Respiratory depression produced by intravenously administered NBQX.

To determine whether blockade of non-N-methyl-D-aspartate (non-NMDA) excitatory amino acid receptors affects breathing, we administered the non-NMDA receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), to anesthetized cats while monitoring phrenic nerve discharge, blood pressure and heart rate. NBQX, 3 and 10 mg/kg, i.v., reduced phrenic amplitude 59 +/- 20% (n = 3) and 88 +/- 6% (n = 5), respectively, and decreased respiratory rate. Phrenic activity was completely silenced in 3 animals. These effects were accompanied by decreased blood pressure and heart rate. Our data indicate that NBQX, a competitive antagonist of non-NMDA receptors, is a powerful depressant of cardiorespiratory activity.

Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion.

Data from a non-randomised study have hinted that in patients with acute pulmonary embolism (PE), thrombolysis followed by heparin more rapidly reverses right-ventricular dysfunction and restores pulmonary tissue perfusion than does heparin alone. We have pursued this idea in a randomised protocol. 46 haemodynamically stable patients were randomised to recombinant tissue plasminogen activator (alteplase, rt-PA) 100 mg over 2 h followed by intravenous heparin and 55 to heparin alone. Right-ventricular wall motion was assessed qualitatively, and right-ventricular end diastolic area was estimated by planimetry from echocardiograms at baseline and at 3 and 24 hours. Pulmonary perfusion scans were obtained at baseline and 24 hours. In 39% of rt-PA patients but in only 17% of heparin alone patients right-ventricular wall motion at 24 hours had improved from baseline and in 2% and 17%, respectively, it worsened (p = 0.005). rt-PA patients also had a significant decrease in right-ventricular end-diastolic area during the 24 hours after randomisation and a significant absolute improvement in pulmonary perfusion (14.6% vs 1.5%). No clinical episodes of recurrent PE were noted among rt-PA patients, but there were 2 fatal and 3 non-fatal clinically suspected recurrent PEs within 14 days in patients randomised to heparin alone. rt-PA rapidly improves right-ventricular function and pulmonary perfusion among patients with PE and may lead to a lower rate of adverse clinical outcomes.

Gamma-aminobutyric acid type A receptor blockade at the intermediate area of the ventral surface of the medulla counteracts the cardiorespiratory depression produced by intravenous midazolam.

Intravenous administration of midazolam (2 mg/kg) to 8 pentobarbital-anesthetized cats produced a significant decrease in minute ventilation, tidal volume, blood pressure and heart rate. Treatment with the gamma-aminobutyric acid (GABA) type A receptor antagonist bicuculline (10 micrograms/side) at the intermediate area of the ventral surface of the medulla (VSM) oblongata completely reversed the cardiorespiratory depressant effects of intravenous midazolam. In contrast, treatment with bicuculline at the same area failed to counteract the respiratory depressant effects of intravenous morphine (1 mg/kg). We conclude that the cardiorespiratory depressant effects of intravenously administered midazolam are due to enhancement of GABAergic transmission at the intermediate area of the VSM.

A beta-carboline derivative (ZK 93426) counteracts the cardiorespiratory depressant effects of intravenous midazolam.

The purpose of this study was to test the effects of the new beta-carboline ZK 93426 on midazolam-induced cardiorespiratory depression. Seven pentobarbital-anesthetized (35 mg/kg i.p.) cats were treated with intravenous midazolam (2 mg/kg) while monitoring the respiratory minute volume (VE), tidal volume, respiratory rate, blood pressure, heart rate and expired CO2. Midazolam caused significant decreases in VE (p less than 0.05) and blood pressure (p less than 0.05). ZK 93426 (5 mg/kg i.v.) antagonized these effects and produced significant increases in VE and blood pressure that resulted in the return of these variables to premidazolam control values. In 4 animals with morphine-induced respiratory depression, intravenous ZK 93426 failed to antagonize the respiratory effects of morphine. Administration of intravenous ZK 93426 alone to 4 pentobarbital-anesthetized animals also failed to produce significant changes in cardiorespiratory activity. We conclude that ZK 93426 is effective in counteracting the cardiorespiratory depressant effects of midazolam and that these effects appear to be specific. The present data suggest that this compound may be useful for the treatment of benzodiazepine oversedation and overdose.

Drug interaction with gamma-aminobutyric acid/benzodiazepine receptors at the ventral surface of the medulla results in pronounced changes in cardiorespiratory activity.

Studies were carried out in chloralose-anesthetized cats while monitoring respiratory (tidal volume and respiratory rate) and cardiovascular (arterial pressure and heart rate) activity. Midazolam applied bilaterally to the intermediate area of the ventral surface of the medulla in doses of 0.75, 7.5 and 75 micrograms/side reduced tidal volume by -6 +/- 3, -10 +/- 1 and -11 +/- 1 ml, respectively. A dose of 250 micrograms/side produced apnea in each animal tested. Corresponding changes in arterial pressure were -35 +/- 9, -44 +/- 6, -43 +/- 9 and -64 +/- 17 mm Hg, respectively. Larger doses of chlordiazepoxide (e.g., 1000 micrograms/side) were required to produce similar effects. Intravenous administration of midazolam in doses of 1.5 to 150 micrograms had no significant effect on cardiorespiratory activity. However, larger doses of midazolam given i.v. produced cardiorespiratory depression that was similar to that observed with centrally applied drug. Pretreatment or treatment with centrally applied flumazenil or bicuculline counteracted the cardiorespiratory effects of centrally applied midazolam. Most importantly, ventral surface application of flumazenil counteracted the cardiorespiratory depressant effects of i.v. midazolam. Central administration of ethyl-beta-carboline-3-carboxylate produced cardiorespiratory effects opposite to those seen with midazolam, and these stimulatory effects were also counteracted by centrally applied flumazenil. These results indicate that alterations in cardiorespiratory activity can be produced by drugs interacting with gamma-aminobutyric acid/benzodiazepine receptors at the ventral surface of the medulla.

Respiratory depressant effects of GABA alpha- and beta-receptor agonists in the cat.

The aim of this study was to evaluate the cardiorespiratory effects of intravenously administered gamma-aminobutyric acid (GABA) alpha-(4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, THIP) and beta-(baclofen) receptor agonists and to locate the site of action of these drugs in the brain. THIP and baclofen were administered to alpha-chloralose-anesthetized cats while minute ventilation (VE), arterial blood pressure (AP), and heart rate were monitored. THIP, in doses of 0.5 to 2 mg/kg decreased VE, tidal volume (VT), and AP. No changes in respiratory rate (f) or inspiratory (TI) or expiratory (TE) duration were observed. Baclofen, in doses of 0.5 to 4 mg/kg, decreased VE, f, and AP. VT and TI increased and an "apneustic" breathing pattern was seen. THIP (9.5 micrograms), applied bilaterally to the glycine-sensitive area of the ventral medulla, reproduced the effects seen with intravenous administration. Application of 10 micrograms of bicuculline bilaterally to this area reversed the effects of intravenous THIP but not those of baclofen. Baclofen (5.6-56 micrograms), administered by the intracisternal route, produced the same respiratory effects seen with intravenous administration. We conclude that activation of GABA alpha- and beta-receptors produces cardiorespiratory depression. However, this is accomplished by different mechanisms and by actions exerted at different central nervous system sites.

Chemical stimulation of the area postrema induces cardiorespiratory changes in the cat.

The purpose of our study was to determine the cardiorespiratory effects of exciting cell bodies of the area postrema of the cat. This was accomplished by local application of L-glutamic acid (bilateral application of 5 microliter of a 250-1000 mM solution) and kainic acid (bilateral application of 5 microliter of a 40 mM solution) to the area postrema of chloralose-anesthetized cats while monitoring arterial pressure, heart rate, tidal volume and respiratory rate. These excitatory amino acids activate neuronal cell bodies but not axons of passage. L-Glutamic acid produced a dose-dependent increase in arterial pressure, decreases in respiratory rate and minute volume and, occasionally, ventricular tachyarrhythmias. Kainic acid produced effects similar to those seen with L-glutamic acid except the changes in respiratory activity were more pronounced with each animal exhibiting respiratory arrest. In artificially respired animals, kainic acid produced similar cardiovascular changes as those occurring in spontaneously breathing animals (i.e. increases in arterial pressure of 61 +/- 5.7 mm Hg, and in heart rate of 32 +/- 8.3 beats/min). Finally, application of kainic acid to the area postrema abolished the pressor and tachycardic responses to bilateral occlusion of the carotid arteries. These results suggest that activation of cell bodies in the area postrema can result in pronounced cardiorespiratory changes.

Peritonitis, dialysate infusion and lung function in continuous ambulatory peritoneal dialysis (CAPD).

Pulmonary function tests were done in seven CAPD patients with acute peritonitis on the day of admission to the hospital and after recovery. Subsequently, the effect of dialysate infusion alone on lung function was studied in 19 patients initiated on CAPD and nine of these patients were restudied 7.6 +/- 4.1 months later. Peritonitis was associated with a 30% reduction in vital capacity and a significant fall in arterial oxygen tension (7 to 11 mmHg) (p less than 0.01). Dialysate infusion alone decreased functional residual capacity (FRC) and produced small changes in PaO2 which were more pronounced in the supine position. The decrease in PaO2 observed in changing from sitting prior to dialysate infusion, to supine after dialysate infusion was due to the development of airways closure at resting lung volumes. Follow-up studies in nine patients demonstrated a continued and significant fall in FRC with dialysate infusion, without however, any changes in PaO2. We conclude that peritonitis in CAPD patients is accompanied by significant changes in lung function which are probably due to a decrease in diaphragmatic mobility resulting in atelectasis and underventilation of dependent lung zones. In CAPD patients without peritonitis, dialysate infusion in the supine position produces significant changes in PaO2, but with time, compensatory mechanisms develop to abolish the changes in PaO2.

Cardiorespiratory effects produced by application of L-glutamic and kainic acid to the ventral surface of the cat hindbrain.

The purpose of our study was to determine the cardiorespiratory effects of exciting cell bodies at the rostral (area M), intermediate (area S), and caudal (area L) chemosensitive sites on the ventral surface of the medulla. To do this, L-glutamic and kainic acid were applied bilaterally to each chemosensitive site while monitoring tidal volume (VT), respiratory rate (f), mean arterial pressure (BP), and heart rate (HR) in chloralose-anesthetized cats. Application of solutions (5 microliter) of L-glutamic acid ranging from 62.5 to 2000 mM to the intermediate area produced concentration-dependent increases in VT (from 2.0 +/- 0.6 ml to 14 +/- 1.1 ml) and BP (from 2.0 +/- 1.7 mm Hg to 39 +/- 5.3 mm Hg). No significant changes in f and HR were noted. Similar effects were observed with application of kainic acid. Application of L-glutamic acid to the caudal area produced hypotension (-24 +/- 5.4 mm Hg) with no accompanying changes in VT and f. No responses were observed after application of L-glutamic acid to the rostral area. These data suggest that activation of cell bodies on the intermediate area produces simultaneous stimulatory effects on BP and VT, whereas activation of cell bodies at the caudal area produces selective depressant effects on BP.

Central nervous system site of action for the respiratory depressant effect of diacetylmorphine (heroin) in the cat.

The purpose of our study was to identify central nervous system sites involved in the respiratory depressant effect of drugs that stimulate opioid receptors. Diacetylmorphine (heroin) was administered into several cerebroventricular regions of chloralose-anesthetized cats, while monitoring pulmonary ventilation with a Fleisch pneumotachograph. Administration of heroin (17, 50, 150, and 450 micrograms) into the forebrain ventricles, which was restricted to these ventricles, resulted in no significant respiratory effects. In contrast, administration of heroin into either the fourth ventricle or the cisterna magna resulted in a significant (P less than 0.05) decrease in respiratory minute volume (VE). In the fourth ventricle this was because of a decrease in frequency (f) and in the cisterna magna, to a decrease in tidal volume (VT). Intravenous administration of heroin in the same dose-range produced a decrease in VE, which was primarily due to a decrease in f. Bilateral application of heroin (70 micrograms/side) to each of three ventral medullary surface sites (Mitchell's, Schlaefke's, and Loeschcke's areas) known to influence respiration elicited a decrease in VE only at Mitchell's area. This decrease was due to decreases in f and VT. The role of this site in the action of intravenously administered heroin was tested by topical application of naloxone to this area in animals with respiratory depression evoked by intravenous heroin. Bilateral application of naloxone (15 micrograms/side) to Mitchell's area restored breathing to normal. These results lead us to suggest that the site of heroin-induced respiratory depression is a specific area (Mitchell's area) on the ventral surface of the medulla.

Cardiovascular findings in a patient with severe tetanus.

We report a case of tetanus associated with the syndrome of sympathetic overactivity. BP changes were associated with changes in systemic vascular resistance index (SVRI). Cardiac index (CI) varied independently from changes in SVRI and was correlated with the stroke volume. Oxygen consumption during the hypotensive periods was normal. Among several pharmacologic agents, only curare was effective in decreasing the severity and number of the hypertensive episodes. Physical stimulation of the patient rapidly reversed the hypotension. The potential mechanisms involved in producing these cardiovascular abnormalities are discussed.

Central respiratory stimulant effect of bombesin in the cat.

Bombesin (0.62-6.2 nmol) was administered into the cisterna magna of chloralose-anesthetized cats while monitoring tracheal airflow with a pneumotachograph. The peptide produced dose-related increases in respiratory activity which were seen primarily as increases in tidal volume. Intravenous administration of bombesin (6.2 nmol) did not cause any respiratory effects. These results indicate that bombesin acts in the brain to stimulate respiration.

Respiratory depression produced by centrally administered taurine in the cat.

The effects of taurine (0.8-64.8 mumol) were studied on respiratory activity following intracisternal (cisterna magna) and intracerebroventricular (lateral ventricle) injections in cats anesthetized with alpha-chloralose. Respiratory activity was measured by using a Fleisch pneumotachograph and monitoring tracheal airflow. The flow signal was integrated to obtain tidal volume (VT) and respiratory rate (f) was obtained by counting the number of VT excursions over one minute. Inspiratory (TI), expiratory (TE) and total (TTOT) cycle durations were also determined during this time period. In addition, end-tidal CO2 was continuously monitored. Associated changes in arterial pressure (femoral artery cannula) and heart rate were also determined. After injections into the cisterna magna, taurine caused dose-related decreases in minute ventilation (VE). The maximal decrease in VE was from 495 +/- 59 to 64 +/- 14 ml/min (p less than 0.05), and was due to both decreases in VT (from 27 +/- 3 to 5 +/- 1 ml; p less than 0.05) and f (from 18 +/- 1 to 12 +/- 2 breaths/min; p less than 0.05). TE and TTOT were increased from 2.4 +/- 0.4 to 4.5 +/- 0.6 sec (p less than 0.05) and from 3.7 +/- 0.4 to 6.4 +/- 0.8 sec (p less than 0.05), respectively. Mean inspiratory flow (VT/TI), a measure of inspiratory drive, was decreased from 21 +/- 4 to 4 +/- 2 ml/sec (p less than 0.05). Apnea occurred in 5 of 6 animals after the 64.8 mumol dose. This respiratory depression occurred without any significant change in arterial pressure. After lateral ventricle injections, taurine also caused dose-related, but not as pronounced, decreases in respiratory activity. In addition, taurine caused significant decreases (p less than 0.05) in arterial pressure in doses that decreased VE. Taurine administered intravenously had no significant cardiorespiratory depressant effects. These data indicate that centrally administered taurine produces respiratory depression and, depending on the route of CNS administration, also produces hypotension.

Respiratory and cardiovascular effects of intraventricular cholecystokinin.

Cholecystokinin (1-300 ng) was administered into the lateral brain ventricle of chloralose-anesthetized cats while monitoring tracheal airflow, arterial blood pressure, and heart rate. Dose-related increases in respiratory activity occurred in each animal tested, and were due to an increase in tidal volume. When 300-1000 ng of cholecystokinin was administered intravenously, no respiratory stimulant effect was observed. These results indicate that cholecystokinin acts in the brain to stimulate respiration.

Effect of smoking a cigarette on the density dependence of maximal expiratory flow.

We have shown that tobacco smoke causes an increase in airways resistance and a drop in expiratory flow at 50% of the vital capacity (FEF50). To better define the nature and site of this bronchoconstrictive effect we measured maximal expiratory flow while breathing air and a low-density gas mixture (helium-oxygen), in 12 healthy volunteers, before and after smoking a cigarette. There was a significant drop in FEF50 while breathing air (FEF50Air) (5.52 +/- 1.83--5.05 +/- 1.86 liters/s; p less than 0.001). No changes were observed in the helium-oxygen FEF50 (FEF50 He) after smoking. The increase in FEF50 after breathing the low-density gas as a percentage of FEF50Air (delta Vmax50) increased from 47.1 +/- 11.4% before smoking to 57.0 +/- 13.3% after smoking (p less than 0.05). There were no changes in forced vital capacity (FVC), flow at 75% FVC and volume of isoflow. We discuss these observations in light of the equal pressure points (EPP) analysis and wave speed theory of flow limitation. We conclude that after smoking flow becomes more density dependent because there is constriction of a flow-limiting segment downstream from the EPP, located in lobar and segmental bronchi. No acute effect of tobacco smoke on the small airways could be demonstrated.

Airways response to inhaled tobacco smoke: time course, dose dependence and effect of volume history.

We have measured puff by puff the effect of smoking three brands of cigarettes with different composition on airways resistance (Raw) thoracic gas volume (TGV) and the maximal expiratory flow volume (MEFV) curve. Raw increased significantly with all three brands of cigarettes after one puff. The maximum effect was reached after three puffs. Instantaneous flow at 50% of vital capacity (FEF50) decreased significantly with cigarettes high in nicotine content, but not so after smoking a low nicotine (0.31 mg) cigarette. Instantaneous flow at 75% of vital capacity out (FEF75) increased significantly 30 min after the low nicotine cigarette was smoked. A deep inspiration prior to Raw determination reduced by approximately one third the bronchoconstrictor effect of cigarette smoke. All effects were reversible within 30 min, except the delayed effect of the low nicotine cigarette on the FEF75. We conclude that the probable site of action of tobacco smoke is in the large and central airways. The bronchoconstrictor effect rapidly reaches a plateau. A delayed bronchodilation of the small airways observed after smoking the low nicotine cigarette might represent a response usually masked by other long-acting components in smoke. We suggest that the airway response to tobacco smoke is complex and probably a result of several components present in smoke which still have to be identified.

Reversible respiratory failure due to intravascular leukostasis in chronic myelogenous leukemia. Relationship of oxygen transfer to leukocyte count.

In a 49 year old man with blast crisis and massive leukocytosis due to chronic myelogenous leukemia, severe hypoxic respiratory failure developed despite a normal chest film. Correction of hypoxemia was observed after reduction of the white blood cell count by hydroxy-urea therapy. A similar episode occurred prior to death, and necropsy examination revealed extensive plugging of the pulmonary vasculature by leukemic blast cells but no infection or pulmonary edema. An inverse linear correlation was demonstrated between the peripheral white blood cell count and the efficiency of oxygen transfer in the lung as determined by the arterial to alveolar oxygen tension ratio. We postulate that mechanical obstruction and/or leukocyte mediated capillary endothelial injury caused the severe leukocyte mediated capillary endothelial injury caused the severe hypoxemia. Abnormalities of pulmonary gas exchange may be common in leukemic patients with markedly increased leukocyte counts.

The effect on expiratory flow rates of smoking three cigarettes in rapid succession.

The effect of smoking three cigarettes in rapid succession on maximal and partial expiratory flow rates was studied in ten healthy smokers. The mean decrease in maximal midexpiratory flow and partial midexpiratory and end-expiratory flow was statistically significant. The response was maximal after the first cigarette. These results suggest that the instantaneous midexpiratory flow after 50% of the forced vital capacity has been exhaled is a useful indicator of irritation of the airways. Reduction of partial expiratory flow rates was three times greater than reduction of maximal expiratory flow rates. We suggest the use of partial expiratory flow curves as a screening test for irritants of the airways.

Aspirin and exercise-induced asthma.

In four subjects with exercise-induced asthma, aspirin and placebo were administered prior to exercise in a double blind study. Pulmonary function tests did not reveal any difference between the response after aspirin or placebo. We conclude that in these four subjects aspirin did not prevent the bronchoconstrictor response. This might suggest that prostaglandins have no significant role in exercise-induced asthma.