CASE REPORT

Fentanyl Overdose Caused by Malfunction of SynchroMed II Intrathecal Pump Two Case Reports Paolo Maino, MD,* Eva Koetsier, MD,* and Roberto S.G.M. Perez, PhD† Objective: Intrathecal drug delivery systems (intrathecal pumps) are used to treat patients with chronic refractory pain syndromes and spasticity. The objective of our case report was to demonstrate that intrathecal pump malfunction can lead to intrathecal overdosing of drugs. Case Report: We present 2 cases of intrathecal pump malfunction leading to overinfusion. The first case concerns a patient with an intrathecal pump that was implanted almost 5 years before the reported incident. During a refill procedure, 12.5 mL was aspirated instead of the expected 21.8 mL. Analysis of the pump revealed that the pump was overinfusing. The second case concerns a patient with an intrathecal pump that was implanted more than 5 years before the reported incident. Ten hours after a regular refill of the pump, she was found in a comatose state, and when the intrathecal pump was emptied, only 16 mL was aspirated instead of the 19.6 mL expected. Analysis of the pump revealed that the inner tubing was not running smoothly over the roller arms, possibly causing spurts, which could have caused an overinfusion. Conclusions: We present 2 cases of intrathecal pump malfunction, which most likely led to overinfusion of fentanyl intrathecally. To reduce the risk of this complication, particular attention should be paid to drug reservoir volume discrepancies and overdose symptoms reported by patients. (Reg Anesth Pain Med 2014;39: 434–437)

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ntrathecal drug delivery systems (IDDS) are used to treat patients with chronic refractory pain syndromes and spasticity.1,2 These programmable devices deliver medication directly into the intrathecal space, reducing systemic exposure and achieving pain or spasticity relief with much smaller doses than required with oral or parenteral routes. Medtronic introduced the SynchroMed IDDS brand in the 1980s and more than 200,000 SynchroMed IDDS have been implanted worldwide.3 The pump is implanted in the abdominal wall and dispenses the medication from its reservoir through a catheter that passes subcutaneously around the flank into the intrathecal space. The reservoir of the pump permits the medication supply to be refilled periodically (typically every 1 to 3 months). The SynchroMed II pump was launched in 2004. At the refill of a SynchroMed II pump, the medication enters the pump through the reservoir fill port and passes the reservoir valve into the pump reservoir. Pressurized gas that is stored below the reservoir exerts constant pressure on the reservoir and

From the *Centro per la Terapia del Dolore EOC, Neurocentro della Svizzera Italiana, Lugano, Switzerland; and †Department of Anesthesiology, VU University Medical Center, Amsterdam, the Netherlands. Accepted for publication June 17, 2014. Address correspondence to: Eva Koetsier, MD, Centro per la Terapia del Dolore EOC, Ospedale Italiano, Via Capelli, 6962 Viganello, Switzerland (e‐mail: [email protected]; eva.koetsier@eoc). The authors declare no conflict of interest. Paolo Maino and Eva Koetsier contributed equally and, therefore, share first authorship. Copyright © 2014 by American Society of Regional Anesthesia and Pain Medicine ISSN: 1098-7339 DOI: 10.1097/AAP.0000000000000132

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forces the drug through the filter to the pump rollers, which move the drug through the inner pump tubing and catheter into the intrathecal space.4 All functions of the system are controlled externally using a handheld programmer. Because it is battery driven, the SynchroMed II infusion system has an expected longevity of 4 to 7 years, depending on the flow rate. Complications related to IDDS may involve the surgical procedure, the medication, human error in programming or refilling the pump, the catheter, and malfunction of the IDDS.5 We present the cases of 2 patients who experienced an intrathecal overdose of fentanyl due to malfunction of the SynchroMed II intrathecal pump. Both patients gave permission to publish this report.

CASE REPORT Case 1 A 44-year-old white woman experiencing chronic intractable lumbar back pain was implanted in September 2006 with a SynchroMed II programmable pump (model 8637-40, 40 mL reservoir; SynchroMed, Medtronic Inc, Minneapolis, Minnesota). In May 2011, she informed us that she felt much sleepier and noticed a significant pain reduction in the last weeks. No augmentation had taken place in the last months. The pump contained fentanyl (Pharmacie Internationale Golaz, Lausanne, Vaud, Switzerland) 3 mg/mL and the infusion rate was 1740 μg (0.58 mL) per day. According to standard practice, we emptied the residual volume of the reservoir before refilling it with the new solution. Although the telemetric programmer had indicated that the pump was expected to have 21.8 mL of fentanyl left in the reservoir, only 12.5 mL of fentanyl was aspirated. Six days later, the IDDS was surgically removed because of suspicion of overinfusion. The removed SynchroMed II pump was sent to the manufacturer for analysis and dispense testing revealed that the pump was overinfusing. Internal inspection of the pump motor compartment showed that a significant amount of drug precipitant was present in the pump head and in the pump tube compartments. The inner tubing of the pump had a significant amount of precipitant deposited on it preventing the tube from occluding properly (Fig. 1). According to the analysis, this insufficient tube occlusion was the most likely cause of the overinfusion.

Case 2 A 47-year-old white woman was implanted in March 2008 with a SynchroMed II programmable pump (model 8637-20, 20 mL reservoir; SynchroMed, Medtronic Inc) for intractable discogenic pain. At the time of a regular refill procedure in May 2013, the pump contained fentanyl (Pharmacie Internationale Golaz) 6 mg/mL and the infusion rate was 3100 μg (0.52 mL) per day. The patient reported not being aware of any symptoms of overdose or withdrawal in the latest period. No medication could be aspirated from the reservoir, although the telemetric programmer had indicated an expected residual volume of 5 mL. The

Regional Anesthesia and Pain Medicine • Volume 39, Number 5, September-October 2014

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Regional Anesthesia and Pain Medicine • Volume 39, Number 5, September-October 2014

FIGURE 1. The inner tubing of the pump has white precipitant deposited on it.

pump was refilled with a fentanyl solution of the same concentration. The physician, alerted for a possible overrunning pump, reduced the rate of fentanyl from 3100 to 2700 μg/d and marked to recheck the residual volumes precisely at the next refill. The refill procedure was uneventful, and the patient left our hospital 30 minutes after the procedure with no indication of any problem. Five hours after the refill, the patient started to fill dizzy, and 10 hours after the refill, she was found unresponsive by her husband. The paramedics found the patient in a comatose state with a Glasgow Coma Score of 3 and pinpoint pupils with faint reaction to light. A fentanyl overdose was suspected and the paramedics administered 0.4 mg of naloxone. The patient awakened immediately and the Glasgow Coma Score went up to 14. She was admitted to the intensive care unit with a continuous infusion of naloxone 1.6 mg/h intravenously. The intrathecal pump was immediately emptied. A 16 mL of fentanyl was aspirated instead of the expected 19.6 mL, and therefore, 21,600 μg of fentanyl were missing from the reservoir. Overinfusion was suspected, and the reservoir was refilled with saline and set on minimal flow rate. A urine screening test (Multi Drug of Abuse Urine Test) performed was negative for opioids, but later it was determined that this test was not suitable for detecting fentanyl. The patient recovered completely in 2 days. The pump was removed and not replaced. The pump was sent to the manufacturer for analysis. A review of the pump’s interrogation report confirmed that the motor had a hard stall. Internal inspection of the pump motor compartment revealed significant residue, a lot of moisture, and severe corrosion of the motor gear assembly. The inner tubing of the pump was breached and showed a lot of wearing and rigidity. The condition of the inner tubing made it possible that drug had leaked into to the pump, which had caused the corrosion. This corrosion might have resulted in a motor stall. The rigidity of the inner tubing likely resulted in the tubing not running smoothly over the roller arms (Fig. 2) and making spurts. According to the manufacturer’s analysis, this could have caused the overinfusion.

Overdose & Intrathecal Pump Malfunction

company proposed no explanation for the malfunction. Apart from pump malfunction, other causes can lead to an overdose in patients with IDDS, such as inadvertent injection of the drug into the patient’s subcutaneous tissue during refill (called a pocket fill), inappropriate flow-rate setting due to a programming error, or a backflow of the medication by a leaking silicone septum.6,10 Overdose symptoms after a pocket fill typically occur immediately.6 As our first patient complained of sleepiness during the whole period of the last weeks before the refill and in our second patient the overdose symptoms started 5 hours after the pump refill, a pocket fill in both patients was unlikely. Furthermore, in both of our patients, pump analysis confirmed the possibility of an overinfusion. Drugs for which the SynchroMed II Infusion System is approved are Infumorph (preservative-free morphine); Prialt (ziconotide), Lioresal, and Gablofen (manufactured forms of baclofen); floxuridine and methotrexate.11 Corrosive agents originating from drug formulations can permeate through the inner silicone tubing and initiate corrosion of internal pump components.7 Factors that can increase the permeation rate through the inner tubing include hydrophobicity, impurities, preservatives, pH adjustments, and concentrations adjustments of the drug formulation.7 Damage can further occur because of a leak in the inner tube, resulting in direct exposure of internal pump components to corrosive agents. Higher permeation rates are associated with hydrophobic drugs like fentanyl and bupivacaine.6 Drug formulations with a pH less than or equal to 3 are not compatible with the infusion system.7 Admixture solutions may alter the material properties of the infusion system components and exhibit chemical properties that are not compatible with the infusion system.7 Both pumps of our patients contained fentanyl with a pH of around 6.4 without preservatives, and they were never filled with other agents than fentanyl. Drug concentration is directly proportional to the risk of more serious events in the case of overdosage. The concentration of fentanyl of our patients was in the range recommended by the Polyanalgesic Consensus Panelists (2012), as they recommend a maximum concentration of intrathecal fentanyl of 10 mg/mL.1 The choice of drug concentration is determined by patient daily dosage and pump reservoir volume. High concentrations are used to make the interval of the refills acceptable for the patient. If the pump empties earlier than expected due to overinfusion, there may be an interruption of intrathecal medication. This may present as lack of therapeutic effect (more pain or

DISCUSSION Intrathecal pump malfunction is a complication that mostly results in underdosing or cessation of therapy.6,7 In contrast, in our patients presented previously, intrathecal pump failure very likely led to an overinfusion. An earlier published case reported an intrathecal overinfusion of baclofen due to pump failure,8 and a retrospective study assessing the efficacy of intrathecal morphine infusion, reported 1 complication of overinfusion of morphine.9 The intrathecal pump containing baclofen was reported to be functioning correctly in bench testing afterward, and the © 2014 American Society of Regional Anesthesia and Pain Medicine

FIGURE 2. The tube was rigid and deformed. The rigidity of the inner tubing resulted in the tubing not running smoothly over the roller arms. The circle indicates the location of a breach of the tube.

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Maino et al

Regional Anesthesia and Pain Medicine • Volume 39, Number 5, September-October 2014

spasticity) and withdrawal symptoms. An interruption of medication is of particular concern for patients treated with baclofen, as its withdrawal is a potentially life-threatening event characterized by rebound spasticity and symptoms including tachycardia, hyperthermia, and seizures.12 From August 2003 to July 2012, Medtronic followed 4828 intrathecal pumps prospectively for adverse events.13 From this database resulted that failure rate of the Medtronic SynchroMed II pump was increasing significantly from 3 years postimplantation. At 3 years postimplantation, pump failure occurred in 0.9% of the pumps with approved drugs and in 1.3% of the pumps with unapproved drugs. At 6 years postimplantation, pump failure occurred in 2.4% of the pumps with approved drugs and 7.0% of the pumps with unapproved drugs. In 2012, Medtronic sent a safety notification to physicians who implant Medtronic pumps warning them not to use unapproved drugs in the SynchroMed pump, stating that the use of unapproved drugs could lead to intermittent or permanent pump motor stalls.14 Despite of Medtronic’s warning, unapproved medications are commonly used for intrathecal analgesia including fentanyl, sufentanil, hydromorphone, bupivacaine, and clonidine. This is confirmed by the fact that according to the aforementioned Medtronic database, 96.1% and 78.5% of the IDDS for malignant and nonmalignant pain therapy, respectively, were filled with unapproved medications.13 The prescription of unapproved medications for intrathecal therapy is supported by the Polyanalgesic Consensus Conference of 2012, which recommends the use of unapproved medications,1 and stimulated by the fact that many experienced implanters believe that these medications are more effective and better tolerated in certain patients.15 The Polyanalgesic Consensus Conference recommends fentanyl as one of the first-line drugs in patients with nociceptive pain and as a third-line drug for patients with neuropathic pain.1 Arguments in favor of using fentanyl are the fact that this drug has a lower risk for granuloma formation and a lipophilic nature, which makes it ideal for treatment of focal pain issues.1 Investigation of the manufactures to make the IDDS suitable for fentanyl would, therefore, be welcome. In recent years, several other companies have released programmable pumps without gears, tubes, motors, or rotating parts to wear out or stall. However, further research is required to determine if these pumps are suitable for fentanyl.

Furthermore, to increase safety for patients with intrathecal pumps containing opioids, they could be provided with the recently Food and Drug Administration–approved automatic injector of naloxone.16 This handheld autoinjector rapidly delivers a single dose of the drug intramuscular or subcutaneously and can be used by family members or caregivers to treat a person suspected to have had an (intrathecal) opioid overdose. In conclusion, we presented 2 cases of intrathecal pump malfunction, which most likely led to intrathecal overinfusion of fentanyl. Physicians associated with the care of patients having intrathecal pumps should be alert and aware that pump malfunctioning could potentially lead to overinfusion. To reduce the risk of this complication, they should pay particular attention to drug reservoir volume discrepancies during the refill procedures and overdose symptoms reported by their patients. These incidents were reported to the regulatory authority of Switzerland, as they meet the requirements of Vigilance Reporting according to the European Medical Device Directives.

After these events, we implemented the following measures to prevent an overdose due to a pump failure: • Aspirate at every refill procedure first the residual volume from the reservoir and check if the volume of drug removed from the reservoir is within 3 mL of the volume predicted by the telemetric programmer.5 • Give patients information on the symptoms of overdose and interruption of medication, and emphasize the importance of contacting their health care provider immediately if these symptoms appear.13 • Be aware that the use of an unapproved drug can increase the risk of a pump failure. • Pay particular attention to possible SynchroMed II pump failure from 3 years postimplantation, especially in case of signs of overdose or withdrawal. • In case of a reservoir volume discrepancy of more than 3 mL and signs of overdose: ▪ Stop the pump or (for SynchroMed II pumps) set the pump on minimum flow rate, ▪ Monitor the patient at least for 24 hours, ▪ Consider removing the pump and sending it to the manufacturer for analysis.

7. Medtronic. Increased risk of motor stall and loss of or change in therapy with unapproved drug formulations. Updated November 2012. Available at: http://professional.medtronic.com/wcm/groups/mdtcom_sg/ @mdt/@neuro/documents/documents/risk-motor-stall.pdf. Accessed March 17, 2014.

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REFERENCES 1. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15:436–464. 2. Francisco GE, Saulino MF, Yablon SA, Turner M. Intrathecal baclofen therapy: an update. PM R. 2009;1:852–858. 3. Medtronic pain pump blamed for 14 deaths. National Pain Report.com. Available at: http://americannewsreport.com/nationalpainreport/medtronicpain-pump-blamed-for-14-deaths-8820647.html. Accessed May 26, 2014. 4. Medtronic for healthcare professionals. Targeted drugs delivery. Products and procedures. Features and specifications. Available at: http://professional.medtronic.com/pt/neuro/idd/prod/synchromed-ii/ features-specifications/index.htm. Accessed May 12, 2014. 5. Deer TR, Levy R, Prager J, et al. Polyanalgesic Consensus Conference—2012: recommendations to reduce morbidity and mortality in intrathecal drug delivery in the treatment of chronic pain. Neuromodulation. 2012;15:467–482. 6. Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain. Neuromodulation. 2014;17:354–372.

8. Sgouros S, Charalambides C, Matsota P, Tsangaris I, Kostopanagiotou G. Malfunction of SynchroMed II baclofen pump delivers a near-lethal baclofen overdose. Pediatr Neurosurg. 2010;46:62–65. 9. Reig E1, Abejón D. Continuous morphine infusion: a retrospective study of efficacy, safety, and demographic variables. Neuromodulation. 2009;12:122–129. 10. Perruchoud C, Bovy M, Rutschmann B, Durrer A, Buchser E. Silicone septum leakage at the origin of a drug overdose in a patient implanted with an intrathecal pump. Neuromodulation. 2013;16:467–470. 11. Medtronic. Summary of approved drugs, SynchroMed II infusion system. Updated November 2012. Available at: http://professional.medtronic.com/ wcm/groups/mdtcom_sg/@mdt/@neuro/documents/documents/app-drugsummary.pdf. Accessed March 17, 2014. 12. Watve SV, Sivan M, Raza WA, Jamil FF. Management of acute overdose or withdrawal state in intrathecal baclofen therapy. Spinal Cord. 2012;50:107–111.

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Regional Anesthesia and Pain Medicine • Volume 39, Number 5, September-October 2014

Overdose & Intrathecal Pump Malfunction

groups/mdtcom_sg/@mdt/@neuro/documents/documents/synch-ii-finalhcp.pdf. Accessed March 17, 2014.

13. Medtronic. 2012 Addendum to the Medtronic neurostimulation and intrathecal drug delivery systems product performance report: product: performance of SynchroMed II pumps exposed to on-label and off-label medications. Available at: http://professional.medtronic.com/wcm/groups/ mdtcom_sg/@mdt/@neuro/documents/ documents/2012_ppr_synch_ii_final.pdf. Accessed March 17, 2014.

15. Rezai A, Kloth DS, Hansen H, Schultz DM, Thompson S, Deer TR. Physician response to Medtronic’s position on the use of off-label medications in the SynchroMed Pump. Pain Physician. 2013;16:415–417.

14. Medtronic. Urgent medical device safety notification, use of unapproved drugs with the SynchroMed® implantable infusion pump. Updated November 2012. Available at: http://professional.medtronic.com/wcm/

16. FDA News release. FDA approves new hand-held auto-injector to reverse opioid overdose. Available at: http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm391465.htm. Accessed May 23, 2014.

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Fentanyl overdose caused by malfunction of SynchroMed II intrathecal pump: two case reports.

Intrathecal drug delivery systems (intrathecal pumps) are used to treat patients with chronic refractory pain syndromes and spasticity. The objective ...
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