Christian Wunder

Re-evaluating currently available data and suggestions for planning randomised controlled studies regarding the use of hydroxyethyl starch in critically ill patients - a multidisciplinary statement

IntroductionHydroxyethyl starch (HES) is a commonly used colloid in critically ill patients. However, its safety has been questioned in recent studies and meta-analyses.MethodsWe re-evaluated prospective randomised controlled trials (RCT) from four meta-analyses published in 2013 that compared the effect of HES with crystalloids in critically ill patients, focusing on the adherence to presumably correct indication. Regarding the definition of presumably correct indication, studies were checked for the following six criteria (maximum six points): short time interval from shock to randomisation (<6 h), restricted use for initial volume resuscitation, use of any consistent algorithm for haemodynamic stabilisation, reproducible indicators of hypovolaemia, maximum dose of HES, and exclusion of patients with pre-existing renal failure or renal replacement therapy.ResultsDuration of fluid administration ranged from 90 min up to a maximum of 90 days. Four studies considered follow-up until 90-day mortality, three studies 28-/30-day mortality, whereas four studies reported only early mortality. Included studies showed a large heterogeneity of the indication score ranging between 1 and 4 points with a median (25%; 75% quartile) of 4 (2; 4).ConclusionsThe most important question, whether or not HES may be harmful when it is limited to immediate haemodynamic stabilisation, cannot be answered yet in the absence of any study sufficiently addressing this question. In order to overcome the limitations of most of the previous studies, we now suggest an algorithm emphasising the strict indication of HES. Additionally, we give a list of suggestions that should be adequately considered in any prospective RCT in the field of acute volume resuscitation in critically ill patients.

The impact of crystalloid and colloid infusion on the kidney in rodent sepsis

PurposeVolume replacement remains one of the pillars of sepsis therapy. The effect of different volume solutions on kidney function in sepsis still remains unclear. We therefore determined the impact of crystalloid and colloid solutions on kidney function in a rodent model of abdominal sepsis induced by cecal ligation and puncture (CLP).MethodsAnesthetized rats underwent the CLP procedure, whereas control animals were sham operated. Septic animals were treated with crystalloid and colloid solutions. Hemodynamic variables and blood gases were measured. After 24xa0h animals were re-anesthetized, the kidneys were harvested, and creatinine (crea), urea, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were investigated.ResultsSeptic animals exhibited a mortality rate of 19% after 24xa0h. Gelatin-treated animals showed significantly increased levels of crea and urea. Colloids [gelatin 4% (Gel) or hydroxyethyl starch 6% 130/0.4 (HES)] as volume replacement resulted in elevated levels of NGAL. The histopathological observations revealed that Gel- and HES-treated animals showed vesicles within epithelial cells of the tubulus system and an overall increased injury. In contrast, total injury scores in groups treated with crystalloids [0.9% NaCl (NaCl) and Sterofundin® ISO (SteroIso)] were not significantly different compared to sham-treated animals.ConclusionNone of the examined volume solution was inert to the kidney. In a CLP rodent sepsis model, animals infused with balanced crystalloid SteroIso exhibited the least effects on kidney function. Both hydroxyethyl starch 6% 130/0.4 and gelatin 4% derogated the kidney, whereas gelatin was more harmful when compared with hydroxyethyl starch.

High-frequency oscillatory ventilation reduces lung inflammation: a large-animal 24-h model of respiratory distress

ObjectiveHigh-frequency oscillatory ventilation (HFOV) may reduce ventilator-induced lung injury in experimental neonatal respiratory distress. However, these data permit no conclusions for large animals or adult patients with acute respiratory distress syndrome (ARDS), because in neonates higher frequencies and lower amplitudes can be used, resulting in lower tidal volumes (VT) and airway pressures. The aim of this study was to compare gas exchange, lung histopathology and inflammatory cytokine expression during lung-protective pressure-controlled ventilation (PCV) and HFOV in axa0long-term large-animal model of ARDS.DesignProspective, randomized, controlled pilot study.SettingUniversity animal laboratory.SubjectsSixteen female pigs (55.3u202f±u202f3.9u202fkg).InterventionsAfter induction of ARDS by repeated lavage, the animals were randomly assigned to PCV (VTu202f=u202f6u202fml/kg) and HFOV (6u202fHz). After lung injury, axa0standardised lung recruitment was performed in both groups, and ventilation was continued for 24u202fh. Measurements and results: After lung recruitment sustained improvements in the oxygenation index were observed in both groups. The mean airway pressure (mPaw) was significantly lower in the HFOV group during the experiment (u202fpu202f<u202f0.01). Histologically, lung inflammation was significantly ameliorated in the HFOV group (u202fpu202f<u202f0.05). The messenger RNA expression of IL-1-β in lung tissue was significantly lower in the HFOV-treated animals (u202fpu202f<u202f0.01).ConclusionsThese data suggest that HFOV compared with conventional lung-protective ventilation can reduce lung inflammation in axa0large-animal 24-h model of ARDS. Furthermore, it was shown that lung recruitment leads to sustained improvements in gas exchange with axa0significantly lower mPaw when HFOV is used.

Phosphodiesterase-4 inhibition as a therapeutic approach to treat capillary leakage in systemic inflammation

•u2002 A specific therapy to treat capillary leakage in systemic inflammation and sepsis is not available at present. •u2002 Recent studies demonstrated that reduced cAMP levels in endothelial cells contribute to inflammation‐induced breakdown of the endothelial barrier. •u2002 The present study demonstrates that systemically applied phosphodiesterase‐4 inhibitors to increase endothelial cAMP are effective to prevent and to treat capillary leakage followed by improved microcirculation in a rodent model of systemic inflammation. •u2002 These data suggest a highly clinically relevant and applicable approach to stabilize capillary leakage in sepsis and systemic inflammation.

Arteriovenous extracorporeal lung assist as integral part of a multimodal treatment concept : a retrospective analysis of 22 patients with ARDS refractory to standard care

Background and objectives: Pumpless arteriovenous extracorporeal lung assist is increasingly used as a rescue therapy in acute respiratory distress syndrome. Arteriovenous extracorporeal lung assist is highly efficient in eliminating carbon dioxide and allows the application of ventilator techniques that prioritize lung protection and aim to reduce ventilator‐induced lung injury and remote organ dysfunction. Methods: Retrospective data analysis performed in a 12‐bed university hospital ICU. In all, 22 patients with acute respiratory distress syndrome refractory to standard care were included. Arteriovenous extracorporeal lung assist as central part of a multimodal treatment concept was combined with tidal volume (VT) reduction below 4 mL kg−1 predicted body weight, a positive end‐expiratory pressure titrated to optimize oxygenation and continuous axial rotation. Results: Hypercapnia was reversed within 24 h in survivors (39 mmHg (35‐42) (median and interquartile range) vs. 65 mmHg (54‐72), P < 0.05) and non‐survivors (5.2 kPa (5.5‐6.0) vs. 10 kPa (6.9‐13.9), P < 0.05). Oxygenation was significantly improved in survivors after 24 h (PaO2/FiO2 ratio 20.7 kPa (17.4‐22.7) vs. 11.7 kPa (7.3‐20.8), P < 0.05). All patients required norepinephrine infusion and volume resuscitation. The overall complication rate was 23%, predominantly due to reversible lower limb ischaemia. One patient (5%) was permanently disabled due to amputation of a seriously injured lower leg 9 days after initiation of arteriovenous extracorporeal lung assist therapy; however, the patient survived without neurological deficits despite an initial oxygenation index of 4.4 kPa. The overall mortality rate was 27%. Conclusions: A multimodal treatment concept with arteriovenous extracorporeal lung assist as its central part provides reversal of hypercapnia and stabilization of oxygenation. In an attempt to maximize lung protection and potentially reduce ventilator‐induced lung injury, a further VT reduction below 4 mL kg−1predicted body weight combined with a high mean airway pressure and continuous axial rotation is safely possible.

Soluble VE-cadherin is involved in endothelial barrier breakdown in systemic inflammation and sepsis

AIMSnMicrovascular endothelial barrier breakdown in sepsis precedes organ failure and death in patients. We tested the hypothesis that the formation of endothelium-derived soluble vascular endothelial (VE)-cadherin fragments (sVE-cadherin) is involved in inflammation-induced endothelial barrier disruption.nnnMETHODS AND RESULTSnIncubation of human dermal microvascular endothelial cells (HDMEC) with tumour necrosis factor-α (TNF-α) and bacterial lipopolysaccharide (LPS) led to endothelial barrier disruption which correlated with significantly increased sVE-cadherin at a size of ∼90 kDa in cell culture supernatants. Inhibition of the VE-cadherin-cleaving disintegrin and metalloproteinase ADAM10 using GI254023X attenuated inflammation-induced formation of sVE-cadherin and endothelial barrier disruption, suggesting ADAM10-mediated shedding as a mechanism underlying sVE-cadherin release. Formation of VE-cadherin fragments at 90 and 110 kDa was observed when recombinant VE-cadherin (rVE-cadherin) was digested with recombinant ADAM10. Mass spectrometry of the VE-cadherin fragments showed that they originated from cleavage of the extracelluar domain and thereby several cleavage sites of ADAM10 were identified. Atomic force microscopy measurements demonstrated that cell culture supernatants containing sVE-cadherin and application of rVE-cadherin blocked VE-cadherin binding. Accordingly rVE-cadherin dose-dependently led to loss of endothelial barrier functions in HDMEC monolayers. Finally, in patients suffering from severe sepsis or septic shock with clinical signs of a microvascular leackage, serum levels of sVE-cadherin were significantly increased.nnnCONCLUSIONnTaken together, formation of sVE-cadherin is associated and contributes to inflammation-induced breakdown of endothelial barrier functions by inhibition of VE-cadherin binding. The underlying mechanism of VE-cadherin cleavage involves ADAM10 and appears to be of clinical relevance since sVE-cadherin was augmented in patients with severe sepsis.

Liver dysfunction after lung recruitment manoeuvres during pressure-controlled ventilation in experimental acute respiratory distress

IntroductionConsequences of lung recruitment with prolonged high positive end-expiratory pressure (PEEP) ventilation for liver function are unclear. We therefore investigated liver dysfunction during two different ventilation treatment regimens of experimental acute respiratory distress syndrome.MethodsSixteen anaesthetised juvenile pietrain pigs were ventilated in the pressure-controlled mode (PCV) with an inspiratory fraction of oxygen (FiO2) of 1.0, a respiratory frequency of 30 per minute, a tidal volume of 6 ml/kg, and a PEEP of 5 cm H2O. After lung injury was induced by repeated pulmonary lavage with normal saline, animals were randomly assigned into two groups (n = 8 each) for a 24-hour trial: PCV (unchanged ventilation) and PCV with recruitment (PCV+R) (starting with a sustained inflation of 50 cm H2O for 1 minute, the ventilation was continued while increasing PEEP in increments of 3 cm H2O every 15 minutes as long as arterial oxygen tension [PaO2] improved). After recruitment, FiO2 was reduced to 0.4 and the PEEP was lowered every 15 minutes until PaO2 decreased to 12.0 to 14.7 kPa (90 to 110 torr). Serum levels of hyaluronic acid (HA), routine liver serum markers, and plasma disappearance rate of indocyanine green (ICG) were tested before and after lung injury, and 6 and 18 hours after randomisation. Liver serum markers were also tested at 24 hours. Paraffin sections of liver tissue stained by haematoxylin and eosin were made after euthanisation.ResultsThe PCV+R group exhibited more polymorphonuclear neutrophils and lymphocytes in the liver sinusoids: median score (interquartile range) of 1.5 (1.4 to 1.5) compared to 0.9 (0.7 to 1.1) (p = 0.01). Elevation of bilirubin, aspartate aminotransferase, and lactate dehydrogenase was more prominent in the PCV+R group. Plasma disappearance rate of ICG indicated no liver dysfunction. HA levels in the PCV+R group gradually increased and were significantly higher (p < 0.001) at 6 and 18 hours with 59 (57 to 64) and 75 (66 to 84) ng/ml, respectively, than in the PCV group with 34 (32 to 48) and 41 (38 to 42) ng/ml, respectively.ConclusionThe PCV+R group showed a more prominent inflammatory reaction in their liver sinusoids accompanied by increased serum levels of liver enzymes and HA. Therefore, recruitment with higher PEEP levels for treatment of respiratory failure might lead to liver dysfunction.

Carbon monoxide has antioxidative properties in the liver involving p38 MAP kinase pathway in a murine model of systemic inflammation.

Please cite this paper as: Brugger, Schick, Brock, Baumann, Muellenbach, Roewer and Wunder (2010). Carbon Monoxide has Antioxidative Properties in the Liver Involving p38 MAP Kinase Pathway in a Murine Model of Systemic Inflammation. Microcirculation17(7), 504–513.

Effects of crystalloids and colloids on liver and intestine microcirculation and function in cecal ligation and puncture induced septic rodents

BackgroundSeptic acute liver and intestinal failure is associated with a high mortality. We therefore investigated the influence of volume resuscitation with different crystalloid or colloid solutions on liver and intestine injury and microcirculation in septic rodents.MethodsSepsis was induced by cecal ligation and puncture (CLP) in 77 male rats. Animals were treated with different crystalloids (NaCl 0.9% (NaCl), Ringer’s acetate (RA)) or colloids (Gelafundin 4% (Gel), 6% HES 130/0.4 (HES)). After 24 h animals were re-anesthetized and intestinal (nu2009=u20096/group) and liver microcirculation (nu2009=u20096/group) were obtained using intravital microscopy, as well as macrohemodynamic parameters were measured. Blood assays and organs were harvested to determine organ function and injury.ResultsHES improved liver microcirculation, cardiac index and DO2-I, but significantly increased IL-1β, IL-6 and TNF-α levels and resulted in a mortality rate of 33%. Gel infused animals revealed significant reduction of liver and intestine microcirculation with severe side effects on coagulation (significantly increased PTT and INR, decreased haemoglobin and platelet count). Furthermore Gel showed severe hypoglycemia, acidosis and significantly increased ALT and IL-6 with a lethality of 29%. RA exhibited no derangements in liver microcirculation when compared to sham and HES. RA showed no intestinal microcirculation disturbance compared to sham, but significantly improved the number of intestinal capillaries with flow compared to HES. All RA treated animals survided and showed no severe side effects on coagulation, liver, macrohemodynamic or metabolic state.ConclusionsGelatine 4% revealed devastated hepatic and intestinal microcirculation and severe side effects in CLP induced septic rats, whereas the balanced crystalloid solution showed stabilization of macro- and microhemodynamics with improved survival. HES improved liver microcirculation, but exhibited significantly increased pro-inflammatory cytokine levels. Crystalloid infusion revealed best results in mortality and microcirculation, when compared with colloid infusion.

ACUTE RESPIRATORY DISTRESS INDUCED BY REPEATED SALINE LAVAGE PROVIDES STABLE EXPERIMENTAL CONDITIONS FOR 24 HOURS IN PIGS

Surfactant depletion is most often used to study acute respiratory failure in animal models. Because model stability is often criticized, the authors tested the following hypotheses: Repeated pulmonary lavage with normal saline provides stable experimental conditions for 24 hours with a PaO2/FiO2 ratio < 300 mm Hg. Lung injury was induced by bilateral pulmonary lavages in 8 female pigs (51.5 ± 4.8 kg). The animals were ventilated for 24 hours (PEEP: 5 cm H2O; tidal volume: 6 mL/kg; respiratory rate: 30/min). After 24 hours the animals were euthanized. For histopathology slides from all pulmonary lobes were obtained. Supernatant of the bronchoalveolar fluid collected before induction of acute respiratory distress syndrome (ARDS) and after 24 hours was analyzed. A total of 19 ± 6 lavages were needed to induce ARDS. PaO2/FiO2 ratio and pulmonary shunt fraction remained significantly deteriorated compared to baseline values after 24 hours (P <. 01). Slight to moderate histopathologic changes were detected. Significant increases of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were observed after 24 hours (P <. 01). The presented surfactant depletion–based lung injury model was associated with increased pulmonary inflammation and fulfilled the criteria of acute ling injury (ALI) for 24 hours.