Impact of Medical and Neurologic Complications on the Outcome of Patients with Aneurysmal Subarachnoid Hemorrhage in a Middle-Income Country.

OBJECTIVE: Almost two thirds of the world's aneurysmal subarachnoid hemorrhage (aSAH) are in low- and middle-income countries. Herein, we aimed to evaluate the impact of complications on the outcome of aSAH in a middle-income country. METHODS: Baseline data (age, sex, World Federation of Neurosurgical Society, time ictus-treatment, treatment modality) and medical and neurologic complications from a cohort in Brazil (2016-2019) were evaluated: delayed cerebral ischemia; hydrocephalus; meningitis; seizures; intracranial hypertension; infections (pneumonia, bloodstream, urinary tract infection infection of undetermined source); sodium disturbances; acute kidney injury; and cardiac and pulmonary complications. The primary outcome was the modified Rankin scale (mRS) at hospital discharge. Univariate and multivariate models were employed. RESULTS: From 212 patients (71.7% female, age 52.7 ± 12.8), 92% developed at least 1 complication (any infection-43.9%, hydrocephalus-34.4%, intracranial hypertension-33%, infection of undetermined source-20.8%, hypernatremia-20.8%, hyponatremia-19.8%, delayed cerebral ischemia-related infarction-18.7%, pneumonia-18.4%, acute kidney injury-16.5%, and seizures-11.8%). In unadjusted analysis, all but hyponatremia and urinary tract infection were associated with mRS 3-6 at discharge; however, complications explained only 12% of the variation in functional outcome (mRS). Most patients were treated by clipping (66.5%), and 15.6% (33 patients) did not receive a definitive treatment. The median time ictus-admission and ictus-treatment were 5 and 9 days, respectively. CONCLUSIONS: While medical and neurologic complications are a recognized opportunity to improve aSAH care, low- and middle-income countries comprise 70% of the world population and still encounter difficulties concerning early definitive aneurysm treatment, rebleeding, and human and material resources.

Association of Lack of Fear of Dying With New Organ Failure: Results of a Multicenter Prospective Cohort Study.

BACKGROUND: Patients' anxiety on intensive care unit (ICU) admission is associated with subsequent deterioration. OBJECTIVE: To assess whether patients' fears/anxiety are predictive of new organ failure within 7 days of ICU admission. METHODS: In a prospective 3-center cohort study of non-comatose patients without delirium or invasive mechanical ventilation, 9 specific fears were evaluated through yes/no questions. Illness severity was assessed using the Simplified Acute Physiology Score II (SAPS II) and the Sequential Organ Failure Assessment (SOFA). Intensity of acute and chronic anxiety was assessed with the state and trait components of the State-Trait Anxiety Inventory (STAI). Patients were followed up for 7 days. RESULTS: From April 2014 to December 2017, 373 patients (median [IQR] age, 63 [48-74] years; 152 [40.8%] women; median (IQR) SAPS II, 27 [19-37]) were included. Feelings of vulnerability and fear of dying were reported by 203 (54.4%) and 172 (46.1%) patients, respectively. The STAI-State score was 40 or greater in 192 patients (51.5%). Ninety-four patients (25.2%) had new organ failure. Feelings of vulnerability (odds ratio, 1.96 [95% CI, 1.12-3.43]; P=.02) and absence of fear of dying (odds ratio, 2.38 [95% CI, 1.37-4.17]; P=.002) were associated with new organ failure after adjustment for STAI-State score (≥40), SAPS II, and SOFA score. CONCLUSION: Absence of fear of dying is associated with new organ failure within the first 7 days after ICU admission. Fear of dying may protect against subsequent deterioration by mobilizing patients' homeostatic resources. ClinicalTrials.gov Identifier: NCT02355626.

Mixed methods study protocol for combining stakeholder-led rapid evaluation with near real-time continuous registry data to facilitate evaluations of quality of care in intensive care units.

Background: Improved access to healthcare in low- and middle-income countries (LMICs) has not equated to improved health outcomes. Absence or unsustained quality of care is partly to blame. Improving outcomes in intensive care units (ICUs) requires delivery of complex interventions by multiple specialties working in concert, and the simultaneous prevention of avoidable harms associated with the illness and the treatment interventions. Therefore, successful design and implementation of improvement interventions requires understanding of the behavioural, organisational, and external factors that determine care delivery and the likelihood of achieving sustained improvement. We aim to identify care processes that contribute to suboptimal clinical outcomes in ICUs located in LMICs and to establish barriers and enablers for improving the care processes. Methods: Using rapid evaluation methods, we will use four data collection methods: 1) registry embedded indicators to assess quality of care processes and their associated outcomes; 2) process mapping to provide a preliminary framework to understand gaps between current and desired care practices; 3) structured observations of processes of interest identified from the process mapping and; 4) focus group discussions with stakeholders to identify barriers and enablers influencing the gap between current and desired care practices. We will also collect self-assessments of readiness for quality improvement. Data collection and analysis will be led by local stakeholders, performed in parallel and through an iterative process across eight countries: Kenya, India, Malaysia, Nepal, Pakistan, South Africa, Uganda and Vietnam. Conclusions: The results of our study will provide essential information on where and how care processes can be improved to facilitate better quality of care to critically ill patients in LMICs; thus, reduce preventable mortality and morbidity in ICUs. Furthermore, understanding the rapid evaluation methods that will be used for this study will allow other researchers and healthcare professionals to carry out similar research in ICUs and other health services.

Effects of Tranexamic Acid in Patients with Subarachnoid Hemorrhage in Brazil: A Prospective Observational Study with Propensity Score Analysis.

BACKGROUND: Rebleeding from a ruptured aneurysm increases the risk of unfavorable outcomes after subarachnoid hemorrhage (SAH) and is prevented by early aneurysm occlusion. The role of antifibrinolytics before aneurysm obliteration remains controversial. We investigated the effects of tranexamic acid on long-term functional outcomes of patients with aneurysmal SAH (aSAH). METHODS: This was a single-center, prospective, observational study conducted in a high-volume tertiary hospital in a middle-income country from December 2016 to February 2020. We included all consecutive patients with aSAH who either received or did not receive tranexamic acid (TXA) treatment. Multivariate logistic regression analysis using propensity score was used to evaluate the association of TXA use with long-term functional outcomes, measured by the modified Rankin Scale (mRS) at 6 months. RESULTS: A total of 230 patients with aSAH were analyzed. The median (interquartile range) age was 55 (46-63) years, 72% were women, 75% presented with good clinical grade (World Federation of Neurological Surgeons grade 1-3), and 83% had a Fisher scale of 3 or 4. Around 80% of patients were admitted up to 72 h from ictus. The aneurysm occlusion method was surgical clipping in 80% of the patients. A total of 129 patients (56%) received TXA. In multivariable logistic regression using inverse probability treatment weighting, the long-term rate of unfavorable outcomes (modified Rankin scale 4-6) was the same in the TXA and non-TXA groups (61 [48%] in TXA group vs. 33 [33%] in non-TXA group; odds ratio [OR] 1.39, 95% confidence interval [CI] 0.67-2.92; p = 0.377). The TXA group had higher in-hospital mortality (33 vs. 11% in non-TXA group; OR 4.13, 95% CI 1.55-12.53, p = 0.007). There were no differences between the groups concerning intensive care unit length of stay (16 ± 11.22 days in TXA group vs. 14 ± 9.24 days in non-TXA group; p = 0.2) or hospital (23 ± 13.35 days in TXA group vs. 22 ± 13.36 days in non-TXA group; p = 0.9). There was no difference in the rates of rebleeding (7.8% in TXA group vs. 8.9% in non-TXA group; p = 0.31) or delayed cerebral ischemia (27% in TXA group vs. 19% in non-TXA group; p = 0.14). For the propensity-matched analysis, 128 individuals were selected (64 in TXA group and 64 in non-TXA group), and the rates of unfavorable outcomes at 6 months were also similar between groups (45% in TXA group and 36% in non-TXA group; OR 1.22, 95% CI 0.51-2.89; p = 0.655). CONCLUSIONS: Our findings in a cohort with delayed aneurysm treatment reinforce previous data that TXA use before aneurysm occlusion does not improve functional outcomes in aSAH.

A Survey on Monitoring and Management of Cerebral Vasospasm and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: The Mantra Study.

INTRODUCTION: Cerebral infarction from delayed cerebral ischemia (DCI) is a leading cause of poor neurological outcome after aneurysmal subarachnoid hemorrhage (aSAH). We performed an international clinical practice survey to identify monitoring and management strategies for cerebral vasospasm associated with DCI in aSAH patients requiring intensive care unit admission. METHODS: The survey questionnaire was available on the European Society of Intensive Care Medicine (May 2021-June 2022) and Neurocritical Care Society (April - June 2022) websites following endorsement by these societies. RESULTS: There were 292 respondents from 240 centers in 38 countries. In conscious aSAH patients or those able to tolerate an interruption of sedation, neurological examination was the most frequently used diagnostic modality to detect delayed neurological deficits related to DCI caused by cerebral vasospasm (278 respondents, 95.2%), while in unconscious patients transcranial Doppler/cerebral ultrasound was most frequently used modality (200, 68.5%). Computed tomography angiography was mostly used to confirm the presence of vasospasm as a cause of DCI. Nimodipine was administered for DCI prophylaxis by the majority of the respondents (257, 88%), mostly by an enteral route (206, 71.3%). If there was a significant reduction in arterial blood pressure after nimodipine administration, a vasopressor was added and nimodipine dosage unchanged (131, 45.6%) or reduced (122, 42.5%). Induced hypertension was used by 244 (85%) respondents as first-line management of DCI related to vasospasm; 168 (59.6%) respondents used an intra-arterial procedure as second-line therapy. CONCLUSIONS: This survey demonstrated variability in monitoring and management strategies for DCI related to vasospasm after aSAH. These findings may be helpful in promoting educational programs and future research.

Clinical Characteristics and Outcomes of Patients with Aneurysmal Subarachnoid Hemorrhage: A Prospective Multicenter Study in a Middle-Income Country.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is associated with high mortality and long-term functional impairment. Data on clinical management and functional outcomes from developing countries are scarce. We aimed to define patient profiles and clinical practices and evaluate long-term outcomes after SAH in a middle-income country. METHODS: This was a prospective study including consecutive adult patients admitted with SAH to two reference centers in Brazil from January 2016 to February 2020. The primary outcome was functional status at 6 months using the modified Rankin Scale. Mixed multivariable analysis was performed to determine the relationship between clinical variables and functional outcomes. RESULTS: From 471patients analyzed, the median time from symptom onset to arrival at a study center was 4 days (interquartile range 0-9). Median age was 55 years (interquartile range 46-62) and 353 (75%) patients were women. A total of 426 patients (90%) were transferred from nonspecialized general hospitals, initial computed tomography revealed thick hemorrhage in 73% of patients (modified Fisher score of 3 or 4), and 136 (29%) had poor clinical grade (World Federation of Neurological Surgeons score of 4 or 5). A total of 312 (66%) patients underwent surgical clipping, and 119 (25%) underwent endovascular coiling. Only 34 patients (7%) underwent withdrawal or withholding of life-sustaining therapy during their hospital stay, and in-hospital mortality was 24%. A total of 187 (40%) patients had an unfavorable long-term functional outcome (modified Rankin Scale score of 4 to 6). Factors associated with unfavorable outcome were age (adjusted odds ratio [OR] 1.05, 95% confidence interval [CI] 1.03-1.08), hypertension (adjusted OR 1.81, 95% CI 1.04-3.16), poor clinical grade (adjusted OR 4.92, 95% CI 2.85-8.48), external ventricular drain (adjusted OR 3.8, 95% CI 2.31-6.24), postoperative deterioration (adjusted OR 2.33, 95% CI 1.32-4.13), cerebral infarction (adjusted OR 3.16, 95% CI 1.81-5.52), rebleeding (adjusted OR 2.95, 95% CI 1.13-7.69), and sepsis (adjusted OR 2.68, 95% CI 1.42-5.05). CONCLUSIONS: Our study demonstrated that SAH management in a middle-income country diverges significantly from published cohorts and current guidelines, despite comparable clinical profiles on presentation and admission to high-volume referral centers. Earlier aneurysm occlusion and increased use of endovascular therapy could potentially reduce modifiable in-hospital complications and improve functional outcomes in Brazil.

Human endogenous retrovirus K in the respiratory tract is associated with COVID-19 physiopathology.

BACKGROUND: Critically ill 2019 coronavirus disease (COVID-19) patients under invasive mechanical ventilation (IMV) are 10 to 40 times more likely to die than the general population. Although progression from mild to severe COVID-19 has been associated with hypoxia, uncontrolled inflammation, and coagulopathy, the mechanisms involved in the progression to severity are poorly understood. METHODS: The virome of tracheal aspirates (TA) from 25 COVID-19 patients under IMV was assessed through unbiased RNA sequencing (RNA-seq), and correlation analyses were conducted using available clinical data. Unbiased sequences from nasopharyngeal swabs (NS) from mild cases and TA from non-COVID patients were included in our study for further comparisons. RESULTS: We found higher levels and differential expression of human endogenous retrovirus K (HERV-K) genes in TA from critically ill and deceased patients when comparing nasopharyngeal swabs from mild cases to TA from non-COVID patients. In critically ill patients, higher HERV-K levels were associated with early mortality (within 14 days of diagnosis) in the intensive care unit. Increased HERV-K expression in deceased patients was associated with IL-17-related inflammation, monocyte activation, and an increased consumption of clotting/fibrinolysis factors. Moreover, increased HERV-K expression was detected in human primary monocytes from healthy donors after experimental SARS-CoV-2 infection in vitro. CONCLUSION: Our data implicate the levels of HERV-K transcripts in the physiopathology of COVID-19 in the respiratory tract of patients under invasive mechanical ventilation. Video abstract.

Platelet-monocyte interaction amplifies thromboinflammation through tissue factor signaling in COVID-19.

Accumulating evidence into the pathogenesis of COVID-19 highlights a hypercoagulability state with high risk of life-threatening thromboembolic complications. However, the mechanisms of hypercoagulability and their link to hyperinflammation remain poorly understood. Here, we investigate functions and mechanisms of platelet activation and platelet-monocyte interactions in inflammatory amplification during SARS-CoV-2 infection. We used a combination of immunophenotyping, single-cell analysis, functional assays, and pharmacological approaches to gain insights on mechanisms. Critically ill patients with COVID-19 exhibited increased platelet-monocyte aggregates formation. We identified a subset of inflammatory monocytes presenting high CD16 and low HLA-DR expression as the subset mainly interacting with platelets during severe COVID-19. Single-cell RNA-sequencing analysis indicated enhanced fibrinogen receptor Mac-1 in monocytes from patients with severe COVID-19. Monocytes from patients with severe COVID-19 displayed increased platelet binding and hyperresponsiveness to P-selectin and fibrinogen with respect to tumor necrosis factor-α and interleukin-1ß secretion. Platelets were able to orchestrate monocyte responses driving tissue factor (TF) expression, inflammatory activation, and inflammatory cytokines secretion in SARS-CoV-2 infection. Platelet-monocyte interactions ex vivo and in SARS-CoV-2 infection model in vitro reciprocally activated monocytes and platelets, inducing the heightened secretion of a wide panel of inflammatory mediators. We identified platelet adhesion as a primary signaling mechanism inducing mediator secretion and TF expression, whereas TF signaling played major roles in amplifying inflammation by inducing proinflammatory cytokines, especially tumor necrosis factor-α and interleukin-1ß. Our data identify platelet-induced TF expression and activity at the crossroad of coagulation and inflammation in severe COVID-19.