Aggravation of myocardial dysfunction by injurious mechanical ventilation in LPS-induced pneumonia in rats.

BACKGROUND: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo, through calcium (Ca2+)-dependent mechanism. MATERIALS AND METHODS: N = 35 male anesthetized and paralyzed male Wistar rats were randomized to intratracheal instillation of 2 mg/kg LPS or nothing and subsequent MV with lung-protective settings (low tidal volume (Vt) of 6 mL/kg and 5 cmH2O positive end-expiratory pressure (PEEP)) or injurious ventilation (high Vt of 19 mL/kg and 1 cmH2O PEEP) for 4 hours. Myocardial function ex vivo was evaluated in a Langendorff setup and Ca2+ exposure. Key mediators were determined in lung and heart at the mRNA level. RESULTS: Instillation of LPS and high Vt MV impaired gas exchange and, particularly when combined, increased pulmonary wet/dry ratio; heat shock protein (HSP)70 mRNA expression also increased by the interaction between LPS and high Vt MV. For the heart, C-X-C motif ligand (CXCL)1 and Toll-like receptor (TLR)2 mRNA expression increased, and ventricular (LV) systolic pressure, LV developed pressure, LV +dP/dtmax and contractile responses to increasing Ca2+ exposure ex vivo decreased by LPS. High Vt ventilation aggravated the effects of LPS on myocardial inflammation and dysfunction but not on Ca2+ responses. CONCLUSIONS: Injurious MV by high Vt aggravates the effects of intratracheal instillation of LPS on myocardial dysfunction, possibly through enhancing myocardial inflammation via pulmonary release of HSP70 stimulating cardiac TLR2, not involving Ca2+ handling and sensitivity.

Global end-diastolic volume increases to maintain fluid responsiveness in sepsis-induced systolic dysfunction.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 23 higher in the latter, regardless of GEF (P = 0.004). Prior to fluid loading, GEDVI (and CI) was higher in responding (1007 ± 306 mL/m(2)) than non-responding steps (870 ± 236 mL/m(2)) 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). CONCLUSIONS: 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.

Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study.

INTRODUCTION: Blood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI). METHODS: We performed a case control study in a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Cardiac surgery patients (n = 45) were grouped as follows: those who received no transfusion, those who received a restrictive transfusion (one two units of blood) or those who received multiple transfusions (at least five units of blood). Nondirected bronchoalveolar lavage fluid (BALF) and blood were obtained within 3 hours postoperatively. Normal distributed data were analyzed using analysis of variance and Dunnett's post hoc test. Nonparametric data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests. RESULTS: Restrictive transfusion increased BALF levels of interleukin (IL)-1ß and D-dimer compared to nontransfused controls (P < 0.05 for all), and IL-1ß levels were further enhanced by multiple transfusions (P < 0.01). BALF levels of IL-8, tumor necrosis factor α (TNFα) and thrombin-antithrombin complex (TATc) were increased after multiple transfusions (P < 0.01, P < 0.001 and P < 0.01, respectively) compared to nontransfused controls, but not after restrictive transfusions. Restrictive transfusions were associated with increased pulmonary levels of plasminogen activator inhibitor 1 compared to nontransfused controls with a further increase after multiple transfusions (P < 0.001). Concomitantly, levels of plasminogen activator activity (PAA%) were lower (P < 0.001), indicating impaired fibrinolysis. In the systemic compartment, transfusion was associated with a significant increase in levels of TNFα, TATc and PAA% (P < 0.05). CONCLUSIONS: Transfusion during cardiac surgery is associated with activation of inflammation and coagulation in the pulmonary compartment of patients who do not meet TRALI criteria, an effect that was partly dose-dependent, suggesting transfusion as a mediator of acute lung injury. These pulmonary changes were accompanied by systemic derangement of coagulation.

High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study.

BACKGROUND: To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses. METHODS: Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured. RESULTS: Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed. CONCLUSIONS: During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.

Less invasive indicators of changes in thermodilution cardiac output by ventilatory changes after cardiac surgery.

BACKGROUND AND OBJECTIVE: We studied whether changes in less invasive, noncalibrated pulse-contour cardiac output (by modified ModelFlow, COmf) and derived stroke volume variations (SVV), as well as systolic and pulse pressure variations, predict changes in bolus thermodilution cardiac output (COtd), evoked by continuous and cyclic increases in intrathoracic pressure by increases in positive end-expiratory pressure (PEEP) and tidal volume (Vt), respectively. METHODS: Prospective study on 17 critically ill postcardiac surgery patients on full mechanical ventilatory support, in the intensive care unit. RESULTS: In contrast to systolic pressure variation and pulse pressure variation, SVV increased from (mean +/- SD) 6.2 +/- 4.4 to 8.1 +/- 5.6 at PEEP 10 cmH2O (P = 0.064) and to 7.8 +/- 3.5% at PEEP 15 cmH2O (P = 0.031), concomitantly with a 12 +/- 7 and 11 +/- 8% decrease in COmf and COtd (P < 0.001), respectively. For pooled data, changes in COmf correlated with those in COtd (r = 0.55, P = 0.002), but changes in SVV did not. Variables did not change when Vt was increased up to 50%. CONCLUSION: A fall in COmf is more sensitive than a rise in SVV, which is more sensitive than systolic pressure variation and pulse pressure variation, in tracking a fall in COtd during continuous (and not cyclic) increases in intrathoracic pressure, in mechanically ventilated patients after cardiac surgery. This suggests a reduction in biventricular preload as the main factor in decreasing cardiac output and increasing SVV with PEEP.

Circulating cardiovascular markers and mediators in acute illness: an update.

An update is given of the circulating markers and mediators of cardiovascular dysfunction in acute illness. Some of these circulating markers reflect mediator action on the peripheral vasculature, such as endothelium-derived endothelin and nitrite/nitritate, the stable end products of nitric oxide. Other markers mainly reflect actions on the heart, such as the natriuretic peptide family, released from the heart upon dilatation, serving as a marker of congestive heart failure and potentially having negative inotropic effects. Indeed, some factors may be both markers as well as mediators of cardiovascular dysfunction of the acutely ill and bear prognostic significance. Assessing circulating levels may help refine clinical judgment of the cardiovascular derangements encountered at the bedside, together with clinical signs and hemodynamic variables. For instance, assessing natriuretic peptides in patients with pulmonary edema of unclear origin may help to diagnose congestive heart failure and cardiogenic pulmonary edema, when the pulmonary capillary wedge pressure is not measured or inconclusive. Future aligning of hemodynamic abnormalities with patterns of circulating cardiovascular markers/mediators may help to stratify patients for inclusion in studies to assess the causes, response to therapy and prognosis of cardiovascular derangements in the acutely ill.

Dose and type of crystalloid fluid therapy in adult hospitalized patients.

OBJECTIVE: In this narrative review, an overview is given of the pros and cons of various crystalloid fluids used for infusion during initial resuscitation or maintenance phases in adult hospitalized patients. Special emphasis is given on dose, composition of fluids, presence of buffers (in balanced solutions) and electrolytes, according to recent literature. We also review the use of hypertonic solutions. METHODS: We extracted relevant clinical literature in English specifically examining patient-oriented outcomes related to fluid volume and type. RESULTS: A restrictive fluid therapy prevents complications seen with liberal, large-volume therapy, even though restrictive fluid loading with crystalloids may not demonstrate large hemodynamic effects in surgical or septic patients. Hypertonic solutions may serve the purpose of small volume resuscitation but carry the disadvantage of hypernatremia. Hypotonic solutions are contraindicated in (impending) cerebral edema, whereas hypertonic solutions are probably more helpful in ameliorating than in preventing this condition and improving outcome. Balanced solutions offer a better approach for plasma composition than unbalanced ones, and the evidence for benefits in patient morbidity and mortality is increasing, particularly by helping to prevent acute kidney injury. CONCLUSIONS: Isotonic and hypertonic crystalloid fluids are the fluids of choice for resuscitation from hypovolemia and shock. The evidence that balanced solutions are superior to unbalanced ones is increasing. Hypertonic saline is effective in mannitol-refractory intracranial hypertension, whereas hypotonic solutions are contraindicated in this condition.

Activated protein C in the treatment of acute lung injury and acute respiratory distress syndrome.

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) frequently necessitate mechanical ventilation in the intensive care unit. The syndromes have a high mortality rate and there is at present no treatment specifically directed at the underlying pathogenesis. Central in the pathophysiology of ALI/ARDS is alveolocapillary inflammation leading to permeability edema. As a result of the crosstalk between inflammation and coagulation, activation of proinflammatory and procoagulant/antifibrinolytic pathways contributes to disruption of the endothelial barrier. Protein C (PC) plays a central role in maintaining the equilibrium between coagulation and inflammation. Additionally, natural anticoagulants, such as PC, are depleted, both in blood as well as in the lung. Therefore, the PC system is of interest as a therapeutic target in patients with ALI/ARDS. METHOD: This review is based on a Medline search of relevant basic and clinical studies. OBJECTIVE: It discusses the potential role of activated PC in modulating the proinflammatory/procoagulant state for enhancing endothelial barrier function in animal models and human ALI/ARDS.