Rita Laufenberg-Feldmann

A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery

BACKGROUND Remote ischemic preconditioning (RIPC) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains. METHODS We conducted a prospective, double-blind, multicenter, randomized, controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol. The trial compared upper-limb RIPC with a sham intervention. The primary end point was a composite of death, myocardial infarction, stroke, or acute renal failure up to the time of hospital discharge. Secondary end points included the occurrence of any individual component of the primary end point by day 90. RESULTS A total of 1403 patients underwent randomization. The full analysis set comprised 1385 patients (692 in the RIPC group and 693 in the sham-RIPC group). There was no significant between-group difference in the rate of the composite primary end point (99 patients [14.3%] in the RIPC group and 101 [14.6%] in the sham-RIPC group, P=0.89) or of any of the individual components: death (9 patients [1.3%] and 4 [0.6%], respectively; P=0.21), myocardial infarction (47 [6.8%] and 63 [9.1%], P=0.12), stroke (14 [2.0%] and 15 [2.2%], P=0.79), and acute renal failure (42 [6.1%] and 35 [5.1%], P=0.45). The results were similar in the per-protocol analysis. No treatment effect was found in any subgroup analysis. No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium. No RIPC-related adverse events were observed. CONCLUSIONS Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery. (Funded by the German Research Foundation; RIPHeart ClinicalTrials.gov number, NCT01067703.).

Comparative sequence analysis of the Clostridium difficile toxins A and B.

SummaryThe six clones pTB112, pTB324, pTBs12, pCd122, pCd14 and pCdl3 cover thetox locus ofClostridium difficile VPI 10463. This region of 19 kb of chromosomal DNA contains four open reading frames including the completetoxB andtoxA genes. The two toxins show 63% amino acid (aa) homology, a relatedness that had been predicted by the cross-reactivity of some monoclonal antibodies (mAb) but that is in contrast to the toxin specificity of polyclonal antisera. A special feature of ToxA and ToxB is their repetitive C-termini. We define herein 19 individual CROPS (combinedrepetitiveoligopeptides of 20–50 as length) in the ToxB C-terminus, which are separable into five homologous groups. Comparison of the as sequences of the N-terminal two-thirds of ToxA and ToxB revealed three marked structures, a cluster of 172 hydrophobic, highly conserved as in the centre of both toxins, a sequence of 120 residues with an accumulation of highly conserved arginine, cysteine, histidine, methionine, and tryptophan residues, and a stretch of 248 less conserved aa. The probable function of these domains is discussed. Structural and functional homologies of ToxA and ToxB indicate that both genes have a common ancestor and may have evolved by gene duplication, with subsequent recombination and mutation, as has been reported for streptococcal glucosyltransferases (Gtf).

Cloning of Clostridium difficile toxin B gene and demonstration of high N-terminal homology between toxin A and B.

High titered Clostridium sordellii lethal toxin antiserum, cross-reactive with C. difficile cytotoxin B (ToxB), was used to isolate toxB fragments from a C. difficile expression library. Recombinant clones containing toxB fragments of the 5′ and 3′ end were isolate. A 2.5-kb HincII fragment of chromosomal DNA overlaps both groups of clones. A partial restriction map of the total toxB gene is presented. The gene is positioned upstream of utxA and toxA toxB has a size of 6.9kb, corresponding to a 250-kDa polypeptide. A partial sequence of the 5′ end of toxB was determined. The sequence contains 398 bp upstream of toxB with a putative Shine-Dalgarno box (AGGAGA) and 609 bp of the toxB open reading frame. The N-terminal 203 amino acids of ToxB were compared with the N-terminal amino acids of the enterotoxin A (ToxA). A homology of 64% of the residues was detected, which proves the relatedness of ToxA and ToxB of C. difficile.

Assessing preoperative anxiety using a questionnaire and clinical rating: a prospective observational study.

BACKGROUND Preoperative anxiety and need for information can be detected during preoperative consultation via structured and standardised screening by the Amsterdam Preoperative Anxiety and Information Scale (APAIS) questionnaire. OBJECTIVE To identify the prevalence of preoperative anxiety and need for information, with regard to influencing factors such as age, sex, previous operation and grade of surgery, and to examine the level of agreement between patients’ self-rating and physicians’ ratings. DESIGN Prospective observational study. SETTING Department of Anaesthesiology, University Medical Centre of the Johannes Gutenberg University Mainz, Germany. PATIENTS Two hundred seventeen patients scheduled for elective surgery. INTERVENTIONS The patients completed questionnaires prior to the interaction with the anaesthesiologist. Physicians were blinded to the patients’ ratings and provided their subjective ratings about patients’ anxiety and need for information immediately after seeing the patient. MAIN OUTCOME MEASURE Degree of anxiety and need for information, agreement of patients’ self-reports and physicians rating. RESULTS 18.9% of patients were classified as ’anxiety cases’ (31.8% in women and 10.6% in men). The grade of the intended surgery but no other investigated factor was related to patients’ anxiety. Age (older patients) was correlated with information requirement (r = 0.21, P = 0.002). Analysis of agreement showed only weak correlations between patients’ self-reports and physicians’ ratings, demonstrated in low weighted Kappa-coefficients (0.12 to 0.32). CONCLUSION The APAIS is a useful instrument to assess the level of patients’ preoperative anxiety and the need for information. Given the relationship between preoperative anxiety and postoperative outcome, it seems justified to incorporate this approach into the preoperative consultation. TRIAL REGISTRATION German Clinical Trials Register DRKS00003084.

Kinetics of plasma biomarkers of inflammation and lung injury in surgical patients with or without postoperative pulmonary complications.

BACKGROUND Postoperative pulmonary complications (PPCs) are common after major abdominal surgery. The kinetics of plasma biomarkers could improve identification of patients developing PPCs, but the kinetics may depend on intraoperative ventilator settings. OBJECTIVE To test whether the kinetics of plasma biomarkers are capable of identifying patients who will develop PPCs, and whether the kinetics depend on the intraoperative level of positive end-expiratory pressure (PEEP). DESIGN A preplanned substudy of a randomised controlled trial. SETTING Operation room of five centres. PATIENTS Two hundred and forty-two adult patients scheduled for abdominal surgery at risk of developing PPCs. INTERVENTIONS High (12 cmH2O) versus low (⩽2 cmH2O) levels of PEEP. MAIN OUTCOME MEASURES Individual PPCs were combined as a composite endpoint. Plasma samples were collected before surgery, directly after surgery and on the fifth postoperative day. The levels of the following were measured: tumour necrosis factor (TNF)-&agr;, interleukin (IL)-6 and IL-8, the soluble form of the Receptor for Advanced Glycation End–products (sRAGE), Surfactant Protein (SP)-D, Clara Cell protein (CC)-16 and Krebs von den Lungen 6 (KL6). RESULTS Blood sampling was complete in 242 patients: 120 patients in the high PEEP group and 122 patients in the low PEEP group. Increases in plasma levels of TNF- IL-6, IL-8 and CC-16, and a decrease in plasma levels of SP-D were greater in patients who developed PPCs; however, the area under the receiver operating characteristic curve was low for all biomarkers. CC-16 was the only biomarker whose level increased more in patients who had received high levels of PEEP. CONCLUSION In patients undergoing abdominal surgery and at risk of developing PPCs, plasma levels of biomarkers for inflammation or lung injury showed distinct kinetics with development of PPCs, but none of the biomarkers showed sufficient prognostic value. The use of high levels of PEEP was associated with increased levels of CC-16, suggesting lung overdistension. TRIAL REGISTRATION The PROVHILO trial, including this substudy, was registered at clinicaltrials.gov (NCT01441791).

RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study: Myocardial Dysfunction, Postoperative Neurocognitive Dysfunction, and 1 Year Follow‐Up

Background Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham‐RIPC. Methods and Results In this follow‐up paper, we present 1‐year follow‐up of the composite primary end point and its individual components (all‐cause mortality, myocardial infarction, stroke and acute renal failure), in a sub‐group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1‐year composite primary end point (RIPC versus sham‐RIPC 16.4% versus 16.9%) and its individual components (all‐cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively. Conclusions Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long‐term outcome in cardiac surgery patients undergoing propofol anesthesia. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703.

Improve hip fracture outcome in the elderly patient (iHOPE): a study protocol for a pragmatic, multicentre randomised controlled trial to test the efficacy of spinal versus general anaesthesia

Introduction Hip fracture surgery is associated with high in-hospital and 30-day mortality rates and serious adverse patient outcomes. Evidence from randomised controlled trials regarding effectiveness of spinal versus general anaesthesia on patient-centred outcomes after hip fracture surgery is sparse. Methods and analysis The iHOPE study is a pragmatic national, multicentre, randomised controlled, open-label clinical trial with a two-arm parallel group design. In total, 1032 patients with hip fracture (>65 years) will be randomised in an intended 1:1 allocation ratio to receive spinal anaesthesia (n=516) or general anaesthesia (n=516). Outcome assessment will occur in a blinded manner after hospital discharge and inhospital. The primary endpoint will be assessed by telephone interview and comprises the time to the first occurring event of the binary composite outcome of all-cause mortality or new-onset serious cardiac and pulmonary complications within 30 postoperative days. In-hospital secondary endpoints, assessed via in-person interviews and medical record review, include mortality, perioperative adverse events, delirium, satisfaction, walking independently, length of hospital stay and discharge destination. Telephone interviews will be performed for long-term endpoints (all-cause mortality, independence in walking, chronic pain, ability to return home cognitive function and overall health and disability) at postoperative day 30±3, 180±45 and 365±60. Ethics and dissemination iHOPE has been approved by the leading Ethics Committee of the Medical Faculty of the RWTH Aachen University on 14 March 2018 (EK 022/18). Approval from all other involved local Ethical Committees was subsequently requested and obtained. Study started in April 2018 with a total recruitment period of 24 months. iHOPE will be disseminated via presentations at national and international scientific meetings or conferences and publication in peer-reviewed international scientific journals. Trial registration number DRKS00013644; Pre-results