The effect of emergency department pharmacists on drug overuse and drug underuse in patients with an ADE-related hospitalisation: a controlled intervention study.

BACKGROUND: Drug overuse or drug underuse are the most common causes of adverse drug events and can lead to hospital admissions. Using clinical pharmacists in the emergency department may improve patient safety as they are specialised in recognising of adverse drug events and tackling drug overuse and drug underuse. This study tested the effect of an emergency department pharmacist on the number of medication changes for drug overuse and drug underuse taking place in patients with an adverse drug event-related hospitalisation following an emergency department visit. METHODS: A multicenter prospective non-randomized controlled intervention study was conducted in a university hospital and a general teaching hospital. Trained emergency department pharmacists included patients in the intervention group with a hospital admission related to an adverse drug event. The interdisciplinary intervention consisted of a pharmacist-led medication review, patient counselling regarding medication, and information transmission to general practitioners and community pharmacies after discharge. The control patients were also admitted after an emergency department visit and received the usual care. The primary outcome was the number of medication changes for drug overuse and drug underuse that took place during hospital admission and persisted 6 months thereafter. Poisson regression analysis was used to estimate the difference in these medication changes between the intervention group and the control group. RESULTS: A total of 216 patients were included (intervention group 104, control group 112). In the intervention group, 156 medication changes for drug overuse and drug underuse persisted 6 months after admission compared to 59 in the control group (adjusted rate ratio 1.22 [95%CI 1.01-1.49] p = 0.039). CONCLUSION: Emergency department pharmacists do contribute to reduction of drug overuse and drug underuse of medication in patients with a hospitalisation related to adverse drug events after an emergency department visit.

Optimal anatomical location for needle chest decompression for tension pneumothorax: A multicenter prospective cohort study.

OBJECTIVE: Tension Pneumothorax (TP) can occur as a potentially life threatening complication of chest trauma. Both the 2nd intercostal space in the midclavicular line (ICS2-MCL) and the 4th/5th intercostal space in the anterior axillary line (ICS 4/5-AAL) have been proposed as preferred locations for needle decompression (ND) of a TP. In the present study we aim to determine chest wall thickness (CWT) at ICS2-MCL and ICS4/5-AAL in normal weight-, overweight- and obese patients, and to calculate theoretical success rates of ND for these locations based on standard catheter length. METHODS: We performed a prospective multicenter study of a convenience sample of adult patients presenting in Emergency Departments (ED) of 2 university hospitals and 6 teaching hospitals participating in the XXX consortium. CWT was measured bilaterally in ISC2-MCL and ISC4/5-AAL with point of care ultrasound (POCUS) and hypothetical success rates of ND were calculated for both locations based on standard equipment used for ND. RESULTS: A total of 392 patients was included during a 2 week period. Mean age was 51 years (range 18-89), 52% was male and mean BMI was 25.5 (range 16.3-45.0). Median CWT was 26 [IQR 21-32] (range 9-52) mm in ISC2-MCL, and 26 [21-33] (range 10-78) mm in ICS4/5-AAL (p<0.001). CWT in ISC2-MCL was significantly thinner than ICS4/5-AAL in overweight- (BMI 25-30, p<0.001), and obese (BMI>30, p=0.016 subjects, but not in subjects with a normal BMI. Hypothetical failure rates for 45mm Venflon and 50mm Angiocatheter were 2.5% and 0.8% for ICS2-MCL and 6.2% and 2.5% for ISC4/5-AAL (p=0.016 and p=0.052 respectively). CONCLUSION: In overweight- and obese subjects, the chest wall is thicker in ICS 4/5-AAL than in ICS2-MCL and theoretical chances of successful needle decompression of a tension pneumothorax are significantly higher in ICS2-MCL compared to ICS 4/5-AAL.

Allergic acute coronary syndrome in exercise-induced anaphylaxis.

In this case report we present a 49-year-old male who was seen in the emergency department after collapsing due to anaphylactic shock, with ECG findings suggesting myocardial ischaemia. We linked both diagnoses to Kounis syndrome, which describes an acute coronary syndrome due to an allergic event. His circulatory collapse was explained by exercise-induced anaphylaxis.

Role of IL-2 and IL-4 in exacerbations of murine antigen-induced arthritis.

In this study the roles of different T-cell subsets, and produced cytokines, were investigated in an animal model for acute exacerbations. Flare-up reactions are inducible in the chronic phase of a smouldering antigen-induced inflammation by injection of a small amount of an antigen into a hyper-reactive knee joint. In vivo treatment with anti-CD4 monoclonal antibodies (mAb) almost totally blocked the flare reaction, whereas anti-CD8 treatment did not exert any effect. The role of T-helper 1 (Th1) cells in delayed-type hypersensitivity-resembling diseases is generally entitled proinflammatory, whereas Th2 cells act in an anti-inflammatory manner. To investigate the role of these T-cell subsets in flare-up reactions, anti-interleukin-2 (IL-2) and anti-IL-4 mAb treatments were performed. Anti-IL-2 treatment partly blocked the flare reaction, and anti-IL-4 treatment, although the result was unexpected, blocked the flare more efficiently. Furthermore, when human recombinant IL-2 (hrIL-2) and murine recombinant IL-4 (mrIL-4) were co-injected with the antigen to test their ability respectively to potentiate or down-regulate the flare reaction, both cytokines demonstrated additional pro-inflammatory effects, although hrIL-2 was more potent than mrIL-4. The mere effect of hrIL-2 and mrIL-4 was studied by direct injection into a hyperreactive joint. No flare-up reaction or cell-influx could be induced, suggesting that other mediators are needed to exert pro-inflammatory effects of IL-2 or IL-4. We conclude that not only Th1 cells, but also Th2 lymphocytes (at least regarding IL-4 production) may play a pro-inflammatory role in flare-up reactions of chronic arthritis. Considering therapeutic application of Th2 cell-derived cytokines, one should be aware of the possible pro-inflammatory potential of IL-4.

Anergy of antigen-specific T lymphocytes is a potent mechanism of intravenously induced tolerance.

Intravenous (i.v.) injection of an antigen before immunization has been shown to be a potent way to induce suppression at the T-cell level. In this study we demonstrate an almost complete suppression of arthritis (using antigen-induced arthritis as a model) by i.v. injection of 100 micrograms hen egg lysozyme (HEL) 7 days before immunization. Underlying mechanisms, including suppression by CD8+ T lymphocytes, suppression by T-helper 2 (Th2) or anergy of antigen-specific T lymphocytes, were studied. In vivo treatment with either anti-CD8 or anti-interleukin-4 (IL-4) could not abrogate i.v.-induced tolerance. Lymphocyte stimulation assays showed reduced antigen-specific proliferative responses and IL-2 production in tolerized mice. The possible role of soluble suppressive cytokines was examined in vitro by adding anti-IL-4, anti-IL-10 or anti-transforming growth factor-beta (TGF-beta). Neutralization of these factors could not diminish suppression. Finally, anergy of antigen-specific T lymphocytes was tested as a possible mechanism for i.v.-induced tolerance. Results demonstrated that reduced proliferative T-cell responses were reversible: incubation of tolerized lymph node cells for 5 days in added recombinant (r)IL-2 fully restored proliferative capacity back to normal. We therefore conclude that the main mechanism of i.v.-induced tolerance in our model is anergy of antigen-specific T lymphocytes.

Suppression of hen egg lysozyme-induced arthritis by intravenous antigen administration: no role in this for antigen-driven bystander suppression.

The induction of tolerance, particularly by intervention before established immunity, is widely accepted. We studied the effects of intravenous (i.v.) administration of hen egg lysozyme (HEL), before as well as after immunization, on a HEL-induced arthritis. Arthritis and also cartilage destruction were almost completely suppressed when 100 micrograms HEL was injected before immunization. Antigen-specific proliferative T cell responses and IL-2 production in vitro were inhibited. Antigen-specific immunoglobulin and IgG1 titres were equal in control and tolerized mice, in contrast to lowered IgG2a titres in tolerized animals. Detailed histological studies showed that the immune complex-dependent polymorphonuclear cell phase (< 24 h after arthritis induction) was equal for control and HEL-injected mice. Only in the T cell-dependent phase of the arthritis (> 24 h), did suppression become pronounced in tolerized mice. I.v. administration of 100 micrograms HEL after immunization could only marginally reduce infiltrate and exudate, and no reduction of cartilage destruction was seen. An elegant way to interfere in an established immunity can be offered by creation of bystander suppression. We show that i.v. administration of HEL followed by triggering with HEL, at the moment either of immunization or of arthritis induction, does not reduce a methylated bovine serum albumin (BSA)-arthritis. We conclude that arthritis can be suppressed almost totally when HEL is injected intravenously before immunization. Treatment after immunization is less effective. The i.v. induced suppression is T cell-mediated and and antigen-specific: no bystander suppression circuit can be generated.

Early cartilage degradation in cationic immune complex arthritis in mice: relative role of interleukin 1, the polymorphonuclear cell (PMN) and PMN elastase.

OBJECTIVE: To determine the relative role of interleukin 1 (IL-1), polymorphonuclear cell (PMN) and PMN elastase in early cartilage degradation in cationic immune complex mediated arthritis (ICA) in mice. ICA is characterized by early production of IL-1, pronounced influx of PMN and marked cartilage degradation within one day. METHODS: IL-1 was neutralized by polyclonal antibodies against IL-1 alpha and IL-1 beta, given shortly before arthritis induction. The role of PMN was studied in mice made neutropenic by whole body irradiation (750 rad). The effect of elastase was examined in beige mice with PMN deficient in elastase. RESULTS: Neutralizing IL-1 during arthritis induction reduced PMN infiltration significantly and diminished cartilage degradation by 50%. In neutropenic mice, joint inflammation was virtually absent and cartilage proteoglycan loss was abolished. Finally arthritis was induced in beige mice. Although elastase appeared to be the dominant cartilage degrading factor in vitro, we found no difference in cartilage degradation in arthritic joints of beige mice and their normal littermates. CONCLUSIONS: Our data suggest that IL-1 is a crucial factor regulating PMN influx in ICA. The PMN are involved in cartilage degradation but a direct destructive role (e.g., by elastase) seems unlikely.

Induction of tolerance by T-cell vaccination is possible beyond the area of autoimmunity: down-regulation of immunity directed to foreign protein antigens.

T-cell vaccination using antigen-specific lines or clones has been shown to be effective in down-regulating immunity in various experimental autoimmune models. Anti-idiotypic networks developing during differentiation of the immune system are considered to be a safeguard against autoimmunity and these pre-existing networks are supposed to be a prerequisite for successful vaccination. However, the interesting question of feasibility of T-cell vaccination beyond the area of autoimmunity remains to be answered. The present study is the first one providing evidence of successful T-cell vaccination in mice immunized against foreign protein antigens (in this system supposedly no pre-existing network exists). Intraperitoneal (i.p.) administration of hen egg lysozyme (HEL)- and chicken egg albumin (OVA)-specific lymph node cells (LNC) were shown to effectively down-regulate immunity (as measured in a delayed type of hypersensitivity) to HEL and OVA, respectively. In contrast, vaccination was unsuccessful with methylated bovine serum albumin (mBSA)-specific LNC in mBSA immunity. Suppression induced by HEL- and OVA-specific LNC was antigen specific. Unlike the greater part of other studies, in which antigen-specific lines or clones were used, we used draining LNC of immunized mice, which after activation were fixed with glutardialdehyde and injected i.p. 10 days before immunization. Finally, effects of T-cell vaccination were studied in a chronic HEL-induced arthritis. Joint swelling, cell influx and cartilage matrix depletion were significantly less in mice treated with antigen-specific cells. We conclude that successful vaccination is feasible in mice rendered immune to foreign protein antigens using a pool of LNC as source of vaccine, suggesting no necessity of a strong pre-existing network.

In vivo role of phagocytic synovial lining cells in onset of experimental arthritis.

The in vivo role of phagocytic synovial lining cells (SLC) was studied in acute experimental arthritis in the mouse. SLCs were selectively depleted by injecting liposomes encapsulating the drug dichloromethylene diphosphonate (CL2MDP, Clodronate). Optimal depletion of phagocytic lining cells occurred 7 days after CL2MDP liposome injection. Eliciting an immune complex-mediated arthritis in SLC-depleted knee joints largely prevented inflammation if compared to control arthritic knee joints. Joint swelling and influx of inflammatory cells into the joint cavity was markedly diminished. Cartilage damage, in this model related to influx of inflammatory cells, was significantly decreased. Reduced influx of inflammatory cells (mainly polymorphonuclear neutrophils) was correlated to a decreased production of chemotactic factors as measured in washouts of arthritic joints in a two-compartment Transwell system. Interleukin-1-driven chemotactic factors seem to be involved. Interleukin-1 levels were significantly lowered in SLC-depleted arthritic knee joints as compared to controls. Injection of recombinant murine interleukin-1 in SLC-depleted knee joints caused less influx of inflammatory cells as compared to injection into control knee joints. A specific damage of CL2MDP liposome treatment to synovial blood vessels was excluded as intraarticular injection of human recombinant C5a in lining-depleted knee joints showed similar influx of inflammatory cells if compared to human recombinant C5a injection in control knee joints. This study indicates that in immune complex-mediated arthritis, phagocytic lining cells regulate the onset of the inflammatory response.

Reversible depletion of synovial lining cells after intra-articular treatment with liposome-encapsulated dichloromethylene diphosphonate.

We studied the depletion and repopulation of synovial lining cells in mice. A single intra-articular injection of liposomes encapsulating the drug dichloromethylene diphosphonate (CL2MDP) in the mouse knee joint caused selective elimination of synovial lining cells. Depletion of cells occurred within a few days as evidenced by light microscopic, electronmicroscopic and immunohistochemical studies. Maximal depletion was seen on day 7. Repopulation was observed in the following weeks, starting at the bone side of the joint. Until day 30, full recovery (60% recovery) was not observed in the lining lying adjacent to the dermis. Side effects on cartilage metabolism, such as inhibition of proteoglycan synthesis or degradation of proteoglycans from the matrix was minor but significant, 1 and 2 days after liposome treatment but thereafter full recovery was observed. Selective elimination of lining cells from the joint enabled us to study the in vivo role of these cells in the onset and subsequent pathology of experimental arthritis. An immune-complex-mediated experimental arthritis elicited in lining cell depleted joints that had received CL2MDP-liposomes 7 days earlier prevented inflammation as compared to controls.

Aberrant tolerance induction with cationic antigens.

We studied the induction of tolerance in female C57B1/6 mice by oral and intravenous (i.v.) administration of protein antigens before immunization. Native proteins [chicken egg albumin (OVA), bovine serum albumin (BSA)] and their cationic derivatives [amidated (a)OVA, aBSA, methylated (m)BSA] were compared in their capacity to suppress cell-mediated immunity (CMI), as measured by a delayed type hypersensitivity test (DTH). Oral feeding of 0.5 mg negative proteins gave a clear suppression. By contrast, cationic derivatives (50 micrograms to 50 mg) did not suppress CMI. Data from cross-experiments, where aOVA was fed in OVA-immune mice, showed no suppression at all. When OVA was fed in aOVA-immune mice, only a partial suppression was achieved. The potency to induce tolerance differed also when the antigens were administered i.v.: 25 micrograms OVA was sufficient to induce a clear suppression, whereas a much higher amount of aOVA (500 micrograms) caused marginal suppression in OVA- and aOVA-immune mice, respectively. Nevertheless, when concentrations of aOVA up to 2.5 mg were tested in a chronic model of arthritis, a significant suppression was achieved. The differences in inducing a CMI suppression may have implications for the feasibility of immunointervention. Successful modulation of human arthritis may be highly dependent on the nature of the antigen involved.

Role of phagocytic synovial lining cells in experimental arthritis.

We investigated the in vivo role of phagocytic synovial lining cells (SLC) in the onset of experimental arthritis by depleting phagocytic SLC prior to arthritis induction. Phagocytic SLC were depleted by a single intra-articular injection of liposomes encapsulating the drug dichloromethylene diphosphonate (CL2MDP). Seven days after injection optimal depletion was observed and this time point was chosen for induction of arthritis in SLC depleted joints. Joint swelling was highly reduced after elicitation with either zymosan, immune complexes or antigen, as compared to observations in normal non-depleted joints. In addition cellular infiltration was markedly reduced. Further study in the immune complex mediated arthritis revealed that reduced cell influx in SLC depleted knee joints was correlated to lowered chemotactic activity and IL-1 levels as measured in washouts of joint tissues. This indicates that IL-1 driven chemotactic factors might be involved. Furthermore reduced cell influx was also correlated to significantly diminished loss of 35S-prelabeled PG from the cartilage. Out data indicate that SLC are directly involved in the onset of joint inflammation.

Cationic immune complex arthritis in mice--a new model. Synergistic effect of complement and interleukin-1.

A novel cationic immune-complex-mediated arthritis (ICA) model was developed in mice. The highly cationic protein lysozyme was coupled to poly-L-lysine (PLL) and injected intra-articularly into the knee joint of the mouse, shortly after systemic administration of specific antibodies. A vehement joint inflammation developed, characterized by severe joint swelling and the influx of predominantly polymorphonuclear (PMN) leukocyte. Unique properties were combined in this protein. First, an excellent retention of the antigen in joint structures was found, facilitating sufficient IC formation in the synovial tissue and at the cartilage surface. Secondly, PLL.lysozyme appeared to be a potent inducer of interleukin-1 (IL-1). Similar IL-1 production was measured at 6 hours, in both immune or nonimmune mice. Neutralization with antibodies against either IL-1 alpha or IL-1 beta revealed that IL-1 alpha was the dominant cytokine. Resident cells were responsible for this IL-1 production since a comparable IL-1 signal was measured after intra-articular injection of PLL.lys in neutropenic mice. We further investigated whether IL-1 and complement factors were involved in the onset of this ICA. Neutralizing the IL-1 production with antibodies directed against IL-1 alpha and beta showed a significant decrease in joint swelling. Complement depletion by cobra venom factor also prevented the onset of arthritis for the greater part. Only a minor swelling remained at 6 hours after eliciting arthritis, which was similar to the swelling after injecting the antigen alone and probably reflects IL-1 mediated inflammation. In this study, the authors show a synergistic action of IL-1 and complement in the onset of cationic ICA. Unique properties of the antigen such as excellent retention and its ability to induce IL-1 are combined within one molecule and make this antigen arthritogenic in the presence of antibodies and complement activation.