Koichi Takita

Actions of opioids on respiratory activity via activation of brainstem μ-, δ- and κ-receptors; an in vitro study

Abstract Opioid-induced respiratory depression is well documented. However, exact sites of action and mechanisms for opioid-induced effects on respiration have not yet been elucidated. The present study was carried out on isolated brainstem–spinal cord preparations from newborn rats in order to explore the opioid activity on brainstem μ-, δ- and κ-receptors. The brainstem–spinal cord was isolated from 0- to 4-day-old Sprague-Dawley rats. The preparation was perfused with artificial cerebrospinal fluid (28.5°C) equilibrated with 95% O2 and 5% CO2 at a pH of 7.4. Neuronal respiratory activity was recorded from the ventrolateral part of the medulla oblongata and efferent impulses from C4 or C5 ventral roots. Effects of the μ-receptor agonist DAGO, the δ-receptor agonist DPDPE and the κ-receptor agonist U50,488 on respiratory frequency (fR), inspiratory time (Ti) and peak integrated C4 amplitude (IntC4) were measured. In addition, the effect of pre-treatment with the μ1 receptor antagonist naloxanazine (35 mg/kg, subcutaneous injection) was evaluated. DAGO reduced fR and Ti in a concentration-dependent manner and caused a reduction of IntC4 at high concentrations (10 μM). The μ1 receptor antagonist naloxanazine shifted the fR concentration–response curve for DAGO to the right (P

Tracheal lidocaine attenuates the cardiovascular response to endotracheal intubation.

PurposeIn order to examine the efficacy of tracheal lidocaine (TL) for attenuation of the cardiovascular responses to endotracheal intubation (EI), we compared the cardiovascular responses to TL alone and EI with TL, with those to EI without TL.MethodsSeventy-five patients (ASA I–II) were studied. Anesthesia was induced with fentanyl 2 μg·kg−1 iv, thiamylal 5 mg·kg−1 iv and sevoflurane 1.0% in oxygen. Vecuronium 0.12 mg·kg−1 was used to facilitate EI. In Group A (n = 25), three minutes after induction, EI was performed. In Group B (n = 25), three minutes after induction, the patients received TL (4% lidocaine, 4 mL). This was followed by immediate EI. In Group C (n = 25), EI was performed two minutes after TL. Heart rate, arterial blood pressure and rate-pressure product (RPP) were measured from one minute before induction until five minutes after EI.ResultsThe changes of RPP caused by TL alone in Group C (TL; + 34.6 ± 29.0%, mean ± SD) were significantly (P < 0.0l) less than those caused by EI without TL in Group A (+77.3 ± 42.6%). EI after TL in Group C did not cause significant changes in RPP (+5.4 ± 15.2%). There were no significant differences between Groups A and B (+58.3 ± 36.6%).ConclusionWe conclude that the cardiovascular responses to TL alone are half as great as those to EI without TL, and that TL is effective for attenuation of the cardiovascular responses to EI. EI should be performed more than two minutes after TL.RésuméObjectifÉvaluer l’efficacité de l’administration trachéale de lidocaïne (LT) utilisée pour atténuer les réactions cardio-vasculaires à l’intubation endotrachéale (IE) en comparant les réponses cardio-vasculaires à la LT seule et à l’IE avec LT, avec les réponses à l’IE sans LT.MéthodeL’étude a porté sur 75 patients d’état physique ASA I–II. Lanesthésie a été induite avec 2μg·kg−1 de fentanyl iv, 5 mg·kg−1 de thiamylal iv et du sévoflurane à 1,0 % dans de l’oxygène. On a utilisé 0,12 mg·kg−1 de vécuronium pour faciliter l’IE. Dans le groupe A(n = 25), on a réalisé l’IE trois minutes après l’induction. Dans le groupe B (n = 25), les patients ont reçu la LT (4 mLà 4 %) trois minutes après l’induction. Ce qui a été immédiatement suivi de l’IE. Dans le groupe C (n = 25), l’IE a été faite deux minutes après la LT. La fréquence cardiaque, la tension artérielle et le produit de la tension systolique par la fréquence des contractions cardiaques (PTF) ont été mesurés à partir d’une minute avant l’induction jusqu’à cinq minutes après l’IE.RésultatsLes changements de PTF causés par la LT seule dans le groupe C (LT; +34,6 ± 29,0%, moyenne ± écart type) ont été significativement (P < 0,01) moindres que ceux qui ont été causés par l’IE sans LT dans le groupe A (+ 77,3 ± 42,6 %). LIE qui a suivi la LT dans le groupe C n’a pas modifié significativement le PTF (+5,4 ± 15,2 %). Les différences n’étaient pas significatives entre les groupes A et B (+58,3 ± 36,6%).ConclusionLes réponses cardio-vasculaires à la LT seule sont moitié moins importantes que les réponses à l’IE sans LT et la LT est efficace pour diminuer les réponses cardio-vasculaires à l’IE. LIE doit toutefois être faite plus de deux minutes après l’injection de LT.

Neonatal exposure to sevoflurane causes significant suppression of hippocampal long-term potentiation in postgrowth rats.

BACKGROUND: The inhaled anesthetic sevoflurane is commonly used for neonates in the clinical setting. Recent studies have indicated that exposure of neonatal rodents to sevoflurane causes acute widespread neurodegeneration and long-lasting neurocognitive dysfunction. Although acute toxic effects of sevoflurane on cellular viability in the hippocampus have been reported in some studies, little is known about the effects of neonatal sevoflurane exposure on long-term hippocampal synaptic plasticity, which has been implicated in the processes of learning and memory formation. Our study is the first to examine the long-term electrophysiological impact of neonatal exposure to a clinically relevant concentration of sevoflurane. METHODS: On postnatal day 7, rats were exposed to sevoflurane (1% or 2% for 2 hours) with oxygen. To eliminate the influence of blood gas abnormalities caused by sevoflurane-induced respiratory suppression, a group of rats were exposed to a high concentration of carbon dioxide (8% for 2 hours) to duplicate respiratory disturbances caused by 2% sevoflurane exposure. RESULTS: Exposure of neonatal rats to 2% sevoflurane for 2 hours caused significant suppression of long-term potentiation (LTP) induction in the postgrowth period. There was no significant difference between the control group and the CO2-exposed group in LTP induction, indicating that sevoflurane-induced LTP suppression was not caused by blood gas abnormalities. CONCLUSION: Our present findings indicate that neonatal exposure to sevoflurane at a higher concentration can cause alterations in the hippocampal synaptic plasticity that persists into adulthood.

Neonatal administration with dexmedetomidine does not impair the rat hippocampal synaptic plasticity later in adulthood

Background and objective:  The use of dexmedetomidine (DEX), a selective alpha‐2 agonist, in pediatric practice is expanding as a result of its desirable properties. To clarify the long‐term neurological consequences of neonatal administration of DEX, we investigated the long‐term effects of neonatal administration of DEX on hippocampal synaptic activity.

The height-based formula for prediction of left-sided double-lumen tracheal tube depth

In the commonly used double-lumen tube (DLT) intubation procedure, the tip of a DLT is inserted into the mainstem bronchus in a blind fashion, followed by determination of precise DLT position by a fiberoptic bronchoscope. Several studies have suggested that insertion depth for a left-sided DLT is correlated with physical factors including height and neck length.1-3 However, there are no widely used clinical guides based on physical factors for preliminary estimation of depth of the initial blind insertion of a DLT. In the current study, the authors retrospectively analyzed data from patients whose tracheas were intubated with left-sided DLTs and explored methods that are clinically available to aid in prediction of the appropriate depth of the initial blind insertion of a left-sided DLT. The authors reviewed the data from patients aged more than 20 years whose tracheas were intubated orally with left-sided DLTs (Broncho-Cath Left; Mallinckrodt Medical, Athlone, Ireland) in the operating rooms of Hokkaido University Hospital between September 1, 1992, and May 31, 2002. The data included age (years), sex, height (cm), weight (kg), size (French size) of the

Do age-based formulae predict the appropriate endotracheal tube sizes in Japanese children?

AbstractPurpose. Age-based formulae have been widely used to predict the appropriate size of the endotracheal tube (ETT) in children. These formulae are based on old data from Western countries. The current study was undertaken to assess the effectiveness of these formulae in Japanese children. Methods. We reviewed data for the past 5 years from children (0–8 years of age) intubated orally with the regular uncuffed ETT or RAE type. The data included the childs age in years and months and the internal diameter (ID) of the ETT. Results. Data from 1301 children were reviewed. The IDs of the most frequently used ETT were 3.0 mm for patients less than 1 month old, 3.5 mm for those 1 to 4 months old, 4.0 mm for those 5 to 17 months old, and 4.5 mm for those 18 to 23 months old. In children 2 to 8 years old, the ID of the most frequently used ETT was in accordance with the ID predicted by the formula ID (mm) = [age in years + 16]/4. However, the ID predicted by this formula applied to only 53.5% of our patients. Conclusion. The age-based formula, ID (mm) = [age in years + 16]/4, is applicable to Japanese children. However, we recommend that three sizes be available before endotracheal intubation.

Serum and urine inorganic fluoride levels following prolonged low-dose sevoflurane anesthesia combined with epidural block

STUDY OBJECTIVES To determine whether serum and urine inorganic fluoride levels with prolonged (more than 7 hours) low-dose (0.8 to 2.0 vol %) sevoflurane anesthesia plus epidural anesthesia were increased as compared with isoflurane anesthesia plus epidural anesthesia. To measure the urine tubular enzymes N-acetyl-beta-glucosaminidase (NAG), alpha 1-microglobulin (alpha 1-M), and beta 2-microglobulin (beta 2-M) for renal tubular injury in both groups. DESIGN Randomized, prospective study. SETTING University hospital. PATIENTS 15 ASA physical status I and II adults (7 males, 8 females) who were scheduled for prolonged laparotomy (lasting 9.5 to 10.2 hours) with general anesthesia. MEASUREMENTS AND MAIN RESULTS Epidural anesthesia was administered before induction of general anesthesia. General anesthesia was induced with thiamylal administered intravenously (IV), and the trachea was intubated following administration of vecuronium IV. It was maintained with either sevoflurane or isoflurane in nitrous oxide and oxygen. Standard monitoring was used in all patients. Serum and urine inorganic fluoride and urine tubular enzymes were measured periodically. Serum inorganic fluoride was 54 mumol/L at 4.3 minimum alveolar concentration (MAC) hours of sevoflurane; the peak level for isoflurane was 8 mumol/L at the same MAC hours. Sevoflurane also increased urine inorganic fluoride excretion to 96 mumol/hr 8 hours. NAG excretion started to increase after inhalation of either sevoflurane or isoflurane. alpha 1-M and beta 2-M excretion increased markedly postoperatively. Even though fluoride levels and tubular enzymes were high, there was no evidence of postoperative renal dysfunction. CONCLUSIONS There was no increase in urinary enzymes, which are indicators of tubular injury, specific to sevoflurane. There was no postoperative renal dysfunction, as indicated by unchanged serum creatinine and blood urea nitrogen levels.

Effects of sevoflurane on respiratory rhythm oscillators in the medulla oblongata

Using in vitro newborn rat brainstem-spinal cord preparations with and without the parafacial respiratory group (pFRG), we examined the effects of the volatile anaesthetic sevoflurane on the respiratory rhythm oscillators of the pFRG and the preBötzinger complex (preBötC). Our study indicated that sevoflurane depressed pre-inspiratory neurons (Pre-Is) in the pFRG via gamma-aminobutyric acid-A (GABA(A))ergic and glycinergic inhibition and that it depressed preBötC inspiratory neurons via GABA(A)ergic but not via glycinergic inhibition. We also found that sevoflurane had stimulant effects on the respiratory rhythm oscillators. Our results shed light on respiratory rhythm generation. In all preparations (n=16) in which Pre-Is activity was recorded, inspiratory-related cervical motor output remained after application of 0.47 mM sevoflurane, despite the disappearance of the burst activity of Pre-Is. This finding shows that Pre-Is are not essential for respiratory rhythm generation and suggests that sevoflurane, when applied at a proper concentration, might offer a pharmacological means to eliminate pFRG function while preserving preBötC activity.

Neonatal exposure to high concentration of carbon dioxide produces persistent learning deficits with impaired hippocampal synaptic plasticity

Although respiratory complications with blood gas abnormalities contribute significantly to neurodevelopment in the immature brain, little is known about the mechanisms via which blood gas abnormalities, such as hypoxic hypercapnia, impair neurocognitive outcomes. To investigate the possible long-term consequences of neonatal exposure to hypoxic hypercapnia regarding learning ability, we investigated the effect of neonatal hypoxic hypercapnia on later functions in the hippocampus, which is a structure that has been implicated in many learning and memory processes. Neonatal rat pups (postnatal day 7; P7) were exposed to a high concentration of carbon dioxide (CO2; 13%) for 2 or 4h. Exposure to CO2 in P7 rat pups caused blood gas abnormalities, including hypercapnia, hypoxia, and acidosis, and disrupted later learning acquisition, as assessed in 10-week-old adult rats subjected to a Morris water maze test. Induction of long-term potentiation (LTP) in the synapses of the hippocampal CA1 area was also impaired, whereas the paired-pulse responses of population spikes exhibited a significant increase, in CO2-exposed rats, suggesting decreased recurrent inhibition in the hippocampus. Such long-lasting modifications in hippocampal synaptic plasticity may contribute to the learning impairments associated with perinatal hypoxic hypercapnia and acidosis.

Isoflurane bidirectionally modulates the paired-pulse responses in the rat hippocampal CA1 field in vivo.

BACKGROUND:We studied the effects of isoflurane on hippocampal synaptic transmission and paired-pulse plasticity, under in vivo intact interneuron circuitry. METHODS:Using rats chronically implanted with electrodes, excitatory postsynaptic potential (EPSP) and population spike amplitude (PSA) were measured in the hippocampal CA1 field by stimulating Schaffer collaterals. The lungs of the rats were mechanically ventilated with 0.25–1.5 minimum alveolar anesthetic concentration (MAC) isoflurane. A control value was obtained in the absence of isoflurane. RESULTS:Isoflurane depressed EPSP responses and enhanced synaptic efficacy. PSA was not depressed except under high concentrations, presumably reflecting a well-balanced combination with the decreased EPSP and enhanced synaptic efficacy. Low concentrations of isoflurane (0.25 and 0.5 MAC) increased paired-pulse facilitation (PPF), whereas a high concentration of isoflurane (1.5 MAC) prolonged the paired-pulse depression. CONCLUSIONS:Isoflurane appeared to affect multiple sites of CA1 synapses: 1) the depression of presynaptic glutamatergic transmission as shown by depressed EPSP and increased PPF; 2) the depression of pyramidal neurons as shown by prolonged PPF and depressed PSA under high concentration; and 3) the depression of interneurons as shown by the greater synaptic efficacy. The degree of each of these inhibitory effects seemed to vary at different concentrations, and the overall direction of the synaptic properties may depend on the balances between these inhibitory effects in vivo.