Management of hepatorenal syndrome and treatment-related adverse events.

Hepatorenal Syndrome is a critical complication of liver failure, mainly in cirrhotic patients and rarely in patients with acute liver disease. It is a complex spectrum of conditions that leads to renal dysfunction in the liver cirrhosis population; the pathophysiology is characterized by a specific triad: circulatory dysfunction, nitric oxide (NO) dysfunction and systemic inflammation but a specific kidney damage has never been demonstrated, in a clinicopathological study, kidney biopsies of patients with cirrhosis showed a wide spectrum of kidney damage. In addition, the absence of significant hematuria or proteinuria does not exclude renal damage. It is estimated that 40% of cirrhotic patients will develop hepatorenal syndrome with in-hospital mortality of about one-third of these patients. The burden of the problem is dramatic considering the worldwide prevalence of more than 10 million decompensated cirrhotic patients, and the age-standardized prevalence rate of decompensated cirrhosis has gone through a significant rise between 1990 and 2017. Given the syndrome's poor prognosis, the clinician must know how to manage early treatment and any complications. The widespread adoption of albumin and vasopressors has increased Hepatorenal syndrome-acute kidney injury reversal and may increase overall survival, as previously shown. Further research is needed to define whether the subclassification of patients may allow to find a personalized strategy to treat Hepatorenal Syndrome and to define the role of new molecules and extracorporeal treatment may allow better outcomes with a reduction in treatment-related adverse effects. This review aims to examine both pharmacological and non-pharmacological treatment of hepatorenal syndrome, with a particular focus on managing adverse events caused by treatment.

The Impact of Inotropes and Vasopressors on Cerebral Oxygenation in Patients with Traumatic Brain Injury and Subarachnoid Hemorrhage: A Narrative Review.

Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are critical neurological conditions that necessitate specialized care in the Intensive Care Unit (ICU). Managing cerebral perfusion pressure (CPP) and mean arterial pressure (MAP) is of primary importance in these patients. To maintain targeted MAP and CPP, vasopressors and/or inotropes are commonly used. However, their effects on cerebral oxygenation are not fully understood. The aim of this review is to provide an up-to date review regarding the current uses and pathophysiological issues related to the use of vasopressors and inotropes in TBI and SAH patients. According to our findings, despite achieving similar hemodynamic parameters and CPP, the effects of various vasopressors and inotropes on cerebral oxygenation, local CBF and metabolism are heterogeneous. Therefore, a more accurate understanding of the cerebral activity of these medications is crucial for optimizing patient management in the ICU setting.

Cardiac Injury After Traumatic Brain Injury: Clinical Consequences and Management.

Traumatic brain injury (TBI) is a significant public health issue because of its increasing incidence and the substantial short-term and long-term burden it imposes. This burden includes high mortality rates, morbidity, and a significant impact on productivity and quality of life for survivors. During the management of TBI, extracranial complications commonly arise during the patient's stay in the intensive care unit. These complications can have an impact on both mortality and the neurological outcome of patients with TBI. Among these extracranial complications, cardiac injury is a relatively frequent occurrence, affecting approximately 25-35% of patients with TBI. The pathophysiology underlying cardiac injury in TBI involves the intricate interplay between the brain and the heart. Acute brain injury triggers a systemic inflammatory response and a surge of catecholamines, leading to the release of neurotransmitters and cytokines. These substances have detrimental effects on the brain and peripheral organs, creating a vicious cycle that exacerbates brain damage and cellular dysfunction. The most common manifestation of cardiac injury in TBI is corrected QT (QTc) prolongation and supraventricular arrhythmias, with a prevalence up to 5 to 10 times higher than in the general adult population. Other forms of cardiac injury, such as regional wall motion alteration, troponin elevation, myocardial stunning, or Takotsubo cardiomyopathy, have also been described. In this context, the use of ß-blockers has shown potential benefits by intervening in this maladaptive process. ß-blockers can limit the pathological effects on cardiac rhythm, blood circulation, and cerebral metabolism. They may also mitigate metabolic acidosis and potentially contribute to improved cerebral perfusion. However, further clinical studies are needed to elucidate the role of new therapeutic strategies in limiting cardiac dysfunction in patients with severe TBI.

The effect of increased positive end expiratory pressure on brain tissue oxygenation and intracranial pressure in acute brain injury patients.

Cerebral hypoxia is an important cause of secondary brain injury. Improving systemic oxygenation may increase brain tissue oxygenation (PbtO2). The effects of increased positive end-expiratory pressure (PEEP) on PbtO2 and intracranial pressure (ICP) needs to be further elucidated. This is a single center retrospective cohort study (2016-2021) conducted in a 34-bed Department of Intensive Care unit. All patients with acute brain injury under mechanical ventilation who were monitored with intracranial pressure and brain tissue oxygenation (PbtO2) catheters and underwent at least one PEEP increment were included in the study. Primary outcome was the rate of PbtO2 responders (increase in PbtO2 > 20% of baseline) after PEEP increase. ΔPEEP was defined as the difference between PEEP at 1 h and PEEP at baseline; similarly ΔPbtO2 was defined as the difference between PbtO2 at 1 h after PEEP incrementation and PbtO2 at baseline. We included 112 patients who underwent 295 episodes of PEEP increase. Overall, the median PEEP increased form 6 (IQR 5-8) to 10 (IQR 8-12) cmH2O (p = 0.001), the median PbtO2 increased from 21 (IQR 16-29) mmHg to 23 (IQR 18-30) mmHg (p = 0.001), while ICP remained unchanged [from 12 (7-18) mmHg to 12 (7-17) mmHg; p = 0.42]. Of 163 episode of PEEP increments with concomitant PbtO2 monitoring, 34 (21%) were PbtO2 responders. A lower baseline PbtO2 (OR 0.83 [0.73-0.96)]) was associated with the probability of being responder. ICP increased in 142/295 episodes of PEEP increments (58%); no baseline variable was able to identify this response. In PbtO2 responders there was a moderate positive correlation between ΔPbtO2 and ΔPEEP (r = 0.459 [95% CI 0.133-0.696]. The response in PbtO2 and ICP to PEEP elevations in brain injury patients is highly variable. Lower PbtO2 values at baseline could predict a significant increase in brain oxygenation after PEEP increase.

Serum LDH levels may predict poor neurological outcome after aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Serum lactate dehydrogenase (LDH) levels are often elevated in cardiovascular diseases. Their prognostic role after subarachnoid hemorrhage (SAH) remains poorly evaluated. METHODS: This is a retrospective single-center study of patients with non-traumatic SAH admitted to the intensive care unit (ICU) of an University Hospital from 2007 to 2022. Exclusion criteria were pregnancy and incomplete medical records or follow-up data. Baseline information, clinical data, radiologic data, the occurrence of neurological complications as well as serum LDH levels during the first 14 days of ICU stay were collected. Unfavorable neurological outcome (UO) at 3 months was defined as a Glasgow Outcome Scale of 1-3. RESULTS: Five hundred and forty-seven patients were included; median serum LDH values on admission and the highest LDH values during the ICU stay were 192 [160-230] IU/L and 263 [202-351] IU/L, respectively. The highest LDH value was recorded after a median of 4 [2-10] days after ICU admission. LDH levels on admission were significantly higher in patients with UO. When compared with patients with favorable outcome (FO), patients with UO had higher serum LDH values over time. In the multivariate logistic regression model, the highest LDH value over the ICU stay (OR 1.004 [95% CI 1.002 - 1.006]) was independently associated with the occurrence of UO; the area under the receiving operator (AUROC) curve for the highest LDH value over the ICU stay showed a moderate accuracy to predict UO (AUC 0.76 [95% CI 0.72-0.80]; p < 0.001), with an optimal threshold of > 272 IU/L (69% sensitivity and 74% specificity). CONCLUSIONS: The results in this study suggest that high serum LDH levels are associated with the occurrence of UO in SAH patients. As a readily and available biomarker, serum LDH levels should be evaluated to help with the prognostication of SAH patients.

REVersal of nEuromusculAr bLocking Agents in Patients Undergoing General Anaesthesia (REVEAL Study).

Background: Neuromuscular blocking agent (NMBA) monitoring and reversals are key to avoiding residual curarization and improving patient outcomes. Sugammadex is a NMBA reversal with favorable pharmacological properties. There is a lack of real-world data detailing how the diffusion of sugammadex affects anesthetic monitoring and practice. Methods: We conducted an electronic health record analysis study, including all adult surgical patients undergoing general anesthesia with orotracheal intubation, from January 2016 to December 2019, to describe changes and temporal trends of NMBAs and NMBA reversals administration. Results: From an initial population of 115,046 surgeries, we included 37,882 procedures, with 24,583 (64.9%) treated with spontaneous recovery from neuromuscular block and 13,299 (35.1%) with NMBA reversals. NMBA reversals use doubled over 4 years from 25.5% to 42.5%, mainly driven by sugammadex use, which increased from 17.8% to 38.3%. Rocuronium increased from 58.6% (2016) to 94.5% (2019). Factors associated with NMBA reversal use in the multivariable analysis were severe obesity (OR 3.33 for class II and OR 11.4 for class III obesity, p-value < 0.001), and high ASA score (OR 1.47 for ASA III). Among comorbidities, OSAS, asthma, and other respiratory diseases showed the strongest association with NMBA reversal administration. Conclusions: Unrestricted availability of sugammadex led to a considerable increase in pharmacological NMBA reversal, with rocuronium use also rising. More research is needed to determine how unrestricted and safer NMBA reversal affects anesthesia intraoperative monitoring and practice.

Effect of inotropic agents on oxygenation and cerebral perfusion in acute brain injury.

Introduction: Tissue hypoxia and insufficient energy delivery is one of the mechanisms behind the occurrence of several complications in acute brain injured patients. Several interventions can improve cerebral oxygenation; however, the effects of inotropic agents remain poorly characterized. Methods: Retrospective analysis including patients suffering from acute brain injury and monitored with brain oxygen pressure (PbtO2) catheter, in whom inotropic agents were administered according to the decision of the treating physician's decision; PbtO2 values were collected before, 1 and 2 h after the initiation of therapy from the patient data monitoring system. PbtO2 "responders" were patients with a relative increase in PbtO2 from baseline values of at least 20%. Results: A total of 35 patients were included in this study. Most of them (31/35, 89%) suffered from non-traumatic subarachnoid hemorrhage (SAH). Compared with baseline values [20 (14-24) mmHg], PbtO2 did not significantly increase over time [19 (15-25) mmHg at 1 h and 19 (17-25) mmHg at 2 h, respectively; p = 0.052]. A total of 12/35 (34%) patients were PbtO2 "responders," in particular if low PbtO2 was observed at baseline. A PbtO2 of 17 mmHg at baseline had a sensibility of 84% and a specificity of 91% to predict a PbtO2 responder. A significant direct correlation between changes in PbtO2 and cardiac output [r = 0.496 (95% CI 0.122 to 0.746), p = 0.01; n = 25] and a significant negative correlation between changes in PbtO2 and cerebral perfusion pressure [r = -0.389 (95% CI -0.681 to -0.010), p = 0.05] were observed. Conclusions: In this study, inotropic administration significantly increased brain oxygenation in one third of brain injured patients, especially when tissue hypoxia was present at baseline. Future studies should highlight the role of inotropic agents in the management of tissue hypoxia in this setting.

The Normobaric Oxygen Paradox-Hyperoxic Hypoxic Paradox: A Novel Expedient Strategy in Hematopoiesis Clinical Issues.

Hypoxia, even at non-lethal levels, is one of the most stressful events for all aerobic organisms as it significantly affects a wide spectrum of physiological functions and energy production. Aerobic organisms activate countless molecular responses directed to respond at cellular, tissue, organ, and whole-body levels to cope with oxygen shortage allowing survival, including enhanced neo-angiogenesis and systemic oxygen delivery. The benefits of hypoxia may be evoked without its detrimental consequences by exploiting the so-called normobaric oxygen paradox. The intermittent shift between hyperoxic-normoxic exposure, in addition to being safe and feasible, has been shown to enhance erythropoietin production and raise hemoglobin levels with numerous different potential applications in many fields of therapy as a new strategy for surgical preconditioning aimed at frail patients and prevention of postoperative anemia. This narrative review summarizes the physiological processes behind the proposed normobaric oxygen paradox, focusing on the latest scientific evidence and the potential applications for this strategy. Future possibilities for hyperoxic-normoxic exposure therapy include implementation as a synergistic strategy to improve a patient's pre-surgical condition, a stimulating treatment in critically ill patients, preconditioning of athletes during physical preparation, and, in combination with surgery and conventional chemotherapy, to improve patients' outcomes and quality of life.

Critical Care Outreach Team During COVID-19: Ventilatory Support in the Ward and Outcomes.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) outbreak, a critical care outreach team was implemented in our hospital to guarantee multidisciplinary patient assessment at admission and prompt ICU support in medical wards. In this paper, we report the activity plan results and describe the baseline characteristics of the referred subjects. METHODS: We retrospectively evaluated data from 125 subjects referred to the critical care outreach team from March 22 to April 22, 2020. We considered subjects with a ceiling of care decision, with those deemed eligible assigned to level 3 care (ward subgroup), and those deemed ineligible admitted to the ICU (ICU subgroup). Quality indicators of the outreach team plan delivery included number of cardiac arrest calls, number of intubations in level 2 areas, and ineffective palliative support. RESULTS: We enrolled 125 consecutive adult subjects with a confirmed diagnosis of COVID-19. We did not report any emergency endotracheal intubations in the clinical ward. In the care ceiling subgroup, we had 2 (3.3%) emergency calls for cardiac arrest, whereas signs of ineffective palliative support were reported in 5 subjects (12.5%). Noninvasive forms of respiratory assistance were delivered to 40.0% of subjects in the ward subgroup (median 3 d [interquartile range (IQR) 2-5]), to 45.9% of subjects in the care ceiling subgroup (median 5 d [IQR 3-7]), and to 64.7% of subjects in the ICU subgroup (median 2.5 d [IQR 1-3]). Thirty of the 31 ward subjects (96.7%), 26 of the 34 ICU subjects, (76.4%), and 19 of the 61 ceiling of care subjects (31.1%) were discharged. CONCLUSIONS: In the context of a hospital and ICU surge, a multidisciplinary daily plan supported by a dedicated critical care outreach team was associated with a low rate of cardiac arrest calls, no emergency intubations in the ward, and appropriate palliative care support for subjects with a ceiling of care decision.

Maraviroc in addition to cART during primary HIV infection: Results from MAIN randomized clinical trial and 96-weeks follow-up.

BACKGROUND: Multi-targeted treatment strategies including maraviroc (MVC) during Primary HIV Infection (PHI) may benefit from the immune-modulatory properties of this CCR5-inhibitor. OBJECTIVES: We conducted a proof-of-concept clinical trial aimed at assessing whether maraviroc in addition of a combination antiretroviral therapy (cART) initiated during PHI would improve immunological and virological parameters. STUDY DESIGN: The MAIN (Maraviroc in HIV Acute INfection) study was a randomized open-label clinical trial (EUDRACT number: 2008-007004-29) which enrolled 29 patients with PHI. Subjects were randomly assigned to receive cART-only (cART), cART+8 weeks of MVC (ST-MVC) or cART+48 weeks of MVC (LT-MVC), regardless of predicted co-receptor usage. After 48 weeks patients in ST-MVC and LT-MVC groups discontinued MVC. Patients were evaluated at week 48 and at week 96 of follow-up to assess differences in CD4 T-cell gain and plasma HIV-RNA. RESULTS: Twenty-nine patients were enrolled. Seven patients (24%) had a predicted CXCR4 co-receptor usage. At week 48, 27 patients (93.1%) reached HIV-RNA<50cps/mL. Median CD4 T-cell count increase was 313 cells/µL (p<0.001, Wilcoxon signed-rank test). At multivariate linear regression analysis, LT-MVC arm had the greatest CD4 T-cell increase, while patients in ST-MVC arm had the least gain in CD4 T-cells (p=0.007). At week 96, multivariate analysis showed no associations between former treatment arm and CD4 T-cell gain. CONCLUSIONS: The MAIN study showed that MVC for 48 weeks in addition to cART during PHI was able to enhance CD4 T-cell gain, regardless of co-receptor usage. After MVC discontinuation, the difference between treatment arms was lost.