Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium.

BACKGROUND: The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. METHODS: Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer's disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. RESULTS: Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. CONCLUSIONS: Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

Delirium is a syndrome in which there are substantial changes in a person's ability to focus, understand, or pay attention to events. Delirium often occurs in response to sudden trauma and is more common in persons with pre-existing cognitive impairment. What happens in the brain during delirium is not well understood. To learn more, we have studied whether markers in the cerebrospinal fluid were altered in people with delirium compared to people without delirium. To understand differences specifically caused by delirium, we included two control groups without acute trauma, one with cognitively healthy participants and one with dementia patients. We found several markers altered in people with delirium, with most of the markers similarly altered in people with cognitive impairment due to dementia. One marker was directly linked to delirium and could potentially shed light on the brain processes that cause the syndrome.

Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial.

Importance: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. Objectives: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. Design, Setting, and Participants: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. Interventions: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher). Main outcomes and measures: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. Results: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). Conclusions: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common. Trial Registration: ClinicalTrials.gov Identifier: NCT02908308.

Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial.

BACKGROUND: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. METHODS: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4-6 on modified Rankin scale). RESULTS: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84-1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80-1.26). CONCLUSIONS: Using a hospital's average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.

Reduced heart rate variability is related to the number of metabolic syndrome components and manifest diabetes in the sixth Tromsø study 2007-2008.

Both diabetes mellitus (DM) and the metabolic syndrome (MetS) are associated with autonomic neuropathy, which predisposes to cardiac events and death. Measures of heart rate variability (HRV) can be used to monitor the activity of the autonomic nervous system (ANS), and there are strong indications that HRV can be used to study the progression of ANS-related diabetes complications. This study aims to investigate differences in HRV in healthy, MetS and diabetic populations. Based on 7880 participants from the sixth health survey in Tromsø (Tromsø 6, 2007-2008), we found a significant negative association between the number of MetS components and HRV as estimated from short-term pulse wave signals (PRV). This decrease in PRV did not appear to be linear, instead it leveled off after the third component, with no significant difference in PRV between the MetS and DM populations. There was a significant negative association between HbA1c and PRV, showing a decrease in PRV occurring already within the normal HbA1c range. The MetS and DM populations are different from healthy controls with respect to PRV, indicating impaired ANS in both conditions. In the future, a study with assessment of PRV measurements in relation to prospective cardiovascular events seems justified.

Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. METHODS: Plasma was collected during hospital admission and after 3 months from the NOR-Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene. RESULTS: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low-grade inflammation and respiratory dysfunction after 3 months. CONCLUSION: Respiratory dysfunction after COVID-19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.

Feasibility of prehospital identification of non-ST-elevation myocardial infarction by ECG, troponin and echocardiography.

BACKGROUND: Prehospital identification and selection of treatment strategy in patients with suspected non-ST-elevation myocardial infarction (NSTEMI) is challenging. The aim of this study was to evaluate the feasibility and diagnostic accuracy of prehospital ECG, troponin T (TnT) and transthoracic echocardiography (TTE) acquired by paramedics in early identification of NSTEMI. METHODS: Consecutive patients requesting an ambulance from Sorlandet Hospital, Norway due to chest pain between November 2017 and January 2020 were screened for inclusion in the study. One ambulance was equipped with ECG recorder, point-of-care TnT test and TTE scanner, and six paramedics were given necessary training. ECG, TnT result and TTE images were acquired prehospitally and transferred to an in-hospital cardiologist. NSTEMI was suspected in patients with ischaemic ECG changes, elevated TnT or myocardial regional wall motion abnormalities (RWMA) at TTE. RESULTS: A total of 253 patients were included in the study. ECG was interpretable by cardiologists in 243 (96%), TnT in 238 (94%) and TTE images in 240 (95%) patients. NSTEMI was the discharge diagnosis in 22 (9%) of these patients. Four (18%) patients with NSTEMI had ischaemic ECG changes, elevated TnT and RWMA at TTE. Eight (36%) patients with NSTEMI had positive findings at two of the diagnostic methods, six (27%) patients had positive findings at one, and four (18%) patients had no positive findings in any of the diagnostic methods. In three patients (14%) with NSTEMI, RWMA was the only positive test. The negative and positive predictive values for RWMA were 42% and 96%, respectively. CONCLUSIONS: Prehospital acquisition of ECG, TnT and interpretable TTE images by paramedics were feasible in most patients with chest pain. Based on these examinations, it was possible to identify the majority of cases with NSTEMI prehospitally and admit the patients directly to a hospital with facilities for percutaneous coronary intervention (PCI) for further treatment. TRIAL REGISTRATION NUMBER: NCT04223986.

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial.

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Measurement of skin conductance responses to evaluate procedural pain in the perioperative setting.

Background and aims The subjective nature of pain makes objective, quantitative measurements challenging. The current gold standard for evaluating pain is patient self-reporting using the numeric rating scale (NRS) or Visual Analog Scale. Skin conductance responses per second (SCR) measured in the palmar region reflect the emotional part of the autonomous nervous system. SCR ≥0.20 have been shown to indicate moderate or severe pain in the postoperative setting. We examined whether SCR can detect procedure-related pain before major surgery. Methods In 20 patients being prepared for major surgery SCR was recorded before and during arterial cannulation, after induction of anaesthesia, and on the first postoperative day. Self-reported pain was evaluated using NRS. NRS >3 was considered to represent moderate or severe pain. Results NRS was 0 [0-0] before arterial cannulation, increasing to 5 [3-6] during arterial cannulation (p<0.05). Before arterial cannulation SCR was 0.27 [0.20-0.27], increasing to 0.33 [0.30-0.37] during arterial cannulation (p<0.01). On the first postoperative day both SCR and reported pain indicated no more than mild pain, SCR 0.13 [0.00-0.20] and NRS 2.0 [0.5-2.0]. The sensitivity of SCR to indicate moderate or severe pain (NRS >3) was 0.93 (0.68-1.0) and specificity was 0.33 (0.25-0.35) when the cut-off established in the postoperative setting (SCR ≥0.20) was used on all data. Conclusions SCR increased during arterial cannulation. Before major surgery the SCR was above the threshold demonstrated to indicate pain in the postoperative setting, even without painful stimuli and no reported pain. Using the threshold established for postoperative pain, SCR cannot reliably discriminate between pain and other stressors before major surgery. Implications Before major surgery, the diagnosis of moderate or severe pain should not be made based on SCR ≥0.20.

Chronic pain-related changes in cardiovascular regulation and impact on comorbid hypertension in a general population: the Tromsø study.

Heart rate variability (HRV) and baroreflex sensitivity (BRS) are indexes reflecting the ability to maintain cardiovascular homeostasis amidst changing conditions. Evidence primarily from small studies suggests that both HRV and BRS may be reduced in individuals with chronic pain (CP), with potential implications for cardiovascular risk. We compared HRV and BRS between individuals with CP (broadly defined) and pain-free controls in a large unselected population sample. Participants were 1143 individuals reporting clinically meaningful CP and 5640 pain-free controls who completed a 106-second cold pressor test (CPT). Participants self-reported hypertension status. Resting HRV and BRS were derived from continuous beat-to-beat blood pressure recordings obtained before and after the CPT. Hierarchical regressions for the pre-CPT period indicated that beyond effects of age, sex, and body mass index, the CP group displayed significantly lower HRV in both the time domain (SDNN and rMSSD) and frequency domain (high-frequency HRV power), as well as lower BRS. Results were somewhat weaker for the post-CPT period. Mediation analyses indicated that for 6 of 7 HRV and BRS measures tested, there were significant indirect (mediated) effects of CP status on the presence of comorbid hypertension via reduced HRV or BRS. Results confirm in the largest and broadest sample tested to date that the presence of CP is linked to impaired cardiovascular regulation and for the first time provide support for the hypothesis that links between CP and comorbid hypertension reported in previous population studies may be due in part to CP-related decrements in cardiovascular regulation.

Chronic pain and cardiovascular stress responses in a general population: the Tromsø Study.

We tested whether cardiovascular stress responsiveness is elevated in individuals experiencing chronic pain in a large general population sample. Blood pressure (BP) and heart rate (HR) were assessed at rest, during the cold pressor test, and during subsequent recovery in 554 individuals reporting daily chronic pain and 3,082 individuals free of chronic pain. After correcting for potential confounds, differences as a function of chronic pain status were noted for only 5 of 23 cardiovascular outcomes despite very high statistical power. Compared to the pain-free group, the chronic pain group displayed higher baseline HR/mean arterial pressure (MAP) ratio (p = .03), greater systolic BP (SBP) reactivity during the cold pressor test (p = .04), and higher HR/MAP ratio (p = .047) and significantly less SBP (p = .017) and MAP (p = .041) return to baseline during recovery. Findings suggest that changes in cardiovascular stress responsiveness associated with chronic pain are of limited clinical significance and unlikely to contribute to increased cardiovascular risk in the chronic pain population.

Gender differences in blood pressure-related hypoalgesia in a general population: the Tromsø Study.

UNLABELLED: An inverse association between resting blood pressure (BP) and acute pain sensitivity is well documented. Whether BP-related hypoalgesia differs by gender is unclear from prior work. Whether it increases proportionally with BP throughout the full BP range is also unknown. We examined BP-related hypoalgesia in a general population sample (n = 10,371, aged 30-87) of equal gender distribution reflecting the extremely low through hypertensive BP range. Resting BP was assessed and individuals participated in a standardized cold pressor test, providing pain ratings every 9 seconds. For systolic BP (SBP), a significant SBP × Gender interaction was observed on mean pain ratings (P < .001). Females displayed significant BP-related hypoalgesia (P < .001), with males showing a 38% smaller effect (P < .001). A similar DBP × Gender interaction was also observed (P < .05). Spline regression indicated a significant (P < .001) change in slope of the SBP-pain association at 140 mmHg. Among individuals with lower resting SBP (<140/90), increasing hypoalgesia with increasing SBP levels was observed (P < .001), with no further increases in those with higher BP (≥140/90; P > .10). This is the first large-scale study to confirm past results suggesting that BP-related hypoalgesia differs by gender; that is, females exhibited greater hypoalgesia. BP-related hypoalgesia appears subject to ceiling effects in the hypertensive BP range. PERSPECTIVE: Females show greater BP-related hypoalgesia than males, highlighting gender differences in endogenous antinociceptive systems. Extent of BP-related hypoalgesia does not increase further once resting pressures reach the hypertensive range, suggesting persistent maximal demands on these antinociceptive systems among hypertensive individuals.

Hypertension prevalence and diminished blood pressure-related hypoalgesia in individuals reporting chronic pain in a general population: the Tromsø study.

Resting blood pressure (BP) is inversely related to pain sensitivity in individuals free of chronic pain, reflecting homeostatic interactions between cardiovascular and pain modulatory systems. Several laboratory studies indicate that BP-related hypoalgesia is diminished in chronic pain patients, suggesting dysfunction in these interacting systems. Separate epidemiological findings reveal elevated hypertension prevalence in the chronic pain population. This study for the first time simultaneously evaluated both hypertension prevalence and BP-related hypoalgesia as they relate to chronic pain in the same sample. Resting BP and pain sensitivity were evaluated in a large general population sample (n=10,135, aged 30-87years). Subjects participated in a standardized 106s cold pressor test, providing pain ratings at 9s intervals. Self-reported presence of chronic pain and history of hypertension and use of antihypertensive medication were assessed. Significant interactions between chronic pain status and resting systolic (P<.001) and diastolic BP (P<.001) on mean pain ratings were observed. These interactions were due to significant (P<.001) BP-related hypoalgesia in individuals free of chronic pain that was twice the magnitude of the hypoalgesia observed in the group reporting chronic pain. Presence of chronic pain was associated with significantly increased odds of comorbid hypertension (P<.001). Within the chronic pain group, higher chronic pain intensity was a significant predictor of positive hypertension status beyond the effects of traditional demographic risk factors (P<.05). Results are consistent with the hypothesis that increased hypertension risk in the chronic pain population might be linked in part to chronic pain-related dysfunction in interacting cardiovascular-pain modulatory systems.