{"id":9841,"date":"2026-04-08T12:53:49","date_gmt":"2026-04-08T12:53:49","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/paolo-antonio-ernesto-maino\/"},"modified":"2026-04-23T07:53:48","modified_gmt":"2026-04-23T07:53:48","slug":"paolo-antonio-ernesto-maino","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/paolo-antonio-ernesto-maino\/","title":{"rendered":"Paolo Antonio Ernesto Maino"},"content":{"rendered":"","protected":false},"excerpt":{"rendered":"","protected":false},"author":8,"featured_media":13044,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-9841","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"Implantable Intrathecal Drug Delivery in Treatment of Chronic Intractable Pain and Spasticity: Improvement of Safety and the Use of Imaging Techniques","samenvatting":"Er is geen Nederlandse samenvatting beschikbaar. De Engelse samenvatting vind je <a href=\"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/paolo-antonio-ernesto-maino\/\">hier<\/a>.","summary":"IDD is utilized to treat patients with chronic refractory non-cancer pain, cancer pain and spasticity. The aim of the research as described in this thesis was to investigate technical procedures and the use of imaging techniques to improve efficiency and safety in intrathecal drug delivery (IDD) management (see Introduction Chapter 1, page 9). Recognition as well as prevention of complications are important aspects to improve safety. Complications related to intrathecal drug delivery systems (IDDS) 1\u20133 may involve the implantation procedure, drug reactions and side effects, human error in programming or refilling the device, pump malfunction and intrathecal granuloma formation.\n\nCurrent drugs approved by the US Food and Drug Administration (FDA) for IDD are morphine, ziconotide, and baclofen. A number of other agents commonly used \u2018off label\u2019 for IDD include fentanyl, sufentanil, hydromorphone, bupivacaine and clonidine. In 2012 Medtronic sent a safety notification with the warning to not use unapproved drugs in the SynchroMed II IDDS, stating that the use of unapproved drugs could increase the risk of intermittent or permanent pump motor stalls.\n\nOn the other hand, the prescription of these unapproved drugs for IDD is highly supported by the recommendations of the PACC. An argument in favor of using fentanyl instead of morphine for IDD is the fact that this drug has a lower risk for granuloma formation. Furthermore, the lipophilic nature of fentanyl makes it ideal for treatment of focal pain issues. However, corrosive agents originating from fentanyl can permeate through the inner tubing, initiate corrosion of internal pump components in the SynchroMed II IDDS, and might therefore result in malfunction of these pumps. To obtain insight into the complication of a pump malfunction RQ1a of this thesis was the question which symptoms and exams can confirm this complication and a consequential overdose and which actions should be taken. IDDS malfunction is a complication that mostly results in under-dosing or cessation of therapy, which can lead to increase in pain or spasticity and withdrawal symptoms.\n\nAlthough less frequent, pump malfunction can also lead to overdosing. In Chapter 2 two patients are presented who experienced an intrathecal overdose of fentanyl due to over-infusion because of pump malfunction. Symptoms of overdose are somnolence, pinpoint pupils, nausea and respiratory depression. Naloxone, an opioid antagonist, should be administered, and a sudden reversal of the symptoms after the injection of naloxone, confirms the suspicion of an opioid overdose. In case of signs of overdose and suspicion of pump malfunction it is advisable to stop the pump (or program it on minimum flow rate), to monitor the patient at least for 24 hours, and to consider removing the pump and sending it to the manufacturer for analysis.\n\nInvestigations of the manufacturers to make the IDDS suitable for fentanyl would be welcome. However, IDDS malfunction is not only related to the use of unapproved drugs. Furthermore, aside from opioids, an over-infusion or interruption of baclofen and clonidine can also be life threatening. In July 2016, Medtronic investigated adverse events of 238,000 implanted SynchroMed II IDDSs, and in 103 cases it was reasonable to conclude that over-infusion due to IDDS malfunction was a contributing factor. Patient outcomes associated with these adverse events ranged from temporary discomfort to life threatening overdose and\/or withdrawal as well as two reports of death. However, over-infusion is not always associated with clinically relevant symptoms. Furthermore, the number of adverse events caused by over-infusion might be underestimated because of under-reporting. We suggest further large scale studies to investigate the occurrence of IDDS malfunction and the necessity to make IDDS suitable for unapproved drugs.\n\nAnother cause of under-dosing or cessation of therapy, can be a granuloma formation. To obtain further insight into the complications of granuloma formation the research question RQ1b was which symptoms and exams can confirm a granuloma formation and which actions should be taken. In Chapter 3 we present a patient who was treated with IDD of morphine for eight years. The patient developed pain in the lower extremities and an urge to move the legs without meningeal signs. A lumbar puncture revealed an inflammatory reaction in the cerebrospinal fluid (CSF), while neuroimaging results were negative for granuloma formation. The morphine daily rate was gradually reduced and a ziconotide infusion was introduced, according to the Polyanalgesic Consensus Conference (PACC) recommendations. Three months after the decrease in spinal morphine infusion and the switch to ziconotide, CSF analysis showed a reduction in the inflammatory reaction, suggesting an iatrogenic arachnoiditis secondary to morphine infusion. The influence of morphine on lymphocyte proliferation is well known and human immune cells have been found to express \u03b4, \u03bc, and \u03ba opioid receptors like neuronal cells. Morphine can trigger \u03bc receptors on the lymphocyte surface, causing an increased expression of mitogen-activated protein kinase cascade proteins, resulting in lymphocyte activation and proliferation. Early CSF inflammatory reaction might be the first step to granuloma formation and an early diagnosis of aseptic arachnoiditis with a lumbar puncture, might therefore prevent late granuloma development. In response to RQ1b symptoms of pain in the lower extremities and an urge to move the legs can be initial signs of granuloma formation. If these symptoms are not resolved, and if neuroimaging results are negative, we advise to perform a lumbar puncture to exclude an inflammatory reaction in the CSF. In case of an inflammatory reaction in the CSF the switch to another intrathecal drug should be performed.\n\nStructural differences between various IDDSs (see Introduction Chapter 1, page 6, and Raised-Septum-IDDS (RS-IDDS) Figure 1 and Flat-Surface-IDDS (FS-IDDS), Figure 2) may require different RFP identification approaches. The conventional refill technique for the most commonly utilized SynchroMed II IDDS is performed with the aid of a template which is included in the refill kit. The template has the shape of the outer borders of the pump. In order to locate the puncture site, its edges have to be aligned with the edges of the pump, followed by the identification of the puncture site in the template\u2019s circular hole. However, this alignment frequently fails due to difficulties of palpating the exact location and orientation of the pump through the overlying skin. When the hole of the template does not correspond to the location of the RFP, there is a risk of multiple futile access attempts being performed, which subsequent patient discomfort and an increased risk of a pocket fill. Clinical scenarios that may make locating the RFP difficult or impossible are excessive subcutaneous fat, the presence of fluid collections above the pump, and scar formation. The PACC panel recommends the use of fluoroscopy or ultrasound (US) for refill procedures in difficult cases.\n\nWith RQ2 of this thesis the question was addressed how accurate the conventional refill technique actually is as controlled with fluoroscopic imaging. In Chapter 4 the results from a prospective observational comparison study regarding the accuracy of the conventional refill technique in a FS-IDDS are described. The accuracy of the identification of the puncture site of the RFP using the conventional refill technique with the template, was controlled with fluoroscopic imaging. A distance surpassing that between the center and the margin of the RFP (3.5 mm) was considered a clinically relevant deviation. The mean difference distance between identification markings of the RFP with fluoroscopic guidance and with the template was 8.2 mm (SD = 2.7 mm). Only seven template guided attempts (6.4%) were within the margins of the RFP. This significant difference between the templated-guided versus the fluoroscopic-guided identification of the puncture site suggests a poor accuracy of the template-guided technique in FS-IDDS and highlights the potential risk of errors related to identification of the puncture site with this technique.\n\nRegarding the RS-IDDS model, Chapter 5 presents a similar prospective comparison study, which aimed to assess the accuracy of determining the localization of the RFP center using the conventional manual technique, controlled fluoroscopically. A distance surpassing that between the center and the margin of the RFP (4 mm for the MedStream RS-IDDS) was considered a clinically relevant deviation. The mean deviation from the RFP center was 4.9 mm (SD = 3.7). The RFP identification accuracy in the RS-IDDS cohort deviated more than the clinically relevant difference in 17 out of 31 (54.8%) times. Comparing both studies, the mean deviations in the RS-IDDS cohort were lower compared to the FS-IDDS cohort (first refill procedure 4.0 vs 8.5, p < 0.001, second procedure 5.9 vs 8.1, p = 0.074). In response to RQ2, the results of Chapter 5 suggest that the conventional refill technique for the RS-IDDS is moderately accurate, and at least more accurate if compared to the template-guided technique for the FS-IDDS. The fact that the raised septum can be palpated through the skin seems to facilitate the manual localization of the RFP. Based on the results as described in Chapters 4 and 5 it is concluded that the RS-IDDS model is preferable above FS-IDDS model. The higher accuracy of the manual RFP identification in the RS-IDDSs might improve patient safety and decrease patient discomfort.\n\nFluoroscopic imaging of the RFP might increase safety during refill procedures although fluoroscopy is associated with higher health care costs and has the drawback of patient radiation exposure. Therefore, other methods to localize the RFP need to be developed. US is a promising approach to localize the RFP and has several advantages over fluoroscopy including the portability of the machine and the lack of radiation exposure. This provided a background for RQP which questioned whether US-guided imaging can ameliorate the efficiency of RFP identification during IDDS refill procedures. Two prospective comparison studies (Chapters 6 and 7) investigated the efficacy of RFP access comparing the US-guided refill technique to the conventional blind refill technique, performed by experienced clinicians. The results of the first trial, which focused at the RS-IDDS model, are presented in Chapter 6. One hundred and eleven refill procedures were assessed in 19 patients over a period of 24 months. The median number of attempts to enter the RFP with the needle differed significantly between the US-guided technique and the blind technique (4 [IQR: 1\u20136] vs. 1 [IQR: 1\u20133], p=0.018) in favor of, surprisingly, the blind technique. The median time to enter the RFP differed also significantly between the US-guided technique and the blind technique (58 sec [IQR: 38\u201394] vs. 22 sec [IQR: 16\u201340], p<0.001). From this it is concluded that in RS-IDDS US-guided imaging does not ameliorate the efficiency of RFP identification, if performed by experienced staff. The results of this study even suggest that US guidance slightly worsens efficiency of the RFP needle access in comparison to the blind refill technique.\n\nThe results of a second trial (Chapter 7) presents the assessment of the efficiency of RFP access with the US-guided versus the blind refill technique in a FS-IDDS model. Fourteen adult patients underwent a total of 75 refills of their FS-IDDS in a period of 24 months. The median number of attempts to enter the RFP did not differ significantly between the US-guided technique and the blind technique (2.0 (IQR: 1 \u2013 5) vs. 1.5 (IQR: 1 \u2013 5.0), p = 0.572). In addition, the median time to enter the RFP with the needle did not differ significantly between the US-guided technique and the blind technique (35.0 seconds (IQR: 26.0 \u2013 58.0) vs. 41.0 seconds (IQR: 25.5 \u2013 46.8), p = 0.878). The results of this study suggest that for a FS-IDDS the US-guided refill technique does not lead to significant differences in number of attempts and time to enter the RFP with the needle. From Chapter 7 it is concluded that there is no difference in the RFP needle access efficiency between the US-guided and the blind refill technique in superficially-located FS-IDDSs, if performed by experienced practitioners. In answer to RQP it can be concluded that in FS-IDDSs US-guided imaging does not seem to ameliorate but neither to worsen the efficiency of RFP identification. This outcome in FS-IDDS differed from that in RS-IDDS, (see Chapter 6), where US-guidance resulted in a significantly higher number of needle attempts and procedural time compared to conventional manual refill technique. Based on our experiences during the refill procedures, we hypothesized that this difference in outcome between FS-IDDS and RS-IDDS is caused by the raised septum, which leads to an insufficient plate support of the US probe, making the US-guided technique less easy to perform in the RS-IDDS as compared to the FS-IDDS. US-guidance has the additional drawback of costs and requires training. However, both studies as in Chapter 6 and Chapter 7 did not address efficiency of the RFP needle access in IDDSs with aberrancy location, neither did they assess refills performed by inexperienced staff. The use of US guidance remains therefore recommended in IDDSs with difficult-to-access RFPs, like for example deep located or rotated pumps and the presence of fluid collections or scar formation.\n\nWith regard to the risk of the complication of overdose due to pocket fills, particular attention should be paid to drugs reservoir volume discrepancies and overdose symptoms reported by patients. Unlike the existing models, the MedStream IDDS (see Introduction Chapter 1, Figure 1) is equipped with a \u2018fill level sensor\u2019 which measures the effective drug volume inside the reservoir. If the reservoir\u2019s drug volume is measured directly after a refill procedure with this sensor, a pocket fill could be recognized immediately. Nevertheless, little volume discrepancies between the injected volume and the volume that actually reached the reservoir might be normal, because of micro air bubbles in the syringes and residuals of the solution in the tubing. Hence, RQ4 was formulated (see Introduction Chapter 1) \u201cwhich volume discrepancy should be regarded as \u2018out of normal range\u2019 and require precautions to prevent life-threatening complications caused by drug overdose?\u201d. In Chapter 8 the mean volume discrepancy between the injected and the effective drug volume inside the reservoir (of the MedStream IDDS) was assessed. Two hundred and twenty-one refill procedures performed in 19 adult patients were evaluated and symptoms of overdose were monitored. Based on the results of this study a volume discrepancy of <1 and <2 mL, respectively, in the 20 and 40 mL IDDSs, should be regarded as in the normal range. Higher volume discrepancies are potentially consequential, especially in case of opioids, and symptoms of overdose are likely to appear. In these patients precautions to prevent life-threatening complications caused by drug overdose should be taken. Hospitalization and monitoring is recommended to preclude late overdose symptoms outside the hospital. Chapter 8 additionally describes six cases of drug overdoses and provides a list of recommendations around pocket fills regarding prevention, diagnosis and actions to be taken. The results from these six cases suggest that regular measurement of the volume discrepancies after the refill may significantly contribute to the prevention and reduction of major complications in patients who benefit from intrathecal therapy. The production of MedStream IDDSs was stopped in 2014. Therefore, at present time there is no other model of IDDS available with the option to measure the effective drugs volume inside the reservoir. Hence, there is a high urgency for manufacturers to provide IDDSs with the option to directly measure the effective drug volume inside the pump reservoir.\n\nIn conclusion, this thesis aimed to investigate technical procedures like the conventional intrathecal refill technique and the use of imaging techniques to improve efficiency and safety in IDDS management. The recognition and management of IDDS malfunction and granuloma formation is addressed as well as the application of imaging guidance for RFP identification. The conventional refill technique for FS-IDDSs lacks accuracy, while the conventional refill technique of the RS-IDDS seems to be more accurate. The regular use of US-guidance for the refill of FS-IDDSs can be justified as this technique is as efficient as the blind conventional technique and, additionally, might improve safety. In RS-IDDSs, the US-guided refill technique should be utilized for challenging refills and in case of fluid accumulation and pocket fills. In addition, US-guidance can be very useful if the septum is not manually identified, in case of a suspicion of a pocket fill or seroma accumulation, and in case of a pump inversion. Lastly, physicians should pay particular attention to overdose symptoms and drug reservoir volume discrepancies during the refill procedures to reduce the risk of the complication of overdose in IDDS management.\n\nBased on the results of the studies as presented in this thesis, the following recommendations for future studies and developments can be made:\n\u2022 As various IDDSs without gears, tubes, motors or rotating parts to wear out or stall were launched on the market over the last years, follow-up studies are encouraged to investigate the suitability of these IDDSs for FDA unapproved but effective and recommended drugs like fentanyl.\n\u2022 There is a high need to improve IDDS designs (raised septum, fill sensors, and making the IDDSs suitable for other medications like fentanyl), which needs to be supported by scientific evidence.\n\u2022 There is a high urgency to provide IDDSs with a sensor to directly measure the effective drug volume inside the pump reservoir.","auteur":"Paolo Antonio Ernesto Maino","auteur_slug":"paolo-antonio-ernesto-maino","publicatiedatum":"6 december 2019","taal":"EN","url_flipbook":"https:\/\/ebook.proefschriftmaken.nl\/ebook\/paoloantonioernestomaino?iframe=true","url_download_pdf":"","url_epub":"","ordernummer":"FTP-202604081251","isbn":"","doi_nummer":"","naam_universiteit":"Universiteit Maastricht","afbeeldingen":13044,"naam_student:":"","binnenwerk":"","universiteit":"Universiteit Maastricht","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/9841","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio"}],"about":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/types\/us_portfolio"}],"author":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/users\/8"}],"replies":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/comments?post=9841"}],"version-history":[{"count":1,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/9841\/revisions"}],"predecessor-version":[{"id":9842,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/9841\/revisions\/9842"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/13044"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=9841"}],"wp:term":[{"taxonomy":"us_portfolio_category","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio_category?post=9841"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}