Standard care versus individualized blood pressure targets among critically ill patients with shock: A multicenter feasibility and preliminary efficacy study.

PURPOSE: Emerging evidence suggests that minimizing mean perfusion pressure (MPP) deficit during vasopressor therapy for shock can potentially reduce adverse kidney-related outcomes in ICU. We assessed feasibility and preliminary efficacy of individualizing MPP targets based on patients' own pre-illness basal-MPP among vasopressor-treated patients with shock. MATERIAL AND METHODS: In this prospective before-and-after trial, 31 patients during the 'before'/observational phase and 31 patients during the 'after'/intervention phase were enrolled at two tertiary-level Australian ICUs. Feasibility endpoint was time-weighted average MPP-deficit during vasopressor therapy. Preliminary efficacy outcomes were new significant AKI, major adverse kidney events within 14 days (MAKE-14), and 90-day mortality. RESULTS: Patients in the after group had lower MPP-deficit (median 18%, [interquartile range [IQR]: 11-23] vs. 4%, [IQR: 2-9], p < 0.001) and lower incidence of new significant AKI (8/31 [26%] vs. 1/31 [3%], p = 0.01) than the before group. The between-group differences in MAKE-14 (9/31 [29%] vs. 4/31 [13%], p = 0.12) and 90-day mortality (6/31 [19%] vs. 2/31 [6%], p = 0.13) were not statistically significant. CONCLUSIONS: An individualized blood pressure target strategy during vasopressor therapy in ICU was feasible and appeared to be efficacious in this preliminary study. Testing this strategy in a larger randomized controlled trial is warranted. STUDY REGISTRATION: ACTRN12617001459314.

High-flow nasal cannula versus standard oxygen therapy assisting sedation during endoscopic retrograde cholangiopancreatography in high risk cases (OTHER): study protocol of a randomised multicentric trial.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an increasingly common intervention in the treatment of pancreaticobiliary disorders. Patients are often elderly with complex co-morbidities. While monitored anaesthesia care with sedation is commonly used for most cases, few would require general anaesthesia with an endotracheal tube. Both low-flow and high-flow nasal cannulas (HFNC) are established ways of delivering supplemental oxygen, but it is unclear whether one technique is better than the other. HFNC seems a promising tool for advanced procedures but evidence to support its application in high-risk ERCP cases is limited. The rate of oxygen desaturation during endoscopy has been reported to be as high as 11%-50% and the method of oxygen delivery for ERCP merits further study. METHODS/DESIGN: This is a prospective, randomised, multicentre trial comparing the efficacy of oxygen supplementation through HFNC versus low-flow nasal cannula during ERCP, in a cohort of patients at risk of adverse respiratory events. A total of 132 patients will be recruited across three sites and randomly assigned to either the low-flow or the HFNC group. The primary outcome is the proportion of patients experiencing hypoxia, defined by any event of SpO2 < 90%. The secondary outcomes include parameters centred on oxygenation, requirement of airway manoeuvres, successful completion of procedure, perioperative complications, patient satisfaction and cost analysis of the consumables. An intention-to-treat principle will be applied while analysing. DISCUSSION: The demand for ERCPs is likely to increase in the future with the aging population. Our study results may lead to improved outcomes and reduce airway-related complications in patients undergoing ERCPs. The results will be presented at national and international meetings and published in peer-reviewed journals. TRIAL REGISTRATION: www.ANZCTR.org.au, CTRN12619000397112. Registered on 12 March 2019.

Validity of a protocol to estimate patients' pre-morbid basal blood pressure.

PURPOSE: The pre-illness basal mean arterial BP (MAP) is an important reference point to gauge the degree of relative hypotension among unwell patients. We aimed to assess mean bias, correlation, and agreement between basal MAP measured during nighttime ambulatory BP monitoring (ABPM) and basal MAP estimated using a standardized protocol. MATERIALS AND METHODS: For a cohort of 137 consecutive patients, aged ≥40 years, who recently underwent ABPM, a blinded investigator estimated basal MAP from up to five most recent clinic BP measurements. Both basal MAP values, measured and estimated, were compared pairwise for each participant. RESULTS: We traced a median of 4 [interquartile range 3-5] previous BP measurements per patient over a median period of 132 [interquartile range 55-277] days up until the ABPM test. The estimated basal MAP (mean 88 ± 8 mmHg) was linearly related (Pearson's r = 0.41, p = 0.0001) to the measured basal MAP (mean 88 ± 12 mmHg). Bland-Altman plot revealed a mean bias of 0.3 mmHg with agreement limits of ±22 mmHg. CONCLUSIONS: The mean bias between estimated and measured values for basal MAP was insignificant and modest. When a recent nighttime ABPM is unavailable, a protocol based on recent clinic BP readings can be used to estimate patient's basal MAP. STUDY REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613001382763.

Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics.

BACKGROUND: Halogenated anesthetics activate cardiac ryanodine receptor 2-mediated sarcoplasmic reticulum Ca release, leading to sarcoplasmic reticulum Ca depletion, reduced cardiac function, and providing cell protection against ischemia-reperfusion injury. Anesthetic activation of ryanodine receptor 2 is poorly defined, leaving aspects of the protective mechanism uncertain. METHODS: Ryanodine receptor 2 from the sheep heart was incorporated into artificial lipid bilayers, and their gating properties were measured in response to five halogenated anesthetics. RESULTS: Each anesthetic rapidly and reversibly activated ryanodine receptor 2, but only from the cytoplasmic side. Relative activation levels were as follows: halothane (approximately 4-fold; n = 8), desflurane and enflurane (approximately 3-fold,n = 9), and isoflurane and sevoflurane (approximately 1.5-fold, n = 7, 10). Half-activating concentrations (Ka) were in the range 1.3 to 2.1 mM (1.4 to 2.6 minimum alveolar concentration [MAC]) with the exception of isoflurane (5.3 mM, 6.6 minimum alveolar concentration). Dantrolene (10 µM with 100 nM calmodulin) inhibited ryanodine receptor 2 by 40% but did not alter the Ka for halothane activation. Halothane potentiated luminal and cytoplasmic Ca activation of ryanodine receptor 2 but had no effect on Mg inhibition. Halothane activated ryanodine receptor 2 in the absence and presence (2 mM) of adenosine triphosphate (ATP). Adenosine, a competitive antagonist to ATP activation of ryanodine receptor 2, did not antagonize halothane activation in the absence of ATP. CONCLUSIONS: At clinical concentrations (1 MAC), halothane desflurane and enflurane activated ryanodine receptor 2, whereas isoflurane and sevoflurane were ineffective. Dantrolene inhibition of ryanodine receptor 2 substantially negated the activating effects of anesthetics. Halothane acted independently of the adenine nucleotide-binding site on ryanodine receptor 2. The previously observed adenosine antagonism of halothane activation of sarcoplasmic reticulum Ca release was due to competition between adenosine and ATP, rather than between halothane and ATP.

Influence of the timing of internal fixation of femur fractures during shock resuscitation on remote organ damage.

BACKGROUND: Reamed intramedullary nailing is the gold standard for management of femur fractures. Nailing within 24 h is proven to reduce complications from ongoing bleeding, soft-tissue damage and pain. However, when combined with haemorrhagic shock, femur fracture and intramedullary nailing are associated with immune-mediated damage to remote organs. We studied whether delaying fracture fixation until resuscitation was succeeding would lead to a significant reduction in remote organ damage. METHODS: Twenty male rabbits underwent closed femur fracture, haemorrhagic shock, resuscitation and either immediate nailing (group: ImmFix, n = 9), delayed nailing (group: DelFix, n = 8) or just splinting (group: NoFix, n = 3). Haemorrhagic shock was maintained for 60 min. Resuscitation was with shed blood and Hartmann's solution. Animals were euthanized 8 h after fixation; the lungs and small bowel were scored histologically by two pathologists. RESULTS: Groups did not differ in weight, haemorrhage volume or magnitude of shock. At 8 h, there was no difference in end-organ damage between ImmFix and DelFix groups (11.3 ± 1.6 and 13.2 ± 1.6 versus 8.1 ± 1.3 and 12.9 ± 1.1, P = 0.26 between groups). However, the NoFix group had significantly greater end-organ damage when compared with the fixation at any time groups (17.3 ± 2.7 and 17.0 ± 3.3 versus 9.8 ± 1.1 and 13.1 ± 1, P = 0.01 between groups). CONCLUSION: In this laboratory model, we have demonstrated that timely femur fracture fixation outweighs the potential harmful effects of surgery performed during haemorrhagic shock with simultaneous resuscitation. We have failed to demonstrate a difference between immediate and delayed fixation during resuscitation.

Differences in the regulation of RyR2 from human, sheep, and rat by Ca²âº and Mg²âº in the cytoplasm and in the lumen of the sarcoplasmic reticulum.

Regulation of the cardiac ryanodine receptor (RyR2) by intracellular Ca(2+) and Mg(2+) plays a key role in determining cardiac contraction and rhythmicity, but their role in regulating the human RyR2 remains poorly defined. The Ca(2+)- and Mg(2+)-dependent regulation of human RyR2 was recorded in artificial lipid bilayers in the presence of 2 mM ATP and compared with that in two commonly used animal models for RyR2 function (rat and sheep). Human RyR2 displayed cytoplasmic Ca(2+) activation (K(a) = 4 µM) and inhibition by cytoplasmic Mg(2+) (K(i) = 10 µM at 100 nM Ca(2+)) that was similar to RyR2 from rat and sheep obtained under the same experimental conditions. However, in the presence of 0.1 mM Ca(2+), RyR2s from human were 3.5-fold less sensitive to cytoplasmic Mg(2+) inhibition than those from sheep and rat. The K(a) values for luminal Ca(2+) activation were similar in the three species (35 µM for human, 12 µM for sheep, and 10 µM for rat). From the relationship between open probability and luminal [Ca(2+)], the peak open probability for the human RyR2 was approximately the same as that for sheep, and both were ~10-fold greater than that for rat RyR2. Human RyR2 also showed the same sensitivity to luminal Mg(2+) as that from sheep, whereas rat RyR2 was 10-fold more sensitive. In all species, modulation of RyR2 gating by luminal Ca(2+) and Mg(2+) only occurred when cytoplasmic [Ca(2+)] was <3 µM. The activation response of RyR2 to luminal and cytoplasmic Ca(2+) was strongly dependent on the Mg(2+) concentration. Addition of physiological levels (1 mM) of Mg(2+) raised the K(a) for cytoplasmic Ca(2+) to 30 µM (human and sheep) or 90 µM (rat) and raised the K(a) for luminal Ca(2+) to ~1 mM in all species. This is the first report of the regulation by Ca(2+) and Mg(2+) of native RyR2 receptor activity from healthy human hearts.

Differential effects of inhaled methacholine on circumferential wall and vascular smooth muscle of third-generation airways in awake sheep.

Evolution and natural selection ensure that specific mechanisms exist for selective airway absorption of inhaled atmospheric molecules. Indeed, nebulized cholinoceptor agonists used in asthma-challenge tests may or may not enter the systemic circulation. We examined the hypothesis that inhaled cholinoceptor agonists have selective access. Six sheep were instrumented under general anesthesia (propofol 5 mg/kg iv, 2-3% isoflurane-oxygen), each with pulsed-Doppler blood flow transducers mounted on the single bronchial artery and sonomicrometer probes mounted on the intrapulmonary third-generation lingula lobe bronchus. Continuous measurements were made of bronchial blood flow (Q(br)), Q(br) conductance (C(br)), bronchial hemicircumference (CIRC(br)), and bronchial wall thickness (WALL TH(br)) in recovered, standing, awake sheep. Methacholine (MCh; 0.125-2.0 µg/kg iv), at the highest dose, caused a 233% rise in Q(br) (P < 0.05) and a 286% rise in C(br) (P < 0.05). CIRC(br) fell to 90% (P < 0.05); WALL TH(br) did not change. In contrast, nebulized MCh (1-32 mg/ml), inhaled through a mask at the highest dose, caused a rise in ventilation and a rise in Q(br) proportional to aortic pressure without change in C(br). CIRC(br) fell to 91% (P < 0.01), and WALL TH(br) did not change. Thus inhaled MCh has access to cholinoceptors of bronchial circumferential smooth muscle to cause airway lumen narrowing but effectively not to those of the systemic bronchovascular circulation. It is speculated that the mechanism is selective neuroparacrine inhibition of muscarinic acetylcholine receptors (M3 bronchovascular cholinoceptors) by prostanoids released by intense MCh activation of epithelial and mucosal cells lining the airway.

The interpretation of intra-abdominal pressures from animal models: the rabbit to human example.

INTRODUCTION: The importance of the abdominal wall characteristics in intraabdominal pressure (IAP), intraabdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are poorly understood. The applicability of laboratory research findings to human scenarios is unknown due to the potential differences in abdominal wall elastance (AWE) amongst species. The aims of the study are to describe the AWE curve in rabbits and to compare it to the available human data. MATERIALS AND METHODS: Prospective experimental animal study in the setting of research laboratory. Male New Zealand White rabbits weighting 2.7 kg ± 0.1 kg, were anesthetized and the AWE was determined by infusion of lactated Ringer's solution into the peritoneal cavity whilst the IAP was measured. A meta-analysis of peer-reviewed studies was conducted to define human AWE. RESULTS: The described AWE was lower in the rabbit than in humans. The function comparing human and rabbit was: log(e) human IAP = (0.58 log(e) rabbit IAP+1.6). CONCLUSIONS: The AWE can vary amongst species. This study determined the relationship to allow the comparison of rabbit and human IAP. The proposed mathematical function is important for the advancement of interpretation and understanding of animal research into IAH and ACS. We recommend developing model-specific functions comparing individual animal models' IAP and that of humans.

Postexercise hypotension in conscious SHR is attenuated by blockade of substance P receptors in NTS.

In hypertensive subjects, a single bout of dynamic exercise results in an immediate lowering of blood pressure back toward normal. This postexercise hypotension (PEH) also occurs in the spontaneously hypertensive rat (SHR). In both humans and SHRs, PEH features a decrease in sympathetic nerve discharge, suggesting the involvement of central nervous system pathways. Given that substance P is released in the nucleus tractus solitarius (NTS) by activation of baroreceptor and skeletal muscle afferent fibers during muscle contraction, we hypothesized that substance P acting at neurokinin-1 (NK-1) receptors in the NTS might contribute to PEH. We tested the hypothesis by determining, in conscious SHRs, whether NTS microinjections of the NK-1 receptor antagonist SR-140333 before exercise attenuated PEH. The antagonist, in a dose (60 pmol) that blocked substance P- and spared D,L-homocysteic acid-induced depressor responses, significantly attenuated the PEH by 37%, whereas it had no effect on blood pressure during exercise. Vehicle microinjection had no effect. The antagonist also had no effect on heart rate responses during both exercise and the PEH period. The data suggest that a substance P (NK-1) receptor mechanism in the NTS contributes to PEH.