Carmine Simone

Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro.

Our objective was to study the characteristics of transfer and biotransformation of nicotine in the human term placenta. Nicotine transfer was studied by dually perfusing an isolated cotyledon of the human placenta in vitro. Nicotine metabolism to cotinine was investigated in intact tissue during perfusion and in placental microsomal fractions. Following the addition of nicotine (40 ng/ml) to the maternal side of the placenta, distribution into placental tissue (0.43 +/- 0.13 ng/ml/min) was three times higher than transfer to the fetal side of the placenta (0.15 +/- 0.01 ng/ml/min). The steady-state maternal-to-fetal transfer of nicotine was approximately 90% that of antipyrine (a marker of flow-dependent transfer). There was no evidence of nicotine metabolism to cotinine by intact placental tissue or in microsomal fractions. The observation that nicotine readily crosses the human placenta with no evidence of metabolism suggests that nicotine has the potential to cause adverse affects on the developing fetus.

Transfer of cocaine and benzoylecgonine across the perfused human placental cotyledon

OBJECTIVE Our aim was to measure the transfer of cocaine and its major metabolite benzoylecgonine across the human term placenta. STUDY DESIGN By means of in vitro perfusion of the human term placental cotyledon the transfer of these compounds was measured. RESULTS The steady-state maternal-to-fetal transfer of cocaine (0.18 +/- 0.05 microgram/ml/min) was significantly greater than benzoylecgonine transfer (0.02 +/- 0.01 microgram/ml/min) (p < 0.05). When the perfused tissue was analyzed 32% +/- 7% of the maternal cocaine dose was retained by the placental tissue, whereas only 12% +/- 12% of the maternal benzoylecgonine dose was retained by the placental compartment. CONCLUSIONS These results suggest (1) the placenta may serve as a depot for large amounts of cocaine, thus offering some degree of fetal protection after bolus administration; (2) fetal exposure may be prolonged by placental retention and subsequent release of cocaine and benzoylecgonine; and (3) benzoylecgonine does not cross the placenta as readily as does cocaine. Variability in placental handling of cocaine and benzoylecgonine may therefore determine fetal exposure to these agents.

Activated protein C in normal human pregnancy and pregnancies complicated by severe preeclampsia: a therapeutic opportunity?

ObjectivesGiven the efficacy and safety of recombinant human activated protein C (rhAPC) in the systemic inflammatory response syndrome, this study was designed to review the evidence for a role for APC in the pathogenesis of preeclampsia. Preeclampsia is a proinflammatory and procoagulant state, and it is a pregnancy-specific condition that mimics the systemic inflammatory response syndrome. rhAPC reduces mortality in patients with systemic inflammatory response syndrome and could potentially have a role as disease-modifying therapy in preeclampsia. To determine which patients would be offered rhAPC, the literature pertaining to fetal/neonatal outcomes for preeclampsia remote from term, transplacental transport of protein C, and pregnancy experience with the compound were reviewed. Data SourcesMEDLINE, review papers, hand searches of relevant nonindexed journals, and the bibliographies of relevant textbooks and articles reviewed. Study SelectionRandomized controlled trials were considered to provide the best quality of clinical data. Case-control series were considered over uncontrolled data. Some data were not available in the published literature (e.g., neonatal outcomes at various gestational ages and birthweights after a hypertensive pregnancy; and transplacental transfer of protein C), and these data were determined by us. Data ExtractionData were extracted by systematic review onto data collection sheets. Because of the quality of the data, this review is primarily qualitative. Data SynthesisAPC levels fall during normal gestation, returning to normal values by 6 wks postpartum. Limited data suggest that early onset preeclampsia is a state of further, and inappropriate, reduction in APC. Preeclampsia resembles systemic inflammatory response syndrome in this regard. After hypertensive pregnancies, neonates have a 50% chance of intact survival if delivered after 27 + 0 wks of gestation with a birthweight of >600 g. It would seem ethical to offer women with preeclampsia with <50% chance of intact perinatal survival novel and potentially disease-modifying therapy such as rhAPC, especially as there is no transplacental transfer of protein C. Limited evidence would support the use of rhAPC in women with severe postpartum preeclampsia. ConclusionsSufficient data exist to support the use of rhAPC in phase II clinical studies for women with either early onset preeclampsia or severe or deteriorating postpartum disease.

Transfer of morphine across the human placenta and its interaction with naloxone

The purpose of this investigation was to measure the transfer rate and clearance of morphine across the placenta with and without naloxone. Term human placental cotyledons were perfused in vitro. The placenta was perfused with 50 ng/mL of morphine in the absence (n=4) and presence (n=5) of 100 ng/mL of naloxone. Maternal and fetal samples were collected. Students t-test or one-way repeated measures ANOVA were used for all comparisons. The maternal-to-fetal morphine transfer rate was 0.73+/-0.44 ng/mL/min in the morphine and 0.69+/-0.26 ng/mL/min in the morphine-naloxone experiments (p=0.89). The clearance of morphine was 0.89+/-0.39 mL/min without naloxone and 0.87+/-0.27 mL/min with naloxone (p=0.92). Final morphine concentrations in the morphine experiments were 9.78+/-6.17 ng/mL (maternal) and 3.43+/-2.14 ng/mL (fetal) and 10.04+/-3.89 ng/mL (maternal) and 4.16+/-1.64 ng/mL (fetal) in the morphine-naloxone experiments. Morphine readily crosses the term human placenta. Naloxone does not alter placental transfer or clearance of morphine, suggesting that transfer across the placental barrier is not altered by changes in vascular resistance. Placental retention of morphine prolongs fetal exposure to morphine.

Quality assessment of economic evaluations in selected pharmacy, medical, and health economics journals

Objective: To assess and compare the quality of economic studies in selected pharmacy, medical, and health economics journals. Data Sources: DICP The Annals of Pharmacotherapy, American Journal of Hospital Pharmacy, Hospital Pharmacy, New England Journal of Medicine, Medical Care, Journal of the American Medical Association, PharmacoEconomics, International Journal of Technology Assessment in Health Care, and Journal of Health Economics using MEDLINE, EMBASE, and International Pharmaceutical Abstracts. Search terms included “economic,” “cost,” and “cost analysis.” Study Selection: Reviewers appraised abstracts to identify original research published during 1989-1993 comparing costs and outcomes between drugs, treatments, and/or services. Initially, 123 articles met criteria; 16 were inappropriate, 17 were randomized out, and 90 (73%) were used (30/group). Data Extraction: Quality was assessed using a 13-item checklist. Interrater reliability was 0.91 (p < 0.05) for 9 raters, test-retest reliability was 0.94 (p < 0.001). Data Synthesis: A 2-way ANOVA, with overall quality scores as a dependent variable with journal type and year as independent variables, was significant (F = 2.79, p = 0.002, r2 = 0.34), with no significant interaction (F = 0.71, p = 0.68) or time effect (F = 0.70, p = 0.60). Journal types differed; pharmacy journals scored significantly lower (χ2= 53.89, df = 2, p < 0.001). Items rated adequate (i.e., correct or acceptable) increased over time (χ2 = 21.18, df = 4, p < 0.001). Ethical issues and study perspective most needed improvement. Conclusions: Article quality for all journal types increased over time nonsignificantly; health economics journals scored highest, then medical journals, with pharmacy journals significantly lower (and having the highest standard deviation). We recommend that authors and reviewers pay closer attention to study perspective and ethical implications.

Drug transfer across the placenta. Considerations in treatment and research.

Using the pregnant woman as a means to medicate her fetus represents a new and exciting therapeutic approach in clinical pharmacology. In years to come, we will see an increase in the use of the currently accepted fetal therapies and an increase in the number of therapies available to the caregiver or clinician aimed at assisting the unborn child. The pharmacologist, through in vitro research that aids our understanding of the role of the placenta in fetal drug therapy, can contribute to the growth of this new field within the realm of obstetric medicine.

When should a diagnosis of influenza be considered in adults requiring intensive care unit admission? Results of population-based active surveillance in Toronto.

IntroductionThere is a paucity of data about the clinical characteristics that help identify patients at high risk of influenza infection upon ICU admission. We aimed to identify predictors of influenza infection in patients admitted to ICUs during the 2007/2008 and 2008/2009 influenza seasons and the second wave of the 2009 H1N1 influenza pandemic as well as to identify populations with increased likelihood of seasonal and pandemic 2009 influenza (pH1N1) infection.MethodsSix Toronto acute care hospitals participated in active surveillance for laboratory-confirmed influenza requiring ICU admission during periods of influenza activity from 2007 to 2009. Nasopharyngeal swabs were obtained from patients who presented to our hospitals with acute respiratory or cardiac illness or febrile illness without a clear nonrespiratory aetiology. Predictors of influenza were assessed by multivariable logistic regression analysis and the likelihood of influenza in different populations was calculated.ResultsIn 5,482 patients, 126 (2.3%) were found to have influenza. Admission temperature ≥38°C (odds ratio (OR) 4.7 for pH1N1, 2.3 for seasonal influenza) and admission diagnosis of pneumonia or respiratory infection (OR 7.3 for pH1N1, 4.2 for seasonal influenza) were independent predictors for influenza. During the peak weeks of influenza seasons, 17% of afebrile patients and 27% of febrile patients with pneumonia or respiratory infection had influenza. During the second wave of the 2009 pandemic, 26% of afebrile patients and 70% of febrile patients with pneumonia or respiratory infection had influenza.ConclusionsThe findings of our study may assist clinicians in decision making regarding optimal management of adult patients admitted to ICUs during future influenza seasons. Influenza testing, empiric antiviral therapy and empiric infection control precautions should be considered in those patients who are admitted during influenza season with a diagnosis of pneumonia or respiratory infection and are either febrile or admitted during weeks of peak influenza activity.

Pro/con clinical debate: are steroids useful in the management of patients with septic shock?

Decision-making in the intensive care unit is often very difficult. Although we are encouraged to make evidence-based decisions, this may be difficult for a number of reasons. To begin with, evidence may not exist to answer the clinical question. Second, when there is evidence it may not be applicable to the patient in question or the clinician may be reluctant to apply it to the patient based on a number of secondary issues such as costs, premorbid condition or possible complications. Finally, emotions are often highly charged when caring for patients that have a significant chance of death, and care-givers as well as families are frequently prepared to take chances on a therapy whose benefit is not entirely clear. Steroid use in septic shock is an example of a therapy that makes some sense but has conflicting support in the literature. In this issue of Critical Care Forum, the two sides of this often heated debate are brought to the forefront in an interesting format.

Incidence and characteristics of needlestick injuries among medical trainees at a community teaching hospital: A cross-sectional study

This field study aimed to determine the incidence and distribution of needlestick injuries among medical trainees at a community teaching hospital in Toronto, Canada.