"Right to die": ...but context of limited resources can be encountered in developed countries too.
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Humans↗
Biomedical subjects
William O Tarnow-Mordi
Publications and source records attributed to William O Tarnow-Mordi.
What have we learned about randomized, controlled trials in neonatal sepsis?
OBJECTIVE: To identify strategies to enable randomized, controlled trials in neonatal sepsis to recognize therapies that increase disability-free survival. METHODS: Rapid literature review. RESULTS: Randomized, controlled trials are the gold standard for testing a therapy because they minimize bias. However, randomized, controlled trials must also minimize random error if they are to detect moderate (and realistic) improvements in rates of disability-free survival reliably. This requires surprisingly large samples (i.e., thousands rather than hundreds). Against this perspective, most neonatal trials have been too small to be conclusive, so most neonatal therapies remain incompletely evaluated. As in specialties like cardiology and obstetrics, achieving reliable trials in neonatal sepsis will require international collaboration, simpler data sets, more cost-effective recruitment strategies, less exclusive criteria for selecting collaborators and patients, and an appreciation by clinicians and data-monitoring committees that substantially greater sample sizes are needed to limit the play of chance. Prospective meta-analysis using individual patient data is a promising strategy. It requires researchers to obtain funding from their national agencies to conduct similar trials according to an agreed protocol with prespecified hypotheses, interventions, power calculations, data sets, and measures of outcome. Prospective meta-analysis combines the methodologic advantages of a single "megatrial" with the practical advantages that financial burdens are spread internationally and different national funding cycles can be more flexibly accommodated. CONCLUSIONS: Prospective meta-analysis using individual patient data is a promising strategy for achieving large-scale, randomized evidence in neonatal sepsis.
Critical Illness↗
What is the role of neonatal organ dysfunction and illness severity scores in therapeutic studies in sepsis?
The goal of therapeutic studies in neonatal sepsis is to increase disability-free survival. Mortality may not be an adequate measure of outcome if it is reduced at the cost of increased disability. No neonatal organ dysfunction score has yet been validated as a reliable surrogate for disability-free survival. To validate a score as a surrogate would require randomized trials showing 1) a causal connection between change in the score and change in disability-free survival and 2) that the score fully captured all the effects of treatment on disability-free survival. Neonatal illness severity scores provide a convenient, but imperfect, tool to adjust for risk of sepsis in observational studies. They can help to stratify infants by risk of sepsis at entry to trials, allowing analyses of outcome in predefined subgroups. However, they cannot circumvent the need for randomized trials of adequate size in neonatal sepsis, which address disability-free survival as the primary outcome.
Clinical Trials as Topic↗
Noninvasive ventilation.
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Data Interpretation, Statistical↗
An illness severity score and neonatal mortality in retrieved neonates.
UNLABELLED: The Clinical Risk Index for Babies (CRIB) score is a simple tool to measure clinical risk and illness severity in very low birth weight infants. The aim of this study was to determine if a modified CRIB score (MCRIB) used at first telephone contact with a transport service differentiated between retrieved infants who did or did not die in the neonatal period and hence might be a useful triage tool. A retrospective cohort study of 2504 infants, median gestational age 36 weeks and birth weight 2782 g, transported by the New South Wales Newborn and Paediatric Emergency Transport Service (NETS) was performed. MCRIB was calculated at four time points during the retrieval process. The MCRIB score at the time of the first call and the change in the MCRIB score over the retrieval process were related to outcome (neonatal death or survival). The mean MCRIB score at the time of first call was higher in those infants who died during the neonatal period (4.37) than in those who survived (2.63), (P < 0.0001). MCRIB performed better (area under the receiver operator characteristic curves of 0.72) with regard to predicting mortality than gestational age (0.56) or birth weight (0.52). The mean MCRIB score fell progressively from the time of first call to admission at the accepting NICU (P < 0.0001); infants whose MCRIB score increased were more likely to die (P < 0.0001). CONCLUSION: these results suggest an illness severity score, applied at the time of first call to a transport service would be helpful in setting priorities for retrievals.
Analysis of Variance↗
The mortality index for neonatal transportation score: a new mortality prediction model for retrieved neonates.
OBJECTIVE: To develop a mortality prediction score for retrieved neonates based on the information given at the first telephone contact with a retrieval service. METHODS: Data from the New South Wales Newborn and Pediatric Emergency Transport Service database were examined. Analysis was performed with the results for 2504 infants (median gestational age: 36 weeks; range: 24-43 weeks) who were <72 hours of age at the time of referral and whose outcome (neonatal death or survival) was known. The study population was divided randomly into 2 halves, the derivation and validation cohorts. Univariate analysis was performed to identify variables in the derivation cohort related to neonatal death. The variables were entered into a multivariate logistic regression analysis with neonatal death as the outcome. Receiver operator characteristic (ROC) curves were constructed with the regression model and data from the derivation cohort and then the validation cohort. The results were used to generate an integer-based score, the Mortality Index for Neonatal Transportation (MINT) score. ROC curves were constructed to assess the ability of the MINT score to predict perinatal and neonatal death. RESULTS: A 7-variable (Apgar score at 1 minute, birth weight, presence of a congenital anomaly, and infant's age, pH, arterial partial pressure of oxygen, and heart rate at the time of the call) model was constructed that generated areas under ROC curves of 0.82 and 0.83 for the derivation and validation cohorts, respectively. The 7 variables were then used to generate the MINT score, which gave areas under ROC curves of 0.80 for both neonatal and perinatal death. CONCLUSION: Data collected at the first telephone contact by the referring hospital with a regionalized transport service can identify neonates at the greatest risk of dying.
Analysis of Variance↗
Immunopharmacological potential of selective phosphodiesterase inhibition. I. Differential regulation of lipopolysaccharide-mediated proinflammatory cytokine (interleukin-6 and tumor necrosis factor-alpha) biosynthesis in alveolar epithelial cells.
In an attempt to elaborate in vitro on a therapeutic strategy that counteracts an inflammatory signal, we previously reported a novel immunopharmacological potential of glutathione, an antioxidant thiol, in regulating inflammatory cytokines. In the present study, we investigated the hypothesis that selective regulation of phosphodiesterases (PDEs), a family of enzymes that controls intracellular cAMP/cGMP degradation, differentially regulates proinflammatory cytokines. Selective PDE1 inhibition (8-methoxymethyl-3-isobutyl-1-methylxanthine) blockaded lipopolysaccharide-endotoxin (LPS)-mediated biosynthesis of interleukin (IL)-6, but this pathway had no inhibitory effect on tumor necrosis factor-alpha (TNF-alpha). Furthermore, inhibition of PDE3 (amrinone) abolished the effect of LPS on IL-6, but attenuated TNF-alpha production. Reversible competitive inhibition of PDE4 (rolipram) exhibited a potent inhibitory effect on IL-6 and a dual, biphasic (excitatory/inhibitory) effect on TNF-alpha secretion. Blockading PDE5 (4-[[3',4'-(methylenedioxy)benzyl] amino]-6-methoxyquinazoline) showed a high potency in reducing IL-6 production, but in a manner similar to the inhibition of PDE4, exhibited a biphasic effect on TNF-alpha biosynthesis. Simultaneous inhibition of PDE5, 6, and 9 (zaprinast), purported to specifically elevate intracellular cGMP, reduced, in a dose-independent manner, IL-6 and TNF-alpha biosynthesis. Finally, nonselective inhibition of PDE by pentoxifylline suppressed LPS-mediated secretion of IL-6 and TNF-alpha. The involvement of specific PDE isoenzymes in differentially regulating LPS-mediated inflammatory cytokine biosynthesis indicates a novel approach to unravel the potential therapeutic targets that these isozymes constitute during the progression of inflammation within the respiratory epithelium.
Animals↗
Immunopharmacological potential of selective phosphodiesterase inhibition. II. Evidence for the involvement of an inhibitory-kappaB/nuclear factor-kappaB-sensitive pathway in alveolar epithelial cells.
In this report we investigated the immunopharmacological role of selective and nonselective phosphodiesterase (PDE) inhibition in regulating the inhibitory-kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF-kappaB) signaling transduction pathway. In fetal alveolar type II epithelial cells, PDE blockade at the level of the diverging cAMP/cGMP pathways differentially regulated the phosphorylation and degradation of IkappaB-alpha, the major cytosolic inhibitor of NF-kappaB. Whereas selective inhibition of PDEs 1, 3, and 4, by the action of 8-methoxymethyl-3-isobutyl-1-methylxanthine, amrinone, and rolipram, respectively, exhibited a tendency to augment the translocation of NF-kappaB(1) (p50), RelA (p65), RelB (p68), and c-Rel (p75), selective blockade of PDE 5, 6, and 9, by the action of 4-[[3',4'-(methylenedioxy)benzyl]amino]-6-methoxyquinazoline and zaprinast, attenuated lipopolysaccharide-endotoxin (LPS)-mediated NF-kappaB translocation. Pentoxifylline, a nonspecific PDE inhibitor, reversed the excitatory effect of LPS on NF-kappaB subunit nuclear localization, in a dose-dependent manner. Furthermore, analysis of NF-kappaB activation under the same conditions revealed a biphasic effect mediated by LPS. PDEs 1, 3, and 4 inhibition was associated with up-regulating NF-kappaB transcriptional activity. In contrast, blockading the activity of PDEs 5, 6, and 9 negatively attenuated LPS-mediated NF-kappaB activation, similar to the effect of 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione (pentoxifylline). These results indicate that selective and nonselective interference with the control of the dynamic equilibrium of cyclic nucleotides via PDE isoenzyme regulation represents an immunoregulatory mechanism that requires the differential, biphasic targeting of the IkappaB-alpha/NF-kappaB pathway.
Actins↗