Nonclinical reproductive and developmental safety evaluation of the MAGE-A3 Cancer Immunotherapeutic, a therapeutic vaccine for cancer treatment.

We assessed potential toxic effects of the MAGE-A3 Cancer Immunotherapeutic on female fertility and embryo-fetal, pre- and post-natal development in rats and on male fertility in rats and monkeys. Three groups of 48 female (Study 1) or 22 male (Study 2) CD rats received 5 or 3 injections of 100µL of saline, AS15 immunostimulant, or MAGE-A3 Cancer Immunotherapeutic (MAGE-A3 recombinant protein combined with AS15) at various timepoints pre- or post-mating. Male Cynomolgus monkeys (Study 3) received 8 injections of 500µL of saline (n=2) or the MAGE-A3 Cancer Immunotherapeutic (n=6) every 2 weeks. Rats were sacrificed on gestation day 20 or lactation day 25 (Study 1) or 9 weeks after first injection (Study 2) and monkeys, 3 days or 8 weeks after last injection. Injections were well tolerated. Female rat mating performance or fertility, pre- and post-natal survival, offspring development up to 25 days of age, and male mating performance (rats) or fertility parameters (rats and monkeys) were unaffected.

End-of-life issues in intensive care units: a national random survey of nurses' knowledge and beliefs.

OBJECTIVE: To investigate the knowledge, beliefs, and ethical concerns of nurses caring for patients dying in intensive care units. METHODS: A survey was mailed to 3000 members of the American Association of Critical-Care Nurses. The survey contained various scenarios depicting end-of-life actions for patients: pain management, withholding or withdrawing life support, assisted suicide, and voluntary and nonvoluntary euthanasia. RESULTS: Most of the respondents (N = 906) correctly identified the distinctions among the end-of-life actions depicted in the scenarios. Almost all (99%-100%) agreed with the actions of pain management and withholding or withdrawing life support. A total of 83% disagreed with assisted suicide, 95% disagreed with voluntary euthanasia, and 89% to 98% disagreed with nonvoluntary euthanasia. Most (78%) thought that dying patients frequently (31%) or sometimes (47%) received inadequate pain medicine, and almost all agreed with the double-effect principle. Communication between nurses and physicians was generally effective, but unit-level conferences that focused on grief counseling and debriefing staff rarely (38%) or never (49%) occurred. Among the respondents, 37% had been asked to assist in hastening a patient's death. Although 59% reported that they seldom acted against their consciences in caring for dying patients, 34% indicated that they sometimes had acted against their conscience, and 6% had done so to a great extent. CONCLUSIONS: Intensive care unit nurses strongly support good pain management for dying patients and withholding or withdrawing life-sustaining therapies to allow unavoidable death. The vast majority oppose assisted suicide and euthanasia. Wider professional and public dialogue on end-of-life care in intensive care units is warranted.

Effect of dialysis membranes and middle molecule removal on chronic hemodialysis patient survival.

The type of dialysis membrane used for routine therapy has been recently shown to correlate with the survival of chronic hemodialysis patients. We examined whether this effect of dialysis membrane could be explained by differences in dialyzer removal of middle molecules using data from the 1991 Case Mix Adequacy Study of the United States Renal Data System. The sample analyzed included patients who had been treated by hemodialysis for 1 year or more, who were dialyzed with the 19 most commonly used dialyzers in 1991, and for whom delivered urea Kt/V could be calculated from predialysis and postdialysis blood urea nitrogen concentrations. Vitamin B12 (1,355 daltons) was used as a marker for middle molecules, and the clearance of vitamin B12 was estimated based on in vitro data. After adjustments for case mix, comorbidities, and urea Kt/V, the relative risk of mortality for a 10% higher calculated total cleared volume of vitamin B12 was 0.953 (P < 0.0001 v 1.000). Similar results were obtained when middle molecule removal was adjusted for body size. We conclude that both small and middle molecule removal indices appear to be independently associated with the risk of mortality in chronic hemodialysis patients. Differences in mortality when using different types of dialysis membrane may be explained by differences in middle molecule removal.

Relationship of dialysis membrane and cause-specific mortality.

A number of studies have suggested that type of dialysis membrane is associated with differences in long-term outcome of patients undergoing hemodialysis, both in terms of morbidity and mortality. The purpose of this study was to determine the relationship of membrane type and specific causes of death. Data from the United States Renal Data System Case Mix Adequacy Study, a national random sample of hemodialysis patients who were alive on December 31, 1990, were used. Our study was limited to patients in this data set who were undergoing dialysis for at least 1 year (n = 4,055). For the main analytic models, membrane type was classified into two categories: unmodified cellulose or MC/SYN (which combines modified cellulose [MC] and synthetic membranes [SYN]). The relationships of membrane type and major causes of mortality were analyzed using Cox proportional hazards models, which adjusted for multiple (21) covariates, including demographics, comorbidity, Kt/V, and other parameters. Patients were censored at transplantation or 60 days after a switch to peritoneal dialysis. Compared with patients dialyzed with unmodified cellulose membranes, the adjusted relative mortality risk (RR) from infection was 31% lower (RR = 0.69; P = 0.03) and from coronary artery disease was 26% lower (RR = 0.74; P = 0.07) for patients dialyzed with MC/SYN membranes. No statistically significant difference (all P > 0.1) was found in mortality risk from cerebrovascular disease (RR = 1.08), other cardiac causes (RR = 0.86), malignancy (RR = 0.90), or other known causes (RR = 0.82) between patients dialyzed with MC/SYN compared with unmodified cellulose membranes. These results offer support to reported experimental and observational clinical studies that have found that unmodified cellulose membranes may increase the risk for both infection and atherogenesis. Further studies are necessary to evaluate the possibility of confounding factors, compare more specific membrane types, and determine the pathophysiology linking membrane type to cause-specific mortality.

Relationship between behavioral and physiological indicators of pain, critical care patients' self-reports of pain, and opioid administration.

OBJECTIVES: To examine the accuracy of inferences about critical care patients' pain based on physiological and behavioral indicators and to assess the relationship between registered nurse and patient pain scores and doses of opioids administered. DESIGN: Descriptive, comparative analysis. SETTING: Three intensive care units and two postanesthesia care units in two hospitals. SUBJECTS: Fourteen critical care nurses who conducted 114 pain assessments on 31 surgical patients. INTERVENTIONS: Nurses used a pain assessment and intervention notation algorithm that contained lists of behavioral and physiological indicators of pain to make inferences about a patient's pain intensity. Fourteen registered nurses completed up to five pain assessments on each patient over a 4-hr period. Following both the physiological and behavioral ratings, nurses rated the patients' pain intensity, using a 0 to 10 numeric rating scale, and they asked patients to provide a self-report of pain intensity, using a similar numeric rating scale. Nurses then administered an intravenous dose of an opioid from a sliding scale prescription. MEASUREMENTS AND MAIN RESULTS: Moderate-to-strong correlations were found between the number of behavioral indicators at times 1 through 5 and between the number of physiological indicators and nurses' ratings of the patients' pain intensity at times 1 through 4 (p < .05). Although nurses' pain ratings were consistently lower than patients' pain ratings across the five time points, these differences were not significant. The amount of opioid analgesic administered by the nurse correlated more frequently with nurses' pain ratings than with patients' self-reports of pain intensity. CONCLUSIONS: The use of a detailed, standardized pain assessment and intervention notation algorithm that incorporates behavioral and physiological indicators may assist healthcare professionals in making relatively accurate assessments of a patient's pain intensity. Further research is needed to determine the specific decision-making processes and criteria that healthcare professionals use to choose doses of analgesics to administer to critically ill patients.

Breakdown in the nursing care of families in the ICU.

BACKGROUND: Factors that can lead to breakdown in the care of the families of patients in the ICU include gaps in the healthcare providers' education and skill in working with families, unclear lines of responsibility for various aspects of family care, and insufficient support or supervision for the difficult emotional work of family care. OBJECTIVE: The purpose of this study was to highlight instances in which negative or difficult aspects of nursing care of family members of ICU patients were evident, so that needed changes in caring for the families could be emphasized. METHOD: Interpretive phenomenology was used to analyze transcribed audiotape recordings of interviews with 130 nurse participants and clinical observations of 48 nurse participants. The interpretive account is based on more than 100 narratives of patient care relayed in interviews and on observational notes that focused on care of the family. RESULTS: The five general nursing approaches that constrained family care in ICUs were nurses' efforts to (1) distance the family physically from the patient and the patient's bedside, (2) distance themselves from the patient and the patient's family, (3) characterize the family's perspective as pathological, (4) dissipate responsibility for family care, and (5) take an elemental rather than a systemic perspective. CONCLUSIONS: The breakdowns in family care observed in this study were neither new nor unique. In order to truly realize a patient- and family-focused healthcare system, an infusion of knowledge and skill must occur at the bedside with individual nurses.

Clinical judgment and management of postoperative pain in critical care patients.

BACKGROUND: Acute pain is a significant problem in critical care patients. Although many barriers to successful assessment and management of pain in critical care patients have been noted, little is known about how critical care nurses make clinical judgments when assessing and managing patients' pain. OBJECTIVE: This qualitative analysis is part of a pilot study evaluating nurses' use of a pain assessment and intervention notation algorithm in patients in critical care areas who have limited communication abilities after abdominal or thoracic surgery. METHOD: Transcribed audiotapes of nurse participants' "thinking aloud" while using the pain assessment and intervention notation algorithm were analyzed by using interpretive phenomenology. The interpretive account is based on 31 tape recordings of 14 nurses caring for 41 patients (12 patients in the ICU and 29 patients in the postanesthesia care unit). FINDINGS: The two domains of clinical judgment found were (1) assessing the patient and (2) balancing interventions. CONCLUSIONS: Many nurses' reports showed that they accurately assessed their patients' needs for analgesics. Through testing of and learning from their patients' responses, nurses were able to give amounts of analgesics that diminished patients' postoperative pain. Additionally, nurses had to balance analgesic administration against the patients' hemodynamic and respiratory conditions, medical plan and prescriptions, and the desires of the patients and the patients' families.

ESRD patient mortality with adjustment for comorbid conditions in Lombardy (Italy) versus the United States.

The present study evaluated end-stage renal disease (ESRD) patient survival in Lombardy, Italy, and the United States (U.S.) using data from two registries, the Lombardy Dialysis and Transplant Registry (RLDT) and the U.S. Renal Data System (USRDS), respectively. For this purpose, 4,196 white patients (2,900 from the USRDS Case Mix Severity Study and all 1296 from RLDT) who started renal replacement therapy in 1986 and 1987 were studied. Compared to Lombardy patients, those in the USA were significantly older (mean age 59.9 +/- 16.4 vs. 55.9 +/- 14.7 years), had a lower proportion of males (53.7 vs. 62.1%), a greater proportion with diabetic nephropathy (29.9 vs. 9.7%) and a significantly greater proportion of patients with the recorded comorbid conditions (heart disease, peripheral vascular disease, cirrhosis, cachexia, malignancy). U.S. patients were less frequently treated with peritoneal dialysis (PD) by day 30 of ESRD (21.2 vs. 30.7). Survival was compared in the Cox proportional hazard regression model, using age, sex, comorbid conditions and early modality of treatment as explanatory covariates. Overall, 48% of the 4196 patients died during the 48 to 72 months follow-up to 12/31/91. Per 100 patient-years the gross death rate for USRDS patients was 28.7 compared to 13.0 of RLDT patients. The unadjusted death relative risk for RLDT was 0.439, that is, 56% lower death rate compared to USRDS patients. Age, sex, diabetic status, each of the recorded comorbid conditions and treatment modality were significantly related to survival and included in the model. The Cox cumulative survival adjusted for all these explanatory covariates survival was for U.S. patients 84.4% at one year, 67.0% at two years and 33.4% at five years, and for RLDT patients 88.3% at one year, 75.9% at two years and 45.9% at five years. The relative mortality risk (RR) for the patients treated in Lombardy adjusted for all the reported covariates was 29% lower than for US patients (RR = 0.71; P < 0.0001). This comparative risk varied significantly by age (P < 0.0001) and was 65 percent lower for Lombardy compared to U.S. patients in the age range 25 to 44 years (RR = 0.35) and about 20% lower for patients over age 65 years (RR = 0.80). This relative risk was mainly related to hemodialysis and was not statistically significant for PD patients. The observed lower mortality risk in Lombardy was less pronounced when adjusted for demographic and comorbid covariates, but was still large and therefore suggests the need for further studies regarding treatment related factors and unmeasured patient factors, particularly in hemodialysis patients.

The dose of hemodialysis and patient mortality.

The relationship between the delivered dose of hemodialysis and patient mortality remains somewhat controversial. Several observational studies have shown improved patient survival with higher levels of delivered dialysis dose. However, several other unmeasured variables, changes in patient mix or medical management may have impacted on this reported difference in mortality. The current study of a U.S. national sample of 2,311 patients from 347 dialysis units estimates the relationship of delivered hemodialysis dose to mortality, with a statistical adjustment for an extensive list of comorbidity/risk factors. Additionally this study investigated the existence of a dose beyond which more dialysis does not appear to lower mortality. We estimated patient survival using proportional hazards regression techniques, adjusting for 21 patient comorbidity/risk factors with stratification for nine Census regions. The patient sample was 2,311 Medicare hemodialysis patients treated with bicarbonate dialysate as of 12/31/90 who had end-stage renal disease for at least one year. Patient follow-up ranged between 1.5 and 2.4 years. The measurement of delivered therapy was based on two alternative measures of intradialytic urea reduction, the urea reduction ratio (URR) and Kt/V (with adjustment for urea generation and ultrafiltration). Hemodialysis patient mortality showed a strong and robust inverse correlation with delivered hemodialysis dose whether measured by Kt/V or by URR. Mortality risk was lower by 7% (P = 0.001) with each 0.1 higher level of delivered Kt/V. (Expressed in terms of URR, mortality was lower by 11% with each 5 percentage point higher URR; P = 0.001). Above a URR of 70% or a Kt/V of 1.3 these data did not provide statistical evidence of further reductions in mortality. In conclusion, the delivered dose of hemodialysis therapy is an important predictor of patient mortality. In a population of dialysis patients with a very high mortality rate, it appears that increasing the level of delivered therapy offers a practical and efficient means of lowering the mortality rate. The level of hemodialysis dose measured by URR or Kt/V beyond which the mortality rate does not continue to decrease, though not well defined with this study, appears to be above current levels of typical treatment of hemodialysis patients in the U.S.

Relationship of dose of hemodialysis and cause-specific mortality.

A number of studies have found a relationship of lower all-cause mortality risk for ESRD patients treated with increasing dose of dialysis. The objective of this study was to determine the relationship of delivered dose of dialysis with cause-specific mortality. Data from the USRDS Case Mix Adequacy Study, which includes a national random sample of hemodialysis patients, were utilized. To minimize the contribution of unmeasured residual renal function, the sample used in this analysis (N = 2479) included only patients on dialysis for one year or more. Cox proportional hazards models, stratified for diabetes, were used to analyze the effect of delivered dose of dialysis (measured and reported by both Kt/V and URR) on major causes of death and withdrawal from dialysis, adjusting for other covariates including demographics, comorbid diseases present at start of study, functional status, laboratory values and other dialysis parameters. Patient follow-up for mortality was censored at the earliest of time of transplantation, 60 days after a switch to peritoneal dialysis or at the time of data abstraction. For each 0.1 higher Kt/V, the adjusted relative risk of death due to coronary artery disease was 9% lower (RR = 0.91, P < 0.05), due to other cardiac causes was 12% lower (RR = 0.88, P < 0.01), due to cerebrovascular disease (CVD) was 14% lower (RR = 0.86, P < 0.05), due to infection was 9% lower (RR = 0.91, P = 0.05), and due to other known causes was 6% lower (RR = 0.94, P < 0.05). There was no statistically significant relationship of Kt/V and risk of death among patients who died of malignancy (RR = 0.84, P = 0.10) or among patients whose death cause was missing (RR = 0.95, P = 0.41). The risk of withdrawal from dialysis prior to death due to any cause was 9% lower (RR = 0.91, P < 0.05) for each 0.1 higher Kt/V. The relationships of delivered dose of dialysis, as measured by URR, and cause-specific mortality were essentially similar in relative magnitude and statistical significance as the relationships observed using Kt/V as the measurement of dialysis dose, with the exception that the relationship was less significant for cerebrovascular disease and withdrawal from dialysis. The relationship of dialysis dose with risk of death due to each cause of death category except other cardiac causes and "other" causes appeared to be of greater magnitude and of greater statistical significance among diabetics than non-diabetics. These results indicate that low dose of dialysis is not associated with mortality due to just one isolated cause of death, but rather is due to a number of the major causes of death in this population. This study is consistent with hypotheses that low doses of dialysis may promote atherogenesis, infection, malnutrition and failure to thrive through a variety of pathophysiologic mechanisms. Further study is necessary to confirm these results and to test hypotheses that are developed.

Effect of the dialysis membrane on mortality of chronic hemodialysis patients.

Mortality of prevalent chronic hemodialysis patients remains high. The potential effect of the dialysis membrane on this mortality has not been previously investigated in a large population of chronic hemodialysis patients. Using data from the United States Renal Data System (USRDS), we analyzed a random sample of 6,536 patients receiving hemodialysis on December 31, 1990. The study design was a historical prospective study. By limiting the study to patients dialyzed for at least one year with bicarbonate dialysate, in whom the dose of dialysis could be calculated, and in whom dialysis membrane and co-existing morbidities were defined, the sample size was reduced to 2,410 patients. A Cox proportional hazards model was used to estimate relative mortality risk. The types of dialysis membranes used were broadly classified into three categories: unsubstituted cellulose, modified cellulose (generally cellulose membranes that have been modified by substitutions of some or most of their hydroxyl moieties) and synthetic membranes that are not cellulose-based. The results of the study suggest that after adjusting for the dose of dialysis and the presence of co-morbid factors, the relative risk of mortality of patients dialyzed with modified cellulose or synthetic membranes was at least 25% less than that of patients treated with unsubstituted cellulose membranes (P < 0.001). To account for the possibility that these differences were due to regional practice patterns, we further stratified the data for nine different regions. There was still a 20% difference in relative risk of mortality between membrane groups with the mortality statistically significantly less in patients treated with synthetic membranes (P < 0.045) compared to patients dialyzed with unsubstituted cellulose membranes. The results of this study suggest that the dialysis membrane plays an important role in the outcome of chronic hemodialysis patients. However, more definitive studies are needed before a cause and effect relationship can be proven.

Comparison of mortality with home hemodialysis and center hemodialysis: a national study.

We sought to determine whether lower mortality rates reported with hemodialysis (HD) at home compared to hemodialysis in dialysis centers (center HD) could be explained by patient selection. Data are from the United States Renal Data System (USRDS) Special Study Of Case Mix Severity, a random national sample of 4,892 patients who started renal replacement therapy in 1986 to 1987. Intent-to-treat analyses compared mortality between home HD (N = 70) and center HD patients (N = 3,102) using the Cox proportional hazards model. Home HD patients were younger and had a lower frequency of comorbid conditions. The unadjusted relative risk (RR) of death for home HD patients compared to center HD was 0.37 (P < 0.001). The RR adjusted for age, sex, race and diabetes, was 44% lower in home HD patients (RR = 0.56, P = 0.02). When additionally adjusted for comorbid conditions, this RR increased marginally (RR = 0.58, P = 0.03). A different analysis using national USRDS data from 1986/7 and without comorbid adjustment showed patients with training for self care hemodialysis at home or in a center (N = 418) had a lower mortality risk (RR = 0.78, P = 0.001) than center HD patients (N = 43,122). Statistical adjustment for comorbid conditions in addition to age, sex, race, and diabetes explains only a small amount of the lower mortality with home HD.

A "thinking-in-action" approach to teaching clinical judgment: a classroom innovation for acute care advanced practice nurses.

The complexity of the evolving advanced practice nurse (APN) role demands new teaching strategies. Based on the challenges that clinicians face daily, we have developed a teaching-learning strategy that addresses five central issues: (a) learning to perceive or identify relevant clinical problems; (b) learning to address the limits of formalism by situating clinical problem solving according to the most relevant goals and intents; (c) learning to reason in transition about the particular clinical situation; (d) learning the ethical skill of problem engagement and interpersonal involvement; and (e) learning to take a stand as a responsible agent by making clinical judgments, acting on them, and advocating for the patient/family. Although these five central issues are typically excluded from classic academic approaches, they are addressed in the "Thinking-in-Action" approach. This teaching-learning strategy offers a different way of teaching clinical judgment that closely resembles the way in which expert nurses actually think and reason in patient situations as they unfold.

Entry: a new approach.

Despite all of the protections promised through grandfathering and pathways to educational mobility, the entry movement tends to be perceived by many to be "demoting" the lives and livelihoods of hundreds of thousands of RNs who do not possess the education to meet the proposed standard. Here is a proposal for a way out of the quagmire.