Early Metabolic Disruption and Predictive Biomarkers of Delayed-Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) is a major cause of complications and death. Here, we set out to identify high-performance predictive biomarkers of DCI and its underlying metabolic disruptions using metabolomics and lipidomics approaches. This single-center prospective observational study enrolled 61 consecutive patients with severe aSAH; among them, 22 experienced a DCI. Nine patients without aSAH were included as validation controls. Blood and cerebrospinal fluid (CSF) were sampled within the first 24 h after admission. We identified a panel of 20 metabolites that, together, showed high predictive performance for DCI. This panel of metabolites included lactate, cotinine, salicylate, 6 phosphatidylcholines, and 4 sphingomyelins. The interplay of the metabolome and the lipidome found between CSF and plasma in our patients underscores that aSAH and its associated DCI complications can extend beyond cerebral implications, with a peripheral dimension as well. As an illustration, early biological disruptions that might explain the subsequent DCI found systemic hypoxia driven mainly by higher blood lactate, arginine, and proline metabolism likely associated with vascular NO and disrupted ceramide/sphingolipid metabolism. We conclude that targeting early peripheral hypoxia preceding DCI could provide an interesting strategy for the prevention of vascular dysfunction.

Dynamic lung aeration and strain with positive end-expiratory pressure individualized to maximal compliance versus ARDSNet low-stretch strategy: a study in a surfactant depletion model of lung injury.

BACKGROUND: Positive end-expiratory pressure (PEEP) individualized to a maximal respiratory system compliance directly implies minimal driving pressures with potential outcome benefits, yet, raises concerns on static and dynamic overinflation, strain and cyclic recruitment. Detailed accurate assessment and understanding of these has been hampered by methodological limitations. We aimed to investigate the effects of a maximal compliance-guided PEEP strategy on dynamic lung aeration, strain and tidal recruitment using current four-dimensional computed tomography (CT) techniques and analytical methods of tissue deformation in a surfactant depletion experimental model of acute respiratory distress syndrome (ARDS). METHODS: ARDS was induced by saline lung lavage in anesthetized and mechanically ventilated healthy sheep (n = 6). Animals were ventilated in a random sequence with: (1) ARDSNet low-stretch protocol; (2) maximal compliance PEEP strategy. Lung aeration, strain and tidal recruitment were acquired with whole-lung respiratory-gated high-resolution CT and quantified using registration-based techniques. RESULTS: Relative to the ARDSNet low-stretch protocol, the maximal compliance PEEP strategy resulted in: (1) improved dynamic whole-lung aeration at end-expiration (0.456 ± 0.064 vs. 0.377 ± 0.101, P = 0.019) and end-inspiration (0.514 ± 0.079 vs. 0.446 ± 0.083, P = 0.012) with reduced non-aerated and increased normally-aerated lung mass without associated hyperinflation; (2) decreased aeration heterogeneity at end-expiration (coefficient of variation: 0.498 ± 0.078 vs. 0.711 ± 0.207, P = 0.025) and end-inspiration (0.419 ± 0.135 vs. 0.580 ± 0.108, P = 0.014) with higher aeration in dorsal regions; (3) tidal aeration with larger inspiratory increases in normally-aerated and decreases in poorly-aerated areas, and negligible in hyperinflated lung (Aeration × Strategy: P = 0.026); (4) reduced tidal strains in lung regions with normal-aeration (Aeration × Strategy: P = 0.047) and improved regional distributions with lower tidal strains in middle and ventral lung (Region-of-interest [ROI] × Strategy: P < 0.001); and (5) less tidal recruitment in middle and dorsal lung (ROI × Strategy: P = 0.044) directly related to whole-lung tidal strain (r = 0.751, P = 0.007). CONCLUSIONS: In well-recruitable ARDS models, a maximal compliance PEEP strategy improved end-expiratory/inspiratory whole-lung aeration and its homogeneity without overinflation. It further reduced dynamic strain in middle-ventral regions and tidal recruitment in middle-dorsal areas. These findings suggest the maximal compliance strategy minimizing whole-lung dynamically quantified mechanisms of ventilator-induced lung injury with less cyclic recruitment and no additional overinflation in large heterogeneously expanded and recruitable lungs.

Post-cardiac surgery fungal mediastinitis: clinical features, pathogens and outcome.

OBJECTIVES: The occurrence of mediastinitis after cardiac surgery remains a rare and severe complication associated with poor outcomes. Whereas bacterial mediastinitis have been largely described, little is known about their fungal etiologies. We report incidence, characteristics and outcome of post-cardiac surgery fungal mediastinitis. METHODS: Multicenter retrospective study among 10 intensive care units (ICU) in France and Belgium of proven cases of fungal mediastinitis after cardiac surgery (2009-2019). RESULTS: Among 73,688 cardiac surgery procedures, 40 patients developed fungal mediastinitis. Five were supported with left ventricular assist device and five with veno-arterial extracorporeal membrane oxygenation before initial surgery. Twelve patients received prior heart transplantation. Interval between initial surgery and mediastinitis was 38 [17-61] days. Only half of the patients showed local signs of infection. Septic shock was uncommon at diagnosis (12.5%). Forty-three fungal strains were identified: Candida spp. (34 patients), Trichosporon spp. (5 patients) and Aspergillus spp. (4 patients). Hospital mortality was 58%. Survivors were younger (59 [43-65] vs. 65 [61-73] yo; p = 0.013), had lower body mass index (24 [20-26] vs. 30 [24-32] kg/m2; p = 0.028) and lower Simplified Acute Physiology Score II score at ICU admission (37 [28-40] vs. 54 [34-61]; p = 0.012). CONCLUSION: Fungal mediastinitis is a very rare complication after cardiac surgery, associated with a high mortality rate. This entity should be suspected in patients with a smoldering infectious postoperative course, especially those supported with short- or long-term invasive cardiac support devices, or following heart transplantation.

Perioperative Pulmonary Atelectasis: Part I. Biology and Mechanisms.

Pulmonary atelectasis is common in the perioperative period. Physiologically, it is produced when collapsing forces derived from positive pleural pressure and surface tension overcome expanding forces from alveolar pressure and parenchymal tethering. Atelectasis impairs blood oxygenation and reduces lung compliance. It is increasingly recognized that it can also induce local tissue biologic responses, such as inflammation, local immune dysfunction, and damage of the alveolar-capillary barrier, with potential loss of lung fluid clearance, increased lung protein permeability, and susceptibility to infection, factors that can initiate or exaggerate lung injury. Mechanical ventilation of a heterogeneously aerated lung (e.g., in the presence of atelectatic lung tissue) involves biomechanical processes that may precipitate further lung damage: concentration of mechanical forces, propagation of gas-liquid interfaces, and remote overdistension. Knowledge of such pathophysiologic mechanisms of atelectasis and their consequences in the healthy and diseased lung should guide optimal clinical management.

Perioperative Pulmonary Atelectasis: Part II. Clinical Implications.

The development of pulmonary atelectasis is common in the surgical patient. Pulmonary atelectasis can cause various degrees of gas exchange and respiratory mechanics impairment during and after surgery. In its most serious presentations, lung collapse could contribute to postoperative respiratory insufficiency, pneumonia, and worse overall clinical outcomes. A specific risk assessment is critical to allow clinicians to optimally choose the anesthetic technique, prepare appropriate monitoring, adapt the perioperative plan, and ensure the patient's safety. Bedside diagnosis and management have benefited from recent imaging advancements such as lung ultrasound and electrical impedance tomography, and monitoring such as esophageal manometry. Therapeutic management includes a broad range of interventions aimed at promoting lung recruitment. During general anesthesia, these strategies have consistently demonstrated their effectiveness in improving intraoperative oxygenation and respiratory compliance. Yet these same intraoperative strategies may fail to affect additional postoperative pulmonary outcomes. Specific attention to the postoperative period may be key for such outcome impact of lung expansion. Interventions such as noninvasive positive pressure ventilatory support may be beneficial in specific patients at high risk for pulmonary atelectasis (e.g., obese) or those with clinical presentations consistent with lung collapse (e.g., postoperative hypoxemia after abdominal and cardiothoracic surgeries). Preoperative interventions may open new opportunities to minimize perioperative lung collapse and prevent pulmonary complications. Knowledge of pathophysiologic mechanisms of atelectasis and their consequences in the healthy and diseased lung should provide the basis for current practice and help to stratify and match the intensity of selected interventions to clinical conditions.

Fatal underhanded chronic enterovirus infection associated with anti-CD20 monotherapy for central nervous system demyelinating disease.

We report a fatal case of coxsackievirus B4 chronic infection in a 30-year-old woman with a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disorder controlled by rituximab monotherapy for 3 years. Initially presenting as self-limited meningitis, the infection remained silent for 8 months before the sudden onset of fulminant myocarditis. Analysis of the complete genome showed that the same virus was responsible for both episodes.

STABILISE Technique for a Non-A Non-B Acute Aortic Dissection in Marfan Syndrome.

A 35-year-old man, with a deep pectus excavatum due to a Marfan syndrome treated 9 years before for an acute type A dissection involving only the aortic arch, by a Bentall surgery, was admitted for acute chest pain. Computed tomography (CT) scan showed an acute type non-A non-B dissection extending to the iliac. After 5 days with strict arterial blood pressure management, the patient had recurrent refractory chest pain and a hybrid technique associating full supra-aortic vessels debranching and STABILISE technique during the same procedure was performed. The patient had an uneventful recovery with CT scan showing complete aortic arch aneurysm exclusion.

Perioperative Open-lung Approach, Regional Ventilation, and Lung Injury in Cardiac Surgery.

BACKGROUND: In the Protective Ventilation in Cardiac Surgery (PROVECS) randomized, controlled trial, an open-lung ventilation strategy did not improve postoperative respiratory outcomes after on-pump cardiac surgery. In this prespecified subanalysis, the authors aimed to assess the regional distribution of ventilation and plasma biomarkers of lung epithelial and endothelial injury produced by that strategy. METHODS: Perioperative open-lung ventilation consisted of recruitment maneuvers, positive end-expiratory pressure (PEEP) = 8 cm H2O, and low-tidal volume ventilation including during cardiopulmonary bypass. Control ventilation strategy was a low-PEEP (2 cm H2O) low-tidal volume approach. Electrical impedance tomography was used serially throughout the perioperative period (n = 56) to compute the dorsal fraction of ventilation (defined as the ratio of dorsal tidal impedance variation to global tidal impedance variation). Lung injury was assessed serially using biomarkers of epithelial (soluble form of the receptor for advanced glycation end-products, sRAGE) and endothelial (angiopoietin-2) lung injury (n = 30). RESULTS: Eighty-six patients (age = 64 ± 12 yr; EuroSCORE II = 1.65 ± 1.57%) undergoing elective on-pump cardiac surgery were studied. Induction of general anesthesia was associated with ventral redistribution of tidal volumes and higher dorsal fraction of ventilation in the open-lung than the control strategy (0.38 ± 0.07 vs. 0.30 ± 0.10; P = 0.004). No effect of the open-lung strategy on the dorsal fraction of ventilation was noted at the end of surgery after median sternotomy closure (open-lung = 0.37 ± 0.09 vs. control = 0.34 ± 0.11; P = 0.743) or in extubated patients at postoperative day 2 (open-lung = 0.63 ± 0.18 vs. control = 0.59 ± 0.11; P > 0.999). Open-lung ventilation was associated with increased intraoperative plasma sRAGE (7,677 ± 3,097 pg/ml vs. 6,125 ± 1,400 pg/ml; P = 0.037) and had no effect on angiopoietin-2 (P > 0.999). CONCLUSIONS: In cardiac surgery patients, open-lung ventilation provided larger dorsal lung ventilation early during surgery without a maintained benefit as compared with controls at the end of surgery and postoperative day 2 and was associated with higher intraoperative plasma concentration of sRAGE suggesting lung overdistension.

Is the Natural Anatomical Evolution of Type B Intramural Hematomas Reliable to Identify the Patients at Risk of Aneurysmal Progression?

BACKGROUND: The natural history of type B intramural hematomas is little-known. Aneurysmal progression or an aortic dissection occurs in 15 to 20% of the cases. The study of the natural anatomical evolution could help identify the patients at risk of unfavorable evolution. METHODS: All the patients monitored for a type B intramural hematoma between 2009 and 2018 were included in this monocentric retrospective study. Computed tomography angiography centerline measurement of diameters was obtained in various points of aortic segmentation on day (D) 0 and at one month (M1). Aortic volumes (lumen, intramural hematoma, and total volume) were calculated. The circulating volume was calculated using the volume rendering method. The volume of the intramural hematoma was measured using a manual section-by-section segmentation tool, and the total volume was obtained by summing up the two preceding volumes. Two groups of patients were compared: group 1 (favorable anatomical evolution) and group 2 (unfavorable anatomical evolution). RESULTS: Between January 2008 and August 2018, 25 patients were managed for a type B intramural hematoma in our center. After an average follow-up of 15.5 months (1-52), 13 patients (52%) presented a favorable evolution and 12 (48%) an unfavorable evolution. At M1, a significant increase of the luminal diameters (37 mm vs. 32 mm; P < 0.01) and a significant reduction in the longitudinal extension (19 mm vs. 26 mm; P < 0.01) were observed. The maximum aortic diameter evolved significantly between D0 and M1 in the unfavorable evolution group (49 mm vs. 44 mm, respectively; P = 0.038). Such a difference was not found in the favorable evolution group (37.4 vs. 37.1, respectively; P = 0.552). An overall significant reduction in the total aortic volume (166 cm3 vs. 219 cm3; P < 0.01), the circulating volume (124 cm3 vs. 145 cm3; P = 0,026), and the volume of the hematoma (42 cm3 vs. 39 cm3; P < 0.01) was observed. The circulating volume decreased significantly between D0 and M1 in the favorable evolution group (110 cm3 vs. 135 cm3; P = 0.05), whereas no difference was noted in the unfavorable group (142 cm3 vs, 157 cm3; P = 0.24). CONCLUSIONS: The progression of the maximum aortic diameter and of the circulating volume after one month of follow-up could be predictive factors of the poor long-term evolution of type B intramural hematomas.

Paired acute-baseline serum tryptase levels in perioperative anaphylaxis: An observational study.

BACKGROUND: Anaphylaxis is recognized mainly through clinical criteria, which may lack specificity or relevance in the perioperative setting. The transient increase in serum tryptase has been proposed since 1989 as a diagnostic tool. Sampling for well-defined acute and baseline determinations has been recommended. We assessed the performance of four proposed algorithms with tightly controlled time frames for tryptase sampling, their robustness with inadequate sampling times, and the possible use of mature tryptase determination. METHODS: A retrospective study was performed on 102 adult patients from the Aix-Marseille University Hospitals who had experienced a perioperative hypersensitivity reaction clinically suggesting anaphylaxis. EAACI and ICON criteria were used to diagnose anaphylaxis. Mature and total serum tryptase levels were measured. RESULTS: Based on EAACI guidelines, clinical diagnostic criteria for anaphylaxis were found in 76 patients and lacking in 26. The most effective algorithm was the international consensus recommendation of 2012 that acute total tryptase levels should be greater than ([1.2×baseline tryptase] + 2] µg/L to be considered a clinically significant rise. In our cohort, this algorithm achieved 94% positive predictive value (PPV), 53% negative predictive value (NPV), 75% sensitivity, 86% specificity, and a Youden's index value of 0.61. A detectable acute mature tryptase level showed lower sensitivity, particularly in patients with acute total tryptase levels lower than 16 µg/L. Acute tryptase levels varied as a function of the clinical severity of anaphylaxis. CONCLUSION: Total tryptase levels in serum discriminated between nonanaphylactic and anaphylactic events in a perioperative setting when acute and baseline levels were collected and analyzed by the consensus algorithm.

Thromboxane-prostaglandin receptor antagonist, terutroban, prevents neurovascular events after subarachnoid haemorrhage: a nanoSPECT study in rats.

BACKGROUND: Several lipid metabolites in cerebrospinal fluid are correlated with poor outcomes in aneurysmal subarachnoid haemorrhage. Most of these metabolites bind to ubiquitous thromboxane-prostaglandin (TP) receptors, causing vasoconstriction and inflammation. Here, we evaluated terutroban (TBN), a specific TP receptor antagonist, for the prevention of post-haemorrhage blood-brain barrier disruption, neuronal apoptosis and delayed cerebral hypoperfusion. METHODS: The rat double subarachnoid haemorrhage model was produced by twice injecting (days 1 and 2) autologous blood into the cisterna magna. Seventy-eight male Sprague-Dawley rats were assigned to experimental groups. Rats exposed to subarachnoid haemorrhage were allocated to no treatment (SAH group) or TBN treatment by gastric gavage during the first 5 days after haemorrhage (SAH+TBN group). Control rats received artificial cerebrospinal fluid injections (CSF group). Sham-operated rats with or without TBN administration were also studied. Body weight and Garcia neurological scores were assessed on day 2 and day 5. We used nanoscale single-photon emission computed tomography (nanoSPECT) to measure brain uptake of three radiolabelled agents: 99mTechnetium-diethylenetriaminepentacetate (99mTc-DTPA), which indicated blood-brain barrier permeability on day 3, 99mTechnetium-annexin V-128 (99mTc-Anx-V128), which indicated apoptosis on day 4, and 99mTechnetium-hexamethylpropyleneamineoxime (99mTc-HMPAO), which indicated cerebral perfusion on day 5. Basilar artery narrowing was verified histologically, and cerebral TP receptor agonists were quantified. RESULTS: 99mTc-DTPA uptake unveiled blood-brain barrier disruption in the SAH group. TBN mitigated this disruption in the brainstem area. 99mTc-Anx-V128 uptake was increased in the SAH group and TBN diminished this effect in the cerebellum. 99mTc-HMPAO uptake revealed a global decreased perfusion on day 5 in the SAH group that was significantly counteracted by TBN. TBN also mitigated basilar artery vasoconstriction, neurological deficits (on day 2), body weight loss (on day 5) and cerebral production of vasoconstrictors such as Thromboxane B2 and Prostaglandin F2α. CONCLUSIONS: Based on in vivo nanoscale imaging, we demonstrated that TBN protected against blood-brain barrier disruption, exerted an anti-apoptotic effect and improved cerebral perfusion. Thus, TP receptor antagonists showed promising results in treating post-haemorrhage neurovascular events.

Peri-operative oral caffeine does not prevent postoperative atrial fibrillation after heart valve surgery with cardiopulmonary bypass: A randomised controlled clinical trial.

BACKGROUND: Raised plasma levels of endogenous adenosine after cardiac surgery using cardiopulmonary bypass (CPB) have been related to the incidence of postoperative atrial fibrillation (POAF). OBJECTIVE: We wished to assess if caffeine, an adenosine receptor antagonist could have a beneficial effect on the incidence of POAF. DESIGN: A randomised controlled study. SETTING: Single University Hospital. PATIENTS: One hundred and ten patients scheduled for heart valve surgery with CPB. INTERVENTIONS: We randomly assigned patients to receive peri-operative oral caffeine (400 mg every 8 h for 2 days) or placebo. Adenosine plasma concentrations and caffeine pharmacokinetic profile were evaluated in a subgroup of 50 patients. MAIN OUTCOME MEASURES: The primary endpoint was the rate of atrial fibrillation during postoperative hospital stay. RESULTS: The current study was stopped for futility by the data monitoring board after an interim analysis. The incidence of atrial fibrillation was similar in the caffeine and in the placebo group during hospital stay (33 vs. 29%, P = 0.67) and the first 3 postoperative days (18 vs. 15%; P = 0.60). Basal and postoperative adenosine plasma levels were significantly associated with the primary outcome. Adenosine plasma levels were similar in the two treatment groups. Caffeine administration was associated with a higher incidence of postoperative nausea and vomiting (27 vs. 7%, P = 0.005). CONCLUSION: Oral caffeine does not prevent POAF after heart valve surgery with CPB but increased the incidence of postoperative nausea and vomiting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, no.: NCT01999829.

Early matrix metalloproteinase-9 concentration in the first 48 h after aneurysmal subarachnoid haemorrhage predicts delayed cerebral ischaemia: An observational study.

BACKGROUND: Delayed cerebral ischaemia from vasospasm is an important cause of complications and death after aneurysmal subarachnoid haemorrhage. There is currently no established biomarker for identifying patients at high risk of delayed cerebral ischaemia. OBJECTIVE: Considering the important role of inflammation in the pathogenesis of delayed cerebral ischaemia, we investigated whether matrix metalloproteinase-9 (MMP-9) may be an efficient biomarker for predicting elayed cerebral ischaemia after subarachnoid haemorrhage. DESIGN: Single-centre prospective observational study. SETTING: Neuroscience Critical Care Unit of a teaching hospital. PARTICIPANTS: Thirty consecutive patients with severe subarachnoid haemorrhage requiring external ventricular drainage were enrolled during 2013 and 2014. INTERVENTIONS: Blood and cerebrospinal fluid (CSF) were sampled within the first 24 h and between 48 and 72 h after admission. We evaluated the activity and concentrations of MMP-9 and endothelin-1 with zymography and ELISA. Patients were allocated to groups with delayed cerebral ischaemia (n = 16) or without delayed cerebral ischaemia (n = 14). RESULTS: Within 24 h, median [interquartile range] MMP-9 concentrations in CSF were significantly higher in patients with delayed cerebral ischaemia (47 [21 to 102] ng ml) than in those without delayed cerebral ischaemia (4 [2 to 13] ng ml, P = 0.001). CSF MMP-9 activity and endothelin-1 concentrations were correlated (r = 0.6, P = 0.02). The areas under the receiver operating characteristic curves were 0.73 (95% confidence interval [0.53 to 0.87]) and 0.91 (95% confidence interval [0.75 to 0.98]) for MMP-9 concentrations in plasma and CSF, respectively, at 24 h to predict delayed cerebral ischaemia CSF MMP-9 concentrations more than 14.3 ng ml at 24 h predicted the occurrence of delayed cerebral ischaemia with a sensitivity and specificity of 88 and 86%, respectively. After multivariate logistic analysis, only CSF MMP-9 concentrations at 24 h predicted the occurrence of delayed cerebral ischaemia (P = 0.01). CONCLUSION: MMP-9 concentrations in both plasma and CSF, measured within 48 h after subarachnoid haemorrhage, were highly predictive of the occurrence of delayed cerebral ischaemia within the first 2 weeks. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02397759.

Resuscitation and Forensic Factors Influencing Outcome in Penetrating Cardiac Injury.

BACKGROUND: Cardiac injury caused by a sharp object is a medical and surgical therapeutic challenge. Mortality risk factors have been identified but there are major discrepancies in the literature. The aim of this study was to analyse the management of victims of penetrating cardiac injuries before and after admission to hospital and the anatomical characteristics of these injuries in order to facilitate diagnosis of the most critical patients. METHODS: To carry out this study, we conducted a retrospective analytical study with epidemiological data on victims of penetrating cardiac injuries. We included two types of patients, with those who underwent autopsy in our institution after death from sharp injury to the heart or great vessels and those who survived with treatment in the emergency department or intensive care unit between January 2015 and February 2022. RESULTS: We included 30 autopsied patients and 12 survivors aged between 18 and 73 years. Higher mortality was associated with prehospital or in-hospital cardiorespiratory arrest (OR = 4, CI [1.71-9.35]), preoperative mechanical ventilation (OR = 10, CI [1.53-65.41]), preoperative catecholamines (OR = 7, CI [1.12-6.29]), preoperative and perioperative adrenaline (OR = 13, CI [1.98-85.46] and [1.98-85.46]), penetrating cardiac injury (OR = 14, CI [2.10-93.22]), multiple cardiac injuries (OR = 1.5, CI [1.05-2.22]) and an Organ Injury Scaling of the American Association for the Surgery of Trauma (AAST-OIS) score of 5 (OR = 2.9, CI [1.04-8.54]; p = 0.0329) with an AUC-ROC curve value of 0.708 (CI [0.543-0.841]). CONCLUSIONS: This study identified risk mortality factors in penetrating cardiac injury patients. These findings can help improve the diagnosis and management of these patients. The AAST-OIS score may be a good tool to diagnose critical patients.

Mechanical ventilation guided by driving pressure optimizes local pulmonary biomechanics in an ovine model.

Mechanical ventilation exposes the lung to injurious stresses and strains that can negatively affect clinical outcomes in acute respiratory distress syndrome or cause pulmonary complications after general anesthesia. Excess global lung strain, estimated as increased respiratory system driving pressure, is associated with mortality related to mechanical ventilation. The role of small-dimension biomechanical factors underlying this association and their spatial heterogeneity within the lung are currently unknown. Using four-dimensional computed tomography with a voxel resolution of 2.4 cubic millimeters and a multiresolution convolutional neural network for whole-lung image segmentation, we dynamically measured voxel-wise lung inflation and tidal parenchymal strains. Healthy or injured ovine lungs were evaluated as the mechanical ventilation positive end-expiratory pressure (PEEP) was titrated from 20 to 2 centimeters of water. The PEEP of minimal driving pressure (PEEPDP) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEPDP compared with PEEP values above this threshold. PEEPDP similarly characterized a breaking point in the relationships between PEEP and SD of local tidal parenchymal strain, the 95th percentile of local strains, and the magnitude of tidal overdistension. These findings advance the understanding of lung collapse, tidal overdistension, and strain heterogeneity as local triggers of ventilator-induced lung injury in large-animal lungs similar to those of humans and could inform the clinical management of mechanical ventilation to improve local lung biomechanics.

ß-Lactam Pharmacokinetic/Pharmacodynamic Target Attainment in Intensive Care Unit Patients: A Prospective, Observational, Cohort Study.

BACKGROUND: The aims of this study were to describe pharmacokinetic/pharmacodynamic target attainment in intensive care unit (ICU) patients treated with continuously infused ß-lactam antibiotics, their associated covariates, and the impact of dosage adjustment. METHODS: This prospective, observational, cohort study was performed in three ICUs. Four ß-lactams were continuously infused, and therapeutic drug monitoring (TDM) was performed at days 1, 4, and 7. The primary pharmacokinetic/pharmacodynamic target was an unbound ß-lactam plasma concentration four times above the bacteria's minimal inhibitory concentration during the whole dosing interval. The demographic and clinical covariates associated with target attainment were evaluated. RESULTS: A total of 170 patients were included (426 blood samples). The percentages of empirical ß-lactam underdosing at D1 were 66% for cefepime, 43% for cefotaxime, 47% for ceftazidime, and 14% for meropenem. Indexed creatinine clearance was independently associated with treatment underdose if increased (adjusted odds ratio per unit, 1.01; 95% CI, 1.00 to 1.01; p = 0.014) or overdose if decreased (adjusted odds ratio per unit, 0.95; 95% CI, 0.94 to 0.97; p < 0.001). Pharmacokinetic/pharmacodynamic target attainment was significantly increased after ß-lactam dosage adjustment between day 1 and day 4 vs. no adjustment (53.1% vs. 26.2%; p = 0.018). CONCLUSIONS: This study increases our knowledge on the optimization of ß-lactam therapy in ICU patients. A large inter- and intra-patient variability in plasmatic concentrations was observed, leading to inadequate exposure. A combined indexed creatinine clearance and TDM approach enables adequate dosing for better pharmacokinetic/pharmacodynamic target attainment.