Dexmedetomidine-associated hyperthermia: a retrospective cohort study of intensive care unit admissions between 2009 and 2016.

Dexmedetomidine-associated hyperthermia has not been previously studied. Analysis is warranted to determine whether this potentially dangerous complication is more prevalent than previously realised. We aimed to examine the association between dexmedetomidine and temperature ≥39.5°C, including patient characteristics, temporality and potential risk factors. We conducted a retrospective cohort study of all intensive care unit (ICU) admissions between 1 July 2009 and 31 May 2016 in a tertiary ICU in Australia. Temperature data was available for 9,782 ICU admissions. Dexmedetomidine was given intravenously to 611 (6.3%) patients at a dose of 0 to 1.5 g/kg/hour. Temperatures ≥39.5°C were recorded in 341 (3.5%) patients. Overall hospital mortality was 10.8% for all admissions and 29.3% for patients with temperatures ≥39.5°C. Dexmedetomidine exposure was more frequent in patients with temperature recordings ≥39.5°C compared to those with temperatures <39.5°C, 11.94% versus 2.94% (odds ratio [OR] 4.49; 95% confidence intervals [CI] 3.37, 5.92; P <0.001). The association was stronger for patients post-open heart surgery (OHS) with temperatures ≥39.5°C (OR 12.9; 95% CI 5.01, 31.62; P <0.001). Multivariate analysis showed an independent association between dexmedetomidine and a temperature ≥39.5°C in two particular patient groups: OHS (OR 2.72; 95% CI 1.1, 6.9; P <0.001), and obesity (OR 3.44; 95% CI 1.5, 7.9; P <0.001). Dexmedetomidine exposure is associated with an increased risk of hyperthermia. Possible risk factors are open heart surgery and obesity.

Prospective observational study of emergency airway management in the critical care environment of a tertiary hospital in Melbourne.

The objective of this study is to describe the population of patients receiving emergency airway management outside operating theatres at our institution, a tertiary referral centre in Melbourne. A registry of all patients receiving emergency airway management in the emergency department, ICU and on the wards as part of Medical Emergency Response teams' care, was prospectively collected. There were 128 adults and one paediatric patient requiring emergency airway management recruited to the study. Data for analysis included patient demographics, pre-oxygenation and apnoeic oxygenation, staff, drugs, details of laryngoscopic attempts, adjuncts, airway manoeuvres, complications sustained and method of confirmation of endotracheal tube placement. Over a 12-month period, there were 139 intubations of 129 patients, requiring a total of 169 attempts. Respiratory failure was the most common indication for intubation. Intubation was successful on the first episode of laryngoscopy in 116 (83.5%) patients. Complications occurred in 48 patients. In the cohort of patients without respiratory failure, nasal cannulae apnoeic oxygenation significantly reduced the incidence of hypoxaemia (0 out of 31 [0.0%] versus 10 out of 60 [16.7%], P=0.016; absolute risk reduction 16.7%; number needed to treat: 6). Waveform capnography was used to confirm endotracheal tube placement in 133 patients and there were four episodes of oesophageal intubation, all of which were recognised immediately. In the critical care environment of our institution, emergency airway management is achieved with a first-attempt success rate that is comparable to overseas data. Nasal cannulae apnoeic oxygenation appears to significantly reduce the risk of hypoxaemia in patients without respiratory failure and the use of waveform capnography eliminates episodes of unrecognised oesophageal intubation.

Intensive care unit admission in patients following rapid response team activation: call factors, patient characteristics and hospital outcomes.

Rapid Response Systems (RRSs) have been widely introduced throughout hospital health systems, yet there is limited research on the characteristics and outcomes of patients admitted to an intensive care unit (ICU) following RRS activation. Using database extraction, this study examined the factors associated with ICU admission and patient outcome in patients receiving RRS activation in a tertiary level hospital between 2009 and 2013. Of 3004 RRS activations, 392 resulted in ICU admissions. Call factors associated with ICU admission and increased hospital mortality included tachypnoea (P <0.001 and P <0.001, respectively), hypoxia (P <0.001 and P <0.001, respectively) and having multiple Medical Emergency Team call triggers breached simultaneously (P <0.001 and P <0.001, respectively). Patients with seizures (P <0.001) and tachycardia (P=0.004) were more likely to survive to hospital discharge. Patient factors associated with ICU admission included young age (P <0.001) and having severe liver disease (P <0.001). Factors associated with increased hospital mortality included delayed RRS activation (P <0.001), increased age (P <0.001) and comorbidities including ischaemic heart disease (P=0.006), congestive heart failure (P <0.001), chronic kidney disease (P <0.001) and severe liver disease (P <0.001). Multiple factors relating to both the nature of the RRS activation call and patient characteristics are associated with ICU admission and hospital mortality post RRS activation. This information may be useful for risk stratification of deteriorating patients and determination of appropriate escalation.

Heatwave hyponatraemia: a case series at a single Victorian tertiary centre during January 2014.

Heatwaves are a major public health threat for Australians. Hyponatraemia is common, with an increased incidence previously described during heatwaves. We report a series of 10 patients admitted with moderate to profound hyponatraemia, the majority with a history of excess water consumption, during the January 2014 heatwave.

Isoxazolines as potent antagonists of the integrin alpha(v)beta(3).

Starting with lead compound 2, we sought to increase the selectivity for alpha(v)beta(3)-mediated cell adhesion by examining the effects of structural changes in both the guanidine mimetic and the substituent alpha to the carboxylate. To prepare some of the desired aminoimidazoles, a novel reductive amination utilizing a trityl-protected aminoimidazole was developed. It was found that guanidine mimetics with a wide range of pK(a)'s were potent antagonists of alpha(v)beta(3). In general, it appeared that an acylated 2-aminoimidazole guanidine mimetic imparted excellent selectivity for alpha(v)beta(3)-mediated adhesion versus alpha(IIb)beta(3)-mediated platelet aggregation, with selectivity of approximately 3 orders of magnitude observed for compounds 3g and 3h. It was also found in this series that the alpha-substituent was required for potent activity and that 2,6-disubstituted arylsulfonamides were optimal. In addition, the selective alpha(v)beta(3) antagonist 3h was found to be a potent inhibitor of alpha(v)beta(3)-mediated cell migration.

Rhizobial Nod factors stimulate somatic embryo development in Picea abies.

Nod factors are lipochitooligosaccharides (LCOs) secreted by rhizobia. Nod factors trigger the nodulation programme in a compatible host. A bioassay was set up to test how crude (NGR234) and purified (NodS) Nod factors influence cell division and somatic embryogenesis in a conifer, Norway spruce (Picea abies). The Nod factors promoted cell division in the absence of auxin and cytokinin. More detailed studies showed that NodS stimulates development of proembryogenic masses from small cell aggregates and further embryo development. However, stimulation was only observed in low-density cell cultures. Our data suggest that rhizobial Nod factors substitute for conditioning factors in embryogenic cultures of Norway spruce.

Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action.

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.

Isoxazoline GPIIb/IIIa antagonists bearing a phosphoramidate.

Isoxazolinylacetamides bearing a phosphoramidate group alpha- to the carboxylate moiety (3) were prepared and evaluated for in vitro antiplatelet efficacy. They were found to bind GPIIb/IIIa with high affinity and were potent antagonists of ADP mediated platelet aggregation.

Dictyostelium discoideum fatty-acyl amidase II has deacylase activity on Rhizobium nodulation factors.

Dictyostelium discoideum (Amoebidae) secretes cell-lysing enzymes: esterases, amidases, and glycosylases, many of which degrade soil bacteria to provide a source of nutrients. Two of these enzymes, fatty-acyl amidases FAA I and FAA II, act sequentially on the N-linked long chain acyl groups of lipid A, the lipid anchor of Gram-negative bacterial lipopolysaccharide. FAA I selectively hydrolyzes the 3-hydroxymyristoyl group N-linked to the proximal glucosamine residue of de-O-acylated lipid A. Substrate specificity for FAA II is less selective, but does require prior de-N-acylation of the proximal sugar, i.e. bis-N-acylated lipid A is not a substrate. We have synthesized a 14C-labeled substrate analog for FAA II and used this in a novel assay to monitor its purification. Inhibitory studies indicate that FAA II is not a serine protease, but may have a catalytic mechanism similar to metalloprotein de-N-acetylases such as LpxC. Interestingly, rhizobial Nod factor signal oligosaccharides that induce root nodules on leguminous plants have many of the structural requirements for substrate recognition by FAA II. In vitro evidence indicates that Rhizobium fredii Nod factors are selectively de-N-acylated by purified FAA II, suggesting that the enzyme may reduce the N2-fixing efficiency of Rhizobium-legume symbioses. In contrast, N-methylated Nod factors from transgenic R. fredii carrying the rhizobial nodS gene were resistant to FAA II, suggesting a mechanism by which Nod factors may be protected from enzymatic de-N-acylation. Since FAA II and Nod factors are both secreted, and Nod factors that lack the N-acyl group are unable to induce nodules, dictyostelial FAA II may decrease the efficiency of symbiotic nitrogen fixation in the environment by reducing the available biologically active nodule inducer signal.

Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists.

Using isoxazoline XR299 (1a) as a starting point for the design of highly potent, long-duration GPIIb/IIIa antagonists, the effect of placing lipophilic substituents at positions alpha and beta to the carboxylate moiety was evaluated. Of the compounds studied, it was found that the n-butyl carbamate 24u exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.

Discovery of potent isoxazoline glycoprotein IIb/IIIa receptor antagonists.

Using the isoxazoline as a common structural feature, three series of glycoprotein IIb/IIIa receptor antagonists were evaluated, culminating in the discovery of XR299 (30). In an in vitro assay of platelet inhibition, XR299 had an IC50 of 0.24 microM and was a potent antiplatelet agent when dosed intravenously in a canine model. It was shown through X-ray studies of the cinchonidine salt 49 that the receptor required the 5(R)-stereochemistry for high potency. The ethyl ester prodrug of XR299, XR300 (29), was orally active in the dog.