Christina Klose

Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study

BACKGROUND Osteoporosis and related fractures are a major complication after organ transplantation. The aim of this study was to find out the frequency and predictors of osteoporotic fractures after cardiac or liver transplantation. METHODS 235 consecutive patients who had a cardiac transplant (n=105; 88 men, 17 women) or a liver transplant (130; 75 men, 55 women) were followed. Vertebral fractures were assessed by a standardised analysis of spinal radiographs before and annually after transplantation. Clinical and non-vertebral fracture data were noted from hospital records. FINDINGS In the first and second years after transplantation, the proportion of patients (Kaplan-Meier estimates) who had at least one vertebral fracture was slightly higher in the cardiac group (first year 21%, second year 27%) than in the liver group (first year 14%, second year 21%). In the third and fourth years, one third of patients from both groups had had one or more vertebral fractures. Non-vertebral fractures occurred in nine patients (7%) after liver transplantation and avascular necrosis of the hip head in three patients (3%) after cardiac transplantation. In both groups, no dose-dependent effect of immunosuppressive therapy on fracture development could be identified. Independent predictors assessed by multivariate analysis were age (hazard ratio [95% CI] increase of 5 years, 1.71 [1.1-2.7]) and lumbar bone-mineral density (decrease of 1 SD t score, 1.97 [1.2-3.2]) in cardiac transplantation patients, and vertebral fractures before transplantation (6.07 [1.7-21.7]) in the liver group. INTERPRETATION The high frequency of osteoporotic fractures in the 2 years after transplantation and the limitations of reliable fracture-risk predictions, show the need to investigate preventive therapies.

Effect of Conscious Sedation vs General Anesthesia on Early Neurological Improvement Among Patients With Ischemic Stroke Undergoing Endovascular Thrombectomy: A Randomized Clinical Trial

Importance Optimal management of sedation and airway during thrombectomy for acute ischemic stroke is controversial due to lack of evidence from randomized trials. Objective To assess whether conscious sedation is superior to general anesthesia for early neurological improvement among patients receiving stroke thrombectomy. Design, Setting, and Participants SIESTA (Sedation vs Intubation for Endovascular Stroke Treatment), a single-center, randomized, parallel-group, open-label treatment trial with blinded outcome evaluation conducted at Heidelberg University Hospital in Germany (April 2014-February 2016) included 150 patients with acute ischemic stroke in the anterior circulation, higher National Institutes of Health Stroke Scale (NIHSS) score (>10), and isolated/combined occlusion at any level of the internal carotid or middle cerebral artery. Intervention Patients were randomly assigned to an intubated general anesthesia group (n = 73) or a nonintubated conscious sedation group (n = 77) during stroke thrombectomy. Main Outcomes and Measures Primary outcome was early neurological improvement on the NIHSS after 24 hours (0-42 [none to most severe neurological deficits; a 4-point difference considered clinically relevant]). Secondary outcomes were functional outcome by modified Rankin Scale (mRS) after 3 months (0-6 [symptom free to dead]), mortality, and peri-interventional parameters of feasibility and safety. Results Among 150 patients (60 women [40%]; mean age, 71.5 years; median NIHSS score, 17), primary outcome was not significantly different between the general anesthesia group (mean NIHSS score, 16.8 at admission vs 13.6 after 24 hours; difference, -3.2 points [95% CI, -5.6 to -0.8]) vs the conscious sedation group (mean NIHSS score, 17.2 at admission vs 13.6 after 24 hour; difference, -3.6 points [95% CI, -5.5 to -1.7]); mean difference between groups, -0.4 (95% CI, -3.4 to 2.7; P = .82). Of 47 prespecified secondary outcomes analyzed, 41 showed no significant differences. In the general anesthesia vs the conscious sedation group, substantial patient movement was less frequent (0% vs 9.1%; difference, 9.1%; P = .008), but postinterventional complications were more frequent for hypothermia (32.9% vs 9.1%; P < .001), delayed extubation (49.3% vs 6.5%; P < .001), and pneumonia (13.7% vs 3.9%; P = .03). More patients were functionally independent (unadjusted mRS score, 0 to 2 after 3 months [37.0% in the general anesthesia group vs 18.2% in the conscious sedation group P = .01]). There were no differences in mortality at 3 months (24.7% in both groups). Conclusions and Relevance Among patients with acute ischemic stroke in the anterior circulation undergoing thrombectomy, conscious sedation vs general anesthesia did not result in greater improvement in neurological status at 24 hours. The study findings do not support an advantage for the use of conscious sedation. Trial Registration clinicaltrials.gov Identifier: NCT02126085.

Strong Gametocytocidal Effect of Methylene Blue-Based Combination Therapy against Falciparum Malaria: A Randomised Controlled Trial

Background With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso. Methods An open-label randomised controlled phase II study in 180 children aged 6–10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB–artesunate (AS), MB–amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days. Findings The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline. Interpretation MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies. Trial Registration ClinicalTrials.gov NCT00354380

Effectiveness of triclosan-coated PDS Plus versus uncoated PDS II sutures for prevention of surgical site infection after abdominal wall closure: the randomised controlled PROUD trial

BACKGROUND Postoperative surgical site infections are one of the most frequent complications after open abdominal surgery, and triclosan-coated sutures were developed to reduce their occurrence. The aim of the PROUD trial was to obtain reliable data for the effectiveness of triclosan-coated PDS Plus sutures for abdominal wall closure, compared with non-coated PDS II sutures, in the prevention of surgical site infections. METHODS This multicentre, randomised controlled group-sequential superiority trial was done in 24 German hospitals. Adult patients (aged ≥18 years) who underwent elective midline abdominal laparotomy for any reason were eligible for inclusion. Exclusion criteria were impaired mental state, language problems, and participation in another intervention trial that interfered with the intervention or outcome of this trial. A central web-based randomisation tool was used to randomly assign eligible participants by permuted block randomisation with a 1:1 allocation ratio and block size 4 before mass closure to either triclosan-coated sutures (PDS Plus) or uncoated sutures (PDS II) for abdominal fascia closure. The primary endpoint was the occurrence of superficial or deep surgical site infection according to the Centers for Disease Control and Prevention criteria within 30 days after the operation. Patients, surgeons, and the outcome assessors were masked to group assignment. Interim and final analyses were by modified intention to treat. This trial is registered with the German Clinical Trials Register, number DRKS00000390. FINDINGS Between April 7, 2010, and Oct 19, 2012, 1224 patients were randomly assigned to intervention groups (607 to PDS Plus, and 617 to PDS II), of whom 1185 (587 PDS Plus and 598 PDS II) were analysed by intention to treat. The study groups were well balanced in terms of patient and procedure characteristics. The occurrence of surgical site infections did not differ between the PDS Plus group (87 [14·8%] of 587) and the PDS II group (96 [16·1%] of 598; OR 0·91, 95% CI 0·66-1·25; p=0·64). Serious adverse events also did not differ between the groups-146 of 583 (25·0%) patients treated with PDS Plus had at least one serious adverse event, compared with 138 of 602 (22·9%) patients treated with PDS II; p=0·39). INTERPRETATION Triclosan-coated PDS Plus did not reduce the occurrence of surgical site infection after elective midline laparotomy. Innovative, multifactorial strategies need to be developed and assessed in future trials to reduce surgical site infections. FUNDING Johnson & Johnson Medical Limited.

Application of a time-varying covariate model to the analysis of CA 19-9 as serum biomarker in patients with advanced pancreatic cancer

Purpose: The clinical relevance of CA 19-9 as surrogate biomarker in advanced pancreatic cancer is a matter of debate. Experimental Design: This retrospective multicenter study included patients with histologically confirmed advanced pancreatic cancer treated with first-line therapy. Analysis of CA 19-9 was done using the Elecsys assay (Roche Diagnostics). For an analysis of CA 19-9 kinetics, at least three measurements during first-line chemotherapy had to be available. The effect of pretreatment CA 19-9 levels on time-to-progression (TTP) and overall survival (OS) was modeled by Cox proportional hazards regression. The effect of CA 19-9 kinetics was also modeled by Cox proportional hazards regression where CA 19-9 was treated as a time-varying covariate. Results: One hundred and fifteen patients from five German centers were included; 73% of them were treated within prospective clinical trials. Median TTP was 4.4 months and median OS was 9.4 months; univariate analysis indicated that pretreatment CA 19-9 [as continuous variable, log (CA 19-9)] was significantly associated with TTP [hazard ratio (HR), 1.24; P < 0.001] and OS (HR, 1.16; P = 0.002). These associations remained significant within multivariate analysis. For CA 19-9 kinetics during chemotherapy, data from 69 patients (TTP) and 84 patients (OS) were available, respectively; log (CA 19-9) kinetics after start of treatment were found to be a significant predictor for TTP in univariate (HR, 1.48; P < 0.001) and multivariate (HR, 1.45; P < 0.001) analyses, and also for OS (univariate: HR, 1.34; P < 0.001; multivariate: HR, 1.38; P < 0.001). Conclusion: Pretreatment CA 19-9 and CA 19-9 kinetics may serve as a useful serum biomarker in advanced pancreatic cancer. Clin Cancer Res; 16(3); 986–94

Efficacy of methylene blue monotherapy in semi-immune adults with uncomplicated falciparum malaria: a controlled trial in Burkina Faso

Objective  To assess the efficacy of methylene blue (MB) monotherapy in semi‐immune adults with uncomplicated malaria in Burkina Faso.

DeloRes trial: study protocol for a randomized trial comparing two standardized surgical approaches in rectal prolapse - Delorme’s procedure versus resection rectopexy

BackgroundMore than 100 surgical approaches to treat rectal prolapse have been described. These can be done through the perineum or transabdominally. Delorme’s procedure is the most frequently used perineal, resection rectopexy the most commonly used abdominal procedure. Recurrences seem more common after perineal compared to abdominal techniques, but the latter may carry a higher risk of peri- and postoperative morbidity and mortality.Methods/DesignDeloRes is a randomized, controlled, observer-blinded multicenter trial with two parallel groups. Patients with a full-thickness rectal prolapse (third degree prolapse), considered eligible for both operative methods are included. The primary outcome is time to recurrence of full-thickness rectal prolapse during the 24 months following primary surgery. Secondary endpoints are time to and incidence of recurrence of full-thickness rectal prolapse during the 5-year follow-up, duration of surgery, morbidity, hospital stay, quality of life, constipation, and fecal incontinence. A meta-analysis was done on the basis of the available data on recurrence rates from 17 publications comprising 1,140 patients. Based on the results of a meta-analysis it is assumed that the recurrence rate after 2 years is 20% for Delorme’s procedure and 5% for resection rectopexy. Considering a rate of lost to follow-up without recurrence of 30% a total of 130 patients (2 x 65 patients) was calculated as an adequate sample size to assure a power of 80% for the confirmatory analysis.DiscussionThe DeloRes Trial will clarify which procedure results in a smaller recurrence rate but also give information on how morbidity and functional results compare.Trial registrationGerman Clinical Trial Number DRKS00000482

Early tracheostomy in ventilated stroke patients: Study protocol of the international multicentre randomized trial SETPOINT2 (Stroke-related Early Tracheostomy vs. Prolonged Orotracheal Intubation in Neurocritical care Trial 2).

Background Tracheostomy is a common procedure in long-term ventilated critical care patients and frequently necessary in those with severe stroke. The optimal timing for tracheostomy is still unknown, and it is controversial whether early tracheostomy impacts upon functional outcome. Method The Stroke-related Early Tracheostomy vs. Prolonged Orotracheal Intubation in Neurocritical care Trial 2 (SETPOINT2) is a multicentre, prospective, randomized, open-blinded endpoint (PROBE-design) trial. Patients with acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage who are so severely affected that two weeks of ventilation are presumed necessary based on a prediction score are eligible. It is intended to enroll 190 patients per group (n = 380). Patients are randomized to either percutaneous tracheostomy within the first five days after intubation or to ongoing orotracheal intubation with consecutive weaning and extubation and, if the latter failed, to percutaneous tracheostomy from day 10 after intubation. The primary endpoint is functional outcome defined by the modified Rankin Scale (mRS, 0–4 (favorable) vs. 5 + 6 (unfavorable)) after six months; secondary endpoints are mortality and cause of mortality during intensive care unit-stay and within six months from admission, intensive care unit-length of stay, duration of sedation, duration of ventilation and weaning, timing and reasons for withdrawal of life support measures, relevant intracranial pressure rises before and after tracheostomy. Conclusion The necessity and optimal timing of tracheostomy in ventilated stroke patients need to be identified. SETPOINT2 should clarify whether benefits in functional outcome can be achieved by early tracheostomy in these patients.

The Impact of Conscious Sedation versus General Anesthesia for Stroke Thrombectomy on the Predictive Value of Collateral Status: A Post Hoc Analysis of the SIESTA Trial

Using imaging data from the Sedation versus Intubation for Endovascular Stroke TreAtment (SIESTA) trial, the authors assessed collateral status with the score of Tan et al and graded it from absent to good collaterals (0–3). They examined the association of collateral status with 24-hour improvement of the NIHSS score, infarct volume, and mRS at 3 months according to the sedation regimen in a cohort of 104 patients. The sedation mode, conscious sedation or general anesthesia, did not influence the predictive value of collaterals in patients with large-vessel occlusion anterior circulation stroke undergoing thrombectomy in the SIESTA trial. BACKGROUND AND PURPOSE: Radiologic selection criteria to identify patients likely to benefit from endovascular stroke treatment are still controversial. In this post hoc analysis of the recent randomized Sedation versus Intubation for Endovascular Stroke TreAtment (SIESTA) trial, we aimed to investigate the impact of sedation mode (conscious sedation versus general anesthesia) on the predictive value of collateral status. MATERIALS AND METHODS: Using imaging data from SIESTA, we assessed collateral status with the collateral score of Tan et al and graded it from absent to good collaterals (0–3). We examined the association of collateral status with 24-hour improvement of the NIHSS score, infarct volume, and mRS at 3 months according to the sedation regimen. RESULTS: In a cohort of 104 patients, the NIHSS score improved significantly in patients with moderate or good collaterals (2–3) compared with patients with no or poor collaterals (0–1) (P = .011; mean, −5.8 ± 7.6 versus −1.1 ± 10.7). Tan 2–3 was also associated with significantly higher ASPECTS before endovascular stroke treatment (median, 9 versus 7; P < .001) and smaller mean infarct size after endovascular stroke treatment (median, 35.0 versus 107.4; P < .001). When we differentiated the population according to collateral status (0.1 versus 2.3), the sedation modes conscious sedation and general anesthesia were not associated with significant differences in the predictive value of collateral status regarding infarction size or functional outcome. CONCLUSIONS: The sedation mode, conscious sedation or general anesthesia, did not influence the predictive value of collaterals in patients with large-vessel occlusion anterior circulation stroke undergoing thrombectomy in the SIESTA trial.

Association of Blood Pressure With Short- and Long-Term Functional Outcome After Stroke Thrombectomy: Post Hoc Analysis of the SIESTA Trial

Background and Purpose— Outcome after mechanical thrombectomy for ischemic stroke may be influenced by blood pressure (BP). This study aims to assess the association of BP changes during general anesthesia versus conscious sedation with functional outcome after mechanical thrombectomy. Methods— SIESTA (Sedation vs Intubation for Endovascular Stroke Treatment) was a monocentric randomized trial of general anesthesia versus conscious sedation during mechanical thrombectomy involving BP target protocols. In this post hoc analysis, BP measurements were divided into 4 phases: preintervention, prerecanalization, postrecanalization, and postintervention. We examined the association between BP and functional outcomes (defined by improvement of 24-hour National Institutes of Health Stroke Scale [NIHSS] and 3-month modified Rankin Scale). Results— We found no association between the difference in systolic BP, diastolic BP, and mean arterial pressure from baseline to the different phases of intervention and NIHSS change after 24 hours. Only baseline diastolic BP was associated with a reduced improvement in NIHSS (&bgr;=0.17, P<0.01). There was no association of BP drops with a change in modified Rankin Scale at 3 months. About sedation, only baseline mean arterial pressure preintervention revealed significant associations (&bgr;=0.16, P<0.01) with less change in 24-hour NIHSS in conscious sedation group. Otherwise, there was no association for differences of any of the BP measurements with a change in 24-hour NIHSS and long-term functional outcome either in general anesthesia or the conscious sedation group when analyzed separately, consistent with our findings in the entire cohort. Doses of propofol (&bgr;=0.84, P=0.04) and norepinephrine (&bgr;=1.87, P=0.01) administered during intervention before recanalization were associated with reduced improvement of NIHSS at 24 hours. Conclusions— In a setting, where both sedation regimes general anesthesia and conscious sedation were performed according to strict protocols directed at avoiding BP extremes, our findings suggest that peri-interventional BP drops were not associated with either early neurological improvement or long-term functional outcome. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT02126085.