Min Of Inhalation Research Articles

Contribution of a cholinergic reflex mechanism to allergen-induced bronchial hyperreactivity in permanently instrumented, unrestrained guinea-pigs.

1. In conscious, permanently instrumented, unrestrained, ovalbumin-sensitized guinea-pigs the development of allergen-induced bronchial hyperreactivity to histamine- and methacholine-inhalation was investigated after the early as well as after the late asthmatic response. 2. The allergen-induced increase in bronchial reactivity to histamine was significantly higher than to methacholine. 3. The muscarinic receptor antagonist, ipratropium bromide (1.0 mM, 3 min inhalation), blocked methacholine-induced bronchoconstriction and caused a significant 1.7 fold inhibition of the histamine-induced bronchoconstriction of control animals. 4. A lower dose of ipratropium bromide (0.1 mM, 3 min inhalation) had no significant effect on histamine-induced bronchoconstriction in control animals, but significantly reduced the allergen-induced increase in bronchial reactivity to histamine between the early and late asthmatic response. At 1.0 mM ipratropium bromide, no further reduction was observed. 5. These results clearly indicate that an exaggerated cholinergic reflex mechanism contributes to allergen-induced bronchial hyperreactivity to histamine.

Préoxygénation avant induction pour césarienne

In pregnant women at term, the oxygen reserve is decreased while the oxygen consumption is increased, carrying the risk of hypoxaemia during periods of apnea. Moreover, intubation of the trachea can be difficult. Therefore preoxygenation is of particular importance. The conventional method of preoxygenation consists in a 3–5 min breathing of 100 % O 2. However, in some obstetric emergencies, there may not be an adequate delay of time available for this technique. Recently, 4 maximally deep inspirations were demonstrated to be as effective as a 5-min inhalation of 100 % O 2 for preoxygenation. To determine whether these two techniques were equivalent before induction of a general anaesthesia for Caesarean section, 27 pregnant women at term (ASA 1 or 2) were studied. Following premedication with atropin sulfate (0.5 mg), the patients were randomly allocated into two groups. Group A (n = 12) was denitrogenated with 100 % O 2 for 4 min and group B (n = 15) with 4 maximally deep inspirations of 100 % O 2 within 30 s. Oxygen was administred at a flow rate of 10 L · min −1 via a non rebreathing anaesthesia system and a tight fitting face mask. Arterial saturation was assessed by pulse oximetry. General anaesthesia was induced with thiopentone (7 mg · kg −1) and succinylcholine (1.5 mg · kg −1). The trachea was intubated without previous ventilation and the delay required for the SpO 2 to decrease to 93 % was measured. This time was 137.9 ± 79.2 s (extremes 85–320) in group A and 144.5 ± 57.3 s (extremes 60–285) in group B respectively. These times were not significantly different. Apgar scores at 5 min were equivalent. These results show that pregnant women are at increased risk of developing hypoxaemia in apneic conditions and that either 4 min of O 2 breathing or 4 deep O 2 breaths are equivalent for preoxygenation prior to rapid sequence induction of general anaesthesia for Caesarean section.

Effect of acute systemic hypoxia on vascular permeability and leucocyte adherence in the anaesthetised rat

The aim was to investigate the effect of acute systemic hypoxia on vascular permeability to macromolecules and on leucocyte adherence to vascular endothelium in vivo. Experiments were performed on anaesthetised rats with either the intestinal mesentery or the spinotrapezius muscle prepared for in vivo microscopy. To quantify changes in vascular permeability, fluorescein isothiocyanate conjugated with serum albumin (FITC-albumin) was given intravenously and the microcirculation was viewed using a mercury source for 30 s periods during air breathing; or before, during, and after breathing 6% O2 for 3 or 20 min. On each occasion the number of FITC leakage sites was counted. In separate experiments acridine orange was given to stain leucocytes and the microcirculation was viewed using a mercury source during air breathing and during a 3 min period of systemic hypoxia. The number of leucocytes that adhered to venular walls for > 30 s was counted. Using mesentery, the effects were tested of BW755C, a lipoxygenase inhibitor, and of SM9064, a LTB4 receptor antagonist, upon the increase in leucocyte adherence observed during hypoxia. In rats that breathed air throughout, the number of leakage sites for FITC-albumin in both the spinotrapezius and mesentery remained constant. Moreover, in rats that breathed 6% O2 for 3 or 20 min, the number of leakage sites was not changed in either mesentery or spinotrapezius by hypoxia, but was substantially increased in both preparations by topical application of histamine. However, the number of leucocytes that adhered to the inside of venular walls was significantly increased in both mesentery and spinotrapezius by a 3 min inhalation 6% O2 from 2.83(SEM 0.56) to 4.66(1.77) per 100 microns length of venule and from 2.44(0.33) to 3.35(0.49) respectively during the first period of hypoxia. Between periods of hypoxia the number of adherent leucocytes returned to control in both preparations. Leucocyte adherence was not affected by BW755C (50 or 500 micrograms.ml-1 applied topically or 10 mg.kg-1 intravenously) or by SM9064 (3 mg.kg-1 intravenously). Acute systemic hypoxia does not affect the vascular permeability to albumin. However, 3 min periods of systemic hypoxia induce significant, but reversible, increases in leucocyte adherence in both muscle and mesenteric venules which in mesentery, at least, is not mediated by LTB4 or other products of the lipoxygenase pathway.

Effect of pyridostigmine pretreatment, HI-6 and Toxogonin treatment on rat tracheal smooth muscle response to cholinergic stimulation after organophosphorus inhalation exposure.

The ex vivo contraction response of the rat tracheal smooth muscle was examined after 10 min in vivo inhalation of soman and/or pretreatment with pyridostigmine and/or post-exposure treatment with HI-6 ([[[(4-aminocarbonyl)pyridinio]methoxy]methyl]-2[(hydroxy imino) methyl]pyridinium dichloride) or Toxogonin (1,1'-[oxybis-(methylene)]bis[4-[(hydroxyimino)methyl]-py rid inium] dichloride). In vivo pretreatment with pyridostigmine was achieved by subcutaneous (s.c.) implantation of an osmotic pump that delivered pyridostigmine continuously (0.01 mg/h) in the neck region of the rat 18 h before soman exposure. The ex vivo cholinergic tracheal smooth muscle response increased during the first 60 min after soman exposure in animals pretreated with pyridostigmine. The amplitude of the contraction response in pyridostigmine pretreated animals was about 60% of control, compared to 15% of control without pyridostigmine pretreatment. Pyridostigmine pretreatment also produced significant recovery of the total cholinesterase (ChE) activity in plasma, but not in trachea and lung. Intraperitoneal (i.p.) injection of HI-6 or Toxogonin (50 mg/kg), immediately after 10 min inhalation exposure to soman, also significantly improved the ex vivo cholinergic contraction response of the trachea (decapitation 15 min after oxime administration). The recovery of the physiological response with Toxogonin was, however, not stable. HI-6 was superior to Toxogonin with respect to the initial airway contraction response, and the response increased up to a stable level not significantly different from control. There was no significant reactivation of the ChE activity after treatment with the oximes. Combination of pyridostigmine pretreatment and oxime treatment enhanced the recovery of the tracheal contraction response and the ChE activity in the trachea compared to treatment with oximes alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Supramaximal Second Gas Effect

To elucidate the mechanism of the second gas effect, we enhanced halothane uptake by a method other than by increasing the inspiratory concentration of N2O. We determined the effect of N2O elimination via the right lung, which is not receiving N2O (halothane and oxygen), on the halothane uptake in the left lung with N2O added to an inspiratory gas mixture during a differential ventilation using a double-lumen tube. Under the setting, some N2O which was absorbed in the left lung, and eventually eliminated via the right lung, decreased end-tidal (ET) N2O and thereby increased the inspired to end-tidal gradient for N2O in the left lung which was receiving N2O. The situation thus created was equivalent to administering N2O in a higher concentration than the initial concentration. This process enhanced the halothane uptake in the left lung. The study consisted of 15 patients assigned to three groups with five patients in each group. Control groups received a standard, single-lumen endotracheal tube using a gas mixture of O2 + halothane with and without N2O. The experimental group received a double-lumen tube for differential lung ventilation. A N2O + O2 + halothane mixture was administered to the left lung, and simultaneously O2 + halothane was administered to the right lung. On-line gas measurement was performed using Raman spectrometers. The second gas effect was observed between the control groups. N2O was detected in the exhaled gas from the right lung after 3 min of inhalation into the left lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Sodium Hypochlorite on Specific Airway Resistance and Airway Reactivity in Guinea Pigs

To evaluate the effect of sodium hypochlorite (NaOCl) on specific airway resistance (SRaw) and the possibility that NaOCl is involved in causing airway hyperreactivity, we studied the effect of exposure to NaOCl aerosol on SRaw and airway reactivity to inhaled histamine aerosol in intact, unanesthetized, spontaneously breathing guinea pigs. A 1-min inhalation of 1.2–10.0% NaOCl caused an increase in SRaw in three of six animals in a concentration-dependent manner. To assess the airway reactivity, the effective concentration of histamine that produced a doubling of baseline SRaw (EC200His) was determined. A 5-min inhalation of 3.6% NaOCl aerosol caused an acute decrease in EC200His without a corresponding change in SRaw, whereas a 5-min inhalation of normal saline caused no significant changes in SRaw and EC200His. Therefore, a 5-min inhalation of 3.6% NaOCl induced airway hyperreactivity. On the contrary, a 15-min inhalation of 3.6% NaOCl did not cause significant changes in mean EC200His values at 5 min, 5 hr, and 1 week after exposure. The mean SRaw at 5 hr after a 15-min inhalation of 3.6% NaOCl was higher than that of the baseline value. A 15-min inhalation of normal saline aerosol caused an increase in EC200His i.e., reduced airway reactivity, 5 min after exposure. The increased EC200His returned to baseline level at 5 hr and 1 week after exposure. A 15-min inhalation of normal saline caused no significant change in SRaw during the study period.Our study indicates that acute NaOCl aerosol inhalation causes a temporary increase in SRaw and airway hyperreactivity to inhaled histamine in guinea pigs.

Effect of clonidine on the cerebrovascular system in cats.

The effects of clonidine, a potent alpha 2 adrenergic agonist and an imidazole/imidazoline receptor agonist, were examined in the cat cerebrovascular system, measuring cerebral oxygen and carbon dioxide tension (BrPo2, BrPco2) and arterial blood pressure. Intracarotid injection of clonidine (2 micrograms/kg) produced a gradual decrease in systemic blood pressure without initial hypertension, while BrPo2 decreased slightly but significantly. Before and after intracarotid administration of clonidine, cerebrovascular reactivity to carbon dioxide was estimated by changes in BrPo2 and BrPco2 during and after 3 min inhalation of 5% CO2. Clonidine significantly enhanced cerebrovascular reactivity to carbon dioxide. The data suggest that the alpha 2-adrenoceptor and/or imidazoline receptor play an important role in the regulation of cerebral circulation.

Changes of pial vessel diameter and CO2 reactivity during insulin-induced hypoglycemia and in the recovery period following glucose administration.

The present study examined the changes of cerebrovascular CO2 reactivity during insulin-induced hypoglycemia and in the recovery period following glucose administration in cats. The diameters of pial vessels were continuously measured using the vidicon camera system. Hypoglycemia was induced by intraperitoneal injection of Actrapid insulin (100 IU/kg). Cerebrovascular CO2 reactivity was estimated by the changes of pial vessel diameters during 3 min inhalation of 5% CO2 in air at each stage of glucose level. CO2 reactivity was impaired in the hypoglycemic stage and this impairment was further enhanced in the early recovery stage. In the late recovery stage, CO2 reactivity was restored particularly in the small arteries which were less innervated by autonomic nerves. These results suggest that the sympathetic activity plays an important role in the impairment of cerebrovascular CO2 reactivity during hypoglycemia.

Role of cyclooxygenase system in cerebrovascular responsiveness: different effects of indomethacin on CO2 responsiveness and dilatation by Ca(2+)-channel blocker.

To investigate roles of prostaglandins in the regulation of cerebral blood flow, we compared effects of indomethacin, a cyclooxygenase inhibitor, on the cerebrovascular CO2 responsiveness with those on the cerebrovascular dilatory action of diltiazem, a Ca(2+)-channel blocker. Fifteen adult cats were used. The cerebral tissue oxygen tension, carbon dioxide tension, pH and blood pressure were measured continuously. Indomethacin (1 mg/kg) was infused into the carotid artery. In 8 cats, 3 min inhalation of 5% CO2 in air was performed before and after the indomethacin infusion. In 7 cats, diltiazem (100 micrograms/kg) was infused into the carotid artery for 3 min before and after the indomethacin infusion. The cerebrovascular CO2 responsiveness was significantly decreased (p < 0.05) after the administration of indomethacin. On the other hand, the cerebrovascular dilatation induced by the Ca(2+)-channel blocker was significantly increased (p < 0.05) after the administration of indomethacin. It is concluded that the products of cyclooxygenase system are involved in the cerebrovascular responsiveness both to CO2 and to Ca(2+)-channel blocker, but action mechanisms of prostaglandins may be different, that is, prostaglandians may enhanced cerebrovascular responsiveness to CO2 but diminish it to Ca(2+)-channel blocker.

Brain Perfusion Studies by Xenon-Enhanced CT Using Washin/Washout Study Protocols

Very short inhalation times and short total examination times are desirable in cerebral blood flow measurements by xenon enhanced CT to minimize the possibility of flow activation and--more importantly for practical purposes--the probability of patient motion due to the effects of xenon. We have investigated washin/washout procedures and have compared them with conventional washin scanning protocols by simulation and in clinical studies. Examination protocols with only 3 min of inhalation and up to eight scans, all taken at 1 min intervals, provide flow estimates with smaller SDs than would be obtained for washin studies taken with the same total radiation dose. Compared with a standard 8 min washin procedure, a 3 min washin/5 min washout study using the same dose yields an SD reduction by a factor of 1.3 for low flow areas and of 1.8 for high flow gray matter. A 3 min washin/3 min washout study, employing only 78% of the dose of an 8 min washin study, will still provide an SD reduction factor of 1.7 in gray matter. These results have been confirmed qualitatively by studies carried out both in volunteers and in patients.

Na+, K+-ATPase; characterization and interactions with neurotransmitters

To elucidate the mechanisms of cationic protein-induced airway hyperresponsiveness (AHR), the airway response to methacholine, and the concentrations of thromboxane B2 (TXB2) and 6-keto-PGF1α in the bronchoalveolar lavage fluid (BALF) of guinea-pigs were measured after inhalation of poly-L-lysine (P-L-L). The airway responsiveness (AR) was evaluated by specific airway resistance. The inhalation of P-L-L significantly enhanced AR to methacholine, and increased TXB2 and 6-keto-PGF1α in the BALF. The enhanced AR and the increase of TXB2 and 6-keto-PGF1α were both significantly inhibited by pretreatment with low molecular weight heparin (LMWH; anionic protein; 10 mg/mL for 6 min inhalation). Furthermore, thromboxane (TX) synthase inhibitor (ozagrel), thromboxane A2 (TXA2) receptor antagonist (ONO-3708), and bradykinin B2 receptor antagonist (BBRA; Nα-adamantaneacetyl-D-Arg [Hyp3, Thi5,8, D-Phe7]-bradykinin) inhibited the cation-induced AHR. BBRA significantly inhibited the increase of those mediators in the BALF. The data suggest that TXA2, which is newly generated by the stimulation of the bradykinin B2 receptor after inhalation of cationic proteins, plays an important role in cationic protein-induced AHR in guinea pigs.

A new aerosol delivery system to dogs

We have developed an aerosol delivery system to dogs based on breath actuated nebulization. The deposited dose of 99mTc-DTPA to the dog lungs was less than 10% after mouth breathing and increased at nose breathing to 31% and 52% for the two dogs. After 10 min inhalation a dose of 2 mg terbutaline was deposited in the respiratory tract, based on pharmacokinetic calculations. This aerosol delivery system can be used in pharmacological and toxicological studies when new drugs need to be tested by the inhaled route.

COMPARISON OF THE EFFECTS OF SUBANAESTHETIC CONCENTRATIONS OF ISOFLURANE OR NITROUS OXIDE IN VOLUNTEERS

A cross-over trial was performed in 12 volunteers to compare the relative potency of 25% nitrous oxide and 0.4% isoflurane when breathed for a period of 20 min. Oxygen was used as a control. The effects were observed for 35 min after drug administration. Choice reaction time, ability to tap two areas on a board and ability to perform mathematical problems were significantly impaired when inhaling nitrous oxide, the maximum effect being obtained within 5 min. With isoflurane, the effects were significantly greater than with nitrous oxide. The effect obtained after 15 min inhalation was greater than that at 5 min. Tests returned promptly to the base line after the discontinuation of the test agent. Subjective assessments were made using a series of eight visual analogue scales. Results of the scales represented by physical and mental sedation indicated that 0.4% isoflurane was more potent than 25% nitrous oxide. Significant effects were detected up to 15 min after the inhalation of the agent was stopped. Subanaesthetic concentrations of isoflurane warrant further study in patients undergoing dental treatment in which a rapid recovery from sedation is important.

Fixed ventilation during tidal volume breathing bronchial challenge may improve repeatability.

Tidal breathing during bronchial challenge shows both between- and within-subject variation. A challenge protocol permitting controlled ventilation was designed in order to improve repeatability of the method. Twenty-five patients were challenged twice with an interval of 2 h. The 2 min ventilation was kept constant at each concentration administered. During the 2 min inhalation of aerosol all expired air (VE) was led through a dry gas meter and respiratory frequency was counted concomitantly. The patients were instructed to achieve the same 2 min ventilation at each dosage. All patients accomplished the two challenges without problems. A PC20 was determined by interpolation on the log dose-response curve. Repeatability was improved compared to what has been found in previous studies on adults, although statistically non-significant when compared to one study. The 95% confidence interval for PC20 based on a single determination was rather narrow, being the observed value +/- 0.58 two-fold concentration differences.

Effect of posture on ventilatory response to steady-state hypoxia and hypercapnia

The ventilatory response to steady-state normocapnic hypoxia and hypercapnia was measured in eight normal subjects after 15 min inhalation of 10.5% oxygen (with added CO2) or 4.2% CO2 in air through a loose-fitting high-flow Venturi mask. The erect (sitting) and the supine postures were studied. Ventilation was measured with inductance coils around the chest and the abdomen (Respitrace). Oxygen saturation was measured with an ear oximeter and PCO2 was measured transcutaneously on forearm skin using a modified pH electrode (Radiometer). In the erect posture (without stimulation), compared to supine, V̇E(21%) and VT/TI(32%) were greater but TI(19%) and TE(8%), abdominal contribution to tidal volume (24%) and ‘arterial’ PCO2 (0.6 mm Hg) were less. The mean ventilatory response to hypoxia at an ‘arterial’ PCO2 of 41 ± 4 mm Hg (SD) was 0.61 ± 0.34 L · min−1 · SaO2−1 erect and 0.84 ± 0.58 supine and to hypercapnia 2.89 ± 1.4 L · min−1 · mm Hg−1 erect and 3.73 ± 2.35 supine. The postural differences did not reach statistical significance. The pattern of response to both stimuli was similar, with doubling of VT, constant TI and slight shortening of TE. The abdominal contribution to tidalvolume decreased by 9% with both forms of stimulation. In the steady state, the response to peripheral and central chemoreceptor stimuli was identical and essentially independent of position.

Standardization of Inhalation Provocation Tests: Dose vs Concentration of Histamine

The importance of histamine dose vs histamine concentration in determining the response to inhaled histamine was evaluated by comparing the effect of 30 sec and two min inhalation times on duplicate histamine inhalation tests in 15 asthmatic patients. The histamine provocation concentration required to produce a 20 percent FEV1 fall after 30 sec inhalations (30 sec PC20) was on average 3.6-fold greater than the two min PC20. Individually, ten of the 15 fell within the range of dose reproducibility (+/- one doubling dose), while five subjects fell outside this range, three with 30 sec PC20 less than twice two min PC20 and two with 30 sec PC20 greater than 8 X two min PC20. Seven subjects had duplicate measurements of both 30 sec PC20 and two min PC20; the two min PC20 was more reproducible than the 30 sec PC20 in all seven. The better reproducibility of the two min PC20 is likely due to a more reproducible inspiratory time over the two-minute breathing period. These findings have relevance in standardization of inhalation challenge tests, and in comparing results of such tests done by different techniques.

The effect of CO2-breathing on cochlear blood flow.

The cochlear blood flow was measured with the microsphere methods, before and during CO2-inhalation, in anesthetized rabbits. Different gas mixtures and exposure times were used. The greatest increase of cochlear blood flow was measured after 5 min inhalation of 7% CO2 in air (115%) and the least increase (44%) in animals breathing 7% CO2 in oxygen. The difference is explained as due to a vasoconstriction caused by a high oxygen tension counteracting the vasodilating effect of CO2.

Effects of CO2 inhalation on cochlear blood circulation.

The cochlear blood flow was measured with the microsphere method before, during and after CO2 inhalation in anesthetized rabbits. Different gas mixtures and exposure times were used. The greatest increase of cochlear blood flow was measured after 5 min inhalation of 7% CO2 in air (115%) and the least increase (44%) in animals breathing 7% CO2 in oxygen. The difference is explained as due to a vasoconstriction caused by a high oxygen tension counteracting the vasodilating effect of CO2. The treatment with CO2 of supposed vascular diseases in the cochlea is discussed and the negative effects due to respiratory acidosis are emphasized.

Blood flow in the dental pulp of dogs determined by hydrogen polarography and radioactive microsphere methods

A platinum electrode was implanted in the canine tooth via the buccal surface (1 mm bared tip, dia 0.125 mm) (Group I), or via the canine tip (4–5 mm bared tip) (Group II). Pulp and arterial hydrogen concentrations were measured during and after a 2–5 min inhalation period. Microspheres (MS) of 8 and 15 μm were then injected simultaneously to measure total pulp blood flow (Gp I) and regional blood flow in the coronal portion (Gp II). The clearance analysis of the pulp H 2 curves showed that only a single rate constant existed for Gp I and two rate constants for Gp II. The blood flows obtained with 8 μm MS and H 2 averaged 24 and 20 ml/min/g for Gp I; whereas, for Gp II flow values were 18 (MS and H 2) for the main coronal portion and 67 and 55 for the coronal tip respectively. Flows determined with 15 μm MS were 2–3 times greater. Convolution analysis, using the entire pulp and arterial H 2 curves, provided similar rate constants to the clearance analysis. Assuming that the 15 μm MS provide the accurate measure, H 2 must shunt between the small arteries and veins during both the uptake and clearance phases. Vascular shunts of the order of 10 μm would have to exist.

A MODEL FOR REGIONAL CEREBRAL OXYGEN DISTRIBUTION DURING CONTINUOUS INHALATION OF 15O2, C15O. AND C15O2

Subramanyam, Rajeshwari; Alpert, Nathaniel M.; Hoop, Bernard Jr.; Brownell, Gordon L.; Taveras, Juan M. Author Information