Intubation of critically ill patients: A pilot study of minute-by-minute physiological changes within an Australian tertiary intensive care unit.

BACKGROUND: There are no published minute-by-minute physiological assessment data for endotracheal intubation (ETT) performed in the intensive care unit (ICU). The majority of physiological data is available from Europe and North America where etomidate is the induction agent administered most commonly. AIMS: The aim of this study was to describe the feasibility of obtaining minute-by-minute physiological and medication data surrounding ETT in an Australian tertiary ICU and to assess its associated outcomes. METHODS: We performed a single-centre feasibility observational study. We obtained minute-by-minute data on physiological variables and medications for 15 min before and 30 min after ETT. We assessed feasibility as enrolled to screened patient ratio and completeness of data collection in enrolled patients. Severe hypotension (systolic blood pressure < 65 mmHg) and severe hypoxaemia (pulse oximetry saturation < 80%) were the secondary clinical outcomes. RESULTS: We screened 43 patients and studied 30 patients. The median age was 58.5 (interquartile range: 49-70) years, and 18 (60%) were male. Near-complete (97%) physiological and medication data were obtained in all patients at all times. Overall, 15 (50%) ETTs occurred after hours (17:30-08:00) and 90% were by video laryngoscopy with a 90% first-pass success rate. Prophylactic vasopressors were used in 50% of ETTs. Fentanyl was used in all except one ETT at a median dose of 2.5 mcg/kg. Propofol (63%) or midazolam (50%) were used as adjuncts at low dose. Rocuronium was used in all but one patient. There were no episodes of severe hypotension and only one episode of short-lived severe hypoxaemia. CONCLUSION: Minute-by-minute recording of ETT-associated physiological changes in the ICU was feasible but only fully available in two-thirds of the screened patients. ETT was based on fentanyl induction, low-dose adjunctive sedation, and frequent prophylactic vasopressor therapy and was associated with no severe hypotension and a single short-lived episode of severe hypoxaemia.

Haemodynamic changes during prone versus supine position in patients with COVID-19 acute respiratory distress syndrome.

BACKGROUND: Prone positioning improves oxygenation in patients with acute respiratory distress syndrome (ARDS) secondary to COVID-19. However, its haemodynamic effects are poorly understood. OBJECTIVES: The objective of this study was to investigate the acute haemodynamic changes associated with prone position in mechanically ventilated patients with COVID-19 ARDS. The primary objective was to describe changes in cardiac index with prone position. The secondary objectives were to describe changes in mean arterial pressure, FiO2, PaO2/FiO2 ratio, and oxygen delivery (DO2) with prone position. METHODS: We performed this cohort-embedded study in an Australian intensive care unit, between September and November 2021. We included adult patients with severe COVID-19 ARDS, requiring mechanical ventilation and prone positioning for respiratory failure. We placed patients in the prone position for 16 h per session. Using pulse contour technology, we collected haemodynamic data every 5 min for 2 h in the supine position and for 2 h in the prone position consecutively. RESULTS: We studied 18 patients. Cardiac index, stroke volume index, and mean arterial pressure increased significantly in the prone position compared to supine position. The mean cardiac index was higher in the prone group than in the supine group by 0.44 L/min/m2 (95% confidence interval, 0.24 to 0.63) (P < 0.001). FiO2 requirement decreased significantly in the prone position (P < 0.001), with a significant increase in PaO2/FiO2 ratio (P < 0.001). DO2 also increased significantly in the prone position, from a median DO2 of 597 mls O2/min (interquartile range, 504 to 931) in the supine position to 743 mls O2/min (interquartile range, 604 to 1075) in the prone position (P < 0.001). CONCLUSION: Prone position increased the cardiac index, mean arterial pressure, and DO2 in invasively ventilated patients with COVID-19 ARDS. These changes may contribute to improved tissue oxygenation and improved outcomes observed in trials of prone positioning.

Sodium glucose co-transporter-2 inhibitors in intensive care unit patients with type 2 diabetes: a pilot case control study.

BACKGROUND: Sodium glucose co-transporter-2 (SGLT2) inhibitors improve long-term cardiovascular and renal outcomes in individuals with type 2 diabetes. However, the safety of SGLT2 inhibitors in ICU patients with type 2 diabetes is uncertain. We aimed to perform a pilot study to assess the relationship between empagliflozin therapy and biochemical, and clinical outcomes in such patients. METHODS: We included 18 ICU patients with type 2 diabetes receiving empagliflozin (10 mg daily) and insulin to target glucose range of 10-14 mmol/l according to our liberal glucose control protocol for patients with diabetes (treatment group). Treatment group patients were matched on age, glycated hemoglobin A1c, and ICU duration with 72 ICU patients with type 2 diabetes exposed to the same target glucose range but who did not receive empagliflozin (control group). We compared changes in electrolyte and acid-base parameters, hypoglycemia, ketoacidosis, worsening kidney function, urine culture findings, and hospital mortality between the groups. RESULTS: Median (IQR) maximum increase in sodium and chloride levels were 3 (1-10) mmol/l and 3 (2-8) mmol/l in the control group and 9 (3-12) mmol/l and 8 (3-10) mmol/l in the treatment group (P = 0.045 for sodium, P = 0.059 for chloride). We observed no differences in strong ion difference, pH or base excess. Overall, 6% developed hypoglycemia in each group. No patient in the treatment group and one patient in the control group developed ketoacidosis. Worsening kidney function occurred in 18% and 29% of treatment and control group patients, respectively (P = 0.54). Urine cultures were positive in 22% of treatment group patients and 13% of control group patients (P = 0.28). Overall, 17% of treatment group patients and 19% of control group patients died in hospital (P = 0.79). CONCLUSIONS: In our pilot study of ICU patients with type 2 diabetes, empagliflozin therapy was associated with increases in sodium and chloride levels but was not significantly associated with acid-base changes, hypoglycemia, ketoacidosis, worsening kidney function, bacteriuria, or mortality.

Mega-dose sodium ascorbate: a pilot, single-dose, physiological effect, double-blind, randomized, controlled trial.

BACKGROUND: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown. METHODS: We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score. RESULTS: We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes. CONCLUSION: In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.

Trajectory of plasma syndecan-1 and heparan sulphate during major surgery: A retrospective observational study.

BACKGROUND: Surgical trauma-induced inflammation during major surgery may disrupt endothelial integrity and affect plasma concentrations of glycocalyx constituents, such as syndecan-1 and heparan sulphate. To date, no studies have focused on their perioperative temporal changes. METHODS: As part of a trial, we obtained plasma and urine specimens sampled during the perioperative period in 72 patients undergoing major abdominal surgery. The plasma concentration of syndecan-1 and heparan sulphate was measured on five occasions, from baseline to the second postoperative day. Plasma and urinary creatinine and urinary syndecan-1 concentrations were measured before surgery and on the first postoperative morning. RESULTS: We observed three different temporal patterns of plasma syndecan-1 concentration. Group 1 'low' (64% of patients) showed only minor changes from baseline despite a median heparan sulphate increase of 67% (p < .005). Group 2 'increase' (21% of patients) showed a marked increase in median plasma syndecan-1 from 27 µg/L to 118 µg/L during the first postoperative day (p < .001) with a substantial (+670%; p < .005) increase in median plasma heparan sulphate from 279 to 2196 µg/L. Group 3 'high' (14% of patients) showed a constant elevation of plasma syndecan-1 to >100 µg/L, but low heparan sulphate levels. The plasma C-reactive protein concentration did not differ across the three groups and 90% of colon surgeries occurred in Group 1. Treatment with dexamethasone was similar across the three groups. Surgical blood loss, duration of surgery and liver resection were greatest in Group 2. CONCLUSION: Changes in syndecan-1 and heparan sulphate after surgery appear to show three different patterns, with the greatest increases in those patients with greater blood loss, more liver surgery and longer operations. These observations suggest that increases in syndecan-1 and heparan sulphate reflect the degree of surgical injury.

Glycemic control and blood gas sampling frequency during continuous glucose monitoring in the intensive care unit: A before-and-after study.

BACKGROUND: Whether subcutaneous continuous glucose monitoring (CGM) can safely replace intermittent arterial blood gas glucose analyses in intensive care unit (ICU) patients remains uncertain. We aimed to compare CGM to blood gas glucose values and assess whether CGM use reduces blood gas sampling frequency and glucose variability in ICU patients with type 2 diabetes managed with liberal glucose control. METHODS: We used the FreeStyle Libre CGM in 15 ICU patients and compared their blood glucose metrics with a pre-CGM control population of 105 ICU patients with type 2 diabetes. Both groups received insulin to target glucose range of 10-14 mmol/L. We used linear regression analysis adjusted for illness severity to assess the association of CGM use with blood gas sampling frequency and glucose variability. We used mean absolute relative difference (MARD) and Clarke error grid analysis to assess accuracy of matched CGM-blood glucose values overall, across glucose stata (<10, 10-14, >14 mmol/L), and over time (≤48, 48-96, >96 h). RESULTS: We analyzed 483 matched glucose values. Overall MARD was 11.5 (95% CI, 10.7-12.3)% with 99% of readings in Clarke zones A and B. MARD was 15.5% for glucose values <10 mmol/L, 11.1% at 10-14 mmol/L, and 11.4% >14 mmol/L. MARD was 13.8% in the first 48 h, 10.9% at 48-96 h, and 8.9% beyond 96 h. CGM use was associated with 30% reduction in blood gas sampling frequency. CGM use was not associated with glucose variability as determined by glycemic lability index or standard deviation of blood glucose. CONCLUSIONS: In our cohort of ICU patients with type 2 diabetes receiving liberal glycemic control, CGM showed acceptable accuracy and was associated with a reduction in blood gas sampling frequency without compromising glucose control. Lowest accuracy was observed at glucose values below 10 mmol/L and during the first 48 h of CGM use.

Subsegmental pulmonary embolism and anticoagulant therapy: the impact of clinical context.

BACKGROUND: Anticoagulation for subsegmental pulmonary embolism (SSPE) is controversial. AIM: To assess the impact of clinical context on anticoagulation and outcomes of SSPE. METHODS: We electronically searched computed tomography pulmonary angiogram reports to identify SSPE. We extracted demographic, risk factor, investigations and outcome data from the electronic medical record. We stratified patients according to anticoagulation and no anticoagulation. RESULTS: From 1 January 2017 to 31 December 2019, we identified 166 patients with SSPE in 5827 pulmonary angiogram reports. Of these, 123 (74%) received anticoagulation. Compared with non-anticoagulated patients, such patients had a different clinical context: higher rates of previous venous thromboembolism (11% vs 0%; P = 0.019), more recent surgery (26% vs 9%; P = 0.015), more elevated serum D-dimer (22% vs 5%; P = 0.004), more lung parenchymal abnormalities (76% vs 61%; P = 0.037) and were almost twice as likely to require inpatient care (76% vs 42%; P < 0.001). Such patients also had twice the all-cause mortality at 1 year (32% vs 16%). CONCLUSIONS: SSPE is diagnosed in almost 3% of pulmonary angiograms and is associated with high mortality, regardless of anticoagulation, due to coexistent disease processes rather than SSPE. Anticoagulation appears dominant but markedly affected by the clinical context of risk factors, alternative indications and illness severity. Thus, the controversy is partly artificial because anticoagulation after SSPE is clinically contextual with SSPE as only one of several factors.

Evaluating an inquiry-based learning program.

Inquiry-based learning (IBL) is a promising educational framework that is understudied in graduate medical education. To determine participant satisfaction and engagement with phases of an IBL postgraduate education program, a mixed-methods study collected data via survey statements and open-ended responses. The authors included participants attending an intensive care medicine (ICM) IBL program from May to November 2020. Quantitative outcomes included participants' satisfaction with the IBL format and impact of engagement with IBL on the learning experience. Qualitative outcomes explored determinants of engagement with IBL phases and the impact on the learning experience. Of 378 attendees, 167 submitted survey responses (44.2%). There was strong agreement relating to overall satisfaction (93.4%). Responses indicated engagement with "orientation" (94.6%), "conceptualization" (97.3%), "discussion" (91.1%), and "conclusion" (91.0%) but limited engagement with the "investigation" phase (48.1%). Greater engagement with IBL phases had positive impacts, with repeat attenders having clearer learning objectives (79.1% vs. 56.6%, P < 0.05) and enhanced learning through collaborative discussion (65.9% vs. 48.7%, P < 0.05). Qualitative analysis showed that ICM learners value active learning principles, clear objectives, and a safe environment to expand their "knowledge base." Sessions facilitated "clinically relevant learning," with application of theoretical knowledge. Learners transformed and "reframed their understanding," using the input of others' experiences. ICM learners were highly satisfied with the IBL format and reported valuable learning. Participants engaged strongly with all IBL phases except the investigation phase during the sessions. IBL facilitated learners' active construction of meaning, facilitating a constructivist approach to learning.NEW & NOTEWORTHY An inquiry-based learning (IBL) program was launched as part of a novel binational intensive care medicine education program. Postgraduate intensive care medicine practitioners participated in this education intervention, where facilitated group discussions explored core intensive care medicine concepts. Survey responses indicated overall satisfaction, engagement with the IBL format, and a constructivist approach to learning. This study provided new insights into the benefits and challenges of an IBL program in the context of practicing clinicians.

The relationship between Nephrocheck® test values, outcomes, and urinary output in critically ill patients at risk of acute kidney injury.

BACKGROUND: Nephrocheck® was approved for acute kidney injury (AKI) risk assessment in critically illness. However, new studies suggest that urinary concentration affects Nephrocheck® and previous studies did not provide data on urinary output (UO) at the time of measurement. METHODS: We performed a prospective cohort study of the Nephrocheck® in intensive care unit patients fulfilling standard inclusion criteria. The primary outcome was Stage 2 or 3 AKI defined by both UO and creatinine Kidney Disease Improving Global Outcomes (KDIGO) criteria in the subsequent 12 h. The secondary outcome was the relationship of UO with Nephrocheck® measurement. RESULTS: Among 98 patients, the primary outcome occurred in 53 (54.1%) overall, but in 23 (23.5%) by creatinine criteria alone. The median (interquartile range) Nephrocheck® in patients with subsequent Stage 2 or 3 AKI was greater than in Stage 1 or no-AKI patients (0.97 [0.48-1.99] vs. 0.46 [0.22-1.17]; p = .005). However, its area under the receiver characteristic curve was 0.66 (95% confidence interval [CI], 0.56-0.77). Moreover, Nephrocheck® was significantly and inversely correlated with UO (ρ = -.46, p < .001) at the time of measurement and, on a multivariable logistic regression, Nephrocheck® was not associated with subsequent Stage 2 or 3 AKI (OR 1.06 [95% CI, 0.74-1.53], p = .73). In contrast, the UO had an OR of 0.98 for each ml/h increase (95% CI, 0.97-1.00, p = .007). CONCLUSION: Nephrocheck®'s predictive performance was limited and its value was inversely correlated with UO. Nephrocheck® had no independent relationship with outcome once UO at measurement was considered.

The Effects of Targeted Changes in Systemic Blood Flow and Mean Arterial Pressure on Urine Oximetry During Cardiopulmonary Bypass.

OBJECTIVES: Poor medullary oxygenation is implicated in the evolution of acute kidney injury. The authors sought to determine if increasing systemic flow and mean arterial pressure could improve urine oxygen tension (PuO2) measured in the bladder, a surrogate of kidney medullary oxygenation, in patients undergoing on-pump cardiac surgery. DESIGN: Randomized crossover study. SETTING: University-affiliated hospital. PARTICIPANTS: Twenty adult patients undergoing cardiopulmonary bypass (CPB) with expected cross-clamp time of >60 minutes and estimated glomerular filtration rate of >30 mL/min/1.73m2. INTERVENTIONS: Sequential 20-minute periods of 2 interventions: Intervention H ("High") or Intervention N ("Normal"). The order of interventions was determined by randomization. Intervention H: targeted CPB flow 3.0 L/min/m2 and mean arterial pressure (MAP) 80 mmHg. Intervention N: targeted CPB flow 2.4 L/min/m2 and MAP 65 mmHg. MEASUREMENTS AND MAIN RESULTS: PuO2 was measured by an oxygen sensor introduced into the bladder via a urinary catheter. Clear separation was achieved in CPB flow and MAP between intervention periods (p < 0.001 for group-time interaction). PuO2 during Intervention H was higher than during Intervention N (p < 0.001 for group-time interaction). After 17 minutes, PuO2 was statistically higher in Intervention H at each time point. There were no differences in markers of hemolysis between interventions. CONCLUSIONS: PuO2 was higher when systemic flow and MAP were increased during CPB. These findings suggest that PuO2 is responsive to changes in hemodynamics and that higher flow and pressure may improve medullary oxygenation.

The hemodynamic effects of warm versus room-temperature crystalloid fluid bolus therapy in post-cardiac surgery patients.

INTRODUCTION: The contribution of fluid temperature to the effect of crystalloid fluid bolus therapy (FBT) in post-cardiac surgery patients is unknown. We evaluated the hemodynamic effects of FBT with fluid warmed to 40°C (warm FBT) versus room-temperature fluid. METHODS: In this single centre prospective before-and-after study, we evaluated the effects of 500 ml of warm versus room-temperature compound sodium lactate administered over <30 minutes, in 50 cardiac surgery patients admitted to ICU. We recorded hemodynamics continuous before and for 30 minutes after the first FBT. We defined CI responsiveness (CI-R) as an CI increase >15% of baseline immediately after FBT and effect dissipation if the CI returned to <5% of baseline and MAP responsiveness as >10% increase and dissipation as return to <3 mmHg of baseline. RESULTS: Hypotension (56%) and low CI (40%) typically triggered FBT. Temperature decreased >0.3°C in 13 (52%) patients after room-temperature FBT versus 0 (0%) after warm FBT (p < 0.01). CI and MAP responsiveness was similar (16 [64%] versus 11 [44%], p = 0.15 and 15 [60%] versus 17 [68%], p = 0.77, respectively). Among CI responders, CI increased more with room-temperature FBT (+0.6 [IQR, 0.5-1.1] versus +0.5 [IQR, 0.4-0.6] L/min/m2, p = 0.01). However, dissipation was more common after room-temperature versus warm FBT (9/16 [56%] versus 1/11 [9%], p = 0.02). CONCLUSION: In postoperative cardiac surgery patients, warm FBT preserved core temperature and induced smaller but more sustained CI increases among responders. Fluid temperature appears to impact both core temperature and the duration of CI response.

Immediate Higher-Dose Prothrombin Complex Concentrate Without Fresh Frozen Plasma or Fibrinogen Concentrate for Significant Coagulopathic Cardiac Surgical Field Bleeding.

BACKGROUND: Treatment of significant coagulopathic cardiac surgical field bleeding with immediate higher-dose prothrombin complex concentrate (PCC) without fresh frozen plasma (FFP) or fibrinogen concentrate is unexplored. AIMS: To study characteristics, chest drainage, and clinical outcomes of patients with significant coagulopathic surgical field bleeding treated with immediate higher-dose (defined at >15 IU/kg based on factor IX) PCC without FFP or fibrinogen concentrate. METHODS: We screened sequential cardiac surgery patients. We reviewed electronic blood bank data, Australian Society of Cardiothoracic Surgery database information and anaesthetic, intensive care unit (ICU), ward and radiological charts and electronic data. We identified patients deemed by the operating surgeon to require treatment for significant coagulopathic surgical field bleeding who underwent immediate higher-dose PCC without FFP or fibrinogen concentrate. RESULTS: Among 168 patients, we identified 30 who underwent immediate higher-dose PCC without FFP or fibrinogen concentrate. Median age was 68 years, 23 were male, 17 underwent coronary artery bypass surgery and three underwent complex surgery (David procedure, redo mitral valve surgery, and redo thoraco-abdominal aneurysm repair). Median dose of PCC was 2,500 IU. In addition, 27% underwent platelets and one underwent cryoprecipitate. Chest drainage at 24 hours was 505 ml. Survival to hospital discharge was 100%. There were no cases of pulmonary embolism, stroke, or other thrombotic events. Stage 1 AKI occurred in one patient. CONCLUSION: In a pilot cohort of patients with significant coagulopathic surgical field bleeding, immediate higher-dose PCC without FFP or fibrinogen concentrate was feasible and had an acceptable efficacy and safety profile, which justifies future controlled studies.

Time to Initiation of Renal Replacement Therapy Among Critically Ill Patients With Acute Kidney Injury: A Current Systematic Review and Meta-Analysis.

OBJECTIVES: The optimal time to initiate renal replacement therapy in critically ill patients with acute kidney injury is controversial. We investigated the effect of such earlier versus later initiation of renal replacement therapy on the primary outcome of 28-day mortality and other patient-centered secondary outcomes. DESIGN: We searched MEDLINE (via PubMed), EMBASE, and Cochrane databases to July 17, 2020, and included randomized controlled trials comparing earlier versus later renal replacement therapy. SETTING: Multiple centers involved in eight trials. PATIENTS: Total of 4,588 trial participants. INTERVENTION: Two independents investigators screened and extracted data using a predefined form. We selected randomized controlled trials in critically ill adult patients with acute kidney injury and compared of earlier versus later initiation of renal replacement therapy regardless of modality. MEASUREMENTS AND MAIN RESULTS: Overall, 28-day mortality was similar between earlier and later renal replacement therapy initiation (38.43% vs 38.06%, respectively; risk ratio, 1.01; [95% CI, 0.94-1.09]; I2 = 0%). Earlier renal replacement therapy, however, shortened hospital length of stay (mean difference, -2.14 d; [95% CI, -4.13 to -0.14]) and ICU length of stay (mean difference, -1.18 d; [95% CI, -1.95 to -0.42]). In contrast, later renal replacement therapy decreased the use of renal replacement therapy (relative risk, 0.69; [95% CI, 0.58-0.82]) and lowered the risk of catheter-related blood stream infection (risk ratio, 0.50, [95% CI, 0.29-0.86). Among survivors, renal replacement therapy dependence at day 28 was similar between earlier and later renal replacement therapy initiation (risk ratio, 0.98; [95% CI, 0.66-1.40]). CONCLUSIONS: Earlier or later initiation of renal replacement therapy did not affect mortality. However, earlier renal replacement therapy was associated with significantly shorter ICU and hospital length of stay, whereas later renal replacement therapy was associated with decreased use of renal replacement therapy and decreased risk of catheter-related blood stream infection. These findings can be used to guide the management of critically ill patients with acute kidney injury.

The Effect of Early Sedation With Dexmedetomidine on Body Temperature in Critically Ill Patients.

OBJECTIVES: Previous case series reported an association between dexmedetomidine use and hyperthermia. Temperature data have not been systematically reported in previous randomized controlled trials evaluating dexmedetomidine. A causal link between dexmedetomidine administration and elevated temperature has not been demonstrated. DESIGN: Post hoc analysis. SETTING: Four ICUs in Australia and New Zealand. PATIENTS: About 703 mechanically ventilated ICU patients. INTERVENTIONS: Early sedation with dexmedetomidine versus usual care. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mean daily body temperature. Secondary outcomes included the proportions of patients with body temperatures greater than or equal to 38.3°C and greater than or equal to 39°C, respectively. Outcomes were recorded for 5 days postrandomization in the ICU. The mean daily temperature was not different between the dexmedetomidine (n = 351) and usual care (n = 352) groups (36.84°C ± sd vs 36.78°C ± sd; p = 0.16). Over the first 5 ICU days, more dexmedetomidine group (vs usual care) patients had a temperature greater than or equal to 38.3°C (43.3% vs 32.7%, p = 0.004; absolute difference 10.6 percentage points) and greater than or equal to 39.0°C (19.4% vs 12.5%, p = 0.013; absolute difference 6.9 percentage points). Results were similar after adjusting for diagnosis, admitting temperature, age, weight, study site, sepsis occurrence, and the time from dexmedetomidine initiation to first hyperthermia recorded. There was a significant dose response relationship with temperature increasing by 0.30°C ±0.08 for every additional 1 µg/kg/hr of dexmedetomidine received p < 0.0002. CONCLUSIONS: Our study suggests potentially important elevations in body temperature are associated with early dexmedetomidine sedation, in adults who are mechanically ventilated in the ICU.

Reversal of the Pathophysiological Responses to Gram-Negative Sepsis by Megadose Vitamin C.

OBJECTIVES: Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis. DESIGN: Interventional study. SETTING: Research Institute. SUBJECTS: Adult Merino ewes. INTERVENTIONS: Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (~80 mm Hg). MEASUREMENTS AND MAIN RESULTS: Sepsis-induced fever (41.4 ± 0.2°C; mean ± se), tachycardia (141 ± 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 ± 1 to 67 ± 2 mm Hg), arterial Po2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue Po2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 ± 0.3°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary Po2 (48 ± 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 ± 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours. CONCLUSIONS: IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients.

Early net ultrafiltration rate and mortality in critically ill patients receiving continuous renal replacement therapy.

BACKGROUND: In patients treated with continuous renal replacement therapy (CRRT), early net ultrafiltration (NUF) rates may be associated with differential outcomes. We tested whether higher early NUF rates are associated with increased mortality in CRRT patients. METHODS: We performed a retrospective, observational study of all patients treated with CRRT within 14 days of intensive care unit admission. We defined the early (first 48 h) NUF rate as the volume of fluid removed per hour adjusted for patient body weight and analysed as a categorical variable (>1.75, 1.01-1.75 and <1.01 mL/kg/h). The primary outcome was 28-day mortality. To deal with competing risk, we also compared different time epochs. RESULTS: We studied 347 patients {median age 64 [interquartile range (IQR) 53-71] years and Acute Physiology and Chronic Health Evaluation III score 73 [IQR 54-90]}. Compared with NUF rates <1.01 mL/kg/h, NUF rates >1.75 mL/kg/h were associated with greater mortality rates in each epoch: Days 0-5, adjusted hazard ratio (aHR) 1.27 [95% confidence interval (CI) 1.21-1.33]; Days 6-10, aHR 1.62 (95% CI 1.55-1.68); Days 11-15, aHR 1.87 (95% CI 1.79-1.94); Days 16-26, aHR 1.92 (95% CI 1.84-2.01) and Days 27-28, aHR 4.18 (95% CI 3.98-4.40). For every 0.5 mL/kg/h NUF rate increase, mortality similarly increased during these epochs. CONCLUSION: Compared with early NUF rates <1.01 mL/kg/h, NUF rates >1.75 mL/kg/h are associated with increased mortality. These observations provide the rationale for clinical trials to confirm or refute these findings.

A Randomized, Multicenter, Open-Label, Blinded End Point, Phase 2, Feasibility, Efficacy, and Safety Trial of Preoperative Microvascular Protection in Patients Undergoing Major Abdominal Surgery.

BACKGROUND: The endothelial glycocalyx, a carbohydrate-rich layer coating all endothelial surfaces, plays a fundamental role in the function of microcirculation. The primary aim of this study was to evaluate the feasibility of using dexamethasone and albumin to protect the endothelial glycocalyx in patients undergoing abdominal surgery. Secondary and exploratory outcomes included efficacy and safety. METHODS: We conducted a multicenter, open-label, blinded end point, phase 2, randomized trial. Patients undergoing colorectal, pancreas, or liver surgery were recruited and randomized to receive either intravenous dexamethasone (16 mg) and 20% albumin (100 mL) at induction of anesthesia, then 200 mL of 20% albumin with each subsequent 1000 mL of crystalloid administered (dexamethasone and albumin [Dex-Alb] group), or crystalloid fluid only with no dexamethasone (control group). Feasibility end points included patient recruitment and retention, consent rate, and successful study drug administration. The primary efficacy end point was the measurement of plasma syndecan-1 level on postoperative day (POD) 1, and secondary end points were heparan sulfate levels and inflammatory markers measured at 4 perioperative timepoints. Safety end points included errors in administration of the intervention, hyperglycemia, occurrence of postoperative complications, and patient retention. RESULTS: Seventy-two patients were randomized. All feasibility end points were achievable. There were no statistically significant differences observed in median (interquartile range) syndecan-1 levels on POD 1 (39 ng·mL-1 [20-97] in the Dex-Alb group versus 41 ng·mL-1 [19-84] in the control group; difference in medians -2.1, 95% confidence interval [CI], -13 to 8.6; P = .69). The Dex-Alb group had lower POD 1 heparan sulfate levels (319 ng·mL-1 [161-717] in the Dex-Alb group versus 1422 [670-2430] ng·mL-1 in the control group; difference in medians -1085, 95% CI, -1779 to -391) and C-reactive protein (CRP) levels on POD 1 (48 [29-77] mg·L-1 in the Dex-Alb group versus 85 mg·L-1 [49-133] in the control group; difference in medians -48, 95% CI, -75 to -21). Fewer patients had one or more postoperative complication in the Dex-Alb group than in the control group (6 [17%] vs 18 patients [50%]; odds ratio = 0.2, 95% CI, 0.06-0.6). CONCLUSIONS: Intravenous dexamethasone and albumin administration was feasible but did not reduce syndecan-1 on POD 1 in patients undergoing abdominal surgery. Given the clinically important CIs observed between the groups for heparan sulfate, CRP, and postoperative complications, a larger trial assessing the associations between dexamethasone and albumin administration and these outcomes is warranted.

Efficacy and Safety of Parenteral High-Dose Vitamin C Therapy in Pediatric Patients: A Scoping Review.

OBJECTIVES: Recently, several adult trials have investigated the potential benefit of high-dose vitamin C therapy in critically ill patients. In pediatric patients, little is known on the efficacy, safety, and risk of high-dose vitamin C therapy. We aimed to review the efficacy and potential harm associated with high-dose vitamin C treatment. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Library, and National Institute of Health Clinical Trials Register. STUDY SELECTION: We included studies in neonatal and pediatric patients who received IV or intra-arterial high-dose vitamin C (ascorbic acid) defined as greater than or equal to 75 mg/kg/d. DATA EXTRACTION: Two independent investigators screened articles and extracted data. DATA SYNTHESIS: We found 1,364 articles, assessed 193 full texts for eligibility, and identified 12 eligible studies. These studies included 855 patients, with 194 receiving high-dose vitamin C. The age of patients who received high-dose vitamin C ranged from 2 hours after delivery to 8.4 years (median 2.4 yr), and the vitamin C dose ranged from 100 to 1,500 mg/kg/d (median 260.5 mg/kg/d). Four studies were double-blind randomized controlled trials, and no clinical efficacy outcome was reported in favor of or against vitamin C. Furthermore, no adverse event or signal of harm was reported with high-dose vitamin C. CONCLUSIONS: In 12 studies with 194 children treated with parenteral high-dose vitamin C, there was no evidence of clinical efficacy or inferior clinical outcomes in double-blind randomized controlled trials, and no reported harmful effects. These findings justify further investigations of this treatment in children.

Extracorporeal Ammonia Clearance for Hyperammonemia in Critically Ill Patients: A Scoping Review.

INTRODUCTION: Hyperammonemia is a life-threatening condition. However, clearance of ammonia via extracorporeal treatment has not been systematically evaluated. METHODS: We searched EMBASE and MEDLINE databases. We included all publications reporting ammonia clearance by extracorporeal treatment in adult and pediatric patients with clearance estimated by direct dialysate ammonia measurement or calculated by formula. Two reviewers screened and extracted data independently. RESULTS: We found 1,770 articles with 312 appropriate for assessment and 28 studies meeting eligibility criteria. Most of the studies were case reports. Hyperammonemia was typically secondary to inborn errors of metabolisms in children and to liver failure in adult patients. Ammonia clearance was most commonly reported during continuous renal replacement therapy (CRRT) and appeared to vary markedly from <5 mL/min/m2 to >250 mL/min/m2. When measured during intermittent hemodialysis (IHD), clearance was highest and correlated with blood flow rate (R2 = 0.853; p < 0.001). When measured during CRRT, ammonia clearance could be substantial and correlated with effluent flow rate (EFR; R2 = 0.584; p < 0.001). Neither correlated with ammonia reduction. Peritoneal dialysis (PD) achieved minimal clearance, and other extracorporeal techniques were rarely studied. CONCLUSIONS: Extracorporeal ammonia clearance varies widely with sometimes implausible values. Treatment modality, blood flow, and EFR, however, appear to affect such clearance with IHD achieving the highest values, PD achieving minimal values, and CRRT achieving substantial values especially at high EFRs. The role of other techniques remains unclear. These findings can help inform practice and future studies.

NephroCheck® Quality Test.

BACKGROUND: The acute kidney injury (AKI) risk score helps detect moderate and severe AKI in the next 12-24 h. However, inappropriate urine collection may impact its results. AIM: The aim of this study was to evaluate the stability of NephroCheck® after urine storage at different temperatures. METHODS: The urine sample was centrifuged and split into 3 tubes. One was tested as soon as possible by the laboratory. The other 2 samples were frozen at -20 and -80°C, and the NephroCheck® test was performed 8 weeks later. RESULTS: The mean values of the AKI risk score were 1.19 ± 0.93, 1.15 ± 1.14, and 1.20 ± 1.11 (ng/mL)2/1,000 for fresh urine, -20, and -80°C, respectively (p = 0.70). Spearman's rank correlation for -20 and -80°C versus immediate processing was strong with a rho of 0.82 and 0.98, respectively. CONCLUSION: The AKI risk score was relatively stable. Urine could be collected without dry ice or liquid nitrogen and kept for up to 8 weeks with either -20 or -80°C freezing with stable NephroCheck® results.