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.

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.

Is there a familial association between obstructive sleep apnoea/hypopnoea and the sudden infant death syndrome?

BACKGROUND: One postulated cause of the sudden infant death syndrome (SIDS) is upper airway obstruction during sleep. Several studies have suggested that SIDS may be more common in families with obstructive sleep apnoea/hypopnoea syndrome (OSAHS), but were limited by uncertainty as to whether the deaths were due to SIDS. We have tested the hypothesis that parents of true SIDS cases have an increased frequency of apnoeas and hypopnoeas during sleep. METHODS: The parents of 269 rigorously determined SIDS cases were invited for single night polysomnography and daytime ventilatory control measurement. RESULTS: Parents of 198 cases were identified but 152 did not respond or declined. Fifty five parents of 34 cases were studied and matched for age, height, and weight to 55 subjects from general practice registers. There was no difference in breathing during sleep between the parents of SIDS cases (median (IQR) 5.9 (3.2, 10.7) apnoeas+hypopnoeas/h) and controls (6.7 (4.0, 12.2) apnoeas+hypopnoeas/h; p = 0.47), but the SIDS parents had lower minimum nocturnal oxygen saturation (median (IQR) 92 (89, 93)%) than controls (92 (90, 94)%; p = 0.048). There were no major differences in control of breathing when awake between SIDS parents and controls. CONCLUSIONS: These results provide no evidence to support an association between SIDS and OSAHS. However, the minor impairment of oxygenation during sleep in SIDS parents requires further study.

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 tramadol on the ventilatory response to hypoxia in humans.

We studied the effect of tramadol on the ventilatory response to 7 min acute isocapnic hypoxia (SpO2 85.1 (SD 0.4)%) during steady mild hypercapnia (PE'CO2 0.7 kPa above normoxic baseline) in 14 healthy volunteers (seven male). The acute hypoxic response was measured before and 1 h after oral placebo or tramadol (100 mg). After tramadol, ventilation during mild hypercapnia (mean 11.28 litres min-1) was significantly less (P < 0.05) than during placebo baseline (13.93 litres min-1), tramadol baseline (14.63 litres min-1), or after placebo (14.95 litres min-1), confirming that tramadol has a small depressive effect on the hypercapnic ventilatory response. There was no significant difference in the hypoxic ventilation/SpO2 response (1 min-1 %-1) measured during the placebo baseline (0.99), placebo (1.18), tramadol baseline (0.78) or tramadol (0.68) runs. These data suggest that tramadol does not depress the hypoxic ventilatory response.

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.

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.

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.

Does sleep enhance the effect of subanesthetic isoflurane on hypoxic ventilation?

After surgery, patients may receive little audiovisual stimulation and may sleep. Lack of audiovisual stimulation enhances the suppression of the hypoxic ventilatory response (HVR) by 0.1 minimum alveolar anesthetic concentration (MAC) isoflurane. Sleep also reduces the HVR and may thus increase the risk of hypoxia in patients at this time. We therefore measured the ventilatory response in volunteers to a sustained step hypoxic stimulus (mean arterial oxygen saturation [SaO2] 80% [SEM 0.3] for 20 min) in the presence of 0.1 MAC isoflurane, with subjects in the awake and asleep states. The behavioral states were studied in random order in nine male subjects. The combination of isoflurane and sleep significantly reduced (P < 0.05) normoxic ventilation (6.71 [0.39] vs 8.24 [0.29] L/min) and increased end-tidal PCO2 (PETCO2) (43.1 [0.5] vs 40.4 [0.8] mm Hg) compared with the awake state. However, ventilation was similar in the asleep and awake states during early (15.10 [1.35] vs 15.50 [1.61] L/min) and late (10.45 [0.97] vs 11.03 [0.99] L/min) hypoxia in the presence of isoflurane. Thus sleep did not reduce ventilation during hypoxia in the presence of isoflurane sedation. The increase in PETCO2 during sleep may have offset suppression of the HVR.

Interaction of the effects of domperidone and sub-anaesthetic concentrations of isoflurane on the immediate and sustained hypoxic ventilatory response in humans.

Twenty normal male subjects with brisk hypoxic ventilatory responses were recruited and ventilatory responses to sustained isocapnic hypoxia (SaO2 80.4 (SD 1.3)% for 20 min) were studied on separate days under four conditions: hypoxia alone, with or without domperidone, and 0.1 MAC of end-tidal isoflurane, with or without domperidone. Ventilatory variables were subjected to analysis of variance with estimation of the effects of isoflurane and domperidone, and their interaction. Isoflurane reduced the initial increase in ventilation significantly by 3.12 (95% confidence limits 1.69, 4.55) litre min-1 (P < 0.05) and domperidone increased the initial increase in ventilation by 1.78 (0.35, 3.21) litre min-1 (P < 0.05). Neither isoflurane nor domperidone affected the subsequent ventilatory decline. No interaction was found between these agents. These results confirm that 0.1 MAC of isoflurane suppressed the initial hypoxic ventilatory response but not the subsequent ventilatory decline when hypoxia was sustained. Domperidone offset the suppressive effect of isoflurane on the hypoxic ventilatory response but no interaction was detected.

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.

Exponential analysis of the pressure-volume characteristics of ovine lungs.

Static pressure-volume curves were generated from data obtained from 18 normal anaesthetized adult sheep. Lung volumes were determined by helium dilution. An exponential curve of the form V = Vmax - Ae-KP was fitted to the pressure-volume data from each sheep where P is the static recoil pressure, Vmax represents the volume asymptote, A is the difference between Vmax and the intercept on the volume axis and K defines the slope and hence the shape of the P-V curve. Quality of fit of the data was assessed visually, by means of a sign test and a runs test and by the coefficient of determination (r2). Exponential equations were found to adequately describe the shape of the pressure-volume curve in sheep. The exponent K was not correlated with effective alveolar volume (VAeff) (rs = 0.183; P > 0.05). Static lung compliance was determined over a volume range from the end-expiratory level (VEEL) to VEEL plus 400 ml. Measurements of static lung compliance were significantly correlated with measurements of effective alveolar volume (VAeff) (rs = 0.505; P < 0.025). In the ovine, the exponent K, an index of distensibility, is independent of lung volume and offers a means of assessing lung distensibility in this species.

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.

Modelling the dynamic ventilatory response to hypoxia in normal subjects.

We have developed a mathematical model to describe the dynamic ventilatory response to hypoxia. The ventilatory response to both transient (two to three breaths nitrogen) and 3 min step change hypoxic stimuli were measured in ten normal subjects during moderate exercise (oxygen consumption 0.96 +/- 0.08 1 min-1). The simplest model relating ventilation to ear oxygen saturation which adequately described the responses in all subjects consisted of two linear differential equations in parallel; both using the fall in oxygen saturation as input, and with the outputs summed to give the rise in ventilation. One equation had a fast time constant (< 3 sec), and the other a slow time constant. Non-linear terms included were (i) a "saturating" effect, similar to that described by the Michaelis-Menten equation, reducing the gain of the equation with the slow time constant as oxygen saturation falls, and (ii) "inhibition" or "potentiation" of the gain of the equation with a slow time constant as the output of the fast time constant equation increased. Repeated measurements in four subjects showed intra- and inter-subject variability for all parameters, with significant between-subject variability for the gain of the fast time constant equation. The final model structure is similar to that describing the peripheral chemoreceptor-mediated hypoxic ventilatory response in anaesthetized cats.

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.

Effect of posture and breathing route on genioglossal electromyogram activity in normal subjects and in patients with the sleep apnea/hypopnea syndrome.

Patients with the sleep apnea/hypopnea syndrome (SAHS) often have more apneas supine that sitting. We have shown radiologically that although the retropalatal airway narrows on lying down, the retroglossal airway widens. We have thus investigated the effect of posture on genioglossal EMG activity in 10 normal subjects and 10 patients with SAHS (58 +/- 29 SD apneas + hypopneas/h) using peroral intramuscular EMG electrodes. Data were analyzed by three-way analysis of variance, with diagnosis, posture, and route as factors. Peak inspiratory and tonic expiratory genioglossal EMG were both than sitting, with no significant difference between normal subjects and SAHS higher (p < 0.001) supine patients, although there was a trend (p < 0.09) toward the supine posture having a greater effect on peak inspiratory EMG in the SAHS patients. There was no significant effect of breathing route on either peak inspiratory (p > 0.9) or tonic expiratory (p > 0.8) genioglossal EMG, but there were significant differences between the groups (p < 0.01), the SAHS patients having higher and the normal subjects lower EMG tone with nasal in comparison with oral breathing on both inspiration and expiration. This study therefore shows that both body posture and breathing route are important determinants of genioglossal EMG tone.

Relation between distal airspace size, bronchiolar attachments, and lung function.

BACKGROUND--Smoking related fixed airway obstruction may be due to airway scarring and narrowing or decreased support due to loss of adjacent alveolar walls. In this study of resected specimens, preoperative pulmonary function was compared with results of a morphometric study of lung structure. METHODS--Morphometric measurements were made on 42 inflation fixed lung specimens as follows: airspace wall surface area per unit volume (AWUV) was measured on at least 25 l mm2 histological fields from each specimen, expressed as a mean, and the mean of the lowest five measurements for each case (LF5). Minimum diameter, maximum diameter, diameter ratio (ellipticality), lumen area, and lumen circumference were measured on at least 16 non-respiratory bronchioles from each lung. Peribronchiolar alveolar support was measured as mean interalveolar attachment distance (IAAD). Measurements of pulmonary function included forced expiratory volume in one second (FEV1) (absolute and % predicted values; n = 42), slope of phase III (single breath nitrogen test; n = 28), closing volume (expressed as a percentage of vital capacity (CV/VC%); n = 28). RESULTS--Bronchiolar size was not independently related to the tests of lung function used. Percentage predicted FEV1 was related to mean IAAD, ellipticality, and mean AWUV. CV/VC% showed significant relation with ellipticality, mean AWUV, and LF5 AWUV. Slope of phase III increased with increasing IAAD. Significant correlations were found between ellipticality and AWUV (mean and LF5), and between ellipticality and IAAD. Both IAAD and ellipticality were significantly increased in patients with abnormally low FEV1. CONCLUSION--Destruction of airspace walls, particularly those attached to the peripheral bronchioles, is more influential in determining airflow limitation than bronchiolar size.

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.

Parenchymal emphysema measured by CT lung density correlates with lung function in patients with bullous disease.

In subjects with chronic obstructive pulmonary disease (COPD) computed tomographic (CT) lung density correlates with direct pathological measurements of the size of the distal airspaces, as well as with measurements of airflow limitation and impairment of the diffusing capacity. Thus, CT lung density can be used to quantify emphysema in life. We wanted to assess the use of CT scanning to detect and measure the extent of bullous lung, and to quantify the severity of emphysema in the non-bullous areas of the lungs. In patients with bullous emphysema (21 males and 2 females; aged 31-69 yrs; forced expiratory volume in one second (FEV1) 14-84% predicted; volume corrected diffusing capacity of the lungs for carbon monoxide (DLCO/VA) 17-114% predicted). CT lung density was measured in electromagnetic imaging (EMI) units. The extent of bullous emphysema correlated poorly with all respiratory function measurements. In contrast, the severity of emphysema in the non-bullous parts of the lungs, expressed as either the mean EMI number, or the EMI number of the lowest 5th percentile of the CT lung density histogram, correlated well with measurements of airflow limitation and diffusing capacity. Our findings, thus, suggest that in patients with bullae the major determinant of respiratory function is the severity of the emphysema in non-bullous lung, and that the extent of the bullae has less functional importance.(ABSTRACT TRUNCATED AT 250 WORDS)

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)