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Perioperative Management of a Patient With an Intrathecal Drug Delivery Device Infusing Ziconotide: A Case Report

Patel, Sephalie MD*; Hafez, Osama MD*; Sexton, Wade J. MD; Edwards, David A. MD, PhD

doi: 10.1213/XAA.0000000000000432
Case Reports: Case Report
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Intrathecal ziconotide is used for the treatment of chronic pain and is delivered by an implanted drug delivery device. Anesthesiologists should be familiar with the perioperative management of the pump as well as the potential adverse events related to continued ziconotide infusion during general anesthesia. A case is presented demonstrating the perioperative management of an intrathecal drug delivery device infusing ziconotide in a patient presenting for radical cystectomy with pelvic lymphadenectomy and ileal conduit diversion.

From the Departments of *Anesthesiology and Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida; and Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee.

Accepted for publication August 18, 2016.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Sephalie Patel, MD, Department of Anesthesiology, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612. Address e-mail to Sephalie.Patel@moffitt.org.

Multimodal care of chronic pain is a constantly evolving field, especially given the data that high-dose opioids in isolation fail to improve chronic pain outcomes.1 Ziconotide, a selective N-type calcium channel inhibitor, is 1 of 2 US Food and Drug Administration-approved medications to be given intrathecally (IT) for the treatment of chronic pain refractory to opioids.2 The use of ziconotide alone, or in combination with IT morphine or hydromorphone, is an effective treatment for chronic neuropathic and nociceptive pain.2 Little is known about the effect of ziconotide on acute postoperative pain or potential adverse effects during anesthesia. We review the anesthetic management of a patient with IT ziconotide undergoing radical cystectomy and the adverse events the patient experienced potentially related to the drug infusion. Health Insurance Portability and Accountability Act authorization consent was provided by the patient.

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CASE DESCRIPTION

A 74-year-old man presenting with recurrent high-grade noninvasive urothelial cancer of the bladder refractory to intravesical therapies (cTaN0) was scheduled for radical cystectomy, pelvic lymphadenectomy, and ileal conduit diversion. His medical history was significant for hypertension and chronic debilitating low back pain. Subjective descriptors of the pain included a dullness that was continuous and radiated down both legs. He rated the pain 8 out of 10 on a verbally applied numeric rating scale. Three months before surgery, IT therapy had been started and ziconotide titrated up to a dose of 0.6 μg/h. His pain had improved, and he had increased mobility by the date of surgery.

On the day of surgery, his blood pressure measured 144/69 mm Hg, heart rate was 76 beats per minute, respiratory rate was 16 breaths per minute, and pulse oximetry measured 98% on room air. He weighed 76 kg and was nil per os for 8 hours except for daily metoprolol. After proceeding to the operating room, anesthesia was initiated with 60 mg lidocaine intravenously (IV), 100 μg fentanyl IV, up to 200 mg propofol IV in divided doses, and 120 mg succinylcholine IV. After endotracheal intubation, the patient exhibited profound vasoplegia for a prolonged period unresponsive to IV fluids, decrease of volatile anesthetic, and phenylephrine, ephedrine, and vasopressin (Figure). The operation was cancelled because of hemodynamic instability and rescheduled for a later date.

Figure.

Figure.

In the interim, possible causes for the severe hypotension were considered, including induction doses of medications, preoperative β-blockade with metoprolol, and continuous IT delivery of ziconotide. After a literature review and discussion with a pain specialist, the patient was rescheduled for the operation. This time the patient was instructed to continue to drink clear liquids up to 2 hours before surgery and to hold metoprolol in the morning. Induction proceeded with 16 mg etomidate IV, 60 mg lidocaine IV, 100 mg fentanyl IV, and 50 mg rocuronium IV. With these changes, induction was uneventful (Figure), and his intraoperative course proceeded with few episodes of transient hypotension, which responded to treatment. Postoperatively, the patient’s back pain and surgical pain were well controlled with the existing IT ziconotide and IV hydromorphone for the first 48 hours. Pain was managed with oral oxycodone/acetaminophen for the remainder of the hospitalization. The patient was able to ambulate and participate with physical therapy with this pain regimen.

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DISCUSSION

Ziconotide is the synthetic peptide version of the ω-conotoxin used by the fish-eating marine snail Conus magus to paralyze its prey.3 Ziconotide is US Food and Drug Administration-approved for IT administration and indicated for the management of severe chronic pain refractory to systemic analgesics and IT morphine. Ziconotide acts directly and specifically on N-type voltage-gated calcium channels on somata, dendrites, axons, and nerve terminals indiscriminately across neuronal pain and sensory fibers (C and A fibers), preventing the release of neurotransmitters such as glutamate and substance P.4 It is a large hydrophilic polypeptide with limited tissue penetration and poorly crosses the blood–brain barrier. Consequently, its clearance is slow,1 and adverse effects of ziconotide are slow to resolve after a decrease in dose or with cessation of delivery.

There is no literature directly discussing the potential adverse effects of continuing ziconotide infusion in the perioperative period. Adverse events published from clinical trials are listed here for the anesthesiologist’s reference and consideration (Table). There are no reports of respiratory depression even at high doses.5 Relevant side effects to anesthesia, especially given the current case report, include postural hypotension, dizziness, nystagmus, and confusion.1,2 Sympatholysis and postural hypotension that result from ziconotide are expected side effects, especially with doses approaching 0.8 μg/h, the upper recommended limit (dosing range: 0.2–0.8 μg/h).2,6 Hypotension from ziconotide can be further exacerbated by general anesthesia because of the vasodilatory side effects of IV and inhaled anesthetic agents. Maintaining vascular volume and peripheral vascular resistance during induction and maintenance of anesthesia would be a prudent strategy as demonstrated in our patient with avoidance of β-blockade and continuing clear liquids up to 2 hours before induction of anesthesia. Although discontinuation of β-blockade in the perioperative period is not recommended,7 it might be tolerated in a patient without cardiac disease. If enough time is provided for preoperative optimization, there should be consideration to change antihypertensive medications from a β-blocker to either a diuretic and angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker to avoid concerns about β-blocker withdrawal. Furthermore, these medications would be a more appropriate choice for the treatment of essential hypertension. Finally, episodes of intraoperative hypotension may optimally be treated with calcium chloride because of the pre-existing calcium blockade.

Table.

Table.

Less than 1% of IT-delivered ziconotide crosses the blood–brain barrier but given the prolonged blockade on calcium channels, peripheral-induced dose-dependent side effects may persist for days to weeks.7 Ziconotide is cleared at a rate of 0.38 mL/min, roughly the same rate as cerebrospinal fluid turnover, indicating that ziconotide duration of action depends mostly on the rate of clearance rather than by metabolism. It is therefore possible that medications or pathologies that slow cerebrospinal fluid circulation and turnover may result in escalating concentration of ziconotide and increased adverse effects. Given ziconotide’s IT administration and possible sedative side effects, it is important to understand how a patient’s minimum alveolar concentration (MAC) requirement may change in the presence of this medication. Although it has been well established that neuraxial anesthesia8 and increased age9 are associated with decreased requirement of inhaled anesthetic agent, the effects of ziconotide on MAC remain unknown. Our patient’s age allowed the use of decreased MAC, which may have prevented potential episodes of hypotension seen when combining inhaled anesthetic agent with IT ziconotide.

In consideration of the time-sensitive surgical treatment needed in our patient’s situation, and the general recommendation against making large changes in dosing,2 we decided against turning off the medication before rescheduling the operation. However, it also may be reasonable to discontinue the infusion before an operation if a patient continues to experience signs of hypotension (lightheadedness and dizziness). In reports of abrupt discontinuation of IT ziconotide after severe side effects, no adverse events or rebound occurred.5,10 In these instances, side effects resolved over days to several weeks.

Currently, there are no published reports of intraoperative management of patients on ziconotide. The only published use of ziconotide in the perioperative period involves a short-term, intraoperative administration of the drug. Although this intervention did help with pain, the patients experienced unbearable side effects such as dizziness, blurred vision, nystagmus, and confusion, similar to patients on long-term infusions.2

Ziconotide is used most frequently in patients with chronic pain intolerant to opioids. Given recent emphasis on multimodal polyanalgesia to reduce opioid requirement in chronic pain populations, use of ziconotide and other adjuvant medications in IT drug delivery devices is likely to increase. It is important for anesthesiologists and surgeons to be aware of what medications their patients are on before the day of surgery and the potential impact of those medications in the perioperative period for the safe outcome of their patients.

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DISCLOSURES

Name: Sephalie Patel, MD.

Contribution: This author helped complete the manuscript.

Name: Osama Hafez, MD.

Contribution: This author helped complete the manuscript.

Name: Wade J. Sexton, MD.

Contribution: This author helped complete the manuscript.

Name: David A. Edwards, MD, PhD.

Contribution: This author helped complete the manuscript.

This manuscript was handled by: Raymond C. Roy, MD.

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REFERENCES

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