A vanguard randomised feasibility trial comparing three regimens of peri-operative oxygen therapy on recovery after major surgery.

International recommendations encourage liberal administration of oxygen to patients having surgery under general anaesthesia, ostensibly to reduce surgical site infection. However, the optimal oxygen regimen to minimise postoperative complications and enhance recovery from surgery remains uncertain. The hospital operating theatre randomised oxygen (HOT-ROX) trial is a multicentre, patient- and assessor-blinded, parallel-group, randomised clinical trial designed to assess the effect of a restricted, standard care, or liberal peri-operative oxygen therapy regimen on days alive and at home after surgery in adults undergoing prolonged non-cardiac surgery under general anaesthesia. Here, we report the findings of the internal vanguard feasibility phase of the trial undertaken in four large metropolitan hospitals in Australia and New Zealand that included the first 210 patients of a planned overall 2640 trial sample, with eight pre-specified endpoints evaluating protocol implementation and safety. We screened a total of 956 participants between 1 September 2019 and 26 January 2021, with data from 210 participants included in the analysis. Median (IQR [range]) time-weighted average intra-operative Fi O2 was 0.30 (0.26-0.35 [0.20-0.59]) and 0.47 (0.44-0.51 [0.37-0.68]) for restricted and standard care, respectively (mean difference (95%CI) 0.17 (0.14-0.20), p < 0.001). Median time-weighted average intra-operative Fi O2 was 0.83 (0.80-0.85 [0.70-0.91]) for liberal oxygen therapy (mean difference (95%CI) compared with standard care 0.36 (0.33-0.39), p < 0.001). All feasibility endpoints were met. There were no significant patient adverse events. These data support the feasibility of proceeding with the HOT-ROX trial without major protocol modifications.

A pilot randomised controlled trial of the management of systolic blood pressure during endovascular thrombectomy for acute ischaemic stroke.

It is unknown whether systolic blood pressure augmentation during endovascular thrombectomy improves clinical outcomes. This pilot randomised controlled trial aimed to assess the feasibility of differential systolic blood pressure targeting during endovascular thrombectomy procedures for anterior circulation ischaemic stroke. Fifty-one eligible patients fulfilling the national criteria for endovascular thrombectomy were randomly assigned to receive either standard or augmented systolic blood pressure management from the start of anaesthesia to recanalisation of the target vessel. Systolic blood pressure targets for the standard and augmented groups were 130-150 mmHg and 160-180 mmHg, respectively. The study achieved all feasibility targets, including a recruitment rate of 3.5 participants per week and median (IQR [range]) of mean systolic blood pressure separation between groups of 139 (135-143 [115-154]) vs. 167 (150-175 [113-188]) mmHg, p < 0.001. Data completeness was 99%. Independent functional recovery at 90 days (modified Rankin Scale 0, 1 or 2) was achieved in 30 (59%) patients, which is consistent with previously published data. There were no safety concerns with trial procedures. In conclusion, a large randomised controlled efficacy trial of standard vs. augmented systolic blood pressure management during endovascular thrombectomy is feasible.

National risk prediction model for perioperative mortality in non-cardiac surgery.

BACKGROUND: Many multivariable models to calculate mortality risk after surgery are limited by insufficient sample size at development or by application to cohorts distinct from derivation populations. The aims of this study were to validate the Surgical Outcome Risk Tool (SORT) for a New Zealand population and to develop an extended NZRISK model to calculate 1-month, 1-year and 2-year mortality after non-cardiac surgery. METHODS: Data from the New Zealand National Minimum Data Set for patients having surgery between January 2013 and December 2014 were used to validate SORT. A random 75 per cent split of the data was used to develop the NZRISK model, which was validated in the other 25 per cent of the data set. RESULTS: External validation of SORT in the 360 140 patients who underwent surgery in the study period showed good discrimination (area under the receiver operating characteristic curve (AUROC) value of 0·906) but poor calibration (McFadden's pseudo-R2 0·137, calibration slope 5·32), indicating it was invalid in this national surgical population. Internal validation of the NZRISK model, which incorporates sex and ethnicity in addition to the variables used in SORT for 1-month, 1-year and 2-year outcomes, demonstrated excellent discrimination with AUROC values of 0·921, 0·904 and 0·895 respectively, and excellent calibration (McFadden's pseudo-R2 0·275, 0·308 and 0·312 respectively). Calibration slopes were 1·12, 1·02 and 1·02 respectively. CONCLUSION: The SORT performed poorly in this national population. However, inclusion of sex and ethnicity in the NZRISK model improved performance. Calculation of mortality risk beyond 30 days after surgery adds to the utility of this tool for shared decision-making.

ANTECEDENTES: Muchos modelos multivariados de estimación del riesgo de mortalidad después de la cirugía están limitados por haberse desarrollado a partir de tamaños muestrales insuficientes o por haberse aplicados a cohortes distintas de las poblaciones de derivación. Los objetivos de este estudio fueron validar el Surgical Outcome Risk Tool (SORT) para una población de Nueva Zelanda y desarrollar un modelo NZRISK extendido para calcular la mortalidad al mes y a los 1 y 2 años de una cirugía no cardíaca. MÉTODOS: Para validar el SORT se utilizó el Conjunto Mínimo Básico de Datos de Nueva Zelanda para los pacientes sometidos a cirugía entre enero de 2013 y diciembre de 2014. Se realizó una división aleatoria del 75% de los datos para desarrollar el modelo NZRISK que, posteriormente, se validó en el otro 25% del conjunto de datos. RESULTADOS: La validación externa de SORT en 360.140 pacientes intervenidos en el periodo analizado mostró una buena discriminación (área bajo las curvas de característica operativa del receptor (area under the receiver-operator characteristic curves (AUROC) 0,906)) pero con una mala calibración (pseudo-R2 de McFaddens 0,137 y pendiente de calibración 5,32), lo que indicaba que SORT no era válido para esta población quirúrgica nacional. La validación interna del modelo NZRISK, que incorpora el género y la etnia además de las variables utilizadas en el SORT, para los resultados al mes y a los 1 y 2 años demostró una excelente capacidad de discriminación con una AUROC de 0,921, 0,904, 0,895 respectivamente y una calibración excelente, con una pseudo-R2 de McFaddens de 0,275, 0,308 y 0,312 respectivamente. Las pendientes de calibración fueron de 1,12, 1,02 y 1,02, respectivamente. CONCLUSIÓN: El SORT no fue útil en esta población nacional. Sin embargo, la inclusión del género y la etnia en el modelo NZRISK mejoró sus resultados. El cálculo del riesgo de mortalidad más allá de 30 días después de la cirugía añade utilidad a esta herramienta para la toma de decisiones compartida.

A pilot study using preoperative cerebral tissue oxygen saturation to stratify cardiovascular risk in major non-cardiac surgery.

This prospective pilot study evaluated whether low preoperative cerebral tissue oxygen saturation is associated with unfavourable outcomes after major elective non-cardiac surgery. Eighty-one patients over 60 years of age, American Society of Anesthesiologists physical status 3 or 4, were recruited. Resting cerebral tissue oxygen saturation was recorded on room air, and after oxygen supplementation, using cerebral oximetry. The primary outcome was 30-day major adverse event of combined mortality or severe morbidity, and the secondary outcome was 30-day new disability. Eleven patients (13.6%) suffered a major adverse event, and 28 patients (34.6%) experienced new disability. Room air cerebral tissue oxygen saturation was significantly different between patients who had a major adverse event, 67% (95% confidence interval [CI] 65-70) versus unaffected, 71% (95% CI 70-72; P=0.04). No statistical difference was found between patients for new disability (range 70%-74%; P=0.73). Room air cerebral tissue oxygen saturation was significantly associated with major adverse events (odds ratio 1.36 (95% CI 1.03-1.79), P=0.03). Saturation levels ≤68% carried a positive likelihood ratio of 2.2 for death or severe morbidity, P=0.04. A definitive trial is required to confirm if cerebral oximetry can be used to stratify the cardiovascular risk of patients presenting for non-cardiac surgery.

Intraoperative dexamethasone does not increase the risk of postoperative wound infection: a propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX).

BACKGROUND: In a post hoc analysis of the ENIGMA-II trial, we sought to determine whether intraoperative dexamethasone was associated with adverse safety outcomes. METHODS: Inverse probability weighting with estimated propensity scores was used to determine the association of dexamethasone administration with postoperative infection, quality of recovery, and adverse safety outcomes for 5499 of the 7112 non-cardiac surgery subjects enrolled in ENIGMA-II. RESULTS: Dexamethasone was administered to 2178 (40%) of the 5499 subjects included in this analysis and was not associated with wound infection [189 (8.7%) vs 275 (8.3%); propensity score-adjusted relative risk (RR) 1.10; 95% confidence interval (CI) 0.89-1.34; P=0.38], severe postoperative nausea and vomiting on day 1 [242 (7.3%) vs 189 (8.7%); propensity score-adjusted RR 1.06; 95% CI 0.86-1.30; P=0.59], quality of recovery score [median 14, interquartile range (IQR) 12-15, vs median 14, IQR 12-16, P=0.10), length of stay in the postanaesthesia care unit [propensity score-adjusted median (IQR) 2.0 (1.3, 2.9) vs 1.9 (1.3, 3.1), P=0.60], or the primary outcome of the main trial. Dexamethasone administration was associated with a decrease in fever on days 1-3 [182 (8.4%) vs 488 (14.7%); RR 0.61; 95% CI 0.5-0.74; P<0.001] and shorter lengths of stay in hospital [propensity score-adjusted median (IQR) 5.0 (2.9, 8.2) vs 5.3 (3.1, 9.1), P<0.001]. Neither diabetes mellitus nor surgical wound contamination status altered these outcomes. CONCLUSION: Dexamethasone administration to high-risk non-cardiac surgical patients did not increase the risk of postoperative wound infection or other adverse events up to day 30, and appears to be safe in patients either with or without diabetes mellitus. CLINICAL TRIAL REGISTRATION: NCT00430989.

Accuracy and reliability of the i-STAT point-of-care device for the determination of haemoglobin concentration before and after major blood loss.

We investigated the accuracy of i-STAT(®) (Abbott Point of Care Inc., Princeton, NJ, USA) haemoglobin (Hb) measurement in surgical patients with an estimated blood loss of ≥25% of total blood volume. Blood tests for i-STAT(®) Hb, laboratory Hb (Sysmex XE-2100(™), Sysmex Corporation, Kobe, Japan) and total plasma proteins were obtained at the start of surgery (T=0) and when an estimated 25% total blood volume loss had occurred (T=1). Thirty-one patients were recruited. The coefficient of variation of the paired i-STAT(®) Hb estimates was 2.8% and 2.9% at T=0 and T=1, respectively. The mean difference between i-STAT(®) and laboratory Hb was -7.6 g/l (standard deviation 6.5) at T=0 and -5.1 g/l (standard deviation 12) at T=1. The mean total plasma protein difference (total plasma protein T=0 minus T=1) was 13.6 g/l (95% confidence interval 10.2 to 17.0). There was poor correlation between total plasma protein and bias in i-STAT(®) measurements. The i-STAT(®) Hb had an acceptable coefficient of variation, but the Hb levels were lower than those estimated by the laboratory. The standard deviation of i-STAT(®) Hb was greater after ≥25% estimated total blood volume loss. Clinicians should not use the i-STAT(®) Hb in isolation for clinical decision-making when considering blood transfusion in a situation of 25% or greater blood loss.

Beta-blocker management in high-risk patients presenting for non-cardiac surgery: before and after the POISE Trial.

The POISE Trial was a randomised, placebo-controlled, double-blind study of the effectiveness of perioperative beta-blockade in preventing cardiac events including death in 8351 patients. Our hypothesis was that knowledge of the results of the POISE Trial would either increase or decrease the use of effective perioperative beta-blockade, depending on the result. Patients presenting for non-cardiac surgery and at risk of perioperative cardiac events were recruited in two cohorts before and after the release of the POISE Trial results. Effective perioperative beta-blockade was defined as heart rate <65 beats per minute for at least 80% of the perioperative period in patients prescribed beta-blockers. Effective perioperative beta-blockade was achieved in 22 (11.5%) of 191 patients prescribed perioperative beta-blockade in the first cohort (n=392) and seven (6%) of 118 patients in the second cohort (n=241) (P=0.10). Effective heart rate control was achieved in 29 (9%) patients prescribed perioperative beta-blockers compared with 10 (3%) patients not prescribed perioperative beta-blockers (P=0.001). The rate of implementation of effective beta-blockade was low before POISE and this did not change significantly after publication. Our finding does not provide reliable evidence of a change in practice as a result of the POISE Trial.

Recovery from bispectral index-guided anaesthesia in a large randomized controlled trial of patients at high risk of awareness.

Electroencephalographic monitors of anaesthetic depth are reported to assist anaesthetists in reducing recovery times. We explored the effect of bispectral index (BIS) monitoring on recovery times in a double-blind, randomized controlled trial of 2,463 patients at high risk of awareness. Patients were randomized to BIS-guided anaesthesia or routine care. In the BIS group, anaesthesia was adjusted to maintain a BIS value of 40-60 from the commencement of laryngoscopy to the start of wound closure, and 55-70 during wound closure. In the routine care group, anaesthesia was adjusted according to traditional clinical signs. In multivariate models, BIS monitoring, female gender, lower American Society of Anesthesiologists' physical status and shorter duration of anaesthesia predicted faster time to eye-opening after anaesthesia, and faster time to post-anaesthesia care unit discharge. BIS monitoring did not affect times to tracheal extubation among patients admitted to the intensive care unit. We conclude that BIS monitoring has statistically significant, but clinically modest, effects on recovery times in high risk surgical patients.

Drug error in anaesthetic practice: a review of 896 reports from the Australian Incident Monitoring Study database.

Eight hundred and ninety-six incidents relating to drug error were reported to the Australian Incident Monitoring Study. Syringe and drug preparation errors accounted for 452 (50.4%) incidents, including 169 (18.9%) involving syringe swaps where the drug was correctly labelled but given in error, and 187 (20.8%) due to selection of the wrong ampoule or drug labelling errors. The drugs most commonly involved were neuromuscular blocking agents, followed by opioids. Equipment misuse or malfunction accounted for a further 234 (26.1%) incidents; incorrect route of administration 126 (14.1%) incidents; and communication error 35 (3.9%) incidents. The outcomes of these events included minor morbidity in 105 (11.7%), major morbidity in 42 (4.7%), death in three (0.3%) and awareness under anaesthesia in 40 (4.4%) incidents. Contributing factors included inattention, haste, drug labelling error, communication failure and fatigue. Factors minimising the events were prior experience and training, rechecking equipment and monitors capable of detecting the incident. The information gained suggests areas where improved guidelines are required to reduce the incidence of drug error. Further research is required into the effectiveness of preventive strategies.

Dreaming during anaesthesia in patients at high risk of awareness.

Dreaming during anaesthesia is commonly reported but remains poorly understood. In this study, adult surgical patients at high risk of awareness were randomly assigned to receive bispectral index (BIS)-guided anaesthesia or routine care, and were interviewed about dreaming three times postoperatively. Dreaming patients (n = 134) were compared with all other patients who were interviewed at least once (n = 2251). Intraoperative dreaming was reported by 4.2%, 3.9% and 3.4% of patients at 2-4 h, 24-36 h and 30 days after surgery, respectively. Fewer BIS-monitored patients reported intra-operative dreaming at 2-4 h than control patients (2.7% vs. 5.7%; p = 0.004). Reports of dreaming were similar in the two groups at 24-36 h and 30 days. Dreaming patients were younger (p = 0.001); healthier (p < 0.001) and more likely to be women (p < 0.001), and were less satisfied with anaesthetic care (p = 0.004) than other patients.

Awareness during general anaesthesia: a review of 81 cases from the Anaesthetic Incident Monitoring Study.

Because of recent studies suggesting that awareness is still a major issue in anaesthetic practice, we reviewed 8372 incidents reported to the Anaesthetic Incident Monitoring Study. There were 81 cases in which peri-operative recall was consistent with awareness. There were 50 cases of definite awareness and 31 cases with a high probability of awareness. In 13 of the 81 incidents, the patients appeared to receive adequate doses of anaesthetic drugs. Where the cause could be determined, awareness was mainly due to drug error resulting in inadvertent paralysis of an awake patient (n = 32) and failure of delivery of volatile anaesthetic (n = 16). Less common causes included prolonged attempts at intubation of the trachea (n = 5), deliberate withdrawal of volatile anaesthetic (n = 4) or muscle relaxant apnoea with inadequate administration of hypnotic (n = 3). An objective central nervous system depth of anaesthesia monitor may have prevented 42 of these incidents and an improved drug administration system may have prevented 32. On the basis of these reports, we have developed guidelines that may have prevented the majority of these incidents.

Closed loop control of anaesthesia: an assessment of the bispectral index as the target of control.

We investigated the performance of a closed-loop system for administration of general anaesthesia, using the bispectral index as a target for control. One hundred patients undergoing gynaecological or general surgery were studied. In 60 patients, anaesthesia was maintained by intravenous infusion of a propofol/alfentanil mixture. In 40, an isoflurane/nitrous oxide based technique was used. For each technique, patients were randomly allocated to receive either closed-loop or manually controlled administration of the relevant agents (propofol/alfentanil or isoflurane), with an intra-operative target bispectral index of 50 in all cases. Closed-loop and manually controlled administration of anaesthesia resulted in similar intra-operative conditions and initial recovery characteristics. During maintenance of anaesthesia, cardiovascular and electro-encephalographic variables did not differ between closed-loop and manual control groups and deviation of bispectral index from the target value was similar. Intra-operative concentrations of propofol, alfentanil and isoflurane were within normal clinical ranges. Episodes of light anaesthesia were more common in the closed-loop group for patients receiving propofol/alfentanil anaesthesia and in the manual group for patients receiving isoflurane/nitrous oxide anaesthesia. Convenience aside, the closed-loop system showed no clinical advantage over conventional, manually adjusted techniques of anaesthetic administration.

The sedative and electroencephalographic effects of regional anaesthesia.

We studied sedation scores, the processed electroencephalogram and mean arterial pressure pre-operatively in patients before and after spinal (n = 15) and lumbar epidural (n = 15) anaesthesia. We compared them with changes occurring over time in a control group (n = 15), using the responsiveness component of the Observer Assessment of Alertness and Sedation rating scale. The electroencephalographic variables studied were bispectral index, 95% spectral edge frequency, median frequency and the power distribution between frequency bands alpha, beta, theta and delta. No differences were detected within groups in sedation scores before and after intervention, or between groups at either stage. No between-group differences were detected in electroencephalographic variables. In the spinal group, spinal anaesthesia caused an increase in bispectral index, 95% spectral edge frequency, median frequency and beta frequencies, and a decrease in delta frequencies and mean arterial pressure. The increase in beta frequencies is similar to that seen in patients with low plasma concentrations of midazolam and may represent subclinical sedation.

Response surface model for anesthetic drug interactions.

BACKGROUND: Anesthetic drug interactions traditionally have been characterized using isobolographic analysis or multiple logistic regression. Both approaches have significant limitations. The authors propose a model based on response-surface methodology. This model can characterize the entire dose-response relation between combinations of anesthetic drugs and is mathematically consistent with models of the concentration-response relation of single drugs. METHODS: The authors defined a parameter, theta, that describes the concentration ratio of two potentially interacting drugs. The classic sigmoid Emax model was extended by making the model parameters dependent on theta. A computer program was used to estimate response surfaces for the hypnotic interaction between midazolam, propofol, and alfentanil, based on previously published data. The predicted time course of effect was simulated after maximally synergistic bolus dose combinations. RESULTS: The parameters of the response surface were identifiable. With the test data, each of the paired combinations showed significant synergy. Computer simulations based on interactions at the effect site predicted that the maximally synergistic three-drug combination tripled the duration of effect compared with propofol alone. CONCLUSIONS: Response surfaces can describe anesthetic interactions, even those between agonists, partial agonists, competitive antagonists, and inverse agonists. Application of response-surface methodology permits characterization of the full concentration-response relation and therefore can be used to develop practical guidelines for optimal drug dosing.

The use of propofol infusions in paediatric anaesthesia: a practical guide.

Children require higher infusion rates of propofol than adults to maintain clinical anaesthesia. We aimed to produce a manual infusion regimen capable of maintaining a steady-state blood concentration of 3 microg ml(-1) in children aged 3-11 years. Pharmacokinetic parameter estimates were taken from published studies of infusion data in children and used in a pharmacokinetic simulation programme to predict likely propofol blood concentrations during infusions. A variability of 5% was allowed about the target concentration of 3 microg ml(-1). A loading dose of 2.5 mg x kg(-1) followed by an infusion rate of 15 mg x kg(-1) x h(-1) for the first 15 min, 13 mg x kg(-1) x h(-1) from 15 to 30 min, 11 mg x kg(-1) x h(-1) from 30 to 60 min, 10 mg x kg(-1) x h(-1) from 1 to 2 h and 9 mg x kg(-1) x h(-1) from 2 to 4 h resulted in a pseudo-steady state target concentration of 3 microg x ml(-1) in children 3-11 years. We were unable to predict similar rates by applying size models to adult data. The context sensitive half-time in children was longer than in adults, rising from 10.4 min at 1 h to 19.6 min at 4 h compared to adult estimates of 6.7 min and 9.5 min, respectively. Children require higher infusion rates than adults to maintain steady state concentrations of 3 microg x ml(-1) and have longer context sensitive half-times than adults. These differences can be attributed to altered pharmacokinetics in this age group.