Predictors of Delayed Postoperative Respiratory Depression Assessed from Naloxone Administration.

BACKGROUND: The aim of this study was to identify patient and procedural characteristics associated with postoperative respiratory depression or sedation requiring naloxone intervention. METHODS: We identified patients who received naloxone to reverse opioid-induced respiratory depression or sedation within 48 hours after discharge from anesthetic care (transfer from the postanesthesia care unit or transfer from the operating room to postoperative areas) between July 1, 2008, and June 30, 2010. Patients were matched to 2 control subjects based on age, sex, and exact type of procedure performed during the same year. A chart review was performed to identify patient, anesthetic, and surgical factors that may be associated with risk for intervention requiring naloxone. In addition, we identified all patients who developed adverse respiratory events (hypoventilation, apnea, oxyhemoglobin desaturation, pain/sedation mismatch) during phase 1 anesthesia recovery. We performed conditional logistic regression taking into account the 1:2 matched set case-control study design to assess patient and procedural characteristics associated with naloxone use. RESULTS: We identified 134 naloxone administrations, 58% within 12 hours of discharge from anesthesia care, with an incidence of 1.6 per 1000 (95% confidence interval [CI], 1.3-1.9) anesthetics. The presence of obstructive sleep apnea (odds ratio [OR] = 2.45; 95% CI, 1.27-4.66; P = 0.008) and diagnosis of an adverse respiratory event in the postanesthesia recovery room (OR = 5.11; 95% CI, 2.32-11.27; P < 0.001) were associated with an increased risk for requiring naloxone to treat respiratory depression or sedation after discharge from anesthesia care. After discharge from anesthesia care, patients administered naloxone used a greater median dose of opioids (10 [interquartile range, 0-47.1] vs 5 [0-24.8] IV morphine equivalents, P = 0.020) and more medications with sedating side effects (n = 41 [31%] vs 24 [9%]; P < 0.001). CONCLUSIONS: Obstructive sleep apnea and adverse respiratory events in the recovery room are harbingers of increased risk for respiratory depression or sedation requiring naloxone after discharge from anesthesia care. Also, patients administered naloxone received more opioids and other sedating medications after discharge from anesthetic care. Our findings suggest that these patients may benefit from more careful monitoring after being discharged from anesthesia care.

Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling.

G-protein receptor kinase 2 (GRK2) is 1 of 7 mammalian GRKs that phosphorylate ligand-bound 7-transmembrane receptors, causing receptor uncoupling from G proteins and potentially activating non-G-protein signaling pathways. GRK2 is unique among members of the GRK family in that its genetic ablation causes embryonic lethality. Cardiac abnormalities in GRK2 null embryos implicated GRK2 in cardiac development but prevented studies of the knockout phenotype in adult hearts. Here, we created GRK2-loxP-targeted mice and used Cre recombination to generate germline and cardiac-specific GRK2 knockouts. GRK2 deletion in the preimplantation embryo with EIIa-Cre (germline null) resulted in developmental retardation and embryonic lethality between embryonic day 10.5 (E10.5) and E11.5. At E9.5, cardiac myocyte specification and cardiac looping were normal, but ventricular development was delayed. Cardiomyocyte-specific ablation of GRK2 in the embryo with Nkx2.5-driven Cre (cardiac-specific GRK2 knockout) produced viable mice with normal heart structure, function, and cardiac gene expression. Cardiac-specific GRK2 knockout mice exhibited enhanced inotropic sensitivity to the beta-adrenergic receptor agonist isoproterenol, with impairment of normal inotropic and lusitropic tachyphylaxis, and exhibited accelerated development of catecholamine toxicity with chronic isoproterenol treatment. These findings show that cardiomyocyte autonomous GRK2 is not essential for myocardial development after cardiac specification, suggesting that embryonic developmental abnormalities may be attributable to extracardiac effects of GRK2 ablation. In the adult heart, cardiac GRK2 is a major factor regulating inotropic and lusitropic tachyphylaxis to beta-adrenergic agonist, which likely contributes to its protective effects in catecholamine cardiomyopathy.

Abnormal neurodevelopment, neurosignaling and behaviour in Npas3-deficient mice.

Npas3 is a member of the bHLH-PAS superfamily of transcription factors that is expressed broadly in the developing neuroepithelium. To study the function of this gene, mice deficient in Npas3 were generated and characterized. Npas3-/- mice were growth-retarded and exhibited developmental brain abnormalities that included a reduction in size of the anterior hippocampus, hypoplasia of the corpus callosum and enlargement of the ventricles. A number of behavioural abnormalities were identified in Npas3-/- mice including locomotor hyperactivity, subtle gait defects, impairment of prepulse inhibition of acoustic startle, deficit in recognition memory and altered anxiety-related responses. Characterization of neurosignaling pathways using several pharmacological agents revealed dysfunctional glutamate, dopamine and serotonin neurotransmitter signaling. Consistent with these findings, we identified a significant alteration in cortical PSD-95 expression, a PDZ-containing protein that has been shown to be involved in postsynaptic signal transduction. Together, our observations indicate an important role for Npas3 in controlling normal brain development and neurosignaling pathways.