The impact of acquired coagulation factor XIII deficiency in traumatic bleeding and wound healing.

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60-70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.

Warning criteria for MEP monitoring during carotid endarterectomy: a retrospective study of 571 patients.

Monitoring of transcranial electrical motor evoked potentials (tcMEP) during carotid endarterectomy (CEA) has been shown to effectively detect intraoperative cerebral ischemia. The unique purpose of this study was to evaluate changes of MEP amplitude (AMP), area under the curve (AUC) and signal morphology (MOR) as additional MEP warning criteria for clamping-associated ischemia during CEA. Therefore, the primary outcome was the number of MEP alerts (AMP, AUC and MOR) in the patients without postoperative motor deficit (false positives). We retrospectively reviewed data from 571 patients who received CEA under general anesthesia. Monitoring of somatosensory evoked potentials (SSEP) and tcMEP was performed in all cases (all-or-none MEP warning criteria). The percentages of false positives (primary parameter) of AMP, AUC and MOR were evaluated according to the postoperative motor outcome. In the cohort of 562 patients, we found significant SSEP/MEP changes in 56 patients (9.96%). In 44 cases (7.83%) a shunt was inserted. Nine patients (1.57%) were excluded due to MEP recording failure. False positives were registered for AMP, AUC and MOR changes in 121 (24.01%), 148 (29.36%) and 165 (32.74%) patients, respectively. In combination of AMP/AUC and AMP/AUC/MOR false positives were found in 9.52% and 9.33% of the patients. This study is the first to evaluate the correctness of the MEP warning criteria AMP, AUC and MOR with regard to false positive monitoring results in the context of CEA. All additional MEP warning criteria investigated produced an unacceptably high number of false positives and therefore may not be useful in carotid surgery for adequate detection of clamping-associated ischemia.

Intraoperative multimodal evoked potential monitoring during carotid endarterectomy: a retrospective study of 264 patients.

BACKGROUND: Methods for detecting intraoperative cerebral ischemia arising from internal carotid artery (ICA) cross-clamping during carotid endarterectomy (CEA) should be sensitive, specific, and rapid to prevent intraoperative stroke. We had 3 objectives pertaining to this: (1) investigation of the rates of success of multimodal evoked potential (mEP) monitoring using a combination of median nerve (m) somatosensory (SS) EPs, tibial nerve SSEPs (tSSEPs), and transcranial electrical stimulated motor EPs (tcMEPs); (2) evaluation of the rates of false-negative mEP results; and (3) analysis of the relationship between different time periods associated with ICA cross-clamping and the postoperative outcome of motor function in patients with significant changes in mEP monitoring. METHODS: Two hundred sixty-four patients undergoing CEA using general anesthesia with monitoring of bilateral mSSEPs, tSSEPs, and tcMEPs were retrospectively reviewed between 2009 and 2012. The rates of successful assessment of mEPs were investigated, and the rate of false-negative mEP results was analyzed. Different time periods (T1--time of clamping, T2--clamping to significant mEP changes, T3--significant mEP change to intervention, and T4--intervention to recovery of EP) were tested using Welch t test for significant association with postoperative motor deficit. RESULTS: (1) Multimodal EP monitoring was achieved in 241 patients (91.3%, point estimate [PE] 0.91, confidence interval [CI] 0.87 to 0.94), whereas none of the modalities were recordable in one case (PE 0.0038, CI 0.0002 to 0.019). Additionally, tSSEP was not recordable in 21 patients (PE 0.08, CI 0.05 to 0.12), and we found one case of isolated failure of tcMEP recording (PE 0.0038, CI 0.0002 to 0.019). (2) False-negative mEP results were found in 1 patient (0.4%; PE 0.0038, CI 0.0002 to 0.019). Significant mEP changes occurred in 32 patients (12.1%), and thus, arterioarterial shunt was performed in 17 (6.4%) patients. Eleven patients (4.2%) showed transient and 1 showed permanent postoperative motor deficit. (3) There was no significant difference regarding any of the time periods associated with ICA cross-clamping and postoperative alteration of motor function (T1: P = 0.19, CI -30.1 to 6.8 minutes; T2: P = 0.38, CI -23 to 9.5 minutes; T3: P = 0.25, -9.7 to 2.8 minutes; T4: P = 0.42, CI to -15.5 to 7.0 minutes). CONCLUSIONS: Multimodal EP monitoring is applicable during CEA. The 0.4% false-negative rate suggests an advantage of mEP monitoring when compared with isolated mSSEP monitoring. Our data suggest that periods of time during cross-clamping were not significantly associated with postoperative motor deficit. However, the small number of patients limits the conclusiveness of these findings. mEP monitoring could not prevent a postoperative motor deficit in all patients, but our results suggest that it is a useful adjunct to mSSEP monitoring.

Comparison of Enk Fibreoptic Atomizer with translaryngeal injection for topical anaesthesia for awake fibreoptic intubation in patients at risk of secondary cervical injury: A randomised controlled trial.

BACKGROUND: Two methods of topical anaesthesia for awake fibreoptic intubation (FOI) in patients at risk of secondary cervical injury were compared: the translaryngeal injection (TLI) technique and the Enk Fibreoptic Atomizer. OBJECTIVE: The objective of this study was to determine which system of topical anaesthesia provides the fastest and most comfortable awake FOI, using the oral approach. DESIGN: A randomised controlled study. SETTING: A single centre trial between 2009 and 2011. PATIENTS: One hundred and twenty patients (63 women, 57 men) who underwent neurosurgery of the spine at Klinikum St. Georg Leipzig were randomly allocated into two groups (group TLI, 61 patients; group ENK-ATOMIZER, 59 patients). Inclusion criteria were an American Society of Anesthesiology (ASA) physical status of 1 to 3, age 18 to 80 years, and those who met any one of three indications for FOI - cervical instability, predicted difficult airway, a BMI greater than 40 kg m(-2), and who gave written informed consent.Exclusion criteria were emergency awake FOI, mental disability/delirium, polytrauma and contraindication to TLI. INTERVENTIONS: Two anaesthesiologists experienced in both techniques performed all anaesthesia procedures within the study. MAIN OUTCOME MEASURES: The primary outcome was the timing sequence of awake FOI. The incidence of coughing/gagging, ease of tracheal tube placement, mucosal bleeding, cardiopulmonary stability and postoperative outcomes were also investigated. RESULTS: Awake FOI was significantly faster using the TLI technique (mean, 191 s; range, 123 to 447 s; SD, 83.5) than the Enk Fibreoptic Atomizer [mean, 430 s; range, 275 to 773 s; SD, 124.9; (P = 0.0001)]. Patients in group TLI exhibited significantly less gagging (P = 0.047) but more mucosal bleeding (P <  .001). CONCLUSION: Awake FOI using the TLI technique was faster and provided better topical anaesthesia with less gagging during endoscopic intubation. However, the TLI technique was also more invasive. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00948350.

Antithrombin III, but not C1 esterase inhibitor reduces inflammatory response in lipopolysaccharide-stimulated human monocytes in an ex-vivo whole blood setting.

In order to examine the immunomodulatory effects of antithrombin III (AT-III) and C1 esterase inhibitor (C1-INH) in human monocytes, we investigated the intracellular expression of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in an ex-vivo laboratory study in a whole blood setting. Heparinized whole blood samples from 23 healthy male and female volunteers (mean age: 27±7years) were pre-incubated with clinically relevant concentrations of AT-III (n=11) and C1-INH (n=12), then stimulated with 0.2 ng/mL lipopolysaccharide (LPS) for 3h. After phenotyping CD14⁺ monocytes, intracellular expression of IL-6, IL-8, and TNF-α was assessed using flow cytometry. In addition, 12 whole blood samples (AT-III and C1-INH, n=6 each) were examined using hirudin for anticoagulation; all samples were processed in the same way. To exclude cytotoxicity effects, 7-amino-actinomycin D and Nonidet P40 staining were used to investigate probes. This study is the first to demonstrate the influence of C1-INH and AT-III on the monocytic inflammatory response in a whole blood setting, which mimics the optimal physiological setting. Cells treated with AT-III exhibited significant downregulation of the proportion of gated CD14⁺ monocytes for IL-6 and IL-8, in a dose-dependent manner; downregulation for TNF-α did not reach statistical significance. There were no significant effects on mean fluorescence intensity (MFI). In contrast, C1-INH did not significantly reduce the proportion of gated CD14⁺ monocytes or the MFI regarding IL-6, TNF-α, and IL-8. When using hirudin for anticoagulation, no difference in the anti-inflammatory properties of AT-III and C1-INH in monocytes occurs. Taken together, in contrast to TNF-α, IL-6 and IL-8 were significantly downregulated in monocytes in an ex-vivo setting of human whole blood when treated with AT-III. This finding implicates monocytes as an important point of action regarding the anti-inflammatory properties of AT-III in sepsis. C1-INH was unable to attenuate the monocytic response, which supports the hypothesis that other cellular components in whole blood (e.g., neutrophils) might be responsible for the known effects of C1-INH in inflammation.

Comparison of Aintree and Fastrach techniques for low-skill fibreoptic intubation in patients at risk of secondary cervical injury: a randomised controlled trial.

BACKGROUND: We compared two methods of asleep fibreoptic intubation in patients at risk of secondary cervical injury: the Aintree Intubation Catheter via a classic laryngeal mask airway (cLMA) versus the Fastrach technique via the intubating laryngeal mask airway (iLMA). OBJECTIVE: To test which system has the highest rate of successful intubations in the clinical setting. DESIGN: A randomised controlled study. SETTING: Single-centre, between 2007 and 2010. PATIENTS: We randomly allocated 80 patients (30 women and 50 men) who underwent elective neurosurgery of the cervical spine to either group, placed in a neutral position and wearing a soft cervical collar. Entry criteria were ASA status 1 to 3, age 18 to 80 years and written informed consent. Exclusion criteria were patients with cervical instability, known or predicted difficult airway, BMI greater than 40  kg  m⁻² and symptomatic gastro-oesophageal reflux. INTERVENTIONS: Two anaesthetists who were experienced in both techniques performed all anaesthesia procedures within the study. There was a maximum of three attempts for performing each technique. MAIN OUTCOME MEASURES: The primary outcome was the rate of successful fibreoptic intubation in a neutral position. We also investigated the timing sequence for both techniques, the Brimacombe and Berry Bronchoscopy Score, and differences in technical aspects. RESULTS: All 40 patients in the Aintree group but only 31 patients in the Fastrach group were intubated successfully. Thus, fibreoptic intubation failed significantly less using the Aintree technique (P = 0.002). For secondary outcomes, the cLMA was faster (260 versus 289  s, P = 0.039) and easier (P = 0.036) to insert than the iLMA. The fibreoptic view of the glottis according to the Brimacombe and Berry Bronchoscopy Score was better (P = 0.016) and the tracheal tube was easier to insert (P = 0.010) in the Aintree group. CONCLUSION: Fibreoptic intubation using the Aintree system was more successful than the Fastrach technique in our population of patients in a neutral position wearing a soft cervical collar. The differences in the time to successful intubation between the two groups are unlikely to be clinically relevant.

High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial.

IMPORTANCE: Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines. OBJECTIVE: To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: The MetaPlus study, a randomized, double-blind, multicenter trial, was conducted from February 2010 through April 2012 including a 6-month follow-up period in 14 intensive care units (ICUs) in the Netherlands, Germany, France, and Belgium. A total of 301 adult patients who were expected to be ventilated for more than 72 hours and to require enteral nutrition for more than 72 hours were randomized to the IMHP (n = 152) or HP (n = 149) group and included in an intention-to-treat analysis, performed for the total population as well as predefined medical, surgical, and trauma subpopulations. INTERVENTIONS: High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days. MAIN OUTCOMES AND MEASURES: The primary outcome measure was incidence of new infections according to the Centers for Disease Control and Prevention (CDC) definitions. Secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according CDC definitions. RESULTS: There were no statistically significant differences in incidence of new infections between the groups: 53% (95% CI, 44%-61%) in the IMHP group vs 52% (95% CI, 44%-61%) in the HP group (P = .96). No statistically significant differences were observed in other end points, except for a higher 6-month mortality rate in the medical subgroup: 54% (95% CI, 40%-67%) in the IMHP group vs 35% (95% CI, 22%-49%) in the HP group (P = .04), with a hazard ratio of 1.57 (95% CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score comparing the groups. CONCLUSIONS AND RELEVANCE: Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of IMHP nutrients in these patients. TRIAL REGISTRATION: trialregister.nl Identifier: NTR2181.

The predictive role of Interleukin 6 in burn patients with positive blood cultures.

Interleukin 6 (IL-6) is an established biomarker of inflammation with one of the earliest responses in sepsis. Serum levels can easily be measured within a few hours. The clinical significance of IL-6 in the early stage of sepsis in burned patients has not yet been confirmed. The purpose of our research was to investigate the predictive value of IL-6 for positive blood cultures in comparison to Procalcitonin (PCT), white blood cell (WBC) count, body temperature and the Sequential Organ Failure Assessment (SOFA) score in the presence of suspected sepsis in burn patients. In a retrospective study, we included all patients admitted to a regional burn centre in a 7-year period. Patients with a clinical suspicion of sepsis and complete laboratory tests underwent further analysis. Patients were categorized following culture results into either positive or negative bloodstream infection (BSI or non-BSI) groups. 39 of the 101 included patients had positive blood cultures (BSI). The serum IL-6 levels were significantly higher in the BSI group [1047 (339.9; 9000.5) vs. 198.5 (112.4; 702.5) ng/l; P = 0.001]. Receiver operating characteristic (ROC) curve analysis showed an AUC of 0.7 (59; 80.8%). The optimal IL-6 cut-off level was 312.8 ng/l (sensitivity 79.5%, specificity 56.5%). Other biomarkers (PCT, WBC), the maximum body temperature and increase of SOFA score were not different between the groups. IL-6 can be used to predict a positive blood culture even in the early stage of suspected sepsis in burned patients. In this context, other biomarkers (PCT, WBC) and body temperature are of limited clinical utility.

Evaluation of MR-proANP and copeptin for sepsis diagnosis after burn injury.

PURPOSE: The significance of the validated biomarkers of sepsis Mid-regional pro-atrial natriuretic peptide (MR-proANP) and copeptin have not been tested in a burn injury setting. MATERIALS AND METHODS: 42 consecutive patients were included in a prospective observational study. Daily blood specimens collected over the initial 20 days of treatment were quantitatively analysed by immunoluminometric sandwich assay (Kryptor, BRAHMS, Berlin, Germany) for MR-proANP, copeptin and procalcitonin (PCT). RESULTS: In patients with absence of sepsis, copeptin levels initially increased post-burn injury and thereafter rapidly declined. In contrast, MR-proANP was only slightly elevated within the first few days. MR-proANP [199.8 (115.6; 399.5) vs 160.1 (93.7; 280.6), P < .007] and PCT [1.12 (0.32; 2.22) vs 0.32 (0.16; 0.53), P < .001] levels were significantly higher on days of sepsis. Copeptin, however, showed no significant differences [20.7 (11.8; 42.2) vs 16.8 (11.0; 30.6), P = .11]. Both, MR-proANP and PCT level increases were noted upon the first day of sepsis. CONCLUSION: Burn injury itself maybe associated with copeptin and to a lesser degree MR-proANP level increases. Subsequent increases in MR-proANP may be considered diagnostic for sepsis but demonstrated no advantages over PCT. The role of copeptin remains inappropriate for diagnosing sepsis after burn injury (ClinicalTrials.gov number, NCT01055587).

[Consumption of antibiotics in a burns intensive care unit]. / Antibiotikaverbrauch auf einer Intensivstation für Schwerbrandverletzte.

INTRODUCTION: Burn-injured patients are at particularly high risk of infection; as such one would expect an increased requirement of antibiotics compared to other intensive care patients. There is no data in the literature investigating this hypothesis in Germany. The aim of this study was to determine the antibiotic consumption in severe burn patients and to compare this data with those from surgical intensive care units. PATIENTS AND METHODS: The retrospective study included 136 patients treated in the period from 2013 to 2016 due to a severe burn in the ICU intensive care unit of a regional burn centre. The use of antibiotics was recorded using the electronic medical record. The number of daily doses in Recommended Daily Dose (RDD) and Defined Daily Dose (DDD) based on patient days was calculated. RESULTS: Median [interquartile range] age and total burned surface area were 56.5y [43-75y] and 17 % [8,75; 31] with an ABSI 7 [6; 9]. Antibiotic therapy was given to 82 patients (60.3 %). Antibiotic consumption totaled 77.38 RDD/100 PT or 937.64 DDD/1000 PT. This result was marginally lower than for surgical intensive care units. The most frequently used antibiotics in the burn care setting were fluorquinolones (16.90 RDD/100 PT, 259.91 DDD/1000 PT), followed by carbapenems (12.76 RDD/100 PT, 128.44 DDD/1000 PT) and aminopenicillins/ BLI (11.54 RDD/100 PT, 115.39 DDD/1000 PT). Whilst, the most frequently detected pathogens were Staphylococcus aureus (54.4 %), Enterococcus faecalis (54.4 %), E. coli (37.5 %) and Pseudomonas aeruginosa (36.8 %). CONCLUSION: The total antibiotic consumption in severe burns was not increased compared to other surgical intensive care patients. With regard to individual substance classes, peculiarities can be identified reflecting the particular germ spectrum in this cohort.

Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.

BACKGROUND: In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death. METHODS: We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected. RESULTS: Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01). CONCLUSIONS: The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.

Evaluation of sE-Selectin and sICAM-1 as parameters for renal function.

INTRODUCTION: In order to monitor acute renal failure, intensive care patients were examined, and routine as well as specialized parameters were compared. MATERIALS AND METHODS: Thirty-three patients at the Surgical Intensive Care Unit (ICU) were examined daily over the entire period for which they stayed in the ICU. The patients were retrospectively classified as being either with or without acute renal failure. Group 1 consisted of 22 patients who resided in the ICU for 11-15 (median 14) days without ARF. Group 2 consisted of 11 patients who developed an ARF during their stay of 13-18 (median 16) days in the ICU. In addition to the routine parameters of diuresis, serum creatinine/urea, and clearance of creatinine, specialized parameters for kidney function, including the excretion rates of alpha1-microglobulin, N-acetyl-beta-D-glucosaminidase, and total protein, were compared with the excretion rate of soluble ICAM-1 and sE-Selectin. RESULTS: Diuresis, serum creatinine, urea, and enzyme elimination were pathological among patients with ARF. Already on the day of admission, raised elimination rates of sICAM-1 were found in the urine of patients who had developed an ARF. While high values were still shown upon discharge, levels kept falling among patients without ARF. Clearly raised values were also shown for sE-Selectin compared to patients without ARF. CONCLUSIONS: sICAM-1 and sE-Selectin as supplementary parameters indicating renal function revealed early signs of kidney damage. These parameters may play a major role in the development of novel therapeutic approaches for ARF (antibodies against ICAM-1 or sE-Selectin).

[Dysregulation of homeostasis in severe sepsis: relevance and therapeutic options]. / Gestörte Homöostase in der Sepsis - Bedeutung und Therapie.

Severe sepsis and septic shock may have a lasting effect on all human endocrinologic, coagulatory and metabolic regulatory circuits with the consequence of severe dysregulation of homoeostasis. Adjunctive therapeutic options like intensive insulin therapy, low-dose hydrocortisone and modulation of coagulation by drotrecogin alfa (activated) are still controversial discussed, but should be used according to the national and international guidelines for a sophisticated treatment of septic heterostasis.

Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: Updated recommendations from the Cologne Consensus Conference 2018.

In June 2016, members of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) met for a Consensus Conference in Cologne, Germany. Aim of this Conference was to compile consensus based practice recommendations based on the 2015 European Pulmonary Hypertension guidelines, aiming at their practical implementation, considering country-specific issues, and including new evidence, where available. This article summarizes the results and updated recommendations 2018 of the working group on decompensated right heart failure (RHF), intensive care and perioperative management in patients with pulmonary hypertension. The RHF section comprises definition and pathophysiology, diagnosis and monitoring, identification of triggering factors and supportive therapy of RHF, volume management as well as PAH targeting therapy, therapy with inotropic, inodilator and vasopressor drugs, extracorporeal support and transplantation. The second part of this article summarizes preoperative management, perioperative monitoring and choice of anesthesia.

General measures and supportive therapy for pulmonary arterial hypertension: Updated recommendations from the Cologne Consensus Conference 2018.

In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines aiming at their practical implementation, considering country-specific issues, and including new evidence, where available. To this end, a number of working groups was initiated, one of which was specifically dedicated to general measures (i.e. physical activity/supervised rehabilitation, pregnancy/contraception, elective surgery, infection prevention, psychological support, travel) and supportive therapy (i.e. anticoagulants, diuretics, oxygen, cardiovascular medications, anaemia/iron deficiency, arrhythmias) for PAH. While the European guidelines provide detailed recommendations for the use of targeted PAH therapies as well as supportive care, detailed treatment decisions in routine clinical care may be challenging, and the relevance of supportive care is often not sufficiently considered. In addition, new evidence became available, thus requiring a thorough reevaluation of specific recommendations. The detailed results and recommendations of the working group on general measures and supportive therapy for PAH, which were last updated in the spring of 2018, are summarized in this article.

International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: analysis of efficacy and safety data in a large surgical cohort.

BACKGROUND: The International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy includes an extensive cohort of surgical patients (1659/4459; 37%). This database broadens the experience reported on a comparatively small set of surgical patients from the pivotal Protein C Worldwide Evaluation in Severe Sepsis trial to examine issues of safety and efficacy in a much larger cohort. METHODS: We conducted a retrospective analysis of prospectively defined outcomes from 5 integrated clinical studies of severe sepsis. Multivariable analyses incorporated propensity scores, treatment, and significant baseline risk factors as independent variables in logistic regression models for 2 outcomes: serious adverse events that were observed during infusion and 28-day, all-cause mortality rates. Adjusted odds ratios were calculated for clinically important strata. Multiple subcategories of serious bleeding-event rates are presented. RESULTS: Although surgical patients who were treated with drotrecogin alfa [activated] (DrotAA) experienced a greater proportion of serious bleeding events during the infusion period, most of the patients were treated without fatal consequence. A 10.7% absolute all cause mortality risk reduction (adjusted odds ratio, 0.66; 95% CI, 0.45-0.97) was observed for DrotAA-treated, high-risk (Acute Physiology and Chronic Health Evaluation II, >/= 25) surgical patients. We could not demonstrate a survival benefit in DrotAA-treated, low-risk (Acute Physiology and Chronic Health Evaluation II, <25) surgical patients. When surgical patients were stratified by number of organ dysfunctions, absolute risk reductions were observed in both categories: multiorgan (4.3%) and single (4.5%). CONCLUSION: International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy analyses affirmed the favorable benefit/risk profile of DrotAA for surgical patients. The serious adverse event rate that was experienced by surgical patients during the study drug infusion period was 7.5% in the DrotAA-treated group versus 6.3% in the placebo-treated group (odds ratio, 1.41; 95% CI, 0.89-2.25). The clinical benefit of DrotAA therapy paralleled baseline risk of death and substantiated findings from the Protein C Worldwide Evaluation in Severe Sepsis study. Future analyses are needed to evaluate the special relationships among sepsis severity, bleeding management, and the postoperative timing of DrotAA administration.

MR-proADM: A New Biomarker for Early Diagnosis of Sepsis in Burned Patients.

Mid regional pro-adrenomedullin (MR-proADM) has been used as a marker of sepsis, but its dynamics and role in a burn injury setting has not been tested. In a prospective observational study, we included 42 consecutive patients with >15% TBSA. Daily blood specimens collected over the initial 20 days of treatment were submitted for laboratory analysis of MR-proADM and procalcitonin (PCT) via immunoluminometric sandwich assay (Kryptor, BRAHMS, Berlin, Germany). In patients with an absence of sepsis, an initial increase in MR-proADM and PCT levels was noted post-burn injury, peaking on the second day postadmission and thereafter demonstrated a continued decline in MR-proADM and PCT levels. In those patients who went on to develop sepsis (n = 27, 64.3%), the levels of MR-proADM and PCT were significantly higher (P < .001) on days categorized as septic, than on days categorized as nonseptic. The increase in PCT levels was noted on the first day to be categorized as septic. In contrast, the MR-proADM levels demonstrated an increase one day earlier. The optimal relationship between the specificity and sensitivity of MR-proADM and PCT for the detection of sepsis was an increase of 31% and at least 0.015 nmol/L (area under curve 0.76) or of >39% and at least 0.15 µg/L (area under the curve 0.83), respectively. Burn injury is associated with increased levels of MR-proADM. Subsequent increases may be considered as diagnostic of sepsis onset. In this context, PCT displayed higher specificity and sensitivity, while MR-proADM may be more suitable for the early recognition of sepsis (ClinicalTrials.gov number, NCT01055587).

International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: analysis of efficacy and safety data in a large surgical cohort.

BACKGROUND: The International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy includes an extensive cohort of surgical patients (1659/4459; 37%). This database broadens the experience reported on a comparatively small set of surgical patients from the pivotal Protein C Worldwide Evaluation in Severe Sepsis trial to examine issues of safety and efficacy in a much larger cohort. METHODS: We conducted a retrospective analysis of prospectively defined outcomes from 5 integrated clinical studies of severe sepsis. Multivariable analyses incorporated propensity scores, treatment, and significant baseline risk factors as independent variables in logistic regression models for 2 outcomes: serious adverse events that were observed during infusion and 28-day, all-cause mortality rates. Adjusted odds ratios were calculated for clinically important strata. Multiple subcategories of serious bleeding-event rates are presented. RESULTS: Although surgical patients who were treated with drotrecogin alfa [activated] (DrotAA) experienced a greater proportion of serious bleeding events during the infusion period, most of the patients were treated without fatal consequence. A 10.7% absolute all cause mortality risk reduction (adjusted odds ratio, 0.66; 95% CI, 0.45-0.97) was observed for DrotAA-treated, high-risk (Acute Physiology and Chronic Health Evaluation II, >or=25) surgical patients. We could not demonstrate a survival benefit in DrotAA-treated, low-risk (Acute Physiology and Chronic Health Evaluation II, <25) surgical patients. When surgical patients were stratified by number of organ dysfunctions, absolute risk reductions were observed in both categories: multiorgan (4.3%) and single (4.5%). CONCLUSION: International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy analyses affirmed the favorable benefit/risk profile of DrotAA for surgical patients. The serious adverse event rate that was experienced by surgical patients during the study drug infusion period was 7.5% in the DrotAA-treated group versus 6.3% in the placebo-treated group (odds ratio, 1.41; 95% CI, 0.89-2.25). The clinical benefit of DrotAA therapy paralleled baseline risk of death and substantiated findings from the Protein C Worldwide Evaluation in Severe Sepsis study. Future analyses are needed to evaluate the special relationships among sepsis severity, bleeding management, and the postoperative timing of DrotAA administration.

Inhaled aerosolized iloprost in the evaluation of heart transplant candidates--experiences with 45 cases.

PURPOSE: Pulmonary hypertension represents a significant predictor of postoperative right heart insufficiency and increased mortality in patients undergoing orthotopic heart transplantation. As the use of intravenous vasodilators is limited by their systemic effects, we evaluated the pulmonary and systemic hemodynamic effects of inhaled aerosolized iloprost in heart transplant candidates with elevated pulmonary vascular resistance. METHODS: Forty-five male heart transplant candidates with dilated or ischemic cardiomyopathy were included in the study. After assessing baseline hemodynamics, 20 microg of aerosolized iloprost was administered by ultrasonic inhalation. All patients were breathing spontaneously. RESULTS: Inhalation of iloprost reduced pulmonary vascular resistance index (395 +/- 205 vs 327 +/- 222 dyne.s.cm(-5).m(-2); P < 0.05) and mean pulmonary arterial pressure (28.7 +/- 10 vs 24.3 +/- 10 mm Hg; P < 0.05). An additional improvement of ventricular performance with an increase of cardiac index (2.7 +/- 0.7 vs 3.0 +/- 0.8 L.min(-1).m(-2); P < 0.05) and a decrease of pulmonary capillary wedge pressure (16.6 +/- 7.7 vs 13.4 +/- 7.3 mm Hg; P < 0.05) was accompanied by a slight decrease of systemic vascular resistance (1280 +/- 396 vs 1172 +/- 380 dyne.s.cm(-5); P < 0.05). However, the mean arterial pressure remained uninfluenced. CONCLUSIONS: Inhaled aerosolized iloprost effectively reduces mean pulmonary arterial pressure and also induces an increase in cardiac index. Further advantages of iloprost inhalation are the lack of adverse reactions and ease of administration. Iloprost represents a useful drug to screen for vascular reactivity in cardiac transplantation patients.

Reducing the Indication for Ventilatory Support in the Severely Burned Patient: Results of a New Protocol Approach at a Regional Burn Center.

Initial management of the severely injured routinely includes sedation and mechanical ventilatory support. However, nonjudiciously applied mechanical ventilatory support can itself lead to poorer patient outcomes. In an attempt to reduce this iatrogenic risk, a standardized, in-house, five-point protocol providing clinical guidance on the use and duration of ventilation was introduced and analyzed, and the impact on patient outcomes was assessed. In 2007, a protocol for early spontaneous breathing was introduced and established in clinical practice. This protocol included: 1) early extubation (≤6 hours after admission) in the absence of absolute ventilatory indication; 2) avoidance of "routine intubation" in spontaneously breathing patients; 3) early postoperative extubation, including patients requiring multiple surgical interventions; 4) intensive chest and respiratory physiotherapy with routine application of expectorants; and 5) early active mobilization. A retrospective clinical study compared patients (group A) over a 2-year period admitted under the new protocol with a historical patient group (group B). Patients in group A (n = 38) had fewer ventilator days over the time-course of treatment (3 [1; 5.8] vs 18.5 days [0.5; 20.5]; P = .0001) with a lower rate of tracheostomies (15.8 vs 54%; P = .0003). Patients on ventilation at admission in group A had shorter ventilation periods after admission (4.75 [4; 22.25] vs 378 hours [8.5; 681.5]; P = .0003), and 66.7% of these patients were extubated within 6 hours of admission (vs 9.1% in group B). No patients fulfilling the inclusion criteria required re- or emergency intubation. In the first 5 days of treatment, significantly lower Sequential Organ Failure Assessment scores were recorded in group A. There was also a trend for lower mortality rates (0 [0%] vs 6 [14%]), sepsis rates (24 [63.2%] vs 37 [88.1%]), and cumulative fluid balance on days 3 and 7 in group A. In contrast, group A demonstrated an elevated rate of pneumonia (15 [39.5%] vs 8 [19%]). These trends, however, lacked statistical significance. Our five-point protocol was safe and easily translated into clinical practice. In the authors experience, this protocol significantly reduced the ventilatory period in severely injured. Furthermore, this study suggests that many injured may be over-treated with routine ventilation, which carries accompanying risks.