The phenylephrine concentration-response relationship for blood pressure after nasal delivery in children.

BACKGROUND: Intranasal phenylephrine is commonly used to vasoconstrict the nasal mucosa, reducing bleeding associated with nasotracheal intubation or endoscopic sinus surgery. There are few data quantifying either absorption pharmacokinetics or phenylephrine concentration effect on blood pressure in children. METHODS: Published observations of plasma concentration and blood pressure changes after phenylephrine nasal administration (0.1 mL kg-1 , 0.25% or 0.5%) in children (n = 52, 2-12 years, 10-40 kg) were pooled with those in adults (23-81 years) given phenylephrine 2.5% (n = 10) and 10% (n = 10) eyedrops. Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, 45 minutes and 1, 2, 3, 6 hours (n = 28). Intravenous time-concentration data were available from four healthy volunteers given phenylephrine 1 mg and who had blood taken for assay on 17 occasions over the subsequent 4 hours. Data were analyzed using an integrated pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed-effects models. Allometry, scaled to a 70-kg person, was used for PK size standardization. Effect was described using an EMAX model. RESULTS: A two-compartment model was used to fit PK data while an additional compartment, linked by an equilibration half-time (T1/2 keo), was used to describe effect. PK parameter estimates for the nasal formulation were clearance (CL) 160 L h-1 , central volume of distribution (V1) 13.3 L, intercompartment clearance (Q) 25.3 L h-1 , peripheral volume of distribution (V2) 225 L, absorption half-time (Tabs) 6.2 minutes, absorption lag time (Tlag) 1.5 minutes, and bioavailability (F) 0.183. Bioavailability and absorption of the ophthalmic solution were concentration dependent (F 0.13, Tabs 5.5 minutes for 2.5% solution; F 0.15, Tabs 9.6 minutes for 10% solution). Absorption of the oral formulation was slow (Tabs 48 minutes) with poor bioavailability (F 0.0128). The pediatric PD interrogation revealed a baseline mean arterial pressure of 60 mm Hg, a maximum effect (EMAX ) of 25 mm Hg, and an EC50 of 10.3 µg L-1 . The effect on vasculature was immediate and T1/2 keo was not estimable. CONCLUSION: Absorption of phenylephrine through the nasal mucosa was rapid and similar to the ophthalmic formulation. Bioavailability was also similar to the ophthalmic formulation. The maximum effect (EMAX ) in children was half that in adults (EMAX 50 mm Hg).

Hemodynamic responses and plasma phenylephrine concentrations associated with intranasal phenylephrine in children.

INTRODUCTION: Intranasal phenylephrine, an alpha-1 adrenergic agonist, causes vasoconstriction of the nasal mucosa and is used to reduce bleeding associated with nasotracheal intubation or endoscopic sinus surgery. The purpose of this study was to describe the hemodynamic effects associated with plasma phenylephrine concentrations following topical intranasal administration of 0.25% and 0.5% phenylephrine in children. METHODS: After Institutional Review Board and parental approval, 77 children between the ages of 2 and 12 years were studied in a prospective, double-blind manner and randomized into three groups. Group 1 received intranasal saline, while groups 2 and 3 received 0.1 mL/kg of 0.25% or 0.5% phenylephrine, respectively. All received the same anesthetic of halothane, N2 O, O2 , and vecuronium. After inhalation induction, endtidal halothane and PaCO2 were maintained at 1.5% and 35 mm Hg, respectively. Heart rate and rhythm, systolic, diastolic, and mean, noninvasive arterial blood pressures were recorded and venous blood was obtained for measurement of plasma phenylephrine concentration by high-performance liquid chromatography at baseline and at 2, 5, 10, and 20 minutes following intranasal spray application of the study drug. Nasotracheal intubation was performed immediately following the 5-minute measurements, and the presence of bleeding was assessed. Hemodynamic data were compared by analysis of variance for repeated measures. Bleeding and arrhythmia incidence among groups were analyzed using chi-squared tests. Phenylephrine levels were correlated with hemodynamic values via regression analysis. RESULTS: Fifty-two patients received intranasal phenylephrine. Increases in blood pressure correlated with increasing plasma phenylephrine concentration. Systolic blood pressure increased 8%, and mean blood pressure increased 14%, which were statistically significant but clinically insignificant. Heart rate did not change, and the incidence of arrhythmia was low and similar among groups. Bleeding following nasotracheal intubation was less frequent in Group 3 (11/27 subjects) than in Group 1 (17/25). Peak plasma phenylephrine concentrations were observed by 14±7 minutes following intranasal administration, and were highly variable among individuals (37.8±39.7 and 49.6±93.9 ng/mL [mean±SD] in Groups 2 and 3). DISCUSSION: Administration of intranasal phenylephrine, 0.25% and 0.50%, results in rapid but highly variable systemic absorption that is associated with mild increases of blood pressure that are clinically insignificant. Bleeding associated with nasotracheal intubation was less following administration of 0.5% intranasal phenylephrine than following intranasal saline.

Using the capnograph to confirm lung isolation when using a bronchial blocker.

The endotracheal tube and bronchial blocker combination is an accepted lung isolation technique used during thoracic surgery. A reliable and inexpensive method of confirming lung isolation that uses capnographic monitoring of the bronchial blocker central lumen is presented. As the bronchial blocker balloon is inflated, lung isolation is confirmed when the normal respiratory variation of carbon dioxide (CO(2)) is replaced by a persistent plateau CO(2) waveform.

Qualitative thrombelastographic detection of tissue factor in human plasma.

BACKGROUND: Tissue factor (TF) is the principal in vivo initiator of coagulation, with normal circulating TF concentrations reported to be approximately 23-158 pg/mL. However, patients with atherosclerosis or cancer have been reported to have TF concentrations ranging between 800 and 9000 pg/mL. Of interest, thrombelastographic (TEG)-based measures of clot initiation and propagation have demonstrated hypercoagulability in such patients at risk for thromboembolic events. Thus, our goal in the present investigation was to establish a concentration-response relationship of the effect of TF on TEG variables, and determine specificity of TF-mediated events with a monoclonal TF antibody. METHODS: Thrombelastography was performed on normal human plasma exposed to 0, 500, 1000, or 2000 pg/mL TF. Additional experiments with plasma exposed to 0 or 750 pg/mL TF in the presence or absence of a monoclonal TF antibody (1:360 dilution, 10 min incubation) were also performed. Clot initiation time (R) and the speed of clot propagation (MRTG, maximum rate of thrombus generation) were determined. RESULTS: The addition of TF to normal plasma resulted in a significant, concentration-dependent decrease in R and increase MRTG values. The addition of TF antibody to samples with TF significantly increased R and decreased MRTG values compared to samples with TF addition. CONCLUSIONS: In conclusion, changes in TEG variables in conjunction with use of a TF antibody can detect pathological concentrations of TF in human plasma in vitro. Further investigation is warranted to determine if TEG(R)-based monitoring could assist in the detection and prevention of TF-initiated thromboembolic events.

Antimicrobial effects of liquid anesthetic isoflurane on Candida albicans.

Candida albicans is a dimorphic fungus that can grow in yeast morphology or hyphal form depending on the surrounding environment. This ubiquitous fungus is present in skin and mucus membranes as a potential pathogen that under opportunistic conditions causes a series of systemic and superficial infections known as candidiasis, moniliasis or simply candidiasis. There has been a steady increase in the prevalence of candidiasis that is expressed in more virulent forms of infection. Although candidiasis is commonly manifested as mucocutaneous disease, life-threatening systemic invasion by this fungus can occur in every part of the body. The severity of candidal infections is associated with its morphological shift such that the hyphal morphology of the fungus is most invasive. Of importance, aberrant multiplication of Candida yeast is also associated with the pathogenesis of certain mucosal diseases. In this study, we assessed the anti-candidal activity of the volatile anesthetic isoflurane in liquid form in comparison with the anti-fungal agent amphotericin B in an in vitro culture system. Exposure of C. albicans to isoflurane (0.3% volume/volume and above) inhibited multiplication of yeast as well as formation of hyphae. These data suggest development of potential topical application of isoflurane for controlling a series of cutaneous and genital infections associated with this fungus. Elucidiation of the mechanism by which isoflurane effects fungal growth could offer therapeutic potential for certain systemic fungal infections.

The impact of tissue factor pathway inhibitor on coagulation kinetics determined by thrombelastography.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a 40-kDa, endogenous protein that inhibits tissue factor (TF)-initiated coagulation by bonding with activated factor X (FXa). The TFPI/FXa complex then subsequently binds with TF/activated factor VII (FVIIa) complex, ultimately inhibiting thrombin generation. Heparin administration causes endothelial release of TFPI concentrations up to sixfold normal values. Thrombelastography (TEG) is often used to monitor hemostasis in the perioperative period, and TFPI could potentially affect the diagnostic interpretation of TEG-based data, given its inhibition of both common and TF coagulation pathways. Thus, in this study we characterized the effect of TFPI on coagulation kinetics via TEG. METHODS: Whole blood, Factor VII-deficient plasma, and normal plasma were exposed in vitro to various concentrations of TFPI, after which unmodified, celite-activated, and TF-activated TEG were performed. RESULTS: The addition of 87.5 ng/mL TFPI (twice normal concentration) was required to prolong clot propagation in whole blood, with propagation and strength only significantly affected by the addition of 175 ng/mL concentrations. Experiments with Factor VII-deficient plasma demonstrated that TFPI-mediated suppression of coagulation kinetics at these concentrations was secondary to FXa inhibition. Celite activation markedly attenuated TFPI-mediated effects on coagulation kinetics, whereas TF activation accentuated TFPI-mediated prolongation of clot initiation and diminution of propagation. CONCLUSIONS: In settings involving heparin administration (e.g., cardiopulmonary bypass), TFPI-mediated inhibition of coagulation should be considered during TEG-based hemostatic monitoring.

An unusual case of emergence delirium.

We present a case of postoperative delirium following endoscopic sinus surgery. We postulate a mechanism for this rare event.

Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect.

One of the key mediators of the hypoxic response in animal cells is the hypoxia-inducible transcription factor-1 (HIF-1) complex, in which the alpha-subunit is highly susceptible to oxygen-dependent degradation. The hypoxic response is manifested in many pathophysiological processes such as tumor growth and metastasis. During hypoxia, cells shift to a primarily glycolytic metabolic mode for their energetic needs. This is also manifested in the HIF-1-dependent up-regulation of many glycolytic genes. Paradoxically, tumor cells growing under conditions of normal oxygen tension also show elevated glycolytic rates that correlate with the increased expression of glycolytic enzymes and glucose transporters (the Warburg effect). A key regulator of glycolytic flux is the relatively recently discovered fructose-2,6-bisphosphate (F-2,6-P2), an allosteric activator of 6-phosphofructo-1-kinase (PFK-1). Steady state levels of F-2,6-P2 are maintained by the bifunctional enzyme PFK-2/F2,6-Bpase, which has both kinase and phosphatase activities. Herein, we show that one isozyme, PFKFB3, is highly induced by hypoxia and the hypoxia mimics cobalt and desferrioxamine. This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau (VHL)-dependent destabilization and tagging of HIF-1 alpha. The absolute dependence of the PFKFB3 gene on HIF-1 was confirmed by its overexpression in VHL-deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF-1 alpha.