 25 [21 to 32]; P =0.02). A compensated/normal MD pattern (MD-LPR <25) was observed in the majority of patients (22/23, 96%) without focal ischemia, whereas 4 of 11 (36%) patients with a MD pattern of poor substrate supply (MD-LPR >25, MD-pyruvate <120 µM) had focal ischemia as did 5 of 20 (25%) patients with a pattern of mitochondrial dysfunction (MD-LPR >25, MD-pyruvate >120 µM) ( P =0.04). Global CBF and CDO 2 , and focal CDO 2 , were not associated with the MD variables. CONCLUSIONS: While MD is a feasible tool to study cerebral energy metabolism, its validity is limited to a focal area around the MD catheter. Cerebral energy disturbances were more related to low CBF than to low CDO 2 . Considering the high rate of mitochondrial dysfunction, treatments that increase CBF but not CDO 2 , such as hemodilution, may still benefit glucose delivery to drive anaerobic metabolism.

NT-proBNP and troponin I in high-grade aneurysmal subarachnoid hemorrhage: Relation to clinical course and outcome.

PURPOSE: To investigate the association between two cardiac biomarkers, NT-proBNP and TnI, with intracranial pressure (ICP)-/cerebral perfusion pressure (CPP)-insults, cerebral pressure autoregulation, delayed ischemic neurological deficits (DIND), and clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In this retrospective study, 196 aSAH patients treated at the neurointensive care unit, Uppsala University Hospital, Sweden, 2011-2018, with ICP-monitoring and serial NT-proBNP and TnI measurements were included. The first 10 days were divided into early phase (day 1-3) and vasospasm phase (day 4-10). RESULTS: NT-proBNP and TnI were elevated above the reference interval at least once the first 10 days in 175 (89%) and 116 (59%) patients, respectively. In the vasospasm phase, higher NT-proBNP and TnI were associated with increased percentage of CPP below 60 mmHg. Higher TnI also correlated with more ICP-insults above 20 mmHg. NT-proBNP and TnI did not predict worse pressure autoregulation and DIND. Higher NT-proBNP and TnI were associated with mortality and unfavorable outcome in univariate, but not multivariate, analyses. CONCLUSION: Elevated NT-proBNP and TnI correlated with an increased burden of secondary ICP-/CPP-insults, but not with worse pressure autoregulation, DIND, and without independent association with clinical outcome.

Cerebral Blood Flow and Oxygen Delivery in Aneurysmal Subarachnoid Hemorrhage: Relation to Neurointensive Care Targets.

BACKGROUND: The primary aim was to determine to what extent continuously monitored neurointensive care unit (neuro-ICU) targets predict cerebral blood flow (CBF) and delivery of oxygen (CDO2) after aneurysmal subarachnoid hemorrhage. The secondary aim was to determine whether CBF and CDO2 were associated with clinical outcome. METHODS: In this observational study, patients with aneurysmal subarachnoid hemorrhage treated at the neuro-ICU in Uppsala, Sweden, from 2012 to 2020 with at least one xenon-enhanced computed tomography (Xe-CT) obtained within the first 14 days post ictus were included. CBF was measured with the Xe-CT and CDO2 was calculated based on CBF and arterial oxygen content. Regional cerebral hypoperfusion was defined as CBF < 20 mL/100 g/min, and poor CDO2 was defined as CDO2 < 3.8 mL O2/100 g/min. Neuro-ICU variables including intracranial pressure (ICP), pressure reactivity index, cerebral perfusion pressure (CPP), optimal CPP, and body temperature were assessed in association with the Xe-CT. The acute phase was divided into early phase (day 1-3) and vasospasm phase (day 4-14). RESULTS: Of 148 patients, 27 had underwent a Xe-CT only in the early phase, 74 only in the vasospasm phase, and 47 patients in both phases. The patients exhibited cerebral hypoperfusion and poor CDO2 for medians of 15% and 30%, respectively, of the cortical brain areas in each patient. In multiple regressions, higher body temperature was associated with higher CBF and CDO2 in the early phase. In a similar regression for the vasospasm phase, younger age and longer pulse transit time (lower peripheral resistance) correlated with higher CBF and CDO2, whereas lower hematocrit only correlated with higher CBF but not with CDO2. ICP, CPP, and pressure reactivity index exhibited no independent association with CBF and CDO2. R2 of these regressions were below 0.3. Lower CBF and CDO2 in the early phase correlated with poor outcome, but this only held true for CDO2 in multiple regressions. CONCLUSIONS: Systemic and cerebral physiological variables exhibited a modest association with CBF and CDO2. Still, cerebral hypoperfusion and low CDO2 were common and low CDO2 was associated with poor outcome. Xe-CT imaging could be useful to help detect secondary brain injury not evident by high ICP and low CPP.

Temporal patterns of inflammation-related proteins measured in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage using multiplex Proximity Extension Assay technology.

BACKGROUND: The complexity of the inflammatory response post subarachnoid hemorrhage (SAH) may require temporal analysis of multiple protein biomarkers simultaneously to be more accurately described. METHODS: Ventricular cerebrospinal fluid was collected at days 1, 4 and 10 after SAH in 29 patients. Levels of 92 inflammation-related proteins were simultaneously measured using Target 96 Inflammation ® assay (Olink Proteomics, Uppsala, Sweden) based on Proximity Extension Assay (PEA) technology. Twenty-eight proteins were excluded from further analysis due to lack of >50% of measurable values. Temporal patterns of the remaining 64 proteins were analyzed. Repeated measures ANOVA and its nonparametric equivalent Friedman's ANOVA were used for comparisons of means between time points. RESULTS: Four different patterns (Groups A-D) were visually observed with an early peak and gradually decreasing trend (11 proteins), a middle peak (10 proteins), a late peak after a gradually increasing trend (30 proteins) and no specific pattern (13 proteins). Statistically significant early peaks defined as Day 1 > Day 4 values were noticed in 4 proteins; no significant decreasing trends defined as Day 1 > Day 4 > Day 10 values were observed. Two proteins showed significant middle peaks (i.e. Day 1 < Day 4 > Day 10 values). Statistically significant late peaks (i.e. Day 4 < Day 10 values) and increasing trends (i.e. Day 1 < Day 4 < Day 10 values) were observed in 14 and 10 proteins, respectively. Four of Group D proteins showed biphasic peaks and the rest showed stable levels during the observation period. CONCLUSION: The comprehensive data set provided in this explorative study may act as an illustration of an inflammatory profile of the acute phase of SAH showing groups of potential protein biomarkers with similar temporal patterns of activation, thus facilitating further research on their role in the pathophysiology of the disease.