Variation in hydration use after reinfusion of autologous stem cells in dimethyl sulfoxide (DMSO): a survey of EBMTcenters on behalf of the EBMT Nurses Group

TO THE EDITOR: Cryopreservation of hematopoietic stem cells (HSCs) using Dimethyl sulfoxide (DMSO) is the most commonly used procedure allowing infusion of collected stem cells at a later date [1]. Unfortunately, DMSO is known to cause a range of adverse events (AEs) in the recipient of the HSC-suspension. Most clinical side effects of DMSO include nausea, vomiting, and hypotension [2]. Almost all recipients of DMSO-cryopreserved HSCs experience AEs or serious complications during the infusion [3]. Strategies to reduce DMSO related toxicity include use of premedications (e.g., corticosteroids, antihistamines, acetaminophen), hydration given post-reinfusion of HCSs, reduced DMSO concentration, removal of DMSO after thawing or using alternative cryoprotectants for DMSO [3–5]. Post-reinfusion hydration is a standardized amount of intravenous fluid given shortly after HSC reinfusion (<24 h). Consensus is lacking regarding hydration volume and there appears to be no scientific background for this strategy. One aim of intravenous hydration is reduction of DMSO plasma concentration by dilution. DMSO has a high distribution volume (Vd) [6]. Vd is a constant ratio of the total amount of drug in the body to the plasma concentration of the drug at a given time. A drug with a high Vd enters the extravascular compartments of the body easily after infusion [7], therefore a low concentration of DMSO is measured in the plasma after infusion. Dilution of this low plasma concentration of DMSO by intravenous hydration, may not give the intended effect of reducing toxicity, because the remaining concentration of DMSO is in the extravascular tissue. To our knowledge, many EBMT hospitals still use the practice strategy of post-reinfusion hydration to reduce DMSO toxicity, which does not appear to be evidence-based. This survey describes the current post-reinfusion hydration practices of EBMT centers and the rationale. The EBMT Nurses Group Research Committee conducted a survey investigating current practices in hydration after autologous stem cell transplantation and to gain insight into the reasons behind this practice. All EBMT centers were invited to participate (N= 510). Questions were identified following review of literature regarding hydration post-infusion of HSCs [8]. The questionnaire (supplementary information 1) consisted of 37 questions including information regarding the center and respondent, questions concerning the use of hydration in relation to HSC reinfusion, practice prior to and after HSC reinfusion, and AEs after HSC reinfusion. Data were analyzed by the EBMT Leiden Study Unit, the Netherlands. Descriptive statistics were used to provide summaries on current practice regarding to hydration after auto-HSCT among EBMT member centers. Eighty-eight centers from 24 countries responded. Results from 24 centers were excluded from analysis as they treated only children, only performed allogeneic transplantations, removed DMSO before reinfusion or had missing data (>40% items missing). Sixty-four questionnaires from 64 centers were analyzed (for summary statistics, see Supplementary Information 2). Sixty-three centers reported having a Standard Operating Procedure (SOP) for HSC reinfusion (98.4%) (Table 1). Preand post-reinfusion hydration was included in the SOP of 32 centers (50.8%). Twelve centers (19.0%) only gave pre-reinfusion hydration and just six (9.5%) only hydration post-reinfusion. To prevent adverse reactions, premedication was given prior to the reinfusion in 58 (93.6%) centers. Most centers (n= 31; 48.4%) used a 10% concentration DMSO-solution. A smaller percentage of centers used 7.5% DMSO solution (n= 2; 3.1%) or 5% DMSO solution (n= 9; 14.1%). The remaining 22 respondents (34.4%) did not know which solution was used in their center (Table 1). Most responding centers gave some form of hydration after autologous HSC reinfusion. Thirty-four centers (53.0%) gave the same amount of post-hydration to each patient (Table 1). Eighteen centers (28.1%) gave hydration depending on patient characteristics or the regimen of chemotherapy chosen. Two centers (3.1%) gave hydration only when there was insufficient oral intake. Ten centers (15.6%) stated they never gave post-reinfusion hydration. Sixteen (26.2%) centers responded that there was a scientific background for this practice, with six centers also responding that this practice was based on a published article or textbook. On requesting the reference for this evidence, none of the six responders provided this detail. Respondents were asked for the reasons why hydration was given, with multiple answers being permitted (Table 1). The most frequently reported reason for postreinfusion hydration was ‘to protect the kidneys from DMSO’ and ‘to flush out DMSO’ (84.3%). In 27 of the 43 responses (62.8%) multiple reasons for hydration were given not only related to DMSO. Thirty-seven percent of respondents gave non DMSOrelated reasons for hydration post-reinfusion. A wide variation of responses in type of fluid was observed (Table 1). Over half of centers used normal saline (51.9%). Other fluids used included saline-glucose solutions (24.1%), Ringers Lactate/Hartmann’s solution (11.1%) and glucose 5% (1.9%). The questionnaire asked an estimation of AE frequency after HSC reinfusion. In the first hour after reinfusion, taste changes, nausea and flushing were most frequently reported AEs. From 1 to 24 h after reinfusion, taste changes, and nausea and vomiting were most common (Supplementary Information 2).


TO THE EDITOR:
Cryopreservation of hematopoietic stem cells (HSCs) using Dimethyl sulfoxide (DMSO) is the most commonly used procedure allowing infusion of collected stem cells at a later date [1]. Unfortunately, DMSO is known to cause a range of adverse events (AEs) in the recipient of the HSC-suspension. Most clinical side effects of DMSO include nausea, vomiting, and hypotension [2]. Almost all recipients of DMSO-cryopreserved HSCs experience AEs or serious complications during the infusion [3].
Post-reinfusion hydration is a standardized amount of intravenous fluid given shortly after HSC reinfusion (<24 h). Consensus is lacking regarding hydration volume and there appears to be no scientific background for this strategy. One aim of intravenous hydration is reduction of DMSO plasma concentration by dilution. DMSO has a high distribution volume (Vd) [6]. Vd is a constant ratio of the total amount of drug in the body to the plasma concentration of the drug at a given time. A drug with a high Vd enters the extravascular compartments of the body easily after infusion [7], therefore a low concentration of DMSO is measured in the plasma after infusion. Dilution of this low plasma concentration of DMSO by intravenous hydration, may not give the intended effect of reducing toxicity, because the remaining concentration of DMSO is in the extravascular tissue. To our knowledge, many EBMT hospitals still use the practice strategy of post-reinfusion hydration to reduce DMSO toxicity, which does not appear to be evidence-based. This survey describes the current post-reinfusion hydration practices of EBMT centers and the rationale.
The EBMT Nurses Group Research Committee conducted a survey investigating current practices in hydration after autologous stem cell transplantation and to gain insight into the reasons behind this practice. All EBMT centers were invited to participate (N = 510). Questions were identified following review of literature regarding hydration post-infusion of HSCs [8]. The questionnaire (supplementary information 1) consisted of 37 questions including information regarding the center and respondent, questions concerning the use of hydration in relation to HSC reinfusion, practice prior to and after HSC reinfusion, and AEs after HSC reinfusion. Data were analyzed by the EBMT Leiden Study Unit, the Netherlands. Descriptive statistics were used to provide summaries on current practice regarding to hydration after auto-HSCT among EBMT member centers.
Eighty-eight centers from 24 countries responded. Results from 24 centers were excluded from analysis as they treated only children, only performed allogeneic transplantations, removed DMSO before reinfusion or had missing data (>40% items missing). Sixty-four questionnaires from 64 centers were analyzed (for summary statistics, see Supplementary Information 2).
Most responding centers gave some form of hydration after autologous HSC reinfusion. Thirty-four centers (53.0%) gave the same amount of post-hydration to each patient (Table 1). Eighteen centers (28.1%) gave hydration depending on patient characteristics or the regimen of chemotherapy chosen. Two centers (3.1%) gave hydration only when there was insufficient oral intake. Ten centers (15.6%) stated they never gave post-reinfusion hydration. Sixteen (26.2%) centers responded that there was a scientific background for this practice, with six centers also responding that this practice was based on a published article or textbook. On requesting the reference for this evidence, none of the six responders provided this detail. Respondents were asked for the reasons why hydration was given, with multiple answers being permitted ( Table 1). The most frequently reported reason for postreinfusion hydration was 'to protect the kidneys from DMSO' and 'to flush out DMSO' (84.3%). In 27 of the 43 responses (62.8%) multiple reasons for hydration were given not only related to DMSO. Thirty-seven percent of respondents gave non DMSOrelated reasons for hydration post-reinfusion. A wide variation of responses in type of fluid was observed (Table 1). Over half of centers used normal saline (51.9%). Other fluids used included saline-glucose solutions (24.1%), Ringers Lactate/Hartmann's solution (11.1%) and glucose 5% (1.9%).
The questionnaire asked an estimation of AE frequency after HSC reinfusion. In the first hour after reinfusion, taste changes, nausea and flushing were most frequently reported AEs. From 1 to 24 h after reinfusion, taste changes, and nausea and vomiting were most common ( Supplementary Information 2). This survey shows that the use of intravenous hydration postreinfusion of HSCs is still common practice in many transplant centers, but there is no consensus in the choice of fluid or volume and the evidence regarding hydration in literature is scarce. The 'Oxford Handbook of Cancer Nursing' states that the patient should be pre-and post-hydrated to counter the dehydrating effects of DMSO [9], however the basis of this statement is unclear. Ferrucci et al. (2000) suggest post-reinfusion hydration and allopurinol administration may facilitate cell debris elimination by the renal tract [5]. Similarly, the rationale for this statement is unclear and evidence is lacking to be able to confirm these hypotheses.
The scientific rationale for using hydration post-reinfusion was assumed by some of the respondents, but the sources of this information were unfortunately not shared. It is not possible to verify what evidence is available for these healthcare professionals to support this clinical practice. The use of DMSO was the most commonly cited reason for giving hydration, but often there were various combinations of reasons for hydrating patients.
Adverse events due to post-hydration, such as acute decompensated heart failure, are known [10], however this questionnaire investigated only AEs occurring post HSC reinfusion. Nevertheless post-reinfusion hydration is not useful to wash out DMSO, and may be contraindicated. Greater understanding about the mechanisms of DMSO and ways to prevent AEs are needed.
While this study provides an insight into clinical practice in relation to hydration post HSC reinfusion, there are limitations with the study. Survey questions were designed, reviewed, and pretested by the same group of hematology professionals which may be a source of bias. Responses to questions regarding the incidence of AEs are subjective, dependent respondent recall. While this provides interesting information from the sample, it is difficult to draw conclusions from these answers. Although not all invited centers responded, the survey was completed by staff with significant experience, and this will surely contribute to the knowledge base regarding this particular practice.
In conclusion, hydration post-reinfusion appears a common practice among EBMT centers, but there is no consensus in the choice of fluid or volume. Scientific rationale for hydration postreinfusion was assumed but not provided, and evidence is lacking to suggest hydration post-reinfusion will reduce the toxicity of DMSO in a relevant way. Further research is necessary to explore ways to implement the existing knowledge of DMSO use and hydration post-reinfusion of stem cells.  SOP standard operating procedure, DMSO dimethylsulfoxide. *Among those indicating using hydration after reinfusion of autologous stem cell, whether always or depending on patient/treatment characteristics or insufficient oral intake.