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1.  Early childhood general anaesthesia exposure and neurocognitive development 
BJA: British Journal of Anaesthesia  2010;105(Suppl 1):i61-i68.
A great deal of concern has recently arisen regarding the safety of anaesthesia in infants and children. There is mounting and convincing preclinical evidence in rodents and non-human primates that anaesthetics in common clinical use are neurotoxic to the developing brain in vitro and cause long-term neurobehavioural abnormalities in vivo. An estimated 6 million children (including 1.5 million infants) undergo surgery and anaesthesia each year in the USA alone, so the clinical relevance of anaesthetic neurotoxicity is an urgent matter of public health. Clinical studies that have been conducted on the long-term neurodevelopmental effects of anaesthetic agents in infants and children are retrospective analyses of existing data. Two large-scale clinical studies are currently underway to further address this issue. The PANDA study is a large-scale, multisite, ambi-directional sibling-matched cohort study in the USA. The aim of this study is to examine the neurodevelopmental effects of exposure to general anaesthesia during inguinal hernia surgery before 36 months of age. Another large-scale study is the GAS study, which will compare the neurodevelopmental outcome between two anaesthetic techniques, general sevoflurane anaesthesia and regional anaesthesia, in infants undergoing inguinal hernia repair. These study results should contribute significant information related to anaesthetic neurotoxicity in children.
PMCID: PMC3000523  PMID: 21148656
anaesthesia, paediatric; children; neurocognitive outcome; neurotoxicity; risk
2.  Prothrombin complex concentrate mitigates diffuse bleeding after cardiopulmonary bypass in a porcine model 
BJA: British Journal of Anaesthesia  2010;105(5):576-582.
Extracorporeal circuit priming and intravascular volume expansion during cardiopulmonary bypass (CPB) may lead to dilutional coagulopathy and excessive diffuse postoperative bleeding. Prothrombin complex concentrate (PCC) containing clotting factors II (FII), VII (FVII), IX (FIX), and X (FX) could be of potential value in correcting dilutional coagulopathy and reducing blood loss.
Anaesthetized pigs underwent CPB with hypothermia for 2 h at 25°C followed by 1 h of normothermia. Approximately 1 h after CPB, animals randomly received either isotonic saline 1 ml kg−1 or PCC 30 IU kg−1 in a volume of 1 ml kg−1. Diffuse coagulopathic bleeding was assessed as suture hole blood loss from a Gore-Tex patch placed over a full-thickness incision in the left carotid artery.
After CPB, levels of FII, FVII, FIX, and FX declined from baseline by 32% to 48%, and PCC fully or partially reversed those deficits. Median suture hole blood loss after administration of saline placebo was 74 ml. PCC reduced suture hole bleeding by a median of 54 ml with a 95% confidence interval of 6–112 ml (P=0.026) compared with saline. PCC, but not saline, normalized skin bleeding time. Peak thrombin generation markedly decreased after CPB, but then returned in PCC-treated animals to a level higher than baseline by 28.7 nM (14.5–41.1 nM; P=0.031).
PCC was effective in correcting dilutional coagulopathy and reducing diffuse bleeding in an in vivo large-animal CPB model. Further research is warranted on PCC as a haemostatic agent in CPB.
PMCID: PMC2955534  PMID: 20716565
blood coagulation disorders; cardiopulmonary bypass; haemodilution; haemorrhage; prothrombin complex concentrates
3.  Monitoring non-invasive cardiac output and stroke volume during experimental human hypovolaemia and resuscitation 
Multiple methods for non-invasive measurement of cardiac output (CO) and stroke volume (SV) exist. Their comparative capabilities are not clearly established.
Healthy human subjects (n=21) underwent central hypovolaemia through progressive lower body negative pressure (LBNP) until the onset of presyncope, followed by termination of LBNP, to simulate complete resuscitation. Measurement methods were electrical bioimpedance (EBI) of the thorax and three measurements of CO and SV derived from the arterial blood pressure (ABP) waveform: the Modelflow (MF) method, the long-time interval (LTI) method, and pulse pressure (PP). We computed areas under receiver-operating characteristic curves (ROC AUCs) for the investigational metrics, to determine how well they discriminated between every combination of LBNP levels.
LTI and EBI yielded similar reductions in SV during progressive hypovolaemia and resuscitation (correlation coefficient 0.83) with ROC AUCs for distinguishing major LBNP (−60 mm Hg) vs resuscitation (0 mm Hg) of 0.98 and 0.99, respectively. MF yielded very similar reductions and ROC AUCs during progressive hypovolaemia, but after resuscitation, MF-CO did not return to baseline, yielding lower ROC AUCs (ΔROC AUC range, −0.18 to −0.26, P<0.01). PP declined during hypovolaemia but tended to be an inferior indicator of specific LBNP levels, and PP did not recover during resuscitation, yielding lower ROC curves (P<0.01).
LTI, EBI, and MF were able to track progressive hypovolaemia. PP decreased during hypovolaemia but its magnitude of reduction underestimated reductions in SV. PP and MF were inferior for the identification of resuscitation.
PMCID: PMC3000628  PMID: 21051492
arterial pressure, measurement; blood, loss; cardiovascular system, responses; equipment, finapres; monitoring, cardiopulmonary
4.  Revised cardiac risk index and postoperative morbidity after elective orthopaedic surgery: a prospective cohort study 
BJA: British Journal of Anaesthesia  2010;105(6):744-752.
The revised cardiac risk index (RCRI) is associated strongly with increased cardiac ischaemic risk and perioperative death. Associations with non-cardiac morbidity in non-cardiac surgery have not been explored. In the elective orthopaedic surgical population, morbidity is common but preoperative predictors are unclear. We hypothesized that RCRI would identify individuals at increased risk of non-cardiac morbidity in this surgically homogenous population.
Five hundred and sixty patients undergoing elective primary (>90%) and revision hip and knee procedures were studied. A modified RCRI (mRCRI) score was calculated, weighting intermediate and low risk factors. The primary endpoint was the development of morbidity, collected prospectively using the Postoperative Morbidity Survey, on postoperative day (POD) 5.
Morbidity on POD 5 was more frequent in patients with mRCRI ≥3 {relative risk 1.7, [95% confidence interval (CI): 1.4–2.1]; P<0.001}. Time to hospital discharge was delayed in patients with mRCRI score ≥3 (log-rank test, P=0.0002). Pulmonary (P<0.001), infectious (P=0.001), cardiovascular (P=0.0003), renal (P<0.0001), wound (P=0.02), and neurological (P=0.002) morbidities were more common in patients with mRCRI score ≥3. Pre/postoperative haematocrit, anaesthetic/analgesic technique, and postoperative temperature were similar across mRCRI groups. There were significant associations with hospital stay, as measured by the area under the receiver-operating characteristic curves for mRCRI 0.64 (95% CI: 0.58–0.70) and POSSUM 0.70 (95% CI: 0.63–0.75).
mRCRI score ≥3 is associated with increased postoperative non-cardiac morbidity and prolonged hospital stay after elective orthopaedic procedures. mRCRI can contribute to objective risk stratification of postoperative morbidity.
PMCID: PMC2982697  PMID: 20876700
assessment, preanaesthetic; complications, morbidity; surgery, non-cardiac; surgery, orthopaedic
5.  Incidence and risk factors for fatal pulmonary embolism after major trauma: a nested cohort study† 
BJA: British Journal of Anaesthesia  2010;105(5):596-602.
Venous thromboembolism is common after major trauma. Strategies to prevent fatal pulmonary embolism (PE) are widely utilized, but the incidence and risk factors for fatal PE are poorly understood.
Using linked data from the intensive care unit, trauma registry, Western Australian Death Registry, and post-mortem reports, the incidence and risk factors for fatal PE in a consecutive cohort of major trauma patients, admitted between 1994 and 2002, were assessed. Non-linear relationships between continuous predictors and risk of fatal PE were modelled by logistic regression.
Of the 971 consecutive trauma patients considered in the study, 134 (13.8%) died after their injuries. Fatal PE accounted for 11.9% of all deaths despite unfractionated heparin prophylaxis being used in 44% of these patients. Fatal PE occurred in those who were older (mean age 51- vs 37-yr-old, P=0.01), with more co-morbidities (Charlson's co-morbidity index 1.1 vs 0.2, P=0.01), had a larger BMI (31.8 vs 24.5, P=0.01), and less severe head and systemic injuries when compared with those who died of other causes. Sites of injuries were not significantly related to the risk of fatal PE. Fatal PE occurred much later than deaths from other causes (median 18 vs 2 days, P=0.01), and the estimated attributable mortality of PE was 49% (95% confidence interval 36–62%).
Fatal PE appeared to be a potential preventable cause of late mortality after major trauma. Severity of injuries, co-morbidity, and BMI were important risk factors for fatal PE after major trauma.
PMCID: PMC2955535  PMID: 20861095
mortality; prevention; thromboembolism; traumatic injuries
6.  Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and economic evaluation† 
BJA: British Journal of Anaesthesia  2010;105(5):558-567.
The cost-effectiveness of sugammadex for the routine reversal of muscle relaxation produced by rocuronium or vecuronium in UK practice is uncertain. We performed a systematic review of randomized controlled trials of sugammadex compared with neostigmine/glycopyrrolate and an economic assessment of sugammadex for the reversal of moderate or profound neuromuscular block (NMB) produced by rocuronium or vecuronium. The economic assessment aimed to establish the reduction in recovery time and the ‘value of time saved’ which would be necessary for sugammadex to be potentially cost-effective compared with existing practice. Three trials indicated that sugammadex 2 mg kg−1 (4 mg kg−1) produces more rapid recovery from moderate (profound) NMB than neostigmine/glycopyrrolate. The economic assessment indicated that if the reductions in recovery time associated with sugammadex in the trials are replicated in routine practice, sugammadex would be cost-effective if those reductions are achieved in the operating theatre (assumed value of staff time, £4.44 per minute), but not if they are achieved in the recovery room (assumed value of staff time, £0.33 per minute). However, there is considerable uncertainty in these results. Sugammadex has the potential to be cost-effective compared with neostigmine/glycopyrrolate for the reversal of rocuronium-induced moderate or profound NMB, provided that the time savings observed in trials can be achieved and put to productive use in clinical practice. Further research is required to evaluate the effects of sugammadex on patient safety, predictability of recovery from NMB, patient outcomes, and efficient use of resources.
PMCID: PMC2955536  PMID: 20935005
clinical trials; neuromuscular block, recovery; neuromuscular block, rocuronium
7.  Sugammadex for reversal of neuromuscular block after rapid sequence intubation: a systematic review and economic assessment† 
BJA: British Journal of Anaesthesia  2010;105(5):568-575.
Sugammadex 16 mg kg−1 can be used for the immediate reversal of neuromuscular block 3 min after administration of rocuronium and could be used in place of succinylcholine for emergency intubation. We have systematically reviewed the efficacy and cost-effectiveness and made an economic assessment of sugammadex for immediate reversal. The economic assessment investigated whether sugammadex appears cost-effective under various assumptions about the value of any reduction in recovery time with sugammadex, the likelihood of a ‘can't intubate, can't ventilate’ (CICV) event, the age of the patient, and the length of the procedure. Three trials were included in the efficacy review. Sugammadex administered 3 or 5 min after rocuronium produced markedly faster recovery than placebo or spontaneous recovery from succinylcholine-induced block. No published economic evaluations were found. Our economic analyses showed that sugammadex appears more cost-effective, where the value of any reduction in recovery time is greater, where the reduction in mortality compared with succinylcholine is greater, and where the patient is younger, for lower probabilities of a CICV event and for long procedures which do not require profound block throughout. Because of the lack of evidence, the value of some parameters remains unknown, which makes it difficult to provide a definitive assessment of the cost-effectiveness of sugammadex in practice. The use of sugammadex in combination with high-dose rocuronium is efficacious. Further research is needed to clarify key parameters in the analysis and to allow a fuller economic assessment.
PMCID: PMC2955537  PMID: 20937718
complications, intubation tracheal; neuromuscular block, recovery; neuromuscular block, rocuronium; neuromuscular block, succinylcholine
9.  Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain 
BJA: British Journal of Anaesthesia  2010;105(2):201-207.
Choline is a dietary supplement that activates α7 nicotinic receptors. α7 nicotinic activation reduces cytokine production by macrophages and has antinociceptive activity in inflammatory pain models. We hypothesized that systemic administration of choline would reduce the inflammatory response from macrophages and have antinociceptive efficacy in a murine model of postoperative pain.
We studied the response of wild-type and α7 nicotinic knockout mice to heat and punctate pressure after a model surgical procedure. We investigated the effect of genotype and choline treatment on α-bungarotoxin binding to, and their production of tumour necrosis factor (TNF) from, macrophages.
Choline provided moderate antinociception. The ED50 for choline inhibition of heat-induced allodynia was 1.7 mg kg−1 h−1. The ED50 for punctate pressure threshold was 4.7 mg kg−1 h−1 choline. α7 nicotinic knockout mice had no change in hypersensitivity to heat or pressure and were significantly different from littermate controls when treated with choline 5 mg kg−1 h−1 (P<0.05, 0.01). Choline 100 mM reduced binding of α-bungarotoxin to macrophages by 72% and decreased their release of TNF by up to 51 (sd 11)%. There was no difference by genotype in the inhibition of TNF release by choline.
Systemic choline is a moderately effective analgesic via activation of α7 nicotinic acetylcholine receptors. The antinocicepive effect may not be mediated by a reduction of TNF pathway cytokine release from macrophages. Although choline at millimolar concentrations clearly inhibits the release of TNF, this effect is not α7 subunit-dependent and occurs at concentrations likely higher than reached systemically in vivo.
PMCID: PMC2903311  PMID: 20511332
acetylcholine; acute pain, novel techniques; pharmacodynamics; pharmacology, dose–response; pharmacology, general
10.  Clinically relevant doses of lidocaine and bupivacaine do not impair cutaneous wound healing in mice† 
BJA: British Journal of Anaesthesia  2010;104(6):768-773.
Lidocaine and bupivacaine are commonly infiltrated into surgical cutaneous wounds to provide local anaesthesia after surgical procedures. However, very little is known about their effects on cutaneous wound healing. If an inhibitory effect is demonstrated, then the balance between the benefits of postoperative local anaesthesia and the negatives of impaired cutaneous wound healing may affect the decision to use local anaesthesia or not. Furthermore, if a difference in the rate of healing of lidocaine- and bupivacaine-treated cutaneous wounds is revealed, or if an inhibitory effect is found to be dose-dependent, then this may well influence the choice of agent and its concentration for clinical use.
Immediately before incisional wounding, we administered lidocaine and bupivacaine intradermally to adult female mice, some of which had been ovariectomized to act as a model of post-menopausal women (like post-menopausal women, ovariectomized mice heal wounds poorly, with increased proteolysis and inflammation). Day 3 wound tissue was analysed histologically and tested for expression of inflammatory and proteolytic factors.
On day 3 post-wounding, wound areas and extent of re-epithelialization were comparable between the control and local anaesthetic-treated animals, in both intact and ovariectomized groups. Both tested drugs significantly increased wound activity of the degradative enzyme matrix metalloproteinase-2 relative to controls, while lidocaine also increased wound neutrophil numbers.
Although lidocaine and bupivacaine influenced local inflammatory and proteolytic factors, they did not impair the rate of healing in either of two well-established models (mimicking normal human wound healing and impaired age-related healing).
PMCID: PMC2867659  PMID: 20418532
anaesthetics local, bupivacaine; anaesthetics local, lidocaine; mouse
11.  Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery 
BJA: British Journal of Anaesthesia  2010;104(5):555-562.
Normalization of plasma fibrinogen levels may be associated with satisfactory haemostasis and reduced bleeding. The aim of this retrospective study was to assess fibrinogen recovery parameters after administration of fibrinogen concentrate (Haemocomplettan® P) to patients with diffuse bleeding in cardiovascular surgery. Data on transfusion and patient outcomes were also collected.
Patient characteristic and clinical data were obtained from patient records. Results of the thromboelastometry (FIBTEM®) and of the standard coagulation tests, including plasma fibrinogen level, measured before surgery, before and after haemostatic therapy, and on the following day, were retrieved from laboratory records.
Thirty-nine patients receiving fibrinogen concentrate for diffuse bleeding requiring haemostatic therapy after cardiopulmonary bypass were identified. The mean fibrinogen concentrate dose administered was 6.5 g. The mean fibrinogen level increased from 1.9 to 3.6 g litre−1 (mean increment of 0.28 g litre−1 per gram of concentrate administered); maximum clot firmness increased from 10 to 21 mm. The mean fibrinogen increase was 2.29 (sd 0.7) mg dl−1 per mg kg−1 bodyweight of concentrate administered. Thirty-five patients received no transfusion of fresh-frozen plasma (FFP) or platelet concentrate after receiving fibrinogen concentrate; the remaining four patients received platelet concentrate intraoperatively. Eleven patients received platelets, FFP, or both during the first postoperative day. No venous thromboses, arterial ischaemic events, or deaths were registered during hospitalization.
In this retrospective study, fibrinogen concentrate was effective in increasing plasma fibrinogen level, and contributed to the correction of bleeding after cardiovascular surgery.
PMCID: PMC2855672  PMID: 20348140
blood, coagulation; fibrinogen concentrate; pharmacokinetics, uptake; surgery, cardiovascular
12.  A pilot study evaluating predictors of postoperative outcomes after major abdominal surgery: physiological capacity compared with the ASA physical status classification system 
BJA: British Journal of Anaesthesia  2010;104(4):465-471.
This pilot study compared the risk predictive value of preoperative physiological capacity (PC: defined by gas exchange measured during cardiopulmonary exercise testing) with the ASA physical status classification in the same patients (n=32) undergoing major abdominal cancer surgery.
Uni- and multivariate logistic regression models were fitted to measurements of PC and ASA rank data determining their predictive value for postoperative morbidity. Receiver operating characteristic (ROC) curves were used to discriminate between the predictive abilities, exploring trade-offs between sensitivity and specificity.
Individual statistically significant predictors of postoperative morbidity included the ASA rank [P=0.038, area under the curve (AUC)=0.688, sensitivity=0.630, specificity=0.750] and three newly identified measures of PC: PAT (% predicted anaerobic threshold achieved, <75% vs ≥75%), ΔHR1 (heart rate response from rest to the anaerobic threshold), and HR3 (heart rate at the anaerobic threshold). A two-variable model of PC measurements (ΔHR1+PAT) was also shown to be statistically significant in the prediction of postoperative morbidity (P=0.023, AUC=0.826, sensitivity=0.813, specificity=0.688).
Three newly identified PC measures and the ASA rank were significantly associated with postoperative morbidity; none showed a statistically greater association compared with the others. PC appeared to improve predictive sensitivity. The potential for new unidentified measures of PC to predict postoperative outcomes remains unexplored.
PMCID: PMC2837548  PMID: 20190255
assessment, preanaesthetic; complications, morbidity; measurement techniques, gas exchange metabolic; metabolism, oxygen consumption; oxygen uptake; risk; surgery, postoperative
13.  Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial 
Acetaminophen is often used with a non-steriodal anti-inflammatory drug for acute pain. Hitherto, these drugs have had to be given separately, typically at different time intervals. Maxigesic® tablets combine acetaminophen and ibuprofen in clinically appropriate doses to simplify administration and dosage regimen. We compared this combination with each of the constituent drugs for the relief of pain after extraction of third molar teeth.
Adults (more than 16 yr) having one or more wisdom teeth removed under general or local anaesthesia were instructed to take two tablets before operation, then two tablets every 6 h for up to 48 h of: (i) a combination of acetaminophen 500 mg and ibuprofen 150 mg per tablet (Maxigesic®); (ii) acetaminophen 500 mg per tablet alone; or (iii) ibuprofen 150 mg per tablet alone. The primary outcome measure was the area under the curve (AUC) of the 100 mm visual analogue scale pain measurements taken for up to 48 h after surgery, divided by time, at rest and on activity. Pharmacokinetic data were collected in a subset of patients.
The mean (sem) time-corrected AUC on rest and activity, respectively, were: combination group 22.3 (3.2) and 28.4 (3.4); acetaminophen group 33.0 (3.1) and 40.4 (3.3); and ibuprofen group 34.8 (3.2) and 40.2 (3.4); P<0.01 for each of the four comparisons of combination vs constituent drug. There was no pharmacokinetic interaction between acetaminophen and ibuprofen administered together.
Maxigesic® tablets provide superior pain relief after oral surgery to acetaminophen or ibuprofen alone.
PMCID: PMC2791549  PMID: 20007794
anaesthesia, dental; analgesia, postoperative; analgesics non-opioid, acetaminophen; analgesics non-opioid, ibuprofen; non-steroidal anti-inflammatory drugs

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