++
The potential complications associated with spinal drug delivery
systems, along with cost, are the biggest barriers to the widespread
use of these techniques. Before considering the use of invasive devices,
the practitioner must be fully aware of all the potential complications
of the procedure, the devices, and the associated drugs. Complications
associated with long-term spinal drug delivery systems fall into
four major groups: infection, drug toxicity, practitioner errors,
and mechanical problems. Physicians, patients, caregivers, and those
offering home care services must be proficient in avoiding the avoidable,
troubleshooting problems, and correcting or treating the complications.
Practitioners who are aware of these potential problems will identify
them earlier and resolve problems as they occur. The procedures
themselves do not create the problems; the problems usually arise
out of a misunderstanding of the implantable devices, their care,
and use.
++
Intraspinal infections are the most feared consequence of chronic
epidural and intrathecal catheterization. Epidural infections are
predictable in those pain management practices that use significant
long-term epidural catheters, particularly in the immunosuppressed
cancer patients. Our initial infection rate with the Du Pen epidural
catheter was reported at 5.4%.90 From
1990 to 1996 the epidural infection rate within our practice has
ranged between 5% and 15% in our long-term patients.
Patient care provided by multiple home care agencies, multiple caregivers,
and with variable filtering, tubing, and reservoir change procedures
has made tracking of infection risk difficult. However, frequency
of tubing and filter replacement was noted as a variable that changed
over time. A protocol of changing filters weekly resulted in our
previously reported 5.4% infection risk in our practice.
The hospital epidemiology committee established a protocol of changing
the filter and tubing every 3 days; this resulted in an increased
infection rate (10% to 15%). An internal study
showed no correlation between infection rate and any known factors
except for duration of implantation. A colleague (William Baumgartl,
MD, personal communication, July 14, 1997) reported his low incidence
of epidural infections with a dual-filter system technique. He reported
using two PALL epidural filters in series, the inner filter never
being changed and the outer filter and pump tubing changed on a
monthly basis (Fig. 71-10). The reports of intrathecal catheters
used for chronic pain management from Sweden also reported a very
low incidence of meningitis (0.5%). In these reports the
intrathecal filters were changed once a month. There have been no
studies to prove the benefits of the double-filter system or to
indicate that the PALL filter is superior to other epidural filters.
++
+++
Identification
and Treatment of Epidural Infection
++
Early diagnosis and treatment of epidural space infections are
key to a successful outcome. The most common infection occurs at
the exit site. The exit site appears red, may have an exudate, and will
often be painful. These infections are treated effectively with
aggressive site care, often with topical antibiotic ointment, and
more rarely with systemic antibiotic therapy. Of greater concern is
the potential for infection inside the epidural space. The epidural
infection may manifest itself from one of three sources: the drug
infusate, the catheter track, or from a hematologic or local abscess
source. In the 1997 calendar year, 75 permanent epidural catheters
were placed at Swedish Medical Center, which is a regional pain
management referral center for the northwest. Nine confirmed epidural
space infections (12%) were treated in 1997. Only one of
the patients presented with signs of epidural tunnel-track spread
(1.3%), three patients had bowel tumors and episodic septicemia
that potentially seeded hematologically (4%), and five
patients had no known etiology, no exit site or track signs, and
were presumed to have contaminant sources (6.6%). We adopted
the double-filter protocol in 1997, and in three years we have had
only four epidural infections in a total population of 145 epidural
catheters, a 2.7% epidural infection rate. Clinicians should
examine the potential for contamination within their institutional
policies very carefully. The finding of three patients in the sample
with advanced colorectal cancer suggests a higher index of suspicion
in patients with bowel tumors; however, this phenomenon requires
prospective clinical study.
++
The signs of epidural space infection include acute loss of analgesia,
fever, and white blood count (WBC) elevations.91 In
the immunosuppressed cancer population, fever and WBC elevation
may be delayed. Epidural space infection and catheter encapsulation
present with three clinical symptoms:
++
- 1. Pain on injection
- 2. Retrograde flow of infusate with pooling in the paravertebral
tissues
- 3. Loss of analgesia.
++
The pooling of fluid and exudate in the paravertebral tissues
is the result of material tracking back out of the epidural space,
often within a fibrin-like sheath surrounding the catheter. The
catheter entry site through the ligamentum flavum becomes a drain,
and the exudate leaks out around the catheter, causing a significant
inflammatory process to occur in the soft tissues.92
++
Diagnosis is made by obtaining an epidural aspirate, Gram stain,
and culture. The culture must be obtained from the epidural space.
In the past, epidural catheters were immediately removed when signs
and symptoms of infection were present. Catheter tip culturing was
commonly used to identify infection in the epidural space and is
still reported in the literature, despite being clearly problematic.93 Bevacqua
and others examined cultures from spinal catheters used for postoperative pain
management (mean indwelling time, 66 hours). Cerebrospinal fluid
cultures were done concurrently with removal of the catheters and
culturing of the catheter tip. Semiquantitative culture methods
demonstrated a relationship between the positive catheter tip cultures
and contamination of the catheter that occurred on removal.94
++
Culturing of the catheter tip after removal will result in a
composite culture of the epidural space, paraspinal soft tissues,
catheter track, and superficial exit site. An aspirate culture from
inside the epidural space prior to catheter removal with subsequent
identification of the organism and its sensitivity is mandatory
for best treatment outcomes in these patients. When the volume in
the epidural space is sparse and fluid cannot be aspirated, 2 mL
of normal saline may be injected for sampling. Table 71-4 summarizes
the procedure for performing an epidural aspirate culture.
++
++
Epidural space infections can result in accumulation of up to
20 mL of exudate in the epidural space. A syringe attached to the
catheter can decompress the space of any exudate while antibiotic therapy
is being initiated. Withdrawal of exudate can continue on an every
8-hour basis until no fluid can be withdrawn. This technique may
help to avoid the risk of cord compression from the accumulation
of fluid in the epidural space.
++
Epidural space infections have been treated primarily by removal
of the catheter and systemic administration of antibiotic therapy
directed toward the specified organism identified with the culture.
Our policy, established 10 years ago in collaboration with our infectious
disease staff, was that removal of the catheter (after no exudate
could be withdrawn and culture results had been reported by the
laboratory) was mandatory for complete resolution of the infection.
This policy has been applied to over 70 patients with positive epidural
space cultures over the last 12 years, during which time no patients
had to be surgically decompressed. Appraisal of response to treatment
can be done with a “wait-and-watch” approach to
resolution of symptoms, or in cases where neurologic signs are present,
it is best accomplished with either a MRI or a contrast CT scan.
++
Many clinicians have considered sterilizing the epidural catheter
with epidurally infused vancomycin (with sensitive organisms) rather
than removing the catheter, treating, and replacing the catheter.
Hahn et al first reported a case of sterilizing an infected epidural
catheter with epidurally infused vancomycin.95 We
have treated three cases of epidural infections attributed to Staphylococcus
aureus with systemic vancomycin (1 g every 12 hours, given intravenously)
for 10 days and concomitant epidural infusion of 150 μg
per hour of vancomycin for 3 weeks. This treatment was done in collaboration
with the infectious disease staff and with full disclosure to the
patient of unknown risks. All three patients wanted to proceed with
the therapy in lieu of losing their epidural catheters. In each
case we followed the patients with repeat epidural cultures on a
monthly basis for 3 to 6 months. In each case the epidural cultures
were negative until one patient developed a second epidural infection
at month 4 from a different organism. The longest time to postepidural
infection was in a patient who had an epidural infusion that lasted
for 1½ years without infection.
There is currently no data on potential toxicity of vancomycin in
the epidural space. Clearly, further examination of risk versus
benefit in using this therapy is indicated. The standard of care
continues to be device removal, aggressive systemic treatment, and
replacement of the device after antibiotic therapy is completed.
++
Filtering should be a standard of care for chronic intraspinal
infusions. The acute pain specialist argues that filters are a site
of obstruction during therapy, a barrier to aspiration of the catheter when
testing for the presence of spinal fluid, and have an unproved outcome
with added cost. The lack of controlled studies adds fuel to this
controversy. The use of filtered epidural catheters to prevent infection
in long-term epidural catheters has been generally accepted and
more commercially available epidural catheter sets are now being
manufactured with in-line filters. We have noted that most epidural
space infections occur in the absence of exit site inflammation
and negative exit site cultures. It would seem logical that the
contamination is occurring through the catheter rather than alongside
the catheter. Contamination occurs at the time of bag and tubing
changes, and any policy that increases the incidence of those changes
will increase the risk of contamination. Figure 71-10 illustrates
the Du Pen epidural catheter with the double PALL epidural filter configuration.
+++
Intrathecal
Device Infections
++
The intrathecal space may be accessed either by an externalized
intrathecal catheter, port, or by placement of an intrathecal pump
device. This technique has had limited use because of the fear of
meningitis. Meningitis is exceedingly rare with the implanted pumps.
The process of refilling the pump may result in contamination unless
sterile conditions are maintained. We have had one pump-pocket infection
requiring explant that was time correlated to an incident where
multiple sticks were done at the time of a difficult refill. Reports
of infections in implantable pumps are rare. Albright reported on
infection during intrathecal baclofen therapy in children, a 5% infection rate “requiring
pump removal” when utilizing the Medtronic’s system.96 Intrathecal
vancomycin has been used to treat meningitis associated with pump
infections,97 and in unrelated meningitis.98,99
++
Nitescu and his colleagues at the University of Gothenburg, Sweden,
have reported on the use of intrathecal exteriorized catheters to
treat both chronic pain and cancer-related pain. This approach has
not gained support in the US literature. The fear of meningitis
has always been such a great deterrent that its use has been limited.
These reports have brought a new focus to the use of intrathecal
catheters. The first report described their technique in a report
detailing 142 cancer patients treated with externalized spinal catheters.100 The
Portex nylon catheters were inserted at the lumbar level and tunneled
paravertebrally up and over the shoulder. This first report included patients
treated for 1 month using a syringe driver pump system. There were
no reported cases of infection so the authors expanded the study
in a second report to include another 89 patients. In this study
the authors used a very low infusion rate of high concentration
drug and reused CADD pump cassettes, but the cassettes were only
changed or recharged on a monthly bases.101 Again, the
authors reported no infections and there was no affect on the drug
concentrations when the cassettes were left in place for a full
month. Nitescu et al in their report did not make a point of the reuse
of the cassettes or the monthly filter changes. Their conclusions
were that this is a safe and effective means of intrathecal analgesic
infusion when trained nurses exchanged the cassettes and filters
on a monthly basis.102 In that same study, Nitescu,
now reporting on 200 patients receiving the infusion over 7242 catheter
days of use, had only a 0.5% rate of meningitis development.
This low infection rate is far better than we were able to achieve
during epidural infusions with filter and tubing changes every 48
to 72 hours. The only variable seems to be the frequency of “breaking
into the system” or filter and tubing changes.
++
Another European group of investigators cited the use of externalized
intrathecal systems because they were the “least costly
and easiest to apply” for short periods.103 Fifteen
patients were treated with externalized intrathecal systems; 13
of the patients had the system implanted at home. No infections
were reported. Devulder and colleagues studied 33 patients with
tunneled intrathecal catheters connected to subcutaneous ports.
Three patients developed meningitis (9+%).
The authors were able to correlate the 9% infection rate
to accidental disconnections in the external tubing of the pump
systems with presumed contaminant events; they further recommended
in-line filters.104 Wagemans and others used externalized
intrathecal catheters in 40 terminal cancer patients and reported
meningitis in two patients, a 5% infection rate.105 We
have used externalized intrathecal catheters in five cancer patients
over the last 3 years. These patients had no epidural space available
(tumor or surgical ablation of the epidural space), or in one case
the catheter was intended for epidural placement and was found post-procedure
to be in the intrathecal space. One of these patients was treated
for up to 1 year with no reported infections. In each case the infusion
was maintained at the lowest possible infusion rate with highly
concentrated drugs, to keep the infusion rates at or below 2 mL/hour.
The lower infusion rates allow a single infusion bag to last several
weeks, with bag changes only done by the visiting nurses. Long-term
studies are needed, but there may not be a cost advantage in the
United States. In the United States, pumps and infusion bags are
supplied by home care agencies who rent the pump and charge for
the drug preparation; these charges may exceed the expectation of
the managed care organizations and providers.
+++
Drug-Related
Complications
++
Infusion of analgesic agents into the epidural and intrathecal
spaces may be associated with complications from unexpected reactions
to drugs or drug combinations, drug errors, mixing errors, or infusion
errors. Analgesic titration to effect or side effects is a standard
of analgesic therapy. Those side effects are identified, classified
for treatment priority, and treated to allow continued analgesic
titration. The practitioner must be concerned about the complications
of intraspinal analgesic drug therapy and how to identify, treat,
and avoid drug-related complications.
++
Morphine appears to cause suppression of hormone production in
some individual patients, resulting in endocrine alterations. Studies
in animals, heroin addicts, and patients receiving long-term intraspinal
morphine have demonstrated a decrease in testosterone associated
with opioids.106,107 Paice and coworkers showed
a decrease in testosterone in men and a decrease in FSH in women
receiving intraspinal opioids.108 Patients exhibit
decreased libido, fertility, and fatigue. Male patients may have
erectile dysfunction and female patients may have amenorrhea. Testosterone
and hormone replacement therapy has been successful in reversing
these effects. These findings are not predictable and may be a rare
occurrence. This is an area that the pain management community clearly
needs to further study because sexuality can be a significant factor
in our patient’s lives.
++
Preservative content of many opioid and other drugs used for
intraspinal analgesia must be watched carefully. The addition of
preservatives to multidose drug preparations is common in the United
States, but less common in other countries. Practitioners must be
aware of the total content of any drug preparations considered for
compounding into neuraxial infusions. We published a case report
of a patient who received a morphine preparation containing phenol
and formaldehyde in a long-term epidural infusion that was associated
with neuropathic pain and the development of epidural space adhesions.109 In
this case the symptoms were reversed by removal of the preservative-containing
morphine preparation. These errors may be corrected by education
and information availability.
++
The infusion of concentrated analgesic combination into the neuraxial
spaces have been studied by Yaksh, who has voiced concern over the
use of untested drug combinations and concentrations and complications
that may arise.110 Neurotoxicity with high-dose
intraspinal drug therapy has been reported in humans. Interestingly,
two reports in the literature indicate a higher degree of risk might
exist in patients with preexisting neuropathology.111,112 Neuropathologic
findings in 15 cancer patients status-post intrathecal morphine-bupivacaine therapy
were reported by Sjoberg et al.113 The majority
of neuropathologic changes were cancer-related. There were changes
identified within the spinal canal; however, no changes could be
correlated to the cumulative dose of morphine, bupivacaine, or the
oxidants contained in the formulation in this small sample. The
use of subcutaneous intrathecal infusion pumps in chronic pain patients
requires the use of high concentrations of the infusion drugs. Without
such concentrations, the pump would require frequent access and
refilling. The interventionist should maintain a high level of attention
to the current literature on the neurotoxicity of concentrated drugs
on the spinal cord.
++
Local anesthetic toxicity is rare when analgesic dose concentrations
are used during epidural infusions.34 Local anesthetic
side effects include postural hypotension, skin anesthesia, and
motor loss. These side effects are treated by vascular volume replacement
and drug concentration adjustments. Once normovolemia is achieved,
postural hypotension is rarely a problem unless the patient becomes dehydrated.
High concentration local anesthetic agents have been used in intrathecal
pumps; no neurotoxicity has been reported, but there have also been
no controlled animal or clinical studies.
++
Clonidine is increasingly being used epidurally and intrathecally.
Hypotension can be problematic, particularly early; however, volume
replacement and slow upward titration is generally sufficient to
normalize blood pressure. Intrathecal clonidine, although not approved
for intrathecal use, is being used in intrathecal pumps using high
concentration preparations. Yaksh has completed animal studies with
concentrations as high as 6000 μg/mL (personal
communication, 1998). These studies have not shown any signs of
neurotoxicity. Controlled clinical trials are needed in this area
to better define safety and efficacy. The more problematic issue
is potential for rebound hypertension with abrupt discontinuation
of spinal clonidine. Slow, downward titration of spinal clonidine,
or prompt replacement with systemic clonidine, is indicated. Patients
with intraspinal pumps may have mechanical failure of the pump; this
unexpected failure could lead to a hypertensive crisis. Patients
should be protected with an emergency kit of oral and transcutaneous
clonidine.
++
Practical experience indicates that human error in drug administration
needs to be considered. Pharmacy errors in mixing the drug for infusion
have and will occur. Patients within our institution have received
concentrations of drugs that were many times more or less potent
than ordered, as well as the wrong drugs mixed in solution. These
pharmacy errors are not predictable, so the clinician must consider
these possibilities when the patient has an unexpected response
to a recent refilling of the pump. When symptoms of drug withdrawal,
overdose, or toxicity are noted soon after pump refills, the pump
should be drained and refilled. The withdrawn solution should be saved
for future analyses, if necessary. The multiple bag changes for
patients receiving epidural infusions are a perfect setup for drug
errors. Nursing errors in hanging the right solution for the right
patient will occur, more likely in the hospital than in the home
care setting. Patients within our institution have had hyperalimentation,
heparin, and antibiotics inadvertently administered through permanent
epidural catheters, both on the hospital floor and in the emergency
room. It is important for the provider to be aware of these possibilities
and to check all possible causes of any unexpected reaction and
to correct the errors as they occur.
+++
Mechanical Complications
++
Mechanical problems may be associated with the catheter, pump,
filter, or the implanted device. One clinical dilemma associated
with use of short-term epidural catheters is the failure of the adapter
and connector. The connectors may become dislodged or the catheter
material may become more brittle over time and break near the connector.
The second most common problem is unexpected catheter withdrawal
or migration outside of the epidural space. Tunneling the short-term
catheter may add stability, but the durability of both catheter
and connector are the major issues in maintaining the catheter for
long-term use.114 Mechanical complications of both
epidural and intrathecal drug administration have been alleviated
to a great extent with the advent of the permanent silicone-rubber
epidural catheters.
++
Epidural hematoma is exceedingly rare under normal conditions.115 Cancer
patients with low platelet counts or those receiving anticoagulation
therapy are, however, commonly encountered. Our policy, developed
in close collaboration with the medical oncology staff, is to proceed
if the platelet count is at least 20,000 without any signs of subcutaneous
ecchymosis. Reversal of anticoagulation therapy is done on a case-by-case
basis with consultation from the oncologist. This policy is consistent
with the guidelines established by the consensus conference on anticoagulation
and regional anesthesia organized by the American Society of Regional Anesthesia.
++
The most common cause of loss of analgesia encountered during
epidural infusion is catheter or filter obstruction. Filter failure
should be ruled out first when catheter obstruction is encountered. After
catheter obstruction, failure of the externalized pump due to program
input errors or an air bubble “lock” in the system
is the next most common cause of analgesic failure. Utilizing aseptic technique
and preservative-free saline, inject in the line above the filter
and then below the filter to determine the source of the obstruction.
Catheter obstruction may be further investigated by lumbar spine
radiography or an epidurogram. Kinking of the catheter is easily
seen on simple x-ray films. We have had one case of “crystallized” infusate
in the catheter causing obstruction. This event occurred in a patient
who had not been using the catheter for several months after obtaining
pain relief with radiation therapy. The catheter was removed and
subsequent dissection of the lumen revealed a solid mass of what
was believed to be “old drug.” Subsequently, our
policy became to flush all unused epidural catheters with 3 mL of
preservative-free saline at least once a week. Once the catheter
occlusion is diagnosed, then a surgical repair or repositioning
of the catheter can be accomplished. Fibrosis around the catheter
in the epidural space is discussed, but in our experience this occurs
only in the face of a subacute epidural space infection. A survey study
of 519 implanters reported a series of patients with granulomatous
catheter tip masses in the intrathecal space.18 A
second paper reports three cases of granuloma formation on an intrathecal catheter,
with neurologic deficit. This a rare complication for which a cause
has not been established, but infection and high concentration morphine
have been suspected.16
++
Anderson and Burchiel reported that 20% of patients
experience device-related complications with the implanted pump
that require a repeat operation.11 General system
failure of implantable infusion devices was reported by Paice15 and
Penn as 21.6%, which is consistent with reports in the
literature that vary from 10% to 40%. These system
failures include catheter, pump, and connection problems. As with
all multicenter, retrospective survey studies, the data are dependent
on the rate of response from the implanters and the memory and recall
of those clinicians.
++
Both external and internal pumps may be misprogrammed. It is
important that two individuals check all pump programming of concentrated
drugs that could endanger patient safety. A careful determination
of the drug order and content of the infusion bag, pump infusion
orders, and actual settings should follow any unexpected clinical
outcome. In our practice, we felt the practice standards were in
place, so we assumed this could not happen. We have had a major
programming error event, which was corrected without sequelae; this
event could have been avoided by simply having another nurse check
the pump settings. The opioid-tolerant patient will tolerate most
drug infusion errors, but may be placed in danger by errors of both
drug concentration and infusion volume. Any abnormal patient response
with signs of oversedation, neurologic deficits (not explained by
tumor progress or metastatic lesions), or a combination of symptoms
should alert the staff to turn down the pump significantly or stop
until the cause of the symptom complex is determined. Consistent
education and rational policies and procedures can minimize these
human errors.