Canadian Guidelines for Controlled Pediatric Donation After Circulatory Determination of Death-Summary Report

OBJECTIVES: Create trustworthy, rigorous, national clinical practice guidelines for the practice of pediatric donation after circulatory determination of death in Canada. METHODS: We followed a process of clinical practice guideline development based on World Health Organization and Canadian Medical Association methods. This included application of Grading of Recommendations Assessment, Development, and Evaluation methodology. Questions requiring recommendations were generated based on 1) 2006 Canadian donation after circulatory determination of death guidelines (not pediatric specific), 2) a multidisciplinary symposium of national and international pediatric donation after circulatory determination of death leaders, and 3) a scoping review of the pediatric donation after circulatory determination of death literature. Input from these sources drove drafting of actionable questions and Good Practice Statements, as defined by the Grading of Recommendations Assessment, Development, and Evaluation group. We performed additional literature reviews for all actionable questions. Evidence was assessed for quality using Grading of Recommendations Assessment, Development, and Evaluation and then formulated into evidence profiles that informed recommendations through the evidence-to-decision framework. Recommendations were revised through consensus among members of seven topic-specific working groups and finalized during meetings of working group leads and the planning committee. External review was provided by pediatric, critical care, and critical care nursing professional societies and patient partners. RESULTS: We generated 63 Good Practice Statements and seven Grading of Recommendations Assessment, Development, and Evaluation recommendations covering 1) ethics, consent, and withdrawal of life-sustaining therapy, 2) eligibility, 3) withdrawal of life-sustaining therapy practices, 4) ante and postmortem interventions, 5) death determination, 6) neonatal pediatric donation after circulatory determination of death, 7) cardiac and innovative pediatric donation after circulatory determination of death, and 8) implementation. For brevity, 48 Good Practice Statement and truncated justification are included in this summary report. The remaining recommendations, detailed methodology, full Grading of Recommendations Assessment, Development, and Evaluation tables, and expanded justifications are available in the full text report. CONCLUSIONS: This process showed that rigorous, transparent clinical practice guideline development is possible in the domain of pediatric deceased donation. Application of these recommendations will increase access to pediatric donation after circulatory determination of death across Canada and may serve as a model for future clinical practice guideline development in deceased donation

Age-dependent metabolic effects of repeated hypoxemia in piglets.

The aim of this study was to determine whether repeated exposure to hypoxemia would modify the response to hypoxemia during maturation. We exposed piglets to three 1-h cycles of hypoxemia (PaO2 = 30 to 35 mmHg; 1 mmHg = 133.3 Pa) at 1 week (n = 9), 2-3 weeks (n = 10), and 4-5 weeks of age (n = 10). O2 consumption (V(O2)) and CO2 production (V(CO2)) were measured, and alveolar ventilation (V(A)) was derived from V(CO2) and PaCO2. Levels of lactic acid (lactate) and serum catecholamines were also measured. With hypoxemia, time had a significant effect on V(O2) and body temperature in an age-dependent fashion: that is, whereas the 1 week group and the 4-5 week group showed both variables decreasing over time, the 2-3 week group showed no drop in V(O2) and a small increase in body temperature over time. Lactate levels increased with hypoxemia in all animals during the first exposure. However, with repeated exposures to hypoxemia, only the 2-3 week group continued to increase its lactate levels. Furthermore, the changes in lactate levels paralleled the changes in epinephrine levels with hypoxemia. We found, too, that although V(A) increased significantly with hypoxemia in all animals, this change was not modified by age or repeated exposures. No significant effects of age or repeated exposures were found in the cardiovascular response to hypoxemia. We concluded that, from a metabolic viewpoint, after repeated exposures to hypoxemia the 2-3 week animals responded differently.

An evaluation of the carcinogenic hazard of 1,4-dichlorobenzene based on internationally recognized criteria.

1,4-Dichlorobenzene (1,4-DCB) was shown to induce the formation of male rat renal tubule tumors and male and female mouse liver tumors when administered in a chronic bioassay. Since the original carcinogenicity findings, an extensive body of mechanistic information has been developed to elucidate the mode of action by which 1,4-DCB induces these effects and to evaluate the human relevance of the observed animal tumors. In addition, some regulatory and authoritative bodies (U.S. EPA and IARC) have developed rigorous scientific criteria for the amount and types of evidence needed to establish that a material causes kidney toxicity and tumors in male rats through a specific mechanism, alpha-2u-globulin nephropathy. This paper summarizes the mechanistic data developed for 1,4-DCB, which affords an understanding of the lack of human relevance of the male rat renal tubule tumors and mouse liver tumors; assesses that mechanistic data set utilizing the defined set of evaluation criteria formulated by U.S. EPA and IARC for alpha-2u-globulin nephropathy; and discusses the predictive power of mechanistic data developed to elucidate the mode of action of 1,4-DCB in inducing mouse liver tumors. Finally, there is a discussion of how some, but not all, regulatory and authoritative bodies have incorporated this substantial mechanistic data set for 1, 4-DCB into their cancer hazard evaluations and concluded that 1, 4-DCB presents little, if any, cancer hazard to humans.

Prolonged oral etoposide in recurrent or advanced leiomyosarcoma of the uterus: a gynecologic oncology group study.

OBJECTIVE: In a previous study by the Gynecologic Oncology Group only modest activity was seen with bolus etoposide in leiomyosarcoma of the uterus (an 11% response rate). To exploit the schedule dependency of etoposide, which favors longer exposure, a Phase II trial of prolonged oral etoposide was conducted in this tumor. METHODS: Eligibility included leiomyosarcoma of the uterus, measurable disease, one prior chemotherapy regimen which did not include etoposide, WBC >/= 3000/microliter, platelet count >/=100, 000/microliter, serum creatinine

Exposure to inescapable but not escapable shock increases extracellular levels of 5-HT in the dorsal raphe nucleus of the rat.

The effects of escapable and yoked inescapable electric tailshocks on extracellular levels of serotonin (5-HT) in the dorsal raphe nucleus were measured by in vivo microdialysis. In comparison to either control rats or to their own preshock baseline, rats exposed to inescapable shock showed an increase in extracellular 5-HT within 25 min of shock initiation, and 5-HT levels continued to rise during the remainder of the shock session. Rats that were exposed to comparable shock treatment, but that were given the opportunity to escape, did not show an increase in 5-HT. Rats that were restrained but not shocked also did not show an increase in 5-HT. These results add further support to suggestions that serotonergic changes occur in the dorsal raphe nucleus during inescapable shock and that such changes may contribute to the behavioral effects of inescapable shock.

Evaluation of unscheduled DNA synthesis (UDS) and replicative DNA synthesis (RDS) following treatment of rats and mice with p-dichlorobenzene.

p-Dichlorobenzene (PDCB) has been reported to produce tumors in the male and female mouse liver and in the male rat kidney in 2-year gavage studies (NPT, 1987). To elucidate the possible mechanisms of carcinogenicity more fully, UDS and RDS were evaluated in B6C3F1 mouse hepatocytes and F-344 rat kidney cells by autoradiography following in vivo administration of PDCB. All corn oil gavage doses of PDCB (300, 600, and 1,000 mg/kg) and the negative control resulted in < 0 net grains/nucleus (NG) in the mouse liver and rat kidney, indicating that PDCB does not induce UDS in either tissue. Compared to controls with < or = 0.29% hepatocytes in S-phase (%S), treatment of mice induced 0.46, 1.90, and 1.52 %S (males) and 2.61, 1.18, and 4.45 %S (females), which indicates that PDCB acts as an inducer of cell proliferation in the liver. In male rat kidney cells, the same doses produced 0.87, 0.67, and 1.01 %S (0.38% in controls) and in females 0.48, 0.43, and 0.32 %S (0.52% in controls), indicating that PDCB induces cell replication in the male but not the female rat kidney. Therefore, these data demonstrate that PDCB is not genotoxic in the mouse liver or rat kidney at single oral doses comparable to the daily doses given in the National Toxicology Program (NTP) bioassay (NTP, 1987). Furthermore, the increases in RDS support the hypotheses that mouse liver tumor formation occurs via stimulation of hepatocyte proliferation and male rat kidney carcinogenesis via increased renal cell proliferation.

Ethnic differences in knowledge and attitudes about BRCA1 testing in women at increased risk.

Informed consent for BRCA1 mutation testing will require adequate knowledge of patterns of inheritance of cancer and the benefits, limitations, and risks of DNA testing. This study examined knowledge about the inheritance of breast cancer and attitudes about genetic testing for breast-ovarian cancer susceptibility in women at increased risk. Knowledge and attitudes were measured in 407 African American and Caucasian women aged 18-75 who had at least one first-degree relative (FDR) with breast and/or ovarian cancer. The average knowledge score was 6.0 out of a total of 11 (S.D. = 2.15). Compared to Caucasian women, African American women had lower levels of knowledge and had more positive attitudes about the benefits of genetic testing. There were no significant ethnic differences in attitudes about the limitations and risks of testing, however, income was negatively associated with this outcome. Ethnic differences in knowledge and attitudes about genetic testing for breast-ovarian cancer risk may be attributable to differences in exposure to genetic information and referral by health care providers.

Imaging surface-wave analyzer for liquid surfaces.

We have developed a wave-height sensor that can be used to measure surface height directly and simultaneously over a two-dimensional imaged area of an air-liquid interface, thus permitting real-time two-dimensional wave-height spectra to be obtained directly by fast Fourier transform. The absolute interface height (or surface-wave amplitude) is obtained directly from the measured volume attenuation of the transmitted light through the medium rather than by tedious reconstruction from surface slope data obtained by light refraction or reflection methods. A surface-height resolution of tens of micrometers has been achieved. For this demonstration, two-dimensional gray-scale wave-height images of cylindrical surface waves are presented with corresponding two-dimensional fast Fourier transforms. Line scans across the images indicate the ready utility of the instrument to obtain surface-height information at any location on the imaged area. Applications of this diagnostic and design issues of a two-dimensional wave-height spectrum analyzer are presented.

Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer.

Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m2.

Polarimetric optical imaging of scattering surfaces.

A polarimetric optical specular event detector (OSED) has been developed to provide spatially and temporally resolved polarimetric data of backscattering in the visible from water wave surfaces. The OSED acquires simultaneous, two-dimensionally resolved images of the remote target in two orthogonal planes of polarization. With the use of plane-polarized illumination the OSED presently can measure, in an ensemble of breaking waves, the equivalent four-element polarization matrix common to polarimetric radars. Upgrade to full Stokes parameter state of polarization measurements is straightforward with the use of present single-aperture, multi-imager CCD camera technology. The OSED is used in conjunction with a coherent pulse-chirped radar (PCR), which also measures the four-element polarization matrix, to provide direct time-correlated identification of backscattering mechanisms operative during wave-breaking events which heretofore have not been described theoretically. We describe the instrument and its implementation, and examples of spatially resolved polarimetric data are displayed as correlated with the PCR backscatter cross section and polarization ratio records.

Spontaneous preoperative internal jugular and subclavian vein thrombosis associated with an early-stage synchronous ovarian/endometrial malignancy.

A case of preoperative spontaneous internal jugular/subclavian vein thrombosis documented with magnetic resonance imaging associated with a synchronous stage II ovarian/stage I endometrial malignancy is presented. This unusual deep venous thrombosis site is classically associated with trauma, infection, head and neck malignancies, or central venous catheterization and is rarely associated with distant malignancies. Neck pain and swelling in a gynecologic oncology patient should prompt consideration of this diagnosis.

Ineffectiveness of continuous 5-fluorouracil as salvage therapy for ovarian cancer.

5-Fluorouracil (5-FU) is an antimetabolite chemotherapy, which selectively functions at the S phase of the cell cycle. It is a short-acting agent with a serum half-life of approximately 11 minutes. Increased efficacy with this drug could theoretically be provided by sustained infusion over the doubling time of a tumor. Ovarian cancer that recurs or persists after treatment with platinum-based chemotherapy has a poor prognosis. This study examines the use of long-term infusional 5-FU as a salvage chemotherapy for ovarian cancer. 14 patients with epithelial ovarian cancer were studied. All were stage III or IV disease and all were initially treated with platinum-based chemotherapy with either persistence or recurrence of disease. Patients received 5-FU as 300 mg/m2/day via a continuous infusion for a 10-week cycle with discontinuation occurring for severe toxicity or documented progression. The average infusion per patient was 8 weeks (3-10). Three patients had drug discontinued secondary to toxicity (severe mucositis) and 4 patients had progression prior to the completion of 10 weeks. All patients had progression by the end of the first cycle. The average survival post-5-FU was 8.9 months (range: 0.75-22 months). The lack of response in 14 patients indicates that, statistically, the likelihood of an overall response rate of 20% is less than 0.05. Infusional 5-FU appears to be ineffective as salvage therapy for ovarian cancer.

Vulvar reconstruction using a mons pubis pedicle flap.

The treatment of early vulvar carcinoma has moved toward less radical surgery with reconstruction. This report describes our preliminary experience with a mons pubis flap that is simple and appears safe, reliable, and gives excellent cosmetic and functional results following radical hemivulvectomy. Four patients have undergone this procedure with excellent results. The flap brings pliable, hair-bearing skin which authentically mimics the normal side, thus providing good sexual function. The mons pubis pedicle flap should be considered in patients undergoing radical hemivulvectomy where an excellent cosmetic result is desirable.

Second-look laparotomy.

The second-look laparotomy has become an important means of assessing therapy response in ovarian cancer patients. This procedure enables the gynecologic oncologist to diligently search for small volume persistent disease, which often escapes detection by less invasive means. Subsequent treatment, if required, may then be tailored to the initial biologic response to therapy. However, many patients with negative findings at second look will develop recurrent disease, dampening enthusiasm for the operation. Although controversial, this procedure remains the gold standard for the detection of disease status following chemotherapy for ovarian cancer.

Intraperitoneal therapy administered through a Groshong catheter.

This report describes a new device for delivery of intraperitoneal therapy. From October 1989 through March 1991, 27 externally accessed Groshong (Bard Access Systems, UT) catheters were placed transabdominally into 24 patients with presumed epithelial ovarian cancer at the conclusion of primary or second-look laparotomy. Total duration of catheter use was 81 months (range, 1-62 weeks). Fifty-seven cycles of intraperitoneal therapy were administered through 18 catheters (range, 1-11). Nine catheters were removed without being used after patients randomized off intraperitoneal treatment arms or were ineligible for intraperitoneal protocols. There were no complications associated with catheter placement or removal. None of the catheters became obstructed or dislodged while in place. There were no cases of infectious peritonitis, although one patient developed an exit-site skin infection. Surgery is not required to remove the Groshong catheter which fosters empiric placement of the device at the time of laparotomy in all patients potentially eligible for intraperitoneal therapy. The device-related infection rate of 4.2 per 100 patients is similar to that described using other implanted devices. Catheter maintenance is easy and patient acceptance is good. The Groshong catheter is a safe, reliable, and acceptable means of delivering intraperitoneal therapy.

Preservation of multiple oncogenic human papillomavirus types in recurrences of early-stage cervical cancers.

OBJECTIVES: Our purpose was to determine the relationship between human papillomavirus genotypes contained in primary early stage cervical cancers and those contained in the respective recurrences. STUDY DESIGN: Six early-stage cervical cancers that were considered cured by surgical extirpation subsequently recurred within 21 months of the original surgery. The primary tumors and the recurrences underwent polymerase chain reaction for human papillomavirus typing with confirmation of types performed by means of diagnostic restriction fragments. RESULTS: All primary tumors and recurrences contained human papillomavirus, with all primary tumors positive for multiple types. The concordance rate between the primary tumors and recurrences for specific types was 73% (11/15). Among the highly oncogenic types 16 and 18 there was 100% concordance between primary and recurrent tumors. CONCLUSIONS: Highly oncogenic types of human papillomavirus are preserved between primary tumors and their recurrences in cervical cancers. This further supports the role of oncogenic types in the maintenance of the malignant state and supports the clonogenic nature of cervical cancer recurrence.

Insertion of Groshong central venous catheters utilizing fluoroscopic techniques.

Groshong central line indwelling catheters are extensively used in gynecologic oncology patients for administration of chemotherapy, intravenous fluids, and pain medications. They are easy to maintain and have a good safety record. We report on the placement of these central venous catheters under direct fluoroscopic visualization as a method which is safe, inexpensive, and efficacious in high-risk patients. Fluoroscopic visualization during insertion provides several advantages: visualization of bony landmarks, placement of the guidewire into the subclavian vein and superior vena cava under direct visualization, and confirmation of appropriate distal placement of the Groshong catheter. Patient advantages include the following: (1) avoidance of unnecessary punctures to access the subclavian vein; (2) verification of guidewire placement to avoid cephalic placement; (3) passage of the guidewire only as far as the right atrium to avoid potential dysrrhythmias secondary to right ventricular irritation; and (4) a savings of approximately 60% over insertion in the general operating room. Thirty patients had placement under fluoroscopic visualization in the angiography suite of Georgetown University Hospital. The average age of the patients was 58 years (42-78). Sixteen patients had ovarian cancer, 6 had endometrial cancer, 5 had cervical cancer, and 3 had other gynecologic malignancies. Fifteen patients had catheters placed for chemotherapy, 14 for hydration, and 1 for pain control. Ten patients had had previous central venous catheters: 6 had been removed for infection, 2 for thrombus, 1 for completion of chemotherapy, and 1 for catheter kinkage. All 10 with previous catheters had successful placement of catheters in the angiography suite. Complications from insertion were minimal with one asymptomatic pneumothorax and one proximal port in an extravascular position. We present the technique of fluoroscopic insertion of Groshong catheters which is an effective method of placement in high-risk patients.