Cognitive decline in the elderly after surgery and anaesthesia: results from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort.

Concerns have been raised about the effects on cognition of anaesthesia for surgery, especially in elderly people. We recorded cognitive decline in a cohort of 394 people (198 women) with median (IQR) age at recruitment of 72.6 (66.6-77.8) years, of whom 109 had moderate or major surgery during a median (IQR) follow-up of 4.1 (2.0-7.6) years. Cognitive decline was more rapid in people who on recruitment were: older, p = 0.0003; male, p = 0.027; had worse cognition, p < 0.0001; or carried the ε4 allele of apoliprotein E (APOEε4), p = 0.008; and after an operation if cognitive impairment was already diagnosed, p = 0.0001. Cognitive decline appears to accelerate after surgery in elderly patients diagnosed with cognitive impairment, but not other elderly patients.

The first intravenous anaesthetic: how well was it managed and its potential realized?

Our speciality commonly traces its origin to a demonstration of the inhalation of ether by a patient undergoing surgery in Boston in 1846. Less well known is the demonstration of the i.v. injection of opium with alcohol into a dog in Oxford in 1656, leading to anaesthesia followed by full long-term recovery. After gaining i.v. access, a mixture of opium and alcohol was injected, resulting in a brief period of anaesthesia. After a period during which the dog was kept moving to assist recovery, a full recovery was made. Details from this momentous experiment allow us to compare the technique used with modern management. It is important to consider why there was a failure to translate the results into clinical practice and nearly 200 yr of potentially pain-free surgery. Possible factors include lack of equipment for i.v. access, lack of understanding of dose-response effects, and a climate of scientific discovery rather than clinical application. Given the current interest in total i.v. anaesthesia, it seems appropriate to identify its origins well before those of inhalation anaesthesia.

The obligatory role of the kidney in long-term arterial blood pressure control: extending Guyton's model of the circulation.

We describe a model for the essential role of the kidney in long-term blood pressure regulation. We begin with a simple hydraulic model for the circulation, with a constant circulating volume. We show, with the help of a modification of Guyton's classic diagram, that cardiac output and mean arterial pressure are functions of circulating volume, peripheral resistance, venous and arterial compliances, and the cardiac Starling curve. This approach models only acute changes in a 'closed' circulation--one where there is no intake or excretion of fluid. The model is then adapted to 'open' the circulation, include a role for the kidney, and represent more chronic changes. Arterial pressure is then a sole function of renal behaviour and daily sodium (and liquid) intake, and becomes independent of other cardiovascular variables. As well as generating specific hypotheses for further investigation, these models can be used for the purpose of education in cardiovascular control and the treatment of hypertension.

Can intravenous endothelin-1 be used to enhance hypoxic pulmonary vasoconstriction in healthy humans?

BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) helps match pulmonary perfusion to ventilation. The peptide endothelin-1 (ET-1) may be involved in the cellular mechanisms of this response. We hypothesized that increasing plasma ET-1 concentration during hypoxia would enhance HPV in humans and might represent a strategy for improving gas exchange during single-lung anaesthesia or respiratory disease. METHODS: Nine healthy volunteers were each exposed twice to a 7-h protocol consisting of 1 h breathing air, 4 h of eucapnic hypoxia (end-tidal Po(2), 50 mm Hg), and 2 h of eucapnic euoxia (end-tidal Po(2), 100 mm Hg). Volunteers received a 7-h i.v. infusion of ET-1 during one protocol (1.0-2.5 ng kg(-1) min(-1)) and normal saline during the other. At intervals of 30-60 min, cardiac output and the maximum tricuspid pressure gradient during systole (DeltaP(max), an index of HPV) were measured using Doppler echocardiography, systemic arterial pressure was measured using sphygmomanometry, and plasma samples were obtained to determine ET-1 concentration. RESULTS: During hypoxia, DeltaP(max) increased for around 2 h before reaching a plateau. Compared with saline, ET-1 had no effect on DeltaP(max), either at baseline or during hypoxia. ET-1 infusion slightly increased diastolic arterial pressure and reduced cardiac output, but had no specific effect on the change in these variables during hypoxia. During the final 1 h of hypoxia, plasma ET-1 concentration was 1.7 (0.4) pg ml(-1) [mean (sd)] in the saline protocol and 21.9 (12.2) pg ml(-1) in the ET-1 protocol. CONCLUSIONS: ET-1 infusion seems unlikely to represent a therapeutic strategy for enhancing HPV during acute (<4 h) hypoxia.

Human pulmonary vascular responses to hypoxia and hypercapnia.

The ability of alveolar gas composition to influence pulmonary vascular tone has been appreciated for over 50 years. In particular, it has been proposed that both O2 and CO2 could play a role in the matching of perfusion to ventilation within the lung, improving the overall efficiency of gas exchange. A wide variety of experimental approaches has been used to investigate pulmonary vascular effects of the respiratory gases in a range of mammalian species. In this article, we review experiments performed in healthy humans, identify particular difficulties in the interpretation of such experiments, and discuss possible approaches to future study.

Release by hypoxia of a soluble vasoconstrictor from rabbit small pulmonary arteries.

BACKGROUND: Soluble pulmonary vasoconstrictors released in response to hypoxia have been reported in pig and rat preparations, but not in rabbit preparations. METHODS: We used myography to evaluate the contribution of a soluble factor to constriction in rabbit small pulmonary arteries (external diameter 300-475 microm) exposed to 45 min hypoxia (PO(2)=9 mm Hg). RESULTS: Hypoxia produced gradually intensifying constriction. Return to euoxia (PO(2)=145 mm Hg) for 30 min relaxed only approximately 30% of the constriction, whereas elution of the myograph bath yielded full relaxation. Reapplication of the eluent gradually restored the constriction to its pre-elution level over a 30-min period. CONCLUSIONS: In this closed system, a soluble factor contributes substantially to hypoxic pulmonary vasoconstriction.

Effects of 8 h of isocapnic hypoxia with and without muscarinic blockade on ventilation and heart rate in humans.

This study examined the role of muscarinic parasympathetic mechanisms in generating the progressive increases in ventilation (V(E)) and heart rate previously reported with 8 h exposures to hypoxia. The sensitivities of V(E) (G(p)) and heart rate (G(HR)) to acute variations in hypoxia, and V(E) and heart rate during acute hyperoxia were assessed in 10 subjects before and after two 8 h exposures to isocapnic hypoxia (end-tidal P(O2) = 50 mmHg). The responses were measured during muscarinic blockade with glycopyrrolate (0.015 mg kg(-1)) and without glycopyrrolate, as a control. There were significant increases in G(p) (P < 0.01) and V(E) during hyperoxia (P < 0.01) following hypoxic exposure, but these were unaffected by glycopyrrolate. G(HR) increased significantly by 0.29 +/- 0.08 beats min(-1) %(-1) (mean +/- S.E.M.) following exposure to hypoxia under control conditions, but only non-significantly by 0.10 +/- 0.08 beats min(-1) %(-1) with glycopyrrolate. This difference was significant. Changes in heart rate during hyperoxia were slight and inconclusive. We conclude that muscarinic mechanisms play little role in the progressive ventilatory changes that occur over 8 h of hypoxia, but that they do mediate much of the progressive increase in heart rate. Experimental Physiology (2001) 86.4, 529-538.

Respiratory control in humans after 8 h of lowered arterial PO2, hemodilution, or carboxyhemoglobinemia.

In humans exposed to 8 h of isocapnic hypoxia, there is a progressive increase in ventilation that is associated with an increase in the ventilatory sensitivity to acute hypoxia. To determine the relative roles of lowered arterial PO2 and oxygen content in generating these changes, the acute hypoxic ventilatory response was determined in 11 subjects after four 8-h exposures: 1) protocol IH (isocapnic hypoxia), in which end-tidal PO2 was held at 55 Torr and end-tidal PCO2 was maintained at the preexposure value; 2) protocol PB (phlebotomy), in which 500 ml of venous blood were withdrawn; 3) protocol CO, in which carboxyhemoglobin was maintained at 10% by controlled carbon monoxide inhalation; and 4) protocol C as a control. Both hypoxic sensitivity and ventilation in the absence of hypoxia increased significantly after protocol IH (P < 0.001 and P < 0.005, respectively, ANOVA) but not after the other three protocols. This indicates that it is the reduction in arterial PO2 that is primarily important in generating the increase in the acute hypoxic ventilatory response in prolonged hypoxia. The associated reduction in arterial oxygen content is unlikely to play an important role.

Inhibition of active sodium absorption leads to a net liquid secretion into in vivo rabbit lung at two levels of alveolar hypoxia.

Active sodium transport across alveolar epithelium is known to contribute to the resolution of pulmonary oedema. We have attempted to assess whether sodium transport is essential to prevent liquid accumulation in healthy pulmonary alveoli exposed to mild hypoxia, and whether its contribution to liquid absorption differs between mild and moderate levels of hypoxia. In twenty-four anaesthetized adult rabbits we used direct bronchial cannulation to measure liquid movement from the liquid-filled left lung over 3.5 h. Half of the rabbits were studied at a level of mixed venous (and alveolar) oxygen partial pressure, PVO2, of 6.5 kPa and half at 4.5 kPa. PVO2 was altered by changing the inspired oxygen fraction in the ventilated right lung. Alveolar hydrostatic pressure was 0.3 kPa. In each group of 12, six animals with inhibitors of sodium transport in the isosmotic instillate were compared with six controls. We have shown an alveolar liquid secretion (approximately 0.6 microl min(-1) (kg body weight)(-1)) in the presence of inhibitors of active transport and an absorption (approximately 4 microl min(-1) (kg body weight)(-1)) in controls. Changing PVO2 had no influence on these movements. We conclude that, in this model of pulmonary oedema, active sodium transport appears to be essential for prevention of alveolar liquid accumulation via secretion. Furthermore, the contribution of active sodium transport to liquid absorption remains constant at oxygen tensions between 4.5 and 6.5 kPa.

Inhibition of nitric oxide synthesis augments pulmonary oedema in isolated perfused rabbit lung.

The role of nitric oxide (NO) in precipitating pulmonary oedema in acute lung injury remains unclear. We have investigated the mechanism of involvement of NO in the maintenance of liquid balance in the isolated rabbit lung. Thirty pairs of lungs were perfused with colloid for up to 6 h, during which pulmonary vascular resistance (PVR) and capillary pressure (PCP) were measured frequently, and time to gain 5 g in weight (t5) was recorded. Four protocols with different perfusate additives were studied: (i) none (control, n = 11); (ii) 10 mmol NG-nitro-L-arginine methyl ester (L-NAME) (n = 6); (iii) 10 mmol L-NAME with 100 mumol lodoxamide, an inhibitor of mast cell degranulation (n = 7); (iv) 10 mmol L-NAME with 10 mumol 8-bromo-3',5'-cyclic guanosine monophosphate (8Br-cGMP), an analogue of cGMP that may reduce vascular permeability by relaxing contractile elements in endothelial cells (n = 6). Neither PVR nor PCP differed between protocols. L-NAME markedly reduced t5 from 248 (27) min (mean (SEM)) in protocol (i) to 144 (5) min in protocol (ii) (P < 0.05). Both lodoxamide (t5 = 178 (7) min) and 8Br-cGMP (t5 = 204 (10) min) substantially corrected the effect of L-NAME (P < 0.005). Results suggest that maintenance of a low permeability by NO may involve mast cell stabilization and endothelial cell relaxation.

Cardiovascular effects of 8 h of isocapnic hypoxia with and without beta-blockade in humans.

This study seeks to confirm the progressive changes in cardiac output and heart rate previously reported with 8 h exposures to constant hypoxia, and to examine the role of sympathetic mechanisms in generating these changes. Responses of ten subjects to four 8 h protocols were compared: (1) air breathing with placebo; (2) isocapnic hypoxia (end-tidal PO2 = 50 mm Hg) with placebo; (3) isocapnic hypoxia with beta-blockade; and (4) air breathing with beta -blockade. Regular measurements of heart rate and cardiac output (using ultrasonography and N2O rebreathing techniques) were made with subjects seated in the upright position. The sensitivity of heart rate to rapid variations in hypoxia (GHR) and heart rate in the absence of hypoxia were measured at times 0, 4 and 8 h. No significant progressive effect of hypoxia on cardiac output was detected. There was a gradual rise in heart rate with hypoxia of 11+/-2 beats min(-1) in the placebo protocol and of 10+/-2 beats min(-1) in the beta-blockade protocol over 8 h, compared to the air breathing protocols. The rise in heart rate was progressive (P<0.001) and accompanied by progressive increases in both GHR (P<0.001) and heart rate measured in the absence of hypoxia (P<0.05). No significant effect of beta-blockade was detected on any of these progressive changes. We conclude that sympathetic mechanisms that act via beta -receptors play little role in the progressive changes in heart rate observed over 8 h of moderate hypoxia.

Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans.

In cell culture, hypoxia stabilizes a transcriptional complex called hypoxia-inducible factor-1 (HIF-1) that increases erythropoietin (Epo) formation. One hallmark of HIF-1 responses is that they can be induced by iron chelation. The first aim of this study was to examine whether an infusion of desferrioxamine (DFO) increased serum Epo in humans. If so, this might provide a paradigm for identifying other HIF-1 responses in humans. Consequently a second aim was to determine whether an infusion of DFO would mimic prolonged hypoxia and increase the acute hypoxic ventilatory response (AHVR). Sixteen volunteers undertook two protocols: 1) continuous infusion of DFO over 8 h and 2) control. Epo and AHVR were measured at fixed times during and after the protocols. The results show that 1) compared with control, Epo increased in most subjects at 8 h [52.8 +/- 57.7 vs. 6.9 +/- 2.5 (SD) mIU/ml, for DFO = 4 g/70 kg body wt, P < 0.05] and 12 h (63.7 +/- 76.3 vs. 7.3 +/- 2.5 mIU/ml, P < 0.001) after the start of DFO administration and 2) DFO had no significant effect on AHVR. We conclude that, whereas infusions of DFO mimic hypoxia by increasing Epo, they do not mimic prolonged hypoxia by augmenting AHVR.

Effects of somatostatin on the control of breathing in humans.

1. Somatostatin depresses the ventilatory response to hypoxia (AHVR). This study sought to determine whether somatostatin also reduced the peripheral chemoreflex sensitivity to hypercapnia, and if so, whether this was related to the reduction in AHVR. 2. Nine subjects completed the study. AHVR and the ventilatory responses to hypercapnia under both hyperoxic and hypoxic conditions were assessed both without and with an infusion of somatostatin (0.5 BsBs5mgBs5 h-1). Peripheral (fast) and central (slow) responses to hypercapnia were distingushed by use of a multi-frequency binary sequence input in end-tidal PCO2 (PET,CO2) that included 13 steps into and out of hypercapnia. 3. The acute ventilatory response to a reduction in end-tidal PO2 (PET,O2) from 100 to 50 Torr (at a PET, CO2 of +1.5-2.0 Torr above normal) was reduced from (mean +/- s.e.m. ) 16.4 +/- 3.3 to 9.5 +/- 3.2 l min-1 (P < 0.005, Student's t test) by somatostatin. The magnitude of the ensuing hypoxic ventilatory decline was unaltered (8.8 +/- 2.7 l min-1 in control vs. 8.0 +/- 2. 9 l min-1 with somatostatin). 4. The peripheral chemoreflex sensitivity to CO2 in hypoxia was reduced from 2.42 +/- 0.36 to 1.18 +/- 0.20 l min-1 Torr-1 (P < 0.005) with somatostatin. The reduction under hyperoxic conditions from 0.75 +/- 0.34 to 0.49 +/- 0.09 l min-1 Torr-1 did not reach significance. Central chemoreflex sensitivity to CO2 was unchanged. Changes in peripheral chemoreflex sensitivity to CO2 in hypoxia correlated with changes in AHVR. 5. We conclude that peripheral chemoreflex sensitivity to CO2 is reduced by somatostatin, probably via the same mechanism as that by which somatostatin exerts its effects on AHVR.

Ventilatory effects of 8 h of isocapnic hypoxia with and without beta-blockade in humans.

This study investigated whether changing sympathetic activity, acting via beta-receptors, might induce the progressive ventilatory changes observed in response to prolonged hypoxia. The responses of 10 human subjects to four 8-h protocols were compared: 1) isocapnic hypoxia (end-tidal PO2 = 50 Torr) plus 80-mg doses of oral propranolol; 2) isocapnic hypoxia, as in protocol 1, with oral placebo; 3) air breathing with propranolol; and 4) air breathing with placebo. Exposures were conducted in a chamber designed to maintain end-tidal gases constant by computer control. Ventilation (VE) was measured at regular intervals throughout. Additionally, the subjects' ventilatory hypoxic sensitivity and their residual VE during hyperoxia (5 min) were assessed at 0, 4, and 8 h by using a dynamic end-tidal forcing technique. beta-Blockade did not significantly alter either the rise in VE seen during 8 h of isocapnic hypoxia or the changes observed in the acute hypoxic ventilatory response and residual VE in hyperoxia over that period. The results do not provide evidence that changes in sympathetic activity acting via beta-receptors play a role in the mediation of ventilatory changes observed during 8 h of isocapnic hypoxia.

Effects of dopamine and domperidone on ventilatory sensitivity to hypoxia after 8 h of isocapnic hypoxia.

Acclimatization to altitude involves an increase in the acute hypoxic ventilatory response (AHVR). Because low-dose dopamine decreases AHVR and domperidone increases AHVR, the increase in AHVR at altitude may be generated by a decrease in peripheral dopaminergic activity. The AHVR of nine subjects was determined with and without a prior period of 8 h of isocapnic hypoxia under each of three pharmacological conditions: 1) control, with no drug administered; 2) dopamine (3 microg. min-1. kg-1); and 3) domperidone (Motilin, 40 mg). AHVR increased after hypoxia (P

Effects of subanaesthetic sevoflurane on ventilation. 1: Response to acute and sustained hypercapnia in humans.

We have determined the influence of 0.1 minimum alveolar concentration (MAC) of sevoflurane on ventilation, the acute ventilatory response to a step change in end-tidal carbon dioxide and the ventilatory response to sustained hypercapnia in 10 healthy adult volunteers. Subjects undertook a preliminary 10-min period of breathing air without sevoflurane to determine their normal ventilation and natural end-tidal PCO2. This 10-min period was repeated while breathing 0.1 MAC of sevoflurane. Subjects then undertook two procedures: end-tidal PO2 was maintained at 13.3 kPa and end-tidal PCO2 at 1.3 kPa above the subject's normal value for 30 min of data collection, first with and then without 0.1 MAC of sevoflurane. A dynamic end-tidal forcing system was used to generate these gas profiles. Sevoflurane did not significantly change ventilation: 10.1 (SEM 1.0) litre min-1 without sevoflurane, 9.6 (0.9) litre min-1 with sevoflurane. The response to acute hypercapnia was also unchanged: mean carbon dioxide response slopes were 20.2 (2.7) litre min-1 kPa-1 without sevoflurane and 18.8 (2.7) litre min-1 kPa-1 with sevoflurane. Sustained hypercapnia caused a significant gradual increase in ventilation and tidal volume over time and significant gradual reduction in inspiratory and expiratory times. Sevoflurane did not affect these trends during sustained hypercapnia. These results suggest that 0.1 MAC of sevoflurane does not significantly affect the acute ventilatory response to hypercapnia and does not modify the progressive changes in ventilation and pattern of breathing that occur with sustained hypercapnia.

Effects of subanaesthetic sevoflurane on ventilation. 2: Response to acute and sustained hypoxia in humans.

We have determined the influence of 0.1 minimum alveolar concentration (MAC) of sevoflurane on the acute ventilatory response to hypoxia (AHVR), hypoxic ventilatory decline (HVD) and the magnitude of the rapid decline in ventilation on relief of sustained hypoxia (the off-response) in eight healthy adult volunteers. The following design was used with and without 0.1 MAC of sevoflurane: end-tidal PO2 was maintained at 13.3 kPa for 5 min, at 7.9 kPa for 20 min and at 13.3 kPa for 5 min. End-tidal PCO2 was held constant throughout at 1.3 kPa above the subject's normal value. A dynamic end-tidal forcing system was used to generate these gas changes. Sevoflurane reduced AHVR from 14.5 (SEM 1.2) to 11.6 (1.6) litre min-1, and the off-response at cessation of hypoxia from 7.1 (1.1) to 6.3 (1.4) litre min-1. The magnitude of HVD was slightly increased by sevoflurane from 8.2 (1.1) to 10.6 (2.8) litre min-1. None of these changes was significant (ANOVA). These results suggest that 0.1 MAC of sevoflurane had very little effect on the AHVR, and that it did not markedly alter the processes underlying HVD during sustained hypoxia.