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Incidence, types and acceptability of pharmaceutical interventions about drug related problems in a general hospital: an open prospective cohort

Objectives To evaluate the incidence and types of drug-related problems (DRP) in a general teaching hospital and to evaluate the acceptability of pharmaceutical interventions by the medical team. Design Prospective cohort study during 2 years. Setting Conducted in a Brazilian University Hospital. Participants The patient cohort consisted of 9303 patients with a total of 12 286 hospitalisation episodes. Primary outcome measures DRP detected by pharmacists’ review of 100% medication orders using Pharmaceutical Care Network Europe 6.2 classification. Results Patients with a mean age of 52.6±17.7 years and 50.9% females. A total of 3373 DRP in 1903 hospital episodes were identified, corresponding to a cumulative incidence of 15.5%. ‘Treatment ineffectiveness’ (11.5%) and ‘Treatment costs’ (5.90%) were the most common DRP and ‘Drug use process’ (18.4%) and ‘Treatment duration’ (31.0%) the main causes of DRP. The medicines involved most often involved in DRP were anti-infectives (36.0%), mainly cephalosporins (20.2%), antiulcer (38.6%), analgesics/antipyretics (61.2%), propulsives (51.2%), opioids (38.5%) and antiemetics (57.4%). From 1939 pharmaceutical interventions, at least, 21.4% were not approved by the medical team. Conclusion DRP detected by 100% medication order review by hospital pharmacists occur in a significant proportion of hospital episodes, the most frequent being related to treatment effectiveness and treatment costs. The medications mostly involved were cephalosporins, penicillins, antidyspeptics, analgesics, antipyretics, opioids and antiemetics. Pharmaceutical interventions had low acceptability by the medical staff.

Results: -Page 10 line 8. Why did not all the interventions were followed? -It is not clear to what the authors are refereeing when they say that an intervention was not approved by the prescriber, because did not generate positive impact on the prescription. How did the evaluate this? Discussion -Page 11, second paragraph. When explaining the possible reasons because the results are different, I think that one that the authors did not pointed out is age. Many studies of these characteristics have been done in elderly patients, as they are more prone to have DRP, due to the polymedication usually present.
-Page 15, the authors say that there are no other studies where the communication is done through a writing system. This is not true, there are studies published where the communication with the prescriber is not done only orally.
In view of the results, I think that the authors should address the principal problems detected and suggest possible improvements or actions.

GENERAL COMMENTS
Thank you for the opportunity to review this manuscript. This paper reports the results of an observational study aimed to evaluate the incidence and types of drug-related interventions in a single general hospital. It is an important topic of interest to better understand the process of medication errors. The manuscript is well written, well-balanced and easy to read. However, I have concerns regarding the scientific contribution of this work because of the large number of similar studies published in international literature. It is a single-centre study with a large sample and the methodology is clear and well-described but of limited originality. I have the feeling that this study probably contributes to the knowledge at a national level in Brazil but with a limited contribution for an international audience. 2. Page 7 lines 7-9, the authors explain that when they detect a DRP they write the intervention for the physician. How do they send the form to the physician? Via email? Or other? It is important the way as sometimes one of the main problems is that the communication do not reach the physician.

Response:
It is really a challenge to sensitize the prescriber to potential DRPs in the medical orders. As a way to minimize the problem, we send small notes strategically positioned to be seen before the next prescription. We add the following text to the methodology (Page 7: Lines 159 -164): All DRP were recorded manually in a log book, along with the patient identification and detailed description of the DRP, and a pharmaceutical intervention was issued, containing a proposal to change the MO in order to prevent the occurrence of DRP. The intervention proposal was written on a Pharmaceutical Intervention (PI) form and sent by messenger to the patient ward. There, the PI form was attached to the patient chart to be viewed before the next prescription.
3. How were registered the interventions? What kind of database of software was used? Response: We do not have specific software for registering pharmaceutical interventions. All inconsistencies in the medical orders are written daily in a log book. The following text in the methods (Page 7: Lines 158 -161): The interventions were written in a form standardized by the institution, containing a proposal to change the MO for the purpose of preventing the occurrence of DRP.
was changed to: (Page 7: Lines 159 -164) All DRP were recorded manually in a log book, along with the patient identification and detailed description of the DRP, and a pharmaceutical intervention was issued, containing a proposal to change the MO in order to prevent the occurrence of DRP. The intervention proposal was written on a Pharmaceutical Intervention (PI) form and sent by messenger to the patient ward. There, the PI form was attached to the patient chart to be viewed before the next prescription. Results: 1. Page 10 line 8. Why did not all the interventions were followed? Response: The following text in the results (Page 10: Lines 236 -241): Interventions whose impact on the medical orders could not be followed (for example, medical records unavailable during follow-up or intervention related to any specific technique of drug preparation, physical-chemical stability of the drug or administration of the drug) accounted for 1,433 (42.5%) of cases and were classified as "unknown".
was changed to (Page 10: Lines 241 -247): Some pharmaceutical interventions could not be evaluated regarding acceptability by the healthcare team because they would not dictate a change in the respective MO. These include cases where the patient was discharged or died before a MO could be changed, when the pharmaceutical intervention proposed a change in the technique of drug preparation, mentioned an issue related to the physicalchemical stability of the drug, or provided instructions on the correct administration of the drug. These situations accounted for 1,433 (42.5%) of cases and were classified as "unknown".
2. It is not clear to what the authors are refereeing when they say that an intervention was not approved by the prescriber, because did not generate positive impact on the prescription. How did the evaluate this? Response: After the reviewer's comment, we reflect and consider the term "positive" would not be appropriate in this context. Since we did not evaluate beneficial outcomes resulting from the interventions, we chose to readjust the text excluding this expression. The following text in the results (Page 10: Lines 236 -240): From the 3,373 pharmaceutical interventions performed, 1,939 were followed up to assess their acceptability by the prescriber. From these, 1,217 (36.10%) were considered "approved", since they demonstrated a positive influence on the prescription, that is, changes compatible with the proposed pharmaceutical intervention were observed. In 722 (21.4%) cases, the interventions were classified as "not approved" by the prescriber, since they did not generate positive impact on the prescription.
was changed to (Page 10: Lines 236 -240): From the 3,373 pharmaceutical interventions performed, 1,939 were followed up to assess their acceptability by the prescriber. From these, 1,217 (36.10%) were considered "approved" because there was a change in the MO in the same sense as the proposed pharmaceutical intervention. In 722 (21.4%) cases, the interventions were classified as "not approved" by the prescriber, since they did not generate changes on the MO.

Discussion
1. Page 11, second paragraph. When explaining the possible reasons because the results are different, I think that one that the authors did not pointed out is age. Many studies of these characteristics have been done in elderly patients, as they are more prone to have DRP, due to the polymedication usually present.

Response:
We thank the Reviewer for this tip, which of course is an important cause of discrepancy between our estimates of the incidence of DRP and the estimates reported in other studies.. The following text was added in the Discussion section (Page 11: Lines 267 -269): In addition, many published studies on the DRP incidence have been done in elderly hospitalized patients who, because of the polymedication often present in that population, are at increased risk of DRP.
2. Page 15, the authors say that there are no other studies where the communication is done through a writing system. This is not true, there are studies published where the communication with the prescriber is not done only orally. Response: The statement contained in the text was not really adequate. The following text in the discussion (Page 16: Lines 368): We also did not find other studies in the literature in which pharmaceutical interventions were made through written communication with prescribers, acting as a warning system; other studies deal only with interventions made verbally during ward rounds.
was changed to (Page 16: Lines 368): Very few studies have been published in the literature in which pharmaceutical interventions were made through written communication with prescribers, acting as a warning system; other studies deal only with interventions made verbally during ward rounds.
3. In view of the results, I think that the authors should address the principal problems detected and suggest possible improvements or actions. Response: The following text was added to the discussion (Page 16: Lines 384 -392): According to the findings of this study, a significant part of DRP can be prevented. Therapeutic ineffectiveness related to inadequacy in the use process is likely to be minimized through constant training of health teams, especially in relation to the rational use of antimicrobials, resulting in lower cost and less occurrence of bacterial resistances. Point-of-care access to updated and quality literature on drugs, in addition to regular updating of computerized warning and prescription assistance systems, would probably decrease DRP related to Treatment Effectiveness, the most often observed DRP in patient wards. It is also likely that the inclusion of clinical pharmacists as members of the health care would contribute largely to a significant decrease in the incidence of potential DRP.
Reviewer: 2 Reviewer Name: Pierrick Bedouch Institution and Country: Université Grenoble Alpes, France Please state any competing interests or state 'None declared': none declared Please leave your comments for the authors below Thank you for the opportunity to review this manuscript. This paper reports the results of an observational study aimed to evaluate the incidence and types of drug-related interventions in a single general hospital. It is an important topic of interest to better understand the process of medication errors.