# Anti-infective prescribing practices in critically ill children on continuous renal replacement therapy: a multicenter survey of French-speaking countries

Michaël Thy, Jérôme Naudin, Mathieu Genuini, Stéphane Leteurtre, Morgan Recher

, Mehdi Oualha

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► To cite this version:

Michaël Thy, Jérôme Naudin, Mathieu Genuini, Stéphane Leteurtre, Morgan Recher, et al.. Anti-infective prescribing practices in critically ill children on continuous renal replacement therapy: a multicenter survey of French-speaking countries. Journal of Nephrology, 2023, 36 (9), pp.2541-2547. 10.1007/s40620-023-01762-1 . hal-05464281

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# Anti-infective prescribing practices in critically ill children on continuous renal replacement therapy: a multicenter survey of French-speaking countries

Michaël Thy¹,²,³, Jérôme Naudin⁴, Mathieu Genuini⁴,⁵, Stéphane Leteurtre⁶, Morgan Recher⁶, Mehdi Oualha²,³

On the behalf of the Groupe Francophone de Réanimation et d'Urgences Pédiatriques (GFRUP)

1 Department of intensive care and infectious diseases, AP-HP, Université Paris Cité, Bichat Hospital, Paris, France

2 Pediatric Intensive Care Unit, AP-HP, Université Paris Cité, Necker - Enfants Malades Hospital, Paris, France

3 EA 7323 - Pharmacology and Therapeutic Evaluation in Children and Pregnant Women, Université Paris Cité, Paris, France

4 Pediatric Intensive Care Unit, Hôpital Robert Debré, AP-HP, Université Paris Diderot, Paris, France.

5 Pediatric Intensive Care Transport Unit, Hôpital Robert Debré, AP-HP, Université Paris Diderot, Paris, France.

6 Univ. Lille, CHU Lille, ULR 2694 - METRICS: Évaluation des Technologies de Santé et des Pratiques Médicales, Lille, France

## Keywords

Renal replacement therapy; anti-infective; therapeutic drug monitoring; children

## Acknowledgments

Thanks to all participating pediatric ICUs from : Bruxelles, Caen, Clermont Ferrand, Geneve, Grenoble, La Réunion, Marseille, Lausanne, Liège, Lille, Lyon, Mayotte, Montpellier, Montréal, Nancy, Nantes, Paris (Kremlin-Bicêtre, Necker-Enfants Malades, Robert Debré, Trousseau), Reims, Rennes, Rouen, Strasbourg, Toulouse, Tours.
# ABSTRACT

## Background

Use of continuous renal replacement therapy (CRRT) in children receiving anti-infective drugs may lead to inappropriate concentrations with risks of treatment failure, toxicity and emergence of multidrug-resistant bacteria. We aimed to describe anti-infective prescribing practices in critically ill children undergoing CRRT.

## Methods

An online survey to assess CRRT, anti-infective prescribing and therapeutic drug monitoring (TDM) practices was sent by e-mail to physicians working in pediatric intensive care units (PICUs) through the French-speaking Group of Pediatric Intensive Care and Emergency medicine (GFRUP).

## Results

From April 1st 2021 to May 1st 2021, 26/40 different PICUs participated in the survey, corresponding to a response rate of 65%. Twenty-one were located in France and five abroad. All PICU practiced CRRT mainly with Prismaflex™ System. Anti-infective prescriptions were adjusted to the presence of CRRT in 23 (88%) PICUs mainly according to the molecular weight in 6 (23%), the molecule protein binding in 6 (23%) and the elimination routes in 15 (58%) including the residual diuresis in 9 (35%), to the CRRT flow in 6 (23%) and to the modality of CRRT used in 15 (58%), PICUs. There was a wide variability noticed between PICUs and between physicians in the
same unit. Barriers to TDM were mainly an excessive delay in obtaining results in 11 (42%) and the lack of an on-site laboratory in 8 (31%) PICUs.

## Conclusions

Our survey reported wide variability in anti-infective prescribing practices in children undergoing CRRT highlighting the gap in the knowledge and the need for education and recommendations.
## Background

Infections are a source of morbidity and mortality in critically ill children in pediatric intensive care units (PICU) [1]. In addition to the choice of the right anti-infective drug, the corresponding dosage must be optimal to reach an effective concentration in the infected site quickly and durably [1, 2]. Therapeutic drug monitoring (TDM) is the clinical pharmacological practice of measuring drug concentrations at specific intervals to maintain effective drug concentrations and thus optimize individual dosing regimens. The expected benefits are optimization of drug exposure, especially for drugs with narrow therapeutic margins, i.e. drugs that can be easily under or overdosed such as anti-infective agents [3]. In fact, many variables can affect drug concentrations: route of administration and dosage, time of blood collection, storage conditions, accuracy and precision of the analytical method, co-medications and the patient's clinical status (i.e. disease, renal/hepatic status, biological tolerance to drug therapy, etc.) [2, 4]. Overall, inter-subject variability in drug distribution and elimination is significant due to specificities related to patient age (growth, organ maturation) and severity of infectious disease (organ failures, alteration of drug protein binding, and fluid repartition) [5, 6]. Critical illness-related pharmacokinetic (PK) changes are amplified by the use of continuous renal replacement therapy (CRRT) [6]. CRRT is widely used in septic children with associated acute kidney injury [7]. Unlike adults, no suggestions nor recommendations for anti-infective dosing are available in children undergoing CRRT [8, 9]. In France, several tools are available, such as the French-language summary of product characteristics from VIDAL® paper or online version (https://www.vidal.fr/) or the GPR® website dedicated to dose adjustment to renal failure (http://sitegpr.com/fr/). Therefore, drug dosing in critically ill children is often based on extrapolation from studies in adult or non-
critically ill children [6, 10]. Neglecting the PK specificities of PICU patients could lead
to inappropriate and unpredictable anti-infective exposure, especially when they
require CRRT and thus risks of treatment failure, toxicities or emergence of resistant
bacteria.

Through an online survey, we aimed to describe anti-infective prescribing practices in
children undergoing CRRT to highlight issues and barriers to anti-infective dose
adjustment.

## Methods

### Construction of the questionnaire

The questions were written in French and distributed to all members of the research
group (JN, MG, MO) for comments using a modified Delphi technique. After several
revisions, the final questionnaire was approved. The questionnaire is available in the
Supplemental appendix. The report of this survey was written in accordance with the
“Checklist for Reporting Results of Internet E-Surveys” (CHERRIES) [11] (eTable 1).
The questionnaire was registered at the French Data Protection Authority
(Commission Nationale de l'Informatique et des Libertés - CNIL).

### Description of the survey

The survey was divided into three descriptive sections: 1) characteristics of the PICU, 2) practices of CRRT (continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis (CVVHD) or continuous veno-venous hemodiafiltration (CVVHDF)) or intermittent hemodialysis (IHD) or peritoneal dialysis (PD) (we excluded plasma exchanges and adsorption techniques) and management of CRRT
prescription (blood flow, dialysate flow, filtration flow rates), 3) adjustment strategies to optimize the dosing and the use of TDM for daily practice. Participants were asked whether they adjusted anti-infectives doses on CRRT. This included adjusting the dose (increasing or decreasing the dose per injection) and/or changing the infusion rate (increasing or decreasing the number of doses per day, increasing the duration of the infusion, including continuous infusion over 24 hours). When adjusting anti-infective dosing, participants were asked if they were basing their adjustments on: 1) PK parameters (molecular weight, protein-bound fraction, hydrophilic or lipophilic property, natural elimination routes, and residual diuresis) and/or 2) CRRT-related parameters (CRRT modalities: CVVH, CVVHD or CVVHDF), filtration, dialysis or diafiltration flow rates). We also aimed to explore what, if any, resources were used to adjust the dose of anti-infective drugs. Several suggestions were made at regarding potential barriers to the use of TDM, including the lack of an on-site laboratory, the complexity of the sampling process, delay in obtaining results, lack of advice on dose adjustment. A free response was also possible.

## Study population

We invited physicians in PICUs belonging to the French-speaking Group of Pediatric Intensive Care and Emergency Medicine (Groupe Francophone de Réanimation et d'Urgences Pédiatriques (GFRUP)) to participate in an online survey by e-mail. For the French PICUs, physician contact information was obtained from the GFRUP Pediatric Intensive Care Unit Registry (PICURe Registry), which included 339 e-mail addresses from 40 different PICUs at the time of mailing [12]. For the five foreign PICUs from Canada (n=1, Montreal), Switzerland (n=2, Geneva and Lausanne) and
Belgium (n=2, Brussels and Liège), the contact information was already known to the authors and these centers were included in the survey.

We sent the first e-mail on April 1st 2021 with an email reminder 15 days later. We closed the survey on May 1st 2021.

## Analysis

Responses were analyzed at two levels: by PICU and individually. If there were multiple responses for a PICU, the most complete form was used for analysis by PICU. Individual responses were then examined to assess heterogeneity of responses within a same PICU. We calculated the percentage within the PICU with more than one response to analyze the different responses within a same team. Results were expressed as median and interquartile range (IQR [25%–75%]) for continuous variables, and as numbers and percentages for categorical variables.

## Results

### Description of the PICU

In total, the form was completed by 26/40 different PICUs corresponding to a response rate of 65%. A total of 11/26 PICUs got more than one answer with a total of 45 respondents (13%). Of the 26 departments that responded, 11 were mixed pediatric and neonatal ICUs. The median number of intensive care beds was 12 [8-16] and intermediate care beds was 5 [2-8].

All PICUs (n=26/26) performed CRRT. The Prismaflex™ system (Baxter Healthcare Corporation, Chicago, IL, USA) was predominantly used (n=23, 88%) with dedicated
HF20, ST60, ST150 or Oxiris™ filters. The Carpediem™ (Cardio-Renal Pediatric Dialysis Emergency Machine) system (Medtronic Inc., Minneapolis, MN) with dedicated filters (polysulphone membranes) was used by 3 PICUs (12%). Peritoneal dialysis was also used by 22 PICUs (85%). The number of patients on CRRT per year reported by PICUs was classified as follows: <5 (n=3), between 5 and 10 (n=9), between 10 and 15 (n=8), between 15 and 20 (n=3), and >20 (n=3). Most CRRTs (n=16, 62%) were managed by the PICU team but 10 were managed by both the nephrology and PICU teams.

## Anti-infective dose adjustment on RRT

Anti-infective dosing was adjusted in the presence of CRRT in 23 (88%) PICUs. Anti-infective dose adjustment according to CRRT characteristics and dose adjustment modalities according to the anti-infective are shown in Figures 1 and 2 respectively. While CRRT modality was a parameter used to adjust anti-infectives (n=15, 58%), CRRT effluent flow rate (n=6, 23%) and presence of residual diuresis (n=9, 35%) were less considered. PK parameters such as molecular weight (n=6, 23%), drug-protein binding (n=6, 23%), lipophilic/hydrophilic nature of the drug (n=4, 15%) were poorly integrated into anti-infective dose adjustment strategies during CRRT sessions, with the exception for elimination routes (n=15, 58%).

Most PICUs reported not having protocols (n=20, 77%). More than half (n=16, 62%) of the PICUs used summaries of product characteristics in French, either general (n=12, 46% for VIDAL® paper or online version: https://www.vidal.fr/) or dedicated to renal failure (n=4, 15% for GPR® website: http://sitegpr.com/fr/). Anti-infective stewardship with a pharmacologist or an infectious disease specialist was available in 11 PICUs (42%).
## Anti-infective therapeutic drug monitoring

Available blood concentration measurements and TDM practices are shown in Table 1. Blood concentration measurements were primarily available for aminoglycosides (n=26, 100%) and glycopeptides (n=23, 88%). These were the two main anti-infectives currently monitored (69% and 65% of PICUs, respectively). For betalactams, blood concentration measurement was less available (n=17, 65%) and rarely monitored (n=8, 31%).

The main barriers to TDM were excessive delay (> 24h) in obtaining the results (n=11, 42%), lack of an on-site laboratory (n=8, 31%) and lack of advice on dose adjustment (n=8, 31%).

## Heterogeneity in the same PICU

In 11 PICUs where there was more than one response, it was possible to analyze different responses within the same team. In these PICUs, between two and five responses were discordant. Although complete agreement (100%) was reported on the need to adjust the dose, dose adjustment was performed disparately within the same PICU by the physician himself in an empirical manner or after expert advice (pharmacologist or infectious disease specialist). Practices differed regarding adjustment to molecular weight and protein binding in 3/11 (27%), to hydrophilic/lipophilic characteristics and residual diuresis in 4/11 (36%), and to elimination modality of RRT in 6/11 (55%) of the PICUs. Responses also varied regarding adjustment to effluent flow rate in 8/11 (73%) and means of obtaining information in 11/11 (100%) of the PICUs. Systematic differences in dose adjustment
therapy within the same PICU were reported, with some physicians increasing and
others decreasing the dose of all anti-infectives.

Discussion

To the best of our knowledge, our survey from the GFRUP's PICU network is the first to address the management of anti-infective drugs dosing in critically ill children on CRRT. Analysis of the survey responses showed two main results (i) a consensus on the need to adjust the dose of anti-infective drugs to the presence of CRRT; (ii) a large variability in the modalities of anti-infective dose adjustment in critically ill children on CRRT.

We hypothesize that this heterogeneity may be related to the lack of consensus
resources, guidelines and education reported by the PICUs and every physician of
our survey. Heterogeneity also concerned CRRT modalities which is consistent with
a previous study examining CRRT management in PICUs [13], further complicating
dose adjustment. Differences in practice appeared to be particularly important with
respect to the strategy for adjusting anti-infective doses according to CRRT
modalities and consideration of PK properties [2, 4, 5, 8] which was consistent with a
previous study in adult ICU regarding dose adjustment to CRRT [14].

While obviously influencing the drug elimination, CRRT parameters and PK
properties of anti-infective drugs were rarely considered for dose adjustment. We
noticed an important heterogeneity in the responses from the same PICU, especially
for the adjustment to effluent flow, even for low protein-binding and hydrophilic anti-
infectives where the elimination by CRRT may be the most affected (e.g. some beta-
lactams such as Meropenem). A significant proportion of the heterogeneity was due
to participants' unfamiliarity with dose adjustment. Although specific training courses
exist, training in the correct use of antibiotics during CRRT should be more widely
disseminated.

Most of the data come from adult studies and results from studies in critically ill
children are scarce and inconsistent [15–17]. This explains the lack of consensus
guidelines for dose adjustment during CRRT in critically ill children. Available
resources are therefore imperfect as they are based on adult studies and guidelines
[15]. In France, respondents reported the use of VIDAL® and GPR© [18, 19].
However, these sources did not provide specific data on the adjustment of anti-
infective doses in this particular context.

The lack of data and recommendations could be partially compensated by accessible
TDM. PK targets are known and dosing can be adjusted a posteriori according to
observed drug levels and microbiological findings [20–22]. However, the present
survey also highlighted the barriers to the use of TDM. Improving the accessibility of
TDM could be helpful in such situations to obtain results quickly. The development of
a point-of-care laboratory for on-site TDM of anti-infectives with pharmacological
advice seems crucial [23]. In addition, PK studies using population approach
modelling may be useful to optimize the dosing regimen for each patient [24].

Our study is the first comprehensive multicenter survey on this topic. However, it has
several limitations. Although the response rate was good [25], the conclusions may
not be representative of all PICUs. The intensivists who were more involved in this
topic were probably more likely to respond to our survey. This could have induced a
selection bias that could have underestimate practice variability. We could not
distinguish the physicians with potential two specialties including nephrology but the
experience in RRT (estimated by the number of patients on CRRT per year) was not
associated to different answers.

Nevertheless, the present survey highlighted the need for (i) improving knowledge of the PK of anti-infectives when used in critically ill children on CRRT; (ii) the familiarization of intensivists with the routine use of TDM; and (iii) the development of PK modelling and model-based precision dosing approaches. The main lines for adaptation of anti-infective dose adjustment in CRRT should integrate (i) PK parameters, especially for molecules with low protein binding, small volume of distribution and low molecular weight; (ii) dosing modification according to CRRT flow rates; (iii) use of TDM and bayesian adjustment, with model-informed precision dosing approach [26-28].

Conclusion

Our survey showed consensus on the importance of adjusting anti-infective doses in
PICU patients on CRRT, but there was a wide variation in how these doses were
adjusted. These findings highlight the need for education, additional research in this
area, and specific guidelines. Writing recommendations that review important PK
concepts, the potential impact of the different CRRT modalities, and good dosing
practices could be a first step toward improving the use of anti-infective drugs in
pediatric patients treated with CRRT in the PICU.
<table><caption>Table 1: Therapeutic drug monitoring (TDM) practices among the 26 PICUs</caption><thead><tr><th>n (%)</th><th>Dosing available</th><th>TDM currently performed</th><th>Systematically if it was available</th><th>In case of toxicity or inefficiency</th></tr></thead><tbody><tr><td>Beta-lactams</td><td>17 (65%)</td><td>8 (31%)</td><td>19 (73%)</td><td>5 (19%)</td></tr><tr><td>Aminoglycosides</td><td>26 (100%)</td><td>18 (69%)</td><td>22 (85%)</td><td>2 (8%)</td></tr><tr><td>Macrolides and relatives</td><td>3 (12%)</td><td>5 (19%)</td><td>5 (19%)</td><td>7 (27%)</td></tr><tr><td>Glycopeptides</td><td>23 (89%)</td><td>17 (65%)</td><td>21 (81%)</td><td>4 (15%)</td></tr><tr><td>Quinolones</td><td>2 (8%)</td><td>1 (4%)</td><td>7 (27%)</td><td>6 (23%)</td></tr><tr><td>Oxazolidinones (linezolid)</td><td>5 (19%)</td><td>2 (8%)</td><td>13 (50%)</td><td>7 (27%)</td></tr><tr><td>Rifampicin</td><td>3 (12%)</td><td>3 (12%)</td><td>9 (35%)</td><td>6 (23%)</td></tr><tr><td>Cotrimoxazole</td><td>2 (8%)</td><td>1 (4%)</td><td>10 (39%)</td><td>6 (23%)</td></tr><tr><td>Antivirals</td><td>4 (15%)</td><td>2 (8%)</td><td>16 (62%)</td><td>4 (15%)</td></tr><tr><td>Antifungals</td><td>9 (35%)</td><td>3 (12%)</td><td>15 (58%)</td><td>7 (27%)</td></tr></tbody></table>
<figure><img src="image_3.png" /><figcaption>Figure 1: Anti-infective dose adjustment according to CRRT characteristics per PICU</figcaption></figure>
<caption>**Figure 2: Adjustment modalities of anti-infective doses in children undergoing CRRT per PICU (n=26)**</caption>

**Legend:** No adjustment: No adjustment needed to CRRT or renal function; Unused drugs: Drugs not prescribed in the unit; Do not know: Do not know what strategy is appropriate for this molecule.

<figure><img src="image_4.png" /></figure>
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https://doi.org/10.1007/s00134-022-06921-9
<table><caption>eTable 1. Checklist for Reporting Results of Internet E Surveys (CHERRIES)</caption><caption>eTable 1. Checklist for Reporting Results of Internet E-Surveys (CHERRIES)</caption><thead><tr><th>Item category</th><th>Checklist item</th><th>Explanation</th><th>Text in manuscript is typed in italics</th></tr></thead><tbody><tr><td>Design</td><td>Describe survey design</td><td>Describe target population, sample frame. Is the sample a convenience sample? (In "open" surveys this is most likely).</td><td>"Mailing lists were provided by the Groupe Francophone de Réanimation et Urgences Pédiatriques (GFRUP)."</td></tr><tr><td rowspan="3">Institutional Review Board (IRB) approval and informed consent process</td><td>IRB approval</td><td>Mention whether the study has been approved by an IRB.</td><td>The study was approved by and registered at the French Data Protection Authority (Commission Nationale de l'Informatique et des Libertés - CNIL</td></tr><tr><td>Informed consent</td><td>Describe the informed consent process. Where were the participants told the length of time of the survey, which data were stored and where and for how long, who the investigator was, and the purpose of the study?</td><td>Initial contact with the potential participants was made by e-mail; the IRB considered it acceptable that consent was considered obtained if the respondent agreed to complete the questionnaire. Response to the survey was voluntary.</td></tr><tr><td>Data protection</td><td>If any personal information was collected or stored, describe what mechanisms were used to protect unauthorized access.</td><td>We did not collect any personal information.</td></tr><tr><td>Development and pre-testing</td><td>Development and testing</td><td>State how the survey was developed, including whether the usability and technical functionality of the electronic questionnaire had been tested before fielding the questionnaire.</td><td>The entire questionnaire is presented in Appendix in the supplemental digital content. To pretest and validate the</td></tr></tbody></table>
<table><tr><td></td><td></td><td></td><td>questionnaire, we first ensured its clarity, relevance, completeness and accuracy in group meetings with 7 pediatric intensivists</td></tr><tr><td>Recruitment process and description of the sample having access to the questionnaire</td><td>Open survey versus closed survey</td><td>An "open survey" is a survey open for each visitor of a site, while a closed survey is only open to a sample which the investigator knows (password-protected survey).</td><td>The survey was open to members of the Groupe Francophone de Réanimation et Urgences Pédiatriques (GFRUP).</td></tr><tr><td></td><td>Contact mode</td><td>Indicate whether or not the initial contact with the potential participants was made on the Internet. (Investigators may also send out questionnaires by mail and allow for Web based data entry.)</td><td>The questionnaire was sent by e-mail on April 1st 2021 with an email reminder 15 days later. The survey was closed on May 1st 2021.</td></tr><tr><td></td><td>Advertising the survey</td><td>How/where was the survey announced or advertised? Some examples are offline media (newspapers), or online (mailing lists - If yes, which ones?) or banner ads (Where were these banner ads posted and what did they look like?). It is important to know the wording of the announcement as it will heavily influence who chooses to participate. Ideally the survey announcement should be published as an appendix.</td><td>The questionnaire was sent by e-mail to intensivists working in academic PICUs in France. The survey was not announced or advertised.</td></tr><tr><td>Survey administration</td><td>Web/E-mail</td><td>State the type of e-survey (e.g. one posted on a Web site, or one sent out through e-mail). If it is an e-mail survey, were the responses entered manually into a database, or was there an automatic method for capturing responses?</td><td>Respondents accessed the questionnaire directly from a link in the e-mail they received. The study data were collected and managed using</td></tr></table>
<table><tr><td></td><td></td><td></td><td>Excel and electronic data entry tools hosted at the Necker Hospital.</td></tr><tr><td>Context</td><td>Describe the Web site (for mailing list/newsgroup) in which the survey was posted. What is the Web site about, who is visiting it, what are visitors normally looking for? Discuss to what degree the content of the Web site could pre-select the sample or influence the results. For example, a survey about vaccination on a anti-immunization Web site will have different results from a Web survey conducted on a government Web site.</td><td>The study data were collected and managed using Excel with electronic data capture tools hosted at Necker Hospital. There was no website.</td></tr><tr><td>Mandatory/ voluntary</td><td>Was it a mandatory survey to be filled in by every visitor who wanted to enter the Web site, or was it a voluntary survey?</td><td>Completion of the survey was voluntary.</td></tr><tr><td>Incentives</td><td>Were any incentives offered (e.g. monetary, prizes, or non-monetary incentives such as an offer to provide the survey results)?</td><td>The only incentive was that we offered to send the survey results to respondents once the article was published.</td></tr><tr><td>Time/date</td><td>In what timeframe were the data collected?</td><td>From April 1st 2021 and May 1st 2021.</td></tr><tr><td>Randomization of items or questionnaire</td><td>To prevent biases items can be randomized or alternated.</td><td>Not done.</td></tr><tr><td>Adaptive questioning</td><td>Adaptive questioning (certain items, or only conditionally displayed based on responses to other items) to reduce number and complexity of the questions.</td><td>No adaptive questioning. eTable 2 shows the complete questionnaire.</td></tr><tr><td>Number of items</td><td>What was the number of questionnaire items per page? The number of items is an important factor for the completion rate.</td><td>The questionnaire was not printed. It included 23 questions formatted in Google Form® with three sections :</td></tr></table>
<table><tr><td></td><td></td><td></td><td>1) characteristics of the PICU,<br/>2) practices of RRT (CRRT (hemofiltration (CVVH), dialysis (CVVHD) or diafiltration (CVVHDF) or intermittent hemodialysis (IHD) or peritoneal dialysis (PD)) and management of RRT (blood flow, dialysate flow, filtration flow rates),<br/>3) usual anti-infective prescription, adjustment strategies and drug monitoring only for patient undergoing CRRT.</td></tr><tr><td>Number of screens</td><td>Over how many pages was the questionnaire distributed? The number of items is an important factor for the completion rate.</td><td>The questionnaire was not printed. It included 23 questions formatted in Google Form® with three sections :<br/>1) characteristics of the PICU,<br/>2) practices of RRT (CRRT (hemofiltration (CVVH), dialysis (CVVHD) or diafiltration (CVVHDF) or intermittent hemodialysis (IHD) or peritoneal dialysis (PD)) and management of RRT (blood flow, dialysate flow, filtration flow rates),<br/>3) usual anti-infective prescription, adjustment strategies and drug monitoring only for patient undergoing CRRT.</td></tr></table>
<table><tr><td></td><td></td><td></td><td>prescription, adjustment strategies and drug monitoring only for patient undergoing CRRT.</td></tr><tr><td></td><td>Complete-ness check</td><td>It is technically possible to do consistency or completeness checks before the questionnaire is submitted. Was this done, and if “yes”, how (usually JAVASCRIPT)? An alternative is to check for completeness after the questionnaire has been submitted (and highlight mandatory items). If this has been done, it should be reported. All items should provide a non-response option such as “not applicable” or “rather not say”, and selection of one response option should be enforced.</td><td>To pretest and validate the questionnaire, we first ensured its clarity, relevance, completeness and accuracy in group meetings with authors who are pediatric intensivists In addition, all items had a non-response option such as “not applicable” or “not used”. The selection of one answer option per question was imposed.</td></tr><tr><td></td><td>Review step</td><td>State whether respondents were able to review and change their answers (e.g. through a Back button or a Review step which displays a summary of the responses and asks the respondents if they are correct).</td><td>Respondents were able to review and edit their responses until they check the “submit” button at the end of the survey.</td></tr><tr><td>Response rates</td><td>Unique site visitor</td><td>If you provide view rates or participation rates, you need to define how you determined a unique visitor. There are different techniques available, based on IP addresses or cookies or both.</td><td>Visitors were asked to respond only once. The IP address of the client computer was used to identify possible duplicate entries from the same user.</td></tr><tr><td></td><td>View rate (ratio unique site visitors /unique</td><td>Require counting unique site visitors (not page views) divided by the number of unique visitors of the first page of the survey. It is not unusual to have views rates of less than 0.1% if the survey is voluntary.</td><td>Not reported. There would be a confidentiality issue if we asked respondents to disclose which PICU they work in.</td></tr></table>
<table><tr><td></td><td>survey visitors</td><td></td><td>Therefore, we did not collect data on the number of respondents per site.</td></tr><tr><td></td><td>Participation rate (ratio unique survey page visitors /agreed to participate.</td><td>Count the unique number of visitors who visit the first page of the survey (or the informed consents page, if present) divided by the number of people who filled in the first survey</td><td>The questionnaire was completed by 26 (63%) PICUs among 40 PICUs with 50 participants among 399 eligible respondents (12.5%) in 4 countries.</td></tr><tr><td></td><td>Completion rate (ratio agreed to participate /finished survey)</td><td>The number of people agreeing to participate (or submitting the first survey page) divided by the number of people submitting the last questionnaire page. This is only relevant if there is a separate "informed consent" page or if the survey goes over several pages. This is a measure for attrition. Note that "completion" can involve leaving questionnaire items blank. This is not a measure for how completely questionnaires were filled in. (If you need a measure for this, use the word "completeness rate".)</td><td>Irrelevant: there was no attrition.</td></tr><tr><td rowspan="2">Preventing multiple entries from the same individual</td><td>Cookies used</td><td>Indicate whether cookies were used to assign a unique user identifier to each client computer. If so, mention the page on which the cookie was set and read, and how long the cookie was valid. Were duplicate entries avoided by preventing users access to the survey twice; or were duplicate database entries having the same user ID eliminated before analysis? In the latter case, which entries were kept for analysis (e.g. the first entry or the most recent)?</td><td>No cookies were used.</td></tr><tr><td>IP check</td><td>Indicate whether the IP address of the client computer was used to identify potential duplicate entries from the same user. If so, mention the period of time for</td><td>The IP address of the client computer was used to identify possible duplicate entries</td></tr></table>
<table><tr><td></td><td>which no two entries from the same IP address were allowed (e.g. 24 hours). Were duplicate entries avoided by preventing users with the same IP address access to the survey twice; or were duplicate database entries having the same IP address within a given period of time eliminated before analysis? If the latter, which entries were kept for analysis (e.g., the first entry or the most recent?</td><td>from the same user.<br/>Visitors were asked to complete the survey only once.</td></tr><tr><td>Log file analysis</td><td>Indicate whether other techniques to analyze the log file for identification of multiple entries were used. If so, please describe.</td><td>We did not use any other techniques to analyze the log file to identify multiple entries.</td></tr><tr><td>Registration</td><td>In "closed" (non-open) surveys, users need to login first and it is easier to prevent duplicate entries from the same user. Describe how this was done. For example, was the survey never displayed a second time once the user had filled it in, or was the username stored together with the survey results and later eliminated? If the latter, which entries were kept for analysis (e.g. the first entry or the most recent)?</td><td>The survey was open.</td></tr><tr><td>Analysis</td><td>Handling of incomplete questionnaire<br/>Were only completed questionnaires analyzed? Were questionnaires which terminated early (where, for example, users did not go through all questionnaire pages) also analyzed.</td><td>All completed questionnaires were analyzed</td></tr><tr><td></td><td>Questionnaires submitted with an atypical timestamp<br/>Some investigators may measure the time people needed to fill in a questionnaire and exclude questionnaires that were submitted too soon. Specify the timeframe that was used as a cut-off point, and describe how this point was determined.</td><td>N/A</td></tr><tr><td></td><td>Statistical correction<br/>Indicate whether any methods such as weighting of items or propensity scores have been used to adjust for</td><td>N/A</td></tr></table>
<table><tr><td></td><td></td><td>the non-representative sample; if so, please describe the methods.</td></tr></table>

Eysenbach G. (2004). Improving the quality of web surveys: the checklist for reporting results of internet e- surveys (cherries). *Journal of Medical Internet Research*, 6(3)e34 doi:10.2196/jmir.6.3.e34 http://www.jmir.org/2004/3/e34/
**<u>Supplemental appendix : Survey form (translated from French)</u>**

1. In which department do you work ?

specifying the hospital and the city

2. Number of critical care beds in your department

3. Number of intermediate care or critical care beds in your ward

4. Population:

Only one possible answer

Pediatrics

Pediatrics and Neonatology

Neonatology

**Your use of extrarenal replacement therapy (RRT)**

**5. What techniques of RRT are used in your department ?**

Several answers are possible.

*Several possible answers.*

Continuous veno-venous hemofiltration (CVVH)

Continuous veno-venous hemodialysis (CVVHD)

Continuous veno-venous hemodiafiltration (CVVHDF)

Intermittent hemodialysis (IHD)

Peritoneal dialysis (PD)

Other :

6. Your department's RRT is managed :

Only one possible answer.

By your unit

By the nephrology unit

Both

Other :

7. Approximate number of children on RRT per year ?
Only one possible answer

< 5

Between 5 and 10

Between 10 and 15

Between 15 and 20

> 20

8. What is the brand of your RRT generator?

Several answers are possible.

Several possible answers.

FRESENIUS MULTIFILTRATE

BAXTER-PRISMAFLEX

INFOMED HF440

AQUARIUS

BRAUN

CARPEDIEM

Do not know

Other :

9. What type(s) of membrane/filter do you use ?

Several answers are possible.

Several possible answers.

HF20

ST60

ST150

Other :
Use of anti-infectives under RRT

N.B.: For a given patient and a given RRT technique (CRRT, IHD or PD)

10. Do you adjust a priori (without knowing the plasma assays) the dosage of anti-infectives in a patient on RRT ?

"Dose adjustment" = increase or decrease in dose per injection;
and/or

"Infusion rate modification" = increase or decrease in number of doses per day, increase in duration of infusion, including continuous infusion over 24 hours.

Only one possible answer.

Yes

No

I don't know

11. If Yes, which of the following do you consider when making a priori adjustments to the dosage of anti-infectives in a patient on RRT ?

*Only one answer possible per line.*

Yes No

Molecular weight

Protein-bound fraction

Hydrophilic or lipophilic
character

Natural elimination pathways

Residual diuresis

The modality of RRT
(Hemofiltration, dialysis or
diafiltration)

The flow rates of filtration,
dialysis or diafiltration

Other
12. For a given patient and a given RRT technique (CRRT, IHD or PD), do you use drug databases to adjust "a priori" the dosage of anti-infectives ?

A priori = when initiating anti-infective treatment in a patient on RRT OR when initiating RRT in a patient already under anti-infective treatment and therefore without knowledge of the results of the plasma assays.

*Several possible answers*

VIDAL®

Thériaque®

Thésorimed®

Clickadoc®

Claude Bernard®

IBM-Micromedex®

AntibioClic®

None

Other : _________________

13. For a given patient and a given RRT technique (CRRT, IHD or PD), do you use government agency guidelines to adjust anti-infective dosing "a priori" ?

A priori = initiation of anti-infective treatment in a patient on RRT OR initiation of an RRT in a patient already under anti-infective treatment and therefore without knowledge of the results of the plasma assays.

*Several possible answers*

EMA: European Medicine Agency

FDA: U.S. Food and Drug Administration

None

Other : _________________

14. For a given patient and a given RRT technique (CRRT, IHD or PD), do you use dedicated websites or expert societies to adjust “a priori” the dosage of anti-infectives?

A priori = when initiating anti-infective treatment in a patient on RRT OR when initiating RRT in a patient already under anti-infective treatment and therefore without knowledge of the results of the plasma assays.

*Several possible answers*

GPR®

ICARE®

None

Other : _________________
15. For a given patient and a given RRT technique (CRRT, IHD or PD), do you use other sources to adjust “a priori” the anti-infective dosage?

A priori = when initiating anti-infective treatment in a patient on RRT OR when initiating RRT in a patient already under anti-infective treatment and therefore without knowledge of the results of the plasma assays.

Several possible answers

Literature

Expert opinion (nephrology/antibiotic stewardship team/pharmacology department)

Service protocol

None

Other : _________________

16. Do you usually adjust a priori (without knowing the plasma assays) the dosing of the anti-infectives listed below in a patient on RRT?

A priori = the initiation of anti-infective treatment in a patient on RRT OR the initiation of an RRT in a patient already on anti-infectives and therefore without knowledge of the result of plasma assays.
Several answers are possible.

*Only one answer possible per line.*

<u>Possible choices:</u>

Decrease in daily dose

Increase in daily dose

Switching to continuous or extended infusion

No adaptation

Unused drug

Do not know

<u>Molecules:</u>

Penicillins

Cephalosporins

Carbapenems

Aminoglycosides

Glycopeptides

Macrolides and related

Quinolones

Oxazolidones (linezolide)

Rifampicin

Cotrimoxazole
Antivirals (aciclovir, ganciclovir, cidofovir)

Azole antifungals (puconazole, posaconazole, voriconazole, itraconazole)

Antifungal Echinocandins

Therapeutic drug monitoring

17. Do you have a pharmaco/toxicology department in or near your center ?

Only one possible answer.

Yes

No

18. What concentrations of anti-infectives are measured in your center ?

Several answers are possible

Beta-Lactam

Aminoglycosides

Macrolides and related

Glycopeptides

Quinolones

Oxazolidones (linezolide)

Rifampicin

Cotrimoxazole

Antivirals (aciclovir, ganciclovir, cidofovir)

Azole antifungals (puconazole, posaconazole, voriconazole, itraconazole)

Echinocandins

None

Other :

19. Do you do therapeutic drug monitoring (plasma assays) under RRT?

Several answers are possible.

Yes systematically for all anti-infectives

Beta-lactams

Aminoglycosides

Macrolides and related:

Glycopeptides

Quinolones

Oxazolidones (linezolide)

Rifampicin

Cotrimoxazole

Antivirals (aciclovir, ganciclovir, cidofovir)

Azole antifungals (puconazole, posaconazole, voriconazole, itraconazole)

Echinocandins

No

Other :
20. If available, in the patient under RRT, would you do therapeutic drug monitoring (plasma assays)?

Several possible answers

**Possible choices:**

- Systematically

- If toxicity is suspected

- If ineffectiveness is suspected

- No

- Drug little or not used

**Molecules:**

- Beta-lactams

- Aminoglycosides

- Macrolides and related

- Quinolone glycopeptides

- Oxazolidones (linezolide)

- Rifampicin

- Cotrimoxazole

- Antivirals (aciclovir, ganciclovir, cidofovir)

- Azole antifungals (puconazole, posaconazole, voriconazole, iitraconazole)

- Anti-fungal Echinocandins

21. What are the barriers to therapeutic drug monitoring of anti-infectives on RRT when you find it useful ?

Several answers are possible.

- No dedicated lab

- Complexity of the sampling process

- Time to obtain results

- Lack of dosing adjustment advice

- Other:

22. How do you adjust the dosage according to the measured concentration (plasma assays)?

Several answers are possible.

- Empirically

- According to specialized opinion (pharmacologist, infectiologist)

- Based on pharmacological models

- I don't know

- Other:
23. Would you be interested in participating in a study involving :

Several possible answers

Therapeutic drug monitoring of the majority of anti-infective classes

A (Bayesian) dose adjustment based on pharmacological models

No

Other : _________________________________