Anti-inflammatory therapies are associated with delayed onset of anemia and reduction in transfusion requirements in critically ill patients: results from two studies.

BACKGROUND: Anemia is a hallmark of critical illness, which is largely inflammatory driven. We hypothesized that the use of anti-inflammatory agents limits the development of anemia and reduces the need for red blood cell (RBC) transfusions in patients with a hyper-inflammatory condition due to COVID-19. METHODS: An observational cohort (n = 772) and a validation cohort (a subset of REMAP-CAP, n = 119) of critically ill patients with hypoxemic respiratory failure due to COVID-19 were analyzed, who either received no treatment, received steroids or received steroids plus IL-6 blocking agents. The trajectory of hemoglobin (Hb) decline and the need for RBC transfusions were compared using descriptive statistics as well as multivariate modeling. RESULTS: In both cohorts, Hb level was higher in the treated groups compared to the untreated group at all time points. In the observational cohort, incidence and number of transfused patients were lower in the group receiving the combination treatment compared to the untreated groups. In a multivariate analysis controlling for baseline Hb imbalance and mechanical ventilation, receipt of steroids remained associated with a slower decline in Hb level and the combination treatment remained associated with a slower decline of Hb and with less transfusions. Results remained the same in the validation cohort. CONCLUSION: Immunomodulatory treatment was associated with a slower decline in Hb level in critically ill patients with COVID-19 and with less transfusion. Findings point toward inflammation as an important cause for the occurrence of anemia in the critically ill.

Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial.

PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

The Impact of Nursing Delirium Preventive Interventions in the ICU: A Multicenter Cluster-randomized Controlled Clinical Trial.

Rationale: Delirium is common in critically ill patients and is associated with deleterious outcomes. Nonpharmacological interventions are recommended in current delirium guidelines, but their effects have not been unequivocally established. Objectives: To determine the effects of a multicomponent nursing intervention program on delirium in the ICU. Methods: A stepped-wedge cluster-randomized controlled trial was conducted in ICUs of 10 centers. Adult critically ill surgical, medical, or trauma patients at high risk of developing delirium were included. A multicomponent nursing intervention program focusing on modifiable risk factors was implemented as standard of care. The primary outcome was the number of delirium-free and coma-free days alive in 28 days after ICU admission. Measurements and Main Results: A total of 1,749 patients were included. Time spent on interventions per 8-hour shift was median (interquartile range) 38 (14-116) minutes in the intervention period and median 32 (13-73) minutes in the control period (P = 0.44). Patients in the intervention period had a median of 23 (4-27) delirium-free and coma-free days alive compared with a median of 23 (5-27) days for patients in the control group (mean difference, -1.21 days; 95% confidence interval, -2.84 to 0.42 d; P = 0.15). In addition, the number of delirium days was similar: median 2 (1-4) days (ratio of medians, 0.90; 95% confidence interval, 0.75 to 1.09; P = 0.27). Conclusions: In this large randomized controlled trial in adult ICU patients, a limited increase in the use of nursing interventions was achieved, and no change in the number of delirium-free and coma-free days alive in 28 days could be determined. Clinical trial registered with www.clinicaltrials.gov (NCT03002701).

Satisfaction with quality of ICU care for patients and families: the euroQ2 project.

BACKGROUND: Families' perspectives are of great importance in evaluating quality of care in the intensive care unit (ICU). This Danish-Dutch study tested a European adaptation of the "Family Satisfaction in the ICU" (euroFS-ICU). The aim of the study was to examine assessments of satisfaction with care in a large cohort of Danish and Dutch family members and to examine the measurement characteristics of the euroFS-ICU. METHODS: Data were from 11 Danish and 10 Dutch ICUs and included family members of patients admitted to the ICU for 48 hours or more. Surveys were mailed 3 weeks after patient discharge from the ICU. Selected patient characteristics were retrieved from hospital records. RESULTS: A total of 1077 family members of 920 ICU patients participated. The response rate among family members who were approached was 72%. "Excellent" or "Very good" ratings on all items ranged from 58% to 96%. Items with the highest ratings were concern toward patients, ICU atmosphere, opportunities to be present at the bedside, and ease of getting information. Items with room for improvement were management of patient agitation, emotional support of the family, consistency of information, and inclusion in and support during decision-making processes. Exploratory factor analysis suggested four underlying factors, but confirmatory factor analysis failed to yield a multi-factor model with between-country measurement invariance. A hypothesis that this failure was due to misspecification of causal indicators as reflective indicators was supported by analysis of a factor representing satisfaction with communication, measured with a combination of causal and reflective indicators. CONCLUSIONS: Most family members were moderately or very satisfied with patient care, family care, information and decision-making, but areas with room for improvement were also identified. Psychometric assessments suggest that composite scores constructed from these items as representations of either overall satisfaction or satisfaction with specific sub-domains do not meet rigorous measurement standards. The euroFS-ICU and other similar instruments may benefit from adding reflective indicators.

Mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microSOAP post hoc analysis.

BACKGROUND: Mildly elevated lactate levels (i.e., 1-2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. METHODS: This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow) to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements, and outcome were analyzed. RESULTS: In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels ≤ 2 mmol/L (median [IQR] 1.04 [0.80-1.40] mmol/L) were included. Crude ICU mortality increased with each lactate quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR 2.5, 95% CI 1.1-5.7, P = 0.027). CONCLUSIONS: In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated lactate levels. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01179243 . Registered on August 3, 2010.

Right Ventricular Function After Cardiac Surgery Is a Strong Independent Predictor for Long-Term Mortality.

OBJECTIVE: To establish the all-cause mortality of right ventricular dysfunction after cardiac surgery in a heterogeneous group of cardiac surgery patients. DESIGN: Retrospective analysis of a heterogeneous group of 1,109 cardiac surgery patients in a 4-year period. SETTING: Single-center study in a tertiary teaching hospital. PARTICIPANTS: One thousand one hundred nine cardiac surgery patients. By protocol, patients were monitored with a pulmonary artery catheter, enabling continuous right ventricular ejection fraction (RVEF) measurements. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measurements were performed once per minute for the first 24 postoperative hours and expressed as average over the complete period. Primary outcome was 2-year all-cause mortality. RVEF was categorized into 3 subgroups: <20%, 20-30%, and >30%. Median follow-up time was 739 days. Two-year mortality was significantly different across groups: 4.1% for patients with RVEF >30%, 8.2% in the group with RVEF 20-30%, and 16.7% for patients with RVEF <20%, p < 0.001. Additional risk factors for a poor RVEF were age, body weight, New York Heart Association class, chronic obstructive pulmonary disease, poor left ventricular function, and higher risk scores (Acute Physiology and Chronic Health Evaluation and European System for Cardiac Operative Risk Evaluation). In a multivariate analysis, RVEF as a continuous variable was associated independently with the primary outcome (odds ratio 0.95 confidence interval 0.91-0.99, p = 0.011.) Odds ratios for RVEF <20% were 1.88 (confidence interval 1.18-3.00, p = 0.008). CONCLUSIONS: Right ventricular function is associated independently with 2-year all-cause mortality in a heterogenic cardiac surgery population.

Targeted temperature management at 33°C versus 36°C after cardiac arrest.

BACKGROUND: Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. METHODS: In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. RESULTS: In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. CONCLUSIONS: In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).

Plasma glutamine levels in patients after non-elective or elective ICU admission: an observational study.

BACKGROUND: A low plasma glutamine level at the time of acute admission to the intensive care unit (ICU) is an independent predictor of an unfavourable outcome in critically ill patients. The primary objective of this study was to determine whether there are differences in plasma glutamine levels upon non-elective or elective ICU admission. The secondary objective was to compare glutamine levels over time, and to determine correlations between glutamine levels and the severity of illness and presence of infection in ICU patients. METHODS: We performed a single-centre observational study in a closed-format, 22-bed, mixed ICU. Plasma glutamine levels were measured at admission and every morning at 6.00 a.m. during the ICU stay. We aimed to include at least 80 patients per group. The study was approved by the local Medical Ethics Committee. RESULTS: In 88 patients after elective surgery, the median plasma glutamine level at admission was significantly higher compared with that in 90 non-elective patients (0.43 mmol/l [0.33-0.55 mmol/l] versus 0.25 mmol/l [0.09-0.37 mmol/l], P = 0.001). During the ICU stay, plasma glutamine levels remained significantly higher in elective patients than in non-elective patients. There was a significant correlation between the APACHE IV score and glutamine levels (R = 0.52, P < 0.001). Moreover, backward linear regression analysis showed that this correlation was independently associated with the APACHE IV score and the presence of infection, but not with the type of admission. CONCLUSIONS: Plasma glutamine levels are significantly lower after non-elective admission compared with elective admission to the ICU. A considerable amount of elective and non-elective patients have decreased plasma glutamine levels, but this is not independently associated with the type of admission. In contrast to previous studies, we found that plasma glutamine levels were determined by the severity of illness and the presence of an infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02310035.

International study on microcirculatory shock occurrence in acutely ill patients.

OBJECTIVES: Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables. DESIGN: Multicenter observational point prevalence study. SETTING: The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide. PATIENTS: A heterogeneous ICU population consisting of 501 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10-21), a Sequential Organ Failure Assessment score of 5 (2-8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67-4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963-0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11-3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28-3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30-8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients. CONCLUSIONS: In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.

'Sepsis-related anemia' is absent at hospital presentation; a retrospective cohort analysis.

BACKGROUND: Anemia is a common feature during sepsis that occurs due to iatrogenic blood loss, depression of serum iron levels and erythropoietin production, and a decreased lifespan of erythrocytes. However, these mechanisms are unlikely to play a role in anemia at the start of sepsis. Moreover, sequestration of fluids, renal failure and increase of intravascular space may additionally influence the change in hemoglobin concentration during intravenous fluid administration in the acute phase of sepsis. METHODS: In this retrospective study, patients who were admitted acutely to the Intensive Care Unit (ICU) were included. Patients who fulfilled the international criteria for severe sepsis or septic shock were included in the sepsis group (S-group). The remaining patients were allocated to the control group (C-group). Laboratory data from blood samples taken at first presentation to the hospital and at admission to the ICU, the amount of intravenous fluid administration and length of stay in the emergency department were collected and tested for significant differences between groups. RESULTS: The difference in hemoglobin concentration between the S-group (n = 296) and C-group (n = 320) at first presentation in hospital was not significant (8.8 ± 1.2 versus 8.9 ± 1.2 mmol/l, respectively, p = 0.07). The reduction in hemoglobin concentration from the first presentation at the emergency department to ICU admission was significantly greater in the S-group compared to the C-group (1 [0.5-1.7] versus 0.5 [0.1-1.1] mmol/l, (p < 0.001)). Spearman rho correlation coefficients between the reduction in hemoglobin concentration and the amount of intravenous fluids administered or the creatinine level in the emergency department were significant (0.3 and 0.4, respectively, p < 0.001). In a multivariate regression analysis, creatinine, the amount of fluid administration and the presence of sepsis remained independently associated. CONCLUSIONS: Prior to in-hospital intravenous fluid administration, there is no significant difference in hemoglobin concentration between acute septic patients and acutely ill controls. Within several hours after hospital admission, there is a significant reduction in hemoglobin concentration, not only associated with the amount of intravenous fluids administered and the creatinine level, but also independently with sepsis itself.

Influence of Two Colloidal Extracorporeal Primes on Coagulation of Cardiac Surgical Patients: A Prospectively Randomized Open-Label Pilot Trial.

The search for the ideal priming fluid continues as more evidence is discovered about side effects of volume expanders. With the availability of modern, balanced hydroxyethyl starch (HES) solutions with less side effects than former HES solutions, we considered to replace our gelatin- (modified gelatin) based extracorporeal circuit prime for a HES (130/.42) prime. Therefore, we studied the influence of two colloidal priming fluids on postoperative coagulation in patients undergoing cardiac surgery. The primary endpoint was to compare clot formation time between the HES group and the gelatin group with rotational thromboelastometry (ROTEM). Additionally we compared colloid osmotic pressure and fluid balance of both groups. Forty patients, undergoing elective first time coronary artery bypass grafting or single-valve surgery, were included in this prospectively randomized open-label pilot study. Laboratory data and ROTEM data were collected and analyzed for differences between the two groups. ROTEM data show significantly more prolongation in Extem clot formation time and significant more decrease in Extem alpha in the HES group. Fibtem maximum clot firmness was significantly smaller in the HES group; this was consistent with fibrinogen concentration measurement, which decreased more in the HES group than in the gelatin group and recovered more over time in the gelatin group. We found no significant difference in colloid. osmotic pressure between the groups. In this trial, HES (130/.42) impairs coagulation significantly more compared with gelatin. These differences in influence on coagulation did not lead to a difference in blood loss or fluid balance, so clinical relevance could not be proven.

Phosphodiesterase 3 inhibitors do not influence lactate kinetics and clinical outcomes in patients with septic shock: A multicentre cohort study.

PURPOSE: We investigated the association between the administration of phosphodiesterase 3 inhibitors (PDE3i) and lactate kinetics, resolution of organ failure, ICU and hospital length of stay (LOS) and hospital mortality in a retrospective cohort of patients with septic shock and persistently elevated lactate concentrations. MATERIAL AND METHODS: Patients with septic shock and two arterial lactate concentrations ≥4 mmol/L with at least 4 h between measurements were eligible. Clinical data of the first four days of admission were collected in an online database. For each patient, the area between the actual lactate concentrations and 2.2 mmol/L (AUClact2.2), was calculated for three days. RESULTS: Data on 229 patients from 10 hospitals were collected, of whom 123 received PDE3i (54%). First, a linear multivariate model was developed to predict AUClact2.2 (R2 = 0.57). Adding PDE3i as a cofactor did not affect R2. Second, 60 patients receiving PDE3i at any time between days 0 and 2 were compared to 60 propensity matched no-PDE3i patients. Third, 30 patients who received PDE3i from ICU admission to day 3 were compared to 30 propensity-matched no-PDE3i patients. These analyses showed no differences in AUClact2.2, SOFA scores, ICU or hospital LOS or hospital mortality between treatment groups. CONCLUSIONS: No association was found between the administration of PDE3i and lactate kinetics, resolution of organ failure, ICU or hospital LOS or hospital mortality.

Enteral Vancomycin to Eliminate MRSA Carriership of the Digestive Tract in Critically Ill Patients.

BACKGROUND: Carriership with methicillin resistant Staphylococcus aureus (MRSA) is a risk for the development of secondary infections in critically ill patients. Previous studies suggest that enteral vancomycin is able to eliminate enteral carriership with MRSA. Data on individual effects of this treatment are lacking. METHODS: Retrospective analysis of a database containing 15 year data of consecutive patients from a mixed medical-(cardio)surgical 18 bedded intensive care unit was conducted. All consecutive critically ill patients with enteral MRSA carriership detected in throat and/or rectal samples were collected. We analyzed those with follow-up cultures to determine the success rate of enteral vancomycin. Topical application of 2% vancomycin in a sticky oral paste was performed combined with a vancomycin solution of 500 mg four times daily in the nasogastric tube. This treatment was added to a regimen of selective digestive tract decontamination (SDD) to prevent ICU acquired infection. RESULTS: Thirteen patients were included. The mean age was 65 years and the median APACHE II score was 21. MRSA was present in the throat in 8 patients and in both throat and rectum in 5 patients. In all patients MRSA was successfully eliminated from both throat and rectum, which took 2-11 days with a median duration until decontamination of 4 days. Secondary infections with MRSA did not occur. CONCLUSIONS: Topical treatment with vancomycin in a 2% sticky oral paste four times daily in the nasogastric tube was effective in all patients in the elimination of MRSA and prevented secondary MRSA infections.

Microcirculatory changes during open label magnesium sulphate infusion in patients with severe sepsis and septic shock.

BACKGROUND: Microcirculatory alterations play a pivotal role in sepsis and persist despite correction of systemic hemodynamic parameters. Therefore it seems tempting to test specific pro-microcirculatory strategies, including vasodilators, to attenuate impaired organ perfusion. As opposed to nitric oxide donors, magnesium has both endothelium-dependent and non-endothelium-dependent vasodilatory pathways. METHODS: In a single-center open label study we evaluated the effects of magnesium sulphate (MgS) infusion on the sublingual microcirculation perfusion in fluid resuscitated patients with severe sepsis and septic shock within the first 48 hours after ICU admission. Directly prior to and after 1 hour of magnesium sulphate (MgS) infusion (2 gram) systemic hemodynamic variables, sublingual SDF images and standard laboratory tests, were obtained. RESULTS: Fourteen patients (12 septic shock, 2 severe sepsis) with a median APACHE II score of 20 were enrolled. No significant difference of the systemic hemodynamic variables was found between baseline and after MgS infusion. We did not observe any significant difference pre and post MgS infusion in the primary endpoint microvascular flow index (MFI) of small vessels: 2.25(1.98-2.69) vs. 2.33(1.96-2.62), p = 0.65. Other variables of microcirculatory perfusion were also unaltered. In the overall unchanged microvascular perfusion there was a non-significant trend to an inverse linear relationship between the changes of MFI and its baseline value (y = -0.7260 × + 1.629, r2 = 0.270, p = 0.057). The correlation between baseline Mg concentrations and the change in MFI pre- and post MgS infusion was non-significant (rs = -0.165, p = 0.67). CONCLUSIONS: In the setting of severe sepsis and septic shock sublingual microcirculatory alterations were observed despite fulfillment of sepsis resuscitation guidelines. After infusion of a limited and fixed dose of MgS, microcirculatory perfusion did not improve over time. TRIAL REGISTRATION: ClinicalTrials.gov NTC01332734.

Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial.

OBJECTIVES: Microcirculatory alterations have been associated with morbidity and mortality in human sepsis. Such alterations occur despite pressure-guided resuscitation. Earlier data suggested that impaired microcirculatory blood flow could be corrected with intravenous nitroglycerin in these patients. We tested this concept after fulfillment of preset systemic hemodynamic resuscitation end points in the early phase of sepsis. DESIGN: Prospective, single center, randomized, placebo-controlled, double-blind clinical trial. SETTING: Closed-format 22-bed mixed intensive care unit in a tertiary teaching hospital. PATIENTS: Patients > or =18 yrs with sepsis, according to international criteria, and at least one early sign of organ dysfunction, as the principal reason for intensive care unit admission, were eligible for enrollment. INTERVENTIONS: Patients were randomly assigned to receive nitroglycerin (n = 35) or placebo (n = 35) after fulfillment of protocol-driven resuscitation end points. This trial is registered with ClinicalTrials.gov as NCT00493415. MEASUREMENTS AND MAIN RESULTS: Primary outcome was sublingual microcirculatory blood flow of small vessels, as assessed by side-stream dark field imaging. After protocolized resuscitation, we observed recruitment of sublingual microcirculation in both groups, as indicated by a significant improvement in the microcirculatory flow index after 24 hrs, in comparison to baseline. However, no difference in the sublingual microvascular flow index was observed between groups. The median microvascular flow index in sublingual small-sized vessels was 2.71 (1.85-3) in the nitroglycerin group and 2.71 (1.27-3), p = .80, in the placebo group. In medium-sized vessels, the respective values were 3 (2.75-3) vs. 2.86 (2.19-3), p = .21, and in large-sized vessels, 3 (3-3) vs. 3 (2.89-3), p = .06. In-hospital mortality, as a secondary outcome, was 34.3% in the nitroglycerin group and 14.2% in the placebo group, p = .09. CONCLUSIONS: In the context of a strict resuscitation protocol, based upon fulfillment of systemic hemodynamic end points in patients with early-phase severe sepsis or septic shock, we conclude that intravenous nitroglycerin does not promote sublingual microcirculatory blood flow.

No agreement of mixed venous and central venous saturation in sepsis, independent of sepsis origin.

INTRODUCTION: Controversy remains regarding the relationship between central venous saturation (ScvO(2)) and mixed venous saturation (SvO(2)) and their use and interchangeability in patients with sepsis or septic shock. We tested the hypothesis that ScvO(2) does not reliably predict SvO(2) in sepsis. Additionally we looked at the influence of the source (splanchnic or non-splanchnic) of sepsis on this relationship. METHODS: In this prospective observational two-center study we concurrently determined ScvO(2) and SvO(2) in a group of 53 patients with severe sepsis during the first 24 hours after admission to the intensive care units in 2 Dutch hospitals. We assessed correlation and agreement of ScvO(2) and SvO(2), including the difference, i.e. the gradient, between ScvO(2) and SvO(2) (ScvO(2) - SvO(2)). Additionally, we compared the mean differences between ScvO(2) and SvO(2) of both splanchnic and non-splanchnic group. RESULTS: A total of 265 paired blood samples were obtained. ScvO(2) overestimated SvO(2) by less than 5% with wide limits of agreement. For changes in ScvO(2) and SvO(2) results were similar. The distribution of the (ScvO(2) - SvO(2)) (< 0 or ≥ 0) was similar in survivors and nonsurvivors. The mean (ScvO(2) - SvO(2)) in the splanchnic group was similar to the mean (ScvO(2) - SvO(2)) in the non-splanchnic group (0.8 ± 3.9% vs. 2.5 ± 6.2%; P = 0.30). O(2)ER (P = 0.23) and its predictive value for outcome (P = 0.20) were similar in both groups. CONCLUSIONS: ScvO(2) does not reliably predict SvO(2) in patients with severe sepsis. The trend of ScvO(2) is not superior to the absolute value in this context. A positive difference (ScvO(2) - SvO(2)) is not associated with improved outcome.

Improvement of sidestream dark field imaging with an image acquisition stabilizer.

BACKGROUND: In the present study we developed, evaluated in volunteers, and clinically validated an image acquisition stabilizer (IAS) for Sidestream Dark Field (SDF) imaging. METHODS: The IAS is a stainless steel sterilizable ring which fits around the SDF probe tip. The IAS creates adhesion to the imaged tissue by application of negative pressure. The effects of the IAS on the sublingual microcirculatory flow velocities, the force required to induce pressure artifacts (PA), the time to acquire a stable image, and the duration of stable imaging were assessed in healthy volunteers. To demonstrate the clinical applicability of the SDF setup in combination with the IAS, simultaneous bilateral sublingual imaging of the microcirculation were performed during a lung recruitment maneuver (LRM) in mechanically ventilated critically ill patients. One SDF device was operated handheld; the second was fitted with the IAS and held in position by a mechanic arm. Lateral drift, number of losses of image stability and duration of stable imaging of the two methods were compared. RESULTS: Five healthy volunteers were studied. The IAS did not affect microcirculatory flow velocities. A significantly greater force had to applied onto the tissue to induced PA with compared to without IAS (0.25 +/- 0.15 N without vs. 0.62 +/- 0.05 N with the IAS, p < 0.001). The IAS ensured an increased duration of a stable image sequence (8 +/- 2 s without vs. 42 +/- 8 s with the IAS, p < 0.001). The time required to obtain a stable image sequence was similar with and without the IAS. In eight mechanically ventilated patients undergoing a LRM the use of the IAS resulted in a significantly reduced image drifting and enabled the acquisition of significantly longer stable image sequences (24 +/- 5 s without vs. 67 +/- 14 s with the IAS, p = 0.006). CONCLUSIONS: The present study has validated the use of an IAS for improvement of SDF imaging by demonstrating that the IAS did not affect microcirculatory perfusion in the microscopic field of view. The IAS improved both axial and lateral SDF image stability and thereby increased the critical force required to induce pressure artifacts. The IAS ensured a significantly increased duration of maintaining a stable image sequence.

Family ratings of ICU care. Is there concordance within families?

PURPOSE: To examine heterogeneity of quality-of-care ratings within families and to examine possible predictors of concordance. MATERIALS AND METHODS: We examined two aspects of agreement within families: response similarity and the amount of exact concordance in responses in a cohort of Danish ICU family members participating in a questionnaire survey (the European Quality Questionnaire: euroQ2). RESULTS: Two hundred seventy-four family respondents representing 122 patients were included in the study. Identical ratings between family members occurred in 28%-59% of families, depending upon the specific survey item. In a smaller sample of 28 families whose patients died, between 39% and 86% gave identical responses to items rating end-of-life care. There was more response variance within than between families, yielding low estimates of intrafamily correlation. Statistics correcting for chance agreement also suggested modest within-family agreement. CONCLUSIONS: The finding that variance is higher within than between families suggests the value of including multiple participants within a family in order to capture varying points of view.

Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: A retrospective single-centre study.

Post-intensive care unit (ICU) sequelae, including physical and mental health problems, are relatively unexplored. Characteristics commonly used to predict outcome lack prognostic value when it comes to long-term physical recovery. Therefore, the objective of this study was to assess the incidence of non-recovery in long-stay ICU-patients. In this single-centre study, retrospective data of adults with an ICU stay >48 hours who visited the specialized post-ICU clinic, and completed the Dutch RAND 36-item Short Form questionnaire at 3 and 12 months post-ICU, were retrieved from electronic patient records. In cases where physical functioning scores at 12 months were below reference values, patients were allocated to the physical non-recovery (NR) group. Significantly different baseline and (post-)ICU-characteristics were assessed for correlations with physical recovery at 12 months post-ICU. Of 250 patients, 110 (44%) fulfilled the criteria for the NR-group. Neither the severity of illness, type of admission, nor presence of sepsis did not differ between groups. However, NR-patients had a higher age, were more often female, and had a higher incidence of co-morbidities. Shorter LOS ICU, lower incidence of medical comorbidities, and better physical performance at 3 months were significantly correlated with 1-year physical recovery. Comorbidities and reduced physical functioning at 3 months were identified as independent risk-factors for long-term physical non-recovery. In conclusion, a substantial proportion of long-stay ICU-patients who visited the standard care post-ICU clinic did not fulfil the criteria for full physical recovery at 12 months post-ICU. Commonly used ICU-characteristics, such as severity of illness, do not have sufficient prognostic value when it comes to long-term recovery of health-related quality of life.

Prevalence and management of delirium in intensive care units in the Netherlands: An observational multicentre study.

OBJECTIVES: This study aimed to determine the prevalence, risk factors of delirium and current practice of delirium management in intensive care units of various levels of care. RESEARCH METHODOLOGY/DESIGN: Prospective multicentre cohort study. SETTING: In all adult patients admitted to one of the participating intensive care units on World Delirium Awareness Day 2018, delirium point and period prevalence rates were measured between ICU admission and seven days after the index day. RESULTS: In total, 28 (33%) Dutch intensive care units participated in this study. Point-prevalence was 23% (range 41), and period-prevalence was 42% (range 70). University intensive care units had a significantly higher delirium point-prevalence compared with non-university units (26% vs.15%, p = 0.02). No significant difference were found in period prevalence (50% vs. 39%, p = 0.09). Precipitating risk factors, infection and mechanical ventilation differed significantly between delirium and non-delirium patients. No differences were observed for predisposing risk factors. A delirium protocol was present in 89% of the ICUs. Mean delirium assessment compliance measured was 84% (±19) in 14 units and estimated 59% (±29) in the other 14. CONCLUSION: Delirium prevalence in Dutch intensive care units is substantial and occurs with a large variation, with the highest prevalence in university units. Precipitating risk factors were more frequent in patients with delirium. In the majority of units a delirium management protocol is in place.