Remifentanil hydrochloride is an ultra-short-acting opioid that undergoes rapid metabolism by tissue and plasma esterases. We aimed to characterize the pharmacokinetics and determine the hemodynamic ...profile of remifentanil after a single-bolus dose in children aged 0 to 18 yr. Forty-two children undergoing elective surgical procedures received remifentanil 5 microg/kg infused over 1 min. Patients were divided into age groups as follows: young infants (< or =2 mo), older infants (> 2 mo to < 2 yr), young children (2 to < 7 yr), older children (7 to < 13 yr), adolescents (13 to < 16 yr), and young adults (16 to < 18 yr). Arterial blood samples were collected and analyzed by mass spectroscopy to determine remifentanil pharmacokinetic profiles. Hemodynamic measurements for remifentanil's effect were made after the infusion. Methods of statistical analysis included analysis of variance and linear regression, with significance at P < or = 0.05. Complete remifentanil pharmacokinetic data were obtained from 34 patients. The volume of distribution was largest in the infants < 2 mo (mean, 452 mL/kg) and decreased to means of 223 to 308 mL/kg in the older patients. There was a more rapid clearance in the infants < 2 mo of age (90 mL. kg(-1). min(-1)) and infants 2 mo to 2 yr (92 mL. kg(-1). min(-1)) than in the other groups (means, 46 to 76 mL. kg(-1). min(-1)). The half-life was similar in all age groups, with means of 3.4 to 5.7 min. Seven subjects (17%) developed hypotension related to the remifentanil bolus. Remifentanil showed an extremely rapid elimination similar to that in adults. The fast clearance rates observed in neonates and infants, as well as the lack of age-related changes in half-life, are in sharp contrast to the pharmacokinetic profile of other opioids. Remifentanil in a bolus dose of 5 microg/kg may cause hypotension in anesthetized children.
The pharmacokinetics of remifentanil were studied in children from birth to 18 yr. Remifentanil was found to have age-related changes in clearance and volume of distribution, but not half-life. The increased clearance observed in young infants is in contrast to other opioids.
There have been significant changes in the management of neonates and infants undergoing cardiac surgery in the past decade. We have evaluated in this prospective, randomized, double-blinded study ...the effect of large-dose fentanyl anesthesia, with or without midazolam, on stress responses and outcome. Forty-five patients < 6 mo of age received bolus fentanyl (Group 1), fentanyl by continuous infusion (Group 2), or fentanyl-midazolam infusion (Group 3). Epinephrine, norepinephrine, cortisol, adrenocortical hormone, glucose, and lactate were measured after the induction (T1), after sternotomy (T2), 15 min after initiating cardiopulmonary bypass (T3), at the end of surgery (T4), and after 24 h in the intensive care unit (T5). Plasma fentanyl concentrations were obtained at all time points except at T5. Within each group epinephrine, norepinephrine, cortisol, glucose and lactate levels were significantly larger at T4 (P values < 0.01), but there were no differences among groups. Within groups, fentanyl levels were significantly larger in Groups 2 and 3 (P < 0.001) at T4, and among groups, the fentanyl level was larger only at T2 in Group 1 compared with Groups 2 and 3 (P < 0.006). There were no deaths or postoperative complications, and no significant differences in duration of mechanical ventilation or intensive care unit or hospital stay. Fentanyl dosing strategies, with or without midazolam, do not prevent a hormonal or metabolic stress response in infants undergoing cardiac surgery.
We demonstrated a significant endocrine stress response in infants with well compensated congenital cardiac disease undergoing cardiac surgery, but without adverse postoperative outcome. The use of large-dose fentanyl, with or without midazolam, with the intention of providing "stress free" anesthesia, does not appear to be an important determinant of early postoperative outcome.
OBJECTIVES
We reviewed the management and outcome of patients experiencing pulmonary artery (PA) trauma during balloon dilation (BD).
BACKGROUND
Balloon dilation of the PA is important in the ...management of peripheral pulmonary stenosis. Successful BD requires a controlled tear of the PA; excessive tearing can produce complications ranging from pseudoaneurysms to rupture and death. The incidence and optimum management for such complications are unreported.
METHODS
All records of patients who underwent branch PA dilation between June 1984 and October 1997 were reviewed; those with a significant complication were analyzed.
RESULTS
Of 1,286 catheterizations in 782 patients, PA trauma (excluding isolated pulmonary edema and PA aneurysms) was identified in 29 catheterizations in 26 patients. Tears occurred distal to the area of stenosis in most cases (62%). Intensive medical management, with and without catheter directed therapy, was employed. The damaged PA was successfully coil embolized in five patients, four of whom survived; temporary balloon occlusion did not prevent death in two patients. There were six deaths from pulmonary hemorrhage. A case control analysis demonstrated that PA trauma was significantly associated with pulmonary hypertension.
CONCLUSIONS
Pulmonary artery trauma associated with BD occurs mostly distal to the site of narrowing, is associated with underlying pulmonary hypertension and is frequently (5/12 or 42%) fatal in those with unconfined tears. Intensive management strategies as well as attention to distal balloon position may reduce incidence and mortality. Coil occlusion of the damaged PA appears to be a valuable strategy to prevent fatal hemorrhage.
Pyloric stenosis is sometimes associated with hemodynamic instability and postoperative apnea. In this multicenter study we examined the hemodynamic response and recovery profile of remifentanil and ...compared it with that of halothane in infants undergoing pyloromyotomy. After atropine, propofol, and succinylcholine administration and tracheal intubation, patients were randomized (2:1 ratio) to receive either remifentanil with nitrous oxide and oxygen or halothane with nitrous oxide and oxygen as the maintenance anesthetic. Pre- and postoperative pneumograms were done and evaluated by an observer blinded to the study. Intraoperative hemodynamic data and postanesthesia care unit (PACU) discharge times, PACU recovery scores, pain medications, and adverse events (vomiting, bradycardia, dysrhythmia, and hypoxemia) were recorded by the study's research nurse. There were no significant differences in patient age or weight between the two groups. There were no significant differences in hemodynamic values between the two groups at the various intraoperative stress points. The extubation times, PACU discharge times, pain medications, and adverse events were similar for both groups. No patient anesthetized with remifentanil who had a normal preoperative pneumogram had an abnormal postoperative pneumogram, whereas three patients with a normal preoperative pneumogram who were anesthetized with halothane had abnormal pneumograms after.
The use of ultra-short-acting opioids may be an appropriate technique for infants less than 2 mo old when tracheal extubation after surgery is anticipated.
Desflurane is a new potent, inhaled anesthetic agent with low blood-gas solubility that should allow for the rapid induction of and emergence from anesthesia. However, its extreme pungency makes ...desflurane unacceptable for induction of anesthesia in children. This study was undertaken to determine the airway properties of desflurane administered by mask after anesthetic induction with halothane and nitrous oxide, and to compare the emergence and recovery properties of minimum alveolar concentration (MAC)-equivalent concentrations of desflurane or halothane in nitrous oxide in pediatric patients undergoing ambulatory surgery.
Forty-five children undergoing ambulatory surgery for inguinal hernia repair, orchiopexy, and/or circumcision were randomized into two groups. Both groups were premedicated with intranasal midazolam and given halothane and nitrous oxide by mask to induce anesthesia. A caudal block was placed in children in both groups after anesthetic induction. For maintenance of anesthesia, group I patients (n = 22) were switched over to desflurane (1 MAC) and nitrous oxide, and group II patients (n = 23) continued to receive halothane (1 MAC) and nitrous oxide. All patients breathed spontaneously throughout the entire procedure, and all anesthetics were terminated abruptly at the conclusion of surgery. Recovery indicators (time to first response, length of time in the recovery room and length of time in the hospital) and the quality of the anesthetic emergence were assessed by a nurse blinded to each patient's anesthetic. This observer was present with the patient throughout his or her ambulatory hospitalization and continuously assessed the recovery indicators according to preset criteria.
The groups did not differ with respect to age, weight, or dose of midazolam. Although group I (desflurane) had a longer anesthesia time (52 +/- 12 min vs. 42 +/- 10 min), their time to first response (9.5 +/- 6.8 min vs. 20.9 +/- 14.7 min) and their recovery room time (21 +/- 10.7 min vs. 29 +/- 14.6 min) were less than those in group II (halothane). There was a trend for patient emergence from desflurane anesthesia to be associated with a higher incidence of emergence delirium (50% vs. 21%). The two groups were similar with respect to overall duration of postoperative ambulatory hospitalization.
In children premedicated with intranasal midazolam, desflurane maintenance anesthesia allows for a faster recovery. However, depending on the institution's criteria for ambulatory surgical patient discharge, desflurane may or may not affect the overall hospitalization time.
We hypothesized that the alterations in vasomotor tone and adaptive remodeling responses that occur in the circulation because of hypoxia were dependent on changes in cell to cell communication ...through regulation of gap junction protein expression and function. Consequently, we studied the amount, distribution, and permeability of the principal vascular smooth muscle cell (VSMC) gap junction protein, connexin43, in rat aortic cultures exposed to oxygen partial pressures of 150 or 15 mm Hg.
Immunohistochemical staining, immunoblot assays, and Northern blot analyses demonstrated that connexin43 expression was reversibly increased in hypoxic cultures. As a result, hypoxic cells exhibited greater intercellular communication as determined by fluorescence recovery after photobleaching experiments. Using a fluorogenic substrate, hypoxic VSMCs showed increased reactive oxygen species generation, which could be prevented by the glutathione peroxidase mimic ebselen and the mitochondrial complex I inhibitor rotenone but not with the redox-sensitive thiol pyrrolidine dithiocarbamate. The rise in connexin43 expression attributable to hypoxia could be attenuated by ebselen and rotenone treatment. Interestingly, the previously reported induction of connexin43 expression by tensile stretch was also contingent on oxidative activity.
Hypoxia and stretch increased gap junctional intercellular communication in VSMCs attributable to enhanced connexin43 expression initiated by reactive oxygen species formation.
In the heart, lipopolysaccharide (LPS) induces the production of proinflammatory cytokines that cause myocardial dysfunction; however, the signaling pathways involved in cardiomyocyte responses are ...poorly understood. We studied LPS-induced signaling by treating cardiomyocyte cultures with 0.01-10 microgram/ml LPS for 0-24 h in the presence or absence of 2.5% serum. Cytosolic and nuclear proteins were analyzed for expression and activation of protein kinases. Members of the extracellular signal-regulated kinase (ERK) and signal transducer and activators of transcription (STAT) protein families were uniformly expressed and specifically phosphorylated in response to LPS. Activation was biphasic; peaking at 5-10 min and 24 h after treatment. Inhibitor experiments provided evidence that ERK proteins may regulate STAT activity. Serum did not augment endotoxin-induced phosphorylation. Although cardiomyocytes expressed low levels of CD14 and LPS-binding protein, specific enzymatic removal of glycosyl phosphatidylinositol-linked receptors or incubation with an anti-CD14 antibody had no effect on kinase activation. Treatment of cells with an excess of detoxified LPS attenuated endotoxin-induced signaling. In addition, endotoxin stimulated specific binding of nuclear factors to AP-1, nuclear factor-kappaB (NF-kappaB), STAT1 (SIE, sis-inducible element), and STAT3 consensus-binding sequences. Finally, inhibition of ERK phosphorylation reduced, and NF-kappaB nuclear translocation prevented, tumor necrosis factor-alpha production. Our results indicate that LPS-induced activation of signal transduction in cardiomyocytes occurs by a CD14-independent mechanism.
We tested the hypothesis that bacterial lipopolysaccharide (LPS) must be internalized to facilitate endotoxin-dependent signal activation in cardiac myocytes. Fluorescently labeled LPS was used to ...treat primary cardiomyocyte cultures, perfused heart preparations, and the RAW264.7 macrophage cell line. Using confocal microscopy and spectrofluorometry, we found that LPS was rapidly internalized in cardiomyocyte cultures and Langendorff-perfused hearts. Although LPS uptake was also observed in macrophages, only a fraction of these cells were found to internalize endotoxin to the extent seen in cardiomyocytes. Colocalization experiments with organelle or structure-specific fluorophores showed that LPS was concentrated in the Golgi apparatus, lysosomes, and sarcomeres. Similar intracellular localization was demonstrated in cardiomyocytes by transmission electron microscopy using gold-labeled LPS. The internalization of LPS was dependent on endosomal trafficking, because an inhibitor of microfilament reorganization prevented uptake in both cardiomyocytes and whole hearts. Inhibition of endocytosis specifically restricted early activation of extracellular signal-regulated kinase proteins and nuclear factor-kappaB as well as later tumor necrosis factor-alpha production and inducible nitric oxide synthase expression. In conclusion, we have demonstrated that bacterial endotoxin is internalized and transported to specific intracellular sites in heart cells and that these events are obligatory for activation of LPS-dependent signal transduction.
Although former preterm birth infants are at risk for postoperative apnea after surgery, it is unclear whether the same is true of full-term birth infants. We evaluated the incidence of apnea in 60 ...full-term neonates and infants undergoing pyloromyotomy both before and after anesthesia. All subjects were randomized to a remifentanil- or halothane-based anesthetic. Apnea was defined by the presence of prolonged apnea (>15 s) or frequent brief apnea, as observed on the pneumocardiogram. Apnea occurred before surgery in 27% of subjects and after surgery in 16% of subjects, with no significant difference between subjects randomized to remifentanil or halothane anesthesia. This apnea was primarily central in origin, occurred throughout the recording epochs, and was associated with severe desaturation in some instances. Of the subjects with normal preoperative pneumocardiograms, new onset postoperative apnea occurred in 3 (23%) of 13 subjects who received halothane-based anesthetics versus 0 (0%) of 22 subjects who received remifentanil-based anesthetics (P = 0.04). Thus, postoperative apnea can follow anesthesia in otherwise healthy full-term infants after pyloromyotomy and is occasionally severe with desaturation. New-onset postoperative apnea was not seen with a remifentanil-based anesthetic.
Abnormal breathing patterns can follow anesthesia in infants after surgical repair of pyloric stenosis. Occasionally, these patterns can be associated with desaturation. New-onset postoperative apnea was not seen with a remifentanil-based anesthetic.
Summary
Compression of the paediatric airway is a relatively common and often unrecognized complication of congenital cardiac and aortic arch anomalies. Airway obstruction may be the result of an ...anomalous relationship between the tracheobronchial tree and vascular structures (producing a vascular ring) or the result of extrinsic compression caused by dilated pulmonary arteries, left atrial enlargement, massive cardiomegaly, or intraluminal bronchial obstruction. A high index of suspicion of mechanical airway compression should be maintained in infants and children with recurrent respiratory difficulties, stridor, wheezing, dysphagia, or apnoea unexplained by other causes. Prompt diagnosis is required to avoid death and minimize airway damage. In addition to plain chest radiography and echocardiography, diagnostic investigations may consist of barium oesophagography, magnetic resonance imaging (MRI), computed tomography, cardiac catheterization and bronchoscopy. The most important recent advance is MRI, which can produce high quality three‐dimensional reconstruction of all anatomic elements allowing for precise anatomic delineation and improved surgical planning. Anaesthetic technique will depend on the type of vascular ring and the presence of any congenital heart disease or intrinsic lesions of the tracheobronchial tree. Vascular rings may be repaired through a conventional posterolateral thoracotomy, or utilizing video‐assisted thoracoscopic surgery (VATS) or robotic endoscopic surgery. Persistent airway obstruction following surgical repair may be due to residual compression, secondary airway wall instability (malacia), or intrinsic lesions of the airway. Simultaneous repair of cardiac defects and vascular tracheobronchial compression carries a higher risk of morbidity and mortality.
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