Effects of Energy Delivery Guided by Indirect Calorimetry in Critically Ill Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: The utility of using indirect calorimetry (IC) to estimate energy needs and methods for its application to this purpose remain unclear. This systematic review investigated whether using IC to estimate energy expenditure in critically ill patients is more meaningful for improving survival than other estimation methods. METHODS: Comprehensive searches were conducted in MEDLINE using PubMed, Cochrane Central Register of Controlled Trials, and Igaku-Chuo-Zasshi up to March 2023. RESULTS: Nine RCTs involving 1178 patients were included in the meta-analysis. The evidence obtained suggested that energy delivery by IC improved short-term mortality (risk ratio, 0.86; 95% confidence interval [CI], 0.70 to 1.06). However, the use of IC did not appear to affect the length of ICU stay (mean difference [MD], 0.86; 95% CI, -0.98 to 2.70) or the duration of mechanical ventilation (MD, 0.66; 95% CI, -0.39 to 1.72). Post hoc analyses using short-term mortality as the outcome found no significant difference by target calories in resting energy expenditure, whereas more frequent IC estimates were associated with lower short-term mortality and were more effective in mechanically ventilated patients. CONCLUSIONS: This updated meta-analysis revealed that the use of IC may improve short-term mortality in patients with critical illness and did not increase adverse events.

Characteristics and outcomes of out-of-hospital cardiac arrest in a hilly area: Utstein Registry data from the Nagasaki Medical Region, Japan.

Aim: To analyze characteristics and investigate prognostic indicators of out-of-hospital cardiac arrest (OHCA) in a hilly area in Japan. Methods: A retrospective population-based study was conducted using the Utstein Registry for 4280 OHCA patients in the Nagasaki Medical Region (NMR) registered over the 10-year period from 2011 to 2020. The main outcome measure was a favorable cerebral performance category (CPC 1-2). Sites at which OHCA occurred were classified into "sloped places (SPs)" (not easily accessible by emergency medical services [EMS] personnel due to slopes) and "accessible places (APs)" (EMS personnel could park an ambulance close to the site). The characteristics and prognosis based on CPC were compared between SPs and APs, and multivariable analysis was performed. Results: No significant improvement in prognosis occurred in the NMR from 2011 to 2020. Prognosis in SPs was significantly worse than that in APs. However, multivariable analysis did not identify SP as a prognostic indicator. The following factors were associated with survival and CPC 1-2: age group, witness status, first documented rhythm, bystander-initiated cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) use, use of mechanical CPR (m-CPR) device or esophageal obturator airway (EOA), and year. Both m-CPR and EOA use were associated with a poor prognosis. Conclusion: In a hilly area, OHCA patients in SPs had a worse prognosis than those in APs, but SPs was not significantly associated with prognosis by multivariable analysis. Interventions to increase bystander-initiated CPR and AED use could potentially improve outcomes of OHCA in the NMR.

Balance of the prooxidant and antioxidant system is associated with mortality in critically ill patients.

It is well known that oxidative stress causes certain diseases and organ damage. However, roles of oxidative stress in the acute phase of critical patients remain to be elucidated. This study aimed to investigate the balance of oxidative and antioxidative system and to clarify the association between oxidative stress and mortality in critically ill patients. This cohort study enrolled 247 patients transported to our emergency department by ambulance. Blood was drawn on hospital arrival, and serum derivatives of reactive oxidant metabolites (dROMs, oxidative index) and biological antioxidant potential (BAP, antioxidative index) were measured. Modified ratio (MR) is also calculated as BAP/dROMs/7.51. There were 197 survivors and 50 non-survivors. In the non-survivors, dROMs were significantly lower (274 vs 311, p<0.01), BAP was significantly higher (2,853 vs 2,138, p<0.01), and MR was significantly higher (1.51 vs 0.92, p<0.01) compared to those in the survivors. The AUC of MR was similar to that for the APACHE II score. Contrary to our expectations, higher BAP and lower dROMs were observed on admission in non-survivors. This may suggest that the antioxidative system is more dominant in the acute phase of severe insults and that the balance toward a higher antioxidative system is associated with mortality.

Relationship Between Urinary 8-hydroxydeoxyguanine (8-OHdG) Levels and Clinicopathological Findings in Hepatobiliary Malignancies.

BACKGROUND/AIM: Oxidative stress is defined as an imbalance between the pro-oxidant and antioxidant potential of cells leading to intracellular DNA damage. To clarify the oxidative stress response as a tumor marker, we investigated measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in hepatobiliary diseases. MATERIALS AND METHODS: Relationships between urinary 8-OHdG levels and clinicopathological factors were analyzed in 101 patients, including 84 with hepatobiliary malignancies, and 18 healthy volunteers. Co-existing biliary inflammation was detected in 8 patients. RESULTS: Urinary 8-OHdG levels did not correlate with any clinical or liver functional parameters. The existence of inflammation and any tumor-related factor did not correlate with urinary 8-OHdG levels either. Urinary 8-OHdG levels were significantly higher in patients with benign and malignant diseases than in healthy volunteers (p<0.05), but not significantly different between benign and malignant diseases. Among patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma, urinary 8-OHdG levels tended to be higher in patients with lymph node metastasis-positive than in those with lymph node-negative disease (p=0.057). CONCLUSION: The clinical significance of oxidative DNA damage and increases in its urinary metabolites in patients with hepatobiliary malignancies or inflammatory diseases remain unknown. Further studies are necessary to clarify the relationship between node metastasis and oxidative stress as a prognostic marker.

Infectious episodes lead to the oxidative stress response after lung transplantation.

BACKGROUND: Reactive oxygen species function as key metabolites that can impair biological processes. In lung transplantation, severe oxidative stress is expected when ischemia/reperfusion injury, acute allograft rejection, and various infections occur. CASE REPORT: Two clinical cases in which serial measurements of the oxidative stress response (levels of diacron-reactive oxygen metabolites) were taken during hospitalization using a Free Radical Elective Evaluator are reported. In the first case, a 30-year-old man underwent right single lung transplantation for juvenile pulmonary emphysema. Immunosuppression was maintained using tacrolimus, mycophenolate mofetil, and steroid. The oxidative stress response fluctuated significantly (p<0.01) during the infections caused by bronchial stenosis compared to the stable condition. No acute rejection was seen during hospitalization. In the second case, a 44-year-old woman underwent right single lung transplantation for lymphangioleiomyomatosis. Immunosuppression was maintained by the same regimen as in case 1. The patient's postoperative course was uneventful, and there was no allograft rejection or infection. The oxidative stress response remained at the non-stress level. CONCLUSIONS: The oxidative stress response was measured by the levels of diacron-reactive oxygen metabolites in lung transplantation. High oxidative stress responses were seen during exposure to infections. This might become a non-invasive marker of complications after transplantation.

Portable system for monitoring of regional cerebral oxygen saturation during prehospital cardiopulmonary resuscitation: a pilot study.

Aim: We aimed to create a system for monitoring of regional cerebral oxygen saturation (rSO 2) in patients with prehospital cardiopulmonary arrest and clarify the changes in rSO 2 during cardiopulmonary resuscitation. Methods: We measured rSO 2 in cardiopulmonary arrest patients who were transferred by the emergency response vehicle of Nagasaki University Hospital. We developed a portable rSO 2 monitor (HAND ai TOS), which is small enough to carry during prehospital treatment. The sensor is attached to the forehead of the patient and monitors rSO 2 continuously during treatment and transfer. Results: No difficulties were experienced in monitoring rSO 2 during patient treatment and transfer. Median time (interquartile range) from the emergency medical service call to emergency response vehicle arrival was 15.0 min (11.0-19.5 min). Median rSO 2 on emergency response vehicle arrival at the scene was 46.3% (44.0-48.2%) (n = 9; median age, 74.0 years; four men, five women). Median rSO 2 showed significant increase within 5 min after return of spontaneous circulation (n = 6, 46.6% versus 58.7%, P < 0.05). There was no significant increase in rSO 2 during prehospital cardiopulmonary resuscitation until return of spontaneous circulation was established. Conclusions: We developed an rSO 2 monitoring system for use during prehospital cardiopulmonary resuscitation. The monitoring system showed a significant increase in rSO 2 after return of spontaneous circulation, whereas there was no significant increase in rSO 2 during cardiopulmonary resuscitation after intubation but before return of spontaneous circulation.

Difference in pulmonary permeability between indirect and direct acute respiratory distress syndrome assessed by the transpulmonary thermodilution technique: a prospective, observational, multi-institutional study.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by the increased pulmonary permeability secondary to diffuse alveolar inflammation and injuries of several origins. Especially, the distinction between a direct (pulmonary injury) and an indirect (extrapulmonary injury) lung injury etiology is gaining more attention as a means of better comprehending the pathophysiology of ARDS. However, there are few reports regarding the quantitative methods distinguishing the degree of pulmonary permeability between ARDS patients due to pulmonary injury and extrapulmonary injury. METHODS: A prospective, observational, multi-institutional study was performed in 23 intensive care units of academic tertiary referral hospitals throughout Japan. During a 2-year period, all consecutive ARDS-diagnosed adult patients requiring mechanical ventilation were collected in which three experts retrospectively determined the pathophysiological mechanisms leading to ARDS. Patients were classified into two groups: patients with ARDS triggered by extrapulmonary injury (ARDSexp) and those caused by pulmonary injury (ARDSp). The degree of pulmonary permeability using the transpulmonary thermodilution technique was obtained during the first three intensive care unit (ICU) days. RESULTS: In total, 173 patients were assessed including 56 ARDSexp patients and 117 ARDSp patients. Although the Sequential Organ Failure Assessment (SOFA) score was significantly higher in the ARDSexp group than in the ARDSp group, measurements of the pulmonary vascular permeability index (PVPI) were significantly elevated in the ARDSp group on all days: at day 0 (2.9 ± 1.3 of ARDSexp vs. 3.3 ± 1.3 of ARDSp, p = .008), at day 1 (2.8 ± 1.5 of ARDSexp vs. 3.2 ± 1.2 of ARDSp, p = .01), at day 2 (2.4 ± 1.0 of ARDSexp vs. 2.9 ± 1.3 of ARDSp, p = .01). There were no significant differences in mortality at 28 days, mechanical ventilation days, and hospital length of stay between the two groups. CONCLUSIONS: The results of this study suggest the existence of several differences in the increased degree of pulmonary permeability between patients with ARDSexp and ARDSp. TRIAL REGISTRATION: This report is a sub-group analysis of the study registered with UMIN-CTR (IDUMIN000003627).

Global end-diastolic volume is an important contributor to increased extravascular lung water in patients with acute lung injury and acuterespiratory distress syndrome: a multicenter observational study.

BACKGROUND: Extravascular lung water (EVLW), as measured by the thermodilution method, reflects the extent of pulmonary edema. Currently, there are no clinically effective treatments for preventing increases in pulmonary vascular permeability, a hallmark of lung pathophysiology, in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In this study, we examined the contributions of hemodynamic and osmolarity factors, for which appropriate interventions are expected in critical care, to EVLW in patients with ALI/ARDS. METHODS: We performed a subgroup analysis of a multicenter observational study of patients with acute pulmonary edema. Overall, 207 patients with ALI/ARDS were enrolled in the study. Multivariate regression analysis was used to evaluate the associations of hemodynamic and serum osmolarity parameters with the EVLW index (EVLWI; calculated as EVLW/Ideal body weight). We analyzed factors measured on the day of enrollment (day 0), and on days 1 and 2 after enrollment. RESULTS: Multivariate regression analysis showed that global end-diastolic volume index (GEDVI) was significantly associated with EVLWI measured on days 0, 1, and 2 (P = 0.002, P < 0.001, and P = 0.003, respectively), whereas other factors were not significantly associated with EVLWI measured on all 3 days. CONCLUSIONS: Among several hemodynamic and serum osmolarity factors that could be targets for appropriate intervention, GEDVI appears to be a key contributor to EVLWI in patients with ALI/ARDS. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000003627.

Early-phase changes of extravascular lung water index as a prognostic indicator in acute respiratory distress syndrome patients.

BACKGROUND: The features of early-phase acute respiratory distress syndrome (ARDS) are leakage of fluid into the extravascular space and impairment of its reabsorption, resulting in extravascular lung water (EVLW) accumulation. The current study aimed to identify how the initial EVLW values and their change were associated with mortality. METHODS: This was a post hoc analysis of the PiCCO Pulmonary Edema Study, a multicenter prospective cohort study that included 23 institutions. Single-indicator transpulmonary thermodilution-derived EVLW index (EVLWi) and conventional prognostic factors were prospectively collected over 48 h after enrollment. Associations between 28-day mortality and each variable including initial (on day 0), mean, maximum, and Δ (subtracting day 2 from day 0) EVLWi were evaluated. RESULTS: We evaluated 192 ARDS patients (median age, 69 years (quartile, 24 years); Sequential Organ Failure Assessment (SOFA) score on admission, 10 (5); all-cause 28-day mortality, 31%). Although no significant differences were found in initial, mean, or maximum EVLWi, Δ-EVLWi was significantly higher (i.e., more reduction in EVLWi) in survivors than in non-survivors (3.0 vs. -0.3 mL/kg, p = 0.006). Age, maximum, and Δ-SOFA scores and Δ-EVLW were the independent predictors for survival according to the Cox proportional hazard model. Patients with Δ-EVLWi > 2.8 had a significantly higher incidence of survival than those with Δ-EVLWi ≤ 2.8 (log-rank test, χ (2) = 7.08, p = 0.008). CONCLUSIONS: Decrease in EVLWi during the first 48 h of ARDS may be associated with 28-day survival. Serial EVLWi measurements may be useful for understanding the pathophysiologic conditions in ARDS patients. A large multination confirmative trial is required.

Effect of a selective neutrophil elastase inhibitor on mortality and ventilator-free days in patients with increased extravascular lung water: a post hoc analysis of the PiCCO Pulmonary Edema Study.

BACKGROUND: Neutrophil elastase plays an important role in the development and progression of acute respiratory distress syndrome (ARDS). Although the selective elastase inhibitor, sivelestat, is widely used in Japan for treating ARDS patients, its effectiveness remains controversial. The aim of the current study was to investigate the effects of sivelestat in ARDS patients with evidence of increased extravascular lung water by re-analyzing a large multicenter study database. METHODS: A post hoc analysis of the PiCCO Pulmonary Edema Study was conducted. This multicenter prospective cohort study included 23 institutions in Japan. Adult mechanically ventilated ARDS patients with an extravascular lung water index of >10 mL/kg were included and propensity score analyses were performed. The endpoints were 28-day mortality and ventilator-free days (VFDs). RESULTS: Patients were categorized into sivelestat (n = 87) and control (n = 77) groups, from which 329 inverse probability-weighted group patients (162 vs. 167) were generated. The overall 28-day mortality was 31.1% (51/164). There was no significant difference in 28-day mortality between the study groups (sivelestat vs. control; unmatched: 29.9% vs. 32.5%; difference, -2.6%, 95% confidence interval (CI), -16.8 to 14.2; inverse probability-weighted: 24.7% vs. 29.5%, difference, -4.8%, 95% CI, -14.4 to 9.6). Although administration of sivelestat did not alter the number of ventilator-free days (VFDs) in the unmatched (9.6 vs. 9.7 days; difference, 0.1, 95% CI, -3.0 to 3.1), the inverse probability-weighted analysis identified significantly more VFDs in the sivelestat group than in the control group (10.7 vs. 8.4 days, difference, -2.3, 95% CI, -4.4 to -0.2). CONCLUSIONS: Although sivelestat did not significantly affect 28-day mortality, this treatment may have the potential to increase VFDs in ARDS patients with increased extravascular lung water. Prospective randomized controlled studies are required to confirm the results of the current study.

Relationship between extravascular lung water and severity categories of acute respiratory distress syndrome by the Berlin definition.

INTRODUCTION: The Berlin definition divides acute respiratory distress syndrome (ARDS) into three severity categories. The relationship between these categories and pulmonary microvascular permeability as well as extravascular lung water content, which is the hallmark of lung pathophysiology, remains to be elucidated. The aim of this study was to evaluate the relationship between extravascular lung water, pulmonary vascular permeability, and the severity categories as defined by the Berlin definition, and to confirm the associated predictive validity for severity. METHODS: The extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPI) were measured using a transpulmonary thermodilution method for three consecutive days in 195 patients with an EVLWi of ≥10 mL/kg and who fulfilled the Berlin definition of ARDS. Collectively, these patients were seen at 23 ICUs. Using the Berlin definition, patients were classified into three categories: mild, moderate, and severe. RESULTS: Compared to patients with mild ARDS, patients with moderate and severe ARDS had higher acute physiology and chronic health evaluation II and sequential organ failure assessment scores on the day of enrollment. Patients with severe ARDS had higher EVLWi (mild, 16.1; moderate, 17.2; severe, 19.1; P <0.05) and PVPI (2.7; 3.0; 3.2; P <0.05). When categories were defined by the minimum PaO2/FIO2 ratio observed during the study period, the 28-day mortality rate increased with severity categories: moderate, odds ratio: 3.125 relative to mild; and severe, odds ratio: 4.167 relative to mild. On independent evaluation of 495 measurements from 195 patients over three days, negative and moderate correlations were observed between EVLWi and the PaO2/FIO2 ratio (r = -0.355, P<0.001) as well as between PVPI and the PaO2/FIO2 ratio (r = -0.345, P <0.001). ARDS severity was associated with an increase in EVLWi with the categories (mild, 14.7; moderate, 16.2; severe, 20.0; P <0.001) in all data sets. The value of PVPI followed the same pattern (2.6; 2.7; 3.5; P <0.001). CONCLUSIONS: Severity categories of ARDS described by the Berlin definition have good predictive validity and may be associated with increased extravascular lung water and pulmonary vascular permeability. TRIAL REGISTRATION: UMIN-CTR ID UMIN000003627.

Limitations of global end-diastolic volume index as a parameter of cardiac preload in the early phase of severe sepsis: a subgroup analysis of a multicenter, prospective observational study.

BACKGROUND: In patients with severe sepsis, depression of cardiac performance is common and is often associated with left ventricular (LV) dilatation to maintain stroke volume. Although it is essential to optimize cardiac preload to maintain tissue perfusion in patients with severe sepsis, the optimal preload remains unknown. This study aimed to evaluate the reliability of global end-diastolic volume index (GEDI) as a parameter of cardiac preload in the early phase of severe sepsis. METHODS: Ninety-three mechanically ventilated patients with acute lung injury/acute respiratory distress syndrome secondary to sepsis were enrolled for subgroup analysis in a multicenter, prospective, observational study. Patients were divided into two groups-with sepsis-induced myocardial dysfunction (SIMD) and without SIMD (non-SIMD)-according to a threshold LV ejection fraction (LVEF) of 50% on the day of enrollment. Both groups were further subdivided according to a threshold stroke volume variation (SVV) of 13% as a parameter of fluid responsiveness. RESULTS: On the day of enrollment, there was a positive correlation (r = 0.421, p = 0.045) between GEDI and SVV in the SIMD group, whereas this paradoxical correlation was not found in the non-SIMD group and both groups on day 2. To evaluate the relationship between attainment of cardiac preload optimization and GEDI value, GEDI with SVV ≤13% and SVV >13% was compared in both the SIMD and non-SIMD groups. SVV ≤13% implies the attainment of cardiac preload optimization. Among patients with SIMD, GEDI was higher in patients with SVV >13% than in patients with SVV ≤13% on the day of enrollment (872 [785-996] mL/m(2) vs. 640 [597-696] mL/m(2); p < 0.001); this finding differed from the generally recognized relationship between GEDI and SVV. However, GEDI was not significantly different between patients with SVV ≤13% and SVV >13% in the non-SIMD group on the day of enrollment and both groups on day 2. CONCLUSIONS: In the early phase of severe sepsis in mechanically ventilated patients, there was no constant relationship between GEDI and fluid reserve responsiveness, irrespective of the presence of SIMD. GEDI should be used as a cardiac preload parameter with awareness of its limitations.

The clinical usefulness of extravascular lung water and pulmonary vascular permeability index to diagnose and characterize pulmonary edema: a prospective multicenter study on the quantitative differential diagnostic definition for acute lung injury/acute respiratory distress syndrome.

INTRODUCTION: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by features other than increased pulmonary vascular permeability. Pulmonary vascular permeability combined with increased extravascular lung water content has been considered a quantitative diagnostic criterion of ALI/ARDS. This prospective, multi-institutional, observational study aimed to clarify the clinical pathophysiological features of ALI/ARDS and establish its quantitative diagnostic criteria. METHODS: The extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI) were measured using the transpulmonary thermodilution method in 266 patients with PaO2/FiO2 ratio ≤ 300 mmHg and bilateral infiltration on chest radiography, in 23 ICUs of academic tertiary referral hospitals. Pulmonary edema was defined as EVLWI ≥ 10 ml/kg. Three experts retrospectively determined the pathophysiological features of respiratory insufficiency by considering the patients' history, clinical presentation, chest computed tomography and radiography, echocardiography, EVLWI and brain natriuretic peptide level, and the time course of all preceding findings under systemic and respiratory therapy. RESULTS: Patients were divided into the following three categories on the basis of the pathophysiological diagnostic differentiation of respiratory insufficiency: ALI/ARDS, cardiogenic edema, and pleural effusion with atelectasis, which were noted in 207 patients, 26 patients, and 33 patients, respectively. EVLWI was greater in ALI/ARDS and cardiogenic edema patients than in patients with pleural effusion with atelectasis (18.5 ± 6.8, 14.4 ± 4.0, and 8.3 ± 2.1, respectively; P < 0.01). PVPI was higher in ALI/ARDS patients than in cardiogenic edema or pleural effusion with atelectasis patients (3.2 ± 1.4, 2.0 ± 0.8, and 1.6 ± 0.5; P < 0.01). In ALI/ARDS patients, EVLWI increased with increasing pulmonary vascular permeability (r = 0.729, P < 0.01) and was weakly correlated with intrathoracic blood volume (r = 0.236, P < 0.01). EVLWI was weakly correlated with the PaO2/FiO2 ratio in the ALI/ARDS and cardiogenic edema patients. A PVPI value of 2.6 to 2.85 provided a definitive diagnosis of ALI/ARDS (specificity, 0.90 to 0.95), and a value < 1.7 ruled out an ALI/ARDS diagnosis (specificity, 0.95). CONCLUSION: PVPI may be a useful quantitative diagnostic tool for ARDS in patients with hypoxemic respiratory failure and radiographic infiltrates. TRIAL REGISTRATION: UMIN-CTR ID UMIN000003627.