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BACKGROUND: Epidural analgesia is considered optimal for postoperative pain management after major abdominal surgery. The potential to decrease anesthetic and opioid exposure is particularly desirable for infants, given their vulnerability to respiratory depression and concern for anesthetic neurotoxicity. We reviewed our experience with infants undergoing major abdominal surgery to determine if epidural catheter use decreased anesthetic and opioid exposure and improved postoperative analgesia. METHODS: This retrospective cohort study included infants (<12 months) who underwent exploratory laparotomy, ureteral reimplantation, or bladder exstrophy repair between November 2011 and November 2014. Primary outcomes of anesthetic exposure (mean endtidal sevoflurane) and intraoperative opioid administration were compared between infants who received epidural catheters and those who did not. Secondary outcomes included postoperative pain and sedation scores and morphine equivalents administered 0-24 and 24-48 hours after surgery. RESULTS: Of 158 eligible infants, 82 were included and 47 received epidurals. Patients with epidurals underwent bladder exstrophy repair (N = 9), ureteral reimplantation (N = 8), and exploratory laparotomy (N = 30). Infants with epidurals received less intraoperative fentanyl (2.6 mcg/kg (0,4.5) vs 3.3 mcg/kg (2.4,5.8), P = 0.019) and morphine (6% (3/47) vs 26% (9/35), P = 0.014) in univariate analysis. After controlling for age and emergency surgery, differences in long-acting opioid administration persisted, with significantly less morphine given in the epidural group (OR 0.181; 95% CI 0.035-0.925; P = 0.040). Mean endtidal sevoflurane concentrations were similar between groups. There was no significant difference in postoperative median morphine equivalents. CONCLUSION: Placement of epidural catheters in infants undergoing major abdominal surgery is associated with decreased long-acting opioid requirements intraoperatively. Epidural placement does not preclude opioid exposure however, as opioids may be administered for indications other than nociceptive pain in the difficult-to-assess postoperative infant. Further prospective studies are warranted to better quantify the effect of epidural analgesia on intraoperative anesthetic exposure in infants.
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Analgesia Epidural , Analgesia/métodos , Analgésicos Opioides/administración & dosificación , Anestésicos/administración & dosificación , Dolor Postoperatorio/tratamiento farmacológico , Humanos , Lactante , Recién Nacido , Estudios RetrospectivosRESUMEN
UNLABELLED:  Background. Erythropoietin (Epo) and its cognate receptor (EpoR) have been recently identified in nonhematopoietic cells. Epo structural variants, which possess tissue protective effects while exhibiting no effect on erythropoiesis, appear to require a second distinct receptor component, the common ßreceptor (ßcR) of IL-3, IL-5, and GM-CSF for ligand signal transduction. The goal of this work was to determine the temporal and spatial presence of Epo, EpoR, and ßcR in porcine wound fluid and granulation tissue. METHODS: A ventral hernia, surgically created in the abdominal wall of female swine (n = 8), was repaired with silicone sheeting and skin closure. Over time, a fluid-filled wound compartment formed, bounded by subcutaneous and omental granulation tissue; its thickness was measured by ultrasonography. Serial wound fluid samples were obtained by percutaneous aspiration. On day 14, the animals were sacrificed. Protein isolated from skin, kidney, granulation tissue, and peritoneal and wound fluids was analyzed by Western blotting. Sections of formalin-fixed abdominal wall tissue were stained for immunoreactivity to Epo, EpoR, and ßcR. RESULTS: A progressive increase in granulation tissue thickness was measured during the 14-day interval. Western blot analysis of serial wound fluid samples demonstrated an 8-fold increase in local wound fluid Epo concentration. Immunoblotting of day 0 skin and day 14 granulation tissue homogenates demonstrated presence of Epo, EpoR, and ßcR in wound granulation tissue but not in control skin. Immunostaining demonstrated localization of Epo and its receptors in granulation endothelial cells, fibroblasts, macrophages, and smooth muscle cells. CONCLUSION: Temporal expression of soluble Epo was associated with a progressive increase in porcine granulation tissue formation. Receptor expression, spatially localized to cellular constituents of granulation tissue, increased in the wound environment compared to control tissue. Epo variants, which signal via a heteroreceptor complex including both EpoR and ßcR, may be an effective therapeutic approach to improve wound healing.
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Sleep apnea, defined as intermittent respiratory arrest during sleep, is associated with increased incidence of hypertension and peripheral vascular disease. Exposure of rodents to brief periods of intermittent hypercarbia/hypoxia (H-IH) during sleep mimics the cyclical hypoxia-normoxia of sleep apnea. Endothelin-1, an upstream activator of nuclear factor of activated T cells (NFAT), is increased during H-IH. Therefore, we hypothesized that NFATc3 is activated by H-IH and is required for H-IH-induced hypertension. Consistent with this hypothesis, we found that H-IH (20 brief exposures per hour to 5% O(2)-5% CO(2) for 7 h/day) induces systemic hypertension in mice [mean arterial pressure (MAP) = 97 +/- 2 vs. 124 +/- 2 mmHg, P < 0.05, n = 5] and increases NFATc3 transcriptional activity in aorta and mesenteric arteries. Cyclosporin A, an NFAT inhibitor, and genetic ablation of NFATc3 [NFATc3 knockout (KO)] prevented NFAT activation. More importantly, H-IH-induced hypertension was attenuated in cyclosporin A-treated mice and prevented in NFATc3 KO mice. MAP was significantly elevated in wild-type mice (Delta = 23.5 +/- 6.1 mmHg), but not in KO mice (Delta = -3.9 +/- 5.7). These results indicate that H-IH-induced increases in MAP require NFATc3 and that NFATc3 may contribute to the vascular changes associated with H-IH-induced hypertension.
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Presión Sanguínea , Calcineurina/metabolismo , Hipertensión/etiología , Hipoxia/complicaciones , Factores de Transcripción NFATC/metabolismo , Síndromes de la Apnea del Sueño/complicaciones , Animales , Aorta/metabolismo , Aorta/fisiopatología , Presión Sanguínea/efectos de los fármacos , Inhibidores de la Calcineurina , Ciclosporina/farmacología , Ciclosporina/uso terapéutico , Modelos Animales de Enfermedad , Endotelina-1/genética , Endotelina-1/metabolismo , Hipertensión/genética , Hipertensión/metabolismo , Hipertensión/fisiopatología , Hipertensión/prevención & control , Hipoxia/tratamiento farmacológico , Hipoxia/genética , Hipoxia/metabolismo , Hipoxia/fisiopatología , Pulmón/metabolismo , Masculino , Arterias Mesentéricas/metabolismo , Arterias Mesentéricas/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Factores de Transcripción NFATC/antagonistas & inhibidores , Factores de Transcripción NFATC/deficiencia , Factores de Transcripción NFATC/genética , ARN Mensajero/metabolismo , Síndromes de la Apnea del Sueño/tratamiento farmacológico , Síndromes de la Apnea del Sueño/genética , Síndromes de la Apnea del Sueño/metabolismo , Síndromes de la Apnea del Sueño/fisiopatología , Factores de Tiempo , Transcripción Genética , Regulación hacia ArribaRESUMEN
We reported previously that simulating sleep apnea by exposing rats to eucapnic intermittent hypoxia (E-IH) causes endothelin-dependent hypertension and increases constrictor sensitivity to endothelin-1 (ET-1). In addition, augmented ET-1-induced constriction in small mesenteric arteries (sMA) is mediated by increased Ca(2+) sensitization independent of Rho-associated kinase. We hypothesized that exposing rats to E-IH augments ET-1-mediated vasoconstriction by increasing protein kinase C (PKC)-dependent Ca(2+) sensitization. In sMA, the nonselective PKC inhibitor GF-109203x (3 microM) significantly inhibited ET-1-stimulated constriction in E-IH arteries but did not affect ET-1-stimulated constriction in sham arteries. Phospholipase C inhibitor U-73122 (1 microM) also inhibited constriction by ET-1 in E-IH but not sham sMA. In contrast, the classical PKC (cPKC) inhibitor Gö-6976 (1 microM) had no effect on ET-1-mediated vasoconstriction in either group, but a PKCdelta-selective inhibitor (rottlerin, 3 microM) significantly decreased ET-1-mediated constriction in E-IH but not in sham sMA. ET-1 increased PKCdelta phosphorylation in E-IH but not sham sMA. In contrast, ET-1 constriction in thoracic aorta from both sham and E-IH rats was inhibited by Gö-6976 but not by rottlerin. These observations support our hypothesis that E-IH exposure significantly increases ET-1-mediated constriction of sMA through PKCdelta activation and modestly augments ET-1 contraction in thoracic aorta through activation of one or more cPKC isoforms. Therefore, upregulation of a PKC pathway may contribute to elevated ET-1-dependent vascular resistance in this model of hypertension.
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Dióxido de Carbono/fisiología , Endotelina-1/farmacología , Hipoxia/fisiopatología , Proteína Quinasa C-delta/fisiología , Vasoconstricción/efectos de los fármacos , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diglicéridos/metabolismo , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/fisiología , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Proteína Quinasa C-delta/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Fosfolipasas de Tipo C/antagonistas & inhibidores , Vasoconstricción/fisiologíaRESUMEN
Vascular alpha(2B)-adrenoceptors (alpha(2B)-AR) may mediate vasoconstriction and contribute to the development of hypertension. Therefore, we hypothesized that blood pressure would not increase as much in mice with mutated alpha(2B)-AR as in wild-type (WT) mice following nitric oxide (NO) synthase (NOS) inhibition with N(omega)-nitro-l-arginine (l-NNA, 250 mg/l in drinking water). Mean arterial pressure (MAP) was recorded in heterozygous (HET) alpha(2B)-AR knockout mice and WT littermates using telemetry devices for 7 control and 14 l-NNA treatment days. MAP in HET mice was increased significantly on treatment days 1 and 4 to 14, whereas MAP did not change in WT mice (days 0 and 14 = 113 +/- 3 and 114 +/- 4 mmHg in WT, 108 +/- 0.3 and 135 +/- 13 mmHg in HET, P < 0.05). MAP was significantly higher in HET than in WT mice days 10 through 14 (P < 0.05). Thus blood pressure increased more rather than less in mice with decreased alpha(2B)-AR expression. We therefore examined constrictor responses to phenylephrine (PE, 10(-9) to 10(-4) M) with and without NOS inhibition to determine basal NO contributions to arterial tone. In small pressurized mesenteric arteries (inner diameter = 177 +/- 5 microm), PE constriction was decreased in untreated HET arteries compared with WT (P < 0.05). l-NNA (100 microM) augmented PE constriction more in HET arteries than in WT arteries, and responses were not different between groups in the presence of l-NNA. Acetylcholine dilated preconstricted arteries from HET mice more than arteries from WT mice. Endothelial NOS expression was increased in HET compared with WT mesenteric arteries by Western analysis. Griess assay showed increased NO(x) concentrations in HET plasma compared with those in WT plasma. These data demonstrate that diminished alpha(2B)-AR expression increases the dependence of arterial pressure and vascular tone on NO production and that vascular alpha(2B)-AR either directly or indirectly regulates vascular endothelial NOS function.