IRON NOF trial: IV iron for anaemic patients with femoral fracture.

Background: Preoperative anaemia is associated with increased use of blood transfusions, a greater risk of postoperative complications, and patient morbidity. The IRON NOF trial aimed to investigate whether the administration of i.v. iron in anaemic patients during hip fracture surgery reduced the need for blood transfusion and improved patient outcomes. Methods: This phase III double-blind, randomised, placebo-controlled trial included patients >60 yr old with preoperative anaemia undergoing surgery for femoral neck or subtrochanteric fracture across seven Australian Hospitals. Patients were randomly allocated on a 1:1 basis to receive either i.v. iron carboxymaltose 1000 mg or placebo (saline) at operation. The primary endpoint was blood transfusion use, with secondary endpoints of haemoglobin concentration at 6 weeks, length of hospital stay, rehabilitation duration to discharge, and 6-month mortality. Subgroup analysis compared outcomes in patients <80 yr old and patients >80 yr old. All analyses were performed by intention-to-treat. This trial was terminated early because of jurisdictional changes of more restrictive transfusion practices and changes in consent requirements. Results: Participants (n=143) were recruited between February 2013 and May 2017. There was no difference observed in the incidence of blood transfusion between the treatment group (18/70) (26%) compared with the placebo group (27/73) (37%) (odds ratio for transfusion if receiving placebo: 1.70; 95% confidence interval [CI] 0.83-3.47; P=0.15) and there was no overall difference in the median number of blood units transfused between groups (odds ratio 1.52; 95% CI 0.77-3.00; P=0.22). Patients receiving i.v. iron had a higher haemoglobin 6 weeks after intervention compared with the placebo group (Hb 116 g L-1vs 108 g L-1; P=0.01). No difference was observed in length of hospital stay, rehabilitation duration to discharge, or 6-month mortality. However, in younger patients without major bleeding, the use of placebo compared with i.v. iron was associated with an increased number of units of blood transfused (placebo transfusion incidence rate ratio 3.88; 95% CI 1.16-13.0; P=0.03). Conclusions: In anaemic patients undergoing surgery for hip fracture, i.v. iron did not reduce the overall proportion of patients receiving blood transfusion. The use of i.v. iron may reduce the amount of blood transfused in younger patients. The use of i.v. iron is associated with increased haemoglobin concentrations 6 weeks after the operation. Clinical trial registration: ACTRN12612000448842.

Dexamethasone and persistent wound pain: a prespecified analysis of the randomised Perioperative Administration of Dexamethasone and Infection (PADDI) trial.

BACKGROUND: Dexamethasone is commonly administered intraoperatively to prevent postoperative nausea and vomiting and is believed to have analgesic properties. It is unknown whether it has an impact on chronic wound pain. METHODS: In this prespecified embedded superiority substudy of the randomised PADDI trial, patients undergoing non-urgent noncardiac surgery received dexamethasone 8 mg or placebo intravenously after induction of anaesthesia, and were followed up for 6 months postoperatively. The primary outcome was the incidence of pain in the surgical wound at 6 months. Secondary outcomes included acute postoperative pain and correlates of chronic postsurgical pain. RESULTS: We included 8478 participants in the modified intention-to-treat population (4258 in the dexamethasone group and 4220 in the matched placebo group). The primary outcome occurred in 491 subjects (11.5%) in the dexamethasone arm and 404 (9.6%) subjects in the placebo arm (relative risk 1.2, 95% confidence interval 1.06-1.41, P=0.003). Maximum pain scores at rest and on movement in the first 3 postoperative days were lower in the dexamethasone group compared with the control group {median 5 (inter-quartile range [IQR] 3.0-8.0) vs 6 (IQR 3.0-8.0) and median 7 (IQR 5.0-9.0) vs 8 (IQR 6.0-9.0), P<0.001 for both}. Severity of postoperative pain was not predictive of chronic postsurgical pain. The severity of chronic postsurgical pain and the frequency of neuropathic features did not differ between treatment groups. CONCLUSION: Administration of dexamethasone 8 mg i.v. was associated with an increase in the risk of pain in the surgical wound 6 months after surgery. CLINICAL TRIAL REGISTRATION: ACTRN12614001226695.

Dexamethasone and clinically significant postoperative nausea and vomiting: a prespecified substudy of the randomised perioperative administration of dexamethasone and infection (PADDI) trial.

BACKGROUND: Clinically significant postoperative nausea and vomiting (PONV) is a patient-reported outcome which reflects patient experience. Although dexamethasone prevents PONV, it is unknown what impact it has on this experience. METHODS: In this prespecified embedded superiority substudy of the randomised Perioperative Administration of Dexamethasone and Infection (PADDI) trial, patients undergoing non-urgent noncardiac surgery received dexamethasone 8 mg or placebo intravenously after induction of anaesthesia, and completed a validated PONV questionnaire. The primary outcome was the incidence of clinically significant PONV on day 1 or day 2 postoperatively. Secondary outcomes included the incidence of clinically significant PONV and severe PONV on days 1 and 2 considered separately. RESULTS: A total of 1466 participants were included, with 733 patients allocated to the dexamethasone arm and 733 to matched placebo. The primary outcome occurred in 52 patients (7.1%) in the dexamethasone arm and 66 (9%) patients in the placebo arm (relative risk [RR]=0.79; 95% confidence interval [CI], 0.56-1.11; P=0.18). Severe PONV occurred on day 2 in 27 patients (3.9%) in the dexamethasone arm and 47 patients (6.7%) in the placebo arm (RR=0.58; 95% CI, 0.37-0.92; P=0.02; number needed-to-treat (NNT)=36.7; 95% CI, 20-202). In the entire cohort of 8880 PADDI patients, lower nausea scores, less frequent administration of antiemetics, and fewer vomiting events were recorded by patients in the dexamethasone arm up to day 2 after surgery. CONCLUSIONS: Administration of dexamethasone 8 mg i.v. did not influence clinically significant PONV. Dexamethasone administration did, however, decrease the incidence and severity of PONV, and was associated with less frequent administration of antiemetic agents. CLINICAL TRIAL REGISTRATION: ACTRN12614001226695.

Compatibility of intravenous acetaminophen with morphine, fentanyl and ketamine in acute pediatric pain setting.

BACKGROUND: Intravenous acetaminophen and opioid analgesics are routinely given concurrently to children after major surgery, where intravenous access can be limited. There is limited information about the compatibility of acetaminophen with opioid analgesics and ketamine in concentrations commonly used in pediatric setting. AIMS: We aimed to determine the physical and chemical compatibility in mixtures of intravenous acetaminophen 10 mg/mL with morphine (0.025, 0.05, 0.1, 0.2, 1, and 2 mg/ml), fentanyl (0.5, 0.75, 1, 1.5, 2, and 5 mcg/ml) and ketamine (0.01, 0.1, 0.5, 1, 1.5, and 3 mg/ml). METHODS: Acetaminophen was mixed with all 18 solutions and was examined at time 0, 15, 30, and 60 min. In Phase one of the study, we used a colorimetric method to assess preliminary feasibility and acetaminophen recovery. In Phase two study, we used high-performance liquid chromatography to evaluate the recovery of all components of the mixtures. RESULTS: All solutions tested, for both acetaminophen and the three analgesics, had more than 90% of the drug recovery, up to 60 min after mixing. CONCLUSION: Our data demonstrated the stability of acetaminophen, in combination with fentanyl, morphine, and ketamine at clinical concentrations used in acute pediatric pain setting.

Two-year outcomes from the Australian and New Zealand Emergency Laparotomy Audit-Quality Improvement pilot study.

BACKGROUND: The aim of the Australian and New Zealand Emergency Laparotomy Audit-Quality Improvement (ANZELA-QI) pilot study was to determine (i) the outcomes of emergency laparotomy (EL) and (ii) the feasibility of a national, multi-disciplinary quality improvement (QI) project based on a bundle of evidence-based care standards. METHODS: An online database was created using the Research Electronic Data Capture (REDCap) programme. National ethics approval with waiver of consent was obtained. Data were entered directly onto REDCap and extracted monthly for eight care standards (preoperative consultant radiologist reporting of computed tomography scans, preoperative mortality risk score, consultant presence in theatre, timely access to theatre and critical care commensurate with risk and involvement of aged care). Monthly QI run charts using 'traffic' light graphics (green ≥80%, amber ≥50% to <80% and red <50%) reported compliance with the standards. RESULTS: Sixty hospitals indicated interest, but difficulties with site-specific ethics approval resulted in only 24 hospitals participating (2886 EL in 2755 patients). The overall in-hospital mortality was 7.1% (2.3%-13.3%) and average length of stay 15.5 (8.6-22.7) days. Both significantly declined. Preoperative risk assessment (overall 45%) improved almost three-fold during the study. Only 60% had timely access to theatre and only 70% with a predicted mortality risk of >10% were admitted to critical care. CONCLUSION: Overall mortality compared favourably with similar international studies and declined in association with participation in the audit. Compliance with some care standards shows considerable scope to improve EL care using QI methodology.

Dexamethasone and Surgical-Site Infection.

BACKGROUND: The glucocorticoid dexamethasone prevents nausea and vomiting after surgery, but there is concern that it may increase the risk of surgical-site infection. METHODS: In this pragmatic, international, noninferiority trial, we randomly assigned 8880 adult patients who were undergoing nonurgent, noncardiac surgery of at least 2 hours' duration, with a skin incision length longer than 5 cm and a postoperative overnight hospital stay, to receive 8 mg of intravenous dexamethasone or matching placebo while under anesthesia. Randomization was stratified according to diabetes status and trial center. The primary outcome was surgical-site infection within 30 days after surgery. The prespecified noninferiority margin was 2.0 percentage points. RESULTS: A total of 8725 participants were included in the modified intention-to-treat population (4372 in the dexamethasone group and 4353 in the placebo group), of whom 13.2% (576 in the dexamethasone group and 572 in the placebo group) had diabetes mellitus. Of the 8678 patients included in the primary analysis, surgical-site infection occurred in 8.1% (354 of 4350 patients) assigned to dexamethasone and in 9.1% (394 of 4328) assigned to placebo (risk difference adjusted for diabetes status, -0.9 percentage points; 95.6% confidence interval [CI], -2.1 to 0.3; P<0.001 for noninferiority). The results for superficial, deep, and organ-space surgical-site infections and in patients with diabetes were similar to those of the primary analysis. Postoperative nausea and vomiting in the first 24 hours after surgery occurred in 42.2% of patients in the dexamethasone group and in 53.9% in the placebo group (risk ratio, 0.78; 95% CI, 0.75 to 0.82). Hyperglycemic events in patients without diabetes occurred in 22 of 3787 (0.6%) in the dexamethasone group and in 6 of 3776 (0.2%) in the placebo group. CONCLUSIONS: Dexamethasone was noninferior to placebo with respect to the incidence of surgical-site infection within 30 days after nonurgent, noncardiac surgery. (Funded by the Australian National Health and Medical Research Council and others; PADDI Australian New Zealand Clinical Trials Registry number, ACTRN12614001226695.).

Perioperative ADministration of Dexamethasone And blood Glucose concentrations in patients undergoing elective non-cardiac surgery - the randomised controlled PADDAG trial.

BACKGROUND: The hyperglycaemic effect of dexamethasone in diabetic and nondiabetic patients in the peri-operative period is unknown. OBJECTIVE: To assess the effect of a single dose of intra-operative dexamethasone on peri-operative blood glucose. DESIGN: Multicentre, stratified, randomised trial. SETTING: University hospitals in Australia and Hong Kong. PATIENTS: A total of 302 adults scheduled for elective, noncardiac and nonobstetric surgical procedures under general anaesthesia, stratified by diabetes mellitus status, were randomised to receive placebo, 4 or 8 mg dexamethasone administered intravenously after induction of anaesthesia. MAIN OUTCOME MEASURES: Maximum blood glucose within 24 h of surgery, and the interaction between glycated haemoglobin (HbA1c) and dexamethasone were the primary and secondary outcomes. RESULTS: The median [IQR] baseline blood glucose in the nondiabetes stratum in the placebo (n=81), 4 mg (n=81) and 8 mg dexamethasone (n=77) trial arms were respectively 5.3 [4.6 to 5.8], 5.0 [4.7 to 5.4] and 5.0 [4.2 to 5.9] mmol l-1. In the diabetes stratum these values were 6.6 [6.0 to 8.3]; (n=22), 6.1 [5.5 to 10.4]; (n=22) and 6.7 [5.6 to 8.3]; (n=19) mmol l-1. The median [IQR] maximum peri-operative blood glucose values in the nondiabetes stratum were 6.0 [5.3 to 6.8], 6.3 [5.5 to 7.3] and 6.3 [5.8 to 7.4] mmol l-1 in the control, dexamethasone 4 mg and dexamethasone 8 mg arms, respectively. In the diabetes stratum these values were 10.3 [8.1 to 12.4], 12.6 [10.3 to 18.3] and 13.6 [11.2 to 20.1] mmol l-1. There was a significant interaction between pre-operative HbA1c value and 8 mg dexamethasone: every 1% increment in HbA1c produced a 4.0 mmol l-1 elevation in maximal peri-operative glucose concentration. CONCLUSION: Dexamethasone 4 mg or 8 mg did not induce greater hyperglycaemia compared with placebo for nondiabetic and well controlled diabetic patients. Maximal peri-operative blood glucose concentrations in patients with diabetes were related to baseline HbA1c values in a concentration-dependent fashion after 8 mg of dexamethasone. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry (ACTRN12614001145695): URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367272.

Hyperbaric oxygen therapy is not associated with oxidative stress assessed using plasma F2-isoprostanes and isofurans.

BACKGROUND AND AIMS: Hyperbaric oxygen (HBO) therapy is increasingly used in medical practice as a means of enhancing the formation of collagen matrix and angiogenesis, thus promoting healing in wounds and necrotic tissue. However, there are concerns that oxygen can also associate with increased production of oxygen free radicals and oxidative stress. F2-Isoprostanes (F2-IsoPs) formed by non-enzymatic oxidation of arachidonic acid (AA) are reliable measures for assessing oxidative stress in vivo. In addition, under conditions of high oxygen tension isofurans (IsoFs) are preferentially formed from AA and are considered to better reflect oxidative stress in the setting of high oxygen tension. This study aimed to measure plasma IsoFs and F2-IsoP in patients receiving HBO therapy to treat osteonecrosis secondary to radiation therapy. Our hypothesis was that IsoFs would continue to rise with increasing oxygen pressures in contrast to F2-IsoPs whose synthesis would be reduced. METHODS: Twelve patients receiving hyperbaric therapy to treat osteonecrosis secondary to radiation therapy were studied during hyperbaric treatment. Blood samples were collected prior to, during and after cessation of HBO therapy that lasted for 119min. Seven serial blood samples were collected for measurement of plasma F2-IsoPs and IsoFs, blood gases and haemoglobin. RESULTS: Oxygen saturation and venous oxygen partial pressure (PvO2) rose significantly during hyperbaric therapy. However, there were no significant changes in plasma IsoFs or F2-IsoPs during the hyperbaric therapy session. CONCLUSION: In this study of patients with osteonecrosis, HBO therapy at a maximum pressure of 2.4atm with up to 100% oxygen did not worsen oxidative stress assessed using plasma F2- IsoFs and IsoPs.

Controlled moderate hypovolaemia in healthy volunteers is not associated with the development of oxidative stress assessed by plasma F2-isoprostanes and isofurans.

Hypovolaemia can be associated with substantial morbidity, particularly when it occurs in the setting of trauma and in patients with comorbid diseases. Hypovolaemia and inflammation such as occur in the setting of trauma and surgery, are associated with systemic oxidative stress and free-radical injury. Free-radical injury that results from hypovolaemia-induced organ reperfusion may further augment inflammatory processes. It is unknown exactly what proportion of free-radical injury is associated with isolated hypovolaemia as opposed to the contribution from inflammation from surgery or trauma. In the first human study of its kind, we exposed 8 adult male volunteers to venesection-induced hypovolaemia in progressive aliquots of 5% of total blood volume until 20% had been removed. This blood was subsequently reinfused. Plasma F2-isoprostanes and isofurans, markers of in vivo lipid oxidation, were measured by gas chromatography-mass spectrometry at each 5% aliquot venesected and at each 5% reinfused. Between baseline and maximal blood loss there was a minor fall in haemoglobin concentration from 143.9g/l to 138.8g/l (p=0.004, 95% CI 2.2, 8.0g/L). No significant change from baseline occurred in the concentrations of either plasma F2-isoprostanes or isofurans during venesection (p=0.116 and p=0.152, respectively) or blood reinfusion (p=0.553 and p=0.736, respectively). We can conclude that in healthy adult volunteers, isolated hypovolaemia to 20% total blood volume loss is not associated with detectable systemic oxidative stress. The free-radical injury identified in surgical and trauma patients may represent the effects of tissue damage and inflammation, with an uncertain contribution from tissue ischemia as may occur with hypovolaemia.

Intravenous iron in clinical concentrations does not impair haemoglobin measurement.

BACKGROUND: Intravenous iron is commonly administered to anaemic patients to treat iron deficiency, but due to its ferric colouration, it may interfere with the spectrophotometric assessment of haemoglobin concentrations. This paper investigates the potential interference of three clinically used intravenous iron preparations on the measurement of haemoglobin. METHODS: Haemoglobin concentration was measured for neat and Hartmann's solution-diluted iron polymaltose, carboxymaltose and sucrose solutions using bedside (Radiometer HemoCue®), point-of-care (Radiometer ABL800 Flex) and laboratory (Abbott CellDyne Sapphire™) devices. Haemoglobin concentration was then assessed with the same devices utilizing anaemic whole blood with the iron solutions added. RESULTS: Neat iron preparations registered clinically significant haemoglobin concentrations on bedside and laboratory measurements. When intravenous iron preparations were diluted to clinical concentrations, their effect on haemoglobin measurements, either in isolation or mixed with anaemic blood, was negligible. CONCLUSION: Although neat preparations of intravenous iron do interfere with spectrophotometric analysis of haemoglobin, concentrations likely to be seen post iron infusion do not significantly interfere with haemoglobin measurement.

Prophylactic ondansetron does not prevent shivering or decrease shivering severity during cesarean delivery under combined spinal epidural anesthesia: a randomized trial.

OBJECTIVES: Cesarean delivery is commonly performed under regional anesthesia, which is often associated with maternal shivering. This can cause distress and interfere with monitoring. The study objective was to evaluate the antishivering efficacy of ondansetron, which reduces the incidence and severity of shivering in nonobstetric patients. We hypothesized that there would be a significant decrease in the incidence and/or severity of shivering in women who are given intravenous ondansetron 8 mg before combined spinal epidural (CSE) anesthesia, when compared with placebo. METHODS: This was a randomized, double-blinded, parallel-group, placebo-controlled trial of 118 women scheduled for elective cesarean surgery. Women received either intravenous ondansetron 8 mg (n = 58) or saline (n = 60) before CSE anesthesia (intrathecal hyperbaric bupivacaine 0.5% 2.2-2.5 mL plus fentanyl 15 µg). The incidence and severity of shivering, measured on a validated 5-point scale, and other outcomes, such as nausea, pruritus, headache, or satisfaction, were assessed at 3 time points during the surgery and postoperative period. RESULTS: The incidence of shivering at any time point did not differ significantly between groups: ondansetron 41% versus placebo 47% (P = 0.54). The incidence of severe shivering at any time was not significantly different: ondansetron 32% versus placebo 33% (P = 0.79). There were no significant differences between the groups for any secondary outcomes. CONCLUSIONS: Intravenous ondansetron 8 mg before performing CSE anesthesia in women undergoing elective cesarean delivery does not decrease the incidence or severity of shivering.