Effect of computer order entry on prevention of serious medication errors in hospitalized children.

OBJECTIVE: Although initial research suggests that computerized physician order entry reduces pediatric medication errors, no comprehensive error surveillance studies have evaluated the effect of computerized physician order entry on children. Our objective was to evaluate comprehensively the effect of computerized physician order entry on the rate of inpatient pediatric medication errors. METHODS: Using interrupted time-series regression analysis, we reviewed all charts, orders, and incident reports for 40 admissions per month to the NICU, PICU, and inpatient pediatric wards for 7 months before and 9 months after implementation of commercial computerized physician order entry in a general hospital. Nurse data extractors, who were unaware of study objectives, used an established error surveillance method to detect possible errors. Two physicians who were unaware of when the possible error occurred rated each possible error. RESULTS: In 627 pediatric admissions, with 12,672 medication orders written over 3234 patient-days, 156 medication errors were detected, including 70 nonintercepted serious medication errors (22/1000 patient-days). Twenty-three errors resulted in patient injury (7/1000 patient-days). In time-series analysis, there was a 7% decrease in level of the rates of nonintercepted serious medication errors. There was no change in the rate of injuries as a result of error after computerized physician order entry implementation. CONCLUSIONS: The rate of nonintercepted serious medication errors in this pediatric population was reduced by 7% after the introduction of a commercial computerized physician order entry system, much less than previously reported for adults, and there was no change in the rate of injuries as a result of error. Several human-machine interface problems, particularly surrounding selection and dosing of pediatric medications, were identified. Additional refinements could lead to greater effects on error rates.

Characterization of the action of drug-induced stress responses on the immune system: evaluation of biomarkers for drug-induced stress in rats.

Toxicological testing of compounds often is conducted at the maximum tolerated dose to identify potential target organs. Toxicities observed at these high doses may result in decreased body weight gain, food consumption and activity. These clinical signs are often associated with a generalized stress response. It has been known that stress may cause increased levels of corticosterone, which causes changes in circulating leukocyte profiles, decreases in thymus and spleen weights and changes in the microscopic structure of lymphoid organs. This makes it difficult to differentiate between stress-related changes and direct toxicity to the immune system in standard non-clinical toxicity testing in rats. In mice, MHC Class II expression was found to be a very sensitive biomarker of stress and maybe useful for the rat. Therefore, the objective of studies presented was to further characterize the effects of corticosterone and stressors on the immune system and identify potential biomarkers of stress in rats. Rats were treated with exogenous corticosterone (20 or 30 mg/kg BID) or ethanol (5 g/kg) for either 1 or 4 days. Restraint stress was also evaluated for a 3-day period. Blood and urine samples were collected during the treatment period for corticosterone measurements. At necropsy, blood samples for leukocyte differentials were collected. Spleen and thymus weights, cellularity, lymphocyte subpopulations and histopathology were also evaluated. Urine corticosterone levels were also investigated as a surrogate to measuring serum corticosterone. The results demonstrate that the pattern of responses to corticosterone or the stressors is different in mice and rats. Although, decreases in MHC Class II were found to be a sensitive indicator of stress in mice, only slight decreases were observed in rats with similar serum corticosterone AUC levels. Decreases in thymus weight were greater than spleen weight with corticosterone or ethanol or restraint stressor. No other single parameter or combination of parameters tested were obvious candidates as sensitive biomarkers of stress in rats. However, the good correlation between urine and serum corticosterone levels suggest that urine corticosterone may be a potential biomarker of stress induced changes to the immune response.

Medication errors related to computerized order entry for children.

OBJECTIVE: The objective of this study was to determine the frequency and types of pediatric medication errors attributable to design features of a computerized order entry system. METHODS: A total of 352 randomly selected, inpatient, pediatric admissions were reviewed retrospectively for identification of medication errors, 3 to 12 months after implementation of computerized order entry. Errors were identified and classified by using an established, comprehensive, active surveillance method. Errors attributable to the computer system were classified according to type. RESULTS: Among 6916 medication orders in 1930 patient-days, there were 104 pediatric medication errors, of which 71 were serious (37 serious medication errors per 1000 patient-days). Of all pediatric medication errors detected, 19% (7 serious and 13 with little potential for harm) were computer related. The rate of computer-related pediatric errors was 10 errors per 1000 patient-days, and the rate of serious computer-related pediatric errors was 3.6 errors per 1000 patient-days. The following 4 types of computer-related errors were identified: duplicate medication orders (same medication ordered twice in different concentrations of syrup, to work around computer constraints; 2 errors), drop-down menu selection errors (wrong selection from a drop-down box; 9 errors), keypad entry error (5 typed instead of 50; 1 error), and order set errors (orders selected from a pediatric order set that were not appropriate for the patient; 8 errors). In addition, 4 preventable adverse drug events in drug ordering occurred that were not considered computer-related but were not prevented by the computerized physician order entry system. CONCLUSIONS: Serious pediatric computer-related errors are uncommon (3.6 errors per 1000 patient-days), but computer systems can introduce some new pediatric medication errors that are not typically seen in a paper ordering system.

Modeling and predicting stress-induced immunosuppression in mice using blood parameters.

Previous studies have shown that the area under the corticosterone concentration vs. time curve (AUC) can be used to model and predict the effects of restraint stress and chemical stressors on a variety of immunological parameters in the mouse spleen and thymus. In order to complete a risk assessment parallelogram, similar data are needed with blood as the source of immune system cells, because this is the only tissue routinely available from human subjects. Therefore, studies were conducted using treatments for which the corticosterone AUC values are already known: exogenous corticosterone, restraint, propanil, atrazine, and ethanol. Immunological parameters were measured using peripheral blood from mice treated with a series of dosages of each of these agents. Flow cytometry was used to quantify MHC II, B220, CD4, and CD8 cells. Leukocyte and differential counts were done. Spleen cell number and NK cell activity were evaluated to confirm similarity to previous studies. Immune parameter data from mouse blood indicate that MHC II expression has consistent quantitative relationships to corticosterone AUC values, similar to but less consistent than those observed in the spleen. Other immune parameters tended to have greater variability in the blood than in the spleen. The pattern observed in the spleen in which the chemical stressors generally produced very similar effects as noted for restraint stress (at the same corticosterone AUC values) was not observed for blood leukocytes. Nevertheless, MHC class II expression seems to provide a reasonably consistent indication of stress exposure in blood and spleen.

Ethanol decreases natural killer cell activation but only minimally affects anatomical distribution after administration of polyinosinic:polycytidylic acid: role in resistance to B16F10 melanoma.

BACKGROUND: Natural killer (NK) cells are critical in resistance to B16F10 lung metastases in B6C3F1 mice. Activation of NK cells by polyinosinic:polycytidylic acid (poly I:C; 0.1 mg, intraperitoneally) increases resistance to B16F10 cells. This effect is reduced after administration of ethanol (EtOH; 6 g/kg by oral gavage). The present study was conducted to determine whether decreased resistance is due to alteration of the distribution and/or the activation of NK cells. METHODS: These parameters were measured in the spleen, lungs, and peripheral blood 4 and 12 hr after EtOH and poly I:C administration. For assessing the time after poly I:C administration during which NK cells are important in resistance to B16F10 cells, anti-NK1.1 antibody was used to deplete NK cells in vivo 48 hr before and 0, 6, 12, and 24 hr after intravenous injection of B16F10 tumor cells. RESULTS: Depletion of NK cells at any time up to 12 hr after B16F10 administration significantly increased the number of tumor nodules in the lungs, but depletion at 24 hr had a smaller effect. Flow cytometry revealed that there was a small but significant increase in the percentage of NK cells in the lungs at 12 hr, which was not changed by EtOH. Corresponding NK cell lytic function in the lungs was increased significantly at both 4 and 12 hr by poly I:C. However, the increase was not significantly different from the naive control value at 4 hr in mice treated with poly I:C plus EtOH, indicating that EtOH decreased activation of NK cells in the lungs at 4 hr. In the spleen, no treatment significantly altered the percentage of NK cells at 4 or 12 hr. However, poly I:C significantly enhanced lytic function, and this enhancement was suppressed by EtOH (by approximately 50%). In the blood, the only significant change in NK cell percentage or lytic activity was an increase in the percentage of NK cells at 12 hr, which was equivalent in the poly I:C and the poly I:C plus EtOH groups. CONCLUSIONS: These results demonstrate that EtOH partially abrogates the poly I:C-induced enhancement of resistance to B16F10 cells and that decreased activation of NK cells in the lungs at a critical time early in the response to poly I:C may contribute to this effect. Other parameters could also contribute, but there was little support for an important role for changes in NK cell distribution.

Modeling and predicting immunological effects of chemical stressors: characterization of a quantitative biomarker for immunological changes caused by atrazine and ethanol.

Previous studies demonstrate that the effects of one chemical stressor on selected immunological parameters can be predicted on the basis of the area under the corticosterone concentration vs. time curve. However, it is not clear if this is applicable to other chemical stressors. The present study was conducted to determine if the stress-induced immunological effects of atrazine and ethanol could be predicted, and if it is feasible to use one immunological parameter as a biomarker of stress to predict the quantity of changes expected in other immunological parameters. The area under the corticosterone concentration-versus-time curve (AUC) was measured in mice treated with ethanol (EtOH, 4, 5, 6, or 7 g/kg by oral gavage) or atrazine (ATZ, 100, 200, or 300 mg/kg, ip). The effects of the same dosages of these chemicals on thymus and spleen cellularity, lymphocyte subpopulations in the thymus and spleen, expression of MHC class II protein on splenocytes, antibody responses to keyhole limpet hemocyanin, and natural killer-cell activity were determined. Models were derived describing the relationship between corticosterone AUC and immunological changes induced by these chemicals. The results for these chemical stressors were more similar to results obtained from mice subjected to restraint stress than from mice treated with exogenous corticosterone. Some effects were greater than predicted on the basis of the stress response alone, indicating other mechanisms of immunotoxicity. One of the parameters (MHC class II expression) was evaluated as a predictive biomarker for stress-related immunosuppression, and the results suggest it could be suitable for that purpose.

Ethanol suppresses polyinosinic:polycytidylic acid-induced activation of natural killer cells primarily by acting on natural killer cells, not through effects on other cell types.

Natural killer (NK) cells can be activated in vitro and in vivo by polyinosinic:polycytidylic acid (poly I:C) through induction of type I interferons or other cytokines. Ethanol suppresses in vivo and ex vivo poly I:C activation of NK cell activity in a mouse model for binge drinking, but it is not known whether this effect is mediated by changes in NK cells or in other cell types (e.g., those that produce NK cell-activating cytokines). Splenocytes were obtained from C57BL/6 [NK cell-competent (NKc)] and C57BL/6 perforin knockout [NK cell-incompetent (NKi)] mice 6 h after administration of ethanol (6 g/kg) or vehicle (VH; dH(2)O). Cells were incubated in vitro 18 h with poly I:C (100 micro g/ml), followed by a 4-h 51Cr release assay with the use of YAC-1 target cells. Results of cell-mixing experiments involving all relevant combinations of splenocytes obtained from NKc and NKi mice treated with VH or ethanol strongly supported the suggestion that NK cells, not other cell types, are the primary target of ethanol-induced suppression of NK cell activation. For example, mixing of splenocytes obtained from ethanol-treated NKc and VH-treated NKi mice or from ethanol-treated NKc and ethanol-treated NKi mice yielded similar cytolytic function. However, mixing of splenocytes obtained from ethanol-treated NKc and VH-treated NKi mice yielded significantly less cytolytic activity than that of splenocytes from VH-treated NKc and ethanol-treated NKi mice. In addition, mixing of splenocytes obtained from VH-treated NKc and NKi mice resulted in lower cytolytic activity than when splenocytes from the NKi mice were treated with ethanol instead of with VH, demonstrating that ethanol did not decrease the function of other cell types. A strikingly similar pattern of results was observed when B6C3F1 mice, rendered NK cell deficient by administration of anti-NK 1.1 monoclonal antibody, were used instead of perforin knockout mice. These results indicate that ethanol suppresses activation of NK cells primarily by suppressing the NK cell response to poly I:C, not by acting on another cell type.

Histological enzyme and flow cytometric analysis of channel catfish intestinal tract immune cells.

Channel catfish, Ictalurus punctatus, gastrointestinal tract leukocytes were characterized using flow cytometry, histochemistry, and enzyme staining techniques. Cells obtained from the lamina propria by collagenase digestion were found to be primarily neutrophils, with fewer than 6% B lymphocytes as determined by flow cytometry. Histochemical and enzyme stains were used to determine leukocyte distribution in gastrointestinal tract tissue. Macrophages and T lymphocytes were observed throughout the gastrointestinal tract. As in flow cytometry studies, few B lymphocytes and many neutrophils were observed in the channel catfish gastrointestinal tract. Since cells involved in specific immunity appear to be limited in gastrointestinal tract tissue of channel catfish, we speculate that catfish may rely more heavily on a highly developed innate response for intestinal mucosal immunity than other teleost species studied.