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.).

Communicating with conscious and mechanically ventilated critically ill patients: a systematic review.

BACKGROUND: Ventilator-dependent patients in the ICU often experience difficulties with one of the most basic human functions, namely communication, due to intubation. Although various assistive communication tools exist, these are infrequently used in ICU patients. We summarized the current evidence on communication methods with mechanically ventilated patients in the ICU. Secondly, we developed an algorithm for communication with these patients based on current evidence. METHODS: We performed a systematic review. PubMed, Embase, Cochrane, Cinahl, PsychInfo, and Web of Science databases were systematically searched to November 2015. Studies that reported a communication intervention with conscious nonverbal mechanically ventilated patients in the ICU aged 18 years or older were included. The methodological quality was assessed using the Quality Assessment Tool. RESULTS: The search yielded 9883 publications, of which 31 articles, representing 29 different studies, fulfilled the inclusion criteria. The overall methodological quality varied from poor to moderate. We identified four communication intervention types: (1) communication boards were studied in three studies-they improved communication and increased patient satisfaction, but they can be time-consuming and limit the ability to produce novel utterances; (2) two types of specialized talking tracheostomy tubes were assessed in eight studies-audible voicing was achieved in the majority of patients (range 74-100 %), but more studies are needed to facilitate safe and effective use; (3) an electrolarynx improved communication in seven studies-its effectiveness was mainly demonstrated with tracheostomized patients; and (4) "high-tech" augmentative and alternative communication (AAC) devices in nine studies with diverse computerized AAC devices proved to be beneficial communication methods-two studies investigated multiple AAC interventions, and different control devices (e.g., touch-sensitive or eye/blink detection) can be used to ensure that physical limitations do not prevent use of the devices. We developed an algorithm for the assessment and selection of a communication intervention with nonverbal and conscious mechanically intubated patients in the ICU. CONCLUSIONS: Although evidence is limited, results suggest that most communication methods may be effective in improving patient-healthcare professional communication with mechanically ventilated patients. A combination of methods is advised. We developed an algorithm to standardize the approach for selection of communication techniques.

Endothelial hyperpermeability after cardiac surgery with cardiopulmonary bypass as assessed using an in vitro bioassay for endothelial barrier function.

BACKGROUND: The mechanisms causing increased endothelial permeability after cardiopulmonary bypass (CPB) have not been elucidated. Using a bioassay for endothelial barrier function, we investigated whether endothelial hyperpermeability is associated with alterations in plasma endothelial activation and adhesion markers and can be attenuated by the use of pulsatile flow during CPB. METHODS: Patients undergoing cardiac surgery were randomized to non-pulsatile (n=20) or pulsatile flow CPB (n=20). Plasma samples were obtained before (pre-CPB) and after CPB (post-CPB), and upon intensive care unit (ICU) arrival. Changes in plasma endothelial activation and adhesion markers were determined by enzyme-linked immunosorbent assay. Using electric cell-substrate impedance sensing of human umbilical vein endothelial monolayers, the effects of plasma exposure on endothelial barrier function were assessed and expressed as resistance. RESULTS: Cardiopulmonary bypass was associated with increased P-selectin, vascular cell adhesion molecule-1, and von Willebrand factor plasma concentrations and an increase in the angiopoietin-2 to angiopoietin-1 ratio, irrespective of the flow profile. Plasma samples obtained after CPB induced loss of endothelial resistance of 21 and 23% in non-pulsatile and pulsatile flow groups, respectively. The negative effect on endothelial cell barrier function was still present with exposure to plasma obtained upon ICU admission. The reduction in endothelial resistance after exposure to post-CPB plasma could not be explained by CPB-induced haemodilution. CONCLUSION: The change in the plasma fingerprint during CPB is associated with impairment of in vitro endothelial barrier function, which occurs irrespective of the application of a protective pulsatile flow profile during CPB. CLINICAL TRIAL REGISTRATION: NTR2940.

Intravascular versus surface cooling speed and stability after cardiopulmonary resuscitation.

BACKGROUND AND OBJECTIVE: Mild therapeutic hypothermia (MTH) is used to limit neurological injury and improve survival after cardiac arrest (CA) and cardiopulmonary resuscitation, but the optimal mode of cooling is controversial. We therefore compared the effectiveness of MTH using invasive intravascular or non-invasive surface cooling with temperature feedback control. METHODS: This retrospective study in post-CA patients studied the effects of intravascular cooling (CoolGard, Zoll, n=97), applied on the intensive care unit (ICU) in one university hospital compared with those of surface cooling (Medi-Therm, Gaymar, n=76) applied in another university hospital. RESULTS: Time to reach target temperature and cooling speeds did not differ between groups. During the maintenance phase, mean core temperature was 33.1°C (range 32.7-33.7°C) versus 32.5°C (range 31.7-33.4°C) at targets of 33.0 and 32.5°C in intravascularly versus surface cooled patients, respectively. The variation coefficient for temperature during maintenance was higher in the surface than the intravascular cooling group (mean 0.85% vs 0.35%, p<0.0001). ICU survival was 60% and 50% in the intravascularly and surface cooled groups, respectively (NS). Lower age (OR 0.95; 95% CI 0.93 to 0.98; p<0.0001), ventricular fibrillation/ventricular tachycardia as presenting rhythm (OR 7.6; 95% CI 1.8 to 8.9; p<0.0001) and lower mean temperature during the maintenance phase (OR 0.52; 95% CI 0.25 to 1.08; p=0.081) might be independent determinants of ICU survival, while cooling technique and temperature variability did not contribute. CONCLUSIONS: In post-CA patients, intravascular cooling systems result in equal cooling speed, but less variation in temperature during the maintenance phase, as surface cooling. This may not affect the outcome.

Comparative performance of intensive care mortality prediction models based on manually curated versus automatically extracted electronic health record data.

INTRODUCTION: Benchmarking intensive care units for audit and feedback is frequently based on comparing actual mortality versus predicted mortality. Traditionally, mortality prediction models rely on a limited number of input variables and significant manual data entry and curation. Using automatically extracted electronic health record data may be a promising alternative. However, adequate data on comparative performance between these approaches is currently lacking. METHODS: The AmsterdamUMCdb intensive care database was used to construct a baseline APACHE IV in-hospital mortality model based on data typically available through manual data curation. Subsequently, new in-hospital mortality models were systematically developed and evaluated. New models differed with respect to the extent of automatic variable extraction, classification method, recalibration usage and the size of collection window. RESULTS: A total of 13 models were developed based on data from 5,077 admissions divided into a train (80%) and test (20%) cohort. Adding variables or extending collection windows only marginally improved discrimination and calibration. An XGBoost model using only automatically extracted variables, and therefore no acute or chronic diagnoses, was the best performing automated model with an AUC of 0.89 and a Brier score of 0.10. DISCUSSION: Performance of intensive care mortality prediction models based on manually curated versus automatically extracted electronic health record data is similar. Importantly, our results suggest that variables typically requiring manual curation, such as diagnosis at admission and comorbidities, may not be necessary for accurate mortality prediction. These proof-of-concept results require replication using multi-centre data.

[End of life decisions, the Dutch form through Spanish eyes]. / Toma de decisiones al final de la vida, el modo neerlandés a traves de ojos españoles.

Abroad, but also in The Netherlands, there are many misunderstandings concerning end of life decisions and euthanasia. In general, euthanasia does not play any role in the intensive care units, simply because it does not fulfill the conditions to carry it out. However, there is still confusion, merely due to the assumption that the Dutch situation is different because of their legislation on euthanasia. The use of the unclear terminology such as "passive euthanasia", "voluntary euthanasia" or "involuntary euthanasia" contributes to the confusion of lay people and physicians, and should therefore be avoided. End of life decisions in intensive care patients are in fact a structural part of work of intensivists. Collecting all necessary information including the wishes and will of the patient, medical expertise and acknowledging limitations of medical treatment will help to determine futility of treatment goals. Once it is determined that surviving the intensive care unit with a quality of life acceptable for the patient is beyond reach, the goal of treatment should be improved and the dying process optimized. Stopping a treatment modality at the request of a will-competent patient or because of futility is not euthanasia.

Between-trial heterogeneity in ARDS research.

PURPOSE: Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome. METHODS: A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity. RESULTS: In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I2 = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001). CONCLUSION: Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics.

The effect of rosiglitazone on asymmetric dimethylarginine (ADMA) in critically ill patients.

Asymmetric dimethylarginine (ADMA) plays a crucial role in the arginine-nitric oxide pathway. Critically ill patients have elevated levels of ADMA which proved to be a strong and independent risk factor for ICU mortality. The aim of this study was to investigate the effect of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone on ADMA plasma levels in critically ill patients. In a randomized controlled pilot study, ADMA, arginine and symmetric dimethylarginine (SDMA) were measured in 21 critically ill patients on the intensive care unit (ICU). Twelve patients received 4mg rosiglitazone once a day for a maximum of 6 weeks or until discharge or death. Nine patients served as control patients. In addition, total sequential organ failure assessment (SOFA score), kidney function and liver function were determined. Compared to the ADMA levels of healthy individuals as specified in earlier studies, ADMA plasma levels of critically ill patients were significantly higher (0.42+/-0.06 versus 0.73+/-0.2micromol/L, respectively; p<0.001). Both ADMA (B=3.5; 95% CI: 0.5-6.5; p=0.023) and SDMA (B=1.7; 95% CI: 0.7-2.7; p=0.001) were independently related to SOFA scores. Overall, rosiglitazone treatment had no effect on ADMA levels, which only significantly differed between the rosiglitazone and control groups at day 7 (p=0.028). The SOFA score in the rosiglitazone group was lower compared to the control group but the difference was only statistically significant at day 10 (p=0.01). In conclusion, in critically ill patients plasma ADMA levels were elevated and associated with the extent of multiple organ failure, but no significant ADMA-lowering effect of the PPAR-gamma agonist rosiglitazone was observed.

Achieving protein targets without energy overfeeding in critically ill patients: A prospective feasibility study.

BACKGROUND & AIMS: High protein delivery during early critical illness is associated with lower mortality, while energy overfeeding is associated with higher mortality. Protein-to-energy ratios of traditional enteral formulae are sometimes too low to reach protein targets without energy overfeeding. This prospective feasibility study aimed to evaluate the ability of a new enteral formula with a high protein-to-energy ratio to achieve the desired protein target while avoiding energy overfeeding. METHODS: Mechanically ventilated non-septic patients received the high protein-to-energy ratio nutrition during the first 4 days of ICU stay (n = 20). Nutritional prescription was 90% of measured energy expenditure. Primary endpoint was the percentage of patients reaching a protein target of ≥1.2 g/kg ideal body weight on day 4. Other endpoints included a comparison of nutritional intake to matched historic controls and the response of plasma amino acid concentrations. Safety endpoints were gastro-intestinal tolerance and plasma urea concentrations. RESULTS: Nineteen (95%) patients reached the protein intake target of ≥1.2 g/kg ideal body weight on day 4, compared to 65% in historic controls (p = 0.024). Mean plasma concentrations of all essential amino acids increased significantly from baseline to day 4. Predefined gastro-intestinal tolerance was good, but unexplained foul smelling diarrhoea occurred in two patients. In one patient plasma urea increased unrelated to acute kidney injury. CONCLUSIONS: In selected non-septic patients tolerating enteral nutrition, recommended protein targets can be achieved without energy overfeeding using a new high protein-to-energy ratio enteral nutrition.

Acute refractory hyperkalaemia and fatal cardiac arrest related to administration of liposomal amphotericin B.

A 36-year-old male with acute myeloid leukaemia was treated with liposomal amphotericin B for a breakthrough fungal infection with Absidia corymbifera during voriconazole and caspofungin therapy for invasive pulmonary aspergillosis. Four episodes of hyperkalaemia developed with a highly probable relation to infusion of liposomal amphotericin B, of which the last episode was characterised by severe, refractory hyperkalaemia and fatal cardiac arrest. The available literature on severe hyperkalaemia and cardiac arrest during administration of both conventional and liposomal amphotericin B is reviewed here and revealed only four similar cases. The most likely mechanism of toxicity is the release of potassium from a variety of mammal cells including erythrocytes and endothelial cells. Whether prevention of toxicity can be established by decreasing the infusion rate is unclear but conceivable.

Caregivers' perceptions towards communication with mechanically ventilated patients: The results of a multicenter survey.

PURPOSE: The purpose of this study was to investigate ICU health care providers' perception towards communication and associated problems with mechanically ventilated (MV) patients. The primary aim was to quantify the extent of the problem and to determine its effect on patient care and job satisfaction. METHODS: A multicenter survey study was conducted among nurses, residents and intensivists of 15 ICUs in the Netherlands using an online questionnaire. RESULTS: Out of 1740 caregivers, 457 responses were received. Communication difficulties were experienced in half of the interactions with MV patients. Over 75% of participants indicated that patient care was negatively affected. Job satisfaction was negatively affected in 43% of the participants, primarily with feelings of unfulfillment (76%) and frustration (72%). Patient factors considered relevant to communication difficulties were delirium, disease severity and anxiety, among others. To facilitate communication, the use of basic gestures remained the most preferred method. CONCLUSIONS: In half of the interactions with MV patients, health care professionals experience significant communication difficulties. The respondents indicated that these difficulties frequently lead to negative effects on patient care and job satisfaction. These results emphasize the need for improvements such as the development of communication protocols, skills training and continued research into new communication methods.

Management of invasive pulmonary aspergillosis in non-neutropenic critically ill patients.

During recent years, a rising incidence of invasive pulmonary aspergillosis (IPA) in non-neutropenic critically ill patients has been reported. Critically ill patients are prone to develop disturbances in immunoregulation during their stay in the ICU, which render them more vulnerable for fungal infections. Risk factors such as chronic obstructive pulmonary disease (COPD), prolonged use of steroids, advanced liver disease, chronic renal replacement therapy, near-drowning and diabetes mellitus have been described. Diagnosis of IPA may be difficult and obtaining histo- or cytopathological demonstration of the fungus in order to meet the gold standard for IPA is not always feasible in these patients. Laboratory markers used as a non-invasive diagnostic tool, such as the galactomannan antigen test (GM), 1,3-beta-glucan, and Aspergillus PCR, show varying results. Antifungal therapy might be considered in patients with persistent pulmonary infection who exhibit risk factors together with positive cultures or sequentially positive GM and Aspergillus PCR in serum, in whom voriconazole is the drug of choice. The benefit of combination antifungal therapy lacks sufficient evidence so far, but this treatment might be considered in patients with breakthrough infections or refractory disease.

[Abbreviations in daily language: stop it]. / Afkortingen in het dagelijks taalgebruik: stop ermee.

Abbreviations are used more and more in physician common parlance and it seems they are on the way to becoming a new jargon. However, identical abbreviations may have different meanings, especially in different medical specialties. Moreover, many physicians do not know the meaning of specific abbreviations or are attributing the wrong meaning to the abbreviation. This will lead to misunderstanding and therefore danger to the patient. The authors are calling for a stop on the use of spoken abbreviations and for minimising the use of abbreviations in clinical notes and medical prescriptions.

[Healthcare professionals back in the driving seat]. / Zorgprofessionals moeten stuur weer overnemen.

This commentary discusses the increasingly observed managerilisation of healthcare. Managerilisation frequently results in a framework of rules, regulations and accompanying time-consuming forms and procedures to guide decision-making. Although likely developed with the best of intentions in mind, this framework may be of limited value and tends to leave healthcare professionals feeling frustrated and distrusted. In addition, overzealous bureaucracy and rigid adherence to protocols may be disadvantageous to patient care and outcomes. Instead, we advocate a renewed focus on common sense and in particular on a renewed trust in healthcare professionals. Their professional judgement is based on many years of education and bedside experience. Hospital management should once again seek to embrace their expertise, while healthcare professionals should actively seek to regain the reins when it comes to delivering healthcare.

Hyperoxia does not directly affect vascular tone in isolated arteries from mice.

Hospitalized patients often receive oxygen supplementation, which can lead to a supraphysiological oxygen tension (hyperoxia). Hyperoxia can have hemodynamic effects, including an increase in systemic vascular resistance. This increase suggests hyperoxia-induced vasoconstriction, yet reported direct effects of hyperoxia on vessel tone have been inconsistent. Furthermore, hyperoxia-induced changes in vessel diameter have not been studied in mice, currently the most used mammal model of disease. In this study we set out to develop a pressure-myograph model using isolated vessels from mice for investigation of pathways involved in hyperoxic vasoconstriction. Isolated conduit and resistance arteries (femoral artery and gracilis arteriole, respectively) from C57BL/6 mice were exposed to normoxia (PO2 of 80 mmHg) and three levels of hyperoxia (PO2 of 215, 375 and 665 mmHg) in a no-flow pressure myograph setup. Under the different PO2 levels, dose-response agonist induced endothelium-dependent vasodilation (acetylcholine, arachidonic acid), endothelium-independent vasodilation (s-nitroprusside), as well as vasoconstriction (norepinephrine, prostaglandin F2α) were examined. The investigated arteries did not respond to oxygen by a change in vascular tone. In the dose-response studies, maximal responses and EC50 values to any of the aforementioned agonists were not affected by hyperoxia either. We conclude that arteries and arterioles from healthy mice are not intrinsically sensitive to hyperoxic conditions. The present ex-vivo model is therefore not suitable for further research into mechanisms of hyperoxic vasoconstriction.

Hyperoxia: At what level of SpO2 is a patient safe? A study in mechanically ventilated ICU patients.

BACKGROUND: Concerns have been expressed regarding a possible association between arterial hyperoxia and adverse outcomes in critically ill patients. Oxygen status is commonly monitored noninvasively by peripheral saturation monitoring (SpO2). However, the risk of hyperoxia above specific SpO2 levels in critically ill patients is unknown. The purpose of this study was to determine a threshold value of SpO2 above which the prevalence of arterial hyperoxia distinctly increases. METHODS: This is a cross-sectional study in adult mechanically ventilated intensive care patients in a tertiary referral center. In 100 patients, we collected 200 arterial blood gases (ABG) and simultaneously registered SpO2 levels, as well as hemodynamic and ventilation parameters and vasoactive medication. Patients under therapeutic hypothermia were excluded. RESULTS: The risk of arterial hyperoxia, defined as PaO2>100mmHg or >125mmHg, was negligible when SpO2 was ≤95% or ≤96%, respectively. The majority (89% and 54%, respectively for PaO2>100mmHg and 125mmHg) of ICU patients with SpO2 of 100% had arterial hyperoxia. The relation between SpO2 and PaO2 was not clearly affected by hemodynamic or other clinical variables (pH, pCO2, body temperature, recent blood transfusion). CONCLUSION: In critically ill patients, the prevalence of arterial hyperoxia increases when SpO2 is >95%. Above this saturation level, supplemental oxygen should be administered with caution in patients potentially susceptible to adverse effects of hyperoxia.

Fecal energy losses in enterally fed intensive care patients: an explorative study using bomb calorimetry.

BACKGROUND & AIMS: Early enteral nutrition and tailored supply of nutrients have become standard in most of the intensive care units (ICU). So far little attention has been given to losses of energy in the stools. The purpose of this explorative study was to evaluate the energy losses of patients with loose stools, necessitating the use of a feces-collector device in a tertiary academic ICU. METHODS: In a group of 13 fully enterally fed and mechanically ventilated patients with loose stools, the daily energy loss in feces was determined, using bomb calorimetry. Malabsorption was defined as an absorption capacity of 85% or less. Energy expenditure was determined with indirect calorimetry. RESULTS: Six out of 13 (46%) patients fulfilled the criterion of malabsorption. The mean total energetic absorption capacity was 84.6+/-13.3%. The mean capacity of absorption of fat was 89.7+/-16.3%. The caloric value of energy loss had a mean of 301+/-259 kcal/day. Fecal fat loss proved not to be a good indicator of total fecal energy loss. A total of 4/13 patients (31%) had a net negative energy balance of over 500 kcal/day. A daily feces production of 250 g or more was a good predictor of malabsorption. Energy loss could accurately be predicted by using a factor 4.87 for the combined energetic value of protein and carbohydrates, if dry weight and fecal fat content are known. CONCLUSIONS: In this clinical study on ICU patients with loose stools, malabsorption proved to be a frequently occurring and so far unrecognized problem, contributing strongly to negative energy balances in 1/3 of the patients.

Effects of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha and melphalan on the human fibrinolytic system.

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha (r-TNF-alpha) and melphalan, with or without pretreatment with recombinant IFN-gamma (r-IFN-gamma). Twenty patients were treated with r-TNF-alpha and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-alpha and melphalan, eight received r-IFN-gamma for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-alpha from the perfusion circuit to the systemic circulation was observed in all r-TNF-alpha-treated patients (mean maximum TNF-alpha, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF-alpha-treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controls; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 micrograms/liter in 22 h, respectively). No additional effect of IFN-gamma pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF-alpha and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF-alpha from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of microthrombi in the systemic circulation.

Neutrophil CD64 expression as a longitudinal biomarker for severe disease and acute infection in critically ill patients.

INTRODUCTION: Neutrophilic granulocytes express cluster of differentiation 64 (CD64) antigen upon activation. CD64 can be used as a marker of bacterial infection and sepsis. The goal of this study was to determine whether CD64 is a useful biomarker for critically ill patients and analyze longitudinal measurements with regard to outcome and sepsis severity. METHODS: In this prospective observational study, CD64 analysis was performed daily until discharge from ICU or death. Demographics, clinical, laboratory data, and outcome defined as 28-day survival were recorded. Patients were included when admitted to the ICU with sepsis, severe sepsis, or septic shock and within 24 h from start of antibiotic treatment. RESULTS: Hundred and fifty-five consecutive patients were enrolled. At baseline, a difference in CD64 of 2.26 (1.33-4.47) vs. 1.49 (0.89-2.24) (P = 0.004) was seen between patients with a positive culture and negative culture. CD64 at day 1 was higher with patients with septic shock when compared with sepsis (P = 0.012). No difference of CD64 between survivors and nonsurvivors was seen. CONCLUSION: This study demonstrated that CD64 discriminates between critically ill patients with culture positive and negative sepsis and correlates with severity of disease. However, CD64 index is not a good predictor for 28-day mortality in the critically ill patient.

Renal function, neurohormonal activation, and survival in patients with chronic heart failure.

BACKGROUND: Because renal function is affected by chronic heart failure (CHF) and it relates to both cardiovascular and hemodynamic properties, it should have additional prognostic value. We studied whether renal function is a predictor for mortality in advanced CHF, and we assessed its relative contribution compared with other established risk factors. In addition, we studied the relation between renal function and neurohormonal activation. METHODS AND RESULTS: The study population consisted of 1906 patients with CHF who were enrolled in a recent survival trial (Second Prospective Randomized study of Ibopamine on Mortality and Efficacy). In a subgroup of 372 patients, plasma neurohormones were determined. The baseline glomerular filtration rate (GFR(c)) was calculated using the Cockroft Gault equation. GFR(c) was the most powerful predictor of mortality; it was followed by New York Heart Association functional class and the use of angiotensin-converting enzyme inhibitors. Patients in the lowest quartile of GFR(c) values (<44 mL/min) had almost 3 times the risk of mortality (relative risk, 2. 85; P<0.001) of patients in the highest quartile (>76 mL/min). Impaired left ventricular ejection fraction (LVEF) was only modestly predictive (P=0.053). GFR(c) was inversely related with N-terminal atrial natriuretic peptide (ANP; r=-0.53) and, to a lesser extent, with ANP itself (r=-0.35; both P<0.001). CONCLUSIONS: Impaired renal function (GFR(c)) is a stronger predictor of mortality than impaired cardiac function (LVEF and New York Heart Association class) in advanced CHF, and it is associated with increased levels of N-terminal ANP. Moreover, impaired renal function was not related to LVEF, which suggests that factors other than reduced cardiac output are causally involved.