Ventilatory responses after major surgery and high dependency care.

BACKGROUND: Disturbed breathing during sleep, with episodic upper airway obstruction, is frequent after major surgery. Ventilatory responses to hypercapnia and hypoxia during episodes of airway obstruction are difficult to investigate because the usual measure, that of ventilation, has been attenuated by the obstruction. We simulated the blood gas stimulus associated with obstruction to allow investigation of the responses. METHODS: To assess ventilatory responses, we studied 19 patients, mean age 59 (19-79), first at discharge from high dependency care after major abdominal surgery and then at surgical review, ~6 weeks later. Exhaled gas was analysed and inspired gas adjusted to simulate changes that would occur during airway obstruction. Changes in ventilation were measured over the following 45-70 s. Studies were done from air breathing if possible, and also from an increased inspired oxygen concentration. RESULTS: During simulated obstruction, hypercapnia developed similarly in all the test conditions. Arterial oxygen saturation decreased significantly more rapidly when the test was started from air breathing. The mean ventilatory response was 5.8 litre min(-2) starting from air breathing and 4.5 litre min(-2) with oxygen breathing. The values 6 weeks later were 5.9 and 4.3 litre min(-2), respectively (P=0.05, analysis of variance). There was no statistical difference between the responses starting from air and those on oxygen. CONCLUSIONS: After major surgery, ventilatory responses to hypercapnia and hypoxaemia associated with airway obstruction are small and do not improve after 6 weeks. With air breathing, arterial oxygen desaturation during simulated rebreathing is substantial.

Methadone maintenance: effect of urinary pH on renal clearance in chronic high and low doses.

The subjects were 12 male patients stabilized on methadone for many months or years. A comparison was made of the plasma levels and renal clearance of methadone between patients on "high" doses (80 to 110 mg/day) and those on "low" doses (15 to 40 mg/day). A general trend to higher renal clearance was seen in the "high" -dose group, but on more detailed examination there was a direct correlation only when the patients were categorized by urinary pH. At low pHs, there was nearly a 3-fold increase in renal clearance which was associated with a decreased major metabolite to methadone ratio. No evidence for a difference in rate of metabolism between the two groups was found nor were there differences in hepatic function. It was concluded that urinary pH was a major factor in renal clearance of methadone.

Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema.

In five patients with hypoxic chronic bronchitis and emphysema we measured ear O2 saturation (SaO2), chest movement, oronasal airflow, arterial and mixed venous gas tensions, and cardiac output during nine hypoxemic episodes (HE; SaO2 falls greater than 10%) in rapid-eye-movement (REM) sleep and during preceding periods of stable oxygenation in non-REM sleep. All nine HE occurred with recurrent short episodes of reduced chest movement, none with sleep apnea. The arterial PO2 (PaO2) fell by 6.0 +/- 1.9 (SD) Torr during the HE (P less than 0.01), but mean arterial PCO2 (PaCO2) rose by only 1.4 +/- 2.4 Torr (P greater than 0.4). The arteriovenous O2 content difference fell by 0.64 +/- 0.43 ml/100 ml of blood during the HE (P less than 0.05), but there was no significant change in cardiac output. Changes observed in PaO2 and PaCO2 during HE were similar to those in four normal subjects during 90 s of voluntary hypoventilation, when PaO2 fell by 12.3 +/- 5.6 Torr (P less than 0.05), but mean PaCO2 rose by only 2.8 +/- 2.1 Torr (P greater than 0.4). We suggest that the transient hypoxemia which occurs during REM sleep in patients with chronic bronchitis and emphysema could be explained by hypoventilation during REM sleep but that the importance of changes in distribution of ventilation-perfusion ratios cannot be assessed by presently available techniques.

Reduced DNA repair capacity and increased cytotoxicity following split doses of the mutagen 4-nitroquinoline-1-oxide in cultured human cells.

Cultured human fibroblasts were exposed to single doses of 4-nitroquinoline-1-oxide(4NQO) and to two equimolar doses of 4NQO at intervals varying from 0.5 to 12 h. DNA repair synthesis as measured by an unscheduled uptake of tritium-labelled thymidine ([3-H]TdR), cell survival as estimated by the clone-forming capacity, and frequency of chromosome aberrations were used as endpoints. Cells respond with a reduced level of DNA repair synthesis when the second 4NQO dose (5 X 10 minus 7 or 1 X10-minus 7 M) is given within 3 h of the first 4NQO dose. If the interval between the two doses is 5 h or more, the level of DNA repair synthesis which is induced by the second 4NQO dose is comparable to that following a single 60-min 4NQO application. In this 3-h period the cultured cells show an increased sensitivity to the lethal effect and chromosome-damaging action of the second 4NQO dose. The reduced period of DNA repair capacity seems to increase the mutagenic effect of the chemical carcinogen.

Lung compliance, lung volume and transfer factor for carbon monoxide in anaesthetised sheep: normal values and reproducibility of measurements.

Measurements of quasistatic compliance (Cqst), effective alveolar volume (VA,eff) and single-breath transfer factor for carbon monoxide (TL,CO, 'sb') were completed in 16 normal, anaesthetised, adult Texel ewes. Regression equations were computed for these variables as a function of bodyweight and the optimal equations selected. The 95 per cent prediction intervals for the equations were calculated such that normal lung function in similar sheep could be accurately predicted. The long term reproducibility of these measurements was assessed in nine sheep, measured at monthly intervals over a period of five months. Although measurements made in individual sheep were often highly variable, the variation between repeated measurements on the separate days for the group was insignificant.

Effects on lung compliance, lung volume, and single-breath transfer factor for carbon monoxide in sheep with lentivirus-induced lymphoid interstitial pneumonia.

Static lung compliance, static lung volumes, and transfer factor for carbon monoxide were measured in 12 anesthetized adult Texel ewes seropositive for maedi-visna virus (MVV) and in 11 breed-, sex-, and age-matched seronegative controls. Median static lung compliance in MVV-infected sheep (1.24 L.kPa-1; range, 0.27 to 2.20 L.kPa-1) was not significantly different from that in controls (1.58 L.kPa-1; range, 0.82 to 2.08 L.kPa-1). Median body weight of MVV-infected sheep (56 kg; range, 40 to 75 kg) was significantly (P < 0.05) less than that of controls (65 kg; range, 53 to 87 kg). Median effective alveolar lung volume in MVV-infected sheep (3.36 L; range, 1.44 to 4.52 L) was significantly (P < 0.01) less than that in controls (4.12 L; range, 3.75 to 4.90 L). Median effective end expiratory lung volume in MVV-infected sheep (1.20 L; range, 0.56 to 1.99 L) was significantly (P < 0.001) less than that of controls (1.98 L; range: 1.76 to 2.78 L). Median lung volumes expressed per unit of body weight did not differ significantly between the groups. Median single-breath transfer factor for carbon monoxide in MVV-infected sheep (7.89 mmol.min-1.kPa-1; range, 3.45 to 12.74 mmol.min-1.kPa-1) was significantly (P < 0.001) less than that in controls (14.10 mmol.min-1.kPa-1; range, 10.02 to 18.30 mmol.min-1.kPa-1).(ABSTRACT TRUNCATED AT 250 WORDS)

The Objective Structured Clinical Examination and student collusion: marks do not tell the whole truth.

OBJECTIVE: To determine whether the marks in the third year Objective Structured Clinical Examination (OSCE) were affected by the collusion reported by the students themselves on an electronic discussion board. DESIGN: A review of the student discussion, examiners' feedback and a comparison of the marks obtained on the 2 days of the OSCE. PARTICIPANTS: 255 third year medical students. SETTING: An OSCE consisting of 15 stations, administered on three sites over 2 days at a UK medical school. RESULTS: 40 students contributed to the discussion on the electronic discussion board. The main points raised were perceived inequity between students who did, or did not, have prior knowledge of the station content, and the lack of honesty and professionalism of their peers. Most contributors claimed to have received, or knew of others receiving, prior knowledge, but none confessed to passing on information. No significant difference (p = 0.16) was observed in the overall mark for the OSCE on day 1 (mean 390 (SD 37)) and day 2 (mean 397 (38)). On day 2, marks were considerably greater for four stations and markedly lower for three stations. It was not obvious why collusion should affect these station marks. A clear indication of the effects of collusion could only be obtained from a single subsection of an individual station (pathology) where 82 students on day 2 incorrectly gave the diagnosis from day 1. CONCLUSION: Marks do not provide a sound inference of student collusion in an OSCE and may mask the aspects of professional development of students.

Should we judge a mask by its cover?

BACKGROUND: A table of the approximate ranges of inspired oxygen delivered at given oxygen flow rates is often given on the packaging of oxygen masks. A study was carried out to check the inspired oxygen concentration given by one of the new masks, which has been designed to be used with or without the Venturi attachment as a result of the proposal to use it without the Venturi attachment as a general purpose mask for emergency use. METHODS: Measurements were made at resting respiratory rate and 26 breaths/min in 12 normal subjects. Continuous oxygen and carbon dioxide concentrations were recorded at the lips with a mass spectrometer, and inspired oxygen concentrations were calculated from end tidal values by means of the alveolar gas equation. Measurements were made at oxygen flow rates of 2, 4, and 6 l/min for the mask alone and at 2 and 4 l/min with both the 24% and the 28% Venturi attachments. RESULTS: Without the Venturi attachment the mask gave average inspired oxygen concentrations 8-10% greater than are stated on the packaging at oxygen flow rates of 2, 4, and 6 l/min at resting respiratory rates of 8-20 breaths/min, some individuals receiving 30% more than expected. Addition of the interchangeable Venturi attachments designed to give 24% and 28% inspired oxygen delivered average concentrations within 2% of the expected concentrations, no individual receiving more than 5% above the expected concentrations. CONCLUSIONS: The labelling on the packaging of oxygen masks may lead to inappropriate use by those not expert in prescribing oxygen therapy. Caution is still needed when a single multipurpose mask is being selected for emergency use, where accurate delivery of low concentrations of oxygen is vital for some patients.

Oxygen uptake during rebreathing in a Mapleson A system.

We have measured oxygen uptake (VO2) and carbon dioxide production under steady-state conditions in 14 conscious volunteer subjects breathing from the Mapleson A system at different fresh gas flow rates, by collecting gas vented from the breathing system. Mixed vented gas concentration was measured with a mass spectrometer and volume with a water spirometer. Gas exchange and total ventilation were measured with subjects under resting conditions breathing room air, and then whilst breathing from a Magill system. Mean values of VO2 at mean fresh gas flow rates 1.43, 0.88, 0.67 and 0.49 times the resting total ventilation of the subject, were 3.30, 3.30, 3.34 and 3.56 ml min-1 kg-1 (STPD), respectively. Rebreathing occurred at ratios of 0.67 and 0.49. We were unable to demonstrate any increase in VO2 in the Mapleson A system with rebreathing.

Effect of domperidone on the ventilatory response to transient hyperoxia in patients anaesthetized with isoflurane.

We have studied the ventilatory responses to transient hyperoxia in two groups of patients (n = 10) anaesthetized with isoflurane (0.3 MAC); patients were allocated randomly to receive either domperidone or placebo orally before anaesthesia. In each patient, five two-breath oxygen tests were averaged and minute ventilation (VEinst) or mean inspiratory flow rate (VT/TI) for each post-test breath was compared with the mean values for these variables during baseline ventilation. A decrease to less than the 95% confidence limits of mean baseline values was considered a definite response. According to this definition, transient hyperoxia decreased VEinst in nine of 10 patients in the placebo group and in all patients in the domperidone group. Similar changes occurred in VT/TI, with eight of 10 definite responses in the placebo group and 10 of 10 in the domperidone group. Compared with placebo, in the domperidone group there were larger changes in VEinst (0.30 vs 0.55 litre min-1 (P = 0.05) and VT/TI (8.5 vs 26.6 ml s-1 (P = 0.02)) from respective baselines. Peripheral chemoreceptors appeared to be active during isoflurane anaesthesia and domperidone pretreatment enhanced this activity by increasing respiratory drive.

Effect of almitrine on hypoxic ventilatory drive measured by transient and progressive isocapnic hypoxia in normal men.

1. In a double-blind placebo-controlled study, we have investigated the effect of the peripheral chemoreceptor stimulant drug almitrine bismesylate on hypoxic ventilatory drive (expressed as the slope of the minute ventilation/arterial oxygen saturation relationship in litres min-1+-1) as measured by both progressive isocapnic hypoxia at rest and transient hypoxia (three breaths of 100% N2) during moderate exercise, in seven normal men, to determine if the ventilatory response to the transient hypoxic stimulus is a more specific measure of peripheral chemoreceptor sensitivity to hypoxia. 2. Hypoxic ventilatory drive measured using progressive isocapnic hypoxia ranged from -0.13 to -2.65 litres min-1%-1 after placebo and from -0.20 to -6.48 litres min-1%-1 after almitrine. The response was greater after almitrine in six of the seven subjects, and the difference was significant for the whole group (P less than 0.05). 3. Hypoxic ventilatory drive measured using transient hypoxia ranged from -0.19 to -1.59 litres min-1%-1 after placebo and from -0.09 to -1.62 litres min-1%-1 after almitrine. The response was not consistently greater after almitrine, and the difference was not significant for the group. 4. Difficulties in accurately quantifying a brief rise in minute ventilation after transient hypoxia, particularly in subjects with a low hypoxic ventilatory drive, may have masked small changes in the slope of the minute ventilation/arterial oxygen saturation relationship with this method.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute hypercapnic respiratory failure in patients with chronic obstructive lung disease: risk factors and use of guidelines for management.

BACKGROUND: On the basis of a retrospective survey by this unit it was suggested that patients with acute ventilatory failure should be given sufficient controlled oxygen treatment to raise the arterial oxygen tension (PaO2) to above 6.6 kPa, with the addition of a respiratory stimulant if the hydrogen ion concentration ([H+]) rose above 55 nmol/l and assisted ventilation if the patient remained acidotic despite these measures. This study was designed to verify the prognostic factors that determine survival in acute ventilatory failure and determine the outcome when our guidelines were implemented. METHODS: One hundred and thirty nine episodes of acute hypercapnic (type II) respiratory failure were studied prospectively in 95 patients admitted with acute exacerbations of chronic obstructive lung disease. Patients had to have a PaO2 below 6.6 kPa and an arterial carbon dioxide tension (PaCO2) above 6.6 kPa while breathing air. RESULTS: The mortality associated with episodes of acute ventilatory failure was 12%. Patients who died tended to be older and were significantly more acidotic, hypotensive, and uraemic on admission than those who survived, but they had similar degrees of hypoxaemia and hypercapnia. Death occurred in 10 of the 39 episodes in which arterial [H+] rose to 55 nmol/l or above, compared with seven of the 100 episodes in which it remained below 55 nmol/l. The respiratory stimulant doxapram was used in 37 episodes and was associated with a reduction in [H+] below 55 nmol/l within 24 hours in 23 episodes. Assisted ventilation was used in only four episodes. CONCLUSION: Arterial [H+] is an important prognostic factor for survival. Most patients treated according to the guidelines outlined above can be managed successfully without assisted ventilation.

Influence of oral clonidine on the ventilatory response to acute and sustained isocapnic hypoxia in human males.

Animal studies suggest that alpha 2 agonists inhibit the chemoreceptor response to hypoxia. We have examined the effect of oral clonidine on the ventilatory response to sustained, isocapnic hypoxia (SpO2 79.7% (SD 1.1%) for 20 min) in eight male subjects. The hypoxic ventilatory response was measured before and after both clonidine and placebo. Clonidine had no significant effect on baseline ventilation or gas exchange. After clonidine, the acute hypoxic response (AHR) (mean 5.81 (95% confidence limits 1.94, 9.68) litre min-1) was significantly less than control (10.40 (5.97, 14.83) litre min-1) and hypoxic ventilatory decline (HVD) (3.42(2.35, 4.49) litre min-1) was also significantly less than control (6.49(3.92, 9.06) litre min-1) (P < 0.05). After placebo, AHR was similar to control but HVD was significantly larger (6.82(5.28, 8.36) litre min-1) than control (4.79(3.03, 6.55) litre min-1) (P < 0.05). Thus clonidine reduced both AHR and HVD but the absolute level of ventilation at the end of hypoxia was unchanged.

Effect of a sub-anaesthetic concentration of halothane on the ventilatory response to sustained hypoxia in healthy humans.

We selected nine normal subjects (8M, 1F; aged 25-43 yr) with brisk hypoxic ventilatory responses, and studied their ventilatory response to sustained isocapnic hypoxia (SaO2 82 (SEM 0.1) % for 25 min) in the presence and absence of 0.1% inspired halothane. Halothane had no significant effect on baseline ventilation or gas exchange. In the absence of halothane, ventilation increased initially from mean 7.57 (0.35) litre min-1 to 14.54 (0.91) litre min-1, and decreased subsequently to 10.74 (0.32) litre min-1 during hypoxia (both P < 0.05). In the presence of 0.1% inspired halothane, ventilation increased initially from 7.19 (0.47) litre min-1 to 12.08 (0.99) litre min-1 (P < 0.05), then decreased to 10.12 (0.28) litre min-1 during sustained hypoxia (ns compared with baseline normoxic ventilation). Halothane reduced significantly the initial increase in ventilation (P < 0.05), but did not enhance the subsequent decrease. These results confirm that a sub-anaesthetic concentration of halothane depresses the initial hypoxic ventilatory response; the response during prolonged periods of hypoxia is, however, less than the initial response and is reduced in the presence or absence of a sub-anaesthetic concentration of halothane.

Microscopic and macroscopic measurements of emphysema: relation to carbon monoxide gas transfer.

BACKGROUND: Studies of the relation between the severity of structural change in emphysema and physiological abnormality have been based on macroscopic assessments, which have not been truly quantitative or sensitive enough to detect early changes. With a highly reproducible method for measuring emphysema using histological sections and a semiautomatic image analysis system, this quantitative assessment of emphysema was compared with a semiquantitative macroscopic assessment of emphysema and measurements of carbon monoxide gas transfer. METHODS: Microscopic and macroscopic measurements of emphysema on 44 thoracotomy specimens were compared; only two were from non-smokers. Airspace wall surface area per unit volume was measured microscopically with an automatic image analyser and expressed as both the mean airspace wall surface area per unit volume and the mean value of the five fields with the lowest values. Macroscopic emphysema was measured directly on a tracing of the midsagittal slice using a digitising tablet attached to a microcomputer and expressed as a percentage of the total area of lung. In cases with centriacinar emphysema the number of discrete lesions was counted. RESULTS: The area of macroscopic emphysema ranged from 0 to 78% of the total area of lung examined, but most patients had less than 1% involvement so that the distribution was highly skewed. Both mean airspace wall surface area per unit volume and the mean of five fields with the lowest airspace wall surface area per unit volume were normally distributed, with mean airspace areas ranging from 8.8 to 25.4 mm2/mm3 (mean 18.1 mm2/mm3). In lobes with centriacinar emphysema the number of discrete lesions correlated with airspace wall surface area per unit volume and with preoperative carbon monoxide transfer factor (TLCO) per unit lung volume. However, other measurements of macroscopic emphysema did not correlate with loss of alveolar wall surface area, and there was considerable overlap between subjects with no or minimal macroscopic emphysema and those with more severe disease. TLCO correlated with both mean airspace wall surface area per unit volume and the mean of five fields with the lowest airspace wall surface area per unit volume but not with the severity of macroscopic emphysema. CONCLUSION: If emphysema is to be quantified it must be measured microscopically; macroscopic measurements do not, in general, reflect the microscopic loss of airspace wall.

Influence of oral tramadol on the dynamic ventilatory response to carbon dioxide in healthy volunteers.

We tested the effect of tramadol on ventilatory control by quantifying its effect on the steady-state ventilatory carbon dioxide response and by locating its site of respiratory action within the ventilatory control system. We imposed square-wave changes in end-tidal carbon dioxide (approximately 1 kPa; end-tidal oxygen concentration kept constant at resting levels) in 10 healthy volunteers (six men, four women) before and after oral ingestion of 100 mg tramadol, and measured the ventilatory responses. Each hypercapnic response was separated into a fast, peripheral and a slow, central component. Two control and two tramadol carbon dioxide studies were performed in each subject. Tramadol reduced the total ventilatory carbon dioxide sensitivity by approximately 30% from 12.8 (6.1) [lower (25%) and upper (75%) quartiles 7.4 and 16.6 litre min(-1) kPa(-1)] to 9.1 (5.3) (5.3-14.1) litre min(-1) kPa(-1) (P<0.001). The fast and slow response gains were reduced by 23 (46) (3-54)% (P<0.05) and 30 (22) (15-54)% (P<0.01) respectively. The ratio of these carbon dioxide sensitivities and the apnoeic threshold were not significantly changed by tramadol. We suggest that tramadol affects the ventilatory control system by acting at the mu-opioid receptors in the respiratory integrating centres within the brainstem.

Influence of dose of domperidone on the acute ventilatory response to hypoxia in humans.

We have studied the ventilatory responses to acute isocapnic hypoxia (SpO2 78.8 (SD 1.4)% for 10 min) in 10 male volunteers given three different doses of oral domperidone: placebo, domperidone tablets 10 mg, 20 mg or 30 mg every 8 h for 48 h on separate days. Neither baseline ventilation nor the acute hypoxic ventilatory response was significantly different from placebo for any of the domperidone doses. However, hypoxic responses were either increased with increments of domperidone or subjects were not sensitive. We arbitrarily divided subjects into two groups according to their hypoxic response-plasma domperidone concentration relationship. Analysis of subjects (n = 5) who demonstrated at least a 2-litre min-1 increase in ventilation per 10 ng ml-1 increase in plasma domperidone concentration showed the greatest augmentation of hypoxic responses with the 20-mg dose (median 19.45 (range 13.37, 22.30) litre min-1) compared with placebo (median 8.21 (3.74, 9.47)) (P = 0.003). We were unable to predict which subjects would be sensitive to the effects of domperidone.

Pathophysiologic correlations in lymphoid interstitial pneumonia.

Effective alveolar volume, diffusing capacity for carbon monoxide (DCOsb), volume-corrected diffusing capacity (D/VA), static lung compliance (Cst), and lung distensibility were measured in 16 sheep seropositive for maedi-visna virus (MVV) immediately before they were killed. Lungs were inflation-fixed, and the left lung was randomly sampled for morphometric analysis. The total lung weight, total fixed lung volume, volume densities of tissue (Vvt) and air (Vva), and the alveolar surface density were measured and correlated with the physiologic measurements. The density of surface forces could not account for the variation in the distensibility of the lungs, indicating that tissue-related forces may be important in determining lung distensibility in lymphoid interstitial pneumonia (LIP) associated with MVV infection. Possible sources of tissue-related forces are the contractile tissue associated with lung parenchyma, airways, or vasculature. When DCOsb was corrected for volume, a strong negative correlation with Vvt was noted, indicating that factors distinct from lung-volume reduction are important in limiting gas exchange in LIP associated with MVV infection. More sheep demonstrated abnormal D/VA values than any other physiologic measurement, with reduced values being apparent even in sheep considered clinically normal and with little or no morphometric evidence of lung disease. Measurements of diffusing capacity are thus considered the most sensitive functional index of disease progression.