Effects of rapid fluid infusion on hemoglobin concentration: a systematic review and meta-analysis.

BACKGROUND: Rapid fluid administration may decrease hemoglobin concentration (Hb) by a diluting effect, which could limit the increase in oxygen delivery (DO2) expected with a positive response to fluid challenge in critically ill patients. Our aim was to quantify the decrease in Hb after rapid fluid administration. METHODS: Our protocol was registered in PROSPERO (CRD42020165146). We searched PubMed, the Cochrane Database, and Embase from inception until February 15, 2022. We selected studies that reported Hb before and after rapid fluid administration (bolus fluid given over less than 120 min) with crystalloids and/or colloids in adults. Exclusion criteria were studies that included bleeding patients, or used transfusions or extracorporeal circulation procedures. Studies were divided according to whether they involved non-acutely ill or acutely ill (surgical/trauma, sepsis, circulatory shock or severe hypovolemia, and mixed conditions) subjects. The mean Hb difference and, where reported, the DO2 difference before and after fluid administration were extracted. Meta-analyses were conducted to assess differences in Hb before and after rapid fluid administration in all subjects and across subgroups. Random-effect models, meta-regressions and subgroup analyses were performed for meta-analyses. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. RESULTS: Sixty-five studies met our inclusion criteria (40 in non-acutely ill and 25 in acutely ill subjects), with a total of 2794 participants. Risk of bias was assessed as "low" for randomized controlled trials (RCTs) and 'low to moderate' for non-RCTs. Across 63 studies suitable for meta-analysis, the Hb decreased significantly by a mean of 1.33 g/dL [95% CI - 1.45 to - 1.12; p < 0.001; I2 = 96.88] after fluid administration: in non-acutely ill subjects, the mean decrease was 1.56 g/dL [95% CI - 1.69 to - 1.42; p < 0.001; I2 = 96.71] and in acutely ill patients 0.84 g/dL [95% CI - 1.03 to - 0.64; p = 0.033; I2 = 92.91]. The decrease in Hb was less marked in patients with sepsis than in other acutely ill patients. The DO2 decreased significantly in fluid non-responders with a significant decrease in Hb. CONCLUSIONS: Hb decreased consistently after rapid fluid administration with moderate certainty of evidence. This effect may limit the positive effects of fluid challenges on DO2 and thus on tissue oxygenation.

Alterations in Skin Blood Flow at the Fingertip Are Related to Mortality in Patients With Circulatory Shock.

OBJECTIVES: Skin blood flow is rapidly altered during circulatory shock and may remain altered despite apparent systemic hemodynamic stabilization. We evaluated whether changes in skin blood flow during circulatory shock were related to survival. DESIGN: Prospective study. SETTING: Thirty-five-bed medical-surgical university hospital department of intensive care. SUBJECTS: Twenty healthy volunteers and 70 patients with circulatory shock (< 12 hr duration), defined as the need for vasopressors to maintain mean arterial pressure greater than or equal to 65 mm Hg and signs of altered tissue perfusion. INTERVENTIONS: We assessed skin blood flow using skin laser Doppler on the fingertip for 3 minutes at basal temperature (SBFBT) and at 37°C (SBF37) (thermal challenge test) once in volunteers and at the time of inclusion and after 6, 24, 48, 72, and 96 hours in patients with shock. Capillary refill time and peripheral perfusion index were measured at the same time points on the contralateral hand. MEASUREMENTS AND MAIN RESULTS: The thermal challenge response (ΔSBF/ΔT) was calculated using the following formula: (SBF37-SBFBT)/(37-basal temperature). Area under the receiver operating characteristic curves were calculated to evaluate variables predictive of ICU mortality. At inclusion, skin blood flow and ΔSBF/ΔT were lower in patients than in volunteers. Baseline skin blood flow (31 [17-113] vs 16 [9-32] arbitrary perfusion units; p = 0.01) and ΔSBF/ΔT (4.3 [1.7-10.9] vs 0.9 [0.4-2.9] arbitrary perfusion unit/s) were greater in survivors than in nonsurvivors. Capillary refill time was shorter in survivors than in nonsurvivors; peripheral perfusion index was similar in the two groups. ΔSBF/ΔT (area under the receiver operating characteristic curve 0.94 [0.88-0.99]) and SBFBT (area under the receiver operating characteristic curve 0.83 [0.73-0.93]) had the best predictive value for ICU mortality with cutoff values less than or equal to 1.25 arbitrary perfusion unit/°C (sensitivity 88%, specificity 89%) and less than or equal to 21 arbitrary perfusion unit (sensitivity 84%, specificity 81%), respectively. CONCLUSIONS: Alterations in fingertip skin blood flow can be evaluated using a laser Doppler thermal challenge technique in patients with circulatory shock and are directly related to outcome. These novel monitoring techniques could potentially be used to guide resuscitation.

Systematic Review and Meta-Analysis of Effects of Transfusion on Hemodynamic and Oxygenation Variables.

OBJECTIVES: RBC transfusions can increase oxygen availability to the tissues, but studies have provided conflicting results. The objectives of this study were, therefore, to evaluate, using systematic review and meta-analysis, the effects of transfusion on hemodynamic/oxygenation variables in patients without acute bleeding. DATA SOURCES: PubMed, Scopus, Cochrane Database of Systematic Reviews, and Embase from inception until June 30, 2019. STUDY SELECTION: All articles that reported values of prespecified hemodynamic or oxygenation variables before and after RBC transfusion. DATA EXTRACTION: Publication year, number of patients, number of transfusions and the type of population studied, hemodynamic and oxygenation data (heart rate, cardiac index, mixed venous oxygen saturation or central venous oxygen saturation, oxygen delivery index, oxygen consumption index, oxygen extraction ratio, arteriovenous oxygen difference and arterial blood lactate) before and after transfusion. We performed a meta-analysis for each variable for which there were sufficient data to estimate mean differences. We also performed subgroup analyses comparing septic with nonseptic patients. DATA SYNTHESIS: We retrieved 6,420 studies; 33 met the inclusion criteria, 14 of which were in patients with sepsis. In the meta-analysis, the estimated mean differences and 95% CIs comparing the periods before and after transfusion were -0.0 L/min/m (-0.1 to 0.1 L/min/m) (p = 0.86) for cardiac index; -1.8 beats/min (-3.7 to 0.1 beats/min) (p = 0.06) for heart rate; 96.8 mL/min/m (71.1-122.5 mL/min/m) (p < 0.01) for oxygen delivery index; 2.9% (2.2-3.5%) (p < 0.01) for mixed venous oxygen saturation or central venous oxygen saturation; -3.7% (-4.4% to -3.0%) (p < 0.01) for oxygen extraction ratio; and 4.9 mL/min/m (0.9-9.0 mL/min/m) (p = 0.02) for oxygen consumption index. The estimated mean difference for oxygen consumption index in the patients with sepsis was 8.4 mL/min/m (2.3-14.5 mL/min/m; p = 0.01). CONCLUSIONS: Transfusion was not associated with a decrease in mean cardiac output or mean heart rate. The increase in mean oxygen delivery following transfusion was associated with an increase in mean oxygen consumption after transfusion, especially in patients with sepsis.

Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients.

OBJECTIVES: To characterize renin in critically ill patients. Renin is fundamental to circulatory homeostasis and could be a useful marker of tissue-perfusion. However, diurnal variation, continuous renal replacement therapy and drug-interference could confound its use in critical care practice. DESIGN: Prospective observational study. SETTING: Single-center, mixed medical-surgical ICU in Europe. PATIENTS: Patients over 18 years old with a baseline estimated glomerular filtration rate greater than 30 mL/min/1.73 m and anticipated ICU stay greater than 24 hours. Informed consent was obtained from the patient or next-of-kin. INTERVENTIONS: Direct plasma renin was measured in samples drawn 6-hourly from arterial catheters in recumbent patients and from extracorporeal continuous renal replacement therapy circuits. Physiologic variables and use of drugs that act on the renin-angiotensin-aldosterone system were recorded prospectively. Routine lactate measurements were used for comparison. MEASUREMENTS AND MAIN RESULTS: One-hundred twelve arterial samples (n = 112) were drawn from 20 patients (65% male; mean ± SD, 60 ± 14 yr old) with septic shock (30%), hemorrhagic shock (15%), cardiogenic shock (20%), or no circulatory shock (35%). The ICU mortality rate was 30%. Renin correlated significantly with urine output (repeated-measures correlation coefficient = -0.29; p = 0.015) and mean arterial blood pressure (repeated-measures correlation coefficient = -0.35; p < 0.001). There was no diurnal variation of renin or significant interaction of renin-angiotensin-aldosterone system drugs with renin in this population. Continuous renal replacement therapy renin removal was negligible (mass clearance ± SD 4% ± 4.3%). There was a significant difference in the rate of change of renin over time between survivors and nonsurvivors (-32 ± 26 µU/timepoint vs +92 ± 57 µU/timepoint p = 0.03; mean ± SEM), but not for lactate (-0.14 ± 0.04 mM/timepoint vs +0.15 ± 0.21 mM/timepoint; p = 0.07). Maximum renin achieved significant prognostic value for ICU mortality (receiver operator curve area under the curve 0.80; p = 0.04), whereas maximum lactate did not (receiver operator curve area under the curve, 0.70; p = 0.17). CONCLUSIONS: In an heterogeneous ICU population, renin measurement was not significantly affected by diurnal variation, continuous renal replacement therapy, or drugs. Renin served as a marker of tissue-perfusion and outperformed lactate as a predictor of ICU mortality.

Updates in Glycemic Management in the Hospital.

PURPOSE OF REVIEW: To provide an update of glycemic management during metabolic stress related to surgery or critical illness. RECENT FINDINGS: There is a clear association between severe hyperglycemia, hypoglycemia, and high glycemic variability and poor outcomes of postoperative or critically ill patients. However, the impressive beneficial effects of tight glycemic management (TGM) by intensive insulin therapy reported in one study were never reproduced. Hence, the recommendation of TGM is now replaced by more liberal blood glucose (BG) targets (< 180 mg/dL or 10 mM). Recent data support the concept of targeting individualized blood glucose (BG) values according to the presence of diabetes mellitus/chronic hyperglycemia, the presence of brain injury, and the time from injury. A more liberal glycemic management goal is currently advised during metabolic stress and could be switched to individualized glycemic management once validated by prospective trials.

Current management of Gram-negative septic shock.

PURPOSE OF REVIEW: Sepsis is a common condition in critically ill patients and associated with high morbidity and mortality. Sepsis is the result of infection by many potential pathogens, including Gram-negative bacteria. There are no specific antisepsis therapies and management relies largely on infection control and organ support, including hemodynamic stabilization. We discuss these key aspects and briefly mention potential immunomodulatory strategies. RECENT FINDINGS: New aspects of sepsis management include the realization that early treatment is important and that fluids and vasopressor agents should be administered simultaneously to insure rapid restoration of an adequate perfusion pressure to limit development and worsening of organ dysfunction. New immunomodulatory therapies, both suppressive and stimulatory, are being tested. SUMMARY: Early diagnosis enabling rapid treatment can optimize outcomes. The multiple components of adequate sepsis management necessitate a team approach.

Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial.

BACKGROUND: Authors of recent meta-analyses have reported that prolonged glucocorticoid treatment is associated with significant improvements in patients with severe pneumonia or acute respiratory distress syndrome (ARDS) of multifactorial etiology. A prospective randomized trial limited to patients with sepsis-associated ARDS is lacking. The objective of our study was to evaluate the efficacy of hydrocortisone treatment in sepsis-associated ARDS. METHODS: In this double-blind, single-center (Siriraj Hospital, Bangkok), randomized, placebo-controlled trial, we recruited adult patients with severe sepsis within 12 h of their meeting ARDS criteria. Patients were randomly assigned (1:1 ratio) to receive either hydrocortisone 50 mg every 6 h or placebo. The primary endpoint was 28-day all-cause mortality; secondary endpoints included survival without organ support on day 28. RESULTS: Over the course of 4 years, 197 patients were randomized to either hydrocortisone (n = 98) or placebo (n = 99) and were included in this intention-to-treat analysis. The treatment group had significant improvement in the ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen and lung injury score (p = 0.01), and similar timing to removal of vital organ support (HR 0.74, 95 % CI 0.51-1.07; p = 0.107). After adjustment for significant covariates, day 28 survival was similar for the whole group (HR 0.80, 95 % CI 0.46-1.41; p = 0.44) and for the larger subgroup (n = 126) with Acute Physiology and Chronic Health Evaluation II score <25 (HR 0.57, 95 % CI 0.24-1.36; p = 0.20). With the exception of hyperglycemia (80.6 % vs. 67.7 %; p = 0.04), the rate of adverse events was similar. Hyperglycemia had no impact on outcome. CONCLUSIONS: In sepsis-associated ARDS, hydrocortisone treatment was associated with a significant improvement in pulmonary physiology, but without a significant survival benefit. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01284452 . Registered on 18 January 2011.

An increase in skin blood flow induced by fluid challenge is associated with an increase in oxygen consumption in patients with circulatory shock.

PURPOSE: To investigate whether an increase in skin blood flow (SBF) after fluid challenge was associated with an increase in oxygen consumption (VO2) in patients with circulatory shock. MATERIALS AND METHODS: We studied 62 patients with shock who required fluid challenge. Using laser Doppler, we measured finger SBF at basal temperature (SBFBT) and after a thermal challenge test (SBFTCT), before and after a fluid challenge (500 ml of Plasmalyte®). In fluid responders (i.e., increase in cardiac index ≥15%), VO2 responders (VO2R) were those with a ≥15% increase in VO2. RESULTS: Of the 62 patients, 33 were fluid responders and 16 of these were VO2R. At baseline, VO2R had lower SBFBT (21[14-52] vs 83[24-116] PU, p = 0.03) and SBFTCT (2.1[1.2-3.3] vs 4.4[2.2-5.6] PU/°C, p = 0.02) than VO2 non-responders (VO2NR); hemodynamic variables were not significantly different. The increase in SBFBT (∆SBFBT) after fluid challenge was greater in VO2R than in VO2NR (141[83-174] vs 57[17-150]%, p = 0.03). Areas under the curves for baseline SBFTCT (0.83 ± 0.07 [0.68-0.98]) and ∆SBFBT (0.90 ± 0.05 [0.75-1.0]) to predict ∆VO2 ≥ 15% were higher than for other variables. CONCLUSION: A lower baseline SBFTCT and a greater ∆SBFBT can identify patients in whom VO2 will increase after fluid challenge, suggesting an improvement in cellular metabolism.

Prediction of Fluid Responsiveness by the Effect of the Lung Recruitment Maneuver on the Perfusion Index in Mechanically Ventilated Patients During Surgery.

Introduction: Excessive or inadequate fluid administration during perioperative period affects outcomes. Adjustment of volume expansion (VE) by performing fluid responsiveness (FR) test plays an important role in optimizing fluid infusion. Since changes in stroke volume (SV) during lung recruitment maneuver (LRM) can predict FR, and peripheral perfusion index (PI) is related to SV; therefore, we hypothesized that the changes in PI during LRM (ΔPILRM) could predict FR during perioperative period. Methods: Patients who were scheduled for elective non-laparoscopic surgery under general anesthesia with a mechanical ventilator and who required VE (250 mL of crystalloid solution infusion over 10 min) were included. Before VE, LRM was performed by a continuous positive airway pressure of 30 cm H2O for 30 sec; hemodynamic variables with their changes (PI, obtained by pulse oximetry; and ΔPILRM, calculated by using [(PI before LRM-PI after LRM)/PI before LRM]*100) were obtained before and after LRM. After SV (measured by esophageal doppler) and PI had returned to the baseline values, VE was infused, and the values of these variables were recorded again, before and after VE. Fluid responders (Fluid-Res) were defined by an increase in SV ≥10% after VE. Receiver operating characteristic curves of the baseline values and ΔPILRM were constructed and reported as areas under the curve (AUC) with 95% confidence intervals, to predict FR. Results: Of 32 mechanically ventilated adult patients included, 13 (41%) were in the Fluid-Res group. Before VE and LRM, there were no differences in the mean arterial pressure (MAP), heart rate, SV, and PI between patients in the Fluid-Res and fluid non-responders (Fluid-NonRes) groups. After LRM, SV, MAP, and, PI decreased in both groups, ΔPILRM was greater in the Fluid-Res group than in Fluid-NonRes group (55.2 ± 17.8% vs. 35.3 ± 17.3%, p < 0.001, respectively). After VE, only SV and cardiac index increased in the Fluid-Res group. ΔPILRM had the highest AUC [0.81 (0.66-0.97)] to predict FR with a cut-off value of 40% (sensitivity 92.3%, specificity 73.7%). Conclusions: ΔPILRM can be applied to predict FR in mechanical ventilated patients during the perioperative period.

Monitoring skin blood flow to rapidly identify alterations in tissue perfusion during fluid removal using continuous veno-venous hemofiltration in patients with circulatory shock.

BACKGROUND: Continuous veno-venous hemofiltration (CVVH) can be used to reduce fluid overload and tissue edema, but excessive fluid removal may impair tissue perfusion. Skin blood flow (SBF) alters rapidly in shock, so its measurement may be useful to help monitor tissue perfusion. METHODS: In a prospective, observational study in a 35-bed department of intensive care, all patients with shock who required fluid removal with CVVH were considered for inclusion. SBF was measured on the index finger using skin laser Doppler (Periflux 5000, Perimed, Järfälla, Sweden) for 3 min at baseline (before starting fluid removal, T0), and 1, 3 and 6 h after starting fluid removal. The same fluid removal rate was maintained throughout the study period. Patients were grouped according to absence (Group A) or presence (Group B) of altered tissue perfusion, defined as a 10% increase in blood lactate from T0 to T6 with the T6 lactate ≥ 1.5 mmol/l. Receiver operating characteristic curves were constructed and areas under the curve (AUROC) calculated to identify variables predictive of altered tissue perfusion. Data are reported as medians [25th-75th percentiles]. RESULTS: We studied 42 patients (31 septic shock, 11 cardiogenic shock); median SOFA score at inclusion was 9 [8-12]. At T0, there were no significant differences in hemodynamic variables, norepinephrine dose, lactate concentration, ScvO2 or ultrafiltration rate between groups A and B. Cardiac index and MAP did not change over time, but SBF decreased in both groups (p < 0.05) throughout the study period. The baseline SBF was lower (58[35-118] vs 119[57-178] perfusion units [PU], p = 0.03) and the decrease in SBF from T0 to T1 (ΔSBF%) higher (53[39-63] vs 21[12-24]%, p = 0.01) in group B than in group A. Baseline SBF and ΔSBF% predicted altered tissue perfusion with AUROCs of 0.83 and 0.96, respectively, with cut-offs for SBF of ≤ 57 PU (sensitivity 78%, specificity 87%) and ∆SBF% of ≥ 45% (sensitivity 92%, specificity 99%). CONCLUSION: Baseline SBF and its early reduction after initiation of fluid removal using CVVH can predict worsened tissue perfusion, reflected by an increase in blood lactate levels.

Development of the Gastrointestinal Dysfunction Score (GIDS) for critically ill patients - A prospective multicenter observational study (iSOFA study).

BACKGROUND & AIMS: To develop a five grade score (0-4 points) for the assessment of gastrointestinal (GI) dysfunction in adult critically ill patients. METHODS: This prospective multicenter observational study enrolled consecutive adult patients admitted to 11 intensive care units in nine countries. At all sites, daily clinical data with emphasis on GI clinical symptoms were collected and intra-abdominal pressure measured. In five out of 11 sites, the biomarkers citrulline and intestinal fatty acid-binding protein (I-FABP) were measured additionally. Cox models with time-dependent scores were used to analyze associations with 28- and 90-day mortality. The models were estimated with stratification for study center. RESULTS: We included 540 patients (224 with biomarker measurements) with median age of 65 years (range 18-94), the Simplified Acute Physiology Score II score of 38 (interquartile range 26-53) points, and Sequential Organ Failure Assessment (SOFA) score of 6 (interquartile range 3-9) points at admission. Median ICU length of stay was 3 (interquartile range 1-6) days and 90-day mortality 18.9%. A new five grade Gastrointestinal Dysfunction Score (GIDS) was developed based on the rationale of the previously developed Acute GI Injury (AGI) grading. Citrulline and I-FABP did not prove their potential for scoring of GI dysfunction in critically ill. GIDS was independently associated with 28- and 90-day mortality when added to SOFA total score (HR 1.40; 95%CI 1.07-1.84 and HR 1.40; 95%CI 1.02-1.79, respectively) or to a model containing all SOFA subscores (HR 1.48; 95%CI 1.13-1.92 and HR 1.47; 95%CI 1.15-1.87, respectively), improving predictive power of SOFA score in all analyses. CONCLUSIONS: The newly developed GIDS is additive to SOFA score in prediction of 28- and 90-day mortality. The clinical usefulness of this score should be validated prospectively. TRIAL REGISTRATION: NCT02613000, retrospectively registered 24 November 2015.

Non-antibiotic therapies for sepsis: an update.

INTRODUCTION: Sepsis, defined as infection plus some degree of organ dysfunction, is still associated with high mortality and morbidity rates. Management focuses on three key areas: infection control, hemodynamic stabilization and organ support, and modulation of the sepsis response. Areas covered: This review will not cover infection control. Hemodynamic stabilization essentially involves the use of adequate fluid resuscitation and vasopressors. Fluid and vasopressor choices and targets are discussed, and the need to adapt these to the individual patient is stressed. No drugs are currently available that modulate the sepsis response, with the possible exception of corticosteroids in the most severe cases. The place of vasopressin is not well defined. Some of the immunomodulatory agents currently in development are briefly discussed. Expert opinion: Management of the patient with sepsis remains a challenge and needs to be personalized. The search for new immunomodulatory drugs continues and will be facilitated by better characterization of patients using modern 'omics' technology and complex analysis of the large quantities of clinical data increasingly available.

Skin microcirculatory reactivity assessed using a thermal challenge is decreased in patients with circulatory shock and associated with outcome.

BACKGROUND: Shock states are characterized by impaired tissue perfusion and microcirculatory alterations, which are directly related to outcome. Skin perfusion can be noninvasively evaluated using skin laser Doppler (SLD), which, when coupled with a local thermal challenge, may provide a measure of microcirculatory reactivity. We hypothesized that this microvascular reactivity would be impaired in patients with circulatory shock and would be a marker of severity. METHODS: We first evaluated skin blood flow (SBF) using SLD on the forearm and on the palm in 18 healthy volunteers to select the site with maximal response. Measurements were taken at 37 °C (baseline) and repeated at 43 °C. The 43 °C/37 °C SBF ratio was calculated as a measure of microvascular reactivity. We then evaluated the SBF in 29 patients with circulatory shock admitted to a 35-bed department of intensive care and in a confirmatory cohort of 35 patients with circulatory shock. RESULTS: In the volunteers, baseline SBF was higher in the hand than in the forearm, but the SBF ratio was lower (11.2 [9.4-13.4] vs. 2.0 [1.7-2.6], p < 0.01) so we used the forearm for our patients. Baseline forearm SBF was similar in patients with shock and healthy volunteers, but the SBF ratio was markedly lower in the patients (2.6 [2.0-3.6] vs. 11.2 [9.4-13.4], p < 0.01). Shock survivors had a higher SBF ratio than non-survivors (3.2 [2.2-6.2] vs. 2.3 [1.7-2.8], p < 0.01). These results were confirmed in the second cohort of 35 patients. In multivariable analysis, the APACHE II score and the SBF ratio were independently associated with mortality. CONCLUSIONS: Microcirculatory reactivity is decreased in patients with circulatory shock and has prognostic value. This simple, noninvasive test could help in monitoring the peripheral microcirculation in acutely ill patients.