Incidence of hyperoxia in trauma patients receiving pre-hospital emergency anaesthesia: results of a 5-year retrospective analysis.

BACKGROUND: Previous studies have demonstrated an association between hyperoxia and increased mortality in various patient groups. Critically unwell and injured patients are routinely given high concentration oxygen in the pre-hospital phase of care. We aim to investigate the incidence of hyperoxia in major trauma patients receiving pre-hospital emergency anesthesia (PHEA) in the pre-hospital setting and determine factors that may help guide clinicians with pre-hospital oxygen administration in these patients. METHODS: A retrospective cohort study was performed of all patients who received PHEA by a single helicopter emergency medical service (HEMS) between 1 October 2014 and 1 May 2019 and who were subsequently transferred to one major trauma centre (MTC). Patient and treatment factors were collected from the electronic patient records of the HEMS service and the MTC. Hyperoxia was defined as a PaO2 > 16 kPA on the first arterial blood gas analysis upon arrival in the MTC. RESULTS: On arrival in the MTC, the majority of the patients (90/147, 61.2%) had severe hyperoxia, whereas 30 patients (20.4%) had mild hyperoxia and 26 patients (19.7%) had normoxia. Only 1 patient (0.7%) had hypoxia. The median PaO2 on the first arterial blood gas analysis (ABGA) after HEMS handover was 36.7 [IQR 18.5-52.2] kPa, with a range of 7.0-86.0 kPa. SpO2 pulse oximetry readings before handover were independently associated with the presence of hyperoxia. An SpO2 ≥ 97% was associated with a significantly increased odds of hyperoxia (OR 3.99 [1.58-10.08]), and had a sensitivity of 86.7% [79.1-92.4], a specificity of 37.9% [20.7-57.8], a positive predictive value of 84.5% [70.2-87.9] and a negative predictive value of 42.3% [27.4-58.7] for the presence of hyperoxemia. CONCLUSION: Trauma patients who have undergone PHEA often have profound hyperoxemia upon arrival at hospital. In the pre-hospital setting, where arterial blood gas analysis is not readily available a titrated approach to oxygen therapy should be considered to reduce the incidence of potentially harmful tissue hyperoxia.

Differential activation of the human costal and crural diaphragm during voluntary and involuntary breaths.

The diaphragm is the primary muscle that generates the negative intrathoracic pressure to drive inspiratory airflow. The diaphragm consists of two parts, the costal and crural portions, with different roles during inspiration in animals, particularly when the stimulus to breathe is increased. In this study, the neural drive to the costal and crural portions of the diaphragm was assessed in nine healthy participants [8 male, aged 32 ± 13 yr (mean ± SD)]. Inspiratory electromyographic activity (EMG) was recorded from the costal diaphragm by using an intramuscular electrode and from the crural diaphragm with a multipair gastroesophageal catheter. Participants performed voluntary augmented breaths at 120%, 140%, and 160% of their tidal volume and also underwent progressive hypercapnia to induce involuntary breathing. Irrespective of the task, the increase in crural activity (normalized to quiet breathing) was only ~60% of the increase in costal activity (slope: 0.56 ± 0.30, P < 0.001). The onset and peak timing of EMG activity was similar for the costal and crural diaphragm during quiet breathing. Thus, when stimulated by either a voluntary or involuntary drive to breathe above tidal volume, the neural drive to the diaphragm was greater to the costal than to the crural portion.NEW & NOTEWORTHY Simultaneous electromyographic recordings from the human costal and crural diaphragm during voluntary augmented breathing and involuntary rebreathing show that the increase in inspiratory crural diaphragm activity was ~60% of the increase in costal diaphragm activity. However costal to crural diaphragm activation did not differ between the two tasks. The dissociation in the amplitude of activation of the costal and crural diaphragm becomes apparent only as the drive to breathe increases above tidal breathing.

Increased diaphragm motor unit discharge frequencies during quiet breathing in people with chronic tetraplegia.

KEY POINTS: Respiratory muscle strength is compromised in people with tetraplegia, which may be compensated for by an increase in neural drive to the diaphragm. We found that the discharge frequencies of diaphragm motor units are higher in people with chronic tetraplegia compared with able-bodied people during quiet breathing. Furthermore, we found that the area of single motor unit potentials was increased in people with tetraplegia. These results suggest an increased motoneurone output to the diaphragm and remodelling of diaphragm motor units to maintain ventilation in tetraplegia. ABSTRACT: People with tetraplegia have reduced inspiratory muscle strength, ∼40% of able-bodied individuals. Paralysed or partially paralysed respiratory muscles as a result of tetraplegia compromise lung function, increase the incidence of respiratory infections and can cause dyspnoea. We hypothesised that reduced inspiratory muscle strength in tetraplegia may increase neural drive to the inspiratory muscles to maintain ventilation. We recorded the discharge properties of single motor units from the diaphragm in participants with chronic tetraplegia (8 males, 42-78 years, C3-C6 injury, AIS A-C) and able-bodied control participants (6 males matched for age and body mass index). In each group, 117 and 166 single motor units, respectively, were discriminated from recordings in the costal diaphragm using a monopolar electrode. A linear mixed-effects model analysis showed higher peak discharge frequencies of motor units during quiet breathing in tetraplegia (17.8 ± 4.9 Hz; mean ± SD) compared with controls (12.4 ± 2.2 Hz) (P < 0.001). There were no differences in tidal volume, inspiratory time or mean air flow between groups. Motor unit potentials in tetraplegia, compared with controls, were larger in amplitude (1.1 ± 0.7 mV and 0.5 ± 0.3 mV, respectively, P = 0.007) and area (1.83 ± 1.49 µV ms and 0.69 ± 0.52 µV ms, respectively, P = 0.003). The findings indicate that diaphragm motor unit remodelling is likely to have occurred in people with chronic tetraplegia and that there is an increase in diaphragm motor unit discharge rates during quiet breathing. These neural changes ensure that ventilation is maintained in people with chronic tetraplegia.

Discharge properties of human diaphragm motor units with ageing.

KEY POINTS: Ageing is associated with changes in the respiratory system including in the lungs, rib cage and muscles. Neural drive to the diaphragm, the principal inspiratory muscle, has been reported to increase during quiet breathing with ageing. We demonstrated that low-threshold motor units of the human diaphragm recruited during quiet breathing have similar discharge frequencies across age groups and shorter discharge times in older age. With ageing, motor unit action potential area increased. We propose that there are minimal functionally significant changes in the discharge properties of diaphragm motor units with ageing despite remodelling of the motor unit in the periphery. ABSTRACT: There are changes in the skeletal, pulmonary and respiratory neuromuscular systems with healthy ageing. During eupnoea, one study has shown relatively higher crural diaphragm electromyographic activity (EMG) in healthy older adults (>51 years) than in younger adults, but these measures may be affected by the normalisation process used. A more direct method to assess neural drive involves the measurement of discharge properties of motor units. Here, to assess age-related changes in neural drive to the diaphragm during eupnoea, EMG was recorded from the costal diaphragm using a monopolar needle electrode in participants from three age groups (n ≥ 7 each): older (65-80 years); middle-aged (43-55 years) and young (23-26 years). In each group, 154, 174 and 110 single motor units were discriminated, respectively. A mixed-effects linear model showed no significant differences between age groups for onset (group mean range 9.5-10.2 Hz), peak (14.1-15.0 Hz) or offset (7.8-8.5 Hz) discharge frequencies during eupnoea. The motor unit recruitment was delayed in the older group (by ∼15% of inspiratory time; p = 0.02 cf. middle-aged group) and had an earlier offset time (by ∼15% of inspiratory time; p = 0.04 cf. young group). However, the onset of multiunit activity was similar across groups, consistent with no global increase in neural drive to the diaphragm with ageing. The area of diaphragm motor unit potentials was ∼40% larger in the middle-aged and older groups (P < 0.02), which indicates axonal sprouting and re-innervation of muscle fibres associated with ageing, even in middle-aged participants.

Abdominal Functional Electrical Stimulation to Augment Respiratory Function in Spinal Cord Injury.

Background: Functional electrical stimulation (FES) is the application of electrical pulses to a nerve to achieve a functional muscle contraction. Surface electrical stimulation of the nerves that innervate the abdominal muscles, termed abdominal FES, can cause the abdominal muscles to contract, even when paralysed after spinal cord injury. As the abdominal muscles are the major expiratory muscles, and commonly partially or completely paralysed in tetraplegia, abdominal FES offers a promising method of improving respiratory function for this patient group. Objective: The aim of the article is to provide readers with a better understanding of how abdominal FES can be used to improve the health of the spinal cord-injured population. Methods: A narrative review of the abdominal FES literature was performed. Results: Abdominal FES can achieve an immediate effective cough in patients with tetraplegia, while the repeated application over 6 weeks of abdominal FES can improve unassisted respiratory function. Ventilator duration and tracheostomy cannulation time can also be reduced with repeated abdominal FES. Conclusion: Abdominal FES is a noninvasive method to achieve functional improvements in cough and respiratory function in acute and chronically injured people with tetraplegia. Potential practical outcomes of this include reduced ventilation duration, assisted tracheostomy decannulation, and a reduction in respiratory complications. All of these outcomes can contribute to reduced morbidity and mortality, improved quality of life, and significant potential cost savings for local health care providers.

Riemannian Geometry Applied to Detection of Respiratory States From EEG Signals: The Basis for a Brain-Ventilator Interface.

GOAL: During mechanical ventilation, patient-ventilator disharmony is frequently observed and may result in increased breathing effort, compromising the patient's comfort and recovery. This circumstance requires clinical intervention and becomes challenging when verbal communication is difficult. In this study, we propose a brain-computer interface (BCI) to automatically and noninvasively detect patient-ventilator disharmony from electroencephalographic (EEG) signals: a brain-ventilator interface (BVI). METHODS: Our framework exploits the cortical activation provoked by the inspiratory compensation when the subject and the ventilator are desynchronized. Use of a one-class approach and Riemannian geometry of EEG covariance matrices allows effective classification of respiratory states. The BVI is validated on nine healthy subjects that performed different respiratory tasks that mimic a patient-ventilator disharmony. RESULTS: Classification performances, in terms of areas under receiver operating characteristic curves, are significantly improved using EEG signals compared to detection based on air flow. Reduction in the number of electrodes that can achieve discrimination can be often desirable (e.g., for portable BCI systems). By using an iterative channel selection technique, the common highest order ranking, we find that a reduced set of electrodes (n = 6) can slightly improve for an intrasubject configuration, and it still provides fairly good performances for a general intersubject setting. CONCLUSION: Results support the discriminant capacity of our approach to identify anomalous respiratory states, by learning from a training set containing only normal respiratory epochs. SIGNIFICANCE: The proposed framework opens the door to BVIs for monitoring patient's breathing comfort and adapting ventilator parameters to patient respiratory needs.

EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.

BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.

Quetiapine and Buspirone Both Elevate Cortical Levels of Noradrenaline and Dopamine In vivo, but Do Not have Synergistic Effects.

Decreased cognitive ability is a significant problem in schizophrenia, and it has been proposed that augmentation of antipsychotics with 5HT(1A) receptor agonists may improve cognitive performance. Clinical studies have been mixed but there have been no studies specifically examining the effects of combining the atypical antipsychotic quetiapine with the 5HT(1A) receptor partial agonist, buspirone on monoamine release. This is of interest given previous evidence that monoamine release can alter cognition in schizophrenia. In the present study we measured in vivo levels of monoamines in the frontal cortex of Sprague Dawley rats and examined if buspirone (2.5 mg/kg i.p.), altered monoamine release both when given alone and when combined with quetiapine (10 mg/kg i.p.). We found that serotonin levels were not altered by either drug, either alone or in combination. In contrast, both buspirone and quetiapine monotherapy significantly increased release of noradrenaline (112 and 160% respectively) and dopamine (169 and 191% respectively) compared to controls. However, there were no additional increases in in vivo monoamine release when the combination of these drugs were given. One possible explanation for these negative findings could be that the intrinsic 5HT(1A) agonist activity of quetiapine on its own is of such significance that it is not further enhanced by buspirone. These findings do not support clinical studies combining buspirone and quetiapine, if these were to be used on the basis of enhanced monoamine neurotransmission. These findings may also have implications for the atypical antipsychotic drugs in development which combine dopamine D(2) antagonism with 5HT(1A) partial agonism.

Pharmacological characterisation of the electrically evoked release of monoamines from chicken brain in vitro.

1. A study was conducted to develop an in vitro model for examining the basal and electrical-stimulation-induced release of [3H]monoamines from chicken hyperstriatal neurones in order to demonstrate the presence of presynaptic autoreceptors for the three main monoamine transmitters: noradrenaline, dopamine and 5-HT. 2. Two sets of experiments were carried out: the first was to evaluate the effect of calcium and tetrodotoxin (TTX, sodium channel conductance inhibitor) in order to demonstrate that evoked release of monoamines was a consequence of exocytotic processes; the second to investigate the effect of selective agonists and antagonists on neurotransmitter release. 3. Ross and Cobb broiler chickens of either sex (approximately 7 to 8 weeks old) were used. Slices of hyperstriatal tissue were preincubated with [3H]noradrenaline, [3H]dopamine or [3H]5-hydroxytryptamine (5-HT), washed, perfused and electrically stimulated at three time points (S1, S2 and S3) which released [3H]noradrenaline, [3H]dopamine and [3H]5-HT, as determined by scintillation spectrometry. 4. When calcium was removed from, or TTX added to, the superfusion medium prior to and including the second period of electrical stimulation (S2) the evoked releases of [3H]noradrenaline, [3H]dopamine and [3H]5-HT at S2 were abolished. 5. In the presence of the selective alpha2-adrenoceptor agonist UK 14304 during the S2 period, the S2/S1 ratio was lower than the control ratio due to a reduction in the stimulated release of [3H]noradrenaline. The selective alpha2-adrenoceptor antagonist RX 821002 blocked the UK 14304-induced reduction of evoked release and the S2/S1 ratio was similar to the control ratio. 6. The D2-like receptor agonist quinpirole reduced the S2/S1 ratio for [3H]dopamine release, an effect blocked by the antagonist AJ 76. The 5-HT1B receptor agonist CP 94253 during S2 reduced the S2/S1 ratio due to a reduction in evoked [3H]5-HT. This effect was blocked by the 5-HT1B receptor antagonist GR 55562. 7. The results demonstrate, for the first time, the functional presence of presynaptic alpha2-adrenoceptors, presynaptic 5-HT1B autoreceptors and presynaptic D2-like autoreceptors in broiler chicken hyperstriatal neurones in vitro.

Invited review: the evolution of antidepressant mechanisms.

Present antidepressants are all descendents of the serendipitous findings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. The identification of their mechanism of action, and those of reserpine and amphetamine, in the 1960s, led to the monoamine theories of depression being postulated; first, with noradrenaline then 5-hydroxytryptamine being considered the more important amine. These monoamine theories of depression predominated both industrial and academic research for four decades. Recently, in attempts to design new drugs with faster onsets of action and more universal therapeutic action, downstream alterations common to current antidepressants are being examined as potential antidepressants. Additionally, the use of animal models has identified a number of novel targets some of which have been subjected to clinical trials in humans. However, monoamine antidepressants remain the best current medications and it may be some time before they are dislodged as the market leaders.

2-(4,5-dihydro-1H-imidazol-2-yl)indazole (indazim) derivatives as selective I(2) imidazoline receptor ligands.

A series of variously substituted 2-(4,5-dihydro-1H-imidazol-2-yl)indazoles 3a-j and 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5,6,7-tetrahydroindazole 6 were prepared by the regiospecific heteroalkylation of corresponding indazoles 1a-k with 2-chloro-4,5-dihydroimidazole (2). Their affinity to imidazoline I(2) receptors and alpha(2)-adrenergic receptors was determined by radioligand binding assay carried out on P(2) membrane preparations obtained from rat whole brains. 4-Chloro-2-(4,5-dihydro-1H-imidazol-2-yl)indazole (3f, 4-Cl-indazim) showed a 3076-fold difference in affinity for the [(3)H]2BFI-labeled imidazoline I(2) receptors relative to the [(3)H]RX821001-labeled alpha(2)-adrenergic receptors. This highly selective compound should prove to be useful tool in further understanding the functions of the imidazoline I(2) receptors.

Symptom experience and functional status among HIV-infected women.

Irrespective of powerful drug therapies, there has been a slight increase in newly diagnosed cases of AIDS in women. HIV/AIDS-related symptoms develop from the illness itself, treatments or medications. Symptoms and their reoccurrence remain problematic. This study is a secondary analysis of data exploring symptoms, symptom distress and functional status in 104 ethnically diverse HIV-positive women. Measures included the Brief Symptom Inventory, a General Symptom Questionnaire, the Center for Epidemiological Studies Depression Scale, and the Inventory of Functional Status. Findings indicate that this sample of women was distressed, at risk for depression and had a moderate level of physical functioning. These findings support the need for symptom management interventions that enhance emotional wellbeing and self-care activities for HIV-infected women.

Endogenous beta-carbolines as clonidine-displacing substances.

Endogenous beta-carbolines, such as harmane, are known to occur in mammalian species including humans. Radioligand binding studies have revealed that certain beta-carbolines display high affinity for both I(1) and I(2) imidazoline-binding sites (IBS). Functional studies have shown that the beta-carboline harmane elicits many characteristics expected of an endogenous ligand IBS. This article discusses the evidence relating to beta-carbolines as endogenous ligands and presents a case for harmane and related compounds as endogenous ligands for IBS.

Characterization of [(3)H]harmane binding to rat whole brain membranes.

This study investigates the binding of [(3)H]harmane to rat whole brain homogenates. Saturation studies revealed [(3)H]harmane labels a single, saturable, high-capacity population with high affinity. All the test compounds displaced [(3)H]harmane completely and in an apparently monophasic manner. The displacement profile of the test ligands indicated labeling of MAO-A. Given the high level of MAO-A binding, it is unlikely that a low-capacity I(2) site would be distinguishable from the total [(3)H]harmane population.

BU98008, a highly selective imidazoline(1)-receptor ligand.

BU98008 (1-(4, 5-dihydro-1H-imidazol-2-yl)isoquinoline) is a novel isoquinoline derivative. Radioligand binding studies revealed it had high affinity for the I(1) receptor in rat kidney membranes but low affinity for the I(2) binding site and alpha(2)-adrenoceptor in rat brain membranes. Further evaluation of BU98008 in vivo revealed no effect on blood pressure following peripheral administration. These preliminary data suggest BU98008 may be an antagonist at I(1) receptors. Further evaluation following central administration must be performed before a hypotensive action can be excluded.

Novel ligands for the investigation of imidazoline receptors and their binding proteins.

New ligands for imidazoline receptors are described so that these receptors can be more fully explored and understood. BU224, (2-(4,5-dihydroimidaz-2-yl)-quinoline, shows high affinity and is selective for the imidazoline-2 (I(2)) class of receptors. BU224 was tested in the rat Porsolt forced swim paradigm where it was found to decrease time spent immobile and increase the time spent swimming, consistent with an antidepressant profile. BU224 was tritiated and, in radioligand binding studies, was found to label a single population of saturable sites with high affinity. In vitro brain autoradiography with [(3)H]BU224 also showed a pattern of distribution similar to the known labeling of I(2) receptors. A new series of four 2BFI (2-(benzofuranyl)-2-imidazoline) derivatives were investigated as potential ligands for imaging brain I(2) receptors using positron emission tomography (PET). At least two, BU20012 and BU20013, retained high affinity and moderate selectivity and penetrated the brain when administered peripherally in the mouse. 2BFI has undergone the Mannich reaction to immobilized diaminodipropyl amine to fabricate an affinity column, which was used to isolate a protein from rabbit brain; this protein was sequenced and identified as the enzyme creatine kinase.

Relationship between imidazoline(2) sites and monoamine oxidase.

I(2) site-selective compounds are known to interact with and inhibit monoamine oxidase (MAO), but it remains unclear as to whether this interaction occurs through an allosteric or competitive interaction. This study used the new selective, irreversible I(2) ligand BU99006, to clarify the relationship between MAO and the I(2) binding sites (I(2)-BS). Results demonstrate that irreversible binding of BU99006 to rat brain membranes does not inhibit the enzyme or interfere with its interaction with other imidazoline enzyme inhibitors. This finding suggests that the I(2) sites that react with BU99006 are not those implicated in MAO inhibition and points to the existence of at least two distinct I(2) binding proteins.

Initial evaluation of novel selective ligands for imidazoline(2) receptors in rat whole brain.

Indazim, the indazole analogue of 2BFI, and four methyl-substituted analogues were tested for their affinity at the imidazoline(2) binding site (I(2)-BS), and this affinity was compared with their affinity at the alpha(2)-adrenoceptor to determine their structure, affinity relationship, and selectivity at the I(2)-BS. These studies showed that these ligands were highly selective for the I(2)-BS compared with 2BFI and that substitution at the 4 and 7 positions increased affinity without affecting selectivity.

Investigation of the affinities of two new beta-carbolines for rat brain imidazoline(2) receptors.

The beta-carbolines are possible endogenous ligands and modulators of the imidazoline binding sites (I-BSs). Relatively little is known about this class of compound and its interaction with the I-BS. Presented here are the binding data for two aryl ring substituted dihydro-beta-carbolines at the imidazoline(2) binding site (I(2)-BS) and alpha(2)-adrenoceptor: BG-326 (5-bromo-4,9-dihydro-3H-b-carboline) and BG-350 (5-methoxy-4,9-dihydro-3H-b-carboline). Both compounds show good affinity and selectivity for the I(2)-BS.