A longitudinal study of pain in hospice and pre-hospice patients.

Pain continues to be a very formidable foe in the care of the hospice patient. The incidence among hospice admissions may range from 50 to 80 percent. With such a high initial incidence of pain, the rapidity with which pain can be controlled becomes a very high priority for the hospice effort. The assessment and management of pain in a home-based hospice program presents some unique problems--and opportunities, in that much of this work is done by hospice nurses on site, rather than by the physician, who might remain quite removed from the process. In the study described below, 250 consecutive admissions to either a hospice, or pre-hospice (bridge) program were assessed for pain on admission. Those with pain scores of 5 or greater (on a 1 to 10 scale) were followed daily for 15 days by phone to reassess pain and treatment effects. Of the 250 consecutive patients surveyed, 41 (16 percent) gave pain scores of 5 or greater. Mean pain scores for the 41 patients dropped to < 5 within 24 hours of admission.

A pilot program to evaluate pain assessment skills of hospice nurses.

A program was developed to evaluate pain assessment skills of hospice nurses in the home setting, utilizing standardized patients (SPs). Hospice nurses were sent on a routine visit to a "patient's" home to evaluate someone dying of pancreatic cancer. They were not informed in advance that the "patient" was actually an SP, who had undergone intensive training from the staff to prepare him for his role. They performed their usual evaluation and then reported back to the referring physician by telephone. The referring physician, who used a written series of evaluation criteria, graded their assessments. The SP also evaluated the assessment skills of each nurse. After the exercise, the nurses were informed of the "patient's" identity and were provided with the written critique prepared by the SP. A second part of the program included a written examination of their pain assessment and treatment skills, followed by a didactic presentation. This is the first report we know of that has utilized SPs in the home setting to evaluate pain assessment skills in a blind fashion. Our findings indicate that this can be an effective method for measuring pain assessment skills as well as a valuable teaching device.

Aurin tricarboxylic acid inhibits adhesion of platelets to subendothelium.

Aurin-tricarboxylic acid (ATA) is a polycarboxylated compound which binds to high molecular weight multimers of von Willebrand factor (vWf), effectively preventing binding of vWf to platelet membrane GPIb. By this mechanism, ATA inhibits shear-induced platelet aggregation as well as ristocetin-induced platelet aggregation/agglutination, both of which require interaction of platelets and vWf. Although it is reasonable to assume that ATA might also interfere with platelet adhesion, the effects of ATA on this aspect of platelet function have not been described. We report effects of ATA on adhesion of freshly prepared radiolabeled platelets to subendothelium of everted rabbit aorta utilizing a model which permits observations at varying shear rates. Using concentrations of ATA that inhibited aggregation induced by either ristocetin or the more potent agonist, thrombin, ATA was found to inhibit adhesion of platelets in a dose-dependent manner. In addition, ATA was found to inhibit platelet aggregation in response to the agonists ristocetin or thrombin. The inhibitory effect of ATA on thrombin-induced aggregation was completely erased by washing and resuspension in a thrombin-free medium, indicating that ATA does not have any lasting effects on the platelet response to thrombin. In plasma coagulation tests, using either the prothrombin time, activated partial thromboplastin time of thrombin time, ATA prolonged clotting times in a dose-dependent manner.

Influence of type of exchange fluid on survival in therapeutic apheresis for thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a potentially lethal disease that may respond favorably to plasma infusion or therapeutic plasma exchange (TPE) with frozen plasma (FP) as the exchange fluid. Frozen plasma from which the cryo-precipitated fraction has been removed (cryopoor plasma, CP) has reportedly been useful in refractory cases in which a response to FP is not being observed. We report a retrospective analysis of all cases of TTP treated by TPE with either FP (1985-1989) or CP (1989-1993) as exchange fluid at a large tertiary care hospital between the years 1985 and 1993. A severity score index was compiled for each patient using the platelet count, mental status, hematocrit, and renal function at the time of diagnosis. Nineteen patients were treated with FP (group 1) and 18 patients with CP (group 2). Groups did not differ in age, gender, race, hematologic parameters, or severity scores. Patients treated with CP, however, had more plasma exchange (14 +/- 10 vs. 12 +/- 8, respectively) and more fluid exchanged than these treated with FP (50 L +/- 36 vs. 37 L +/- 40, respectively). Survival was 72% in the CP group and 47% in the FP group. Although a survival advantage for the use of CP as exchange fluid in the treatment of TTP is suggested by our observations, the retrospective nature of the study, lack of randomization, and sequential rather than concurrent use of FP and CP indicates caution in interpretation. The data do indicate, however, that use of CP is acceptable as the initial exchange fluid in TTP.

Platelet microvesicles adhere to subendothelium and promote adhesion of platelets.

A role in hemostasis has been suggested for platelet membrane microvesicles (mv). The objectives of the studies reported here include functional analysis of platelet mv in models developed for study of platelet adhesion, as well as investigation of possible interactions between mv and intact platelets in these same adhesion models. Microvesicles were prepared from washed platelet concentrates by repeated freezing and thawing. Adhesion to subendothelium was measured quantitatively by radiolabelling mv with 111-In, and morphologically by scanning electron microscopy. Platelet mv adhered to subendothelium quantitatively over time. Using a modified Baumgartner chamber, we found adhesion of mv to subendothelium significantly increased with increasing shear rates. With this same model we found that prior exposure of subendothelium to mv greatly increased subsequent adhesion of platelets to the same everted vessel, compared to platelet adhesion in the absence of mv. All of these experiments were conducted with mv suspended in ACD/saline, indicating that plasma components are not essential for adhesion of mv. Our studies show that platelet mv adhere to subendothelium in much the same way as do platelets, and support the concept of a hemostatic role for mv in that they appear to increase platelet adhesion.

Effects of ionic and nonionic radiographic contrast agents on endothelial cells in vitro.

Intravenous administration of radiographic contrast agents results in the occasional occurrence of thrombotic complications, which are more common after the use of ionic agents than nonionic agents. To investigate the pathophysiologic basis of this thrombotic tendency, we compared the effects of ionic and nonionic contrast agents on endothelial cells in vitro. Exposure of cultured human umbilical vein endothelial cells to ionic contrast medium for 10 minutes resulted in lifting of 76% +/- 8% of cells, significantly greater than that after exposure to nonionic medium (6% +/- 4%; p less than 0.005). A modified Baumgartner chamber was used to evaluate the effects of contrast agents on adhesion of platelets in anticoagulated whole blood to everted segments of fresh or stored deendothelialized rabbit aorta segments. Exposure of fresh vessels to ionic contrast medium led to a significant increase in platelet adhesion (31% +/- 7%; p less than .01), whereas the increase was smaller after exposure to nonionic contrast medium (25% +/- 3%). Platelet adhesion to stored vessels (41% +/- 4%) was significantly greater than adhesion to fresh aorta segments (15% +/- 2%; p less than 0.001), and contrast agents did not further increase adhesion. Microscopic examination of perfused aorta segments exposed to ionic contrast medium showed platelet adherence to intact endothelial cells, a phenomenon that did not occur without prior exposure of fresh aorta segments to ionic contrast medium. These findings demonstrate that exposure of endothelial cells to ionic contrast medium results in marked changes in cell viability and adhesive properties that may contribute to their thrombotic potential.

Dietary fish lipids do not diminish platelet adhesion to subendothelium.

Clinical trials suggest that dietary fish lipids offer protection against pathologic thrombosis. Measurements of platelet aggregation and bleeding time indicate that these protective effects are mediated in part through alterations of platelet function. We studied the effects of supplementary fish lipids (MaxEPA) on platelet adhesion to arterial subendothelium utilizing a modified Baumgartner flow chamber. Template bleeding times were also performed, and platelet lipid composition was determined by gas chromatographic analysis. The results showed that platelet lipid composition was altered significantly during the study. However, total platelet adhesion to arterial subendothelium was not changed by ingestion of fish lipids during the study period. Bleeding times showed some prolongation in most subjects (range: -1.0 to +6.75 min), with a mean change of +0.75 min. We conclude that, in individuals maintained on ad libitum diets, the supplemental amount of fish oil used in this study was enough to induce a significant alteration in platelet lipid composition, but these changes were unaccompanied by any impairment in the ability of platelets to adhere to subendothelium in our model system.

Effectiveness of attenuated chemotherapy in myelodysplastic syndromes: a preliminary report.

A small group of elderly male patients received attenuated doses of daunomycin, cytosine arabinoside (Ara-C), and 6-thioguanine for treatment of myelodysplastic syndrome (MDS). Three patients had refractory anemia with excess blasts (RAEB), and two had chronic myelomonocytic leukemia (CMMoL). All five patients had developed severe transfusion requirements for platelets and red blood cells before therapy was begun. One patient developed necrosis of the cecum and expired 19 days after therapy, but the other four all showed substantial benefit from treatment. Three of those patients received multiple courses of chemotherapy which led to improvement in peripheral blood counts in each case. Duration of responses as noted by improvement in peripheral blood counts compared to pretreatment levels ranged from 1.5 to 9 months. Despite considerable improvement in peripheral blood parameters, some of the abnormal morphologic features of MDS persisted after each course of chemotherapy. These results obtained with attenuated chemotherapy schedules in a small group of patients are sufficiently encouraging to warrant an expanded phase II trial, which is under way at the University of Rochester Cancer Center.

Testosterone effects on biosynthesis of coagulation proteins.

Studies were performed to assess the effects of testosterone on synthesis of selected coagulation proteins using the isolated rat liver perfused in vitro for 10 hours, as well as effects of testosterone on plasma levels of these same proteins. Pretreatment of castrated male rat liver donors for 14 days with pellets containing placebo or testosterone, 0.5 mg, 5.0 mg or 15.0 mg had no significant effects on cumulative biosynthesis of Factor II, Factor VII, antithrombin III, plasminogen or fibrinogen. Plasma concentrations of these proteins in liver donor animals were also unchanged by such hormonal manipulations. In contrast, biosynthesis of fibronectin was increased significantly by increasing doses of testosterone, and plasma concentrations of fibronectin in liver donor rats showed a similar effect.

Heparin is not metabolized by the perfused rat liver.

The role of the liver in metabolism of heparin was studied using the isolated rat liver perfused in vitro for 10 hr. Porcine intestinal heparin (1000 u) was added to the recirculating liver perfusate, and serial heparin measurements were performed on the liver perfusate every 2 hr, as well as on bile samples secreted by the perfused liver. Heparin concentration remained at a constant level throughout the 10 hr of perfusion, and there was no detectable heparin secreted into bile samples. The findings suggest that hepatic metabolism/clearance plays a minimal role in heparin kinetics in plasma.

Measurements of rat plasma coagulation proteins during prolonged exposure to diethylstilbesterol.

The effects of diethylstilbesterol (DES) on concentration of selected plasma coagulation proteins in male rats was studied sequentially over a 28-day period. At the outset of the study, male rats underwent orchiectomy and implantation of a pellet containing DES 5.0 mg or a placebo pellet. At intervals of 7 days, 3 of the animals from each treatment group were sacrificed and blood samples were withdrawn for assay. Plasma concentrations of Factor II (prothrombin) and Factor VII, two vitamin K-dependent coagulation proteins, were significantly decreased in DES-treated animals (approximately 70% normal activity for both Factors) compared to placebo-treated animals. In contrast, Factor VIII activity was higher with DES treatment than with placebo. Plasma concentrations of both antithrombin III (AT III) and plasminogen were decreased in DES-treated animals compared to placebo by immunologic as well as activity assays. Albumin concentrations were not different between the two groups at any point of study, although both were increased at day 21 compared to beginning values. Fibronectin concentrations were slightly decreased in DES-treated animals compared to those which received placebo. The combination of orchiectomy and treatment with DES had profound metabolic effects on the animals; the DES treated animals had a mean body weight loss of 100 g after 28 days, while the placebo group gained an average of 78 g compared to a control group (no surgery) which had average weight gain of 85 g during the 28 day period of study.

Diethylstilbestrol selectively modulates plasma coagulation protein synthesis by the perfused rat liver.

The combined effects of orchiectomy and estrogen administration on synthesis of selected hepatic secretory proteins--antithrombin (AT) III, plasminogen, fibrinogen, factor II (prothrombin), factor VII, fibronectin, and albumin--were studied using the isolated rat liver perfused in vitro for ten hours. Male rat liver donors underwent orchiectomy under ether anesthesia and then received 5.0 mg of diethylstilbestrol (DES) by subcutaneous pellet implantation or a placebo pellet; 14 days later the livers were extracted and perfused in vitro for ten hours. In DES experiments, 1.0 mg of DES was also added directly to the liver perfusate at the outset. Pretreatment with DES resulted in significant increases in cumulative synthesis of factors II (65%) and VII (76%) and significant reduction in cumulative synthesis of both antithrombin III (20%; P = .03) and plasminogen (27%; P less than .01) compared to control perfusions, but synthesis of fibrinogen, fibronectin, and albumin was not significantly affected by addition of the hormone. Plasma samples collected from rat liver donors that had received DES showed similar effects on protein concentrations: significant decreases in concentration of plasminogen and antithrombin III were apparent with no significant changes in concentrations of fibrinogen, fibronectin, or albumin. In additional perfusions, "dose-response" experiments were conducted in which rat liver donors received a subcutaneous DES pellet of 0.5, 5.0, or 50 mg. Synthesis of plasminogen in this group of perfusions was progressively decreased as the concentration of DES administered to the rat liver donor increased. Synthesis of AT III was reduced to the same degree by 5.0 or 50 mg of DES, both being substantially lower than the 0.5-mg experiments. Concentrations of these two proteins in plasma samples from rat liver donors showed changes quite similar to those seen in perfusion experiments; however, plasma fibrinogen concentrations were not different among the three groups of rats.

Biosynthesis of plasminogen by the perfused rat liver.

We investigated synthesis of plasminogen by the isolated rat liver perfused in vitro for 10 hours. Studies were performed under basal conditions as well as under conditions of hormone stimulation known to augment synthesis of acute-phase reactant proteins by the isolated perfused rat liver. In six control perfusions, mean cumulative synthesis of plasminogen after 10 hours of perfusion was 1.61 +/- 0.11 mg/300 cm2 body surface area of the rat liver donor, and in six "acute-phase" experiments, mean cumulative synthesis was 1.55 +/- 0.07 mg. When cycloheximide was added to the liver perfusate at the outset to inhibit protein synthesis, production of plasminogen was greatly reduced. Synthesis of fibrinogen in these same perfusions was characteristic of the known acute-phase reactant proteins. In control perfusions, 68.85 +/- 6.19 mg fibrinogen was produced in 10 hours compared with 106.20 +/- 6.93 mg in acute-phase perfusions. These studies indicate substantial synthesis of plasminogen by the isolated perfused rat liver, but suggest that synthesis of this protein is not affected by those conditions that enhance synthesis of known acute-phase reactant proteins.

Prolymphocytic leukemia: histologic findings in atypical cases.

Significant enlargement of peripheral lymph nodes is not characteristic of prolymphocytic leukemia. The absence of this physical feature of the disease has been so consistent in previous reports that it has come to have considerable importance in the differential diagnosis of prolymphocytic leukemia. We describe two cases of prolymphocytic leukemia, in which, in sharp contrast to other published cases, striking lymphadenopathy was present throughout the clinical course. In one case, the disease responded dramatically, but briefly, to L-asparaginase. The immunologic characteristics of cells from lymph nodes suggested that in both cases, the leukemic process was B-cell type. The features of the prolymphocytic proliferation in lymph nodes and the utility of Wright-Giemsa stained touch preparations have been emphasized.

A plasma factor enhances activity of vitamin K-dependent coagulation proteins.

A plasma factor, "coagulopoietin", present in animals with depleted vitamin K-dependent coagulation factors, appears to enhance activity of these factors in normal animals. We have investigated the effects of "coagulopoietin" on synthesis of certain coagulation proteins by the isolated rat liver perfused for eight hours. Liver donor rats received plasma injections from vitamin K-deficient rats or from normal rats 24 hr before sacrifice. Coagulation activity of Factor VII and Factor II in liver perfusate samples was measured with a coagulation assay; Factor II synthesis was also measured by rocket immunoelectrophoresis and by activation with E. carinatus venom. Cumulative hepatic synthesis of Factor VII coagulation activity was increased by 43% when rat liver donors received vitamin K-deficient rat plasma compared to normal rat plasma. Cumulative synthesis of Factor II coagulation activity was increased by 51%, but synthesis of the protein measured immunologically or by activation with venom was not affected. The "coagulopoietin" factor in these studies appears to increase measurable coagulation factor activity without increasing total protein synthesis.