The impact of emergency department patient-controlled analgesia (PCA) on the incidence of chronic pain following trauma and non-traumatic abdominal pain.

The effect of patient-controlled analgesia during the emergency phase of care on the prevalence of persistent pain is unkown. We studied individuals with traumatic injuries or abdominal pain 6 months after hospital admission via the emergency department using an opportunistic observational study design. This was conducted using postal questionnaires that were sent to participants recruited to the multi-centre pain solutions in the emergency setting study. Patients with prior chronic pain states or opioid use were not studied. Questionnaires included the EQ5D, the Brief Pain Inventory and the Hospital Anxiety and Depression scale. Overall, 141 out of 286 (49% 95%CI 44-56%) patients were included in this follow-up study. Participants presenting with trauma were more likely to develop persistent pain than those presenting with abdominal pain, 45 out of 64 (70%) vs. 24 out of 77 (31%); 95%CI 24-54%, p < 0.001. There were no statistically significant associations between persistent pain and analgesic modality during hospital admission, age or sex. Across both abdominal pain and traumatic injury groups, participants with persistent pain had lower EQ5D mobility scores, worse overall health and higher anxiety and depression scores (p < 0.05). In the abdominal pain group, 13 out of 50 (26%) patients using patient-controlled analgesia developed persistent pain vs. 11 out of 27 (41%) of those with usual treatment; 95%CI for difference (control - patient-controlled analgesia) -8 to 39%, p = 0.183. Acute pain scores at the time of hospital admission were higher in participants who developed persistent pain; 95%CI 0.7-23.6, p = 0.039. For traumatic pain, 25 out of 35 (71%) patients given patient-controlled analgesia developed persistent pain vs. 20 out of 29 (69%) patients with usual treatment; 95%CI -30 to 24%, p = 0.830. Persistent pain is common 6 months after hospital admission, particularly following trauma. The study findings suggest that it may be possible to reduce persistent pain (at least in patients with abdominal pain) by delivering better acute pain management. Further research is needed to confirm this hypothesis.

The cost-effectiveness of patient-controlled analgesia vs. standard care in patients presenting to the Emergency Department in pain, who are subsequently admitted to hospital.

The clinical effectiveness of patient-controlled analgesia has been demonstrated in a variety of settings. However, patient-controlled analgesia is rarely utilised in the Emergency Department. The aim of this study was to compare the cost-effectiveness of patient-controlled analgesia vs. standard care in participants admitted to hospital from the Emergency Department with pain due to traumatic injury or non-traumatic abdominal pain. Pain scores were measured hourly for 12 h using a visual analogue scale. Cost-effectiveness was measured as the additional cost per hour in moderate to severe pain avoided by using patient-controlled analgesia rather than standard care (the incremental cost-effectiveness ratio). Sampling variation was estimated using bootstrap methods and the effects of parameter uncertainty explored in a sensitivity analysis. The cost per hour in moderate or severe pain averted was estimated as £24.77 (€29.05, US$30.80) (bootstrap estimated 95%CI £8.72 to £89.17) for participants suffering pain from traumatic injuries and £15.17 (€17.79, US$18.86) (bootstrap estimate 95%CI £9.03 to £46.00) for participants with non-traumatic abdominal pain. Overall costs were higher with patient-controlled analgesia than standard care in both groups: pain from traumatic injuries incurred an additional £18.58 (€21.79 US$23.10) (95%CI £15.81 to £21.35) per 12 h; and non-traumatic abdominal pain an additional £20.18 (€23.67 US$25.09) (95%CI £19.45 to £20.84) per 12 h.

Ranking animal carcinogens: a proposed regulatory approach.

The nature and extent of positive evidence associated with animal carcinogens vary widely, yet present regulatory policy does not permit adequate discrimination among the many carcinogenic substances. Most are treated as if they pose equal potential risk to humans, and this is not consistent with the available data. Without knowledge of carcinogenic mechanisms, the evaluation of responses in intact mammalian surrogates best reflects the potential levels of human risk. An example of a scoring system is proposed by which animal carcinogens are ranked according to the most relevant toxicological evidence derived from animal and genotoxicity studies. Different classes of animal carcinogens could thus be recognized and would permit several regulatory options and provide a means to establish priorities for public and scientific concerns.

Viral hemorrhagic encephalopathy of rats.

A virus has been isolated and serially passed in suckling rats; it causes an acute fatal paralysis associated with hemorrhage and necrosis in the brain and spinal cord. The agent is relatively resistant to heat and ether, is about 20 millimicrons in diameter, and is antigenically closely related to rat virus. Its isolation resulted from the study of occasional cases of paralysis in adult rats after administration of cyclophosphamide.

13-cis-retinoic acid: inhibition of bladder carcinogenesis in the rat.

Transitional cell and squamous cell cancer of the bladder was induced in Wistar/Lewis female rats by direct instillation of N-methyl-N-nitrosourea into the bladder. Feeding of the synthetic retinoid, 13-cis-retinoid acid, inhibited the incidence and extent of bladder cancer in these rats, even when 13-cis-retinoic acid administration was begun after completion of the carcinogen treatment.

13-cis-Retinoic acid: inhibition of bladder carcinogenesis induced in rats by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Transitional cell carcinoma was induced in the bladders of male Fischer rats by 12 oral doses of the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine. Feeding of 13-cis-retinoic acid after completion of carcinogen treatment diminished the number and severity of cancers and other proliferative lesions of the bladder.

Pathology of esophageal neoplasms and associated proliferative lesions induced in rats by N-methyl-N-benzylnitrosamine.

Multiple squamous cell neoplasms of the esophagus were induced in 24 inbred F344 rats by sc injection of N-methyl-N-benzylnitrosamine at a dose level of 2.5 mg/kg weekly for 20 weeks. All of these rats also developed papillomas, 67% developed pedunculated papillary carcinomas, and 63% developed carcinomas that invaded the wall. Of 191 total neoplasms, 66% were papillomas, 17% were papillary carcinomas, and 17% were carcinomas that invaded the wall. The neoplasms were well differentiated with various degrees of keratinization. Anaplastic areas were found in most lesions, but were more common in carcinomas. Neoplasms that invaded the wall were sessile, with prominent intraluminal growth, or infiltrating, with predominant intramural growth. Penetration through the wall was observed, but neither metastases nor invasion of adjacent tissues was found. In addition to neoplasms, atypical endophytic proliferation of basal and spinous cells was observed in some of these rats. Proliferative or neoplastic changes were not observed outside the upper gastrointestinal tract.

Experimental pancreatic carcinogenesis. II. Lifetime carcinogenesis studies in the outbred Syrian golden hamster with N-nitroso-bis(2-hydroxypropyl)amine.

A high incidence of pancreatic duct neoplasms was induced in outbred male Syrian golden hamsters following weekly sc injection of N-nitroso-bis(2-hydroxypropyl)amine for life. The first such tumors appeared as early as 16 experimental weeks; the maximum incidence reached 100% by the termination of the study. Tumors in the respiratory tracts and angiosarcomas of the livers of the hamsters were also observed in high frequency. Latency of the induced neoplasms was significantly decreased by the substitution of distilled water for olive oil as the vehicle for the carcinogen.

Neoplastic and nonneoplastic lesions in aging (C57BL/6N x C3H/HeN)F1 (B6C3F1) mice.

Neoplastic and nonneoplastic lesions in untreated (C57BL/6N x C3H/HeN)F1 (B6C3F1) mice used as controls in carcinogenesis tests were tabulated and evaluated. The most common neoplasms in 2,543 male mice were hepatocellular adenomas and carcinomas. In 2,522 female mice, common tumors were lymphomas, leukemias, pulmonary adenomas and carcinomas, hepatocellular adenomas and carcinomas, and pituitary adenomas. The risk of developing most neoplasms increased with the age of the mouse. Hepatocellular carcinomas metastasized in 12% of the animals with these tumors. Other than lymphomas and leukemias, few other tumors metastasized. Nonneoplastic lesions included cystic hyperplasia of the uterus, nephritis, ovarian and uterine cysts, inflammatory lesions of the lung, mineralization in the brain, and focal hyperplasias in several tissues. The focal hyperplasias in lung and pituitary, adrenal, and thyroid glands were suggestive of the early stages of neoplasia. Comparative aspects of lesions in aging mice and their interpretation in carcinogenesis tests are discussed.

A carcinogenicity assay of Mirex in Charles River CD rats.

The long-term administration of 50 and 100 ppm of Mirex in the diets of male and female Charles River CD rats was associated with a spectrum of liver lesions, from foci or areas of cellular alteration and neoplastic nodules to hepatocellular carcinoma. Statistically significant numbers of neoplastic nodules were observed in the livers of male rats receiving the high dose. Neoplastic nodules and hepatocellular carcinomas were not observed in control rats.

Induction of liver tumor in Sherman strain female rats by polychlorinated biphenyl aroclor 1260.

Sherman strain female rats (200) were fed 100 ppm of polychlorinated biphenyl (Aroclor 1260) for apporximately 21 months, and 200 female rats were kept as controls. The rats were killed when 23 months old. Twenty-six of 184 experimental animals and 1 of 173 controls had hepatocellular carcinomas. None of the controls but 146 of 184 experimental rats had neoplastic nodules in their livers, and areas of hepatocellular alteration were noted in 28 of 173 controls and 182 of 184 experimental animals. Thus the polychlorinated biphenyl Aroclor 1260, when fed in the diet, had a hepatocarcinogenic effect in these rats. The incidence of tumors in other organs did not differ appreciably between the experimental and control groups.

Specific radioimmunotherapy using 90Y-labeled monoclonal antibody in erythroleukemic mice.

Radioimmunotherapy using 90Y-labeled diethylenetriamine pentaacetic acid-antibody conjugates was studied in Rauscher erythroleukemia virus-infected mice. Preliminary experiments showed that biodistribution profiles for nonrelevant mouse monoclonal antibody and polyclonal bovine immunoglobulin were identical in both normal and leukemic mice. Therefore, bovine immunoglobulin G was selected as the control immunoglobulin in order to permit comparison to current clinical trials of radioimmunotherapy regimens. Specific monoclonal antibody was two- to three-fold more potent than bovine immunoglobulin G in therapy, as assessed by reduction of splenomegaly (dose required for half-maximal effect, 9 microCi versus 16 to 27 microCi). Mice treated with 50 microCi 90Y-labeled control immunoglobulin had spleens which were twice the normal size and showed extensive areas of erythropoiesis indicative of the presence of tumor foci; in contrast, doses as low as 27 microCi 90Y-labeled specific antibody resulted in complete remission with no microscopic evidence of tumor foci in either spleen or liver. Although reversible marrow toxicity was observed it was not dose limiting. These results demonstrate that tumor-specific therapy is possible using 90Y-labeled antibody.

Effective alpha-particle-mediated radioimmunotherapy of murine leukemia.

The specificity, toxicity, and efficacy of alpha-particle-mediated radioimmunotherapy of murine erythroleukemia was assessed by use of tumor-specific monoclonal antibody 103A labeled with 212Bi. Forty % of the injected dose/g tissue targeted to neoplastic spleens within 1 h after i.v. injection. When 212Bi-103A was injected on day 13 of disease, a dose-dependent response was achieved, as measured by a reduction in splenomegaly and absence of liver metastasis. Mice treated with 212Bi-103A on day 8 of disease showed no histological evidence of erythroleukemia on day 22 and survived significantly longer (median, 118 days) than mice treated with 212Bi-control IgG (78 days) or untreated mice (63 days), indicating successful specific radioimmunotherapy.

Histopathological evaluation of the inhibition of rat bladder carcinogenesis by 13-cis-retinoic acid.

An objective system for histopathological and statistical evaluation of rat bladder lesions induced by the carcinogen, N-methyl-N-nitrosourea, is described. This system has been used to measure the inhibitory effects of 13-cis-retinoic acid on the development of bladder cancer in female Wistar/Lewis rats. 13-cis-Retinoic acid caused significant inhibition of development of both preneoplastic and neoplastic lesions in bladder epithelium.

Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model.

Cohorts of 4- to 5-wk-old female Fischer 344 rats received four biweekly 1.5-mg doses of N-methyl-N-nitrosourea (MNU) intravesically and were sacrificed at various intervals. By 13 wk after initiation of the carcinogen, all animals have flat epithelial atypia and/or papillary transitional cell bladder carcinomas, and 67% of the lesions are histological Grade II or III. By 20 wk, 83% have gross bladder wall muscle-invasive tumors that eventually kill the host. There was no gross evidence of visceral metastases in any animal. This rat model of transitional cell carcinoma of the bladder is useful because: (a) all animals develop progressive neoplastic changes in situ within 4 mo after initiation of MNU treatment; (b) these lesions progress to grossly detectable bladder tumors which invade the bladder wall and kill the host; (c) this full progression of bladder epithelial cells from atypical hyperplasia through flat carcinoma in situ to transitional cell carcinoma occurs at discrete time points; (d) the histology of the grossly detectable tumors is that of invasive transitional cell carcinomas; and (e) no leukemias, breast cancers, lymphomas, or other non-bladder tumors are induced. Six MNU-induced bladder wall-invasive tumors were karyotyped, and all tumors were diploid with 42 chromosomes. Three of the tumors had apparently normal karyotypes, while three tumors had karyotypes containing one or more cytogenetic structural markers. One of these markers (i.e., 8p+) was observed in two of the three tumors. The level of expression of total ras p21 (N-, Ki-, and Ha-ras p21) and codon 12-mutated c-Ha-ras p21 (i.e., glycine to glutamic acid mutation in codon 12) in a series of these MNU-induced bladder tumors was determined by Western blot analysis. No increase in the total ras p21 nor any expression of codon 12-mutated c-Ha-ras p21 was detected in any of these tumors.

Long-term effect of 2-hydroxyethyl retinamide on urinary bladder carcinogenesis and tumor transplantation in Fischer 344 rats.

The effects of HER upon early and late stages of BBN-induced bladder cancer in rats were examined. Female Fischer 344 rats were administered HER in the diet either before and during or continuously after BBN administration and were monitored periodically for up to 2 years. The total dose of BBN was 600 mg administered over a 6-week period. In a separate experiment, the effects of HER administration to syngeneic recipients of a transplanted primary bladder cancer were examined. No effects on neoplastic development were observed as the result of HER treatment before and during carcinogen administration. However, at the 1-year sacrifice, there was a significant increase in bladder tumor incidence in the animals receiving BBN followed by continuous retinoid treatment versus animals receiving BBN only. At the 2-year sacrifice, there was a significant increase in tumor progression in the continuous retinoid group versus the animals receiving BBN alone, based upon grading and staging of tumors, although tumor incidences were not significantly different. In the transplantation experiment, more recipients (9/20 versus 2/20) receiving continuous HER had large, anaplastic tumors following 9 months of observation than did control animals. This study supports the view that retinoids should not be considered as only inhibitors of carcinogenesis, but rather as modifiers which vary in their effects depending upon factors yet to be understood.

Inhibitory effect of 13-cis-retinoic acid on urinary bladder carcinogenesis induced in C57BL/6 mice by N-butyl-N-(4-hydroxybutyl)-nitrosamine.

The effect of 13-cis-retinoic acid on the induction of urinary bladder carcinoma by N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) was studied in male C57BL/6 mice. Animals received a total dose of either 90 or 140 mg of OH-BBN via gastric intubations of 7.5 or 10.0 mg of OH-BBN 2 times each week for 6 or 7 weeks, respectively. Seven days after the last OH-BBN intubation, animals were fed laboratory chow diet supplemented with either 200 mg of 13-cis-retinoic acid per kg or its placebo. Animals were killed at 6 months after the first carcinogen intubation. Highly invasive squamous and transitional cell carcinomas of the urothelium were found at autopsy. In the majority of these carcinomas, invasion of the bladder muscle wall by tumor cells had occurred. At the two dose levels of OH-BBN, feeding of 13-cis-retinoic acid reduced the incidence of both carcinomas and noninvasive papillomas, as well as the extent of neoplastic development in the urinary bladder. In mice receiving the lower dose of OH-BBN, the feeding of 13-cis-retinoic acid prevented the appearance of both squamous and transitional cell carcinomas with a reduction in incidence from 33 to 0% (p less than 0.01). The results of this study indicate that 13-cis-retinoic acid reduced not only the severity of highly invasive urinary bladder carcinomas but also the incidence of such cancers.

Direct effects of colchicine on myocardial function: studies in hypertrophied and failing spontaneously hypertensive rats.

-The aging spontaneously hypertensive rat (SHR) is a model in which the transition from chronic stable left ventricular hypertrophy to overt heart failure can be observed. Although the mechanisms for impaired function in hypertrophied and failing cardiac muscle from the SHR have been studied, none accounts fully for the myocardial contractile abnormalities. The cardiac cytoskeleton has been implicated as a possible cause for myocardial dysfunction. If an increase in microtubules contributes to dysfunction, then myocardial microtubule disruption by colchicine should promote an improvement in cardiac performance. We studied the active and passive properties of isolated left ventricular papillary muscles from 18- to 24-month-old SHR with evidence of heart failure (SHR-F, n=6), age-matched SHR without heart failure (SHR-NF, n=6), and age-matched normotensive Wistar-Kyoto rats (WKY, n=5). Mechanical parameters were analyzed before and up to 90 minutes after the addition of colchicine (10(-5), 10(-4), and 10(-3) mol/L). In the baseline state, active tension (AT) developed by papillary muscles from the WKY group was greater than for SHR-NF and SHR-F groups (WKY 5.69+/-1.47 g/mm2 [mean+/-SD], SHR-NF 3.41+/-1.05, SHR-F 2.87+/-0.26; SHR-NF and SHR-F P<0.05 versus WKY rats). The passive stiffness was greater in SHR-F than in the WKY and SHR-NF groups (central segment exponential stiffness constant, Kcs: SHR-F 70+/-25, SHR-NF 44+/-17, WKY 41+/-13 [mean+/-SD]; SHR-F P<0.05 versus SHR-NF and WKY rats). AT did not improve after 10, 20, and 30 minutes of exposure to colchicine (10(-5), 10(-4), and 10(-3) mol/L) in any group. In the SHR-F group, AT and passive stiffness did not change after 30 to 90 minutes of colchicine exposure (10(-4) mol/L). In summary, the data in this study fail to demonstrate improvement of intrinsic muscle function in SHR with heart failure after colchicine. Thus, in the SHR there is no evidence that colchicine-induced cardiac microtubular depolymerization affects the active or passive properties of hypertrophied or failing left ventricular myocardium.