Extracorporeal organ support for critically ill patients: Overcoming the past, achieving the maximum at present, and redefining the future.

Extracorporeal organ support (ECOS) has made remarkable progress over the last few years. Renal replacement therapy, introduced a few decades ago, was the first available application of ECOS. The subsequent evolution of ECOS enabled the enhanced support to many other organs, including the heart [veno-arterial extracorporeal membrane oxygenation (ECMO), slow continuous ultrafiltration], the lungs (veno-venous ECMO, extracorporeal carbon dioxide removal), and the liver (blood purification techniques for the detoxification of liver toxins). Moreover, additional indications of these methods, including the suppression of excessive inflammatory response occurring in severe disorders such as sepsis, coronavirus disease 2019, pancreatitis, and trauma (blood purification techniques for the removal of exotoxins, endotoxins, or cytokines), have arisen. Multiple organ support therapy is crucial since a vast majority of critically ill patients present not with a single but with multiple organ failure (MOF), whereas, traditional therapeutic approaches (mechanical ventilation for acute respiratory failure, antibiotics for sepsis, and inotropes for cardiac dysfunction) have reached the maximum efficacy and cannot be improved further. However, several issues remain to be clarified, such as the complexity and cost of ECOS systems, standardization of indications, therapeutic protocols and initiation time, choice of the patients who will benefit most from these interventions, while evidence from randomized controlled trials supporting their use is still limited. Nevertheless, these methods are currently a part of routine clinical practice in intensive care units. This editorial presents the past, present, and future considerations, as well as perspectives regarding these therapies. Our better understanding of these methods, the pathophysiology of MOF, the crosstalk between native organs resulting in MOF, and the crosstalk between native organs and artificial organ support systems when applied sequentially or simultaneously, will lead to the multiplication of their effects and the minimization of complications arising from their use.

Liver replacement therapy with extracorporeal blood purification techniques current knowledge and future directions.

Clinically, it is highly challenging to promote recovery in patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Despite recent advances in understanding the underlying mechanisms of ALF and ACLF, standard medical therapy remains the primary therapeutic approach. Liver transplantation (LT) is considered the last option, and in several cases, it is the only intervention that can be lifesaving. Unfortunately, this intervention is limited by organ donation shortage or exclusion criteria such that not all patients in need can receive a transplant. Another option is to restore impaired liver function with artificial extracorporeal blood purification systems. The first such systems were developed at the end of the 20th century, providing solutions as bridging therapy, either for liver recovery or LT. They enhance the elimination of metabolites and substances that accumulate due to compromised liver function. In addition, they aid in clearance of molecules released during acute liver decompensation, which can initiate an excessive inflammatory response in these patients causing hepatic encephalopathy, multiple-organ failure, and other complications of liver failure. As compared to renal replacement therapies, we have been unsuccessful in using artificial extracorporeal blood purification systems to completely replace liver function despite the outstanding technological evolution of these systems. Extracting middle to high-molecular-weight and hydrophobic/protein-bound molecules remains extremely challenging. The majority of the currently available systems include a combination of methods that cleanse different ranges and types of molecules and toxins. Furthermore, conventional methods such as plasma exchange are being re-evaluated, and novel adsorption filters are increasingly being used for liver indications. These strategies are very promising for the treatment of liver failure. Nevertheless, the best method, system, or device has not been developed yet, and its probability of getting developed in the near future is also low. Furthermore, little is known about the effects of liver support systems on the overall and transplant-free survival of these patients, and further investigation using randomized controlled trials and meta-analyses is needed. This review presents the most popular extracorporeal blood purification techniques for liver replacement therapy. It focuses on general principles of their function, and on evidence regarding their effectiveness in detoxification and in supporting patients with ALF and ACLF. In addition, we have outlined the basic advantages and disadvantages of each system.

Prevention, diagnostic evaluation, management and prognostic implications of liver disease in critically ill patients with COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, broke out in December 2019 in Wuhan city of China and spread rapidly worldwide. Therefore, by March 2020, the World Health Organization declared the disease a global pandemic. Apart from the respiratory system, various other organs of the human body are also seriously affected by the virus. Liver injury in patients with a severe form of COVID-19 is estimated to be 14.8%-53.0%. Elevated levels of total bilirubin, aspartate aminotransferase and alanine aminotransferase and low levels of serum albumin and prealbumin are the main laboratory findings. Patients with pre-existing chronic liver disease and cirrhosis are much more prone to develop severe liver injury. This literature review presented the recent scientific findings regarding the pathophysiological mechanisms responsible for liver injury in critically ill patients with COVID-19, the various interactions between drugs used to treat the disease and the function of the liver and the specific tests providing the possibility of early diagnosis of severe liver injury in these patients. Moreover, it highlighted the burden that COVID-19 put on health systems worldwide and its effect on transplant programs and the care provided to critically ill patients in general and particularly to those with chronic liver disease.

Impact of secondary sepsis on mortality in adult intensive care unit patients.

RATIONALE: Septic patients admitted to the intensive care unit (ICU) suffer from immune dysregulation, potentially leading to a secondary sepsis episode. This study aims to (i) assess the secondary sepsis rate, (ii) compare the second with the first episodes in terms of demographics, clinical and laboratory characteristics, and outcomes, and iii) evaluate the outcome of secondary sepsis. METHODS: A single-center, retrospective study (2014-2017) was conducted in a Greek ICU, including consecutive cases of adult patients admitted to the ICU for at least 48 h with a principal admission diagnosis of sepsis and stayed for at least 48 h. We searched for a secondary episode of sepsis following the primary-one. We performed survival analyses with Cox proportional hazard, Fine-Gray, and multistate models. RESULTS: In this study, 121 patients that fulfilled the eligibility criteria were included. The secondary sepsis group included 28 (23.1 %) patients, with episode onset, median (interquartile range), 9.5 (7.7-16.2) days after ICU admission, who had less frequently had a medical admission diagnosis, a microbiologically confirmed first episode, and the C-reactive protein was lower. The overall ICU mortality of the cohort was 44.6 %. The group that developed secondary sepsis had higher mortality, but significance was lost in Cox regression [Hazard ratio (95 % CI) 0.59(0.31-1.16)]. However, after multistate modeling adjustment, the attributable mortality was estimated at 43.9 % (95 %CI ± 14.8 %). CONCLUSION: Secondary sepsis was evident in a quarter of the study participants and may be associated with an increased risk of death.

Gastroenterology and liver disease during COVID-19 and in anticipation of post-COVID-19 era: Current practice and future directions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major threat to global public health. The virus causes the clinical syndrome known as coronavirus disease 2019 (COVID-19), in which multiple organs can get affected. Apart from manifestations of the respiratory system, which predominate, its clinical presentation is frequently accompanied by symptoms of the gastro-intestinal (GI) tract and liver abnormalities. The correlation of symptoms and abnormalities with disease severity is discussed, leading to ambiguous results from international literature. Moreover, the disease infects patients with co-existing liver and GI disorders affecting both their health status and the availability of healthcare services provided to them. The risk of transmission of the disease during aerosol-generating procedures has changed the diagnostic approach and follow-up algorithms for liver and GI diseases. For the safety of both doctors and patients, telemedicine and distant evaluation have become everyday practice, whereas several routines and emergency visits at outpatient and emergency departments have been postponed or delayed. Vaccination against SARS-CoV-2 is underway, providing hope to humanity and the expectation that the post-COVID-19 era is near. This review aims to update knowledge about the manifestations of COVID-19 related to liver and GI diseases and the effect of the pandemic on the diagnostic and therapeutic procedures for these diseases with a special focus on how current practices have changed and what changes will possibly remain in the future.

Metabolic Syndrome in Patients with Coexistent Obstructive Sleep Apnea Syndrome and Chronic Obstructive Pulmonary Disease (Overlap Syndrome).

Background: Evidence suggests that metabolic syndrome (MetS) is highly prevalent in patients with obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD). However, data on the prevalence of MetS in patients having both OSAS and COPD, or overlap syndrome (OS), are scarce. The aim of this study was to evaluate the prevalence and identify predictors of MetS in patients with OS. Methods: MetS was evaluated in consecutive patients who were diagnosed with OS by polysomnography and pulmonary function testing. Results: A total of 163 subjects (138 males and 25 females) were included. MetS was present in 38% of OS patients. Patients were divided into group A (OS without MetS group: 101 patients) and group B (OS with MetS group: 62 patients). Groups were similar in terms of pulmonary function and sleep parameters. In group B, abdominal obesity was the most prevalent component of MetS (100%), followed by hypertension (82.3%), hypertriglyceridemia (72.6%), and hyperglycemia (51.6%). Age (P = 0.009) and body mass index (P = 0.029) were independent predictors of MetS in patients with OS. Conclusions: An increased prevalence of MetS was observed in a group of patients with OS. Early identification and treatment of MetS may play a significant role in prevention of complications related to OS.

Increased risk for cardiovascular disease in patients with obstructive sleep apnoea syndrome-chronic obstructive pulmonary disease (overlap syndrome).

INTRODUCTION: Accumulating evidence suggests that cardiovascular disease (CVD) is highly prevalent among patients with concurrent obstructive sleep apnoea syndrome (OSAS) and chronic obstructive pulmonary disease, otherwise known as overlap syndrome (OS). OBJECTIVES: The aim of this study was to investigate the 10-year risk for CVD in OS patients compared with OSAS patients and controls. METHODS: Consecutive patients, referred for symptoms suggestive of OSAS, were evaluated with polysomnography and pulmonary function testing. Cardiovascular risk was assessed using the Framingham risk score (FRS) and systematic coronary risk evaluation (SCORE). RESULTS: Overall, 244 participants (184 males) without CVD and diabetes were divided into 3 groups: controls (n = 63), OSAS (n = 139) and OS (n = 42). Both FRS and SCORE were found to be elevated in the OS group compared with the OSAS and control groups (P < .001 for all). In multivariate analysis, age (ß = .461, P < .001), forced expiratory volume in first second (ß = -.285, P = .036) and oxygen desaturation index (ODI) (ß = .234, P = .007) were major determinants for the SCORE, whereas age (ß = .308, P < .001) and apnoea-hypopnoea index (ß = .252, P = .010) for the FRS. CONCLUSION: In our study, an increased risk for CVD was observed in a group of patients with OS at the time of their initial evaluation. Further studies are needed in the field of OS in order to investigate, prevent and manage early CVD in this population.

Serum levels of NGAL and cystatin C as markers of early kidney dysfunction in patients with obstructive sleep apnea syndrome.

PURPOSE: Obstructive sleep apnea syndrome (OSAS) has been recently proposed as an independent risk factor for chronic kidney disease. Cystatin C (Cyst C) and neutrophil gelatinase-associated lipocalin (NGAL) are novel biomarkers for the earlier detection of latent kidney disease. The aim of the study was to assess serum Cyst C and NGAL levels in otherwise healthy OSAS patients and to explore possible associations with sleep parameters. METHODS: Consecutive subjects (n = 96, 79.2% males), without known comorbidities, with symptoms suggestive of OSAS were included. All of them underwent polysomnography (PSG) and blood examination for the measurement of serum Cyst C and NGAL levels. RESULTS: Based on apnea-hypopnea index (AHI), subjects were classified into two groups: 32 controls and 64 OSAS patients, with no significant differences in terms of age (50.1 ± 11.7 vs 51 ± 12.2 years, p = 0.747) and BMI (33.9 ± 8.8 vs 35.9 ± 13.1 kg/m2, p = 0.449). Serum Cyst C and NGAL mean levels were higher in OSAS patients compared to those in controls (1155.2 ± 319.3 vs 966.8 ± 173 ng/ml, p = 0.001, and 43.7 ± 23.2 vs 35.6 ± 13.8 ng/ml, p = 0.035, respectively). After adjustment for age and BMI in OSAS patients, serum NGAL levels were associated with AHI (ß = 0.341, p = 0.015) and minimum oxyhemoglobin saturation during sleep (ß = - 0.275, p = 0.032), while serum Cyst C levels were associated with percentage of time with oxyhemoglobin saturation < 90% (ß = 0.270, p = 0.043), average (ß = - 0.308, p = 0.018), and minimum (ß = - 0.410, p = 0.001) oxyhemoglobin saturation during sleep. CONCLUSIONS: Higher risk for latent kidney disease in otherwise healthy OSAS patients is indicated. Sleep hypoxia seems to be a significant contributor in the pathogenetic process of renal dysfunction in OSAS.

Cardiovascular Risk Assessment in a Cohort of Newly Diagnosed Patients with Obstructive Sleep Apnea Syndrome.

OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular morbidity and mortality. The aim of this study was to assess whether the 10-year risk for cardiovascular disease in newly diagnosed patients with OSAS is increased. MATERIALS AND METHODS: Recently diagnosed, with polysomnography, consecutive OSAS patients were included. The Systematic Coronary Risk Evaluation (SCORE) and the Framingham Risk Score (FRS) were used to estimate the 10-year risk for cardiovascular disease. RESULTS: Totally, 393 individuals (73.3% males), scheduled to undergo a polysomnographic study with symptoms indicative of OSAS, were enrolled. According to apnea-hypopnea index (AHI), subjects were divided in four groups: mild OSAS (AHI 5-14.9/h) was diagnosed in 91 patients (23.2%), moderate OSAS (AHI 15-29.9/h) in 58 patients (14.8%), severe OSAS (AHI > 30/h) in 167 patients (42.5%), while 77 individuals (19.6%) had an AHI < 5/h and served as controls. Increased severity of OSAS was associated with increased SCORE (p < 0.001) and FRS values (p < 0.001). More specifically, a significant correlation was observed both between AHI and SCORE (r=0.251, p < 0.001) and AHI and FRS values (r=0.291, p < 0.001). Furthermore, a negative correlation was observed between FRS values and sleep efficiency (r=-0.224, p=0.006). CONCLUSIONS: The 10-year risk for cardiovascular morbidity and mortality seems to increase with severity of OSAS. Physicians should bear this finding in mind, in order to seek for and consecutively eliminate risk factors for cardiovascular disease and to prevent future cardiovascular events in OSAS patients.

Metabolic Syndrome and Vitamin D Levels in Patients with Obstructive Sleep Apnea Syndrome.

BACKGROUND: Numerous studies have indicated that obstructive sleep apnea syndrome (OSAS), may contribute to the development of metabolic syndrome (MetS) and diabetes. Moreover, OSAS has been associated with lowered vitamin D (Vit D) levels, but reports are inconclusive. Aim of the study was to compare Vit D levels according to the presence of MetS and its components in OSAS patients. METHODS: The presence of MetS was evaluated and serum 25-hydroxy vitamin D [25(OH)D] levels were measured in consecutive newly diagnosed, by polysomnography, subjects with OSAS. RESULTS: A total of 107 subjects (88 men) with OSAS were included in the study. Patients were divided into group A (OSAS with MetS group: 55 subjects) and group B (OSAS without MetS: 52 subjects). There were no differences between the two groups in terms of age, body mass index, and sleep parameters. Patients in group A exhibited higher levels of daytime sleepiness, as expressed by Epworth Sleepiness Scale score (12 ± 5.5 vs. 9.3 ± 4.8 for groups A vs. B, p = 0.008). Serum 25(OH)D levels were significantly decreased in group A, as compared with group B (18 ± 8.6 ng/mL vs. 23.9 ± 14.1 ng/mL, respectively, p = 0.012). Group A was then subdivided in two smaller groups, according to patients' metabolic index: OSAS patients with metabolic score = 3 and OSAS patients with metabolic score >3. Serum 25(OH)D levels were higher in OSAS patients with metabolic score = 3 compared with OSAS patients with metabolic score >3 (19.8 ± 8.9 ng/mL vs. 15.1 ± 7.3 ng/mL respectively, p = 0.038). CONCLUSIONS: OSAS patients with concurrent MetS exhibit lower serum Vit D levels, as compared with those without MetS.

Cystatin C Levels in Middle-Aged Patients with Obstructive Sleep Apnea Syndrome.

Background. Obstructive sleep apnea syndrome (OSAS) is associated with systemic inflammation and increased risk of cardiovascular and chronic kidney disease. Cystatin C (Cyst C) is a novel biomarker of both latent renal damage and cardiovascular disease. Aim of the study was to measure serum levels of Cyst C, as well as IL-8 and CRP, in otherwise healthy OSAS patients. Methods. 84 individuals examined with polysomnography for OSAS symptoms without known comorbidities were prospectively recruited. Results. According to apnea hypopnea index (AHI) subjects were divided in two groups: OSAS group (AHI > 5/hour, n = 64) and controls (AHI < 5/hour, n = 20), which were age- and BMI-matched. Cyst C levels were higher in OSAS patients versus controls (1176.13 ± 351.33 versus 938.60 ± 245.83 ng/mL, resp.; p = 0.017) while serum IL-8 and CRP levels did not differ significantly. Positive correlation was found between Cyst C levels and respiratory disturbance index (RDI) (r = 0.240, p = 0.039) and percentage of time with oxygen saturation <90% (r = 0.290, p = 0.02) and negative correlation was found between Cyst C levels and average oxygen saturation during sleep (r = -0.291, p = 0.012). After adjustment for age and BMI, RDI was the only independent predictor of Cyst C levels (ß = 0.256, p = 0.039). Conclusion. Cyst C serum levels are increased in OSAS patients without comorbidities, suggesting an increased renal and cardiovascular disease risk.

Serum Levels of Vascular Endothelial Growth Factor and Insulin-like Growth Factor Binding Protein-3 in Obstructive Sleep Apnea Patients: Effect of Continuous Positive Airway Pressure Treatment.

BACKGROUND AND AIM: Hypoxia, a major feature of obstructive sleep apnea (OSA), modifies Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) levels, which contribute to atherogenesis and occurrence of cardiovascular (CV) events. We assessed and compared serum levels of VEGF and IGFBP-3 in newly diagnosed OSA patients and controls, to explore associations with anthropometric and sleep parameters and to study the effect of continuous positive airway pressure (CPAP) treatment on these levels. MATERIALS AND METHODS: Serum levels of VEGF and IGFBP-3 were measured in 65 OSA patients and 31 age- and body mass index- matched controls. In OSA patients, measurements were repeated after 6 months of CPAP therapy. All participants were non-smokers, without any comorbidities or systemic medication use. RESULTS: At baseline, serum VEGF levels in OSA patients were higher compared with controls (p<0.001), while IGFBP-3 levels were lower (1.41±0.56 vs. 1.61±0.38 µg/ml, p=0.039). VEGF levels correlated with apnea-hypopnea index (r=0.336, p=0.001) and oxygen desaturation index (r=0.282, p=0.007). After 6 months on CPAP treatment, VEGF levels decreased in OSA patients (p<0.001), while IGFBP-3 levels increased (p<0.001). CONCLUSION: In newly diagnosed OSA patients, serum levels of VEGF are elevated, while IGFBP-3 levels are low. After 6 months of CPAP treatment these levels change. These results may reflect an increased CV risk in untreated OSA patients, which is ameliorated after CPAP therapy.