Effect of high-flow nasal oxygen on hypoxaemia during procedural sedation: a systematic review and meta-analysis.

We conducted a systematic review to evaluate the effect of high-flow nasal oxygen and conventional oxygen therapy during procedural sedation amongst adults and children. We searched MEDLINE, EMBASE and CINAHL for randomised controlled trials that reported the effects of high-flow nasal oxygen during procedural sedation. The primary outcome measure was hypoxaemia and the secondary outcomes were minimum oxygen saturation; hypercarbia; requirement for airway manoeuvres; and procedure interruptions. The quality of evidence was assessed using the revised Cochrane risk-of bias tool and grading of recommendations, assessment, development and evaluation (GRADE). Nineteen randomised controlled trials (4121 patients) including three in children were included. Administration of high-flow nasal oxygen reduced hypoxaemia, risk ratio (95%CI) 0.37 (0.24-0.56), p < 0.001; minor airway manoeuvre requirements, risk ratio (95%CI) 0.26 (0.11-0.59), p < 0.001; procedural interruptions, risk ratio (95%CI) 0.17 (0.05-0.53), p = 0.002; and increased minimum oxygen saturation, mean difference (95%CI) 4.1 (2.70-5.50), p < 0.001; as compared with the control group. High-flow nasal oxygen had no impact on hypercarbia, risk ratio (95%CI) 1.24 (0.97-1.58), p = 0.09, I2 = 0%. High-flow nasal oxygen reduced the incidence of hypoxaemia regardless of the procedure involved, degree of fractional inspired oxygen, risk-profile of patients and mode of propofol administration. The evidence was ascertained as moderate for all outcomes except for procedure interruptions. In summary, high-flow nasal oxygen compared with conventional oxygenation techniques reduced the risk of hypoxaemia, increased minimum oxygen saturation and reduced the requirement for airway manoeuvres. High-flow nasal oxygen should be considered in patients at risk of hypoxaemia during procedural sedation.

Predicting patients at risk of early postoperative adverse events.

Adverse events after surgery are common. Identification of markers of at-risk patients may facilitate efficient and effective perioperative resource allocation. This pilot study aimed to identify simple preoperative factors associated with postoperative adverse events. In 1291 surgical patients, the relationship between patient and surgical factors and adverse events in the post-anaesthesia care unit was examined using binomial logistic regression analysis. Adverse events in the postoperative care unit were common, including desaturation (13.6%), hypotension (5.8%) and apnoea (5.5%), with 19.9% of cases requiring attendance by an anaesthetist to manage unexpected complications. Average length of stay in the post-anaesthesia care unit was 120 minutes and prolonged stay for medical reasons was common. A number of patient and surgical factors, including surgical complexity, preoperative arrhythmia, previous anaesthetic issues and heart failure were strongly associated with these adverse events. Areas under receiver operating characteristic curves ranged from 0.63 to 0.80. Patients with adverse events in the post-anaesthesia care unit appeared to have a higher risk of intervention in postoperative wards from a medical emergency or intensive care unit team. Our preliminary findings suggest that preoperative identification of key factors may have utility in determining risk of early postoperative problems and hence, aid perioperative planning.

Pharmacokinetics of oxycodone after subcutaneous administration in a critically ill population compared with a healthy cohort.

This study aimed to characterise and compare the absorption pharmacokinetics of a single subcutaneous dose of oxycodone in critically ill patients and healthy subjects. Blood samples taken at intervals from two minutes to eight hours after a subcutaneous dose of oxycodone in patients (5 mg) and healthy volunteers (10 mg) were assayed using high performance liquid chromatography. Data were analysed using a non-compartmental approach and presented as mean (SD). Parameters were corrected for dose differences between the groups assuming linear kinetics. Ten patients (eight male, two female) and seven healthy male subjects were included. Maximum venous concentration and area under the concentration curve were approximately two-fold lower in the patient group for an equivalent dose, suggesting either reduced bioavailability or increased clearance: maximum venous concentration 0.14 ± 0.06 vs 0.05 ± 0.02 µg/ml (P <0.0001); area under the concentration curve 19.50 ± 9.15 vs 9.72 ± 2.71 µg/ml/minute (P <0.001) respectively. However, time to maximum venous concentration and mean residence time were not different, suggesting similar absorption rates: time to maximum venous concentration 22.10 ± 18.0 vs 20.50 ± 16.10 minutes (P=0.81); mean residence time 353 ± 191 vs 291 ± 80 minutes (P=0.26). Kinetic parameters were less variable in patients than in volunteers. The patients therefore had reduced exposure to subcutaneous oxycodone. This warrants further model-based analysis and experimentation. Dose regimens for subcutaneous oxycodone developed in healthy volunteers cannot be directly translated to critically ill patients.

An analysis of computer-assisted pre-screening prior to elective surgery.

In order to assess the potential utility of guided patient self-assessment as an early preoperative triage tool, a computer-assisted questionnaire delivered by a non-clinician via telephone was 1) compared to face-to-face interview and examination by anaesthetists in outpatient clinics and 2) evaluated as a mechanism to stream patients to day of surgery assessment. In total, 514 patients scheduled for elective surgery in two tertiary public hospitals were assessed initially by telephone and then in an outpatient clinic. Both forms of assessment were marked by panels of specialist anaesthetists, who also provided an opinion on which patients would have been suitable to bypass preoperative anaesthetic outpatient assessment based upon information provided by the telephone interview. Overall, the quality of assessment provided by non-clinician telephone interview was comparable to face-to-face interview by anaesthetists, although more complex issues required face-to-face assessment. Panel review considered that 398 patients (60%) would not have required evaluation by an anaesthetist until the day of surgery, thus avoiding the need to separately attend a preoperative outpatient clinic. The sensitivity of telephone interview provided information to correctly classify patients as suitable for day of surgery evaluation was 98% (95% confidence interval 96 to 99%) with a specificity of 97% (95% confidence interval 92 to 98%). This study demonstrates that remote computer-assisted assessment can produce quality patient health information and enable early patient work-up and triage with the potential to reduce costs through more efficient use of resources.

Crisis management during anaesthesia: myocardial ischaemia and infarction.

BACKGROUND: Myocardial ischaemia and infarction are significant perioperative complications which are associated with poor patient outcome. Anaesthetic practice should therefore focus, particularly in the at risk patient, on their prevention, their accurate detection, on the identification of precipitating factors, and on rapid effective management. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK" supplemented by a specific sub-algorithm for myocardial ischaemia and infarction in the management of myocardial ischaemia and/or infarction 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: Of the 125 incidents retrieved from the 4000 reports, 40 (1%) were considered to demonstrate myocardial infarction or ischaemia. The use of the structured approach described in this paper would have led to appropriate management in 90% of cases, with the remaining 10% requiring other sub-algorithms. It was considered that the application of this structured approach would have led to earlier recognition and/or better management of the problem in 45% of cases. CONCLUSION: Close and continuous monitoring of patients at risk of myocardial ischaemia during anaesthesia is necessary, using optimal ECG lead configurations, but sensitivity of this monitoring is not 100%. Coronary vasodilatation with glyceryl trinitrate (GTN) should not be withheld when indicated and the early use of beta blocking drugs should be considered even with normal blood pressures and heart rates.

Crisis management during anaesthesia: desaturation.

BACKGROUND: Desaturation occurs for many reasons under anaesthesia, some rare and obscure, and many potentially life threatening. The rapidity with which the cause is determined and appropriate management is instituted varies considerably between anaesthetists. OBJECTIVES: To examine the role of a previously described "core" algorithm COVER ABCD-A SWIFT CHECK, supplemented by a specific sub-algorithm for desaturation, in the management of incidents of desaturation 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: Amongst the first 4000 incidents reported to AIMS there were 584 episodes of desaturation in association with general anaesthesia; 41% were dealt with by COVER, 48% by ABCD, and 11% required a specific desaturation sub-algorithm. Nearly a fifth of all desaturations were caused by endobronchial intubation. Within the specific desaturation subgroup, half were due to pulmonary problems in the form of underlying lung disease, excessive secretions or obesity and a third could not be diagnosed. CONCLUSION: Desaturation may have many causes, some of which are obscure, and failure to respond promptly may place the patient at risk. In the face of persistent desaturation, management should consist of hand ventilation with 100% oxygen, completion of COVER ABCD-A SWIFT CHECK, and a return to a supine posture. Blood gases, chest radiography, and bronchoscopy may be required where desaturation is persistent and/or no apparent causes can be found.

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.

Recirculatory model of fentanyl disposition with the brain as the target organ.

BACKGROUND: The factors affecting the concentrations of fentanyl in the brain after intravenous administration have not been completely quantified. METHODS: A model integrating the role of brain, lung and systemic kinetics was developed based on data from conscious instrumented sheep. Brain kinetics were inferred from arterio-sagittal sinus concentration gradients and cerebral blood flow, and lung kinetics from the pulmonary artery-aortic gradient and cardiac output. The best models of the lung and brain were incorporated into a recirculatory model of the whole-body disposition of fentanyl. The validity of the model structure was tested by its ability to describe published data on the effect of hypo-, normo- and hypercarbia on the blood and brain concentrations of fentanyl in anaesthetized dogs. RESULTS: The cerebral kinetics of fentanyl were consistent with partial membrane limitation: the time to 50% equilibration with arterial blood was 10.0 min. Lung kinetics had two distinct components: a shallow compartment that was 50% equilibrated with blood in 0.72 min, and a loss term probably representing sequestration. Despite its simplicity, the recirculatory model was an adequate description of the sheep data. The dog data could be described if cerebral blood flow and cardiac output in the model were allowed to differ between hypo-, normo- and hypercarbic states. The required flow changes were in good agreement with the known effect of these states in the dog. CONCLUSIONS: A recirculatory model with the brain as a target organ defined the quantitative relationship between the brain concentrations of fentanyl and the circulatory state.

Cerebral and lung kinetics of morphine in conscious sheep after short intravenous infusions.

BACKGROUND: The analgesic effects of morphine are delayed relative to its concentration in blood. The rate of equilibration of morphine between blood and brain may contribute to this delay, but the kinetics of this process have not been modelled. This was determined in conscious instrumented sheep. The lung kinetics of morphine were also determined given their importance in defining systemic kinetics after i.v. bolus administration. METHODS: Sheep were given short i.v. infusions of morphine (30 mg over 4 min). Cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and cerebral blood flow, and lung kinetics from the pulmonary artery-aortic gradient and cardiac output. These data were fitted to flow- and membrane-limited models of the kinetics in each organ. RESULTS: Morphine had minimal cardiovascular effects, did not alter cerebral blood flow and caused insignificant respiratory depression. Lung kinetics were best described by a single distribution volume (2036 ml) with a first-order loss (1370 ml min(-1)), which was attributed to deep distribution. The cerebral kinetics of morphine were characterized by a significant permeability barrier. Permeability across the barrier (7.44 ml min(-1)) was estimated with good precision, and was approximately one-fifth of the nominal cerebral blood flow. The distribution volume of morphine in the brain was estimated with less precision, but was described by a brain:blood partition coefficient of approximately 1.4. The time required for 50% equilibration between brain and blood concentrations was approximately 10.3 min. CONCLUSION: The cerebral equilibration of morphine was relatively slow, and was characterized by significant membrane limitation.

Cerebrovascular carbon dioxide reactivity in sheep: effect of propofol or isoflurane anaesthesia.

Propofol and isoflurane are commonly used in neuroanaesthesia. Some published data suggest that the use of these agents is associated with impaired cerebral blood flow/carbon dioxide (CO2) reactivity. Cerebrovascular CO2 reactivity was therefore measured in three cohorts of adult merino sheep: awake (n=6), anaesthetized with steady-state propofol (15 mg/min; n=6) and anaesthetized with 2% isoflurane (n=6). Changes in cerebral blood flow were measured continuously from changes in velocities of blood in the sagittal sinus via a Doppler probe. Alterations in the partial pressure of carbon dioxide in arterial blood (PaCO2) over the range 18-63 mmHg were achieved by altering either the inspired CO2 concentration or the rate of mechanical ventilation. Cerebral blood flow/CO2 relationships were determined by linear regression analysis, with changes in cerebral blood flow expressed as a percentage of the value for a PaCO2 of 35 mmHg. Propofol decreased cerebral blood flow by 55% relative to pre-anaesthesia values (P=0.0001), while isoflurane did not significantly alter cerebral blood flow (88.45% of baseline, P=0.39). Significant linear relationships between cerebral blood flow and CO2 tension were determined in all individual studies (r2 ranged from 0.72 to 0.99). The slopes of the lines were highly variable between individuals for the awake cohort (mean 4.73, 1.42-7.12, 95% CI). The slopes for the propofol (mean 2.67, 2.06-3.28, 95% CI) and isoflurane (mean 2.82, 219-3.45, 95% CI) cohorts were more predictable. However, there was no significant difference between these anaesthetic agents with respect to the CO2 reactivity of cerebral blood flow.

A mixture of alfentanil and morphine for rapid postoperative loading with opioid: theoretical basis and initial clinical investigation.

Pharmacokinetic modelling of estimated central nervous system concentrations was used to devise the optimal mixture of morphine and alfentanil for the treatment of postoperative pain. Modelling revealed that an intravenous opioid pain protocol using an alfentanil-morphine mixture in the proportions 0.75 : 10 mg would provide a profile of analgesia of rapid onset, yet slow offset. The regimen was evaluated in 58 patients in the recovery ward who were randomly allocated to receive analgesia using pain protocols with either morphine or the mixture. Groups were well matched for age, weight and initial pain scores. The mean (SD) time to patient comfort was 27.6 (20.2) min for the mixture and 41.2 (18.6) min for morphine (p = 0.01). Multiple regression analysis revealed that that initial pain score (p = 0.009) and drug group (p = 0.02), but not age, weight or gender were independent predictors of the time to comfort. Drug group was not a significant predictor of adverse effects.

Acute cardiovascular effects of magnesium and their relationship to systemic and myocardial magnesium concentrations after short infusion in awake sheep.

The temporal relationship between the systemic and myocardial concentrations of magnesium and some of its acute cardiovascular effects were examined after short i.v. infusion administration of magnesium (30 mmol over 2 min) in five awake chronically instrumented sheep. Magnesium decreased mean arterial blood pressure and systemic vascular resistance (SVR) by 23 and 41% from baseline, respectively. These hemodynamic changes were consistent with magnesium producing primary reductions in SVR with partial heart rate (HR)-mediated compensation of blood pressure. Cardiac output and HR increased by 38 and 38% from baseline, respectively. Magnesium had little effect on myocardial contractility, but substantially increased myocardial blood flow (MBF, 77% above baseline) primarily due to direct myocardial vasodilation. The peak arterial and coronary sinus serum magnesium concentrations were 6.94 +/- 0.26 (mean +/- S.E.M.) and 6.51 +/- 0.20 mM, respectively, at 2 min. Both arterial and coronary sinus magnesium concentrations at the end of the study were still more than 3 mM, whereas all the cardiovascular effects were back to baseline. The myocardial kinetics of magnesium was consistent with rapid equilibration of magnesium (half-life 0.4 min) with a small distribution volume (71 ml) consistent with the extracellular space of the heart. In conclusion, magnesium was shown to have a rapid equilibration between the plasma/serum concentrations of magnesium and its extracellular concentration in the myocardium. However, the primary cardiovascular effect of magnesium (reductions in SVR) preceded its extracellular concentrations, and was a direct function of its arterial concentration. A "threshold" model for changes in SVR was preferred when linked to the arterial magnesium concentration.

In vivo cerebral pharmacokinetics and pharmacodynamics of diazepam and midazolam after short intravenous infusion administration in sheep.

The cerebral pharmacokinetics and pharmacodynamics of midazolam and diazepam were examined in chronically instrumented sheep via measurements of their arterio-venous concentration difference across the brain during and after 2-min i.v. infusions. Diazepam (30 mg) or midazolam (10 mg) were administered on 5 separate occasions to 4 sheep. For both drugs, rapid cerebral uptake occurred during the infusion, which quickly turned to elution in the postinfusion period. However, this process was more rapid for midazolam than diazepam. The cerebral pharmacokinetics of both was better described by a kinetic model with slight membrane limitation rather than flow limitation. For diazepam, the estimated brain:plasma partition coefficient was 2.67, and the first and second compartments filled with half-lives of 2.2 and 0.5 min, respectively. For midazolam, these values were 0.27, 0.26 and 1.34 min, respectively. In a subset of sheep, pulmonary arterial-arterial gradients were too small to measure suggesting limited metabolism and small distribution volumes for both drugs in the lungs. Simultaneous dynamic measurements of cerebral blood flow and algesimetry lagged behind both the arterial and sagittal sinus blood concentrations. The changes in cerebral blood flow were best described by a previously published a dynamic model that incorporated long half-lives for drug dissociation from the benzodiazepine receptor (13.3 and 5.5 min for midazolam and diazepam, respectively). Effect compartment modeling of the cerebral blood flow data showed apparent effect compartment half-lives (t1/2,keo) that were longer than the half-lives of cerebral equilibration.

The cerebral and systemic kinetics of thiopentone and propofol in halothane anaesthetized sheep.

The cerebral and systemic kinetics of intravenous thiopentone (250 mg over 2 minutes, n=5) and propofol (100 mg over 2 minutes, n=6) were determined in sheep anaesthetized with halothane (2.0%) and mechanically ventilated to an end-expired carbon dioxide tension of 40 mmHg. The sheep were previously instrumented with arterial and sagittal sinus (effluent from the brain) blood sampling catheters. Systemic kinetics were inferred from the time-course of the arterial blood concentrations, and cerebral kinetics from the time-course of the arterio-sagittal sinus concentration difference across the brain. Under halothane anaesthesia, the peak arterial concentrations of each drug occurred at the end of the two-minute infusion, and was 42.3 mg/l and 12.3 mg/l for thiopentone and propofol, respectively. Propofol had a significantly larger systemic clearance (3.19 l/min) than thiopentone (0.99 l/min). The brain concentrations of propofol equilibrated more slowly with the arterial concentrations than those of thiopentone. The extraction ratio across the brain near the end of the infusions (1.5 min) were 0.85 and 0.46 respectively. These data were also compared to analogous previously published data for initially conscious sheep. The systemic kinetics of thiopentone were little affected by halothane anaesthesia. For propofol, halothane anaesthesia was associated with a statistically significant reduction in clearance (50% of awake), a slower initial half-life (247% of awake), and the emergence of a second slower half-life in some sheep. The cerebral kinetics of both drugs were subtly altered by halothane anaesthesia.

The effect of altered cerebral blood flow on the cerebral kinetics of thiopental and propofol in sheep.

BACKGROUND: Thiopental and propofol are highly lipid-soluble, and their entry into the brain often is assumed to be limited by cerebral blood flow rather than by a diffusion barrier. However, there is little direct experimental evidence for this assumption. METHODS: The cerebral kinetics of thiopental and propofol were examined over a range of cerebral blood flows using five and six chronically instrumented sheep, respectively. Using anesthesia (2.0% halothane), three steady state levels of cerebral blood flow (low, medium, and high) were achieved in random order by altering arterial carbon dioxide tension. For each flow state, 250 mg thiopental or 100 mg propofol was infused intravenously over 2 min. To quantify cerebral kinetics, arterial and sagittal sinus blood was sampled rapidly for 20 min from the start of the infusion, and 1.5 h was allowed between consecutive infusions. Various models of cerebral kinetics were examined for their ability to account for the data. RESULTS: The mean baseline cerebral blood flows for the "high" flow state were over threefold greater than those for the low. For the high-flow state the normalized arteriovenous concentration difference across the brain was smaller than for the low-flow state, for both drugs. The data were better described by a model with partial membrane limitation than those with only flow limitation or dispersion. CONCLUSIONS: The cerebral kinetics of thiopental and propofol after bolus injection were dependent on cerebral blood flow, despite partial diffusion limitation. Higher flows produce higher peak cerebral concentrations.