Systemic inflammation relates to neuroaxonal damage associated with long-term cognitive dysfunction in COVID-19 patients.

BACKGROUND AND OBJECTIVES: Cognitive deficits are increasingly recognized as a long-term sequela of severe COVID-19. The underlying processes and molecular signatures associated with these long-term neurological sequalae of COVID-19 remain largely unclear, but may be related to systemic inflammation-induced effects on the brain. We studied the systemic inflammation-brain interplay and its relation to development of long-term cognitive impairment in patients who survived severe COVID-19. Trajectories of systemic inflammation and neuroaxonal damage blood biomarkers during ICU admission were analyzed and related to long-term cognitive outcomes. METHODS: Prospective longitudinal cohort study of patients with severe COVID-19 surviving ICU admission. During admission, blood was sampled consecutively to assess levels of inflammatory cytokines and neurofilament light chain (NfL) using an ultrasensitive multiplex Luminex assay and single molecule array technique (Simoa). Cognitive functioning was evaluated using a comprehensive neuropsychological assessment six months after ICU-discharge. RESULTS: Ninety-six patients (median [IQR] age 61 [55-69] years) were enrolled from March 2020 to June 2021 and divided into two cohorts: those who received no COVID-19-related immunotherapy (n = 28) and those treated with either dexamethasone or dexamethasone and tocilizumab (n = 68). Plasma NfL concentrations increased in 95 % of patients during their ICU stay, from median [IQR] 23 [18-38] pg/mL at admission to 250 [160-271] pg/mL after 28 days, p < 0.001. Besides age, glomerular filtration rate, immunomodulatory treatment, and C-reactive protein, more specific markers of systemic inflammation at day 14 (i.e., interleukin (IL)-8, tumour necrosis factor, and IL-1 receptor antagonist) were significant predictors of blood NfL levels at day 14 of ICU admission (R2 = 44 %, p < 0.001), illustrating the association between sustained systemic inflammation and neuroaxonal damage. Twenty-six patients (27 %) exhibited cognitive impairment six months after discharge from the ICU. NfL concentrations showed a more pronounced increase in patients that developed cognitive impairment (p = 0.03). Higher NfL predicted poorer outcome in information processing speed (Trail Making Test A, r = -0.26, p = 0.01; Letter Digit Substitution Test, r = -0.24, p = 0.02). DISCUSSION: Prolonged systemic inflammation in critically ill COVID-19 patients is related to neuroaxonal damage and subsequent long-term cognitive impairment. Moreover, our findings suggest that plasma NfL concentrations during ICU stay may possess prognostic value in predicting future long-term cognitive impairment in patients that survived severe COVID-19.

Fatigue during acute systemic inflammation is associated with reduced mental effort expenditure while task accuracy is preserved.

BACKGROUND: Earlier work within the physical domain showed that acute inflammation changes motivational prioritization and effort allocation rather than physical abilities. It is currently unclear whether a similar motivational framework accounts for the mental fatigue and cognitive symptoms of acute sickness. Accordingly, this study aimed to assess the relationship between fatigue, cytokines and mental effort-based decision making during acute systemic inflammation. METHODS: Eighty-five participants (41 males; 18-30 years (M = 23.0, SD = 2.4)) performed a mental effort-based decision-making task before, 2 h after, and 5 h after intravenous administration of 1 ng/kg bacterial lipopolysaccharide (LPS) to induce systemic inflammation. Plasma concentrations of cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)) and fatigue levels were assessed at similar timepoints. In the task, participants decided whether they wanted to perform (i.e., 'accepted') arithmetic calculations of varying difficulty (3 levels: easy, medium, hard) in order to obtain rewards (3 levels: 5, 6 or 7 points). Acceptance rates were analyzed using a binomial generalized estimated equation (GEE) approach with effort, reward and time as independent variables. Arithmetic performance was measured per effort level prior to the decisions and included as a covariate. Associations between acceptance rates, fatigue (self-reported) and cytokine concentration levels were analyzed using partial correlation analyses. RESULTS: Plasma cytokine concentrations and fatigue were increased at 2 h post-LPS compared to baseline and 5 h post-LPS administration. Acceptance rates decreased for medium, but not for easy or hard effort levels at 2 h post-LPS versus baseline and 5 h post-LPS administration, irrespective of reward level. These reductions in acceptance rates occurred despite improved accuracy on the arithmetic calculations itself. Reduced acceptance rates for medium effort were associated with increased fatigue, but not with increased cytokine concentrations. CONCLUSION: Fatigue during acute systemic inflammation is associated with alterations in mental effort allocation, similarly as observed previously for physical effort-based choice. Specifically, willingness to exert mental effort depended on effort and not reward information, while task accuracy was preserved. These results extend the motivational account of inflammation to the mental domain and suggest that inflammation may not necessarily affect domain-specific mental abilities, but rather affects domain-general effort-allocation processes.

Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3.

Sepsis represents one of the major medical challenges of the 21st century. Despite substantial improvements in the knowledge on pathophysiological mechanisms, this has so far not translated into novel adjuvant treatment strategies for sepsis. In sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock, which is strongly related to the development of organ dysfunction and mortality. In this review, we focus on dipeptidyl peptidase 3 (DPP3) and adrenomedullin (ADM), two molecules that act on the vasculature and are involved in the pathophysiology of sepsis and septic shock. DPP3 is an ubiquitous cytosolic enzyme involved in the degradation of several important signalling molecules essential for regulation of vascular tone, including angiotensin II. ADM is a key hormone involved in the regulation of vascular tone and endothelial barrier function. Previous studies have shown that circulating concentrations of both DPP3 and ADM are independently associated with the development of organ failure and adverse outcome in sepsis. We now discuss new evidence illustrating that these molecules indeed represent two distinct pathways involved in the development of septic shock. Recently, both ADM-enhancing therapies aimed at improving endothelial barrier function and vascular tone and DPP3-blocking therapies aimed at restoring systemic angiotensin responses have been shown to improve outcome in various preclinical sepsis models. Given the current lack of effective adjuvant therapies in sepsis, additional research on the therapeutic application of these peptides in humans is highly warranted.

Downregulation of synapse-associated protein expression and loss of homeostatic microglial control in cerebrospinal fluid of infectious patients with delirium and patients with Alzheimer's disease.

Delirium is a complex and multifactorial condition associated with long-term cognitive decline. Due to the strong links between systemic inflammation, delirium and dementia we hypothesized that responses within the brain in patients who develop delirium could show biochemical overlap with patients with Alzheimer's disease (AD). In this observational study we analyzed protein expression signatures in cerebrospinal fluid (CSF) from 15 patients with infectious delirium and compared these to 29 patients with AD, 30 infectious patients without delirium and 15 non-infectious controls free of neurological disease. A proximity extension assay was performed measuring a total of 184 inflammatory and neurology-related proteins. Eight inflammatory proteins (4%), including the key neuron-microglia communication marker CX3CL1 (fractalkine), were significantly upregulated in both delirium and AD, compared to infectious patients without delirium. Likewise, 23 proteins (13%) showed downregulation in both delirium and AD, relative to infectious patients without delirium, which interestingly included CD200R1, another neuron-microglia communication marker, as well as a cluster of proteins related to synapse formation and function. Synaptopathy is an early event in AD and correlates strongly with cognitive dysfunction. These results were partially mediated by aging, which is an important predisposing risk factor among many others for both conditions. Within this study we report the first in vivo human evidence suggesting that synapse pathology and loss of homeostatic microglial control is involved in the pathophysiology of both infectious delirium and AD and thus may provide a link for the association between infections, delirium and long-term cognitive decline.

Remote ischaemic preconditioning does not modulate the systemic inflammatory response or renal tubular stress biomarkers after endotoxaemia in healthy human volunteers: a single-centre, mechanistic, randomised controlled trial.

BACKGROUND: Remote ischaemic preconditioning (RIPC) consists of repeated cycles of limb ischaemia and reperfusion, which may reduce perioperative myocardial ischaemic damage and kidney injury. We hypothesised that RIPC may be beneficial by attenuating the systemic inflammatory response. We investigated whether RIPC affects the response in humans to bacterial endotoxin (lipopolysaccharide [LPS]) by measuring plasma cytokines and renal cell-cycle arrest mediators, which reflect renal tubular stress. METHODS: Healthy male volunteers were randomised to receive either daily RIPC for 6 consecutive days (RIPCmultiple, n=10) plus RIPC during the 40 min preceding i.v. LPS (2 ng kg-1), RIPC only during the 40 min before LPS (RIPCsingle, n=10), or no RIPC preceding LPS (control, n=10). As a surrogate marker of renal tubular stress, the product of urinary concentrations of two cell-cycle arrest markers was calculated (tissue inhibitor of metalloproteinases-2 [TIMP2]*insulin-like growth factor binding protein-7 [IGFBP7]). Data are presented as median (inter-quartile range). RESULTS: In both RIPC groups, RIPC alone increased [TIMP2]*[IGFBP7]. LPS administration resulted in fever, flu-like symptoms, and haemodynamic alterations. Plasma cytokine concentrations increased profoundly during endotoxaemia (control group: tumor necrosis factor alpha [TNF-α] from 14 [9-16] pg ml-1 at baseline to 480 [284-709] pg ml-1 at 1.5 h after LPS; interleukin-6 [IL-6] from 4 [4-4] pg ml-1 at baseline to 659 [505-1018] pg ml-1 at 2 h after LPS). LPS administration also increased urinary [TIMP2[*[IGFBP7]. RIPC had no effect on LPS-induced cytokine release or [TIMP2]*[IGFBP7]. CONCLUSIONS: RIPC neither modulated systemic cytokine release nor attenuated inflammation-induced tubular stress after LPS. However, RIPC alone induced renal markers of cell-cycle arrest. CLINICAL TRIAL REGISTRATION: NCT02602977.

Sustainability of clinical pathway guided care in cardiac surgery ICU patients; 9-years experience in over 7500 patients.

OBJECTIVE: To determine trends over time regarding inclusion of post-operative cardiac surgery intensive care unit (ICU) patients in a clinical pathway (CP), and the association with clinical outcome. DESIGN: Retrospective cohort study. SETTING: ICU of an academic hospital. PARTICIPANTS: All cardiac surgery patients operated between 2007 and 2015. MEASURES AND RESULTS: A total of 7553 patients were operated. Three patient groups were identified: patients treated according to CP (n = 6567), patients excluded from the CP within the first 48 h (n = 633) and patients never included in CP (n = 353). Patients treated according to CP increased significantly over time from 74% to 95% and the median Log EuroSCORE (predicted mortality score) in this group increased significantly over time (P = 0.016). In-hospital length of stay (LOS) decreased in all groups, but significantly in CP group (P < 0.001). Overall, the in-hospital, and 1-year mortality decreased from 1.5 to 1.1% and 3.7 to 2.9%, respectively (both P < 0.05). Patients with a Log EuroSCORE >10 were more likely excluded from CP (P < 0.001), but, if included in CP, these patients had a significantly shorter Intensive Care stay and in-hospital stay compared to excluded patients with a Log EuroSCORE >10 (both P < 0.001). CONCLUSIONS: The use of a CP for all post-operative cardiac surgery patients in the ICU is sustainable. While more complex patients were treated according to the CP, clinical outcome improved in the CP group.

Pharmacokinetics of Anidulafungin in Critically Ill Intensive Care Unit Patients with Suspected or Proven Invasive Fungal Infections.

Echinocandins, such as anidulafungin, are the first-line treatment for candidemia or invasive candidiasis in critically ill patients. There are conflicting data on the pharmacokinetic properties of anidulafungin in intensive care unit (ICU) patients. Adult ICU patients (from 3 hospitals) receiving anidulafungin for suspected or proven fungal infections were included in the present study. Patients were considered evaluable if a pharmacokinetic curve for day 3 could be completed. Twenty-three of 36 patients (7 female and 16 male) were evaluable. The median (range) age and body weight were 66 (28 to 88) years and 76 (50 to 115) kg, respectively. Pharmacokinetic sampling on day 3 (n = 23) resulted in a median anidulafungin area under the concentration-time curve from 0 to 24 h (AUC0-24) of 72.1 (interquartile range [IQR], 61.3 to 94.0) mg · h · liter-1, a median daily trough concentration (C24) of 2.2 (IQR, 1.9 to 2.9) mg/liter, a median maximum concentration of drug in serum (Cmax) of 5.3 (IQR, 4.1 to 6.0) mg/liter, a median volume of distribution (V) of 46.0 (IQR, 32.2 to 60.2) liters, and a median clearance (CL) of 1.4 (IQR, 1.1 to 1.6) liters · h-1 Pharmacokinetic sampling on day 7 (n = 13) resulted in a median AUC0-24 of 82.7 (IQR, 73.0 to 129.5) mg · h · liter-1, a median minimum concentration of drug in serum (Cmin) of 2.8 (IQR, 2.2 to 4.2) mg/liter, a median Cmax of 5.9 (IQR, 4.6 to 8.0) mg/liter, a median V of 39.7 (IQR, 32.2 to 54.4) liters, and a median CL of 1.2 (IQR, 0.8 to 1.4) liters · h-1 The geometric mean ratio for the AUCday7/AUCday3 term was 1.13 (90% confidence interval [CI], 1.03 to 1.25). The exposure in the ICU patient population was in accordance with previous reports on anidulafungin pharmacokinetics in ICU patients but was lower than that for healthy volunteers or other patient populations. Larger cohorts of patients or pooled data analyses are necessary to retrieve relevant covariates. (This study has been registered at ClinicalTrials.gov under identifier NCT01438216.).

Crew Resource Management in the Intensive Care Unit: a prospective 3-year cohort study.

BACKGROUND: Human factors account for the majority of adverse events in both aviation and medicine. Human factors awareness training entitled "Crew Resource Management (CRM)" is associated with improved aviation safety. We determined whether implementation of CRM impacts outcome in critically ill patients. METHODS: We performed a prospective 3-year cohort study in a 32-bed ICU, admitting 2500-3000 patients yearly. At the end of the baseline year, all personnel received CRM training, followed by 1 year of implementation. The third year was defined as the clinical effect year. All 7271 patients admitted to the ICU in the study period were included. The primary outcome measure was ICU complication rate. Secondary outcome measures were ICU and hospital length of stay, and standardized mortality ratio. RESULTS: Occurrence of serious complications was 67.1/1000 patients and 66.4/1000 patients during the baseline and implementation year respectively, decreasing to 50.9/1000 patients in the post-implementation year (P = 0.03). Adjusted odds ratios for occurrence of complications were 0.92 (95% CI 0.71-1.19, P = 0.52) and 0.66 (95% CI 0.51-0.87, P = 0.003) in the implementation and post-implementation year. The incidence of cardiac arrests was 9.2/1000 patients and 8.3/1000 patients during the baseline and implementation year, decreasing to 3.5/1000 patients (P = 0.04) in the post-implementation year, while cardiopulmonary resuscitation success rate increased from 19% to 55% and 67% (P = 0.02). Standardized mortality ratio decreased from 0.72 (95% CI 0.63-0.81) in the baseline year to 0.60 (95% CI 0.53-0.67) in the post-implementation year (P = 0.04). CONCLUSION: Our data indicate an association between CRM implementation and reduction in serious complications and lower mortality in critically ill patients.

Pharmacokinetics of caspofungin in ICU patients.

OBJECTIVES: Caspofungin is used for treatment of invasive fungal infections. As the pharmacokinetics (PK) of antimicrobial agents in critically ill patients can be highly variable, we set out to explore caspofungin PK in ICU patients. METHODS: ICU patients receiving caspofungin were eligible. Patients received a loading dose of 70 mg followed by 50 mg daily (70 mg if body weight >80 kg); they were evaluable upon completion of the first PK curve at day 3. Additionally, daily trough samples were taken and a second PK curve was recorded at day 7. PK analysis was performed using a standard two-stage approach. RESULTS: Twenty-one patients were evaluable. Median (range) age and body weight were 71 (45-80) years and 75 (50-99) kg. PK sampling on day 3 (n = 21) resulted in the following median (IQR) parameters: AUC0-24 88.7 (72.2-97.5) mg·h/L; Cmin 2.15 (1.40-2.48) mg/L; Cmax 7.51 (6.05-8.17) mg/L; V 7.72 (6.12-9.01) L; and CL 0.57 (0.54-0.77) L/h. PK sampling on day 7 (n = 13) resulted in AUC0-24 107.2 (90.4-125.3) mg·h/L, Cmin 2.55 (1.82-3.08) mg/L, Cmax 8.65 (7.16-9.34) mg/L, V 7.03 (5.51-7.73) L and CL 0.54 (0.44-0.60) L/h. We did not identify any covariates significantly affecting caspofungin PK in ICU patients (e.g. body weight, albumin, liver function). Caspofungin was well tolerated and no unexpected side effects were observed. CONCLUSIONS: Caspofungin PK in ICU patients showed limited intraindividual and moderate interindividual variability, and caspofungin was well tolerated. A standard two-stage approach did not reveal significant covariates. Our study showed similar caspofungin PK parameters in ICU patients compared with non-critically ill patients.

The effect of immunosuppressive therapies on the endothelial host response in critically ill COVID-19 patients.

While several effective therapies for critically ill patients with COVID-19 have been identified in large, well-conducted trials, the mechanisms underlying these therapies have not been investigated in depth. Our aim is to investigate the association between various immunosuppressive therapies (corticosteroids, tocilizumab and anakinra) and the change in endothelial host response over time in critically ill COVID-19 patients. We conducted a pre-specified multicenter post-hoc analysis in a Dutch cohort of COVID-19 patients admitted to the ICU between March 2020 and September 2021 due to hypoxemic respiratory failure. A panel of 18 immune response biomarkers in the complement, coagulation and endothelial function domains were measured using ELISA or Luminex. Biomarkers were measured on day 0-1, day 2-4 and day 6-8 after start of COVID-19 treatment. Patients were categorized into four treatment groups: no immunomodulatory treatment, corticosteroids, anakinra plus corticosteroids, or tocilizumab plus corticosteroids. The association between treatment group and the change in concentrations of biomarkers was estimated with linear mixed-effects models, using no immunomodulatory treatment as reference group. 109 patients with a median age of 62 years [IQR 54-70] of whom 72% (n = 78) was male, were included in this analysis. Both anakinra plus corticosteroids (n = 22) and tocilizumab plus corticosteroids (n = 38) were associated with an increase in angiopoietin-1 compared to no immune modulator (n = 23) (beta of 0.033 [0.002-0.064] and 0.041 [0.013-0.070] per day, respectively). These treatments, as well as corticosteroids alone (n = 26), were further associated with a decrease in the ratio of angiopoietin-2/angiopoietin-1 (beta of 0.071 [0.034-0.107], 0.060 [0.030-0.091] and 0.043 [0.001-0.085] per day, respectively). Anakinra plus corticosteroids and tocilizumab plus corticosteroids were associated with a decrease in concentrations of complement complex 5b-9 compared to no immunomodulatory treatment (0.038 [0.006-0.071] and 0.023 [0.000-0.047], respectively). Currently established treatments for critically ill COVID-19 patients are associated with a change in biomarkers of the angiopoietin and complement pathways, possibly indicating a role for stability of the endothelium. These results increase the understanding of the mechanisms of interventions and are possibly useful for stratification of patients with other inflammatory conditions which may potentially benefit from these treatments.

Vitamin D status is not associated with inflammatory cytokine levels during experimental human endotoxaemia.

Vitamin D has been shown to modulate innate immune responses in vitro and ex vivo; however, human in-vivo data are lacking. At high latitudes, seasonal vitamin D deficiency is common due to alternating ultraviolet (UV)-B radiation exposure. In the present study, we investigated whether levels of 25 hydroxyvitamin D(3) [25(OH)D(3) ] and its active metabolite 1,25 dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] are subject to seasonal variation and whether plasma levels of these vitamin D metabolites correlate with the in-vivo cytokine response during experimental human endotoxaemia [administration of lipopolysaccharide (LPS) in healthy volunteers]. Plasma levels of 25(OH)D(3) and 1,25(OH)(2) D(3) were determined in samples obtained just prior to administration of an intravenous bolus of 2 ng/kg LPS (derived from Escherichia coli O:113) in 112 healthy male volunteers. In the same subjects, plasma levels of the inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 were analysed serially after endotoxin administration. Plasma levels of 1,25(OH)(2) D(3) , but not 25(OH)D(3) , were subject to significant seasonal variation, with lower levels in autumn and winter. 25(OH)D(3) and 1,25(OH)(2) D(3) levels did not correlate with plasma cytokine responses. Furthermore, 25(OH)D(3) deficient subjects (< 50 nmol/l) displayed an identical cytokine response compared with sufficient subjects. In conclusion, plasma levels of vitamin D are not correlated with the LPS-induced TNF, IL-6 and IL-10 cytokine response in humans in vivo. These findings question the direct role of vitamin D in modulation of the innate immune response.

Decontamination of the digestive tract and oropharynx in ICU patients.

BACKGROUND: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) are infection-prevention measures used in the treatment of some patients in intensive care, but reported effects on patient outcome are conflicting. METHODS: We evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 intensive care units (ICUs), all in The Netherlands. Patients with an expected duration of intubation of more than 48 hours or an expected ICU stay of more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and standard care) were applied in random order over the course of 6 months. Mortality at day 28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application only of the same antibiotics. Monthly point-prevalence studies were performed to analyze antibiotic resistance. RESULTS: A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively. CONCLUSIONS: In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials number, ISRCTN35176830.)

Non-adherence to antimicrobial treatment guidelines results in more broad-spectrum but not more appropriate therapy.

Mortality in patients admitted with sepsis is high and the increasing incidence of infections with multiresistant bacteria is a worldwide problem. Many hospitals have local antimicrobial guidelines to assure effective treatment and limit the use of broad-spectrum antibiotics, thereby reducing the selection of resistant bacteria. We evaluated adherence to the antimicrobial treatment guidelines of our hospital in patients presenting to the emergency department (ED) with sepsis and assessed the in vitro susceptibility of isolated pathogens to the guideline-recommended treatment and the prescribed treatment. We included all adult patients with a known or suspected infection and two or more extended systemic inflammatory response syndrome (SIRS) criteria. Patients who did not receive antimicrobial treatment, presented with infections not included in the guidelines, or had more than one possible focus of infection were excluded. A total of 276 ED visits (262 patients) were included. Guideline-concordant treatment was prescribed in 168 visits (61%). In the case of guideline-disconcordant treatment, 87% was more broad-spectrum than guideline-recommended treatment. A microbiological diagnosis was established in 96 visits (35%). The susceptibility of the pathogens isolated from patients treated with guideline-concordant treatment (n=68) and guideline-disconcordant treatment (n=28) to guideline-recommended treatment (91% versus 89%) and to prescribed treatment (91% versus 93%) was similar (p=0.77 and p=0.79, respectively). In conclusion, non-adherence to the guidelines occurred frequently and resulted in more broad-spectrum empirical therapy. This did not result in a higher rate of susceptibility of the isolated pathogens to the prescribed empirical therapy.

Dynamic indices do not predict volume responsiveness in routine clinical practice.

BACKGROUND: Dynamic indices, including pulse pressure, systolic pressure, and stroke volume variation (PPV, SPV, and SVV), are accurate predictors of fluid responsiveness under strict conditions, for example, controlled mechanical ventilation using conventional tidal volumes (TVs) in the absence of cardiac arrhythmias. However, in routine clinical practice, these prerequisites are not always met. We evaluated the effect of regularly used ventilator settings, different calculation methods, and the presence of cardiac arrhythmias on the ability of dynamic indices to predict fluid responsiveness in sedated, mechanically ventilated patients. METHODS: We prospectively evaluated 47 fluid challenges in 29 consecutive cardiac surgery patients. Patients were divided into different groups based on TV. Dynamic indices were calculated in various ways: calculation over 30 s, breath-by-breath (with and without excluding arrhythmias), and with correction for TV. RESULTS: The predictive value was optimal in the group ventilated with TVs >7 ml kg(-1) with correction for TV, calculated breath-by-breath, and with exclusion of arrhythmias [area under the curve (AUC)=0.95, 0.93, and 0.90 for PPV, SPV, and SVV, respectively]. Including patients ventilated with lower TVs decreased the predictive value of all dynamic indices, while calculating dynamic indices over 30 s and not excluding cardiac arrhythmias further reduced the AUC to 0.51, 0.63, and 0.51 for PPV, SPV, and SVV, respectively. CONCLUSIONS: PPV, SPV, and SVV are the only reliable predictors of fluid responsiveness under strict conditions. In routine clinical practice, factors including low TV, cardiac arrhythmias, and the calculation method can substantially reduce their predictive value.

Hypoxemia in the presence or absence of systemic inflammation does not increase blood lactate levels in healthy volunteers.

PURPOSE: Elevated lactate levels are a sign of critical illness and may result from insufficient oxygen delivery. We investigated whether hypoxemia and/or systemic inflammation, results in increased lactate levels in healthy volunteers. MATERIALS AND METHODS: 30 healthy volunteers were exposed to either 3.5 h of hypoxemia (FiO2 ± 11.5%), normoxemic endotoxemia (FiO2 21%, administration of 2 ng/kg endotoxin), or hypoxemic endotoxemia (n = 10 per group). Blood lactate, hemoglobin, SpO2, PaO2, PaCO2, pH, and hemodynamic parameters were serially measured. RESULTS: Hypoxemic treatment resulted in lower SpO2 (81.7 ± 2.6 and 81.4 ± 2.4% in the hypoxemia and hypoxemic endotoxemia groups, respectively) and hyperventilation with a PaCO2 decrease of 0.8 ± 0.5 and 1.5 ± 0.6 kPa and an increase in pH. Arterial oxygen content (CaO2) decreased by 20.5 ± 2.9 and 23.5 ± 4.4%, respectively. Lactate levels were slightly, but significantly higher in both hypoxemic groups compared with the normoxemic endotoxemia group over time (p < 0.0001 for both groups), but remained below 2.3 mmol/L in all subjects. Whereas PaO2 and SpO2 did not correlate with lactate levels, PaCO2, pH and CaO2 did. CONCLUSIONS: Hypoxemia, in the absence or presence of inflammation does not result in relevant increases of lactate. The small increases in lactate observed are likely to be due to hyperventilation-related decreases in glycolysis.

Non-invasive measurement of pulse pressure variation and systolic pressure variation using a finger cuff corresponds with intra-arterial measurement.

BACKGROUND: Pulse pressure variation (PPV) and systolic pressure variation (SPV) are reliable predictors of fluid responsiveness in patients undergoing controlled mechanical ventilation. Currently, PPV and SPV are measured invasively and it is unknown if an arterial pressure (AP) signal obtained with a finger cuff can be used as an alternative. The aim of this study was to validate PPV and SPV measured using a finger cuff. METHODS: Patients receiving mechanical ventilation under sedation after cardiac artery bypass graft (CABG) surgery were included after arrival on the intensive care unit. AP was measured invasively in the radial artery and non-invasively using the finger cuff of the Nexfin™ monitor. I.V. fluid challenges were administered according to clinical need. The mean value of PPV and SVV was calculated before and after administration of a fluid challenge. Agreement of the calculated PPV and SPV from both methods was assessed using the Bland-Altman analysis. RESULTS: Nineteen patients were included and 28 volume challenges were analysed. Correlation between the two methods for PPV and SPV [mean (sd)=6.9 (4.3)% and 5.3 (2.6)%, respectively] was r=0.96 (P<0.0001) and r=0.95 (P<0.0001), respectively. The mean bias was -0.95% for PPV and -0.22% for SPV. Limits of agreement were -4.3% and 2.4% for PPV and -2.2% and 1.7% for SPV. The correlation between changes in PPV and SPV as a result of volume expansion measured by the two different methods was r=0.88 (P<0.0001) and r=0.87 (P<0.0001), respectively. CONCLUSIONS: In patients receiving controlled mechanical ventilation after CABG, PPV and SPV can be measured reliably non-invasively using the inflatable finger cuff of the Nexfin™ monitor.

α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-α production and lung injury.

BACKGROUND: Mechanical ventilation (MV) induces an inflammatory response that can lead to lung injury. The vagus nerve can limit the inflammatory response through the cholinergic anti-inflammatory pathway. We evaluated the effects of stimulation of the cholinergic anti-inflammatory pathway with the selective partial α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 on inflammation and lung injury induced by MV using clinically relevant ventilator settings. Furthermore, we investigated whether altering endogenous cholinergic signalling, by administration of the non-specific nAChR antagonist mecamylamine and the peripherally acting acetylcholinesterase inhibitor neostigmine, modulates the MV-induced inflammatory response. METHODS: C57BL6 mice were injected i.p. with either the selective α7nAChR agonist GTS-21 (8 mg kg(-1)), the acetylcholinesterase inhibitor neostigmine (80 µg kg(-1)), the nAChR antagonist mecamylamine (1 mg kg(-1)), or a placebo; followed by 4 h of MV (8 ml kg(-1), 1.5 cm H(2)O PEEP). RESULTS: MV resulted in release of cytokines in plasma and lungs compared with unventilated mice. Lung and plasma levels of tumour necrosis factor (TNF)-α, but not of interleukin-10, were lower in GTS-21-treated animals compared with placebo (P<0.05). In addition, GTS-21 lowered the alveolar-arterial gradient, indicating improved lung function (P=0.04). Neither neostigmine nor mecamylamine had an effect on MV-induced inflammation or lung function. CONCLUSIONS: MV with clinically relevant ventilator settings results in pulmonary and systemic inflammation. Stimulation of the cholinergic anti-inflammatory pathway with GTS-21 attenuates MV-induced release of TNF-α, which was associated with reduced lung injury. Modulation of endogenous cholinergic signalling did not affect the MV-induced inflammatory response. Selective stimulation of the cholinergic anti-inflammatory pathway may represent new treatment options for MV-induced lung injury.

Clinical pharmacology of exogenously administered alkaline phosphatase.

PURPOSE: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). METHODS: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg(-1) 24 h(-1)) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. RESULTS: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. CONCLUSIONS: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis.