OBJECTIVES:The role of ketamine for analgosedation in the ICU remains unclear. This study aimed to assess the efficacy of low-dose ketamine infusion for adjunct analgosedation in adults receiving mechanical ventilation. DESIGN:A prospective, double blind, randomized, placebo-controlled trial. SETTING:The study was conducted at two university-affiliated ICUs in Melbourne, Australia, between September 2022 and December 2024. PATIENTS:Adult patients receiving mechanical ventilation in the ICU who were also receiving opioid infusion for analgosedation (excluding cardiac surgical patients). INTERVENTIONS:Patients were randomized to receive low-dose ketamine infusion (0.15 mg/kg/hr) or placebo during the period of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS:The primary outcome was the hourly dose of opioids. Secondary outcomes included, among others, delirium, as well as ventilator, ICU, and hospital-free days to day 28. A total of 538 patients were screened for inclusion. Of these, 413 patients were ineligible based on exclusion criteria. A further five patients had consent withdrawn, leaving 120 patients (59 ketamine and 61 placebo) included for primary analysis. The median (interquartile range) hourly dose of opioids in fentanyl equivalents was 64 µg/hr (36-89 µg/hr) in the ketamine group and 77 µg/hr (47-100 µg/hr) in the placebo group (median difference, -13.0 [95% credible interval, -26.6 to 2.4]; probability of benefit, 95.1%). There were no differences between groups for most of the secondary outcomes, including delirium and significant adverse events. CONCLUSIONS:Low-dose ketamine infusion appeared safe and was associated with a reduction in hourly opioid requirements in ICU patients receiving mechanical ventilation. Larger randomized controlled trials are required to assess effects on other patient-centered outcomes.

PURPOSE:The impact of augmenting enteral protein delivery on nitrogen balance, urea generation, and kidney function in critically ill patients remains poorly defined. This study aimed to investigate these effects in a nested cohort within the TARGET Protein trial. METHODS:We conducted a single-center study nested within a cluster randomized crossover trial. Consecutive patients were enrolled during either the usual protein intake period (n = 52) or the augmented protein intake period (n = 55). Nitrogen balance, its components, plasma urea concentrations, and urea nitrogen accumulation were compared between groups. Multivariable analyses identified factors independently associated with nitrogen balance and incident acute kidney injury (AKI). A causal mediation analysis was performed to assess whether the effect of augmented protein delivery on urea concentrations was mediated through incident AKI. RESULTS:From day 1 to day 7, mean protein intake was 0.84 ± 0.73 g·kg-1·day-1 in the usual-protein group and 1.35 ± 0.94 g·kg-1·day-1 in the augmented-protein group. Patients receiving augmented protein achieved a less negative nitrogen balance than those receiving usual protein (mean difference, +5 g per day; 95% confidence interval [CI], 0.4 to 10; P = 0.033), driven by greater nitrogen intake (mean difference, +7 g per day; 95% CI, 5 to 10; P < 0.001). Independent predictors of nitrogen balance were ideal body weight (-0.18 g.kg-1; 95% CI, -0.35 to -0.01; P = 0.040), AKI at ICU admission (+4.7 g; 95% CI, 0.10 to 9.3; P = 0.046), and allocation to augmented protein therapy (+5.1 g; 95% CI, 0.43 to 9.7; P = 0.033). Compared with usual protein delivery, augmented protein delivery resulted in higher plasma urea concentrations (median, 14 vs. 11 mmol/L) and greater urea nitrogen accumulation (+3 g; 95% CI, 1.0 to 6.0; P = 0.035). Approximately 60% of the additional positive nitrogen balance was accounted for by urea generation. Among patients without AKI at ICU admission, augmented protein delivery was independently associated with incident AKI (odds ratio, 4.79; 95% CI, 1.14 to 26.4; P = 0.046). In mediation analyses, most of the increase in urea concentrations associated with augmented protein delivery was attributable to a direct effect rather than mediation through incident AKI. CONCLUSIONS:In critically ill patients, augmented protein delivery resulted in a less negative nitrogen balance but substantially increased urea generation and plasma urea concentrations. These findings suggest that a substantial proportion of additional protein intake may be directed toward nitrogen waste production rather than net anabolic utilization.

Objective:To evaluate critical care professionals' perceptions of the burden of metabolic acidosis (MA) in the intensive care unit (ICU), and assess agreement on indications, modalities, risks, and benefits of sodium bicarbonate therapy. Design:A multinational, web-based survey administered at different times to Chinese and international ICU practitioners. Main outcome measures:The survey comprised 20 items across four domains: 1) perceived epidemiology and research relevance of MA; 2) rationale, indications, and treatment modalities; 3) potential benefits of sodium bicarbonate; and 4) potential adverse effects of sodium bicarbonate. Responses were recorded on a 5-point Likert scale and classified as "Agreed", "Disagreed", or "Uncertain". Results:A total of 1279 responses from 20 countries were analysed. MA was widely recognised as common, clinically relevant, a frequent cause of ICU admission, and an area requiring further research. Most clinicians supported targeted therapy beyond treating underlying causes, though uncertainty remained regarding sodium bicarbonate. Chinese respondents favoured early correction and continuous infusion, while international opinions varied on timing and approach. Perceived benefits, such as reduced vasopressor use and respiratory workload, were supported by Chinese clinicians, whereas international ones remained uncertain. Opinions on adverse effects also diverged. Chinese physicians highlighted risks of hypernatraemia, severe alkalosis, and hypokalemia, while international respondents viewed sodium bicarbonate as safe regarding the risk of fluid overload or pulmonary oedema. Conclusions:This international survey shows broad agreement that MA is a clinically important and understudied condition in the ICU but reveals substantial variability and uncertainty in clinicians' perceptions of sodium bicarbonate therapy, with notable differences between Chinese and international respondents. These findings underscore key knowledge gaps and the need for well-designed clinical trials.

AIM:This study aimed to assess the characteristics, transfusion events, and clinical outcomes of cardiac surgery patients treated with three-factor prothrombin complex concentrate (3F-PCC). METHOD:A retrospective observational study was performed in three cardiac surgery centres in Australia. We studied sequential cardiac surgeries and collected data on 3F-PCC, fresh frozen plasma (FFP) and red blood cell (RBC) use from blood banks and clinical outcomes from the Australian Society of Cardiothoracic Surgery database. We compared 3F-PCC treated to PCC-untreated patients. RESULTS:For 1,698 patients, 254 (15%) received 3F-PCC, with a median dose of 2,000 IU (Interquartile range [IQR]: 1,000 to 2,000), administered almost exclusively in the operating theatre. After adjustment by overlap weighting, 3F-PCC was associated with a reduction in post-surgical FFP transfusions (Relative risk [RR]: 0.47; 95% confidence interval [CI] 0.29 to 0.77). Similarly, 14% of 3F-PCC patients needed ≥2 RBC units after surgery compared to 21% in controls (RR: 0.63; 95% CI 0.45 to 0.88). Both groups displayed similar safety profiles and clinical outcomes. However, pulmonary embolism occurred in 1.8% of 3F-PCC patients versus 0.8% of controls. CONCLUSIONS:In a multicentre study, 3F-PCC use during cardiac surgery was independently associated with a significantly reduction of postoperative FFP and RBC transfusions. A phase III trial of early PCC at 2,000 IU appears justified.

PURPOSE:In intensive care unit (ICU) patients receiving unfractionated heparin (UFH) infusion, activated partial thromboplastin time (aPTT) and anti-factor Xa (anti-Xa) levels have limited correlation and significant discordance. We aimed to test whether thromboelastographic-derived citrated kaolin reaction time (CKR) and/or the difference (R-difference) and/or ratio (R-ratio) between CKR and heparinase-corrected CKR might help resolve such discordance METHODS: We obtained simultaneous triple-paired samples for aPTT, anti-Xa and thromboelastography (TEG) in ICU patients receiving UFH infusion. We assessed correlation between UFH dose and R-difference and concordance for therapeutic ranges between aPTT, anti-Xa, and CKR or R-difference or R-ratio. On multivariate analysis, we assessed factors associated with TEG R-based measurements RESULTS: We studied 136 samples from 24 patients with a median APACHE III score of 50 and median UFH dose of 14.6 [10.5, 18.3] units/kg/h. for each 1 unit/kg increase in UFH dose, the R-difference increased by 2 min (95% C.I. 0.23-3.7, p < 0.05) but the correlation was weak (R2 = 0.1). The Cohen's kappa coefficient for agreement was 0.39 for CKR-aPTT and 0.17 for CKR-anti-Xa. Similar results were seen for R-difference and R-ratio. When aPTT and anti-Xa were discordant for therapeutic ranges, TEG did not resolve discordance. On multivariate analysis, CKR, R-difference and R-ratio were independently positively associated with UFH dose but also with APACHE III score and, negatively, with iCa CONCLUSIONS: In ICU patients receiving UFH infusion, TEG R-based measurements have limited correlation and concordance with anti-Xa and aPTT for defined therapeutic ranges and do not help resolve their discordance.

Background: High respiratory effort may be common in invasively ventilated patients receiving pressure support ventilation, but its epidemiologic characteristics are unclear. Research Question: What are the epidemiologic characteristics of high respiratory efforts in critically ill patients, does agreement exist between high respiratory drive and high respiratory effort, what are clinician responses during such events, and what is the relationship between those with clinical parameters and outcomes? Study Design and Methods: This clinician-masked, prospective, observational study in 2 centers measured the drop in airway pressure during the first 100 ms of an inspiratory effort with an occluded airway (P-0.1), a validated noninvasive measure of respiratory drive, in patients receiving pressure support ventilation for > 24 hours. We also measured estimated respiratory muscle pressure (P-e(musc)), a validated surrogate of inspiratory effort. We measured P-e(musc) and P-0.1 twice daily. Results: Of 528 ventilated patients, 80 patients received pressure support ventilation for > 24 hours. Among them, 33 patients (41%) exhibited high respiratory effort, which was more common in COVID-19 ARDS, with 19 of such patients (58%) reached the predefined threshold vs 14 patients (27%) in the non-COVID-19 cohort (OR, 5.0; 95% CI, 1.9-14.9; P = .001). Moreover, 36% of P-0.1 values were >= 4 cm H2O, indicating high respiratory drive. Moderate agreement was found between P-e(musc) and P-0.1 measurements (intraclass correlation coefficient, 0.65), suggesting significant discrepancies between those 2 parameters. Clinician-directed management based on usual clinical observations (but masked to P-0.1 and P-e(musc)) rarely changed in the presence of high respiratory effort. Higher P-e(musc) and its concomitant elevation with P-0.1 were associated with worse blood gas parameters and respiratory mechanics. A concomitant elevation of both P-e(musc) and P-0.1 was associated independently with a decreased likelihood of being alive and ventilator-free up to day 28 (OR, 0.26; 95% CI, 0.06-0.87; P = .037). Interpretation: In this study, many critical care patients receiving invasive pressure support ventilation exhibited high respiratory efforts. In these patients, adjustments to ventilator settings were uncommon, despite association with worse clinical parameters and outcomes.

Introduction: Angiotensin II may reduce muscle ischemia during intermittent hemodialysis and thereby decrease the incidence and/or intensity of intradialytic muscle cramps. We aimed to test whether angiotensin II infusion during intermittent hemodialysis is safe, feasible, and effective in the attenuation of muscle cramps. Methods: We performed a pilot, single-blinded, randomized crossover trial of patients receiving intermittent hemodialysis who frequently experience intradialytic muscle cramps. Patients were randomly allocated to receive either intravenous angiotensin II or placebo for the duration of their first dialysis session of the week. They crossed over to the alternate arm each week for four weeks. The primary outcome was safety. Secondary outcomes included cramp-related symptoms, hemodynamic parameters, dialysis prescription alterations, and biomarkers. Results: We studied 24 sessions in 6 patients. Intradialytic hypertension (systolic blood pressure >180mmHg) occurred more often with angiotensin II than with placebo (33% vs 17% sessions, P=0.64). There were no other adverse events. Compared with placebo, muscle cramps were less frequent (33% vs. 92% sessions, P=0.009) and of lower intensity with angiotensin II (median Brief Pain Inventory score 1.4 vs. 5.3; P<0.001; maximal Brief Pain Inventory score 1.2 vs. 6.0; P<0.001). Fluid bolus administration for cramps was less common during angiotensin II infusion than placebo (0% vs. 42% sessions, P=0.037). Conclusion: Angiotensin II increased blood pressure and heart rate but not cardiac output or levels of troponin, creatine kinase or renin. In conclusion, angiotensin II infusion during intermittent hemodialysis appears safe and effective at reducing intradialytic muscle cramps. These observations justify further investigation in larger controlled studies.

Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Protein loading appears nephroprotective; thus, continuous hyperoncotic albumin infusion may impact AKI following high-risk cardiac surgery. To evaluate the effect of postoperative 20% albumin infusion compared with usual care on the occurrence of AKI in high-risk cardiac surgery patients. This was an investigator-initiated randomized multicenter open-label pragmatic clinical trial. Participants were stratified by site and estimated glomerular filtration rate (eGFR) above and below 60 mL/min/1.73 m2. The study was conducted at 7 cardiac centers in Australia and Italy between July 2019 and August 2024. Patients undergoing on-pump cardiac surgery with a preoperative eGFR of greater than 15 mL/min/1.73 m2 and less than 60 mL/min/1.73 m2 or undergoing a combined cardiac surgical procedure or major aortic surgery were included, excluding those who were in intensive care for longer than 6 hours following the index surgery, had a serum albumin level less than 20 g/L, were dialysis dependent, had a previous kidney transplant, were receiving extracorporeal life support or ventricular assist device, or had an objection to receiving albumin or blood products. Participants were randomized 1:1 within 6 hours after surgery to receive a 300-mL infusion of 20% albumin over 15 hours or usual care, as per clinician discretion. All patients received volume resuscitation and hemodynamic treatment according to participating centers’ protocols. The primary outcome was stage 1-3 AKI according to the creatinine-based Kidney Disease Improving Global Outcomes definition. The main secondary outcomes included major adverse kidney events and mortality at hospital discharge or day 28 following randomization. The primary analysis included 307 patients randomized to the 20% albumin group and 304 to usual care. The mean (SD) age was 69 (10.8) years, and 281 patients (45.8%) had an eGFR less than 60 mL/min/1.73 m2. The median (IQR) European System for Cardiac Operative Risk Evaluation score-II was 3.23 (1.91-5.30). AKI occurred in 150 of 307 patients in the albumin group (48.9%) vs 132 of 304 in usual care (43.4%) (unadjusted relative risk, 1.13; 95% CI, 0.95-1.34; P = .18; strata-adjusted relative risk, 1.12; 95% CI, 1.04-1.21; P = .003). This effect was more pronounced in patients with an eGFR of <60 mL/min/1.73 m2 (adjusted relative risk, 1.14; 95% CI; 1.07-1.22; P < .001). There were more blood transfusions given in the albumin group (116 [37.8%] vs 91 [29.9%]; P = .04) but no other significant differences in secondary outcomes. In this study of cardiac surgery patients at high risk of AKI, an infusion of 20% albumin increased the risk of AKI. These findings do not support the routine use of hyperoncotic albumin infusion in patients undergoing high-risk cardiac surgery. Anzctr.org.au Identifier: ACTRN12619001355167

BACKGROUND:Hypernatremia is relatively common in acutely ill patients and associated with mortality. Guidelines recommend a slow rate of correction (≤ 0.5 mmol/L per hour). However, a faster correction rate may be safe and improve outcomes. OBJECTIVES:To evaluate the impact of sodium correction rates on mortality and hospital length of stay and to assess types of hypernatremia treatment and treatment side effects. METHODS:We conducted a systematic review and meta-analysis according to PRISMA guidelines, searching Ovid MEDLINE, Embase, and CENTRAL databases from inception to August 2024. Studies reporting sodium correction rates and clinical outcomes in hospitalized adults were included. A random-effects meta-analysis assessed mortality and hospital length of stay, with subgroup analyses exploring correction timing and severity. Treatment method and side effects were analyzed qualitatively. RESULTS:We reviewed 4445 articles and included 12 studies. Faster correction rates (> 0.5 mmol/L/h) overall showed no significant change in mortality and a high level of heterogeneity (OR 0.68, 95 % CI: 0.38-1.24, I2 = 95 %). However, subgroup analyses found significantly lower mortality with faster correction of hypernatremia at the time of hospital admission (OR 0.48, 95 % CI: 0.35-0.68, I2 = 2 %), with fast correction within the first 24 h of diagnosis (OR 0.48, 95 % CI: 0.31-0.73, I2 = 65 %), and for severe hypernatremia (OR 0.55, 95 % CI: 0.33-0.92, I2 = 79 %). There was no significant different in hospital length of stay by correction rate. No major neurological complications were reported when the correction rate was < 1 mmol/L/h. CONCLUSION:Faster sodium correction appears safe and may benefit patients with severe admission-related hypernatremia, particularly within the first 24 h. Further studies are needed to refine correction protocols.

PURPOSE:To detect changes in cardiac output and blood pressure during intermittent hemodialysis (IHD) in patients recovering from severe acute kidney injury (AKI) after transition from continuous renal replacement therapy (CRRT). MATERIAL AND METHODS:In this single-center pilot feasibility study, we applied continuous hemodynamic monitoring (ClearSight System™) before and during IHD sessions in patients recovering from severe AKI. We also measured relative blood volume (BV; CRIT-LINE®IV) and Net Ultrafiltration Rate (NUF). CI changes were categorized as follows: Increase (>5 %), Stable (-5 % to 5 %), Mild Decrease (-5 % to -15 %), Moderate Decrease (-15 % to -25 %), and Severe Decrease (<-25 %). RESULTS:We enrolled 10 AKI patients. Overall, there were 119 episodes of severe and 286 episodes of moderate reductions in cardiac index (CI). The median time spent with severe and moderate intradialytic reductions in CI was 8.2 min [2.1-115.8] and 49.5 min [21.6-57.5], respectively. Severe CI reductions happened in nine patients out of 10, and in three patients, they lasted more than 2 h. During IHD, mean arterial pressure increased or remained stable in >78 % of measurements, regardless of changes in CI. Overall, CI decreased by -1.14 L/min/m2 during a moderate BV decrease (p < 0.001) and by -0.57 L/min/m2 when NUF rate was high (p < 0.001). CONCLUSIONS:CI often, repeatedly, and markedly decreased during IHD. Such decreases were not detected by MAP monitoring and were extreme in some patients.

Background: Severe intensive care unit-acquired hypernatraemia (ICU-AH) is a serious complication of critical illness. However, there is no detailed information on how this condition develops. Objectives: The objective of this study was to study the prevalence, risk factors, trajectory, management, and outcome of severe ICU-AH (>155 mmol center dot L-1). Methods: A retrospective study was conducted in a 40-bed ICU in a university-affiliated hospital. Assessment of sodium levels, factors associated with severe ICU-AH, urinary electrolyte measurements, water therapy, fluid balance, correction rate, and delirium was made. Results: We screened 11,642 ICU admissions and identified 109 patients with severe ICU-AH. The median age was 57 years, 63% were male, and the median Acute Physiology and Chronic Health Evaluation III score was 64 (52; 80). On the day of ICU admission, 64% of patients were ventilated; 71% received vasopressors, and 22% had acute kidney injury. The median peak sodium level was 158 (156; 161) mmolL-1 at a median of 4(1; 11) days after ICU admission. Only eight patients (7%) had urine sodium measurement (median concentration: 17 mmol center dot L-1). On the day of peak hypernatraemia, 80% of patients were unable to drink due to invasive ventilation; 34% were on diuretics; 25% had fever, and 50% did not receive hypotonic fluids. When available, the median electrolyte-free water clearance was-1.1 L (-1.7;-0.5), representing half of the urine output. After peak hypernatraemia, the correction rate was-2.8 mmol center dot L-1 per day (95% confidence interval: [-2.9 to-2.6]) during the first 3 d. Conclusions: Severe hypernatraemia occurred in the setting of inability to drink, near-absent measurement of urinary free water losses, diuretic therapy, fever, renal impairment, and near-absent or limited or delayed water administration. Correction was slow. (c) 2024 Published by Elsevier B.V. on behalf of College of Intensive Care Medicine of Australia and New Zealand. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

INTRODUCTION:Paracetamol (acetaminophen)-induced acute liver failure (ALF) with severe hyperammonemia (ammonia >100 µmol⋅L-1) is a life-threatening condition. A strategy based on high-intensity continuous renal replacement therapy (CRRT) without early (up to day seven) transplantation may enable clinicians to safely identify which patients can recover and survive and which patients require transplantation. METHODS:We conducted a single-center, retrospective cohort study of patients with severely hyperammonemic paracetamol-induced ALF. The primary outcome was early transplant-free survival. RESULTS:We studied 84 patients (median age: 38; female sex: 79 [85%]) over a 12-year period (median ammonia level at ICU admission: 153 µmol⋅L-1; median peak aspartate aminotransferase (AST): 10,029 U⋅L-1; median lactate: 5.0 mmol⋅L-1; and median INR: 4.4) and 55 (65%) with King's College criteria for transplantation. Overall, 87% received high-intensity CRRT (92% in 2020-2023). Median CRRT intensity was 54 mL⋅kg-1⋅hr-1 within the first 48 h and increased by 1.8 mL⋅kg-1⋅hr-1 per year during the study period (p = 0.002). Transplant-free survival to day 7 was 86% in 2011-2023 and 96% in 2020-2023. Overall, only 4 patients were transplanted and only 1 (4%) in 2020-2023. On multivariable Cox analysis, factors independently associated with failure to achieve day seven transplant-free survival were higher APACHE III score (HR = 1.05, 95% CI: 1.02-1.08), higher lactate (HR = 1.27, 95% CI: 1.12-1.44), and lower platelet count at ICU admission (HR = 0.85, 95% CI: 0.78-0.93) and the median effluent dose applied within the first 48 h of ICU admission (HR = 0.67, 95% CI: 0.46-0.98). CONCLUSIONS:Early transplant-free survival is achievable in most patients with paracetamol-induced ALF and severe hyperammonemia with a treatment based on high-intensity CRRT. Such transplant-free survival increased over time together with increased CRRT dose.

BACKGROUND:Normothermic machine perfusion (NMP) aims to reduce ischemia-reperfusion injury in donor livers and its clinical manifestation, early allograft dysfunction (EAD) by maintaining perfusion and oxygenation. However, there is limited data on which NMP perfusate biomarkers might be associated with such EAD and the role of perfusate hemoglobin has not been assessed. METHODS:We performed a pilot retrospective analysis of adult donor livers undergoing NMP between 2020 and 2022 at our center. NMP was commenced at the recipient hospital after initial static cold storage. All NMP circuits were primed in the same manner according to the manufacturer's instructions. Livers were stratified by initial perfusate hemoglobin below (≤5.2 mmol/L) or above (>5.2 mmol/L) the median. The association between hemoglobin levels and EAD or recipient peak transaminase levels was assessed. RESULTS:Among 23 livers, eight were considered unsuitable for transplantation, leaving 15 livers for assessment. Higher initial hemoglobin was associated with a lower risk of EAD (0% vs. 55.6%, p = 0.04). Perfusate hemoglobin decreased after NMP initiation (p = 0.003) and negatively correlated with recipient peak transaminase levels (ALT: ρ = -0.72, p = 0.002; AST: ρ = -0.79, p < 0.001). Consistently, higher hemoglobin livers also demonstrated lower perfusate liver enzymes. CONCLUSIONS:Perfusate hemoglobin levels decreased during NMP, and lower perfusate hemoglobin levels were associated with a higher incidence of EAD and higher levels of liver injury markers. Maintaining higher hemoglobin levels during NMP may help reduce ischemia-reperfusion injury and prevent or attenuate EAD. Larger prospective studies are needed to validate the findings of this pilot study.

Angiotensin II is approved for catecholamine-refractory vasodilatory shock but the conversion dose ratio from norepinephrine to angiotensin II remains unclear. We conducted a post-hoc analysis of the Acute Renal effects of Angiotensin II Management in Shock (ARAMIS) trial involving patients with vasodilatory hypotension. We determined the norepinephrine equivalent dose immediately prior to angiotensin II initiation and calculated the conversion dose ratio between norepinephrine and angiotensin II. We performed subgroup analyses based on recent exposure to angiotensin receptor blockers (ARBs) and renin levels at baseline. In 37 patients, the median conversion dose ratio between norepinephrine equivalent and angiotensin II was to 10:1 for norepinephrine bitartrate (5:1 for norepinephrine base). The conversion ratio was not affected by the baseline renin, with a median ratio of 10 (7–21) in the high renin group versus 12 (5–22) in the low renin group. Finally, exposure to ARBs prior admission appeared to diminish the conversion ratio with a median ratio of 7 (4–13) in ARB patients vs. 12 (7–22) in non-ARB patients. The norepinephrine to angiotensin II conversion dose ratio is 10:1 in a vasodilatory hypotension population. These findings can guide clinicians and researchers in the use, dosing, and study of angiotensin II in critical care.

PURPOSE:Angiotensin II is approved for catecholamine-refractory vasodilatory shock but the conversion dose ratio from norepinephrine to angiotensin II remains unclear.METHODS:We conducted a post-hoc analysis of the Acute Renal effects of Angiotensin II Management in Shock (ARAMIS) trial involving patients with vasodilatory hypotension. We determined the norepinephrine equivalent dose immediately prior to angiotensin II initiation and calculated the conversion dose ratio between norepinephrine and angiotensin II. We performed subgroup analyses based on recent exposure to angiotensin receptor blockers (ARBs) and renin levels at baseline.RESULTS:In 37 patients, the median conversion dose ratio between norepinephrine equivalent and angiotensin II was to 10:1 for norepinephrine bitartrate (5:1 for norepinephrine base). The conversion ratio was not affected by the baseline renin, with a median ratio of 10 (7-21) in the high renin group versus 12 (5-22) in the low renin group. Finally, exposure to ARBs prior admission appeared to diminish the conversion ratio with a median ratio of 7 (4-13) in ARB patients vs. 12 (7-22) in non-ARB patients.CONCLUSIONS:The norepinephrine to angiotensin II conversion dose ratio is 10:1 in a vasodilatory hypotension population. These findings can guide clinicians and researchers in the use, dosing, and study of angiotensin II in critical care.

Aim: Higher nitric oxide (NO) levels correlate with adverse sepsis outcomes but are challenging to measure. Methemoglobin (MetHb), a measurable product of NO, has not been utilized for risk stratification.Methodology: All patients with sepsis admitted to the intensive care unit (ICU) that had at least one MetHb measurement within 24 h of ICU admission were retrospectively analyzed. We assessed the epidemiology and associations of MetHb with hospital mortality.Results: Among 7724 patients, 1046 qualified. Those with MetHb ≥1.6% showed significantly higher mortality and fewer days alive outside the hospital by day 28. MetHb levels ≥1.6% independently predicted increased 28-day mortality.Conclusion: Our findings suggest MetHb, easily obtainable from arterial blood gases, can significantly enhance sepsis risk stratification.

BACKGROUND:Cardiac surgery with cardiopulmonary bypass (CPB) is associated with hemolysis. Yet, there is no easily available and frequently measured marker to monitor this hemolysis. However, carboxyhemoglobin (CO-Hb), formed by the binding of carbon monoxide (a product of heme breakdown) to hemoglobin, may reflect such hemolysis. We hypothesized that CO-Hb might increase after cardiac surgery and show associations with operative risk factors and indirect markers for hemolysis. METHODS:We conducted a retrospective descriptive cohort study of data from on-pump cardiac surgery patients. We analyzed temporal changes in CO-Hb levels and applied a generalized linear model to assess patient characteristics associated with peak CO-Hb levels. Additionally, we examined their relationship with red blood cell (RBC) transfusion and bilirubin levels. RESULTS:We studied 38,487 CO-Hb measurements in 1735 patients. CO-Hb levels increased significantly after cardiac surgery, reaching a peak CO-Hb level 2.1 times higher than baseline ( P < .001) at a median of 17 hours after the initiation of surgery. Several factors were independently associated with higher peak CO-Hb, including age ( P < .001), preoperative respiratory disease ( P = .001), New York Heart Association Class IV ( P = .019), the number of packed RBC transfused ( P < .001), and the duration of CPB ( P = .002). Peak CO-Hb levels also significantly correlated with postoperative total bilirubin levels (Rho = 0.27, P < .001). CONCLUSIONS:CO-Hb may represent a readily obtainable and frequently measured biomarker that has a moderate association with known biomarkers of and risk factors for hemolysis in on-pump cardiac surgery patients. These findings have potential clinical implications and warrant further investigation.

Objective To assess current evidence regarding guanfacine use in hospitalized patients with delirium. Introduction Delirium is a common and important complication of critical illness. Central alpha-2 agonists are often used for symptomatic management. Guanfacine is an enteral central alpha-2 agonist approved for the treatment of attention deficit hyperactivity disorders. However, its use for delirium treatment has not been systematically assessed. Inclusion criteria All studies of guanfacine to treat patients with delirium during hospitalization. We excluded reviews, letters, commentaries, correspondence, conference abstracts, expert opinions or editorials. Methods We performed a systematic search of the literature using: MEDLINE (Ovid), Embase (Ovid), CENTRAL and SCOPUS (Elsevier) from inception until 29 February, 2024. Two independent reviewers assessed the identified citations and abstracts. Data on study and patient characteristics, as well as efficacy and safety outcomes, were extracted. Efficacy was defined by guanfacine's ability to relieve delirium and improve clinical outcomes, including intensive care unit (ICU) length of stay (LOS), hospital LOS, and mortality. Safety was assessed for hemodynamic stability or other reported side effects. Results We screened 908 articles and included two case reports, one case series, two retrospective descriptive cohorts, and one retrospective analytic cohort. Guanfacine therapy was associated with delirium attenuation and a reduction in the use of sedative agents. Median dosage was 1.5 mg daily, with a median time to delirium improvement of 3 days. However, guanfacine therapy was not associated with decreased ICU or hospital LOS. The most frequently reported adverse events were mild hypotension and bradycardia. Conclusion There is limited data on the efficacy of guanfacine for the treatment of delirium. However, given its pharmacologic properties and its available safety data, controlled investigations may be justified.

OBJECTIVES:Carboxyhemoglobin (CO-Hb) is a marker of hemolysis and inflammation, both risk factors for cardiac surgery-associated AKI (CSA-AKI). However, the association between CO-Hb and CSA-AKI remains unknown. DESIGN:A retrospective cohort study. SETTING:Tertiary university-affiliated metropolitan hospital: single center. PARTICIPANTS:Adult on-pump cardiac surgery patients from July 2014 to June 2022 (N = 1,698). INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Patients were stratified into quartiles based on CO-Hb levels at intensive care unit (ICU) admission. A progressive increased risk of CSA-AKI was observed with higher CO-Hb levels at ICU admission. On multivariable logistic regression analysis, the highest quartile (CO-Hb ≥ 1.4%) showed an independent association with the occurrence of CSA-AKI (odds ratio 1.45 compared to the lowest quartile [CO-Hb < 1.0%], 95% CI 1.023-2.071; p = 0.038). Compared to patients with CO-Hb <1.4%, patients with CO-Hb ≥ 1.4% at ICU admission had significantly higher postoperative creatinine (135 vs 116 μmol/L, p < 0.001), higher rates of postoperative RRT (6.7% vs 2.3%, p < 0.001) and AKI (p < 0.001) on univariable analysis and shorter time to event for AKI or death (p < 0.001). CONCLUSIONS:CO-Hb ≥ 1.4% at ICU admission is an independent risk factor for CSA-AKI, which is easily obtainable and available on routine arterial blood gas measurements. Thus, CO-Hb may serve as a practical and biologically logical biomarker for risk stratification and population enrichment in trials of CSA-AKI prevention.

PURPOSE:Furosemide is the most commonly used diuretic in intensive care units (ICU). We aimed to evaluate the physiological effects of adjunctive acetazolamide with furosemide on diuresis and the prevention of potential furosemide-induced metabolic alkalosis. MATERIALS AND METHODS:We performed a two-center, pilot, open-label, randomized trial. Where the treating physicians planned intravenous diuretic therapy, we randomized ICU patients to a bolus of furosemide (40 mg) plus acetazolamide (500 mg) (n = 15) or furosemide alone (40 mg) (n = 15). Urine output, additional furosemide use, acid-base parameters, and electrolytes were compared following a Bayesian framework. RESULTS:Adjunctive acetazolamide didn't increase urine output in the first six hours (mean difference: -112 ml, credible interval: [-742, 514]). However, compared with furosemide alone, it maintained a greater urine output response to furosemide over 24 h, with 100 % probability. Acetazolamide also acidified plasma (pH difference: -0.045, [-0.081, -0.008]) while alkalinizing urine (1.10, [0.04, 2.11]) at six hours, compared to furosemide alone with >95 % probability. Finally, we didn't observe severe acidosis or electrolyte disturbances over 24 h. CONCLUSIONS:Adjunctive acetazolamide may increase diuretic efficacy and counterbalance furosemide-induced metabolic alkalosis without safety concerns. Larger trials are warranted to verify these findings and assess their impacts on clinical outcomes. REGISTRATION NUMBER:ACTRN12623000624684. REGISTRATION TITLE:A pilot trial of single versus dual diuretic therapy in the intensive care unit.