Petre Nitescu

Neuropathologic Findings after Long-term Intrathecal Infusion of Morphine and Bupivacaine for Pain Treatment in Cancer Patients

Epidural or intrathecal infusions of morphine and bupivacaine mixtures are presently used for the treatment of refractory cancer pain even though the neurotoxic potential of such mixtures is unknown. The pathologic findings of the spinal column, the meninges, the nerve roots, and the spinal cord, and the clinical neurologic deficits were recorded in 15 patients (5 men and 10 women), aged 26-83 (median 68) yr, treated for 4-274 (median 81) days with intrathecal infusions of morphine (with preservatives [sodium metabisulfite and sodium edetate]) and bupivacaine mixtures, given through open, subcutaneously tunneled nylon catheters. Six patients had been subjected to radiation therapy (20-96 Gy), applied over the spinal column, and four had been treated with antineoplastics believed to be neurotoxic. Ten patients had various neurologic deficits before the intrathecal treatment. The cumulative doses (ranges) given intrathecally were: morphine 33-11,900 mg, sodium metabisulfite 3.3-1,050 mg, sodium edetate 0.33-105 mg, and bupivacaine 10-41,400 mg; cumulative volumes were 16-9,400 ml. The concentrations of the drugs in the mixtures were: morphine 0.25-4.0 mg/ml, sodium metabisulfite 0.025-0.40 mg/ml, sodium edetate 0.0025-0.04 mg/ml, and bupivacaine 3.0-4.75 mg/ml. The osmolality of the mixtures in vitro ranged from 282 to 286 mOsm/kg and the pH from 4.1 to 4.6. The pathologic findings consisted of vertebral metastases (n = 6), epidural and/or intrathecal tumor masses (n = 8), focal subdural fibrosis (n = 6), infiltration of mononuclear cells in the subarachnoid space (n = 10), and discrete injuries (nerve fiber degeneration or fibrosis) to the anterior (five patients) and posterior (seven) nerve roots, and spinal cord (tumor compression [one], slight thickening of the leptomeninges [one], and thrombosis of a spinal artery and medullary infarction [one]). In none of the cases was any reaction against the nylon catheter within its subarachnoid course recorded. The neuropathologic findings were not related to the duration or cumulative doses of the intrathecal treatment. No new neurologic deficits that could be attributed to the intrathecal administration of the opiate-bupivacaine mixtures were recorded. The neuropathologic and clinical neurologic findings in cancer patients treated with intrathecal morphine-bupivacaine mixtures appeared similar to those in animals and humans reported with either intrathecal morphine or bupivacaine alone.

Complications of Intrathecal Opioids and Bupivacaine in the Treatment of “refractory” Cancer Pain

ObjectiveTo test the concept that externalized tunneled intrathecal catheters lead to a high risk of complications, such as meninigitis and epidural abscess, and therefore should not be used for durations of intrathecal pain treatment of > 1 week. DesignProspective, cohort, nonrandomized, consecutive, historical control trial. SettingTertiary care center, institutional practice, hospitalized and ambulatory care. PatientsTwo hundred adults (107 women, 93 men) with refactory cancer pain treated for 1–575 (median, 33; total, 14,485) days; 79 patients were treated at home for 2–226 (median, 36; total, 4, 711) days. All patients had died by the close of the study. InterventionsInsertion of intrathecal tunneled nylon (Portex) catheters (223 in 200 patients) with Millipore filters. The catheter hubs were securely fixed to the skin with steel sutures. Standardized care after insertion: (a) daily phone contact with the patients, their families, or the nurses in charge; (b) weekly dressing change at the tunnel outlet by the nurses; (c) refilling of the infusion containers by the nurses; (d) exchange of the infusion systems when empty (within 1 month) and of the antibacterial filter once a month by specially instructed Pain Department nurses. All contact between the connections of the syringes, cassettes, and needles with the operators hands was carefully avoided during filling and refilling of the infusion containers and exchange of the antibacterial filters; no other aseptic precautions were taken. Main Outcome MeasuresWe recorded the rates of perfect function and complications of the systems. The rates of complications recorded in this study with externalized tunneled intrathecal catheters are discussed and compared with the rates reported in the literature with externalized (tunneled and nontunneled) epidural and intrathecal catheters, as well as with internalized (both epidural and intrathecal catheters connected to subcutaneous ports, reservoirs, and pumps. ResultsThe following rates (as a percentage of number of patients) of perfect function and complications of the systems were recorded (the ranges of rates reported in the literature are given in parentheses): perfect function of the system, 93% (31–90%); accidental injury of an unknown epidural tumor followed by an epidural hematoma, 0.5% (04%); skin breakdown at the insertion site, 2% (2–50%); postdural puncture headache, 15.5% (10%); external leakage of CSF, 3.5% (427%); CSF hygroma (“pseudomeningocele”), 1.5% (4− 6.25%); hearing loss and MBniBre-like syndrome, 0% (12%); pain on injection, 0% with continuous infusion and 4.5% with intermittent injections (3–36% with intermittent injections); catheter tip dislodgement, 1.5% (633%); catheter (system) occlusion, 1% (3–12%); accidental catheter withdrawal, 4% (3–22%); catheter (system) leakage, 1.5% (2.1–26.6%); all mechanical complications, 8.5% (1044%); local (catheter entry site) infection, 0.5% (2–33%); catheter track infection, 0% (625%); epidural abscess, 0% (0.625%); meningitis, 0.5% (1–25%); systemic infection, 0% (3%); incidence of all infections (nhreatment days), 1 /7,242 ( 1 / 168− 1 /2,446). ConclusionsIn our population and with the technique of insertion and care reported here, the use of externalized tunneled intrathecal catheters has not been associated with higher rates of complications when compared with earlier reported rates of externalized epidural catheters and internalized (both epidu- ral and intrathecal) catheters connected to subcutaneously implanted ports, reservoirs, and pumps. The opinion that the use of externalized tunneled in- trathecal catheters should be restricted only to patients who need pain treat- ment for <1 week (because of the potential risk of infection, particularly men- ingitis and epidural abscess) is unfounded.

Long-term intrathecal morphine and bupivacaine in “refractory” cancer pain. I. Results from the first series of 52 patients

Neither epidural (EDA) or intrathecal (IT) morphine nor EDA opiate + bupivacaine provides acceptable relief of some types of cancer pain, e. g. pain originating from mucocutaneous ulcers, deafferentation pain, continuous and intermittent visceral and ischaemic pain, and that occurring with body movement as a result of a fracture. To improve pain relief in such conditions, we gave combinations of morphine and bupivacaine through open IT‐catheters to 52 patients with “refractory”, severe (VAS 7–10 out of 10), complex cancer pain (Edmonton Stage‐3), for periods of 1–305 (median = 23) days. The efficacy of the treatment was estimated from: 1) daily dosage (intraspinal and total opiates, and intraspinal bupivacaine), and 2) scores of non‐opiate analgesic and sedative consumption, gait and daily activities, and amount and pattern of sleep. Forty‐four patients obtained continuous and acceptable pain relief (VAS 0–2), 26 of them with daily doses of IT‐bupivacaine of <30 mg/day (<1. 5 mg/h). Higher IT‐bupivacaine doses (>60–305 mg/day), not always giving acceptable pain relief, were necessary in 13 patients with deafferentation pain from the spinal cord or brachial or lumbosacral plexuses or pain from the coeliac plexus, or from large, ulcerated mucocutaneous tumours. By combining IT‐bupivacaine with IT‐morphine, it was possible to use relatively low IT‐morphine doses (10–25 mg/day during the first 2 months of treatment) in more than half of the patients. The IT‐treatment significantly decreased the total (all routes) opiate consumption and significandy improved sleep, gait and daily activities. For the whole period of observation (6 months), the IT‐treatment was assessed as adequate in 3. 8%, good in 23. 1%, very good in 59. 6% and excellent in 13. 5% of the cases. Adverse effects of the IT‐bupivacaine (paraesthesiae, paresis, gait impairment, urinary retention, anal sphincter disturbances and orthostatic hypotension) did not occur with doses of 2. 5–3. 0 mg/h (approx. 60–70 mg/day).

Long-term Intrathecal Morphine and Bupivacaine in Patients with Refractory Cancer Pain Results from a Morphine, Bupivacaine Dose Regimen of 0.5:4.75 mg/ml

BackgroundThere are no clinical data regarding the ratios and concentrations in which morphine and bupivacaine should be combined, when given intrathecally, to improve analgesia while decreasing adverse effects. This study was undertaken to test the clinical efficacy of a constant infusion of 0.5 mg/ml morphine plus 4.75 mg/ml bupivacaine (morphine: bupivacaine ≈1:10), given through open intrathecal catheters. MethodsIn 53 patients, the clinical efficacy was estimated from: pain relief (visual analog scale scores 0–10); daily dosages (intrathecal and total opioid and intrathecal bupivacaine); scores (0–5) of nonopioid analgesic and sedative consumption, gait and daily activity, and amount of sleep; and rates of adverse effects. ResultsDuring the intrathecal period (7–334, median 29 days), all 53 patients obtained acceptable pain relief (visual analog scale scores 0–2 vs. 6–10 in the pre-intrathecal stage). The total opioid daily consumption decreased (median 10 vs. 120 mg), the sleep was about two times longer, the nonopioid analgesic and sedative consumption about two times lower, and the gait ability pattern was unchanged. The daily dose of intrathecal morphine (median 6 mg) and the daily intrathecal volumes (median 10 ml) were low, whereas the daily dose of intrathecal bupivacaine was relatively high (median 50 mg). Side effects potentially related to intrathecal morphine (seizures, cerebral, and spinal clonus) were not recorded. Side effects attributable to intrathecal bupivacaine (in patients not having these complications before the intrathecal treatment) occurred in the forms of late urinary retention (9 of 27), paresthesias (11 of 27), paresis/gait impairment (9 of 27), and occasional episodes of orthostatic arterial hypotension (1 of 53 patients). ConclusionsA constant intrathecal infusion with a morphine:bupivacaine ratio of = 1:10 and concentrations of morphine of 0.5 mg/ml and bupivacaine of 4.75 mg/ml may significantly improve the relief of refractory cancer pain with a certain risk of adverse effects (which should be balanced against pain by the patient) from the relatively high intrathecal bupivacaine doses and concentration.

Epidural versus intrathecal morphine-bupivacaine: Assessment of consecutive treatments in advanced cancer pain

Twenty-five patients with multifocal and multitype (somatic, visceral, and neurogenic) advanced cancer pain who experienced severe pain despite extradural (ED) morphine and bupivacaine were converted to intrathecal (IT) morphine and bupivacaine. The consecutive ED and IT periods (2-174 days, median = 50 days, and 1-305 days, median = 37 days, respectively) were assessed in clinical terms (daily analgesic dosages giving acceptable pain relief and quality of life expressed as sleeping hours and walking/daily activities). With the IT treatment, the total (all routes) opiate consumption and the daily doses of spinal morphine and spinal bupivacaine decreased significantly at the beginning of the treatment compared to the ED period, and continued to be significantly reduced for up to 1 wk for spinal opiate and bupivacaine and 6 mo for total opiate. The spinal opiate and bupivacaine doses were still lower in 50% of the patients at the end of the IT treatment compared to the end of the ED period. When final ED versus initial (2nd day) IT doses were assessed, the daily median dose ratios were 7.5 for total opiate and 4 for both spinal opiate and bupivacaine. Subsequently, lower daily volumes and higher concentrations were needed for IT administration of the drugs. During the first month of the IT treatment, sleeping and walking scores improved compared to ED treatment. Thus, the IT treatment gave more satisfactory pain relief, and--because of lower daily doses and volume--proved to be more suitable for treatment at home (continuous infusion from external pumps) than the ED treatment.

Efficacy and technical complications of long-term continuous intraspinal infusions of opioid and/or bupivacaine in refractory nonmalignant pain : A comparison between the epidural and the intrathecal approach with externalized or implanted catheters and infusion pumps

OBJECTIVEnTo compare efficacies, failure rates, and technical complication rates of intraspinal treatments in patients with refractory nonmalignant pain conditions in relation to the approach (epidural/intrathecal), the drug (opioid/opioid-bupivacaine or bupivacaine), and the type of system used (externalized/internalized). In these comparisons, recent data from a companion paper (Nitescu et al., Clin J Pain 1998;14:17-28) were used as a reference to be compared with data from a literature review of different intraspinal treatment modalities in nonmalignant pain.nnnDESIGNnProspective, cohort, nonrandomized, consecutive trial.nnnSETTINGnTertiary care center, institutional practice, hospitalized, and ambulatory care.nnnPATIENTSnFive groups according to treatment modality: (a) externalized, long-term intrathecal nylon catheters, connected to external, electronic infusion pumps (companion paper), n = 90; (b) internalized, long-term intrathecal catheters (Silastic) connected to implanted SynchroMed pumps, n = 330 (literature review); (c) externalized, short-term epidural catheters for temporary infusions, n = 565 (literature review); (d) externalized, long-term epidural catheters, n = 50 (literature review); (e) internalized, long-term epidural catheters, n = 111, connected to implanted systems: Port-A-Cath injection ports, n = 58; Infusaid pumps, n = 46; and SynchroMed pumps, n = 7 (literature review).nnnINTERVENTIONSnIn reviewing the literature, we found 21 studies that reported on the intraspinal (epidural or intrathecal) administration of opioids with or without local anesthetics (usually bupivacaine). These studies were analyzed with respect to the rates of the variables satisfactory pain relief (efficacy), failures, and technical complications. A rate is the number of observations of a variable divided by the number of patients or the number of catheters or infusion systems, as logically indicated (e.g., the numbers of complications, such as epidural abscess and meningitis, were related to the number of patients and those of catheter occlusion or leakage to the number of the catheters). The variables were expressed as the means of the rates of a variable from studies belonging to various treatment modalities: approach (epidural vs. intrathecal), duration (short vs. long term), drugs administered intraspinally (opioid vs. opioid and/or local anesthetic), and type of infusion system (externalized vs. internalized). Further, the sums of all observations of one variable in different studies with various treatment modalities were related to the corresponding sums of the patients (alternatively, catheters or implanted devices). The proportions of these sums were tested for significance in relation to treatment modality.nnnMAIN OUTCOME MEASURESnComparative rates of successful intraspinal treatment and its failures and complications.nnnRESULTSn(a) The intrathecal approach, compared with the epidural approach, was associated with higher rates of satisfactory pain relief for both externalized (86/90, 95% vs. 17/40, 42.5%, p < .0001) and internalized (295/336, 89% vs. 33/56, 59%, p < .0001) catheters; higher rates of treatment failures with externalized epidural catheters than with internalized intrathecal catheters (24/47, 51%, vs. 36/338, 11%, p < .0001); lower rates of treatment failures with internalized intrathecal catheters than with internalized epidural catheters (36/338, 11% vs. 29/76, 38%, p < .0001); higher rates of system replacement with internalized epidural catheters than with internalized intrathecal catheters (23/32, 72% vs. 6/49, 12%, p < .0001; higher rates of system removal with internalized epidural catheters than with internalized intrathecal catheters (22/49, 45% vs. 5/49, 10%, p < .001); higher rates of catheter-related complications with epidural than with intrathecal catheters (dislodgement 13/126, approximately 10% vs. 6/150, 4%, p < .05; leakage 5/51, approximately 10% vs. 1/116, 0.9%, p < .05; obstruction 2

Continuous infusion of opioid and bupivacaine by externalized intrathecal catheters in long-term treatment of refractory nonmalignant pain

OBJECTIVEnTo explore the possibility of obtaining pain relief by continuous intrathecal infusion of bupivacaine and opioid in patients with intractable nonmalignant pain.nnnDESIGNnProspective, cohort, nonrandomized, consecutive trial.nnnSETTINGnTertiary care center, institutional practice, hospitalized, and ambulatory care.nnnPATIENTSnA total of 90 patients, 40 men and 50 women, 20 to 96 years old (median, 70 years), with various nonmalignant refractory pain conditions lasting for 0.3 to 50 years (median, 3 years) with nociceptive (n = 9), neurogenic/neuropathic (n = 17), and mixed pain (n = 64) were consecutively included in the study when (a) the pain dominated their lives totally, (b) other methods failed to provide acceptable pain relief, and (c) unacceptable side effects from opioids had occurred. Moribund patients and those with overt psychoses at the time of the assessment were excluded from the study.nnnINTERVENTIONSn(a) Insertion of externalized, tunnelled intrathecal catheters (101 in 90 patients). (b) Intrathecal infusion of opioid (morphine 0.5 mg/ml, or buprenorphine 0.015 mg/ml, and/or bupivacaine 4.75-5.0 mg/ml) from external electronic pumps was started in the operating room at a basic rate of 0.2 ml/hour, with optional bolus doses (0.1 ml 1-4 times/hour) by patient-controlled analgesia (PCA). Thereafter, the daily volumes were tailored to give the patients satisfactory to excellent (60-100%) pain relief, with acceptable side effects from the infused drugs, by increase or decrease of the basic rates and/or of the bolus doses, and their timing. (c) Supervision of the patients for 24 hours after catheterization in the postoperative ward. (d) Daily phone contact with the patients, their families, or the nurses in charge. (e) The patients had ad libitum access to nonopioid analgesics/sedatives and to opioids administered by various routes, until they obtained satisfactory pain and anxiolytic relief.nnnMAIN OUTCOME MEASURESn(a) Pain intensity (visual analog scores 0-10) and pain relief (0-100%). (b) Daily dosages (opioid administered by intrathecal and other routes, and intrathecal bupivacaine). (c) Scores (0-5) of nonopioid analgesics, gait and ambulation, duration of nocturnal sleep, and (d) rates of adverse effects.nnnRESULTSnDuring the intrathecal period [range, 3-1,706 days; median, 60 days; totaling 14,686 days, 7,460 (50% of which were spent at home)], 86 patients (approximately 95%) obtained acceptable (60-100%) pain relief. The nocturnal sleep duration increased from <4 to 7 hours (median values), nonopioid analgesic and sedative daily consumption became approximately two times lower, whereas the gait ability and ambulation patterns remained practically unchanged. Five patients still had ongoing treatment after durations of 30 to 1,707 (median, 206) days at the close of the study. In the remaining 85 patients, the intrathecal treatment was terminated because of patients death (n = 23), replacement of the intrathecal treatment by dorsal column stimulation (n = 1), pain resolution (n = 32), refusal to continue the intrathecal treatment (n = 19), lack of cooperation due to delirium or to manipulation of the pump (n = 8), and loss of efficacy of the intrathecal treatment (n = 2). Thus, in the long run, the intrathecal treatment failed in 29 of the 85 patients with terminated treatment (34%). The principal side-effects and complications, except those attributed to the dural puncture, the equipment, and the long-term catheterization of the subarachnoid space, which are presented separately, were severe bradypnea (n = 1), transient paresthesiae (n = 26), short-lasting pareses (n = 16), temporary urine retention (n = 34), episodic orthostatic arterial hypotension (n = 11), and attempted suicide (n = 5, 3 of which were successful). No neurologic sequelae or death could be attributed to the intrathecal procedure. (ABSTRACT TRUNCATED)

Bacteriology, drug stability and exchange of percutaneous delivery systems and antibacterial filters in long-term intrathecal infusion of opioid drugs and bupivacaine in refractory' pain

ObjectiveTo provide a basis for recommendations on the exchange of containers (syringes and cassettes) and antibacterial filters, and for choice of administration device in patients with “refractory” pain treated with long-term percutaneous intrathecal (IT) infusions of opioid (morphine or buprenorphine) and bupivacaine mixtures. DesignProspective, cohort, nonrandomized control trial-case series, with consecutive sample, no standard criterion, and cost-benefit analysis. SettingTertiary care center, institutional practice as well as hospitalized and ambulatory care. PatientsEighty-nine (51 women and 38 men); 81 with malignant pain and 8 with benign “refractory” pain. Interventions(a) The chemical stability of the drugs in the containers during 30 days, (b) The results of bacteriologic culture of the residual volumes of the analgesic mixtures from used and reused (1–16 times) syringes (n = 135) and cassettes (n = 258), and of 5 ml of sterile isotonic saline filtered through the used Millipore filters (n = 149). The bacteriologic samples from the 89 patients were taken after 1–40 (median = 7), 1–86 (median = 20), and 5–78 (median =31) days of IT treatment, respectively. Main Outcome MeasuresChemical stability: buprenorphine and bupivacaine concentrations-liquid chromatography; morphine concentrations-gas chromatography. Bacteriologic cultures: standard laboratory procedures. The hypothesis (repeated use of the infusion systems and their exchange once a month does not significantly affect drug concentrations or increase the infection risk) was elaborated before data collection began. ResultsThe bupivacaine-opioid mixtures were found to be chemically stable within 3–10% of the original doses up to 30 days. Seventeen cultures (from five syringes, six cassettes, and six filters) in 13 patients (having no signs of meningeal infection) were found to be colonized with Staphylococcus.

Long-Term, Open Catheterization of the Spinal Subarachnoid Space for Continuous Infusion of Narcotic and Bupivacaine in Patients with “Refractory” Cancer Pain A Technique of Catheterization and its Problems and Complications

The technique of long-term, open catheterization of the spinal subarachnoid space for infusion of analgesics in patients with refractory cancer pain is sparsely reported in the literature. We report on a technique using 18G Portex nylon catheters and 16G-17G Tuohy needles, and its problems and complications. One hundred fifty-seven catheters were inserted in 142 patients, in most of them (79%) under deep sedation and local anesthesia. Attempts were made to place the catheter tip as close to the painful segments as possible. The catheters were tunneled subcutaneously (87% of them paravertebrally, over the shoulder, and further parasternally to the third chondrocostal cartilage). The Luer connections of the catheters were fixed to the patients skin with monofilament steel sutures of dimension 0 and connected to a bacterial filter. At the end of the procedure, 10 ml isotonic saline was injected intrathecally to prevent postspinal puncture headache. Absorbent and impermeable dressings were applied over the tunnel exit, catheter Luer connection and bacterial filter. Antibiotics were given on the day of insertion and 2 days thereafter. During the insertion procedure, the following problems and complications were encountered; two or more attempts before successful spinal-dural puncture (32%), accidental puncture of an extradural vessel (10%), difficult dural puncture (18%), absence of free dripping of cerebrospinal fluid (CSF) in spite of successful dural puncture (4%), blood-stained CSF (9%), radicular pain and paresthesiae (4%), difficult advancement of the catheter (6%), difficult tunneling (11%), and bleeding in the tunnel (0.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous Intracisternal and High Cervical Intrathecal Bupivacaine Analgesia in Refractory Head and Neck Pain

Background The upper cervical component of the spinomesencephalic tract and cranial nerves V, VII (nervus intermedius), IX, and X are involved in mechanisms of acute and chronic pain from head and neck structures. To date there is no reliable method for relief of refractory pain (i.e., pain that cannot be relieved by conventional pharmacologic therapies) from these structures. Therefore, we explored continuous intracisternal infusion of bupivacaine for the treatment of refractory pain of the head and neck. Methods Intracisternal catheters were inserted in 13 adults with refractory nonmalignant (n = 4) and malignant (n = 9) pain from the head, face, mouth, neck, and upper extremities; 0.5% plain bupivacaine was infused continuously at rates of 1-7 (median 1.5) mg/h with optional bolus doses of 0.5-2.0 mg 4-2 times/h. The efficacy was assessed from pain relief (daily VASmax, VASmin, and VASmean scores 0-10), daily doses of intracisternal bupivacaine and total opioid (expressed as mg parenteral morphine-eq), amount of nocturnal sleep, and rates of adverse effects. Results The 13 patients were treated for 3-182 days (median 37, total 712 days), 3 patients being treated at home for 10-112 days (median 88, total 210 days). In one patient, the efficacy of the treatment could not be estimated because of advanced senility. Eleven of the remaining 12 patients obtained acceptable pain relief with daily doses of intracisternal bupivacaine ranging from 20 to 118 mg (median 37 mg): VAS sub mean scores decreased from 7 to 2, mean pain relief increased from 30% to 80%, total opioid daily dose decreased from 53 to 36 mg parenteral morphine-eq, and nocturnal sleep increased from 2 to > 6 h (all figures are median values). Speech, eating, walking, and natural functions were generally not affected. Side effects such as tiredness and malaise, somnolence and sleep, feeling of coldness in the neck and skull base, transient post-spinal puncture headache, paresthesias, hoarseness, dysphagia, transient paresis of the upper/lower extremities, episodic miosis and conjunctival hyperemia, and transient orthostatic arterial hypotension were each observed in one or two patients. No patient presented clinical evidence of phrenic nerve paralysis. There was no nausea or vomiting. No persistent neurologic deficit or death could be attributed to the intracisternal pain treatment. Conclusions Continuous intracisternal infusion of bupivacaine may be a useful method in exceptional, well selected patients with refractory pain from the head and neck structures. Further studies are necessary to establish the indications and the safety of the method.