‘Reviewer's report
Title:Adverse drug events identified by triggers at a teaching hospital in Brazil
Version:5Date:17 September 2014
Reviewer:Katja Marja Hakkarainen
Reviewer's report:
Although the authors have addressed some of the comments, several comments
remain, below (also in the attached file where the comments are in yellow):
# MAJOR COMPULSORY REVISIONS 2
The abstract shall be re-written, according to the following changes suggested for
the entire manuscript.
- Authors: The abstract was rewritten.
- Reviewer: The abstract has become better but still requires editing. See the
following points on the method and conclusions. The aim in the abstract should
be the same as at the end of the introduction. The method should include many
more aspects e.g. on analysis, please see the STROBE guidelines for
conference abstracts. The results should not include elaboration on the results.
See the comments on conclusions – the abstract conclusion should be the same
as at the end of the discussion (but probably summarized due to word limits in
the abstract).
Authors: As suggested, the aim was rewritten and in the methods the sentence
“Co-morbidities were examined using the Charlson index. Drugs were coded
according to the first and second levels of the Anatomical Therapeutic Chemical
classification. The indicators of ADE frequency were: incidence of patients with
ADEs and ADE rate per 100 patients with their respective confidence intervals
(95% CI)” was included. In the paragraph on result the sentence “Analgesics,
antibacterials for systemic use, classes of drugs for acid-related disorders and
antithrombotic agents should be used parsimoniously, because they are widely
prescribed and related with the highest number of events. Also high-alert
medications, such as insulin, heparin and midazolam call for special care” was
omitted. As regards the conclusion, the paragraph was modified.
- Reviewer: I would encourage the authors to harmonise the methods and results
sections of the abstract, so that what is reported in the results is also described inthe methods.
This way, the abstract would be more understandable without the
full text.
Please also harmonise the use of words ”incidence”, ”frequency” and ”rate” in the
aim, methods and results, also in the full text of the manuscript. Summary
measures that are mentioned in the aim should be the same as in the methods
and the results.
Please re-write the conclusions also in the abstract, according to other comments
given on conclusions.
- Authors: As suggested, the abstract was harmonized with de methods and
results sections, and the conclusions were rewritten. The use of words
”incidence”, ”frequency” and ”rate” were harmonized. The abstract was rewritten.
- Reviewer: The comment has not been addressed sufficiently. For example, the
aim still includes “to identify factors”, which is not in the methods. Further, the
aim still includes only “incidence”, although other terminology is used in other
parts of the abstract. Please harmonise these.
ABSTRACT – TO MEET THE SUGGESTIONS OF REVIEWER:
1- THE FOLLOWING EXCERPT WAS DELETED: “AND TO IDENTIFY FACTORS ASSOCIATED
WITH THE OCURRENCE OF ADES”.
2- THE PHRASE “THE INDICATORS OF ADE FREQUENCY WERE: INCIDENCE OF PATIENTS
WITH ADES AND THE RATE PER 100 PATIENTS” WAS REPLACED BY “THE INDICATORS OF
ADE INCIDENCE WERE PATIENTS WITH ADES AND RATES PER 100 PATIENTS”.
ACCORDINGLY THE SENTENCE IN RESULTS SESSION WAS MODIFIED.
3- THE FOLLOWING EXCERPT: “REFLETING ADE INCIDENCE OF 14.6% AND A RATE OF
18.3% ADES PER 100 PATIENTS” WAS REPLACED BY “WITH 14.6% OF PATIENTS
PRESENTING ADE AND A RATE OF 18.3% ADES PER 100 PATIENTS”.
4- THE FOLLOWING EXCERPT WAS INCLUDED :” IN THE FUTURE STUDIES WITH HIGHER
NUMBER OF PATIENTS MAY OFFER EVIDENCES OF THE ASSOCIATION.
5- TO SHORTEN THE TEXT AND STANDARDIZE THE ABSTRACT THE FOLLOWING SENTENCE
WAS INCLUDED: “THIS IS A RETROSPECTIVE STUDY OF CHART REVIEW”. THE
FOLLOWING EXCERPTS WERE EXCLUDED:” BY RETROSPECTIVE REVIEW OF PATIENT
RECORDS”; “TO IDENTIFY THE PRESENCE OF AT LEAST ONE OF THE TRIGGERS
PROPOSED BY THE IHI”.
INTRODUCTION- TO MEET THE SUGGESTIONS OF REVIEWER:
6- THE FOLLOWING EXCERPT WAS DELETED: “AND TO IDENTIFY FACTORS ASSOCIATED
WITH THE OCURRENCE OF ADE”.
# MAJOR COMPULSORY REVISIONS 6
Please clarify how the Naranjo algorithm, developed for ADRs, was
operationalised to detect ADEs that are not ADRs, such as lack of effect due to a
sub-therapeutic dose, e.g. a wrong dose calculation. Or did the study exclusively
detect ADRs? In that case, the title, introduction and discussion must be
re-written.
- Authors: The paragraph clarifying use of the Naranjo algorithm is: “Possible
associations between events and suspect drugs were examined according to the
drugs’ properties [13, 14], the patient’s clinical condition and the time until the
occurrence of the event. The Naranjo algorithm [16] was applied to determine the
strength of the causal relationship with the drugs used by the patient and
implicated in the occurrence of each ADE. The total scores allowed us to classify
the ADEs as doubtful (< 1), possible (1-4), probable (5-8) or definite (# 9)” Since
the 1980s the Naranjo algorithm has been applied in an attempt to make
assessment of the causal relationship between use of medicines and ADRs
objective. However, it has been also used to assess ADEs, which include errors,
as in the articles listed below:
Mycyk MB, McDaniel MR, Fotis MA, Regalado J. Hospitalwide adverse drug
events before and after limiting weekly work hours of medical residents to 80. Am
J Health Syst Pharm 2005; 62:1592-5.
Kilbridge PM, Campbell UC, Cozart HB, Mojarrad MG. Automated surveillancefor adverse drug
events at a community hospital and an academic medical
center. J Am Med Inform Assoc 2006; 13:372-7.
Chen YC, Fan JS, Chen MH, Hsu TF, Huang HH, Cheng KW, Yen DH, Huang
CI, Chen LK, Yang CC. Risk factors associated with adverse drug events among
older adults in emergency department. Eur J Intern Med. 2014 Jan;25(1):49-55.
- Reviewer: The added text does clarify the assessment. However, please still
clarify whether the assessment could capture lacking effect due to e.g.
non-adherence by patients or sub-therapeutic dose. These would be included in
many ADE studies, but as they are not ADRs, instruments designed for ADRs
may not detect them. This could also be clarified in the section on definition of
ADEs.
- Authors: The trigger tool is not appropriate to identify cases of non adherence
or subtherapeutic doses, as it is an approach to be applied in hospitals, were
these situations may not be as frequent as in ambulatory settings, specially the
non adherence. Beside, in our sample we did not identified any of these cases.
- Reviewer: Please add the clarification in the article.
As suggest, the paragraph clarifying use of the Naranjo algorithm “Since the
1980s the Naranjo algorithm has been applied in an attempt to make assessment
of the causal relationship between use of medicines and adverse drug reaction.
However, it has been also used to assess ADEs [18,19,20], which include errors
like non adherence or subtherapeutic doses.
- Reviewer: The clarification in the article text differs from the clarification given in
this review. It should be clarified in the article, how the Naranjo algorithm was
operationalised to detect ADE and what kind of ADEs. If the study excluded
sub-therapeutic effects, it should be clarified and the terminology changed
accordingly (probably under “definition for ADE”).
METHODS AND DISCUSSION- TO MEET THE SUGGESTIONS OF REVIEWER:
1- THE FOLLOWING PARAGRAH WAS EXCLUDED (METHODS):
“SINCE THE 1980S THE NARANJO ALGORITHM HAS BEEN APPLIED IN AN ATTEMPT TO
MAKE ASSESSMENT OF THE CAUSAL RELATIONSHIP BETWEEN USE OF MEDICINES AND
ADVERSE DRUG REACTION. HOWEVER, IT HAS BEEN ALSO USED TO ASSESS ADES
[18,19,20], WHICH INCLUDE ERRORS LIKE NON ADHERENCE OR SUBTHERAPEUTIC
DOSES. “
2- THE PARAGRAPH THAT BEGINS WITH “THE CONCEPT…WAS EXTENSIVELY MODIFIED.
PLEASE, SEE ALSO THE REVISION 13. (DISCUSSION).
THE CONCEPT OF ADE WE USED INCLUDED DRUG ADVERSE REACTIONS (ADR) AND ERRORS.
IT DOES NOT CONFLICT WITH THE CONCEPT OF ADR THAT SUSTAINS THE ALGORITHM USED
TO DETERMINE THE STRENGTH OF THE CAUSAL RELATIONSHIP WITH THE DRUGS IN OUR
STUDY AND OTHERS [18,19,20]. STEADY CONCEPTUAL ADVANCES IN THE FIELD OF
PHARMACOEPIDEMIOLOGY ARE PERMITTING STUDIES FOCUSSING PRIMARILY ON
OCCURRENCES OF PATIENT HARM, REGARDLESS OF WHETHER OR NOT SUCH HARM IS
ASSOCIATED WITH ERRORS IN THERAPEUTIC INDICATION OR DRUG ADMINISTRATION.
BESIDES, THE EXAMINATION OF PATIENT CHARTS IN OUR SAMPLE DID NOT SHOW ANY
CASE OF ERROR LIKE NON ADHERENCE, SUBTHERAPEUTIC DOSES ETC
# MAJOR COMPULSORY REVISIONS 7
The number of variables in the logistic regression analysis, with 35 case patients,
is too large, based on the advice of many textbooks on logistic regression (rough
rule of tum: maximum of 1 variable per 10 cases). How do the authors justify
thelarge number of variables? Based on my best judgement, the number of
variables must be decreased radically, or preferably the logistic regression
analysis omitted from the manuscript, due to too few cases for such analysis.
- Authors: We added a second model where variables were included if p-value
was 0.05 or less in model 1. Although the fit of model 2 showed a slight
improvement, the estimates and their interpretation were basically the same.
Therefore, the penultimate paragraph of the Methods section has been rewritten:“Logistic
regression analysis was used to determine the relationship between the
occurrence of an adverse drug event and independent variables. The
independent variables whose values differed between strata in the bivariate
analysis with p-value < 0.25 entered the model 1. In the second model variables
with p-values of 0.05 or less were included.”
- Reviewer: Adding the second model still does not save the model 1 from being
inappropriate, with too many variables in such a small sample. The fact that
many variables lack significance in table 1 may just be due to the small sample,
which makes inclusion based on significance uncertain. At least the model 1
should be omitted from the manuscript, possibly also the model 2. Leaving only
descriptive data and simple analysis (table 1), and discussing the findings based
on that, is better than conducting regression analyses inappropriately. I urge the
authors to consult literature on logistic regression analysis as well as a
statistician on appropriate model building. Moreover, the choice of the cut-offs is
still unclear. For example, why does the number of medicines have a cut of at 10
medicines?
- Authors: As suggested, the logistic regression analysis was omitted.
- Reviewer: Please modify other parts of the article accordingly, including the
abstract, possibly the aim at the end of the introduction and the discussion. In the
methods section, wording referring to “independent” variables can be omitted.
The phrase about the independent variables was maintained because details the
variables shown in Table 1, however the term "independent variables " was
replaced by "evaluated variables". In the discussion section the phrase “…
although the analysis was not adjusted for confounders” was added.
- Reviewer: Otherwise ok, but now the methods section in the abstract says
nothing about this analysis, although it is in the aim, result and conclusions for
the abstract. Please add a sentence or two about this analysis in the abstract.
TO MEET THE SUGGESTIONS OF REVIEWER (ABSTRACT AND METHODS):
1- THE FOLLOWING PHRASES WERE INCLUDED: “ PATIENTS WITH AND WITHOUT ADE
WERE COMPARED IN THE BIVARIATE ANALYSIS. TO IDENTIFY THE DRUGS CLASSES MOST
OFTEN ASSOCIATED WITH EVENTS, THE NUMBER OF PRESCRIPTIONS OF EACH CLASS OF
DRUG WAS RELATED TO THE NUMBER OF EVENTS ASSIGNED TO IT”.(INTRODUCTION).
2- BESIDES IN METHODS SESSION WE INCLUDED ALDO THE SENTENCE:” TO PERFORM
THIS THE NUMBER OF PRESCRIPTINS OF EACH DRUG CLASS ASSOCIATED TO AN ADE
WAS DIVIDED BY THE NUMBER OR PRESCRIPTIONS OF THE DRUG CLASS.
# MAJOR COMPULSORY REVISIONS 13
Please add confidence intervals for the main descriptive outcomes, in the results
section and describe it in the methods section.
- Authors: As suggested, the confidence interval was included in Methods and
Results sections.
- Reviewer: As seen from the confidence intervals, they are very wide and reveal
the insecurity in the estimates of this small study. In the introduction, the authors
state that the trigger method enables organizations to monitor how ADE rates
change over time, followed by e.g. interventions. Based on the results of this
small study, comparisons over time would not be appropriate as we are only 95%
sure that the “real” incidence is between 10 and 19%. The authors may
re-consider the statement in the introduction and/or explain in the discussion how
these results could possibly be used for monitoring changes over time, with much
larger samples.
- Authors: The phrase “the trigger tool enables organizations to monitor changes
in the rates of ADE over time in response to strategies aimed at improving clinical
safety when sample sizes are suitable” was included in conclusion section.
- Reviewer: Firstly, I again urge the authors to re-consider this statement, as
most hospitals probably wouldn’t have resources to use this method repeatedly
for thousands of patients, which would be required for acceptable precision to
detect changes over time. I also encourage the authors to read Shojania KG,
Thomas EJ: Trends in adverse events over time: why are we not improving? BMJ
Qual Saf. 2013 Apr;22(4):273-7. doi: 10.1136/bmjqs-2013-001935. Secondly,
conclusions should not include new views. See the comment on conclusions.
The conclusion section was reorganized
We included the
- Reviewer: the conclusion still includes overstatements that are not supported by
the results and other literature. This study does not provide reliable evidence on
medicines “of particular importance” or which patient characteristics “favour the
occurrence” or “usefulness of triggers”. At most, it might provide preliminary
results or suggest these, but need to be confirmed in additional research. Shojania KG,
Thomas EJ: Trends in adverse events over time: why are we not improving? BMJ
Qual Saf. 2013 Apr;22(4):273-7. doi: 10.1136/bmjqs-2013-001935.
TO MEET THE SUGGESTIONS (INTRODUCTION, DISCUSSION, CONCLUSION):
1-THE FOLLOWING PHRASE WAS EXCLUDED FROM INTRODUCTION AND INCLUDED ON
DISCUSSION: “ACCORDING TO ROZICH (2003) THE TRIGGER ENABLES ORGANISATIONS TO
MONITOR LONGITUDINALLY HOW ADE RATES CHANGE IN RESPONSE TO STRATEGIES DESIGNED
TO IMPROVE CLINICAL SAFETY [8]. (INTRODUCTION).
2-THE FOLLOWING PHRASES WERE INCLUDED: “ACCORDING TO ROZICH (2003) THE TRIGGER
ENABLES ORGANISATIONS TO MONITOR LONGITUDINALLY HOW ADE RATES CHANGE IN
RESPONSE TO STRATEGIES DESIGNED TO IMPROVE CLINICAL SAFETY [8]. HOWEVER, THIS
STRATEGY IS NOWADAYS MAINLY THEORETICAL, SINCE THERE ARE SEVERAL OBSTACLES TO
BE OVERCOME. AMONG THEM: SCANT EVIDENCE OF IMPACT OF ONGOING STRATEGIES; THE
EXISTENCE OF DIFERENT SUBCATEGORIES OF DRUG ADVERSE EVENTS REQUIRING DIFFERENT
IMPROVEMENT INTERVENTIONS; THE FACT THAT MANY COMMON ADVERSE EVENTS REQUIRE
MORE COMPLEX DETECTION STRATEGIES”. SHOJANIA (2013); CLASSEN (2003) (DISCUSSION)
3-THE CONCLUSION WAS RE-WRITTEN. WE AGREE WITH THE REVIEWER THAT THE EXCERPTS
“OF PARTICULAR IMPORTANTE”, “FAVOR THE OCURRENCE” AND “USEFULNESS OF TRIGGERS”
ARE EXAGERATED, SO THEY WERE EXCLUDED. AS THE LAST PARAGRAPH DOES NOT HAVE
SUPPORT IN OUR RESULTS IT WAS EXCLUDED. BESIDES, WE ELIMINATED THE REFERENCE OF
HIGH-ALERT MEDICATION.
4-WE INCLUDED IN CONCLUSION SESSION THREE EXCERPTS:
“THIS STUDY DRAWS ATTENTION TO THE PROBLEM OF ADE IN HOSPITALIZED PATIENTS AND
OFFERS A METHODOLOGICAL ALTERNATIVE FOR FUTURE RESEARCH IN BRAZIL. OUR RESULTS
SUGGESTS THAT TRIGGER TOOL MAY BE USEFUL TO IDENTIFY ADE IN HOSPITALS.”
“THESE RESULTS SHOULD BE EXAMINED WITH CAUTION, AS THE NUMBER OF ADE IS SMALL
(44/240 PATIENTS).
"BUT ADDITIONAL RESEARCH SHOULD TEST THIS HYPOTHESIS. OUR RESULTS SUGGESTS THAT
THE TRIGGER TOOL MAY BE USEFUL TO IDENTIFY ADE IN HOSPITALS".
# MAJOR COMPULSORY REVISIONS 19
The discussion and the conclusions do not entirely reflect the aim of the study.
Large parts of the discussion and in particular the conclusions concern the use of
the trigger tool, although the aim of the study was not to evaluate the method.
Therefore, the discussion and in particular the conclusions should more directly
reflect the aim of the study. Currently, the results of the study (answering the aim:
incident and rate; ADE characteristics; factors associated) are not adequately
compared to and contrasted with previous literature on ADEs during hospital
stay. The authors should more actively questions whether their findings are
accurate, also considering their very small sample size.
- Authors: The discussion section has been completely re-written in order to
reflect the aim of the study. We have reduced the paragraphs on trigger tools.
We have improved the comparison with previous literature. Paragraphs 9, 10 e11 are new,
dealing with precision, and internal and external validity. Indeed, the
sample is not very large, but nonetheless we succeeded in observing estimates
with statistically significant differences between subgroups. In the multivariate
analysis, occurrence of ADEs was found to associate positively with use of 10 or
more drugs (OR = 3.6; CI 95%: 1.4-9.1) and with hospital stay of 10 or more days
(OR = 2.9; CI 95%: 1.3-6.6).
- Reviewer: The discussion now better reflects the aim, but still requires
extensive editing.
FROM HERE ON THE REVIEWER'S COMMENTS WERE CHECKED STEP BY STEP.
o Statements repeating methods and results of the study should be minimized
and discussion relating the results to other studies’ results further improved.
DONE.
o Mixing the results of the current study and references should be clarified, e.g.
“Life-threatening events were much less common [23]”.
DONE.
o The discussion should not focus on individual drugs that “were the most
common”, because they could be more common just due to chance, considering
the small sample.
DONE.
o If the authors discuss that some events/drugs are more common, the
statements should be referenced to strengthen the argumentation. The
argumentation should also acknowledge that there is insecurity in the authors’
estimates. Currently, the authors discuss the results as if the results were the
absolute reflection of true events.
DONE.
o In particular the discussion parts referring to the results of the regression
analysis should be toned down – the results of this study are not as certain asthe
authors discuss in the discussion. See previous comments on the regression
analysis.
DONE.
o The paragraphs “Determining the degree of severity” and “Identification of
adverse events contributes to…” can be omitted – they do not provide valuable
content.
THE FIRST PARAGRAPH WAS ALREADY OMITTED. THE SECOND ONE IS REMOVED FROM ATUAL
VERSION.
o The discussion on high alert medicines requires further elaboration. How do the
results of this study relate to using the high alert medicines lists in Brazilian
hospitals?
WE ELIMINATED THE TEXT AND THE REFERENCES OF HIGH-ALERT MEDICATION.
- Authors: We seek to meet the guidelines of STROBE, describing and
summarizing the main findings in the first paragraph. In the end of the phrase
“Life-threatening events were much less common” the sentence “as in other
studies “ was included. The individual drugs listed are considered dangerous or
very used in hospitals, hence the importance of mentioning them in a study of thefield of public
health. As suggest, the phrase ” Determining the degree of harm
severity is not an easy task, as it depends on the patient’s clinical condition.” was
omitted. Regarding the high alert medicines, the phrase “The high alert
medicines are still little studied in Brazil. Recently, a branch of the Institute for
Safe Medication Practice was established in our country and so we hope to it can
draw attention to these drugs” was introduced.
- Reviewer: The discussion still requires extensive editing. See my previous
comments from the previous rounds. As mentioned, the discussed issues should
better reflect the aim, and the reported results in accordance with the aim. These
results should then be contracted to previous relevant research. It is not
appropriate to lift selected results in the discussion, results which are not
reported in the results section. For example, the paragraph on ranitidine includes
results that are not reported in the results section. This paragraph is not
believable because it is unknown based on which analysis IV ranitidine became a
major issue, compared to other drugs that were equally or more frequent
according to the results section. Further, there were only 4 cases of ranitidine.
Does the size of the study allow lifting a specific drug as “particularly striking”? If
a confidence interval for the frequency of ranitidine cases was calculated,
wouldn’t the interval be very large, and overlap with confidence interval for other
drugs?
TO MEET THE SUGGESTIONS OF REVIEWER THE FOLLOWING PHRASES WERE INCLUDED:
- “THE DRUG SUB CLASSES MOST PRESCRIBED WERE ANALGESICS, ANTIBACTERIAL FOR
SYSTEMIC USE, ANTITHROMBOTIC AGENTS AND DRUGS FOR ACID RELATED DISORDERS.
AMONG THEM THE SUBCLASS OF DRUGS FOR ACID RELATED DISORDERS IS THE MOST
STRONGLY ASSOCIATED WITH ADES (3.6%)”. ( RESULTS)
- “RANITIDINE IS A DRUG FROM THIS LAST SUBCLASS, AS IT IS A HISTAMINE H2 RECEPTOR
ANTAGONISTS, AND SERVES TO ILLUSTRATE THE PROBLEM. ITS ADVERSE REACTIONS INCLUDE
RESPIRATORY INFECTIONS, DEPRESSION, PANCREATITIS, SEXUAL IMPOTENCE [16].”
[DISCUSSION].
TO MEET THE SUGGESTIONS OF REVIEWER THE FOLLOWING PHRASES WAS EXCLUDED:
- “PARTICULARLY STRIKING AMONG THE EVENTS AT THE HOSPITAL STUDIED WAS THE
PROPORTION RELATED TO THE USE OF INTRAVENOUS RANITIDINE.”(DISCUSSION)
- IN ORDER TO IMPROVE THE COMPARISONS OF OUR DATA WITH THE LITERATURE THE FIRST 5
PARAGRAPHS WERE ALTERED. THE TEXT IS NOW MORE CONSISTENT. BESIDES WE ADDED TWO
ARTICLES. (Discussion).
It is also still unclear how the results of this study relate to high alert medicines.
Some drugs were the same but many were not. As in scientific papers usually,
wouldn’t it be more fruitful to contrast the findings of this paper to other similar
research studies?
WE ELIMINATED THE TEXT AND THE REFERENCES OF HIGH-ALERT MEDICATION.
Also, please adjust the discussion on associated factors, making it clear to the
reader that the analyses which found the associations were not adjusted for any
confounders (as the logic regression is omitted).
BESIDES THE CHANGES ALREADY DONE ABOUT THIS SUBJECT IN THE PREVIOUS VERSIONS THE
FOLLOWING PHRASE WAS INCLUDED:
HOWEVER STUDIES WITH LARGER SAMPLES SHOULD TEST THE HYPOTHESIS OF ASSOCIATION.
- Reviewer: I repeat myself from the previous round as the changes made in the
discussion are small and insufficient: “The discussion still requires extensive
editing. See my previous comments from the previous rounds. As mentioned, the
discussed issues should better reflect the aim, and the reported results in
accordance with the aim. These results should then be contracted to previous
relevant research. It is not appropriate to lift selected results in the discussion,
results which are not reported in the results section.” The discussion still includes
many statements without scientific references and argumentation based on other
evidence. For example, when interventions are discussed, it is necessary to cite
and discuss them in relation to theoretical work on improving safety andintervention studies in
the field, i.e. how does this study link to such work? Only
based on such scientific elaboration the authors can make claims about how this
study contributes in improving medication safety in hospitals. This is just an
example of poor/non-existent argumentation in the discussion. The authors
should go carefully through each claim in the discussion and critically consider: Is
it really supported by the results AND other evidence? The authors need to cite
other evidence much more broadly than in the current version of the article.
TO MEET THE SUGGESTIONS (DISCUSSION):
- THE FOLLOWING SENTENCE WAS INCLUDED: “ALTHOUGH THE EVENT RATE IN THE LAST
STUDY IS HIGHER THAN OURS THE PROPORTION OF PEOPLE WITH ADE ESTIMATED BY THE
AUTHORS [10] IS SIMILAR TO OURS, AROUND 15%.
- THE FOLLOWING SENTENCE, AND REFERENCE, WAS INCLUDED: “THE DOUBLE EVALUATION
PROCESS WITH TWO PHYSICIANS OF PATIENT RECORDS TO ASSESS ADE IS NOT MORE RELIABLE
THAN A RECORD REVIEW PROCESS WITH ONE PHYSICIAN (ZEGHERS, 2010).
We thought to be relevant the discussion about the use of ranitidine because:
- it is a drug widely used in the hospitals;
- its use could lead to harm to inpatients
- and in many cases the use is unnecessary
- Reviewer: Although ranitidine is now mentioned in the results, the results (4
cases frin ranitidine) do not support concluding that it was “particularly striking”,
considering the power of the study and that other drugs were equally common.
According to the results, nalbuphine and heparin should get equal attention. If
this issue is kept in the discussion, it needs to be a) acknowledged that the
results only indicate the drug may be common cause of ADEs, considering the
small study size, and b) the points the authors list above need to be argued more
strongly, as the authors base that paragraph on other arguments than the results.
In the discussion section the phrase “… although the analysis was not adjusted
for confounders” was added
DONE.
- Reviewer: Ok.
In discussion section a phase “This study has limitations in terms…” was
rewritten.
- Reviewer: This is not sufficient, because the interpretation and conclusion still
do not consider this major limitation.
The phrase “We also identified events that required intervention to keep the
patient alive….” was as follows “We also identified events that required
intervention to keep the patient alive, such as hypoglycemia, cardiac tamponade
and over-sedation, related, respectively, to the use of insulin, heparin and
midazolam. These drugs are classified as high-alert medications by the Institute
for Safe Medication Practices [25].”
- Reviewer: This issue is still not discussed scientifically, interpreting the result of
the study against scientific literature. The reference is not from scientific
literature. See previous comments.
WE ELIMINATED THE TEXT AND THE REFERENCES OF HIGH-ALERT MEDICATION
# MAJOR COMPULSORY REVISIONS 20
The limitations should include discussion on the generalizability of the finding in
one hospital, and well as the consequences of using such a small sample. Also
the influence of chosen definitions for ADEs/ADRs should bediscussed,considering the
inconsistency of definitions in the field.
- Authors: We included the texts: 1-” The study was conducted at only one
hospital, which makes external validity troublesome and places limitations on
how far the results can be generalised. Nonetheless, they may be applied to
other tertiary hospitals in medical schools in Brazil and in other countries.”
2-“Identification of adverse events contributes to recognition of errors occurring in
the processes of care; such information is valuable to assess patient safety and
quality of care [7]. Steady conceptual advances in the field of
pharmaco-epidemiology are permitting studies focussing primarily on
occurrences of patient harm, regardless of whether or not such harm is
associated with errors in therapeutic indication or drug administration. This
approach is favoured by growth in, and recognition for, the field of safety and
improved quality of care for patients, particularly inpatients”.
- Reviewer: The first part is good. The second part can be omitted in my opinion.
The other commented items for the limitations are still not discussed.
- Authors: Given the inconsistencies in the definitions of the field about ADE/ADR
we consider important to keep the phrases - “Identification of adverse events
contributes to recognition of errors occurring in the processes of care; such
information is valuable to assess patient safety and quality of care [8]. Steady
conceptual advances in the field of pharmaco-epidemiology are permitting
studies focussing primarily on occurrences of patient harm, regardless of whether
or not such harm is associated with errors in therapeutic indication or drug
administration. This approach is favoured by growth in, and recognition for, the
field of safety and improved quality of care for patients, particularly inpatients”.
- Reviewer: Please add discussion on the effect of the chosen case definitions
(ADR vs ADE) on your results.
In the paragraph on study size, doesn’t the small sample lead to imprecision also
for the estimates in the hospital in question? Which “statistical significance
between groups” are the authors referring to?
As suggest, the paragraph on study size was rewrite.
- Reviewer: The definitions are still not discussed.
TO MEET THE SUGGESTIONS (DISCUSSION) THE PARAGRAPH WAS RE-WRITTEN AND NEW
SENTENCES WERE INCLUDED, SPECIALLY ON HOW THE DEFINITIONS IMPACT OUR RESULTS.
PLEASE SEE MAJOR COMPULSORY REVISION 6.
# MAJOR COMPULSORY REVISIONS 21
An important part largely missing in the discussion is elaboration on how the
results of the study may be used to decrease the burden of ADEs in hospitals in
the particular hospital, all hospitals in Brazil and/or elsewhere. This relates to theprevious
comment on identifying the knowledge gap in the introduction: what is
this particular study needed for? It is stated in the conclusions that the study
provides “areas on which target strategies for improving the quality of drug use”.
This is a big statement and requires further elaboration under the discussion
section, with references on previously suggested strategies for reducing ADEs in
hospitals. The conclusion statement in the abstract, referring to the number of
medicines, is not well-grounded and should be omitted, or at least problematized
in the discussion.
1-WE AGREE WITH THE REVIEWER. THE TEXT MENTIONED DOES NOT TAKE INTO ACCOUNT THE
SMALL SAMPLE, AND THE LIMITS OF THE STATISTIC ANALYSIS PERFORMED. THE TEXT GOES
BEYOND THE EMPIRICAL RESULTS. ACCORDINGLY THE PARAGRAPH WAS RE-WRITTEN AND THE
FOLLOWING EXCERPT INCLUDED : “GIVEN THAT FRAMEWORK, WE BELIEVE THE RESULTS OF
THIS STUDY CAN HELP TO CALL ATTENTION TO THE NEED OF DEVELOP RESEARCHS AIMING TO
ESTIMATE AND CHARACTERIZE ADE AND MEDICATION INVOLVED AS WELL AS THE ROLE OF
NUMBER OF DRUGS PRESCRIBED FOR INPATIENTS.”(DISCUSSION).
2- THE STATEMENTS ALONG THE TEXT ABOUT THE BIVARIATE ANALYSES WERE
PROBLEMATIZED AND SMOOTHED.
Authors: We included the text: [all text in conclusions]
- Reviewer: Firstly, the new conclusions are too long, as conclusions should
notinclude references nor new information that has not been discussed in
previous
parts of the discussion. Instead, conclusions should be “to-the-point” and easy to
comprehend with a quick read. I suggest moving text to the main discussion part.
Secondly, the conclusions should more strongly relate to the objectives of the
study - interventions and the trigger method are not in the objectives.
- Authors: As suggest, the conclusion section was reorganized and rewrite. The
paragraph “In 2013 Brazil’s Ministry of Health…” was moved to discussion
section.
- Reviewer: Please consider the previously given comments on the contribution
of the study and the conclusions. Currently, the conclusions do not reflect the aim
of the study and are not supported by the results of the study.
The conclusion section was reorganized
- Reviewer: See previous comments.
CONCLUSIONS
1-CHECKING THE PREVIOUS COMMENTS OF THE REVIEWER, STEP BY STEP: WE SHORTENED
THE CONCLUSIONS, AND WENT TO THE POINT IN ORDER TO REFLECT THE AIM OF THE STUDY;
PART OF THE TEXT WAS MOVED TO THE DISCUSSION SESSION; THE CONCLUSIONS WERE REWRITTEN BASED EXCLUSIVELY ON RESULTS; ASPECTS OF INTERVENTIONS AND TRIGGERS WERE
EXCLUDED.
2-PLEASE SEE MAJOR COMPULSORY REVISION 7.
MINOR ESSENTIAL REVISIONS
- Please harmonise the use of ”adverse drug events” vs ”ADEs”, throughout the
text.
As suggest, the use of “adverse drug events” and “ADEs” was harmonized.
- Reviewer: Please still replace “adverse drug events” with “ADEs” in these
sentences:
o Introduction: Accordingly, the trigger method was used in this study to evaluate
the incidence of adverse drug events and characterise them in terms of degree of
harm, medication implicated and patient symptoms, and to identify factors
associated with the occurrence of ADEs at a Brazilian university hospital.
DONE.
o Definition of ADE: Adverse drug event was defined as any injury occurring
during the patient’s drug therapy and…- New comment from Reviewer: In the beginning of
discussion, please modify
DONE.
“almost 15.0%”, to something less exact, e.g. close to one-sixth. The same for
other precise numbers.
DONE.
Level of interest:An article whose findings are important to those with closely
related research interests
Quality of written English:Acceptable
Statistical review:Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
'I declare that I have no competing interests