The responsiveness of cerebral blood flow to changes in arterial carbon dioxide is maintained during propofol-nitrous oxide anesthesia in humans. Because it is common to manipulate PaCO2 during neurosurgery, it is essential to characterize the relationship between cerebral blood flow (CBF) and changes in PaCO2. The purpose of this study was to investigate the effects of propofol-N2O anesthesia on the CBF response to changes in PaCO2 in healthy subjects. In seven patients, anesthesia was induced with propofol 2.0-2.5 mg/kg and then maintained with a propofol infusion of 12 mg.kg-1.h-1 for 10 min and then 9 mg.kg-1.h-1 for 10 min and then was reduced to 3-6 mg.kg-1.h-1 for the remainder of the study. The subjects' lungs were ventilated with N2O in O2 (FIO2 0.3) to the end-tidal CO2 present before anesthesia, and then CBF was measured using intravenous 133Xe and ten scintillation counters, five over each cerebral hemisphere. ETCO2 then was increased to 50 mmHg and CBF measurement repeated; ETCO2 then was reduced to 30 mmHg and CBF measurement repeated. Concurrent with each CBF measurement, arterial blood was sampled for PaCO2 and hemoglobin measurement. CBF at normocapnia (PaCO2 42 +/- 2 mmHg) was 33 +/- 7 ml.100 g-1.min-1, which increased to 58 +/- 10 ml.100 g-1.min-1 and decreased to 19 +/- 4 ml.100 g-1.min-1 on increasing PaCO2 (53 +/- 4 mmHg) and decreasing PaCO2 (31 +/- 2 mmHg), respectively. Both the PaCO2 and CBF values were statistically different from those measured at any other time (CBF P less than 0.002, PaCO2 P less than 0.001). The slope of CBF versus PaCO2 was 1.56 ml.100 g-1.min-1.mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)


Central effects of epidural and intravenous clonidine in patients anesthetized with enflurane/nitrous oxide. An electroencephalographic analysis. Epidural clonidine produces regional anesthesia as well as sedation and a decrease in anesthetic requirements. To assess these effects, the electroencephalogram (EEG) was recorded after epidural or intravenous (iv) injection of clonidine during enflurane/N2O anesthesia. Eighteen ASA physical status 1 women undergoing vaginal hysterectomy were allocated randomly to receive epidural clonidine (8 micrograms.kg-1 in 4 ml over 2 min) and iv saline (10 ml over 14 min); or epidural saline (4 ml over 2 min) and iv clonidine (8 micrograms.kg-1 in 10 ml over 14 min); or epidural saline (4 ml over 2 min) and iv saline (10 ml over 14 min). The level of anesthesia was kept constant beginning 10 min before and until 44 min after epidural injection. EEG power spectral analysis was performed throughout the study period using a 2-min average of 8-9-s epochs. Clonidine significantly reduced EEG total power only after epidural administration (P less than 0.05). Relative power increased in the delta band in both the epidural and iv clonidine groups (P less than 0.001). The depression of the total EEG power after epidural injection could be explained neither by systemic absorption alone nor by hemodynamic variations. It may represent the contribution of the direct spinal action of this alpha 2-adrenergic agonist to general anesthesia.


Transdermal fentanyl for postoperative pain management in patients recovering from abdominal gynecologic surgery. The current placebo-controlled double-blinded study was undertaken to assess the safety and efficacy, as well as the potential clinical role, of the transdermal therapeutic system (TTS) of fentanyl delivery in the postoperative setting. TTS patches releasing 25 micrograms.h-1 or 50 micrograms.h-1 or placebo were applied to 95 women 1 h before abdominal gynecologic surgery during general anesthesia. Postoperatively, patients self-administered intravenous morphine as required using patient-controlled analgesia with a 1-mg incremental dose and a 6-min lockout interval. Each was assessed upon admission to the postanesthesia care unit and at intervals over the following 72 h with respect to vital signs, visual analogue scale pain and satisfaction scores, side effects, and cumulative morphine use. Data were analyzed using analysis of variance, Kruskal-Wallis, and chi-square. P less than 0.05 was considered significant. There were no demographic differences among groups. Beginning 32 h after TTS application, a statistically significant morphine-sparing effect was seen with the 50 micrograms.h-1 patch. There were no significant differences among groups with regard to visual analogue scale pain scores at rest, patient satisfaction, or the incidence of side effects; a significant reduction in pain upon movement was noted at 24 h in patients treated with TTS 50 micrograms.h-1. This finding constituted the only benefit noted with this form of analgesic therapy in the present investigation.


Identification of the pharmacogenetic determinants of alfentanil metabolism: cytochrome P-450 3A4. An explanation of the variable elimination clearance. There is considerable variability in the elimination clearance of the opioid analgesic alfentanil. It has been shown previously that alfentanil clearance is independent of the polymorphic debrisoquine hydroxylase (P-450 2D6), and it is therefore of interest to identify the human cytochrome P-450 enzymes involved in noralfentanil formation, the primary reaction involved in the oxidative N-dealkylation at the piperidine nitrogen. Purified human P-450 3A4 showed appreciable catalytic activity, and yeast recombinant P-450 3A4 also showed alfentanil oxidation activity. When microsomes prepared from different human liver samples were compared, noralfentanil formation activity was well correlated (r = 0.95,P less than 0.005) with nifedipine oxidation (a P-450 3A4 marker) but not with markers of other P-450s, including phenacetin O-deethylation (P-450 1A2), chlorzoxazone 6-hydroxylation (P-450 2E1), and (S)-mephenytoin 4'-hydroxylation (a P-450 2C enzyme). Using antibodies that recognize specific human P-450 enzymes (immunoinhibition techniques), it was possible to demonstrate that anti-P-450 3A4 nearly completely inhibited alfentanil oxidation activity in the human liver microsomes, but no other antibodies showed a measurable inhibitory effect. Selective chemical inhibitors of P-450 3A4, gestodene and troleandomycin, inhibited as much as 90% of the microsomal noralfentanil formation activity, but other chemical inhibitors did not show a detectable inhibitory effect. 7,8-Benzoflavone inhibited as much as 90% of the alfentanil oxidation activity of the microsomal or reconstituted P-450 3A4 system. This work indicates that P-450 3A4 contributes significantly to human liver microsomal alfentanil oxidation, whereas P-450 2D6 does not contribute.(ABSTRACT TRUNCATED AT 250 WORDS)


Prolongation of spinal anesthesia. Differential action of a lipid drug carrier on tetracaine, lidocaine, and procaine. This study evaluates prolongation of spinal anesthesia by incorporating local anesthetics in lipid formulation. The duration and intensity of local anesthetic effect produced by different concentrations of procaine (1%, 2%, 4%), lidocaine (1%, 2%, 4%), or tetracaine (0.5%, 1%, 2%) dissolved in normal saline were compared to those produced by the same concentration of drugs in lipid (iophendylate) solution. Fifty rabbits with chronic indwelling subarachnoid catheters were divided into ten equal groups. Three days after the operation the catheters were injected with aqueous solutions of the anesthetics, and 24 h later each animal received an equivalent dose of the corresponding drug in free-base form dissolved in iophendylate. The duration and intensity of motor blockade were assessed using a modified Bromage scale. A separate group of animals received plain normal saline and, 24 h later, iophendylate alone. The Kruskal-Wallis test followed by the Tukey-type test for nonparametric multiple comparisons and the Mann-Whitney and Friedman tests were used for statistical analysis at P less than 0.05. Normal saline or iophendylate alone did not produce any motor blockade. Our data show that iophendylate preparations of local anesthetics produce prolonged but less intense motor blockade than the aqueous solutions, except for tetracaine 0.5% in iophendylate, which produced shorter duration of motor blockade. The reduced intensity of motor blockade may be explained by decreased availability of local anesthetic at the nerve tissue due to storage of drug in the lipid depot. The increased duration of blockade signifies a sustained release of drug from the depot.


Modification of GABA-mediated inhibition by various injectable anesthetics. Increasing doses of the injectable anesthetics etomidate, Saffan, thiopental, ketamine, and xylazine and the vehicles saline and propylene glycol were administered to urethane-anesthetized rats. Their effects in vivo on perforant pathway-evoked field excitatory post-synaptic potentials and population spikes in the hippocampal dentate gyrus were determined. The primary purpose was to ascertain whether these compounds affect hippocampal excitability in a manner consistent with their proposed mechanisms of action. Compared with their respective vehicles, thiopental, etomidate, and xylazine reduced the amplitude of population spikes to single perforant pathway stimulation by 20-30% at the highest doses tested. Xylazine also increased the latency to onset of the population spike. No other effects were observed. Using paired pulse paradigms, it was determined that etomidate produced a dramatic, prolonged reduction in granule cell excitability at interpulse intervals of 10-100 ms. The magnitude of the effect was dose related and was reversible with the discontinuance of administration of the drug. Similar changes occurred with Saffan (althesin) and thiopental. Ketamine produced a small but significant depression in granule cell excitability during intervals of 10-200 ms. Xylazine had no effect. These data corroborate the importance of a prolongation of gamma-aminobutyric acid A-mediated inhibition to the mechanism of actions of etomidate, thiopental, and Saffan at relevant exposure concentrations in vivo.


Decreased sensitivity to metocurine during long-term phenytoin therapy may be attributable to protein binding and acetylcholine receptor changes. Long-term phenytoin therapy induces resistance to the neuromuscular blocking effects of metocurine. The hypothesis that this is attributable to increased plasma protein binding of the drug (decreased free fraction) related to increased concentrations of alpha 1-acid glycoprotein (AAG) or attributable to the proliferation of acetylcholine receptors (AChR) at the muscle membrane was tested in the rat. After 14 days of phenytoin 40 mg.kg-1, administered intraperitoneally twice daily (n = 12), the neuromuscular pharmacodynamics were evaluated and compared with those of time-matched controls (n = 10). Protein binding was measured by equilibrium dialysis, AAG concentrations by radial immunodiffusion assay, and AChR by 125I-alpha-bungarotoxin binding. The effective dose for 50% inhibition of baseline twitch height (ED50) was significantly greater in the phenytoin group than in the control group (15.03 +/- 1.65 micrograms.kg-1 vs. 9.98 +/- 0.69 micrograms.kg-1, respectively). The concentrations of AAG increased gradually from 133.8 +/- 7.8 micrograms.ml-1 at day 0, to 343.1 +/- 58.0 micrograms.ml-1 at day 7, to 1,729.5 +/- 422.3 micrograms.ml-1 at day 14 in the phenytoin group. The induction of AAG concentrations in plasma was dependent on plasma phenytoin concentrations and was most prominent after 14 days of phenytoin (r = 0.77; P less than 0.01; n = 22). The free fraction of metocurine was significantly decreased in the phenytoin group compared to the control group (67.2 +/- 0.18% vs. 74.5 +/- 2.5%). There was a significant negative correlation between increased AAG concentrations and decreased free fraction (r = 0.65).(ABSTRACT TRUNCATED AT 250 WORDS)


Anesthesia and muscle relaxation with intrathecal injections of AR636 and AG489, two acylpolyamine spider toxins, in rat. Acylpolyamine toxins are constituents isolated from many invertebrate predator venoms. These toxins are structurally novel and potent noncompetitive ligand-mediated ion channel antagonists. This study was designed to explore the sensory and motor effects of intrathecally applied acylpolyamine toxin. AR636 and AG489, acylpolyamine toxins from the spiders Argiope aurantia and Agelenopsis aperta, respectively, were injected intrathecally into rats prepared with chronic spinal catheters, and the effect on spinal function was assessed. AR636 was found to evoke a dose-dependent incidence of muscle flaccidity as well as a blockade of the agitation otherwise evoked by noxious mechanical and thermal stimuli applied to the tail or hind paws. AR636 has a calculated effective concentration (EC50) of 2 micrograms for motor inhibition and 7 micrograms for sensory inhibition. In contrast, AG489 was not found to have any effects at the highest tested dose of 50 micrograms. The precise mechanism whereby AR636 exerts its action in the rat spinal cord is not known, but in insect models, this agent is known to act as a postsynaptic, noncompetitive antagonist at a glutamate receptor and to block cholinergic-gated ion channels. Thus, this agent, a representative of the acylpolyamine toxins, has prominent effects on the sensory and motor systems of mammals, and this class of agents may be found to have potential application as spinally acting muscle relaxants and/or anesthetics.


Liposome encapsulation prolongs alfentanil spinal analgesia and alters systemic redistribution in the rat. The effect of liposome encapsulation on the analgesia produced by intrathecally administered alfentanil was examined in the rat. In rats prepared with chronic intrathecal catheters, alfentanil in doses of 1-50 micrograms was administered intrathecally in either saline or in multilamellar liposomes (dipalmitoylphosphatidylcholine and cholesterol). Animals were then tested for analgesia by hot-plate and paw-pressure tests. A second group of animals received intrathecal injections of 30 micrograms alfentanil in saline or liposomes, and blood samples were obtained at 5, 15, 45, and 135 min thereafter for measurement of alfentanil plasma concentrations. The liposome preparation markedly prolonged spinal analgesia in the paw-pressure test and to a lesser extent in the hot-plate test. Neither the time to peak analgesia nor the intensity of analgesia differed between the saline and liposome groups. Liposome encapsulation significantly reduced the peak alfentanil plasma concentration at 5 min and prolonged the period in which low but measurable levels of alfentanil could be measured in plasma. These pharmacokinetic data demonstrate that liposome encapsulation resulted in a slow but prolonged appearance of free alfentanil into a diffusible pool available for uptake into the spinal cord. Consistent with the lower peak plasma concentration of alfentanil, the liposome group demonstrated a significantly lower incidence of catalepsy, indicating less systemic redistribution of alfentanil to supraspinal sites. Liposome encapsulation thus appears to produce a significant reduction in peak plasma concentration with a concomitant reduction in systemic side effects and an increase in the duration of action for a given intrathecal dose of the otherwise rapidly cleared alfentanil.


Deliberate arterial hypotension does not reduce intraocular pressure in pigs. Among the accepted advantages of general anesthesia in ophthalmic surgery is improved control of intraocular pressure (IOP). Although standard textbooks advocate deliberate arterial hypotension to facilitate intraocular surgery by reducing IOP, scientific proof of such an effect is lacking. The authors investigated effects of induced arterial hypotension on IOP in an anesthetized porcine model. Forty-two piglets were anesthetized with piritramide, were placed in the prone position, and had the anterior chamber of one eye punctured with a small Teflon cannula to measure IOP. Six pigs were used in a pilot study to establish dose-response relationships for the hypotensive agents; 36 pigs were randomly allocated to one of three groups (n = 12) to receive nitroprusside, adenosine, or isoflurane to reduce mean arterial pressure (MAP) by 50%. Measurements were made after initial stabilization of hemodynamic variables and IOP (control), when a stable MAP of 0.5x control was maintained for 10 min or longer, and after return of MAP to a posthypotensive steady state. The median of differences between time intervals was analyzed statistically for all variables. Nitroprusside and adenosine produced hyperdynamic hypotension (cardiac index increased); isoflurane-induced hypotension was hypodynamic. Control IOPs were 12.9, 12.5, and 11.1 mmHg in the nitroprusside, adenosine, and isoflurane groups, respectively. Median change in IOP during hypotension was -1.5, +1.5, and 0 mmHg in the nitroprusside, adenosine, and isoflurane groups, respectively. The IOP during adenosine-induced hypotension was significantly higher than that during either nitroprusside- or isoflurane-induced hypotension. Return of MAP to control levels was frequently associated with intraocular rebound hypertension when arterial hypotension had been induced with adenosine or nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of sevoflurane and isoflurane on hepatic circulation in the chronically instrumented dog. To compare the effects of sevoflurane and isoflurane on hepatic circulation, eighteen dogs were chronically instrumented for measurements of mean aortic blood pressure and cardiac output and for simultaneous measurements of hepatic and portal blood flows. Each animal was studied while awake and during 1.2 and 2 MAC of either isoflurane or sevoflurane. Both anesthetics induced tachycardia and a dose-dependent decrease in mean aortic blood pressure (isoflurane -27% and -39%; sevoflurane -22% and -37%). Cardiac output decreased only at the highest concentration (isoflurane -10%; sevoflurane -21%). During sevoflurane, portal blood flow decreased at both 1.2 and 2 MAC (-14 and -33%, respectively), whereas an increase in hepatic arterial blood flow was recorded at 2 MAC (+33%). During isoflurane, the only significant change was a decrease in portal blood flow (-16%) at 1.2 MAC. Neither anesthetic significantly changed renal blood flow. Therefore, both anesthetics led to similar systemic and hepatic vasodilation.


Greater effect of inhaled budesonide on adenosine 5'-monophosphate-induced than on sodium-metabisulfite-induced bronchoconstriction in asthma. Inhaled glucocorticosteroids (GCS) decrease airway responsiveness (AR) in asthma by mechanisms that may involve suppressing airway inflammation and a reduction in the number of inflammatory cells in the airways. To investigate the functional response to a reduction in airway inflammatory cells in asthma, we studied the effects of inhaled budesonide on AR to three different bronchial challenges, adenosine 5'-monophosphate (AMP), which primarily activates mast cells; methacholine (MCh), a direct stimulus, and sodium metabisulfite (MBS), a neural stimulus. In a double-blind randomized crossover manner, with a washout period of 28 days, 12 subjects with mild asthma underwent inhalation challenge with doubling increments of MCh, MBS, and AMP before and after 14 days of treatment with budesonide 0.8 mg twice daily from a multidose dry-powder delivery system (Turbohaler) or matched placebo. Treatment with budesonide reduced AR to MCh and MBS to a similar degree, displacing the dose-response curve of each agonist to the right by 1.17 (95% confidence intervals, 0.34 to 2.00) and 1.06 (0.34 to 1.78) doubling dilutions, respectively, when compared with placebo (p less than 0.01). Budesonide caused an additional and significantly greater reduction in AR to AMP, displacing the dose-response curve to the right by 2.92 (2.12 to 3.72) doubling dilutions when compared with placebo (p less than 0.001) and to the other challenges (p less than 0.01). We conclude that budesonide reduces AR to MCh and MBS by an action common to the effects of both direct and neural stimuli on airway smooth muscle contraction. The greater reduction in AR to AMP suggests that budesonide may have an additional action by reducing airway mast cell numbers and/or function.


Effect of allergen inhalation on the maximal response plateau of the dose-response curve to methacholine. Methacholine dose response curves (DRC) in asthmatic subjects are characterized by a leftward shift and increased maximal response. Allergen inhalation in atopic subjects shifts the DRC to the left, but the effect on the shape is unknown. This study was designed to investigate the effect of allergen inhalation on the maximal response plateau of the methacholine DRC in 16 atopic subjects; nine had mild asthma and seven had rhinitis. They were challenged with allergen and with control solutions in a single-blind design. Methacholine challenges (up to 199 mumol) were performed at baseline and 24 h after the control and allergen challenges. A plateau of the DRC was defined as a difference of less than 5% in FEV1 between the last two or more doses. The maximal response was obtained by averaging the values on the plateau and was reached by all except one subject. Allergen inhalation induced an early asthmatic response (EAR) in all subjects and an additional late asthmatic response (LAR) in 6 subjects. In subjects with an EAR alone the maximal response to methacholine 24 h after allergen challenge was not different from control (mean difference, 2.9% fall in FEV1; p greater than 0.05). In subjects with LAR, the mean value for the maximal response increased from 28.5% after control to 36.5% after allergen (mean difference, 8.0%; p less than 0.05). Of six subjects who developed LAR two lost the plateau on the DRC after allergen challenge. We conclude that allergen inhalation increases the maximal response to methacholine in those subjects who have a LAR.


Respiratory input impedance from 4 to 256 Hz in normals and chronic airflow obstruction: comparisons and correlations with spirometry. Measurement of respiratory system input impedance (Zrs) by forced oscillation (FO) has generally been limited to frequencies less than or equal to 50 Hz, and correlations with spirometry have been variable. Using FO from 4 to 256 Hz in normals, Jackson and colleagues recently described a first acoustic antiresonance frequency (Far,1) at approximately 170 Hz. Using the same frequency range, we compared several Zrs spectral characteristics with spirometry in 12 chronic airflow obstruction (CAO) patients (range FEV1 0.8 to 2.0 L) and 10 matched controls. Compared with controls, patients had a higher first resonance frequency (Fr,1) (mean +/- SD = 15 +/- 5 versus 10 +/- 2 Hz, p less than 0.02) and a higher Far,1 (196 +/- 11 versus 172 +/- 13 Hz, p less than 0.0002). Good correlations occurred between % predicted FVC and the Far,1 (r = -0.81, p less than 0.0000), between FEV1/FVC and the reactance at 20 Hz (r = -0.6, p less than 0.003), between FEV1 and Far,1 (r = -0.74, p less than 0.0001). Because Far,1 may be affected by airway wall mechanical properties, the shift in Far,1 seen in these patients may be due to airway wall properties in CAO. We conclude that measurement of Zrs up to 256 Hz requires little patient cooperation and may be clinically useful. It can differentiate CAO patients from controls and correlates well with spirometry. The first acoustic antiresonance frequency may reflect airway mechanical properties and provide information not available from Zrs measured at lower frequencies.


Changes in cross-sectional airway areas induced by methacholine, histamine, and LTC4 in asthmatic subjects. To examine whether leukotrienes, histamine, and methacholine have different sites of bronchoconstrictor action, we studied 8 stable asthmatic subjects (mean age +/- SD, 26 +/- 5 yr) on 3 different days. On each day, a randomized challenge with LTC4, methacholine, or histamine was performed until the dose that provoked a fall of 20% in FEV1 (PC20) was obtained. Complete and partial flow-volume curves as well as area-distance profiles generated by the acoustic reflection technique (ART) at a fixed lung volume were obtained in all subjects before and after each inhalation challenge. No significant differences were found in pulmonary function or baseline cross-sectional airway areas for the different study days. The three agonists provoked significant (p less than 0.05) bronchoconstriction at the level of the main bronchi when identical falls of FEV1 were achieved. Similarly, equal reductions of V30p were elicited by the three agonists. However, LTC4 and methacholine induced additional tracheal constriction but histamine inhalation did not. These differences in the degree of tracheal constriction were statistically significant (p less than 0.05; ANOVA). These results may be explained by distinct pharmacologic properties of the agents used and may have relevance in the understanding of the pathophysiology of asthma.


Upper airway anesthesia induces airflow limitation in awake humans. Upper airway receptors are thought to contribute to upper airway stability by reducing collapsing forces. Their activity can be abolished by topical anesthesia. We have measured in 16 healthy volunteers (mean +/- SD age, 23.7 +/- 1.6 yr) specific airway conductance (SGaw), maximal inspiratory (MIFR) and expiratory (MEFR) flow rates before and 15, 35, and 45 min after extensive upper airway anesthesia (UAA) with 10% lidocaine. Average values of MIFR decreased (p less than 0.01) 15 min after UAA, but they returned to or near to control values at 45 min: MIF25 (4.8 versus 6.0 L/s); MIF50 (5.1 versus 6.2 L/s); MIF75 (4.4 versus 5.3 L/s). Transient decreases in flow (V) rates, reaching zero flow in some subjects, were observed in 13 subjects during forced inspiratory vital capacity (FIVC) maneuvers and in seven subjects during forced expiratory vital capacity (FEVC) maneuvers. MEFR at 25, 50, and 75% FVC, SGaw, and FVC did not change after anesthesia. Simultaneous measurements of supraglottic pressure, V, and lung volume in 12 of the 16 subjects showed that the site of flow limitation was localized at the level of the glottis in all except one subject in whom there was both a glottic and a supraglottic obstruction. We conclude that extensive upper airway anesthesia induced a profound but transitory upper airway obstruction during FIVC and FEVC maneuvers. These findings are compatible with the concept of reflex regulation of upper airway caliber.


Decreased airway mucosal prostaglandin E2 production during airway obstruction in an animal model of asthma. Heaves is a respiratory disorder of horses and ponies characterized by bouts of acute airway obstruction and airway hyperresponsiveness. We measured prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (15-HETE) production in vitro in tracheal epithelium obtained from six affected horses at the time of acute airway obstruction as compared with six matched control horses. Strips of epithelium and subepithelial tissue were prepared and stimulated with A23187, histamine, and bradykinin. The PGE2 and 15-HETE in media from strips was quantitated by radioimmunoassay. 15-HETE above the limits of accurate detection was found in epithelial strips of only two principal animals and in none of the control horses, and the amount of 15-HETE was not increased when strips were stimulated. Epithelial strips from affected horses tended to produce less PGE2 than did strips from control horses, and there was a significant correlation between epithelial PGE2 production and the time taken for affected animals to develop airway obstruction. Subepithelial tissue strips from control horses produced significantly more PGE2 in response to A23187 and bradykinin than did strips from affected horses. We conclude that equine tracheal epithelium is not a significant source of 15-HETE. Airway mucosal PGE2 production is reduced in horses with heaves, which suggests that a relative decrease in this bronchorelaxant substance may be a factor in the pathogenesis of this model of asthma.


Mucociliary clearance in adult asthma.

Mucociliary clearance in adult asthma. Severe impairment of mucociliary clearance (MC) in hospitalized asthmatics has recently been demonstrated in peripheral and central airways. MC was also shown to improve with clinical recovery and hospital discharge (2). In the present study, we measure MC in chronic, stable asthma in subjects with a wide range of obstruction to see if MC was related to the severity of chronic disease. We separated the subjects into those with severe obstruction with expiratory flow limitation during tidal breathing (FL subjects) and those without tidal flow limitation (NFL subjects) to see if the presence of chronic flow limitation was associated with regional MC abnormalities. Seventeen asthmatic patients were studied. Mucociliary clearance was assessed using inhaled radioaerosol and serial measurements of the retention of radioactivity over 2 h. By controlling breathing pattern, the initial pattern of deposition in the lungs was matched, with all subjects having a predominance of particles in the central airways. This pattern was normalized for regional lung volume using a xenon equilibrium scan and expressed as a specific central to peripheral (sC/P) ratio. The percentage retention of deposited radioactivity at 120 min ranged from 19 to 83% (mean, 52%). FL subjects had a mean retention at 120 min of 66% (range, 55 to 83%). The NFL subjects had a mean retention at 120 min of 33% (range, 19 to 51%). Throughout the 2-h study period, retention by the FL group was significantly greater than that of the NFL group with separation of 95% confidence intervals.(ABSTRACT TRUNCATED AT 250 WORDS)


Sputum ECP levels correlate with parameters of airflow obstruction. Growing evidence suggests that eosinophils play an important role as proinflammatory cells in asthma, possibly by releasing toxic cationic proteins. In this study concentrations of serum and sputum eosinophil cationic protein (ECP) from 134 patients with productive cough and a history suggestive of airflow obstruction were measured by radioimmunoassay. Small sputum volumes were suspended in saline, vortexed, and centrifuged and ECP measured in the supernatant. Serum ECP levels ranged from 0.002 to 0.095 mg/L (0.016 +/- 0.0014), whereas sputum ECP concentrations were between 0.024 and 5.66 mg/L ECP per g sputum (0.878 +/- 0.092). Only 17 of the 134 patients (14 asthma, one cystic fibrosis, one bronchiectasis, and one bronchitis) had not been pretreated with corticosteroids. Sputum but not serum ECP levels of the 14 patients with asthma were inversely correlated with impairment of FEV1 (r = -0.73). Airway resistance (Raw) (r = 0.71) as well as the change in FEV1 (r = 0.79) and Raw (r = 0.84) after inhalation of 0.2 mg albuterol were positively correlated. This relationship was not observed in the remaining 117 patients on topical and/or systemic corticosteroids, suggesting that corticosteroid treatment influences sputum ECP levels. Also, sputum ECP levels and the degree of sputum eosinophilia were not correlated in any of the patient groups. Neither did serum ECP levels predict sputum ECP concentrations. We conclude that sputum ECP concentrations serve as a marker of eosinophil degranulation in the sputum, and this marker correlates with airflow obstruction. Sputum ECP levels are more closely related to lung function parameters than serum ECP concentrations and/or microscopic sputum analysis.


Risk factors for morbidity in mechanically ventilated patients with acute severe asthma. Acute severe asthma is associated with significant morbidity and mortality. We retrospectively quantified hypotension, pulmonary barotrauma, and cardiac arrhythmias in all patients with severe asthma admitted to the intensive care unit (ICU) and prospectively evaluated the predictive value of a measurement of dynamic hyperinflation (DHI) in those patients who required mechanical ventilation. In the first study, 88 ICU admissions for severe asthma over 5 yr (73 patients, 40 +/- 18 yr, 36 men, 37 women) were evaluated. Fifty-one admissions were mechanically ventilated, 29 were not, and 8 previously ventilated patients remained briefly intubated but were not ventilated in the ICU. Hypotension (18/88, 20%), pulmonary barotrauma (12/88, 14%), and arrhythmias (9/88, 10%) were entirely confined to patients who had been mechanically ventilated. There were no significant differences in ventilatory parameters, airway pressures, or blood gases between mechanically ventilated patients with and without complications. Two patients with previous severe hypoxic cerebral damage died from this complication after ICU discharge. In the second study, the end-inspiratory lung volume (VEI) (1) was compared with standard ventilatory parameters in 22 patients. There were no ICU deaths, but high incidences of pulmonary barotrauma (27%) and hypotension (41%) were found. Both minute ventilation (VE and VEI) were significantly higher in patients who developed complications (VE 13.7 +/- 3.0 versus 11.2 +/- 2.5 L/min, VEI 26.1 +/- 4.7 versus 20.0 +/- 7.4 ml/kg, p less than 0.05) but only VEI had a threshold value significantly predictive of complications. For VEI less than 1.4 L, 0/5 (0%) patients had complications; for VEI greater than or equal to 1.4 L, 11/17 (65%) had complications (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of leukotriene C4 on theophylline disposition in guinea pigs. The pharmacokinetics of theophylline in acutely ill patients show wide intraindividual variability associated with the severity of clinical status. To investigate the mechanism of this variability, we studied the effects of leukotriene C4 (LTC4)-induced pathophysiologic changes on the disposition of theophylline. The plasma concentration-time profiles were measured after simultaneous intravenous bolus injection of theophylline and antipyrine in guinea pigs. The animals received 5 micrograms/kg of LTC4 intravenously 60 min later. The plasma theophylline concentration 30 min after LTC4 treatment was significantly lower (p less than 0.05) than that of nontreated control animals, whereas the plasma antipyrine concentration at that time was not affected. In addition, the treated animals showed significantly slower declines in plasma concentrations of both drugs (0.0805 +/- 0.0199 and 0.291 +/- 0.020 h-1 for theophylline and antipyrine, respectively, mean +/- SEM) than did controls (0.197 +/- 0.010 and 0.439 +/- 0.028 h-1). Leukotriene C4 treatment also induced moderate bronchoconstriction and metabolic acidosis, increased blood hemoglobin concentration and hematocrit, and decreased concentration of serum proteins. In connection with these changes, the plasma unbound fraction of theophylline increased significantly (p less than 0.001, 94.4 +/- 3.3% in treatment versus 58.2 +/- 4.4% in control), but that of antipyrine was unchanged (94.9 +/- 3.0% in treatment versus 92.1 +/- 0.9% in control). These findings indicated that an increase in the volume of distribution was responsible for the abrupt change in plasma theophylline concentration following LTC4 treatment, and the apparent change in the volume of distribution was estimated as 26.1 +/- 5.6%.(ABSTRACT TRUNCATED AT 250 WORDS)


Sulfuric acid aerosol exposure in humans assessed by bronchoalveolar lavage. Epidemiologic and experimental evidence suggests that exposure to acidic aerosols may affect human health. Brief exposures to acidic aerosols alter mucociliary clearance and increase airway responsiveness, but effects on host defense mechanisms at the alveolar level have not been studied in humans. Twelve healthy, nonsmoking volunteers between 20 and 39 yr of age were exposed for 2 h to aerosols of approximately 1,000 micrograms/m3 sulfuric acid (H2SO4) or sodium chloride (NaCl [control]), with intermittent exercise, in a randomized, double-blind fashion. Each subject received both exposures, separated by at least 2 wk. Bronchoalveolar lavage (BAL) was performed 18 h after exposure in order to detect evidence of an inflammatory response, changes in alveolar cell subpopulations, or changes in alveolar macrophage (AM) function, which is important in host defense. When compared with NaCl, exposure to H2SO4 did not increase polymorphonuclear leukocytes in BAL fluid. The percentage of T lymphocytes decreased in association with H2SO4 exposure, but the difference was not statistically significant (14.9% after NaCl, 11.5% after H2SO4; p = 0.14). Antibody-mediated cytotoxicity of AM increased in association with H2SO4 exposure (percent lysis 19.1 after NaCl, 23.6 after H2SO4; p = 0.16). No significant change was seen in release of superoxide anion or inactivation of influenza virus in vitro. Brief exposures to H2SO4 aerosol at 1,000 micrograms/m3 do not cause an influx of inflammatory cells into the alveolar space, and no evidence was found for alteration in antimicrobial defense 18 h after exposure.


Toward a definition of asthma for epidemiology. Because there is no "gold standard" for defining asthma for epidemiology, we have defined current asthma as bronchial hyperresponsiveness (BHR) plus recent wheeze (in the 12 months prior to study). To describe the characteristics of groups categorized by these measurements, we studied two samples of children aged 7 to 12 yr: 210 from a population sample and 142 self-identified asthmatics. Bronchial responsiveness to histamine was measured by the rapid method, respiratory symptom history, and asthma medication use by self-administered questionnaire to parents and atopy by skin prick tests to 14 allergens. Children recorded daily Airflometer readings and symptom scores for 2 wk. Children with current asthma had more severe bronchial responsiveness, greater Airflometer variability, more symptoms, more atopy (particularly to house dust mites), and used more asthma medication than children with BHR or recent wheeze alone. Children with BHR, but not with recent wheeze, were intermediate between the current asthma and normal groups in terms of bronchial responsiveness, Airflometer variability, and atopy. Children with recent wheeze and normal responsiveness differed from the normal group only in symptoms and medication use. Our definition of current asthma discriminates a group of children that is clearly different in terms of both clinical features and physiologic measures. As such, it is the most useful definition to date for measuring the prevalence of clinically important asthma in populations.


Relationship of skin test reactivity and eosinophilia to level of pulmonary function in a community-based population study. We studied the relationship of skin test reactivity (sumscore greater than or equal to 3) and eosinophilia (greater than or equal to 275 cells/mm3 blood), separately and combined, to the level of FEV1 in a community cohort. We used the regression analysis technique, adjusting for age and area of residence, and stratifying by gender and cigarette smoking. Eosinophilia, among men, was associated with lower levels of FEV1 in skin test negative subjects with moderate cigarette smoking (greater than or equal to 10 pack-yr: beta = -250 ml, p = 0.02; greater than or equal to 10 pack-yr: beta = -234 ml, p less than 0.01) and in skin test positive subjects who either never smoked (beta = -228 ml, p = 0.06) or had only a brief history of smoking (beta = -428 ml, p less than 0.01). Eosinophilia, among women, was significantly associated with lower levels of FEV1 in never smokers (beta = -95 ml, p less than 0.01), especially if subjects were skin test positive as well (beta = -289 ml, p less than 0.01). Moderate cigarette smoking was uncommon in women. These data suggest an association of indices of inflammation (eosinophilia alone) and allergic inflammation (eosinophilia combined with skin test reactivity) with lower levels of FEV1, independent of the effect of cigarette smoking.


Are race and sex differences in lung function explained by frame size? The CARDIA Study. Using the CARDIA cohort of 20- to 32-yr-old black and white men and women, FVC and FEV1 were standardized for standing height, sitting height, leg height, elbow breadth, and biacromial diameter in such a way that the standardized lung function showed minimal statistical dependence on these measures of frame size. Race and sex differences in lung function have been reported even after adjustment for height; however, these differences might depend on aspects of frame size other than height. We found that within this age group height2 provided robust standardization for FVC and FEV1 for all race and sex strata of the population. Height explained approximately 40% of the variance of FVC and FEV1 in whites, 30% in black women, and 20% in black men. In black men only, standardization for the combination of sitting height, leg height, elbow breadth, and biacromial diameter improved explained variance to nearly 40% for FVC and nearly 30% for FEV1. After standardization for height, FVC and FEV1 were found to be 14 to 19% higher in whites than in blacks, and in men than in women. Standardization of FVC and FEV1 for sitting height, leg height, elbow breadth, and biacromial diameter combined reduced these differences to 13-16%. Thus, race and sex differences in lung function exist even after detailed adjustment for frame size.


Silo filler's disease in New York State. Twenty new cases of Silo filler's disease (SFD) have been collected, documenting the incidence and clinical features of exposure to nitrogen oxides present in freshly filled silos. Cases of SFD were identified using a statewide computerized discharge diagnosis system. Fifteen of these were identified in the index period, allowing us to calculate an approximate annual incidence of 5.0 cases/100,000 silo-associated farm workers/yr in New York State. All cases occurred during harvest periods, with 80% in September and October. Corn silage was the gas source in 18 (90%). All cases involved young white men (mean age, 31.5 yr). The most common presenting feature was dyspnea. All victims entered a silo during the peak danger period, and only one used recommended ventilation techniques. Four cases ended in death (20% mortality). Silo filler's disease, although rare, is a potentially devastating disease involving otherwise young, healthy farm workers. It is readily prevented.


Delayed effects of NO2 exposure on alveolar permeability and glutathione peroxidase in healthy humans. Potential toxic effects of prolonged NO2 exposure below the current threshold limit value (TLV) were examined in 14 healthy, nonsmoking adults. The subjects were exposed to 2.3 ppm NO2 and to clean air for 5 h with a 1-wk interval between exposures. Physiologic and biochemical measurements were obtained during the exposures and until 24 h after. A 14% decrease in serum glutathione peroxidase activity (GSH-Px) was observed 24 h after the start of the NO2 exposure, while indications of a 22% decrease in alveolar permeability were found 11 h after the start. There were no indications of mucous membrane irritation or of decreased lung function during or after NO2 exposures. The results support the assumption that a delayed response is a feature of the human reaction to NO2 even below the current TLV of 3 ppm, and they stress the importance of an extended period of observation in future NO2 exposure studies.


Corticosteroid administration modifies ozone-induced increases in sheep airway blood flow. Recently, we have shown that exposure of intubated conscious sheep to 3 to 4 ppm ozone (O3) for 3 h increases bronchial blood flow (Qbr). The purpose of the present study was to assess the potential role of corticosteroids in modulating this increase. Six nasally intubated sheep were exposed to filtered room air, 3.5 ppm O3 on two separate occasions, and 3.5 ppm O3 plus methyl-prednisone, for 3 h. Qbr was measured using a chronically implanted 20 MHz pulsed Doppler flow probe. Qbr, mean aortic pressure, cardiac output, pulmonary artery pressure, arterial blood gases, and core temperature were monitored. After 3 h of 3.5 ppm O3, Qbr increased from 3.2 +/- 0.5 (mean +/- SEM) to 8.5 +/- 1.6 KHz, whereas bronchial vascular resistance (BVR) decreased from the baseline value of 43.6 +/- 8.0 to 15.0 +/- 3 mm Hg/KHz. With corticosteroids, baseline Qbr was 3.2 +/- 0.6 and BVR was 44.2 +/- 9.7; after 3 h of 3.5 ppm O3, Qbr was 3.3 +/- 0.5 KHz and BVR was 39.0 +/- 8.0 mm Hg/KHz. The two 3.5-ppm O3 exposures without corticosteroids were impressively reproducible. Except for Qbr and BVR, no other measured cardiovascular parameters were affected by O3. The results indicate that corticosteroids are capable of interfering with mediator, neurohumoral, or inflammatory cell mechanisms responsible for vasodilation of the airway microcirculation after O3 exposure, but do not specifically address the specific processes whereby this attenuation occurs.


Acute effect of oxygen on pulmonary arterial pressure does not predict survival on long-term oxygen therapy in patients with chronic obstructive pulmonary disease. The growing number of patients treated with long-term oxygen therapy (LTOT) poses the question which physiologic variables could predict the patients who may benefit the most from this cumbersome and expensive treatment. We wanted to verify if the acute effect of oxygen on pulmonary arterial pressure (PAP) is related to survival on LTOT as was suggested recently in the literature. We studied 46 chronic obstructive pulmonary disease (COPD) patients qualified for LTOT. The acute effects of O2 on pulmonary hemodynamics were assessed by pressure and flow measurements before and after 30 min of O2 breathing via 28% Ventimask. Thirty-nine patients reacted with a fall of the mean PAP of less than 0.7 kPa 5 (mm Hg). These were termed nonresponders (NR). In seven patients, mean PAP fell greater than or equal to 0.7 kPa 5 (mm Hg). They were called responders (R). After the initial investigations, patients were followed up on LTOT for 2 yr or until death. During the first year, four patients died; three from the NR and one from the R group. After 2 yr of LTOT, 15 patients died (12 from NR and 3 from R groups). The 2-yr survival rate was 69% in NR and 57% in R groups, respectively. We conclude that survival on LTOT is not related to the acute effect of oxygen on the PAP in COPD patients investigated in the steady-state period of the disease.


Adenosine is a pulmonary vasodilator in newborn lambs. We investigated the systemic and pulmonary vascular effects of adenosine and determined plasma adenosine levels in pulmonary circulation in 12 newborn lambs during normoxia and during alveolar hypoxia (10% O2, 5% CO2, and 85% N2). Lambs were instrumented at 7 days of age with catheters in the descending aorta, main pulmonary artery, and right and left atria, and a flow transducer around the main pulmonary artery, and were studied following a 3-day recovery. Adenosine or an equal volume of normal saline (control) was infused into the right atrial line in doses ranging from 0.01 to 2.5 mumol/kg/min. In normoxic lambs, adenosine caused a significant decrease in pulmonary vascular resistance and increase in heart rate in doses of 0.15 to 2.5 mumol/kg/min and a decrease in systemic vascular resistance, with increase in cardiac output in doses of 0.3 to 2.5 mumol/kg/min. Baseline plasma adenosine levels in pulmonary artery and left atrium decreased significantly during alveolar hypoxia. Adenosine infusion in hypoxic lambs caused decreases in pulmonary artery pressure and pulmonary vascular resistance at all the doses tested. Aortic pressure and systemic vascular resistance decreased, and heart rate and cardiac output increased at doses greater than or equal to 0.3 mumol/kg/min in hypoxic lambs during adenosine infusion. The pulmonary vascular effects of adenosine in hypoxic lambs were attenuated by prior treatment of animals with aminophylline. Thus, adenosine appears to be an important regulator of pulmonary vascular response to hypoxia in newborn lambs. Its vasodilator effects were specific for pulmonary circulation when it was infused in doses less than or equal to 0.15 mumol/kg/min into the right atrium and appear to be mediated by P1 purinergic receptors.


Hemodynamic differences between continual positive and two types of negative pressure ventilation. In seven anesthetized dogs, ventilated with matching lung volumes, tidal volumes, and respiratory rates, we compared the effects on cardiac output (CO), arterial venous oxygen saturation difference (SaO2 - SVO2), and femoral and inferior vena cava pressure (1) intermittent positive pressure ventilation with positive end-expiratory pressure (CPPV); (2) iron-lung ventilation with negative end-expiratory pressure (ILV-NEEP); (3) grid and wrap ventilation with NEEP applied to the thorax and upper abdomen (G&W-NEEP). The values of CO and SaO2 - SVO2 with ILV-NEEP were similar to those with CPPV. However, with G&W-NEEP as compared with ILV-NEEP, mean CO was greater (2.9 versus 2.6 L/min, p = 0.02) and mean (SaO2 - SVO2) was lower (26.6% versus 28.3%, p = NS). Mean PFEM-IVC was higher with G&W-NEEP than with the other types of ventilation. We conclude that (1) ILV-NEEP is hemodynamically equivalent to CPPV and (2) G&W-NEEP has less adverse hemodynamic consequences. has less adverse hemodynamic consequences.


Effect of positive end-expiratory pressure on right ventricular function in humans. The effect of positive end-expiratory pressure (PEEP) on right ventricular (RV) function in humans is complex. Previous studies have been limited in their interpretation by not defining either pericardial pressure (Ppc) or RV volumes. Accordingly, we measured RV volumes and pressures and Ppc as PEEP was increased from zero to 15 cm H2O in 12 patients after thoracotomy, using a pulmonary arterial catheter equipped with a rapid responding thermistor that allowed measurement of RV ejection fraction (ef), while Ppc was measured via a pericardial balloon catheter. RV end-diastolic volume (EDV) was estimated as the ratio of stroke volume (SV) to RVef, whereas RV end-systolic volume (ESV) was estimated as RV EDV-SV. Right atrial pressure (Pra) was defined as end-diastolic pressure, and pulmonary arterial pressures (Ppa), both peak and mean, were used as end-systolic pressures. PEEP increased Ppc, Pra, and lung compliance (Cl). Cardiac output also decreased but not significantly. Neither mean nor peak systolic Ppa, nor RVef was significantly altered by PEEP. There was no relation between either RV filling pressure (Pra-Ppc) and EDV or the change in RV filling pressure and EDV, although EDV varied significantly as PEEP varied for individuals (p less than 0.05). Similarly, there was no relation between Ppa and ESV when either mean or peak Ppa values relative to Ppc were used. The relations between EDV and both SV and RVef were weak (r = 0.54 and 0.55, respectively). RVef varied inversely with ESV (r = -0.77), although it showed no relation to transmural peak Ppa (r = 0.28).(ABSTRACT TRUNCATED AT 250 WORDS)


Adaptations of the peripheral circulation to PEEP. The purpose of this study was to determine the role of changes in the parameters of venous return on the homeostatic adaption to the application of PEEP. We studied 13 dogs anesthetized with alpha-chloralose, intubated, and ventilated. We measured central venous pressure (CVP), arterial pressure (Pao) and cardiac output by thermal dilution. The cardiac output was transiently stopped by inflating a balloon in the right atrium, and the subsequent plateau in the CVP was used to obtain mean circulatory filling pressure (MCFP). Total blood volume was measured with Evans blue. To measure vascular capacitance and compliance, we rapidly infused 4 ml/kg or 8 ml/kg of blood and repeated the MCFP measurement. The same volume was withdrawn after the measurement. The volume and MCFP were used to construct pressure-volume (P-V) lines, and the unstressed volume was calculated by extrapolating the P-V to zero pressure. The P-V appeared linear in the range studied. PEEP produced a left shift of the curves and, thus, a decrease in unstressed volume. The shift with 20 cm H2O of PEEP was greater than with 10 cm H2O of PEEP. The rise in MCFP matched the rise in CVP so that the pressure gradient for venous return did not change. However, there was also an increase in the resistance to venous return, which resulted in a lower cardiac output than expected for the rise in MCFP. In conclusion, homeostatic adjustments to PEEP included a decrease in vascular capacitance, which is partially offset by a rise in the resistance to venous return.


Studies on the role of tumor necrosis factor in adult respiratory distress syndrome. Tumor necrosis factor (TNF), rapidly becoming recognized as a mediator of inflammation, may be important in the pathogenesis of acute lung injury. Its role in the development of the adult respiratory distress syndrome (ARDS) in humans, however, has been difficult to clarify. To determine if TNF could be important early in the development of acute lung injury from multiple causes, we enrolled 103 patients within 8 h of meeting the criteria for an at-risk illness (sepsis, aspiration of gastric contents, severe pancreatitis, hypertransfusion, abdominal trauma, chest trauma, multiple fractures) and obtained multiple frequent blood samples for TNF measurements. Using five methods of TNF analysis, we were unable to find an association between TNF and the development of ARDS. However, we found significant differences in TNF measurements depending on the methods of analysis used, which could, at least in part, account for the inconsistencies in the published literature regarding the relationship between TNF and disease processes.


Serum and bronchoalveolar lavage of N-terminal type III procollagen peptides in idiopathic pulmonary fibrosis. Collagen deposition is a prime determinant of clinical course in idiopathic pulmonary fibrosis (IPF). Identification of a marker of connective tissue metabolism would significantly enhance the ability to stage the disease and monitor the course of these patients. Prior studies of IPF have indicated that N-terminal Type III procollagen peptide (N-PIIIP) levels in blood and bronchoalveolar lavage BAL fluid are elevated. We hypothesized that elevated levels of procollagen peptides are a marker of enhanced collagen deposition, which is associated with interstitial fibrosis characterizing active disease. The purpose of the present study was to explore the relationship between N-PIIIP recovery and physiologic parameters of lung function. N-PIIIP levels in sera and bronchoalveolar lavage (BAL) from 24 patients with IPF and 29 volunteers were measured by radioimmunoassay. The extent of disease in IPF was assessed by clinical history, physical examination, chest radiograph, pulmonary physiology evaluation, and confirmatory open-lung biopsy. The severity of disease was graded using a previously described clinical, radiologic, and physiologic (CRP) scoring system. N-PIIIP normalized to albumin was higher in BAL than in serum for both volunteers (1.6-fold; p less than 0.05) and IPF patients (24-fold; p less than 0.05), consistent with local pulmonary production. BAL N-PIIIP was significantly elevated in IPF patients, whether expressed as concentration (healthy volunteer 0.11 +/- 0.06 ng/ml; IPF, 5.0 +/- 14.4; mean +/- SD; p less than 0.05) or normalized to albumin (healthy volunteer, 2.8 +/- 1.2; IPF, 73 +/- 106; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Amelioration of sleep apnea by salicylate-induced hyperventilation. It is well documented that upper airway (UAW) muscle activity is augmented in response to increased respiratory drive, the overall effect being an improvement in UAW patency. We have recently shown that salicylate-induced ventilatory stimulation increased UAW muscle electrical activity and decreased UAW resistance and collapsibility in anesthetized dogs. In the present study, we evaluated the effect of respiratory stimulation produced by high therapeutic doses of aspirin on sleep in nine patients with previously diagnosed sleep apnea. A control, all-night, polysomnographic sleep study, including oximetry and ventilatory monitoring by inductive plethysmography, was compared with a second study undertaken after patients ingested 8 to 10 g of aspirin over a period of 4 to 5 h. Aspirin ingestion resulted in high therapeutic salicylate serum levels (33 +/- 2.5 mg/dl, mean +/- SE) the following morning and was associated with marked ventilatory stimulation. Mean sleep duration and the relative partitioning of sleep stages were not affected by aspirin. However, aspirin-induced hyperventilation was associated with a significant non-rapid decrease in periodic breathing and the frequency of both obstructive and mixed apneas in all non-rapid eye movement (REM) sleep stages. The total number of apneas over the whole night was reduced in all subjects and on average fell from a control rate of 42 +/- 7 to 28 +/- 7 apneas/h (p less than 0.01). Similarly, the mean duration of apneas fell from 23 +/- 2 to 20 +/- 1 s (p less than 0.05), and the overall time spent in apneas decreased from 17 +/- 3 to 10 +/- 3 min/h (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of negative pressure ventilation on ventilatory muscle endurance in patients with severe chronic obstructive pulmonary disease. We studied five men with chronic obstructive pulmonary disease (COPD) (mean age, 65 +/- SEM 2 yr; FEV1, 0.68 +/- 0.08 L; and FEV1/FVC, 38 +/- 2%) to determine the relationship between ventilatory muscle endurance (VME) and ventilatory muscle rest (VMR) elicited by negative-pressure ventilation (NPV). VME was measured as the maximal sustainable ventilation (MSVC) that the subjects could maintain for 12 min. Prior to therapy, MSVC for the subjects was 25.0 +/- 3.6 L/min. During the therapy phase, subjects received 4 wk of daily "in-hospital-supervised" NPV therapy (4 h/day). While subjects received therapy, we quantified VMR by (1) the percentage of breaths that were "in synchrony" and by (2) the percentage of breaths showing "turn-off" of the diaphragmatic EMG signal (EMGdl). During the therapy sessions, 93 +/- 2% of breaths were in synchrony, whereas 66 +/- 11% showed EMGdl turn-off. During post-therapy testing, an increase in MSVC was noted in each of the subjects; the mean increase was 4.0 +/- 1.3 L/min (p less than 0.05), which represented an increase of 16 +/- 4% over pretherapy values. Increases in MSVC were highly correlated with both the percentage of in-synchrony breaths (r = 0.96, p less than 0.01) and the percentage of breaths showing EMGdl turn-off (r = 0.92, p less than 0.02). However, NPV therapy elicited no other improvements in either clinical or laboratory measurements. Moreover, patients exhibited marked dyspnea with initiation and termination of daily NPV therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of N-acetylcysteine on diaphragmatic function and malondialdehyde content in Escherichia coli endotoxemic rats. We evaluated the effects of sublethal Escherichia coli endotoxemia with or without concomitant administration of N-acetylcysteine, an antioxidant agent, on diaphragmatic strength, endurance, and malondialdehyde (MDA) content in rats. One hundred ninety rats were inoculated subcutaneously on 2 successive days with 0.6 and 1.2 mg/100 g body weight of E. coli lipopolysaccharide respectively (E animals, n = 100) or saline (C group, n = 90). E and C animals were divided into two groups based on administration of endotoxin or saline alone (E group, n = 55; C group, n = 47, respectively) or endotoxin or saline plus N-acetylcysteine (1 g/kg body weight/day intraperitoneally) (E-NAC group, n = 45; C-NAC group, n = 43, respectively). Diaphragmatic strength was assessed in vivo 48 h after the first endotoxin or saline administration by measuring the transdiaphragmatic pressure (Pdl) generated during electrical stimulation of the phrenic nerves at 0.5, 10, 20, 30, 50, and 100 Hz. Endurance index was calculated as the percent ratio of Pdl generated after 30 s of phrenic stimulation at 10 Hz divided by the initial force. Diaphragmatic MDA (fluorometric technique) was measured 0, 6, 18, 30, 42, and 48 h after the first dose of endotoxin or saline. Pdl for 50 and 100 Hz was significantly reduced in Group E as compared with group C. This phenomenon was associated with a reduced endurance performance as assessed by a lower diaphragmatic endurance index in E as compared with C animals (90.9 +/- 4.2 versus 114.3 +/- 4.1 respectively; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Influence of Pneumocystis carinii pneumonia on serum and tissue concentrations of pentamidine administered to rats by tracheal injections. Pentamidine isethionate was administered by the tracheal route to control rats and immunodepressed rats with Pneumocystis carinii pneumonia (PCP). The serum concentration of pentamidine base 20 min after the administration was higher in the PCP rats (309 +/- 165 ng/ml) than in the control animals (71 +/- 36 mg/ml; p less than 0.001); 90 min after the injection the proportion of the pentamidine administered was lower in the right lung of the PCP rats (29 +/- 15%) than in the control rats (57 +/- 23%; p = 0.038); the proportion of pentamidine in the left kidney was higher in the PCP rats (14 +/- 4%) than in the control animals (4 +/- 2%; p less than 0.001). Respiratory clearance of 99mTc-DTPA, an index of the permeability of the respiratory epithelium, was higher in the PCP rats (1.84 +/- 0.42 %/min) than in the controls (0.44 +/- 0.11 %/min; p less than 0.001). We conclude that the more rapid diffusion of pentamidine from the alveolar lumen to the pulmonary circulation is explained by the increased alveolocapillary permeability as a result of pneumocystosis.


Higher pentamidine levels in AIDS patients with hypoglycemia and azotemia during treatment of Pneumocystis carinii pneumonia. Trimethoprim-sulfamethoxazole (TMP-SMZ) and pentamidine are both licensed for the treatment of Pneumocystis carinii pneumonia (PCP). However, their use is associated with various adverse side effects. In this prospective study, 26 AIDS patients with 32 episodes of PCP were treated with pentamidine (4 mg/kg/d). Each patient was treated for 12 to 21 days, depending on the rapidity of onset of the clinical response. During the 32 PCP episodes, hypoglycemia occurred in 16 instances, azotemia in 12, liver toxicity in 10, and leukopenia in 8. The occurrence of thrombopenia, leukopenia, and liver toxicity was not related to age, pentamidine levels, or other complications. However, patients who had hypoglycemia during pentamidine treatment had higher serum pentamidine levels than patients who did not have hypoglycemia (107 +/- 40 versus 70 +/- 26 ng/ml, p less than 0.004). In addition, we observed that patients with azotemia showed higher pentamidine levels during treatment (120 +/- 35 versus 64 +/- 22 ng/ml, p less than 0.001). In fact, 100% (11/11) of patients with serum pentamidine concentration greater than 100 ng/ml had fasting hypoglycemia and/or azotemia, while 33% (7/21) of those with pentamidine levels less than 100 ng/ml had these side effects (p less than 0.001). The relative risk of these complications with pentamidine levels greater than 100 ng/ml was 3 (95% confidence interval, 1.6 to 5.5). Fine-tuning the dose of pentamidine may eventually prove useful to avoid toxicity and optimize therapy.


Pulmonary function in human immunodeficiency virus infection. A prospective 18-month study of serial lung function in 474 patients. To investigate the development of a reduced DLCO in patients with HIV-related disease, we studied 474 HIV-seropositive patients and performed serial lung function measurements over 18 months. The mean values of DLCO at presentation were lower in patients with more advanced HIV disease compared with asymptomatic HIV-seropositive patients (DLCO 88% of predicted). When compared with the DLCO in asymptomatic HIV-seropositive patients, the DLCO had reduced values in patients with persistent generalized lymphadenopathy (PGL) (82% of predicted, p less than 0.05), acquired deficiency syndrome-related complex (ARC) (73% predicted, p less than 0.001), nonpulmonary Kaposi's sarcoma (KS) (72% of predicted, p less than 0.001), nonpulmonary complications of AIDS excluding KS (73% of predicted, p less than 0.001), pulmonary KS (63% of predicted, p less than 0.001), pulmonary mycobacterial infection (68% of predicted, p less than 0.05), pyogenic infection (70%, p less than 0.05), acute Pneumocystis carinii pneumonia (PCP; 49%, p less than 0.001), and following recovery from PCP (71%, p less than 0.001). Serial lung function measurements over 18 months revealed no change in DLCO within any patient group, and in particular there was no tendency for a gradual decline. Clinical deterioration due to the development of PCP was associated with a reduction in DLCO. Conversely, in patients recovering from PCP, there was a partial improvement in DLCO over 3 months. Zidovudine (AZT) use did not affect DLCO within any diagnostic group or the recovery in DLCO following PCP. However, cigarette smoking was associated with further reductions in DLCO in all patient groups and with an impaired recovery of DLCO following acute PCP.(ABSTRACT TRUNCATED AT 250 WORDS)


Factors associated with tuberculin reactivity among the foreign-born in Montreal. Because tuberculosis among the foreign-born is of increasing importance in North America, it has recently been recommended that newly arriving immigrants be tuberculin tested and preventive therapy given to all those with significant reactions. The factors affecting the prevalence of tuberculin reactions were assessed in a community-based tuberculin survey among foreign-born schoolchildren and young adults. Of 1,198 foreign-born who were tuberculin tested, 32.4% had significant tuberculin reactions. False-positive tuberculin reactions due to sensitivity to purified protein derivative (PPD)-B (for Mycobacterium avium) were uncommon and those due to BCG vaccination of importance only among immigrants from countries with low tuberculosis rates. Tuberculin reactions of 10+ mm were associated with tuberculosis rates in the country of origin (p less than or equal to 0.001), age when immigrated (p less than or equal to 0.001), bacillus Calmette-Guérin (BCG) vaccination (p less than or equal to 0.01), and residence in poorer neighborhoods in Montreal (p less than or equal to 0.001), but not with number of years resident in Canada. The booster phenomenon, seen in 16% of those undergoing two-step testing, was most strongly associated with prior BCG vaccination (p less than or equal to 0.001) and also with tuberculosis rates in the country of origin (p less than or equal to 0.08), age of immigration (p less than or equal to 0.01), and number of years resident in Canada (p less than or equal to 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Ultrasonographic evaluation of pulmonary consolidation. A total of 161 patients with lobar or segmental consolidation were examined by realtime ultrasound and Doppler ultrasound. Air bronchograms were detected in 141 patients, fluid bronchograms in 27 patients, and parapneumonic effusion in 74 patients. In 36 patients with necrotizing pneumonia, ultrasound detected microabscesses in 33 (91.7%) compared with the air-fluid levels detected by standard chest radiographs in 20 patients (55.6%; p less than 0.05). Of 31 patients with tumors causing obstructive pneumonitis, 29 (93.5%) had tumors detected by chest ultrasound, whereas only 11 patients (35.5%) had chest radiographs that suggested a tumor was causing the obstructive pneumonitis (p less than 0.05). Chest ultrasound was used to guide thoracentesis for parapneumonic effusion in 65 patients, with a 100% success rate. Twenty-six patients with necrotizing pneumonia underwent ultrasound-guided needle aspiration of microabscesses. The procedure was successful in 24 patients (92.3%), and 21 patients (80.8%) had microbiologic confirmation. Twenty patients with tumor-associated obstructive pneumonitis received needle aspiration biopsy under ultrasound guidance; 19 patients (95.0%) had the histology confirmed. Five patients with malignancy manifesting as pulmonary consolidation underwent a diagnostic ultrasound-guided needle aspiration biopsy. Five patients (3.8%) developed complications of minimal pneumothorax or mild hemoptysis in 132 episodes of needle aspiration. We conclude that ultrasonography is useful for the evaluation of pulmonary consolidation. It can also be used for needle aspiration guidance for etiologic diagnosis of patients with complicated pneumonia.


Ultrasound-guided core biopsy of thoracic tumors. Two hundred and eighteen patients, with thoracic tumors larger than 3 cm in size, underwent ultrasound-guided percutaneous transthoracic core biopsy with a large-bore Tru-Cut needle. Fifty-five tumors were in the mediastinum, and 122 tumors were located at subpleural area, and 42 tumors were within the lungs. In 122 subpleural tumors, the sensitivity of ultrasound-guided core biopsy for the diagnosis of malignancy was 96.8%, and accuracy was 97.5%. Sensitivity for the diagnosis of malignant tumors located within the lungs was 94.6%, and accuracy was 95.2%. In 54 patients with mediastinal tumors, definite histologic diagnosis could be obtained in 48 patients (88.9%). The sensitivity of ultrasound-guided biopsy for the diagnosis of malignancy in these 48 mediastinal tumors was 97.1%, with an accuracy of 97.9%. Three patients had complications with minimal pneumothorax and one with mild hemoptysis. We conclude that percutaneous transthoracic core biopsy with Tru-Cut needle under ultrasound guidance is a safe and sensitive way to obtain specimens for accurate histologic diagnosis of thoracic tumors. The diagnostic yield is high, and the technique, relatively simple, can also be used for outpatients.


Tumor necrosis factor alpha and interleukin-6 production by human mononuclear phagocytes from allergic asthmatics after IgE-dependent stimulation. We have previously demonstrated the production of tumor necrosis factor alpha (TNF) and interleukin-6 (IL-6) by alveolar macrophages (AM) from allergic asthmatics developing a late asthmatic reaction after bronchial allergen challenge. In order to explain the modalities of this monokine synthesis, we tested in vitro the effect of an IgE-dependent stimulation on blood monocytes (BM) and AM from control and asthmatic subjects. TNF and IL-6 secretions were evaluated in 24-h supernatants by radioimmunoassay and by the 7TD1 cell proliferation test, respectively. AM from allergic asthmatics secreted spontaneously higher concentrations of TNF and IL-6 than did BM or AM from control subjects. BM from asthmatics also produced spontaneously increased levels of TNF, but at a lesser degree than did AM. The addition of anti-IgE induced a significant increase of TNF and IL-6 secretions by mononuclear phagocytes from control subjects only after previous sensitization with IgE-rich medium. In contrast, the direct stimulation by allergen or anti-IgE of AM and BM from asthmatics enhanced significantly the production of TNF and IL-6 when compared with cells cultured in medium alone. In these conditions, IgE-dependent activation of cells from allergic asthmatics compared with those from control subjects increased monokine production in a similar manner. Costimulation by recombinant human interferon gamma and IgE-dependent triggering had a synergistic effect on TNF production, but it had only an additive action on IL-6 synthesis (respective increase index: 9.8 compared with 2.9 and 9.8 compared with 2.1, respectively, for BM from control and asthmatic subjects).(ABSTRACT TRUNCATED AT 250 WORDS)


Pulmonary hemodynamics and lung function during chronic paraquat poisoning in sheep. Possible role of reactive oxygen species. The purpose of this study was to establish a chronic model of paraquat-induced lung injury. To examine the role of reactive oxygen species in this form of lung injury, we measured malondialdehyde (MDA) and superoxide dismutase (SOD) activity in the lungs. Paraquat (5 mg/kg intramuscularly) caused a significant decrease in dynamic lung compliance from 128.5 +/- 9.2 to 63.3 +/- 11.8 ml/cm H2O (p less than 0.05), with a significant increase in AaPO2 3 wk after paraquat. Histologic findings in the lungs showed a gradual increase in the number of granulocytes and alveolar wall thickening with proliferation of reticular fibers and were coincident with the changes in physiology. A transient decrease in pressor responses to hypoxia was observed 1 wk after paraquat, although pulmonary hemodynamics did not change. The amount of lung MDA 3 wk after paraquat increased from the baseline value of 0.73 +/- 0.04 to 1.12 +/- 0.10 nmol/mg protein (p less than 0.05). SOD activity in the lung tissue significantly decreased from 6.47 +/- 0.20 to 4.82 +/- 0.25 U/mg protein (p less than 0.05) 1 wk after paraquat and remained at low levels for 3 wk. These findings suggest that a small dose of paraquat causes chronic lung injury characterized by granulocyte infiltration and lung fibrosis. Reactive oxygen species may play an important role in this chronic lung injury, and the inability to increase antioxidant defense may contribute to the reaction.


Delta F508 mutation of cystic fibrosis gene is not found in chronic bronchitis with severe obstruction in Japan. Diffuse panbronchiolitis (DPB) in Japan is a chronic bronchitis observed in nonsmoking adults, with severe obstruction and poor prognosis. DPB shares pathologic and clinical characteristics with mild adult cystic fibrosis (CF), except that CF is frequent in whites (Europeans and Americans of European descent) but not in Japanese. Recently, the cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified, and a 3-base pair deletion (delta F508) was confirmed as a major mutation responsible for CF. We extracted genomic DNA from white blood cells of 17 DPB patients and from paraffin-embedded tissues of 4 DPB patients at autopsy. Two polymerase chain reaction (PCR) primers were made in exon 10 of the CFTR gene so that a three-base shorter segment of 78 base pairs was amplified from the CFTR gene with the delta F508 mutation; the DNA segment amplified from the normal gene contains an F508 area with 81 base pairs. Every DNA segment amplified from DPB patients showed a normal 81-base pair length, indicating no DNA sample contained the delta F508 mutation. These results based on delta F508 mutation analysis in the CF gene indicate that DPB may represent a disease different from CF.


Effect of inspiratory flow rate on respiratory output in normal subjects. We wished to determine the independent effect of inspiratory flow rate (VI) on respiratory output in the awake state. Seven normal subjects were connected to a volume-cycled ventilator in the assist/control mode. While the tidal volume setting remained constant, inspiratory flow rate was increased in steps (3 to 4 min each) from 30 to 90 L/min and then back to 30 L/min. Flow pattern was square, and all breaths were subject-triggered. Spontaneous respiratory rate (f) increased in all subjects as VI increased. Mean (+/- SD) f at 30 and 90 L/min were 8.8 (+/- 1.7) and 14.1 (+/- 4.4) min-1, respectively (p less than 0.01). VE increased (10.1 +/- 1.9 at 30 L/min to 16.3 +/- 5.6 at 90 L/min p less than 0.01) and the percentage of end-tidal CO2 decreased (4.7 (+/- 0.5) at 30 L/min to 3.3 (+/- 0.7) at 90 L/min (p less than 0.01)). The response was graded and reversible. The change in f was nearly complete within the first two breaths after transition, and there was no systematic tendency for f to change beyond this early response. The rate of change in airway pressure prior to triggering (dp/dt) increased as VI increased (5.3 +/- 2.0 cm H2O/s at 30 L/min to 10.8 +/- 2.6 cm H2O/s at 90 L/min; p less than 0.01). We conclude that inspiratory flow rate exerts an excitatory effect on respiratory frequency and on the rate of rise of inspiratory activity in conscious humans. This may be relevant to the mechanism of ventilatory response to various respiratory stimuli and to the management of patients receiving mechanical ventilation.


Reference values of maximal respiratory mouth pressures: a population-based study. The aim of our study was to measure values of maximal inspiratory (MIP) and expiratory (MEP) mouth pressures in 625 (266 male, 359 female) clinically and functionally normal subjects drawn out of a sample representative of the general population. MEP (near TLC and FRC) was found to be significantly higher when compared with MIP (near RV and FRC), and pressures in male subjects were significantly higher than those in female subjects. MEP values at TLC and FRC were found to be closely related, as were values of MIP near RV and near FRC. Among the tested body-size variables, body surface area (BSA) for all parameters had the highest degree of correlation. Stepwise linear regression analysis was performed to define the equation of normality for all four parameters, employing BSA, sex, age, and relative interaction terms. R2 values, although the variables employed for the equations were highly significant, were relatively low and didn't fully explain the source of variability. The influence of age was smaller than the influence of BSA, although age did reduce the unexplained variance in MEP and MIP. These results confirm that the most useful employment of MIP and MEP is to monitor their changes in each patient, but they point out, however, the usefulness of reliable reference equations.


Pulmonary edema associated with salt water near-drowning: new insights. In this case report we describe the clinical and laboratory findings of a man who nearly drowned after aspirating a large quantity of seawater. The aspiration of salt water, which is strongly hypertonic with respect to plasma, resulted in severe pulmonary edema, both from the quantity of aspirated seawater and the osmotically driven ultrafiltrate of plasma that accumulated in the air spaces. The initial concentration of protein in the edema fluid sample was very low, 0.7 g/dl, consistent with only a minimal increase in epithelial permeability. Approximately 4 h later, there was a marked increase in the concentration of protein in the residual alveolar fluid associated with improvement in several clinical indices, indicating that the excess alveolar fluid was reabsorbed very rapidly. In addition, the magnesium concentration was markedly elevated because of the aspiration of magnesium-containing seawater, which may have diagnostic importance for near-drowning in salt water. The data from this case provide evidence for well-preserved alveolar epithelial barrier function after aspiration of large quantities of hypertonic salt water.


Improved diaphragmatic function after surgical plication for unilateral diaphragmatic paralysis. We studied pulmonary function tests, maximal voluntary ventilation, arterial blood gases, and respiratory muscle strength and recruitment pattern in a 37-yr-old symptomatic man before and after surgical plication for a left unilateral diaphragmatic paralysis. After plication, FVC, FEV1, TLC and FRC increased, whereas residual volume remained unchanged. Arterial PO2 improved from 70 to 87 mm Hg. Diaphragmatic strength, as expressed by the maximal transdiaphragmatic pressure increased from 30 to 75 cm H2O, and maximal voluntary ventilation increased from 74 to 123 L/min. Ventilatory muscle recruitment also changed: there was a shift from a positive to a negative delta Pg/delta Ppl slope during tidal breathing. This indicates more effective diaphragmatic recruitment after the procedure. We conclude that surgical plication may be of benefit to patients with symptomatic unilateral diaphragmatic paralysis. The improvement is due to improved respiratory muscle function.


Corticosteroid-induced myopathy involving respiratory muscles in patients with chronic obstructive pulmonary disease or asthma. We made observations on two patients with asthma and one with COPD who developed steroid-induced myopathy during prolonged treatment with high doses of corticosteroids. On admission, quadriceps force was on the average reduced to 31% of predicted (range 16 to 46% of predicted, nondominant leg), and urinary excretion of creatine in 24 h averaged 687 mg (range 275 to 1,045 mg/24 hr). Respiratory muscle involvement was evidenced by reductions in PImax and PEmax, being 38% (range 36 to 39) and 48% of predicted (range 36 to 68), respectively. Tapering of treatment with corticosteroids resulted in important recovery of quadriceps force and respiratory muscle force. In all three patients, a correlation between muscle forces and steroid dose was present during reduction of the dose. After 6 months quadriceps force averaged 62% of predicted (range 31 to 85), and PImax and PEmax reached 74% (range 52 to 92) and 92% of predicted (range 80 to 106), respectively, after 3 months. Consequently, respiratory muscle force appeared to recover faster than quadriceps force. The implications of these observations for patients treated with the usual doses of corticosteroids for shorter periods require further investigation.


NHLBI workshop summary. Biology of lung preservation for transplantation. The types of animal models that are used for assessing lung preservation, and the types of interventions that are likely to prove of value, must be carefully selected. For example, the events of warm ischemia are not necessarily the same as those that occur during cold preservation. Warm ischemia has often been used as a means of accelerating the degree of ischemic injury, but the events may not be qualitatively the same. Nonetheless, the use of different types of lung injury models contributes to our overall understanding of mechanisms of lung injury associated with transplantation. Pathologic studies of lung injury ischemia and reperfusion may not prove helpful, as they may be nonspecific and insensitive. To compare results of different preservation methods, a standardized animal model would be most helpful if a universally accepted one could be identified. This would include standard measurements of lung function, standard techniques of transplantation, and follow-up studies of several days' duration after transplantation. Such a model could serve as the ultimate test of preservation methods following its development in a variety of the animal models. It must be emphasized that whereas animal models generally begin with a normal lung that is preserved, the clinical situation differs because the donor lungs may be far from normal at the outset due to the effects of brain death, hemodynamic instability, infection, trauma, and a host of other factors. Thus, the limits of safe preservation in a clinical situation may well be significantly less than the safe preservation time demonstrated in the laboratory.(ABSTRACT TRUNCATED AT 250 WORDS)


Assessment of the extent of implementation of the recommendations made in occupational hygiene survey reports. The extent of implementation of recommendations contained in field reports from the Occupational Hygiene Unit of the Institute for Occupational Health at the Tel Aviv University, was investigated. The results show that 33% were not carried out at all and 16% were only partially carried out. A number of factors influenced the extent of implementation, in particular the degree of involvement of the management in worker health and welfare, an active safety system in operation, the professional skill and seniority of the person in charge of safety, awareness by the workers of health and safety matters, the existence of a specific budget for health and safety and a regulatory system concerning occupational exposure.


Vibrations--discriminant models and possibilities for prognosticating specific and non-specific effects on the organism. The present study involved 290 workers from branches of industry in which they were exposed to intense vibration and 102 patients suffering from disease due to vibration. Some specific (physiological) indices for exposure to vibration, such as the sensation of vibration, cold provocation test, Doppler-ultrasound, etc., and some non-specific (biochemical) indices, such as blood lipids, electrolytes and trace elements were studied. A discriminant analysis was made and 17 discriminant models (including different numbers of physiological and biochemical indices, age, and length of service) were elaborated. These models were used to predict the presence or absence of concomitant diseases, such as hypertension, coronary heart disease and arthritic lesions in persons exposed to vibrations; the stage of the vibration disease; the occurrence of exposure to vibration or of vibration disease. It was shown that physiological (specific) and biochemical (non-specific) indices affected by the exposure to vibration were interrelated, and that their estimation by means of the discriminant analysis revealed the distinction between the states mentioned above.


Ferruginous body counts in sputum as an index of past exposure to mineral fibres. Previous work by our group among vermiculite miners exposed to fibrous tremolite demonstrated that asbestos body counts in sputum closely reflected intensity and duration of past exposure. In the present project sputum samples from nearly 600 volunteers from 11 cohorts of workers exposed to asbestos and other mineral fibres were found to contain much lower numbers of asbestos bodies than had been observed in vermiculite workers and these counts did not reliably reflect past levels of exposure. No evidence was found that occupational exposure to man-made mineral fibres led to any ferruginous body formation. Asbestos body counts appeared to differentiate between mesothelioma cases and controls and between levels of radiological asbestosis, but in both comparisons, based on small numbers, the power of discrimination was low. Substantial variation was found both in asbestos body and in macrophage counts in daily sampling of vermiculite workers but it was not sufficient to invalidate comparison between groups for epidemiological study. In individual subjects, however, little reliance can be put on results from a single sputum sample, particularly if negative.


A survey of chronic bronchitis among brassware workers. A stratified random sample of 580 workers aged between 18 and 50 years representing each sub-occupation in the brassware industry was studied for the prevalence of chronic bronchitis in relation to occupational and environmental factors. The findings were compared with those obtained in a reference group (N = 131) belonging to similar socio-economic status and unexposed to a dusty environment. Although the exposed group showed higher prevalence of chronic bronchitis in comparison to that observed in the controls (10.5 vs 5.3%), the difference was not significant at the 5% level. It was observed that the workers engaged in non-dusty occupations such as brass sheet cutting and engraving showed the lowest prevalence of the disease (5.0%) while those engaged in the dusty occupations viz., casting, soldering, electroplating and polishing showed the highest prevalence (12.0%). The smoking adjusted odds ratios calculated in various sub-occupations showed the highest risk of developing chronic bronchitis among the polishers (2.74). Though the risk in other occupational sub-groups was double, it did not attain a level of significance. The smoking adjusted odds ratios in relation to length of exposure showed that the risk was significantly higher among the workers exposed for over 10 years compared to those who worked for less than 10 years in the grinding, soldering and brass ingot making operations. The study thus showed a dose-response relationship between length of exposure and chronic bronchitis while effect of age on the disease was not discernible probably due to the small number of cases and the young age of the study group. The concentration of various metals in the air samples drawn from the work environment where main processes were in operation, was low compared to the prescribed level by ACGIH.


Quantification of biological variability. Pharmacokinetic models are usually developed to describe the kinetic behaviour of the chemical compounds in an average human body. There are however many situations were the effects of variations in a given pharmacokinetic parameter would be of interest. For example, in biological monitoring, the variability of biological data is a critical parameter when relating air and biological measures of an individual exposure. This paper reviews two possible approaches for the simulation of such variability in occupational pharmacokinetics. In the first, a simple one-compartment model is used together with statistical distributions for the intake and elimination of the compounds involved. Based on realistic distributions, this simple model is applied to the comparison of biological and air monitoring to estimate workers' exposure. The second involves a seven-compartment physiologically based pharmacokinetic model, which includes provision of the means to input satistical distributions for some of the parameters: exposures, physical workload, body height, body weight, liver function and renal function. It makes it possible to predict the pharmacokinetic response of groups of workers, who differ in their exposures and in their physiological parameters. Realistic statistical distributions are then used to describe biological monitoring variability. The advantages and disadvantages of both the simple pharmacokinetic model and the physiological model are discussed in the context of predicting and understanding variability in occupational situations. Other potential developments are also considered.


The extended lateral arm flap: a detailed anatomical study. The lateral arm flap has long been the workhorse of microvascular surgeons in the cover of small and moderate-sized defects, especially in the head, neck, and the extremities. Its versatility, however, has always been restricted by its small skin paddle. The flap traditionally is harvested from the upper arm. This flap derives its blood supply from cutaneous perforators of the posterior radial collateral artery (PRCA) which forms an anastomotic plexus with the interosseous recurrent artery around the lateral aspect of the elbow. As a result of anatomical dissection and dye injection studies, we have re-defined the cutaneous blood supply of the PRCA which is found to continue for some distance into the forearm, and utilise this finding to design an "extended" lateral arm flap for use in microvascular reconstruction.


The Oriental nose: an anatomical basis for surgery. Fifteen Oriental noses were examined macrosurgically and microscopically. Five soft tissue layers overlying the osseocartilaginous framework are identified: the skin, the subcutaneous areolar plane, the vascular-fibromuscular layer, the deep areolar plane and perichondrium/periosteum. Two natural planes of dissection are represented by these areolar planes which separate the nose into an overlying skin envelope, a vascular-fibromuscular layer and an underlying osseocartilaginous framework. The cartilaginous framework provides projection, support and shape to the dorsum and tip of the nose but not to the alar lobule as this is devoid of cartilage. As there is no cartilage in the Alar lobule, the term 'Alar Cartilage' is misleading and the term 'Tip Cartilage' is introduced to replace it. The skin of the nose is specialised and has the ability to retain its shape even after dissection. This is due to an arrangement of elastin fibres in the upper dermis and the subcutaneous areolar plane which confers elasticity to the skin especially in the region of the Alar lobule which is a skin and fibromuscular sandwich. The vascular fibromuscular layer is like a sheet draping the osseocartilaginous framework. The main arteries of the nose lie on this layer. Injection studies of the blood supply reveal many arterial variations but always a distinct alar artery, columellar artery and alar plexus that have not been previously named. The alar groove is a junction between the alar lobule which is soft tissue alone and the tip which is soft tissue, supported by cartilage. The alar groove lies over the lateral edge of the tip cartilage and here there is muscular attachment to the fibromuscular layer.


Hand surgery.

Hand surgery. A historical outline of the development of Hand Surgery in Singapore is presented. It traces its growth from the Orthopaedic Surgery Unit at General Hospital Singapore in the early 1950's, to the present times. During this period, the Singapore Society of Hand Surgery was established in 1982, the Department of Hand Surgery at the Singapore General Hospital in 1985 and the Hand and Reconstructive Microsurgery Department was officially established at the National University Hospital in 1990.


B-mode real-time ultrasound assessment of vocal cord function in recurrent laryngeal nerve palsy. B-mode real-time ultrasound was used to assess vocal cord function in six patients with recurrent laryngeal nerve palsy. The thyroid cartilage acted as an acoustic window through which the true cords appear as hypoechoic structures. Vocal cord palsy detected on ultrasound was compared with fibreoptic direct laryngoscopy and indirect laryngoscopy mirror examination. Good correlation was seen in all the cases.


The effect of chemotherapy on soft tissue and bone healing in the rabbit model. The effect of chemotherapy on soft tissue and bone healing was studied in a rabbit femoral fracture model. Adriamycin was administered at various intervals preoperatively. Results were compared against a control group in which adriamycin was omitted. Post-chemotherapy blood count profiles were monitored. All animals were operated on with a standard skin incision, osteotomy of the femur and fixation with an intramedullary wire. Soft tissue was assessed with daily clinical scoring and tested for wound breaking strength at two weeks postoperatively. Bone healing was assessed at the time of sacrifice six weeks postoperatively by four-point bending to failure. Clinical scoring of wounds did not show significant differences between control and adriamycin-treated groups. Results of wound breaking strength and four-point bending to failure showed significant impairment for animals given adriamycin four and seven days preoperatively, and no significant impairment when given 14 days preoperatively. Contrary to previous studies, our results suggest that it is feasible to combine neoadjuvant chemotherapy and early surgery without compromise of soft tissue healing. Our results show that adriamycin impairs bone healing. We postulate that adriamycin has a temporary and reversible inhibitory effect on bone biology. The clinical implications of these findings are discussed.


The dropped big toe.

The dropped big toe. Surgical procedures for exposure of the upper third of the fibula have been known to cause weakness of the long extensor of the big toe post-operatively. The authors present three representative cases of surgically induced dropped big toe. From cadaveric dissection, an anatomic basis was found for this phenomenon. The tibialis anterior and extensor digitorum longus muscles have their origin at the proximal end of the leg and receive their first motor innervation from a branch that arises from the common peroneal or deep peroneal nerve at about the level of the neck of the fibula. However, the extensor hallucis longus muscle originates in the middle one-third of the leg and the nerves innervating this muscle run a long course in close proximity to the fibula for up to ten centimeters from a level below the neck of the fibula before entering the muscle. Surgical intervention in the proximal one-third of the fibula just distal to the origin of the first motor branch to the tibialis anterior and extensor digitorum longus muscles carries a risk of injury to the nerves innervating the extensor hallucis longus.


Anti-toxoplasma serotitres in uveitis and ocular toxoplasmosis. This study was based on anti-toxoplasma serotitres obtained from 80 normal healthy adults and 103 consecutive patients with anterior, posterior and panuveitis over a 42 month period. Twelve out of 80 (15%) normal healthy sera were found to have low titres (1:64 to 1:256), while 3 (3.8%) had high titres (1:1024 or higher). The distribution of serotitres in patients with clinical toxoplasmosis was significantly different from the population sample (p less than 0.001, chi-squared test). Similarly, the distribution of serotitres in patients with posterior uveitis (of which 28 out of 54 were clinically ocular toxoplasmosis) having serotitres of 1:1024 or greater, was found to be significantly different from the normal population (p less than 0.001, Chi-squared test), but not statistically different from those with clinical ocular toxoplasmosis. Hence, anti-toxoplasma serotitre is useful as a diagnostic screening tool only in patients with posterior uveitis. It is also useful in confirming cases of suspected clinically positive ocular toxoplasmosis in our local population.


Surgery for cardiac arrhythmias.

Surgery for cardiac arrhythmias. From March 1989 to March 1991, 17 patients underwent curative surgical ablation of cardiac arrhythmias at the Singapore General Hospital. In the supraventricular tachycardia group, 13 patients with the Wolff-Parkinson White syndrome (WPW) underwent surgical ablation of the accessory conduction pathway by the classical endocardial approach. Two patients who had atrioventricular nodal tachycardia (AVNRT) underwent surgical dissection around the atrioventricular node to divide one of the dual conduction pathway responsible for the tachycardia. In the ventricular tachycardia group, two patients underwent surgical ablation of the arrhythmic focus. There was no operative mortality in the supraventricular tachycardia group and there were no late deaths to date. All these patients underwent electrophysiological study just before discharge and most of them had a repeat test six months later. In the Wolff-Parkinson White group, surgical ablation was completely successful in 12 patients (92%), preexcitation recurred in one patient (8%) but non had recurrence of supraventricular tachycardia. The two patients who had atrioventricular nodal tachycardia were completely cured of recurrent supraventricular tachycardia and had normal atrioventricular conduction. In the ventricular tachycardia group, one was cured with no recurrence of tachycardia, is not on medication and is in New York Heart Association Class I status. The other died postoperatively of recurrent ventricular tachycardia and low cardiac output syndrome.