Community Opioid Dispensing after Injury (CODI): Cohort characteristics and opioid dispensing patterns.

BACKGROUND: Despite a focus of opioid-related research internationally, there is limited understanding of long-term opioid use in adults following injury. We analysed data from the 'Community Opioid Dispensing after Injury' data linkage study. AIMS: This paper aims to describe the baseline characteristics of the injured cohort and report opioid dispensing patterns following injury-related hospitalisations. METHODS: Retrospective cohort study of adults hospitalised after injury (ICD-10AM: S00-S99, T00-T75) in Queensland, Australia between 1 January 2014 and 31 December 2015, prior to implementation of opioid stewardship programs. Data were person-linked between hospitalisation, community opioid dispensing and mortality collections. Data were extracted for 90-days prior to the index hospital admission, to establish opiate naivety, to 720 days after discharge. Median daily oral morphine equivalents (i.e., dose) were averaged for each 30-day interval. Cumulative duration of dispensing and dose were compared by demographic and clinical characteristics, stratified by drug dependency status. RESULTS: Of the 129,684 injured adults, 61.3 % had no opioids dispensed in the 2-year follow-up period. Adults having any opioids dispensed in the community (38.7 %) were more likely older, female, to have fracture injuries and injuries with a higher severity, compared to those with no opioids dispensed. Longer durations and higher doses of opioids were seen for those with pre-injury opioid use, more hospital readmissions and repeat surgeries, as well as those who died in the 2-year follow-up period. Median dispensing duration was 24-days with a median daily end dose of 13 oral morphine equivalents. If dispensing occurred prior to the injury, duration increased 10-fold and oral morphine equivalents doubled. Adults with a documented dependency prior to, or after, the injury had significantly longer durations of use and higher doses than the rest of the cohort receiving opioids. Approximately 7 % of the total cohort continued to be dispensed opioids at 2-years post injury. CONCLUSION: This is a novel population-level profile of opioid dispensing patterns following injury-related hospitalisation, described for the time period prior to the implementation of opioid stewardship programs and regulatory changes in Queensland. Detailed understanding of this pre-implementation period is critical for evaluating the impact of these changes moving forward.

Meta-analysis of an artery-first approach versus standard pancreatoduodenectomy on perioperative outcomes and survival.

BACKGROUND: The aim of this systematic review and meta-analysis was to evaluate perioperative outcomes and survival in patients undergoing an artery-first approach to pancreatoduodenectomy in comparison with those having standard pancreatoduodenectomy. METHODS: A systematic search of PubMed, MEDLINE, Embase and the Cochrane Database of Systematic Reviews was performed in accordance with PRISMA guidelines. Comparative studies including patients who underwent artery-first pancreatoduodenectomy and standard pancreatoduodenectomy were analysed. RESULTS: Seventeen studies were included in the final analysis. There were 16 retrospective cohort or case-control studies and one RCT. A total of 1472 patients were included in the meta-analysis, of whom 771 underwent artery-first pancreatoduodenectomy and 701 had standard pancreatoduodenectomy. Intraoperative blood loss (mean difference -389 ml; P < 0·001) and the proportion of patients requiring intraoperative transfusion (10·6 per cent (54 of 508) versus 40·1 per cent (186 of 464); P < 0·001) were significantly lower in the artery-first group. Although rates of perioperative mortality were comparable between the two groups, perioperative morbidity (35·5 per cent (263 of 741) versus 44·3 per cent (277 of 625); P = 0·002), and the incidence of grade B/C pancreatic fistula (7·4 per cent (26 of 353) versus 12·8 per cent (42 of 327); P = 0·031) were significantly lower in the artery-first group. The R0 resection rate (75·8 per cent (269 of 355) versus 67·0 per cent (280 of 418); P < 0·001) and overall survival (hazard ratio 0·72, 95 per cent c.i. 0·60 to 0·87; P < 0·001) were significantly higher in the artery-first group. CONCLUSION: The artery-first approach to pancreatoduodenectomy may be associated with improved perioperative outcomes and survival.

Madagascar corals track sea surface temperature variability in the Agulhas Current core region over the past 334 years.

The Agulhas Current (AC) is the strongest western boundary current in the Southern Hemisphere and is key for weather and climate patterns, both regionally and globally. Its heat transfer into both the midlatitude South Indian Ocean and South Atlantic is of global significance. A new composite coral record (Ifaty and Tulear massive Porites corals), is linked to historical AC sea surface temperature (SST) instrumental data, showing robust correlations. The composite coral SST data start in 1660 and comprise 200 years more than the AC instrumental record. Numerical modelling exhibits that this new coral derived SST record is representative for the wider core region of the AC. AC SSTs variabilities show distinct cooling through the Little Ice Age and warming during the late 18(th), 19th and 20th century, with significant decadal variability superimposed. Furthermore, the AC SSTs are teleconnected with the broad southern Indian and Atlantic Oceans, showing that the AC system is pivotal for inter-ocean heat exchange south of Africa.

Systematic review of intraoperative cholangiography in cholecystectomy.

BACKGROUND: Intraoperative cholangiography (IOC) is used to detect choledocholithiasis and identify or prevent bile duct injury. The aim of this study was systematically to review the randomized clinical trials of IOC for these two indications. METHODS: MEDLINE, Embase, the Cochrane Library, clinicaltrials.gov and the World Health Organization database of clinical trials were searched systematically (January 1980 to February 2011) to identify trials. Two authors performed the literature search and extracted data independently. Primary endpoints were bile duct injury and retained common bile duct (CBD) stones diagnosed at any stage after surgery. Preliminary meta-analysis was undertaken, but the trials were too methodologically heterogeneous and the outcome events too infrequent to allow meaningful meta-analysis. RESULTS: Eight randomized trials were identified including 1715 patients. Six trials assessed the value of routine IOC in patients at low risk of choledocholithiasis. Two trials randomized all patients (including those at high risk) to routine or selective IOC. Two cases of major bile duct injury were reported, and 13 of retained CBD stones. No trial demonstrated a benefit in detecting CBD stones. IOC added a mean of 16 min to the total operating time. CONCLUSION: There is no robust evidence to support or abandon the use of IOC to prevent retained CBD stones or bile duct injury. Level 1 evidence for IOC is of poor to moderate quality. None of the trials, alone or in combination, was sufficiently powered to demonstrate a benefit of IOC. Further small trials cannot be recommended.

Systematic review and meta-analysis of enteral nutrition formulations in acute pancreatitis.

BACKGROUND: Although the benefits of enteral nutrition in acute pancreatitis are well established, the optimal composition of enteral feeding is largely unknown. The aim of the study was to compare the tolerance and safety of enteral nutrition formulations in patients with acute pancreatitis. METHODS: Electronic databases (Scopus, MEDLINE, Cochrane Controlled Clinical Trials Register) and the proceedings of major pancreatology conferences were searched. RESULTS: Twenty randomized controlled trials, including 1070 patients, met the inclusion criteria. None of the following was associated with a significant difference in feeding intolerance: the use of (semi)elemental versus polymeric formulation (relative risk (RR) 0.62 (95 per cent confidence interval (c.i.) 0.10 to 3.97); P = 0.611); supplementation of enteral nutrition with probiotics (RR 0.69 (95 per cent c.i. 0.43 to 1.09); P = 0.110); or immunonutrition (RR 1.60 (95 per cent c.i. 0.31 to 8.29); P = 0.583). The risk of infectious complications and death did not differ significantly in any of the comparisons. CONCLUSION: The use of polymeric, compared with (semi)elemental, formulation does not lead to a significantly higher risk of feeding intolerance, infectious complications or death in patients with acute pancreatitis. Neither the supplementation of enteral nutrition with probiotics nor the use of immunonutrition significantly improves the clinical outcomes.

Systematic review of oxidative stress associated with pneumoperitoneum.

BACKGROUND: There have been several reports of ischaemic complications after routine laparoscopy. The aim of this review was to investigate the relationship between this oxidative stress and pneumoperitoneum. METHODS: Medline, Medline in-process, The Cochrane Library, PubMed and EMBASE were searched for papers on oxidative stress and pneumoperitoneum, from 1947 to March 2008 with no language restriction or restriction on trial design. Papers that did not investigate pneumoperitoneum as a causative factor, or did not report outcome measures related to oxidative stress, were excluded. RESULTS: A total of 73 relevant papers were identified: 36 animal studies, 21 human clinical trials, nine case reports, five review articles and two comments. Pneumoperitoneum causes a reduction in splanchnic blood flow, resulting in biochemical evidence of oxidative stress in a pressure- and time-dependent manner. There is evidence that the use of carbon dioxide for insufflation is contributory. Several measures proposed to minimize the oxidative stress have shown promise in animal studies, but few have been evaluated in the clinical setting. CONCLUSION: There is an increasing body of evidence, mainly from animal studies, that pneumoperitoneum decreases splanchnic perfusion with resulting oxidative stress. It is now appropriate to investigate the clinical significance of pneumoperitoneum-associated oxidative stress.

Active counterpositioning or orthotic device to treat positional plagiocephaly?

Active counterpositioning and orthotic helmets are the two main nonsurgical management options for positional plagiocephaly. The purpose of this study was to compare these two management regimens. We included a random sample of infants referred between January 1, 1998 and October 31, 1999 to Middlemore Hospital and Auckland Surgical Center, for management of positional plagiocephaly. Two-dimensional head tracings were taken for each infant, every 3 to 12 months. From these tracings, we obtained Cranial Index and Cranial Vault Asymmetry Index. Seventy-nine infants were assessed during an average of 48.2 weeks. Five infants had normal head tracings, and were therefore excluded from the study. Of the 74 infants included in this study, 45 were managed with active counterpositioning, and 29 with orthotic helmets. Average management time for active counterpositioning was 63.7 weeks, and 21.9 weeks for orthotic helmet treatment. For infants managed with active counterpositioning, the average change in Cranial Vault Asymmetry Index was 1.9%. In the orthotic group, average change in Cranial Vault Asymmetry Index was 1.8%. Orthotic helmets have an outcome comparable to that of active counterpositioning, although the management period is approximately three times shorter. Active counterpositioning generally had a slightly better outcome than orthotic management after the management period.

Stimulation and inhibition of bone formation: use of peripheral quantitative computed tomography in the mouse in vivo.

The purpose of this study was to assess peripheral quantitative computed tomography (pQCT) imaging for measurement of volumetric bone mineral density (BMD) in vivo in mouse tibia following ovariectomy, and following treatment with 17 beta-oestradiol (E2). Two studies were undertaken. In study 1, three groups (n = 10) of mature mice were ovariectomized (OVX) or sham operated (SHAM); one of the OVX groups was dosed weekly with E2 (OVX.E2). Images of the proximal tibia were acquired on the day of surgery and at intervals following surgery until week 6. In study 2, four groups (OVX, SHAM, OVX.E2 and a SHAM group dosed with E2, SHAM.E2) of immature mice (n = 10) were imaged weekly up to 10 weeks post-surgery. Precision of pQCT for measurement of total (trabecular plus cortical) BMD was 2.4%, trabecular 5.2% and cortical 2.6%. In mature animals, significantly slower net bone formation was seen in OVX compared with SHAM animals using paired analysis with each animal as its own control. Group analysis detected no significant difference in BMD between SHAM and OVX at any time point. In immature animals, using paired analysis, with each animal as its own control, a significant difference between SHAM and OVX animals was detectable 3 weeks post-surgery (P < 0.05). As in study 1, group analysis of total BMD failed to detect any significant difference between SHAM and OVX at any time point. Treatment with E2 caused an easily-detected increase in BMD and led to osteopetrosis in both groups. The statistical power of this technique is adequate for testing antiresorptive or bone-forming therapies in the mouse.

Bone mineral density and composition in rat pregnancy: effects of streptozotocin-induced diabetes mellitus and insulin replacement.

A disturbed calcium homeostasis characterizes diabetic pregnancy. This study documents changes in bone mineral composition in diabetic pregnant rats and examines the effect of insulin replacement. Control pregnant (CP), diabetic pregnant (DP) and insulin-treated DP (DPi) rats were assessed for femoral calcium and magnesium content, bone mineral density (BMD) and the ratio of hypertrophic to maturing and proliferative cells in the femoral growth plate. DP rats showed a significantly (P < 0.01) lower body weight, femoral weight and length than CP rats. Femoral calcium and magnesium content was also significantly (P < 0.05) lower in DP rats, as was ash weight. When calcium and magnesium were normalized for ash weight no significant differences were apparent. A significantly (P < 0.05) lower total BMD at the distal femur was seen in DP rats. This comprised a significantly (P < 0.01) lower trabecular BMD with no significant change in cortical BMD. A significantly (P < 0.05) higher ratio of hypertrophic to maturing and proliferative cells of the femoral growth plate was evident in DP animals. DPi rats showed normal blood glucose concentrations and femoral growth plate histology. DPi rats also showed normal femoral weight and length but only partially restored femoral ash weight and mineral content. Insulin failed to normalize total or trabecular BMD. Diabetes mellitus clearly has a marked effect on bone growth and mineral content in pregnancy which may be relevant to overall calcium homeostasis. The lower bone growth, bone calcium content and trabecular BMD may be unfortunate consequences of the marked hypercalciuria reported elsewhere in diabetes and may serve to maintain normocalcaemia in the disease.

Effects of an inhibitor of cathepsin L on bone resorption in thyroparathyroidectomized and ovariectomized rats.

The process of bone resorption by osteoclasts involves the dissolution of mineral salts and enzymatic degradation of the mainly collagenous extracellular matrix. Cysteine proteinases, which can efficiently degrade collagen at acidic pH, have been suggested to play an important role in the bone resorptive process. The cysteine proteinase cathepsin L is secreted by osteoclasts, and inhibitors of this enzyme can prevent bone resorption in vitro. The activity of acetyl-leu-leu-norleucinol (ALLN), a selective inhibitor of cathepsin L, was investigated in two models of bone resorption in vivo. In the first study, the ability of ALLN to inhibit bone resorption was investigated in Ro-13-6298 (arotinoid)-treated thyroparathyroidectomized (TPTX) rats. ALLN [100 mg/kg, intraperitoneally (i.p.)] inhibited hypercalcemia by 62.8% acutely (p < 0.001), compared to 94.9% (p < 0.001) inhibition by salmon calcitonin (sCT) (10 IU/kg, subcutaneously). In rats treated for 3 days with ALLN, arotinoid-induced reduction in cortical bone mineral density measured by peripheral quantitative computed tomography (pQCT) was inhibited by 86.4% (p < 0.05) in rats treated with ALLN 100 mg/kg, i.p., and by 82% in rats treated with 50 mg/kg, i.p. (p < 0.05). In a second study, the efficacy of ALLN was tested in a longitudinal study in ovariectomized (ovx) rats. Bone loss, measured by pQCT, was unaffected by treatment with ALLN. The bisphosphonate alendronate, however, inhibited bone loss in this model. These data demonstrate the ability of a cathepsin L inhibitor to inhibit bone resorption in arotinoid-treated TPTX rats, a process which may be dependent on the activity of cathepsin L-like cysteine proteinases. In contrast to its effects in TPTX rats, ALLN had no inhibitory activity on bone resorption in ovx rats. It is possible that in chronic bone resorption in ovx rats, the activity of other enzymes such as cathepsins OC-2 or K allows the process of resorption to continue even when cathepsin L is inhibited by ALLN. Further studies are required to determine why the activity of ALLN varies between different animal models. These data indicate that there may be variations in the effects of drugs in different animal models of bone resorption which should be considered when investigating novel antiresorptive therapies.

Regional analysis of bone mineral density in the distal femur and proximal tibia using peripheral quantitative computed tomography in the rat In vivo.

The use of peripheral quantitative computed tomography (pQCT) was investigated for the measurement of volumetric bone mineral density (BMD) in mg x cm-3. Two studies were undertaken. In the first study, the precision of pQCT in vivo and ex vivo was tested at 14 weeks postovariectomy (OVX). In the second study, the efficacy of a standard antiresorptive treatment, 17beta-estradiol (E2), was tested 6 weeks post-OVX. The precision for total (compact plus trabecular) BMD was 1.3-1.9%, and that for trabecular BMD was 2.4-2. 7%. There was excellent agreement between trabecular BMD measurements in vivo and ex vivo (r = 0.91). Significant reductions in trabecular BMD were observed in vivo at 14 and 6 weeks following ovariectomy in the femur, in each study. The loss of trabecular BMD depended on slice location, and varied from 0 to 22% at 6 weeks, and from 0 to 26% at 14 weeks (P < 0.001, at the affected locations). The antiresorptive effect of treatment was demonstrated in the 6-week study: there was no significant difference in BMD between sham-operated and E2-treated OVX rats.

Effect of one-kidney, one clip hypertension on the structure and function of porcine intramyocardial small arteries.

OBJECTIVE: To determine the influence of experimental hypertension on the structure and function of porcine coronary small arteries. METHODS: Miniature pigs underwent partial left renal artery constriction and contralateral nephrectomy. Blood pressures were recorded, using indwelling carotid artery catheters. After 4 weeks the pigs were killed, the heart was removed and subepicardial third-order branches of the left anterior descending artery were dissected and mounted in a myograph for morphological and functional assessment. RESULTS: Final mean +/- SEM systolic and diastolic blood pressures were, respectively, 197 +/- 9 and 142 +/- 7 mmHg (n = 21) for the hypertensive pigs and 125 +/- 4 and 80 +/- 4 mmHg (n = 11) for the sham-operated control pigs. Hypertension was associated with significant left ventricular hypertrophy. The media thickness: lumen diameter ratio was increased significantly in hypertensive intramyocardial small arteries, caused mainly by remodelling (remodelling index 92%) rather than by medial growth. Maximal contractile responses to potassium and acetycholine were significantly depressed in the arteries from hypertensive pigs, whereas endothelium-dependent relaxation responses to bradykinin, substance P and serotonin were not significantly influenced by hypertension. CONCLUSIONS: These results demonstrate that even short-term hypertension induces both structural and functional changes in left ventricular intramyocardial small arteries.

Bromhexine plus oxytetracycline: the effect of combined administration upon the rheological properties of mucus from the mini-pig.

Three adult mini-pigs were employed to assess the effects of a twice daily dosage (40 mg kg-1) of oxytetracycline hydrochloride (OTC) and a combination of OTC with (0.5 mg kg-1) bromhexine hydrochloride (BHC) on the rheological properties and wet weight of secreted tracheal mucus. Mucus was collected daily from open-ended tracheal pouches established surgically in the mini-pigs. After a five day control period, either OTC or OTC plus BHC was administered twice daily with the normal diet. Each study period was followed by a five day washout period when mucus was collected but no drug given. The viscoelastic properties of each mucus sample were determined using creep compliance analysis. OTC was shown to increase the residual shear viscosity IP < 0.01) and increase the instantaneous compliance (P < 0.01). An increase in the wet weight of the collected mucus occurred in one pig only (P < 0.01). When BHC was co-administered with OTC, all of these changes were abolished. Evidence was obtained to suggest that BHC increased the concentration of OTC within the secreted mucus. BHC appeared to reverse the mucospissic activity of OTC in-vivo.

The effect of bromhexine hydrochloride on the viscoelastic properties of mucus from the mini-pig.

Mucus was collected daily from open-ended pouches established surgically in three mini-pigs. After a five day control period bromhexine hydrochloride (BHCl) was administered to each pig at dose levels of 0.5, 1.0 and 2.0 mg.kg-1 twice daily for five days. Each study period was followed by a five day washout period, when mucus was collected but no drug given. The viscoelastic properties of each mucus sample were determined using creep compliance analysis. BHCl was shown to reduce the residual shear viscosity (p less than 0.05) and increase the instantaneous shear compliance at all dose levels (p less than 0.005), despite the large inherent intra- and inter-animal variation in the rheological properties of the daily samples. No change was found in the wet weight of the mucus samples throughout any of the study periods. This experimental model would appear to provide a valuable in vivo method of assessing the mucoregulatory potential of administered compounds.

Dextromethorphan attenuates post-ischemic hypoperfusion following incomplete global ischemia in the anesthetized rat.

The effects of dextromethorphan (DM) were tested in an in vivo model of incomplete global cerebral ischemia. Anesthetized rats were divided into 4 groups: Group 1 (saline); Group 2 (DM pre-treatment, 20 mg/kg i.v. bolus followed by 10 mg/kg/h DM infusion); Group 3 (DM post-treatment, 2 mg/kg i.v. bolus followed by 10 mg/kg/h DM infusion at the onset of post-ischemic hypoperfusion); and Group 4 (sham-operated, drug-treated). Groups 1-3 underwent 15 min of 4-vessel occlusion followed by 3 h of reperfusion. Administration of DM in sham-operated animals (Group 4) had no effect on cerebral blood flow or electroencephalographic (EEG) activity. In contrast, when compared to the Group 1 saline controls, significant attenuation of post-ischemic hypoperfusion and EEG dysfunction was demonstrated in ischemic rats treated with DM (both pre- and post-treatment), suggesting an ability of DM to improve cerebral blood flow (CBF) and brain function in cerebral ischemia.

Magnetic resonance imaging of the mini-pig heart: the effect of gadolinium-DTPA on normal myocardium.

The effect of gadolinium-diethylene-triamine-penta-acetic acid (Gd-DTPA) on normal, mini-pig myocardium was investigated with magnetic resonance imaging. Results indicate that intravenous administration of Gd-DTPA produces a significant enhancement of mini-pig myocardial signal intensity, which in all cases was maintained in excess of 50 min. No significant enhancement was demonstrated in skeletal muscle.

Detection of myocardial infarction in the mini-pig using NMR imaging.

Spin-echo images of 10 myocardial infarcts in nine mini-pigs were obtained at 30 h, 3 days, and approximately 10 days postinfarction. Infarcts were not detected at all at 30 h in five out of five cases examined. At 3 days postembolization (six cases) one infarct was certainly detected, whilst at 10 days (nine cases) all infarcts were seen as high-signal areas in long TE spin-echo sequences. After 2 weeks no further infarct signal change was detected (three cases), but myocardial thinning became more evident. Using techniques similar to those reported here, early postinfarct changes in the dog have been detected by other authors. Possible reasons for this difference between pig and dog are discussed.

Three times daily or 8-hourly.

The timing of drug ingestion over 24 hours was assessed in 58 outpatients taking drugs three times daily. The mean time between 1st and 2nd dose was 5.7 hours, 2nd and 3rd 6.1 hours and between 3rd and 1st of the next day 12.2 hours. Based on a simulation of hydralazine pharmacokinetics, such irregular administration would increase peak levels by 10% and decrease trough levels by 64% compared with regular 8-hourly doses.

A clinically relevant model of heart failure: effects of ticlopidine.

A clinically relevant model of heart failure has been developed in chronically instrumented mini-pigs by injecting Sephadex beads into the left main or circumflex coronary arteries under fluoroscopic control. In six control animals, left atrial pressure (LAP) increased from 10 +/- 2 to 19 +/- 2 mmHg (p less than 0.01) and remained elevated for 3 days. Heart rate increased by 26 beats X min-1 (p less than 0.05) and diastolic pressure fell after 24 h but recovered over the next 48 h. In six animals treated with ticlopidine (50 mg X kg-1 p.o.) for four days prior to embolisation, the acute haemodynamic changes were less in the first day but similar to control after 3 days. Infarct size was approximately 20% of the left ventricle in control animals and 9.5% in the treated group (p less than 0.01). ADP-induced platelet activity was reduced in the treated animals suggesting that coronary occlusion followed both physical occlusion by the beads and later development of platelet thrombi.

Effects of inhibitors of collagen maturation on hypertension in rats.

The effects of beta-aminopropionitrile (BAPN), an inhibitor of collagen maturation, have been examined in three models of hypertension in rats. It is shown for the first time that BAPN has a rapidly developing antihypertensive action in rats with renal (one kidney-one clip) hypertension. The compound also lowered blood pressure in spontaneously hypertensive rats. In both these experiments although BAPN lowered blood pressure it did not affect the hypertension-induced hypertrophy of the aorta. BAPN suppressed the rise in blood pressure during the developing phase of deoxycorticosterone acetate-salt-induced hypertension and in this model the compound also prevented the accompanying aortic hypertrophy. However, another inhibitor of collagen synthesis and maturation, 3,4-dehydroproline, completely suppressed aortic hypertrophy but failed to prevent the rise in blood pressure in deoxycorticosterone acetate-salt hypertension. It is concluded that: (1) BAPN may have a direct antihypertensive action, and (2) inhibition of aortic hypertrophy alone cannot prevent the rise in blood pressure in the developing phase of deoxycorticosterone acetate-salt hypertension.