Blood-brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain.

OBJECT: Drug delivery across the blood-brain barrier remains a significant challenge. Based on earlier findings, the authors hypothesized that parasympathetic innervation of the brain vasculature could be used to augment drug delivery to the brain. METHODS: Using a craniotomy-cerebrospinal fluid superfusate paradigm in rats with an intravenous injection of tracer the authors demonstrated that stimulation of the postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) increased the concentration of fluorescein isothiocyanate-dextran (4-250 kD) in the superfusate by two- to sixfold. A histological examination indicated the presence of dextran in the parenchyma. In another experiment the amount of Evans blue dye in the brain following SPG activation was similarly significantly elevated. The chemotherapeutic agents anti-HER2 monoclonal antibody and etoposide were also delivered to the brain and reached therapeutic concentrations. Brain homeostasis was not disturbed by this procedure; a measurement of nicotinamide adenine dinucleotide reduction did not show a decrease in the tissue metabolic state and brain water content did not increase significantly. CONCLUSIONS: Sphenopalatine ganglion activation demonstrates a promising potential for clinical use in the delivery of small and large molecules to the brain.

Increased BBB permeability by parasympathetic sphenopalatine ganglion stimulation in dogs.

The blood-brain barrier (BBB) is a major obstacle for movement of large molecules to and from the brain. Stimulation of the sphenopalatine ganglion (SPG), the major source of parasympathetic innervation to brain vasculature, is known to vasodilate brain vessels, and has recently been shown to also increase the permeability of the BBB in the rat. In this work, we studied the effect of SPG stimulation on BBB permeability in larger animals--Beagle dogs. Left SPG was exposed by lateral approach in five Beagle dogs, and stimulated at 10 Hz. FITC labeled 10 kDa dextran was continuously infused to the left atrium during stimulation, and cerebral angiography was periodically obtained via the vertebral artery. Three control dogs received labeled dextran, without SPG exposure or stimulation. Brains were perfused with saline thoroughly at the end of stimulation, and samples from various regions were taken for fluorescence reading of tissue homogenates. Cerebral vasodilatation was evidenced in all but one dog, whose fluorescence results were consequently excluded from analysis, assuming that its SPG had been damaged by surgery. Fluorescence was significantly higher in the four stimulated compared to the three non-stimulated animals; e.g. mean FITC-dextran concentration in the anterior brain regions was 0.98+/-0.12 ug (mean+/-S.D.) FITC/g brain for experimental animals, and 0.40+/-0.02 for controls (p<0.01). No effect was seen in the pons and cerebellum (0.68+/-0.22 vs. 0.60+/-0.03, NS) whose vascular innervation is supplied by the otic rather than the SPG ganglion. SPG stimulation appears to be an effective way to increase BBB permeability, allowing introduction of large molecules to the brain. This could be a therapeutic method for a wide variety of brain disorders, including tumors and neurodegenerative diseases.

[Spinal anesthesia in premature infants--indications, technical aspects and results].

PURPOSE: To present our experience with spinal anesthesia in premature and former premature infants, and to focus on technical aspects and pitfalls enlightened with increasing experience. METHODS: The perioperative course of all premature and former premature infants below 60 weeks postconceptual age undergoing spinal anesthesia within an 35-month-period was analyzed. Lumbar puncture was performed while the patient was held seated at L4-5 or L5-S1. Anesthetics included hyperbaric tetracaine or bupivacaine, dose 1 mg/kg with adrenaline. The patients were positioned in the reverse Trendelenburg for 2-3 minutes, and later horizontally. RESULTS: Sixty seven infants (gestational age 30.1 +/- 3.6 weeks, postconceptual age 42.9 +/- 3.4, weight 3234 +/- 1165 grams) underwent spinal anesthesia and surgery. Thirty two had other diseases, including congenital heart (12), lung (15) brain pathology (8) and urological findings (6). Sixty five patients underwent hernia repair and two underwent pyloromyotomy. N2O was added in three infants, and two required general anesthesia. All were found to have lower limb motor blockade postoperatively. Intraoperatively, hypoxemia was diagnosed in two infants, short apnea in two cases and bradycardia in one. The apnea and hypoxemia episodes were successfully treated by reverse Trendelenburg positioning and bag and mask ventilation and the bradycardia that did not respond to tactile stimulation was relieved by atropine. Postoperatively, a short episode of apnea and hypoxemia (one patient) and hypoxemia (one patient) responded to free oxygen administration with/without tactile stimulation. Brief bradycardia (three infants) terminated without intervention. Supplementation and postoperative complication rates resembled previous studies. CONCLUSION: Successful spinal anesthesia in premature and former premature infants depends on close attention to preoperative assessment, patient positioning during and immediately after anesthetic induction, drug dosing and perioperative monitoring. A relatively high dose of local anesthetic should be administered.

Spinal anesthesia in 62 premature, former-premature or young infants--technical aspects and pitfalls.

PURPOSE: To highlight technical aspects and pitfalls of spinal anesthesia (SA) in infants. METHODS: The medical history and perioperative course of all infants who underwent SA over a 28-month period were collected (retrospectively in the first 20). RESULTS: Sixty-two infants underwent surgery under SA. Fifty-five were premature and former-premature, postconceptional age 43.3 +/- 5.0 weeks, weight 3261 +/- 1243 g. Of these, 21 had co-existing disease: cerebral (six), cardiac (nine), pulmonary (11) and urological (six). Hyperbaric tetracaine or bupivacaine 1 mg x kg(-1) with adrenaline was administered. Four infants (three premature) required N(2)O supplementation and three needed general anesthesia. The supplementation rate was similar or lower than in previous studies. Postoperatively, all seven were shown to have lower limb motor and sensory blockade. Complications in premature patients included intraoperative hypoxemia (two), apnea (two) and bradycardia (one). Postoperative complications included bradycardia (three), hypoxemia (one) and apnea and hypoxemia (one). The postoperative complication rate was similar to previous studies. CONCLUSION: Successful SA in infants depends on close attention to preoperative assessment, appropriate patient positioning during and after lumbar puncture, drug dosing and intra- and postoperative cardiorespiratory monitoring. A relatively high dose of hyperbaric solution of tetracaine or bupivacaine with adrenaline should be administered.