Abstract: Mechanical ventilation exaggerates pneumonia-associated pulmonary coagulopathy and inflammation. We hypothesized that the administration of plasma-derived human antithrombin (AT), one of the natural inhibitors of coagulation, prevents ventilator-induced pulmonary coagulopathy, inflammation and bacterial outgrowth in a Streptococcus pneumoniae pneumonia model in rats.
Abstract: In the era of lung-protective mechanical ventilation using limited tidal volumes, higher respiratory rates are applied to maintain adequate minute volume ventilation. However, higher respiratory rates may contribute to ventilator-induced lung injury (VILI). Induced hypothermia reduces carbon dioxide production and might allow for lower respiratory rates during mechanical ventilation. We hypothesized that hypothermia protects from VILI and investigated whether reducing respiratory rates enhance lung protection in an in vivo model of VILI. During 4 h of mechanical ventilation, VILI was induced by tidal volumes of 18 mL/kg in rats, with respiratory rates set at 15 or 10 breaths/min in combination with hypothermia (32°C) or normothermia (37°C). Hypothermia was induced by external cooling. A physiologic model was established. VILI was characterized by increased pulmonary neutrophil influx, protein leak, wet weights, histopathology score, and cytokine levels compared with lung protective mechanical ventilation. Hypothermia decreased neutrophil influx, pulmonary levels, systemic interleukin-6 levels, and histopathology score, and it tended to decrease the pulmonary protein leak. Reducing the respiratory rate in combination with hypothermia did not reduce the parameters of the lung injury. In conclusion, hypothermia protected from lung injury in a physiologic VILI model by reducing inflammation. Decreasing the respiratory rate mildly did not enhance protection.
Abstract: There is an association between blood transfusion and pulmonary complications in cardiac surgery. Mediators of increased pulmonary vascular leakage after transfusion are unknown. We hypothesized that factors may include antibodies or bioactive lipids, which have been implicated in transfusion-related acute lung injury.
Abstract: Preventing tissue-factor-(TF-) mediated systemic coagulopathy improves outcome in models of sepsis. Preventing TF-mediated pulmonary coagulopathy could attenuate ventilator-induced lung injury (VILI). We investigated the effect of relative TF deficiency on pulmonary coagulopathy and inflammation in a murine model of VILI. Heterozygous TF knockout (TF(+/-)) mice and their wild-type (TF(+/+)) littermates were sedated (controls) or sedated, tracheotomized, and mechanically ventilated with either low or high tidal volumes for 5 hours. Mechanical ventilation resulted in pulmonary coagulopathy and inflammation, with more injury after mechanical ventilation with higher tidal volumes. Compared with TF(+/+) mice, TF(+/-) mice demonstrated significantly lower pulmonary thrombin-antithrombin complex levels in both ventilation groups. There were, however, no differences in lung wet-to-dry ratio, BALF total protein levels, neutrophil influx, and lung histopathology scores between TF(+/-) and TF(+/+) mice. Notably, pulmonary levels of cytokines were significantly higher in TF(+/-) as compared to TF(+/+) mice. Systemic levels of cytokines were not altered by the relative absence of TF. TF deficiency is associated with decreased pulmonary coagulation independent of the ventilation strategy. However, relative TF deficiency does not reduce VILI and actually results in higher pulmonary levels of inflammatory mediators.
Abstract: Evaluate the effects of methylprednisolone on markers of inflammation, coagulation, and angiogenesis during early acute respiratory distress syndrome.
Abstract: To determine the effect of induced hypothermia on bacterial growth, lung injury, and mitochondrial function in a rat model of pneumococcal pneumosepsis.
Abstract: Although the use of computerized decision support systems (CDSS) in glucose control in the ICU has been reported, little is known about the effect of the systems' operating modes on the quality of glucose control. The objective of this study was to evaluate the effect of providing patient-specific and patient non-specific computerized advice on timing of blood glucose level (BGL) measurements. Our hypothesis was that both levels of support would be effective for improving the quality of glucose regulation and safety, with patient specific advice being the most effective strategy.
Abstract: There is evidence that percutaneous dilatational tracheotomy (PDT) can be safely performed in patients with severe coagulation disorders if these are carefully corrected immediately before the procedure. However, it is currently unclear whether PDT can be performed safely in patients in an Intensive Care Unit (ICU) with uncorrected mild coagulation disorders.
Abstract: To provide clinicians practicing in resource-limited settings with a framework to improve the diagnosis and treatment of pediatric and adult patients with sepsis.
Abstract: In the pathogenesis of sepsis, inflammation and coagulation play a pivotal role. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation not only leads to activation of coagulation but coagulation also considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may not only be relevant for vascular atherothrombotic disease in general but has in certain clinical settings considerable consequences, for example in the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Pro-inflammatory cytokines and other mediators are capable of activating the coagulation system and downregulating important physiological anticoagulant pathways. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by physiological anticoagulant mechanisms and endogenous fibrinolysis. Interestingly, apart from the overall systemic responses, a differential local response in various vascular beds related to specific organs may occur.
Abstract: Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to gross activation of coagulation that may result in localized thrombotic complications or systemic intravascular fibrin deposition. Systemic inflammation results in activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Proinflammatory cytokines, immune cells, and the endothelium play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice-versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Similar mechanisms appear to play a role in the development of atherosclerosis and related arterial thrombosis. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy.
Abstract: BACKGROUND: Cardiac surgery-related pulmonary complications include alterations in lung mechanics and anomalies in gas exchange. Higher levels of positive end-expiratory pressure (PEEP) have been suggested to benefit cardiac surgical patients. We compared respiratory compliance, arterial oxygenation and time till tracheal extubation in 2 cohorts of patients weaned from mechanical ventilation with different levels of PEEP after elective and uncomplicated coronary artery bypass grafting (CABG). We hypothesized that higher PEEP levels improve pulmonary compliance and gas exchange in the first hours of weaning from mechanical ventilation, but not to shorten time till tracheal extubation. MATERIALS AND METHODS: Secondary retrospective analysis of 2 randomized controlled trials: in the first trial patients were weaned with PEEP levels of 10 cmH2O for the first 4 hours followed by PEEP levels of 5 cmH2O until tracheal extubation (high PEEP, HP); and the second trial patients were weaned with PEEP levels of 5 cmH2O during the entire weaning phase (low PEEP, LP). The primary endpoint was pulmonary compliance. Secondary endpoints included arterial oxygenation, duration of mechanical ventilation and post-operative pulmonary complications. RESULTS: The analysis included 121 patients; 60 HP patients and 61 LP patients. Baseline characteristics were similar. Compared to LP patients, HP patients had a better pulmonary compliance, 47.2 ± 14.1 versus 42.7 ± 10.2 ml/cmH2O (P < 0.05), and higher levels of PaO2, 18.5 ± 6.6 (138.75 ± 49.5) versus 16.7 ± 5.4 (125.25 ± 40.5) kPa (mmHg) (P < 0.05). Patients in the HP group were less frequent in need of supplementary oxygen after ICU discharge. These differences remained present during the entire weaning phase, even after reduction of PEEP. However, HP patients had a longer time till tracheal extubation, 16.9 ± 6.1 versus 10.5 ± 5.0 hours (P < 0.001). HP patients had longer durations of postoperative infusion of propofol, 4.9 [2.6 - 7.4] versus 3.5 [1.8 - 5.8] hours (P < 0.05). There were no differences in use of inotropes. Cummulative fluid balances were sligthly higher in HP patients. CONCLUSION: Use of higher PEEP levels after elective uncomplicated CABG improves pulmonary compliance and oxygenation but seems to be associated with a delay in tracheal extubation.
Abstract: OBJECTIVES:: Patients with diabetes mellitus form 23%-30% of published cohorts of critically ill patients. Conflicting published evidence links diabetes mellitus to both higher and lower mortality. Other cohort studies suggest that diabetes mellitus protects against acute lung injury. We hypothesized that diabetes mellitus is an independent risk factor for mortality. We further hypothesized that diabetes mellitus is a risk factor for cardiac overload and not for acute lung injury. DESIGN:: Retrospective cohort study. SETTING:: The intensive care unit of a tertiary referral hospital. PATIENTS:: From November 1, 2004, to October 1, 2007, a cohort of patients admitted ≥48 hrs to the intensive care unit. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Of 2,013 patients, 317 had diabetes mellitus. Ninety-day mortality was higher in the diabetes mellitus patients compared to patients without diabetes mellitus (hazard ratio 1.53, 95% confidence interval 1.29-1.80). This association strengthened after adjusting for confounders and for medication (hazard ratio 1.53, 95% confidence interval 1.07-2.17).We found no association between diabetes mellitus and acute lung injury (relative risk ratio 1.01, 95% confidence interval 0.78-1.32; adjusted relative risk ratio 0.99, 95% confidence interval 0.75-1.31), but diabetes mellitus was a risk factor for cardiac overload (relative risk ratio 1.91, 95% confidence interval 1.30-2.81; adjusted relative risk ratio 1.45, 95% confidence interval 0.97-2.18). Statins were associated with both a reduced risk of mortality (hazard ratio 0.74, 95% confidence interval 0.63-0.87; adjusted hazard ratio 0.53, 95% confidence interval 0.44-0.64) and a decreased risk of developing acute lung injury (relative risk ratio 0.71, 95% confidence interval 0.56-0.89; adjusted relative risk ratio 0.61, 95% confidence interval 0.47-0.79). CONCLUSIONS:: Diabetes mellitus is an independent risk factor for mortality in critically ill patients and failure to adjust for statins underestimates the size of this association. Diabetes mellitus is not associated with acute lung injury but is associated with cardiac overload. A diagnosis of cardiac overload excludes a diagnosis of acute lung injury. Investigators who do not account for cardiac overload as a competing alternative outcome may therefore falsely conclude that diabetes mellitus protects from acute lung injury.
Abstract: Severe hypoglycemia (blood glucose concentration (BG) < 40 mg/dL) is independently associated with an increased risk of mortality in critically ill patients. The association of milder hypoglycemia (BG < 70 mg/dL) with mortality is less clear.
Abstract: Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes (LV(T)) or high tidal volumes (HV(T)). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with HV(T) as compared to LV(T). In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI.
Abstract: Acute renal failure is a common complication of severe malaria in adults, and without renal replacement therapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation may increase mortality. Earlier identification of patients who will need RRT may improve outcomes.
Abstract: Cardiac surgery is associated with post-operative reductions of functional residual capacity (FRC). Manual hyperinflation (MH) aims to prevent airway plugging, and as such could prevent the reduction of FRC after surgery. The main purpose of this study was to determine the effect of MH on post-operative FRC of cardiac surgical patients.
Abstract: Disturbed alveolar fibrin turnover is a characteristic feature of pneumonia. Inhibitors of coagulation could exert lung-protective effects via anticoagulant (inhibiting fibrin deposition) and possibly anti-inflammatory pathways, but could also affect host defense. In this randomized controlled in vivo laboratory study, rats were challenged intratracheally with Pseudomonas aeruginosa, inducing pneumonia, and randomized to local treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin, or danaparoid. Induction of P. aeruginosa pneumonia resulted in activation of pulmonary coagulation and inhibition of pulmonary fibrinolysis, as reflected by increased pulmonary levels of thrombin-AT complexes and fibrin degradation products and decreased pulmonary levels plasminogen activator activity. Pseudomonas aeruginosa pneumonia was accompanied by systemic coagulopathy, since systemic levels of thrombin-AT complexes increased, and systemic levels of plasminogen activator activity decreased. Although rh-APC and plasma-derived AT potently limited pulmonary coagulopathy, neither heparin nor danaparoid affected net pulmonary fibrin turnover. Recombinant human APC also displayed systemic anticoagulant effects. Neither bacterial clearance nor pulmonary inflammation was affected by anticoagulant therapy. Nebulization of rh-APC or plasma-derived AT attenuated pulmonary coagulopathy, but not bacterial clearance or inflammation, in a rat model of P. aeruginosa pneumonia.
Abstract: Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non-infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill.
Abstract: Hematologic factors, in particular platelets and the coagulation system, play an important role in the pathogenesis of organ failure in the intensive care unit. Failure of these hematologic systems is common in intensive care patients and may range from isolated thrombocytopenia or prolonged global clotting tests to complex defects, such as disseminated intravascular coagulation. There are many causes for a deranged coagulation in critically ill patients, and each of these underlying disorders may require specific therapeutic management. Hence, a proper differential diagnosis and initiation of adequate (supportive) treatment strategies are crucial to reduce morbidity and mortality in critically ill patients with coagulation abnormalities.
Abstract: This article discusses coagulation biomarkers in critically ill patients where coagulation abnormalities occur frequently and may have a major impact on the outcome. An adequate explanation for the cause is important, since many underlying disorders may require specific treatment and supportive therapy directed at the underlying condition. Deficiencies in platelets and coagulation factors in bleeding patients or patients at risk for bleeding can be achieved by transfusion of platelet concentrate or plasma products, respectively. Prohemostatic treatment may be beneficial in case of severe bleeding, whereas restoring physiological anticoagulant pathways may be helpful in patients with sepsis and disseminated intravascular coagulation.
Abstract: PURPOSE: Our hypothesis was that both styles are effective to decrease tidal volume (V(T)) but that critiquing comprises the most effective strategy. The purpose of this study is to test this hypothesis by measuring the effect of an active computerized decision support system, in 2 communication styles, consulting and critiquing, on adherence to V(T) recommendations. MATERIALS AND METHODS: We developed and implemented an active computerized decision support system (CDSS) working in a consulting style that always shows the preferred V(T) and in a critiquing style that shows the preferred V(T) only if V(T) is above the desired threshold. A prospective, off-on-off-on study evaluated the system's performance in a mixed medical-surgical intensive care unit of a university hospital. RESULTS: Four thousand seven hundred sixty-four patient-day mechanical ventilation from 757 patients were analyzed. The percentage of ventilation time in excess of 6 and 8 mL/kg predicted body weight decreased significantly after intervening with the consulting style (12% reduction and P < .001; 22% reduction and P < .001) and again increased after stopping the CDSS (11% increase and P < .001; 29% increase and P < .001). With the critiquing CDSS, the percentage of ventilation time in excess of 6 and 8 mL/kg predicted body weight again decreased significantly (6% reduction and P < .001; 15% reduction and P < .001). CONCLUSIONS: The use of a CDSS in both communication styles improved the use of lower V(T)s for ventilated patients. When decision support was not sustained, adherence to low V(T) fell back to its original value. Interestingly, the consulting style had a slightly larger effect. This may stem from the high frequency of showing reminders in this style and the relatively simple underlying guideline where its display implies the associated action of lowering V(T). The consulting style, however, was more interruptive for clinicians, calling upon the need to strike a balance between effect and intrusiveness.
Abstract: Optimal management of mechanical ventilation and weaning requires dynamic and collaborative decision making to minimize complications and avoid delays in the transition to extubation. In the absence of collaboration, ventilation decision making may be fragmented, inconsistent, and delayed. Our objective was to describe the professional group with responsibility for key ventilation and weaning decisions and to examine organizational characteristics associated with nurse involvement.
Abstract: Soluble urokinase-type plasminogen activator receptor (suPAR) has been proposed as a biologic marker of fibrinolysis and inflammation. The aim of this study was to investigate the diagnostic and prognostic value of systemic and pulmonary levels of suPAR in burn patients with inhalation trauma who need mechanical ventilation.
Abstract: To optimize the fluid status of adult patients with severe malaria, World Health Organization (WHO) guidelines recommend the insertion of a central venous catheter (CVC) and a target central venous pressure (CVP) of 0-5 cmH2O. However there are few data from clinical trials to support this recommendation.
Abstract: Mechanically ventilated critically ill patients frequently develop ventilator-associated pneumonia (VAP), a life-threatening complication. Proposed preventive measures against VAP include, but are not restricted to, selective decontamination of the digestive tract (SDD), selective oropharyngeal decontamination (SOD) and the use of probiotics. Probiotics are live bacteria that could have beneficial effects on the host by altering gastrointestinal flora. Similar to SDD and SOD, a prescription of probiotics aims at the prevention of secondary colonization of the upper and/or lower digestive tract.
Abstract: The clinical value of postoperative chest radiographs (CXRs) for surgical intensive care unit (ICU) patients is largely unknown. In the present study, we determined the diagnostic and therapeutic efficacy of postoperative CXRs for different surgical subgroups and related their efficacy to the time after ICU admission.
Abstract: Strict glycemic control (SGC) is reported to have a beneficial effect on critical illness polyneuropathy/myopathy (CINM) and the duration of mechanical ventilation. The methodology used to diagnose CINM differs substantially in studies on this topic. This may influence the reported treatment effect. We reviewed literature on the effect of SGC on CINM and duration of ventilation by conducting a OVID Medline systematic electronic search of literature describing effects of SGC on occurrence of CINM and the effect of SGC on the duration of mechanical ventilation. A beneficial effect of SGC on CINM, diagnosed by needle myography, was reported in three studies. One of these studies showed that the incidence of weakness or failure to wean did not decrease by SGC, as the number of electrophysiological studies (EMG) ordered for these problems remained the same. Another study reported no improvement of muscle strength due to SGC. SGC reduced the duration of mechanical ventilation in three studies while six other studies did not report this beneficial effect. SGC seems to have a beneficial effect on CINM, but the reported risk reduction is likely to be an overestimation of the treatment effect due to the diagnostic methods used. Duration of mechanical ventilation may not be a reliable surrogate marker for CINM and a beneficial effect of SGC on this parameter has not been proven. We propose to use the recently developed diagnostic criteria for ICU-acquired weakness and critical illness neuromyopathy in future studies.
Abstract: To systematically review the medical literature on the association between glucose variability measures and mortality in critically ill patients.
Abstract: To evaluate whether cystatin C in serum (sCyC) and urine (uCyC) can predict early acute kidney injury (AKI) in a mixed heterogeneous intensive care unit (ICU), and also whether these biomarkers can predict the need for renal replacement therapy (RRT).
Abstract: INTRODUCTION: Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. OBJECTIVE: To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI. DESIGN, SETTING, AND PATIENTS: Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (V(T), 10 mL/kg) with low tidal volume (V(T), 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase-associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4. RESULTS: Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P = .88.) The courses of neutrophil gelatinase-associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups. CONCLUSION: In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation.
Abstract: Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway inhibitor (rh-TFPI) attenuates sepsis-induced coagulation and has been evaluated in clinical trials involving patients with sepsis and community-acquired pneumonia.
Abstract: Chest radiographs (CXRs) are obtained frequently in the intensive care unit (ICU). Whether these CXRs should be performed routinely or on clinical indication only is often debated. The aim of our study was to investigate the incidence and clinical significance of abnormalities found on routine postoperative CXRs in cardiac surgery patients and whether a restricted use of CXRs would influence the number of significant findings.
Abstract: 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).
Abstract: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Both antibodies and bioactive lipids that have accumulated during storage of blood have been implicated in TRALI pathogenesis. In a single-center, nested, case-control study, patients were prospectively observed for onset of TRALI according to the consensus definition. Of 668 patients, 16 patients (2.4%) developed TRALI. Patient-related risk factors for onset of TRALI were age and time on the cardiopulmonary bypass. Transfusion-related risk factors were total amount of blood products (odds ratio [OR] = 1.2; 95% confidence interval [CI], 1.03-1.44), number of red blood cells stored more than 14 days (OR = 1.6; 95% CI, 1.04-2.37), total amount of plasma (OR = 1.2; 95% CI, 1.03-1.44), presence of antibodies in donor plasma (OR = 8.8; 95% CI, 1.8-44), and total amount of transfused bioactive lipids (OR = 1.0; 95% CI, 1.00-1.07). When adjusted for patient risk factors, only the presence of antibodies in the associated blood products remained a risk factor for TRALI (OR = 14.2; 95% CI, 1.5-132). In-hospital mortality of TRALI was 13% compared with 0% and 3% in transfused and nontransfused patients, respectively (P < .05). In conclusion, the incidence of TRALI is high in cardiac surgery patients and associated with adverse outcome. Our results suggest that cardiac surgery patients may benefit from exclusion of blood products containing HLA/HNA antibodies.
Abstract: Post-operative pulmonary complications add to the morbidity and mortality of surgical patients, in particular after general anesthesia >2 hours for abdominal surgery. Whether a protective mechanical ventilation strategy with higher levels of positive end-expiratory pressure (PEEP) and repeated recruitment maneuvers; the "open lung strategy", protects against post-operative pulmonary complications is uncertain. The present study aims at comparing a protective mechanical ventilation strategy with a conventional mechanical ventilation strategy during general anesthesia for abdominal non-laparoscopic surgery.
Abstract: Pulmonary coagulopathy is intrinsic to pneumonia and other forms of acute lung injury. We hypothesized patients with burn injuries and inhalation trauma to have similar alterations in pulmonary coagulation and fibrinolysis.
Abstract: A diver was resuscitated after cardiac arrest due to near drowning and was hypothermic on hospital arrival. During rewarming, status epilepticus occurred, previously identified as a predictor of poor outcome. The seizures responded well to treatment with antiepileptic drugs and controlled hypothermia. After six weeks, the patient had completely recovered. This case supports the hypothesis that hypothermia offers neuroprotection, even in the presence of status epilepticus. We recommend that near-drowning victims who are comatose after resuscitation for cardiac arrest be treated with controlled mild hypothermia for 12 to 24 hours.
Abstract: With adaptive support ventilation, respiratory rate and tidal volume (V(T)) are a function of the Otis least work of breathing formula. We hypothesized that adaptive support ventilation in an open lung ventilator strategy would deliver higher V(T)s to patients with acute lung injury.
Abstract: Systemic glucocorticoid therapy may effectively attenuate lung inflammation but also induce severe side-effects. Delivery of glucocorticoids by liposomes could therefore be beneficial. We investigated if liposome-encapsulated dexamethasone inhibited ventilator-induced lung inflammation. Furthermore, we evaluated whether targeting of cellular Fcγ-receptors (FcγRs) by conjugating immunoglobulin G (IgG) to liposomes, would improve the efficacy of dexamethasone-liposomes in attenuating granulocyte infiltration, one of the hallmarks of lung inflammation.
Abstract: Transfusion of erythrocytes is associated with increased morbidity in certain patient groups. Storage time of erythrocytes may contribute to respiratory complications. Using a syngeneic in vivo transfusion model, we investigated whether transfusion of stored rat erythrocytes causes lung injury in healthy and in lipopolysaccharide-primed rats in a "two-hit" model of lung injury.
Abstract: Glucose control (GC) with insulin decreases morbidity and mortality of critically ill patients. In this study we investigated GC performance over time during implementation of GC strategies within three intensive care units (ICUs) and in routine clinical practice.
Abstract: S-ketamine is frequently used for analgosedation, especially during sepsis and cardiovascular instability. Because S-ketamine blocks voltage-gated sodium (Na+) channels in neurons and skeletal muscle, it is conceivable that S-ketamine also blocks alveolar epithelial Na+ channels that are crucial for alveolar fluid clearance (AFC). We studied the effects of alveolar and IV S-ketamine on transalveolar Na+ transport and AFC, and investigated whether IV S-ketamine enters the alveolar space in response to endotoxemia-induced pulmonary inflammation.
Abstract: Glycemic control aiming at normoglycemia, frequently referred to as 'strict glycemic control' (SGC), decreased mortality and morbidity of adult critically ill patients in two randomized controlled trials (RCTs). Five successive RCTs, however, failed to show benefit of SGC with one trial even reporting an unexpected higher mortality. Consequently, enthusiasm for the implementation of SGC has declined, hampering translation of SGC into daily ICU practice. In this manuscript we attempt to explain the variances in outcomes of the RCTs of SGC, and point out other limitations of the current literature on glycemic control in ICU patients. There are several alternative explanations for why the five negative RCTs showed no beneficial effects of SGC, apart from the possibility that SGC may indeed not benefit ICU patients. These include, but are not restricted to, variability in the performance of SGC, differences among trial designs, changes in standard of care, differences in timing (that is, initiation) of SGC, and the convergence between the intervention groups and control groups with respect to achieved blood glucose levels in the successive RCTs. Additional factors that may hamper translation of SGC into daily ICU practice include the feared risk of severe hypoglycemia, additional labor associated with SGC, and uncertainties about who the primarily responsible caregiver should be for the implementation of SGC.
Abstract: Hyperglycemia and glycemic variabilities are associated with adverse outcomes in critically ill patients. Blood glucose control with insulin mandates an adequate and precise assessment of blood glucose levels. Blood glucose levels, however, can change ex vivo after sampling. The aim of this study was to determine whether this phenomenon affects the practice of blood glucose control.
Abstract: A large number of patients resuscitated for primary cardiac arrest arrive in the intensive care unit (ICU) with a body temperature < 35.0 degrees C. The aim of this observational cohort study was to determine the association between ICU admission temperature and neurological outcome in this patient group.
Abstract: Sepsis is associated with a dysregulation of apoptosis in immune cells, which has been implicated in both immunosuppression and multiple organ failure. We describe the expression profiles of genes encoding key regulators of apoptosis in highly purified monocytes, granulocytes and CD4+ T lymphocytes.
Abstract: The efficacy of routinely obtained chest radiographs (CXRs) on admission to the intensive care unit (ICU) is largely unknown. The current study investigated the efficacy of routinely obtained admission CXRs and determined whether the value of this diagnostic test was dependent on patient category.
Abstract: Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation.
Abstract: Adaptive support ventilation (ASV) is a microprocessor-controlled, closed-loop mode of mechanical ventilation that adapts respiratory rates and tidal volumes (V(T)s) based on the Otis least work of breathing formula. We studied calculated V(T)s in a computer simulation model, and V(T)s delivered in a test lung setting as well as in clinical practice.
Abstract: Preventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation.
Abstract: Seasonal and pandemic influenza are frequently complicated by bacterial infections, causing additional hospitalization and mortality. Secondary bacterial respiratory infection can be subdivided into combined viral/bacterial pneumonia and post-influenza pneumonia, which differ in their pathogenesis. During combined viral/bacterial infection, the virus, the bacterium and the host interact with each other. Post-influenza pneumonia may, at least in part, be due to resolution of inflammation caused by the primary viral infection. These mechanisms restore tissue homeostasis but greatly impair the host response against unrelated bacterial pathogens. In this review we summarize the underlying mechanisms leading to combined viral/bacterial infection or post-influenza pneumonia and highlight important considerations for effective treatment of bacterial pneumonia during and shortly after influenza.
Abstract: Transfusion-related acute lung injury is suggested to be a "2-hit" event resulting from priming and activation of pulmonary neutrophils. Activation may result from infusion of lysophosphatidylcholines (LysoPCs), which accumulate during storage of blood products. In the present study, we developed a syngeneic in vivo transfusion model to test whether storage of platelet concentrates (PLTs) results in lung injury in healthy rats as well as in a "2-hit" model using lipopolysaccharide-pretreated rats. In addition, the effect of washing of platelets was studied. In healthy rats, transfusion of aged PLTs caused mild lung inflammation. In LPS-pretreated rats, transfusion of aged PLTs, but not fresh PLTs, augmented pulmonary systemic coagulopathy. When PLTs components were transfused separately, supernatant of aged PLTs, but not washed aged platelets, induced pulmonary injury in the "2-hit" model. Supernatants of aged PLTs contained increased concentrations of LysoPCs compared with fresh PLTs, which enhanced neutrophil priming activity in vitro. We conclude that transfusion of aged PLTs induces lung inflammation in healthy rats. In a "2-hit" model, aged PLTs contribute to pulmonary and systemic coagulopathy, which may be mediated by LysoPCs, which accumulate in the supernatant of PLTs during storage.
Abstract: It is uncertain whether adaptive support ventilation (ASV) accelerates weaning of nonfast-track cardiothoracic surgery patients. A lower operator set %-minute ventilation with ASV may allow for an earlier definite switch from controlled to assisted ventilation, potentially hastening tracheal extubation. We hypothesized that ASV using protocolized de-escalation and escalation of operator set %-minute ventilation (ASV-DE) reduces time until tracheal extubation compared with ASV using a fixed operator set %-minute ventilation (standard ASV) in uncomplicated patients after nonfast-track coronary artery bypass graft.
Abstract: Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation.
Abstract: The goal of this study was to explore the ability of professional judgment to predict the need for tracheotomy early among intensive care unit (ICU) patients.
Abstract: Migration and activation of polymorphonuclear neutrophils (PMN) and apoptosis are central to inflammatory tissue damage. This study examines the relation of these processes, and their expression in the abdominal, systemic, and bronchoalveolar compartments in patients with severe peritonitis.
Abstract: Selective decontamination of the digestive tract (SDD) has been subject of numerous randomized controlled trials in critically ill patients. Almost all clinical trials showed SDD to prevent pneumonia. Nevertheless, SDD has remained a controversial strategy. One reason for why clinicians remained reluctant to implement SDD into daily practice could be that mortality was reduced in only 2 trials. Another reason could be the heterogeneity of trials of SDD. Indeed, many different prophylactic antimicrobial regimes were tested, and dissimilar diagnostic criteria for pneumonia were applied amongst the trials. This heterogeneity impeded interpretation and comparison of trial results. Two other hampering factors for implementation of SDD have been concerns over the risk of antimicrobial resistance and fear for escalation of costs associated with the use of prophylactic antimicrobials. This paper describes the concept of SDD, summarizes the results of published trials of SDD in mixed medical-surgical intensive care units, and rationalizes the risk of antimicrobial resistance and rise of costs associated with this potentially life-saving preventive strategy.
Abstract: Pulmonary coagulopathy may contribute to an adverse outcome in lung injury. We assessed the effects of local anticoagulant therapy on bronchoalveolar and systemic haemostasis in a rat model of endotoxemia-induced lung injury.
Abstract: Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation.
Abstract: Manual hyperinflation (MH) can be performed as part of airway management in intubated and mechanically ventilated patients to mobilize airway secretions. Although previous studies demonstrated MH to be associated with hemodynamic and respiratory instability, we hypothesized MH to cause fewer adverse events (AEs) when performed by experienced and trained nurses in stable critically ill patients.
Abstract: Feedback to clinicians on their past performance is often aimed at increasing adherence to guidelines. We investigate how various analytical approaches influence the interpretation of adherence data. The analytical approaches vary in considering the actual or the intended use of the feedback, and whether outcomes are inspected over time.
Abstract: Conventional methods to establish pleural infection are time-consuming and sometimes inadequate. Biomarkers may aid in making rapid diagnosis of infection. In an observational study we evaluated and compared the diagnostic value of pleural fluid levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), C-reactive protein and procalcitonin in intensive care patients with pleural effusions.
Abstract: Transfusion-related acute lung injury (TRALI) is hypothesized to be a "two-hit" entity, in which an inflammatory condition (e.g., sepsis) predisposes to TRALI. TRALI is a clinical diagnosis. Disciplines involved in managing TRALI may differ in decision-making on the reporting of TRALI.
Abstract: Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation. Systemic inflammation as a result of severe infection leads to activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Proinflammatory cytokines play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy. The relevance of the cross-talk between inflammation and coagulation is underlined by the results of the treatment of severe systemic infection with modulators of coagulation and inflammation.
Abstract: Acute lung injury is characterized by an exaggerated inflammatory response and a high metabolic demand. Mechanical ventilation can contribute to lung injury, resulting in ventilator-induced lung injury (VILI). A suspended-animation-like state induced by hydrogen sulfide (Hâ‚‚S) protects against hypoxia-induced organ injury. We hypothesized that suspended animation is protective in VILI by reducing metabolism and thereby COâ‚‚ production, allowing for a lower respiratory rate while maintaining adequate gas exchange. Alternatively, Hâ‚‚S may reduce inflammation in VILI.
Abstract: Coagulation disorders are common among intensive care patients and may range from isolated thrombocytopenia or prolonged global clotting tests to complex defects, such as disseminated intravascular coagulation. There are many causes for deranged coagulation in critically ill patients and each of these underlying disorders may require specific therapeutic management. Hence, a proper differential diagnosis and the initiation of adequate (supportive) treatment strategies are crucial to reduce morbidity and mortality in critically ill patients with coagulation abnormalities.
Abstract: Coagulation disorders are common among intensive care patients and may range from isolated thrombocytopenia or prolonged global clotting tests to complex defects, such as disseminated intravascular coagulation. There are many causes for deranged coagulation in critically ill patients and each of these underlying disorders may require specific therapeutic management. Hence, a proper differential diagnosis and the initiation of adequate (supportive) treatment strategies are crucial to reduce morbidity and mortality in critically ill patients with coagulation abnormalities.
Abstract: Transfusion-related acute lung injury (TRALI) occurs more often in critically ill patients than in a general hospital population, possibly due to the presence of underlying inflammatory conditions that may prime pulmonary neutrophils. Mechanical ventilation may be a risk factor for developing TRALI. We examined the influence of mechanical ventilation (MV) on the development of TRALI, combining a murine MV model causing ventilator-induced lung injury with a model of antibody-induced TRALl.
Abstract: Adaptive support ventilation (ASV) is a microprocessor-controlled mode of mechanical ventilation that switches automatically from controlled ventilation to assisted ventilation and selects ventilatory settings according to measured lung mechanics.
Abstract: Despite consensus criteria, diagnosing acute lung injury, or its more severe form acute respiratory distress syndrome (ALI/ARDS) remains challenging. Adding objective measures, such as plasma levels of biological markers could facilitate recognition of ALI/ARDS. This study was designed to assess and compare the diagnostic accuracy of biological markers for ALI/ARDS with ventilator-associated pneumonia (VAP).
Abstract: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI). Present models of VILI use exceptionally large tidal volumes, causing gross lung injury and haemodynamic shock. In addition, animals are ventilated for a relative short period of time and only after a 'priming' pulmonary insult. Finally, it is uncertain whether metabolic acidosis, which frequently develops in models of VILI, should be prevented. To study VILI in healthy mice, the authors used a MV model with clinically relevant ventilator settings, avoiding massive damage of lung structures and shock, and preventing metabolic acidosis.
Abstract: In a retrospective study among 35 severely septic patients treated with drotrecogin alfa (activated) (DrotAA) and renal replacement therapy (RRT), Camporota and colleagues demonstrated that the addition of heparin, epoprostenol, or both to DrotAA during RRT did not improve filter survival. Furthermore, in a multivariate logistic regression analysis, they identified the minimum value in platelet count as the only predictive factor of filter clotting during DrotAA infusion. These findings are in line with the previously formulated suggestion that DrotAA alone is as effective as heparin in the prevention of coagulation in the extracorporeal circuit. They also confirm the importance of baseline platelet count in the pathogenesis of extracorporeal circuit thrombosis. In the study by Camporata and colleagues, DrotAA treatment was not associated with an increase in red blood cell requirements. The results of this study supply a background to clinical decision making when choosing an anticoagulant for RRT in septic patients.
Abstract: Treatment strategies for critically-ill patients can and should never be excluded from grading processes that classify the evidence and provide decision support for health care workers involved in the care of these patients. Along with grading the available evidence, implementing new therapies and strategies in daily practice is another important but frequently forgotten step in improving care for critically-ill patients. Explanations for why some trials show benefit while other trials do not or even show harm include differences in the timing and the dose of the studied interventions, differences and heterogeneity of study populations and differences in trial protocols. Potential factors that may hamper the implementation of new therapies and strategies include translational problems, potentially biased expert opinions, concerns about side-effects and costs and problems with the recognition of critically-ill patients who might actually benefit from a new therapy or strategy. We discuss difficulties with grading the evidence for and the implementation of lung protective mechanical ventilation in acute respiratory distress syndrome, glucocorticosteroid therapy in refractory septic shock, glucocorticosteroid therapy in acute respiratory distress syndrome, goal directed fluid therapy in shock, activated protein C in severe sepsis and intensive insulin therapy in critical illness.
Abstract: Two decades ago, transfusion-related acute lung injury (TRALI) was considered a rare complication of transfusion medicine. Nowadays, TRALI has emerged as the leading cause of transfusion-related mortality, presumably as a consequence of reaching international agreement on defining TRALI with subsequent increased recognition and reporting of TRALI cases. Specific patient populations such as critically ill patients have an increased risk of developing TRALI, which may be explained by the two-event hypothesis. The first event is the underlying condition of the patient resulting in priming of neutrophils. The second event is the transfusion of a blood product, after which either antibodies or bioactive lipids activate the primed neutrophils, resulting in pulmonary oedema. As opposed to the traditional view that TRALI has a good prognosis, TRALI may have a significant impact on morbidity and outcome, at least in specific patient groups. The association of transfusion with adverse outcome calls for blood product and donor management strategies aimed at decreasing the risk of acquiring TRALI. Excluding female donors from plasma donation seems to have reduced, but not prevented the occurrence of TRALI . Additional research is needed to determine whether the use of fresh blood products may be an additional measure to reduce TRALI. Studies are also needed to identify at-risk patients. In these studies, we advocate the use of the consensus definition to improve comparability of risk factors and outcome of TRALI across patient populations.
Abstract: Disturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized anticoagulants on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.
Abstract: Data on the rationality of transfusion practice of fresh frozen plasma (FFP) and platelets in the critically ill are sparse and may contribute to efforts to reduce transfusion rates. To provide insight into determinants of the decision of intensive care unit (ICU)-physicians to transfuse, a survey study was performed. The reasons of ICU-physicians to transfuse FFP and platelets were determined during a 10-week period. Transfusion triggers were assessed, as well as correction of prolonged coagulation test results. Of 310 admissions, 44 patients (14%) received a transfusion of FFP and 35 patients (11%) received a platelet transfusion. In 67% patients, FFPs were transfused in bleeding patients and in 33% in non-bleeding patients. FFP was transfused at a prothrombin time (PT) of 19 s (17-22). After FFP transfusion, PT levels of 15-18, 18-20 and 20-26 s decreased with a median of 0.7, 1.9 and 3.5 s, respectively. On average, 3.2 FFP units were ordered, of which 28% was not transfused. The major reason to transfuse platelets was bleeding. Platelets were transfused at a platelet count of 95 (36-116) x 10(9) L(-1) in bleeding and 13 (10-18) x 10(9) L(-1) in non-bleeding patients. On average, 1.4 platelet units were ordered, of which 20% was not transfused. The agreement between physicians reporting a major bleeding and a definition of bleeding was poor (kappa < 0.10 for FFP and 0.20 for platelets). In conclusion, one-third of FFP transfusions was given to non-bleeding patients. FFP transfusion failed to normalize prolonged coagulation test results in the majority of the patients. Transfusion of platelets was restrictive in non-bleeding patients and liberal in bleeding patients. Education on indications of FFP transfusion and improved identification of bleeding may reduce transfusion rates.
Abstract: To determine if neurally adjusted ventilatory assist (NAVA) that delivers pressure in proportion to diaphragm electrical activity is as protective to acutely injured lungs (ALI) and non-pulmonary organs as volume controlled (VC), low tidal volume (Vt), high positive end-expiratory pressure (PEEP) ventilation.
Abstract: Identification of patients with ongoing abdominal infection after emergency surgery for abdominal sepsis is difficult. The purpose of this study was to evaluate whether plasma and abdominal fluid sTREM-1 levels can adequately select patients with ongoing abdominal infection. In a single center retrospective observational study, plasma and abdominal fluid samples were collected every 24 h for 4 days in patients who underwent an emergency laparotomy for severe secondary peritonitis. Patients after elective esophagus surgery served as controls. sTREM-1 levels were measured with an ELISA. Plasma sTREM-1 levels were not elevated compared to controls. Abdominal fluid sTREM-1 levels were initially high (median (246 [IQR 121-455] pg/ml), and declined 24 h after surgery (P=0.01). On day 2 and 3, patients with ongoing infection had significantly higher abdominal fluid sTREM-1 levels (319 [180-671] and 245 [173-541] pg/ml, respectively) compared to patients without infection (85 [49-306] and 121 [20-196] pg/ml, respectively). sTREM-1 levels were moderately predictive for persistent infection but had a high negative predictive value (0.86 (95% CI 0.69-0.94) below a cut-off level of 160 pg/ml. In clinical practice, abdominal fluid sTREM-1 levels may be useful for exclusion but not detection of ongoing abdominal infection after surgery for secondary peritonitis.
Abstract: The incidence of sepsis is increasing continuously, making mortality rate reduction through improved intensive care unit (ICU) care and new treatment modalities a pressing issue. This study aimed to provide insight into the effects of modern ICU care on mortality trends from severe sepsis and to provide a quantitative review of the relative effectiveness of new treatment modalities in reducing deaths.
Abstract: The aim of manual hyperinflation (MH) is to mobilize airway secretions and prevent sputum plugging in intubated and mechanically ventilated patients. With MH, the nurse applies a larger than normal breath with a slow inspiratory flow and, after an inspiratory pause, a high expiratory flow is created by completely releasing the resuscitation bag.
Abstract: We determined how often life support was withheld or withdrawn in patients who died in the intensive care unit (ICU) or early after ICU discharge and evaluated documentation on decisions regarding these changes in life support orders.
Abstract: Ventilator-induced lung injury is mediated, at least in part, by TNF-alpha. We determined the effect of a recombinant human soluble TNF receptor fusion protein (etanercept) on mechanical ventilation (MV)-induced changes in a murine ventilator-induced lung injury model. After pretreatment with etanercept or placebo, C57Bl/6 mice were anesthetized and randomized to MV with either low tidal volumes (VT, approximately 7.5 mL/kg) or high VT ( approximately 15 mL/kg) for 5 h. Instrumented but spontaneously breathing mice served as controls. End points were lung wet-to-dry ratios, lung histopathology scores, protein levels, neutrophil cell counts and thrombin-antithrombin complex levels in bronchoalveolar lavage fluid (BALF), and cytokine levels in lung homogenates. The number of caspase 3-positive cells was used as a measure for apoptosis. Etanercept treatment attenuated MV-induced changes, in particular, in MV with high VT. Compared with placebo, etanercept reduced the number of neutrophils in BALF and thrombin-antithrombin complex levels in BALF and cytokine levels in lung homogenates. Lung wet-to-dry ratios, histopathology scores, and local protein levels in BALF, however, were not influenced by etanercept treatment. The number of caspase 3-positive cells was significantly higher in etanercept-treated animals. Inhibition of TNF by etanercept attenuates, in part, MV-induced changes.
Abstract: A suspended animation-like state has been induced in rodents with the use of hydrogen sulfide, resulting in hypothermia with a concomitant reduction in metabolic rate. Also oxygen demand was reduced, thereby protecting against hypoxia. Several therapeutic applications of induction of a hibernation-like state have been suggested, including ischemia-reperfusion injury. More recently, hydrogen sulfide has been found to be protective in states of exaggerated inflammatory responses, such as acute lung injury. Possible mechanisms of this protective effect may include reduction of metabolism, as well as reduction of inflammation. In this manuscript, the methods of inducing a suspended animation-like state in experimental models using hydrogen sulfide are described. We discuss the effects of hydrogen sulfide-induced hypo-metabolism on hemodynamic, metabolic and inflammatory changes in animal models of various hypoxic and inflammatory diseases. In addition, potential therapeutic possibilities of hydrogen sulfide-induced hibernation are outlined.
Abstract: The purpose of the study was to measure the effect of a computerized decision support system (CDSS) on adherence to tidal volume (V(T)) recommendations.
Abstract: For reasons unknown, a restrictive transfusion policy of red blood cells (RBC) is only gradually being implemented by Intensive Care Unit (ICU) physicians, resulting in a large variation in transfusion practice. Insight into physicians' transfusion decisions may aid efforts to restrict transfusion practice.
Abstract: Delirium is a frequently missed diagnosis in the intensive care unit (ICU). Implementation of the Confusion Assessment Method for the ICU (CAM-ICU) may improve recognition of delirium. However, the ICU team may be reluctant to adopt daily assessment by a screening tool. This report focusses on the obstacles and barriers encountered with respect to organisational context and prevailing opinions and attitudes when implementing the CAM-ICU in daily practice in a Dutch ICU.
Abstract: Incidence reports on acute lung injury (ALI) vary widely. An insight into the diagnostic preferences of critical care physicians when diagnosing ALI may improve identification of the ALI patient population.
Abstract: To study whether selective decontamination of the digestive tract (SDD) results in detectable serum tobramycin concentrations in intensive care unit (ICU) patients with acute renal failure treated with continuous venovenous hemofiltration (CVVH).
Abstract: This study assessed the relative importance of clinical and transport-related factors in physicians' decision-making regarding the interhospital transport of critically ill patients.
Abstract: Two randomized controlled trials confirmed the existence of so-called ventilator-associated lung injury by showing reduced morbidity and mortality with the use of lower tidal volumes in patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). While guidelines now strongly advise using lower tidal volumes in ALI/ARDS patients, at present there are no widely agreed upon guidelines for setting tidal volumes in patients who do not suffer from ALI/ARDS. The literature was searched for clinical studies on lung-protective mechanical ventilation using lower tidal volumes in patients not suffering from ALI/ARDS. The best available evidence comes from large retrospective or observational studies which suggest a causal relation between the use of large tidal volumes and the development of lung injury. The inconsistent results from smaller randomized controlled trials, however, do not definitely support the use of lower tidal volumes. The association with potentially injurious ventilator settings, in particular large tidal volumes, suggests that additional lung injury in mechanically ventilated patients without ALI/ARDS is, in part, a preventable complication. Nevertheless, more prospective studies are needed to evaluate optimal ventilator management strategies for patients not suffering from ALI/ARDS.
Abstract: High-mobility group box (HMGB) 1 is a recently discovered proinflammatory mediator that contributes to acute lung injury. We determined HMGB-1 levels in bronchoalveolar lavage fluid of patients during mechanical ventilation (MV) and ventilator-associated pneumonia (VAP). Bronchoalveolar lavage fluid was obtained from patients who were ventilated for 5 h because of an elective surgical procedure ("short-term MV"; n = 40) or for several days because of respiratory failure without acute lung injury ("long-term MV"; n = 10) and from patients who developed unilateral VAP (n = 4). Ten healthy volunteers served as controls. In healthy volunteers, HMGB-1 levels were low (median, 1.6 ngmL(-1); interquartile range [IQR], 0.7-3.7 ng mL(-1)). Although HMGB-1 levels were elevated after short-term MV, differences were not statistically significant compared with healthy volunteers (1.7 ng mL(-1); IQR, 0.8-8.5 ng mL(-1), P = 0.493 vs. healthy volunteers; P = 0.250 vs. start of MV). However, HMGB-1 levels were significantly higher in "long-term" MV patients (11.7 ng mL(-1); IQR, 8.7-37.0 ng mL(-1); P < 0.0001 vs. healthy volunteers). With unilateral VAP, HMGB-1 levels from the infected lung.were 17.4 (IQR, 8.5-23.2) ng mL(-1) (P = 0.014 vs. healthy controls); these levels were not different from those measured in the contralateral noninfected lung (P = 0.625). Summarized, long-term MV is associated with increased HMGB-1 levels in contrast to "short-term" MV. In addition, HMGB-1 levels during VAP are increased compared with healthy volunteers; however, they are not different from those found in patients intubated and mechanically ventilated for a similar period of time.
Abstract: Despite recent advances in supportive care, acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are clinical entities with high morbidity and high mortality. In systemic inflammation, like sepsis, uncontrolled host defense can lead to systemic activation of coagulation on the one hand, and attenuation of fibrinolysis on the other. In ALI/ARDS similar but local disturbances in fibrin turnover occur, leading to excessive alveolar fibrin deposition compromising pulmonary integrity and function. Therapies in patients with sepsis have specifically focused on coagulation disturbances. Evidence from preclinical and clinical investigations suggests pharmacologically targeting pulmonary "coagulopathy" could be of benefit to patients with ALI/ARDS as well. Recent animal studies have demonstrated that administration of heparins, activated protein C (APC), Antithrombin (AT), Tissue factor-Factor VIIa (TF-FVIIa) pathway inhibitors, plasminogen activators (PA) and thrombomodulin (TM) can attenuate pulmonary coagulopathy and reduce lung injury and/or improve oxygenation. Some of these studies have also shown anti-inflammatory effects of treatment targeting at coagulation. To date there are no published studies that have specifically studied the effects of anticoagulants on ALI/ARDS however there are on-going clinical trials. A solid base has to be provided by preclinical studies to justify clinical studies on new pharmacologic therapies for ALI/ARDS. In this systematic literature review we give an overview of the models for ALI/ARDS that have been used so far on the topic of pulmonary coagulopathy and focus on the pharmacological interventions that have been evaluated with these models. Finally, the applicability of the different approaches for future research on this subject will be discussed.
Abstract: Low mixed or central venous saturation (S(c)vO2) can reveal global tissue hypoxia and therefore can predict poor prognosis in critically ill patients. Early goal directed therapy (EGDT), aiming at an ScvO2 >/= 70%, has been shown to be a valuable strategy in patients with sepsis or septic shock and is incorporated in the Surviving Sepsis Campaign guidelines.
Abstract: Because of their potential for use in advanced electronic, nanomechanical, and other applications, large two-dimensional, carbon-rich networks have become an important target to the scientific community. Current methods for the synthesis of these materials have many limitations including lack of molecular-level control and poor diversity. Here, we present a method for the synthesis of two-dimensional carbon nanomaterials synthesized by Mo- and Cu-catalyzed cross-linking of alkyne-containing self-assembled monolayers on SiO(2) and Si(3)N(4). When deposited and cross-linked on flat surfaces, spheres, cylinders, or textured substrates, monolayers take the form of these templates and retain their structure on template removal. These nanomaterials can also be transferred from surface to surface and suspended over cavities without tearing. This approach to the synthesis of monolayer carbon networks greatly expands the chemistry, morphology, and size of carbon films accessible for analysis and device applications.
Abstract: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that natural inhibitors of coagulation, including activated protein C, antithrombin, and tissue factor pathway inhibitor, exert lung-protective effects via anticoagulant and possibly anti-inflammatory pathways. We investigated the role of these natural anticoagulants in Streptococcus pneumoniae pneumonia.
Abstract: Clara cell protein levels are elevated in plasma of individuals with mild or subclinical lung injury. We studied the influence of two mechanical ventilation strategies on local and systemic levels of Clara cell protein (CC16) and compared them with levels of soluble receptor for advanced glycation end products (sRAGE) and surfactant proteins (SP)-A and -D in patients undergoing elective surgery. Saved samples from a previously reported investigation were used for the study. Forty patients planned for elective surgery were randomized to mechanical ventilation with either a conventional tidal volume (V(T)) of 12 ml/kg without positive end-expiratory pressure (PEEP) or low V(T) of 6 ml/kg and 10 cmH(2)O PEEP. Plasma and bronchoalveolar lavage fluid (BALF) was collected directly after intubation and after 5 h of mechanical ventilation. While systemic levels of SP-A and SP-D remained unchanged, systemic levels of CC16 and sRAGE increased significantly in both groups after 5 h (P < 0.001 for both). BALF levels of SP-A, SP-D, CC16, and sRAGE remained unaffected. No differences were found between the two mechanical ventilation strategies regarding any of the measured biological markers. In conclusion, systemic levels of CC16 and sRAGE rise after 5 h in patients receiving mechanical ventilation for elective surgery. Mechanical ventilation with lower tidal volumes and PEEP did not have a different effect on levels of biomarkers of lung epithelial injury compared with conventional mechanical ventilation.
Abstract: Tracheotomy is considered to be an independent risk factor for ventilator-associated pneumonia (VAP). Antimicrobial prophylaxis, in particular with coverage of Pseudomonas aeruginosa, is presently advocated. Selective decontamination of the digestive tract (SDD) aims to prevent VAP in critically ill patients, including those after tracheotomy. We determined the incidence and microbial spectrum of VAP after tracheotomy in a SDD-setting.
Abstract: Markers of inflammation, coagulation, and fibrinolysis predict an adverse outcome in patients with sepsis. These markers also seem predictive of an adverse outcome in patients with localized infection and inflammation, such as in acute lung injury. Whether this is entirely related to the disease or is also due to ventilation strategies that may be harmful for the lungs, however, is not clear. In the present issue of Critical Care, McClintock and colleagues demonstrate that these biomarkers retain their predictive effect even if lung-protective ventilation strategies are applied. Besides being biomarkers that predict outcome in patients with acute lung injury, their activation of inflammation and coagulation seems also to play a pivotal role in the pathogenesis of acute lung injury, and may thereby represent an interesting novel target for therapeutic intervention.
Abstract: Pseudomonas aeruginosa is a common pathogen in hospital-acquired pneumonia. Especially trauma and postsurgical patients display a profound acute phase protein response and are susceptible to acquiring pneumonia. The objective was to study the influence of the acute phase response induced by sterile tissue injury on pulmonary host defense.
Abstract: To investigate the agreement among clinical experts in their judgments of monitoring data with respect to artifacts, and to examine the effect of reference standards that consist of individual and joint expert judgments on the performance of artifact filters.
Abstract: Taking advantage of the quick and efficient access of vapor to surfaces, a simple, solvent-free method is demonstrated to synthesize Janus colloidal particles in large quantity and with high efficiency. First, at the liquid-liquid interface of emulsified molten wax and water, untreated silica particles adsorb and are frozen in place when the wax solidifies. The exposed surfaces of the immobilized particles are modified chemically by exposure to silane vapor and, in principle, subsequent dissolution of the wax opens up the inner particle surface for further chemical modification. Applying this scheme, this paper describes the production of amphiphilic Janus particles (hydrophobic on one side, hydrophilic on the other) and dipolar Janus particles (positively charged on one side, negatively charged on the other). Janus geometry is confirmed by fluorescence microscopy and flow cytometry. Amphiphilic Janus particles are found to adsorb strongly to the water-oil interface, whereas dipolar particles assemble into chains in the aqueous phase.
Abstract: Mechanical ventilation with high tidal volumes aggravates lung injury in patients with acute lung injury or acute respiratory distress syndrome. The authors sought to determine the effects of short-term mechanical ventilation on local inflammatory responses in patients without preexisting lung injury.
Abstract: Elimination of daily-routine chest radiographs (CXRs) may influence chest computed tomography (CT) and ultrasound practice in critically ill patients.
Abstract: Critically ill patients frequently suffer from sepsis or localized infections. Diagnosing sepsis can be a challenge since several of its signs overlap with those found with other inflammatory states. Recognition of localized infections can at times be difficult too. While microbiological cultures of blood or other specimens are frequently used to distinguish infection from non-infectious conditions, this diagnostic technique lacks sensitivity and specificity. In addition, there is often a considerable time delay since bacterial cultures may require 24-48 h for analysis, which may be too long for a treatment decision in critically ill patients. Also, the reliability of microbiological cultures decreases in case of prior antimicrobial therapy. Use of biologic markers such as procalcitonin (PCT) or soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have been suggested to improve recognition of patients with true infection and facilitate decisions of whether or not to treat. Unfortunately, neither PCT nor sTREM-1 fulfill all expectations. Data on the diagnostic value, in particular of sTREM-1, are contradicting. The combination of systemic PCT and local and/or systemic sTREM-1 could be useful in distinguishing patients with infection from those with non-infectious illness, though. Results from several randomized intervention studies on PCT-guided antimicrobial therapy in sepsis or lower respiratory tract infections show the superiority of PCT in clinical decision making. At present, randomized intervention studies on the potential antimicrobial stewardship of sTREM-1 are lacking.
Abstract: Disturbed alveolar fibrin turnover is intrinsic to acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pneumonia and is important to its pathogenesis. Recent studies also suggest disturbed alveolar fibrin turnover to be a feature of ventilator-induced lung injury (VILI). The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors, and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. Administration of anticoagulant agents (including activated protein C, antithrombin, tissue factor-factor VIIa pathway inhibitors, and heparin) and profibrinolytic agents (including plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ALI/ARDS and pneumonia. In this article, we review the involvement of coagulation and fibrinolysis in the pathogenesis of ALI/ARDS pneumonia and VILI and the potential of anticoagulant and profibrinolytic strategies to reverse pulmonary coagulopathy and pulmonary inflammatory responses.
Abstract: Pneumonia, the main cause of acute lung injury, is characterised by a local pro-inflammatory response and coagulopathy. Mechanical ventilation (MV) is often required. However, MV can lead to additional injury: so-called ventilator-induced lung injury (VILI). Therefore, the current authors investigated the effect of VILI on alveolar fibrin turnover in Streptococcus pneumoniae pneumonia. Pneumonia was induced in rats, followed 48 h later by either lung-protective MV (lower tidal volumes (LV(T)) and positive end-expiratory pressure (PEEP)) or MV causing VILI (high tidal volumes (HV(T)) and zero end-expiratory pressure (ZEEP)) for 3 h. Nonventilated pneumonia rats and healthy rats served as controls. Thrombin-antithrombin complexes (TATc), as a measure for coagulation, and plasminogen activator activity, as a measure of fibrinolysis, were determined in bronchoalveolar lavage fluid (BALF) and serum. Pneumonia was characterised by local (BALF) activation of coagulation, resulting in elevated TATc levels and attenuation of fibrinolysis compared with healthy controls. LV(T)-PEEP did not influence alveolar coagulation or fibrinolysis. HV(T)-ZEEP did intensify the local procoagulant response: TATc levels rose significantly and levels of the main inhibitor of fibrinolysis, plasminogen activator inhibitor-1, increased significantly. HV(T)-ZEEP also resulted in systemic elevation of TATc compared with LV(T)-PEEP. Mechanical ventilation causing ventilator-induced lung injury increases pulmonary coagulopathy in an animal model of Streptococcus pneumoniae pneumonia and results in systemic coagulopathy.
Abstract: Blood glucose control aiming at normoglycemia, frequently referred to as "strict glycemic control", decreases mortality and morbidity of critically ill patients. We searched the medical literature for export opinions, surveys, and clinical reports on blood glucose control in intensive care medicine. While strict glycemic control has been recommended standard of care for critically ill patients, the risk of severe hypoglycemia with strict glycemic control is frequently mentioned by experts. Some rationalize this risk, though others strongly point out the high incidence of hypoglycemia to be (one) reason not to perform strict glycemic control. Implementation of strict glycemic control is far from complete in intensive care units across the world. Frequently local guidelines accept higher blood glucose levels than those with strict glycemic control. Only a minority of retrieved manuscripts are on blood glucose regimens with the lower targets as with strict glycemic control. Hypoglycemia certainly is encountered with blood glucose control, in particular with strict glycemic control. Reports show intensive care-nurses can adequately and safely perform strict glycemic control. Implementation of strict glycemic control is far from complete, at least in part because of the feared risks of hypoglycemia. The preference for hyperglycemia over intermittent hypoglycemia is irrational, however, because there is causal evidence of harm for the former but only associative evidence of harm for the latter. For several reasons it is wise to have strict glycemic control being a nurse-based strategy.
Abstract: To investigate the potential role of serum and alveolar soluble triggering receptor expressed on myeloid cells (sTREM-1) as a biological marker of pulmonary aspiration syndromes.
Abstract: The objectives of this study were to systematically identify and summarize quality indicators of tight glycaemic control in critically ill patients, and to inspect the applicability of their definitions.
Abstract: We determined the need for changes in minute ventilation with adaptive support ventilation after percutaneous dilatational tracheotomy under endoscopic guidance in 34 intensive care unit patients. During the procedure, minute ventilation was not changed; only maximum pressure limits were adjusted, if necessary. After insertion of the tracheotomy, cannula minute ventilation was adjusted only if Paco(2)-values changed >or=0.5 kPa from baseline. In 74% of patients, adaptive support ventilation was unable to maintain minute ventilation during the use of the endoscope, mandating pressure limitation adjustments. In a minority of patients (26%), minute ventilation had to be adjusted to achieve similar Paco(2) values.
Abstract: Coagulopathy is present at admission in 25% of trauma patients, is associated with shock and a 5-fold increase in mortality. The coagulopathy has recently been associated with systemic activation of the protein C pathway. This study was designed to characterize the thrombotic, coagulant and fibrinolytic derangements of trauma-induced shock.
Abstract: In the present study, we investigated the behavior of adaptive support ventilation (ASV) in patients after cardiothoracic surgery. We determined tidal volumes (Vt) and factors that influence Vt with this mode of microprocessor-controlled mechanical ventilation (MV).
Abstract: Unplanned readmission of hospitalized patients to an intensive care unit (ICU) is associated with a worse outcome, but our ability to identify who is likely to deteriorate after ICU dismissal is limited. The objective of this study is to develop and validate a numerical index, named the Stability and Workload Index for Transfer, to predict ICU readmission.
Abstract: Patients after out-of-hospital cardiac arrest (OHCA) benefit from therapeutic hypothermia for 24 hours. The time needed to reach hypothermia (target temperature of 32 degrees C to 34 degrees C) varies widely. In this study, we explore the relation between measures of body composition and the time needed to reach target temperature with hypothermia.
Abstract: Antibiotic resistance among microbes urgently necessitates the development of novel antimicrobial agents. Since ancient times, honey has been used successfully for treatment of infected wounds, because of its antibacterial activity. However, large variations in the in vitro antibacterial activity of various honeys have been reported and hamper its acceptance in modern medicine.
Abstract: Several factors may delay tracheostomy. As many critically ill patients either suffer from coagulation abnormalities or are being treated with anticoagulants, fear of bleeding complications during the procedure may also delay tracheostomy. It is unknown whether such (usually mild) coagulation abnormalities are corrected first and to what extent. The purpose of this study was to ascertain current practice of tracheostomy in the Netherlands with regard to timing, pre-operative correction of coagulation disorders and peri-/intra-operative measures.
Abstract: In patients with suspected heparin-induced thrombocytopenia (HIT) who need renal replacement therapy, a nonheparin anticoagulant has to be chosen to prevent thrombosis in the extracorporeal circuit. Danaparoid, a low-molecular-weight heparinoid consisting of heparan sulphate, dermatan sulphate, and chondroitin sulphate, is recommended for systemic anticoagulation in patients with HIT. However, there are few data on the use of danaparoid in patients with acute renal failure, especially in patients dependent on renal replacement therapy such as continuous venovenous hemofiltration (CVVH). In the present study, we analyzed the pharmacokinetics and pharmacodynamics of danaparoid during CVVH in patients with suspected HIT.
Abstract: To determine the diagnostic efficacy (DE) and therapeutic efficacy (TE) of daily routine chest radiographs (CXRs), and to establish the impact of abandoning this CXR from daily practice on total CXR volume, ICU length of stay (LOS), readmission rate, and ICU mortality.
Abstract: The aim of the study was to assess and classify incidents of electromagnetic interference (EMI) by second-generation and third-generation mobile phones on critical care medical equipment.
Abstract: Critically ill patients are at high risk for developing acute renal failure (ARF). The prevention of ARF is of outmost importance in order to improve the increased morbidity and mortality associated with ARF. Unfortunately, there is lack of adequate endogenous markers that can identify renal dysfunction early - this hampers timely application of measures to prevent further renal damage. The use of exogenous markers of renal function is not only time-consuming but also expensive, and therefore can not be used on a regular basis in the intensive care unit. Both the presently used endogenous and exogenous markers are not reliable during continuous renal replacement therapy (CRRT) because these markers are removed by the therapy itself impeding early detection of recovering of renal function. Cystatin C has been proposed as an alternative endogenous marker of renal function for more than 15 years. In this manuscript we review the literature on the role of cystatin C as marker for renal function, focusing on the critically ill patient. Serum cystatin C concentrations have been found to relate to renal impairment and suggest that cystatin C is more sensitive to detect mild decreases in GFR. Cystatin C could be an important tool both to recognize early renal dysfunction and to identify renal recovery while on CRRT in the critically ill patient, however, we are in need of more studies.
Abstract: As health care resources become increasingly constrained, it is imperative that intensive care unit resources be optimized. In the years to come, a number of challenges to intensive care medicine will need to be addressed as society changes. Last year's Critical Care papers provided us with a number of interesting and highly accessed original papers dealing with health care resources. The information yielded by these studies can help us to deal with issues such as prognostication, early detection and treatment of delirium, prevention of medical errors and use of radiology resources in critically ill patients. Finally, several aspects of scientific research in critically ill patients were investigated, focusing on the possibility of obtaining informed consent and recall of having given informed consent.
Abstract: Transfusion-related (TR)- acute lung injury (ALI) is the leading cause of transfusion-related morbidity and mortality. The pathogenesis of TRALI is thought to be a "two hit"-entity: the "first hit" is (any) proinflammatory pulmonary condition (e.g., pneumonia, sepsis or lung contusion) resulting in activation of lung endothelium with sequestration of polymorphonuclear neutrophils - the "second hit" is provided by transfusion of a blood product. Either antibodies against neutrophils are thought to be implicated in the activation of the sequestrated neutrophils, or bioactive lipids (which accumulate during storage of blood products) induce the "second hit", finally resulting in lung injury. Preventive measures do not prevent all TRALI cases. Also, TRALI is most probably underdiagnosed. In this review, we call for the development of therapeutic approaches for this potentially life-threatening disease. Several interventions which are beneficial in ALI and may also be beneficial in TRALI are discussed. The application of these interventions requires the development of clinically relevant TRALI animal models. We discuss the present TRALI animal models and their shortcomings and propose future animal models, in which clinically relevant "first hits" can be applied, thereby imitating the complex clinical situation.
Abstract: We compared the effects of mechanical ventilation with a lower tidal volume (V(T)) strategy versus those of greater V(T) in patients with or without acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) on the use of opioids and sedatives.
Abstract: Elderly patients and patients with a poor cardiac function have increased morbidity rates when undergoing cardiac surgery. The aim of this study was to determine whether addition of glycine to a standard preoperative oral immune-enhancing nutrition supplement (OIENS) improves outcome. Glycine-enriched OIENS was compared with 2 formulas: standard OIENS and control.
Abstract: Mechanical ventilation practice has changed over the past few decades, with tidal volumes (VT) decreasing significantly, especially in patients with acute lung injury (ALI). Patients without acute lung injury are still ventilated with large--and perhaps too large--VT. Studies of ventilator-associated lung injury in subjects without ALI demonstrate inconsistent results. Retrospective clinical studies, however, suggest that the use of large VT favors the development of lung injury in these patients. Side effects associated with the use of lower VT in patients with ALI seem to be minimal. Assuming that this will be the case in patients without ALI/acute respiratory distress syndrome too, the authors suggest that the use of lower VT should be considered in all mechanically ventilated patients whether they have ALI or not. Prospective studies should be performed to evaluate optimal ventilator management strategies for patients without ALI.
Abstract: Pulmonary coagulopathy and hyperinflammation may contribute to an adverse outcome in sepsis. The present study determines the effects of natural inhibitors of coagulation on bronchoalveolar haemostasis and inflammation in a rat model of endotoxaemia. Male Sprague-Dawley rats were randomised to treatment with normal saline, recombinant human activated protein C (APC), plasma-derived antithrombin (AT), recombinant human tissue factor pathway inhibitor (TFPI), heparin or recombinant tissue plasminogen activator (tPA). Rats were intravenously injected with lipopolysaccharide (LPS), which induced a systemic inflammatory response and pulmonary inflammation. Blood and bronchoalveolar lavage were obtained at 4 and 16 h after LPS injection, and markers of coagulation and inflammation were measured. LPS injection caused an increase in the levels of thrombin-AT complexes, whereas plasminogen activator activity was attenuated, both systemically and within the bronchoalveolar compartment. Administration of APC, AT and TFPI significantly limited LPS-induced generation of thrombin-AT complexes in the lungs, and tPA stimulated pulmonary fibrinolytic activity. However, none of the agents had significant effects on the production of pulmonary cytokines, chemokines, neutrophil influx and myeloperoxidase activity. Natural inhibitors of coagulation prevent bronchoalveolar activation of coagulation, but do not induce major alterations of the pulmonary inflammatory response in rat endotoxaemia.
Abstract: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that recombinant human activated protein C exerts lung-protective effects via anticoagulant and anti-inflammatory pathways. We investigated the role of the protein C system in pneumonia caused by Pseudomonas aeruginosa, the organism that is predominantly involved in ventilator-associated pneumonia.
Abstract: Skin lesions in Sweet's syndrome typically appear as tender, red or purple-red papules or nodules. Cutaneous pathergy can be present in this syndrome, with skin lesions occurring after venapucture, biopsy, or intravenous catheter placement. This skin reaction can be extremely severe, as illustrated by this case-report.
Abstract: This study investigated levels of coagulation and fibrinolysis factors in cerebrospinal fluid (CSF) from adults with bacterial meningitis in relation to development of brain infarction.
Abstract: To determine pathogen-specific kinetic changes in the alveolar procoagulant (PC) activity, tissue factor (TF), and tissue factor pathway inhibitor (TFPI) expression during the course of ventilator-associated pneumonia (VAP) and to assess the relationship between clinical resolution, intra-alveolar bacterial eradication, and restoration of hemostatic balance.
Abstract: The benefit of hemofiltration (HF) as an adjunctive treatment of sepsis or the systemic inflammatory response syndrome (SIRS) in critically ill patients is a subject of severe debate. Firm conclusions on this subject are hampered by the heterogeneity in study populations and HF treatments, and the lack of adequately sized randomized controlled clinical trials. The aim of this review was to determine the importance of ultrafiltration dose and timing on the physiologic and clinical effects of HF in sepsis and SIRS. In addition, we discuss the issue of filter pore size.
Abstract: To determine the impact of elimination of daily routine chest radiographs (CXRs) in a mixed medical-surgical intensive care unit (ICU) on utility of on demand CXRs, length of stay (LOS) in ICU, readmission rate, and mortality rate.
Abstract: We sought to determine the effect of elimination of daily routine chest radiographs on chest radiographic practice in cardiothoracic surgery patients in the intensive care unit and the post-intensive care unit ward.
Abstract: Cell wall constituents of bacteria are potent endotoxins initiating inflammatory responses which may cause dramatic changes in lipid metabolism during the acute phase response. In this study, the sequential changes in lipoprotein composition and lipid transfer and binding proteins during clinical sepsis and during low-dose experimental endotoxemia were followed. In addition, the effect on (phospho)lipid homeostasis by administration of reconstituted HDL (rHDL) prior to low-dose LPS administration was investigated. Changes in (apo)lipoprotein concentrations typical of the acute phase response were observed during clinical sepsis and experimental endotoxemia with and without the rHDL intervention. During clinical sepsis negative correlations between the acute phase marker C-reactive protein (CRP) and lecithin:cholesterol acyltransferase (LCAT) and cholesterylester transfer protein (CETP) activities were seen, whereas positive correlations between plasma phospholipid transfer protein (PLTP) activity and acute phase markers such as CRP and LPS binding protein were observed. Plasma lipid changes upon rHDL/LPS infusion were comparable with the control group (low-dose LPS only). PLTP activity decreased upon LPS infusion and transiently increased during rHDL infusion, whereas LCAT activity slightly decreased upon both LPS infusion and LPS/rHDL infusion. However, long-lasting increases of circulating HDL cholesterol, apo A-I and a high initial processing of both phosphatidylcholine (PC) and lyso-PC, were indicative for extensive rHDL and LDL remodelling. Both sepsis and experimental endotoxemia lead to a disbalance of lipid homeostasis. Depending on the magnitude of the inflammatory stimulus, LCAT and PLTP activities reacted in divergent ways. rHDL infusion did not prevent the lipid alterations seen during the acute phase response. However profound changes in both HDL and LDL phospholipid composition occurred upon rHDL infusion. This may be explained, at least in part, by the fact that PLTP as a positive acute phase protein, can accelerate the alterations in (phospho)lipid homeostasis thereby playing a role in the attenuation of the acute phase response.
Abstract: BACKGROUND: There are clinically relevant discrepancies between prescribed volumes and delivered volumes of enteral nutrition (EN) in intensive care unit (ICU) patients. Next to EN-protocol violations due to insufficient care, we hypothesized technical factors to be responsible for this deficit. The aim of this study was to determine the accuracy of EN feeding pump systems frequently used in the ICU. METHODS: Thirteen commercially available EN feeding pumps with their own delivery systems were tested in 12 sessions with different EN feeding tubes and EN formulas in a laboratory setting. The reproducibility of the measurements was determined for the 8 best performing EN feeding pump systems. RESULTS: There were clinically important differences between prescribed volumes and delivered volumes of EN in the tested EN feeding pump systems. The deficit in volume ranged from +66 mL (surplus of 66 mL) to -271 mL (deficit of 271 mL) per 24 hours (14% of prescribed volume). Viscosity of test fluids (water/EN feeding formulas) and resistance of test tubes had no influence on the delivered volume by the tested EN feeding pump systems, because differences between prescribed volumes and delivered volumes were consistently found for each system while varying these test settings. CONCLUSIONS: Differences between prescribed and delivered EN volumes are caused by the function and construction of EN feeding pump systems. To improve nutrition therapy, the flow rate has to be adjusted or the best-performing EN feeding pump has to be purchased.
Abstract: INTRODUCTION: Translaryngeal intubated and ventilated patients often need sedation to treat anxiety, agitation and/or pain. Current opinion is that tracheotomy reduces sedation requirements. We determined sedation needs before and after tracheotomy of intubated and mechanically ventilated patients. METHODS: We performed a retrospective analysis of the use of morphine, midazolam and propofol in patients before and after tracheotomy. RESULTS: Of 1,788 patients admitted to our intensive care unit during the study period, 129 (7%) were tracheotomized. After the exclusion of patients who received a tracheotomy before or at the day of admittance, 117 patients were left for analysis. The daily dose (DD; the amount of sedatives for each day) divided by the mean daily dose (MDD; the mean amount of sedatives per day for the study period) in the week before and the week after tracheotomy was 1.07 +/- 0.93 DD/MDD versus 0.30 +/- 0.65 for morphine, 0.84 +/- 1.03 versus 0.11 +/- 0.46 for midazolam, and 0.62 +/- 1.05 versus 0.15 +/- 0.45 for propofol (p < 0.01). However, when we focused on a shorter time interval (two days before and after tracheotomy), there were no differences in prescribed doses of morphine and midazolam. Studying the course in DD/MDD from seven days before the placement of tracheotomy, we found a significant decline in dosage. From day -7 to day -1, morphine dosage (DD/MDD) declined by 3.34 (95% confidence interval -1.61 to -6.24), midazolam dosage by 2.95 (-1.49 to -5.29) and propofol dosage by 1.05 (-0.41 to -2.01). After tracheotomy, no further decrease in DD/MDD was observed and the dosage remained stable for all sedatives. Patients in the non-surgical and acute surgical groups received higher dosages of midazolam than patients in the elective surgical group. Time until tracheotomy did not influence sedation requirements. In addition, there was no significant difference in sedation between different patient groups. CONCLUSION: In our intensive care unit, sedation requirements were not further reduced after tracheotomy. Sedation requirements were already sharply declining before tracheotomy was performed.
Abstract: In acute respiratory distress syndrome or pneumonia, a procoagulant shift is observed in bronchoalveolar lavage fluid (BALF). The effect of a primarily extrapulmonary infection on coagulation and fibrinolysis in the pulmonary compartment is unclear.
Abstract: BACKGROUND: To ascertain current chest radiography practice in intensive care units (ICUs) in the Netherlands. METHODS: Postal survey: a questionnaire was sent to all ICUs with > 5 beds suitable for mechanical ventilation; pediatric ICUs were excluded. When an ICU performed daily-routine chest radiographs in any group of patients it was considered to be a "daily-routine chest radiography" ICU. RESULTS: From the number of ICUs responding, 63% practice a daily-routine strategy, in which chest radiographs are obtained on a daily basis without any specific reason. A daily-routine chest radiography strategy is practiced less frequently in university-affiliated ICUs (50%) as compared to other ICUs (68%), as well as in larger ICUs (> 20 beds, 50%) as compared to smaller ICUs (< 20 beds, 65%) (P > 0.05). Remarkably, physicians that practice a daily-routine strategy consider daily-routine radiographs helpful in guiding daily practice in less than 30% of all performed radiographs. Chest radiographs are considered essential for verification of the position of invasive devices (81%) and for diagnosing pneumothorax, pneumonia or acute respiratory distress syndrome (82%, 74% and 69%, respectively). On demand chest radiographs are obtained after introduction of thoracic drains, central venous lines and endotracheal tubes in 98%, 84% and 75% of responding ICUs, respectively. Chest films are also obtained in case of ventilatory deterioration (49% of responding ICUs), and after cardiopulmonary resuscitation (59%), tracheotomy (58%) and mini-tracheotomy (23%). CONCLUSION: There is notable lack of consensus on chest radiography practice in the Netherlands. This survey suggests that a large number of intensivists may doubt the value of daily-routine chest radiography, but still practice a daily-routine strategy.
Abstract: Assessment of residual renal function in critically ill patients with acute renal failure (ARF) treated with continuous venovenous hemofiltration (CVVH) is difficult. Cystatin C (CysC) is a low-molecular-weight protein (13.3 kDa) removed from the body by glomerular filtration. Its serum concentration has been advocated for assessment of renal function in patients with kidney disease. To investigate whether the removal of CysC by CVVH is likely to influence its serum concentration, concentrations of CysC were measured in 3 consecutive samples in 18 patients with oliguric ARF treated with CVVH (2 L/hr). Samples were taken from the afferent and efferent blood lines and from the ultrafiltrate line. Concentrations of CysC did not change during the time interval studied. The mean serum concentrations of CysC were 2.25+/-0.45 mg/L in the afferent and 2.19+/-0.56 mg/L in the efferent samples (NS); ultrafiltrate concentrations of CysC were 1.01+/-0.45 mg/L. The sieving coefficient of CysC was 0.52+/-0.20; the clearance of CysC was 17.3+/-6.6 mL/min; and the quantity of CysC removed averaged 2.13 mg/hr. During CVVH (2 L/hr), the quantity of CysC removed is less than 30% of its production and no rapid changes in its serum concentration are observed. Therefore, CVVH (2 L/hr) is unlikely to influence serum concentrations of CysC significantly, which suggests that it can be used to monitor residual renal function during CVVH.
Abstract: Intensive care units regularly have patients in whom a curative treatment plan is changed to palliative treatment. This does not only concern the medical and technical aspects, but also medical-ethical problems and questions relating to communication and organization. All these play a part in making a correct assessment. It is logical that nurses play an important part in this process as they have the most contact with the patient and his/her family. The optimalization of collaboration between doctors and nurses by means of the mutual exchange of information unique to each different discipline as well as acknowledging one another's talents and skills, forms the basis of good communication and organization concerning end-of-life decisions. It is useful to formalize this collaboration by means of multidisciplinary discussions.
Abstract: To determine the time to wean from mechanical ventilation and time spent off the ventilator per day after tracheotomy in critically ill patients in a 28-bed mixed medical and surgical intensive care unit (ICU) in Amsterdam, Netherlands.
Abstract: Tetanus is a rare infectious disease in Western countries that leads to diagnostic difficulties. Several diseases may mimic tetanus, and diagnostic considerations can at times be difficult, especially in critically ill patients, who need prompt treatment. Two patients are presented who were diagnosed with and treated for tetanus. However, the course of these patients' diseases strongly suggested that the diagnoses were incorrect. The article includes reflections on these 2 difficult diagnostic cases. These 2 cases illustrate the importance of proposing alternative diagnoses in suspected tetanus in Western countries. This may prevent loss of valuable time and prevent a delay of possibly effective therapy.
Abstract: Drug dosing during continuous venovenous hemofiltration (CVVH) is based partly upon the CVVH clearance (Cl(CVVH)) of the drug. Cl(CVVH) is the product of the sieving coefficient (SC) and ultrafiltration rate (Q(uf)). Although it has been suggested that the SC can be replaced by the fraction of a drug not bound to protein (F(up)), the F(up) values as reported in the literature may not reflect the protein binding in critically ill patients with renal failure. We compared the observed Cl(CVVH) (SC x Q(uf)) with the estimated Cl(CVVH) (estimated F(UP) x Q(uf)) and determined the effect on the maintenance dose multiplication factor (MDMF).
Abstract: OBJECTIVES: To determine the effect of a change in the "Dutch Directive on Medical Research Involving Human Subjects" (DD) on the number of eligible intensive care unit (ICU) patients for medical research. In addition, we determined how family members experience their role as acting representative for giving informed consent, and in turn whether patients feel their representatives would do well representing them. DESIGN AND SETTING: Prospective observational study in three Dutch ICUs. PARTICIPANTS: 714 consecutive ICU patients. Analysis was restricted to 211 patients who were incapacitated for more than 24h after ICU admission. MEASUREMENTS AND RESULTS: The old DD left 45.5% of patients without a legal representative; with the new DD this figure declines to 8.1%. Older age was significantly associated with the impossibility of obtaining informed consent in the old DD; after the change there was no effect of age. The median grade of confidence that representatives had in giving informed consent for incapacitated patients was 8.0 (IQR 7.0-9.0) on a scale from 0 to 10. Patients gave an equal median grade to their representatives. CONCLUSION: When patients' adult children are not legally allowed to give informed consent, older patients are excluded from medical research, causing selection bias. The change in the DD has increased the number of surrogates allowed to give informed consent. Representatives felt very confident in their ability to represent the patients. In turn patients were equally confident that their representatives were able to represent them.
Abstract: The aim of the present study was to determine the effects of mechanical ventilation on alveolar fibrin turnover in lipopolysaccharide (LPS)-induced lung injury. In a randomised controlled trial, Sprague-Dawley rats (n = 61) were allocated to three ventilation groups after intratracheal LPS (Salmonella enteritidis) instillations. Group I animals were subjected to 16 cmH(2)O positive inspiratory pressure (PIP) and 5 cmH(2)O positive end-expiratory pressure (PEEP); group II animals to 26 cmH(2)O PIP and 5 cmH(2)O PEEP; and group III animals to 35 cmH(2)O PIP and 5 cmH(2)O PEEP. Control rats (not mechanically ventilated) received LPS. Healthy rats served as a reference group. Levels of thrombin-antithrombin complex (TATc), D-dimer, plasminogen activator inhibitor (PAI) activity and PAI-1 antigen in bronchoalveolar lavage fluid were measured. LPS-induced lung injury increased TATc, D-dimer and PAI activity and PAI-1 antigen levels versus healthy animals. High pressure-amplitude ventilation increased TATc concentrations. D-dimer concentrations were not significantly raised. Instead, PAI activity increased with the amplitude of the pressure, from 0.7 U.mL(-1) in group I to 3.4 U.mL(-1) in group II and 5.0 U.mL(-1) in group III. There was no change in PAI-1 antigen levels. In conclusion, mechanical ventilation creates an alveolar/pulmonary anti-fibrinolytic milieu in endotoxin-induced lung injury which, at least in part, might be due to an increase in plasminogen activator inhibitor activity.
Abstract: Early recognition and prompt treatment of deteriorating patients outside the intensive care unit (ICU) improves hospital survival. Over the past decade, consultative services have been implemented in many institutions. This service is frequently performed by ICU nurses, while little information is available on the workload and type of activities these ICU nurses actually perform.
Abstract: OBJECTIVE: To evaluate whether soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in CSF can serve as a biomarker for the presence of bacterial meningitis and outcome in patients with this disease. DESIGN: Retrospective study of diagnostic accuracy. SETTING AND PATIENTS: CSF was collected from 92 adults with community-acquired bacterial meningitis who participated in the prospective Dutch Meningitis Cohort Study; 8 patients with viral meningitis and 9 healthy control subjects. RESULTS: CSF sTREM-1 levels were higher in patients with bacterial meningitis (median 82 pg/ml, range 0-988) than in those with viral meningitis (0 pg/ml, 0-48) and controls (0 pg/ml, 0-36). The diagnostic accuracy of sTREM-1 in discriminating between patients with and without bacterial meningitis, expressed as the area under the receiver operating characteristic curve, was 0.82. At a cutoff level of 20 pg/ml the sensitivity was 0.73 and specificity 0.77. In patients with bacterial meningitis CSF sTREM-1 levels were associated with mortality (survivors, median 73 pg/ml, range 0-449 pg/ml; nonsurvivors, 15 pg/ml, 0-988). CONCLUSIONS: Measuring sTREM-1 in CSF may be a valuable new additional approach to accurately diagnose bacterial meningitis and identify patients at high risk for adverse outcome. Therefore a prospective study of sTREM-1 as a biomarker in bacterial meningitis is needed.
Abstract: OBJECTIVES: To review the involvement of coagulation and fibrinolysis in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pulmonary infection, and ventilator-induced lung injury (VILI). DATA SOURCE: Published articles on experimental and clinical studies of coagulation and fibrinolysis in ALI/ARDS, pneumonia, and mechanical ventilation. CONCLUSIONS: Alveolar fibrin deposition is an important feature of ALI/ARDS and pulmonary infection. The mechanisms that contribute to disturbed alveolar fibrin turnover are localized tissue factor-mediated thrombin generation and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. These effects on pulmonary coagulation and fibrinolysis are regulated by various proinflammatory cytokines and are similar to those found in the intravascular spaces during severe systemic inflammation. Some studies also suggest that pulmonary coagulopathy is a feature of VILI. Recent studies have demonstrated the beneficial effect of anticoagulant therapy in sepsis. Theoretical considerations suggest that this anticoagulant therapy will benefit patients with primary lung pathology including VILI, but clinical studies are needed to examine this hypothesis before such therapy is to be advocated as a standard of care in critically ill patients.
Abstract: BACKGROUND: Introduction of strict glycemic control has increased the risk for hypoglycemia in the intensive care unit. Little is known about the consequences of hypoglycemia in this setting. We examined short-term consequences (seizures, coma, and death) of hypoglycemia in the intensive care unit. PATIENTS AND METHODS: All occurrences of hypoglycemia (glucose of <45 mg/dL) in our intensive care unit between September 1, 2002, and September 1, 2004, were identified. Patients with hypoglycemia (n = 156) were matched for time to hypoglycemia with control patients drawn from the at-risk population (nested case control method). Seizures observed within 8 hrs after hypoglycemia were scored. Discharge summaries for cases and controls were reviewed for occurrence of possible hypoglycemia-associated coma and death. A hazard ratio for in-hospital death was calculated with Cox regression analysis. RESULTS: The hazard ratio for in-hospital death was 1.03 (95% confidence interval, 0.68-1.56; p = .88) in patients with a first occurrence of hypoglycemia relative to the controls without hypoglycemia, corrected for duration of intensive care unit admittance before hypoglycemia, age, sex, and Acute Physiology and Chronic Health Evaluation II score at admission. No cases of hypoglycemia-associated death were reported. Hypoglycemic coma was reported in two patients. Seizures after hypoglycemia were observed in one patient. CONCLUSIONS: In this study, no association between incidental hypoglycemia and mortality was found. However, this data set is too small to definitely exclude the possibility that hypoglycemia is associated with intensive care unit mortality. In three patients with possible hypoglycemia-associated coma or seizures, a causal role for hypoglycemia seemed likely but could not fully be established.
Abstract: AIM: To test the effects of various contrast media on the pulmonary surfactant system. MATERIAL AND METHODS: In a rat model of acute respiratory distress syndrome (ARDS) induced by lung lavage, the effects of surfactant suspended in saline were compared with surfactant suspended in the contrast media Visipaque, Gastrografin, Omnipaque, Telebrix M, Telebrix and Hexabrix, to establish their influence on oxygenation and lung mechanics. RESULTS: After the induction of ARDS, surfactant instillation improved oxygenation, total lung capacity (TLC(35)), volume at 5 cm H(2)O end-expiration (V(5)) and Gruenwald index. The effects of Visipaque and Gastrografin were comparable with those of surfactant alone from 90 min onwards and at 120 min, respectively. Surfactant suspended in the other contrast media resulted in significantly lower values in the above-mentioned parameters. Surface tension was lowest in surfactant suspended in saline alone. Surfactant suspended in Visipaque and Gastrografin had lower surface tension compared with surfactant suspended in the other contrast media. CONCLUSION: The ionic and non-ionic contrast media used in this study, cause an impairment of the physico-chemical behaviour of exogenous surfactant. Therefore, these contrast media cannot be regarded as safe in case of accidental exposure.
Abstract: Inflammation and coagulation play pivotal roles in host defence. As phylogenetically old responses, there is extensive cross-talk between inflammation and coagulation in enabling an adequate immune response against potentially injurious stimuli. Immune cells are important in the initiation of coagulation pathways, while various inflammatory mediators are capable of altering haemostasis. Vice versa, coagulation proteases have significant immunomodulatory effects. Understanding the mechanisms involved in the crosstalk between inflammation and coagulation may yield new therapeutic strategies for human diseases.
Abstract: Substantial progress has been made in understanding the contribution of alterations in coagulation and fibrinolysis to the pathogenesis of acute lung injury (ALI). Findings from mouse, rat, baboon, and human studies indicate that alterations in coagulation and fibrinolysis may be of major pathogenetic importance in ALI and other inflammatory conditions in the lung including pneumonia, sepsis, and ventilator-induced lung injury. Therapies targeted at both activation of coagulation through the extrinsic coagulation cascade and modulation of coagulation through the protein C system have the potential to favorably impact clinical ALI/acute respiratory distress syndrome.
Abstract: The increase in diagnostic imaging procedures that require infusion of intravenous radiographic contrast has led to a parallel increase in the incidence of contrast-induced nephropathy (CIN). Since CIN accounts for a significant increase of hospital-acquired renal failure, length of stay and mortality, several additive strategies to prevent CIN are presently advocated, including N-acetylcysteine (NAC), sodium bicarbonate, theophylline or fenoldopam, and peri-procedural hemofiltration/hemodialysis. As only one (non-randomized) study has been performed in the intensive care setting, at present it is hard to give firm recommendations on preventive measures for CIN in intensive care patients. Indeed, future studies are needed to determine the true role of the above-mentioned preventive measures in critically ill patients at risk for CIN. Since NAC has only few side-effects, we presently advise NAC as an additive preventive measure in the intensive care setting. Theophylline or sodium bicarbonate hydration are viable options, either in conjunction NAC or as alternatives.
Abstract: OBJECTIVE: To describe the pattern of defecation in critically ill ventilated patients and the influence of selective decontamination (SDD) and other medication. DESIGN: Descriptive cohort study. SETTING: Mixed surgical-medical ICU in a university Hospital. PATIENTS: Ventilated patients with a length of stay >or=7 days taking part in a study on SDD. MEASUREMENTS: Daily registration of defecation, SOFA (sepsis-related organ failure assessment score) score, administration of dopamine, noradrenaline, morphine and other medications. RESULTS: The first defecation occurred after a mean of 6.2 days. Patients with defecation within 6[Symbol: see text]days had lower mean SOFA scores, received more cisapride and lactulose and less dopamine, noradrenaline and morphine, and had a shorter duration of mechanical ventilation and ICU stay. On 57% of the days, no stools were produced; on 31% diarrhea, and on 12%, normal stools. Patients receiving SDD had more days with normal stools and less with diarrhea. Diarrhea was preceded by the administration of lactulose in the majority of patients. CONCLUSION: Time to first defecation correlated with severity of illness, vasoactive medication, administration of morphine, cisapride and lactulose, duration of mechanical ventilation and length of stay. Diarrhea seemed at least partially iatrogenic.
Abstract: BACKGROUND: Alveolar fibrin deposition is a hallmark of acute lung injury, resulting from activation of coagulation and inhibition of fibrinolysis. Previous studies have shown that mechanical ventilation with high tidal volumes may aggravate lung injury in patients with sepsis and acute lung injury. The authors sought to determine the effects of mechanical ventilation on the alveolar hemostatic balance in patients without preexistent lung injury. METHODS: Patients scheduled for an elective surgical procedure (lasting > or = 5 h) were randomly assigned to mechanical ventilation with either higher tidal volumes of 12 ml/kg ideal body weight and no positive end-expiratory pressure (PEEP) or lower tidal volumes of 6 ml/kg and 10 cm H2O PEEP. After induction of anesthesia and 5 h later bronchoalveolar lavage fluid and blood samples were obtained, and markers of coagulation and fibrinolysis were measured. RESULTS: In contrast to mechanical ventilation with lower tidal volumes and PEEP (n = 21), the use of higher tidal volumes without PEEP (n = 19) caused activation of bronchoalveolar coagulation, as reflected by a marked increase in thrombin-antithrombin complexes, soluble tissue factor, and factor VIIa after 5 h of mechanical ventilation. Mechanical ventilation with higher tidal volumes without PEEP caused an increase in soluble thrombomodulin in lavage fluids and lower levels of bronchoalveolar activated protein C in comparison with lower tidal volumes and PEEP. Bronchoalveolar fibrinolytic activity did not change by either ventilation strategy. CONCLUSIONS: Mechanical ventilation with higher tidal volumes and no PEEP promotes procoagulant changes, which are largely prevented by the use of lower tidal volumes and PEEP.
Abstract: OBJECTIVE: The introduction of strict glycemic control in the intensive care unit has increased the risk for hypoglycemia. In this study we examined the association between predefined circumstances and the occurrence of hypoglycemia in the intensive care unit. DESIGN:: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: All episodes of hypoglycemia (glucose value <45 mg/dL) in our intensive care unit between September 2002 and September 2004 were identified. Presence of predefined circumstances previously associated with hypoglycemia was scored around the moment of hypoglycemia using a patient data management system and in-hospital charts. Patients with a first hypoglycemic event were contrasted to controls from the same cohort, who were matched for time since admission, to correct for the effect of length of stay. Data were analyzed using conditional logistic regression analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 2,272 patients, 156 (6.9%) experienced at least one episode of hypoglycemia. Continuous venovenous hemofiltration with bicarbonate-based substitution fluid (odds ratio [OR], 14; 95% confidence interval [CI], 1.8-106), a decrease of nutrition without adjustment for insulin infusion (OR, 6.6; 95% CI, 1.9-23), diabetes mellitus (OR, 2.6; 95% CI, 1.5-4.7), insulin use (OR, 5.3; 95% CI, 2.8-11), sepsis (OR, 2.2; 95% CI, 1.2-4.1), and inotropic support (OR, 1.8; 95% CI, 1.1-2.9) were associated with hypoglycemia. Simultaneous octreotide and insulin use (OR, 6.0; 95% CI, 0.72-50) may also be associated with hypoglycemia. Gastric residual during enteral nutrition without adjusting insulin infusion, liver failure, continuous venovenous hemofiltration with lactate-based substitution fluid, diminished glomerular filtration rate, dose diminishment of glucocorticoids or catecholamines, and use of beta-blocking agents were not associated with hypoglycemia. Adjusting for age, gender, and Acute Physiology and Chronic Health Evaluation II score at admission did not materially change ORs. CONCLUSION: Use of bicarbonate-based substitution fluid during continuous venovenous hemofiltration, a decrease of nutrition without adjustment for insulin infusion, a prior diagnosis of diabetes mellitus, sepsis, and need for inotropic support were found to be associated with hypoglycemia. Simultaneous use of insulin and octreotide may be associated with hypoglycemia.
Abstract: INTRODUCTION: The clinical value of daily routine chest radiographs (CXRs) in critically ill patients is unknown. We conducted this study to evaluate how frequently unexpected predefined major abnormalities are identified with daily routine CXRs, and how often these findings lead to a change in care for intensive care unit (ICU) patients. METHOD: This was a prospective observational study conducted in a 28-bed, mixed medical-surgical ICU of a university hospital. RESULTS: Over a 5-month period, 2,457 daily routine CXRs were done in 754 consecutive ICU patients. The majority of these CXRs did not reveal any new predefined major finding. In only 5.8% of daily routine CXRs (14.3% of patients) was one or more new and unexpected abnormality encountered, including large atelectases (24 times in 20 patients), large infiltrates (23 in 22), severe pulmonary congestion (29 in 25), severe pleural effusion (13 in 13), pneumothorax/pneumomediastinum (14 in 13), and malposition of the orotracheal tube (32 in 26). Fewer than half of the CXRs with a new and unexpected finding were ultimately clinically relevant; in only 2.2% of all daily routine CXRs (6.4% of patients) did these radiologic abnormalities result in a change to therapy. Subgroup analysis revealed no differences between medical and surgical patients with regard to the incidence of new and unexpected findings on daily routine CXRs and the effect of new and unexpected CXR findings on daily care. CONCLUSION: In the ICU, daily routine CXRs seldom reveal unexpected, clinically relevant abnormalities, and they rarely prompt action. We propose that this diagnostic examination be abandoned in ICU patients.
Abstract: The management of intensive care patients have changed dramatically in the last years: from merely supportive care, it has moved to evidence-based strategies that have been demonstrated to reduce mortality of the severely ill patients. Clinical research have brought numerous positive clinical trials offering intensive care physicians specific therapies to improve outcome of intensive care patients. Among them were the trials that tested the infusion of activated protein C in patients with severe sepsis, tight glycemic control in surgical intensive care patients, and use of lung protective mechanical ventilation by using small tidal volumes in patients with acute lung injury. Although results of these trials were sufficiently strong to, at least, consider implementation of these strategies in critical care medicine, published and yet unpublished reports show that there is significant struggle with implementation of these therapies. This manuscript focuses on the potential reasons that underlie this problem.
Abstract: OBJECTIVE: To determine the diagnostic role of soluble triggering receptor expressed on myeloid cells (sTREM)-1 in non-directed bronchial lavage fluid in ventilator-associated pneumonia (VAP). DESIGN: Non-directed bronchial lavage fluid and plasma were collected on alternate days in critically ill mechanically ventilated patients from the start of ventilatory support until complete weaning from the ventilator. Soluble TREM-1 levels were measured by an enzyme-linked immunosorbent assay. SETTING: A general adult medical and surgical university hospital intensive care unit. PATIENTS: Nine patients who developed VAP and 19 patients who did not develop VAP (controls). RESULTS: Plasma levels of sTREM-1 did not change significantly in either patient group. While in controls concentrations of sTREM-1 in non-directed bronchial lavage fluid did not change significantly over time, in patients who developed VAP levels of sTREM-1 in non-directed bronchial lavage fluid increased towards the diagnosis of VAP. A cut-off value for non-directed bronchial lavage fluid sTREM-1 levels of 200 pg/ml on the day of VAP had a diagnostic sensitivity of 75% and a specificity of 84%. Sensitivity increased when taking into account all sTREM-1 levels higher than 200 pg/ml from the 6-day period before the day of diagnosis that were preceded by an increase of at least 100 pg/ml (sensitivity 88%, specificity 84%). CONCLUSIONS: Soluble TREM-1 is a potential biomarker of VAP.
Abstract: An increasing number of diagnostic imaging procedures requires the use of intravenous radiographic contrast agents, which has led to a parallel increase in the incidence of contrast-induced nephropathy. Risk factors for development of contrast-induced nephropathy include pre-existing renal dysfunction (especially diabetic nephropathy and multiple myeloma-associated nephropathy), dehydration, congestive heart failure and use of concurrent nephrotoxic medication (including aminoglycosides and amphotericin B). Because contrast-induced nephropathy accounts for a significant increase in hospital-acquired renal failure, several strategies to prevent contrast-induced nephropathy are currently advocated, including use of alternative imaging techniques (for which contrast media are not needed), use of (the lowest possible amount of) iso-osmolar or low-osmolar contrast agents (instead of high-osmolar contrast agents), hyperhydration and forced diuresis. Administration of N-acetylcysteine, theophylline, or fenoldopam, sodium bicarbonate infusion, and periprocedural haemofiltration/haemodialysis have been investigated as preventive measures in recent years. This review addresses the literature on these newer strategies. Since only one (nonrandomized) study has been performed in intensive care unit patients, at present it is difficult to draw firm conclusions about preventive measures for contrast-induced nephropathy in the critically ill. Further studies are needed to determine the true role of these preventive measures in this group of patients who are at risk for contrast-induced nephropathy. Based on the available evidence, we advise administration of N-acetylcysteine, preferentially orally, or theophylline intravenously, next to hydration with bicarbonate solutions.
Abstract: Preclinical sepsis models have been used for decades to study the pathophysiologic processes during sepsis and shock. Although these studies revealed promising immunomodulating agents for the treatment of sepsis, clinical trials evaluating the efficacy of these new agents in patients with sepsis were disappointing. The main reason for this unsatisfactory experience might be that unlike the clinical situation, most of these preclinical models are devoid of a localized infectious source from which the infection disseminates. Studies on the effects of several immunomodulating strategies have demonstrated strikingly opposite results when sepsis models with a more natural route of infection, such as pneumonia, were used. In this review, we will give insights into pneumonia models and discuss results and differences in the innate immune responses during distinct pulmonary infection models.
Abstract: BACKGROUND: Body packing is a distinct method of drug smuggling. Surgeons and intensive care specialists will be confronted with body packers when packets do not pass spontaneously and rupture, causing drug toxicity. CASE REPORT: We report of a 32-year-old Liberian male who presented with abdominal complaints and anxiety after having ingested 50 cocaine-containing packets of which 49 had passed the natural route in the previous days. X-ray of his abdomen showed a structure possibly compatible with a packet in or projected over the stomach. We decided to transfer the patient to the operation theatre for surgical removal via gastrotomy. However, no packet was found. During his first day in the intensive care unit he did not regain consciousness. Repeated urine analyses for cocaine were negative. After one day he deteriorated: he needed circulatory support because of hypotension, without signs of sepsis. Repeated surgery revealed no packet. In the end he turned out not to be suffering from cocaine intoxication. CONCLUSIONS: When confronted with a case of body packing in which packets do not pass spontaneously and produce bowel obstruction or in which badly wrapped packets rupture, causing drug toxicity, it is of utmost importance to establish the nature of the packet's content.
Abstract: OBJECTIVE: Use of lung-protective mechanical ventilation (MV) by applying lower tidal volumes is recommended in patients suffering from acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Recent data suggest that lung-protective MV may benefit non-ALI/ARDS patients as well. This study analyzed tidal volume settings in three ICUs in The Netherlands to determine the effect of feedback and education concerning use of lung-protective MV. DESIGN AND SETTING: Observational study in one academic and two nonacademic "closed format" ICUs. PATIENTS: Intubated mechanically ventilated subjects.INTERVENTIONS: Feedback and education concerning lung-protective MV with special attention to the importance of closely adjusting tidal volumes to predicted body weight (PBW). RESULTS: Tidal volumes declined significantly within 6 months after intervention (from 9.8+/-2.0 at baseline to 8.1+/-1.7 ml/kg PBW) as the percentage of undesirable ventilation data points, defined as tidal volumes greater than 8 ml/kg PBW (84% vs. 48%). There were no differences between patients meeting the international definition criteria for ALI/ARDS and those not. Only four patients received tidal volumes less than 6 ml/kg PBW. Lower tidal volumes were still used after 12 months. Tidal volumes in patients on mandatory MV and patients breathing on spontaneous modes were similar. CONCLUSIONS: Feedback and education improve physician compliance in use of lung-protective MV.
Abstract: OBJECTIVE: To investigate the effect of mechanical ventilation on alveolar fibrinolytic capacity. DESIGN AND SETTING: Randomized controlled animal study in 66 Sprague-Dawley rats. SUBJECTS AND INTERVENTIONS: Test animals received intratracheal fibrinogen and thrombin instillations; six were killed immediately (fibrin controls), and the others were allocated to three ventilation groups (ventilation period: 225 min) differing in positive inspiratory pressure and positive end-expiratory pressure, respectively: group 1, 16 cmH2O and 5 cmH2O (n=17); group 2, 26 cmH2O and 5 cmH2O (n=16); group 3, 35 cmH2O and of 5 cmH2O (n=17). Ten animals that had not been ventilated served as healthy controls. MEASUREMENTS AND RESULTS: After animals were killed, we measured D-dimers, plasminogen activator inhibitor (PAI) 1, and tumor necrosis factor alpha in the bronchoalveolar lavage fluid and calculated lung weight and pressure/volume (P/V) plots. The median D-dimer concentration (mg/l) decreased with increasing pressure amplitude (192 in group 1, IQR 119; 66 in group 2, IQR 107; 29 in group 3, IQR 30) while median PAI-1 (U/ml) increased (undetectable in group 1; 0.55 in group 2, IQR 4.55; 3.05 in group 3, IQR 4.85). PAI-1 level was correlated with increased lung weight per bodyweight (Spearman's rank correlation 0.708). Tumor necrosis factor alpha concentration was not correlated with PAI-1 level. CONCLUSIONS: Alveolar fibrinolytic capacity is suppressed during mechanical ventilation with high pressure amplitudes due to local production of PAI-1.
Abstract: Two different schools of thought exist on the utility of daily routine chest radiographs in intensive care unit (ICU) patients: some ICU physicians argue that daily routine chest radiographs are indicated in all patients who have cardiopulmonary problems or are receiving artificial ventilation. Others state that chest radiographs should be made on indication only, for example, following a change in clinical status or change of supportive devices. Most studies on this topic have simply reported the existence of several findings on chest radiographs; some investigators tried to determine whether such findings were new and/or unexpected and whether they caused a therapy change. A restrictive strategy has been compared with a daily routine strategy in only 2 clinical trials: 1 study conducted in a pediatric ICU (pediatric ICUs usually have low mortality rates), and the other a rather small (and probably underpowered) study. The debate about discontinuing daily routine chest radiographs in the ICU is still not settled.
Abstract: Respiratory tract obstruction due to a blood clot may result in life threatening ventilatory impairment. Ball valve blood clot obstructions of the airways are rare. A ball valve blood clot acts as a one-way valve, allowing (near) normal air entry into the airways, but (completely) blocking expiration. In a near fatal case of obstruction of the airways by a ball valve blood clot, we performed 'whole tube suction' to resolve the airway problem.
Abstract: OBJECTIVE: Nosocomial pneumonia is a feared complication in the critically ill patient. Serious acute pancreatitis is frequently complicated by infections. The objectives of this study were to determine the influence of acute pancreatitis on host defense against Pseudomonas pneumonia and to determine the influence of Pseudomonas pneumonia on the severity of concurrent pancreatitis. DESIGN: A controlled, in vivo laboratory study. SETTING: Research laboratory of a health sciences university. SUBJECTS: Female C57Bl/6 mice. INTERVENTIONS: Pancreatitis was induced by 12 hourly intraperitoneal injections of cerulein (pancreatitis) or saline (sham) immediately followed by intranasal administration of Pseudomonas aeruginosa (to induce pneumonia) or saline (controls). Mice were killed 24 hrs later. Hence, four groups were studied: sham/control, pancreatitis/control, sham/pneumonia, and pancreatitis/pneumonia mice. MEASUREMENTS AND MAIN RESULTS: When compared with sham/pneumonia mice, pancreatitis/pneumonia mice demonstrated exaggerated lung inflammation, higher bacterial counts in lungs and pancreas, and enhanced dissemination of the infection. Concurrently, pneumonia prolonged the course of pancreatitis, as reflected by histopathology and higher plasma amylase and relative pancreas weights (all p < .05 for the difference between pancreatitis/pneumonia and pancreatitis/control mice), which was associated with the localization of Pseudomonas in the pancreas. CONCLUSIONS: Acute pancreatitis impairs host defense against Pseudomonas pneumonia, whereas pneumonia prolongs the course of pancreatitis.
Abstract: Severe infection is associated with profound alterations in the systemic haemostatic balance, with activation of coagulation and suppressed fibrinolysis. Within the alveolar compartment, similar disturbances have been described during pulmonary inflammation. The current authors investigated whether local haemostasis was influenced during ventilator-associated pneumonia (VAP). In five patients with unilateral VAP, bronchoalveolar lavage fluid (BALF) was obtained from both the infected site (as identified on chest radiograph) and the contralateral noninfected lung (with no clinical or radiographic abnormalities). Markers for coagulation and fibrinolysis were compared between infected and noninfected lungs. A total of 10 healthy volunteers and 10 mechanically ventilated patients without pneumonia served as controls. Strong activation of coagulation (high levels of thrombin-antithrombin complexes, soluble tissue factor and factor VIIa) was detected in BALF from infected lungs, compared with that from noninfected lungs and controls. Furthermore, in infected lungs, fibrinolysis was depressed, with high levels of plasminogen activator inhibitor type 1. In conclusion, ventilator-associated pneumonia is characterised by a hypercoagulant state at the site of infection.
Abstract: The rationale for surfactant replacement therapy in patients with acute respiratory distress syndrome (ARDS) is to restore the normal composition of the surfactant system, as well as to overcome ongoing inactivation of present surfactant. Indeed, surfactant replacement therapy can normalize the composition of the surfactant system and restore its surface activity, which results in restoration of the gas exchange. Several phase II- and phase III-studies have been performed to investigate safety and efficacy of surfactant replacement therapy in patients with ARDS. In this manuscript we will discuss the differences in the composition of exogenous surfactant, the diverse modes of delivery of surfactant, and timing of therapy, in relation to the efficacy of surfactant instillation in several published and yet unpublished studies.
Abstract: Diffuse panbronchiolitis (DPB) is a pulmonary disease characterized by chronic inflammation of the bronchioles and chronic infiltration of inflammatory cells in the lungs. DPB has several features in common with cystic fibrosis (CF). Clinical trials in patients with DPB or CF suggest a potential role for maintenance (long-term and low-dose) macrolide therapy in the treatment of these chronic pulmonary conditions. Indeed, these studies demonstrate improved clinical and physiological states with macrolide therapy. The beneficial effects of long-term low-dose macrolides are not related to their antimicrobial properties, since levels of macrolides with low-dose treatment are too low to have sufficient antimicrobial effects. Data indicate that macrolides may have immunomodulatory activities: (1) in vitro and ex vivo studies clearly show that macrolides can influence cytokine production by several cell types; (2) furthermore, macrolides can alter polymorphonuclear cell functions in vitro and ex vivo. Although immunomodulation may serve as one explanation for the beneficial effects of macrolides in patients with chronic pulmonary inflammation, the effect of low-dose macrolide therapy on biofilm-formation may form a second explanation for the positive effects of long-term low-dose macrolide therapy. In the present paper, the clinical trials on maintenance macrolide therapy in patients with DPB or CF are reviewed. This is followed by a discussion on the immunomodulating effects of macrolides, and the effects of macrolides on biofilm formation.
Abstract: BACKGROUND: Fibrin deposition is a hallmark of pneumonia. To determine the kinetics of alterations in local coagulation and fibrinolysis in relation to ventilator associated pneumonia (VAP), a single centre prospective study of serial changes in pulmonary and systemic thrombin generation and fibrinolytic activity was conducted in patients at risk for VAP. METHODS: Non-directed bronchial lavage (NBL) was performed on alternate days in patients expected to require mechanical ventilation for more than 5 days. A total of 28 patients were studied, nine of whom developed VAP. RESULTS: In patients who developed VAP a significant increase in thrombin generation was observed in the airways, as reflected by a rise in the levels of thrombin-antithrombin complexes in NBL fluid accompanied by increases in soluble tissue factor and factor VIIa concentrations. The diagnosis of VAP was preceded by a decrease in fibrinolytic activity in NBL fluid. Indeed, before VAP was diagnosed clinically, plasminogen activator activity levels in NBL fluid gradually declined, which appeared to be caused by a sharp increase in NBL fluid levels of plasminogen activator inhibitor 1. CONCLUSION: VAP is characterised by a shift in the local haemostatic balance to the procoagulant side, which precedes the clinical diagnosis of VAP.
Abstract: OBJECTIVE: To examine whether cytokine concentrations change in the pulmonary compartment during the development of ventilator-associated pneumonia (VAP). DESIGN: Non-directed bronchial lavage (NBL) was performed every 48 h in critically ill mechanically ventilated patients. Serial measurements of the cytokines tumor necrosis factor (TNF) alpha, interleukin (IL)-1alpha, IL-1beta, IL-6, and IL-10 and the cytokine inhibitors soluble TNFalpha receptor type I (sTNFalphaRI), IL-1 receptor antagonist (IL-1Ra) and soluble IL-1 receptor II (sIL-1RII) were performed on the NBL fluid and matching plasma samples by ELISA. SETTING: An adult medical and surgical university hospital intensive care unit. PATIENTS: Nine patients who developed VAP and nineteen patients who did not develop VAP served as controls. INTERVENTIONS: None. RESULTS: Plasma concentrations of the measured cytokines and cytokine inhibitors did not change significantly in any patients. In control patients, NBL fluid concentrations of sIL-1RII decreased significantly over time (P=0.01). In patients who developed VAP, NBL fluid concentrations of TNFalpha, sTNFalphaRI, IL-1alpha, and IL-1beta increased significantly (P=0.002, P=0.03, P=0.04 and P=0.02, respectively). Furthermore, NBL fluid/plasma concentration ratios for TNFalpha, sTNFalphaRI, IL-1alpha, IL-1Ra and IL-6 increased significantly as VAP developed (P=0.001, P=0.001, P=0.04, P=0.03, and P=0.04, respectively). CONCLUSION: Our results suggest that the production of important cytokines and cytokine inhibitors is compartmentalised within the lung in critically ill mechanically ventilated patients who develop VAP.
Abstract: In the last decades several preclinical models for sepsis have been used to study the pathophysiologic processes during sepsis. Although these studies revealed promising immunomodulating agents for the treatment of sepsis, clinical trials evaluating the efficacy of these new agents in septic patients were disappointing. It should be realized that most of the preclinical models for sepsis lack a localized infectious source from which the infection disseminates. Studies on the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis with a more natural route of infection, such as pneumonia, and when using models for sepsis lacking an infectious focus. In this review we will compare models for sepsis and models for pneumonia. We advise to use a combination of models, including models for sepsis and models for localized infections, to test new immunomodulating strategies before starting any clinical trial evaluating a new immunomodulating therapy.
Abstract: OBJECTIVE: To review potential clinical situations beyond sepsis in which activated protein C might be an effective treatment. DATA SOURCE: Published articles between 1970 and 2003 on experimental and clinical studies of activation of both coagulation and inflammation in various disease states. DATA SYNTHESIS AND CONCLUSION: The efficacy of activated protein C in sepsis might rely on the fact that it can modulate both coagulation and inflammation. Therefore, administration of activated protein C could be beneficial in disease states that are also characterized by the simultaneous activation of these systems. Ischemia-reperfusion injury of various organs may represent such a state. Indeed, the involvement of the protein C system has been demonstrated in various experimental studies of ischemia-reperfusion, including studies in renal ischemia-reperfusion syndromes, coronary atherosclerosis and acute coronary syndromes, and intestinal ischemia and reperfusion. In some of these models, activated protein C administration, or other interventions in the protein C system, was shown to be beneficial.
Abstract: Pulmonary changes in thrombin formation in patients with acute lung injury or pneumonia are remarkably similar to systemic changes in coagulation observed in septic patients. Since anticoagulant therapy has proven to be successful in the treatment of patients with sepsis, the same therapeutic strategy may benefit patients with acute lung injury or pneumonia. Based on the fact that inflammation not only leads to dysregulation of the coagulation system, but vice versa, activation of coagulation amplifies inflammatory processes as well, it can be questioned whether the advantage of anticoagulant therapy is solely related to its influence on disturbed thrombin formation. In this paper we will discuss local changes in the haemostatic balance during acute lung injury, both in pre-clinical and clinical studies. Until now, pre-clinical studies have demonstrated that interventions aimed at correction of coagulation abnormalities may form an important strategy in patients with acute lung injury in the future. Pre-clinical studies on use of anticoagulants during pneumonia are presently performed and data are underway.
Abstract: OBJECTIVES: To review the involvement of coagulation and fibrinolysis in the pathogenesis of acute lung injury during severe infection. To review the cross-talk between coagulation and inflammation that may affect this response. DATA SOURCES: Published articles on experimental and clinical studies of coagulation and fibrinolysis during infection, inflammation, acute lung injury, and evolving acute respiratory distress syndrome. CONCLUSIONS: Fibrin deposition is an important feature of pulmonary infection or severe inflammation. The mechanisms that contribute to this fibrin deposition are bronchoalveolar tissue factor-mediated thrombin generation and localized depression of urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. These effects on pulmonary coagulation and fibrinolysis are regulated by various proinflammatory cytokines. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross-talk. Coagulation and fibrinolytic proteins may have an additional role beyond fibrin turnover and inflammation, e.g., in mechanisms mediating cell recruitment and migration.
Abstract: For patients with acute respiratory distress syndrome (ARDS) the most important objective of mechanical ventilation is opening and keeping open the alveoli to achieve adequate oxygenation, without further damaging the lungs or negatively affecting the circulation. Alveolar recruitment is achieved by making use of positive end-expiratory pressure (PEEP). The best PEEP level is that with which the largest improvement in oxygen transport and lung compliance is achieved, without a decrease in the stroke volume of the left ventricle. In addition to the usual volume-controlled ventilation with PEEP, pressure-limited ventilation is also possible. In this a preselected pressure is never exceeded, whereas a maximum inspiratory airflow at the start of inspiration provides more opportunity for gaseous exchange. The oxygenation can possibly be further improved by increasing the inspiration-expiration ratio. As a result of the reduced expiratory period the alveoli which tend to collapse at the end of a normal expiration are kept open. Mechanical ventilation with a lower tidal volume decreases mortality. Ventilation in a prone position increases the end-expiratory lung volume and reduces the intrapulmonary shunt and the regional differences in the degree of ventilation. These factors possibly contribute to preventing ventilation-induced lung damage. Administration of natural surfactant during the ventilation of patients with ARDS seems to be a highly promising strategy; the clinical effectiveness still needs to be demonstrated.
Abstract: Interleukin-18 (IL-18) is a potent cytokine with many different proinflammatory activities. To study the role of IL-18 in the pathogenesis of Pseudomonas pneumonia, IL-18-deficient (IL-18(-/-)) and wild-type mice were intranasally inoculated with Pseudomonas aeruginosa. IL-18 deficiency was associated with reduced outgrowth of Pseudomonas in the lungs and diminished dissemination of the infection. In addition, pulmonary inflammation (histopathology) and levels of tumor necrosis factor alpha, IL-6, and macrophage inflammatory protein-2 in lungs and plasma were lower in IL-18(-/-) mice. Consistent with results obtained for IL-18(-/-) mice, treatment of wild-type mice with a neutralizing IL-18 binding protein-immunoglobulin G Fc fusion construct also attenuated outgrowth of Pseudomonas compared with that for mice treated with a control protein. These results demonstrate that the presence of endogenous IL-18 activity facilitates inflammatory responses in the lung during Pseudomonas pneumonia, concurrently impairing bacterial clearance.
Abstract: BACKGROUND: Selective decontamination of the digestive tract (SDD) is an infection-prevention regimen used in critically ill patients. We assessed the effects of SDD on intensive-care-unit (ICU) and hospital mortality, and on the acquisition of resistant bacteria in adult patients admitted to intensive care. METHODS: We did a prospective, controlled, randomised, unblinded clinical trial. 934 patients admitted to a surgical and medical ICU were randomly assigned oral and enteral polymyxin E, tobramycin, and amphotericin B combined with an initial 4-day course of intravenous cefotaxime (SDD group n=466), or standard treatment (controls n=468). Primary endpoints were ICU and hospital mortality and the acquisition of resistant bacteria. FINDINGS: In the SDD group 69 (15%) patients died in the ICU compared with 107 (23%) in the control group (p=0.002). Hospital mortality was lower in the SDD groups than in the control group (113 [24%] vs 146 [31%], p=0.02). During their stay in intensive care, colonisation with gram-negative bacteria resistant to ceftazidime, ciprofloxacin, imipenem, polymyxin E, or tobramycin occurred in 61 (16%) of 378 SDD patients and in 104 (26%) of 395 patients in the control group (p=0.001). Colonisation with vancomycin-resistant enterococcus occurred in five (1%) SDD patients and in four (1%) controls (p=1.0). No patient in either group was colonised with meticillin-resistant Staphylococcus aureus. INTERPRETATION: In a setting with low prevalence of vancomycin-resistant enterococcus and meticillin-resistant S aureus, SDD can decrease ICU and hospital mortality and colonisation with resistant gram-negative aerobic bacteria.
Abstract: 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.
Abstract: Pneumonia is associated with elevated concentrations of the proinflammatory cytokine interleukin (IL)-1 in the pulmonary compartment. To study the role of IL-1 in the pathogenesis of Pseudomonas pneumonia, IL-1 receptor type 1 gene-deficient (IL-1R -/-) mice and wild-type mice were intranasally inoculated with Pseudomonas aeruginosa. The absence of the IL-1 signal attenuated the outgrowth of Pseudomonas in lungs, as reflected by an increasing number of colony-forming units (cfu) during Pseudomonas pneumonia in wild-type mice and a concurrently decreasing number of cfu during pulmonary infection in IL-1R -/- mice (P < 0.05, IL-1R -/- mice vs. wild-type mice). Influx of neutrophils was decreased in bronchoalveolar lavage fluids in IL-1R -/- mice compared with wild-type mice. Similarly, lung levels of cytokines (tumor necrosis factor-alpha, IL-6) and chemokines (macrophage inflammatory protein-2 and KC) were lower in IL-1R -/- mice 24 h postinoculation. Consistent with results obtained in IL-1R -/- mice, treatment of wild-type mice with IL-1R antagonist also diminished outgrowth of Pseudomonas when compared with wild-type mice treated with vehicle (P < 0.05). These results demonstrate that an absence or reduction in endogenous IL-1 activity improves host defense against Pseudomonas pneumonia while suppressing the inflammatory response.
Abstract: To determine the role of interferon (IFN)-gamma in pneumonia, IFN-gamma receptor-deficient (IFN-gamma R(-/-)) and 129/Sv (wild-type [wt]) mice were inoculated intranasally with Streptococcus pneumoniae. Although mortality did not differ between the groups 48 h after inoculation, IFN-gamma R(-/-) mice had significantly fewer pneumococci in their lungs than the wt mice. Similarly, IFN-gamma(-/-) mice had fewer colony-forming units in lungs than wt mice. The relatively increased resistance of IFN-gamma R(-/-) mice was not related to favorable effects on defense mechanisms known to contribute to antibacterial immunity-that is, the neutrophilic influx was reduced and the cytokine and nitric oxide levels were similar or lower in IFN-gamma R(-/-) mice. In contrast, mice treated with anti-IFN-gamma did not demonstrate a consistently altered bacterial outgrowth, compared with mice treated with a control antibody. These data suggest that endogenous IFN-gamma, despite its protective role in defense against intracellular pathogens, does not serve a protective role during pneumococcal pneumonia.
Abstract: Optimal alveolar distribution of exogenous surfactant is an important determinant of its beneficial effect. This distribution can be determined by suspending surfactant in a radiological contrast medium before intratracheal instillation, followed by radiological imaging. Iodixanol is reported to be a safe contrast medium that causes no lung injury when instilled intratracheally. In this study, the effects of surfactant suspended in saline were compared with surfactant suspended either in 4:1 saline-iodixanol (64 mg iodine x mL(-1)) or in 1:1 saline-iodixanol (160 mg iodine x mL(-1)), on oxygenation and lung mechanics in a rat model of adult respiratory distress syndrome (ARDS) induced by lung lavage. After the induction of ARDS, surfactant instillation improved oxygenation, total lung volume at inflation with a distending pressure of 35 cmH2O, lung volume at transpulmonary pressure of 5 cmH2O and Gruenwald index. The effects of surfactant suspended in 4:1 saline-iodixanol were similar to those of surfactant alone. However, instillation of surfactant suspended in 1:1 saline-iodixanol resulted in significantly lower values in all measured parameters. Surface tension was the lowest in surfactant suspended in saline alone and addition of iodixanol led to an increase in surface tension in a dose-dependent manner. In conclusion, iodixanol at the higher dose caused an inhibition of the exogenous surfactant effect, characterized as a lack of improvement in oxygen tension in arterial blood, low total lung compliance, volume at 5 cmH2O end-expiration and Gruenwald index. This effect of iodixanol was probably due to its high surface tension, especially if a high concentration was used. Surfactant suspended in a lower concentration of iodixanol seems a better alternative, allowing for radiological imaging of the distribution of surfactant when intratracheally instilled.
Abstract: Sepsis is associated with the activation of several inflammatory cascades, including the cytokine network and the coagulation system, but it can also be associated with an immunodepressed state. This can lead to a situation in which the septic patient becomes more susceptible to secondary infections. In animal experiments, inhibition of the cytokine cascade by administration of tumour necrosis factor alpha (TNF alpha)-receptors or anti-TNF alpha antibodies has led to reduced mortality, but this has not been confirmed in clinical trials. After the data were pooled, there was a statistically significant decrease in mortality of 3-5%. Treatment with endotoxin antibodies, corticosteroids in high doses, other anti-inflammatory agents and agents designed to eliminate immunodepression generally also did not produce a convincing decrease in mortality. Research on antithrombotic agents has yielded, along with disappointing results with antithrombin III and 'tissue factor pathway inhibitor', one study with a positive result. In septic patients with organ failure who were treated with activated protein C, a coagulation inhibitor, the mortality decreased from 30.8 to 24.7%.
Abstract: Several preclinical models for sepsis have been used in the last decades to successfully unravel the pathophysiologic processes during sepsis. Furthermore, these models for sepsis revealed promising immunomodulating agents for the treatment of sepsis. Nevertheless, several clinical trials evaluating the efficacy of these new anti-inflammatory agents in septic patients showed disappointing results. In this article the advantages and disadvantages of different models for sepsis are discussed. Most models for sepsis lack an infectious focus. Importantly, investigations studying the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis lacking an infectious focus and when using models for sepsis with a more natural route of infection. These differences will be discussed in this article. In general, it is advised to use a combination of models to test a new therapeutic agent, before starting a clinical study evaluating this new therapy.
Abstract: Both the increasing number of immunocompromised patients susceptible to pneumonia and the development of bacterial resistance are significant problems related to the treatment of pneumonia. The primary outcome of treatment for pneumonia is to tip the balance towards a successful host response. An ideal approach would be a combination of immunomodulation and conventional antimicrobial therapy. It is of increasing importance to understand the components of innate immunity, before immunomodulatory therapy can be applied to patients. Much of our knowledge of the role of alveolar macrophages, cytokines and chemokines in the pathogenesis of pneumonia is derived from animal studies on experimental pneumonia. This article summarizes current information on the role of an alveolar macrophage (AM) and AM-derived mediators in host defense against pneumonia.
Abstract: Exotoxin A (P-ExA) is considered to be a major virulence factor of Pseudomonas aeruginosa. Neutrophils, cytokines and nitric oxide (NO) have been implicated as important components of an effective host defence against bacterial respiratory tract infection. To study the role of P-ExA in the pathogenesis of P. aeruginosa pneumonia, C57Bl/6 mice were inoculated intranasally with wild-type PA103 or a mutant P. aeruginosa strain that did not produce P-ExA, PA103-29. P-ExA facilitated the outgrowth of P. aeruginosa in lungs, as reflected by an increasing number of cfu during pneumonia with strain PA103, whereas the number of cfu decreased during pulmonary infection with strain PA103-29. Influx of neutrophils was similar in broncho-alveolar lavage fluids (BALF) during pneumonia with strains PA103 and PA103-29. Lung levels of cytokines (tumor necrosis factor-alpha, interleukin-6) and chemokines (macrophage inflammatory protein-2, KC) were higher in mice inoculated with strain PA103, whereas BALF concentrations of NO were similar in mice treated with strains PA103 and PA103-29. These data suggest that P-ExA impairs host defence during pneumonia caused by P. aeruginosa by a mechanism that does not involve effects on neutrophil influx, cytokines, chemokines or NO formation.
Abstract: Erythromycin inhibits the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL6) induced by heat-killed Streptococcus pneumoniae in human whole blood ex-vivo. The objective of the present study was to determine and characterize the concentration-effect relationship of this phenomenon in order to predict its possible clinical relevance.Six healthy volunteers received a single intravenous dose of 1000 mg erythromycin. Blood samples were obtained up to 4 h after drug administration. Samples were assayed for erythromycin concentrations and (after heat-killed Streptococcus pneumoniae stimulation) for TNF-alpha and IL6 concentrations. Effect vs. time data from individual subjects were fitted to the indirect response model with an Emax concentration-effect relationship. Simulations of these effects were performed for therapeutic intravenous and oral erythromycin dosage regimens. The geometric means of the values of Kin, Kout and EC50 were 15.4 microg/h, 0.82/h, 9.4 mg/L for TNF-alpha and 321 microg/h, 2.02/h, 18.3 mg/L for IL6. Simulations revealed a maximal inhibition of TNF-alpha concentrations of 35%, 50%, 16% and 27% at erythromycin dosages of 500 mg i.v., 1000 mg i.v., 500 mg p.o and 1000 mg p.o. q 6 h, respectively, whereas a maximal inhibition of IL6 of 29%, 44%, 13% and 22% are predicted for the respective regimens. The inhibitory effect of erythromycin on TNF-alpha and IL6 production can be adequately described by the indirect response model with an Emax concentration-effect relationship. Simulations predicted a substantial decrease of production of these cytokines at intravenous and to a much lesser extent at oral erythromycin dosage regimens.
Abstract: Erythromycin has been shown to be beneficial for panbronchiolitis, a disorder linked to infection with Pseudomonas aeruginosa. Erythromycin, but not the anti-Pseudomonas antibiotics imipenem, ceftazidime, gentamicin and ciprofloxacin, caused a dose-dependent decrease in the production of tumour necrosis factor (TNF)-alpha by whole blood stimulated with heat-killed P. aeruginosa. The release of interleukin (IL)-10, IL-6, interferon-gamma and IL-8 was inhibited only at the highest erythromycin concentration. Inhibition of TNF-alpha production by erythromycin may, at least in part, explain the efficacy of this macrolide during panbronchiolitis despite its lack of activity for P. aeruginosa.
Abstract: p38 mitogen-activated protein kinase (MAPK) has been suggested as a mediator of cytokine release and is currently being targeted for anti-inflammatory therapy. However, experimental data are contradictory and lack sufficient affirmation in vivo. We tested the effect of p38 MAPK inhibition in several cell types and in different murine models of infectious disease. We observed that most cell types react to p38 MAPK inhibition with diminished cytokine release, but that this treatment induced increased cytokine release in macrophages. Furthermore, we observed increased cytokine production in mouse models of pneumococcal pneumonia and tuberculosis accompanied by severely reduced bacterial clearance. This apparent inefficacy of p38 MAPK inhibition in reducing cytokine release in infectious disease, as well as its immune-compromising action, suggest that targeting p38 MAPK may not be a suitable anti-cytokine strategy in patients with such disease or at risk for infection.
Abstract: Leukotrienes (LTs) are considered important for antibacterial defense in the lung. Multidrug resistance protein 1 (mrp1) is a transmembrane protein responsible for the cellular extrusion of LTC(4). To determine the role of mrp1 in host defense against pneumonia, mrp1(-/-) and wild-type mice were intranasally inoculated with Streptococcus pneumoniae. mrp1(-/-) mice displayed a diminished outgrowth of pneumococci in lungs and a strongly reduced mortality. These findings were related to an effect of mrp1 on LT metabolism, because survival was similar in mrp1(-/-) and wild-type mice treated with the 5-lipoxygenase-activating protein inhibitor MK-886. Although LTC(4) levels remained low in the bronchoalveolar lavage fluid of mrp1(-/-) mice, LTB(4) concentrations were higher than in wild-type mice. These elevated LTB(4) concentrations were important for the relative protection of mrp1(-/-) mice, because the LTB(4) antagonist LTB(4)-dimethyl amide abolished their survival advantage. In vitro experiments suggested that the intracellullar accumulation of LTC(4) in mrp1(-/-) mice results in product inhibition of LTC(4)-synthase, diminishing substrate competition between LTA(4)-hydrolase (which yields LTB(4)) and LTC(4)-synthase for the available LTA(4). We conclude that mrp1(-/-) mice are resistant against pneumococcal pneumonia by a mechanism that involves increased release of LTB(4). These results identify mrp1 as a novel target for adjunctive therapy in pneumonia.
Abstract: Interferon (IFN-)gamma is thought to play a role in the resistance to various pathogens. To study the role of IFN-gamma in the pathogenesis of Pseudomonas pneumonia, IFN-gamma receptor (R) alpha-subunit-deficient [IFN-gammaR(-/-)] mice and wild type mice were intranasally inoculated with Pseudomonas aeruginosa (10(5) CFU). IFN-gammaR(-/-) mice demonstrated an enhanced clearance of P. aeruginosa from their lungs when compared to normal wild type mice (P < 0.05 at 24 hours after the infection), which was associated with a tendency towards an improved survival. These findings were not accompanied by a more effective activation of several components of the innate immune system known to contribute to host defense against pneumonia, i.e. the lung concentrations of cytokines and chemokines were similar in IFN-gammaR(-/-) and wild type mice, while the influx of neutrophils in bronchoalveolar lavage fluid (BALF) was even higher in wild type mice than in IFN-gammaR(-/-) mice. Remarkably, IFN-gammaR(-/-) mice had higher nitric oxide levels in the BALF at 24 hours after infection (P < 0.05). Endogenous IFN-gamma impairs rather than augments host defense during pneumonia caused by P. aeruginosa.
Abstract: Ingestion of thalidomide was associated with a reduction in the upregulation of the granulocyte activation marker CD11b and a reduced capacity to release elastase and lactoferrin after stimulation with lipopolysaccharide or lipoteichoic acid. A single oral dose of thalidomide attenuates neutrophil activation upon ex vivo stimulation with bacterial antigens.
Abstract: Macrolides may influence the inflammatory response to an infection by mechanisms that are unrelated to their antimicrobial effect. Indeed, erythromycin and other macrolides inhibit cytokine production and induce degranulation of neutrophils in vitro. CXC chemokines are small chemotactic cytokines that specifically influence neutrophil functions. To determine the effect of a clinically relevant dose of erythromycin on the production of CXC chemokines and neutrophil degranulation, six healthy humans received a 30 min iv infusion of erythromycin (1000 mg). Whole blood obtained before and at various times after the infusion was stimulated ex vivo with heat-killed Streptococcus pneumoniae. Ex vivo production of the CXC chemokines interleukin 8 (IL-8) and epithelial cell-derived neutrophil attractant 78 (ENA-78), in whole blood obtained after erythromycin infusion, was lower than that in blood drawn before erythromycin infusion (maximum inhibition post-infusion: 32.9 +/- 6.5% and 35.2 +/- 12.6% decrease in production, respectively, expressed as percentage change relative to production before infusion of erythromycin, both P < 0.05). In contrast, infusion of erythromycin was associated with an enhanced capacity of whole blood to release the neutrophil degranulation products bactericidal/permeability increasing protein (BPI), human neutrophil elastase (HNE) and human lactoferrin (HLF) upon stimulation with S. pneumoniae. Effects of erythromycin were greatest 4 h after infusion was stopped, when BPI, HNE and HLF concentrations were increased by +107.6 +/- 33.5%, +134.7 +/- 34.8% and +205.9 +/- 55.9 %, respectively (expressed as percentage change relative to production before infusion of erythromycin) (all P < 0. 05). These results indicate the ability of erythromycin to reduce CXC chemokine production and to enhance neutrophil degranulation in human blood.
Abstract: Monocytes from patients with sepsis have a reduced capacity to produce cytokines, a state referred to as immunoparalysis. To determine whether polymorphonuclear leukocytes (PMNL) can be rendered hyporesponsive, PMNL from 6 healthy volunteers intravenously challenged with lipopolysaccharide (LPS; 4 ng/kg) were stimulated ex vivo with heat-killed bacteria or LPS, and the release of the CXC chemokines interleukin-8, epithelial-derived neutrophil attractant-78, and growth-related oncogen-alpha was measured. At 1 and 2 h after LPS administration in vivo, PMNL produced fewer CXC chemokines after stimulation with bacteria or LPS (all P<.05). Serum obtained 2 h after in vivo administration of LPS did not influence chemokine production by PMNL from 6 healthy volunteers not previously exposed to LPS. Thus, intravenous injection of LPS induces a refractory state of PMNL that is not caused by soluble factors produced in response to in vivo exposure to LPS.
Abstract: To determine the effect of Pseudomonas aeruginosa exotoxin A (P-ExA) on cytokine production, we studied cytokine release induced by heat-killed P. aeruginosa (HKPA) in human whole blood in the presence or absence of P-ExA. P-ExA (0.01-1 microgram ml(-1)) caused a dose-dependent decrease in HKPA-induced production of tumor necrosis factor alpha (TNF), interleukin (IL-) 10, IL-6 and IL-8 (all P<0.05). P-ExA-induced inhibition of IL-10, IL-6 and IL-8 release was not dependent on reduced TNF concentrations, since the relative attenuation of the production of these cytokines was similar in the presence or absence of a neutralizing anti-TNF antibody. The effect of P-ExA on cytokine production may offer a disadvantage to the host with respect to clearance of the infection.
Abstract: To determine the effects of penicillin and erythromycin on cytokine production induced by heat-killed Streptococcus pneumoniae (HKSP), we studied the effects of those drugs on cytokine production induced by S. pneumoniae in human whole blood in vitro and ex vivo. In whole blood in vitro, erythromycin, but not penicillin, caused a dose-dependent decrease in HKSP-induced production of tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6), while the production of IL-10, IL-12, and gamma interferon was inhibited only at the highest erythromycin concentration tested (10(-3) M). The production of TNF and IL-6 in whole blood obtained from healthy subjects after a 30-min infusion of erythromycin (1,000 mg) was lower after ex vivo stimulation with HKSP than that in blood drawn before the infusion. Inhibition of TNF contributed to erythromycin-induced inhibition of IL-6 synthesis. Inhibition of TNF and IL-6 production by erythromycin may have a negative impact on host defense mechanisms during pneumococcal pneumonia.
Abstract: Tranexamic acid has been advocated for patients with severe bleeding tendency due to thrombocytopenia not responding to platelet transfusions. Macroscopic haematuria is a well-known contraindication for its use in such patients. We present three clinical cases with microscopic haematuria, in whom tranexamic acid caused problems of clot formation in the urinary tract, indicating that microscopic haematuria should also be considered as a contraindication for tranexamic acid.
Abstract: Cholera is a disease rarely imported in the Netherlands. Recently a 34-year-old woman who had returned from a trip through Thailand was admitted to our hospital with complaints of vomiting, watery stools and moderate dehydration. Vibrio cholerae OI serotype Ogawa biotype El Tor was isolated from the faeces. She recovered after antimicrobial and fluid therapy. Her 29-year-old travelling companion had only mild symptoms of diarrhoea, but the bacterium was isolated from her stool also. Cholera should be considered in travellers with vomiting and diarrhoea coming back from Thailand.
Abstract: The recently developed artemisinin derivative arteether was administered by intramuscular injection to healthy male subjects in a single dose (n = 23) and a multiple dose study (n = 27). The drug was well tolerated. Clinical, neurological, electrocardiographic and biochemical monitoring did not reveal significant toxicity. Apart from some increase in eosinophil numbers, no haematological abnormality was seen. Preliminary pharmacokinetic data showed a long elimination half life of 25-72 h and marked accumulation in the multiple dose study.
Abstract: Transcutaneous PCO2 studies were performed in 21 healthy preterm infants and in 12 preterm infants with respiratory problems, in order: I. to evaluate the feasibility of transcutaneous PCO2 measurements in the clinical situation; 2. to collect normal values for preterm infants, and 3. to compare transcutaneous tcPCO2 values with PCO2 measured in capillary or arterial blood samples. Normal tcPCO2, measured in 21 healthy preterm infants, mean gestational age 32.5 +/- 2.3 weeks (range 26 6/7-36 1/7, mean birth weight 1547 +/- 498 gram (range 820-2840), postnatal age 2.2 +/- 2.1 days (range 0-6) was 41.2 +/- 5.5 mm Hg. The relation between transcutaneous PCO2 and PCO2 in arterial or capillary blood samples was studied in 12 patients with respiratory problems, 7 boys and 5 girls, mean gestational age 31 4/7, birth weight 1600 gram (range 885-3050). We found a good linear relation between tcPCO2 and arterial PaCO2 (regression coëfficient between 0.66 and 0.96) and a bad correlation between tcPCO2 and capillary PCO2 (regression coefficient 0.14-0.89). We conclude that tcPCO2 measurement is reliable and feasible for clinical use and is more reliable than PCO2 measurement in capillary blood.
