Fluid management in Acute Respiratory Distress Syndrome: A narrative review.

Acute Respiratory Distress Syndrome remains a major source of morbidity and mortality in the modern intensive care unit (ICU). Major advances in the understanding and management of this condition were made in the last two decades. The use of low tidal ventilation is a well-established therapy. Conservative fluid management is now another cornerstone of management. However, much remains to be understood in this arena. Assessing volume status in these patients may be challenging and the tools available to do so are far from perfect. Several dynamic measures including pulse pressures variation are used. Ultrasound of the lungs and the vascular system may also have a role. In addition, the type of fluid to administer when needed is still open to debate. Finally, supportive measures in these patients, early during their ICU stay and later after discharge continue to be crucial for survival and adequate recovery.

Supportive management strategies for disseminated intravascular coagulation. An international consensus.

The cornerstone of the management of disseminated intravascular coagulation (DIC) is the treatment of the underlying condition triggering the coagulopathy. However, a number of uncertainties remain over the optimal supportive treatment. The aim of this study was to provide evidence and expert-based recommendations on the optimal supportive haemostatic and antithrombotic treatment strategies for patients with DIC. A working group defined five relevant clinical scenarios. Published studies were systematically searched in the MEDLINE and EMBASE databases (up to May 2014). Seven internationally recognised experts were asked to independently provide clinical advice. A two-phase blinded data collection technique was used to reach consensus. Only three randomised controlled trials (RCTs) on the supportive management of DIC were identified. The RCTs (overall less than 100 patients) investigated the use of fresh frozen plasma and platelet transfusion and found no differences in survival between the intervention and control groups. The experts' approach was heterogeneous, although there was consensus that supportive management should vary according to the underlying cause, clinical manifestations and severity of blood test abnormalities. Platelet transfusion should be given to maintain platelet count > 50×109/l in case of bleeding while a lower threshold of 20 to 30×109/l may be used in DIC without bleeding. Thromboprophylaxis with low-molecular-weight heparin is advised until bleeding ensues or platelet count drops below 30×109/l. In conclusion, in the absence of solid evidence from RCTs, an individualised supportive management of DIC is advisable based on the type of underlying disease, presence of bleeding or thrombotic complications and laboratory tests results.

Anticoagulant modulation of inflammation in severe sepsis.

Inflammation and coagulation are so tightly linked that the cytokine storm which accompanies the development of sepsis initiates thrombin activation and the development of an intravascular coagulopathy. This review examines the interaction between the inflammatory and coagulation cascades, as well as the role of endogenous anticoagulants in regulating this interaction and dampening the activity of both pathways. Clinical trials attempting to improve outcomes in patients with severe sepsis by inhibiting thrombin generation with heparin and or endogenous anticoagulants are reviewed. In general, these trials have failed to demonstrate that anticoagulant therapy is associated with improvement in mortality or morbidity. While it is possible that selective patients who are severely ill with a high expected mortality may be shown to benefit from such therapy, at the present time none of these anticoagulants are neither approved nor can they be recommended for the treatment of sepsis.

Bronchial responsiveness in patients with restrictive spirometry.

BACKGROUND: Improvement in PFT after bronchodilators is characteristic of obstructive airway diseases such as COPD. However, improvement in patients with restrictive pattern is occasionally seen. We aim to determine the clinical significance of a bronchodilator responsive restrictive defect. METHODS: Patients with restrictive spirometry and a bronchodilator study were identified at the University of Oklahoma and Oklahoma City VAMC between September 2003 and December 2009. Restriction was defined as a decreased FVC and FEV1, with normal FEV1/FVC. Responsiveness to bronchodilators was defined as an improvement in FEV1 and/or FVC of at least 12% and 200 mL. Patients with lung volume measurements had their clinical and radiographic records reviewed. RESULTS: Twenty-one patients were included in the study. Most were current or ex-smokers, with most being on bronchodilators. The average FVC and FEV1 were 65 ± 11% and 62 ± 10% of the predicted, respectively. Most patients (66%) had a normal TLC, averaging 90 ± 16% of the predicted. RV, RV/TLC, and the TLC-VA values strongly suggested an obstructive defect. CONCLUSIONS: Reversible restrictive pattern on spirometry appears to be a variant of obstructive lung disease in which early airway closure results in air trapping and low FVC. In symptomatic patients, a therapeutic trial of bronchodilators may be beneficial.

Iloprost improves gas exchange in patients with pulmonary hypertension and ARDS.

OBJECTIVE: We hypothesized that nebulized iloprost would improve ventilation-perfusion matching in patients with pulmonary hypertension and ARDS as reflected by an improved Pao2/Fio2 ratio and Pao2 without adversely affecting lung mechanics or systemic hemodynamics. METHODS: Patients with ARDS and pulmonary hypertension were enrolled. With constant ventilator settings, hemodynamics, airway pressures, and gas exchange measured at baseline were compared with values 30 min after administration of 10 µg nebulized iloprost, and again 30 min after a second, larger, 20 µg dose of iloprost, and then a final measurement 2 h after the second dose. The primary outcome variable was Pao2; secondary outcomes were Pao2/Fio2 ratio, mean arterial BP, and lung-compliance ventilatory equivalents for oxygen and CO2. RESULTS: After informed consent was obtained, 20 patients (nine men, 11 women; median age, 59 years [interquartile range, 44-66 years]) with ARDS were enrolled. Baseline PaO2 improved from a mean (±SD) of 82 (13) mm Hg to 100 (25) mm Hg after both the first and second doses of iloprost, and the baseline mean (±SD) PaO2/FIO2 ratio of 177 (60) improved to 213 (67) and 212 (70) (all P<.01). PaCO2, peak and plateau airway pressures, systemic BP, and heart rate were not significantly changed after iloprost. CONCLUSIONS: The improvement in gas exchange without any detrimental effects on pulmonary mechanics or systemic hemodynamics suggests nebulized iloprost may be a useful therapeutic agent to improve oxygenation in patients with ARDS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01274481; URL: www.clinicaltrials.gov.

Dornase alpha compared to hypertonic saline for lung atelectasis in critically ill patients.

BACKGROUND: Despite the lack of randomized trials, nebulized Dornase alpha and hypertonic saline are used empirically to treat atelectasis in mechanically ventilated patients. Our objective was to determine the clinical and radiological efficacy of these medications as an adjunct to standard therapy in critically ill patients. METHODS: Mechanically ventilated patients with new onset (<48 h) lobar or multilobar atelectasis were randomized into three groups: nebulized Dornase alpha, hypertonic (7%) saline or normal saline every 12 h. All patients received standard therapy, including chest percussion therapy, kinetic therapy, and bronchodilators. The primary endpoint was the change in the daily chest X-ray atelectasis score. RESULTS: A total of 33 patients met the inclusion criteria and were randomized equally into the three groups. Patients in the Dornase alpha group showed a reduction of 2.18±1.33 points in the CXR score from baseline to day 7, whereas patients in the normal saline group had a reduction of 1.00±1.79 points, and patients in the hypertonic saline group showed a score reduction of 1.09±1.51 points. Pairwise comparison of the mean change of the CXR score showed no statistical difference between hypertonic saline, normal saline, and dornase alpha. Airway pressures as well as oxygenation, expressed as PaO(2)/F(I)O(2) and time to extubation also were similar among groups. During the study period the rate of extubation was 54% (6/11), 45% (5/11), and 63% (7/11) in the normal saline, hypertonic saline, and Dornase alpha groups, respectively (p=0.09). No treatment related complications were observed. CONCLUSIONS: There was no significant improvement in the chest X-ray atelectasis score in mechanically ventilated patients with new onset atelectasis who were nebulized with Dornase alpha twice a day. Hypertonic saline was no more effective than normal saline in this population. Larger randomized control trials are needed to confirm our results.

Pathophysiology, staging and therapy of severe sepsis in baboon models.

We review our baboon models of Escherichia coli sepsis that mimic, respectively, the shock/disseminated intravascular coagulation (DIC) and organ failure variants of severe sepsis, and analyse the pathophysiologic processes that are unique to each. The multi-stage, multi-factorial characteristics of severe sepsis develop as a result of the initial insult, which - depending on its intensity - activates components of the intravascular compartment leading to overwhelming shock/DIC; or initiates a sequence of events involving both the intra- and extravascular (tissues) compartments that lead to organ failure. In the latter case, the disorder passes through two stages: an initial inflammatory/coagulopathic intravascular first stage triggered by E. coli, followed by an extravascular second stage, involving components unique to each organ and triggered by ischemia/reperfusion (oxidative stress and histone release). Although a myriad of overlapping cellular and molecular components are involved, it is the context in which these components are brought into play that determine whether shock/DIC or organ failure predominate. For example, inflammatory and thrombotic responses amplified by thrombin in the first case whereas similar responses are amplified by complement activation products in the second. Rather than blocking specific mediators, we found that attenuation of the thrombin and complement amplification pathways can effectively reverse the shock/DIC and organ failure exhibited by the LD(100) and LD(50) E. coli models of severe sepsis, respectively. Translation of these concepts to successful intervention in the respective baboon models of E. coli sepsis and the application to their clinical counterparts is described.

Optical coherence tomography as an adjunct to flexible bronchoscopy in the diagnosis of lung cancer: a pilot study.

UNLABELLED: Lung cancer is the leading cause of cancer-related deaths in the United States and the second most common type of cancer in both men and women. Optical coherence tomography (OCT) scanning can generate high-resolution cross-sectional images of complex, living tissues in real time. The objectives of this study were to determine the feasibility of using OCT imaging during flexible bronchoscopy and to preliminarily assess the ability of OCT imaging to distinguish an endobronchial malignancy from normal endobronchial mucosa. A Niris OCT probe was introduced into the airways of patients with an endobronchial mass during flexible bronchoscopy. An investigational device exemption was approved by the US Food and Drug Administration for the use of the OCT system in this study. Conventional OCT scans of an endobronchial mass and a control area of normal bronchial mucosa were performed to generate real-time images in each patient. Following OCT imaging, the same sites were biopsied for pathologic correlation. We report on the first five patients enrolled. A total of 60 OCT images with corresponding endobronchial biopsy specimens were obtained. The average procedure time was 29 min. The histopathologic diagnoses of the endobronchial masses included two small cell carcinomas, one squamous cell carcinoma, one adenocarcinoma, and one endobronchial schwannoma. Microstructures of normal bronchial mucosa, including epithelium and lamina propria, were identified with OCT imaging. OCT scan features of malignancy included loss of normal, identifiable microstructures and subepithelial "optical fracture" of tissues. All patients tolerated the endobronchial imaging well without complications. Preliminary results suggest that OCT imaging is a technically feasible adjunct to flexible bronchoscopy in the diagnosis of lung cancer. This is the first reported use of OCT to generate images of endobronchial neoplasms during flexible bronchoscopy in the United States. This technology may in the future provide a noninvasive "optical biopsy," which could potentially guide the bronchoscopist to areas for biopsy or even obviate the need for conventional lung biopsies. TRIAL REGISTRATION: clinicaltrials.gov; Identifier: NCT01039311.

Troponin-I as a prognosticator of mortality in severe sepsis patients.

PURPOSE: The purpose of this retrospective study was to evaluate cardiac troponin-I (cTnI) as a 28-day mortality prognosticator and predictor for a drotrecogin alfa (activated) (DrotAA) survival benefit in recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis patients. METHODS: Cardiac troponin-I was measured using the Access AccuTnI Troponin I assay (Beckman Coulter, Fullerton, CA). There were 598 patients (305 DrotAA, 293 placebo) with baseline cTnI data (cTnI negative [<0.06 ng/mL], n = 147; cTnI positive [>or=0.06 ng/mL], n = 451). RESULTS: Cardiac troponin-I-positive patients were older (mean age, 61 vs 56 years; P = .002), were sicker (mean Acute Physiology and Chronic Health Evaluation II, 26.1 vs 22.3; P < .001), had lower baseline protein C levels (mean level, 49% vs 56%; P = .017), and had higher 28-day mortality (32% vs 14%, P < .0001) than cTnI-negative patients. Elevated cTnI was an independent prognosticator of mortality (odds ratio, 2.020; 95% confidence interval, 1.153-3.541) after adjusting for other significant variables. Breslow-Day interaction test between cTnI levels and treatment was not significant (P = .65). CONCLUSION: This is the largest severe sepsis study reporting an association between elevated cTnI and higher mortality. Cardiac troponin-I elevation was not predictive of a survival benefit with DrotAA treatment.

Iloprost improves gas exchange and exercise tolerance in patients with pulmonary hypertension and chronic obstructive pulmonary disease.

BACKGROUND: Nonselective systemic vasodilators worsen ventilation perfusion (V/Q) matching and gas exchange in patients with chronic obstructive pulmonary disease (COPD). Inhaled iloprost has the potential to act preferentially in ventilated regions of the lung, thereby reducing pulmonary hypertension (PH) while alveolar ventilation is still maintained. OBJECTIVES: To investigate the acute effects of inhaled iloprost on V/Q matching in patients with COPD and PH. METHODS: Ten males with COPD and PH on echocardiography were evaluated before and after inhaling 2 doses of iloprost (2.5 microg). Measurements included lung function, arterial blood gas, 6-min walk test (6MWT) as well as ventilatory equivalents for oxygen (V(E)/VO(2)) and carbon dioxide (V(E)/VCO(2)) taken at baseline, 30 min following each dose of iloprost, and 2 h after the second dose. RESULTS: Mean differences in V(E)/VCO(2) and V(E)/VO(2) were -13.3 (95% CI -36.5 to -2.7; p = 0.002) and -15.0 (95% CI -36.7 to -0.4; p = 0.02), respectively, and the mean change in (A-a) gradient was -3.7 mm Hg (95% CI -6.1 to -1.0; p = 0.01) after a single dose of iloprost, whereas mean improvement in 6MWT was 49.8 m (95% CI 14.8 to 84.7; p = 0.02). Arterial blood gas, venous admixture, dead space fraction and lung functions were maintained after iloprost. The effects of iloprost were reproducible after the second dose. All measurements returned to baseline 2 h after the last dose. No adverse effects on systemic blood pressure or oxygen saturation were seen. CONCLUSIONS: Iloprost inhalation was safe in patients with COPD and PH, and was associated with improved V/Q matching and exercise tolerance.

Tracheal and endobronchial involvement in disseminated histoplasmosis: a case report.

Histoplasmosis is an endemic fungal infection that can involve any organ when disseminated. Although oral, pharyngeal, laryngeal, and endobronchial involvement have been described, direct tracheal involvement has not been reported. We describe the first case of disseminated histoplasmosis with direct involvement of the trachea. The endobronchial manifestations of histoplasmosis are reviewed.

Effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea.

STUDY OBJECTIVE: To examine the long-term effects of continuous positive airway pressure (CPAP) therapy on blood pressure (BP) in patients with obstructive sleep apnea and resistant hypertension. METHODS: Study subjects were 98 patients with obstructive sleep apnea syndrome and hypertension who had 3 or more documented daytime BP measurements taken within 3 months of enrollment and every 3 months after CPAP initiation for 1 year. Resistant hypertension was defined as daytime BP of at least 140 mm Hg systolic or 90 mm Hg diastolic, despite the use of 3 or more antihypertensive medications. Patients in the resistant hypertension group (n = 42) were compared with subjects with controlled hypertension (n = 56). RESULTS: Mean difference in mean arterial pressure was -5.6 (95% confidence interval [CI] -2.0 to -8.7 mm Hg; p = 0.03) in the resistant group and -0.8 mm Hg (95% CI -2.9 to 3.3 mm Hg; p = 0.53) in patients with controlled BP at the end of follow up period. CPAP permitted de-escalation of antihypertensive treatment in 71% of subjects with resistant hypertension but did not significantly alter the antihypertensive regimen in the controlled group. Multivariate regression analysis showed that baseline BP (odds ratio 5.4, 95% CI 2.3 to 8.9; p = 0.01) and diuretic therapy (odds ratio = 3.2, 95% CI 1.8 to 6.1; p = 0.02), but not apnea-hypopnea index or hours of CPAP use, were independently associated with a decrease in mean arterial pressure after 12 months of CPAP therapy. CONCLUSION: In this observational study, CPAP was associated with different effects on blood pressure control in hypertensive patients with sleep apnea. A beneficial response to CPAP therapy was found mainly in subjects with the most severe hypertensive disease.

Prosthetic valve endocarditis caused by Candida lusitaniae, an uncommon pathogen: a case report.

INTRODUCTION: Candida lusitaniae was originally described as a human pathogen in 1979 and typically affects immunocompromised patients. CASE PRESENTATION: We describe a case of prosthetic valve endocarditis with Candida lusitaniae in an immunocompetent 62-year-old woman following aortic valve replacement. In vitro testing demonstrated that our isolate was sensitive to amphotericin B, caspofungin and fluconazole. CONCLUSION: The infection was lethal despite aggressive medical and surgical management and sterilization of blood cultures. The outcome of our case illustrates the need to recognize Candida lusitaniae fungemia as a life-threatening infection in a patient with a prosthetic aortic valve.

Early administration of high-dose antithrombin in severe sepsis: single center results from the KyberSept-trial.

BACKGROUND: The overall finding in the KyberSept trial of no treatment effect of high-dose antithrombin (AT) in severe sepsis was inconsistent for the primary outcome, 28-day mortality, possibly because of patient heterogeneity. No data have been reported on the effects of AT therapy administered early in severe sepsis when microcirculation is disturbed but irreversible organ damage has not yet developed. OBJECTIVE: We report the post hoc results of the KyberSept trial in patients with severe sepsis treated at a single center early after new onset organ failure. METHODS: All study participants from a United States tertiary care intensive care unit were analyzed. Patients had been randomized 1:1 (placebo: n = 41; AT: n = 40) to receive AT (30,000 IU IV over a period of four days) or placebo within 48 h. RESULTS: Baseline variables were well balanced between groups. Eighty percent of patients (n = 65) received study drug within 24 h after onset of severe sepsis; 94% (n = 76) received study drug within 48 h. Nine of 40 participants in the AT group (22.5%) had new organ dysfunction during the first 7 days which was not present at baseline compared with 17 of 39 subjects (43.6%) in the placebo group (P = 0.058; two participants had dysfunction of all organs at baseline and were therefore excluded). At 28 days, 16 of 40 patients (40%) treated with AT died versus 22 of 41 (54%) with placebo [absolute reduction, 14%; odds ratio (95% confidence interval), 0.58 (0.24-1.39)]. In patients receiving AT, a significantly increased bleeding incidence was observed (any bleeding, 8 of 40 (20.0%) for AT group vs 1/41 (2.4%) for placebo group; P < 0.015). CONCLUSIONS: Data from this post hoc analysis confirm an increased bleeding risk seen with AT treatment in these patients. When given early in severe sepsis, though statistically not significant, absolute risk reductions with AT of 21% and 14% for organ failure and mortality, respectively, indicate a potential for treatment benefit in selected sepsis patients. This observation may have implications for continuing sepsis trials with AT that focus on reduced patient heterogeneity.

Multicenter, randomized, placebo-controlled study of the nitric oxide scavenger pyridoxalated hemoglobin polyoxyethylene in distributive shock.

OBJECTIVE: To assess the safety and efficacy of the hemoglobin-based nitric oxide scavenger, pyridoxalated hemoglobin polyoxyethylene (PHP), in patients with distributive shock. DESIGN: Phase II multicenter, randomized (1:1), placebo-controlled study. SETTING: Fifteen intensive care units in North America. PATIENTS: Sixty-two patients with distributive shock, > or = 2 systemic inflammatory response syndrome criteria, and persistent catecholamine dependence despite adequate fluid resuscitation (pulmonary capillary wedge pressure > or = 12). INTERVENTIONS: Patients were randomized to PHP at 0.25 mL/kg/hr (20 mg/kg/hr), or an equal volume of placebo, infused for up to 100 hrs, in addition to conventional vasopressor therapy. Because treatment could not be blinded, vasopressors and ventilatory support were weaned by protocol. MEASUREMENTS AND MAIN RESULTS: Sixty-two patients were randomized to PHP (n = 33) or placebo (n = 29). Age, sex, etiology of shock (sepsis in 94%), and Acute Physiology and Chronic Health Evaluation II scores (33.1 +/- 8.3 vs. 30 +/- 7) were similar in PHP and placebo patients, respectively. Baseline plasma nitrite and nitrate levels were markedly elevated in both groups. PHP infusion increased systemic blood pressure within minutes. Overall 28-day mortality was similar (58% PHP vs. 59% placebo), but PHP survivors were weaned off vasopressors faster (13.7 +/- 8.2 vs. 26.3 +/- 21.4 hrs; p = .07) and spent less time on mechanical ventilation (10.4 +/- 10.2 vs. 17.4 +/- 9.9 days; p = .21). The risk ratio (PHP/placebo) for mortality was .79 (95% confidence interval, .39-1.59) when adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II score, and etiology of sepsis. No excess medical interventions were noted with PHP use. PHP survivors left the intensive care unit earlier (13.6 +/- 8.6 vs. 17.9 +/- 8.2 days; p = .21) and more were discharged by day 28 (57.1 vs. 41.7%). CONCLUSIONS: PHP is a hemodynamically active nitric oxide scavenger. The role of PHP in distributive shock remains to be determined.