Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.

INTRODUCTION: We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals. In answering questions raised regarding our study, we updated our database and repeated all analyses. METHODS: We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first. RESULTS: We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%). The median follow-up duration increased from 7 to 14 days. All patients received pharmacological thromboprophylaxis. The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%). The majority of thrombotic events were PE (65/75; 87%). In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92). Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12). Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8). CONCLUSION: In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.

Incidence of thrombotic complications in critically ill ICU patients with COVID-19.

INTRODUCTION: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available. METHODS: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital. RESULTS: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications. CONCLUSION: The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.

The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer.

INTRODUCTION: The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC. PATIENTS AND METHODS: Data from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (⩾ 50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel. RESULTS: From the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P = 0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0 months, respectively, logrank P = 0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase. CONCLUSION: Our study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.

A randomized trial comparing two intraosseous access devices in intrahospital healthcare providers with a focus on retention of knowledge, skill, and self-efficacy.

INTRODUCTION: Intraosseous access is recommended in vitally compromised patients if an intravenous access cannot be easily obtained. Intraosseous infusion can be initiated by various healthcare providers. Currently, there are two mechanical intraosseous devices approved by the U.S. Food and Drug Administration (FDA) for use in adults and children. A comparison is made in this study of the theoretical and practical performance by anesthesiologists and registered nurses of anesthesia (RNAs) in the use of the battery-powered device (device A) versus the spring-loaded needle device (device B). This study entailed a 12-month follow-up of knowledge, skill retention, and self-efficacy measured by standardized testing. METHODS: A prospective randomized trial was performed, initially comparing 15 anesthesiologists and 15 RNAs, both on using the two types of intraosseous devices. A structured lecture and skill station was given with the educational aids provided by the respective manufacturers. Individual knowledge and practical skills were tested at 0, 3, and 12 months after the initial course. RESULTS: There was no statistical significant difference in the retention of theoretical knowledge between RNAs and anesthesiologists on all testing occasions. However, the self-efficacy of the anesthesiologists is significantly higher (p < 0.01) than the self-efficacy of the RNAs for both devices, on any testing occasion. Insufficient skills were local disinfection (both groups, both devices) and attachment of the needle to the intravenous line (RNAs with both devices). In 33 % of all device B handlings, unsafe practice occurred. CONCLUSION: The use of device A is safer in handling in comparison to device B at 12 months follow-up. The hypothesis that doctors are more qualified in obtaining intraosseous access has been disproven, as anesthesiologists were as successful as RNAs. However, the low self-efficacy of RNAs in the use of intraosseous devices could diminish the chance of them actually using one.

Effect of the colloids gelatin and HES 130/0.4 on blood coagulation in cardiac surgery patients: a randomized controlled trial.

OBJECTIVE: The choice of the prime solution for cardiopulmonary bypass can play an important role in limiting the effect on blood coagulation, but it is still unclear what the effect of colloids on blood coagulation is. The aim of this study was to investigate the effect of synthetic colloids on blood loss and blood coagulation in patients after on-pump coronary artery bypass graft (CABG) procedures. METHODS: Sixty elective, on-pump CABG patients were randomly assigned to receive the prime solutions lactated Ringer's solution combined with hydroxyethyl starch 130/0.4 (HES, 6% Volulyte, Fresenius Kabi Nederland BV, Zeist, the Netherlands) (HES group) or gelatin (Gelofusin(®), B Braun Melsung AG, Melsungen, Germany) (Gelo group). Blood loss was assessed using post-operative chest tube output; secondary endpoints were number of blood component transfusions, routine coagulation test values and rotation thromboelastometry values (Rotem(®) delta, Pentapharm GmbH, Munich, Germany). RESULTS: Total post-operative chest tube output was 500 ± 420 ml in the HES group versus 465 ± 390 ml in the Gelo group (p = 0.48). No significant differences were observed in any of the routine coagulation tests values, thromboelastometry parameters or number of blood component transfusions between the groups. CONCLUSIONS: In this randomized, controlled trial of adults after on-pump CABG procedures, there was no significant difference in blood loss or blood coagulation between the HES group and the Gelo group.

Clinical evaluation of a new tracheal impedance cardiography method.

Non-invasive cardiac output measurement by means of impedance cardiography has been evaluated before, and agreement with other methods has been variable. We decided to study a newly developed tracheal impedance device, that is claimed to be more accurate and reliable. This incorporates new software and mathematical formulae, that are designed to reduce signal noise from diathermy, leading to improved accuracy. In 25 cardiothoracic surgery patients, simultaneous measurements were performed using both pulmonary artery thermodilution and the tracheal impedance device, at five peri-operative time points: before skin incision; after weaning from cardiopulmonary bypass; after sternal closure; and 30 min and 2 h after arrival in the intensive care unit. Mean cardiac output, bias and 95% limits of agreement were 5.3, 0.03 and -2.8 to 2.8 l.min(-1) , respectively. Tracheal impedance showed good correlation with measurement trends using thermodilution in 88% of measurements, with a mean (95% limit of agreement) angular bias of -9.0° (-83.3 to 65.3°). However, the wide limits of agreement and high percentage error of 53% that were apparent in this study mean that, in its present guise, tracheal impedance is not an acceptable alternative to thermodilution in cardiac surgical patients.

Improving compliance to meal-replacement food regimens. Forming implementation intentions (conscious IF-THEN plans) increases compliance.

Creating and changing habits around dieting behaviour can be a way to help consumers to consume more healthy products and to control their weight. Previous studies suggested that implementation intentions - deliberate plans on when, where and how - increase the likelihood that consumers perform the intended behaviour (Armitage, 2004; Gollwitzer & Sheeran, 2006; Jackson et al., 2005). This study investigated the effect of forming implementation intentions on compliance to a regimen based on a range of meal-replacement food products and snacks. Participants (n = 57) were allocated to one of two groups, either: (1) an implementation-intention group, who formed deliberate plans (implementation intentions) to consume the products - these implementation intentions were formed only once at the beginning of the study -, or (2) a control group who formed no implementation intentions. Participants were then instructed to follow a daily regimen, which included the consumption of foods from a range of meal-replacement products and snacks provided gratis for four weeks. Results showed that the implementation-intention group consumed significantly more meal-replacement food products per week (p < 0.05) and decreased their BMI score more than did the control group (p < 0.05). The effect of forming the implementation intentions was apparent for 18 days. These findings indicate that forming implementation intentions may assist individuals in their compliance to a meal-replacement product regimen.

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.)

[Percutaneous dilatating tracheostomy in intensive-care patients: technique, indications and complications]. / Percutane dilaterende tracheostomie bij intensive-carepatiënten: techniek, indicaties en complicaties.

Since tracheal cannulas are increasingly used to wean intensive-care patients from respiratory machines, more doctors and nurses will find themselves having to take care of patients with tracheostomas. Indications for tracheal cannula use include the likelihood of prolonged mechanical ventilation and/or difficult weaning. Percutaneous dilatational tracheotomy is a relatively simple procedure for inserting a tracheal cannula. It is performed using a modified Seldinger technique, carried out under general anaesthesia; use of a bronchoscope during the operation makes the procedure simpler and safer. When it is difficult to pinpoint the source of problems arising in patients fitted with a tracheal cannula, it must always be considered that the cannula might be the cause. Although rare, complications may arise several weeks or months after decanulation, such as stenosis of the trachea, changes in voice and fistula formation between the trachea and skin. A strict surveillance protocol is needed to recognize and treat late complication.

Noninvasive measurement of cardiac output: two methods compared in patients with mitral regurgitation.

In search for the origin of the less reliable cardiac output (CO) estimations by means of electrical impedance cardiography (EIC), the authors hypothesized that cardiac valve pathology might be one of the reasons. Twenty-six patients were examined by means of echo Doppler (ED) and EIC. The cardiac valve status was obtained by means of echocardiography and color Doppler flow, while CO was obtained by means of both methods. Seventeen patients had no valve pathology (nVP) while nine patients had mild to moderate mitral regurgitation (MVR). The overall correlation between the calculation of CO by means of the two methods was good (r = 0.85, p < 0.001, mean difference and standard deviation: 0.20+/-0.74 L/min), while there was no significant difference between the paired values. After division into an nVP and an MVR population, the results showed an even closer agreement between the CO values in the nVP population (r = 0.88, p < 0.001, mean difference and standard deviation: 0.15+/-0.68 L/min). Furthermore, significant differences were found in the first derivative of the impedance (dZ/dt) signals of these groups. Although the agreement between ED and EIC was slightly lower in the MVR population, EIC reliably estimated CO, even in case of MVR. The impedance signal itself gave an indication for the existence of MVR.

Does impedance cardiography reliably estimate left ventricular ejection fraction?

OBJECTIVE: The objective of our study was to evaluate impedance cardiography (IMP) as a noninvasive method to determine the left ventricular ejection fraction (LVEF). METHODS. A total of 24 patients, 8 men and 16 women, aged 45.0 +/- 12.9 years, participated in the study. They used cardiotoxic chemotherapeutic drugs or suffered from cardiac failure. LVEF was measured by means of IMP (LVEFimp) and radionuclide ventriculography (LVEFnuc). LVEFimp was calculated in three ways. Capan and colleagues [13] proposed a formula in which LVEF (LVEFCap) can be calculated from the systolic time intervals, namely, left ventricular ejection time and preejection time. Judy and colleagues [14] described a systolic (S) and a diastolic (D) part in the first derivative curve of the impedance signal. The ratio S/D might equal the LVEF (LVEFJud). A new LVEF calculation was introduced (LVEFimp) in this study based on the first derivative of the impedance signal, the thoracic impedance, and heart rate. RESULTS: Mean LVEFCap was 59.9 +/- 8.4%, which did not differ from LVEFnuc (59.9 +/- 7.1%). However the correlation between both methods was not significant (r = 0.29). Mean LVEFJud was 63.9 +/- 17.4%, which was not significantly different from LVEFnuc, with a fair correlation (r = 0.55). Mean LVEFimp was 59.2 +/- 9.4%, with a better correlation with radionuclide ventriculography (r = 0.75). CONCLUSIONS: The results of this study indicate that the equations that have been used until now can be improved. The new equation provides reliable LVEF values in this group of patients.

Binding studies of a monoclonal antibody specific for 3-deoxy-D-manno-octulosonic acid with a panel of Klebsiella pneumoniae lipopolysaccharides representing all of the O serotypes.

A monoclonal antibody (MAb) raised against Salmonella minnesota R595 and specific for alpha-3-deoxy-D-manno-octulosonic acid (alpha-Kdo) of the inner core was tested for binding to lipopolysaccharides (LPS) of Klebsiella pneumoniae. The MAb was tested in several assay systems (enzyme-linked immunosorbent assay, passive hemolysis, and inhibition of passive hemolysis) with a large panel (n = 23) of K. pneumoniae LPS representing all nine currently known O serotypes. MAb 20 showed reactivity with almost all O serotypes of K. pneumoniae LPS, and this reactivity could be inhibited by synthetic Kdo. This suggests an epitope in the cores of these Klebsiella LPS much like that in the inner core of LPS of S. minnesota. Large differences in reactivity between LPS of different strains belonging to the same O serotype were observed. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis of LPS followed by immunoblotting, reactivity of MAb 20 was observed only with the fast-moving fraction possibly representing the nonsubstituted core. No binding was seen with the high-molecular-weight fraction that contained core material substituted with several units of O-antigen building blocks. The chemical basis for these differences in reactivity remains to be established. As far as we know, this is the first report containing comprehensive immunochemical data on the LPS core of K. pneumoniae.

Antigenic and immunogenic differences in lipopolysaccharides of Escherichia coli J5 vaccine strains of different origins.

Escherichia coli strain J5 mutants of various origins have often been used as vaccines for induction of cross-reactive, cross-protective antibodies directed against the lipopolysaccharide (LPS) core region. The antigenic composition of LPS from J5 strains of different origin, i.e. strains J5(U), J5(UK), J5(2877) and J5(a), was investigated using monoclonal antibodies (mAbs) reactive only with LPS of a given chemotype, i.e. one specific for the incomplete E. coli core of the Rc chemotype, a second mAb reactive only with the E. coli R3 complete core, and a third specific for the O-antigen of E. coli serovar O111. The LPS of strains J5(U) and J5(a) is almost exclusively composed of LPS of the Rc chemotype, LPS of the J5(UK) strain is composed of Rc LPS and R3 complete core, while LPS of the J5(2877) strain contains Rc, R3 complete core and O-antigen. Growth of the bacteria in medium supplemented with galactose led to increased expression of complete core. The immune responses to the various strains were investigated. Antiserum to the J5 strain expressing the largest amount of R3 core [J5(UK)] had much higher anti-R3 LPS antibody titres compared to antiserum to the other strains. mAb 53, representative of the anti-R3 response to J5 strains containing complete core, bound to those E. coli LPS expressing the R3 core. Thus, the R3 LPS, present in some J5 vaccine strains is at least partially responsible for some of the cross-reactivities exhibited by some anti-J5 antisera.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-invasive monitoring of blood volume during hemodialysis: its relation with post-dialytic dry weight.

Hemodialysis has a profound effect on fluid balance. Since fluid is initially withdrawn from the intravascular compartment, blood volume will decrease rapidly. A fluid shift (refill) from the overhydrated interstitium towards the intravascular compartment counteracts hypovolemia. Underestimation of postdialytic dry weight will cause interstitial dehydration and consequently a low refill capacity. This can cause hypovolemia-induced hypotension, a serious problem in the daily practice of hemodialysis: during one out of three sessions a hypotensive episode occurs. Clinical criteria to estimate post-dialytic dry weight are insensitive. We have developed non-invasive methods to estimate dry weight and changes in blood volume (BV) more accurately. The aim of this study was to investigate the relation between hydration state of the patient and changes in BV during treatment. Therefore, 37 hemodialysis patients were divided into three groups according to their post-dialytic extracellular fluid volume (EFV), which was measured by means of the non-invasive conductivity method: de- (N = 11), normo- (N = 18), and overhydrated (N = 8). Using an on-line optical reflection method, changes in BV were measured continuously during hemodialysis. BV decrease, corrected for ultrafiltration, was stronger in the dehydrated (4.4 +/- 1.5%/liter) than in the normohydrated (3.3 +/- 1.5%/liter) and overhydrated (2.7 +/- 1.9%/liter) groups. In the dehydrated group, the frequency of hypotensive episodes (48.5 +/- 20.2%) was significantly greater compared to the normohydrated (20.5 +/- 23.5%) or overhydrated (6.5 +/- 6.5%) group, P < 0.005.(ABSTRACT TRUNCATED AT 250 WORDS)

General event representations of young children in a child psychiatric clinic.

Thirty-nine Children (5-8 years old) in a child psychiatric clinic and 50 5-year-old and 50 7-year-old schoolchildren were interviewed about two events: "getting dressed" and "a day in school". Both the children in the clinical and in the normal group formed general representations of these events. Children in the clinical group mentioned fewer acts, props and locations. Nearly all the children in both groups described how one gets dressed in the correct temporal order, but fewer children in the clinical than in the normal group described a day in school in the correct temporal order. Fewer children in the clinical than in the normal group gave causal explanations. Within the clinical group children with cognitive/attentional deficits tended to have less complete and less organized representations than children whose primary problems are relational.

Subunits VIIa,b,c of human cytochrome c oxidase. Identification of both 'heart-type' and 'liver-type' isoforms of subunit VIIa in human heart.

The N-terminal amino acid sequences and the electrophoretic mobilities of the subunits VIIa, VIIb and VIIc of cytochrome c oxidase purified from human heart were investigated and compared with those from human skeletal muscle and from bovine heart. In purified human heart cytochrome c oxidase, both so-called 'heart-type' and 'liver-type' isoforms of subunit VIIa were found. The first 30 residues of the N-terminal amino acid sequences of these 'heart-type' and 'liver-type' subunits VIIa showed nine differences. The two isoforms of subunit VIIa in human heart were present in almost equal amounts, in contrast to the situation in skeletal muscle, where the 'heart-type' subunit VIIa was predominant. Therefore, our results imply that in human heart a cytochrome c oxidase isoform pattern is present that differs from that found in skeletal muscle. Subunits VIIb and VIIc purified from human heart oxidase proved to be very similar to their bovine heart counterparts. Our direct demonstration of the presence of subunit VIIb, the sequence of which has only recently been identified in the bovine heart enzyme, suggests that human cytochrome c oxidase also contains 13 subunits. We found no evidence for the presence of different isoforms of subunit VIIc in cytochrome c oxidase from human heart and skeletal muscle. We observed clear differences in the electrophoretic mobility of the subunits VIIa,b,c between bovine and human cytochrome c oxidase. On Tricine/glycerol/SDS/polyacrylamide gels the 'heart-type' and 'liver-type' subunits VIIa present in human heart cytochrome c oxidase migrated with almost the same electrophoretic mobility. Subunit VIIb migrated only slightly faster than subunit VIIa, whereas VIIc proved to have the highest electrophoretic mobility on Tricine/SDS/glycerol/polyacrylamide gels. Our findings may have implications for the elucidation of certain tissue-specific cytochrome c oxidase deficiencies in man.