Automated mechanical cardiopulmonary resuscitation devices versus manual chest compressions in the treatment of cardiac arrest: protocol of a systematic review and meta-analysis comparing machine to human.

INTRODUCTION: Cardiac arrest is a leading cause of death in industrialised countries. Cardiopulmonary resuscitation (CPR) guidelines follow the principles of closed chest compression as described for the first time in 1960. Mechanical CPR devices are designed to improve chest compression quality, thus considering the improvement of resuscitation outcomes. This protocol outlines a systematic review and meta-analysis methodology to assess trials investigating the therapeutic effect of automated mechanical CPR devices at the rate of return of spontaneous circulation, neurological state and secondary endpoints (including short-term and long-term survival, injuries and surrogate parameters for CPR quality) in comparison with manual chest compressions in adults with cardiac arrest. METHODS AND ANALYSIS: A sensitive search strategy will be employed in established bibliographic databases from inception until the date of search, followed by forward and backward reference searching. We will include randomised and quasi-randomised trials in qualitative analysis thus comparing mechanical to manual CPR. Studies reporting survival outcomes will be included in quantitative analysis. Two reviewers will assess independently publications using a predefined data collection form. Standardised tools will be used for data extraction, risks of bias and quality of evidence. If enough studies are identified for meta-analysis, the measures of association will be calculated by dint of bivariate random-effects models. Statistical heterogeneity will be evaluated by I2-statistics and explored through sensitivity analysis. By comprehensive subgroup analysis we intend to identify subpopulations who may benefit from mechanical or manual CPR techniques. The reporting follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. ETHICS AND DISSEMINATION: No ethical approval will be needed because data from previous studies will be retrieved and analysed. Most resuscitation studies are conducted under an emergency exception for informed consent. This publication contains data deriving from a dissertation project. We will disseminate the results through publication in a peer-reviewed journal and at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42017051633.

Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling.

BACKGROUND: In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive physostigmine salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. METHODS: In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. RESULTS: Steady state physostigmine plasma concentrations reached 7.60 ±â€¯2.81 ng/mL (mean ±â€¯standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%-50.6% of baseline activity during physostigmine salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. CONCLUSIONS: PK of physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

Effect of physostigmine on recovery from septic shock following intra-abdominal infection - Results from a randomized, double-blind, placebo-controlled, monocentric pilot trial (Anticholium® per Se).

PURPOSE: The cholinergic anti-inflammatory pathway has been shown to be accessible by physostigmine salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated. MATERIALS AND METHODS: In this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The physostigmine group received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days. RESULTS: Administration of physostigmine salicylate was well tolerated. Mean SOFA scores were 8.9 ±â€¯2.5 and 11.3 ±â€¯3.6 (mean ±â€¯SD) for physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (-2.37, 95% CI: -5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability. CONCLUSIONS: Treatment with physostigmine salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock. TRIAL REGISTRATION: EudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322.

Adjunctive use of physostigmine salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se).

BACKGROUND: Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. METHODS: Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with physostigmine salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. DISCUSSION: This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. TRIAL REGISTRATION: EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

Revival of physostigmine - a novel HPLC assay for simultaneous determination of physostigmine and its metabolite eseroline designed for a pharmacokinetic study of septic patients.

BACKGROUND: Physostigmine, commonly used as an antidote in anticholinergic poisoning, is reported to have additional pharmacological effects, such as activation of the cholinergic anti-inflammatory pathway in sepsis models. Due to the narrow therapeutic range of physostigmine and its metabolite eseroline, however, the plasma concentrations of these substances need to be determined so as to understand their effect and ensure safety in the treatment of septic patients. METHODS: To determine physostigmine and its metabolite eseroline, a rapid and sensitive high performance liquid chromatography (HPLC) method has been developed and validated. Spiked plasma samples were cleaned up and concentrated using a simple liquid-liquid extraction (LLE) procedure with N-methylphysostigmine as internal standard. Separation was achieved using reversed-phase HPLC on a Kinetex C18 column with gradient elution and fluorescence detection (254 nm excitation/355 nm emission). RESULTS: LLE produced clean extracts and a mean recovery of 80.3% for eseroline and 84.9% for physostigmine. The HPLC assay revealed a limit of detection (LOD) of 0.025 ng/mL and a lower limit of quantification (LLOQ) of 0.05 ng/mL for both analytes. Linearity was observed at 0.05-10.0 ng/mL (r²>0.999). Intra- and inter-day precision ranged from 0.7% to 6.6%, and intra- and inter-day accuracy 97.5%-110.0%. CONCLUSIONS: The presented method is useful for human drug level monitoring of physostigmine and eseroline in accordance with current guidelines. Remarkably low plasma concentrations can be quantified after LLE with gradient elution and fluorescence detection, making this a suitable method for pharmacokinetic studies in a clinical setting.

Comparative study of prescribing patterns of tigecycline for trial patients versus non-trial patients.

BACKGROUND: Comparing published trial patients and non-trial patients in clinical practice, clinicians often doubt whether critically ill patients are sufficiently represented in randomised clinical trials. PATIENTS AND METHODS: This study evaluated the extent of infection with multidrug-resistant (MDR) pathogens, anti-microbial combination therapy, off-label use and targeted-treatment in trial patients versus non-trial patients. RESULTS: Tigecycline therapy was prescribed for off-label use in more than half of the non-trial patients; 77% of trial patients received study medication as first-line therapy in contrast to 25% of non-trial patients (p<0.001). Tigecycline therapy was targeted for 27% of trial patients versus 73% of non-trial patients (p<0.001). Ninety-six percent of non-trial patients were treated for nosocomial infections compared to 23% of trial patients (p<0.001). In one out of 22 (4.5%) trial patients an ESKAPE pathogen was found, whereas rates of vancomycin- resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus and extended spectrum-ß lactamase- producing Enterobacteriaceae ranged between 13/165 (8%) and 23/165 (14%) for non-trial patients. CONCLUSION: Tigecycline was used for less critical populations in clinical trials than in clinical practice. Our findings confirm the particular need of potent substances such as tigecycline for critically ill patients.

Patients enrolled in randomised clinical trials are not representative of critically ill patients in clinical practice: observational study focus on tigecycline.

It is being increasingly recognised by clinicians and scientists that participants in randomised clinical trials (RCTs) of antibiotics of last resort do not represent the patients who will later be treated with these drugs. Data on this subject are limited and have not been investigated systematically. This observational study aimed to examine this hypothesis quantitatively, using the example of tigecycline. To evaluate the influence of recruitment, patients eligible for clinical trials were retrospectively compared with ineligible patients regarding baseline and clinical characteristics as well as outcome parameters, e.g. length of hospital stay, intensive care unit (ICU) stay, ventilation and mortality. The clinical characteristics of 187 patients illustrated differences in the nature and severity of disease, co-morbidities and outcome. Eligible and ineligible patients differed in a number of parameters, e.g. median APACHE II score (15.5 vs. 28.0), number of liver transplantations (5% vs. 18%; P=0.048), septic shock (21% vs. 49%; P=0.001), need for mechanical ventilation (30% vs. 79%; P<0.001), mean length of ICU stay (19.3 days vs. 40.7 days) and death (19% vs. 46%; P=0.001). Critically ill patients were under-represented in clinical trials. Moreover, only a minority of patients in clinical practice (13%) were potentially eligible for a pivotal RCT. The disparities likely result from strict exclusion criteria in RCTs and recruitment bias. These data emphasise the importance of including critically ill patients in RCTs of antibiotics against multiresistant bacteria in order to account for those who will later be treated.

Design of a prospective clinical study on the agreement between the Continuous GlucoseMonitor, a novel device for CONTinuous ASSessment of blood GLUcose levels, and the RAPIDLab® 1265 blood gas analyser: The CONTASSGLU study.

BACKGROUND: Although a device is needed to continuously measure blood glucose levels within an intensive care setting, and several large-scale prospective studies have shown that patients might benefit from intensive insulin, potassium, or glucose therapy during intensive care, no devices are currently available to continuously assess blood glucose levels in critically ill patients. We conceived the study described here to evaluate the clinical use of the Continuous Glucose Monitor (CGM) performed via a central vein, and to determine the impact of phenomena, such as drift and shift, on the agreement between the CGM and a RAPIDLab® 1265 blood gas analyser (BGA). METHODS/DESIGN: In the CONTinuous ASSessment of blood GLUcose (CONTASSGLU) study, up to 130 patients under intensive care will be fitted with the CGM, an ex vivo device that continuously measures blood glucose and lactate levels. Readings from the device taken 8 h after initial placement and calibration will be compared with values measured by a BGA. For this study, we chose the BGA as it is an established standard point-of-care device, instead of the devices used in certified central laboratories. Nevertheless, we will also independently compare the results from the point-of-care BGA with those determined by a central laboratory-based device. Blood samples will be collected from each patient from the same site in which the CGM will measure blood glucose. Consequently, each participant will serve as their own control, and no randomisation is necessary. The 95% limits of agreement and the corresponding confidence intervals will be calculated and compared with a prespecified clinically acceptable relative difference of 20%. DISCUSSION: Several attempts have been made to develop a device to continuously measure blood glucose levels within an intensive care setting or to use the devices that were originally designed for diabetes management, as several of these devices are already available. However, none of these devices were successful in intensive care settings. CONTASSGLU may well bridge this gap by confirming the ability of the CGM to continuously measure blood glucose levels in intensive care settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01580176.

Ranking of patient and surgeons' perspectives for endpoints in randomized controlled trials--lessons learned from the POVATI trial [ISRCTN 60734227].

INTRODUCTION: Surgical trials focus mainly on mortality and morbidity rates, which may be not the most important endpoints from the patient's perspective. Evaluation of expectations and needs of patients enrolled in clinical trials can be analyzed using a procedure called ranking. Within the Postsurgical Pain Outcome of Vertical and Transverse Abdominal Incision randomized trial (POVATI), the perspectives of participating patients and surgeons were assessed as well as the influence of the surgical intervention on patients' needs. PATIENTS AND METHODS: All included patients of the POVATI trial were asked preoperatively and postoperatively to rank predetermined outcome variables concerning the upcoming surgical procedure (e.g., pain, complication, cosmetic result) hierarchically according to their importance. Preoperatively, the surgeons were asked to do the same. RESULTS: One hundred eighty two out of 200 randomized patients (71 females, 111 males; mean age 59 years) returned the ranking questionnaire preoperatively and 152 patients (67 females, 85 males; mean age 60 years) on the day of discharge. There were no differences between the two groups with respect to the distribution of ranking variables (p > 0.05). Thirty-five surgeons (7 residents, 6 fellows, and 22 consultants) completed the same ranking questionnaire. The order of the four most important ranking variables for both patients and surgeons were death, avoiding of postoperative complications, avoiding of intraoperative complications, and pain. Surgeons ranked the variable "cosmetic result" significantly as more important compared to patients (p = 0.034, Fisher's exact test). CONCLUSION: Patients and surgeons did not differ in ranking predetermined outcomes in the POVATI trial. Only the variable "cosmetic result" is significantly more important from the surgeon's than from the patient's perspective. Ranking of outcomes might be a beneficial tool and can be a proper addition to RCTs.

Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness and safety of infrahepatic inferior vena cava (IVC) clamping for reduction of central venous pressure (CVP) and blood loss during hepatic resection. BACKGROUND: Low CVP during parenchymal transection has been widely accepted to reduce intraoperative hemorrhage via the hepatic veins and is commonly achieved by anesthesiological interventions such as fluid restriction. We hypothesized that infrahepatic clamping of the IVC may lower the intraoperative blood loss more effectively and, moreover, prevent potential adverse effects of fluid restriction such as hemodynamic instability. METHODS: Patients scheduled for elective hepatic resection were enrolled and allocated randomly to CVP reduction by infrahepatic IVC clamping or anesthesiological interventions including primarily fluid restriction with additional use of diuretics, nitro compounds, and opioids (control group). The primary efficacy endpoint was total intraoperative blood loss. Analyses were done following intention-to-treat principles. The protocol was submitted to the clinicaltrials.gov registry (NCT00732979). RESULTS: From April 2007 to December 2009, a total of 152 patients were randomized and 128 were eligible for final analyses. Baseline data were similar between both study groups. Despite higher CVP values during resection (4.0 ± 3.2 vs. 2.6 ± 1.8 mm Hg; P = 0.003), infrahepatic IVC clamping significantly reduced total intraoperative blood loss [550 (350.0-1150) mL vs. 900 (500-1500) mL; P = 0.02] and blood loss during parenchymal transection [150 (85-500) mL vs. 400 (200-700) mL; P = 0.006] compared with the control group. Postoperative mortality [4 (6.1%) vs. 2 (3.2%); P = 0.42] and total morbidity rates [38 (58.5%) vs. 37 (58.7%); P = 0.97] were comparable between both study groups. Although intraoperative hemodynamic instability occurred less frequently in patients with infrahepatic IVC clamping [0 vs. 4 (6.3%); P = 0.04], the incidence of pulmonary embolism was increased in this study arm [4 (6.1%) vs. 0; P = 0.04]. CONCLUSIONS: Infrahepatic IVC clamping is associated with significantly less intraoperative blood loss and may reduce the incidence of intraoperative hemodynamic instability. The potential association with postoperative pulmonary embolism represents a significant concern.

Patients suffering due to complicated peritonitis may not benefit from splenectomy: clinical data from a retrospective study.

BACKGROUND: In this retrospective observational study, we investigated the impact of prior splenectomy on the outcome of patients with complicated peritonitis. MATERIALS AND METHODS: Of the 284 subjects with severe sepsis or septic shock due to intra-abdominal infection, 27 (9.5%) had undergone splenectomy before the development of that infection and 257 (90.5%) had not undergone splenectomy. The intra-abdominal source of infection was surgically confirmed (index operation). RESULTS: The group of patients having undergone splenectomy and that of patients not having undergone the procedure were well balanced in age, gender concomitant disease, as well as medication (prior chemotherapy). Twenty-eight-day estimated mortality did not differ between groups (33.3 versus 25.7%; P = 0.39). Ninety-day estimated mortality did not differ either (57.2 versus 49.7%; P = 0.92). Overall survival was equal between the two groups. More patients having undergone splenectomy required dialysis for renal failure (74.0 versus 44.7%; P < 0.01). A Cox regression analysis left age, sepsis-related organ failure assessment (SOFA) score immediately following index-surgery, and need for administration of norepinephrine exceeding 0.1 µg/kg body weight/min as potential predictors of fatal outcome. CONCLUSIONS: Our results did not support those of earlier reports suggesting that splenectomy protects against polymicrobial sepsis or septic shock. Regarding most effectiveness criteria (28- and 90-d estimated mortality, duration of mechanical ventilation, length of stay in ICU and in hospital), patients having undergone splenectomy fared as well as did those who had not undergone that procedure; regarding some (need for renal replacement), they fared worse. The effect of splenectomy is not large enough to be proven or ruled out with a limited number of cases.

IVC CLAMP: infrahepatic inferior vena cava clamping during hepatectomy--a randomised controlled trial in an interdisciplinary setting.

BACKGROUND: Intraoperative haemorrhage is a known predictor for perioperative outcome of patients undergoing hepatic resection. While anaesthesiological lowering of central venous pressure (CVP) by fluid restriction is known to reduce bleeding during transection of the hepatic parenchyma its potential side effects remain poorly investigated. In theory it may have negative effects on kidney function and tissue perfusion and bears the risk to result in severe haemodynamic instability in case of profound intraoperative blood loss. The present randomised controlled trial evaluates efficacy and safety of infrahepatic inferior vena cava (IVC) clamping as an alternative surgical technique to reduce CVP during hepatic resection. METHODS/DESIGN: The proposed IVC CLAMP trial is a single-centre randomised controlled trial with a two-group parallel design. Patients and outcome-assessors are blinded for the treatment intervention. Patients undergoing elective hepatic resection due to any reason are enrolled in IVC CLAMP. All patients admitted to the Department of General-, Visceral-, and Transplant Surgery, University of Heidelberg for elective hepatic resection are consecutively screened for eligibility and written informed consent is obtained on the day before surgery. The primary objective of this trial is to assess and compare the amount of blood loss during hepatic resection in patients receiving surgical CVP reduction by clamping of the IVC as compared to anaesthesiological CVP without infrahepatic IVC clamping reduction. In addition to blood loss a set of general as well as surgical variables are analysed. DISCUSSION: This is a randomised controlled patient and observer blinded two-group parallel trial designed to assess efficacy and safety of infrahepatic IVC clamping during elective hepatectomy.

Thioredoxin in human and experimental sepsis.

INTRODUCTION: Thioredoxin (TRX) is assumed to be beneficial in acute inflammatory diseases because of its potent antioxidant properties and an inhibitory effect on neutrophil evasion into sites of inflammation. OBJECTIVE: To compare plasma levels of thioredoxin in septic patients and to investigate the role of thioredoxin in a polymicrobial septic mouse model. DESIGN AND INTERVENTIONS: A combined single-center noninterventional clinical observation study and randomized controlled experimental investigation. SETTING: Intensive care unit of a university hospital and laboratories of four university hospitals. MEASUREMENTS AND MAIN RESULTS: To evaluate the role of TRX in sepsis, we measured TRX in plasma of septic patients and compared its levels in survivors and patients who did not survive sepsis. In addition, we examined the effect of neutralization of endogenous TRX as well as of treatment with recombinant TRX in a mouse peritonitis model of cecal ligation and puncture (CLP). We found that the serum plasma levels of TRX were significantly higher in patients with sepsis compared with healthy individuals. Furthermore, nonsurvivors showed even higher TRX levels than survivors of sepsis. The CLP septic mouse model revealed that neutralization of endogenous TRX impaired survival of septic mice, whereas treatment with recombinant TRX after CLP strongly enhanced the survival of mice. CONCLUSIONS: Our results therefore demonstrate a critical role for TRX in the septic inflammatory response and suggest TRX as a potential therapeutic target for septic shock.

Soluble TREM-1 is not suitable for distinguishing between systemic inflammatory response syndrome and sepsis survivors and nonsurvivors in the early stage of acute inflammation.

BACKGROUND AND OBJECTIVE: To evaluate plasma levels of soluble TREM-1 (sTREM-1) in patients with systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock and to determine whether plasma sTREM-1 could be used as a diagnostic and prognostic marker in sepsis in the surgical ICU. METHODS: The study was designed as an observational noninterventional clinical study in a surgical ICU of a university hospital. For this, 65 intensive care patients were enrolled within the first 24 h after onset of SIRS (n = 11), severe sepsis (n = 39) or septic shock (n = 15). In addition, 21 healthy volunteers served as controls. At days 0, 1, and 3 after diagnosis, plasma sTREM-1 was measured by ELISA. RESULTS: Plasma sTREM-1 concentrations in healthy controls did not significantly differ from those in patients with SIRS, severe sepsis, or septic shock at days 0, 1, and 3. Survivors were defined as septic patients surviving for at least 28 days. There were no differences in plasma sTREM-1 levels between survivors (n = 22) and nonsurvivors (n = 27) on any day. CONCLUSIONS: In this study in patients with SIRS, severe sepsis, or septic shock, plasma sTREM-1 levels were not elevated as compared with healthy controls. Measurement of plasma sTREM-1 did not distinguish between patients with SIRS, severe sepsis, or septic shock or between survivors and nonsurvivors. The suggested role of sTREM-1 as a diagnostic and prognostic marker in sepsis should be carefully verified.