Improving Pediatric Drug Safety in Prehospital Emergency Care-10 Years on.

OBJECTIVES: The Pediatric Emergency Ruler (PaedER) is a height-based drug dose recommendation tool that was reported to reduce life-threatening medication errors by 90%. The PaedER was introduced into the Cologne Emergency Medical Service (EMS) in 2008 along with educational measures, publications, and lectures for pediatric drug safety. We reviewed the impact of these continuously ongoing measures on medication errors after 10 years. METHODS: The PaedER was introduced and distributed to all 14 emergency ambulances and 2 helicopters staffed with emergency physicians in the city of Cologne in November 2008. Electronic records and medical protocols of the Cologne EMS over two 20-month periods from March 2007 to October 2008 and March 2018 to October 2019 data sets were retrieved. The administered doses of either intravenous, intraosseous, intranasal, or buccal fentanyl, midazolam, ketamine, or epinephrine were recorded. Primary outcome measure was the rate of severe drug dosing errors with a deviation from the recommended dose of greater than 300%. RESULTS: A total of 59 and 443 drug administrations were analyzed for 2007/08 and 2018/19, respectively. The overall rate of drug dosing errors decreased from 22.0% to 9.9% (P = 0.014; relative risk reduction, 55%). Four of 5 severe dosing errors for epinephrine were avoided (P < 0.021; relative risk reduction, 78%). Documentation of patient's weight increased from 3.2% in 2007/08 to 30.5% in 2018/19 (P < 0.001). CONCLUSIONS: The distribution of the PaedER combined by educational measures significantly reduced the rates of life-threatening medication errors in a large EMS. Those results should motivate further initiatives on pediatric drug safety in prehospital emergency care.

Converse regulation of CCR7-driven human dendritic cell migration by prostaglandin E2 and liver X receptor activation.

Migration and homing of DCs to lymphoid organs is pivotal for inducing adaptive immunity and tolerance. DC homing depends on the chemokine receptor CCR7. However, expression of CCR7 alone is not sufficient for effective DC migration. A second signal, mediated by prostaglandin E(2) (PGE(2)), is critical for the development of a migratory DC phenotype. PGE(2) is important for inducing efficient immune responses, but, if deregulated, contributes to chronic inflammation, autoimmune diseases through Th17-cell development and tumorigenesis. In contrast, activation of liver X receptor (LXR)α has recently been shown to interfere with CCR7 expression and migration of DCs resulting in a reduced immune response. Here, we demonstrate that PGE(2) downregulates LXRα expression in human monocyte derived as well as ex vivo DCs. Moreover, PGE(2) stimulation dampens LXR activation, auto-regulation and LXR-mediated gene transcription. Consequently, we show that PGE(2) enhances CCR7 expression and migration of LXR-activated DCs. Furthermore, we provide evidence that PGE(2) signaling and LXR activation specifically elicit converse effects on CCR7 expression and DC migration. In contrast, production of MMP9, CCL4, COX-2, and IL-23 is solely regulated by PGE(2) , but not by LXR activation, offering new perspectives for therapeutic interventions.

Distinct modulation of chemokine expression patterns in human monocyte-derived dendritic cells by prostaglandin E(2).

Dendritic cells (DCs) are key in regulating immune responses. DCs reside in tissues facing the environment and sample their surrounding for pathogens. Upon pathogen encounter, DCs mature and migrate into secondary lymphoid organs. Distinct maturation signals dictate the ability of DCs to produce distinct patterns of chemokines that orchestrate immunity. Prostaglandin E(2) (PGE(2)) is produced during inflammation and modulates DC functions. We demonstrate that PGE(2) modulates distinct chemokine expression patterns of human monocyte-derived (Mo) DCs upon maturation with various stimuli. PGE(2) dampened early production of the inflammatory chemokines CCL2, CCL4, CCL5 and attenuated the expression of the T cell attractant CXCL10. In contrast, PGE(2) enhanced CXCL8 production early during maturation, whereas CXCL16 levels were continuously elevated, contributing to innate immune cell recruitment. Moreover, PGE(2) induces transcription of the homeostatic chemokines CCL17 and CCL22. Finally, mature MoDCs produced the homing chemokine CCL19 and its expression was down-regulated by PGE(2).

Cross-talk between TCR and CCR7 signaling sets a temporal threshold for enhanced T lymphocyte migration.

Lymphocyte homing to, and motility within, lymph nodes is regulated by the chemokine receptor CCR7 and its two ligands CCL19 and CCL21. There, lymphocytes are exposed to a number of extracellular stimuli that influence cellular functions and determine the cell fate. In this study, we assessed the effect of TCR engagement on CCR7-mediated cell migration. We found that long-term TCR triggering of freshly isolated human T cells through CD3/CD28 attenuated CCR7-driven chemotaxis, whereas short-term activation significantly enhanced CCR7-mediated, but not CXCR4-mediated, migration efficiency. Short-term activation most prominently enhanced the migratory response of naive T cells of both CD4 and CD8 subsets. We identified distinct roles for Src family kinases in modulating CCR7-mediated T cell migration. We provide evidence that Fyn, together with Ca(2+)-independent protein kinase C isoforms, kept the migratory response of naive T cells toward CCL21 at a low level. In nonactivated T cells, CCR7 triggering induced a Fyn-dependent phosphorylation of the inhibitory Tyr505 of Lck. Inhibiting Fyn in these nonactivated T cells prevented the negative regulation of Lck and facilitated high CCR7-driven T cell chemotaxis. Moreover, we found that the enhanced migration of short-term activated T cells was accompanied by a synergistic, Src-dependent activation of the adaptor molecule linker for activation of T cells. Collectively, we characterize a cross-talk between the TCR and CCR7 and provide mechanistic evidence that the activation status of T cells controls lymphocyte motility and sets a threshold for their migratory response.

Prostaglandin E(2) enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells.

Dendritic cell (DC)-based immunotherapy of malignant diseases relies on 2 critical parameters: antigen transport from the periphery to draining lymph nodes and efficient priming of primary and stimulation of secondary immune responses. Prostaglandin E(2) (PGE(2)) signaling has been shown to be pivotal for DC migration toward lymph node-derived chemokines in vitro and in vivo. Here, we demonstrate that PGE(2) induced the expression of the costimulatory molecules OX40L, CD70, and 4-1BBL on human DCs. Short triggering by PGE(2) early during DC maturation was sufficient to induce the costimulatory molecules. The expression of the costimulatory molecules was independent of the maturation stimulus but strictly dependent on PGE(2) on both monocyte-derived (Mo) DCs and peripheral blood myeloid (PB) DCs. PGE(2)-matured MoDCs showed enhanced costimulatory capacities resulting in augmented antigen-specific CD4(+) and CD8(+) T-cell proliferation in primary and recall T-cell responses. Blocking OX40/OX40L signaling impaired the enhanced T-cell proliferation induced by PGE(2)-matured MoDCs. Moreover, MoDCs matured in the presence of PGE(2) induced the expression of OX40, OX40L, and CD70 on T cells facilitating T-cell/T-cell interaction that warrant long-lasting costimulation. This newly identified parameter will help to further optimize DC-based immunotherapy.

Prostaglandin E2 is a key factor for monocyte-derived dendritic cell maturation: enhanced T cell stimulatory capacity despite IDO.

The exclusive ability of dendritic cells (DCs) to stimulate primary and secondary immune responses favors the use of antigen-loaded human monocyte-derived DCs (MoDCs) in vaccinations against tumors. Previous studies demonstrated that PGE(2) is fundamental during MoDC maturation to facilitate migration toward lymph node-derived chemokines. A recent study challenged the use of PGE(2), as PGE(2) induced IDO in mature MoDCs. In MoDCs compatible for clinical use, we now demonstrate that PGE(2) is responsible for IDO induction if matured by soluble CD40 ligand, LPS, or cytokines. In contrast, IDO expression in MoDCs matured by TLR3 triggering occurs independently of PGE(2). It is surprising that despite active IDO protein, MoDCs matured with PGE(2) display a greater potential to stimulate naïve CD4(+) and CD8(+) T cell proliferation, which is not increased further by IDO inhibition. Moreover, we found elevated levels of tryptophanyl-tRNA-synthetase (TTS) in T cells cultured with PGE(2)-matured MoDCs. Our data demonstrate that PGE(2) induces IDO in MoDCs but that T cell-stimulating capacities of PGE(2)-matured MoDCs overcome IDO activity, probably through TTS induction. As PGE(2) is critical for DC migration and enhances the capability of MoDCs to induce T cell proliferation, we highly recommend supplementing DC maturation stimuli with PGE(2) for use in clinical trials.

Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors.

The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. In this study, we demonstrate that the migration of human monocyte-derived (Mo)DCs as well as of ex vivo peripheral blood DCs toward CCL21, CXCL12, and C5a is stringently dependent on the presence of the proinflammatory mediator PGE2, although DCs expressed CXCR4 and C5aR on their surface and DC maturation was accompanied by CCR7 up-regulation independently of PGE2. The necessity of exogenous PGE2 for DC migration is not due to the suppression of PGE2 synthesis by IL-4, which is used for MoDC differentiation, because maturation-induced endogenous production of PGE2 cannot promote DC migration. Surprisingly, PGE2 was absolutely required at early time points of maturation to enable MoDC chemotaxis, whereas PGE2 addition during terminal maturation events was ineffective. In contrast to mouse DCs, which exclusively rely on EP4 receptor triggering for migration, human MoDCs require a signal mediated by EP2 or EP4 either alone or in combination. Our results provide clear evidence that PGE2 is a general and mandatory factor for the development of a migratory phenotype of human MoDCs as well as for peripheral blood myeloid DCs.