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1.  Postoperative delirium and cognitive dysfunction 
BJA: British Journal of Anaesthesia  2009;103(Suppl 1):i41-i46.
Postoperative delirium and cognitive dysfunction (POCD) are topics of special importance in the geriatric surgical population. They are separate entities, whose relationship has yet to be fully elucidated. Although not limited to geriatric patients, the incidence and impact of both are more profound in geriatric patients. Delirium has been shown to be associated with longer and more costly hospital course and higher likelihood of death within 6 months or postoperative institutionalization. POCD has been associated with increased mortality, risk of leaving the labour market prematurely, and dependency on social transfer payments. Here, we review their definitions and aetiology, and discuss treatment and prevention in elderly patients undergoing major non-cardiac surgery. Good basic care demands identification of at-risk patients, awareness of common perioperative aggravating factors, simple prevention interventions, recognition of the disease states, and basic treatments for patients with severe hyperactive manifestations.
PMCID: PMC2791855  PMID: 20007989
age factors; anaesthesia, geriatric; brain; complications
2.  Perioperative visual loss: what do we know, what can we do? 
BJA: British Journal of Anaesthesia  2009;103(Suppl 1):i31-i40.
Perioperative visual loss (POVL), a rare, but devastating complication, can follow non-ocular surgery. Highest rates of visual loss are with cardiac and spine surgery. The main causes of visual loss after non-ocular surgery are retinal vascular occlusion and ischaemic optic neuropathy. This review updates readers on the incidence, suspected risk factors, diagnosis, and treatment of POVL due to these conditions.
PMCID: PMC2791856  PMID: 20007988
complications, neurological; complications, neuropathy; eye, intraocular pressure; eye, pupil; surgery, spinal
3.  Mathematical model for describing cerebral oxygen desaturation in patients undergoing deep hypothermic circulatory arrest 
Surgical treatment for aortic arch disease requiring periods of circulatory arrest is associated with a spectrum of neurological sequelae. Cerebral oximetry can non-invasively monitor patients for cerebral ischaemia even during periods of circulatory arrest. We hypothesized that cerebral desaturation during circulatory arrest could be described by a mathematical relationship that is time-dependent.
Cerebral desaturation curves obtained from 36 patients undergoing aortic surgery with deep hypothermic circulatory arrest (DHCA) were used to create a non-linear mixed model. The model assumes that the rate of oxygen decline is greatest at the beginning before steadily transitioning to a constant. Leave-one-out cross-validation and jackknife methods were used to evaluate the validity of the predictive model.
The average rate of cerebral desaturation during DHCA can be described as: Scto2[t]=81.4−(11.53+0.37×t) (1−0.88×exp (−0.17×t)). Higher starting Scto2 values and taller patient height were also associated with a greater decline rate of Scto2. Additionally, a predictive model was derived after the functional form of a×log (b+c×δ), where δ is the degree of Scto2 decline after 15 min of DHCA. The model enables the estimation of a maximal acceptable arrest time before reaching an ischaemic threshold. Validation tests showed that, for the majority, the prediction error is no more than ±3 min.
We were able to create two mathematical models, which can accurately describe the rate of cerebral desaturation during circulatory arrest at 12–15°C as a function of time and predict the length of arrest time until a threshold value is reached.
PMCID: PMC2791548  PMID: 19933513
brain, ischaemia; brain, oxygen consumption; hypothermia
4.  Pharmacological optimization of tissue perfusion 
After fluid resuscitation, vasoactive drug treatment represents the major cornerstone for correcting any major impairment of the circulation. However, debate still rages as to the choice of agent, dose, timing, targets, and monitoring modalities that should optimally be used to benefit the patient yet, at the same time, minimize harm. This review highlights these areas and some new pharmacological agents that broaden our therapeutic options.
PMCID: PMC2700012  PMID: 19460775
arterial pressure, drug effects; cardiovascular system, effects; heart, cardiac output; oxygen, therapy; pharmacology, agonists adrenergic
5.  Sodium channels and the synaptic mechanisms of inhaled anaesthetics 
General anaesthetics act in an agent-specific manner on synaptic transmission in the central nervous system by enhancing inhibitory transmission and reducing excitatory transmission. The synaptic mechanisms of general anaesthetics involve both presynaptic effects on transmitter release and postsynaptic effects on receptor function. The halogenated volatile anaesthetics inhibit neuronal voltage-gated Na+ channels at clinical concentrations. Reductions in neurotransmitter release by volatile anaesthetics involve inhibition of presynaptic action potentials as a result of Na+ channel blockade. Although voltage-gated ion channels have been assumed to be insensitive to general anaesthetics, it is now evident that clinical concentrations of volatile anaesthetics inhibit Na+ channels in isolated rat nerve terminals and neurons, as well as heterologously expressed mammalian Na+ channel α subunits. Voltage-gated Na+ channels have emerged as promising targets for some of the effects of the inhaled anaesthetics. Knowledge of the synaptic mechanisms of general anaesthetics is essential for optimization of anaesthetic techniques for advanced surgical procedures and for the development of improved anaesthetics.
PMCID: PMC2700013  PMID: 19508978
anaesthetics volatile; anaesthetics volatile, halogenated hydrocarbons; nerve, neurotransmitters; pharmacology, anaesthetic action; pharmacology, neurotransmission
6.  Loss of surface N-methyl-d-aspartate receptor proteins in mouse cortical neurones during anaesthesia induced by chloral hydrate in vivo 
BJA: British Journal of Anaesthesia  2009;102(4):515-522.
Anaesthetics may target ionotropic glutamate receptors in brain cells to produce their biological actions. Membrane-bound ionotropic glutamate receptors undergo dynamic trafficking between the surface membrane and intracellular organelles. Their subcellular distribution is subject to modulation by changing synaptic inputs and determines the efficacy and strength of excitatory synapses. It has not been explored whether anaesthesia has any impact on surface glutamate receptor expression. In this study, the effect of general anaesthesia on expression of N-methyl-d-aspartate (NMDA) receptors in the surface and intracellular pools of cortical neurones was investigated in vivo.
General anaesthesia was induced by intraperitoneal injection of chloral hydrate in adult male mice. Surface protein cross-linking assays were performed to detect changes in distribution of NMDA receptor subunits (NR1, NR2A, and NR2B) in the surface and intracellular compartments of cerebral cortical neurones.
Chloral hydrate did not alter the total amounts of NR1, NR2A, and NR2B proteins in cortical neurones. However, the drug reduced NR1 proteins in the surface pool of these neurones, and induced a proportional increase in NR1 in the intracellular pool. Similar redistribution of NR2B subunits was observed between the two distinct pools. The changes in NR1 and NR2B were rapid and remained throughout the duration of anaesthesia. NR2A proteins were not altered in the surface or intracellular pool in response to chloral hydrate.
These data demonstrate that subcellular expression of NR1 and NR2B in cortical neurones is sensitive to anaesthesia. Chloral hydrate reduces surface-expressed NMDA receptors (specifically NR2B-containing NMDA receptors) in these neurones in vivo.
PMCID: PMC2724878  PMID: 19224925
anaesthetics; cerebral cortex; glutamate receptor; NR1; NR2A; NR2B
7.  Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane 
BJA: British Journal of Anaesthesia  2009;102(3):355-360.
Inhaled anaesthetics (IAs) produce multiple dose-dependent behavioural effects including amnesia, hypnosis, and immobility in response to painful stimuli that are mediated by distinct anatomical, cellular, and molecular mechanisms. Amnesia is produced at lower anaesthetic concentrations compared with hypnosis or immobility. Nicotinic acetylcholine receptors (nAChRs) modulate hippocampal neural network correlates of memory and are highly sensitive to IAs. Activation of hippocampal nAChRs stimulates the release of norepinephrine (NE), a neurotransmitter implicated in modulating hippocampal synaptic plasticity. We tested the hypothesis that IAs disrupt hippocampal synaptic mechanisms critical to memory by determining the effects of isoflurane on NE release from hippocampal nerve terminals.
Isolated nerve terminals prepared from adult male Sprague–Dawley rat hippocampus were radiolabelled with [3H]NE and either [14C]GABA or [14C]glutamate and superfused at 37°C. Release evoked by a 2 min pulse of 100 µM nicotine or 5 µM 4-aminopyridine was evaluated in the presence or absence of isoflurane and/or selective antagonists.
Nicotine-evoked NE release from rat hippocampal nerve terminals was nAChR- and Ca2+-dependent, involved both α7 and non-α7 subunit-containing nAChRs, and was partially dependent on voltage-gated Na+ channel activation based on sensitivities to various antagonists. Isoflurane inhibited nicotine-evoked NE release (IC50=0.18 mM) more potently than depolarization-evoked NE release (IC50=0.27 mM, P=0.014), consistent with distinct presynaptic mechanisms of IA action.
Inhibition of hippocampal nAChR-dependent NE release by subanaesthetic concentrations of isoflurane supports a role in IA-induced amnesia.
PMCID: PMC2642653  PMID: 19189985
anaesthetics volatile, isoflurane; brain, anaesthesia, molecular effects; brain, hippocampus; ions, ion channels, ligand-gated; nerve, neurotransmitters
8.  Regulation of pentraxin-3 by antioxidants 
BJA: British Journal of Anaesthesia  2009;103(6):833-839.
Pentraxin-3 (PTX3) may be a useful biomarker in sepsis, but its regulatory mechanisms are still unclear. Oxidative stress is well defined in patients with sepsis and has a role in regulation of inflammatory pathways which may include PTX3. We undertook an in vitro study of the effect of antioxidants on regulation of PTX3 in endothelial cells combined with a prospective observational pilot study of PTX3 in relation to markers of antioxidant capacity and oxidative stress in patients with sepsis.
Human endothelial cells were cultured with lipopolysaccharide 2 µg ml−1, peptidoglycan G 20 µg ml−1, tumour necrosis factor (TNF) α 10 ng ml−1, interleukin-1 (IL-1) β 20 ng ml−1, or killed Candida albicans yeast cells plus either N-acetylcysteine (NAC) 25 mM, trolox 100 mM, or idebenone 1 µM. Plasma samples were obtained from 15 patients with sepsis and 11 healthy volunteers.
PTX3 levels in plasma were higher in patients with sepsis than in healthy people [26 (1–202) ng ml−1 compared with 6 (1–12) ng ml−1, P=0.01]. Antioxidant capacity was lower in patients with sepsis than healthy controls [0.99 (0.1–1.7) mM compared with 2.2 (1.3–3.3) mM, P=0.01]. In patients with sepsis, lipid hydroperoxide levels were 3.32 (0.3–10.6) nM and undetectable in controls. We found no relationship between PTX3 and antioxidant capacity or lipid hydroperoxides. Cell expression of PTX3 increased with all inflammatory stimulants but was highest in cells treated with TNFα plus IL-1β. PTX3 concentrations were lower in cells co-treated with antioxidants (all P<0.05), associated with lower nuclear factor κB expression for NAC and trolox (P<0.05).
PTX3 expression is down-regulated in vitro by antioxidants. Plasma levels of PTX3 are elevated in sepsis but seem to be unrelated to markers of oxidant stress or antioxidant capacity.
PMCID: PMC2777941  PMID: 19864306
immune response; infection, bacterial; infection, fungal; metabolism, protein, acute phase
9.  Nasal high-flow therapy delivers low level positive airway pressure 
BJA: British Journal of Anaesthesia  2009;103(6):886-890.
The aim of this prospective study was to determine whether a level of positive airway pressure was generated in participants receiving nasal high flow (NHF) delivered by the Optiflow™ system (Fisher and Paykel Healthcare Ltd, Auckland, New Zealand) in a cardiothoracic and vascular intensive care unit (ICU).
Nasopharyngeal airway pressure was measured in 15 postoperative cardiac surgery adult patients who received both NHF and standard facemask therapy at a flow rate of 35 litre min−1. Measurements were repeated in the open mouth and closed mouth positions. Mean airway pressure was determined by averaging the pressures at the peak of inspiration of each breath within a 1 min period, allowing the entire pressure profile of each breath to be included within the calculation.
Low level positive pressure was demonstrated with NHF at 35 litre min−1 with mouth closed when compared with a facemask. NHF generated a mean nasopharyngeal airway pressure of mean (sd) 2.7 (1.04) cm H2O with the mouth closed. Airway pressure was significantly higher when breathing with mouth closed compared with mouth open (P≤0.0001).
This study demonstrated that a low level of positive pressure was generated with NHF at 35 litre min−1 of gas flow. This is consistent with results obtained in healthy volunteers.
Australian Clinical Trials Registry ACTRN012606000139572.
PMCID: PMC2777940  PMID: 19846404
airway pressure; nasal high-flow therapy; Optiflow™; oxygen
10.  Impact of opioid rescue medication for breakthrough pain on the efficacy and tolerability of long-acting opioids in patients with chronic non-malignant pain 
BJA: British Journal of Anaesthesia  2009;103(4):576-585.
There is little evidence that short-acting opioids as rescue medication for breakthrough pain is an optimal long-term treatment strategy in chronic non-malignant pain. We compared clinical studies of long-acting opioids that allowed short-acting opioid rescue medication with those that did not, to determine the impact of opioid rescue medication use on the analgesic efficacy and tolerability of chronic opioid therapy in patients with chronic non-malignant pain.
We searched MEDLINE (1950 to July 2006) and EMBASE (1974 to July 2006) using terms for chronic non-malignant pain and long-acting opioids. Independent review of the search results identified 48 studies that met the study selection criteria. The effect of opioid rescue medication on analgesic efficacy and the incidence of common opioid-related side-effects were analysed using meta-regression.
After adjusting for potentially confounding variables (study design and type of opioid), the difference in analgesic efficacy between the ‘rescue’ and the ‘no rescue’ studies was not significant, with regression coefficients close to 0 and 95% confidence intervals that excluded an effect of more than 18 points on a 0–100 scale in each case. There was also no significant difference between the ‘rescue’ and the ‘no rescue’ studies for the incidence of nausea, constipation, or somnolence in both the unadjusted and the adjusted analyses.
We found no evidence that rescue medication with short-acting opioids for breakthrough pain affects analgesic efficacy of long-acting opioids or the incidence of common opioid-related side-effects among chronic non-malignant pain patients.
PMCID: PMC2742451  PMID: 19736216
analgesics opioid; pain, chronic; pharmacology, analgesics opioid
11.  Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study 
BJA: British Journal of Anaesthesia  2009;102(6):785-792.
Bleeding diathesis after aortic valve operation and ascending aorta replacement (AV–AA) is managed with fresh-frozen plasma (FFP) and platelet concentrates. The aim was to compare haemostatic effects of conventional transfusion management and FIBTEM (thromboelastometry test)-guided fibrinogen concentrate administration.
A blood products transfusion algorithm was developed using retrospective data from 42 elective patients (Group A). Two units of platelet concentrate were transfused after cardiopulmonary bypass, followed by 4 u of FFP if bleeding persisted, if platelet count was ≤100×103 µl−1 when removing the aortic clamp, and vice versa if platelet count was >100×103 µl−1. The trigger for each therapy step was ≥60 g blood absorbed from the mediastinal wound area by dry swabs in 5 min. Assignment to two prospective groups was neither randomized nor blinded; Group B (n=5) was treated according to the algorithm, Group C (n=10) received fibrinogen concentrate (Haemocomplettan® P/Riastap, CSL Behring, Marburg, Germany) before the algorithm-based therapy.
A mean of 5.7 (0.7) g fibrinogen concentrate decreased blood loss to below the transfusion trigger level in all Group C patients. Group C had reduced transfusion [mean 0.7 (range 0–4) u vs 8.5 (5.3) in Group A and 8.2 (2.3) in Group B] and reduced postoperative bleeding [366 (199) ml vs 793 (560) in Group A and 716 (219) in Group B].
In this pilot study, FIBTEM-guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24 h postoperative bleeding in patients undergoing AV–AA.
PMCID: PMC2683341  PMID: 19411671
blood, coagulation; measurement techniques, thrombelastograph; surgery, cardiovascular; transfusion
12.  Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model 
BJA: British Journal of Anaesthesia  2009;102(3):345-354.
Fluid resuscitation following traumatic injury causes haemodilution and can contribute to coagulopathy. Coagulation factor replacement may be necessary to prevent bleeding complications of dilutional coagulopathy. Compared with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) may potentially offer a more rapid and effective means of normalizing coagulation factor levels.
In anaesthetized mildly hypothermic pigs, 65–70% of total blood volume was substituted in phases with hydroxyethyl starch and red cells. Animals were then treated with 15 ml kg−1 isotonic saline placebo, 25 IU kg−1 PCC, or 15 ml kg−1 FFP. Immediately thereafter, either a standardized femur or spleen injury was inflicted, and coagulation function, including thrombin generation, and bleeding were assessed. An additional group received high-dose FFP (40 ml kg−1) before femur injury.
Haemodilution markedly prolonged prothrombin time and reduced peak thrombin generation. PCC, but not FFP, fully reversed those effects. Compared with 15 ml kg−1 FFP, PCC shortened the time to haemostasis after either bone (P=0.001) or spleen (P=0.028) trauma and reduced the volume of blood lost (P<0.001 and P=0.015, respectively). Subsequent to bone injury, PCC also accelerated haemostasis (P=0.003) and diminished blood loss (P=0.006) vs 40 ml kg−1 FFP.
PCC was effective in correcting dilutional coagulopathy and controlling bleeding in an in vivo large-animal trauma model. In light of its suitability for more rapid administration than FFP, PCC merits further investigation as a therapy for dilutional coagulopathy in trauma and surgery.
PMCID: PMC2642652  PMID: 19168856
blood, haemodilution; complications, haemorrhagic disorder; complications, trauma; fresh frozen plasma; prothrombin complex concentrate

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