Role of L-type calcium channels in altered microvascular responses to propofol in hypertension.

BACKGROUND: Propofol acts as an L-type calcium channel (LTCC) antagonist to decrease peripheral resistance and initiate hypotension. This study investigated LTCC sensitivity/expression in hypertension and the role of LTCCs in exaggerated hypotension to propofol in this situation. METHODS: Age-matched 12- to 15-week-old normotensive rats [male Wistar Kyoto (WKY)] and spontaneously hypertensive rats (SHR) were used. Propofol (10 mg kg(-1), 10-50 mg kg(-1) h(-1) i.v.) was administered and the mesenteric microcirculation (<70 µm) observed with fluorescent in vivo microscopy using fluorescein isothiocyanate-conjugated bovine serum albumin (100 mg kg(-1) i.v.). Western blotting was used to measure tissue expression of the α(1C) LTCC subtype. Pressure myography was used to assess isolated mesenteric arterioles (<350 µm) in response to BAYK8644 (0.1 nM-1 µM), a specific LTCC channel agonist. RESULTS: Propofol dilated isolated arterioles {336.6 µM [mean (sd) change 16.2 (5.8)%]}. However, constriction to BAYK8644 was reduced at this concentration of propofol [EC(50)=8.3 (0.1) log mol(-1)] compared with controls [7.4 (0.1) log mol(-1), P<0.05], suggesting that propofol inhibited LTCCs. The sensitivity of LTCCs increased during hypertension, as in vivo there was a greater increase in mean arterial pressure (MAP) to BAYK8644 [10 µg kg(-1), WKY: 59.5 (9.3)%; SHR: 97.7 (6.3)%, P<0.05] with exaggerated constriction of arterioles [10 µg kg(-1), WKY: 9.1 (2.5)%; SHR: 19.1 (2.6)%, P<0.05]. Propofol also decreased MAP in SHR over time (P<0.05), but remained unchanged in WKY. Using western blotting, expression of α(1C) was greater in SHR compared with WKY (P<0.05). CONCLUSIONS: Propofol acts via LTCC channels, with increased channel expression and sensitivity in genetically hypertensive rats. We suggest that increased sensitivity and expression of LTCCs may be a mechanism for exaggerated hypertension during propofol anaesthesia.

Beneficial microvascular and anti-inflammatory effects of pravastatin during sepsis involve nitric oxide synthase III.

BACKGROUND: Sepsis induces microvascular inflammation and production of the vasodilator nitric oxide (NO) via endothelial and inducible nitric oxide synthase (eNOS or NOS III and iNOS or NOS II). Statins are cholesterol-lowering drugs; however, they also attenuate inflammation. This study aimed to determine whether pravastatin protected against sepsis-induced hypotension, loss of vascular tone, and microvascular inflammation via NOS pathways. METHODS: Male Wistar rats (n=18) were anaesthetized and the mesentery prepared for fluorescent intravital microscopy. Animals received either lipopolysaccharide (LPS; n=6); LPS+pravastatin (18 and 3 h before LPS; n=6), or saline as a control, for 4 h. RESULTS: Mean arterial pressure decreased in LPS-treated animals (P<0.05), but not in those also receiving pravastatin. Acetylcholine-induced relaxation of venules was abolished by LPS but improved by pravastatin. Pravastatin also reduced the increase in nitrite concentration and macromolecular leak from venules induced by LPS (P<0.05). The increased leucocyte adhesion seen in LPS-treated rats was also reduced in those also treated with pravastatin. Immunohistochemical analysis showed that pravastatin increased endothelial cell expression of NOS III during sepsis, but had no effect on LPS-induced up-regulation of NOS II. CONCLUSIONS: Pravastatin improved NOS III-mediated vessel relaxation and exerted anti-inflammatory effects within the microcirculation after LPS administration in rats. Pravastatin therefore appears to have beneficial effects during sepsis, as a result of increased microvascular expression and function of NOS III.

Statins for all: the new premed?

The use of statins is widespread and many patients presenting for surgery are regularly taking them. There is evidence that statins have beneficial effects beyond those of lipid lowering, including reducing the perioperative risk of cardiac complications and sepsis. This review addresses the cellular mechanisms by which statins may produce these effects. Statins appear to have actions on vascular nitric oxide through the balance of inducible and endothelial nitric oxide synthase. The clinical evidence for these benefits is also briefly reviewed with the objective of clarifying the current status of statin use in the perioperative period. There is reasonably strong evidence that patients already taking statins should continue on them perioperatively. However, the evidence for the prophylactic use of statins perioperatively is weak and lacks prospective controlled studies.

Vaccine-modified NF-kB and GR signaling in cervicovaginal epithelium correlates with protection.

Cervicovaginal epithelium plays a critical role in determining the outcome of virus transmission in the female reproductive tract (FRT) by initiating or suppressing transmission-facilitating mucosal immune responses in naïve and SIVmac239Δnef-vaccinated animals, respectively. In this study, we examined the very early responses of cervical epithelium within 24 h after vaginal exposure to SIV in naive and SIVmac239Δnef-vaccinated rhesus macaques. Using both ex vivo and in vivo experimental systems, we found that vaginal exposure to SIV rapidly induces a broad spectrum of pro-inflammatory responses in the epithelium associated with a reciprocal regulation of NF-kB and glucocorticoid receptor (GR) signaling pathways. Conversely, maintenance of high-level GR expression and suppression of NF-kB expression in the epithelium were associated with an immunologically quiescent state in the FRT mucosa and protection against vaginal challenge in SIVmac239Δnef-vaccinated animals. We show that the immunologically quiescent state is induced by FCGR2B-immune complexes interactions that modify the reciprocal regulation of NF-kB and GR signaling pathways. Our results suggest that targeting the balance of NF-kB and GR signaling in early cervicovaginal epithelium responses could moderate mucosal inflammation and target cell availability after vaginal infection, thereby providing a complementary approach to current prevention strategies.

Enprostil, in contrast to cimetidine, does not inhibit propranolol metabolism.

Enprostil, an orally active prostaglandin E2 analog, is undergoing clinical trials in the treatment of peptic ulcer disease. Because results of animal studies suggested that prostaglandins might affect both hepatic drug metabolizing ability and hepatic blood flow, the effects of enprostil on drug elimination were studied and compared with those of the standard antiulcer drug cimetidine in a double-blind, randomized, crossover study of nine normal subjects. Cimetidine reduced the oral clearance of propranolol by 50%, consistent with the inhibition of drug metabolism reported in previous studies. On the other hand, enprostil had no effect on propranolol elimination. Neither drug altered liver blood flow as assessed either by the clearance of indocyanine green or by the technique of dual route of administration of propranolol. Thus in contrast to cimetidine, enprostil had no effect on hepatic drug metabolism.

Ultra-short-acting beta-blockade: a comparison with conventional beta-blockade.

Esmolol is a beta 1-selective adrenoceptor blocker that is rapidly metabolized by blood and liver esterases. The beta-receptor and hemodynamic effects of esmolol were determined in a group of 12 healthy men and were compared with those induced by both oral and intravenous propranolol. Esmolol was rapidly effective in inducing at least 90% of steady-state beta-blockade within 5 minutes of either initiating or changing the esmolol infusion rate. More importantly, when esmolol infusion was discontinued the beta-blockade had totally disappeared by 18 minutes after esmolol, 300 micrograms/kg/min, and had been reduced by 50% after 750 micrograms/kg/min. In contrast, 30 minutes after discontinuation of a propranolol infusion, there was no change in the level of beta-blockade. Propranolol was much more potent at blocking isoproterenol-induced tachycardia (dose ratio 33.5 +/- 2.5) than was even the highest dose (750 micrograms/kg/min) of esmolol (dose ratio 13.1 +/- 1.0). The same dose of intravenous propranolol was approximately equipotent to oral propranolol, 40 mg every 8 hours (dose ratio 33.5 +/- 2.5 and 34.5 +/- 3.6, respectively). In contrast, propranolol, 40 mg every 8 hours, and esmolol, 300 micrograms/kg/min, were equipotent in antagonizing exercise-induced tachycardia (40.1% +/- 2.3% and 42.7% +/- 3.2%, respectively). Esmolol had striking hypotensive effects. Systolic blood pressure fell by 20 mm Hg during esmolol infusions of 750 micrograms/kg/min. Esmolol appears to be a potent beta 1-selective adrenoceptor antagonist with a particularly strong hypotensive effect. It is likely to be very useful in the treatment of hemodynamically unstable patients and may be useful in the emergency treatment of hypertension.

New intravenous anaesthetics and neuromuscular blocking drugs. A review of their properties and clinical use.

The newer neuromuscular blocking drugs include vecuronium and atracurium. Vecuronium is a competitive neuromuscular blocking drug with a steroid nucleus. A dose of 0.1 mg/kg has an onset time of 2 minutes and provides surgical paralysis for 20 minutes. Recovery to 90% twitch height occurs in 40 to 50 minutes. Vecuronium has few adverse effects and its use is associated with cardiovascular stability. Atracurium is a competitive neuromuscular blocking drug which undergoes Hofmann degradation and ester hydrolysis in plasma. A dose of 0.6 mg/kg has an onset time of around 2 minutes and provides surgical paralysis for 20 to 30 minutes. Recovery to 90% twitch height occurs in 60 to 80 minutes. Histamine release, usually only localised, has been reported in association with the use of atracurium. The organ-independent metabolism of atracurium allows its use in standard dosage in patients with renal or hepatic disease. Edrophonium, although not a new drug, has recently been re-evaluated for reversal of neuromuscular blockade. In a dose of 0.5 mg/kg it has been shown to be as effective as neostigmine at reversing neuromuscular blockade after recovery has started (greater than 25% twitch height recovery). However, if blockade is profound (less than 10% recovery), edrophonium is less effective. Among the newer intravenous anaesthetics are propofol (disoprofol) and midazolam. In a dose of 1.5 to 2.5 mg/kg, propofol produces sleep rapidly with a prompt recovery in 4 to 6 minutes. Induction of anaesthesia may be associated with a transient apnoea and a fall in systolic pressure. The rapid recovery has led to its use for maintenance of anaesthesia. Midazolam is a water-soluble benzodiazepine which has been used as an anaesthetic agent. The dose needed to induce sleep varies widely (0.15 to 0.5 mg/kg); onset is slow (1.5 to 5 minutes), and recovery may be prolonged. Midazolam is also used in lower doses as a sedative. Ketamine, an intravenous induction agent, has recently been used intrathecally and extradurally to provide analgesia.

Adverse effects of general anaesthetics.

This review deals with the adverse reactions associated with general anaesthetic agents in current use. These reactions fall into 2 categories; those which are more common, predictable and often closely related, and those which are rare, unpredictable and carry a high mortality. Both inhalational and intravenous anaesthetic agents affect the central nervous and cardio-respiratory systems in a dose-related manner. Neuronal inhibition results in decreasing levels of consciousness and depression of the medullary vital centres which can lead to cardiorespiratory failure. Both groups of agents have some depressant effect on the myocardium and vascular smooth muscle leading to a fall in cardiac output and hypotension. Centrally-mediated respiratory depression is common to both groups and the inhalational agents have a direct effect on lung physiology. The most important idiosyncratic reactions to the volatile agents are malignant hyperpyrexia and 'halothane hepatitis'. Malignant hyperpyrexia has an incidence of 1:12,000 with a mortality of about 24%. It is triggered most often by halothane together with suxamethonium. Post halothane hepatic necrosis is rare. Evidence points to 2 distinct syndromes; direct toxicity from the products of reductive metabolism, and a more serious illness, immunologically mediated via haptens formed by liver proteins and the products of oxidative metabolism. Prolonged nitrous oxide exposure can cause bone marrow depression and life-threatening pressure effects by expansion of air-filled spaces within the body. The idiosyncratic reactions to the intravenous agents include anaphylactoid reactions (which are rare) and triggering of acute porphyria. Etomidate is immunologically 'clean', but it inhibits cortisol synthesis.

Self-learning fuzzy control of atracurium-induced neuromuscular block during surgery.

Self-learning fuzzy logic control has the important property of accommodating uncertain, non-linear and time-varying process characteristics. This intelligent control scheme starts with no fuzzy control rules and learns how to control each process presented to it in real time, without the need for detailed process modelling. A suitable medical application to investigate this control strategy is atracurium-induced neuromuscular block (NMB) of patients in the operating theatre. Here, the patient response exhibits high non-linearity, and individual patient dose requirements can vary five-fold during an operating procedure. A portable control system was developed to assess the clinical performance of a simplified self-learning fuzzy controller in this application. A Paragraph (Vital Signs) NMB device monitored T1, the height of the first twitch in a train-of-four nerve stimulation mode. Using a T1 setpoint = 10% of baseline in ten patients undergoing general surgery, a mean T1 error of 0.45% (SD = 0.44%) is found while a 0.13-0.70 mg k-1 h-1 range in the mean atracurium infusion rate is accommodated. The result compares favourably with more complex and computationally-intensive model-based control strategies for the infusion of atracurium.

A survey of general anaesthesia and sedation in dental practice in two cities.

Using a postal questionnaire, the use of general anaesthesia and sedation in general dental practice in two cities over a 4-week period was investigated. Questionnaires were sent to a random sample of one in five dental practitioners in Bristol and Sheffield, and an 82% response rate was attained. More practices in Sheffield administered general anaesthesia than those in Bristol. The differences between the facilities provided are discussed. Equipment and facilities have improved since a larger survey was described in 1976, but the use and availability of monitoring equipment has changed little since then. The results reflect the decline in the use of general anaesthesia in dental practice seen nationally. The survey provides an insight into the current anaesthetic services provided in general dental practice in two cities, both of which contain dental hospitals, and provides a basis for the design of a protocol for a further national survey.

What is the value of routinely testing full blood count, electrolytes and urea, and pulmonary function tests before elective surgery in patients with no apparent clinical indication and in subgroups of patients with common comorbidities: a systematic review of the clinical and cost-effective literature.

BACKGROUND: The evidence base which supported the National Institute for Health and Clinical Excellence (NICE) published Clinical Guideline 3 was limited and 50% was graded as amber. However, the use of tests as part of pre-operative work-up remains a low-cost but high-volume activity within the NHS, with substantial resource implications. The objective of this study was to identify, evaluate and synthesise the published evidence on the clinical effectiveness and cost-effectiveness of the routine use of three tests, full blood counts (FBCs), urea and electrolytes tests (U&Es) and pulmonary function tests, in the pre-operative work-up of otherwise healthy patients undergoing minor or intermediate surgery in the NHS. OBJECTIVE: The aims of this study were to estimate the clinical effectiveness and cost-effectiveness of routine pre-operative testing of FBC, electrolytes and renal function and pulmonary function in adult patients classified as American Society of Anaesthesiologists (ASA) grades 1 and 2 undergoing elective minor (grade 1) or intermediate (grade 2) surgical procedures; to compare NICE recommendations with current practice; to evaluate the cost-effectiveness of mandating or withdrawing each of these tests in this patient group; and to identify the expected value of information and whether or not it has value to the NHS in commissioning further primary research into the use of these tests in this group of patients. DATA SOURCES: The following electronic bibliographic databases were searched: (1) BIOSIS; (2) Cumulative Index to Nursing and Allied Health Literature; (3) Cochrane Database of Systematic Reviews; (4) Cochrane Central Register of Controlled Trials; (5) EMBASE; (6) MEDLINE; (7) MEDLINE In-Process & Other Non-Indexed Citations; (8) NHS Database of Abstracts of Reviews of Effects; (9) NBS Health Technology Assessment Database; and (10) Science Citation Index. To identify grey and unpublished literature, the Cochrane Register of Controlled Trials, National Research Register Archive, National Institute for Health Research Clinical Research Network Portfolio database and the Copernic Meta-search Engine were searched. A large routine data set which recorded the results of tests was obtained from Leeds Teaching Hospitals Trust. REVIEW METHODS: A systematic review of the literature was carried out. The searches were undertaken in March to April 2008 and June 2009. Searches were designed to retrieve studies that evaluated the clinical effectiveness and cost-effectiveness of routine pre-operative testing of FBC, electrolytes and renal function and pulmonary function in the above group of patients. A postal survey of current practice in testing patients in this group pre-operatively was undertaken in 2008. An exemplar cost-effectiveness model was constructed to demonstrate what form this would have taken had there been sufficient data. A large routine data set that recorded the results of tests was obtained from Leeds Teaching Hospitals Trust. This was linked to individual patient data with surgical outcomes, and regression models were estimated. RESULTS: A comprehensive and systematic search of both the clinical effectiveness and cost-effectiveness literature identified a large number of potentially relevant studies. However, when these studies were subjected to detailed review and quality assessment, it became clear that the literature provides no evidence on the clinical effectiveness and cost-effectiveness of these specific tests in the specific patient groups. The postal survey had a 17% response rate. Results reported that in ASA grade 1, patients aged < 40 years with no comorbidities undergoing minor surgery did not have routine tests for FBC, electrolytes and renal function and pulmonary function. The results from the regression model showed that the frequency of test use was not consistent with the hypothesis of their routine use. FBC tests were performed in only 58% of patients in the data set and U&E testing was carried out in only 57%. LIMITATIONS: Systematic searches of the clinical effectiveness and cost-effectiveness literature found that there is no evidence on the clinical effectiveness or cost-effectiveness of these tests in this specific clinical context for the NHS. A survey of NHS hospitals found that respondent trusts were implementing current NICE guidance in relation to pre-operative testing generally, and a de novo analysis of routine data on test utilisation and post-operative outcome found that the tests were not be used in routine practice; rather, use was related to an expectation of a more complex clinical case. The paucity of published evidence is a limitation of this study. The studies included relied on non-UK health-care systems data, which may not be transferable. The inclusion of non-randomised studies is associated with an increased risk of bias and confounding. Scoping work to establish the likely mechanism of action by which tests would impact upon outcomes and resource utilisation established that the cause of an abnormal test result is likely to be a pivotal determinant of the cost-effectiveness of a pre-operative test and therefore evaluations would need to consider tests in the context of the underlying risk of specific clinical problems (i.e. risk guided rather than routine use). CONCLUSIONS: The time of universal utilisation of pre-operative tests for all surgical patients is likely to have passed. The evidence we have identified, though weak, indicates that tests are increasingly utilised in patients in whom there is a reason to consider an underlying raised risk of a clinical abnormality that should be taken into account in their clinical management. It is likely that this strategy has led to substantial resource savings for the NHS, although there is not a published evidence base to establish that this is the case. The total expenditure on pre-operative tests across the NHS remains significant. Evidence on current practice indicates that clinical practice has changed to such a degree that the original research question is no longer relevant to UK practice. Future research on the value of these tests in pre-operative work-up should be couched in terms of the clinical effectiveness and cost-effectiveness in the identification of specific clinical abnormalities in patients with a known underlying risk. We suggest that undertaking a multicentre study making use of linked, routinely collected data sets would identify the extent and nature of pre-operative testing in this group of patients. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Drug absorption after general anaesthesia for minor surgery.

Paracetamol absorption after oral administration was studied in eleven patients immediately after a short general anaesthetic for cystoscopy and also in eight healthy volunteers. There were no statistical differences between the rate of paracetamol absorption in the two groups. This suggests that oral medication may be given immediately following a short general anaesthetic when opioid drugs are avoided.

Recovery of neuromuscular function after infusion or intermittent bolus doses of atracurium or vecuronium.

Neuromuscular block and postoperative recovery of grip strength and peak expiratory flow (PEF) were compared in patients receiving atracurium or vecuronium administered by continuous infusion or intermittent bolus doses. The same total dose of atracurium (0.92-0.98 mg kg-1) or vecuronium (0.16-0.18 mg kg-1) was given by both methods. A similar degree of neuromuscular block was attained in all groups. A control group receiving no neuromuscular blocking drugs was also studied. Grip strength and PEF were reduced significantly in all groups (less than 80% of preoperative value) 15 min after operation. This was most marked following infusion of vecuronium (less than 50%). Grip strength recovered in all groups in 30-60 min. PEF was still significantly less than control value at 90 min in all groups receiving neuromuscular blocking drugs.

Anaesthesia and the obese patient.

The obese patient is likely to have pre-operative impairment of cardiovascular and respiratory function. These impairments will tend to increase in the per- and post-operative period and place the patient at risk of myocardial ischaemia and hypoxaemia. The physical effects of obesity mean that all patients require endotracheal intubation during anaesthesia and this may be difficult to achieve. The difficulties in moving and positioning the patient and difficulties in gaining access for monitoring and venous cannulation add to the problems. Anaesthesia and surgery may present a considerable risk for obese patients and should not be undertaken without full understanding of the potential problems.

Variability of fentanyl pharmacokinetics in man. Computer predicted plasma concentrations for three intravenous dosage regimens.

The derived pharmacokinetic data for the intravenous administration of fentanyl obtained from seven previous studies were compared using computer simulation of predicted plasma concentrations following three intravenous dosage regimens. There was wide discrepancy between the reported calculated pharmacokinetic constants from the various studies, such that the volume of distribution ranged from 4.4 to 59.7 litres, estimates of terminal elimination half-life ranged from 141 to 853 minutes while total body clearance values ranged from 160 to 1530 ml/minute. The differences in predicted plasma concentrations were marked. The peak concentration following a bolus of 500 micrograms ranged from 8.4-113.6 ng/ml and took from 2.9 to 18.9 hours to fall to 0.5 ng/ml. The steady state plasma concentration reached with an infusion of 0.3 microgram/kg/minute varied from 12.2-119.9 ng/ml and the plateau level attained with a two-rate infusion (2.7 micrograms/kg/minute for 20 minutes then 0.3 micrograms/kg/minute) ranged from 10.6-50.8 ng/ml. The aim of descriptive pharmacokinetics is to allow the clinician to predict the plasma concentration achieved by a given dose and to facilitate dosage choice and adjustment. Recent interest has centred on the use of pharmacokinetics to calculate continuous intravenous infusion dosage regimens. The clinical application of current pharmacokinetic data for fentanyl is questionable.