This chapter reviews the critical care management of severe acute ischemic stroke and intracerebral hemorrhage. Some ischemic and hemorrhagic stroke patients have critical care needs, and recent evidence supports treatment in a specialized stroke unit or neurologic intensive care unit (ICU) to be associated with reduced mortality and a more favorable outcome as compared to general ICUs. Therapeutic approaches to even advanced or extensive acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) have increased considerably thereby altering the normal clinical course of previously devastating or otherwise fatal neurologic diagnoses. Numerous studies and guidelines have outlined airway management and ventilation, blood pressure management, the role of osmotherapy, targeted normothermia and hypothermia, and the use of advanced neuromonitoring in this clinical setting. Additionally, patients with AIS and ICH are at risk for secondary brain damage by various neurologic complications including increased intracranial pressure, reperfusion injury, perihematomal edema, and seizure as well as numerous systemic complications that often call for invasive or operative measures. Critical care expertise in the management of these complex patients is invaluable and depending on the collaboration of neurointensivists, vascular neurologists, neurosurgeons, specialized ICU nurses, and therapists. In summary, the initial management of complex AIS and ICH patients in many cases is best facilitated in focused neurologic ICUs with the collaboration of various medical practitioners. Ongoing studies continue to shed light on the most effective means to address primary neurologic injury and prevent secondary complications in these particular stroke patients threatened by death and disability.

Understanding the working principles of anaesthetic equipment and drugs helps us compensate when they don't work as expected. It is presumed to be a foundation of safety, and has therefore become a fundamental part of the postgraduate syllabus. Yet, there are exceptions. The most baffling, perhaps, are the very notions of consciousness and its loss 1. But that, practical clinicians would say, is philosophy. So, how about lipid emulsion as an antidote to local anaesthetic systemic toxicity (LAST)? Nothing is philosophical about fat – and, at first glance, its use might seem amenable to hard empirical graft. Yet, life-threatening LAST is unpredictable, potentially lethal and rare. This makes it impossible to study prospectively and ethically in humans. And so, in 2007, when the AAGBI first recommended the use of lipid in LAST - as a last resort- its mechanism had not been studied in our species. Indeed, it wasn't clear to what degree it worked at all. It just seemed not to do harm, and to have saved some lives in extremis 2, 3. Since then, two putative mechanisms have attracted most speculation. The first has a confusing array of labels: ‘physical’; ‘partitioning’; ‘pharmacokinetic’; and ‘the lipid sink’- they all suggest that the hydrophobic local anaesthetic settles in the suddenly increased lipid phase of the circulating volume, and the concentration in the aqueous phase falls safely away. The second possible set of mechanisms is more biological, or pharmacodynamic: lipid may have direct effects on pertinent tissues, above all the heart and brain. Studied in isolation, in the simplest of models, evidence has accrued for both mechanisms. For example, lipophilic drugs such as bupivacaine will indeed partition into lipid added to a phial of plasma, and work with dyes provides visually striking support for this mechanism 4-6. Similarly, isolated intoxicated hearts are given a fillip when lipid is added to their perfusate 7. But, of course, the price of such simplicity in the laboratory is potential clinical irrelevance. An intoxicated patient dying fast is a far cry from a dangling heart in Langendorff preparation. So, investigators have tackled more complex models, making different compromises. In some work, toxic doses have been studied in animal models; in other work, smaller doses have been studied in humans 8-13. There has also been more work done in vitro and also, more recently, in silico- that is, with computer modelling 14. Over time, lipid's action as an antidote has become somewhat clearer. One group of studies on whole animals is particularly instructive. In the first work on lipid's beneficial effect in LAST, rats were studied 8. From there, investigators scaled up to dogs and rabbits 9, 11. Again, lipid seemed beneficial in LAST. But work on lipid in LAST conducted in pigs has been equivocal 10, 12. These mixed results have sustained sceptics. In the UK, lipid's contribution to resuscitation in LAST is currently accepted. But in Finland, for example, there is no national guideline, and protocols for treatment of LAST include lipid emulsion in only 47% of hospitals 15. It transpires that pigs have an idiosyncratic reaction to lipid emulsion infusion: increases in systolic and pulmonary artery pressures correlate with dose, while heart rate falls. Exactly what mediates the reaction is unclear, though thromboxane is implicated 16. But whatever the reason, the reaction makes pigs a poor model for any studies of lipid as an antidote, and provides a salutary lesson in the dangers of presuming one species approximates another. Researchers studying sub-toxic doses of local anaesthetic in humans have taken another tack. Professor Rosenberg's group, for example, studied healthy male volunteers who were administered a low dose of bupivacaine, and then either saline or lipid 13. Blood samples taken five minutes later yielded fascinating results. If the lipid functions as a sink, it should absorb lipophilic bupivacaine, and this in turn should reduce the concentration of bupivacaine in the aqueous phase of plasma. Amongst Professor Rosenberg's volunteers, those given lipid should have had, in the aqueous phase of their plasma, lower concentrations of bupivacaine. And yet they didn't. Between the two groups, there was little difference five minutes after lipid administration. The only discrepancy will be relevant in a moment: the total bupivacaine concentration in circulating blood decayed faster in the volunteers who got lipid; there was a statistically significant difference 20 and 30 minutes after the lipid was given. So, is the pharmacokinetic hypothesis debunked? Or, if you'll forgive it, is the sink sunk? In short, the answer is ‘yes’. But the damage hasn't been done only by Rosenberg et al.; Professor Weinberg's group has also contributed 14. Looking at rats, Weinberg's group zoomed in on the first minutes after lipid was administered. In their model, action was very fast; five minutes after the lipid had been given as an antidote to intoxication by local anaesthetic, much of relevance was over. In the first minutes after intoxicated rats were given lipid, the antidote made a substantial difference to the distribution of the local anaesthetic through the rats’ bodies; after two minutes, the rats who got lipid had more bupivacaine in their blood, but less in their cardiac tissue and less in their cerebellum. Bupivacaine also washed faster out of the lungs and kidneys of rats treated with lipid. In other words, lipid didn't seem to act as a lipid sink; instead, lipid appeared to serve first as a vehicle. It appeared to scavenge local anaesthetic from the heart, brain and other well-perfused organs, carrying it to other more poorly perfused tissues. Five minutes after lipid had been given to the rats, it scarcely affected the concentration of bupivacaine in whole blood. All this is consistent with Rosenberg et al's results: no evidence for a long-lasting sink, but acceleration of the clearance of local anaesthetic. Weinberg et al's results also add detail to a pharmacodynamic effect. They imply that lipid has little effect on cardiac function while concentrations of local anaesthetic are high. But as the lipid vehicle relieves cardiac tissue of its local anaesthetic burden, then, as a threshold is passed, the lipid begins to boost cardiac output. So the whole process may be summarised thus: lipid carries local anaesthetic from heart and brain to less well-perfused organs, and then, as the concentration of local anaesthetic falls far enough, lipid also acts as a tonic to the depressed hear. One reasonable response to all this is to ask: ‘does it matter’? Three strands braid together to form the predictable answer: ‘yes, with reservations’. First, a better understanding of lipid's action as an antidote will guide design of therapeutic emulsions. After all, Intralipid® has been widely used and studied largely because, in many countries, it is more familiar than alternatives as a foundation for total parenteral nutrition. However, it may not be optimal as an antidote. In the past, researchers have compared different emulsions to identify those which bind more local anaesthetic when mixed up with local anaesthetic and something like plasma 4, 6. Others have gone further to engineer pegylated liposomes, all intended especially to absorb toxins 17. Tinkering further to acidify the liposomes’ interior significantly boosts the nano-carriers’ capacity to capture local anaesthetic 18. But, now it seems that such absorption into circulating lipid may not be what the intoxicated patient needs. Just as haemoglobin is an excellent transport molecule because it not only binds blood gases, but also releases them appropriately, so the affinity of lipid for local anaesthetic may not be the ultimate test. What may matter more is how effective a shuttle an antidote is. Second, the armamentarium of the resuscitator may change. In the latest UK Resuscitation Council Guidelines, epinephrine and amiodarone hold their places, confounding the winds of change, despite a remarkably shallow evidence base 19. Resuscitation in LAST was notoriously difficult before the use of lipid, and nothing has changed in this regard. But it might: levosimendan has its proponents, for example 20. Used in LAST, it may simply complement lipid emulsion;(the sole published study was underpowered 21). But, in the more distant future, some drug may so surpass lipid as to render it redundant. Third, LAST's incidence may be falling, though the causes of this welcome development are unclear. Changes in training, staffing and in the presentation and storage of local anaesthetic may have contributed. Changes in anaesthetic technique may also have played a part. Recognition of the danger of single-shot epidural injections of large volumes of local anaesthetic led to wider adoption of catheters, incremental and test doses. In addition, wider use of ultrasound to guide perineural and fascial blocks may be leading to smaller doses of local anaesthetic, and above all, to operators moving the needle as the dose is delivered 22. A moving needle may cause more physical trauma, but intravascular injections should be smaller. Some have suggested that the danger of LAST is now more ghost than bogeyman 23. Local anaesthetic systemic toxicity lies between the two extremes: it still happens, but not so frequently as to be familiar. So it behoves us to beware, and to incur the small costs of remaining ready to treat it. Complacency is dangerous to all; at least in some settings, the risk of being sued for malpractice rises with the anaesthetist's age. Perhaps the delusion of safety and supranormal ability gathers with success through time, until the very worst occurs 24. No external funding or conflicts of interest declared.

Editor—We read the report of Dr Nielsen and colleagues with great interest.1Nielsen K Scheffer HJ Vieveen JM et al.Anaesthetic management during open and percutaneous irreversible electroporation Br.J. Anaesth. 2014; 113: 985-992Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar We also have had only two transitory benign dysrhythmias in our experience of 175 procedures (93 liver, 6 lung, 55 pancreas and 21 others). One further patient, a man in his 40s undergoing treatment of a lesion in the second segment of his liver, went into atrial fibrillation and underwent DC cardioversion at the procedure’s completion. So we substantiate Dr Nielsen’s suggestion that the procedure is safe. We too have found that after treatments in the liver or lung, patients are relatively comfortable. Indeed, we speculate that IRE in these organs causes less post-procedural discomfort than thermal ablation, particularly when the target is close to sensate pleura or hepatic capsule. Like Dr Nielsen, we have found that patients undergoing treatments of pancreatic lesions have much more severe pain, particularly when the target is in the head of the pancreas. Moreover, we have found that this pain is often refractory to treatment with conventional opioid analgesia, but may be relieved by ketamine. (We have not tried pre-procedural pregabalin or gabapentin). We too have found the pain generally resolves within 24 h. But occasional patients develop refractory nausea which may last two or so days, and one developed urinary symptoms which took months to resolve. Our anaesthetic technique for infra-diaphragmatic targets has evolved in a similar fashion to Dr Nielsen. But our technique for lesions in the lungs is different. In these cases we maintain spontaneous respiration while the needles are placed. We then pre-oxygenate, induce neuromuscular relaxation with rocuronium and then treat the lesion. On several occasions we have (with close co-operation and frequent review of axial images) proceeded to relocate the needles, to target further lesions in the same lung during the same anaesthetic. This has required gentle positive pressure ventilation, but no pneumothorax has developed. Indeed, after six treatments by lung IRE, we have never placed a chest drain. (Our corresponding figure for thermal ablation is around 0.5%). As the last pulse is delivered, we reverse rocuronium’s action with sugammadex and allow the patient to resume spontaneous respiration. The use of the synchroniser warrants further commentary. Its function is imperfect. In particular, its circuitry can be ‘saturated’ by the generator’s pulse, particularly when the synchroniser’s gain is set high. Then, after a short period, the synchroniser may allow the pulse generator to deliver a stimulus, even if the pulse is not synchronized with the patient’s ECG. Setting the gain too low, is however, unhelpful, if the ECG is no longer detected. We find it helpful to set the synchroniser’s gain where the patient’s R waves are just detected, and to choose a lead (amongst I, II, III etc) which is at right angles to a line joining the needles. (So, if the needles are directed approximately posteriorly, one caudad to the other, we choose a lateral lead). In short, we are reassured by the similarity of Dr Nielsen’s results and ours, and by the size of our combined group. We hope our experience encourages other teams to adopt this promising technology, and we look forward to improvements in the patients’ management, (and control of pain and bp in particular), as experience spreads and deepens. None declared.

Anaesthetists are often compared with aviators. We all remain calm under pressure, save lives with cool dexterity and share a dedication to safety and to learning from near misses. Pursuing the comparison, induction of general anaesthesia and emergence is often likened to take-off and landing, but there is another potentially instructive analogy. It arises in the delivery of peripheral regional anaesthesia: nerve and plexus blocks. Until very recently, these blocks were normally conducted with a nerve stimulator: the anaesthetist would taxi out over a foggy airstrip guided by local knowledge and a map (an appreciation of surface anatomy and geometry) and the site of needle puncture of the skin would be chosen. Then – throttles forward – the anaesthetist would plunge the needle through the skin, flying on instruments, unseeing, unaware of potentially important dangers hidden in the fog. Later, the anaesthetist would burst through the cloud ceiling as the nerve stimulator elicited a motor response. From here, a careful titration of the needle’s position and the stimulator’s electrical output would guide the needle tip close to the nerve, close enough to ensure a successful block, but not so close as to cause damage. Two principles guided the practice of peripheral nerve block using peripheral nerve stimulation. First, it was presumed that if the insulated needle was delivering stimuli of about 500 nC (0.5 mA at 100 μs) and no motor response was elicited, then the needle tip could not be in a healthy patient’s nerve. Second, it was presumed that injection within the nerve would cause damage to it, and thence necessarily cause postoperative neurological deficits and so should be avoided. Recently, both principles have been revealed to be utterly illusory. The rot was set in with papers by Choyce et al. and Urmey and Stanton [1, 2]. These had similar designs: patients’ nerves were approached by experienced regional anaesthetists until parasthesiae were reported, suggesting that nerve and needle were extremely close. Then nerve stimulators were turned on, and the threshold charge recorded. In many cases, much more than the traditional 0.5 mA (at 100 μs) were required to elicit a motor response, suggesting that when needles are consistently manipulated until they induce twitches at that level, they will sometimes be intraneural. In the following years, this suspicion was confirmed. Again, a series of papers had similar designs: experienced regional anaesthetists performed nerve blocks with a nerve stimulator, sought motor responses at a conventional threshold stimulus, injected local anaesthetics and then inspected the site of injection with an ultrasound. In many instances, the nerve was swollen, suggesting that the injection was in fact intraneural [3, 4]. So what of the second principle? Regional anaesthetists had believed that they generally avoided nerve injury because they avoided intraneural injection. If intraneural injection is in fact more common, then the link between the site of injection and postoperative functional deficit must be more complex. And so it is: intraneural injections have been bravely reported without sequelae; indeed, in 2006, Bigeleisen purposely gave intraneural injection to 26 patients with no residual neurological deficit reported at 6 months [5, 6]. The explosion of these two long-held principles has excited a vigorous debate in regional anaesthetic circles. Both the histological correlates and clinical implications are unclear. Some believe that injection within the nerve, in the compliant stroma between the fascicles, is benign, whereas injection within the fascicles themselves will cause damage [5]. Some have even suggested that intraneural injections should be the anaesthetist’s aim, as they may accelerate a block’s onset [7]. Conversely, where there is less stroma and more fascicle in the nerve – for example, in the roots of the brachial plexus, where interscalene blocks are targeted – injections further from the nerves may be safer and yet as effective [8, 9], as suggested by the work of Spence et al. in this issue [10]. Of course, in the best of all possible worlds, there would be some sign that a needle was approaching the danger zone before any irreversible damage was done. Even a sign that a needle already was in the danger zone would be useful, if it prevented further damage on injection, but unfortunately there are no irreproachable candidates. For a start, nerve stimulators’ function has been revealed to be much more complex than once widely presumed. (It is just possible that they return as welcomed champions, if ever it is shown that low effective stimuli coincide with danger zones within the nerve). Many authorities set great store on a competent awake patient’s ability to report pain or reveal new signs. Indeed, for this very reason, the American Society of Regional Anesthesia’s Practice Advisory says specifically that ‘interscalene blocks should not be performed in anesthetized or heavily sedated adult or pediatric patients’ [11], but there are also case reports of painless and uneventful procedures that are followed by neurological deficits apparently attributable to injections [12]. The possibility that intraneural injections are particularly dangerous when the needle tip is within a non-compliant fascicle has suggested an ingenious means to avoid damage. Hadzic and his colleagues in particular have proposed that pressure be measured during the injection, and that there should be a limit of 15 lb.in−2 (approximately 100 kPa). If surpassed, the needle may be blocked, or in the fascia, or in a fascicle – in any of these events, the injection should not proceed [13]. Conversely, if the resistance to injection is low, then, in principle, the injection should be safe. In practice, though, this technique has not yet been widely adopted in the UK. Early hopes in high resolution ultrasound have also been disappointed. Above all, this is because even the most expert anaesthetists misdirect their needles. This may in part reflect simple human frailty: needles occasionally are advanced even when the tip is imperfectly seen [14]. In contrast, parenchymal physics conspire against us too: although an incipient intraneural injection can often easily be seen, it may also sometimes be more subtle [15, 16]. It may be, for example, that injection into the stroma compresses or ruptures fascicles without an increase in the diameter of the nerve itself [17]. So, damage to nerves during peripheral regional anaesthesia will continue, even in the age of ultrasound – and so, cannot be excluded as a cause of postoperative neurological deficit. Mercifully, the incidence of damage is low. (Auroy et al.’s landmark study yielded the oft-quoted risk of 1:4185 in 1998–1999 for a neurological deficit attributable to the block – and 1:7175 for a deficit lasting more than 6 months [18]. Barrington et al.’s more recent study suggests marginally higher risks of 1:2300 and 1:3578, respectively [19]). These clearly are the relevant data to quote when techniques are discussed with patients before surgery. At that rate, anaesthetists who rarely perform blocks may never see a case of actual damage. (Similarly, claims of negligence pursued through the National Health Service Litigation Authority are rare: between 1995 and 2007, there were just five claims linking a peripheral block to nerve damage [20]). In contrast, the risk of a neurological deficit (stemming from any cause) following surgery with a peripheral block is much higher. Borgeat et al., for example, found that as many as 14% of patients who underwent elective shoulder surgery with a block reported some form of neurological deficit [21]. Similarly, Barrington et al. (looking at all peripheral blocks combined) clocked up a 1:239 risk of postoperative neurological abnormality [19]. This is clearly much more common than anaphylaxis, malignant hyperpyrexia or systemic intoxication by local anaesthetic. However, although there are carefully prepared action plans for this awful triad, confusion reigns over the management of unexpected postoperative neurological deficit. This may be because there are two elements to what advice does exist: of course the patient’s treatment and prognosis dominates, but the apportionment of blame looms large too. Appropriate management depends, of course, on the patient’s details. If a deficit is reported only weeks, or even years, after surgery, then there is clearly no urgency. If the deficit is resolving, then management can be low-key, reassuring and conservative. The drama arises when a more severe deficit emerges acutely. We believe that in this setting, it is sensible to get three friends to help, Musketeer style. The first step is to consult a radiologist urgently to exclude a compressive – and so easily remediable – cause. A wise anaesthetist will not suggest to a radiologist what modality to employ; although ultrasound may be useful in the arm and at the knee and below, magnetic resonance imaging may be the radiologist’s choice more centrally. Just as when a vertebral canal mass is suspected to compress the theca, this is an emergency that deserves prompt action, even outside conventional working hours. The next friend to recruit is a neurologist who should be encouraged to see the patient and document the precise deficit objectively. This may prove relevant in any future litigation. Moreover, the intervention of a third respected clinician can soothe relations between a surgeon and an anaesthetist when mutual recrimination can otherwise harm the patient’s, let alone the clinicians’, sang-froid. The neurologist can also provide an introduction to neurophysiologists, performing nerve conduction studies and electromyography (EMG). Once again, the wise anaesthetist will not too vehemently suggest timing and investigations to his/her neurophysiologic colleagues: theirs is an arcane world with many elusive subtleties. That said, there is a common misconception that can usefully be dispelled. In general, many neurophysiologists recommend delaying the EMG until 8–14 days after the presumed insult, when weak denervated muscles will develop spontaneous activity pointing towards axonal injury and loss, the extent of which can be quantified and may be localised. But this does not mean that patients’ referral should be delayed when a neurological deficit is detected after a block and surgery. On the contrary, there may be a good reason to perform an initial study earlier: for example, the deficit may in fact stem from trauma or dislocation preceding surgery, or from pre-existing pathology, in which case the abnormalities will be evident immediately. Similarly, denervation changes in muscles nearest to the injury appear much earlier than in more distally placed muscles and therefore some muscle groups may be eloquent far before others. The presence of sub-clinically preserved EMG motor units in a clinically paralysed muscle recorded in the early study can also provide reassurance that the nerve is in continuity. So, an EMG study even soon after the deficit is reported may help identify its cause. Equally, nerve conduction studies can identify peripheral nerve dysfunction even acutely, and so may explain a deficit more distally that might otherwise be attributed to a proximal plexus block. High-voltage electrical stimulation of the cervical roots proximal to the brachial plexus may also be useful to demonstrate conduction block and/or the integrity of the neural pathways to paralysed muscles. It is therefore sensible to discuss cases promptly with neurophysiologists, and welcome early studies, even if they serve only as baselines. Early studies in turn may clarify the cause of a patient’s deficit earlier, informing both the patient’s prognosis and the practice of reflective clinicians. That said, if intraneural injection of local anaesthetic is the cause of a deficit, neurophysiologic studies are unlikely to guide treatment: there are few, if any, circumstances when a surgeon would attempt reconstruction. Returning to aviation, when flying blind, dead-reckoning was replaced by intersecting radio beams. Now the Global Positioning System (GPS) provides perfect positioning. However, a pair of commercial pilots recently was so enrapt in an argument, they flew over 100 miles past their destination without noticing [22]. Similarly, we anaesthetists have increasingly sophisticated navigation devices that successively reveal their predecessors’ weaknesses. We too are subject to human error. The similarities are uncanny, but perhaps in this small regard, anaesthesia has stolen a march on aviation: you can bet the arguing pilots did not have an action card for their predicament! We thank Dr Peter Misra, Consultant Clinical Neurophysiologist, for his wise and generous advice. No external funding and no competing interests declared.

Regional anaesthesia can marvellously dull the pain (and limit some other complications) of trauma, surgery and childbirth. But like all powerful techniques, it may have complications. Here the complications of regional anaesthesia are reviewed. The risks, presentation and the management of these complications are discussed in turn.

Gathering evidence from animal experiments, an editorial in this journal and published human case reports culminated in the Association of Anaesthetists of Great Britain and Ireland recommending in August 2007 that lipid emulsion be immediately available to all patients given potentially cardiotoxic doses of local anaesthetic drugs. This development offered an opportunity to track the adoption of an innovation by anaesthetists in the UK and to gauge the effects of guidelines. Two surveys, each of 66 NHS hospitals delivering acute care within London and its penumbra, examined the adoption of lipid emulsion therapy. After the publication of the editorial in autumn 2006, the spread of ‘lipid rescue’ was rapid. The timing of the adoption and the impetus for innovation varied substantially between the sampled hospitals. When the formal guidelines were published, approximately half of the hospitals surveyed did not have lipid rescue. Of those that subsequently adopted it, half attributed their decision to the guidelines. At the end of 2007, there remained a small number of hospitals that had yet to adopt lipid rescue. Lipid rescue’s adoption by anaesthetists in the UK offers a rare example of swift uptake of an innovation. National guidelines accelerated the adoption of innovation by some hospitals.

Obstetric Anesthesia Digest: March 2010 - Volume 30 - Issue 1 - p 25-26 doi: 10.1097/01.aoa.0000367006.71007.1a

used would have created very abnormal conditions and thus would not have been represented by this study (Fig. 2). We have ruled out a drip-arm phenomenon on the basis that the Intralipid was infused over a short period of time, and the effect on laboratory analysis was consistent and prolonged in both patients. Clearly this could pose a problem in more unstable patients, as it is not entirely clear how paracetamol and salicylate assays would be affected. If Intralipid is given very early, it may necessitate blind treatment with N-Acetylcysteine on the assumption that a toxic dose of paracetamol has been consumed. Discussion with our biochemist has ensued, and we have now agreed to pursue funding for an ultracentrifuge to allow analysis of extremely lipaemic serum. While the rapid acceptance of lipid rescue for local anaesthetic toxicity is to be commended, there is clearly more to be learned on this subject, especially if we are to start introducing it out for the treatment of other forms of drug toxicity.

In Response: We thank Drs. Picard, Meek, and Ward (1) for their interest in our paper (2) and their kind comments. We applaud physicians in the United Kingdom for developing consensus protocols for treatment of local anesthetic intoxication and regret that relevant specialty organizations in North America have not yet gone through the same process. Cardiac toxicity from bupivacaine and similar compounds is every bit as much an “anesthetic disease” as malignant hyperthermia (MH). Moreover, local anesthetic cardiac toxicity may be significantly more common than MH. Therefore, it is surprising that we in the United States have protocols for the rarer disease and disappointing that we have not yet adopted a similar protocol for the more common potentially lethal problem. Leanne Groban, MD J. C. Gerancher, MD Robert S. Weller, MD Department of Anesthesiology Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC [email protected] John Butterworth, MD Indiana University School of Medicine Indianapolis, IN

Regional anaesthesia forms an important part of anaesthesia and pain management. A wide variety of adjuvant agents are used along with local anaesthetic mixtures to enhance and prolong their actions. In this article we examine the adjuvants used in current clinical practice in the UK: the commonly used opioids as well as non-opioid drugs. Opioids are discussed in greater detail as they are the most researched. The mechanism of action of each drug is discussed and the most popular routes of administration are mentioned. Evidence for clinical effectiveness is also covered. The commonly encountered adverse effects and precautions that should be considered are also cited.

Fat is bad for you. It may make our food appetising, but is widely consumed in gross surfeit. In excess, fat harms our patients and impedes any anaesthetic manoeuvre. But fat may also be clinically useful. An intravenous bolus of lipid may save lives in one otherwise lethal situation, namely refractory cardiovascular collapse caused by an overwhelming overdose of local anaesthetic. So, how can lipid help? One lipid emulsion – Intralipid ; (Fresenius Kabi, Runcorn, UK) – is a time-honoured cocktail: an emulsion of soya oil, glycerol and egg phospholipids. It is a component of parenteral nutrition; many anaesthetists inject it every working day as part of their propofol. But for all its familiarity, it has a little known characteristic: in animals it is an effective antidote to the cardiovascular collapse caused by overdose of bupivacaine. This has been shown by Guy Weinberg and his colleagues at the University of Illinois in Chicago, who gave rats varying doses of bupivacaine [1]. When the rats became asystolic, they received cardiopulmonary resuscitation followed by intravenous doses of either saline or lipid. Comparison of the dose–survival curves for the two groups is impressive. The toxic dose was increased by approximately 50% in the group that received lipid. The curves do not even overlap: a universally fatal dose in the saline group was universally survived by all rats that received lipid. Weinberg’s group then moved up the food chain to dogs [2]. Cardiovascular collapse was induced with intravenous bupivacaine and the dogs were resuscitated with standardised cardiopulmonary resuscitation for 10 min (to mimic the inevitable initial confusion surrounding such an unexpected collapse). Then either saline or lipid was given. All six dogs in the saline group died, whereas all six in the lipid group regained normal heart rhythm (all but one within 5 min of treatment). So what is happening? At a molecular level, the precise mechanism of the collapse is unclear. Local anaesthetics bind and inhibit a wide variety of both voltage-gated and ligand-gated channels, and other proteins besides. Indeed, because local anaesthetics have hydrophilic and hydrophobic moieties, they are peculiarly able to bind proteins whether they are dissolved in cytosol or in the lipid bilayer of cell or organelle membrane. One protein that may be particularly important is carnitine acylcarnitine translocase. Normally lost in the mists of preclinical biochemistry, this carrier resumes anaesthetic significance because the heart has a predilection for fatty acids, ketone bodies and lactate. The translocase contributes to the passage of the acyl CoA constituents of the longer fatty acids across the mitochondrial membranes to the site of their oxidation. If it is inhibited by local anaesthetics, then fatty acids will not be fully oxidised, and the heart’s adenosine triphosphate supply will dry up. (This may explain why the collapse is so dreadfully refractory to conventional treatment). Just how lipid reverses local anaesthetic toxicity is also not known. It may act simply as a circulating lipid sink, drawing local anaesthetic out of the plasma. Alternatively, the fat rush may overwhelm the inhibition of the translocase by mass action. This would increase the myocardium’s energy supply and so its susceptibility to resuscitation. Based on these findings, Weinberg has recommended a dose regimen for clinical use (see Box) [3]. But, how safe is it to apply these findings to humans? Sceptics will point out four weaknesses in Weinberg’s evidence. First, his group have experimented with racemic bupivacaine. Would lipid work as well if ropivacaine or levo-bupivacaine were responsible for the collapse? We don’t know; perhaps the corresponding experiments will one day be done. Meanwhile what we do know suggests that lipid may be an effective antidote to overdoses of the single isomer preparations, too. After all, both bupivacaine enantiomers are similarly hydrophobic, and ropivacaine also is known to inhibit carnitine acylcarnitine translocase – albeit less potently than racemic bupivacaine [4]. Second, there is some evidence that intravenous boluses of lipid can adversely affect heart and lungs, causing pulmonary vasoconstriction in particular [5]. Is this a reason now to eschew lipid as an antidote for otherwise overwhelming intoxication by local anaesthetic? We believe not: the animal evidence is that lipid does very much more good than harm. Third, Weinberg’s resuscitation did not include epinephrine, which would surely be used in humans according to current protocols. Would the advantages of lipid persist if used in conjunction with epinephrine? We don’t know; the experimental difficulty is that small animals intoxicated by local anaesthetics are relatively easily resuscitated with epinephrine, whereas humans are not. To demonstrate that any adjunct to epinephrine has statistically significant benefits, the experimenter can either sacrifice large numbers of animals, or omit epinephrine from resuscitation – the more humane, economic and realistic option. Fourth, if small animals react differently to local anaesthetic overdose, is it appropriate to base human clinical practice on these animal studies alone? The stark truth is that we may have no choice. There are currently no case reports of lipid emulsion use in human resuscitation. The very unpredictability, rarity and severity of overwhelming intoxication with local anaesthetic make controlled and ethical human Anaesthesia, 2006, 61, pages 107–109 .....................................................................................................................................................................................................................

We read with glee the letter from Drs Dalgleish and Kathawaroo promoting Intralipid as an antidote to local anaesthetic intoxication [1]. The work published by Dr Weinberg's team has impressed us, too – most recently a bolus and then infusion of Intralipid has been shown effective in a canine model of overwhelming inadvertent intravenous injection of local anaesthetic [2]. Given the rarity and severity of local anaesthetic overdose, higher grade scientific evidence is unlikely. We have therefore introduced 500 ml bags of Intralipid 20% to our recovery and labour wards. In each unit, a single 500 ml bag nestles close to the O negative blood and another crucial antidote: dantrolene. (The Intralipid costs less than £20, and can be returned to pharmacy to be included in total parenteral nutrition towards the end of its shelf life of up to a year.) Attached to each bag is a laminated card describing the dosage suggested by Dr Weinberg: ‘1 ml.kg−1 over 1 min, while continuing chest compressions…repeated every 3–5 min to a maximum of 3 ml.kg−1, converting at that point, or earlier with evidence of recovery, to a continuous infusion of lipid 20% at a rate of 0.25 ml.kg−1.min−1, given until haemodynamic recovery’[3]. We would exhort colleagues who administer large doses of local anaesthetic to do the same.

BACKGROUND:A community-randomised trial was undertaken to assess the impact, cost, and cost-effectiveness of averting HIV-1 infection through improved management of sexually transmitted diseases (STDs) by primary-health-care workers in Mwanza Region, Tanzania.METHODS:The impact of improved treatment services for STDs on HIV-1 incidence was assessed by comparison of six intervention communities with six matched communities. We followed up a random cohort of 12,537 adults aged 15-54 years for 2 years to record incidence of HIV-1 infection. The total and incremental costs of the intervention were estimated (ingredients approach) and used to calculate the total cost per case treated, the incremental cost per HIV-1 infection averted, and the incremental cost per disability-adjusted life-year (DALY) saved.FINDINGS:During 2 years of follow-up, 11,632 cases of STDs were treated in the intervention health units. The baseline prevalence of HIV-1 infection was 4%. The incidence of HIV-1 infection during the 2 years was 1.16% in the intervention communities and 1.86% in the comparison communities. An estimated 252 HIV-1 infections were averted each year. The total annual cost of the intervention was US$59,060 (1993 prices), equivalent to $0.39 per head of population served. The cost for STD case treated was $10.15, of which the drug cost was $2.11. The incremental annual cost of the intervention was $54,839, equivalent to $217.62 per HIV-1 infection averted and $10.33 per DALY saved (based on Tanzanian life expectancy) or $9.45 per DALY saved (based on the assumptions of the World Development Report). In a sensitivity analysis of factors influencing cost-effectiveness, cost per DALY saved ranged from $2.51 to $47.86.INTERPRETATION:Improved management of STDs in rural health units reduced the incidence of HIV-1 infection in the general population by about 40%. The estimated cost-effectiveness of this intervention ($10 per DALY) compares favourably with that of, for example, childhood immunisation programmes ($12-17 per DALY). Cost-effectiveness should be further improved when the intervention is applied on a larger scale. Resources should be made available for this highly cost-effective HIV control strategy.

Malaria patients' loss of effective work time can account for an important proportion of the disease's economic cost. Here the extent, incidence and determinants of this loss are investigated. Data from 695 matched patient-control pairs from Nawal Parasi and Dhanusa districts in Nepal are analysed. Pairwise differences in work time are attributed to malaria, and the individual influences of the differences' determinants identified by regression. The mean pairwise differences in the number of days wholly and partially disabled by illness in the month preceding interview were respectively 5.31 (95% confidence interval 4.82-5.79) and 1.21 days (95% CI 0.95-1.47). The interval between fever onset and presumptive treatment, parasite species, the density of peripheral parasitaemia and district of residence each exerted significant influences over the difference in complete disability. The mean pairwise difference in the number of minutes worked on the day before the interview was 108 (95% CI 97-120). Socioeconomic variables, the interval between interview and perceived complete recovery, the pairwise difference in the number of days' complete disability in the month preceding interview and district of residence were significant to this difference. Poorer patients lose more time. The results corroborate past assumptions of debility, demonstrate that malaria's effect on effective work time may vary between socioeconomic groups, and underline the economic importance of speedy case detection and presumptive treatment.

In recent trials in The Gambia, mass chemoprophylaxis with Maloprim(R) administered over several years by primary health care workers to children aged 3-59 months has reduced both mortality and morbidity without inducing impairment of natural immunity or significant development of drug resistance. Taking expenditure of both time and money, by both public authorities and village volunteers, into account, the costs and the cost effectiveness of such mass chemoprophylaxis are estimated here. The cost per child protected per season was (1990 US) $2.84; the cost per childhood death averted was $143. Both costs compare favourably with those of permethrin bed net impregnation. So in some circumstances where malaria is holoendemic, control of childhood malaria by chemoprophylaxis may be more economically efficient than provision of impregnated bed nets.