Plasma exosomal miR-596: a novel biomarker predicts survival in patients with idiopathic pulmonary artery hypertension

ObjectiveTo determine if plasma exosomal microRNAs (miRNAs) can predict survival in patients with idiopathic pulmonary arterial hypertension (IPAH).MethodsThe study enrolled patients with IPAH that underwent right heart catheterization. Plasma was collected and exosomal miRNAs were extracted. Exosomes were evaluated using transmission electron microscopy, Western blot analysis and particle size distribution analysis. MiRNAs were evaluated using a miRNA microarray and validated using real-time polymerase chain reaction.ResultsThis study included 12 patients with IPAH in the study group and 48 patients with IPAH in the validation group. The mean ± SD follow-up duration was 60.3 ± 35.4 months in the overall cohort. The levels of miR-596 were higher in the nonsurvivors compared with the survivors. The levels of miR-596 significantly correlated with survival time, mean right atrial pressure, pulmonary vascular resistance (PVR) and cardiac index. High levels of miR-596 and PVR were significantly associated with poor overall survival. Multivariate analysis demonstrated that exosomal miR-596 (hazard ratio [HR] = 2.119; 95% confidence interval [CI] 1.402, 3.203) and PVR (HR = 1.146; 95% CI 1.010, 1.300) were independent predictors of survival.ConclusionsHigh levels of plasma exosomal miR-596 were significantly associated with disease severity and poor prognosis of patients with IPAH.     

Serum exosomal miR-377-3p inhibits retinal pigment epithelium proliferation and offers a biomarker for diabetic macular edema

ObjectivesDiabetic macular edema (DME) is a complication of diabetes mellitus that leads to diabetic retinopathy. Thus far, the role of serum exosomal microRNAs (miRNAs) in DME progression remains elusive. This study investigated serum exosomal miRNAs from patients with type 2 diabetes (T2D) and DME to identify miRNAs associated with expression of vascular endothelial growth factor (VEGF), a pivotal component in DME progression; it also evaluated the diagnostic values of these miRNAs for DME.MethodsSerum was collected from patients with T2D who did (n = 20) and did not have DME (n = 24). Exosomes were isolated from serum and subjected to real-time polymerase chain reaction, western blotting, luciferase reporter, and miRNA profiling analyses.ResultsVEGF was significantly upregulated in ARPE-19 cells treated with exosomes from patients with T2D and DME, compared with exosomes from patients with T2D alone. Among the top 10 downregulated miRNAs identified during exosomal miRNA profiling, miR-377-3p inhibited the expression of VEGF. Luciferase reporter assays confirmed that miR-377-3p could directly regulate VEGF expression. Receiver operating characteristic analysis identified serum exosomal miR-377-3p as a potential biomarker for DME.ConclusionSerum exosomal miR-377-3p inhibits VEGF expression to suppress retinal pigment epithelium proliferation and offers a diagnostic biomarker for DME.     

The brain-enriched microRNA miR-124 in plasma predicts neurological outcome after cardiac arrest

Introduction

Early prognostication after successful cardiopulmonary resuscitation is difficult, and there is a need for novel methods to estimate the extent of brain injury and predict outcome. In this study, we evaluated the impact of the cardiac arrest syndrome on the plasma levels of selected tissue-specific microRNAs (miRNAs) and assessed their ability to prognosticate death and neurological disability.

Methods

We included 65 patients treated with hypothermia after cardiac arrest in the study. Blood samples were obtained at 24 hours and at 48 hours. For miRNA-screening purposes, custom quantitative polymerase chain reaction (qPCR) panels were first used. Thereafter individual miRNAs were assessed at 48 hours with qPCR. miRNAs that successfully predicted prognosis at 48 hours were further analysed at 24 hours. Outcomes were measured according to the Cerebral Performance Category (CPC) score at 6 months after cardiac arrest and stratified into good (CPC score 1 or 2) or poor (CPC scores 3 to 5).

Results

At 48 hours, miR-146a, miR-122, miR-208b, miR-21, miR-9 and miR-128 did not differ between the good and poor neurological outcome groups. In contrast, miR-124 was significantly elevated in patients with poor outcomes compared with those with favourable outcomes (P < 0.0001) at 24 hours and 48 hours after cardiac arrest. Analysis of receiver operating characteristic curves at 24 and 48 hours after cardiac arrest showed areas under the curve of 0.87 (95% confidence interval (CI) = 0.79 to 0.96) and 0.89 (95% CI = 0.80 to 0.97), respectively.

Conclusions

The brain-enriched miRNA miR-124 is a promising novel biomarker for prediction of neurological prognosis following cardiac arrest.     

Genetic variant in microRNA-146a gene is associated with risk of rheumatoid arthritis

ObjectiveTo investigated the association between single nucleotide polymorphisms (SNPs) in microRNA-146a (miR-146a) gene and susceptibility of rheumatoid arthritis (RA).MethodsWe systemically extracted the genetic data of miR-146a from previous genome-wide association studies (GWASs) of RA. Subsequently, we performed a replication study in an independent Chinese cohort for selected variant. A meta-analysis combined the previous GWASs with the replication study was also conducted. The epigenetic annotation and cytokine assay were used for exploring potential variant function.ResultsThe extracted genetic association data from three previous GWASs showed that the allele T of functional SNP rs2431697 increased RA susceptibility. The significant association for the SNP was also found in the Chinese replication cohort (OR = 1.24, 95% CI = 1.06–1.46, p = 8.69E-03). The estimated effect size for this SNP was larger in Asian population than that in European population (Asian meta-analysis: OR = 1.15, 95% CI = 1.09–1.22, p = 4.37E-07; Tran-ethnic meta-analysis: OR = 1.07, 95% CI = 1.04–1.10, p = 1.79E-06). The cytokine assay also showed that the risk allele T of the SNP rs2431697 is inversely associated with plasma TNF-α levels in health controls (p = .016).ConclusionsIn summary, this study supports that genetic variant in miR-146a gene is associated with RA risk.

KEY MESSAGES

1. The association between SNPs in miR-146a gene and susceptibility of RA was unclear.
2. We investigated the genetic association using GWASs data and a replication study.
3. The SNP rs2431697 in miR-146a gene is associated with RA risk.

     

Cervicogenic dizziness alleviation after coblation discoplasty: a retrospective study

ObjectiveLittle is known about the therapeutic relationship between coblation discoplasty and cervicogenic dizziness (CGD). CGD can be caused by abnormal proprioceptive inputs from compressed nerve roots, intradiscal mechanoreceptors and nociceptors to the vestibulospinal nucleus in the degenerative cervical disc. The aim was to analyze the efficacy of coblation discoplasty in CGD through intradiscal nerve ablation and disc decompression in a 12-month follow-up retrospective study.MethodsFrom 2015 to 2019, 42 CGD patients who received coblation discolplasty were recruited as the surgery group, and 22 CGD patients who rejected surgery were recruited as the conservative group. Using intent-to-treat (ITT) analysis, we retrospectively analyzed the CGD visual analogue scale (VAS), neck pain VAS, CGD frequency score, and the CGD alleviation rating throughout a 12-month follow-up period.ResultsCompared with conservative intervention, coblation discoplasty revealed a better recovery trend with effect sizes of 1.76, 2.15, 0.92, 0.78 and 0.81 in CGD VAS, and effect sizes of 1.32, 1.54, 0.93, 0.86 and 0.76in neck pain VAS at post-operative 1 week, and 1, 3, 6, 12 months, respectively. The lower CGD frequency score indicated fewer attacks of dizziness until postoperative 3 months (p < 0.01). At post-operative 12 months, the coblation procedure showed increased satisfactory outcomes of CGD alleviation rating (p < .001, −1.00 of effect size).ConclusionsCoblation discoplasty significantly improves the severity and frequency of CGD, which is important inbridging unresponsive conservative intervention and open surgery.

Key messages

• There is a correlation between the degenerative cervical disc and cervicogenic dizziness (CGD).
• CGD can be caused by abnormal proprioceptive inputs from a compressed nerve root and intradiscal mechanoreceptors and nociceptors to the vestibulospinal nucleus in the degenerative cervical disc.
• Cervical coblation discoplasty can alleviate CGD through ablating intradiscal nerve endings and decompressing the nerve root.

     

Circulating miR-26a,miR-106b,miR-107 and miR-133b stratify hepatocellular carcinoma patients according to their response to transarterial chemoembolization

BackgroundA number of hepatocellular carcinoma (HCC) patients have developed resistance against transcatheter arterial chemoembolization (TACE) treatment. In this study, we aimed to develop a panel of microRNAs (miRs) biomarkers to predict clinical outcomes in HCC patients after TACE treatment.MethodsThe expression level of twenty miRs was evaluated in FFPE tissues collected from 33 HCC patients. We selected four differentially expressed miRs in TACE-responders versus non-responders and re-assessed their expression in 51 serum samples. The expressions of miRs associated with overall survival (OS), progression-free survival (PFS), and treatment outcomes were investigated. The diagnostic accuracy of these miRs in predicting patients' response to TACE was also evaluated.ResultsThe baseline of miR-106b, miR-107 and miR-133b was significantly elevated (p < .001) in sera of TACE-responders while miR-26a was elevated (p < .001) in non-responders. miR-26a and miR-133b recorded the highest diagnostic performance as individual classifiers in response to TACE (AUC = 1.0 and 100% sensitivity and specificity). Intriguingly, miR-133b distinguished complete responders from partial responders and non-responders (AUC ≥ 0.90). The PFS was improved (p < .05) in the high expression group of miR-31, miR-200b, miR-133b and miR-181a over their low expression group.ConclusionCirculating miR-133b, miR-26a, miR-107 and miR-106 in serum are potential candidates to be utilized as prognostic biomarkers for predication of TACE treatment outcomes in HCC patients.     

Low Psoas-Muscle index is associated with decreased survival in hepatocellular carcinoma treated with transarterial chemoembolization

PurposeSkeletal muscle index (SMI) is a promising predictor of clinical outcomes in patients with malignant diseases. As a simpler surrogate of sarcopenia-psoas muscle index (PMI), its predict value for overall survival (OS) after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) has not been reported. To determine if changes in the PMI predicted OS in individuals with HCC treated with TACE.Patients and MethodsA retrospective analysis was performed in HCC patients treated with TACE between January 2018 and March 2019. The survival curve according to PMI was estimated by the Kaplan–Meier method and then compared by the log-rank test. Cox proportional hazards models were conducted to identify the prognostic factors for OS. Furthermore, the predictive abilities of PMI and SMI were compared by using Harrell’s concordance index (C-index).ResultsTwo hundred and twenty-eight patients (175 men, mean age 59 ± 11 years) were analysed. The OS was less in patients with low PMI than those with high PMI (median OS: 16.9 vs. 38.5 months, p < .001). Multivariate analysis found that either PMI (hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.45–0.91; p < .001) or SMI (HR = 0.51; 95% CI, 0.36–0.72; p < .001) was significantly associated with OS. In the multivariate analysis, the C-index for PMI was 0.78 and 0.79 for SMI (p = .985).ConclusionPMI is a simple tool to predict OS in HCC patients treated with TACE. The predictive ability of PMI is comparable to that of SMI.

Key messages

1. Low psoas-muscle index is associated with decreased overall survival in hepatocellular carcinoma treated with transarterial chemoembolization (TACE).
2. Psoas-muscle index has advantages of being faster and easier to acquire, which thus makes it more likely to achieve widespread clinical application.

     

Six-month outcomes and effect of pulmonary rehabilitation among patients hospitalized with COVID-19: a retrospective cohort study

BackgroundPatients appear to maintain sequelae post-coronavirus disease 2019 (COVID-19) affecting daily life and physical health. We investigated the changes in and the effects of pulmonary rehabilitation (PR) on exercise capacity and immunology six months after COVID-19 hospitalization.MethodsThis retrospective cohort reviewed 233 COVID-19 patients admitted from 17 January 2020 to 29 February 2020. Ninety-eight patients who completed 2-week and 6-month follow-ups and tests were included. Among 98 patients, 27 completed at least five sessions of PR at the First Hospital of Changsha, China, during the 6-month convalescence were allocated to the PR group; the reminder who had not performed any PR were assigned to the control group. The primary outcome was the change in six-minute walk distance (6-MWD) between the 2-week and 6-month follow-ups, which was assessed via analysis of covariance with a covariate of propensity score that adjusted for the potential confounders. Secondary outcomes were the changes in 6-MWD, SARS-CoV-2 immunoglobulins, T-lymphocytes and blood chemistry, which were evaluated via paired tests.ResultsParticipants’ ages ranged from 19 to 84 years (M = 47, standard deviation (SD)=15) 45.9% identified as male. During the 6-month convalescence, 6-MWD increased 27.0%, with a mean [95% CI] of 113 [92–134] m (p < .001). SARS-CoV-2 IgG and IgM decreased 33.3% (p = .002) and 43.8% (p = .009), CD4+ T cells increased 7.9% (p = .04), and the majority of blood chemistry significantly changed. The patients in the PR group acquired a greater increase in 6-MWD than those in control (unadjusted, 194 [167–221] m, p < .001; adjusted, 123 [68–181] m, p < .001), dose-responsiveness of PR on 6-MWD was observed (p < .001). No differences in immunity variables and blood chemistry were observed between groups.ConclusionsThese findings suggest PR may be a strategy to promote the improvement of exercise capacity after COVID-19.     

Expression profile of plasma microRNAs in nonsyndromic cleft lip and their clinical significance as biomarkers

ObjectiveThe aim of this study was to determine the expression profile of plasma microRNAs in nonsyndromic cleft lip (NSCL) and their clinical significance as biomarkers.MethodsAgilent human miRNA microarray chips were used to analyze three NSCL plasma samples (mixed as CL group) and three normal plasma samples (mixed as Control group). Six selected plasma miRNAs were validated using qRT-PCR between another 13 CL and 11 healthy children. The receiver operating characteristic (ROC) curve analysis was applied for three elevated miRNAs, miR-16-2-3p, miR-365a-3p and miR-877-5p. Their target genes were further assessed using gene ontology and pathway analysis.ResultsThe plasma miRNA differentially expressed (fold change ≥2) amounted to 305. In particular, it had been validated that miR-16-2-3p, miR-365a-3p and miR-877-5p were elevated in NSCL plasma samples. ROC curve analysis revealed that each microRNA was able to significantly discriminate NSCL subjects from normal controls. Gene ontology and pathway analysis revealed that many processes over-represented in CL are related to system development process, regulation of nitrogen compound metabolic process, FoxO signaling pathway and the ErbB signaling pathway.ConclusionOur study demonstrated that plasma miR-16-2-3p, miR-365a-3p and miR-877-5p might become biomarkers to diagnose NSCL and dysregulation of these miRNAs might be involved in the progression of NSCL.     

S100A1 as a potential biomarker for the diagnosis of patients with acute aortic dissection

ObjectiveAcute aortic dissection (AAD) is a common life-threatening cardiovascular disease. This retrospective study was conducted to analyze the plasma concentration of S100A1 and its diagnostic value for AAD through receiver operating characteristic (ROC) curve and logistic regression analyses.MethodsSeventy-eight patients with AAD and 77 healthy controls were included, and the relevant clinical data for each group were collected. According to the Stanford classification, the AAD patients were divided into types A and B. The plasma levels of S100A1, D-dimer, hypersensitive C-reactive protein, and cardiac troponin T were detected by enzyme-linked immunosorbent assays.ResultsThe S100A1 concentrations in the healthy control, Stanford A, and Stanford B groups were 0.7 ± 0.6, 4.9 ± 2.6, and 3.5 ± 2.2 ng/mL, respectively. The concentration of S100A1 was increased in patients with AAD complicated with aortic regurgitation, pericardial effusion, or in-hospital death. ROC curve analysis showed that the area under the curve was 0.89. Logistic regression analysis revealed that the S100A1 level was an important risk factor for the development of AAD.ConclusionPlasma S100A1 is significantly elevated in patients with AAD, and its concentration has potential clinical value for diagnosing AAD.     

Prediabetes as a risk factor for major adverse cardiovascular events

IntroductionType II diabetes mellitus (DM) is a proinflammatory process and a known risk factor for major adverse cardiac events (MACE). The same inflammatory markers may be present in prediabetes (pDM); however, the relationship between pDM by HbA1c and MACE is not well studied. We sought to see if pDM increases one’s risk for MACE.MethodsWe retrospectively studied patients at Beaumont Health, Michigan between 2006 and 2020. We divided patients into groups (G1–G5) based on haemoglobin A1c (HbA1c) trends over the study period as follows: G1: pDM patients who remained pDM; G2: pDM who progressed into DM; G3: pDM who normalized their HbA1c; G4: patients who maintained a normal HbA1c; and G5: patients with HbA1c persistently in the DM range. We compared MACE between the groups by univariate and multivariate regression analyses.ResultsA total of 119,271 patients were included in the study (G1: N = 13,520, G2: N = 6314, G3: N = 1585, G4: N = 15,018, G5: N = 82,834). Pairwise comparison revealed a statistically significant increase in the odds of MACE in all groups compared to those with normal HbA1c values (G4; p < .001). After adjusting for baseline characteristics, multivariate regression revealed elevated odds of MACE in patients with persistent pDM (G1; aOR = 1.087, p = .002) and diabetes (G2/G5; aOR = 1.25 and aOR = 1.18, p < .001) compared to individuals with normal HbA1c values.ConclusionPrediabetes is a risk factor for MACE. Normalization of HbA1c values appears to decrease the adjusted risk for MACE and should be the goal in patients with pDM.

KEY MESSAGES

• Patients with prediabetes (pDM) are at increased risk for major cardiovascular events.
• Normalization of HbA1c in pDM patients may have a clinically significant benefit, in terms of lowering the MACE risk.
• Prediabetes patients who progress into diabetes mellitus may represent a particularly high-risk group.

     

A simple prognostic index based on admission vital signs data among patients with sepsis in a resource-limited setting

IntroductionIn sub-Saharan Africa, vital signs are a feasible option for monitoring critically ill patients. We assessed how admission vital signs data predict in-hospital mortality among patients with sepsis. In particular, we assessed whether vital signs data can be incorporated into a prognostic index with reduced segmentation in the values of included variables.MethodsSubjects were patients with sepsis hospitalized in Uganda, who participated in two cohort studies. Using restricted cubic splines of admission vital signs data, we predicted probability of in-hospital death in the development cohort and used this information to construct a simple prognostic index. We assessed the performance of the index in a validation cohort and compared its performance to that of the Modified Early Warning Score (MEWS).ResultsWe included 317 patients (167 in the development cohort and 150 in the validation cohort). Based on how vital signs predicted mortality, we created a prognostic index giving a score of 1 for: respiratory rates ≥30 cycles/minute; pulse rates ≥100 beats/minute; mean arterial pressures ≥110/<70 mmHg; temperatures ≥38.6/<35.6°C; and presence of altered mental state defined as Glasgow coma score ≤14; 0 for all other values. The proposed index (maximum score = 5) predicted mortality comparably to MEWS. Patients scoring ≥3 on the index were 3.4-fold (95% confidence interval (CI) 1.6 to 7.3, P = 0.001) and 2.3-fold (95% CI 1.1 to 4.7, P = 0.031) as likely to die in hospital as those scoring 0 to 2 in the development and validation cohorts respectively; those scoring ≥5 on MEWS were 2.5-fold (95% CI 1.2 to 5.3, P = 0.017) and 1.8-fold (95% CI 0.74 to 4.2, P = 0.204) as likely to die as those scoring 0 to 4 in the development and validation cohorts respectively.ConclusionAmong patients with sepsis, a prognostic index incorporating admission vital signs data with reduced segmentation in the values of included variables adequately predicted mortality. Such an index may be more easily implemented when triaging acutely-ill patients. Future studies using a similar approach may develop indexes that can be used to monitor treatment among acutely-ill patients, especially in resource-limited settings.     

Placenta-specific plasma miR518b is a potential biomarker for preeclampsia

IntroductionMicroRNAs have a significant role in the pathogenesis of preeclampsia. Circulating microRNAs could represent a potential biomarker for preeclampsia. The aim of this study was to evaluate plasma miR210-3p and miR518b in preeclampsia and healthy pregnancy for the first time by digital droplet PCR (ddPCR).MethodsThirty-six pregnant women (seventeen healthy pregnancies, nineteen preeclampsia patients) were involved from the Clinic for Gynaecology and Obstetrics “Narodni front” in Belgrade, Serbia. Plasma miR210-3p, miR518b and cel-miR-39 as a spike-in control were measured by ddPCR.ResultsMiR518b was significantly elevated in preeclampsia compared to a healthy pregnancy (P = 0.034; 0.302(0.217–0.421) vs. 0.171(0.110–0.266)). MiR210-3p showed no significant difference between the two groups (P = 0.951). The adjustment of miR518b was made for a gestational age and smoking status and the difference between the preeclampsia and healthy pregnancy group was more significant (P = 0.026; 0.300(0.216–0.419) vs. 0.172(0.121–0.245)).Plasma miR-518b was significantly higher in the group of preeclampsia patients with proteinuria above the 75th percentile for the group (P = 0.033), in women who smoked (P = 0.039), and was positively related to uric acid in preeclampsia (P = 0.018, r = 0.536). Plasma miR518b was able to significantly discriminate between preeclampsia and healthy pregnancy, yielding AUC of 0.712 (95%CI:0.539–0.891), P = 0.028.ConclusionsIn this study plasma microRNA were measured for the first time in preeclampsia and healthy pregnancies with ddPCR. Placenta-specific miR-518b could serve as a potential biomarker for discriminating preeclampsia and healthy pregnancy, which should be confirmed on a larger study population. This study has failed to confirm the same potential for miR210-3p.     

Diaphragm ultrasound as indicator of respiratory effort in critically ill patients undergoing assisted mechanical ventilation: a pilot clinical study

IntroductionPressure-support ventilation, is widely used in critically ill patients; however, the relative contribution of patient’s effort during assisted breathing is difficult to measure in clinical conditions. Aim of the present study was to evaluate the performance of ultrasonographic indices of diaphragm contractile activity (respiratory excursion and thickening) in comparison to traditional indices of inspiratory muscle effort during assisted mechanical ventilation.MethodConsecutive patients admitted to the ICU after major elective surgery who met criteria for a spontaneous breathing trial with pressure support ventilation were enrolled. Patients with airflow obstruction or after thoracic/gastric/esophageal surgery were excluded. Variable levels of inspiratory muscle effort were achieved by delivery of different levels of ventilatory assistance by random application of pressure support (0, 5 and 15 cmH₂O). The right hemidiaphragm was evaluated by B- and M-mode ultrasonography to record respiratory excursion and thickening. Airway, gastric and oesophageal pressures, and airflow were recorded to calculate indices of respiratory effort (diaphragm and esophageal pressure–time product).Results25 patients were enrolled. With increasing levels of pressure support, parallel reductions were found between diaphragm thickening and both diaphragm and esophageal pressure–time product (respectively, R = 0.701, p < 0.001 and R = 0.801, p < 0.001) during tidal breathing. No correlation was found between either diaphragm or esophageal pressure–time product and diaphragm excursion (respectively, R = −0.081, p = 0.506 and R = 0.003, p = 0.981), nor was diaphragm excursion correlated to diaphragm thickening (R = 0.093, p = 0.450) during tidal breathing.ConclusionsIn patients undergoing in assisted mechanical ventilation, diaphragm thickening is a reliable indicator of respiratory effort, whereas diaphragm excursion should not be used to quantitatively assess diaphragm contractile activity.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0894-9) contains supplementary material, which is available to authorized users.     

A close association of freedom from pain,migraine-related functional disability,and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN

BackgroundWhile pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing.MethodsPatient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom.ResultsPatients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time.ConclusionsThis study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint.Trial RegistrationSAMURAI ({"type":"clinical-trial","attrs":{"text":"NCT02439320","term_id":"NCT02439320"}}NCT02439320); SPARTAN ({"type":"clinical-trial","attrs":{"text":"NCT02605174","term_id":"NCT02605174"}}NCT02605174).Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01303-w.     

Propofol increases morbidity and mortality in a rat model of sepsis

IntroductionSevere sepsis is associated with approximately 50% mortality and accounts for tremendous healthcare costs. Most patients require ventilatory support and propofol is commonly used to sedate mechanically ventilated patients. Volatile anesthetics have been shown to attenuate inflammation in a variety of different settings. We therefore hypothesized that volatile anesthetic agents may offer beneficial immunomodulatory effects during the course of long-term intra-abdominal sepsis in rats under continuous sedation and ventilation for up to 24 hours.MethodsSham operation or cecal ligation and puncture (CLP) was performed in adult male Wistar rats followed by mechanical ventilation. Animals were sedated for 24 hours with propofol (7 to 20 mg/kg/h), sevoflurane, desflurane or isoflurane (0.7 minimal alveolar concentration each).ResultsSeptic animals sedated with propofol showed a mean survival time of 12 hours, whereas >56% of all animals in the volatile groups survived 24 hours (P <0.001). After 18 hours, base excess in propofol + CLP animals (−20.6 ± 2.0) was lower than in the volatile groups (isoflurane + CLP: -11.7 ± 4.2, sevoflurane + CLP: -11.8 ± 3.5, desflurane + CLP -14.2 ± 3.7; all P <0.03). Plasma endotoxin levels reached 2-fold higher levels in propofol + CLP compared to isoflurane + CLP animals at 12 hours (P <0.001). Also blood levels of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, interleukin-10, CXCL-2, interferon-γ and high mobility group protein-1) were accentuated in propofol + CLP rats compared to the isoflurane + CLP group at the same time point (P <0.04).ConclusionsThis is the first study to assess prolonged effects of sepsis and long-term application of volatile sedatives compared to propofol on survival, cardiovascular, inflammatory and end organ parameters. Results indicate that volatile anesthetics dramatically improved survival and attenuate systemic inflammation as compared to propofol. The main mechanism responsible for adverse propofol effects could be an enhanced plasma endotoxin concentration, leading to profound hypotension, which was unresponsive to fluid resuscitation.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0751-x) contains supplementary material, which is available to authorized users.