Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial.

INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05029050.

Vocal cord function during recurrent laryngeal nerve injury assessed by accelerometry and EMG.

OBJECTIVE: Gradual impairment of nerve conduction is expected to be tightly associated with simultaneous gradual loss of vocal cord contractility, related to the fact that injured axons are connected to a defined number of muscle cells. In clinical studies, there is a time gap between observed adverse electromyographic (EMG) changes and examination of vocal cord function. This study evaluates the impact of intraoperative EMG changes on synchronous vocal cord contractility by simultaneous use of continuous intraoperative neuromonitoring (C-IONM) and accelerometry for registration of actual vocal cord function at a given change of EMG amplitude. METHODS: EMG was obtained following vagus nerve stimulation by use of C-IONM. A vocal cord accelerometer probe that could be attached to the vocal cords was developed based on a LIS3DH ultra low-power high performance three axis linear accelerometer (STMicroelectronics, Geneva, Switzerland). Accelerometer data were registered continuously together with EMG data during traction injury of the recurrent laryngeal nerve (RLN) until an amplitude depression ≤100 µV. RESULTS: Six RLN from four immature domestic pigs were studied. Vocal cord contractility assessed by vocal cord accelerometry decreased in parallel with EMG amplitude, with significant correlations ranging from 0.707 to 0.968. CONCLUSION: Decrease of EMG amplitude during traction injury to the RLN injury is closely associated with a parallel drop in vocal cord contractility. LEVEL OF EVIDENCE: NA Laryngoscope, 130:1090-1096, 2020.

Outcome After Rewarming From Accidental Hypothermia by Use of Extracorporeal Circulation.

BACKGROUND: Accidental hypothermia with arrested circulation remains a condition associated with high mortality. In our institution, extracorporeal circulation (ECC) rewarming has been the cornerstone in treating such patients since 1987. We here explore characteristics and outcomes of this treatment, to identify significant merits and challenges from 3 decades of experience in ECC rewarming. METHODS: Sixty-nine patients rewarmed by ECC during the period from December 1987 to December 2015 were analyzed. One patient was excluded from the analyses because of combined traumatic cerebral injury. The analysis was focused on patient characteristics, treatment procedures, and outcomes were focused. Survivors were evaluated according to the cerebral performance categories scale. Simple statistics with nonparametric tests and χ2 tests were used. Median value and range are reported. RESULTS: Median age was 30 years (minimum 1.5, maximum 76), and the cause of accidental hypothermia was cold exposure (27.9%), avalanche (5.9%), and immersion/submersion accidents (66.2%). Eighteen patients survived (26.5%). The survival rate did not improve during the years. Survivors had lower serum potassium (p = 0.002), higher pH (p = 0.03), lower core temperature (p = 0.02), and shorter cardiopulmonary resuscitation time (p = 0.001), but ranges were wide. Although suspected primary hypoxia and hypothermia were associated with lower survival, we observed a 10.5% survival of these victims. Sixteen survivors had good outcome (cerebral performance category 1 or 2), whereas 2 patients with suspected primary hypoxia survived with severe cerebral disability (cerebral performance category 3). CONCLUSIONS: Despite extended experience with ECC rewarming, improved handling strategies, and intensive care, no overall improvement in survival was observed. Good outcome was observed even among patients with a dismal prognosis.

Intraaortic counterpulsation during cardiopulmonary bypass impairs distal organ perfusion.

BACKGROUND: Recent studies have focused on the use of fixed-rate intraaortic balloon pumping (IABP) during cardiopulmonary bypass (CPB) to achieve pulsatile flow. Because application of an IABP catheter may represent a functional obstruction within the descending aorta, we explored the effect of IABP-pulsed CPB-perfusion with special attention to perfusion above and below the IABP balloon. METHODS: Sixteen animals received an IABP catheter that remained turned off position (NP group, n = 8) or was switched to an automatic mode of 80 beats/min during CPB (PP group, n = 8). Flow-data and pressure-data were obtained above and below the IABP balloon. Tissue perfusion was evaluated by microspheres. RESULTS: IABP-pulsed CPB-perfusion, as assessed at 30 minutes on CPB, increased proximal mean aortic pressure (p < 0.05) and carotid artery blood flow (p < 0.001), but decreased distal mean aortic pressure (p < 0.001). The decrease of distal mean aortic pressure in the PP group was associated with a 75 % decrease (p < 0.001) of renal tissue perfusion. During nonpulsed perfusion the respective variables remained essentially unchanged compared with pre-CPB levels. CONCLUSIONS: Using IABP as a surrogate to achieve pulsatile perfusion during CPB contributes significantly to lowered aortic pressure in the distal portion of aorta and impaired tissue perfusion of the kidneys. The results are focusing on effects that may contribute to organ dysfunction and acute kidney injury. Consequently, assessment of perfusion pressure distal to the balloon should be addressed whenever IABP is used during CPB.

Exploring the human plasma proteome for humoral mediators of remote ischemic preconditioning--a word of caution.

Despite major advances in early revascularization techniques, cardiovascular diseases are still the leading cause of death worldwide, and myocardial infarctions contribute heavily to this. Over the past decades, it has become apparent that reperfusion of blood to a previously ischemic area of the heart causes damage in and of itself, and that this ischemia reperfusion induced injury can be reduced by up to 50% by mechanical manipulation of the blood flow to the heart. The recent discovery of remote ischemic preconditioning (RIPC) provides a non-invasive approach of inducing this cardioprotection at a distance. Finding its endogenous mediators and their operative mode is an important step toward increasing the ischemic tolerance. The release of humoral factor(s) upon RIPC was recently demonstrated and several candidate proteins were published as possible mediators of the cardioprotection. Before clinical applicability, these potential biomarkers and their efficiency must be validated, a task made challenging by the large heterogeneity in reported data and results. Here, in an attempt to reproduce and provide more experimental data on these mediators, we conducted an unbiased in-depth analysis of the human plasma proteome before and after RIPC. From the 68 protein markers reported in the literature, only 28 could be mapped to manually reviewed (Swiss-Prot) protein sequences. 23 of them were monitored in our untargeted experiment. However, their significant regulation could not be reproducibly estimated. In fact, among the 394 plasma proteins we accurately quantified, no significant regulation could be confidently and reproducibly assessed. This indicates that it is difficult to both monitor and reproduce published data from experiments exploring for RIPC induced plasma proteomic regulations, and suggests that further work should be directed towards small humoral factors. To simplify this task, we made our proteomic dataset available via ProteomeXchange, where scientists can mine for novel potential targets.

Integrin alphavbeta3 acts downstream of insulin in normalization of interstitial fluid pressure in sepsis and in cell-mediated collagen gel contraction.

The administration of insulin is recommended to patients with severe sepsis and hyperglycemia. Previously, we demonstrated that insulin may have direct anti-inflammatory properties and counteracted fluid losses from the circulation by normalizing the interstitial fluid pressure (P(IF)). P(IF) is one of the Starling forces determining fluid flux over the capillary wall, and a lowered P(IF) is one of the driving forces in early edema formation in inflammatory reactions. Here we demonstrate that insulin restores a lipopolysaccharide (LPS)-lowered P(IF) via a mechanism involving integrin alpha(v)beta(3). In C57 black mice (n = 6), LPS lowered P(IF) from -0.2 +/- 0.2 to -1.6 +/- 0.3 (P < 0.05) and after insulin averaged -0.8 +/- 0.2 mmHg (P = 0.098 compared with after LPS). Corresponding values in wild-type BALB/c mice (n = 5) were -0.8 +/- 0.1, -2.1 +/- 0.3 (P < 0.05), and -0.8 +/- 0.3 mmHg (P < 0.05 compared with LPS) after insulin administration. In BALB/c integrin beta(3)-deficient (beta(3)(-/-)) mice (n = 6), LPS lowered P(IF) from -0.1 +/- 0.2 to -1.5 +/- 0.3 mmHg (P < 0.05). Insulin did not, however, restore P(IF) in these mice (averaged -1.7 +/- 0.3 mmHg after insulin administration). Cell-mediated collagen gel contraction can serve as an in vitro model for in vivo measurements of P(IF). Insulin induced alpha(v)beta(3)-integrin-dependent collagen gel contraction mediated by C2C12 cells. Our findings suggest a beneficiary effect of insulin for patients with sepsis with regard to the fluid balance, and this effect may in part be due to a normalization of P(IF) by a mechanism involving the integrin alpha(v)beta(3).