Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-choline-deficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture.

Non-alcoholic fatty liver disease can progress to steatohepatitis and fibrosis, and is also associated with impaired liver regeneration. The pathophysiology remains elusive. We recently showed that severe steatosis is associated with an increase in portal pressure, suggesting liver flow impairment. The objective of this study is to directly assess total intrahepatic resistance and its potential functional and structural determinants in an in situ perfusion model. Male Wistar rats fed a control (n = 30) or a methionine-choline-deficient (MCD) diet (n = 30) for 4 weeks were compared. Liver tissue and serum analysis, in vivo haemodynamic measurements, in situ perfusion experiments and vascular corrosion casts were performed. The MCD group showed severe steatosis without inflammation or fibrosis on histology. Serum levels and liver tissue gene expression of interleukin (IL)-6, tumour necrosis factor-α, IL-1ß and interferon-γ, liver tissue myeloperoxidase activity and liver immunohistochemistry with anti-CD68 and anti-α smooth muscle actin were comparable between groups, excluding significant inflammation. Flow-pressure curves were significantly different between groups for all flows (slope values: 0.1636 ± 0.0605 mm Hg/ml/min in controls vs 0.7270 ± 0.0408 mm Hg/ml/min in MCD-fed rats, P < 0.001), indicating an increased intrahepatic resistance, which was haemodynamically significant (portocaval pressure gradient 2.2 ± 1.1 vs 8.2 ± 1.3 mm Hg in controls vs MCD, P<0.001). Dose-response curves to acetylcholine were significantly reduced in MCD-fed rats (P < 0.001) as was the responsiveness to methoxamine (P<0.001). Vascular corrosion casts showed a replacement of the regular sinusoidal anatomy by a disorganized pattern with multiple interconnections and vascular extensions. Liver phosphorylated endothelial NO synthase (eNOS)/eNOS and serum nitrite/nitrate were not increased in severe steatosis, whereas liver thromboxane synthase expression, liver endothelin-1 (ET-1) expression and serum andothelin-1 concentration were significantly increased. Severe steatosis induces a haemodynamically significant increase in intrahepatic resistance, which precedes inflammation and fibrogenesis. Both functional (endothelial dysfunction and increased thromboxane and ET-1 synthesis) and structural factors are involved. This phenomenon might significantly contribute to steatosis-related disease.

Preliminary Evaluation of a Web-Based Psychological Screening Tool in Adolescents Undergoing Minimally Invasive Pectus Surgery: Single-Center Observational Cohort Study.

BACKGROUND: Preoperative anxiety and depression are predominant risk factors for increased postoperative pain. Thoracic wall deformities in adolescents often cause low self-esteem, which contributes to psychological concerns. Several studies have suggested a relationship between preoperative mental health support and enhanced recovery after surgery. OBJECTIVE: This study investigated the validity of screening questionnaires concerning psychological trait and state characteristics via a patient-specific online platform. METHODS: Patients scheduled for elective pectus surgery between June 2017 and August 2017 were invited to participate in clinical interviews and online self-report questionnaires. All patients were recruited in the Anesthesiology Department, Antwerp University Hospital, Belgium. This single-center observational cohort study was performed in accordance with the ethical standards of the International Council for Harmonisation-Good Clinical Practice guidelines and the Declaration of Helsinki after obtaining study approval by the Institutional Review Board and Ethics Committee of the Antwerp University Hospital, Belgium (study identifier: 17/08/082). An online preoperative psychological inventory was performed using the Rosenberg Self-Esteem Scale, Hospital Anxiety and Depression Scale, and State-Trait Anxiety Inventory. Postoperatively, pain intensity and interference were assessed using the Multidisciplinary Pain Inventory, Coping With Pain Questionnaire, and numeric pain rating scale assessment. Patient satisfaction of the Web-based platform was evaluated. RESULTS: A total of 21 adolescent patients used our Web-based psychological perioperative screening platform. Patients rated the mobile phone app, usability, and accessibility of the digital platform as good or excellent in 85% (17/20), 89% (17/19), and 95% (20/21) of the cases, respectively. A total of 89% (17/19) of the patients rated the effort of generating answers to the online questionnaires as low. The results from the completed questionnaires indicated a strong negative correlation between self-esteem and the anxiety trait (R=-0.72, P<.001) and overall anxiety characteristics (R=-0.49, P=.04). There was a positive correlation between depressive and anxiety characteristics and the anxiety trait (R=0.52, P=.03 and R=0.6, P=.02, respectively) measured by the online self-report questionnaires. Moreover, preoperative anxiety was positively correlated with postoperative pain interference (R=0.58, P=.02). Finally, there was a negative correlation between self-esteem and pain interference (R=-0.62, P=.01). Conclusions: Perioperative screening of psychological symptoms and trait characteristics with specific treatment, if necessary, could further improve postoperative pain and overall health status. Research on eHealth technology, even for psychological patient care, is rapidly increasing. TRIAL REGISTRATION: ClinicalTrials.gov NCT03100669; https://clinicaltrials.gov/ct2/show/NCT03100669 (Archived by WebCite at http://www.webcitation.org/6zPvHDhU5).

Implementation of an Enhanced Recovery Pathway for Minimally Invasive Pectus Surgery: A Population-Based Cohort Study Evaluating Short- and Long-Term Outcomes Using eHealth Technology.

BACKGROUND: Pectus excavatum and pectus carinatum are the most common chest wall deformities. Although minimally invasive correction (minimally invasive repair of pectus, MIRP) has become common practice, it remains associated with severe postoperative pain. Preoperative psychosocial factors such as anxiety and low self-esteem can increase postsurgical pain. Early detection of psychological symptoms, effective biopsychosocial perioperative management of patients, and prevention of pain chronification using an enhanced recovery pathway (ERP) may improve outcomes. However, the incidence of the latter is poorly described in adolescents undergoing MIRP. OBJECTIVE: The objective of our study was to evaluate the implementation of an ERP containing early recovery goals and to assess persistent postsurgical pain 3 months postoperatively in pediatric patients undergoing MIRP. The ERP consists of a Web-based platform containing psychological screening questionnaires and extensive telemonitoring for follow-up of patients at home. METHODS: A population-based cohort study was conducted with prospectively collected data from patients undergoing pectus surgery between June 2017 and December 2017. An ERP was initiated preoperatively; it included patient education, electronic health-based psychological screening, multimodal pre-emptive analgesia, nausea prophylaxis as well as early Foley catheter removal and respiratory exercises. After hospital discharge, patients were followed up to 10 weeks using a Web-based diary evaluating pain and sleep quality, while their rehabilitation progress was monitored via Bluetooth-connected telemonitoring devices. RESULTS: We enrolled 29 adolescents using the developed ERP. Pre-emptive multimodal analgesia pain rating scores were low at hospital admission. Optimal epidural placement, defined by T8-9 or T9-10, occurred in 90% (26/29) of the participants; thus, no motor block or Horner syndrome occurred. Mean bladder catheterization duration was 3.41 (SD 1.50) days in ERP patients. Numeric rating scale (NRS) scores for pain and the incidence of nausea were low, contributing to a fluent rehabilitation. Mean NRS scores were 2.58 (SD 1.77) on postoperative day (POD) 1, 2.48 (SD 1.66) on POD 2, and 3.14 (SD 1.98) on POD 3 in ERP-treated patients. Telemonitoring at home was feasible in adolescents after hospital discharge despite adherence difficulties. Although the pain scores at the final interview were low (0.81 [SD 1.33]), 33% (9/27) long-term follow-up ERP patients still experienced frequent disturbing thoracic pain, requiring analgesic administration, school absenteeism, and multiple doctor (re)visits. CONCLUSIONS: Allocating patients to the appropriate level of care preoperatively and immediately postoperatively may improve long-term outcome variables. Internet-based technologies and feasible, objective monitoring tools can help clinicians screen surgical patients for risk factors and initiate early treatment when indicated. Future research should focus on improving risk stratification and include a psychological assessment and evaluation of the effect of perioperative care pathways in children undergoing major surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT03100669; https://clinicaltrials.gov/ct2/show/NCT03100669 (Archived by WebCite at http://www.webcitation.org/72qLB1ADX).