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Purpose We examined the effect of a high-target mean arterial pressure (MAP) on septic shock in a previously underrepresented region. Methods A multicentre, pragmatic, open-label, randomised controlled trial was conducted in 29 hospitals in Japan, where the prevalence of chronic hypertension among older individuals is 66.9%. Patients who were diagnosed with septic shock, aged ≥ 65 years, and admitted to an intensive care unit were randomised 1:1 to the high (target MAP = 80–85 mmHg) or control (target MAP = 65–70 mmHg) groups from 1 July 2021 to 12 December 2023. The target MAP was maintained for 72 h or until vasopressors were no longer required. The primary outcome was the 90-day all-cause mortality. Secondary outcomes included organ support-free days and adverse events. Results The trial was terminated early on the basis of the interim analysis results, suggesting the harm of the high-target strategy. Of the 518 patients, 258 were in the high-target group, and 260 were in the control group. By 90 days after randomisation, 101 patients (39.3%) in the high-target group and 74 (28.6%) in the control group had died from any cause (risk difference = 10.7; 95% confidence interval, 2.6–18.9). Renal replacement therapy-free days at 28 days were shorter in the high-target group. No clinical benefits for any outcome were observed in any subpopulation, including those with known chronic hypertension. Conclusion Among older patients with septic shock, high-target MAP significantly increased mortality compared with standard care. Trial registration UMIN Clinical Trials Registry; UMIN000041775; 13 September 2020.

This trial showed no significant difference in the percentage of patients who died or had severe disability or coma when higher or lower blood-pressure targets were used after an out-of-hospital cardiac arrest.

In this randomized trial involving patients with traumatic brain injury and elevated intracranial pressure, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. In Europe, traumatic brain injury is the most common cause of permanent disability in people younger than 40 years of age, with the annual cost exceeding €33 billion (approximately $37.5 billion in U.S. dollars). 1 , 2 Recent statistics show a 21% increase in the incidence of traumatic brain injury during the past 5 years — three times greater than the increase in population. Despite this, management of traumatic brain injury has been underrepresented in medical research as compared with other health problems. 3 Consequently, there are few data to support the commonly used stage 2 interventions (Figure 1) for the management of . . .

Background The StratosPHere 2 trial will evaluate the efficacy of hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2 by focussing on the novel biomarker and other endpoints including safety. Study design StratosPHere 2 is a three armed, placebo-controlled, phase 2 trial with two strata based on the mutation groups. It is response adaptive where the allocation of treatments follows a Bayesian response-adaptive randomisation algorithm. An expected number of 20 patients will be randomised in each stratum to one of the three arms containing hydroxychloroquine, phenylbutyrate and placebo. The primary outcome is a novel endpoint considering the change in the bone morphogenetic receptor type 2 (BMPR2). Method The final primary analysis on the efficacy of each active treatment against control is assessed using a one-sided nonparametric Wilcoxon test computed on the continuous biomarker data collected up to 8 weeks from the start of treatment. Discussion This manuscript presents the key elements of the StratosPHere 2 implementation and statistical analysis plan. This is submitted to the journal before the first interim analysis to preserve the scientific integrity under a response-adaptive design framework. The StratosPHere 2 trial closely follows published guidelines for the content of Statistical Analysis Plans in clinical trials. Trial registration The ISRCTN Registry ISRCTN10304915 (22/09/2023)

The close relationship between hypertension and dietary sodium intake is widely recognized and supported by several studies. A reduction in dietary sodium not only decreases the blood pressure and the incidence of hypertension, but is also associated with a reduction in morbidity and mortality from cardiovascular diseases. Prolonged modest reduction in salt intake induces a relevant fall in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group, with larger falls in systolic blood pressure for larger reductions in dietary salt. The high sodium intake and the increase in blood pressure levels are related to water retention, increase in systemic peripheral resistance, alterations in the endothelial function, changes in the structure and function of large elastic arteries, modification in sympathetic activity, and in the autonomic neuronal modulation of the cardiovascular system. In this review, we have focused on the effects of sodium intake on vascular hemodynamics and their implication in the pathogenesis of hypertension.

Purpose In shock, hypotension may contribute to inadequate oxygen delivery, organ failure and death. We conducted the Optimal Vasopressor Titration (OVATION) pilot trial to inform the design of a larger trial examining the effect of lower versus higher mean arterial pressure (MAP) targets for vasopressor therapy in shock. Methods We randomly assigned critically ill patients who were presumed to suffer from vasodilatory shock regardless of admission diagnosis to a lower (60–65 mmHg) versus a higher (75–80 mmHg) MAP target. The primary objective was to measure the separation in MAP between groups. We also recorded days with protocol deviations, enrolment rate, cardiac arrhythmias and mortality for prespecified subgroups. Results A total of 118 patients were enrolled from 11 centres (2.3 patients/site/month of screening). The between-group separation in MAP was 9 mmHg (95 % CI 7–11). In the lower and higher MAP groups, we observed deviations on 12 versus 8 % of all days on vasopressors ( p  = 0.059). Risks of cardiac arrhythmias (20 versus 36 %, p  = 0.07) and hospital mortality (30 versus 33 %, p  = 0.84) were not different between lower and higher MAP arms. Among patients aged 75 years or older, a lower MAP target was associated with reduced hospital mortality (13 versus 60 %, p  = 0.03) but not in younger patients. Conclusions This pilot study supports the feasibility of a large trial comparing lower versus higher MAP targets for shock. Further research may help delineate the reasons for vasopressor dosing in excess of prescribed targets and how individual patient characteristics modify the response to vasopressor therapy.

To determine the appropriate mean arterial pressure (MAP) control level for elderly patients with hypertension during the perioperative period. A prospective, randomized study. Three teaching hospitals in China. Six hundred seventy-eight elderly patients with chronic hypertension undergoing major gastrointestinal surgery. Patients were randomly allocated to three groups and the target MAP level was strictly controlled to one of three levels: level I (65-79mmHg), level II (80-95mmHg), or level III (96-110mmHg). The primary outcome was acute kidney injury (AKI) (50% or 0.3mg·dL increase in creatinine level) during the first 7 postoperative days. The secondary outcomes were perioperative adverse complications. Moreover, vasoactive agents were observed during surgery. The overall incidence of postoperative AKI was 10.9% (71/648). AKI occurred significantly less often in patients with level II MAP control (6.3%;13/206) than in patients with level I (13.5%; 31/230) and level III (12.9%; 27/210) (P<0.001) MAP control. Level II was associated with lower incidences of hospital-acquired pneumonia (6.7%; 14/206; P=0.014) and admission to the intensive care unit (ICU) (4.4%; 9/206; P=0.015) and with shorter length of stay in the ICU (P=0.025) when compared with level I and level III. Use of norepinephrine, phenylephrine, and nitroglycerin was significantly higher for patients with level III MAP control than for patients with level I and level II MAP control (P=0.001). For elderly hypertensive patients, controlling intraoperative MAP levels to 80 to 95mmHg can reduce postoperative AKI after major abdominal surgery.

Abstract Rationale Normal mean pulmonary arterial pressure (mPAP) is 14.0 ± 3.3 mm Hg (mean ± SD). The prognostic relevance of mildly elevated mPAP not fulfilling the definition of pulmonary hypertension (PH; mPAP ≥ 25 mm Hg) has not been prospectively evaluated in a real-world setting. Objectives To assess the association of resting mPAP with all-cause mortality in a retrospective and a prospective cohort of patients with unexplained dyspnea and/or at risk of PH. Methods Prognostic cutoffs were calculated by means of 1) classification and regression tree (CART) analysis without any preset thresholds, and 2) preset thresholds on the basis of literature data defining mPAP as lower-normal (≤mean + 1 SD), upper-normal (between mean + 1 SD and mean + 2 SD), borderline (between mean + 2 SD and 25 mm Hg), and manifest PH (≥25 mm Hg). We performed univariate and multivariate survival analysis adjusted for age and comorbidities. Measurements and Main Results We enrolled 547 patients, of whom 137, 56, 64, and 290 presented with lower-normal, upper-normal, or borderline mPAP, and manifest PH, respectively. The CART analysis on mPAP discriminated three prognostic groups: mPAP less than 17 mm Hg, 17 to 26 mm Hg, and greater than 26 mm Hg, with significantly decreasing survival. The univariate analysis on the basis of preset thresholds showed that upper-normal mPAP, borderline mPAP, and manifest PH were significantly associated with poor survival compared with lower-normal mPAP. In the multivariate model, considering age and comorbidities, only borderline mPAP (hazard ratio, 2.37; 95% confidence interval, 1.14–4.97; P = 0.022) and manifest PH (hazard ratio, 5.05; 95% confidence interval, 2.79–9.12; P < 0.001) were significantly associated with poor survival. Conclusions In patients at risk for PH and/or with unexplained dyspnea, CART analysis detects prognostic thresholds at a resting mPAP of 17 mm Hg and 26 mm Hg, and values between 20 mm Hg and 25 mm Hg represent an independent predictor of poor survival. Clinical trial registered with www.clinicaltrials.gov (NCT 01607502).

We hypothesize that personalized perioperative blood pressure management maintaining intraoperative mean arterial pressure (MAP) above the preoperative mean nighttime MAP reduces perfusion-related organ injury compared to maintaining intraoperative MAP above 65 mmHg in patients having major non-cardiac surgery. Before testing this hypothesis in a large-scale trial, we performed this bicentric pilot trial to determine a) if performing preoperative automated nighttime blood pressure monitoring to calculate personalized intraoperative MAP targets is feasible; b) in what proportion of patients the preoperative mean nighttime MAP clinically meaningfully differs from a MAP of 65 mmHg; and c) if maintaining intraoperative MAP above the preoperative mean nighttime MAP is feasible in patients having major non-cardiac surgery. Bicentric pilot randomized trial. University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and RWTH Aachen University Hospital, Aachen, Germany. Patients ≥ 45 years old having major non-cardiac surgery. Personalized blood pressure management. Proportion of patients in whom preoperative automated nighttime blood pressure monitoring was possible; proportion of patients in whom the preoperative mean nighttime MAP clinically meaningfully differed from a MAP of 65 mmHg (difference > ±10 mmHg); intraoperative time-weighted average MAP below the preoperative mean nighttime MAP. We enrolled 105 patients and randomized 98 patients. In 98 patients (93 %), preoperative automated nighttime blood pressure monitoring was possible. In 83 patients (85 %), the preoperative mean nighttime MAP clinically meaningfully differed from a MAP of 65 mmHg. The median time-weighted average MAP below the preoperative mean nighttime MAP was 3.29 (1.64, 6.82) mmHg in patients assigned to personalized blood pressure management. It seems feasible to determine the effect of personalized perioperative blood pressure management maintaining intraoperative MAP above the preoperative mean nighttime MAP on postoperative complications in a large multicenter trial. [Display omitted] •Optimal blood pressure targets during surgery remain unknown.•Individual nighttime mean arterial pressure (MAP) may be a reasonable blood pressure target.•Performing preoperative automated blood pressure monitoring is feasible.•Nighttime MAP meaningfully differs from a MAP of 65 mmHg in most patients.•Targeting nighttime MAP during surgery is feasible.

The objective of this study was to compare acute effects of prolonged sitting, prolonged standing and sitting interrupted with regular activity breaks on vascular function and postprandial glucose metabolism. In a randomized cross-over trial, 18 adults completed: 1. Prolonged Sitting; 2. Prolonged Standing and 3. Sitting with 2-min walking (5 km/h, 10% incline) every 30 min (Regular Activity Breaks). Flow mediated dilation (FMD) was measured in the popliteal artery at baseline and 6 h. Popliteal artery hemodynamics, and postprandial plasma glucose and insulin were measured over 6 h. Neither raw nor allometrically-scaled FMD showed an intervention effect (p = 0.285 and 0.159 respectively). Compared to Prolonged Sitting, Regular Activity Breaks increased blood flow (overall effect of intervention p<0.001; difference = 80%; 95% CI 34 to 125%; p = 0.001) and net shear rate (overall effect of intervention p<0.001; difference = 72%; 95% CI 30 to 114%; p = 0.001) at 60 min. These differences were then maintained for the entire 6 h. Prolonged Standing increased blood flow at 60 min only (overall effect of intervention p<0.001; difference = 62%; 95% CI 28 to 97%; p = 0.001). Regular Activity Breaks decreased insulin incremental area under the curve (iAUC) when compared to both Prolonged Sitting (overall effect of intervention P = 0.001; difference = 28%; 95% CI 14 to 38%; p<0.01) and Prolonged Standing (difference = 19%; 95% CI 4 to 32%, p = 0.015). There was no intervention effect on glucose iAUC or total AUC (p = 0.254 and 0.450, respectively). In normal-weight participants, Regular Activity Breaks induce increases in blood flow, shear stress and improvements in postprandial metabolism that are associated with beneficial adaptations. Physical activity and sedentary behaviour messages should perhaps focus more on the importance of frequent movement rather than simply replacing sitting with standing.