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Item does not contain fulltext, OBJECTIVE: In the prehospital setting, the Nijmegen and Rotterdam helicopter emergency medical services administer packed red blood cells to critically ill or injured pediatric patients. Blood is given on scene or during transport and is derived from nearby hospitals. We summarize our experience with prehospital blood use in pediatric patients. METHODS: The databases from both the Nijmegen and Rotterdam helicopter emergency medical services were reviewed for all pediatric (< 18 years) patients who received packed red blood cells on scene or during transport to the hospital. RESULTS: Between 2007 and 2015, 10 pediatric patients out of approximately 2,400 pediatric patients received blood in the prehospital setting. The median Injury Severity Score was 41. Seven hospitals delivered blood in the prehospital setting at the scene. All patients were in hypovolemic shock. Two patients died. Two patients were believed to be unexpected survivors; 1 was predicted by the Trauma and Injury Severity Score, and a second unexpected survivor was a neonate who was in hypovolemic shock and cardiopulmonary arrest. CONCLUSION: The incidence of prehospital use of blood in injured or critically ill children is low. This intervention presented a potential to limit acid-base disturbance, low hemoglobin levels, and coagulopathy in this group. We believe this cohort also contains 2 unexpected survivors.

Contains fulltext : 175550.pdf (publisher's version ) (Closed access)

Contains fulltext : 177838.pdf (publisher's version ) (Closed access), Introduction Early identification of traumatic brain injury (TBI) is essential. Near-infrared spectroscopy (NIRS) can be used in prehospital settings for non-invasive monitoring and the diagnosis of patients who may require surgical intervention. METHODS: The handheld NIRS Infrascanner (InfraScan Inc.; Philadelphia, Pennsylvania USA) uses eight symmetrical scan points to detect intracranial bleeding. A scanner was tested in a physician-staffed helicopter Emergency Medical Service (HEMS). The results were compared with those obtained using in-hospital computed tomography (CT) scans. Scan time, ease-of-use, and change in treatment were scored. RESULTS: A total of 25 patients were included. Complete scans were performed in 60% of patients. In 15 patients, the scan was abnormal, and in one patient, the scan resulted in a treatment change. Compared with the results of CT scanning, the Infrascanner obtained a sensitivity of 93.3% and a specificity of 78.6%. Most patients had severe TBI with indication for transport to a trauma center prior to scanning. In one patient, the scan resulted in a treatment change. Evaluation of patients with less severe TBI is needed to support the usefulness of the Infrascanner as a prehospital triage tool. CONCLUSION: Promising results were obtained using the InfraScan NIRS device in prehospital screening for intracranial hematomas in TBI patients. High sensitivity and good specificity were found. Further research is necessary to determine the beneficial effects of enhanced prehospital screening on triage, survival, and quality of life in TBI patients. Peters J , Van Wageningen B , Hoogerwerf N , Tan E . Near-infrared spectroscopy: a promising prehospital tool for management of traumatic brain injury. Prehosp Disaster Med. 2017;32(4):414-418.

Contains fulltext : 175639pub.pdf (publisher's version ) (Closed access), OBJECTIVE: Until recently, traumatic cardiac arrest (tCA) was believed to be associated with high mortality and low survival rates. New data suggest better outcomes. The most common error in tCA management is failing to treat a tension pneumothorax (TP). In the prehospital setting, we prefer thoracostomies for decompressing a potential TP in tCA cases; however, interventions can only be recommended with adequate information on their results. Therefore, we reviewed the results of thoracostomies performed by our Helicopter Emergency Medical Service. METHODS: Our Helicopter Emergency Medical Service database was reviewed for all patients who underwent a single or a bilateral prehospital thoracostomy in tCA. We evaluated the incidence of TP, the return of circulation in tCA, the incidence of infections, the incidence of sharps injuries and patient survival. RESULTS: A total of 267 thoracostomies were performed in 144 tCA patients. Thoracic decompression was performed to rule out TP. TP was identified in 14 patients; the incidence of TP in tCA was 9.7%. Two of the tCA patients survived and were discharged from the hospital; neither had clinical signs of TP. No infections or sharps injuries were observed. CONCLUSION: The outcomes of patients with tCA who underwent prehospital thoracostomy were poor in our group. The early identification of TP and strict algorithm adherence in tCA may improve outcomes. In the future, to reduce the risk of unnecessary thoracic interventions in tCA, ultrasound examination may be useful to identify TP before thoracic decompression.

Item does not contain fulltext, INTRODUCTION: Emergency department thoracotomy is an established procedure for cardiac arrest in patients suffering from penetrating thoracic trauma and yields relatively high survival rates (up to 21%) in patients with cardiac tamponade. To minimize the delay between arrest and thoracotomy, some have advocated thoracotomy on the accident scene. The aim of this study was to determine the proportion of patients with return of spontaneous circulation and subsequent survival after out of hospital thoracotomy in the Netherlands. METHODS: A retrospective analysis of data collected on all out of hospital thoracotomies performed in the Netherlands after penetrating trauma between April 1st, 2011 and September 30th, 2016 was performed. Data on patient characteristics, trauma mechanism and outcome were collected and analyzed. Primary outcome measure was return of spontaneous circulation after the intervention. Survival to hospital discharge was the secondary outcome variable. RESULTS: Thirty-three prehospital emergency thoracotomies were performed. Ten patients (30%) had gunshot wounds and 23 patients (70%) had stab wounds. Nine patients (27%) had return of spontaneous circulation and were presented to the hospital. Of these, one patient survived until discharge without neurological damage. Five died in the emergency department or operating room and three died in ICU. CONCLUSION: Return of spontaneous circulation after out of hospital thoracotomy for cardiac arrest due to penetrating thoracic injury is achievable, but a substantial number of patients die during the in hospital resuscitation phase. However, neurologic intact survival can be achieved.

Radboud University, 20 december 2017, Promotores : Edwards, M.J.R., Verhofstad, M.H.J. Co-promotores : Tan, E.C.T.H., Hoogerwerf, N., Contains fulltext : 178926.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, INTRODUCTION: Bleeding remains a leading cause of death in trauma patients. The iTClamp is a temporary wound closure device designed to control external bleeding within seconds of injury. We describe our experience using this device on 10 patients in the prehospital environment. METHODS: We have implemented the iTClamp for prehospital use through our physician-staffed helicopter emergency medical service (HEMS). Indications were massive bleeding that could not be controlled with an ordinary compressive bandage or a haemostatic bandage. RESULTS: Ten patients were treated with the iTClamp. Seven patients had a severe head injury due to various traumas, one patient had a neck injury from a disk cutter, one patient had an open chest wound and one patient had an open femur fracture. After applying the iTClamp, bleeding was controlled in 90% of these patients (n=9), with complete cessation reported in 60% (n=6), partial cessation with adequate control reported in 30% (n=3); in one patient, the bleeding could not be controlled with the iTClamp alone. It took an average of 10s to apply the iTClamp, and the average usage satisfaction score was 7.7. CONCLUSION: We conclude that the iTClamp is a safe, fast and useful tool for stopping or controlling external blood loss in our series of prehospital patients. Further studies of the iTClamp are needed to determine which patients might benefit from this device.

Contains fulltext : 153318.pdf (publisher's version ) (Open Access), Insight into the maintenance of naive T cells is essential to understand defective immune responses in the context of aging and other immune compromised states. In humans, naive CD4+ T cells, in contrast to CD8+ T cells, are remarkably well retained with aging. Here, we show that low-affinity TCR engagement is the main driving force behind the emergence and accumulation of naive-like CD4+ T cells with enhanced sensitivity to IL-2 in aged humans. In vitro, we show that these CD45RA(+) CD25(dim) CD4(+) T cells can develop from conventional naive CD25(-) CD4+ T cells upon CD3 cross-linking alone, in the absence of costimulation, rather than via stimulation by the homeostatic cytokines IL-2, IL-7, or IL-15. In vivo, TCR engagement likely occurs in secondary lymphoid organs as these cells were detected in lymph nodes and spleen where they showed signs of recent activation. CD45RA(+) CD25(dim) CD4+ T cells expressed a broad TCRVbeta repertoire and could readily differentiate into functional T helper cells. Strikingly, no expansion of CD45RA(+) CD25(dim) CD8+ T cells was detected with aging, thereby implying that maintenance of naive CD4+ T cells is uniquely regulated. Our data provide novel insight into the homeostasis of naive T cells and may guide the development of therapies to preserve or restore immunity in the elderly.

Contains fulltext : 152235.pdf (publisher's version ) (Closed access), INTRODUCTION: Endotracheal intubation is a frequently performed procedure for securing the airway in critically injured or ill patients. Performing prehospital intubation may be challenging and intubation skills vary. We reviewed the first-attempt tracheal intubation success rate in a Dutch prehospital setting. PATIENTS AND METHODS: We studied our database for all intubations performed by helicopter emergency medical services (HEMS) physicians, HEMS nurse and ambulance paramedics under HEMS supervision between January 2007 and July 2012. The primary outcome was success rate, number of intubation attempts and alternative airway procedures. RESULTS: In all, 1399 patients were in need of a secured airway. In 571 (40.8%) of these cases, ambulance paramedics made a first intubation attempt under HEMS supervision. If necessary, rapid sequence induction medication was administered. In comparable patient groups, the first intubation success rate was significantly lower in ambulance paramedics compared with helicopter physicians (46.4 vs. 84.5%, P<0.0001). The overall physician intubation success rate was 98.4% after one or more intubation attempts. In 19 cases, a surgical airway was created and in three cases an alternative ventilation method was used. CONCLUSION: Prehospital intubations had a significantly higher success rate when performed by helicopter physicians. We promote a low threshold for HEMS deployment in cases of a potentially compromised airway.

Contains fulltext : 136056pub.pdf (publisher's version ) (Closed access)

Contains fulltext : 134041.pdf (publisher's version ) (Closed access), OBJECTIVE: In the Netherlands, helicopter emergency medical services (HEMS) function as an adjunct to paramedic ambulance service delivering hospital-level medical care to a prehospital location. The main goal of Dutch HEMS is to provide on-scene medical expertise and not primarily to serve as transport. The transportation of patients to specialized hospitals is sometimes mandatory, especially in cases of critically ill or wounded children. In the literature, no support can be found to support the safety of transportation by helicopter. We retrospectively evaluated the safety of this type of transportation and if any problems were encountered transporting children by helicopter. METHODS: We reviewed our local HEMS database for all children (, 16 years) transported by helicopter to a level 1 trauma center between January 2007 and December 2012. RESULTS: A total number of 430 patients were transported by helicopter to a hospital (0-87 years, mean 5 31.6 years). Of these patients, 83 (19%) were younger than 16 years (0-15.7 years, mean 5 6.6 years). Causes for HEMS transport in children varied, but the main groups were road traffic accidents (40%), cardiopulmonary arrests (15%), falls from height (12%), and horse riding accidents (7%). In the children group, 1 accidental extubation of the orotracheal tube was noted while lifting the patient (10 years old) into the helicopter. This was immediately noticed, and the patient was reintubated without complications. No further adverse events were encountered during transportation time. The accidental extubation is not a specific complication of helicopter transportation but is inextricably linked with moving severely injured and intubated patients/children. CONCLUSION: We conclude that transporting children by helicopter is a safe method of transportation for critically ill children to adequately equipped medical centers.

Contains fulltext : 135910.pdf (publisher's version ) (Closed access), OBJECTIVE: Dutch helicopter emergency medical services are available 24/7. Working without daylight brings additional challenges, both in patient care and in-flight operation. We retrospectively evaluated the safety of this nighttime helicopter transportation of patients. METHODS: Our helicopter emergency medical service database was reviewed for all patients transported by helicopter during nighttime. Both interhospital transports and patients transported from the accident location to a hospital were included. The time traveled by helicopter was compared with the time that road transportation of these patients would have taken. RESULTS: In total, 513 patients were transported by helicopter. Of these patients, 72 were transported during nighttime (14%); the median age was 25.3 years (range, 1.1-73.9 years). The median flight time to the hospital was 16 minutes (range, 5-42 minutes). To travel by road, this would have taken a median of approximately 44 minutes (range, 23-100 minutes). When comparing these travel times, a significantly faster transport time by helicopter during nighttime was observed (P < .001). Three non-flight-specific incidents were noted. CONCLUSION: We conclude that helicopter transportation of patients without daylight is safe and fast in a Dutch setting.

Contains fulltext : 119176.pdf (publisher's version ) (Closed access), In endotracheal intubation, a secured airway includes an insufflated cuff distal to the vocal cords. High cuff pressures may lead to major complications occurring after a short period of time. Cuff pressures are not routinely checked after intubation in the prehospital setting, dealing with a vulnerable group of patients. We reviewed cuff pressures after intubation by Helicopter Emergency Medical Services and paramedics noted in a dispatch database. Initial cuff pressures are almost all too high, needing adjustment to be in the safe zone. Dutch paramedics lack manometers and, therefore, only few paramedic intubations are followed by cuff pressure measurements. We recommend cuff pressure measurements after all (prehospital) intubations and, therefore, all ambulances need to be equipped with cuff manometers.

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Radboud Universiteit Nijmegen, 25 maart 2013, Promotores : Joosten, I., Hilbrands, L.B. Co-promotor : Koenen, H.J.P.M., Contains fulltext : 106931.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, BACKGROUND: Both keratinocytes and T-cells are crucial players in cutaneous immune responses. We hypothesized that direct interactions between keratinocytes and T-cell subsets could shape the nature or strength of the local immune response. OBJECTIVE: We investigated direct interactions between keratinocytes and T-cell subsets, focused on keratinocyte chemokine production and T-cell phenotype and cytokine production. METHODS: A newly developed in vitro serum free co-culture model using primary keratinocytes and T-cells subsets from healthy human donors was used. Keratinocyte chemokine production was analyzed with luminex, T-cell phenotype and cytokine production were analyzed with flow cytometry. RESULTS: Our data show that upon co-culture with CD4(pos) or CD8(pos) T-cells primary human keratinocytes increased production of functionally active chemokines CCL2, CCL20 and CXCL10 and that regulatory T-cells did not regulate keratinocyte chemokine production. Next to that, we found that keratinocytes skewed CD4(pos) and CD8(pos) T-cell populations toward an IL-17(pos) CCR6(pos) RORgammat(pos) phenotype in a cell-cell contact independent manner, and that Treg were able to decrease the absolute number of IL-17 producing T-cells in keratinocyte/T-cell co-cultures. Correspondingly, freshly isolated skin-derived T-cell populations contained relatively high percentages of IL-17(pos) cells. CONCLUSION: We provide evidence that keratinocyte/T-cell communication may regulate leukocyte influx in the skin, and that keratinocytes enrich T-cell populations for Th17/Tc17 cells. Accumulation of Th17/Tc17 cells, but not chemokine production, appears under the control of regulatory T-cells. Dysregulation of these processes may well contribute to the pathophysiology of inflammatory skin diseases.

Contains fulltext : 87413.pdf (publisher's version ) (Closed access), Acute compartment syndrome of the anterior and lateral compartment of the lower right leg was diagnosed in a 47-year-old woman after she had taken part in the 'International Four Days Marches Nijmegen', the Netherlands. Initially a fasciotomy was carried out, but later resection of the entire peroneus musculature was also required as it had become necrotic. Acute compartment syndrome of the lower leg is a potentially limb threatening condition, requiring emergency surgical treatment. Known causes are high-energy impact, and reperfusion after vascular procedures, but it can also be caused by prolonged stress such as during sustained walking. Although it is rare, the possibility of acute compartment syndrome of the lower leg should be borne in mind when making a diagnosis in patients presenting with pain after prolonged repetitive stress.

Contains fulltext : 70294.pdf ( ) (Open Access), BACKGROUND: Regulatory T cell (Treg) based immunotherapy is a potential treatment for several immune disorders. By now, this approach proved successful in preclinical animal transplantation and auto-immunity models. In these models the success of Treg based immunotherapy crucially depends on the antigen-specificity of the infused Treg population. For the human setting, information is lacking on how to generate Treg with direct antigen-specificity ex vivo to be used for immunotherapy. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that in as little as two stimulation cycles with HLA mismatched allogeneic stimulator cells and T cell growth factors a very high degree of alloantigen-specificity was reached in magnetic bead isolated human CD4(pos)CD25(high) Treg. Efficient increases in cell numbers were obtained. Primary allogeneic stimulation appeared a prerequisite in the generation of alloantigen-specific Treg, while secondary allogeneic or polyclonal stimulation with anti-CD3 plus anti-CD28 monoclonal antibodies enriched alloantigen-specificity and cell yield to a similar extent. CONCLUSIONS/SIGNIFICANCE: The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants.

Contains fulltext : 69507.pdf ( ) (Open Access), BACKGROUND: Treg based immunotherapy is of great interest to facilitate tolerance in autoimmunity and transplantation. For clinical trials, it is essential to have a clinical grade Treg isolation protocol in accordance with Good Manufacturing Practice (GMP) guidelines. To obtain sufficient Treg for immunotherapy, subsequent ex vivo expansion might be needed. METHODOLOGY/PRINCIPAL FINDINGS: Treg were isolated from leukapheresis products by CliniMACS based GMP isolation strategies, using anti-CD25, anti-CD8 and anti-CD19 coated microbeads. CliniMACS isolation procedures led to 40-60% pure CD4(pos)CD25(high)FoxP3(pos) Treg populations that were anergic and had moderate suppressive activity. Such CliniMACS isolated Treg populations could be expanded with maintenance of suppressive function. Alloantigen stimulated expansion caused an enrichment of alloantigen-specific Treg. Depletion of unwanted CD19(pos) cells during CliniMACS Treg isolation proved necessary to prevent B-cell outgrowth during expansion. CD4(pos)CD127(pos) conventional T cells were the major contaminating cell type in CliniMACS isolated Treg populations. Depletion of CD127(pos) cells improved the purity of CD4(pos)CD25(high)FoxP3(pos) Treg in CliniMACS isolated cell populations to approximately 90%. Expanded CD127(neg) CliniMACS isolated Treg populations showed very potent suppressive capacity and high FoxP3 expression. Furthermore, our data show that cryopreservation of CliniMACS isolated Treg is feasible, but that activation after thawing is necessary to restore suppressive potential. CONCLUSIONS/SIGNIFICANCE: The feasibility of Treg based therapy is widely accepted, provided that tailor-made clinical grade procedures for isolation and ex vivo cell handling are available. We here provide further support for this approach by showing that a high Treg purity can be reached, and that isolated cells can be cryopreserved and expanded successfully.

Contains fulltext : 51504.pdf ( ) (Open Access), BACKGROUND: Glutathione is a tripeptide composed of glutamate, cysteine and glycine, accomplishing a broad range of vital functions. Synthesis of glutathione and cysteine is performed mainly in the liver, whereas most other tissues are supplied with these thiols via sinusoidal efflux into the blood. Since canalicular efflux also occurs, thiols may be present in human bile. However, thiol composition of human gallbladder bile is largely unknown, which makes it difficult to speculate on the exact function of thiols in bile. In this study we report on the levels of non-protein bound thiols in gallbladder bile of patients with various gastrointestinal disorders. METHODS: Gallbladder bile was obtained after cholecystectomy from 30 patients who were operated for pancreatic cancer, duodenal cancer, chronic pancreatitis or cholecystolithiasis. Bile was analysed for non-protein bound total- and oxidised glutathione and related thiols, by high performance liquid chromatography. RESULTS: A more than 100-fold inter-individual variation in non-protein bound thiol levels was found in human gallbladder bile of patients with a variety of gastrointestinal disorders. Bile did contain high amounts of cysteine, whereas much lower levels of glutathione, cysteinylglycine and homocysteine were detected. Most thiols were present in their oxidised forms. CONCLUSION: Thiols are present in considerable amounts in human gallbladder bile of patients with various gastrointestinal disorders, levels of cysteine being much higher than those of glutathione and other thiols. Most thiols were in their oxidised forms, which may indicate the presence of considerable chemical- or oxidative stress in the patients studied here.

Contains fulltext : 48593.pdf (publisher's version ) (Open Access), Understanding immune tolerance mechanisms is a major goal of immunology research, but mechanistic studies have generally required the use of mouse models carrying untargeted or targeted antigen receptor transgenes, which distort lymphocyte development and therefore preclude analysis of a truly normal immune system. Here we demonstrate an advance in in vivo analysis of immune tolerance that overcomes these shortcomings. We show that custom superantigens generated by single chain antibody technology permit the study of tolerance in a normal, polyclonal immune system. In the present study we generated a membrane-tethered anti-Igkappa-reactive single chain antibody chimeric gene and expressed it as a transgene in mice. B cell tolerance was directly characterized in the transgenic mice and in radiation bone marrow chimeras in which ligand-bearing mice served as recipients of nontransgenic cells. We find that the ubiquitously expressed, Igkappa-reactive ligand induces efficient B cell tolerance primarily or exclusively by receptor editing. We also demonstrate the unique advantages of our model in the genetic and cellular analysis of immune tolerance.