Scientific letter
In Vitro and In Vivo Evaluation of the Combination of Oscillating Positive Expiratory Pressure and Nebulization: A Randomized Cross-Over Study
Evaluación in vitro e in vivo de la combinación de presión espiratoria positiva oscilante y nebulización: estudio aleatorizado cruzado
Gregory Reychlera,b,c,
, Teresinha Leald, Anne-Sophie Aubriotb,e, Giuseppe Liistroa,c
Corresponding author
a Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL & Dermatologie, Université Catholique de Louvain, Belgium
b Service de Médecine Physique et Réadaptation, Cliniques universitaires Saint-Luc, Belgium
c Service de Pneumologie, Cliniques universitaires Saint-Luc, Belgium
d Louvain Centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Secteur des Sciences de la Santé, Université Catholique de Louvain, Belgium
e Centre de Référence pour la Mucoviscidose, Cliniques universitaires Saint-Luc, Belgium
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Médecine Physique et Réadaptation, Cliniques universitaires Saint-Luc, Belgium" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Service de Pneumologie, Cliniques universitaires Saint-Luc, Belgium" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Louvain Centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Secteur des Sciences de la Santé, Université Catholique de Louvain, Belgium" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Centre de Référence pour la Mucoviscidose, Cliniques universitaires Saint-Luc, Belgium" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Evaluación in vitro e in vivo de la combinación de presión espiratoria positiva oscilante y nebulización: estudio aleatorizado cruzado" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 706 "Ancho" => 2332 "Tamanyo" => 71883 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Illustration of the experimental model. 1 – Aerobika, 2 – nebulizer, 3 – filter collecting the inhaled dose, 4 – filter collecting the exhaled dose.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Positive expiratory pressure (PEP) as airway clearance technique prevents airway closure during expiration, reduces gas trapping in the lung,<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> increases collateral ventilation<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> and improves spatial ventilation distribution.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> The addition of oscillations promotes mucus mobilization based on the reduced mucus viscosity<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> and distributed flows in more airways.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a> Oscillating PEP devices have been proposed in cystic fibrosis.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> Simultaneous use of PEP and nebulization is sometimes performed in cystic fibrosis patients even if its clinical benefits are still not well established.</p><p id="par0010" class="elsevierStylePara elsevierViewall">As the drug amount reaching the lungs is essential for the clinical response of drug with a dose-dependent effect, this study aims at evaluating the effect of a new oscillating PEP device combined to a nebulizer on the drug delivery to the lungs.</p><p id="par0015" class="elsevierStylePara elsevierViewall">We connected a jet nebulizer (Sidestream<span class="elsevierStyleSup">®</span>, Philips-Respironics) (NEB) at the distal end of an oscillating PEP device (Aerobika<span class="elsevierStyleSup">®</span>, Trudell-Medical) (NEB-OPEP) with a T-piece blocking the extra vent. Each nebulizer was filled with 250<span class="elsevierStyleHsp" style=""></span>mg of amikacin diluted with 3<span class="elsevierStyleHsp" style=""></span>mL of normal saline.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the in vitro part, a dual-chamber test lung (5600i Dual Adult Test Lung; Michigan Instrument Inc.) driven by a ventilator (Servo-i<span class="elsevierStyleSup">®</span>, MAQUET) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) simulated an adult breathing pattern (Vt<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>500<span class="elsevierStyleHsp" style=""></span>mL-RF<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>breaths/min-<span class="elsevierStyleItalic">I</span>/<span class="elsevierStyleItalic">E</span> ratio<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1:2-breath-hold time<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.25<span class="elsevierStyleHsp" style=""></span>s). An absolute bacterial/viral filter (Air Safety Ltd, Lancashire) was placed between the lung model and NEB-OPEP/NEB to measure the inhaled dose (IND). Another filter placed on the expiratory port collected the exhaled dose (ExD). The mass of amikacin collected on filters during nebulization was quantified using the residual gravimetric method.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a> The nebulizer output was calculated by dividing the IND by the nebulization duration. The residual volume was quantified.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">In the in vivo part, after ethical approval (B40320107908) and registration of the trial (<a href="ctgov:NCT02535130">NCT02535130</a>), six non-smoker healthy males were recruited. They signed a written informed consent form. They were excluded if they received any antibiotic or aerosolized drug during the month preceding the experiments, for history of cardiovascular and/or pulmonary disease, for allergy to aminoglycosides and for abnormal pulmonary function.</p><p id="par0030" class="elsevierStylePara elsevierViewall">After (1) selection visit, spirometry and medical examination and (2) training to inhale correctly, (3) inhalation and (4) urine sampling were performed. Each subject repeated the steps 3 and 4 in similar conditions using a randomized crossover setting (<a href="http://www.randomizer.org/">www.randomizer.org</a>) with a one-week washout period between the two configurations (NEB or NEB-OPEP). The subjects breathed spontaneously through mouthpiece wearing a noseclip.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Just before the experiments, the urinary bladder of the subjects was emptied. Then, urine samples were collected at each spontaneous micturition during the 24<span class="elsevierStyleHsp" style=""></span>h following the nebulization. The volume and timing of micturition were recorded.</p><p id="par0040" class="elsevierStylePara elsevierViewall">After sampling by fluorescence polarization immuno-assay, the total daily amount of amikacin excreted in the urine (Cu max) reflecting lung deposition and the elimination rate constant was calculated using the Michaelis–Menten kinetic model from cumulating amikacin amount measured at each micturition (Cu) and represents the lung dose (LD) (Cu max<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>Cu<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>(1<span class="elsevierStyleHsp" style=""></span>−<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">e</span><span class="elsevierStyleSup">−<span class="elsevierStyleItalic">Ke</span>·<span class="elsevierStyleItalic">x</span>·<span class="elsevierStyleItalic">t</span></span>)).</p><p id="par0045" class="elsevierStylePara elsevierViewall">The residual amount of drug was calculated by multiplying residual volume and its final concentration.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In vitro, no difference was found between NEB and NEB-OPEP for IND (34.4% (30.0–38.0) vs 29.6% (26.8–32.0)) and ExD (20.8 (19.6–23.2) vs 25.2% (22.4–28.4)). Nebulizer output was higher for NEB than for NEB-OPEP (1.49<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.14 vs 1.10<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.12<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleHsp" style=""></span>min<span class="elsevierStyleSup">−1</span>; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.032).</p><p id="par0055" class="elsevierStylePara elsevierViewall">Six subjects completed the study (21.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.0 y – 179.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.8<span class="elsevierStyleHsp" style=""></span>cm – 76.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11.7<span class="elsevierStyleHsp" style=""></span>kg – FEV1: 97<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7%). The lung dose was reduced by 40% and the time required to finish the nebulization was 1.2<span class="elsevierStyleHsp" style=""></span>min longer with NEB-OPEP than with NEB (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Lung delivery around 5% of the ND with NEB confirmed previous results.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> In addition, our results showed that interposing this new OPEP device between the nebulizer and the patient's mouth reduced the efficiency of the nebulization similarly to results found with other PEP devices under different conditions.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">9,10</span></a> This is clinically important when dose-dependent drugs are administered. The reduced lung delivery could be explained by the impaction of particles in the PEP device that filters the larger particles.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">9,11</span></a> However, this hypothesis was neither verified in our study (similar IND and ExD) nor in a previous study.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The duration of the nebulization was inversely related to the adherence in CF<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a> and it is therefore considered as a key factor for an optimal treatment.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">14,15</span></a> In the present study, the small increase in time (+1.2<span class="elsevierStyleHsp" style=""></span>min) related to the NEB-OPEP is compensated by the time saved on the total duration of the treatment administered separately (3.1<span class="elsevierStyleHsp" style=""></span>min). This advantage could be important for the patients needing several daily sessions. However, as suggested by our results, the necessity to nearly double the nebulization duration to reach a similar lung delivery with NEB-OPEP must be taken into account. As Berlinsky showed variable delivery depending on the PEP devices,<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> each configuration must be evaluated.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The modified pattern of breathing related to PEP is unfavorable to the nebulization function and explains probably the worst lung delivery related to the combination. The reduction in breathing frequency (7.8 cycles by minutes) when healthy subjects used PEP mask could be considered as advantageous<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">16</span></a> but it was associated to a prolonged expiration that contributes to loose particles during the expiratory phase.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> The concomitant reduction in the inspiratory–expiratory ratio contributes certainly to the reduced lung delivery by losing particles during the expiratory phase and it can explain the difference with in vitro results. Some particles are probably exhaled and others are delivered in the atmosphere or the device during this phase.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Some limitations of the study should be discussed. First, the nebulizer was placed at the distal outlet of the PEP device. This configuration is less efficient than that in which the proximal outlet is used for connection,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> although the latter is recommended by the manufacturer. Second, testing healthy subjects omits the clinical and pathophysiological outcomes related to positive expiratory pressure and its oscillations but it permits to evaluate the nebulization function<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">8,18,19</span></a> and reduces the variability resulting from mucus plugging or lung disease. Furthermore, even if lung delivery in healthy subjects cannot be extrapolated to patients with respiratory diseases, a similar lung deposition was recently found between healthy subjects and patients with CF.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a> Third, each subject was its own control to reduce anatomical, anthropometrical and respiratory influences on lung delivery.</p><p id="par0080" class="elsevierStylePara elsevierViewall">This study suggests that connecting Aerobika at the proximal outlet of a nebulizer is less efficient than using the nebulization alone for drug delivery. However, the gain in time is an argument in favor of the combination.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 706 "Ancho" => 2332 "Tamanyo" => 71883 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Illustration of the experimental model. 1 – Aerobika, 2 – nebulizer, 3 – filter collecting the inhaled dose, 4 – filter collecting the exhaled dose.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Results are expressed as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD. NEB: nebulizer; NEB-OPEP: nebulizer couple with an oscillating positive expiratory pressure device; ND: nominal dose.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NEB \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NEB-OPEP \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lung dose (% ND) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.029<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">*</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Time of nebulization (min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.012<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">*</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Residual volume (mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.85<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.04<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.044<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">*</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1605834.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0005"><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Lung delivery comparison between nebulization used alone and coupled with an oscillating positive expiratory pressure device in 6 healthy subjects.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Positive expiratory pressure (PEP-mask) physiotherapy improves ventilation and reduces volume of trapped gas in cystic fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 2 | 11 |
| 2024 October | 63 | 13 | 76 |
| 2024 September | 50 | 13 | 63 |
| 2024 August | 77 | 40 | 117 |
| 2024 July | 50 | 21 | 71 |
| 2024 June | 47 | 33 | 80 |
| 2024 May | 78 | 26 | 104 |
| 2024 April | 34 | 24 | 58 |
| 2024 March | 44 | 23 | 67 |
| 2024 February | 33 | 19 | 52 |
| 2023 March | 24 | 3 | 27 |
| 2023 February | 74 | 35 | 109 |
| 2023 January | 45 | 43 | 88 |
| 2022 December | 95 | 41 | 136 |
| 2022 November | 101 | 31 | 132 |
| 2022 October | 88 | 44 | 132 |
| 2022 September | 86 | 24 | 110 |
| 2022 August | 63 | 42 | 105 |
| 2022 July | 36 | 39 | 75 |
| 2022 June | 102 | 36 | 138 |
| 2022 May | 44 | 42 | 86 |
| 2022 April | 49 | 29 | 78 |
| 2022 March | 51 | 48 | 99 |
| 2022 February | 44 | 32 | 76 |
| 2022 January | 54 | 48 | 102 |
| 2021 December | 50 | 32 | 82 |
| 2021 November | 56 | 39 | 95 |
| 2021 October | 74 | 63 | 137 |
| 2021 September | 54 | 46 | 100 |
| 2021 August | 48 | 46 | 94 |
| 2021 July | 54 | 30 | 84 |
| 2021 June | 56 | 51 | 107 |
| 2021 May | 49 | 52 | 101 |
| 2021 April | 90 | 119 | 209 |
| 2021 March | 46 | 38 | 84 |
| 2021 February | 53 | 35 | 88 |
| 2021 January | 54 | 25 | 79 |
| 2020 December | 40 | 42 | 82 |
| 2020 November | 40 | 39 | 79 |
| 2020 October | 32 | 36 | 68 |
| 2020 September | 38 | 25 | 63 |
| 2020 August | 32 | 28 | 60 |
| 2020 July | 36 | 35 | 71 |
| 2020 June | 27 | 16 | 43 |
| 2020 May | 25 | 17 | 42 |
| 2020 April | 25 | 25 | 50 |
| 2020 March | 31 | 22 | 53 |
| 2020 February | 33 | 23 | 56 |
| 2020 January | 25 | 26 | 51 |
| 2019 December | 30 | 12 | 42 |
| 2019 November | 32 | 29 | 61 |
| 2019 October | 25 | 22 | 47 |
| 2019 September | 22 | 13 | 35 |
| 2019 August | 36 | 18 | 54 |
| 2019 July | 20 | 19 | 39 |
| 2019 June | 21 | 13 | 34 |
| 2019 May | 44 | 13 | 57 |
| 2019 April | 37 | 31 | 68 |
| 2019 March | 39 | 31 | 70 |
| 2019 February | 27 | 33 | 60 |
| 2019 January | 25 | 19 | 44 |
| 2018 December | 39 | 20 | 59 |
| 2018 November | 100 | 36 | 136 |
| 2018 October | 172 | 51 | 223 |
| 2018 September | 68 | 15 | 83 |
| 2018 August | 5 | 0 | 5 |
| 2018 July | 1 | 0 | 1 |
| 2018 May | 0 | 3 | 3 |
| 2018 April | 43 | 23 | 66 |
| 2018 March | 71 | 29 | 100 |
| 2018 February | 1 | 1 | 2 |
| 2018 January | 2 | 1 | 3 |
| 2017 December | 15 | 4 | 19 |
| 2017 June | 0 | 1 | 1 |
| 2017 May | 0 | 1 | 1 |
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