Hans van der Hoeven

Vascular Endothelial Growth Factor Is Increased During The First 48 Hours Of Human Septic Shock And Correlates With Vascular Permeability

Meningococcal septic shock is an important cause of morbidity and mortality in children and young adults worldwide and is the prototypical gram-negative septic shock. One of the key factors in the development of shock is increased microvascular permeability. Vascular endothelial growth factor (VEGF) is a central factor in angiogenesis and is an important mediator of vascular permeability. Thirteen patients with meningococcal infection (eight presenting with shock) were investigated in the early phase of invasive meningococcal disease. Cytokines, complement activation, and VEGF plasma concentrations were measured during the first 48 h on the pediatric intensive care unit. Increased cytokine concentrations and activation of the complement system were observed. VEGF plasma concentrations were increased (median 193 pg/mL, range 71-1082) and were highest in the presence of shock (208 pg/mL, 169-1082) compared with patients presenting without shock (92 pg/mL range 71-299). VEGF concentration at admission correlated with the severity of disease (pediatric risk of mortality score, R = 0.90 [Spearman], P = 0.0001) and the amount of fluids administered within the first 24 h (R = 0.90, P < 0.0001). In all patients, a decrease in VEGF was associated with a decrease in fluid intake during t = 24 to 48 h. The results suggest that apart from correlation with IL-1β, −10, −12, and complement activation, microvascular permeability in sepsis is also closely linked to the plasma concentration of VEGF. The role of VEGF in sepsis-associated increased microvascular permeability needs further exploration and may represent a new therapeutic target.

Systemic inflammation increases intestinal permeability during experimental human endotoxemia.

Although the gut is often considered the motor of sepsis, the relation between systemic inflammation and intestinal permeability in humans is not clear. We analyzed intestinal permeability during experimental endotoxemia in humans. Before and during experimental endotoxemia (Escherichia coli LPS, 2 ng/kg), using polyethylene glycol (PEG) as a permeability marker, intestinal permeability was analyzed in 14 healthy subjects. Enterocyte damage was determined by intestinal fatty acid binding protein. Endotoxemia induced an inflammatory response. Urinary PEGs 1,500 and 4,000 recovery increased from 38.8 ± 6.3 to 63.1 ± 12.5 and from 0.58 ± 0.31 to 3.11 ± 0.93 mg, respectively (P < 0.05). Intestinal fatty acid binding protein excretion was not affected by endotoxemia. The peak serum IL-10 concentrations correlated with the increase in PEG 1,500 recovery (r = 0.48, P = 0.027). Systemic inflammation results in an increased intestinal permeability. The increase in intestinal permeability is most likely caused by inflammation-induced paracellular permeability, rather than ischemia-mediated enterocyte damage.

Implementation of a delirium assessment tool in the ICU can influence haloperidol use

IntroductionIn critically ill patients, delirium is a serious and frequent disorder that is associated with a prolonged intensive care and hospital stay and an increased morbidity and mortality. Without the use of a delirium screening instrument, delirium is often missed by ICU nurses and physicians. The effects of implementation of a screening method on haloperidol use is not known. The purpose of this study was to evaluate the implementation of the confusion assessment method-ICU (CAM-ICU) and the effect of its use on frequency and duration of haloperidol use.MethodsWe used a tailored implementation strategy focused on potential barriers. We measured CAM-ICU compliance, interrater reliability, and delirium knowledge, and compared the haloperidol use, as a proxy for delirium incidence, before and after the implementation of the CAM-ICU.ResultsCompliance and delirium knowledge increased from 77% to 92% and from 6.2 to 7.4, respectively (both, P < 0.0001). The interrater reliability increased from 0.78 to 0.89. More patients were treated with haloperidol (9.9% to 14.8%, P < 0.001), however with a lower dose (18 to 6 mg, P = 0.01) and for a shorter time period (5 [IQR:2–9] to 3 [IQR:1–5] days, P = 0.02).ConclusionsWith a tailored implementation strategy, a delirium assessment tool was successfully introduced in the ICU with the main goals achieved within four months. Early detection of delirium in critically ill patients increases the number of patients that receive treatment with haloperidol, however with a lower dose and for a shorter time period.

Hypercapnic acidosis attenuates the pulmonary innate immune response in ventilated healthy mice

Background:Mechanical ventilation with small tidal volumes reduces the development of ventilator-induced lung injury and mortality, but may increase Paco2. It is not clear whether the beneficial effect of a lung-protective strategy results from reduced ventilation pressures/tidal volumes or is mediated by the effects of hypercapnic acidosis on the inflammatory response involved in the pathogenesis of ventilator-induced lung injury. Objective:To analyze whether hypercapnic acidosis affects lung tissue cytokine levels and leukocyte influx in healthy ventilated mice. Study Design:Analysis of lung tissue and plasma concentrations of interleukin (IL)-1&bgr;, tumor necrosis factor (TNF)-&agr;, IL-6, IL-10, and keratocyte-derived chemokine after 2 hrs of mechanical ventilation (Vt 8 mL/kg, positive end-expiratory pressure 4 cm H2O) with 0.06% CO2 (room air), 2% CO2, or 4% CO2. Subjects:Healthy C57BL6 mice (n = 40). Measurements/Results:Paco2 and pH were within normal range when ventilated with 0.06% CO2 and significantly changed with 2% and 4% CO2: (mean ± sd) pH 7.23 ± 0.06 and 7.15 ± 0.04, Paco2 7.9 ± 1.4 and 10.8 ± 0.7 kPa, respectively (p < 0.005). Blood pressure remained within normal limits in all animals. Quantitative microscopic analysis showed a 4.7 ± 3.7-fold increase (p < 0.01) in pulmonary leukocyte influx in normocapnic ventilated animals and a significant reduction in leukocyte influx of 57 ± 32% (p < 0.01) and 67 ± 22% (p < 0.01) when ventilated with 2% and 4% CO2, respectively. Normocapnic ventilation induced a significant elevation of lung tissue IL-1&bgr; (1516 ± 119 ng/mL), TNF-&agr; (344 ± 88 ng/mL), IL-6 (6310 ± 807 ng/mL), IL-10 (995 ± 152 ng/mL), and keratocyte-derived chemokine (36,966 ± 15,294 ng/mL) (all p-values <0.01). Hypercapnic acidosis with 2% respectively 4% CO2 significantly attenuated this increase with 25 ± 32% and 54 ± 32% (IL-1&bgr;, p < 0.01); 17 ± 36% and 58 ± 33% (TNF-&agr;, p < 0.02); 22 ± 34% and 89 ± 6% (IL-6, p < 0.01); 20 ± 31% and 67 ± 17% (IL-10, p < 0.01) and 16 ± 44% and 45 ± 30% (keratocyte-derived chemokine, p = 0.07). Conclusion:Hypercapnic acidosis attenuates the mechanical ventilation-induced immune response independent from reduced tidal volumes/pressures and may protect the lung from ventilator induced lung injury.

The effect of systemic iNOS inhibition during human endotoxemia on the development of tolerance to different TLR-stimuli.

The phenomenon of repeated exposure to endotoxin resulting in diminished release of pro-inflammatory cytokines is called endotoxin tolerance, in which there is a putative role for nitric oxide (NO). We investigated the effect of selective inducible NO-synthase (iNOS) inhibition during experimental human endotoxemia on the development of tolerance to various Toll-like receptor (TLR) agonists ex vivo. Volunteers received 2 ng/kg Escherichia coli endotoxin in the absence (n = 7) or presence (n = 7) of the selective iNOS inhibitor aminoguanidine (bolus 5 mM followed by a continuous infusion of 1.5 mmol/h). At 0, 2 and 4 h, blood samples were drawn for ex vivo stimulation with different TLR agonists. Experimental endotoxemia did not induce tolerance to TLR-2 and TLR-7 stimulation. In TLR-3, TLR-4 and TLR-5 stimulated whole blood, pro- and anti-inflammatory cytokine release was attenuated at 4 h, indicating that endotoxin-induced tolerance is not confined to subsequent TLR-4 stimulation alone. Aminoguanidine-treated subjects also developed tolerance to TLR-4 stimulation. In contrast, tolerance to TLR-3 stimulation did not occur for IL-10, and tolerance in TLR-5 stimulated blood did not develop for both pro- and anti-inflammatory cytokines. The role of NO in the development of tolerance is different for the various TLRs stimulated and pro- and anti-inflammatory cytokines measured.

Stewart analysis of apparently normal acid-base state in the critically ill

PURPOSE This study aimed to describe Stewart parameters in critically ill patients with an apparently normal acid-base state and to determine the incidence of mixed metabolic acid-base disorders in these patients. MATERIALS AND METHODS We conducted a prospective, observational multicenter study of 312 consecutive Dutch intensive care unit patients with normal pH (7.35 ≤ pH ≤ 7.45) on days 3 to 5. Apparent (SIDa) and effective strong ion difference (SIDe) and strong ion gap (SIG) were calculated from 3 consecutive arterial blood samples. Multivariate linear regression analysis was performed to analyze factors potentially associated with levels of SIDa and SIG. RESULTS A total of 137 patients (44%) were identified with an apparently normal acid-base state (normal pH and -2 < base excess < 2 and 35 < PaCO2 < 45 mm Hg). In this group, SIDa values were 36.6 ± 3.6 mEq/L, resulting from hyperchloremia (109 ± 4.6 mEq/L, sodium-chloride difference 30.0 ± 3.6 mEq/L); SIDe values were 33.5 ± 2.3 mEq/L, resulting from hypoalbuminemia (24.0 ± 6.2 g/L); and SIG values were 3.1 ± 3.1 mEq/L. During admission, base excess increased secondary to a decrease in SIG levels and, subsequently, an increase in SIDa levels. Levels of SIDa were associated with positive cation load, chloride load, and admission SIDa (multivariate r(2) = 0.40, P < .001). Levels of SIG were associated with kidney function, sepsis, and SIG levels at intensive care unit admission (multivariate r(2) = 0.28, P < .001). CONCLUSIONS Intensive care unit patients with an apparently normal acid-base state have an underlying mixed metabolic acid-base disorder characterized by acidifying effects of a low SIDa (caused by hyperchloremia) and high SIG combined with the alkalinizing effect of hypoalbuminemia.

Abdominal compartment syndrome in neutropenic enterocolitis.

A 56-year-old woman was admitted to our hospital for the treatment of a recently diagnosed high-risk myelodysplastic syndrome (MDS, refractory anaemia with excess blasts, type 2). Remission induction combination chemotherapy consisted of cytarabine, etoposide and clofarabine. During a period of neutropenia she developed fever, which was initially treated empirically with ceftazidime. However, the fever persisted and she developed abdominal pain, diarrhoea and severe hypoalbuminaemia (albumin 13 g/l), raising the suspicion of neutropenic enterocolitis. Progressive abdominal distension, resulting from exudative ascites, was complicated by the occurrence of acute renal failure, respiratory insufficiency and reduced peripheral circulation (left). Contrast-enhanced computed tomography showed, in addition to ascites, bowel wall thickening, most prominently of the caecum and ascending colon (right). She was transferred to the intensive care unit. A compartment syndrome was suspected, which was supported by an elevated bladder pressure of 28 cm H2O (normal 10 cm H2O). Drainage of ascitic fluid resulted in improvement of both renal and respiratory failure. Cultures of blood and ascitic fluid revealed Clostridium tertium and Enterococcus faecalis indicative of severe mucositis with subsequent translocation of gut microbes. Peritonitis with massive exudative ascites causing abdominal compartment syndrome is a rare complication of neutropenic enterocolitis following treatment of leukaemia, which should be suspected when abdominal distension is accompanied by renal failure, respiratory distress and circulatory compromise. The treatment of choice is paracentesis to improve systemic circulation even in the context of sepsis.

Cardiac Surgery for Infective Endocarditis, Complicated by Septic Cardioembolic Stroke

To the Editor: We would like to comment on the recent article written by Dr Ruttmann et al on neurological outcome of cardiac surgery for infective endocarditis complicated by septic cardioembolic stroke.1 We congratulate the authors on their extensive and thorough research, which demonstrates that early surgical intervention appears to be safer than was previously thought. There is, nonetheless, an important question that remains unanswered, and we hope the authors will be able to respond. In our view, the results of the …

Het klinisch pad: een andere manier van werken?

Een klinisch pad moet gezien worden als een ‘day-to-day careplan’ waarin op een tijdlijn - van opname tot ontslag - alle multidisciplinaire activiteiten staan beschreven die nodig zijn om vooraf gestelde resultaten binnen een bepaald tijdskader te behalen.