bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toxicologic Pathology Forum: Current Status on the Use of Animal Models of Human Disease in the Pharmaceutical Industry in Japan in Nonclinical Safety Assessment–Opinion Paper
Authors: Tomohiro Masayuki , Okabe Takeshi , Kimura Yasushi , Kinoshita Kiyoshi , Maeda Mitsunori , Mitobe Yuko , Motoyama Keiko , Yonezawa Riichiro , Sasaki Shoji , Fujiwara Michio , Watanabe Kazuto 
Published: January 2019

In nonclinical safety studies for new drug development, healthy animals have been commonly used. However, in some cases, the use of animal models of human disease is considered to be more favorable in evaluating risks in patients. To elucidate the current status of the use of animal models for nonclinical safety assessment, an internal questionnaire from the Japan Pharmaceutical Manufacturers Association and surveys (questionnaire period: August 27 to September 30, 2015) of both common technical documents and review reports of approved drugs (approval period: May 1999 to May 2017) disclosed by the Pharmaceutical and Medical Devices Agency were conducted. Although there were some concerns and limitations raised, the survey results revealed that animal models have been used in nonclinical safety assessment on a case-by-case basis and that nonclinical safety studies using animal models were included in the data packages of several approved drugs in Japan. The survey results also revealed that nonclinical safety studies using animal models have become more frequent in the past few years. In almost all cases, useful information, such as signs of toxicity under disease conditions and mechanisms of toxic change, was obtained from the results of nonclinical studies using animal models. [Box: see text]
Can We Achieve Consensus on Central Venous Catheter-Related Infections?
Authors: Fraenkel D. J. , Rickard C. , Lipman J. 
Published: January 2019

Central venous catheter-related bacteraemia is a substantial and preventable source of iatrogenic morbidity and mortality. A single episode of catheter-related bacteraemia has an estimated cost of A$50,000, with an attributable mortality between 10 and 35%. Catheter colonization is diagnosed with standard culture techniques. Diagnostic criteria for catheter-related bacteraemia include the results of cultures from the catheter tip, the peripheral blood and other possible sites of infection. The presence of clinical symptoms and subsequent defervescence may assist in making the diagnosis. This review explores the existing definitions of catheter-related infections and proposes a new and more rigorous classification with criteria for definite, probable and possible catheter-related bacteraemia. The authors hope that this classification will enhance the interpretation of the literature and the planning of new investigations. Infection rates can be reduced by appropriate site selection, adequate skin preparation, sterile technique and appropriate dressings. Decreased manipulation of administration sets, with more careful technique and less frequent set replacement, may reduce hub contamination. Infection rates increase with the duration in situ of the catheter, however are not reduced by regular scheduled catheter replacement or guide-wire exchanges. A range of antimicrobial catheter materials and coatings are under investigation, some of which are effective in reducing the rate of catheter-related bacteraemia. Chorhexidine-silver sulphadiazine and rifampicin-minocycline are the best studied combinations to date. Further developments are expected, although none are likely to be as effective as not inserting or removing the central venous catheter when it is not required.
Does Adrenaline Improve Epidural Bupivacaine and Fentanyl Analgesia after Abdominal Surgery?
Authors: Sakaguchi Y. , Sakura S. , Shinzawa M. , Saito Y. 
Published: January 2019

The alpha-adrenergic agonists have been demonstrated to have synergistic effects with opioids and local anesthetics in animal research. The present study was performed to determine whether the addition of adrenaline improves the analgesic effects of an epidural infusion of a combination of fentanyl and bupivacaine after abdominal surgery. We studied 90 ASA 1 or 2 patients scheduled for abdominal surgery under epidural anaesthesia, with or without general anaesthesia. Patients were randomly divided into two groups to receive a postoperative epidural infusion of fentanyl 5 μg/ml in bupivacaine 0.2%, with or without adrenaline 5 μg/ml, at a rate of 2 ml/h for more than 48 hours. Postoperative pain relief was assessed using visual analog scales (VAS), both at rest and during coughing, at 2, 24, and 48 hours after surgery. The number of rescue analgesics and side-effects such as nausea, vomiting, pruritus, respiratory depression, headache, muscle weakness, and hypotension were recorded. Patients who received adrenaline (n=40) reported significantly lower mean VAS scores than those who received no adrenaline (n=37), both at rest at 24 hours postoperatively and during coughing at 24 and 48 hours. The number of additional analgesics and incidence of side-effects did not differ between groups. In conclusion, the results of the present study demonstrate that the addition of adrenaline to a combination of fentanyl and bupivacaine improves the quality of epidural analgesia after abdominal surgery. Under the conditions of the study, we did not detect any disadvantage from the addition of adrenaline.
Estimating the Diameter of the Left Main Bronchus
Authors: Hampton T. , Armstrong S. , Russell W. J. 
Published: January 2019

Two hundred and six standard PA chest X-rays were measured. The mean diameter of the left main bronchus (LMB) was 12.6±1.9 mm. The mean diameter of the 92 male LMB was 13.0±2.6, and for females 11.8±1.6. These data correspond closely to that reported by others. The correlation between the diameter of the LMB and that of the trachea was 0.74 but was not precise enough to be useful as an estimate for clinical use. Similarly there was good correlation between the diameter of the right main bronchus and that of the left (r=0.75) but not precise enough to be clinically useful. In contrast to previous claims, only direct measurement of the left main bronchus has sufficient precision to define the appropriate size of left double-lumen tube to be selected for lung separation.
Severe Convulsant Hypomagnesaemia and Short Bowel Syndrome
Authors: Fagan C. , Phelan D. 
Published: January 2019

Hypomagnesaemia as a primary cause of a generalized seizure is uncommon. A 60-year-old woman with Crohn's disease, who had had recent small bowel surgery and a total colectomy 10 years previously, was admitted complaining of severe nausea, vomiting, fatigue and thirst. Despite oral magnesium therapy she had a generalized seizure due to severe hypomagnesaemia of 0.09 mmol/l (normal range 0.65 to 1.05 mmol/l). Her serum calcium was 1.91 mmol/l (2.03 to 2.63 mmol/l). Hypomagnesaemia can cause generalized convulsions but is usually associated with hypocalcaemia. This patient had an almost normal serum calcium level, and therefore hypomagnesaemia would seem to have been the direct cause of her seizure. Long-term intravenous magnesium was necessary to prevent further seizures.
Increased B-type Natriuretic Peptide (BNP) Level is a Strong Predictor for Cardiac Dysfunction in Intensive Care Unit Patients
Authors: McLean A. S. , Tang B. , Nalos M. , Huang S. J. , Stewart D. E. 
Published: January 2019

Patients admitted to an Intensive Care Unit (ICU) frequently have underlying cardiac dysfunction. Early interventions are sometimes difficult to initiate because of diagnostic uncertainty as to whether cardiac failure is present As B-type natriuretic peptide (BNP) has been shown to be increased in cardiac dysfunction, we sought to demonstrate whether BNP can be used as a screening tool for cardiac dysfunction in patients admitted to ICU. All patients admitted to a combined medical and surgical ICU over a four-week period were included in the study. BNP was measured on the point of admission using a hand-held meter. Clinicians were blinded from the measurement when diagnoses were made as to whether or not the patients had clinically significant cardiac dysfunction. Patients with cardiac dysfunction had a significantly higher level of BNP when compared to the non-cardiac dysfunction group: 516±385 pg/ml (n = 26) v 67±89 pg/ml (n=58) (P< 0.0001) A BNP cut-off value at 144 pg/ml exhibited a 92% sensitivity, 86% specificity and 96% negative predictive value. The sensitivity improved to 96% when the analysis was confined to patients ≥ 55 years. At this cut-off value, BNP is a strong predictor of cardiac dysfunction. BNP measurement offers a rapid and affordable way to screen for cardiac dysfunction in patients admitted to ICU. An increased BNP level warrants further cardiac investigations so as to implement early interventions for cardiac decompensation in ICU patients.
Perioperative Intravenous Ketamine Infusion for the Prevention of Persistent Post-amputation Pain: A Randomized, Controlled Trial
Authors: Hayes C. , Armstrong-Brown A. , Burstal R. 
Published: January 2019

We hypothesized that perioperative ketamine administration would modify acute central sensitization following amputation and hence reduce the incidence and severity of persistent post-amputation pain (both phantom limb and stump pain). In a randomized, controlled trial, 45 patients undergoing above- or below-knee amputation received ketamine 0.5 mg.kg–1 or placebo as a pre-induction bolus followed by an intravenous infusion of ketamine 0.15 mg.kg–1.h–1 or normal saline for 72 hours postoperatively. Both groups received standardized general anaesthesia followed by patient-controlled intravenous morphine. The surface area of allodynia over the stump was mapped at days 3 and 6. Postamputation pain was assessed at days 3 and 6 and at 6 months postoperatively. We found no significant difference between groups in the surface area of stump allodynia or in morphine consumption. There was an unexplained, but significant, increase in the incidence of stump pain in the ketamine group at day 3. At six-month review, the incidence of phantom pain was 47% in the ketamine group and 71% in the control group. This did not reach statistical significance (P=0.28) as the power of the study was based on the search for a large treatment effect. The incidence of stump pain at six months was 47% in the ketamine group and 35% in the control group (P=0.72). There were no significant between-group differences in pain severity throughout the study period. Ketamine at the dose administered did not significantly reduce acute central sensitization or the incidence and severity of post-amputation pain.
Comparison of Disposable and Reusable Laryngeal Mask Airways in Spontaneously Ventilating Adult Patients
Authors: Cao M. M. , Webb T. , Bjorksten A. R. 
Published: January 2019

Recent studies have indicated that despite stringent sterilization processes, the reusable silicone laryngeal mask airway (LMA) has the potential for disease transmission through residual biological debris. As a result, a polyvinyl chloride (PVC) disposable LMA has been introduced. This randomized trial involved 138 spontaneously ventilating adult patients who underwent elective surgery requiring airway management with an LMA to determine whether there is a clinical difference between the disposable Portex® LMA (PLMA) and the standard reusable LMA in terms of ease of insertion, intra-operative cuff pressures and postoperative incidence of sore throat. There was no significant difference in first attempt insertion success rates (79% vs 84%) or difference in the incidence of postoperative sore throat observed between the two groups. Cuff pressure increases with nitrous oxide anaesthesia were significantly larger with the reusable LMA. The disposable PLMA provided a suitable airway in spontaneously ventilating patients without the risk of disease transmission inherent in a reusable device.
Survey of Intensive Care Nurses’ Knowledge Relating to the Pulmonary Artery Catheter
Authors: Johnston I. G. , Jane R. , Fraser J. F. , Kruger P. , Hickling K. 
Published: January 2019

In 2003 there was an increase in the use of pulmonary artery catheters in Australia from 12,000 to 16,000 units in intensive care and peri-operative care. This survey of intensive care nurses in five intensive care units in Queensland addressed knowledge of use, safety and complications of the pulmonary artery catheter, using a previously validated 31 question multiple choice survey. One hundred and thirty-nine questionnaires were completed, a response rate of 46%. The mean score was 13.3, standard deviation ±4.2 out of a total of 31 (42.8% correct). The range was 4 to 25. Scores were significantly higher in those participants with more ICU experience, higher nursing grade, a higher self-assessed level of knowledge and greater frequency of PAC supervision. There was no significant correlation between total score and hospital- or university-based education, or total score and public or private hospital participants. Fifty-one per cent were unable to correctly identify the significant pressure change as the catheter is advanced from the right ventricle to the pulmonary artery.
Systemic Lupus Erythematosus Complicated by HELLP Syndrome
Authors: Osmanagaoglu M. A. , Osmanagaoglu S. , Bozkaya H. 
Published: January 2019

We describe a pregnant woman with systemic lupus erythematosus, complicated by severe pre-eclampsia (the HELLP syndrome) and adult respiratory distress syndrome, who died in the intensive care unit. A 33-year-old multigravid woman was referred to our university hospital at 17 weeks’ gestation because of an exacerbation of systemic lupus erythematosus with elevated liver enzymes and thrombocytopenia. At the time of admission, on physical examination she had revealed a butterfly rash over the cheeks, purpura, acute synovitis and oedema of the legs. Her blood pressure was 180/100 mmHg. The initial laboratory tests and immunological evaluation confirmed active systemic lupus erythematosus complicated by severe pre-eclampsia. One week after admission, she became suddenly confused and had a convulsion with Glascow Coma Score 10 (3+3+4). Therapeutic abortion was induced in the Obstetric Department. She was transferred to the intensive care unit with a diagnosis of respiratory failure, probably due to acute respiratory distress syndrome, and was intubated and ventilated. Dialysis was instituted on two consecutive days from the eighth day. In total she received over 20 units of red blood cells and large quantities of fresh frozen plasma and platelets. On the 24th day her Glascow Coma Score was 2 (1+1+E) and severe hypotension developed. She died from worsening acute respiratory distress syndrome on the 25th day. Women with systemic lupus erythematosus should be advised to become pregnant when the disease is inactive and should be observed at an appropriate centre using a multidisciplinary approach. Therapeutic abortion is an acceptable option if active nephropathy and severe pre-eclampsia are present in early pregnancy.
The Role of Microvascular Thrombosis in Sepsis
Authors: Dixon B. 
Published: January 2019

The acute inflammatory response to sepsis gives rise to significant morbidity and mortality. The mechanisms underlying this form of tissue injury are poorly understood. This review examines the evidence that tissue ischaemia due, to generalized microvascular thrombosis may play an important role. Microvascular thrombosis is probably an adaptive response that prevents bacteria in the tissues reaching the systemic circulation via the capillaries. In time, a definitive response by leucocytes removes the bacteria and repairs the damaged tissues. There is however evidence that if microvascular thrombosis becomes generalized, then extensive tissue ischaemia may precipitate organ failure and death. Post-mortem studies of patients with sepsis demonstrate microvascular thrombi in many organs including the kidney, liver, lung, gut, adrenals and brain, and the degree of organ injury is related to the quantity of thrombi. Furthermore studies in human and animal models of sepsis demonstrate therapies that inhibit coagulation or promote fibrinolysis reduce organ failure and mortality. In view of the personal and economic burdens that tissue injury associated with the acute inflammatory response places on the community, further studies to establish the role of microvascular thrombosis are clearly required. Such studies may lead to new therapies to limit or prevent this form of injury.
Early Experience with Magnesium Administration in Irukandji Syndrome
Authors: Corkeron M. , Pereira P. , Makrocanis C. 
Published: January 2019

The administration of magnesium sulphate is a proposed novel therapy for Irukandji syndrome1. In this non-randomized, unblinded case series, data from ten patients who received magnesium salts are reviewed. Magnesium sulphate boluses of 10 to 20 mmol, in the six patients for which there was adequate data, reduced pain scores immediately after administration from 8.7±1.5 to 2.8±2.8 (Wilcoxon rank-sum test, P=0.03). In ten patients blood pressure decreased with a mean difference of −18 mmHg in mean arterial pressure. Magnesium requirements in individual patients varied markedly. Pain on injection occurred in four patients, three of whom had received peripherally administered magnesium chloride, and one patient reported transient ptosis after administration of magnesium sulphate 166 mmol over 18 hours in the setting of severe Irukandji syndrome. Magnesium sulphate administration appears to attenuate pain and hypertension in Irukandji syndrome and warrants further evaluation in this setting.
Metropolitan Audit of Appropriate Referrals Refused Admission to Intensive Care
Authors: Duke G. J. 
Published: January 2019

We undertook a three-month prospective cohort study of critically ill adult patients referred to the Intensive Care Units 7(ICUs) of public hospitals in metropolitan Melbourne and Geelong, Victoria. The aim was to ascertain the prevalence and immediate consequences of “refused” admission amongst patients appropriately referred to the ICU of first choice. Between August 1 and October 31, 1999, 10 (out of 12) public hospitals collected data. Three thousand and four patients were referred to these ICUs, and “refusals” were reported by all hospitals. A total of 282 (9.4%) patients were unable to be admitted to the ICU of first choice, giving a rate of 3.1 “refusals” per day. The reasons for “refusal” were limited staffing (52%) and shortage of beds (46%.) Acute inter-hospital transfer (1.7 per day) was the most common immediate triage outcome (57%). These rates are higher than previously reported figures. We conclude that refused admission to the ICU of first choice, and acute inter-hospital transfer in this region and time period, were common events.
Dexmedetomidine Infusion without Loading Dose in Surgical Patients Requiring Mechanical Ventilation: Haemodynamic Effects and Efficacy
Authors: Ickeringill M. , Shehabi Y. , Adamson H. , Ruettimann U. 
Published: January 2019

We investigated the haemodynamic effects and the efficacy of a continuous infusion of dexmedetomidine without a loading dose in 50 patients having had cardiac surgery (n=33), complex major surgery (n=9) and multiple trauma (n=8). The mean age was 60 (±16) years, and the mean APACHE II score was 13 (±5). Dexmedetomidine was commenced at an initial rate of 0.2 to 0.4 μg/kg/h (depending on whether anaesthetic or sedative agents had already been used) and rescue analgesia and sedation was administered with morphine and midazolam respectively. Propofol was used if additional sedation was needed. Sedation was targeted to a modified Motor Activity Assessment Score. Eighty percent of patients required no or “minimal” rescue therapy (<10 mg midazolam /day and/or <10 mg morphine/day and/or <100 mg propofol/day). The cardiac surgery group needed the least rescue therapy. A statistically significant but clinically unimportant reduction in mean heart rate and mean systolic blood pressure was observed over the first six hours (P<0.0001, and P=0.009 respectively). The baseline heart rate of 85 (±17) beats per minute (bpm), fell to a low of 78 (±13) bpm at four hours and then remained stable throughout the infusion period. The systolic blood pressure fell from 125 (±22) mmHg to a low of 112 (±20) mmHg at 1.5 hours with minimal change afterwards. Dexmedetomidine was an effective sedative and analgesic in this group of complex surgical and trauma patients with pronounced benefit in the cardiac surgery group. Omitting the loading dose avoided undesirable haemodynamic effects without compromising sedation and analgesia.
Bloodless Intensive Care: A Case Series and Review of Jehovah's Witnesses in ICU
Authors: Maclaren G. , Anderson M. 
Published: January 2019

The objective of this study was to assess the outcome of Jehovah's Witness (JW) patients admitted to a major Australasian ICU and to review the literature regarding the management of critically ill Jehovah's Witness patients. All Jehovah's Witness patients admitted to the ICU between January 1999 and September 2003 were identified from a prospective database. Their ICU mortality, APACHE II scores, APACHE II risk of death and ICU length of stay were compared to the general ICU population. Twenty-one (0.24%) out of 8869 patients (excluding re-admissions) admitted to the ICU over this period were Jehovah's Witness patients. Their mean APACHE II score was 14.1 (±7.0), the mean APACHE II risk of death was 21.2% (±16.6), and the mean nadir haemoglobin (Hb) was 80.2 g/l (±36.4). Four out of 21 Jehovah's Witness patients died in ICU compared to 782 out of 8848 non- Jehovah's Witness patients (19.0% vs 8.8%, P=0.10, chi square). The median ICU length of stay in both groups was two days (P=0.64, Wilcoxon rank sum). The lowest Hb recorded in a survivor was 23 g/l. Jehovah's Witness patients appear to be an uncommon patient population in a major Australasian ICU but are not over-represented when compared with their prevalence in the community. Despite similar severity of illness scores and predicted mortality to those in the general ICU population, there was a trend towards higher mortality in Jehovah's Witness patients.
Some Observations on Early Military Anaesthesia
Authors: Houghton I. T. 
Published: January 2019

Although anaesthesia was discovered in 1846, pain relief had been used for many years previously. Opium, mandragora, and Indian hemp amongst others have been used since the earliest times as alluded to by many of the classical writers. The use of refrigeration anaesthesia is known to have been recommended a millennium ago although it never had much usage. Very soon after the introduction of ether anaesthesia, it was recommended for military use and the first use by the American forces was in Buena Vista early in 1847 and then again at Vera Cruz. Pirogoff taught and used ether anaesthesia on active service with the Russian forces in the Caucasus in the summer of 1847. Meanwhile Spencer Wells, who was serving with the Royal Navy in Malta, was the first British service medical officer recorded to have used anaesthesia. He went on to write up a series of 106 anaesthetics. The Danes were probably next to use anaesthesia in battle using chloroform in 1848. However, it was not until the Crimean War that anaesthesia began to play an important part in battle surgery with many anaesthetics being given with varying results. The War of the Rebellion was the next war in which anaesthesia was important and the first one in which proper statistics were kept allowing useful analysis. Anaesthesia had irrevocably found its place in battlefield surgery.