Anaesthetic subspecialties and sustainable healthcare: a narrative review.

The principles of environmentally sustainable healthcare as applied to anaesthesia and peri-operative care are well documented. Associated recommendations focus on generic principles that can be applied to all areas of practice. These include reducing the use of inhalational anaesthetic agents and carbon dioxide equivalent emissions of modern peri-operative care. However, four areas of practice have specific patient, surgical and anaesthetic factors that present barriers to the implementation of some of these principles, namely: neuroanaesthesia; obstetric; paediatric; and cardiac anaesthesia. This narrative review describes these factors and synthesises the available evidence to highlight areas of sustainable practice clinicians can address today, as well as posing several unanswered questions for the future. In neuroanaesthesia, improvements can be made by undertaking awake surgery, moving towards more reusables and embracing telemedicine in quaternary services. Obstetric anaesthesia continues to present questions regarding how services can move away from nitrous oxide use or limit its release to the environment. The focus for paediatric anaesthesia is addressing the barriers to total intravenous and regional anaesthesia. For cardiac anaesthesia, a significant emphasis is determining how to focus the substantial resources required on those who will benefit from cardiac interventions, rather than universal implementation. Whilst the landscape of evidence-based sustainable practice is evolving, there remains an urgent need for further original evidence in healthcare sustainability targeting these four clinical areas.

Variables associated with survival in patients with invasive bladder cancer with and without surgery.

We recorded the survival of 141 patients assessed for radical cystectomy, which included cardiopulmonary exercise testing. The median Kaplan-Meier survival estimates were: 1540 days for the whole cohort; 2200 days after cystectomy scheduled (n = 108); and 843 days without surgery. The mortality hazard remained double that expected for a matched general population, but survival was better in patients scheduled for surgery than those who were not: the mortality hazard ratio (95%CI) after cystectomy was 0.43 (0.26-0.73) the mortality hazard without surgery, p = 0.001. The mortality hazard ratios for the three-variable Bayesian Model Averaging survival model for all 141 patients were: referral for surgery (0.5); haemoglobin concentration (0.98); and efficiency of carbon dioxide output (1.05). Efficiency of carbon dioxide output was the single variable in the postoperative model (n = 108), mortality hazard 1.08 (per unit increase). The ratio of observed to expected peak oxygen consumption associated best with mortality in 33 patients not referred for surgery, hazard ratio 0.001. Our results can inform consultations with patients with invasive bladder cancer and suggest that interventions to increase fitness and haemoglobin may improve survival in patients who do and who do not undergo radical cystectomy.

The transport of leucine and aminocyclopentanecarboxylate across the intact, energy-depleted rat blood-brain barrier.

The transport across the blood-brain barrier of the large neutral amino acid leucine and the nonmetabolised aminocyclopentanecarboxylate (ACPC), of similar molecular size, was studied in the perfused, energy-depleted rat brain. It was found that when both leucine and ACPC were perfused for periods of up to 10 min their accumulation in the brain increased in a linear fashion. The ratio of perfusate radioactivity per milliliter and tissue radioactivity per gram (Rt/Rp) rose to above unity for both leucine and ACPC, indicating continued uptake against a concentration gradient of the radiolabel within the CNS. When the effect of increasing the concentration of the amino acid upon its influx into the brain was studied, it was found that under these conditions the kinetics of transport for both leucine and ACPC were of a similar order of magnitude to those reported previously in vivo. The values for the Michaelis constant for transport (Km), maximum rate of transport (Vmax), and the constant for the apparently linear, nonsaturable component (Kd) for leucine into the cerebrum were 84.5 +/- 29.0 microM, 45.5 +/- 1.5 nmole/min/g, and 2.62 +/- 0.15 microliters/min/g, respectively, and for ACPC 381 +/- 64 microM, 54.0 +/- 1.5 nmole/min/g and 0.35 +/- 0.10 microliter/min/g, respectively. Comparing this data with previously reported values it is suggested that the transport of leucine into the central nervous system from a perfusate or bolus where no other competing amino acids are present, is flow dependent. Furthermore, ACPC enters the brain almost entirely by a carrier-mediated process, with little or no nonsaturable influx despite a similar oil/water partition coefficient as leucine.

Hyperosmolar opening of the blood-brain barrier in the energy-depleted rat brain. Part 1. Permeability studies.

A simple saline perfusion system was used to investigate the effects of hyperosmolar solutions of arabinose and mannitol upon the permeability of the blood-brain barrier. The small, polar molecule [14C]mannitol and the larger, visual marker Evans blue were used as indicators of barrier integrity in the perfused energy-depleted brain. One-minute perfusion of hyperosmolar solutions consistently opened the barrier suggesting that the mechanism of osmotic barrier opening is independent of energy-producing metabolism. The accumulation of radiolabel in the brain was expressed as the ratio of tissue to perfusate radioactivity (Rt/Rp) and, for cerebrum, this increased from a control value of 0.0022 +/- 0.0007 (mean +/- SEM; n = 4) to a value of 0.0124 +/- 0.0008 (n = 4) following 0.9 M arabinose and to 0.0495 +/- 0.0072 (n = 4) following 1.8 M arabinose. There was a significant reduction of water content of hyperosmolar perfused brains. These findings support the hypothesis that osmotic barrier opening is the result of the passive shrinkage of endothelial cells and the surrounding tissue.

The influence of brain acetaldehyde on oxidative status, dopamine metabolism and visual discrimination task.

The toxic effect of acetaldehyde on brain oxidative capacity and dopamine metabolism has been investigated in rat brains after a single intraperitoneal injection of acetaldehyde (5 mmol/kg) and the results compared with those from chronically ethanol fed rats. Acetaldehyde was present in rat brain 120 hr after a single dose of acetaldehyde, confirming that it is able to cross the blood-brain barrier. Brain catalase increased significantly after acetaldehyde or chronic ethanol administration although there were no other significant changes in the total brain activity of superoxide dismutase, glutathione peroxidase or glutathione reductase. Dopamine turnover was increased in both experimental groups. The acute dose of acetaldehyde reduced the ability of the rats to relearn a computer visual discrimination task.

Transport of thiamin across the blood-brain barrier of the rat in the absence of aerobic metabolism.

By employing an anaerobic brain perfusion technique the dependency of thiamin transport across the blood-brain barrier upon high-energy phosphate production has been studied. Analysis of the data revealed essentially identical influx kinetics as those previously reported in vivo, the influx being considerably greater than that for the non-transported small molecule mannitol. These results provide for the first time direct evidence that, unlike at other cell surfaces, the influx of thiamin at the blood-brain barrier is independent of energy-yielding metabolism.

Maintenance of the integrity of the blood-brain barrier in the rat during an in situ saline-based perfusion.

Integrity of the blood-brain barrier to the small polar tracer mannitol was maintained for up to 30 min during an in situ perfusion of the brain with a saline-based solution containing the metabolic inhibitor 2,4-dinitrophenol. The patency of the capillary bed after perfusion was demonstrated by injecting a solution of Indian ink and gelatin, and ultrastructural examination showed the microvasculature to be well preserved. These findings suggest that the blood-brain barrier can be studied under conditions that are independent of normal cerebral function and metabolism.

The effects of murine muscular dystrophy on the metabolic and homeostatic functions of the skeletal muscles.

The maintenance of blood glucose is largely dependent on the ability of the skeletal muscles to regulate the supply of amino acids for hepatic glucose production. This study shows that when muscles are damaged in muscular dystrophy the mechanisms by which this control is exerted are impaired. In normally fed congenitally dystrophic mice the blood glucose level was raised and there were significant reductions of the levels of the principal gluconeogenic amino acids in the circulation. This was a result of abnormal exchange of amino acids between the dystrophic muscles and the blood, apparently due to the use of amino acids to a considerable extent in place of glucose for energy metabolism within the diseased muscles. When dystrophic animals were fasted, further reductions in the levels of amino acids in the circulation, to abnormally low values, were caused by an increased use of these amino acids by the liver for gluconeogenesis. Although the reason for the excessive metabolism of amino acids in dystrophic muscle is not clear, such changes will favour muscle protein breakdown, and a stress such as fasting will further aggravate the process of muscle wasting by depleting still further the pool of amino acids in the body.

Decrease in oligodendrocyte carbonic anhydrase activity preceding myelin degeneration in cuprizone induced demyelination.

Both immunohistochemical and biochemical evidence is presented to show for the first time that carbonic anhydrase II (CA II) activity falls in the brain of mice in cuprizone (bis(cyclohexanone)oxalyldihydrazone) induced demyelination well before demyelination develops. This fall began during the first week, whereas the first signs of myelin degeneration induced by cuprizone did not appear until 3 weeks and demyelination in the superior cerebellar peduncle in the mouse took 6-8 weeks to develop. The findings suggest that oligodendrocyte CA II activity is essential either for the survival of oligodendrocytes or for the maintenance of central myelin.

Relation between the increase in the diffusional permeability of the blood-central nervous system barrier and other changes during the development of experimental allergic encephalomyelitis in the Lewis rat.

The reduction in the effectiveness of the blood-brain and blood-spinal cord barriers, previously seen in rats at the height of the acute episode of experimental allergic encephalomyelitis, has now been measured at various stages in the development of the disease up to 60 days after inoculation with guinea pig spinal cord in complete Freund's adjuvants. The marker of extracellular space, radioactively labelled mannitol, only crosses the blood-central nervous system barriers very slowly by passive diffusion in normal rats. An abnormal penetration of this marker into the central nervous system began to develop during the second week after inoculation, appearing first in the lower spinal cord, where it also reaches the highest level during the acute phase of the attack. The leak begins before either the clinical signs become evident or cuffing is seen around blood vessels in stained sections. As the clinical signs are disappearing, from about 15 days onwards, the permeability of the barrier returns steadily to its normal low value, starting in the spinal cord, especially the caudal part. The timing of the reduction in the effectiveness of the blood-central nervous system barrier in relation to other clinical and histological changes suggests that it may play a part in the development of the lesion. The relation between the timing of these changes in EAE and that in the development of a new lesion in (exacerbation of) multiple sclerosis is discussed.

The exclusion of L-isoleucine or of L-leucine from the brain of the rat, caused by raised levels of L-valine in the circulation, and the manner in which this exclusion can be partially overcome.

The amino acids L-isoleucine, L-leucine and L-valine appear to compete for a shared transport carrier for entry into the brain of the living rat, since high concentrations of L-valine in the plasma reduced the influx both of L-isoleucine and of L-leucine into the brain to 10-15% of the normal. The exclusion of L-isoleucine or of L-leucine from the brain by a raised level of L-valine in the circulation can be partially overcome by simultaneously raising the concentration of L-isoleucine or of L-leucine in the circulation. These results indicate the important role played by a saturable shared carrier-mediated transport system in ensuring that an adequate supply of these amino acids reaches the brain from the circulation during life. The bearing of our findings on two inborn errors of amino acid metabolism, maple-syrup-urine disease and hypervalinaemia, is discussed.

Changes in the effectiveness of the blood-brain and blood-spinal cord barriers in experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) was induced In Lewis rats by the intradermal inoculation of an homogenate of guinea pig spinal cord in complete Freund's adjuvant. In these animals the effectiveness with which the capillary barrier excluded mannitol (a substance which normally only crosses this barrier very slowly) from the brain and spinal cord involvement were at their height, 14 days after the inoculation, the effectiveness of the barrier was reduced since the rate of diffusion of the mannitol out of the blood into the brain-stem and spinal cord was approximately doubled. Even as early as 7 days after inoculation, before any clinical signs had appeared, the rate of diffusion was significantly increased in the region of the lumbo-sacral cord. These changes roughly paralleled the histological changes seen in many of the small vessels. We believe that the changes are due to an increase in the permeability of the vessels to mannitol. The bearing of these findings on multiple sclerosis is discussed.

The vasculature of experimental brain tumours. Part 4. The quantification of vascular permeability.

In order to quantify changes in vessel permeability seen previously in experimental astrocytomas produced in rats by an intracerebral injection of cultured neoplastic glial cells, the flux of mannitol across the vascular endothelium from the blood into the normal brain or tumour tissue was measured using a specially devised technique by which a steady level of radioactively labelled mannitol can be achieved rapidly and maintained in the bloodstream. This is done by a continuous injection given at a rate which is adjusted by a predetermined programme so as to replace the tracer at the rate at which it has been found to leave the circulation in previous experiments. In separate experiments on both tumour-bearing and control rats steady levels of the tracer were maintained in the circulation for progressively longer times of up to 30 min. The kinetic parameters of the process gave estimates for the apparent transfer constant of mannitol across the vascular endothelium and of the size of the extravascular extracellular mannitol space in the tumours. The apparent transfer constant for the movement of mannitol across the blood-brain barrier was increased more than a hundred-fold in the region of the tumour compared to the values for the brain of control rats or that of tumour-bearing rats remote from the tumour site. The extracellular extravascular space within the tumour was estimated to be 22%, somewhat larger than accepted normal values.

Kinetics of tryptophan transport across the blood-brain barrier.

The transport of tryptophan across the blood-brain barrier in vivo has been analyzed kinetically to assess the influence upon it not only of the concentration of tryptophan in the blood plasma, but also of the inhibitory effect of fourteen other amino acids normally present in the circulation. The transport of tryptophan into the brain conforms to the equations of enzyme kinetics with competitive inhibition, provided appropriate modifications are made to take account of a non-saturable component (possibly passive diffusion) in the transport, and of the normal presence in the blood of other amino acids which act as competitive inhibitors. The inhibitor constant has been evaluated for each amino acid and in many cases it corresponds fairly closely with the Michaelis saturation constant for that amino acid, suggesting that tryptophan and these inhibitors share a common transport carrier. The implications of the kinetic analysis are considered for hormonal and metabolic disturbances which change the proportions of amino acids in the blood. The effect of an increase in competitive inhibition due to raised levels of amino acids is to make the tryptophan influx more directly dependent upon the level of tryptophan in the blood.

Changes in plasma amino acid patterns in chronic alcoholic patients during ethanol withdrawal syndrome: their clinical implications.

Changes or imbalances in plasma amino acid patterns during withdrawal from ethanol were recorded in six randomly selected male chronic alcoholic patients (age range 23-47 years). Duration of drinking ranged from 4-15 years and their average daily amount of ethanol intake was more than 100G. Plasma amino acids (taurine, threonine, serine, glutamate, glutamine, proline, glycine, alanine, cysteine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, histidine, tryptophan, ornithine, lysine and arginine) were estimated by autoanalyzer in all patients on admission before starting conventional detoxification therapy for ethanol withdrawal syndrome, and during therapy on day 3 and day 6. On admission, there was a statistically significant rise in the plasma levels of almost all aminoacids, particularly glutamate, glutamine, phenylalanine, proline, glycine, methionine, cysteine, lysine, tyrosine, valine, isoleucine, leucine, serine, threonine, alanine and arginine (in comparison to those of normal controls) in five out of six patients. During the following six days of treatment and total abstinence, the pattern of plasma aminoacid levels did not change significantly despite considerable clinical improvement. Plasma tryptophan levels were undetectable in all patients on admission, day 3 and also on day 6 except in one patient with lesser amount and shorter duration of drinking, the levels just returned to within normal range only on day 6. Plasma levels of histidine and taurine were found to be slightly lower than normal.