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PubMed1996

Response to nitric oxide inhalation in early acute lung injury.

OBJECTIVE: To evaluate the dose response of inhaled nitric oxide (NO) on gas exchange and central haemodynamics in patients with early acute lung injury (ALI). DESIGN: Prospective, multicentre clinical study. SETTING: General ICUs in university and regional hospitals. PATIENTS: 18 Patients with early ALI according to specified criteria. INTERVENTIONS: During controlled ventilation an inhalation system was used to deliver NO (1000 ppm in N2) and O2/air to the low pressure fresh gas inlet of a Siemens 900C ventilator. Haemodynamics and pulmonary gas exchange variables were measured at baseline and at stepwise increased inspiratory NO concentrations of 0.1, 0.3, 1, 3, 10, 30 and 100 ppm, each dose being maintained for 15 min. Dose testing was repeated the next day, and the response to prolonged (2 h) NO inhalation at 1 and 10 ppm was also tested. MEASUREMENTS AND RESULTS: Inhalation of NO produced a significant increase in PaO2 (P < 0.0025). The degree of response, as well as the optimal NO dose varied in individual patients and between different days. Venous admixture (QVA/QT) was reduced (P < 0.02) from 38% (31-46%) to 33% (26-41%). In our patients with early acute lung injury and only a moderate elevation in pulmonary arterial pressure NO inhalation did not reduce mean pulmonary artery pressure significantly, being 27.0 (21-30) mmHg at baseline and 26.0 (21-30) mm Hg at 100 ppm. CONCLUSIONS: This study shows that improvements in arterial oxygenation in response to inhaled NO may show great inter- as well as intraindividual variability, and that improvements in arterial oxygenation occur without any measurable lowering of the pulmonary artery pressure.

Administration, Inhalation↗
PubMed1993

Long-term inhalation with evaluated low doses of nitric oxide for selective improvement of oxygenation in patients with adult respiratory distress syndrome.

OBJECTIVE: To evaluate the lowest dose of inhaled nitric oxide (NO) in patients with adult respiratory distress syndrome (ARDS), which is able to improve arterial oxygenation more than 30% compared to baseline data. DESIGN: Prospective, clinical study. SETTING: Anesthesiological ICU in a university hospital. PATIENTS: 3 consecutive patients with severe ARDS according to clinical and radiological signs. INTERVENTIONS: Pressure-controlled ventilation with positive end-expiratory pressure of 8-12 cm H2O. Inhalation of NO was performed with a blender system and a Servo 300 ventilator. The lowest effective NO dose was defined by titrating the inspiratory NO dose until reaching a 30% improvement of PaO2/FiO2. This dose was used for the following continuous long-term NO inhalation; controls of efficacy by investigation of hemodynamics and blood gas exchange were performed initially and 2 times per patient after intervals of 3-5 days. MEASUREMENTS AND RESULTS: Initial NO concentrations were found to be effective at 60, 100, and 230 parts per billion (ppb). In all measurements, arterial oxygenation was found to be elevated by NO inhalation with the initially evaluated dose compared to baseline data; in parallel, the venous admixture (Qva/Qt) was reduced. The O2 delivery increased, although O2 consumption and hemodynamics did not change. In 1 patient, interruption of NO inhalation caused remarkable increase of pulmonary resistance. CONCLUSIONS: The improvement of oxygenation by NO inhalation in ARDS does not require reduction of pulmonary resistance and can be performed using low doses in the ppb range, which has to be considered as probably non-toxic.

Administration, Inhalation↗
PubMed1996

A new side effect of inhaled nitric oxide in neonates and infants with pulmonary hypertension: functional impairment of the neutrophil respiratory burst.

INTRODUCTION: Inhaled nitric oxide (NO) may be beneficial in the treatment of pulmonary hypertension, both of the newborn and in the adult respiratory distress syndrome. Up to now, serious systemic side effects have not been reported. OBJECTIVE: The effect of inhaled NO on superoxide anion production by neutrophils. DESIGN: Prospective study of a consecutive series of 15 neonates and infants. SETTING: Neonatal and paediatric ICUs with a total of 17 beds (university hospital). MEASUREMENTS AND RESULTS: Superoxide anion production was determined by a flow cytometric method using dihydrorhodamine 123 (DHR) as an oxidative probe after the priming of neutrophils with N-formyl-methionyl- leucylphenylalanine (fMLP) or with Escherichia coli. The generated fluorescence was expressed as relative fluorescence intensity (RFI). Inhalation of NO for more than 24 h reduced the superoxide anion production by neutrophils stimulated with E. coli to below baseline values before NO inhalation (mRFI = 158 +/- 25 vs 222 +/- 24; P = 0.03). This decrease was more pronounced after more than 72 h (mRFI = 133 +/- 17). At this time, superoxide anion production by fMLP-stimulated neutrophils was also decreased (mRFI = 40 +/- 3, vs 57 +/- 5; P = 0.03). The reduced capacity of superoxide production persisted throughout therapy with NO and lasted up to more than 4 days after the end of NO inhalation. CONCLUSION: The results suggest that inhalation of NO in patients with pulmonary hypertension causes reduced superoxide anion production by neutrophils stimulated with E. coli or with fMLP. To determine the clinical importance of this systemic side effect with respect to bacterial infections, a randomized controlled study is necessary.

Administration, Inhalation↗
PubMed2005

Stimulative and sedative effects of essential oils upon inhalation in mice.

This study investigated the stimulative or sedative effects of inhaling fragrant essential oils (EOs) by using a forced swimming test (FST) with mice. This behavioral test is commonly used to measure the effects of antidepressant drugs. The inhalation by mice of EOs, such as ginger oil (p<0.05), thyme oil (p<0.05), peppermint oil (p<0.05), and cypress oil (p<0.01) resulted in 5% to 22% reduction of immobility. The same results were achieved when over-agitation was artificially induced in the mice by an intraperitoneal injection of caffeine (a psycho-stimulant). In contrast, inhalation of some EOs by the mice resulted in increased immobility. To evaluate more correctly the sedative effects of EOs, the immobility of over-agitated mice induced with caffeine was ascertained after the inhalation of various EOs. Inhalation of lavender oil (p<0.01) and hyssop oil (p<0.01) increased the immobile state in mice that were treated with caffeine. The results of this study indicate that the inhalation of essential oils may induce stimulative or sedative effects in mice.

Administration, Inhalation↗
PubMed1989

Assessment of inhaler technique in general practice.

71 Patients who were using inhalers in an inner city Dublin teaching practice were assessed by the author over a four month period to see if they were using their inhalers properly. 18 (25%) had perfect technique, 26 (37%) had adequate technique and 27 (38%) had poor technique. The patients most likely to have poor technique were those using a Metered Dose Inhaler (M.D.I.), patients using inhalers for less than one year and patients with a diagnosis of C.O.A.D. as opposed to Asthma. Of the 53 patients who had less than perfect technique 37 showed an initial improvement with training. This Author suggests that all patients should be fully evaluated before starting on inhalers and the most appropriate delivery system selected for them. They should be carefully instructed on its correct use and arrangements made for regular follow up to ensure good inhaler technique. This should lead to a greater clinical response and improved patient compliance.

Administration, Inhalation↗
PubMed1997

Inhaled nitric oxide: clinical applications, indications, and toxicology.

PURPOSE: Although the analogy of nitric oxide (NO) to Endothelium-derived Relaxing Factor remains controversial, medical use of exogenous NO gas by inhalation has grown exponentially. This review presents the mechanisms of action of inhaled NO in pulmonary hypertension, hypoxaemia, inflammation and oedema, as well as its therapeutic and diagnostic indications with emphasis on acute respiratory distress syndrome (ARDS) and toxicology. SOURCE: Two medical databases (Current Contents, Medline) were searched for citations containing the above-mentioned key words to December 1996. Moreover, many presentations in congresses such as 4th International Meeting of Biology of Nitric Oxide, 52nd and 53rd Annual Meeting of Canadian Anaesthetists' Society or 10th Annual Meeting of European Association of Cardiothoracic Anaesthesiologists were used. PRINCIPAL FINDINGS: Inhaled NO is now recognized as an invaluable tool in neonatal and paediatric critical care, and for heart/lung surgery. Other clinical applications in adults, such as chronic obstructive pulmonary disease and ARDS, require a cautious approach. The inhaled NO therapy is fairly inexpensive, but it would seem that it is not indicated for everybody with regards to the paradigm of its efficiency and potential toxicity. The recent discovery of its anti-inflammatory and extrapulmonary effects open new horizons for future applications. CONCLUSION: Clinical use of inhaled NO was mostly reported in case series, properly designed clinical trials must now be performed to establish its real therapeutic role. These trials would permit adequate selection of the cardiopulmonary disorders, and subsequently the patients that would maximally benefit from inhaled NO therapy.

Administration, Inhalation↗
PubMed1998

Effect of salmeterol is independent of previously inhaled salbutamol: a clinical controlled study.

The objective of this study was to examine the bronchodilating effect of an inhaled long acting beta2-agonist (salmeterol) after a high dose of an inhaled short acting beta2-agonist (salbutamol) in asthma patients. We used a randomized double-blind, placebo-controlled, crossover design, studying seven subjects with moderate asthma, treated with inhaled steroids and highly reversible to salbutamol and salmeterol. 1.5 h after salmeterol inhalation, the mean difference in FEV1 between salbutamol and placebo pretreatment days was 6.31% and ranged from 0.02 to 1.05%, 2.5-10.5 h after salmeterol inhalation. We concluded that the effect measured as the duration of bronchodilation of salmeterol is not decreased by previously inhaled salbutamol. We only found a trend toward an additive effect of combining salbutamol and salmeterol, probably because the high dose of salbutamol did not give room for further improvement in FEV1. In accordance with other clinical studies we were unable to demonstrate any clinical implications of the salmeterol partial beta2-antagonism known from animal and in vitro studies.

Administration, Inhalation↗
PubMed2002

[Inhaled vasodilators].

First reports on the use of inhaled nitric oxide (NO) in patients were published in 1991. These reports confirmed data from animal experiments which suggested a selective vasodilatory effect of inhaled NO in pulmonary vessels. As the main clinical effects, both improved oxygenation and a drop of pulmonary artery pressure despite unchanged arterial pressure were observed. Since then, many studies have evaluated the effects of inhaled NO as well as of other aerosolised vasodilators (e.g. PGI(2), PGE(1), nitrates, phosphodiesterase-inhibitors) in patients with pulmonary hypertension, acute right heart failure and/or life-threatening hypoxemia. However, primary pulmonary hypertension of the newborn (PPHN) is the only indication for which inhaled NO has been clinically approved so far. Although an obvious clinical benefit in outcome from inhaled vasodilators has never been formally documented, good clinical efficacy has resulted in an increasing "off label" use of the concept both in Germany and worldwide, particularly with respect to anaesthesia and intensive care medicine. The present article aims to review both the pathophysiological and pharmacological basis of inhaled vasodilators, to critically reevaluate their potential clinical indications and to give a perspective on future developments in the field.

Administration, Inhalation↗
PubMed2001

Dose-response relation of liquid aerosol inhaled insulin in type I diabetic patients.

AIMS/HYPOTHESIS: The AERx insulin Diabetes Management system (AERx iDMS) is a liquid aerosol device that enables insulin to be administered to the peripheral parts of the lung. This study aimed to compare the pharmacokinetic and pharmacodynamic properties of insulin which is inhaled using AERx iDMS with insulin which is subcutaneously administered. METHODS: In total, 18 C-peptide negative patients with Type I (insulin-dependent) diabetes mellitus participated in this randomised, open-label, 5-period crossover trial. Human regular insulin was administered subcutaneously (0.12 U/kg body weight) or inhaled by means of the AERx iDMS (dosages 0.3, 0.6, 1.2, and 1.8 U/kg body weight). Thereafter plasma glucose was kept constant at 7.2 mmol/l for a 10-h period (glucose clamp technique). RESULTS: Inhaled insulin provided a dose-response relation that was close to linear for both pharmacokinetic (AUC-Ins(0-10 h); Cmax-Ins) and pharmacodynamic (AUC-GIR(0-10 h); GIRmax) parameters. Time to maximum insulin concentration (Tmax-Ins) and time to maximum glucose infusion rate (TGIRmax) were shorter with inhaled insulin than with subcutaneous administration. The pharmacodynamic system efficiency of inhaled insulin (AUC-GIR(0-6 h) was 12.7% (95% C.I.: 10.2-15.6). CONCLUSION/INTERPRETATION: The inhalation of soluble human insulin using the AERx iDMS is feasible and provides a clear dose response. Further long-term studies are required to investigate safety aspects, HbA1c values, incidence of hypoglycaemic events and the quality of life.

Administration, Inhalation↗
PubMed2000

Inhaled prostacyclin and platelet function after cardiac surgery and cardiopulmonary bypass.

OBJECTIVE: To study the effects of 6 h inhalation of aerosolized prostacyclin (PGI2) on platelet function. DESIGN: In a prospective, double-blind, randomized study, 28 patients scheduled for elective cardiac surgery requiring cardiopulmonary bypass (CPB), received either 0.9% sodium chloride (n = 8), PGI2 5 microg x ml(-1) (n = 10) or PGI2 10 microg x ml(-1) (n = 10) as an aerosol for 6 h postoperatively. SETTING: Cardiothoracic intensive care unit at a university hospital. INTERVENTIONS: All patients were studied immediately after surgery during mechanical ventilation and sedation. The PGI2 solutions or saline were administered with a jet nebulizer. MEASUREMENTS AND RESULTS: Bleeding time and chest tube drainage were measured. Blood samples for platelet aggregation, thrombelastography (TEG) and analysis of coagulation parameters and the stable prostacyclin metabolite 6-keto-PGF1alpha were obtained immediately before inhalation and after 2, 4 and 6 h of inhalation. After 6 h of PGI2 inhalation, regardless of administered dose, there was a lower rate of platelet aggregation and a lower maximal increase in light transmission in response to adenosine diphosphate (ADP) than in the control group. The TEG variable reaction time (R) was prolonged after 4 and 6 h of inhalation in the PGI2 group receiving 10 microg x ml(-1). There were no differences between groups with respect to bleeding time and chest tube drainage or any of the other variables examined. CONCLUSION: Inhalation of PGI2 for 6 h in patients after cardiac surgery is associated with impaired platelet aggregation detected by in vitro techniques, with no in vivo signs of platelet dysfunction.

Administration, Inhalation↗
PubMed1998

Inhaled nitric oxide (NO) for the treatment of early allograft failure after lung transplantation. Munich Lung Transplant Group.

OBJECTIVE: Inhalation of high concentrations of nitric oxide (NO) has been shown to improve gas exchange and to reduce pulmonary vascular resistance in individuals with ischemia-reperfusion injury following orthotopic lung transplantation. We assessed the cardiopulmonary effects of low doses of NO in early allograft dysfunction following lung transplantation. DESIGN: Prospective clinical dose-response study. SETTING: Anesthesiological intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: 8 patients following a single or double lung transplantation who had a mean pulmonary arterial pressure (PAP) in excess of 4.7 kPa (35 mmHg) or an arterial oxygen tension/fractional inspired oxygen ratio (PaO2/FIO2) of less than 13.3 kPa (100 mmHg). INTERVENTIONS: Gaseous NO was inhaled in increasing concentrations (1, 4 and 8 parts per million, each for 15 min) via a Siemens Servo 300 ventilator. MEASUREMENTS AND RESULTS: Cardiorespiratory parameters were assessed at baseline, after each concentration of NO, and 15 min after withdrawal of the agent [statistics: median (25th/75th percentiles: Q1/Q3), rANOVA, Dunnett's test, p < 0.05]. Inhaled NO resulted in a significant, reversible, dose-dependent, selective reduction in PAP from 5.5(5.2/6.0) kPa at control to 5.1(4.7/5.6) kPa at 1 ppm, 4.9(4.3/5.3) kPa at 4 ppm, and to 4.7(4.1/5.1) kPa at 8 ppm. PaO2 increased from 12.7(10.4/17.1) to 19.2(12.4/26.0) kPa at 1 ppm NO, to 23.9(4.67/26.7) kPa at 4 ppm NO and to 24.5(11.9/28.7) kPa at 8 ppm NO. All patients responded to NO inhalation (either with PAP or PaO2), all were subject to long-term inhalation (1-19 days). All were successfully weaned from NO and were discharged from the intensive care unit. CONCLUSION: The present study demonstrates that low-dose inhaled NO may be an effective drug for symptomatic treatment of hypoxemia and/or pulmonary hypertension due to allograft dysfunction subsequent to lung transplantation.

Administration, Inhalation↗
PubMed1999

Inhaled nitric oxide differentiates pulmonary vasospasm from vascular obstruction after surgery for congenital heart disease.

OBJECTIVE: To evaluate whether a trial of inhaled nitric oxide (NO) differentiates reversible pulmonary vasoconstriction from fixed anatomic obstruction to pulmonary blood flow after surgery for congenital heart disease in patients at risk for pulmonary hypertension. DESIGN: Prospective cohort study. SETTING: Tertiary care children's hospital. PATIENTS: 15 neonate and infants with elevated pulmonary artery or right ventricular pressure or with clinical signs suggestive of high pulmonary vascular resistance in the early postoperative period following repair of congenital heart disease. INTERVENTION: 30-min trial of 40 ppm inhaled NO. RESULTS: 5 patients responded to inhaled NO, 2 patients were weaned from extracorporeal support with NO. Four were maintained on continuous inhaled NO for 3 to 5 days. All the responders survived. Ten patients did not respond to NO. An important anatomic obstruction was found with echocardiography or angiography in all 10 patients. Reintervention was performed in 6/10 (4 stent placement, 1 balloon angioplasty of pulmonary arteries and 1 revision of systemic to pulmonary shunt). Six of the nonresponders died. CONCLUSION: A trial of inhaled NO after cardiac surgery in neonates and infants may be useful to differentiate reversible pulmonary vasoconstriction from fixed anatomic obstruction and may provide useful information if temporary support with extracorporeal membrane oxygenation is considered. Failure to respond to inhaled NO should prompt further investigations to rule out a residual obstruction.

Administration, Inhalation↗
PubMed2000

Effects of NO inhalation on pulmonary leukocyte sequestration and blood volume in porcine endotoxaemia.

OBJECTIVE: Sequestration and migration of activated neutrophils plays a major role in the pulmonary injury typical of septic shock and the adult respiratory distress syndrome. Inhaled NO may counteract alveolar-capillary damage attributed to activated neutrophils. The present study describes a method to directly demonstrate the effects of NO inhalation on endotoxin-induced sequestration of 99mTc-labelled leukocytes [As(t)] in the lungs of pigs. DESIGN: Prospective controlled study. SETTING: Laboratory for experimental surgery at a university medical centre. SUBJECTS: Anaesthetised and ventilated pigs. INTERVENTIONS: To induce inflammatory shock 26 animals received a continuous endotoxin infusion. Thirteen animals inhaled NO from the start of the experiments, while 13 served as controls. In 13 animals from both groups, leukocytes were labelled in vitro and reinjected, while in the 13 others erythrocytes were labelled in vivo to provide corrections for changes in blood volume. MEASUREMENTS AND RESULTS: The pulmonary distribution of 99mTc-labelled leukocytes or erythrocytes was studied dynamically for 180 min. After correction for changes in pulmonary and heart blood volume (PBV, HBV), leukocyte sequestration curves were generated. Endotoxin induced pulmonary vasoconstriction, reduced PBV, impaired oxygenation, and caused a maximum increase in As(t) of 30% in the lungs. NO inhalation attenuated pulmonary vasoconstriction and the reduction in PBV. The maximum increase in As(t) was reduced to 15% of baseline. CONCLUSIONS: Inhaled NO exerts its main vascular effects in the pulmonary microvasculature, the primary site of physiological neutrophil margination and pathological adhesion of activated leukocytes. Early use of NO inhalation may offer protection against the development of more lasting pulmonary failure in septic shock by reducing leukocyte sequestration in the lungs.

Administration, Inhalation↗
PubMed2000

Inhaled nitric oxide during partial liquid ventilation shifts pulmonary blood flow to the non-dependent lung regions.

OBJECTIVE: To elucidate the change in pulmonary blood flow brought about by nitric oxide (NO) inhalation during partial liquid ventilation (PLV). DESIGN: Prospective, controlled study. SETTING: A research laboratory at a university medical center. SUBJECTS: Fourteen Japanese white rabbits (3.2 +/- 0.05 kg body weight). INTERVENTIONS: Animals were mechanically ventilated in the right decubitus position. Following saline lung lavage, PLV was started with perflubron (15 ml/kg). In the NO group (n = 7), PLV was supplemented by a 30-min challenge of NO inhalation (10 ppm) from 30 min after the initiation of PLV. In the control group (n = 7), PLV was continued for 60 min. MEASUREMENTS AND MAIN RESULTS: For the pulmonary blood flow analysis, colored microspheres were administered from the right atrium at 30 min (T(PLV1)) and 60 min (T(PLV2)) after the initiation of PLV. The percentage of the left lung blood flow in the total pulmonary blood flow (%Q(L)/Q(T)) was significantly increased by NO inhalation in the NO group (p = 0.0164), while that in the control group was significantly decreased during the same period (p = 0.0107). PaO2 in the NO group was significantly increased by NO inhalation (p = 0.0153), but not in the control group (p = 0.7911). CONCLUSION: Inhaled NO during PLV shifted the pulmonary blood flow to the non-dependent region and improved pulmonary gas exchange. This result suggested that inhaled NO took effect predominantly in the non-dependent region during PLV.

Administration, Inhalation↗
PubMed2004

Are inhaled corticosteroids associated with an increased risk of fracture in children?

Inhaled corticosteroids are widely used in the long-term management of asthma in children. Data on the relationship between inhaled corticosteroid therapy and osteoporotic fracture are inconsistent. We address this issue in a large population-based cohort of children aged 4-17 years in the UK (the General Practice Research Database). The incidence rates of fracture among children aged 4-17 years taking inhaled corticosteroids (n=97,387), taking bronchodilators only (n=70 984) and a reference group (n=345,758) were estimated. Each child with a non-vertebral fracture (n=23,984) was subsequently matched by age, sex, practice, and calendar time to one child without a fracture. Fracture incidence was increased in children using inhaled corticosteroids, as well as in those receiving bronchodilators alone. With an average daily beclomethasone dose of 200 microg or less, the crude fracture risk relative to nonusers was 1.10 [95% confidence interval (CI), 0.96-1.26]; with dosage of 201-400 microg, it was 1.23 (95% CI, 1.08-1.39); and with dosages over 400 microg, it was 1.36 (95% CI, 1.11-1.67). This excess risk disappeared after adjustment for indicators of asthma severity. The increased risk of fracture associated with use of inhaled corticosteroids is likely to be the result of the underlying illness, rather than being directly attributable to inhaled corticosteroid therapy.

Administration, Inhalation↗
PubMed2003

Dermal and inhalation acute toxic class methods: test procedures and biometric evaluations for the Globally Harmonized Classification System.

The acute toxic class (ATC) methods were developed for determining LD(50)/LC(50) estimates of chemical substances with significantly fewer animals than needed when applying conventional LD(50)/LC(50) tests. The ATC methods are sequential stepwise procedures with fixed starting doses/concentrations and a maximum of six animals used per dose/concentration. The numbers of dead/moribund animals determine whether further testing is necessary or whether the test is terminated. In recent years we have developed classification procedures for the oral, dermal and inhalation routes of administration by using biometric methods. The biometric approach assumes a probit model for the mortality probability of a single animal and assigns the chemical to that toxicity class for which the best concordance is achieved between the statistically expected and the observed numbers of dead/moribund animals at the various steps of the test procedure. In previous publications we have demonstrated the validity of the biometric ATC methods on the basis of data obtained for the oral ATC method in two-animal ring studies with 15 participants from six countries. Although the test procedures and biometric evaluations for the dermal and inhalation ATC methods have already been published, there was a need for an adaptation of the classification schemes to the starting doses/concentrations of the Globally Harmonized Classification System (GHS) recently adopted by the Organization for Economic Co-operation and Development (OECD). Here we present the biometric evaluation of the dermal and inhalation ATC methods for the starting doses/concentrations of the GHS and of some other international classification systems still in use. We have developed new test procedures and decision rules for the dermal and inhalation ATC methods, which require significantly fewer animals to provide predictions of toxicity classes, that are equally good or even better than those achieved by using the conventional LD(50)/LC(50) methods. In order to cope with rather narrow dose/concentration classes of the GHS we have, as in our previous publications, combined the outcome of all results that can be obtained during testing for the allocation to one of the defined toxicity classes of the GHS. Our results strongly recommend the deletion of the dermal LD(50) and the inhalation LC(50) test as regulatory tests and the adoption of the dermal and inhalation ATC methods as internationally accepted alternatives.

Administration, Cutaneous↗
PubMed2001

The relevance of physical activity for the kinetics of inhaled gaseous substances.

Inhalation is the most important route of absorption for many volatile substances. The inhaled chemical is distributed via the bloodstream into the organs and tissues. It is eliminated mainly unchanged by exhalation and also via metabolism. The blood concentration can be considered as a surrogate for the body burden of the chemical. It depends on the rate of uptake and on the rate of elimination. The rate of uptake by inhalation is determined by the blood:air partition coefficient of the gaseous compound, the actual concentration of the chemical already in the blood entering the lungs, the blood flow through the lungs, and the alveolar ventilation. The latter is greatly influenced by physical activity, which thus has a crucial impact on the rate of uptake. Consequently, the blood concentration of an inhaled chemical and the resulting alveolar retention, representing the rate of metabolism at steady-state, are dependent on the intensity of physical work. Both parameters can be calculated for steady-state conditions using simple algebraic equations, if one assumes that the rate of metabolic elimination is limited by the blood flow through the metabolizing organs. This assumption is valid for many rapidly metabolized inhaled gases and vapours at low concentrations present under workplace conditions. The derived equations give the theoretical background for the observations presented from a series of experimental studies which demonstrate that physical activity can be a major determinant of the toxicokinetics of inhaled compounds. Practical examples illustrate the procedure. We conclude that workplace-related physical activity should be taken into account for compounds with blood:air partition coefficients above 6 in the determination of occupational limit concentrations in air.

Air Pollutants, Occupational↗
PubMed1997

Temperature dependency of the release and bioavailability of nicotine from a nicotine vapour inhaler; in vitro/in vivo correlation.

OBJECTIVE: To investigate the temperature dependency of the dose released and the plasma levels of nicotine from a vapour inhaler. METHODS: In an open, randomised, three-way cross-over pharmacokinetic study 18 healthy subjects inhaled nicotine for 20 min (80 inhalations) every hour for 10 h (11 administrations) at three different environmental temperatures: 20 degrees, 30 degrees and 40 degrees C. In the in vitro experiment, 5, 10, 15 and 20 l air were forced through the inhaler. With a 15 l air volume, the average amount of nicotine released was 1.44, 3.49, 4.80 and 6.99 mg at 10 degrees C, 22 degrees C, 29 degrees C and 40 degrees C, respectively. The maximum dose released at the highest temperature (40 degrees C) and the largest air volume investigated (20 l) was approximately 7.5 mg. RESULTS: In vivo peak plasma levels obtained at 30 degrees and 40 degrees C were 29.7 and 34.0 ng.ml-1, compared with 22.5 ng.ml-1 at ambient room temperature (20 degrees C). At 20 degrees C, the area under the plasma concentration-time curve (AUC) of the last dosing interval was 20.5 ng.ml-1.h. At 30 degrees C and 40 degrees C, the AUCs were 26.5 and 30.3 ng.ml-1.h, respectively. The results thus showed a mean increase of the in vivo AUC by 29% at 30 degrees C and by 48% at 40 degrees C compared with the AUC at 20 degrees C. These increases should be compared to the in vitro results, showing a mean increase of 59% and 122% respectively, at 30 degrees and 40 degrees C. The in vitro results also showed that a relatively larger fraction of the dose was released into the first 5 l of air at the higher temperatures, at 40 degrees C, about 50% of the total amount released into 20 l. CONCLUSION: It was concluded that the in vitro/in vivo discrepancy was most probably due to increased aversive effects at elevated temperatures, causing the subjects to inhale smaller puff volumes. Further, the inhaler would not produce nicotine plasma levels exceeding those achieved following cigarette smoking, even in a hot climate.

Administration, Inhalation↗