Adult education program in palliative care for nursing facility physicians: design and pilot test.

Nursing facilities (NF) are important sites for the care of dying patients. Curricula likely to improve end-of-life care are needed for NF physicians. To this end, a model medical school palliative care curriculum was modified for experienced NF physicians. Adult learning techniques were emphasized, as well as interactions likely to change physician behavior. Inclusion of the opinion leader, audit with feedback, use of consensus guidelines, and other techniques for changing physician behavior were included. Written materials to supplement the course were identified. This new program was pilot tested and improved. An initial audit of physician practices and survey of the NF staff, a half-day adult educational session, and follow-up with the NF medical director is suggested. This intervention should be tested to determine if it improves patient end-of-life care outcomes in this setting.

Risk factors for noncompliance in a colposcopy clinic.

OBJECTIVE: To evaluate demographic characteristics as risk factors for noncompliance with colposcopy clinic follow-up. STUDY DESIGN: A retrospective, case-control study was performed on patients evaluated in the Women & Infants' Hospital colposcopy clinic between January 1, 1992, and December 31, 1993. Data extracted from chart review included demographic characteristics, insurance status, smoking status, cytologic and histologic grade treatment received, number of appointments kept and missed, number of attempts to contact the patient and degree of compliance with colposcopy follow-up. A scoring system was created to assess a patient's level of compliance by evaluating the number of appointments kept and missed. RESULTS: After review of the first 80 patients, a noncompliance rate of 23% was determined based on our scoring system. A total of 86 noncompliant patients were then compared to 93 compliant patients. Women who were noncompliant with follow-up were more likely to be on Medicaid or to have no insurance when compared to compliant patients (odds ratio [OR] = 2.4, confidence interval [CI] .85, 6.7), but this difference did not reach statistical significance (P = .07). Noncompliant patients were less likely to have high grade lesions than compliant patients (OR = .34; CI .13, .85; P = .01). CONCLUSION: Patients with lower grade lesions may be more likely to be noncompliant with recommended follow-up than patients with high grade lesions. This association may be due to a reduced emphasis on follow-up and patient education in women with low grade lesions. Increased educational efforts should be made to attempt to reduce high rates of noncompliance in this group of women.

Educational program in palliative and hospice care at the University of Maryland School of Medicine.

BACKGROUND: The objective of this enterprise was and is to develop a validatable educational program on palliative and hospice care with a multidisciplinary perspective for the University of Maryland School of Medicine. METHODS: An interdisciplinary education committee consisting of experts in palliative and hospice care and an expert in educational design and evaluation was established to develop the program. Program development, which is ongoing, includes a comprehensive instructional design phase, vertical integration of the program into the medical school curriculum, and outcome evaluation. RESULTS: The instructional design phase has been accomplished; hence, the focus of this paper is on this aspect of program development. In addition, some integration of specific content areas into the medical school curriculum has been implemented. CONCLUSIONS: When complete, the program will focus on developing skills and knowledge using a variety of interactive educational modalities, including problem-based learning, case study discussions, role playing, and practical experience at hospice and palliative care sites. Topics to be covered are symptom control, the compassionate approach to patient care, communication between physicians and patients or family members, professional collaboration on a multidisciplinary palliative care team, ethical and legal issues pertaining to end-of-life care, and the value of palliative medicine as a profession.

Anaesthesia by intravenous emulsified isoflurane in mice.

An emulsion of isoflurane in Intralipid for intravenous (iv) injection was formulated and its anaesthetic properties determined in mice. The major advantage of iv delivery of volatile agents is to accelerate the induction of anaesthesia by circumventing the anesthetic circuitry and the lung's functional residual capacity. Isoflurane was added to Intralipid in varying concentrations. The ED50 (n = 34) and LD50 (n = 20) were determined by a single iv bolus injection. Anaesthesia was also induced and maintained for 30 min (n = 5) by continuous infusion and the time to emergence was measured. The ED50 and LD50 were 0.7 +/- 0.2 microliter and 2.4 +/- 0.2 microliter of isoflurane equivalent respectively. An average infusion rate of 1.6 +/- 0.4 microliters.min-1 of isoflurane equivalent was required for maintenance following which the average emergence time was 193 +/- 35 secs. The only negative effect was local skin ulceration with an inadvertent interstitial injection. We conclude that iv induction and maintenance with emulsified isoflurane in Intralipid can be carried out with safety and reproducibility in the mouse. Further larger animal studies are warranted assessing the haemodynamic, toxicological, physiochemical and pharmacokinetic characteristics of these and other similar preparations.

Brock transventricular pulmonary valvotomy in patients with pulmonary stenosis: long-term results.

As no long-term results of a blind opening up of the pulmonary valve either by balloon valvoplasty or closed Brock valvotomy have been published, we examined the outcome of 12 patients with valvar pulmonary stenosis 17 +/- 5 (11-22) years after surgery. The Brock valvotomy had been carried out at a mean age of 3 +/- 2.8 (0.2-8.5) years. The mean pressure gradient across the right ventricular outflow tract had been 116 +/- 45 (75-97) mmHg at the catheter study or 106 +/- 43 (40-160) mmHg as measured intraoperatively. The right ventricular pressure after the Brock procedure was measured in the operating room in five patients as 46 +/- 15 (30-60) mmHg. Seven patients had been recatheterized at a mean age of 9.5 +/- 2 (7-12.7) years; at that time the gradient across the pulmonary valve had been 20 +/- 14 (10-37) mmHg. At a mean age of 21.7 +/- 3 (15-26) years these and five further patients were reexamined by echo Doppler. This time the pressure gradient across the pulmonary valve was 13 +/- 6 (7-20) mmHg. Moderate pulmonary incompetence was present in four and mild incompetence in eight patients; two had mild tricuspid insufficiency. All except one patient, who had suffered a cerebrovascular accident before surgery, were in NYHA functional class 1 and pursuing a profession. From these data we conclude that the blind opening-up of the pulmonary valve achieves excellent long-term palliation.

Kinetic model for the biodistribution of an 111In-labeled monoclonal antibody in humans.

Using data from 12 patients, we have analyzed the pharmacokinetics of 111In-9.2.27, an antimelanoma monoclonal antibody, following i.v. infusion. Plasma data and scintillation camera images obtained from patients receiving either 1, 50, or 100 mg of monoclonal antibody indicated dose-dependent (i.e., saturable) kinetics. Based on these observations and known immunoglobulin kinetics, we developed a nonlinear compartmental model to describe the biodistribution of 111In-9.2.27 and the other coinjected 111In-associated compounds. The model included (a) three compartments representing intact 111In-9.2.27 ("plasma," "nonsaturable," and "saturable binding" compartments), (b) four compartments representing 111In-diethylenetriaminepentaacetic acid, and (c) one compartment representing 111In in an undetermined chemical form ("extravascular delay" compartment). Analysis of the rate of urinary excretion relative to plasma concentration indicated that the saturable binding compartment was a site for catabolism of monoclonal antibody. Further examination of the urinary data, together with previous studies of the site(s) of immunoglobulin catabolism, suggested that additional elimination took place from either the plasma or the nonsaturable compartment. The model indicated that to fill the saturable sites would require a dose of approximately 0.5 mg and suggested that greater than 3.5 mg would maintain saturation for 200 h. Computer integration of gamma camera counts over the spleen revealed a clear saturable component of uptake, whereas integration over the liver showed no such pattern. The proposed model was fitted to the liver and spleen imaging data by summing fractions of model simulations of each compartment. That analysis confirmed the suspected saturable uptake by the spleen (21% of the saturable binding compartment) and revealed a quantitatively important component of saturation in the liver (35% of the saturable binding compartment) that was not obvious from initial examination of the images. When the results were expressed on a concentration basis, the spleen accounted for 247% of the saturable compartment per kg, whereas the liver accounted for 25%/kg. The bone marrow also showed saturable uptake; hence, the saturable uptake may relate to the sinusoidal blood supply characteristic of liver, spleen, and marrow. The model predicts the dose levels required to overcome saturable background, suggests appropriate doses and schedules for cold loading strategies, and provides a format for explicit inclusion of tumor antigen.

Monoclonal antibody imaging of human melanoma. Radioimmunodetection by subcutaneous or systemic injection.

Fab fragments of monoclonal antibodies (MoAb) to melanoma, radiolabeled with 131I, were evaluated as diagnostic reagents to determine their ability to localize systemic--MoAb injected intravenously (IV)--or nodal metastatic disease--injected subcutaneously (SQ) at a site proximal to draining lymph nodes. Sixty-one scans were performed (40 IV, 21 SQ) in 59 patients who had injections of 0.2-50 mg of 131I coupled (0.2-12 mCi) antibody. These included 48.7, which identifies a high molecular weight antigen (HMW), or 96.5, which identifies a transferrin like molecule, p97. 125I coupled nonspecific Fab 1.4, reacting with murine leukemia virus, or the whole antibody BL3, reactive with a human B cell idiotypic determinant, was generally used in tandem with the patients injected SQ as a nonspecific control. All patients had immunohistochemical studies performed on biopsied lesions and demonstrated binding to the antibodies injected. Of the IV patients, 22/38 (58%) had (+) scans, 13 at SQ or nodal sites, four at visceral sites, and five at visceral and SQ sites. Patients with clinical stage II disease had SQ injection of MoAb, including 11 additional patients injected with the whole antibody 9.2.27 (anti-HMW) labeled with 111In (6 patients) or 131I (5 patients). Nodal dissection was performed 2-4 days later. All 111In coupled antibodies demonstrated excellent nodal delineation without specific identification of tumor deposits. Of the 21 patients injected SQ with MoAb, 17 had confirmed tumor in nodes. Of patients injected with Fab fragments, 4/8 (50%) had specific uptake of MoAb, although only two were successfully imaged. Increased uptake of antimelanoma antibodies was observed in some patients in lymph nodes not containing tumor and was possibly related to antigen shedding. Clearance of labeled antibody from the injection site occurred with a half life of 16-50 hours. Toxicity was limited to local discomfort at the site of SQ injection. Melanoma metastases can be identified with IV or SQ injection or radiolabeled antibodies. These reagents may be useful in the diagnosis or therapy of human melanoma. Further evaluation will be required before they could be considered clinically useful.

Nitrous oxide does not hinder the repair of halothane-induced hepatic injury in the rat.

Nitrous oxide administration may limit DNA synthesis by inactivating methionine synthetase, and may thus hamper the repair of an injured organ such as the liver. To test this possibility, we pretreated rats with phenobarbital and exposed them to 0.3 MAC halothane in 9% oxygen for 46 min, followed immediately and again 24 hr later by 70% nitrous oxide (0.25 MAC) at an FIO2 of 0.30 for 2 hr. The results from this group were compared with an anesthetic control group in which 0.35% isoflurane (0.25 MAC) was substituted for the nitrous oxide. Additional groups were given a third exposure to nitrous oxide or isoflurane 48 hr after the halothane exposure. All rats were killed 24 hr after their last anesthetic exposure. A second (nonanesthetic) control group of phenobarbital-pretreated rats received 0.3 MAC halothane in 9% oxygen for 46 min and no anesthetic thereafter. They were killed 24, 48, or 72 hr later. Histologic changes in the livers of rats did not differ among the groups given nitrous oxide, isoflurane, or no additional anesthetic after exposure to halothane alone. Thus neither nitrous oxide nor isoflurane appears to hinder the repair of hepatic injury produced by halothane in the hypoxic rat model.

Nitrous oxide, too, is hepatotoxic in rats.

Anesthetic hepatotoxicity was tested under various conditions of hypoxia in rats pretreated with phenobarbital. Administration of 0.3 MAC halothane or fentanyl in 9% oxygen (fractional concentration of inspired oxygen = 0.09) for 46 min produced centrilobular hepatic injury in all rats (P less than 0.001 vs all other groups). Isoflurane, nitrous oxide, and thiopental at 0.3 MAC did not produce hepatic injury greater than that produced in control rats given 9% oxygen, nor was significant injury produced in control phenobarbital-pretreated rats who breathed 6 or 7.5% oxygen for 46 min. With an inspired oxygen concentration of 7.5%, hepatic injury occurred after exposure to 92.5% nitrous oxide (P less than 0.05), but not after enflurane, isoflurane, or thiopental. When hypoxia associated with 9% oxygen was extended to 2 hr, 91% nitrous oxide produced significant injury (P less than 0.001 compared with the controls), while enflurane, isoflurane, and thiopental did not. These and previous results suggest that all anesthetics can produce liver injury in the hypoxic rat model and that the ranking of hepatotoxicity (most to least) may be halothane, fentanyl, nitrous oxide, enflurane = isoflurane = thiopental.

Brief periods of hypoxia can produce hepatic injury in rats.

To determine whether brief periods of hypoxia could produce hepatic injury, we pretreated Sprague-Dawley rats with phenobarbital, deprived them of food for 24 hr, and then exposed them to various hypoxic mixtures of nitrogen and oxygen for various lengths of time. Rats exposed to 6% oxygen for 15 or more minutes had centrilobular injury, the severity of which was directly related to the length of exposure (r = 0.71). Extrapolation of these data indicated that no injury would occur if exposures were less than 5 min. Experiments using lower concentrations of oxygen did not reveal hepatic injury, probably because death of the animals occurred before the appearance of detectable injury of the liver. Feeding animals before imposition of hypoxia markedly decreased the risk of hepatic injury. Whether patients who are deprived of food preoperatively and whose liver enzymes are induced incur an increased risk of hepatic injury from brief periods of hypoxia remains to be determined.

Isoflurane does not prevent hepatic injury produced by halothane in rats.

We speculated that the inhibitory effect of isoflurane on the metabolism of halothane might reduce hepatic injury produced by halothane. To test this hypothesis we pretreated male rats with phenobarbital and 24 hr later exposed them to one of three types of anesthesia. One group of rats was anesthetized with 0.6 MAC isoflurane in 21-25% oxygen for 20 min, followed by exposure to 0.3 MAC isoflurane and 0.3 MAC halothane either in 9% oxygen for 46 min (n = 5) or in 12% oxygen for 60 min (n = 11). A second group of rats received 0.3 MAC halothane in 9% oxygen for either 46 min (n = 12) or in 12% oxygen for 60 min (n = 10). The third group received 0.3 MAC isoflurane in 9% oxygen for either 46 min (n = 12) or for 120 min (n = 8). The rats were killed 24 hr after the exposures and liver slides prepared. Histologic examination revealed that rats treated with isoflurane plus halothane, or with halothane alone showed a significant hepatic injury (P less than 0.005) when compared with those treated with isoflurane. Thus isoflurane failed to protect the liver from halothane-induced injury.

Two-factor requirement for murine megakaryocyte colony formation.

WEHI-3 cell-conditioned medium with the capacity to stimulate megakaryocyte colony formation was separated by Sephadex G-150 column chromatography. The development of colonies containing megakaryocytes was observed only when mixing experiments were performed. Individual fractions did not support megakaryocyte colony growth. The two factors in WEHI-3 CM required for megakaryocyte colony growth had apparent average molecular weights of 35,000 daltons (megakaryocyte CSF) and 100,000 daltons (megakaryocyte potentiator). The results were confirmed in serum-free conditions in which colonies were directly identified in the cultures by acetylcholinesterase staining. Two growth factors may be necessary for the genesis of megakaryocytic colonies.

Long-term in vitro culture of murine mast cells. II. Purification of a mast cell growth factor and its dissociation from TCGF.

Procedures are described for the isolation of a mast cell growth factor (MCGF) from medium conditioned by mitogen-activated splenic leukocytes (CM). Although optimal conditions for the production of MCGF in CM are identical to those for the production of T cell growth factor (TCGF), MCGF can be dissociated from TCGF after the first stage of purification on a DEAE-cellulose column. MCGF elutes from the column in the breakthrough fraction, whereas TCGF binds avidly to DEAE and is eluted only at high salt concentration. MCGF also differs from TCGF with respect to m.w. (as estimated by Sephadex G-150 chromatography) and sensitivity to trypsin. In addition, MCGF is produced by the murine myelomonocytic leukemia WEHI-3 and the radiation induced thymic lymphoma LBRM-33 cells, whereas TCGF is produced only by the latter in the presence of a mitogen. Another hemopoietically active factor, granulocyte colony-stimulating factor (G-CSF) present in media conditioned by WEHI-3 and LBRM-33 cells, however, shares a number of properties with MCGF. Although studies with purified or partially purified MCGF have thus far failed to reveal a correlation between MCGF and G-CSF, further biochemical analyses are necessary to dissociate MCGF from G-CSF.

Characterization of a temperature-sensitive membrane alteration in chick embryo fibroblasts infected with a temperature-sensitive mutant of Rous sarcoma virus.

The intramembrane particles of freeze-fractured chick embryo fibroblasts transformed with a temperature-sensitive mutant of Rous sarcoma virus (TS68) are distributed differently at the permissive and non-permissive temperatures if, and only if, the cells are treated with glycerol before fixation. Few aggregates of intramembrane particles are present in glycerol-treated cells grown at the permissive temperature for transformation (36 degrees C), while numerous large aggregates of particles are present at the non-permissive temperature (41 degrees C). Changes in the distribution of particles after cells are shifted from 36 to 41 degrees C are observed after 20 min, while a temperature shift from 41 to 26 degrees C causes changes in glycerol-induced redistributions after 1 h. The changes observed in temperature shifts from 36 to 41 degrees C and from 41 to 36 degrees D do not require protein synthesis or RNA synthesis.