Antiplatelet therapy guided by CYP2C19 point-of-care pharmacogenetics plus multidimensional treatment decisions.

Aim: Implementation of CYP2C19 point-of-care (POC) pharmacogenetic (PGx) testing with personalized treatment recommendations. Methods: POC CYP2C19 genotyping plus expert evaluation of risk factors for ischemic and bleeding events. Results: 167 patients underwent PGx testing, 54 (32.3%) were CYP2C19 loss of function carriers, and POC versus standard PGx analysis results for *2 and *3 variants matched in 100%. Antiplatelet therapy was adjusted in 44 patients (26.3%), but always required consideration of patient-specific factors. Conclusion: CYP2C19 POC-PGx is reliable and offers clinically relevant advantages for immediate evidence-based adaptations of antiplatelet therapy, whereas in less acute cases conventional PGx testing can also have advantages. Antiplatelet therapy has become more complex, and implementation of PGx-based personalized antiplatelet therapy requires complementary expert knowledge.

Identification of Medication Prescription Errors and Factors of Clinical Relevance in 314 Hospitalized Patients for Improved Multidimensional Clinical Decision Support Algorithms.

Potential medication errors and related adverse drug events (ADE) pose major challenges in clinical medicine. Clinical decision support systems (CDSSs) help identify preventable prescription errors leading to ADEs but are typically characterized by high sensitivity and low specificity, resulting in poor acceptance and alert-overriding. With this cross-sectional study we aimed to analyze CDSS performance, and to identify factors that may increase CDSS specificity. Clinical pharmacology services evaluated current pharmacotherapy of 314 patients during hospitalization across three units of two Swiss tertiary care hospitals. We used two CDSSs (pharmaVISTA and MediQ), primarily for the evaluation of drug-drug interactions (DDI). Additionally, we evaluated potential drug-disease, drug-age, drug-food, and drug-gene interactions. Recommendations for change of therapy were forwarded without delay to treating physicians. Among 314 patients, automated analyses by both CDSSs produced an average of 15.5 alerts per patient. In contrast, additional expert evaluation resulted in only 0.8 recommendations per patient to change pharmacotherapy. For clinical pharmacology experts, co-factors such as comorbidities and laboratory results were decisive for the classification of CDSS alerts as clinically relevant in individual patients in about 70% of all decisions. Such co-factors should therefore be used for the development of multidimensional CDSS alert algorithms with improved specificity. In combination with local expert services, this poses a promising approach to improve drug safety in clinical practice.

Long-Term Outcomes of Drug-Eluting Stent Implantation for Patients With Atherosclerotic Erectile Dysfunction not Responding to PDE-5-Inhibitors.

PURPOSE: Endovascular therapy of erection-related arteries was shown to be a promising treatment option for patients with severe erectile dysfunction. Purpose of this study was to assess the longer-term safety and clinical success rate of endovascular revascularization of erection-related arteries with the Angiolite BTK stent in patients with arteriogenic erectile dysfunction. MATERIALS AND METHODS: A total of 147 consecutive men (63.5±9.3 years) with erectile dysfunction due to 345 atherosclerotic lesions underwent endovascular revascularization. Patients received an International Index of Erectile Function (IIEF)-15 questionnaire at 30.3±7.2 months (follow-up [FU] period no less than 18 months) after stenting. An improvement by 4 points in the erectile function domain consisting of 6 questions (IIEF-6) was defined as minimal clinically important difference (MCID). RESULTS: Technical success was achieved in 99% of lesions. One major adverse event occurred after endovascular revascularization. Sixty-eight (46%) patients completed their latest FU at least 18 months following the last intervention. Minimal clinically important difference was achieved in 54% (37/68) of patients. CONCLUSIONS: In patients with arteriogenic erectile dysfunction not responding to phosphodiesterase-5-inhibitors (PDE-5-Is), endovascular therapy with a novel thin-strut sirolimus-eluting stent is a safe and effective treatment option during short- and longer-term FU. CLINICAL IMPACT: Patients with severe erectile dysfunction profit greatly from endovascular therapy of erection-related arteries. Stable clinical outcomes are seen beyond a 1-year timeframe. It is proven that, the drug-eluting stent therapy for atherosclerotic ED in patients who have not responded to PDE-5-I therapy is safe and effective during longer-term follow-up.

Clinical Relevance of a 16-Gene Pharmacogenetic Panel Test for Medication Management in a Cohort of 135 Patients.

There is a growing number of evidence-based indications for pharmacogenetic (PGx) testing. We aimed to evaluate clinical relevance of a 16-gene panel test for PGx-guided pharmacotherapy. In an observational cohort study, we included subjects tested with a PGx panel for variants of ABCB1, COMT, CYP1A2, CYP2B6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, CYP4F2, DPYD, OPRM1, POR, SLCO1B1, TPMT and VKORC1. PGx-guided pharmacotherapy management was supported by the PGx expert system SONOGEN XP. The primary study outcome was PGx-based changes and recommendations regarding current and potential future medication. PGx-testing was triggered by specific drug-gene pairs in 102 subjects, and by screening in 33. Based on PharmGKB expert guidelines we identified at least one "actionable" variant in all 135 (100%) tested patients. Drugs that triggered PGx-testing were clopidogrel in 60, tamoxifen in 15, polypsychopharmacotherapy in 9, opioids in 7, and other in 11 patients. Among those, PGx variants resulted in clinical recommendations to change PGx-triggering drugs in 33 (32.4%), and other current pharmacotherapy in 23 (22.5%). Additional costs of panel vs. single gene tests are moderate, and the efficiency of PGx panel testing challenges traditional cost-benefit calculations for single drug-gene pairs. However, PGx-guided pharmacotherapy requires specialized expert consultations with interdisciplinary collaborations.

Transcranial color-coded duplex sonography assessment of cerebrovascular reactivity to carbon dioxide: an interventional study.

BACKGROUND: The investigation of CO2 reactivity (CO2-CVR) is used in the setting of, e.g., traumatic brain injury (TBI). Transcranial color-coded duplex sonography (TCCD) is a promising bedside tool for monitoring cerebral hemodynamics. This study used TCCD to investigate CO2-CVR in volunteers, in sedated and mechanically ventilated patients without TBI and in sedated and mechanically ventilated patients in the acute phase after TBI. METHODS: This interventional investigation was performed between March 2013 and February 2016 at the surgical ICU of the University Hospital of Zurich. Ten volunteers (group 1), ten sedated and mechanically ventilated patients (group 2), and ten patients in the acute phase (12-36 h) after severe TBI (group 3) were included. CO2-CVR to moderate hyperventilation (∆ CO2 -5.5 mmHg) was assessed by TCCD. RESULTS: CO2-CVR was 2.14 (1.20-2.70) %/mmHg in group 1, 2.03 (0.15-3.98) %/mmHg in group 2, and 3.32 (1.18-4.48)%/mmHg in group 3, without significant differences among groups. CONCLUSION: Our data did not yield evidence for altered CO2-CVR in the early phase after TBI examined by TCCD. TRIAL REGISTRATION: Part of this trial was performed as preparation for the interventional trial in TBI patients (clinicaltrials.gov NCT03822026 , 30.01.2019, retrospectively registered).

Endovascular Therapy for Arteriogenic Erectile Dysfunction With a Novel Sirolimus-Eluting Stent.

BACKGROUND: Arteriogenic erectile dysfunction is a common disease oftentimes not satisfactory treatable with medical therapy. AIM: To assess the safety and clinical success rate of endovascular revascularization of erection-related arteries with the angiolite BTK stent in patients with arteriogenic erectile dysfunction. METHODS: A total of 100 consecutive men (61.8 ± 10 years) with atherosclerotic lesions in erection-related arteries agreed to participate and were included into a single-center all-comers registry. Endovascular therapy with angiolite BTK drug-eluting stents was performed on a total of 211 lesions. Patients received a baseline International Index of Erectile Function (IIEF)-15 questionnaire at first presentation and 3 and 12 months after stenting. An improvement by 4 points in the erectile function domain consisting of 6 questions (IIEF-6) was defined as minimal clinically important difference. A total of 24 patients with 52 stented arterial lesions underwent angiographic follow-up of the initially treated arterial side during secondary revascularization of the contralateral side (angiographic sub-study). OUTCOME: Clinical improvement of erections in 100 patients undergoing endovascular revascularization of erection-related arteries. RESULTS: No major adverse events occurred during endovascular revascularization or within 30 days thereafter. Technical success was achieved in all lesions and procedural success in all patients. At 1 year, 55 of 97 patients (56.7%) improved by at least 4 points in IIEF-6 score and thus achieved a clinically relevant improvement of erectile function.In the angiographic sub-study, arterial patency and binary restenosis were observed in 46 of 52 (88.5%) and in 8 of 52 (15.4%), respectively, after a mean follow-up of 9.6 ± 5.8 months. CLINICAL IMPLICATIONS: In patients with arteriogenic erectile dysfunction, endovascular therapy with a novel thin-strut sirolimus eluting stent is a safe and feasible treatment option. STRENGTHS & LIMITATIONS: This real-world arterial revascularization registry included patients with a multitude of risk factors for ED, thereby representing the heterogeneity in patients in the clinical practice, which is one of its strengths but also one of its weaknesses. Another strength was the focus being laid on analyzing outcomes of patients with arteriogenic ED using only a single endovascular device. Further studies are warranted to better define subgroups of patients with impaired clinical outcomes. CONCLUSION: Within the present all-comers registry, endovascular therapy of erectile dysfunction with the angiolite BTK stent was shown to be a safe and feasible treatment option resulting in clinical improvement rates comparable to earlier clinical trials although also showing that further research is warranted to define patient subgroups with particular benefits of endovascular therapy. Schönhofen J, Räber L, Knöchel J, et al. Endovascular Therapy for Arteriogenic Erectile Dysfunction With a Novel Sirolimus-Eluting Stent. J Sex Med 2021;18:315-326.

Implementation and management outcomes of pharmacogenetic CYP2C19 testing for clopidogrel therapy in clinical practice.

PURPOSE: The antiplatelet prodrug clopidogrel is bioactivated by the polymorphic enzyme CYP2C19. Prospective clinical studies demonstrated an association between CYP2C19 loss of function (LoF) variants and an increased risk of thrombotic events under clopidogrel, but pharmacogenetic (PGx) testing is not frequently implemented in clinical practice. We report our experience with PGx-guided clopidogrel therapy with particular regard to clinically relevant patient management changes. METHODS: We conducted an observational study analyzing patients that underwent PGx testing for clopidogrel therapy at two Swiss hospitals. Primary outcome was the proportion of patients with clinically relevant PGx-based management recommendations and their implementation. The association of recurrent ischemic events under clopidogrel with CYP2C19 LoF variants and other factors was explored in a multivariate case-control analysis. RESULTS: Among 56 patients undergoing PGx testing, 18 (32.1%) were classified as CYP2C19 intermediate or poor metabolizers. This resulted in 17 recommendations for a change of antiplatelet therapy, which were implemented in 12 patients (70.1%). In the remaining five patients, specific reasons for non-implementation could be identified. Recurrent ischemic events under clopidogrel were associated with LoF variants (OR 2.2, 95% CI 0.3-14.4) and several cardiovascular risk factors. Associations were not statistically significant in our small study, but plausible and in line with estimates from large prospective studies. CONCLUSION: PGx-guided clopidogrel therapy can identify patients with an elevated risk of ischemic events and offer evidence-based alternative treatments. Successful implementation in clinical practice requires a personalized interdisciplinary service that evaluates indications and additional risk factors, provides specific recommendations, and proactively follows their implementation.

Incidental findings during computed tomographic angiography diagnostic work-up in patients with arteriogenic erectile dysfunction.

AIM: To analyse the incidental findings during computed tomographic angiography (CTA) diagnostic work-up in patients with arteriogenic erectile dysfunction (ED). PATIENTS AND METHODS: The medical records of all patients with suspected arteriogenic ED were entered into a database. Risk factors and underlying comorbidities were also collected. Pathological CTA findings were extracted from the CT readings and entered into the database. Incidental findings on CTA were classified as those requiring immediate medical treatment, requiring deferred medical treatment or of no clinical importance. RESULTS: A total of 200 patients underwent CTA for suspected arteriogenic ED. Mean patient age was 59.6 ± 11.7 years. Of these, 181 patients (90.5%) had obstructions of erection-related arteries. In 168 patients (84.0%), CTA showed multiple incidental pathological findings. Eighty-five of 200 patients (42.5%) exhibited incidental findings requiring immediate further medical workup and/or treatment: coronary artery calcification was diagnosed in 75/200 (37.5%), aorto-iliac aneurysms in 8/200 (4%) of patients and incidentally detected embolism in 1/200 patient. Pancreatic and liver tumours were less frequent (incidence 1.5% and 1%, respectively). Incidental findings requiring deferred medical workup and/or treatment were detected in 175/200 patients (87.5%). The findings with the highest prevalence were liver steatosis followed by colon diverticulosis and prostate hyperplasia. Findings of little to no clinical importance were reported in 117 (58.5%) patients. These included uncomplicated renal cysts, spinal degeneration and renal vascular anomalies. Almost every second patient presenting with ED had an incidental finding which required immediate treatment. CONCLUSIONS: Incidental findings not directly related to ED were common among patients undergoing CTA scans for suspected arterial obstructions. Coronary artery calcification was the leading finding requiring further medical workup and/or treatment. Thus, the benefit of CTA investigations extends beyond the anatomic description of arterial obstructions of erection-related arteries.

Deceased organ donation activity and efficiency in Switzerland between 2008 and 2017: achievements and future challenges.

BACKGROUND: Various actions have been taken during the last decade to increase the number of organs from deceased donors available for transplantation in Switzerland. This study provides an overview on key figures of the Swiss deceased organ donation and transplant activity between 2008 and 2017. In addition, it puts the evolution of the Swiss donation program's efficiency in relation to the situation in the neighboring countries. METHODS: This study is an analysis of prospective registry data, covering the period from 1 January 2008 to 31 December 2017. It includes all actual deceased organ donors (ADD) in Switzerland. Donor data were extracted from the Swiss Organ Allocation System. The "donor conversion index" (DCI) methodology and data was used for the comparison of donation program efficiency in Switzerland, Germany, Austria, Italy and France. RESULTS: During the study period there were 1116 ADD in Switzerland. The number of ADD per year increased from 91 in 2008 to 145 in 2017 (+ 59%). The reintroduction of the donation after cardiocirculatory death (DCD) program in 2011 resulted in the growth of annual percentages of DCD donors, reaching a maximum of 27% in 2017. The total number of organs transplanted from ADD was 3763 (3.4 ± 1.5 transplants per donor on average). Of these, 48% were kidneys (n = 1814), 24% livers (n = 903), 12% lungs (n = 445), 9% hearts (n = 352) and 7% pancreata or pancreatic islets (n = 249). The donation program efficiency assessment showed an increase of the Swiss DCI from 1.6% in 2008 to 2.7% in 2017 (+ 69%). The most prominent efficiency growth was observed between 2012 and 2017. Even though Swiss donation efficiency increased during the study period, it remained below the DCI of the French and Austrian donation programs. CONCLUSION: Swiss donation activity and efficiency grew during the last decade. The increased donation efficiency suggests that measures implemented so far were effective. The lower efficiency of the Swiss donation program, compared to the French and Austrian programs, may likely be explained by the lower consent rate in Switzerland. This issue should be addressed in order to achieve the goal of more organs available for transplantation.

Pulmonary hypertension is not a risk factor for grade 3 primary graft dysfunction after lung transplantation.

Grade 3 primary graft dysfunction (PGD3) represents the most important risk factor for patient mortality during the first year after lung transplantation (LTX). We investigated whether pretransplant pulmonary hypertension (PH) is a risk factor for the development of PGD3. This retrospective, single-center cohort study included 96 candidates undergoing right heart catheterization (RHC) prior to being listed for LTX between March 2000 and October 2015. Based on their mean pulmonary artery pressure (mPAP) levels, the patients were classified into 3 groups: (1) <25 mm Hg, (2) 25-34 mm Hg and (3) ≥35 mm Hg. Forty-seven patients were classified in group 1, 31 in group 2, and 18 in group 3. Fifteen recipients (16%, 95%-CI 8-23) developed PGD3. In the univariate analysis, the diagnosis of interstitial lung disease (ILD) compared to COPD (OR: 7.06, P = .005), blood transfusion >1000 mL during surgery (OR: 5.25, P = .005), the need for intra-operative cardio-pulmonary bypass (CPB) or extra-corporeal membrane oxygenation (ECMO) (OR: 4, P = .027), mPAP (OR 1.06, P = .007) and serum high density lipoprotein-cholesterol (HDL-C) (OR 0.09, P = .005) were associated with PGD3. In the multivariable logistic regression analysis, only HDL-C (OR 0.10, P = .016) was associated with PGD3 based on our single-center cohort data analysis.

Chronic pain, depression and quality of life in individuals with spinal cord injury: Mediating role of participation.

OBJECTIVE: To test the hypotheses that: (i) pain is associated with depressive symptoms and quality of life; and (ii) participation restriction, satisfaction, and frequency mediate these relationships. DESIGN: Population-based, cross-sectional study. SUBJECTS/PATIENTS: Community-dwelling individuals with spinal cord injury (n = 1,549). METHODS: Hypotheses were tested in individuals with at least moderate chronic pain on the spinal cord injury - Secondary Conditions Scale (n = 834), applying structural equation modelling to data for spinal cord injury subgroups related to lesion severity (paraplegia, tetraplegia, complete, incomplete) and time since injury (≤ 10 vs ≥ 10 years). Model parameters included pain intensity (numerical rating scale), participation frequency, restriction, satisfaction (Utrecht Scale of Evaluation of Rehabilitation-Participation; USER-Participation), depressive symptoms (5-item Mental Health Index of the Short Form Health Survey; MHI-5), and 5 selected quality of life items (World Health Organization Quality of Life Scale; WHOQoL-BREF). RESULTS: Structural equation models confirmed associations of pain with depressive symptoms and quality of life, as well as the mediating role of participation restriction and low satisfaction with participation. These findings were apparent in individuals with tetraplegia or complete lesion and in those ≤ 10 years since paraplegia or incomplete injury. CONCLUSION: Unrestricted or satisfactory participation was found to be a crucial resource for individuals living less than 10 years with a more severe spinal cord injury, since it represents buffering potential for the negative effects of chronic pain on mental health and quality of life.

Applying a Part of the Daily Dose as Boli May Improve Intrathecal Opioid Therapy in Patients With Chronic Pain.

OBJECTIVES: The speed of intrathecal drug administration (slow continuous infusion vs. rapid bolus application) might influence the efficacy of therapy despite the equal daily dose in both administration patterns. We tested this hypothesis in a small prospective single-centre pilot study in a population of chronic pain patients with intrathecal opioid therapy. METHODS: Ten patients receiving intrathecal opioids for chronic pain assessed their pain four times daily on a numeric rating scale (NRS), more than the time course of six weeks divided into three blocks of two weeks each: Baseline evaluation (intrathecal pumps with previously established continuous infusion settings), followed by two blinded trial blocks of continuous (same pump parameters as during evaluation) and bolus (40% of daily dose split into four equal boli applied every six hours, with the remaining 60% as background continuous infusion) regimes. Patients were randomized in a crossover fashion. RESULTS: 6/10 patients reported significantly lower NRS-scores during bolus as compared to continuous trial blocks while only one patient showed the opposite effect. Overall, bolus trial blocks were associated with a small but significant reduction of NRS-scores (mean -0.56; p < 0.0001). Side-effects related to bolus infusions were not reported. CONCLUSIONS: Intermittent bolus administration may be helpful for increasing the efficacy of intrathecal opioid therapy of chronic pain.

Pretransplant dyslipidaemia influences primary graft dysfunction after lung transplantation.

OBJECTIVES: Primary graft dysfunction (PGD) is a major cause of mortality within the first year following lung transplantation. Pulmonary hypertension, elevated body mass index (BMI), prolonged ischaemic time of the graft, intraoperative blood transfusions >1000 ml and the use of cardiopulmonary bypass or extracorporeal membrane oxygenation increase the risk for PGD. We aimed to evaluate whether dyslipidaemia is an additional risk factor for the development of PGD. METHODS: We retrospectively analysed demographic and clinical data of 264 patients who received their first bilateral lung transplantation between March 2000 and October 2013 at our institution. The endpoint was PGD grade 3 at any time, defined according to the International Society for Heart and Lung Transplantation (ISHLT) criteria. Fasting lipid profiles at listing time or just before transplantation (baseline) were documented and dyslipidaemia was defined as any of the parameters being out of range. Comparisons of continuous variables between patients with PGD grade 3 and patients without were performed with the Mann-Whitney U-test, whereas proportions were compared with the χ(2) test. Continuous variables were presented as arithmetic means with standard deviation for ease of comparison, but levels of statistical significance were computed using the appropriate non-parametric statistical test. To identify PGD risk factors, a forward stepwise logistic regression model was used. RESULTS: PGD occurred in 63 recipients (24%). Pretransplant dyslipidaemia was documented in 153 recipients (58%) and was significantly more prevalent among recipients developing PGD (45 vs 108, P < 0.013). Despite various underlying pulmonary pathologies, higher triglyceride (TG) levels (1.41 ± 0.78 vs 1.16 ± 0.78, P < 0.012), lower high-density lipoprotein-cholesterol (HDL-C) concentrations (1.24 ± 0.55 vs 1.57 ± 0.71, P < 0.0005) and higher cholesterol/HDL-C values (3.80 ± 2.02 vs 3.00 ± 0.92, P < 0.0005) were associated with a lower incidence of PGD. Patients with PGD had significantly longer ischaemic time (350 ± 89 vs 322 ± 91, P = 0.017) and higher BMI (23 ± 5 vs 21 ± 4.4, P < 0.007). CONCLUSIONS: Dyslipidaemia seems to be an independent risk factor for PGD after lung transplantation: low circulating levels of HDL-C and hypertriglyceridaemia increase the incidence of PGD. Even if HDL-C levels are difficult to alter today, triglyceride and cholesterol levels can be addressed therapeutically and may have a positive influence on the development of PGD.

ICG-liver test versus new biomarkers as prognostic markers for prolonged length of stay in critically ill patients - a prospective study of accuracy for prediction of length of stay in the ICU.

BACKGROUND: Prognostic abilities of medical parameters, which are scoring systems, measurements and biomarkers, are important for stratifying critically ill patients. Indocyanine green plasma disappearance (ICG-PDR) is an established clinical tool for the assessment of liver perfusion and function. Copeptin, MR-proANP and pro-ADM are biomarkers whose prognostic value is still unclear. The goal of this prospective study was to evaluate ICG-PDR, copeptin, MR-proANP and pro-ADM to predict prolonged length of stay (pLOS) in the ICU. METHODS: This study was conducted as a prospective single center study including 110 consecutively admitted ICU patients. Primary endpoint was prolonged length of stay (pLOS) in the ICU, defined as more than three days of stay there. RESULTS: ROC analysis showed an AUC of 0.73 for ICG-PDR, 0.70 for SAPS II, 0.65 for MR-proANP, 0.64 for pro-ADM and 0.54 for copeptin for pLOS in the ICU. CONCLUSIONS: The prediction of pLOS in the ICU might be better by means of ICG-PDR than with the new biomarkers copeptin, MR-proANP or pro-ADM. Nevertheless, there is more need for research to evaluate whether ICG-PDR is an overall prognostic marker for pLOS. TRIAL REGISTRATION: (ClinicalTrials.gov number, NCT01126554).

Influence on ICU course, outcome and costs for lung transplantation after implementation of the new Swiss transplantation law.

BACKGROUND: The Swiss organ allocation system for donor lungs was implemented on 1 July 2007. The effects of this implementation on patient selection, intensive care unit course, outcomes and intensive care costs are unknown. METHODS: The first 37 consecutive lung transplant recipients following the implementation of the new act were compared with the previous 42 lung transplant recipients. RESULTS: Following implementation of the new law, baseline characteristics and cumulative one-year patient survival were comparable in both groups (88.1% vs 83.8%, P = 0.58). The costs for each case increased by 35,000 euros after adoption of the new law. Stratifying patients after implementation of the law according to urgency status shows that urgent patients required longer mechanical ventilation (P = 0.04), a longer ICU stay (P = 0.045) and a longer hospital stay (P = 0.04) and ICU costs (median 64,050 euros) were higher compared to regular patients. CONCLUSION: The new transplantation law has increased ICU costs with the implementation of the Swiss organ allocation system. Patients listed as 'urgent' contribute significantly to the increase in ICU costs.

Pancreatic stone protein (PSP) and pancreatitis-associated protein (PAP): a protocol of a cohort study on the diagnostic efficacy and prognostic value of PSP and PAP as postoperative markers of septic complications in patients undergoing abdominal surgery (PSP study).

INTRODUCTION: Major abdominal surgery leads to a postoperative systemic inflammatory response, making it difficult to discriminate patients with systemic inflammatory response syndrome from those with a beginning postoperative infectious complication. At present, physicians have to rely on their clinical experience to differentiate between the two. Pancreatic stone protein (PSP) and pancreatitis-associated protein (PAP), both secretory proteins produced by the pancreas, are dramatically increased during pancreatic disease and have been shown to act as acute-phase proteins. Increased levels of PSP have been detected in polytrauma patients developing sepsis and PSP has shown a high diagnostic accuracy in discriminating the severity of peritonitis and in predicting death in intensive care unit patients. However, the prognostic value of PSP/PAP for infectious complications among patients undergoing major abdominal surgery is unknown. METHODS AND ANALYSIS: 160 patients undergoing major abdominal surgery will be recruited preoperatively. On the day before surgery, baseline blood values are attained. Following surgery, daily blood samples for measuring regular inflammatory markers (c-reactive protein, procalcitonin, interleukin-6, tumour necrosis factor-α and leucocyte counts) and PSP/PAP will be acquired. PSP/PAP will be measured using a validated ELISA developed in our research laboratory. Patient's discharge marks the end of his/her trial participation. Complication grade including mortality and occurrence of infectious postoperative complications according to validated diagnostic criteria will be correlated with PSP/PAP values. Total intensive care unit days and total length of stay will be recorded as further outcome parameters. ETHICS AND DISSEMINATION: The PSP trial is a prospective monocentric cohort study evaluating the prognostic value of PSP and PAP for postoperative infectious complications. In addition, a comparison with established inflammatory markers in patients undergoing major abdominal surgery will be performed to help evaluate the role of these proteins in predicting and diagnosing infectious and other postoperative complications. INSTITUTION ETHICS BOARD APPROVAL ID: KEKZH-Nr. STV 11-2009. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01258179.

The combination of MELD score and ICG liver testing predicts length of stay in the ICU and hospital mortality in liver transplant recipients.

BACKGROUND: Early prediction of outcome would be useful for an optimal intensive care management of liver transplant recipients. Indocyanine green clearance can be measured non-invasively by pulse spectrophometry and is closely related to liver function. METHODS: This study was undertaken to assess the predictive value of a combination of the model of end stage liver disease (MELD) score and early indocyanine plasma disappearance rates (ICG-PDR) for length of stay in the intensive care unit (ICU), length of stay in the hospital and hospital mortality in liver transplant recipients. RESULTS: Fifty consecutive liver transplant recipients were included in this post Hoc single-center study. ICG-PDR was determined within 6 hours after ICU admission. Endpoints were length of stay in the ICU, length of hospital stay and hospital mortality. The combination of a high MELD score (MELD >25) and a low ICG-PDR clearance (ICG-PDR < 20%/minute) predicts a significant longer stay in the ICU (p = 0.004), a significant longer stay in the hospital (p < 0.001) and a hospital mortality of 40% vs. 0% (p = 0.003). CONCLUSION: The combination of MELD scores and a singular ICG-PDR measurement in the early postoperative phase is an accurate predictor for outcome in liver transplant recipients. This easy-to-assess tool might be valuable for an optimal intensive care management of those patients.

Early fluid resuscitation with hydroxyethyl starch 130/0.4 (6%) in severe burn injury: a randomized, controlled, double-blind clinical trial.

INTRODUCTION: There are limited data on the efficacy of early fluid resuscitation with third-generation hydroxyethyl starch (HES 130) in burn injury. Adverse effects of HES on survival and organ function have been reported. METHODS: In this randomized, controlled, double-blind trial, 48 patients with severe burn injury were assigned to receive either lactated Ringer's solution plus 6% HES 130/0.4 in a ratio of 2:1 or lactated Ringer's solution with no colloid supplement for the first 72 hours. Primary outcome parameter was the group difference of administered total fluid from intensive care unit (ICU) admission up to day 3. Secondary outcomes included kidney and lung injury and failure, length of stay, and mortality. RESULTS: Three-day totals of administered resuscitation fluid (medians) were 21,190 mL in the lactated Ringer's group and 19,535 mL in the HES group (HES: -1,213 mL; P = 0.39). Creatinine levels from day 1 to 3 (HES: +0.4 µmol/L; 95% confidence interval (CI) -18.7 to 19.5; P = 0.97) and urinary outputs from day 1 to 3 (HES: -58 mL; 95% CI -400 to 283; P = 0.90) were not different. Six patients in each group developed acute respiratory distress syndrome (ARDS) (risk ratio 0.96; 95% CI 0.35 to 2.64; P = 0.95). Length of ICU stay (HES vs. lactated Ringer's: 28 vs. 24 days; P = 0.80) and length of hospital stay (31 vs. 29 days; P = 0.57) were similar. Twenty-eight-day mortality was 4 patients in each group (risk ratio 0.96; 95% CI 0.27 to 4.45; P = 0.95), and in-hospital mortality was 8 in the HES group vs. 5 patients in the lactated Ringer's group (hazard ratio 1.86; 95% CI 0.56 to 6.19; P = 0.31). CONCLUSIONS: There was no evidence that early fluid resuscitation with balanced HES 130/0.4 (6%) in addition to lactated Ringer's solution would lead to a volume-sparing effect in severe burn injury. Together with the findings that early renal function, incidence of ARDS, length of stay, and mortality were not negatively influenced by HES in this setting, balanced HES 130/0.4 (6%) plus lactated Ringer's solution could not be considered superior to lactated Ringer's solution alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01012648.

Intra-operative extracorporeal membrane oxygenation use in pediatric lung transplantation--the Zurich experience.

There is a lack of data regarding use of ECMO in children undergoing lung transplantation. We evaluated our experience of ECMO in pediatric lung transplant recipients. All patients (<18 yr) who underwent lung transplants between 1997 and 2011 were included (17 children; nine males; median age 16 yr), and the use of intra-operative ECMO evaluated. Transplant procedures were carried out with intra-operative ECMO in seven children (all bilateral lung transplants). Demographics of ECMO and non-ECMO patients were comparable. One child was already on ECMO pre-operative. Lung graft size reduction was undertaken in five ECMO and four non-ECMO cases, respectively. Five patients were taken off ECMO intra-operatively; the other patients were weaned off ECMO within 48 h post-operatively. Three-months survival was 100%. By 12 months post-transplantation, one patient each died in the ECMO and in the non-ECMO group. At the end of the study, six of seven ECMO cases were still alive (median survival 48.5 months); one patient required a retransplant at 53 months. Our small case series suggests that lung transplant procedures can be safely carried out in selected children on intra-operative ECMO support; however, our pediatric experience regarding this scenario is very limited but probably almost unique.

Pharmacokinetics of daily daptomycin in critically ill patients undergoing continuous renal replacement therapy.

BACKGROUND: The optimal daptomycin dosing regimen for critically ill patients undergoing continuous renal replacement therapy (CRRT) has still to be established. METHODS: Daptomycin pharmacokinetics was determined in 9 patients after administration of 6 mg/kg/day over 5 days. RESULTS: At steady state, which was reached by day 3, the area under the curve over 24 h (AUC24h) was 667.4 ± 356.6 mg·h/l, and the maximum concentration (Cmax) was 66.9 ±25.3 mg/l. Mean CRRT clearance accounted for 48% (range 32-67%) of total clearance (mean 10.2 ml/min, range 6.1-18 ml/min). Significant correlations were observed between Cmax, minimum concentration (Cmin) and AUC24h (R(2) = 0.91, p < 0.001, and R(2) = 0.94, p < 0.001) and between albumin plasma concentration and free daptomycin (R(2) = 0.7, p = 0.009). CONCLUSION: No significant accumulation occurred with a daily daptomycin dose of 6 mg/kg in patients undergoing CRRT with an effluent flow rate of >30 ml/kg/h. The quantification of trough concentrations (Cmin) appears to be a good surrogate to estimate AUC24h and to monitor daptomycin treatment in patients undergoing CRRT.