PTH regulates fetal blood calcium and skeletal mineralization independently of PTHrP.

PTH and PTHrP both act in the regulation of fetal mineral metabolism. PTHrP regulates placental calcium transfer, fetal blood calcium, and differentiation of the cartilaginous growth plate into endochondral bone. PTH has been shown to influence fetal blood calcium, but its role in skeletal formation remains undefined. We compared skeletal morphology, mineralization characteristics, and gene expression in growth plates of fetal mice that lack parathyroids and PTH (Hoxa3 null) with the effects of loss of PTHrP (Pthrp null), loss of PTH/PTHrP receptor (Pthr1 null), and loss of both PTH and PTHrP (Hoxa3 null x Pthrp null). Loss of PTH alone does not affect morphology or gene expression in the skeletal growth plates, but skeletal mineralization and blood calcium are significantly reduced. In double-mutant fetuses (Hoxa3 null/Pthrp null), combined loss of PTH and PTHrP caused fetal growth restriction, limb shortening, greater reduction of fetal blood calcium, and reduced mineralization. These findings suggest that 1) PTH may play a more dominant role than PTHrP in regulating fetal blood calcium; 2) blood calcium and PTH levels are rate-limiting determinants of skeletal mineral accretion; and 3) lack of both PTH and PTHrP will cause fetal growth restriction.

Hoxb2 and hoxb4 act together to specify ventral body wall formation.

Three different alleles of the Hoxb4 locus were generated by gene targeting in mice. Two alleles contain insertions of a selectable marker in the first exon in either orientation, and, in the third, the selectable marker was removed, resulting in premature termination of the protein. Presence and orientation of the selectable marker correlated with the severity of the phenotype, indicating that the selectable marker induces cis effects on neighboring genes that influence the phenotype. Homozygous mutants of all alleles had cervical skeletal defects similar to those previously reported for Hoxb4 mutant mice. In the most severe allele, Hoxb4(PolII), homozygous mutants died either in utero at approximately E15.5 or immediately after birth, with a severe defect in ventral body wall formation. Analysis of embryos showed thinning of the primary ventral body wall in mutants relative to control animals at E11.5, before secondary body wall formation. Prior to this defect, both Alx3 and Alx4 were specifically down regulated in the most ventral part of the primary body wall in Hoxb4(PolII) mutants. Hoxb4(loxp) mutants in which the neo gene has been removed did not have body wall or sternum defects. In contrast, both the Hoxb4(PolII) and the previously described Hoxb2(PolII) alleles that have body wall defects have been shown to disrupt the expression of both Hoxb2 and Hoxb4 in cell types that contribute to body wall formation. Our results are consistent with a model in which defects in ventral body wall formation require the simultaneous loss of at least Hoxb2 and Hoxb4, and may involve Alx3 and Alx4.

Effect of Carmeda BioActive Surface coating versus Trillium Biopassive Surface coating of the oxygenator on circulating platelet count drop during cardiopulmonary bypass.

An investigation was conducted to evaluate the effect that surface coating of the hollow-fiber membrane oxygenator had on circulating platelet count drop during cardiopulmonary bypass (CPB). Sixty patients undergoing non-emergency myocardial revascularization for coronary artery disease were randomly divided into two groups. Group one (n = 32) received the Carmeda-coated Maxima-Plus PRF oxygenator while the patients in Group two (n=28) received the Trillium-coated Affinity oxygenator during CPB. The net platelet count drops for the pump specimen (15-20 min after the initiation of bypass) for the Carmeda and the Trillium groups were 3.6 +/- 15.8% and 6.2 +/- 10.2%, respectively. The net platelet count drop for the warming specimen for the Carmeda and the Trillium groups were 2.9 +/- 19.4% and 0.5 +/- 11.0%, respectively. There were no statistically significant differences between the groups. The authors conclude that using either the Carmeda-coated Maxima-Plus PRF oxygenator or the Trillium-coated Affinity oxygenator afford similar benefits in regards to preserving circulating platelet counts during bypass.

Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis.

The thymus and parathyroid glands in mice develop from a thymus/parathyroid primordium that forms from the endoderm of the third pharyngeal pouch. We investigated the molecular mechanisms that promote this unique process in which two distinct organs form from a single primordium, using mice mutant for Hoxa3 and Pax1. Thymic ectopia in Hoxa3(+/-)Pax1(-/-) compound mutants is due to delayed separation of the thymus/parathyroid primordium from the pharynx. The primordium is hypoplastic at its formation, and has increased levels of apoptosis. The developing third pouch in Hoxa3(+/-)Pax1(-/-) compound mutants initiates normal expression of the parathyroid-specific Gcm2 and thymus-specific Foxn1 genes. However, Gcm2 expression is reduced at E11.5 in Pax1(-/-) single mutants, and further reduced or absent in Hoxa3(+/-)Pax1(-/-) compound mutants. Subsequent to organ-specific differentiation from the shared primordium, both the parathyroids and thymus developed defects. Parathyroids in compound mutants were smaller at their formation, and absent at later stages. Parathyroids were also reduced in Pax1(-/-) mutants, revealing a new function for Pax1 in parathyroid organogenesis. Thymic hypoplasia at later fetal stages in compound mutants was associated with increased death and decreased proliferation of thymic epithelial cells. Our results suggest that a Hoxa3-Pax1 genetic pathway is required for both epithelial cell growth and differentiation throughout thymus and parathyroid organogenesis.

Gamma -secretase inhibitors repress thymocyte development.

A major therapeutic target in the search for a cure to the devastating Alzheimer's disease is gamma-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of Abeta42 peptides, precipitates of which are thought to cause the disease. Gamma-secretase is also a critical component of the Notch signal transduction pathway; Notch signals regulate development and differentiation of adult self-renewing cells. This has led to the hypothesis that therapeutic inhibition of gamma-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. Here, we show that application of gamma-secretase inhibitors to fetal thymus organ cultures interferes with T cell development in a manner consistent with loss or reduction of Notch1 function. Progression from an immature CD4-/CD8- state to an intermediate CD4+/CD8+ double-positive state was repressed. Furthermore, treatment beginning later at the double-positive stage specifically inhibited CD8+ single-positive maturation but did not affect CD4+ single-positive cells. These results demonstrate that pharmacological gamma-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and present a system in which rapid evaluation of gamma-secretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed in a relevant context.

Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch.

The thymus and parathyroids originate from a common primordium that develops from the third pharyngeal pouch in mice and humans. The molecular mechanism that specifies this primordium into distinct organ domains is not known. The Gcm2 and Foxn1 transcription factors are required for development of the parathyroid and thymus respectively, and are attractive candidates for this role. However, their embryonic expression patterns during pharyngeal pouch development and early thymus and parathyroid organogenesis have not been described. Here we report that Gcm2 is expressed specifically in the developing second and third pharyngeal pouches at E9.5, and is further confined to a small domain of the third pouch endoderm by E10.5. In contrast, Foxn1 is not expressed until after the common primordium is formed, beginning at E11.25. Our results show that Gcm2 and Foxn1 expression mark two complementary domains that prefigure parathyroid and thymus regions within the common primordium before morphological distinctions are present.

Fetal parathyroids are not required to maintain placental calcium transport.

We used Hoxa3 knockout mice and other mouse models to study the role of the fetal parathyroids in fetal calcium homeostasis. Hoxa3-null fetuses lack parathyroid glands, and absence of parathyroid hormone (PTH) was confirmed with a rodent PTH immunoradiometric assay. The ionized calcium level of Hoxa3-null fetuses was significantly lower than that of wild-type or heterozygous littermates or of the mother. Both the rate of placental calcium transfer and the plasma PTHrP level were normal in Hoxa3 mutants and their heterozygous siblings. Because we had previously observed an increase in placental calcium transfer in PTH/PTHrP receptor 1-null (Pthr1-null) fetuses, we assayed plasma PTHrP in those mice. Pthr1-null fetuses had plasma PTHrP levels 11-fold higher than those of their littermates. Northern analysis, immunohistochemical, and in situ hybridization studies of Pthr1-null fetuses indicated that liver and placenta had increased expression of PTHRP: In summary, loss of fetal parathyroids in Hoxa3-null fetuses caused marked hypocalcemia but did not alter placental calcium transfer or the circulating PTHrP level. The findings in the Pthr1-null fetuses indicate that several tissues may contribute to the circulating PTHrP level in fetal mice.

Compendium of chemical carcinogens by target organ: results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys.

A compendium of carcinogenesis bioassay results organized by target organ is presented for 738 chemicals that are carcinogenic in chronic-exposure, long-term bioassays in at least 1 species. This compendium is based primarily on experiments in rats or mice; results in hamsters, monkeys, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites and to determine whether target sites are the same for chemicals positive in more than 1 species. The source of information is the Carcinogenic Potency Database (CPDB). which includes results of 6073 experiments on 1458 chemicals (positive or negative for carcinogenicity) that have been reported in Technical Reports of the National Cancer Institute/National Toxicology Program or in papers in the general published literature. The published CPDB includes detailed analyses of each test and citations. The CPDB is publicly available in several formats (http://potency.berkeley.edu). Chemical carcinogens are reported for 35 different target organs in rats or mice. Target organs in humans are also summarized for 82 agents that have been evaluated as human carcinogens at a particular target site by the International Agency for Research on Cancer (IARC). Comparisons are provided of target organs for mutagens versus nonmutagens and rats versus mice.

Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation.

In the mature thymus, thymocyte maturation depends on interactions with different thymic epithelial subtypes in a three-dimensional thymic architecture. However, the molecular mechanisms that generate these epithelial subtypes are not well understood. Evidence is accumulating that during fetal thymus development, epithelial cells differentiate by successive interactions with differentiating thymocytes. This review presents fetal thymus development as a process of organogenesis, the main function of which is to promote thymic epithelial cell differentiation and the generation of a functional thymic microenvironment. In this model, endoderm-derived epithelial cells are the driving force in generating the thymic primordium, with hematopoietic cells providing later signals that organize and pattern the developing thymus.

Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study.

BACKGROUND: Vitamin A and its metabolites have been shown to be teratogenic in animals and humans producing defects of neural crest derived structures that include abnormalities of the craniofacial skeleton, heart, and thymus. Our prior studies with retinoic acid have established that gestational day (gd) 9 is a sensitive embryonic age in the mouse for inducing craniofacial and thymic defects. METHODS: We exposed pregnant mice to variable doses of vitamin A (retinyl acetate) on gd 9 and embryos were evaluated for changes in developing pharyngeal arch and pouch morphology, neural crest cell migration and marker gene expression. Additionally, we investigated whether a single organ system was more sensitive to low doses of vitamin A and could potentially be used as an indicator of vitamin A exposure during early gestation. RESULTS: High (100 mg/kg) and moderate (50 and 25 mg/kg) doses of vitamin A resulted in significant craniofacial, cardiac outflow tract and thymic abnormalities. Low doses of vitamin A (10 mg/kg) produced craniofacial and thymic abnormalities that were mild and of low penetrance. Exposed embryos showed morphologic changes in the 2nd and 3rd pharyngeal arches and pouches, changes in neural crest migration, abnormalities in cranial ganglia, and altered expression of Hoxa3. CONCLUSIONS: These animal studies, along with recent epidemiologic reports on human teratogenicity with vitamin A, raise concerns about the potential for induction of defects (perhaps subtle) in offspring of women ingesting even moderate to low amounts of supplemental vitamin A during the early gestational period.

Hoxa3 and pax1 transcription factors regulate the ability of fetal thymic epithelial cells to promote thymocyte development.

Thymocyte maturation into T cells depends on interactions between thymocytes and thymic epithelial cells. In this study, we show that mutations in two transcription factors, Hoxa3 and Pax1, act synergistically to cause defective thymic epithelial cell development, resulting in thymic ectopia and hypoplasia. Hoxa3+/-Pax1-/- compound mutant mice exhibited more severe thymus defects than Pax1-/- single mutants. Fetal liver adoptive transfer experiments revealed that the defect resided in radio-resistant stromal cells and not in hematopoietic cells. Compound mutants have fewer MHC class II+ epithelial cells, and the level of MHC expression detected was lower. Thymic epithelial cells in these mutants have reduced ability to promote thymocyte development, causing a specific block in thymocyte maturation at an early stage that resulted in a dramatic reduction in the number of CD4+8+ thymocytes. This phenotype was accompanied by increased apoptosis of CD4+8+ thymocytes and their immediate precursors, CD44-25-(CD3-4-8-) cells. Our results identify a transcriptional regulatory pathway required for thymic epithelial cell development and define multiple roles for epithelial cell regulation of thymocyte maturation at the CD4-8- to CD4+8+ transition.

Effect of Trillium Biopassive Surface coating of the oxygenator on platelet count drop during cardiopulmonary bypass.

The new Trillium Biopassive Surface is a coating designed to minimize the adsorption of protein and the attachment of cells. In previous studies, we were able to demonstrate that, by coating the bypass circuit with small amounts of albumin, the drop in circulating platelet count seen with the newer low-prime hollow-fiber membrane oxygenators is eliminated. A study was undertaken to compare the Avecor Affinity oxygenator with albumin in the prime with the Trillium-coated Affinity. Fifty-six patients undergoing nonemergency open-heart surgery were randomly divided into two groups. One group (Albumin) received the Affinity oxygenator with 10 ml of 25% albumin added to the pump prime. The other group (Trillium) received the Trillium-coated Affinity oxygenator. To normalize the data for the effects of hemodilution, the mean net platelet count drop on bypass was calculated for each group. The Albumin group had a net platelet count drop of 0.81+/-9.78%, while the Trillium group had a drop of 1.58+/-13.0%. There was no significant statistical difference between the two groups. From our investigation, we concluded that Trillium Biopassive Surface coating affords the Affinity oxygenator the same protective effects on circulating platelet counts as adding albumin to the prime.

Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996.

The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of results of chronic, long-term cancer tests. This paper presents a supplemental plot of the CPDB, including 513 experiments on 157 test compounds published in the general literature in 1993 and 1994 and in Technical Reports of the National Toxicology Program in 1995 and 1996. The plot standardizes the experimental results (whether positive or negative for carcinogenicity), including qualitative data on strain, sex, route of compound administration, target organ, histopathology, and author's opinion and reference to the published paper, as well as quantitative data on carcinogenic potency, statistical significance, tumor incidence, dose-response curve shape, length of experiment, duration of dosing, and dose rate. A numerical description of carcinogenic potency, the TD(subscript)50(/subscript), is estimated for each set of tumor incidence data reported. When added to the data published earlier, the CPDB now includes results of 5,620 experiments on 1,372 chemicals that have been reported in 1,250 published papers and 414 National Cancer Institute/National Toxicology Program Technical Reports. The plot presented here includes detailed analyses of 25 chemicals tested in monkeys for up to 32 years by the National Cancer Institute. Half the rodent carcinogens that were tested in monkeys were not carcinogenic, despite usually strong evidence of carcinogenicity in rodents and/or humans. Our analysis of possible explanatory factors indicates that this result is due in part to the fact that the monkey studies lacked power to detect an effect compared to standard rodent bioassays. Factors that contributed to the lack of power are the small number of animals on test; a stop-exposure protocol for model rodent carcinogens; in a few cases, toxic doses that resulted in stoppage of dosing or termination of the experiment; and in a few cases, low doses administered to monkeys or early termination of the experiment even though the doses were not toxic. Among chemicals carcinogenic in both monkeys and rodents, there is some support for target site concordance, but it is primarily restricted to liver tumors. Potency values are highly correlated between rodents and monkeys. The plot in this paper can be used in conjunction with the earlier results published in the CRC Handbook of Carcinogenic Potency and Genotoxicity Databases [Gold LS, Zeiger E, eds. Boca Raton FL:CRC Press, 1997] and with our web site (http://potency.berkeley.edu), which includes a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency (TD50), and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Two summary tables permit easy access to the literature of animal cancer tests by target organ and by chemical. For readers using the CPDB extensively, a combined plot on diskette or other format is available from the first author. It includes all results published earlier and in this paper, ordered alphabetically by chemical. A SAS database is also available.

Albumin in the cardiopulmonary bypass prime: how little is enough?

Previous studies have demonstrated high transoxygenator pressures with noncoated hollow-fiber membrane oxygenators. These reports have been associated with dramatic platelet count drops during cardiopulmonary bypass (CPB). It has also been shown that adding human albumin to the prime of the bypass circuit reduces, if not eliminates, these problems. This study was conducted to determine what is the smallest amount of albumin added to the prime that will still display its protective effects. Eighty patients undergoing nonemergency open-heart surgery were randomly divided into four groups. Groups I and II received the Sarns Turbo 440 oxygenator with 0.0375 g of albumin/100 ml of prime and 0.125 g of albumin/100 ml of prime, respectively, added to the pump prime. Groups III and IV received the Medtronic Maxima-PRF oxygenator with 0.0375 g of albumin/100 ml of prime and 0.125 g of albumin/100 ml of prime, respectively, added to the pump prime. Pre-CPB, on CPB (15-20 min after the initiation of bypass) and warming hemoglobin, hematocrit and platelet counts were drawn on all patients. Net platelet count drop, which accounted for hemodilutional effects, was calculated for all specimens and compared to previous results obtained from the test oxygenators without albumin in the prime. The net platelet count drops for the study groups were as follows: Sarns oxygenator with no albumin in the prime = 11.8+/-12.5%; Sarns oxygenator with 0.0375 g of albumin/100 ml prime = -3.7+/-10.8%; Sarns oxygenator with 0.125 g of albumin/100 ml prime = -2.0+/-12.6%; Medtronic oxygenator with no albumin in the prime = 20.1+/-14.5%; Medtronic oxygenator with 0.0375 g albumin/100 ml prime = -6.9+/-8.7%; and Medtronic oxygenator with 0.125 g albumin/100 ml prime = -14.0+/-12.4%. Our results illustrate that adding as little as 0.0375 g albumin/100 ml prime (3 ml of 25% solution/2000 ml of prime) to the pump prime illicits the beneficial effects of surface coating on platelet loss during CPB.

Effect of surface coating on platelet count drop during cardiopulmonary bypass.

This study was designed to investigate the effect of surface coating on platelet count drop during cardiopulmonary bypass (CPB). Sixty patients undergoing open-heart surgery were randomly divided into three groups each receiving a different type of coated hollow-fiber membrane oxygenator. The patients were given either an uncoated oxygenator (noncoated group), an oxygenator coated with Carmeda (Carmeda group) or an uncoated oxygenator with albumin in the priming solution (albumin group). Comparisons were made in platelet count pre-CPB, on bypass (15-25 min) and during the warming period. Calculations were used to account for the effect of hemodilution. The albumin group had significantly lower platelet count drops (-4.8+/-7.1%) than the Carmeda group (11.0+/-8.3%) and the noncoated group (20.3+/-14.5%). Carmeda surface coating demonstrated some beneficial effects, but to a lesser degree than the albumin.

Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands.

The thymus, thyroid, and parathyroid glands in vertebrates develop from the pharyngeal region, with contributions both from pharyngeal endoderm and from neural crest cells in the pharyngeal arches. Hoxa3 mutant homozygotes have defects in the development of all three organs. Roles for the Hoxa3 paralogs, Hoxb3 and Hoxd3, were investigated by examining various mutant combinations. The thyroid defects seen in Hoxa3 single mutants are exacerbated in double mutants with either of its paralogs, although none of the double-mutant combinations resulted in thyroid agenesis. The results indicate that the primary role of these genes in thyroid development is their effect on the development and migration of the ultimobranchial bodies, which contribute the parafollicular or C-cells to the thyroid. Hoxb3, Hoxd3 double mutants show no obvious defects in the thymus or parathyroids. However, the removal of one functional copy of Hoxa3 from the Hoxb3, Hoxd3 double mutants (Hoxa3 +/-, Hoxb3-/-, Hoxd3-/-) results in the failure of the thymus and parathyroid glands to migrate to their normal positions in the throat. Very little is known about the molecular mechanisms used to mediate the movement of tissues during development. These results indicate that Hoxa3, Hoxb3, and Hoxd3 have highly overlapping functions in mediating the migration of pharyngeal organ primordia. In addition, Hoxa3 has a unique function with respect to its paralogs in thymus, parathyroid, and thyroid development. This unique function may be conferred by the expression of Hoxa3, but not Hoxb3 nor Hoxd3, in the pharyngeal pouch endoderm.

Retinoic acid-induced thymic abnormalities in the mouse are associated with altered pharyngeal morphology, thymocyte maturation defects, and altered expression of Hoxa3 and Pax1.

Exogenous retinoic acid is teratogenic in animals and man, causing a spectrum of abnormalities termed retinoic acid embryopathy. Using a mouse model of retinoic acid embryopathy, our results show that exposure to all-trans retinoic acid (RA) on gestational day (gd) 9 results in thymic ectopia, hypoplasia, and thymocyte maturational defects. Immunohistochemical and flow cytometric analyses showed aberrant expression of stromal and thymocyte markers, and abnormalities in thymocyte development. RNA in situ hybridization for the transcription factors Hoxa3 and Pax1 was used to investigate the basis of this defect. Hoxa3 and Pax1 have been shown to be required for normal thymus development, and are normally expressed in the cells of the third pharyngeal pouch and third and fourth pharyngeal arches, involved in thymus organogenesis RA-exposed embryos showed an increased level of Hoxa3 expression in the neural tube and caudal pharyngeal arches as soon as 6 hr after exposure. The Pax1 expression pattern, in conjunction with analysis of the external pharyngeal morphology, showed that the development and structure of the third pharyngeal pouch and cleft were disrupted, resulting in a reduced third pharyngeal arch and/or fusion of the third and fourth arches. Changes in the expression of cellular retinoic acid binding protein (CRABP) and in the morphology of the cranial ganglia were consistent with altered neural crest cell migration from the caudal hindbrain after RA exposure. Together, our findings suggest that the teratogenic effects of RA on thymus development include changes in both the cranial neural crest and pharyngeal endoderm that contribute to thymus development. Further, the observed defects in thymus development may be mediated by RA-induced alterations in the expression of Hoxa3.

Pesticide residues in food: investigation of disparities in cancer risk estimates.

Much of the public perceives that exposure to synthetic pesticide residues in the diet is a major cause of cancer. The National Research Council (NRC), in a 1987 report, Regulating Pesticides in Food: The Delaney Paradox, evaluated cancer risks for 29 pesticides that are rodent carcinogens and estimated that the risks for 23 were greater than one-in-a-million. In contrast, our group has ranked possible carcinogenic hazards from a variety of human exposures to rodent carcinogens using the HERP (Human Exposure/Rodent Potency) index, and found that dietary residues of synthetic pesticides ranked low. This paper evaluates the disparities in these analyses by examining the two components of risk assessment: carcinogenic potency in rodents and human exposure. Potency estimates based on rodent bioassay data are shown to be similar whether calculated, as in the NRC report, as the regulatory q1* or as TD50. In contrast, estimates of dietary exposure to residues of synthetic pesticides vary enormously, depending on whether they are based on the Theoretical Maximum Residue Contribution (TMRC) calculated by the Environmental Protection Agency vs. the average dietary residues measured by the Food and Drug Administration in the Total Diet Study (TDS). The TMRC is the theoretical maximum human exposure anticipated under the most severe field application conditions, which are far greater than dietary residues measured in the TDS. Several independent exposure studies suggest that the FDA dietary residues are reasonable estimates of average human exposures, whereas TMRC values are large overestimates. Using standard methodology and measured dietary residues in the TDS, the estimate of excess cancer risk from average lifetime exposure to synthetic pesticide residues in the diet appears to be less than one-in-a-million for each of the ten pesticides for which adequate data were available.

A cost analysis of alfentanil+propofol vs morphine+midazolam for the sedation of critically ill patients.

Morphine + midazolam and alfentanil + propofol are regimens offering well tolerated and effective sedation for critically ill patients. However, morphine + midazolam is associated with accumulation in these patients, resulting in prolonged recovery characteristics. Alfentanil+propofol, although more expensive, has a shorter elimination half-life, is not associated with accumulation problems and results in a rapid recovery. This study compared sedation quality, patient recovery characteristics and the cost of alfentanil + propofol and morphine + midazolam for sedating critically ill patients in the intensive care setting. 26 patients were randomly allocated to receive sedation with alfentanil + propofol (n = 17) or morphine + midazolam (n = 9). Outcome measures were the times until extubation, intensive care unit (ICU) transfer and final hospital discharge. Cost analysis assessed both drug-related costs, including drug acquisition and administration, and non-drug-related costs, including bed occupancy. Age, gender, diagnosis, Acute Physiological and Chronic Health Evaluation (APACHE) II scores and sedation quality did not differ significantly between groups. The times to extubation and until patients were fit for transfer from ICU were significantly shorter for patients sedated with alfentanil + propofol than for those sedated with morphine + midazolam. The total costs (at the time of the study Pounds 1 was equivalent to $US1.59) for ICU hospital stay per patient for alfentanil + propofol and morphine + midazolam were 3063 Pounds and 9511 Pounds, respectively, because the shorter recovery characteristics of alfentanil + propofol led to a reduction in ICU stay. Corresponding costss for total hospital stay were 6063 Pounds and 13735 Pounds, respectively. In conclusion, alfentanil + propofol has a better pharmacoeconomic profile than morphine + midazolam for sedating critically ill patients in the ICU setting.