Post-COVID-19 recovery and geriatric rehabilitation care: a European inter-country comparative study.

PURPOSE: There is variation in organization of geriatric rehabilitation across Europe. The purpose of this study was to describe the selection criteria for referral to geriatric rehabilitation, care provided, and recovery trajectories of post-COVID-19 patients referred to geriatric rehabilitation in Europe. METHODS: This observational cohort study included 723 patients in 59 care facilities for geriatric rehabilitation across 10 countries. Patient data were collected from medical records on admission to geriatric rehabilitation (between September 2020 and October 2021), discharge, 6 weeks and 6 months follow-up. The primary and secondary outcomes were recovery in daily functioning (Barthel Index) and Quality of Life (EQ-5D-5L) from admission to discharge. These were examined using linear mixed models with two levels (measurements nested in patients) and country as an independent variable. Random intercept and random linear slope parameters were added when they improved model fit. A survey about organization of geriatric rehabilitation for post-COVID-19 patients was filled out by country coordinators and data were analyzed using descriptive statistics and inductive coding of answers to open questions. RESULTS: Patients had a mean age of 75.7 years old and 52.4% were male. Many countries used various combinations of the selection criteria, such as functional status, age, frailty, Comprehensive Geriatric Assessment, comorbidities, and cognitive impairments. Most patients received physiotherapy (88.8%) and occupational therapy (69.7%), but there was substantial variance between countries in the percentages of patients that received protein or calorie enriched diets, oxygen therapy, and other treatment components. In all countries, patients showed recovery in daily functioning and quality of life, although there was variation in between countries in rate of recovery. Daily functioning seemed to increase most rapidly in the Czech Republic, Germany, and Russia. The steepest increases in quality of life were seen in the Czech Republic, Germany, and Spain. CONCLUSION: Post-COVID-19 patients showed recovery during geriatric rehabilitation, albeit at variable rates. The observed variation may be explained by the heterogeneity in selection criteria and care provided. This study highlights the need for harmonization of measurements in geriatric rehabilitation order to perform explanatory research and optimize geriatric rehabilitation throughout Europe to ensure optimal patient recovery.

Post-COVID-19 patients in geriatric rehabilitation substantially recover in daily functioning and quality of life.

BACKGROUND: After an acute infection, older persons may benefit from geriatric rehabilitation (GR). OBJECTIVES: This study describes the recovery trajectories of post-COVID-19 patients undergoing GR and explores whether frailty is associated with recovery. DESIGN: Multicentre prospective cohort study. SETTING: 59 GR facilities in 10 European countries. PARTICIPANTS: Post-COVID-19 patients admitted to GR between October 2020 and October 2021. METHODS: Patients' characteristics, daily functioning (Barthel index; BI), quality of life (QoL; EQ-5D-5L) and frailty (Clinical Frailty Scale; CFS) were collected at admission, discharge, 6 weeks and 6 months after discharge. We used linear mixed models to examine the trajectories of daily functioning and QoL. RESULTS: 723 participants were included with a mean age of 75 (SD: 9.91) years. Most participants were pre-frail to frail (median [interquartile range] CFS 6.0 [5.0-7.0]) at admission. After admission, the BI first steeply increased from 11.31 with 2.51 (SE 0.15, P < 0.001) points per month and stabilised around 17.0 (quadratic slope: -0.26, SE 0.02, P < 0.001). Similarly, EQ-5D-5L first steeply increased from 0.569 with 0.126 points per month (SE 0.008, P < 0.001) and stabilised around 0.8 (quadratic slope: -0.014, SE 0.001, P < 0.001). Functional recovery rates were independent of frailty level at admission. QoL was lower at admission for frailer participants, but increased faster, stabilising at almost equal QoL values for frail, pre-frail and fit patients. CONCLUSIONS: Post-COVID-19 patients admitted to GR showed substantial recovery in daily functioning and QoL. Frailty at GR admission was not associated with recovery and should not be a reason to exclude patients from GR.

Tetrahydrobiopterin (BH4 ): Targeting endothelial nitric oxide synthase as a potential therapy for pulmonary hypertension.

PURPOSE: Pulmonary Hypertension (PH) is complex disease which is associated with endothelial and cardiac dysfunction. Tetrahydrobiopterin (BH4 ) regulates endothelial nitric oxide synthase (eNOS) to produce nitric oxide rather than superoxide which maintains normal endothelial and cardiac function. This study explores the therapeutic potential of BH4 in experimental PH. METHODS: Monocrotaline-induced PH in rats and Hph-1 deficiency in mice were used for animal experiments. Hemodynamic measurements using pressure transducers were conducted for pulmonary and cardiac pressures, and Langendorff apparatus was used for isolated heart experiments; preventive as well as rescue treatment protocols were conducted; tissues were collected for histological and biochemical studies. RESULTS: In vivo acute BH4 administration reduced pulmonary artery pressure (PAP) only in the MCT rat. In a Langendorff preparation, BH4 increased right ventricular systolic pressure (RVSP) in right ventricular hypertrophy (RVH) but not in control. In "prevention" therapy, BH4 (10 and 100 mg/kg) attenuated the development of PH in rat MCT model. eNOS protein levels in lung homogenates were maintained and cGMP levels were increased. In "rescue" therapy, BH4 (10 and 100 mg/kg) ameliorated pulmonary vascular muscularization in a dose-dependent manner. RVSP was reduced in RVH and pulmonary vascular muscularization was attenuated. BH4 at 10 mg/kg reduced RV myocyte diameter while BH4 at 100 mg/kg reversed it to control level. BH4 restored normal levels of eNOS protein and in a dose of 100 mg/kg enhanced lung tissue levels of BH4 , cGMP, and NO compared to placebo. CONCLUSION: The current study provides scientific evidence for a therapeutic potential of BH4 in PH and invites further investigation.

Effects of tetrahydrobiopterin oral treatment in hypoxia-induced pulmonary hypertension in rat.

Endothelial nitric oxide synthase (eNOS) plays a major role in maintaining pulmonary vascular homeostasis. Tetrahydrobiopterin (BH4), an essential cofactor that stabilizes the dimerization of eNOS and balances nitric oxide (NO) and superoxide production, may have therapeutic potential in pulmonary hypertension. In the isolated perfused lung, we demonstrated a direct effect of exogenous administration of BH4 on pulmonary NO production, leading to acute vasorelaxation during the plateau phase of hypoxia-induced pulmonary vasoconstriction. In the chronic hypoxia-induced pulmonary hypertension rat model, chronic BH4 oral administration attenuated the pressor response to hypoxia (mean pulmonary artery pressure ± standard error of the mean, 31.8 ± 0.5 mmHg at 100 mg/kg/day; placebo group, 36.3 ± 0.6 mmHg; P < 0.05). During telemetric monitoring, right ventricular systolic pressure was reduced by approximately 50% after 1 week of BH4 treatment at 100 mg/kg/day. BH4 at 100 mg/kg/day reduced right ventricular hypertrophy (from 0.55 ± 0.01 to 0.50 ± 0.01; P < 0.05) and pulmonary vascular muscularization (from 79.2% ± 2% to 65.2% ± 3%; P < 0.01). BH4 treatment enhanced lung eNOS activity and reduced superoxide production, with a net increase in cyclic guanosine monophosphate levels. BH4 is effective in attenuating pulmonary hypertension in the hypoxic rat model when given as a rescue therapy.

Differential regulation of ET(A) and ET(B) in the renal tissue of rats with compensated and decompensated heart failure.

Endothelin-1 (ET-1) exerts its biological actions through two receptor subtypes: endothelin-A (ETA) receptor and endothelin-B (ETB) receptor. We demonstrated previously that ET-1 induces systemic and renal cortical vasoconstriction via ETA whereas ETB mediates medullary vasodilation. Congestive heart failure (CHF) is characterized by increased vascular resistance and impaired renal hemodynamic and excretory function. While the pathophysiological effects of ET-1 in CHF are well established, the status of ETA and ETB in the kidney is poorly characterized. The present study examined the immunostaining and localization of ETA and ETB in the renal cortex and medulla of rats with experimental CHF induced by aorto-caval fistula. Rats with CHF were further subdivided, based on their daily urinary sodium excretion, into rats with compensated (urinary sodium excretion > 1200 microEq/day) and decompensated CHF (urinary sodium excretion < 200 microEq/day). ETA is predominantly localized to the cortex mainly in the peritubular capillaries, and is upregulated in rats with compensated and decompensated CHF compared with sham controls. In contrast, ETB is preferentially expressed in the outer and inner medulla, mainly in the vasa recta, the thick ascending limb of Henle's loop and the collecting duct. While compensated CHF is associated with upregulation of ETB in the collecting duct and vasa recta, decompensated CHF is accompanied with enhanced ETB abundance in the vasa recta and remarkable downregulation of this receptor subtype in the collecting duct. The findings suggest that upregulation of ETA may lead to a decrease in cortical blood flow while upregulation of ETB in the vasa recta probably contributes to the preservation of medullary blood flow. Furthermore, downregulation of ETB in the collecting duct, only in rats with decompensated CHF, could contribute to sodium retention in that subgroup.