Problem-Solving in Patients with Targeted Drug Delivery Systems

Abstract

Patients with intrathecal drug delivery systems presenting for after-hours care typically cause angst among physicians staffing emergency rooms and urgent care centers. The chief complaint of “my pump isn’t working” leaves physicians inexperienced with these devices in a defensive position. Fortunately, pump malfunctions are rare. Resources are available to help physicians work through patient concerns. These resources include algorithms to manage possible over- or under-infusion of the various drugs used in these systems as well as technical support from pump manufacturers.

Introduction

Patients with implanted pumps often have complicated medical problems. A common thought upon seeing these patients in the emergent or urgent setting is to quickly conclude that a problem has developed within the drug delivery system itself. Unfortunately, the implantation of a targeted drug delivery system does not immunize these patients from common maladies that exacerbate pain or spasticity. It is critical to complete a thorough history, physical examination and work-up in order to rule out common maladies that may erroneously cause the patient to conclude that their drug delivery system is malfunctioning.

History of Targeted Drug Delivery

The first documented use of targeted drug delivery occurred in 1898 when August Bier and his partner injected their own intrathecal spaces with cocaine in an attempt to produce anesthesia.¹ Opioid receptors were discovered in the spinal cord in 1973 and intrathecal morphine was approved by the Food and Drug Administration (FDA) in 1984. In 1989, Penn et al. reported the use of intrathecal baclofen for the treatment of severe spasticity of spinal origin.² By 1992, baclofen was approved for the treatment of spinal origin spasticity. Lastly, Ziconotide was approved for severe chronic pain in 2004. Ziconotide blocks N-type calcium channels within the dorsal horn. It is unique in that it has no tolerance or addictive properties. As such, abrupt discontinuation of intrathecal ziconotide is not associated with a withdrawal syndrome. Baclofen is a gamma-aminobutyric acid receptor agonist assisting with the reestablishment of inhibitory cortical influences on spinal cord interneurons. Morphine targets the opioid receptors in the dorsal horn by inhibiting the release of Substance P. Though these three drugs are the only approved medications for intrathecal administration, physicians have not limited drug delivery into the intrathecal space to solely those approved by the FDA. Commonly, physicians use non-FDA approved drug combinations containing hydromorphone, fentanyl, bupivicaine, clonidine and others.

Current Therapies

Only two manufacturers have FDA approved devices for intrathecal drug delivery. The most frequently implanted pump is the Medtronic Synchromed II which is FDA approved for the treatment of both pain and spasticity. (See Figure 1) The current model has been in use for over 13 years. It is a programmable infusion peristaltic pump with MRI compatibility to 3 Tesla. The Synchromed II has over 15,000 patient years of clinical use data.^{3, 4} When a patient is in the MRI scanner, the Synchromed II pump will halt drug infusion. Upon exiting the scanner, the pump will reset on its own and resume drug delivery as programmed. The manufacturer’s recommendation is to have the patient see their managing physician after an MRI in order to ensure that the pump is again fully operational. There have been only rare occasions on which the pump has not restarted after an MRI. Recently, Flowonix entered the market with their Prometra II pump. (See Figure 2). The Prometra pump is FDA conditionally approved for use in an MRI. It has a safety valve that closes upon entering a magnetic field. After exposure to an MRI, a Flowonix employee is summoned to open the safety valve so that therapy can resume. Unlike the Synchromed II, the Prometra II pump carries an FDA approval only for the treatment of pain. It is not yet approved for the treatment of spasticity. For either brand of pump, physicians should contact the technical support divisions for the respective pump manufacturer for concerns regarding MRI compatibility.

Figures 1 and 2 .

Only two manufacturers have FDA approved devices for intrathecal drug delivery. The most frequently implanted pump is the Medtronic Synchromed II (left) which is FDA approved for the treatment of both pain and spasticity. Flowonix entered the market with their Prometra II pump. (right)

After a patient has a pump implantation, they should receive a health identification card indicating the manufacturer of their pump and the name of their managing physician. Patients should keep this card with them in the event of an unexpected hospitalization. Obtaining detailed information regarding daily dosages and medications requires interrogation of the pump through the use of proprietary programmers, only available from the respective pump manufacturer. While manufacturer’s technical services departments cannot give medical advice, they may be able to connect requesting physicians to an experienced pump managing consultant.

Troubleshooting

The most common presenting clinical scenario for a pump patient using baclofen is one of increased spasticity. Their chief complaint is often, “my pump is not working”. In the absence of hearing a pump alarm, a patient has no way of knowing whether or not their pump is working properly. Likely, the patient is experiencing a medical condition contributing to their increased muscle tone. Conditions associated with increased spasticity include, but are not limited to: urinary tract infection or retention, constipation, pneumonia, pressure sore development, fracture, ingrown toenail, nephrolithiasis, cholelithiasis, deep venous thrombosis and other noxious stimuli. For those patients in whom frank baclofen withdrawal is a serious diagnostic consideration, clinicians need to consider other syndromes that can mimic baclofen withdrawal including Neuroleptic Malignant Syndrome, Sepsis, Serotonin Syndrome, Malignant Hyperthermia, Autonomic Dysreflexia, Seizure and Autonomic Storming.³ These conditions must be considered in the workup of a patient presenting with increased spasticity while using an intrathecal baclofen pump. The hallmark symptoms of baclofen withdrawal are itching without rash, irritability and an increase in muscle tone. The most important clinical assessment to complete for these patients is to put their chief complaint aside and focus on the conditions that commonly cause an increase in spasticity. The determination of whether or not the pump is actually working may require consultation with a managing clinician who can interrogate the pump, interpret the activity logs of the pump and complete an assessment of the catheter if needed. In general, pump failures occur rarely. Medical conditions exacerbating spasticity occur frequently. Catheter failures are for more common than primary pump malfunctions but both occur infrequently. The product safety profile of the Synchromed II pump indicates that pump motor stalls occur in less than 1% of cases while catheter issues occur in ∼ 8% of all cases.⁵ Over or under-infusion of the drug occurs very rarely. A treatment algorithm may be used to help in the assessment of patients experiencing a loss of efficacy.⁵ (See Figure 3) Clinicians should consider catheter issues instead of pump failure once organic etiologies for increased spasticity have been ruled out. The pump should be interrogated and the pump activity logs should be reviewed. The proper intervention will be dependent on symptoms.

Figure 3.

Loss of efficacy algorithm. AP, anterior-posterior; CAP, catheter access port; CT, computed tomography; ITB, intrathecal baclofen therapy; LP, lumbar puncture.

The physician managing the pump may administer a 50–100 mcg single bolus and observe the patient for a few hours. Checking the integrity of the pump catheter by performing a catheter access port (CAP) aspiration is warranted when the luxury of time does not exist. To complete a CAP access, a physician will need a special kit available only from the manufacturer. These kits are unique to each manufacturer and are not likely to be readily available in the emergency room or urgent care center. In complicated cases, a contrasted spiral CT catheter study may be helpful in determining catheter integrity. However, these studies generally need not be considered or performed in an urgent or emergent setting. If a patient is in baclofen withdrawal, re-initiation of intrathecal baclofen is the definitive treatment.^3,6 Other measures can be used but are temporizing. Baclofen is available in a 50 mcg / one ml trial dose. Physicians should secure an ampule from the hospital pharmacy and perform a lumbar puncture to inject 50 mcg into the intrathecal space to diminish symptoms. A single intrathecal dose may only help to alleviate withdrawal symptoms for 6–8 hours but this might be sufficient time to arrange for a more reliable long term delivery method such as replacement of a faulty catheter or pump. Alternatively, oral baclofen can be given at a dose of 10–20 milligrams every 4 hrs but patients may need additional supplementation with benzodiazepines, dantrolene, cyproheptadine, or even propofol in severe cases.⁷ All patients should receive IV hydration to prevent renal damage associated with rhabdomyolysis. A creatine kinase level may be obtained to assess for rhabdomyolysis.

Patients receiving narcotic or Ziconotide therapy via intrathecal administration may present with complaints of increased pain. In the presence of a pump or catheter failure, patients receiving intrathecal narcotics should present with typical narcotic withdrawal symptoms and will need to be managed accordingly. Patients receiving Ziconotide will present with increased pain. There is no withdrawal syndrome associated with its use. If a patient is in narcotic withdrawal, they should be managed accordingly with an equivalent intravenous dose while waiting for an operative repair of their delivery system malfunction.

In the workup for a lethargic patient, many physicians reflexively request that the pump be turned off to eliminate targeted drug delivery as a potential source of altered mental status. The Synchromed II pump can be damaged if the pump is turned off for more than 48 hours. Patients receiving intrathecal morphine or baclofen could go into drug withdrawal if their therapy is abruptly discontinued.⁸ Rather than turning the pump off, pump flow can be reduced to its minimal rate for four hours to allow for metabolism of the drug within the CSF and then resumed using a dose reduction of 20–30%. Ziconotide has a narrow therapeutic window. Patients may exhibit psychiatric changes with small dose increases. Since there is no associated withdrawal syndrome, patients experiencing mental status changes while receiving ziconotide can have their pump dosage dramatically reduced without restarting therapy. The dose can then be gradually increased once their mental status has improved. Removal of CSF or CSF effleurage (withdrawing CSF in large volumes and exchanging sterile saline in similar volumes) can be done to further dilute the drug concentration within the CSF but is usually not necessary.

A unique concern occurs in the patient who has recently been seen by their pump managing physician. For these patients, an iatrogenic cause of symptoms should be considered. In the event of a programming error leading to drug over infusion, drug infusion can be halted in a few ways. If a Medtronic N’Vision programmer is available, pump infusion can be halted by pressing the red button on the front of the programmer. The Synchromed II pump is sensitive to electromagnetic interference and will cease propulsion when the pump is exposed to a magnetic field as small as one produced by a household magnet. Infusion can be stopped by placing the magnet on the skin overlying the pump. When the magnetic field is removed from the Synchromed II pump, the pump will again start delivering drug as programmed. Lastly, if other means are not available, the pump central reservoir can be accessed via a 22 gauge non-coring needle and the contents of the central reservoir removed. The pump uses peristaltic movement so if the reservoir is empty, flow is discontinued. The central reservoir is covered by a silicone seal. The seal is designed to withstand numerous punctures from a non-coring Huber type needle. In absolute emergencies, a traditional needle could be used to access the central reservoir but doing so might damage the silicone septum. A traditional coring needle should only be used as a last resort.

Post-Operative Complications

Patients may present in the post-operative phase with concerns of infection, swelling over the abdominal or lumbar incision sites, or an abrupt change in symptom control. Preoperative patients should receive a total body wash to reduce their total skin bacterial load. Unfortunately, some patients develop a post-operative infection and present with warm, edematous skin overlying the pump. (See Figure 4) In the absence of abnormal lab-work or systemic symptoms, these patients may be successfully treated with oral antibiotics. ^{9, 10} The risk of meningitis is elevated in patients with implanted intrathecal delivery devices so careful monitoring is warranted. The implanting surgeon should take the lead on acute post-operative concerns. Wound dehiscence can occur at the lumbar or abdominal sites. A post-operative fluid collection occurs commonly in cases of elevated CSF pressure. At implant, a trochar is inserted using a shallow angle, paramedian approach. The intrathecal segment of the catheter is placed through the trochar and advanced to the desired spinal level, usually T6. An incision is made above and below the trochar and a small anchor is attached to the lumbar dorsal fascia to hold the catheter in place. The lumbar surgical site is superficial and is only deep enough to bury the anchor and catheter. When the trochar is removed, the catheter is left in place but CSF may leak around it and flow into the pump pocket itself, following the path of least resistance, causing a pocket of fluid overlying the pump. (See Figure 5) This fluid is usually sterile and remains so until bacteria are introduced. Fluid can be aspirated and tested for beta-2 transferrin, an enzyme largely unique to CSF, but such testing is not necessary and aggressive attempts to aspirate from these otherwise benign fluid collections is rarely helpful and may cause harm by introducing bacteria. Instead, post-operative patients should be given an abdominal binder and pressure dressing along with several days of acetazolamide to reduce CSF pressure. The fluid collection will usually improve without further intervention but it may take several weeks to resolve completely. Efforts should be made to prevent exposing the pump to the environment. An exposed pump necessitates explant in nearly all cases.

Figure 4.

Infection of the pump pocket.

Figure 5.

Non-infected fluid collection (seroma).

Conclusion

The future of targeted drug delivery systems is bright. It is an exciting therapy that is likely to expand. Clinicians need not fear patients with these devices. Being familiar with pump mechanics and problem solving will make caring for these patients easier in the urgent or emergent setting. The physician managing the pump should have clear and concise on-call coverage for pump patients. Most problems can be readily resolved with a single phone call rather than a time consuming and costly after hours visit.

Biography

Rez Farid, MD, is Associate Professor of Clinical PM&R, Department of Physical Medicine and Rehabilitation, University of Missouri Health Care.

Contact: faridrez@health.missouri.edu