Opioid-free anaesthesia with dexmedetomidine and lidocaine versus remifentanil-based anaesthesia in cardiac surgery: study protocol of a French randomised, multicentre and single-blinded OFACS trial.

INTRODUCTION: Intraoperative opioids have been used for decades to reduce negative responses to nociception. However, opioids may have several, and sometimes serious, adverse effects. Cardiac surgery exposes patients to a high risk of postoperative complications, some of which are common to those caused by opioids: acute respiratory failure, postoperative cognitive dysfunction, postoperative ileus (POI) or death. An opioid-free anaesthesia (OFA) strategy, based on the use of dexmedetomidine and lidocaine, may limit these adverse effects, but no randomised trials on this issue have been published in cardiac surgery.We hypothesised that OFA versus opioid-based anaesthesia (OBA) may reduce the incidence of major opioid-related complications after cardiac surgery. METHODS AND ANALYSIS: Multicentre, randomised, parallel and single-blinded clinical trial in four cardiac surgical centres in France, including 268 patients scheduled for coronary artery bypass grafting under cardiac bypass, with or without aortic valve replacement. Patients will be randomised to either a control OBA protocol using remifentanil or an OFA protocol using dexmedetomidine/lidocaine. The primary composite endpoint is the occurrence of at least one of the following: (1) postoperative cognitive disorder evaluated by the Confusion Assessment Method for the Intensive Care Unit test, (2) POI, (3) acute respiratory distress or (4) death within the first 48 postoperative hours. Secondary endpoints are postoperative pain, morphine consumption, nausea-vomiting, shock, acute kidney injury, atrioventricular block, pneumonia and length of hospital stay. ETHICS AND DISSEMINATION: This trial has been approved by an independent ethics committee (Comité de Protection des Personnes Ouest III-Angers on 23 February 2021). Results will be submitted in international journals for peer reviewing. TRIAL REGISTRATION NUMBER: NCT04940689, EudraCT 2020-002126-90.

Pulmonary hypertension after pneumonectomy: a preclinical model in rats and human pulmonary endothelial cells.

OBJECTIVES: Pulmonary hypertension and heart disease contribute to the high morbidity rate following pneumonectomy (PN). The pathophysiology is still poorly understood. The objective was to investigate the consequences of PN on cardiopulmonary function in rats and to explore in vitro the involved mechanisms. METHODS: Sixty Sprague-Dawley male rats randomly underwent either a right PN (PN group) or sham surgery. Ten rats per group were sacrificed on postoperative days 3, 7 and 28. Cardiopulmonary alterations were investigated by echocardiographic, haemodynamic and histological analyses. In vitro, the shear stress was reproduced using a Flexcell Tension™ cyclic stretch on cultured human pulmonary endothelial cells (P-ECs) to investigate the impact on pulmonary artery smooth muscle cell (PA-SMC) growth. Data are expressed as mean ± SD. RESULTS: Mean pulmonary arterial pressure gradually increased in the PN group to reach 35 ± 7 mmHg on postoperative day 28 vs 18 ± 4 in sham (P = 0.001), likewise the proportion of muscularized distal pulmonary arteries, 83 ± 1% vs 5 ± 1%, respectively (P < 0.001), related to in situ PA-SMC proliferation. The right ventricle area and lateral wall thickness were doubled in the PN group on postoperative day 28. The left ventricle ejection fraction decreased on postoperative days 7 and 28 while the right ventricle function was maintained. In vitro, the human PA-SMC growth was significantly greater when seeded with stretched vs non-stretched P-EC media, highlighting the role of shear stress on the P-EC paracrine function. CONCLUSIONS: Right PN led to pulmonary hypertension and proportional right heart remodelling in rats. The shear stress related to high blood flow alters the pulmonary endothelial paracrine control of SMC growth.

Assessment of tissue oxygenation to personalize mean arterial pressure target in patients with septic shock.

OBJECTIVE: To investigate whether assessment of tissue oxygenation could help personalizing the mean arterial pressure (MAP) target in patients with septic shock. METHODS: We prospectively measured near-infrared spectroscopy variables in 22 patients with septic shock receiving norepinephrine with a MAP>75 mmHg within the first six hours of intensive care unit (ICU) stay for patients with community-acquired septic shock and within the first six hours of resuscitation for patients with ICU-acquired septic shock. All measurements were performed at MAP>75 mmHg ("high-MAP") and at MAP 65-70 mmHg ("low-MAP") after decreasing the norepinephrine dose. Relative changes in StO2 recovery slope (RS) >8% were considered clinically relevant. RESULTS: After decreasing the norepinephrine dose by 45 ± 24%, MAP significantly decreased from 81[78;84] to 68[67;69]mmHg, whereas cardiac index did not change. On average, the StO2-RS significantly decreased between high and low-MAP from 2.86[1.87;4.32] to 2.41[1.14;3.72]%/sec with a large interindividual variability: the StO2-RS decreased by >8% in 14 patients, increased by >8% in 4 patients and changes were < 8% in 4 patients. These changes in StO2-RS were correlated with the StO2-RS at low-MAP (r = 0.57,p = 0.006). At high-MAP, there was no difference between patients exhibiting a relevant decrease or increase in StO2-RS. CONCLUSIONS: A unique MAP target may not be suitable for all patients with septic shock as its impact on peripheral oxygenation may widely differ among patients. It could make sense to personalize MAP target through a multimodal assessment including peripheral oxygenation.

Pulse pressure and end-tidal carbon dioxide for monitoring low native cardiac output during veno-arterial ECLS: a prospective observational study.

BACKGROUND: Veno-arterial extracorporeal life support (VA-ECLS) results in cardiopulmonary shunting with reduced native cardiac output (NCO). Low NCO occurrence is common and associated with risk of thromboembolic and pulmonary complications. Practical tools for monitoring NCO during VA-ECLS would therefore be valuable. Pulse pressure (PP) and end-tidal carbon dioxide (EtCO2) are known to be related to cardiac output. We have designed a study to test whether PP and EtCO2 were efficient for the monitoring of NCO during VA-ECLS. METHODS: In this prospective single-center observational study, patients who underwent a VA-ECLS for cardiogenic shock from January 2016 to October 2017 were included, provided low NCO was suspected by a PP < 20 mmHg. NCO was measured with pulmonary artery catheter or echocardiography and compared to PP and EtCO2. The ability of PP and EtCO2 to predict NCO < 1 L/min was evaluated with receiver operating characteristics (ROC) curves. RESULTS: Among the 106 patients treated with VA-ECLS for cardiogenic shock during the study period, 26 were studied, allowing the collection of 196 study points. PP and EtCO2 relationships with NCO were nonlinear and showed strong correlations for NCO < 2 L/min (r = 0.69 and r = 0.78 respectively). A PP < 15 mmHg and EtCO2 < 14 mmHg had good predictive values for detecting NCO < 1 L/min (area under ROC curve 0.93 [95% CI 0.89-0.96] and 0.97 [95% CI 0.94-0.99] respectively, p = 0.058). CONCLUSIONS: PP and EtCO2 may offer an accurate real-time monitoring of low NCO events during VA-ECLS support. Further studies are needed to show if their utilization may help to implement therapeutic strategies in order to prevent thromboembolic and respiratory complications associated with VA-ECLS, and to improve patients' prognosis. TRIAL REGISTRATION: NCT03323268 , July 12, 2016.

The Frontal Bone Window for Transcranial Doppler Ultrasonography in Critically Ill Patients: Validation of a New Approach in the ICU.

BACKGROUND AND OBJECTIVE: The temporal bone window (TBW) for transcranial Doppler (TCD) often fails to insonate the anterior cerebral artery (ACA). The frontal bone window (FBW) has never been evaluated in intensive care units (ICU). The main objective was to determine the ability of the FBW to assess ACA velocities in critically ill patients. METHODS: A prospective study was conducted in two ICUs of the Montpellier University Hospital (France), between November 2014 and September 2016. Adult patients admitted to ICU for brain injury, with a Glasgow Coma Scale score ≤ 13, were enrolled within 3 days after admission. A first TCD examination was carried out bilaterally through the TBW and FBW by an intensivist expert in TCD, repeated by the same examiner, and 15 min later by an intensivist certified in TCD, designated as non-expert, blinded. The success of the FBW examinations was defined by the ability to measure the ACA velocities. Intra- and interobserver agreements were analyzed according to the Bland and Altman method. RESULTS: A total of 147 patients were analyzed. The FBW succeeded in insonating the ACA in 66 patients [45%, CI (37-53)], 45 bilaterally and 21 unilaterally. For 16 patients (11%), the FBW was the only way to measure ACA velocities. By combining the two techniques, the ACA success rate increased from 62% CI (54-70) to 73% CI (65-79) (P = 0.05). Intra- and interobserver mean biases and 95% limits of agreement for ACA systolic velocity measurements through the FBW were 1 (- 33 to 35) and 2 (- 34 to 38) cm s-1, respectively. For paired TBW and FBW measures of ACA velocities, mean biases (± SD) for ACA systolic, and mean and diastolic velocities were relatively close to zero, but negatives (- 7 ± 33, - 2 ± 19, - 1 ± 15 cm s-1, respectively), highlighting that ACA velocities were lower with the FBW (A2 segment) than TBW (A1 segment). The correlation coefficient for ACA systolic velocities measured by the FBW and TBW was R = 0.47, CI (0.28-0.62). No risk factors for failure of the FBW were identified. CONCLUSIONS: In ICU, the FBW was able to insonate the ACA in 45% of patients admitted for brain injury, without the use of contrast agents. The FBW could improve the detection of ACA vasospasms.

Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous.

Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs from explanted lungs of patients with IPAH (IPAH-PASMCs) and from controls (C-PASMCs) were cultured. The IPAH-PASMCs grew faster than the controls; however, both growth curves plateaued, suggesting contact inhibition in IPAH cells. No proliferation was seen without stimulation with exogenous growth factors, suggesting that IPAH cells are incapable of self-sufficient growth. IPAH-PASMCs were more resistant to apoptosis than C-PASMCs, consistent with the increase in the Bcl2/Bax ratio. As cell replication is governed by telomere length, these parameters were assessed jointly. Compared to C-PASMCs, IPAH-PASMCs had longer telomeres, but a limited replicative capacity. Additionally, it was noted that IPAH-PASMCs had a shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis. As DNA damage and genomic instability are strongly implicated in IPAH development a comparative genomic hybridization was performed on genomic DNA from PASMCs which showed multiple break-points unaffected by IPAH severity. Activation of DNA damage/repair factors (γH2AX, p53, and GADD45) in response to cisplatin was measured. All proteins showed lower phosphorylation in IPAH samples than in controls, suggesting that the cells were resistant to DNA damage. Despite the cancer-like processes that are associated with end-stage IPAH-PASMCs, we identified no evidence of self-sufficient proliferation in these cells-the defining feature of neoplasia.

The passive leg raising test to guide fluid removal in critically ill patients.

BACKGROUND: To investigate whether haemodynamic intolerance to fluid removal during intermittent renal replacement therapy (RRT) in critically ill patients can be predicted by a passive leg raising (PLR) test performed before RRT. METHODS: We included 39 patients where intermittent RRT with weight loss was decided. Intradialytic hypotension was defined as hypotension requiring a therapeutic intervention, as decided by the physicians in charge. Before RRT, the maximal increase in cardiac index (CI, pulse contour analysis) induced by a PLR test was recorded. RRT was then started. RESULTS: Ultrafiltration rate was similar in patients with and without intradialytic hypotension. Thirteen patients presented intradialytic hypotension, while 26 did not. In patients with intradialytic hypotension, it occurred 120 min [interquartile range 60-180 min] after onset of RRT. In the 26 patients without intradialytic hypotension, the PLR test induced no significant change in CI. Conversely, in patients with intradialytic hypotension, PLR significantly increased CI by 15 % [interquartile range 11-36 %]. The PLR-induced increase in CI predicted intradialytic hypotension with an area under the ROC curve of 0.89 (95 % interval confidence 0.75-0.97) (p < 0.05 from 0.50). The best diagnostic threshold was 9 %. The sensitivity was 77 % (95 % confidence interval 46-95 %), the specificity was 96 % (80-100 %), the positive predictive value was 91 % (57-100 %), and the negative predictive value was 89 % (72-98 %). Compared to patients without intolerance to RRT, CI decreased significantly faster in patients with intradialytic hypotension, with a slope difference of -0.17 L/min/m(2)/h. CONCLUSION: The presence of preload dependence, as assessed by a positive PLR test before starting RRT with fluid removal, predicts that RRT will induce haemodynamic intolerance.