Increased substance P immunoreactivity and edema formation following reversible ischemic stroke.

Previous results from our laboratory have shown that neurogenic inflammation is associated with edema formation after traumatic brain injury (TBI). This neurogenic inflammation was characterized by increased substance P (SP) immunoreactivity and could be attenuated with administration of SP antagonists with a resultant decrease in edema formation. Few studies have examined whether neurogenic inflammation, as identified by increased SP immunoreactivity, occurs after stroke and its potential role in edema formation. The present study examines SP immunoreactivity and edema formation following stroke. Experimental stroke was induced in halothane anaesthetized male Sprague-Dawley rats using a reversible thread model of middle cerebral artery occlusion. Increased SP immunoreactivity at 24 hours relative to the non-infarcted hemisphere was observed in perivascular, neuronal, and glial tissue, and within the penumbra of the infarcted hemisphere. It was not as apparent in the infarct core. This increased SP immunoreactivity was associated with edema formation. We conclude that neurogenic inflammation, as reflected by increased SP immunoreactivity, occurs following experimental stroke, and that this may be associated with edema formation. As such, inhibition of neurogenic inflammation may represent a novel therapeutic target for the treatment of edema following reversible, ischemic stroke.

Crisis management during anaesthesia: awareness and anaesthesia.

BACKGROUND: Patient awareness during general anaesthesia has considerable potential for severe emotional distress in the patient as well as professional, personal, and financial consequences for the anaesthetist. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for awareness, in the detection and management of potential awareness in association with general anaesthesia. METHOD: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by the anaesthetists involved. RESULTS: Of the first 4000 reports received by AIMS, there were 21 incidents of patient awareness under general anaesthesia, and 20 of patients being paralysed while awake from "syringe swaps" before induction of anaesthesia. In 12 of the 21 reports there was an obvious cause, most commonly a low concentration of volatile agent (8 of 12 reports). The AIMS "core" crisis management algorithm would have detected the cause of awareness in all of these cases. In nine reports the course of anaesthesia appeared unremarkable, and in these the algorithm would not have been expected to detect or prevent awareness. Volatile agent monitoring would have prevented some cases of awareness, as would bispectral index electroencephalographic (BIS) monitoring. The role of BIS monitoring is still contentious, but it should be considered for high risk patients. CONCLUSION: Awareness should be minimised by thorough checking of equipment, particularly vaporisers, and frequent application of a structured scanning routine. Awareness may occur during crisis management and aftermath protocols should include patient follow up to detect and manage awareness when it occurs.

Crisis management during anaesthesia: embolism.

BACKGROUND: Embolism with gas, thrombus, fat, amniotic fluid, or particulate matter may occur suddenly and unexpectedly during anaesthesia, posing a diagnostic and management problem for the anaesthetist. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK" supplemented by a specific sub-algorithm for embolism, in the management of embolism occurring in association with anaesthesia. METHODS: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by the anaesthetists involved. RESULTS: Among the first 4000 incidents reported to AIMS, 38 reports of embolism were found. A sudden fall in end-tidal carbon dioxide and oxygen saturation were the cardinal signs of embolism, each occurring in about two thirds of cases, with hypotension and electrocardiographic changes each occurring in about one third of cases. CONCLUSION: The potential value of an explicit structured approach to the diagnosis and management of embolism was assessed in the light of AIMS reports. It was considered that, correctly applied, it potentially would have led to earlier recognition of the problem and/or better management in over 40% of cases.

Crisis management during anaesthesia: vascular access problems.

BACKGROUND: In confronting an evolving crisis, the anaesthetist should consider the vascular catheter as a potential cause, abandoning assumptions that the device has been satisfactorily placed and is functioning correctly. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for vascular access problems, in the management of crises occurring in association with anaesthesia. METHODS: The potential performance of a structured approach was evaluated for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS). RESULTS: There were 128 incidents involving problems related to vascular access. The structured approach begins distally, checking the infusion device or fluid (12 incidents), moving proximally by way of the fluid giving line (10), the line deadspace (8), then the catheter/skin interface (65), and on to the peripheral vascular tree (3) and central venous space (23), and finally, the interface of the vascular access system and the attending staff (7). The approach was able to accommodate all the vascular access problems among the first 4000 incidents reported to AIMS. CONCLUSION: The approach has potential as an easily remembered and applied clinical tool to lead to early resolution of vascular access problems occurring during anaesthesia.

Crisis management during anaesthesia: water intoxication.

BACKGROUND: Irrigation of closed body spaces may lead to substantial perioperative fluid and electrolyte shifts. A syndrome occurring during transurethral resection of prostate (TURP), and a similar syndrome described in women undergoing transcervical endometrial ablation (TCEA) are both characterised by a spectrum of symptoms which may range from asymptomatic hyponatraemia to convulsions, coma, and death. Such potentially serious consequences require prompt recognition and appropriate management of this "water intoxication" syndrome. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for water intoxication, in the management of this syndrome occurring in association with anaesthesia. METHODS: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by the anaesthetists involved. RESULTS: From the first 4000 incidents reported to AIMS, 10 reports of water intoxication were identified, two from endometrial ablations under general anaesthesia and eight from male urological procedures under spinal anaesthesia. The "core" crisis management algorithm detected a problem in seven cases; however, it was deficient in dealing with neurological presentations. Diagnosis of the cause of the incident would have required a specific water intoxication sub-algorithm in eight cases and a hypotension algorithm in a further two cases. Corrective strategies also required a specific sub-algorithm in eight cases, while the hypotension and cardiac arrest sub-algorithms were required in conjunction with the water intoxication sub-algorithm in the remaining two. CONCLUSION: This relatively uncommon problem is managed poorly using the "core" crisis management sub-algorithm and requires a simple specific sub-algorithm for water intoxication.

Crisis management during anaesthesia: bronchospasm.

BACKGROUND: Bronchospasm in association with anaesthesia may appear as an entity in its own right or be a component of another problem such as anaphylaxis. It may present with expiratory wheeze, prolonged exhalation or, in severe cases, complete silence on auscultation. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for bronchospasm, in the diagnosis and management of bronchospasm occurring in association with anaesthesia. METHODS: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by anaesthetists involved. RESULTS: There were 103 relevant incidents among the first 4000 AIMS reports, 22 of which were associated with allergy or anaphylaxis. Common presenting signs, in addition to wheeze, were decreased pulmonary compliance and falling oxygen saturation. Of the non-allergy/anaphylaxis related incidents, 80% occurred during induction or maintenance of anaesthesia. Of these, the principal causes of bronchospasm were airway irritation (35%), problems with the endotracheal tube (23%), and aspiration of gastric contents (14%). It was considered that, properly used, the structured approach recommended would have led to earlier recognition and/or better management of the problem in 10% of cases, and would not have harmed any patient had it been applied in all of them. CONCLUSION: Bronchospasm may present in a variety of ways and may be associated with other life threatening conditions. Although most cases are handled appropriately by the attending anaesthetist, the use of a structured approach to its diagnosis and management would lead to earlier recognition and/or better management in 10% of cases.

A comparison of iatrogenic injury studies in Australia and the USA. II: Reviewer behaviour and quality of care.

OBJECTIVE: To better understand the remaining three-fold disparity between adverse event (AE) rates in the Quality in Australia Health Care Study (QAHCS) and the Utah-Colorado Study (UTCOS) after methodological differences had been accounted for. SETTING: Iatrogenic injury in hospitalized patients in Australia and America. DESIGN: Using a previously developed classification, all AEs were assigned to 98 exclusive descriptive categories and the relative rates compared between studies; they were also compared with respect to severity and death. MAIN OUTCOME MEASURES: The distribution of AEs amongst the descriptive and outcome categories. RESULTS: For 38 categories, representing 67% of UTCOS and 28% of QAHCS AEs, there were no statistically significant differences. For 33, representing 31% and 69% respectively, there was seven times more AEs in QAHCS than in UTCOS. Rates for major disability and death were very similar (1.7% and 0.3% of admissions for both studies) but the minor disability rate was six times greater in QAHCS (8.4% versus 1.3%). CONCLUSIONS: A similar 2% core of serious AEs was found in both studies, but for the remaining categories six to seven times more AEs were reported in QAHCS than in UTCOS. We hypothesize that this disparity is due to different thresholds for admission and discharge and to a greater degree of under-reporting of certain types of problems as AEs by UTCOS than QAHCS reviewers. The biases identified were consistent with, and appropriate for, the quite different aims of each study. No definitive difference in quality of care was identified by these analyses or a literature review.

A classification for adverse drug events.

There is considerable evidence that a large number of patients suffer adverse events arising from their health-care management. A significant proportion of these iatrogenic injuries occur as a result of medication errors. Before prevention strategies can be developed, it is necessary to understand the types of errors that are occurring. In order to set priorities, it is necessary to identify the frequency and impact of the various types of medication errors. To fully investigate medication incidents, it is necessary to classify the information in a way that allows the frequencies, causes and contributing factors to be analysed. The development of a sub-branch of the 'Generic Occurrence Classification', specific to medication incidents, allows this analysis to occur.

An analysis of Australian adverse drug events.

Previous research has shown that there is a high error rate associated with medication use, resulting in significant patient morbidity and mortality, as well as increasing health care costs. Analysis of available Australian data on adverse drug events shows that incident monitoring and retrospective medical record review provide different, but complementary 'windows' into the errors that occur. While retrospective medical record review provides information on the frequency of specific adverse drug events, incident monitoring gives an insight into the contributing factors. From this information, priorities can be set and preventative strategies can be developed.

Towards safer drug use in general practice.

A voluntary, anonymous incident-monitoring study was set up to identify and characterize events or circumstances which could have or did harm a patient in general practice. The study included 673 practitioners who made 2582 reports, of which half (n = 1294) involved medication problems. Amongst these reports, 1556 adverse drug events (ADE) were identified. More common in general practice than in hospitals were problems with therapeutic use (26% vs. 8%), and prescribing of contraindicated medications (15% vs. 5%). In the latter group, 64 reports (4%) involved the prescription of a medication to which the patient was known to be allergic, 66 (4%) involved medication for which there was a recognized potential for a drug interaction, and 68 (4%) involved contraindicated medications due to pathophysiological factors. It was estimated that computer-based prescribing with decision support could eliminate at least a third of these problems in general practice. Further studies are needed to develop this and other preventive strategies.

Towards the safer use of dosettes.

Patient compliance has long been recognized to be a problem associated with drug treatment. Dosettes constitute a compliance aid; their aim is to maintain patient independence, while facilitating patient compliance. However, those patients most in need of such devices are the least likely to be able to manage them. It was therefore decided to examine incidents in which problems involving dosettes had been identified; 52 such incidents were found. Half the incidents involved filling errors, and most of these involved nurses; some incidents were potentially dangerous systematic errors. A second type of incident involved a problem with use, mainly caused by hurried or confused patients; these sporadic errors were less dangerous than filling errors. The remainder of the incidents involved patients taking medication in addition to the medication in the dosette. Recommendations include objectively assessing that a dosette is appropriate for the individual patient, and education about the need for compliance, meticulous care and checking when filling, and regular checks to confirm correct use.

A classification for incidents and accidents in the health-care system.

Problems that arise from health-care management, rather than from a disease process, are now recognized as making a substantial contribution to patient morbidity and mortality and to the cost of health care. However, most classifications of these problems do not provide sufficient detail to allow comparisons or to develop better strategies for the prevention, detection and management of these problems. A 'Generic Occurrence Classification' was developed to record their salient features, place them in context and elicit any system or human error-based contributing factors. This was done by an iterative process in which 'natural categories', identified from over 2000 incidents and 800 adverse events, were placed in a hierarchical structure created using software written in Microsoft Visual Basic; data were stored in a Microsoft Access database. This was shown to be a valid and reliable way to compare incidents and accidents from different sources and to allow sufficient detail to be retrieved to develop preventive strategies.

Cerebral arterial fat embolism in the rabbit.

This study was designed to measure the effects of cerebral arterial fat embolism on cerebral blood flow and function. Rabbits were injected via the left internal carotid artery with the neutral triglyceride triolein. Left cerebral blood flow was measured by laser Doppler flowmetry, and left sided brain function by electrocorticogram and cortical somatosensory evoked responses following electrical stimulation of the forepaw. Readings were taken for 2 h before injection to establish a baseline, and for 3 h after injection. Cerebral blood flow was significantly decreased at 45 min after the injection of the lipid, then progressively decreased further to approximately 50% of baseline after 2 h, at which level it remained for the last hour of the experiment. The electrocorticogram was rapidly, but transiently, suppressed. The evoked responses did not differ from baseline at each of the time points measured. Using 125I-triolein, 2.49% of the injected dose was measured in the brain 3 min after injection. The results show that in this rabbit model of cerebral arterial fat embolism only a small percentage of injected lipid passes into the brain, but this is sufficient to cause a reduction in cerebral blood flow over the following 2 h. The evoked responses never alter significantly from baseline values.

The relative effects of hypoxic hypoxia and carbon monoxide on brain function in rabbits.

New Zealand white rabbits were exposed to control conditions (n = 11), or to either a progressive hypoxic hypoxia produced by dilution of oxygen (O2) with nitrogen (n = 10) or a 1% carbon monoxide (CO) admixture for 15 min (n = 11). Both exposures caused a significant increase in cerebral blood flow (CBF) of up to 300% such that O2 delivery to the brain was unchanged. In the hypoxia group, a cortical somatosensory evoked response (CSER) was unaffected until the arterial O2 tension was below 20 mmHg. At this time, the rabbits became hypotensive, O2 delivery to the brain decreased dramatically and the CSER could not be elicited. In contrast, despite the maintenance of O2 delivery to the brain during and after the CO exposure, the CSER voltages were halved during the exposure and only recovered to about 80% of baseline subsequently. We conclude that the primary toxicity of CO to the brain in rabbits is not due to a reduction in O2 delivery.

Cerebral blood flow response to increases in arterial CO2 tension during alfentanil anesthesia in the rabbit.

The stability of cerebral function and blood flow (CBF), and the CBF response to changes in arterial carbon dioxide tension (CBF reactivity) during alfentanil anesthesia were examined in rabbits. This model was first shown to provide stable anesthesia, cortical function, and CBF for 4 h. CBF increased significantly to 159% [of baseline] in the left hemisphere and to 167% in the right within 5 min of an exposure to 5% CO2 (p = 0.009 on the left and p = 0.003 on the right), but then decreased to 123% on the left and to 137% on the right (not significantly different from baseline, p = 0.11 on the left and p = 0.07 on the right) while PaCO2 was still rising. Steady state reactivity levels (0.8 ml 100 g-1/min-1/mm Hg-1 CO2 on the left and 0.65 ml 100 g-1/min-1/mm Hg-1 CO2 on the right) were consistent with previous work and were reached at 20 min. These results suggest that mechanisms other than perivascular hydrogen ion concentration mediate the CBF response to changes in arterial CO2 tension during alfentanil anesthesia.

Air embolism of the brain in rabbits pretreated with mechlorethamine.

Infusion of 400 microliters air into the left internal carotid artery of five anesthetized rabbits caused transient pial arteriole air embolism, an immediate 41.9 +/- 0.8% dilatation of the embolized vessels, suppression of the cortical somatosensory evoked response to 29.4 +/- 2.7% of baseline, and a progressive decline in ipsilateral cerebral blood flow (measured by hydrogen clearance) to 46 +/- 4.1% of baseline after 2 hours. These values were significantly different from those at baseline and from the responses of 10 control rabbits given equivalent intracarotid saline infusions. Twelve other rabbits were made leukopenic by treatment with 1.5 mg/kg i.v. mechlorethamine 72 hours prior to study. Mean +/- SEM leukocyte count decreased from 6,320 +/- 73/mm3 to 1,890 +/- 66/mm3 without any change in the leukocyte differential or erythrocyte and platelet counts. Intracarotid infusion of saline into seven of the leukopenic rabbits caused no changes. In the other five leukopenic rabbits, infusion of 400 microliters air caused air embolism but did not produce the anticipated declines in cerebral blood flow or the cortical somatosensory evoked response, both of which remained indistinguishable from baseline values and responses in the seven saline-treated leukopenic controls. Similarly, air-embolized arterioles showed nonsignificant dilatation in leukopenic rabbits. Our data suggest that the decreases in both cerebral blood flow and brain function seen after air embolism require the presence of leukocytes.

Increasing doses of intracarotid air and cerebral blood flow in rabbits.

We studied the natural history of brain air embolism by observing bubbles in the pial vessels of rabbits and the effect of different doses of intracarotid air on brain function and blood flow. We identified and then studied two doses of air; 25 microliters in five rabbits caused rapid bubble transit, recovery, and then deterioration in brain function and blood flow and 400 microliters in five rabbits caused temporary bubble trapping and sustained deterioration in brain function. These dose responses correlate well with the natural history of divers with air embolism of the brain. All doses of air caused both arteriolar dilatation and reduced blood flow, which were independent of dose, whereas the detrimental effect of air embolism of brain function was dose dependent. Our results suggest that this is a good model of brain air embolism.

The effect of gas emboli on rabbit cerebral blood flow.

Many bubbles that enter the brain circulation pass through the arterioles and capillary beds and do not obstruct blood flow. Nevertheless, such bubbles could still disrupt brain function. An open-brain model in five anesthetized rabbits used the minimum dose of air (25 microliters) necessary to cause embolism of the exposed vessels, and these bubbles passed through the vessels without any trapping. Despite their rapid transit, the bubbles provoked a marked dilatation of the affected pial arterioles (mean increase after 15 minutes of 27%) that persisted for 90 minutes after the bubbles had disappeared. The changes in vessel diameter were associated with a delayed, but significant and progressive, reduction in both cerebral blood flow measured by hydrogen clearance and neural function measured by cortical somatosensory evoked response. The decrease in blood flow correlated well with the depression of neural function (r = 0.67). Because both cerebral blood flow and neural function temporarily returned to normal after air embolism, the subsequent changes seen in this model cannot be explained simply by the mechanical obstruction of blood flow by bubbles.

Selective breeding for sensitivity to DFP: generalization of effects beyond criterion variables.

The degree of generalization to the effects of DFP, an organophosphate anticholinesterase, was studied in two lines of Sprague-Dawley derived rats selectively bred for varying sensitivities to DFP. In the S13, S14, S15, and S16 generations the Flinders S-line of rats were still more sensitive to the effects of DFP on the criterion variables upon which selection was based: core body temperature, body weight and a simple operant response for water reward. The flinders S-line were also more sensitive to the effects of DFP on locomotor activity, FR5 responding for a water reward, and analgesia, indicating some degree of generalization. However, diarrhea, a symptom of peripheral effects of DFP, occurred at a similar incidence in the two lines, although males of both lines had higher incidences than the females. Neither of the two lines was affected by DFP for variables in which aversive (i.e. shock) motivation was used: The number of discriminative escape responses and the escape times were similar. These findings indicate that while the effects of DFP do generalize beyond the criterion variables upon which selection was based, the generalization is relatively specific. The data are consistent with the hypothesis that the changes in sensitivity have arisen because of changes in the functioning of a central cholinergic system(s).