The role of guidelines in interventional pain medicine: let us separate apples and oranges.

Practice guidelines are not only an ancient tradition, but they are a fact of life. The first guidelines were developed in the 1840s, shortly after the use of anesthesia was first demonstrated. Even though practice guideline development has spawned an impressive and over-aggressive literature of its own, many unanswered questions exist with regard not only to practice parameters and guidelines in general, but in particular with the application of interventional techniques in managing persistent pain. In spite of the great potential of clinical practice guidelines, and the involvement of numerous medical societies and physician groups, there is still a great debate within the profession not only about the pros and cons of the development and usage of the guidelines, but also conflicting and controversial opinions on both sides of the issue, i.e., providers and patients vs payors. This article discusses the development, usage, advantages, disadvantages and the implications of practice guidelines to interventional pain medicine specialists.

Interventional techniques in the management of chronic pain: Part 2.0.

The practice guidelines for interventional techniques in the management of chronic pain are systematically developed statements to assist physician and patient decisions about appropriate health care related to chronic pain. These guidelines are professionally derived recommendations for practices in the diagnosis and treatment of chronic or persistent pain. They were developed utilizing a combination of evidence and consensus based techniques, to increase patient access to treatment, improve outcomes and appropriateness of care, and optimize cost-effectiveness. The guidelines include a discussion of their purpose, rationale, and importance, including the patient population served, the methodology and the pathophysiologic basis for intervention. Various interventional techniques will be discussed addressing the rationale for their use in chronic pain with analysis of the outcomes data and cost effectiveness. These guidelines do not constitute inflexible treatment recommendations. It is expected that a provider will establish a plan of care on a case-by-case basis, taking into account an individual patient's medical condition, personal needs, and preferences, and the physician's experience. Based on an individual patient's needs, treatment different from that outlined here could be warranted.

Renal autotransplantation for the loin pain-hematuria syndrome: long-term followup of 26 cases.

PURPOSE: We review the long-term results of renal autotransplantation as a form of nephron sparing renal denervation for patients with the loin pain-hematuria syndrome. MATERIALS AND METHODS: From 1985 to 1997, after exclusion of other urological, nephrological and psychiatric causes for severe intractable flank pain and recurrent hematuria, 22 patients with severe debility and heavy narcotic dependency underwent 26 renal autotransplantations for pain control. Postoperative pain relief, narcotic use, level of function in daily activities and status of the autograft were assessed. RESULTS: Median and mean followup was 78.5 and 84.7 months (range 30 to 138), respectively. There were 2 technical failures. Pain recurred within 2 years after 6 procedures, of which 3 resulted in transplant nephrectomy and 3 were managed with a reduced analgesic requirement. Of the 16 patients with minimum 5 years of followup 12 (75%) were pain-free after surgery with 3 additional patients pain-free after transplant nephrectomy. Overall, 18 of the 26 autotransplant procedures (69.2%) resulted in pain relief, in some cases beyond 10 years, with patients returning to normal daily activities. CONCLUSIONS: Renal autotransplantation results in durable narcotic-free favorable results in the majority of meticulously screened loin pain-hematuria syndrome patients. Although some failures, which usually occur within 2 years after surgery, can be expected, autotransplantation is justified as a nephron sparing denervation therapy for select loin pain-hematuria syndrome patients.

Metallothionein expression in prostatic carcinoma: correlation with Gleason grade, pathologic stage, DNA content and serum level of prostate-specific antigen.

OBJECTIVE: To determine the expression of metallothionein (MT) in prostatic carcinoma by immunohistochemical staining. Several lines of evidence have indicated that MT may play a role in carcinogenesis and in drug resistance of tumours. DESIGN: Retrospective pathologic study. INTERVENTIONS: Formalin-fixed, paraffin-embedded archival tissues from 39 radical prostatectomies were analysed. All tumour foci were stained by ABC technique using a primary polyclonal rabbit antibody against rat liver MT. The staining intensity for MT was graded on a scale of 0 to 2+, and the histologic grading was done by the scheme of Gleason. OUTCOME MEASURES: Correlation of MT expression with Gleason grade, preoperative serum prostate-specific antigen (PSA) levels, pathologic stage and DNA content, including S-phase fraction (SPF) and proliferative index (PI). RESULTS: Most of the epithelium of normal prostate tissue had patchy, intense MT staining. All the grade II tumours foci showed intense (2+) staining for MT, while all grade IV and V foci were persistently negative. The grade III tumours foci were heterogeneous. The MT-positive foci showed both nuclear and cytoplasmic staining of variable extent. There were 9, 15, 13 and 2 tumours with pathologic stage B, C1, C2 and D1, respectively. The serum PSA levels ranged from 1 to 16 ng/mL. No apparent correlation existed between the MT staining pattern and the pathologic stage or preoperative PSA level. Thirty-four of the tumours were diploid and 5 were tetraploid. There were significantly higher SPF and PI mean values in the MT-stained tumour cells (p < 0.05), suggesting that MT preferentially stains an epithelial subpopulation, possibly the proliferating cell compartment. CONCLUSION: The positive correlation of MT expression with Gleason grade in prostatic adenocarcinoma suggests a possible role for MT in oncogenesis in prostate cancer.

Short-course intravenous prophylaxis for paclitaxel-related hypersensitivity reactions.

PURPOSE: To estimate the incidence of hypersensitivity reactions using a short-course intravenous prophylactic regimen in patients receiving outpatient therapy with paclitaxel. PATIENTS AND METHODS: Patients were identified from a retrospective search of a computerized pharmacy database covering a two-year period from January 1994 through December 1995. Eligible outpatients received paclitaxel as a one- to three-hour infusion 30 minutes after intravenous dexamethasone (10 or 20 mg), diphenhydramine (50 mg), and cimetidine (300 mg) or ranitidine (50 mg). Charts from all patients were then manually reviewed to verify drug administration and to record any evidence of hypersensitivity reactions during the first two cycles of therapy. RESULTS: A total of 283 outpatients were identified from the pharmacy database and all charts reviewed. All patients received intravenous dexamethasone (5 to 20 mg) 30 minutes prior to paclitaxel without prior oral dexamethasone. Hypersensitivity reactions were documented in 13 patients (4.6%) during the first or second cycle with a 95% confidence interval (CI) of 2.2% to 7.0%. Reactions resolved rapidly without sequelae and did not require hospitalization. Only two reactions (0.7%) were graded as serious with a 95% CI of 0.2% to 1.2%, based on the use of bronchodilators and presence of angioedema. Therapy was continued with modification in 10 patients without recurrent hypersensitivity reaction. Therapy was discontinued in two patients without rechallenge and discontinued in one patient after rechallenge with a recurrent hypersensitivity reaction. CONCLUSION: A short-course single-dose regimen of intravenous dexamethasone, diphenhydramine, and cimetidine (or ranitidine) offers a safe and convenient alternative for prevention of hypersensitivity reactions associated with outpatient paclitaxel administration.

Receiver operating characteristic (ROC) curve analysis of transrectal ultrasonographic prostate cancer detection.

PURPOSE: To provide an overview of receiver operating characteristics (ROC) curve theory and create an ROC curve describing transrectal ultrasound (TRUS) detection of prostate cancer (PCa). METHODS: One hundred thirty-two patients with either an abnormal digital rectal exam (DRE) or a prostate-specific antigen (PSA) above 4 ng/ml or both underwent TRUS and biopsy of the peripheral zone (PZ) of each quadrant. ROC software was used to create an ROC curve. RESULTS: One hundred seventy-nine of 528 quadrants (34%) harbored PCa. The performance of TRUS in detection of PCa as defined by the area below the ROC is 0,809. CONCLUSIONS: Future investigators are encouraged to employ ROC analysis of TRUS to permit more meaningful comparisons of performance.

Intravenous prophylaxis for paclitaxel-related hypersensitivity reactions.

Severe hypersensitivity reactions to paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) were reported during early phase I trials. A premedication regimen consisting of oral steroids 12 and 6 hours before treatment with paclitaxel as well as immediate infusion of diphenhydramine and cimetidine (or ranitidine) before paclitaxel markedly decreased the incidence of hypersensitivity reactions. Subsequently, investigators at the Fox Chase Cancer Center used intravenous dexamethasone, diphenhydramine, and cimetidine immediately before paclitaxel in an effort to obviate the inconvenience of oral steroid administration. Two prospective clinical trials that use carboplatin and paclitaxel were performed in patients with ovarian cancer and in patients with non-small cell lung cancer. In both these trials, all premedication for hypersensitivity reactions was administered intravenously immediately before paclitaxel. No significant hypersensitivity reactions were reported in these two trials, and, subsequently, a large retrospective search of a computerized pharmacy database concluded that a single-dose regimen of intravenous dexamethasone, diphenhydramine, and cimetidine is a safe and convenient alternative for prevention of hypersensitivity reactions associated with outpatient paclitaxel administration.

Acute encephalopathy attributed to 5-FU.

Acute encephalopathy attributable to 5-fluorouracil (5-FU) is rare. A patient experienced this reaction associated with a continuous 5-FU infusion. The etiology of the event remains uncertain, but it is generally reversible and does not preclude retreatment with 5-FU at reduced dosages. Steroids and thiamine may expedite neurologic recovery.

Metallothionein expression and resistance to cisplatin in a human germ cell tumor cell line.

Expression of intracellular metallothionein (MT) has been linked to cis-diamminedichloroplatinum (cDDP) resistance in human germ cell tumor cell lines. To determine whether exposure to cDDP would select for cells with increased MT expression, the MT content of the human teratocarcinoma cell line T7800 was measured after development of resistance to cDDP by exposure to progressively higher drug concentrations (6.25-25 microM). cDDP-resistant cells (T7800R) had significantly higher MT mRNA and MT protein, increased resistance to killing by cDDP and altered in vitro growth kinetics compared to parental T7800 cells. cDDP resistance in a variety of other human tumor cell lines correlated with MT content, with no significant difference in glutathione level. These data indicate that selection in vitro for cDDP resistance in human germ cell tumors coselects for cells with enhanced MT content. However, selected cells differed in characteristics other than MT content. They had a slower growth rate and, although the rank order of MT level in T7800, T7800R and other human tumor cell lines correlated very well with cDDP resistance, differences in the level of MT expression did not correspond with differences in the absolute level of cDDP resistance. These results suggest that increased MT expression is concomitant with increased cDDP resistance in a variety of human tumor cell lines. However, measured differences in MT levels may not accurately reflect the degree of cDDP resistance differences among those cells.

Induction of hepatic metallothionein I in tumour-bearing mice.

Metallothionein (MT) is an intracellular metal-binding protein which has been implicated in various biological roles, including heavy-metal detoxification and zinc and copper homeostasis, and has putative antioxidant properties. High levels of MT have been detected in certain human tumours, but its functions are unclear. The presence of tumour may cause stress conditions along with alterations in host metabolism, such as the redistribution of metals and, subsequently, in changes in hepatic MT isoforms. The distribution of basal levels of MT-1 and MT-11 isoforms in livers of different strains of mice and their induction in mice inoculated with tumour cells are investigated. While Balb-c, C57/BL and CD1 mice strains had an equal distribution of both hepatic MT isoforms, MT-I and MT-II. In addition, MT-I was the predominant isoform synthesised (> 88%) in the livers of all strains of mice at 24 h after injection with either cadmium or zinc salts. After inoculation with human testicular T7800 or T7799 tumour cells, the major form of MT induced in the livers of nude (nu/nu) mice was Zn-MT-I, and its concentration was positively correlated with the size of the inoculated tumours (r2 = 0.85). A similar positive relation was found in the livers of Balb-c mice inoculated with MM45T mouse bladder tumour cells (r2 = 0.96). Following surgical removal of T7800 tumour, hepatic MT concentrations returned to basal values. There was an increase in plasma MT levels in tumour-bearing mice and it was positively correlated with the increase in hepatic MT levels. These results demonstrate a specific increase in hepatic MT-I isoform in tumour-bearing mice, and this may be due to a generalised stress during tumour growth.

Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis.

The role of metallothionein (MT) in cisplatin (cis-DDP) resistance and renal toxicity was investigated in C3H mice inoculated with mouse bladder tumor (MBT-2). C3H mice were inoculated s.c. with 1 x 10(6) MBT-2 cells/mouse on day 0. Mice were given injections of proparglyglycine (PPG) (500 mumol/kg s.c.) once a day for 3 days from day 7 to day 9 and with ZnSO4 (200 mumol/kg s.c.) once a day for 2 days from day 8 to day 9. cis-DDP (50 mumol/kg i.p.) was administered 10 days after MBT-2 cell inoculation. Since MT contents in the tumor and kidneys were significantly increased by administration of ZnSO4, both the antitumor activity of cis-DDP and its renal toxicity were reduced. However, coadministration of PPG reduced MT induction in tumor without affecting the level of renal MT. As a result, PPG could clearly overcome the MT-mediated cis-DDP resistance of tumors without compromising the protective effect exerted by renal MT on nephrotoxicity of the drug. It was suggested, therefore, that PPG may be a promising adjunct in cancer chemotherapy to overcome the drug resistance of tumors caused by the elevated level of MT.

A prospective, randomized double-blind study of the use of antibiotics at the time of mastectomy.

The ability of perioperative cefazolin to reduce the incidence of postoperative wound infection in patients undergoing ablative surgical treatment for carcinoma of the breast was tested in this prospective, randomized, double-blinded study. From May 1983 until December 1985, 118 women were divided into two groups at random. Group 1 consisted of 59 patients and received cefazolin and group 2 was made up of 59 patients who received a placebo. The groups were similar with respect to age, operative procedure, operative time and time to discharge after operation. Three infections occurred among those in group 1 and five among those in group 2 (p = 0.72). The time to onset of infection was delayed in the patients in group 1 versus those in group 2 (17.7 days versus 9.6 days, p = 0.04). Six of eight infections occurred in patients in whom an interval between biopsy and definitive surgical treatment was present. Prophylactic antibiotics in mammary operations did not reduce postoperative wound infections in this study.

A survey of 77 major infectious complications of median sternotomy: a review of 7,949 consecutive operative procedures.

Sternal wound infections developed following 77 (0.97%) of 7,949 operative procedures involving median sternotomy at New York University Medical Center from 1976 to 1984. Risk factors associated with the development of a sternal wound infection included combined revascularization and valve replacement, early reexploration for bleeding, prolonged low cardiac output syndrome, and prolonged ventilatory support (greater than 24 hours). Concomitant infection at other sites with the same organism as cultured from the sternum was present in 42% of the patients. Thirty-seven patients (48%) were treated with radical debridement followed by closed antibiotic irrigation. In 31 other patients (40%), the wounds were debrided and left to heal by open granulation. Both initial treatments had equally high success rates (78.4% and 74.2%, respectively). However, the open granulation method resulted in a hospital stay that was an average of 10 days longer than the closed antibiotic irrigation method. Muscle flaps were used to expedite healing of open granulation in 9 patients. Analysis of the results of different treatment strategies revealed that if debridement was accomplished within 20 days of the initial cardiac procedure, 76% of the patients could be successfully treated with closed antibiotic irrigation. Conversely, if treatment was delayed for longer than 20 days, 81% of the patients were treated with open granulation (p less than 0.001). Also noted was an inverse relationship between the serum blood urea nitrogen (BUN) level and the success rate of initial treatment with closed antibiotic irrigation. Patients with a serum BUN level of less than 40 mg/dl at the time of debridement had a 90% success rate as opposed to a success rate of 38% when the BUN level was 40 mg/dl or greater. The data presented suggest the following conclusions. Early diagnosis is crucial to successful treatment of sternal wound infection. When diagnosis can be established within 20 days, 80% of infections can be eradicated by the simple approach of debridement and closed antibiotic irrigation. When diagnosis is delayed, however, prompt debridement followed by muscle flaps is the procedure of choice. Open granulation alone, while successful, unnecessarily prolongs the hospital course.

Altered gentamicin pharmacokinetics during the perioperative period.

The effect of surgery on the pharmacokinetics of gentamicin sulfate in hospitalized patients was studied. Patients with cancer undergoing surgery of the head and neck were given gentamicin sulfate in doses calculated to achieve peak serum concentrations of 6-8 micrograms/mL and trough concentrations of 1-2 micrograms/mL. Each patient received a loading dose at the time of surgical incision, followed by five maintenance doses at eight-hour intervals. Steady-state peak and trough serum gentamicin concentrations were predicted using a one-compartment open pharmacokinetic model and literature values for volume of distribution (V) and first-order elimination rate constant (k). Serum gentamicin concentrations were measured 0.25 hours before and at 0.5, 3.5, and 6.5 hours after completion of infusion of the second maintenance dose. Peak and trough serum concentrations were obtained by extrapolation from these measured concentrations using weighted, nonlinear least squares regression. Predicted versus measured serum gentamicin concentrations and estimated versus observed values for V and k were compared. Eight men and seven women had evaluable serum gentamicin concentrations. Patients received a mean calculated maintenance dose of 4.4 +/- 0.7 mg/kg/day. Mean extrapolated peak and trough serum gentamicin concentrations were significantly lower than predicted, and observed values of V and k were significantly greater than estimated values. Gentamicin dosages calculated using standard pharmacokinetic variable values may not produce therapeutic concentrations in patients undergoing surgery. Monitoring of serum concentrations with dosage adjustment when indicated is necessary for optimal therapy in these patients.