A comparison of the effectiveness of two online haemodiafiltration modalities: mixed versus post-dilution

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"apellidos" => "Ruiz-Álvarez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Infanta Leonor, Madrid, Spain, " "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Infanta Leonor, Madrid, " "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Laboratorio de Bioquímica, Hospital Universitario Infanta Leonor, Madrid, Spain, " "etiqueta" => "c" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Laboratorio de Bioquímica, Hospital Universitario Infanta Leonor, Madrid, " "etiqueta" => "d" "identificador" => "affd" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Comparación de la eficacia de dos modalidades de hemodiafiltración en línea: mixta frente a posdilucional" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52186_en_t1.12223.jpg" "Alto" => 634 "Ancho" => 2171 "Tamanyo" => 286774 ] ] "descripcion" => array:1 [ "en" => "Main studies that analyse the effect of online haemodiafiltration on mortality in dialysis patients" ] ] ] "textoCompleto" => "INTRODUCTION Haemodiafiltration (HDF) with high reinfusion volumes is the most effective uraemic toxin clearance technique, particularly for medium-sized molecules, whose removal is significantly higher with convective techniques. Several studies have shown that HDF improves some complications in haemodialysis (HD) patients, such as hyperphosphataemia,1 malnutrition,2 growth in children,3 the response to erythropoietin4 and to vitamin D5 and dialysis-associated amyloidosis, amongst others.6 There is currently evidence that shows a higher survival rate in patients who undergo dialysis with online HDF (OL-HDF) compared to those on HD,7-10 as we will discuss later. The good results obtained in these studies were determined by the convective transport volume achieved, which was generally more than 20-24l per session.There are different OL-HDF modalities, depending on the location where the replacement volume is administered in the extracorporeal circuit. In pre-dilution HDF, the dialysate is infused before the entry of blood in the dialyser, which results in haemodilution and decreased diffusive transport. In post-dilution HDF, the dialysate is administered after the dialyser, such that it does not interfere in diffusive transport, but it creates a blood concentration in the dialyser that may increase pressure and cause coagulation problems. Post-dilution HDF is considered the most efficient form. In addition to these most common modalities, there are another two OL-HDL forms in which infusion is carried out simultaneously pre- and post-dilution: mixed OL-HDF and mid-dilution OL-HDF. In mixed OL-HDF, the replacement fluid is infused simultaneously pre- and post-dilution, with the pre- and post-dilution infusion percentage being regulated automatically via transmembrane pressure (TMP) and ultrafiltration (UF) feedback. Mid-dilution requires a special dialyser, in which blood enters through a central fibre bundle and returns in the opposite direction through peripheral fibres. The reinfusion liquid is incorporated between the two dialyser sections; as such, in the first section there is post-dilution HDF and in the second section there is pre-dilution HDF. These mixed OL-HDF forms are a good alternative, since they theoretically avoid the reported disadvantages of pre- and post-dilution OL-HDF. The choice between one modality and the other will depend on the haemorheological characteristics and the blood flow with which the patient is dialysed.The reported benefits of HDF are based on post-dilution OL-HDF results. The convective volume quantity administered seems to be decisive in improving survival rates. This volume per session was 15l in the European Dialysis Outcomes and Practice Pattern Study (DOPPS),7 17.4l in the Turkish study,8 21.9l in the Convective Transport Study (CONTRAST)9 and 23.1l in the Online Haemodiafiltration Study (ESHOL)10 (Table 1). These studies highlight the need to achieve high convective volumes in order to reduce mortality.In spite of the importance of the convective volume quantity shown in these studies, we do not know the infusion volume equivalence between the different OL-HDF modalities. Recently, the EUDIAL group11 advised the use of an OL-HDF dilution factor whenever the volume is fully or partially infused before the dialyser (pre-dilution, mid-dilution and mixed dilution modalities). It also insisted on the importance of measuring the effective convective volume adjusted to the body surface in order to quantify the effectiveness of OL-HDF.The quantity of the convective volume administered has been directly related to the clearance of medium-sized molecules.12,13 Studies that have analysed effectiveness in the removal of solutes comparing convective techniques show that post-dilution infusion is the most effective form for clearing both small, medium-sized and large molecules.14-16 Only Pedrini17 has studied mixed pre-dilution infusion and found a higher reduction percentage in β2-microglobulin (β2m) with mixed HDF in comparison with pre-dilution infusion and similar results to post-dilution infusion (72.1% in mixed, 69.2% in pre-dilution and 74.7% in post-dilution HDF). OBJECTIVE To compare the clearance of small, medium-sized and protein-bound molecules and the convective volume of OL-HDF administered with post-dilution and mixed (pre- and post-dilution) infusion in patients on treatment with OL-HDF, in oder to determine the litres of convective volume required with both techniques to achieve equal clearance efficiency. MATERIAL AND METHOD Design A prospective, randomised, crossover study comparing post-dilution and mixed OL-HDF (Figure 1). Patients were randomly assigned to receive 6 consecutive post-dilution OL-HDF sessions, followed or preceded by 6 mixed OL-HDF sessionsEach patient was a control of themselves and no changes were made to the dialysis regimen or the pharmacological treatment throughout the study.Given that the modern dialysis monitors interrupt the procedures due to auto-checks that increase the safety, making the effective time (ET) or real time of treatment less than the scheduled time (ST) or the time prescribed by the doctor, these variables were taken into account. The regular regimen was followed, dialysing at ST in sessions 1, 3, 4 and 6, while in session 2 and 5, we dialysed at ET, extending it as needed to match the real time and the scheduled time.To assess the effectiveness of the technique, we measured clearance of molecules by the reduction percentage of said substances and the convective volume quantity administered. Patients and dialysis technique The inclusion criteria were: patients older than 18 years of age on dialysis treatment three times a week and with a minimum of three months on OL-HDF treatment.The exclusion criteria were: the presence of haemodynamic instability with frequent hypotension, patients contraindicated for heparin use, presence of residual renal function (RRF) defined as mean urea and creatinine clearance of more than 1ml/min or blood flow (Qs) less than 250ml/min.All patients signed their informed consent at the time of inclusion.All sessions were carried out with one dialysis monitor: ST5008 (Fresenius, FMC, Bad Homburg, Germany) and using the dialyser FXCorDiax1000 (Fresenius, FMC, Bad Homburg, Germany).Characteristics of the dialyser: helixone membrane, area of 2.3m2 and UF ratio: 76ml/h/mmHg.In the dialysis unit we used ultrapure dialysate18 defined by colony forming unit levels/ml less than 0.1 and endotoxins less than 0.03UE/ml.The post-dilution infusion mode was controlled by the monitor, taking into account total protein values, haematocrit and the dialyser’s hydraulic permeability.The mixed infusion mode was controlled by UF-TMP feedback. This feedback automatically adjusted the rate and location of infusion (pre-/post-dilution) to the maximum filtration fraction taking into account the flow conditions, internal pressure and hydraulic permeability of the dialyser and its interactions. The system regulated the degree of pre-/post-infusion by two independent infusion pumps whose infusion speed was modulated by internal software depending on the value of TMP, with the aim of maintaining the TMP between 250 and 300mmHG.19,20 TMP was instantly calculated according to the pressure in the four points through the formula:TMPm = 0.5 x [(P blood dialyser entry + P blood dialyser exit) - (P dialysate entry + P dialysate exit)] Laboratory tests Seventy-two hours before the start of the study (last session before start of study) we measured haematocrit and total protein (values introduced in the monitor in post-dilution OL-HDF).On the middle day of the week (sessions 2 and 5) the patients were dialysed at ET and we obtained pre-dialysis blood samples taken from the arterial line immediately before beginning the technique and post-dialysis blood samples from the arterial line after decreasing the Qs to 50ml/min for 60 seconds.We measured the different uraemic toxins in blood which, in accordance with the classification,21 were defined as small molecules (molecular weight [MW] less than 500Da): urea (60Da), phosphorus (95Da), creatinine (113Da) and uric acid (168Da); we defined the following as medium-sized molecules (MW greater than 500Da): β2m (11,818Da), myoglobin (17,200Da), and protein-bound molecules: retinol transport protein (RTP) (21,200Da).In the dialysate, we measured albumin concentration, collecting samples 30, 60 and 120 minutes after starting the OL-HDF session through a device placed in the drainage tube.We measured β2m by immunoturbidimetry using the immunoassay Immulite® 2000 (Siemens) and RTP was measured by immunonephelometry, using the BN ProSpec® System (Siemens) method. Haematocrit was measured by the autoanalyser ADVIA 2120/2120 and the rest of the biochemical measurements, including albumin in the dialysate, were measured with an autoanalyser (ADVIA® 2400 Chemistry System, Bayer). Demographic and dialysis parameters A series of demographic parameters were collected: age, underlying disease, time on HD and OL-HDF, type of vascular access: fistula and catheter.Dialysis parameters: Qs, dialysate flow, times: ST and ET, conductivity of sodium and bicarbonate, dialysate temperature, heparin type and dose, infusion volumes (total, pre- and post-dilution), mean TMP, the KT measured automatically by the OCM biosensor, UF by session and pre- and post-HDF blood pressure (BP). Calculations The reduction (RR) percentages were calculated with the formula: RR (%) =  [(Cpre – Cpos)/Cpre] x 100.Where Cpre and Cpos were the concentrations of the substances analysed pre- and post-dialysis.For protein-bound substances and β2m, the concentrations at the end of the session were corrected for blood concentration by one correction factor (CF) based on the plasma protein (PT) concentration:CF= PTpre/PTpos22Where PTpre and PTpos were the total pre-dialysis and post-dialysis protein concentrations. Statistical analysisThe statistical analysis was carried out with the SPSS 15.0 software (SPSS INC., Chicago, IL, USA). The descriptive data were presented as the mean and standard deviation (SD).For the comparison of two independent continuous variables we used the Student’s t-test for paired samples. To compare more than two quantitative variables, we used ANOVA. A P value of <.05 was considered to be statistically significant. RESULTS We included 8 patients in the study, 5 males and 3 females; mean age 66 (14) [39-83] years; with a mean time on renal replacement therapy of 14.5 (10) [3-28] years; mean time on OL-HDF of 30.8 (30.9) [4-99] months. The aetiology of chronic kidney disease was glomerulonephritis (3 patients), polycystic kidney disease (2 patients), interstitial nephritis (1 patient) and unknown (2 patients). One patient did not finish the study, completing only the first 6 sessions. We included the data of a total of 89 HDF sessions.Table 2 displays the characteristics of the dialysis parameters. The anticoagulation dose did not change throughout the study. We used enoxaparin in 2 patients (mean dose per session: 60 [28.2] mg) and 1% sodium heparin in 6 patients (mean dose per session: 53.7 [25.6] mg).Table 3 displays the pre-dialysis and post-dialysis values for the different molecules analysed, but no significant differences were found.Figure 2 represents the RR of the substances analysed, with no significant differences having been found in the molecules analysed between post-dilution OL-HDF and mixed OL-HDF.Table 4 displays the infusion volumes obtained using both techniques, with, as expected, there being a significant difference between them for all volumes, except for the UF volume.Table 5 displays the results of the KT obtained in ST and ET in accordance with the technique. As can be observed, we found a statistically significant difference in the KT obtained in both techniques (P=.009) when the patients were dialysed at ST. However, this difference disappeared when dialysis was performed at ET.The difference between ST and ET was greater in mixed HDF than in post-dilution HDF 10.3 [7.4] compared with 6.5 [3.1] minutes), achieving statistical significance (p=.02).We did not find differences in systolic or diastolic BP before or after we carried out both techniques (pre-dialysis systolic BP: 139.7 [14.4] compared with 140.7 [20.4] mmHg, pre-dialysis diastolic BP: 66.5 [11.5] compared with 63.8 [14.7] mmHg, post-dialysis systolic BP: 128 [15] compared with 132.1 [17.1] mmHg and post-dialysis diastolic BP: 64.7 [11.8] compared with 62.9 [1.9] mmHg for post-dilution and mixed OL-HDF, respectively).The mean TMP in both techniques was different: 188.3 (37.3) compared with 229.6 (26.7) mmHg in post-dilution and mixed OL-HDF, respectively (P=.002) (the TMP measurement was carried out differently). We did not find differences in albumin concentration in the dialysate at the times analysed (30, 60 and 120 minutes) (Table 6). DISCUSSION This study compared the effectiveness of uraemic toxin clearance of two OL-HDF modalities, post-dilution and mixed (pre- and post-dilution) and we found that there were no significant differences in the RR of any of the molecules analysed. Most studies have compared the effectiveness of post-dilution HDF with pre-dilution HDF and have shown that post-dilution OL-HDF is more effective in the clearance of both small and medium-sized molecules.14,23 This is attributed to the fact that in pre-dilution HDF, diffusive transport decreases. As such, post-dilution HDF is considered the most efficient convective treatment and our study shows, for the first time, by measuring the removal of multiple molecules, the non-inferiority of mixed OL-HDF compared with the latter, when the ET was identical for both techniques.Pedrini et al.17 compared the effectiveness of mixed HDF with other forms of HDF, observing a greater solute clearance with this modality than with pre-dilution infusion and, as with our study, they did not find differences with post-dilution infusion, although their study only displayed results for β2m. The RR of β2m were less that those obtained in our study, 85.3% and 85.4% in post-dilution and mixed dilution HDF, respectively, which was possibly due to the different characteristics of the dialysers and flows used.Studies that compared the effectiveness of post-dilution OL-HDF with another form of pre-post dilution infusion, mid-dilution,24,25 although carried out with different membranes and surfaces, have found that the reduction percentages of small molecules such as urea and creatinine are slightly higher in post-dilution OL-HDF, while molecules of a larger size, such as β2m, myoglobin, prolactin and RTP presented a higher reduction percentage with mid-dilution. We wish to highlight that the RR of RTP that we obtained (39% and 43.2% in post-dilution and mixed OL-HDL, respectively) were much higher than those of other studies (less than 31%). This is a very interesting finding, since RTP is a protein-bound molecule26 and these molecules have been identified as one of the uraemic toxins responsible for chronic complications in CKD patients, and are characterised as being difficult to remove with HDF, since only their free fraction is removed.27 The good results obtained in our study may be explained by the characteristics of the membrane used that obtains high clearances, thanks to its greater surface area (2.3m2) and the high Qs used. In clinical practice, to measure the effectiveness of OL-HDF, β2m is analysed, which is considered representative of the mean molecules and is related to some of the complications, such as dialysis-related amyloidosis. The convective transport volume has been related to the β2m reduction rate,28 since its clearance is significantly higher in techniques with high convective transport, such as OL-HDF.29Recently, Sakurai30 suggested the suitability of using a biomarker or substance of a higher MW than β2m to evaluate the efficiency of HDF. He based his recommendation on the fact that this molecule may be cleared effectively by diffusion if high-flow dialysers are used, and as such, he proposed the α1 microglobulin (α1-MG), which has a MW of 33,000Da and is removed by convection, as more representative of HDF. Unfortunately, we did not analyse α1-MG, but we did analyse RTP, which also has a high MW (21,200Da), obtaining high RR.In relation to the results obtained with the infusion volumes, in our study we achieved high infusion volumes with both techniques, a quantity that was much higher than that in the different studies mentioned, which decreases mortality. The mean infusion volume achieved was 28.3 and 44.4 litres in post-dilution and mixed OL-HDF, respectively. In mixed OL-HDF, we obtained 24.2 litres in post-dilution (4 litres less than with post-dilution OL-HDF) and 20.2 litres in pre-dilution. Although the litres in post-dilution were not equivalent in both techniques, having obtained similar RR we could infer from our study that around 5 litres of pre-dilution infusion volume are required for each litre less of post-dilution infusion that is achieved with mixed OL-HDF with respect to post-dilution OL-HDF, or at least that the post-dilution volume of mixed OL-HDF is 54% of the total volume achieved.Qs, haematocrit and protein concentration are important determinants of the infusion volume quantity in post-dilution HDF. In the post-dilution HDF, we recommend that the infusion rate in relation to real Qs is not greater than 25-30%, since higher proportions may lead to a high blood concentration, which causes complications. In patients with limited Qs, as in the case of catheter carriers, this maximum rate may compromise the achievement of high infusion volumes in a limited time. Mixed OL-HDF is a more versatile technique that may be used in patients in whom post-dilution OL-HDF does not achieve adequate infusion volumes, either due to high haematocrit or protein or a vascular access that does not allow an appropriate Qs. This is particularly relevant at the present time due to the progressive increase in the proportion of patients who are carriers of permanent catheters.31The third result to underscore in our study is the importance of taking into account the ET or real time of dialysis. Dialysis time is a key parameter that determines not only suitability, but also other aspects such as phosphorus control, blood pressure and more important still, mortality.32-34 In the previous study carried out over 2162 dialysis sessions that included both HD and OL-HDF, we found a statistically significant difference between ST and ET (p<.001). This difference was proportional to ST; specifically, for the 240 minute sessions, it was 9.7 (12.7) minutes.35 As such, in the study design we considered it was necessary to dialyse at ET for a more thorough comparison of both OL-HDF modalities. In fact, the KT at ST was higher in post-dilution OL-HDF, a result that was not maintained on dialysing at ET. This is explained by the difference found between ST and ET in both techniques, since in mixed OL-HDF when the patient is dialysed at ST, the ET was lower, losing 10.3 (7.4) compared with 6.5 (3.1) in mixed and post-dilution, respectively. This is due to the higher number of interruptions in the process due to autochecks and controls carried out by the dialysis monitor. To our knowledge, this is the first study that has compared the effectiveness of OL-HDF taking into account dialysis ET. If this had not been the case, our conclusion would have been that post-dilution OL-HDF achieves higher KT, which was indeed the case when we dialysed at ST. We cannot say that the reduction percentage in the substances analysed also would have been higher, since it was only measured in the four sessions carried out in the mid-week day (sessions 2 and 5 of both post-dilution and mixed modalities), and in the latter, the patients were dialysed at ET. Instead, we can conclude that it is important to individualise the dialysis time not only for the body area, the existence of RRF, BP, etc., but also for the type of technique. Furthermore, in daily clinical practice we should know the real time in which are patients are dialysed and adjust the prescription accordingly.Lastly, it is important to stress that the best clearance of large molecules should not be to the detriment of the excessive loss of useful substances such as albumin. In our study, we did not find differences in albumin concentrations in the ultrafiltrate samples analysed between the two techniques. Although the dialyser screening ratio used did not allow a large passage of albumin to the ultrafiltrate and therefore we could confirm that there are no differences between both techniques, we should have measured the total ultrafiltrate volume. This is a limitation of our study.The main limitation of our study was the small number of patients included, but the fact that the study had a crossover design confirmed the results.In conclusion, mixed OL-HDF at the same ET is not inferior to post-dilution OL-HDF either in the clearance of small or medium-sized molecules or protein-bound molecules. This OL-HDF modality, on administering pre- and post-dilution dialysate simultaneously, avoids some disadvantages present in other forms of OL-HDF and can be used in patients with flow and/or blood concentration problems.  Acknowledgements To the nursing staff at the Dialysis Unit of the Hospital Universitario Infanta Leonor for their collaboration in this study. Conflicts of interestThe authors declare potential conflicts of interest. Lecture fees: Dr. P. de Sequera, Dr. M. Albalate and Dr. R. Pérez García have participated as speakers in meetings organised by Gambro® and Fresenius®.<a href="grande/12223_16025_52186_en_t1.12223.jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52186_en_t1.12223.jpg" alt="Main studies that analyse the effect of online haemodiafiltration on mortality in dialysis patients "></img></a>Table 1. Main studies that analyse the effect of online haemodiafiltration on mortality in dialysis patients <a href="grande/12223_16025_52187_en_t2.12223.jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52187_en_t2.12223.jpg" alt="Haemodialysis characteristics "></img></a>Table 2. Haemodialysis characteristics <a href="grande/12223_16025_52188_en_t3.12223.jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52188_en_t3.12223.jpg" alt="Pre-dialysis and post-dialysis values of the substances analysed in both techniques "></img></a>Table 3. Pre-dialysis and post-dialysis values of the substances analysed in both techniques <a href="grande/12223_16025_52189_en_t4.12223.jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52189_en_t4.12223.jpg" alt="Volumes in both techniques"></img></a>Table 4. Volumes in both techniques<a href="grande/12223_16025_52190_en_t5.12223_copy2.jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52190_en_t5.12223_copy2.jpg" alt="KT at scheduled time and effective time in accordance with the technique"></img></a>Table 5. KT at scheduled time and effective time in accordance with the technique<a href="grande/12223_16025_52191_en_t6.12223.jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52191_en_t6.12223.jpg" alt="Differences in accordance with the technique"></img></a>Table 6. Differences in accordance with the technique<a href="grande/12223_16025_52192_en_f1.12223.jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52192_en_f1.12223.jpg" alt="Study design."></img></a>Figure 1. Study design.<a href="grande/12223_16025_52193_en_f2.12223.jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52193_en_f2.12223.jpg" alt="Reduction percentages of the substances analysed in post-dilution and mixed online haemodiafiltration."></img></a>Figure 2. Reduction percentages of the substances analysed in post-dilution and mixed online haemodiafiltration." "pdfFichero" => "P1-E562-S4392-A12223-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:7 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439447" "palabras" => array:1 [ 0 => "Toxinas urémicas" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439449" "palabras" => array:1 [ 0 => "Volumen convectivo" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439451" "palabras" => array:1 [ 0 => "Mixta" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439453" "palabras" => array:1 [ 0 => "Posdilucional" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439455" "palabras" => array:1 [ 0 => "Hemodiafiltración" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439457" "palabras" => array:1 [ 0 => "Beta2 microglobulina" ] ] 6 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439459" "palabras" => array:1 [ 0 => "Hemodiálisis" ] ] ] "en" => array:7 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439448" "palabras" => array:1 [ 0 => "Uraemic toxins" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439450" "palabras" => array:1 [ 0 => "Convective volume" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439452" "palabras" => array:1 [ 0 => "Mixed" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439454" "palabras" => array:1 [ 0 => "Post-dilution" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439456" "palabras" => array:1 [ 0 => "Haemodiafiltration" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439458" "palabras" => array:1 [ 0 => "Beta2 microglobulin" ] ] 6 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439460" "palabras" => array:1 [ 0 => "Haemodialysis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "Introducción: La hemodiafiltración (HDF) con altos volúmenes de reinfusión es la técnica más eficaz en la depuración de toxinas urémicas. Existen distintas modalidades dependiendo del lugar donde se administra el volumen de sustitución en el circuito extracorpóreo: predilucional, mixta o mid-dilucional y posdilucional, en las que la infusión se realiza pre, de forma simultánea pre y pos, y posdilucional, respectivamente. Objetivo: Comparar la depuración de moléculas pequeñas, medianas y unidas a proteínas y el volumen convectivo administrado en HDF en línea (HDF-OL) con infusión posdilucional y mixta (pre-posdilucional). Material y métodos: Estudio prospectivo, aleatorizado y cruzado, comparando HDF-OL posdilucional y mixta. Los pacientes (n = 8) fueron asignados aleatoriamente para recibir 6 sesiones en cada técnica. Se realizaron 89 sesiones, de las cuales 68 fueron a tiempo programado (TP) y 21 a tiempo efectivo (TE). Se determinaron los porcentajes de reducción (RR) de distintas sustancias y los volúmenes de infusión. El estudio de los RR se realizó con TE. Resultados: El KT obtenido fue mayor con HDF-OL posdilucional [68 (8,1) frente a 64,9 (8,8) litros] (p = 0,009) cuando los pacientes se dializaron a TP. Esta diferencia desaparecía cuando la diálisis se realizaba a TE. La diferencia entre el TP-TE fue mayor en la HDF mixta con respecto a la HDF posdilucional [10,3 (7,4) frente a 6,5 (3,1) minutos, p = 0,02]. No encontramos diferencias en los RR de las sustancias analizadas. Conclusión: La HDF-OL mixta no es inferior a la posdilucional ni en la depuración de moléculas pequeñas y medianas ni en las unidas a proteínas a igual TE." ] "en" => array:1 [ "resumen" => "Introduction: Haemodiafiltration (HDF) with high reinfusion volumes is the most effective technique for clearing uraemic toxins. There are various modalities depending on the location where the replacement volume is administered in the extracorporeal circuit: pre-dilution, mixed or mid-dilution and post-dilution, in which the infusion is carried out pre-dilution, pre- and post-dilution simultaneously and post-dilution, respectively. Objective: Compare the clearance of small, medium-sized and protein-bound molecules and the convective volume administered in online HDF (OL-HDF) in post-dilution and mixed (pre-post-dilution) infusion. Material and method: A prospective, randomised, crossover study comparing post-dilution and mixed OL-HDF. Patients (n=8) were randomly assigned to receive 6 sessions in each technique. We conducted 89 sessions, of which 68 were at a scheduled time (ST) and 21 at an effective time (ET). We determined the reduction rate (RR) percentages for various substances and the infusion volumes. The RR study was performed using ET. Results: The KT value obtained was greater with post-dilution OL-HDF [68 (8.1) compared to 64.9 (8.8) litres] (P=.009) when patients were dialysed at ST. This difference disappeared when dialysis was performed at ET. The difference between ST and ET was greater in mixed HDF than in post-dilution HDF [10.3 (7.4) compared to 6.5 (3.1) minutes, P=.02]. We found no differences in the RR of the substances analysed. Conclusion: Mixed OL-HDF is not inferior to post-dilution OL-HDF either in the clearance of small and medium-sized molecules or in the clearance of protein-bound molecules at the same ET." ] ] "multimedia" => array:8 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52186_en_t1.12223.jpg" "Alto" => 634 "Ancho" => 2171 "Tamanyo" => 286774 ] ] "descripcion" => array:1 [ "en" => "Main studies that analyse the effect of online haemodiafiltration on mortality in dialysis patients" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52187_en_t2.12223.jpg" "Alto" => 257 "Ancho" => 2152 "Tamanyo" => 138859 ] ] "descripcion" => array:1 [ "en" => "Haemodialysis characteristics" ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Tab. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52188_en_t3.12223.jpg" "Alto" => 598 "Ancho" => 2172 "Tamanyo" => 294554 ] ] "descripcion" => array:1 [ "en" => "Pre-dialysis and post-dialysis values of the substances analysed in both techniques" ] ] 3 => array:8 [ "identificador" => "fig4" "etiqueta" => "Tab. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52189_en_t4.12223.jpg" "Alto" => 384 "Ancho" => 2176 "Tamanyo" => 181935 ] ] "descripcion" => array:1 [ "en" => "Volumes in both techniques" ] ] 4 => array:8 [ "identificador" => "fig5" "etiqueta" => "Tab. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52190_en_t5.12223_copy2.jpg" "Alto" => 588 "Ancho" => 2186 "Tamanyo" => 219627 ] ] "descripcion" => array:1 [ "en" => "KT at scheduled time and effective time in accordance with the technique" ] ] 5 => array:8 [ "identificador" => "fig6" "etiqueta" => "Tab. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52191_en_t6.12223.jpg" "Alto" => 487 "Ancho" => 2175 "Tamanyo" => 229601 ] ] "descripcion" => array:1 [ "en" => "Differences in accordance with the technique" ] ] 6 => array:8 [ "identificador" => "fig7" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52192_en_f1.12223.jpg" "Alto" => 808 "Ancho" => 2112 "Tamanyo" => 188053 ] ] "descripcion" => array:1 [ "en" => "Study design." ] ] 7 => array:8 [ "identificador" => "fig8" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "12223_16025_52193_en_f2.12223.jpg" "Alto" => 975 "Ancho" => 2114 "Tamanyo" => 174796 ] ] "descripcion" => array:1 [ "en" => "Reduction percentages of the substances analysed in post-dilution and mixed online haemodiafiltration." ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:35 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Penne EL, Van der Weerd NC, Van den Dorpel MA. 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Comparación de la eficacia de dos modalidades de hemodiafiltración en línea: mixta frente a posdilucional

Patricia de Sequera-Ortiza, Patricia de Sequerab, Marta Albalate-Ramóna, Marta Albalateb, Rafael Pérez-Garcíab, Elena Corchete-Pratsa, Elena Corcheteb, Marta Puerta-Carreteroa, Marta Puertab, Mayra Ortega-Díaza, Mayra Ortegab, Roberto Alcázar-Arroyoa, Roberto Alcázarb, Tamar Talaván-Zanonc, Tamar Talavánd, María J. Ruiz-Álvarezd

a Servicio de Nefrología, Hospital Universitario Infanta Leonor, Madrid, Spain,

b Servicio de Nefrología, Hospital Universitario Infanta Leonor, Madrid,

c Laboratorio de Bioquímica, Hospital Universitario Infanta Leonor, Madrid, Spain,

d Laboratorio de Bioquímica, Hospital Universitario Infanta Leonor, Madrid,

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          "en" => "Main studies that analyse the effect of online haemodiafiltration on mortality in dialysis patients"
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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Haemodiafiltration &#40;HDF&#41; with high reinfusion volumes is the most effective uraemic toxin clearance technique&#44; particularly for medium-sized molecules&#44; whose removal is significantly higher with convective techniques&#46; Several studies have shown that HDF improves some complications in haemodialysis &#40;HD&#41; patients&#44; such as hyperphosphataemia&#44;<span class="elsevierStyleSup">1</span> malnutrition&#44;<span class="elsevierStyleSup">2</span> growth in children&#44;<span class="elsevierStyleSup">3</span> the response to erythropoietin<span class="elsevierStyleSup">4</span> and to vitamin D<span class="elsevierStyleSup">5</span> and dialysis-associated amyloidosis&#44; amongst others&#46;<span class="elsevierStyleSup">6</span> There is currently evidence that shows a higher survival rate in patients who undergo dialysis with online HDF &#40;OL-HDF&#41; compared to those on HD&#44;<span class="elsevierStyleSup">7-10</span> as we will discuss later&#46; The good results obtained in these studies were determined by the convective transport volume achieved&#44; which was generally more than 20-24l per session&#46;</p><p class="elsevierStylePara">There are different OL-HDF modalities&#44; depending on the location where the replacement volume is administered in the extracorporeal circuit&#46; In pre-dilution HDF&#44; the dialysate is infused before the entry of blood in the dialyser&#44; which results in haemodilution and decreased diffusive transport&#46; In post-dilution HDF&#44; the dialysate is administered after the dialyser&#44; such that it does not interfere in diffusive transport&#44; but it creates a blood concentration in the dialyser that may increase pressure and cause coagulation problems&#46; Post-dilution HDF is considered the most efficient form&#46; In addition to these most common modalities&#44; there are another two OL-HDL forms in which infusion is carried out simultaneously pre- and post-dilution&#58; mixed OL-HDF and mid-dilution OL-HDF&#46; In mixed OL-HDF&#44; the replacement fluid is infused simultaneously pre- and post-dilution&#44; with the pre- and post-dilution infusion percentage being regulated automatically via transmembrane pressure &#40;TMP&#41; and ultrafiltration &#40;UF&#41; feedback&#46; Mid-dilution requires a special dialyser&#44; in which blood enters through a central fibre bundle and returns in the opposite direction through peripheral fibres&#46; The reinfusion liquid is incorporated between the two dialyser sections&#59; as such&#44; in the first section there is post-dilution HDF and in the second section there is pre-dilution HDF&#46; These mixed OL-HDF forms are a good alternative&#44; since they theoretically avoid the reported disadvantages of pre- and post-dilution OL-HDF&#46; The choice between one modality and the other will depend on the haemorheological characteristics and the blood flow with which the patient is dialysed&#46;</p><p class="elsevierStylePara">The reported benefits of HDF are based on post-dilution OL-HDF results&#46; The convective volume quantity administered seems to be decisive in improving survival rates&#46; This volume per session was 15l in the European Dialysis Outcomes and Practice Pattern Study &#40;DOPPS&#41;&#44;<span class="elsevierStyleSup">7</span> 17&#46;4l in the Turkish study&#44;<span class="elsevierStyleSup">8</span> 21&#46;9l in the Convective Transport Study &#40;CONTRAST&#41;<span class="elsevierStyleSup">9</span> and 23&#46;1l in the Online Haemodiafiltration Study &#40;ESHOL&#41;<span class="elsevierStyleSup">10</span> &#40;Table 1&#41;&#46; These studies highlight the need to achieve high convective volumes in order to reduce mortality&#46;</p><p class="elsevierStylePara">In spite of the importance of the convective volume quantity shown in these studies&#44; we do not know the infusion volume equivalence between the different OL-HDF modalities&#46; Recently&#44; the EUDIAL group<span class="elsevierStyleSup">11 </span>advised the use of an OL-HDF dilution factor whenever the volume is fully or partially infused before the dialyser &#40;pre-dilution&#44; mid-dilution and mixed dilution modalities&#41;&#46; It also insisted on the importance of measuring the effective convective volume adjusted to the body surface in order to quantify the effectiveness of OL-HDF&#46;</p><p class="elsevierStylePara">The quantity of the convective volume administered has been directly related to the clearance of medium-sized molecules&#46;<span class="elsevierStyleSup">12&#44;13</span> Studies that have analysed effectiveness in the removal of solutes comparing convective techniques show that post-dilution infusion is the most effective form for clearing both small&#44; medium-sized and large molecules&#46;<span class="elsevierStyleSup">14-16</span> Only Pedrini<span class="elsevierStyleSup">17</span> has studied mixed pre-dilution infusion and found a higher reduction percentage in &#946;2-microglobulin &#40;&#946;2m&#41; with mixed HDF in comparison with pre-dilution infusion and similar results to post-dilution infusion &#40;72&#46;1&#37; in mixed&#44; 69&#46;2&#37; in pre-dilution and 74&#46;7&#37; in post-dilution HDF&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">OBJECTIVE</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">To compare the clearance of small&#44; medium-sized and protein-bound molecules and the convective volume of OL-HDF administered with post-dilution and mixed &#40;pre- and post-dilution&#41; infusion in patients on treatment with OL-HDF&#44; in oder to determine the litres of convective volume required with both techniques to achieve equal clearance efficiency&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">MATERIAL AND METHOD</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Design</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A prospective&#44; randomised&#44; crossover study comparing post-dilution and mixed OL-HDF &#40;Figure 1&#41;&#46; Patients were randomly assigned to receive 6 consecutive post-dilution OL-HDF sessions&#44; followed or preceded by 6 mixed OL-HDF sessions</p><p class="elsevierStylePara">Each patient was a control of themselves and no changes were made to the dialysis regimen or the pharmacological treatment throughout the study&#46;</p><p class="elsevierStylePara">Given that the modern dialysis monitors interrupt the procedures due to auto-checks that increase the safety&#44; making the effective time &#40;ET&#41; or real time of treatment less than the scheduled time &#40;ST&#41; or the time prescribed by the doctor&#44; these variables were taken into account&#46; The regular regimen was followed&#44; dialysing at ST in sessions 1&#44; 3&#44; 4 and 6&#44; while in session 2 and 5&#44; we dialysed at ET&#44; extending it as needed to match the real time and the scheduled time&#46;</p><p class="elsevierStylePara">To assess the effectiveness of the technique&#44; we measured clearance of molecules by the reduction percentage of said substances and the convective volume quantity administered&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Patients and dialysis technique</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The inclusion criteria were&#58; patients older than 18 years of age on dialysis treatment three times a week and with a minimum of three months on OL-HDF treatment&#46;</p><p class="elsevierStylePara">The exclusion criteria were&#58; the presence of haemodynamic instability with frequent hypotension&#44; patients contraindicated for heparin use&#44; presence of residual renal function &#40;RRF&#41; defined as mean urea and creatinine clearance of more than 1ml&#47;min or blood flow &#40;Qs&#41; less than 250ml&#47;min&#46;</p><p class="elsevierStylePara">All patients signed their informed consent at the time of inclusion&#46;</p><p class="elsevierStylePara">All sessions were carried out with one dialysis monitor&#58; ST5008 &#40;Fresenius&#44; FMC&#44; Bad Homburg&#44; Germany&#41; and using the dialyser FX<span class="elsevierStyleInf">CorDiax</span>1000 &#40;Fresenius&#44; FMC&#44; Bad Homburg&#44; Germany&#41;&#46;</p><p class="elsevierStylePara">Characteristics of the dialyser&#58; helixone membrane&#44; area of 2&#46;3m<span class="elsevierStyleSup">2</span> and UF ratio&#58; 76ml&#47;h&#47;mmHg&#46;</p><p class="elsevierStylePara">In the dialysis unit we used ultrapure dialysate<span class="elsevierStyleSup">18 </span>defined by colony forming unit levels&#47;ml less than 0&#46;1 and endotoxins less than 0&#46;03UE&#47;ml&#46;</p><p class="elsevierStylePara">The post-dilution infusion mode was controlled by the monitor&#44; taking into account total protein values&#44; haematocrit and the dialyser&#8217;s hydraulic permeability&#46;</p><p class="elsevierStylePara">The mixed infusion mode was controlled by UF-TMP feedback&#46; This feedback automatically adjusted the rate and location of infusion &#40;pre-&#47;post-dilution&#41; to the maximum filtration fraction taking into account the flow conditions&#44; internal pressure and hydraulic permeability of the dialyser and its interactions&#46; The system regulated the degree of pre-&#47;post-infusion by two independent infusion pumps whose infusion speed was modulated by internal software depending on the value of TMP&#44; with the aim of maintaining the TMP between 250 and 300mmHG&#46;<span class="elsevierStyleSup">19&#44;20</span> TMP was instantly calculated according to the pressure in the four points through the formula&#58;</p><p class="elsevierStylePara">TMP<span class="elsevierStyleInf">m </span>&#61; 0&#46;5 x &#91;&#40;P <span class="elsevierStyleInf">blood dialyser entry </span>&#43; P <span class="elsevierStyleInf">blood dialyser exit</span>&#41; - &#40;P <span class="elsevierStyleInf">dialysate entry </span>&#43; P <span class="elsevierStyleInf">dialysate exit</span>&#41;&#93;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Laboratory tests</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Seventy-two hours before the start of the study &#40;last session before start of study&#41; we measured haematocrit and total protein &#40;values introduced in the monitor in post-dilution OL-HDF&#41;&#46;</p><p class="elsevierStylePara">On the middle day of the week &#40;sessions 2 and 5&#41; the patients were dialysed at ET and we obtained pre-dialysis blood samples taken from the arterial line immediately before beginning the technique and post-dialysis blood samples from the arterial line after decreasing the Qs to 50ml&#47;min for 60 seconds&#46;</p><p class="elsevierStylePara">We measured the different uraemic toxins in blood which&#44; in accordance with the classification&#44;<span class="elsevierStyleSup">21</span> were defined as small molecules &#40;molecular weight &#91;MW&#93; less than 500Da&#41;&#58; urea &#40;60Da&#41;&#44; phosphorus &#40;95Da&#41;&#44; creatinine &#40;113Da&#41; and uric acid &#40;168Da&#41;&#59; we defined the following as medium-sized molecules &#40;MW greater than 500Da&#41;&#58; &#946;<span class="elsevierStyleInf">2</span>m &#40;11&#44;818Da&#41;&#44; myoglobin &#40;17&#44;200Da&#41;&#44; and protein-bound molecules&#58; retinol transport protein &#40;RTP&#41; &#40;21&#44;200Da&#41;&#46;</p><p class="elsevierStylePara">In the dialysate&#44; we measured albumin concentration&#44; collecting samples 30&#44; 60 and 120 minutes after starting the OL-HDF session through a device placed in the drainage tube&#46;</p><p class="elsevierStylePara">We measured &#946;<span class="elsevierStyleInf">2</span>m by immunoturbidimetry using the immunoassay Immulite<span class="elsevierStyleSup">&#174;</span> 2000 &#40;Siemens&#41; and RTP was measured by immunonephelometry&#44; using the BN ProSpec<span class="elsevierStyleSup">&#174;</span> System &#40;Siemens&#41; method&#46; Haematocrit was measured by the autoanalyser ADVIA 2120&#47;2120 and the rest of the biochemical measurements&#44; including albumin in the dialysate&#44; were measured with an autoanalyser &#40;ADVIA<span class="elsevierStyleSup">&#174;</span>&#160;2400 Chemistry System&#44; Bayer&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Demographic and dialysis parameters</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A series of demographic parameters were collected&#58; age&#44; underlying disease&#44; time on HD and OL-HDF&#44; type of vascular access&#58; fistula and catheter&#46;</p><p class="elsevierStylePara">Dialysis parameters&#58; Qs&#44; dialysate flow&#44; times&#58; ST and ET&#44; conductivity of sodium and bicarbonate&#44; dialysate temperature&#44; heparin type and dose&#44; infusion volumes &#40;total&#44; pre- and post-dilution&#41;&#44; mean TMP&#44; the KT measured automatically by the OCM biosensor&#44; UF by session and pre- and post-HDF blood pressure &#40;BP&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Calculations</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The reduction &#40;RR&#41; percentages were calculated with the formula&#58; RR &#40;&#37;&#41; &#61;&#160; &#91;&#40;Cpre &#8211; Cpos&#41;&#47;Cpre&#93; x 100&#46;</p><p class="elsevierStylePara">Where Cpre and Cpos were the concentrations of the substances analysed pre- and post-dialysis&#46;</p><p class="elsevierStylePara">For protein-bound substances and &#946;<span class="elsevierStyleInf">2</span>m&#44; the concentrations at the end of the session were corrected for blood concentration by one correction factor &#40;CF&#41; based on the plasma protein &#40;PT&#41; concentration&#58;</p><p class="elsevierStylePara">CF&#61; PTpre&#47;PTpos<span class="elsevierStyleSup">22</span></p><p class="elsevierStylePara">Where PTpre and PTpos were the total pre-dialysis and post-dialysis protein concentrations&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Statistical analysis</span></p><p class="elsevierStylePara">The statistical analysis was carried out with the SPSS 15&#46;0 software &#40;SPSS INC&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46; The descriptive data were presented as the mean and standard deviation &#40;SD&#41;&#46;</p><p class="elsevierStylePara">For the comparison of two independent continuous variables we used the Student&#8217;s t-test for paired samples&#46; To compare more than two quantitative variables&#44; we used ANOVA&#46; A <span class="elsevierStyleItalic">P</span> value of &#60;&#46;05 was considered to be statistically significant&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">We included 8 patients in the study&#44; 5 males and 3 females&#59; mean age 66 &#40;14&#41; &#91;39-83&#93; years&#59; with a mean time on renal replacement therapy of 14&#46;5 &#40;10&#41; &#91;3-28&#93; years&#59; mean time on OL-HDF of 30&#46;8 &#40;30&#46;9&#41; &#91;4-99&#93; months&#46; The aetiology of chronic kidney disease was glomerulonephritis &#40;3 patients&#41;&#44; polycystic kidney disease &#40;2 patients&#41;&#44; interstitial nephritis &#40;1 patient&#41; and unknown &#40;2 patients&#41;&#46; One patient did not finish the study&#44; completing only the first 6 sessions&#46; We included the data of a total of 89 HDF sessions&#46;</p><p class="elsevierStylePara">Table 2 displays the characteristics of the dialysis parameters&#46; The anticoagulation dose did not change throughout the study&#46; We used enoxaparin in 2 patients &#40;mean dose per session&#58; 60 &#91;28&#46;2&#93; mg&#41; and 1&#37; sodium heparin in 6 patients &#40;mean dose per session&#58; 53&#46;7 &#91;25&#46;6&#93; mg&#41;&#46;</p><p class="elsevierStylePara">Table 3 displays the pre-dialysis and post-dialysis values for the different molecules analysed&#44; but no significant differences were found&#46;</p><p class="elsevierStylePara">Figure 2 represents the RR of the substances analysed&#44; with no significant differences having been found in the molecules analysed between post-dilution OL-HDF and mixed OL-HDF&#46;</p><p class="elsevierStylePara">Table 4 displays the infusion volumes obtained using both techniques&#44; with&#44; as expected&#44; there being a significant difference between them for all volumes&#44; except for the UF volume&#46;</p><p class="elsevierStylePara">Table 5 displays the results of the KT obtained in ST and ET in accordance with the technique&#46; As can be observed&#44; we found a statistically significant difference in the KT obtained in both techniques &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;009&#41; when the patients were dialysed at ST&#46; However&#44; this difference disappeared when dialysis was performed at ET&#46;</p><p class="elsevierStylePara">The difference between ST and ET was greater in mixed HDF than in post-dilution HDF 10&#46;3 &#91;7&#46;4&#93; compared with 6&#46;5 &#91;3&#46;1&#93; minutes&#41;&#44; achieving statistical significance &#40;<span class="elsevierStyleItalic">p</span>&#61;&#46;02&#41;&#46;</p><p class="elsevierStylePara">We did not find differences in systolic or diastolic BP before or after we carried out both techniques &#40;pre-dialysis systolic BP&#58; 139&#46;7 &#91;14&#46;4&#93; compared with 140&#46;7 &#91;20&#46;4&#93; mmHg&#44; pre-dialysis diastolic BP&#58; 66&#46;5 &#91;11&#46;5&#93; compared with 63&#46;8 &#91;14&#46;7&#93; mmHg&#44; post-dialysis systolic BP&#58; 128 &#91;15&#93; compared with 132&#46;1 &#91;17&#46;1&#93; mmHg and post-dialysis diastolic BP&#58; 64&#46;7 &#91;11&#46;8&#93; compared with 62&#46;9 &#91;1&#46;9&#93; mmHg for post-dilution and mixed OL-HDF&#44; respectively&#41;&#46;</p><p class="elsevierStylePara">The mean TMP in both techniques was different&#58; 188&#46;3 &#40;37&#46;3&#41; compared with 229&#46;6 &#40;26&#46;7&#41; mmHg in post-dilution and mixed OL-HDF&#44; respectively &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41; &#40;the TMP measurement was carried out differently&#41;&#46; We did not find differences in albumin concentration in the dialysate at the times analysed &#40;30&#44; 60 and 120 minutes&#41; &#40;Table 6&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">This study compared the effectiveness of uraemic toxin clearance of two OL-HDF modalities&#44; post-dilution and mixed &#40;pre- and post-dilution&#41; and we found that there were no significant differences in the RR of any of the molecules analysed&#46; Most studies have compared the effectiveness of post-dilution HDF with pre-dilution HDF and have shown that post-dilution OL-HDF is more effective in the clearance of both small and medium-sized molecules&#46;<span class="elsevierStyleSup">14&#44;23</span> This is attributed to the fact that in pre-dilution HDF&#44; diffusive transport decreases&#46; As such&#44; post-dilution HDF is considered the most efficient convective treatment and our study shows&#44; for the first time&#44; by measuring the removal of multiple molecules&#44; the non-inferiority of mixed OL-HDF compared with the latter&#44; when the ET was identical for both techniques&#46;</p><p class="elsevierStylePara">Pedrini et al&#46;<span class="elsevierStyleSup">17</span> compared the effectiveness of mixed HDF with other forms of HDF&#44; observing a greater solute clearance with this modality than with pre-dilution infusion and&#44; as with our study&#44; they did not find differences with post-dilution infusion&#44; although their study only displayed results for &#946;<span class="elsevierStyleInf">2</span>m&#46; The RR of &#946;<span class="elsevierStyleInf">2</span>m were less that those obtained in our study&#44; 85&#46;3&#37; and 85&#46;4&#37; in post-dilution and mixed dilution HDF&#44; respectively&#44; which was possibly due to the different characteristics of the dialysers and flows used&#46;</p><p class="elsevierStylePara">Studies that compared the effectiveness of post-dilution OL-HDF with another form of pre-post dilution infusion&#44; mid-dilution&#44;<span class="elsevierStyleSup">24&#44;25 </span>although carried out with different membranes and surfaces&#44; have found that the reduction percentages of small molecules such as urea and creatinine are slightly higher in post-dilution OL-HDF&#44; while molecules of a larger size&#44; such as &#946;<span class="elsevierStyleInf">2</span>m&#44; myoglobin&#44; prolactin and RTP presented a higher reduction percentage with mid-dilution&#46; We wish to highlight that the RR of RTP that we obtained &#40;39&#37; and 43&#46;2&#37; in post-dilution and mixed OL-HDL&#44; respectively&#41; were much higher than those of other studies &#40;less than 31&#37;&#41;&#46; This is a very interesting finding&#44; since RTP is a protein-bound molecule<span class="elsevierStyleSup">26</span> and these molecules have been identified as one of the uraemic toxins responsible for chronic complications in CKD patients&#44; and are characterised as being difficult to remove with HDF&#44; since only their free fraction is removed&#46;<span class="elsevierStyleSup">27</span> The good results obtained in our study may be explained by the characteristics of the membrane used that obtains high clearances&#44; thanks to its greater surface area &#40;2&#46;3m<span class="elsevierStyleSup">2</span>&#41; and the high Qs used&#46; In clinical practice&#44; to measure the effectiveness of OL-HDF&#44; &#946;<span class="elsevierStyleInf">2</span>m is analysed&#44; which is considered representative of the mean molecules and is related to some of the complications&#44; such as dialysis-related amyloidosis&#46; The convective transport volume has been related to the &#946;<span class="elsevierStyleInf">2</span>m reduction rate&#44;<span class="elsevierStyleSup">28 </span>since its clearance is significantly higher in techniques with high convective transport&#44; such as OL-HDF&#46;<span class="elsevierStyleSup">29</span></p><p class="elsevierStylePara">Recently&#44; Sakurai<span class="elsevierStyleSup">30</span> suggested the suitability of using a biomarker or substance of a higher MW than &#946;<span class="elsevierStyleInf">2</span>m to evaluate the efficiency of HDF&#46; He based his recommendation on the fact that this molecule may be cleared effectively by diffusion if high-flow dialysers are used&#44; and as such&#44; he proposed the &#945;1 microglobulin &#40;&#945;1-MG&#41;&#44; which has a MW of 33&#44;000Da and is removed by convection&#44; as more representative of HDF&#46; Unfortunately&#44; we did not analyse &#945;1-MG&#44; but we did analyse RTP&#44; which also has a high MW &#40;21&#44;200Da&#41;&#44; obtaining high RR&#46;</p><p class="elsevierStylePara">In relation to the results obtained with the infusion volumes&#44; in our study we achieved high infusion volumes with both techniques&#44; a quantity that was much higher than that in the different studies mentioned&#44; which decreases mortality&#46; The mean infusion volume achieved was 28&#46;3 and 44&#46;4 litres in post-dilution and mixed OL-HDF&#44; respectively&#46; In mixed OL-HDF&#44; we obtained 24&#46;2 litres in post-dilution &#40;4 litres less than with post-dilution OL-HDF&#41; and 20&#46;2 litres in pre-dilution&#46; Although the litres in post-dilution were not equivalent in both techniques&#44; having obtained similar RR we could infer from our study that around 5 litres of pre-dilution infusion volume are required for each litre less of post-dilution infusion that is achieved with mixed OL-HDF with respect to post-dilution OL-HDF&#44; or at least that the post-dilution volume of mixed OL-HDF is 54&#37; of the total volume achieved&#46;</p><p class="elsevierStylePara">Qs&#44; haematocrit and protein concentration are important determinants of the infusion volume quantity in post-dilution HDF&#46; In the post-dilution HDF&#44; we recommend that the infusion rate in relation to real Qs is not greater than 25-30&#37;&#44; since higher proportions may lead to a high blood concentration&#44; which causes complications&#46; In patients with limited Qs&#44; as in the case of catheter carriers&#44; this maximum rate may compromise the achievement of high infusion volumes in a limited time&#46; Mixed OL-HDF is a more versatile technique that may be used in patients in whom post-dilution OL-HDF does not achieve adequate infusion volumes&#44; either due to high haematocrit or protein or a vascular access that does not allow an appropriate Qs&#46; This is particularly relevant at the present time due to the progressive increase in the proportion of patients who are carriers of permanent catheters&#46;<span class="elsevierStyleSup">31</span></p><p class="elsevierStylePara">The third result to underscore in our study is the importance of taking into account the ET or real time of dialysis&#46; Dialysis time is a key parameter that determines not only suitability&#44; but also other aspects such as phosphorus control&#44; blood pressure and more important still&#44; mortality&#46;<span class="elsevierStyleSup">32-34 In the previous study carried out over 2162 dialysis sessions that included both HD and OL-HDF&#44; we found a statistically significant difference between ST and ET &#40;<span class="elsevierStyleItalic">p</span>&#60;&#46;001&#41;&#46; This difference was proportional to ST&#59; specifically&#44; for the 240 minute sessions&#44; it was 9&#46;7 &#40;12&#46;7&#41; minutes&#46;35</span> As such&#44; in the study design we considered it was necessary to dialyse at ET for a more thorough comparison of both OL-HDF modalities&#46; In fact&#44; the KT at ST was higher in post-dilution OL-HDF&#44; a result that was not maintained on dialysing at ET&#46; This is explained by the difference found between ST and ET in both techniques&#44; since in mixed OL-HDF when the patient is dialysed at ST&#44; the ET was lower&#44; losing 10&#46;3 &#40;7&#46;4&#41; compared with 6&#46;5 &#40;3&#46;1&#41; in mixed and post-dilution&#44; respectively&#46; This is due to the higher number of interruptions in the process due to autochecks and controls carried out by the dialysis monitor&#46; To our knowledge&#44; this is the first study that has compared the effectiveness of OL-HDF taking into account dialysis ET&#46; If this had not been the case&#44; our conclusion would have been that post-dilution OL-HDF achieves higher KT&#44; which was indeed the case when we dialysed at ST&#46; We cannot say that the reduction percentage in the substances analysed also would have been higher&#44; since it was only measured in the four sessions carried out in the mid-week day &#40;sessions 2 and 5 of both post-dilution and mixed modalities&#41;&#44; and in the latter&#44; the patients were dialysed at ET&#46; Instead&#44; we can conclude that it is important to individualise the dialysis time not only for the body area&#44; the existence of RRF&#44; BP&#44; etc&#46;&#44; but also for the type of technique&#46; Furthermore&#44; in daily clinical practice we should know the real time in which are patients are dialysed and adjust the prescription accordingly&#46;</p><p class="elsevierStylePara">Lastly&#44; it is important to stress that the best clearance of large molecules should not be to the detriment of the excessive loss of useful substances such as albumin&#46; In our study&#44; we did not find differences in albumin concentrations in the ultrafiltrate samples analysed between the two techniques&#46; Although the dialyser screening ratio used did not allow a large passage of albumin to the ultrafiltrate and therefore we could confirm that there are no differences between both techniques&#44; we should have measured the total ultrafiltrate volume&#46; This is a limitation of our study&#46;</p><p class="elsevierStylePara">The main limitation of our study was the small number of patients included&#44; but the fact that the study had a crossover design confirmed the results&#46;</p><p class="elsevierStylePara">In conclusion&#44; mixed OL-HDF at the same ET is not inferior to post-dilution OL-HDF either in the clearance of small or medium-sized molecules or protein-bound molecules&#46; This OL-HDF modality&#44; on administering pre- and post-dilution dialysate simultaneously&#44; avoids some disadvantages present in other forms of OL-HDF and can be used in patients with flow and&#47;or blood concentration problems&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><br></br><span class="elsevierStyleBold">Acknowledgements</span><br></br> To the nursing staff at the Dialysis Unit of the Hospital Universitario Infanta Leonor for their collaboration in this study&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">The authors declare potential conflicts of interest&#46;<br></br> Lecture fees&#58; Dr&#46; P&#46; de Sequera&#44; Dr&#46; M&#46; Albalate and Dr&#46; R&#46; P&#233;rez Garc&#237;a have participated as speakers in meetings organised by Gambro&#174; and Fresenius&#174;&#46;</p><p class="elsevierStylePara"><a href="grande&#47;12223&#95;16025&#95;52186&#95;en&#95;t1&#46;12223&#46;jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52186_en_t1.12223.jpg" alt="Main studies that analyse the effect of online haemodiafiltration on mortality in dialysis patients "></img></a></p><p class="elsevierStylePara">Table 1&#46; Main studies that analyse the effect of online haemodiafiltration on mortality in dialysis patients </p><p class="elsevierStylePara"><a href="grande&#47;12223&#95;16025&#95;52187&#95;en&#95;t2&#46;12223&#46;jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52187_en_t2.12223.jpg" alt="Haemodialysis characteristics "></img></a></p><p class="elsevierStylePara">Table 2&#46; Haemodialysis characteristics </p><p class="elsevierStylePara"><a href="grande&#47;12223&#95;16025&#95;52188&#95;en&#95;t3&#46;12223&#46;jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52188_en_t3.12223.jpg" alt="Pre-dialysis and post-dialysis values of the substances analysed in both techniques "></img></a></p><p class="elsevierStylePara">Table 3&#46; Pre-dialysis and post-dialysis values of the substances analysed in both techniques </p><p class="elsevierStylePara"><a href="grande&#47;12223&#95;16025&#95;52189&#95;en&#95;t4&#46;12223&#46;jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52189_en_t4.12223.jpg" alt="Volumes in both techniques"></img></a></p><p class="elsevierStylePara">Table 4&#46; Volumes in both techniques</p><p class="elsevierStylePara"><a href="grande&#47;12223&#95;16025&#95;52190&#95;en&#95;t5&#46;12223&#95;copy2&#46;jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52190_en_t5.12223_copy2.jpg" alt="KT at scheduled time and effective time in accordance with the technique"></img></a></p><p class="elsevierStylePara">Table 5&#46; KT at scheduled time and effective time in accordance with the technique</p><p class="elsevierStylePara"><a href="grande&#47;12223&#95;16025&#95;52191&#95;en&#95;t6&#46;12223&#46;jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52191_en_t6.12223.jpg" alt="Differences in accordance with the technique"></img></a></p><p class="elsevierStylePara">Table 6&#46; Differences in accordance with the technique</p><p class="elsevierStylePara"><a href="grande&#47;12223&#95;16025&#95;52192&#95;en&#95;f1&#46;12223&#46;jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52192_en_f1.12223.jpg" alt="Study design&#46;"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Study design&#46;</p><p class="elsevierStylePara"><a href="grande&#47;12223&#95;16025&#95;52193&#95;en&#95;f2&#46;12223&#46;jpg" class="elsevierStyleCrossRefs"><img src="12223_16025_52193_en_f2.12223.jpg" alt="Reduction percentages of the substances analysed in post-dilution and mixed online haemodiafiltration&#46;"></img></a></p><p class="elsevierStylePara">Figure 2&#46; Reduction percentages of the substances analysed in post-dilution and mixed online haemodiafiltration&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducci&#243;n&#58;</span> La hemodiafiltraci&#243;n &#40;HDF&#41; con altos vol&#250;menes de reinfusi&#243;n es la t&#233;cnica m&#225;s eficaz en la depuraci&#243;n de toxinas ur&#233;micas&#46; Existen distintas modalidades dependiendo del lugar donde se administra el volumen de sustituci&#243;n en el circuito extracorp&#243;reo&#58; predilucional&#44; mixta o mid-dilucional y posdilucional&#44; en las que la infusi&#243;n se realiza pre&#44; de forma simult&#225;nea pre y pos&#44; y posdilucional&#44; respectivamente&#46; <span class="elsevierStyleBold">Objetivo&#58;</span> Comparar la depuraci&#243;n de mol&#233;culas peque&#241;as&#44; medianas y unidas a prote&#237;nas y el volumen convectivo administrado en HDF en l&#237;nea &#40;HDF-OL&#41; con infusi&#243;n posdilucional y mixta &#40;pre-posdilucional&#41;&#46; <span class="elsevierStyleBold">Material y m&#233;todos&#58; </span>Estudio prospectivo&#44; aleatorizado y cruzado&#44; comparando HDF-OL posdilucional y mixta&#46; Los pacientes &#40;n&#160;&#61;&#160;8&#41; fueron asignados aleatoriamente para recibir 6 sesiones en cada t&#233;cnica&#46; Se realizaron 89 sesiones&#44; de las cuales 68 fueron a tiempo programado &#40;TP&#41; y 21 a tiempo efectivo &#40;TE&#41;&#46; Se determinaron los porcentajes de reducci&#243;n &#40;RR&#41; de distintas sustancias y los vol&#250;menes de infusi&#243;n&#46; El estudio de los RR se realiz&#243; con TE&#46; <span class="elsevierStyleBold">Resultados&#58;</span> El KT obtenido fue mayor con HDF-OL posdilucional &#91;68 &#40;8&#44;1&#41; frente a 64&#44;9 &#40;8&#44;8&#41; litros&#93; &#40;p&#160;&#61;&#160;0&#44;009&#41; cuando los pacientes se dializaron a TP&#46; Esta diferencia desaparec&#237;a cuando la di&#225;lisis se realizaba a TE&#46; La diferencia entre el TP-TE fue mayor en la HDF mixta con respecto a la HDF posdilucional &#91;10&#44;3 &#40;7&#44;4&#41; frente a 6&#44;5 &#40;3&#44;1&#41; minutos&#44; p&#160;&#61;&#160;0&#44;02&#93;&#46; No encontramos diferencias en los RR de las sustancias analizadas&#46; <span class="elsevierStyleBold">Conclusi&#243;n&#58;</span> La HDF-OL mixta no es inferior a la posdilucional ni en la depuraci&#243;n de mol&#233;culas peque&#241;as y medianas ni en las unidas a prote&#237;nas a igual TE&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction&#58;</span> Haemodiafiltration &#40;HDF&#41; with high reinfusion volumes is the most effective technique for clearing uraemic toxins&#46; There are various modalities depending on the location where the replacement volume is administered in the extracorporeal circuit&#58; pre-dilution&#44; mixed or mid-dilution and post-dilution&#44; in which the infusion is carried out pre-dilution&#44; pre- and post-dilution simultaneously and post-dilution&#44; respectively&#46; <span class="elsevierStyleBold">Objective&#58;</span> Compare the clearance of small&#44; medium-sized and protein-bound molecules and the convective volume administered in online HDF &#40;OL-HDF&#41; in post-dilution and mixed &#40;pre-post-dilution&#41; infusion&#46; <span class="elsevierStyleBold">Material and method&#58;</span> A prospective&#44; randomised&#44; crossover study comparing post-dilution and mixed OL-HDF&#46; Patients &#40;n&#61;8&#41; were randomly assigned to receive 6 sessions in each technique&#46; We conducted 89 sessions&#44; of which 68 were at a scheduled time &#40;ST&#41; and 21 at an effective time &#40;ET&#41;&#46; We determined the reduction rate &#40;RR&#41; percentages for various substances and the infusion volumes&#46; The RR study was performed using ET&#46; <span class="elsevierStyleBold">Results&#58;</span> The KT value obtained was greater with post-dilution OL-HDF &#91;68 &#40;8&#46;1&#41; compared to 64&#46;9 &#40;8&#46;8&#41; litres&#93; &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;009&#41; when patients were dialysed at ST&#46; This difference disappeared when dialysis was performed at ET&#46; The difference between ST and ET was greater in mixed HDF than in post-dilution HDF &#91;10&#46;3 &#40;7&#46;4&#41; compared to 6&#46;5 &#40;3&#46;1&#41; minutes&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;02&#93;&#46; We found no differences in the RR of the substances analysed&#46; <span class="elsevierStyleBold">Conclusion&#58;</span> Mixed OL-HDF is not inferior to post-dilution OL-HDF either in the clearance of small and medium-sized molecules or in the clearance of protein-bound molecules at the same ET&#46;</p>"
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Article information

ISSN: 20132514
Original language: English

DOI:10.3265/Nefrologia.pre2013.Sep.12223

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Year/Month	Html	Pdf	Total

2024 November	6	8	14
2024 October	66	59	125
2024 September	66	62	128
2024 August	79	76	155
2024 July	90	45	135
2024 June	67	52	119
2024 May	102	48	150
2024 April	72	36	108
2024 March	86	46	132
2024 February	57	61	118
2024 January	94	45	139
2023 December	70	40	110
2023 November	53	45	98
2023 October	64	62	126
2023 September	51	55	106
2023 August	59	37	96
2023 July	86	56	142
2023 June	101	30	131
2023 May	73	49	122
2023 April	56	19	75
2023 March	104	31	135
2023 February	53	24	77
2023 January	67	23	90
2022 December	46	33	79
2022 November	85	41	126
2022 October	89	42	131
2022 September	74	42	116
2022 August	82	52	134
2022 July	56	52	108
2022 June	92	31	123
2022 May	69	52	121
2022 April	94	57	151
2022 March	93	41	134
2022 February	109	45	154
2022 January	111	38	149
2021 December	69	53	122
2021 November	66	55	121
2021 October	101	41	142
2021 September	75	46	121
2021 August	82	44	126
2021 July	73	39	112
2021 June	123	38	161
2021 May	116	37	153
2021 April	271	137	408
2021 March	122	51	173
2021 February	115	27	142
2021 January	72	23	95
2020 December	67	21	88
2020 November	74	16	90
2020 October	39	20	59
2020 September	60	16	76
2020 August	59	22	81
2020 July	61	19	80
2020 June	60	24	84
2020 May	56	13	69
2020 April	53	20	73
2020 March	66	24	90
2020 February	81	23	104
2020 January	98	30	128
2019 December	83	27	110
2019 November	72	26	98
2019 October	38	20	58
2019 September	63	22	85
2019 August	46	21	67
2019 July	78	37	115
2019 June	56	16	72
2019 May	44	32	76
2019 April	106	42	148
2019 March	54	32	86
2019 February	45	30	75
2019 January	59	26	85
2018 December	110	38	148
2018 November	109	21	130
2018 October	106	15	121
2018 September	117	28	145
2018 August	73	27	100
2018 July	75	17	92
2018 June	65	19	84
2018 May	78	16	94
2018 April	46	10	56
2018 March	68	15	83
2018 February	63	12	75
2018 January	80	8	88
2017 December	71	13	84
2017 November	86	10	96
2017 October	68	11	79
2017 September	111	16	127
2017 August	103	28	131
2017 July	82	6	88
2017 June	117	15	132
2017 May	122	15	137
2017 April	94	14	108
2017 March	97	5	102
2017 February	164	15	179
2017 January	84	10	94
2016 December	107	14	121
2016 November	152	17	169
2016 October	169	23	192
2016 September	285	14	299
2016 August	300	22	322
2016 July	278	22	300
2016 June	199	0	199
2016 May	202	0	202
2016 April	192	0	192
2016 March	136	0	136
2016 February	135	0	135
2016 January	129	0	129
2015 December	138	0	138
2015 November	127	0	127
2015 October	121	0	121
2015 September	111	0	111
2015 August	100	0	100
2015 July	96	0	96
2015 June	54	0	54
2015 May	58	0	58
2015 April	6	0	6

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