Renin in critically ill patients.

The renin-angiotensin system (RAS) constitutes one of the principal mechanisms to maintain hemodynamic and fluid homeostasis. However, most research until now on RAS primarily focuses on its relationship with hypertension and its role in critically ill hypotensive populations is not well understood. With the approval of angiotensin II (Ang II) in the United States and Europe, following a phase 3 randomized controlled trial showing efficacy in catecholamine-resistant vasodilatory shock, there is growing interest in RAS in critically ill patients. Among the fundamental components of RAS, renin acts as the initial stimulus for the entire system. In the context of hypotension, its release increases in response to low blood pressure sensed by renal baroreceptors and attenuated negative Ang II feedback loop. Thus, elevated renin could reflect disease severity and predict poor outcomes. Studies investigating this hypothesis have validated the prognostic accuracy of renin in various critically ill populations, with several reports indicating its superiority to lactate for mortality prediction. Accordingly, renin reduction has been used to assess the effectiveness of Ang II administration. Furthermore, renin holds potential to identify patients who might benefit from Ang II treatment, potentially paving the way for personalized vasopressor management. Despite these promising data, most available evidence is derived from retrospective analysis and necessitates prospective confirmation. The absence of a rapid, point-of-care and reliable renin assay presents another hurdle to its integration into routine clinical practice. This narrative review aims to describe the current understanding and future directions of renin as a biomarker during resuscitation of critically ill patients.

Comparison between propofol and total inhalational anaesthesia on cardiovascular outcomes following on-pump cardiac surgery in higher-risk patients: a randomised controlled pilot and feasibility study.

OBJECTIVES: Myocardial revascularisation and cardiopulmonary bypass (CPB) can cause ischaemia-reperfusion injury, leading to myocardial and other end-organ damage. Volatile anaesthetics protect the myocardium in experimental studies. However, there is uncertainty about whether this translates into clinical benefits because of the coadministration of propofol and its detrimental effects, restricting myocardial protective processes. METHODS: In this single-blinded, parallel-group randomised controlled feasibility trial, higher-risk patients undergoing elective coronary artery bypass graft (CABG) surgery with an additive European System for Cardiac Operative Risk Evaluation ≥5 were randomised to receive either propofol or total inhalational anaesthesia as single agents for maintenance of anaesthesia. The primary outcome was the feasibility of recruiting and randomising 50 patients across two cardiac surgical centres, and secondary outcomes included the feasibility of collecting the planned perioperative data, clinically relevant outcomes and assessments of effective patient identification, screening and recruitment. RESULTS: All 50 patients were recruited within 11 months in two centres, allowing for a 13-month hiatus in recruitment due to the COVID-19 pandemic. Overall, 50/108 (46%) of eligible patients were recruited. One patient withdrew before surgery and one patient did not undergo surgery. All but one completed in-hospital and 30-day follow-up. CONCLUSIONS: It is feasible to recruit and randomise higher-risk patients undergoing CABG surgery to a study comparing total inhalational and propofol anaesthesia in a timely manner and with high acceptance and completion rates. TRIAL REGISTRATION NUMBER: NCT04039854.

[Management of patent foramen ovale in non-cardiac surgery]. / Gestione della pervietà del forame ovale nella chirurgia non cardiaca.

Patent foramen ovale (PFO) is a remnant of normal fetal anatomy which may persist into adulthood, mostly asymptomatic. In some adults, PFO may result in a potential for shunting venous thromboembolism to the arterial circulation; less frequently it can cause interatrial, right-to-left shunting of deoxygenated blood. The pathogenesis of several medical conditions is related to the presence of PFO. Some randomized clinical trials have shown evidence of benefit for device closure as compared with medical therapy in patients with cryptogenic stroke. The literature reported several cases of carbon dioxide embolism during general laparoscopic surgery and sometimes stroke after laparoscopic or neurosurgery but there are neither prospective studies addressing these issues, nor randomized clinical trials assessing the effectiveness of pharmacotherapy or interventional procedures at decreasing risk. The European position paper suggests routine monitoring in non-cardiac surgery of patients with a PFO and no actual indications for closure. This article aims to further stratify the risk of periprocedural stroke and paradoxical embolism in this category of patients.

Low Versus High Blood Pressure Targets in Critically Ill and Surgical Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Hypotension is associated with adverse outcomes in critically ill and perioperative patients. However, these assumptions are supported by observational studies. This meta-analysis of randomized controlled trials aims to compare the impact of lower versus higher blood pressure targets on mortality. DATA SOURCES: We searched PubMed, Cochrane, and Scholar from inception to February 10, 2024. STUDY SELECTION: Randomized trials comparing lower versus higher blood pressure targets in the management of critically ill and perioperative settings. DATA EXTRACTION: The primary outcome was all-cause mortality at the longest follow-up available. This review was registered in the Prospective International Register of Systematic Reviews, CRD42023452928. DATA SYNTHESIS: Of 2940 studies identified by the search string, 28 (12 in critically ill and 16 in perioperative settings) were included totaling 15,672 patients. Patients in the low blood pressure target group had lower mortality (23 studies included: 1019/7679 [13.3%] vs. 1103/7649 [14.4%]; relative risk 0.93; 95% CI, 0.87-0.99; p = 0.03; I2 = 0%). This corresponded to a 97.4% probability of any increase in mortality with a Bayesian approach. These findings were mainly driven by studies performed in the ICU setting and with treatment lasting more than 24 hours; however, the magnitude and direction of the results were similar in the majority of sensitivity analyses including the analysis restricted to low risk of bias studies. We also observed a lower rate of atrial fibrillation and fewer patients requiring transfusion in low-pressure target groups. No differences were found in the other secondary outcomes. CONCLUSIONS: Based on pooled randomized trial evidence, a lower compared with a higher blood pressure target results in a reduction of mortality, atrial fibrillation, and transfusion requirements. Lower blood pressure targets may be beneficial but there is ongoing uncertainty. However, the present meta-analysis does not confirm previous findings and recommendations. These results might inform future guidelines and promote the study of the concept of protective hemodynamics.

Angiotensin ii therapy in refractory septic shock: which patient can benefit most? A narrative review.

Patients with septic shock who experience refractory hypotension despite adequate fluid resuscitation and high-dose noradrenaline have high mortality rates. To improve outcomes, evidence-based guidelines recommend starting a second vasopressor, such as vasopressin, if noradrenaline doses exceed 0.5 µg/kg/min. Recently, promising results have been observed in treating refractory hypotension with angiotensin II, which has been shown to increase mean arterial pressure and has been associated with improved outcomes. This narrative review aims to provide an overview of the pathophysiology of the renin-angiotensin system and the role of endogenous angiotensin II in vasodilatory shock with a focus on how angiotensin II treatment impacts clinical outcomes and on identifying the population that may benefit most from its use.

Macklin Effect: From Pathophysiology to Clinical Implication.

Air leak syndromes (such as pneumomediastinum, pneumothorax, or subcutaneous emphysema) are frequent complications of acute respiratory distress syndrome (ARDS). Unfortunately, the development of air leaks is associated with worse outcomes. In addition, it has been hypothesized that the development of pneumomediastinum could be a marker of disease severity in patients with respiratory failure receiving noninvasive respiratory support or assisted ventilation. The so-called Macklin effect (or pulmonary interstitial emphysema) is the air dissection of the lung bronchovascular tree from peripheral to central airways following injury to distal alveoli. Ultimately, the progression of the Macklin effect leads to the development of pneumomediastinum, subcutaneous emphysema, or pneumothorax. The Macklin effect is identifiable on a chest computed tomography (CT) scan. The Macklin effect could be an accurate predictor of barotrauma in patients with ARDS (sensitivity = 89.2% [95% CI: 74.6-96.9]; specificity = 95.6% [95% CI: 90.6-98.4]), and may be a marker of disease severity. Accordingly, the detection of the Macklin effect on a chest CT scan could be used to select which patients with ARDS might benefit from different treatment algorithms, including advanced respiratory monitoring, early intubation, or, potentially, the institution of early extracorporeal support with or without invasive ventilation. In this video, the authors summarize the pathophysiology and potential clinical significance and applications of the Macklin effect in patients with acute respiratory failure.

European Association of Cardio-Thoracic Surgery (EACTS) expert consensus statement on perioperative myocardial infarction after cardiac surgery.

Cardiac surgery may lead to myocardial damage and release of cardiac biomarkers through various mechanisms such as cardiac manipulation, systemic inflammation, myocardial hypoxia, cardioplegic arrest and ischaemia caused by coronary or graft occlusion. Defining perioperative myocardial infarction (PMI) after cardiac surgery presents challenges, and the association between the current PMI definitions and postoperative outcomes remains uncertain. To address these challenges, the European Association of Cardio-Thoracic Surgery (EACTS) facilitated collaboration among a multidisciplinary group to evaluate the existing evidence on the mechanisms, diagnosis and prognostic implications of PMI after cardiac surgery. The review found that the postoperative troponin value thresholds associated with an increased risk of mortality are markedly higher than those proposed by all the current definitions of PMI. Additionally, it was found that large postoperative increases in cardiac biomarkers are prognostically relevant even in absence of additional supportive signs of ischaemia. A new algorithm for PMI detection after cardiac surgery was also proposed, and a consensus was reached within the group that establishing a prognostically relevant definition of PMI is critically needed in the cardiovascular field and that PMI should be included in the primary composite outcome of coronary intervention trials.

Renin as a Prognostic Marker in Intensive Care and Perioperative Settings: A Scoping Review.

Serum renin increases in response to sympathetic nerve activation and hypotension. Recent studies have reported the association of serum renin levels with adverse clinical outcomes in acute care settings. This scoping review aimed to systematically review the available literature on renin as a prognostic marker in intensive care and perioperative patients. We searched for studies published since inception until March 31, 2023, which assessed the association between serum renin levels and clinical outcomes or the effect of synthetic angiotensin II administration on serum renin levels in critically ill and perioperative patients in PubMed, Embase, and the Cochrane Library. The primary outcome was mortality at the longest follow-up; the secondary outcomes were adverse renal outcomes (ie, acute kidney injury, the need for renal replacement therapy, and major adverse kidney events), hemodynamic instability, outcomes to angiotensin II administration, and prognostic performance for mortality when compared with lactate. Among the 2081 studies identified, we included 16 studies with 1573 patients (7 studies on shock, 5 on nonspecific critical illness, 2 on cardiac surgery, 1 on noncardiac surgery, and 1 on coronavirus disease 2019). A significant association between serum renin levels and poor outcomes was identified in 14 studies, with 10 studies demonstrating an association with mortality. One post hoc analysis found that angiotensin II administration reduced mortality in patients with markedly elevated renin values. Two studies showed that renin was superior to lactate as a prognostic marker of mortality. Our scoping review showed that elevated serum renin levels may be associated with clinically relevant outcomes among various perioperative and intensive care populations. Increased serum renin levels may identify patients in which synthetic angiotensin II administration improves clinical outcomes and may outperform serum lactate in predicting mortality.

Ketamine versus etomidate as an induction agent for tracheal intubation in critically ill adults: a Bayesian meta-analysis.

BACKGROUND: Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its favorable cardiovascular profile, ketamine is considered less likely to compromise clinical outcomes. This meta-analysis aimed to assess whether ketamine, compared with other agents, reduces mortality in critically ill patients undergoing intubation. METHODS: We searched MEDLINE, Embase, and the Cochrane Library from inception until April 27, 2023, for randomized controlled trials and matched observational studies comparing ketamine with any control in critically ill patients as an induction agent. The primary outcome was mortality at the longest follow-up available, and the secondary outcomes included Sequential Organ Failure Assessment score, ventilator-free days at day 28, vasopressor-free days at day 28, post-induction mean arterial pressure, and successful intubation on the first attempt. For the primary outcome, we used a Bayesian random-effects meta-analysis on the risk ratio (RR) scale with a weakly informative neutral prior corresponding to a mean estimate of no difference with 95% probability; the estimated effect size will fall between a relative risk of 0.25 and 4. The RR and 95% credible interval (CrI) were used to estimate the probability of mortality reduction (RR < 1). The secondary outcomes were assessed with a frequentist random-effects model. We registered this study in Open Science Framework ( https://osf.io/2vf79/ ). RESULTS: We included seven randomized trials and one propensity-matched study totaling 2978 patients. Etomidate was the comparator in all the identified studies. The probability that ketamine reduced mortality was 83.2% (376/1475 [25%] vs. 411/1503 [27%]; RR, 0.93; 95% CrI, 0.79-1.08), which was confirmed by a subgroup analysis excluding studies with a high risk of bias. No significant difference was observed in any secondary outcomes. CONCLUSIONS: All of the included studies evaluated ketamine versus etomidate among critically ill adults requiring tracheal intubation. This meta-analysis showed a moderate probability that induction with ketamine is associated with a reduced risk of mortality.

A Pilot Study of Renin-Guided Angiotensin-II Infusion to Reduce Kidney Stress After Cardiac Surgery.

BACKGROUND: Vasoplegia is common after cardiac surgery, is associated with hyperreninemia, and can lead to acute kidney stress. We aimed to conduct a pilot study to test the hypothesis that, in vasoplegic cardiac surgery patients, angiotensin-II (AT-II) may not increase kidney stress (measured by [TIMP-2]*[IGFBP7]). METHODS: We randomly assigned patients with vasoplegia (cardiac index [CI] > 2.1l/min, postoperative hypotension requiring vasopressors) and Δ-renin (4-hour postoperative-preoperative value) ≥3.7 µU/mL, to AT-II or placebo targeting a mean arterial pressure ≥65 mm Hg for 12 hours. The primary end point was the incidence of kidney stress defined as the difference between baseline and 12 hours [TIMP-2]*[IGFBP7] levels. Secondary end points included serious adverse events (SAEs). RESULTS: We randomized 64 patients. With 1 being excluded, 31 patients received AT-II, and 32 received placebo. No significant difference was observed between AT-II and placebo groups for kidney stress (Δ-[TIMP-2]*[IGFBP7] 0.06 [ng/mL]2/1000 [Q1-Q3, -0.24 to 0.28] vs -0.08 [ng/mL]2/1000 [Q1-Q3, -0.35 to 0.14]; P = .19; Hodges-Lehmann estimation of the location shift of 0.12 [ng/mL]2/1000 [95% confidence interval, CI, -0.1 to 0.36]). AT-II patients received less fluid during treatment than placebo patients (2946 vs 3341 mL, P = .03), and required lower doses of norepinephrine equivalent (0.19 mg vs 4.18mg, P < .001). SAEs were reported in 38.7% of patients in the AT-II group and in 46.9% of patients in the placebo group. CONCLUSIONS: The infusion of AT-II for 12 hours appears feasible and did not lead to an increase in kidney stress in a high-risk cohort of cardiac surgery patients. These findings support the cautious continued investigation of AT-II as a vasopressor in hyperreninemic cardiac surgery patients.

Could CPAP Devices Be Used to Ventilate Cardiac Arrest Patients? A Bench Study.

OBJECTIVES: To investigate the potential efficacy of a commercial continuous positive airway pressure (CPAP) ventilator to provide effective respiratory support in a simulated scenario of out-of-hospital cardiac arrest (OHCA). METHODS: The study was conducted on a high-fidelity manikin (SimMan 3 GTM, Laerdal, NOR) connected to the ASL 5000TM Lung Simulator (IngMar Medical, USA). To simulate OHCA, we set no spontaneous respiratory acts and physiological respiratory system resistance (13 cmH2O/L.sec) and compliance (50 mL/cmH2O). The Respironics BiPAP A40 ventilatorI (Philips, NL) was used to provide ventilatory support while operating in CPAP mode. Tests were performed at different values of positive pressure of the CPAP ventilator (PCPAP: 5, 7.5, 10, 12.5 and 15 cmH2O) and the intrapulmonary volume (tidal volume, Vt) measured via the simulator software computer interface. A trained physician performed the tests. Our primary outcome was a VT of ≈500-600 mL with an intermittent maneuver simulating cardiopulmonary resuscitation (CPR)-like ventilatory support practice according to international guideline-based target (1-sec ventilation followed by 1-sec pause). RESULTS: In intermittent ventilatory support tests, PCPAP levels of 12.5, and 15 cmH2O resulted in a VT equal to 508 ± 13 mL, and 557 ± 44 mL respectively (p = 0.04), thus approaching the VT target. CONCLUSIONS: We provide preliminary evidence of the potential efficacy of CPAP ventilators designed for home use to provide effective respiratory support to a simulated respiratory arrest patient.

Exposure to severe hyperoxemia worsens survival and neurological outcome in patients supported by veno-arterial extracorporeal membrane oxygenation: A meta-analysis.

BACKGROUND: Veno-arterial Extracorporeal Membrane Oxygenation (VA-ECMO) is a rescue treatment in refractory cardiogenic shock (CS) or refractory cardiac arrest (CA). Exposure to hyperoxemia is common during VA-ECMO, and its impact on patient's outcome remains unclear. METHODS: We conducted a systematic review (PubMed and Scopus) and meta-analysis investigating the effects of exposure to severe hyperoxemia on mortality and poor neurological outcome in patients supported by VA-ECMO. When both adjusted and unadjusted Odds Ratio (OR) were provided, we used the adjusted one. Results are reported as OR and 95% confidence interval (CI). Subgroup analyses were conducted according to VA-ECMO indication and hyperoxemia thresholds. RESULTS: Data from 10 observational studies were included. Nine studies reported data on mortality (n = 5 refractory CA, n = 4 CS), and 4 on neurological outcome. As compared to normal oxygenation levels, exposure to severe hyperoxemia was associated with higher mortality (nine studies; OR: 1.80 [1.16-2.78]; p = 0.009; I2 = 83%; low certainty of evidence) and worse neurological outcome (four studies; OR: 1.97 [1.30-2.96]; p = 0.001; I2 = 0%; low certainty of evidence). Magnitude and effect of these findings remained valid in subgroup analyses conducted according to different hyperoxemia thresholds (>200 or >300 mmHg) and VA-ECMO indication, although the association with mortality remained uncertain in the refractory CA population (p = 0.13). Analysis restricted to studies providing adjusted OR data confirmed an increased likelihood of poorer neurological outcome (three studies; OR: 2.11 [1.32-3.38]; p = 0.002) in patients exposed to severe hyperoxemia but did not suggest higher mortality (five studies; OR: 1.68 [0.89-3.18]; p = 0.11). CONCLUSIONS: Severe hyperoxemia exposure after initiation of VA-ECMO may be associated with an almost doubled increased probability of poor neurological outcome and mortality. Clinical efforts should be made to avoid severe hyperoxemia during VA-ECMO support.

Beyond the Surviving Sepsis Campaign Guidelines: a systematic review of interventions affecting mortality in sepsis.

INTRODUCTION: Sepsis-related mortality is decreasing over time after the introduction of "Surviving Sepsis Campaign" Guidelines in 2004. The last Guidelines version collects 93 recommendations, but several interventions supported by randomized evidence of mortality reduction are not included. EVIDENCE ACQUISITION: We performed a systematic review of all randomized controlled trials reporting a statistically significant mortality reduction in septic patients and compared the identified studies to the Surviving Sepsis Campaign Guidelines 2021 to highlight discrepancies. EVIDENCE SYNTHESIS: We identified 83 randomized controlled trials (58 interventions) influencing mortality in sepsis. Only 9/58 of these interventions were included in the Guidelines: lactate measurement and lactate-guided hemodynamic management, procalcitonin-guided antibiotics discontinuation, balanced crystalloids as first choice fluids, albumin infusion, avoidance of starches, noradrenaline as first line vasopressor, vasopressin as an adjunctive vasopressor to noradrenaline, neuromuscular blocking agents in moderate-severe sepsis-associated acute respiratory distress syndrome, and corticosteroids use. Only 11/93 Guidelines recommendations were supported by randomized evidence with mortality difference. Five of the interventions with survival benefit in literature (vitamin C, terlipressin, polymyxin B, liberal transfusion strategy and immunoglobulins) were recommended to avoid in the Guidelines, while 44 interventions were not mentioned, including three interventions (esmolol, omega 3, and external warming) with at least two randomized controlled trials with a documented survival benefit. CONCLUSIONS: Several discrepancies exist between the randomized controlled trials with mortality difference in septic patients and the latest Surviving Sepsis Campaign Guidelines. This systematic review can be of help for improving future guidelines and may guide research on specific promising topics.