Heijden M, Verheij J, van Nieuw Amerongen GP, Groeneveld AB. Crystalloid or colloid fluid loading and pulmonary permeability, edema, and injury in septic and nonseptic critically ill patients with hypovolemia
To compare crystalloid and colloid fluids in their effect on pulmonary edema in hypovolemic septic and nonseptic patients with or at risk for acute lung injury/acute respiratory distress syndrome. We hypothesized that 1) crystalloid loading results in more edema formation than colloid loading and 2) the differences among the types of fluid decreases at high permeability.
Prospective randomized clinical trial on the effect of fluids in 24 septic and 24 nonseptic mechanically ventilated patients with clinical hypovolemia.
Patients were assigned to NaCl 0.9%, gelatin 4%, hydroxyethyl starch 6%, or albumin 5% loading for 90 minutes according to changes in filling pressures.
Twenty-three septic and 10 nonseptic patients had acute lung injury/acute respiratory distress syndrome (p < 0.001). Septic patients had greater pulmonary capillary permeability, edema, and severity of lung injury than nonseptic patients (p < 0.01), as measured by the pulmonary leak index (PLI) for Gallium-labeled transferrin, extravascular lung water (EVLW), and lung injury score (LIS), respectively. Colloids increased plasma volume, cardiac index, and central venous pressure (CVP) more than crystalloids (p < 0.05), although more crystalloids were infused (p < 0.05). Colloid osmotic pressure (COP) increased in colloid and decreased in crystalloid groups (p < 0.001). Irrespective of fluid type or underlying disease, the pulmonary leak index increased by median 5% (p < 0.05). Regardless of fluid type or underlying disease, EVLW and LIS did not change during fluid loading and EVLW related to COP-CVP (rs = -.40, p < 0.01).
Pulmonary edema and LIS are not affected by the type of fluid loading in the steep part of the cardiac function curve in both septic and nonseptic patients. Then, pulmonary capillary permeability may be a smaller determinant of pulmonary edema than COP and CVP. Safety factors may have prevented edema during a small filtration pressure-induced rise in pulmonary protein and thus fluid transport.
"Although improved over the past decade, both sepsis and acute lung injury continue to have mortality rates >25% [8,14,39]. Sepsis itself is associated with pulmonary capillary permeability and pulmonary edema ; this is exacerbated in patients with ARDS, and correlates with mortality . In a murine model of acute lung injury, reduction of endothelial cell contractility was associated with reduced pulmonary neutrophil infiltration, reduced pulmonary edema formation, and improved survival . "
[Show abstract][Hide abstract] ABSTRACT: Sepsis is characterized by systemic immune activation and neutrophil-mediated endothelial barrier integrity compromise, contributing to end-organ dysfunction. Studies evaluating endothelial barrier dysfunction induced by neutrophils from septic patients are lacking, despite its clinical significance. We hypothesized that septic neutrophils would cause characteristic patterns of endothelial barrier dysfunction, distinct from experimental stimulation of normal neutrophils, and that treatment with the immunomodulatory drug beta-glucan would attenuate this effect.
Blood was obtained from critically ill septic patients. Patients were either general surgery patients (Primary Sepsis (PS)) or those with sepsis following trauma (Secondary Sepsis (SS)). Those with acute respiratory distress syndrome (ARDS) were identified. Healthy volunteers served as controls. Neutrophils were purified and aliquots were untreated, or treated with fMLP or beta-glucan. Endothelial cells were grown to confluence and activated with tissue necrosis factor (TNF)-alpha . Electric Cell-substrate Impedance Sensing (ECIS) was used to determine monolayer resistance after neutrophils were added. Groups were analyzed by two-way analysis of variance (ANOVA).
Neutrophils from all septic patients, as well as fMLP-normal neutrophils, reduced endothelial barrier integrity to a greater extent than untreated normal neutrophils (normalized resistance of cells from septic patients at 30 mins = 0.90 +/- 0.04; at 60 mins = 0.73 +/- 0.6 and at 180 mins = 0.56 +/- 0.05; p < 0.05 vs normal). Compared to untreated PS neutrophils, fMLP-treated PS neutrophils caused further loss of barrier function at all time points; no additive effect was noted in stimulation of SS neutrophils beyond 30 min. Neutrophils from ARDS patients caused greater loss of barrier integrity than those from non-ARDS patients, despite similarities in age, sex, septic source, and neutrophil count. Neutrophils obtained after resolution of sepsis caused less barrier dysfunction at all time points. beta-glucan treatment of septic patients' neutrophils attenuated barrier compromise, rendering the effect similar to that induced by neutrophils obtained once sepsis had resolved.
Neutrophils from septic patients exert dramatic compromise of endothelial barrier integrity. This pattern is mimicked by experimental activation of healthy neutrophils. The effect of septic neutrophils on the endothelium depends upon the initial inflammatory event, correlates with organ dysfunction and resolution of sepsis, and is ameliorated by beta-glucan.
"As HES should be limited to hypovolaemic patients, physicians have to pay more attention at haemodynamic parameters and specific triggers for volume therapy before HES infusion starts. However, in the majority of studies [1-4,7,18,20,21], we could not fully reproduce adequate indicators for haemodynamic instability, hypovolaemia, nor increased lactate from published baseline data, respectively. Only three trials [5,6,19] reported data on clinical signs that reasonably indicate hypovolaemia, thereby demonstrating that criteria for 'presumably correct indication' were met. "
[Show abstract][Hide abstract] ABSTRACT: Hydroxyethyl starch (HES) is a commonly used colloid in critically ill patients. However, its safety has been questioned in recent studies and meta-analyses.
We re-evaluated prospective randomised controlled trials (RCT) from four meta-analyses published in 2013 which 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 (max. 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.
Duration 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 to 4 points with a median (25%; 75% quartile) of 4 (2; 4).
The 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 adequately be considered in any prospective RCT in the field of acute volume resuscitation in critically ill patients.
"Up to 200 mL of fluid were given every 10 min, provided that the increase in CVP upon fluid loading did not exceed critical values, and this policy has been proven safe in previous studies (i.e. not evoking pulmonary edema)[24,28]. The maximum amount of fluid infused was 1800 mL. "
[Show abstract][Hide abstract] ABSTRACT: Sepsis-induced cardiac dysfunction may limit fluid responsiveness and the mechanism thereof remains unclear. Since cardiac function may affect the relative value of cardiac filling pressures, such as the recommended central venous pressure (CVP), versus filling volumes in guiding fluid loading, we studied these parameters as determinants of fluid responsiveness, according to cardiac function.
A delta CVP-guided, 90 min colloid fluid loading protocol was performed in 16 mechanically ventilated patients with sepsis-induced hypotension and three 30 min consecutive fluid loading steps of about 450 mL per patient were evaluated. Global end-diastolic volume index (GEDVI), cardiac index (CI) and global ejection fraction (GEF) were assessed from transpulmonary dilution. Baseline and changes in CVP and GEDVI were compared among responding (CI increase >=10% and >=15%) and non-responding fluid loading steps, in patient with low (<20%, n = 9) and near-normal (>=20%) GEF (n = 7) at baseline.
A low GEF was in line with other indices of impaired cardiac (left ventricular) function, prior to and after fluid loading. Of 48 fluid loading steps, 9 (of 27) were responding when GEF <20% and 6 (of 21) when GEF >=20. Prior to fluid loading, CVP did not differ between responding and non-responding steps and levels attained were higher in the former, regardless of GEF (P = 0.004). Prior to fluid loading, GEDVI (and CI) was higher in responding (1007 +/- 306 mL/m2) than non-responding steps (870 +/- 236 mL/m2) when GEF was low (P = 0.002), but did not differ when GEF was near-normal. Increases in GEDVI were associated with increases in CI and fluid responsiveness, regardless of GEF (P < 0.001).
As estimated from transpulmonary dilution, about half of patients with sepsis-induced hypotension have systolic cardiac dysfunction. During dysfunction, cardiac dilation with a relatively high baseline GEDVI maintains fluid responsiveness by further dilatation (increase in GEDVI rather than of CVP) as in patients without dysfunction. Absence of fluid responsiveness during systolic cardiac dysfunction may be caused by diastolic dysfunction and/or right ventricular dysfunction.
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