Introduction

Sudden cardiac arrest is one of the most frequent causes of death in the world. In highly qualified emergency medical service (EMS) systems, including well-trained emergency physicians, spontaneous circulation may be restored in up to 53% of patients at least until admission to hospital. Compared with these highly qualified EMS systems, markedly lower success rates are observed in other systems. These data clearly show that there are considerable differences between EMS systems concerning treatment success following cardiac arrest and resuscitation, although in all systems international guidelines for resuscitation are used. In this study, we investigated the impact of response time reliability (RTR) on cardiopulmonary resuscitation (CPR) incidence and resuscitation success by using the return of spontaneous circulation (ROSC) after cardiac arrest (RACA) scores and data from seven German EMS systems participating in the German Resuscitation Registry.

Methods

Anonymised patient data after out-of-hospital cardiac arrest gathered from seven EMS systems in Germany from 2006 to 2009 were analysed with regard to socioeconomic factors (population, area and EMS unit-hours), process quality (RTR, CPR incidence, special CPR measures and prehospital cooling), patient factors (age, gender, cause of cardiac arrest and bystander CPR). End points were defined as ROSC, admission to hospital, 24-hour survival and hospital discharge rate. χ2 tests, odds ratios and the Bonferroni correction were used for statistical analyses.

Results

Our present study comprised 2,330 prehospital CPR patients at seven centres. The incidence of sudden cardiac arrest ranged from 36.0 to 65.1/100,000 inhabitants/year. We identified two EMS systems (RTR < 70%) that reached patients within 8 minutes of the call to the dispatch centre 62.0% and 65.6% of the time, respectively. The other five EMS systems (RTR > 70%) reached patients within 8 minutes of the call to the dispatch centre 70.4% up to 95.5% of the time. EMS systems arriving relatively later at the patients side (RTR < 70%) initiate CPR less frequently and admit fewer patients alive to hospital (calculated per 100,000 inhabitants/year) (CPR incidence (1/100,000 inhabitants/year) RTR > 70% = 57.2 vs RTR < 70% = 36.1, OR = 1.586 (99% CI = 1.383 to 1.819); P < 0.01) (admitted to hospital with ROSC (1/100,000 inhabitants/year) RTR > 70% = 24.4 vs RTR < 70% = 15.6, OR = 1.57 (99% CI = 1.274 to 1.935); P < 0.01). Using ROSC rate and the multivariate RACA score to predict outcomes, we found that the two groups did not differ, but ROSC rates were higher than predicted in both groups (ROSC RTR > 70% = 46.6% vs RTR < 70% = 47.3%, OR = 0.971 (95% CI = 0.787 to 1.196); P = n.s.) (ROSC RACA RTR > 70% = 42.4% vs RTR < 70% = 39.5%, OR = 1.127 (95% CI = 0.911 to 1.395); P = n.s.)

Conclusion

This study demonstrates that, on the level of EMS systems, faster ones more often initiate CPR and increase the number of patients admitted to hospital alive. Furthermore, we show that, with very different approaches, all centres that adhere to and are intensely trained according to the 2005 European Resuscitation Council guidelines are superior and, on the basis of international comparisons, achieve excellent success rates following CPR.

Introduction

Cardiac arrest following trauma occurs infrequently compared with cardiac aetiology. Within the German Resuscitation Registry a traumatic cause is documented in about 3% of cardiac arrest patients. Regarding the national Trauma Registry, only a few of these trauma patients with cardiac arrest survive. The aim of the present study was to analyze the outcome of cardiopulmonary resuscitation (CPR) after traumatic cardiac arrest by combining data from two different large national registries in Germany.

Methods

This study includes 368 trauma patients (2.8%) out of 13,329 cardiac arrest patients registered within the Resuscitation Registry, whereby 3,673 patients with a cardiac cause and successful CPR served as a cardiac control group. We further analyzed a second group of 1,535 trauma patients with cardiac arrest and early CPR registered within the Trauma Registry, whereby a total of 25,366 trauma patients without any CPR attempts served as a trauma control group. The relative frequencies from each database were used to calculate relative percentages for patients with traumatic cardiac arrest in whom resuscitation was attempted.

Results

Within the Resuscitation Registry, cardiac arrest was present in 331 patients (89.9%) when the EMS personal arrived at the scene and in 37 patients (10.1%) when cardiac arrest occurred after arrival. Spontaneous circulation could be achieved in 107 patients (29.1%). A total of 101 (27.4%) were transferred to hospital, 95 of whom (25.8%) had return of spontaneous circulation (ROSC) on admission. According to the Trauma Registry, the overall hospital mortality rate for cardiac arrest patients following trauma was 73% (n = 593 of 814). About half of the patients who were admitted alive to hospital died within 24 hours, resulting in 13% survivors within 24 hours. 7% of the patients survived until hospital discharge, and only 2% of the patients had good neurological outcome.

Conclusions

Our present study encourages CPR attempts in cardiac arrest patients following severe trauma. When a manageable number of patients is present, the decision on whether to start CPR or not should be done liberally, using comparable criteria as in patients with cardiac etiology. In this respect, trauma management programs that restrict CPR attempts should not be encouraged.

Specific genomic alterations, such as loss of the chromosomal region 11q or amplification of the oncogene MYCN, are well established markers of poor outcome in neuroblastoma. The advent of microarray-based comparative genomic hybridization (array-CGH) has enabled the analysis of pangenomic alteration profiles in the cancer genome, offering the possibility of identifying new prognostic markers from complex aberration patterns. Results from recent studies examining large primary neuroblastoma cohorts by array-CGH show that global genomic profiles may add significant prognostic information. Here, we discuss potential implications for risk estimation of neuroblastoma patients in clinical practice as well as for the understanding of neuroblastoma pathogenesis.

BACKGROUND

More accurate prognostic assessment of patients with neuroblastoma is required to improve the choice of risk-related therapy. The aim of this study is to develop and validate a gene expression signature for improved outcome prediction.

METHODS

Fifty-nine genes were carefully selected based on an innovative data-mining strategy and profiled in the largest neuroblastoma patient series (n=579) to date using RT-qPCR starting from only 20 ng of RNA. A multigene expression signature was built using 30 training samples, tested on 313 test samples and subsequently validated in a blind study on an independent set of 236 additional tumours.

FINDINGS

The signature accurately classifies patients with respect to overall and progression-free survival (p<0·0001). The signature has a performance, sensitivity, and specificity of 85·4% (95%CI: 77·7–93·2), 84·4% (95%CI: 66·5–94·1), and 86·5% (95%CI: 81·1–90·6), respectively to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor after controlling for currently used riskfactors. Patients with high molecular risk have a higher risk to die from disease and for relapse/progression than patients with low molecular risk (odds ratio of 19·32 (95%CI: 6·50–57·43) and 3·96 (95%CI: 1·97–7·97) for OS and PFS, respectively). Patients with increased risk for adverse outcome can also be identified within the current treatment groups demonstrating the potential of this signature for improved clinical management. These results were confirmed in the validation study in which the signature was also independently statistically significant in a model adjusted for MYCN status, age, INSS stage, ploidy, INPC grade of differentiation, and MKI. The high patient/gene ratio (579/59) underlies the observed statistical power and robustness.

INTERPRETATION

A 59-gene expression signature predicts outcome of neuroblastoma patients with high accuracy. The signature is an independent risk predictor, identifying patients with increased risk in the current clinical risk groups. The applied method and signature is suitable for routine lab testing and ready for evaluation in prospective studies.

FUNDING

The Belgian Foundation Against Cancer, found of public interest (project SCIE2006-25), the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid’s Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders (grant number: G•0198•08), the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek (IWT-SBO 60848), the Fondation Fournier Majoie pour l’Innovation, the Instituto Carlos III,RD 06/0020/0102 Spain, the Italian Neuroblastoma Foundation, the European Community under the FP6 (project: STREP: EET-pipeline, number: 037260), and the Belgian program of Interuniversity Poles of Attraction, initiated by the Belgian State, Prime Minister's Office, Science Policy Programming.

Introduction

Mild therapeutic hypothermia (MTH) has been shown to result in better neurological outcome after cardiopulmonary resuscitation. Percutaneous coronary intervention (PCI) may also be beneficial in patients after out-of-hospital cardiac arrest (OHCA).

Methods

A selected cohort study of 2,973 prospectively documented adult OHCA patients within the German Resuscitation Registry between 2004 and 2010. Data were analyzed by backwards stepwise binary logistic regression to identify the impact of MTH and PCI on both 24-hour survival and neurological outcome that was based on cerebral performance category (CPC) at hospital discharge. Odds ratios (95% confidence intervals) were calculated adjusted for the following confounding factors: age, location of cardiac arrest, presumed etiology, bystander cardiopulmonary resuscitation, witnessing, first electrocardiogram rhythm, and thrombolysis.

Results

The Preclinical care dataset included 2,973 OHCA patients with 44% initial return of spontaneous circulation (n = 1,302) and 35% hospital admissions (n = 1,040). Seven hundred and eleven out of these 1,040 OHCA patients (68%) were also registered within the Postresuscitation care dataset. Checking for completeness of datasets required the exclusion of 127 Postresuscitation care cases, leaving 584 patients with complete data for final analysis. In patients without PCI (n = 430), MTH was associated with increased 24-hour survival (8.24 (4.24 to 16.0), P < 0.001) and the proportion of patients with CPC 1 or CPC 2 at hospital discharge (2.13 (1.17 to 3.90), P < 0.05) as an independent factor. In normothermic patients (n = 405), PCI was independently associated with increased 24-hour survival (4.46 (2.26 to 8.81), P < 0.001) and CPC 1 or CPC 2 (10.81 (5.86 to 19.93), P < 0.001). Additional analysis of all patients (n = 584) revealed that 24-hour survival was increased by MTH (7.50 (4.12 to 13.65), P < 0.001) and PCI (3.88 (2.11 to 7.13), P < 0.001), while the proportion of patients with CPC 1 or CPC 2 was significantly increased by PCI (5.66 (3.54 to 9.03), P < 0.001) but not by MTH (1.27 (0.79 to 2.03), P = 0.33), although an unadjusted Fisher exact test suggested a significant effect of MTH (unadjusted odds ratio 1.83 (1.23 to 2.74), P < 0.05).

Conclusions

PCI may be an independent predictor for good neurological outcome (CPC 1 or CPC 2) at hospital discharge. MTH was associated with better neurological outcome, although subsequent logistic regression analysis did not show statistical significance for MTH as an independent predictor for good neurological outcome. Thus, postresuscitation care on the basis of standardized protocols including coronary intervention and hypothermia may be beneficial after successful resuscitation. One of the main limitations may be a selection bias for patients subjected to PCI and MTH.

Background

HAND2, a key regulator for the development of the sympathetic nervous system, is located on chromosome 4q33 in a head-to-head orientation with DEIN, a recently identified novel gene with stage specific expression in primary neuroblastoma (NB). Both genes are expressed in primary NB as well as most NB cell lines and are separated by a genomic sequence of 228 bp. The similar expression profile of both genes suggests a common transcriptional regulation mediated by a bidirectional promoter.

Results

Northern Blot analysis of DEIN and HAND2 in 20 primary NBs indicated concurrent expression levels of the two genes, which was confirmed by microarray analysis of 236 primary NBs (Pearson's correlation coefficient r = 0.65). While DEIN expression in the latter cohort was associated with stage 4S (p = 0.02), HAND2 expression was not associated with tumor stage. In contrast, both HAND2 and DEIN transcript levels were highly associated with age at diagnosis <12 months (p = 0.001). The intergenic region shows substantial homology in different species (89%, 72% and 53% identity between human and mouse, chicken and zebrafish, respectively) and contains many highly conserved putative transcription factor binding sites. Using luciferase reporter gene constructs, asymmetrical bidirectional promoter activity was found in four NB cell lines: In DEIN orientation, an average 3.4 fold increase in activity was observed as compared to the promoterless vector, whereas an average 15.4 fold activation was detected in HAND2 orientation. The presence of two highly conserved putative regulatory elements, one of which was shown to enhance HAND2 expression in branchial arches previously, displayed weak repressor activity for both genes.

Conclusion

HAND2 and DEIN represent a gene pair that is tightly linked by a bidirectional promoter in an evolutionary highly conserved manner. Expression of both genes in NB is co-regulated by asymmetrical activity of this promoter and modulated by the activity of two cis-regulatory elements acting as weak repressors. The concurrent quantitative and tissue specific expression of HAND2 and DEIN suggests a functional link between both genes.

Differences in MYCN/c-MYC target gene expression are associated with distinct neuroblastoma subtypes and clinical outcome.

Background

Amplified MYCN oncogene resulting in deregulated MYCN transcriptional activity is observed in 20% of neuroblastomas and identifies a highly aggressive subtype. In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously (stage 4s-non-amplified). In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes.

Results

We defined a core set of direct MYCN/c-MYC target genes by applying gene expression profiling and chromatin immunoprecipitation (ChIP, ChIP-chip) in neuroblastoma cells that allow conditional regulation of MYCN and c-MYC. Their transcript levels were analyzed in 251 primary neuroblastomas. Compared to localized-non-amplified neuroblastomas, MYCN/c-MYC target gene expression gradually increases from stage 4s-non-amplified through stage 4-non-amplified to MYCN amplified tumors. This was associated with MYCN activation in stage 4s-non-amplified and predominantly c-MYC activation in stage 4-non-amplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-non-amplified but not in stage 4s-non-amplified neuroblastomas. In line with this, high expression of a subset of MYCN/c-MYC target genes identifies a patient subtype with poor overall survival independent of the established risk markers amplified MYCN, disease stage, and age at diagnosis.

Conclusions

High MYCN/c-MYC target gene expression is a hallmark of malignant neuroblastoma progression, which is predominantly driven by c-MYC in stage 4-non-amplified tumors. In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression.

Background

Neuroblastoma patients show heterogeneous clinical courses ranging from life-threatening progression to spontaneous regression. Recently, gene expression profiles of neuroblastoma tumours were associated with clinically different phenotypes. However, such data is still rare for important patient subgroups, such as patients with MYCN non-amplified advanced stage disease. Prediction of the individual course of disease and optimal therapy selection in this cohort is challenging. Additional research effort is needed to describe the patterns of gene expression in this cohort and to identify reliable prognostic markers for this subset of patients.

Methods

We combined gene expression data from two studies in a meta-analysis in order to investigate differences in gene expression of advanced stage (3 or 4) tumours without MYCN amplification that show contrasting outcomes (alive or dead) at five years after initial diagnosis. In addition, a predictive model for outcome was generated. Gene expression profiles from 66 patients were included from two studies using different microarray platforms.

Results

In the combined data set, 72 genes were identified as differentially expressed by meta-analysis at a false discovery rate (FDR) of 8.33%. Meta-analysis detected 34 differentially expressed genes that were not found as significant in either single study. Outcome prediction based on data of both studies resulted in a predictive accuracy of 77%. Moreover, the genes that were differentially expressed in subgroups of advanced stage patients without MYCN amplification accurately separated MYCN amplified tumours from low stage tumours without MYCN amplification.

Conclusion

Our findings support the hypothesis that neuroblastoma consists of two biologically distinct subgroups that differ by characteristic gene expression patterns, which are associated with divergent clinical outcome.

Introduction

Sedation and analgesia are provided by using different agents and techniques in different countries. The goal is to achieve early spontaneous breathing and to obtain an awake and cooperative pain-free patient. It was the aim of this study to conduct a survey of the agents and techniques used for analgesia and sedation in intensive care units in Germany.

Methods

A survey was sent by mail to 261 hospitals in Germany. The anesthesiologists running the intensive care unit were asked to fill in the structured questionnaire about their use of sedation and analgesia.

Results

A total of 220 (84%) questionnaires were completed and returned. The RAMSAY sedation scale was used in 8% of the hospitals. A written policy was available in 21% of hospitals. For short-term sedation in most hospitals, propofol was used in combination with sufentanil or fentanyl. For long-term sedation, midazolam/fentanyl was preferred. Clonidine was a common part of up to two-thirds of the regimens. Epidural analgesia was used in up to 68%. Neuromuscular blocking agents were no longer used.

Conclusion

In contrast to the US 'Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult', our survey showed that in Germany different agents, and frequently neuroaxial techniques, were used.