Open Lung Approach for the Acute Respiratory Distress Syndrome: A Pilot, Randomized Controlled Trial.

OBJECTIVE: The open lung approach is a mechanical ventilation strategy involving lung recruitment and a decremental positive end-expiratory pressure trial. We compared the Acute Respiratory Distress Syndrome network protocol using low levels of positive end-expiratory pressure with open lung approach resulting in moderate to high levels of positive end-expiratory pressure for the management of established moderate/severe acute respiratory distress syndrome. DESIGN: A prospective, multicenter, pilot, randomized controlled trial. SETTING: A network of 20 multidisciplinary ICUs. PATIENTS: Patients meeting the American-European Consensus Conference definition for acute respiratory distress syndrome were considered for the study. INTERVENTIONS: At 12-36 hours after acute respiratory distress syndrome onset, patients were assessed under standardized ventilator settings (FIO2≥0.5, positive end-expiratory pressure ≥10 cm H2O). If Pao2/FIO2 ratio remained less than or equal to 200 mm Hg, patients were randomized to open lung approach or Acute Respiratory Distress Syndrome network protocol. All patients were ventilated with a tidal volume of 4 to 8 ml/kg predicted body weight. MEASUREMENTS AND MAIN RESULTS: From 1,874 screened patients with acute respiratory distress syndrome, 200 were randomized: 99 to open lung approach and 101 to Acute Respiratory Distress Syndrome network protocol. Main outcome measures were 60-day and ICU mortalities, and ventilator-free days. Mortality at day-60 (29% open lung approach vs. 33% Acute Respiratory Distress Syndrome Network protocol, p = 0.18, log rank test), ICU mortality (25% open lung approach vs. 30% Acute Respiratory Distress Syndrome network protocol, p = 0.53 Fisher's exact test), and ventilator-free days (8 [0-20] open lung approach vs. 7 [0-20] d Acute Respiratory Distress Syndrome network protocol, p = 0.53 Wilcoxon rank test) were not significantly different. Airway driving pressure (plateau pressure - positive end-expiratory pressure) and PaO2/FIO2 improved significantly at 24, 48 and 72 hours in patients in open lung approach compared with patients in Acute Respiratory Distress Syndrome network protocol. Barotrauma rate was similar in both groups. CONCLUSIONS: In patients with established acute respiratory distress syndrome, open lung approach improved oxygenation and driving pressure, without detrimental effects on mortality, ventilator-free days, or barotrauma. This pilot study supports the need for a large, multicenter trial using recruitment maneuvers and a decremental positive end-expiratory pressure trial in persistent acute respiratory distress syndrome.

Platelet cytochrome c oxidase activity and quantity in septic patients.

OBJECTIVE: The cytopathic hypoxia theory proposes that there is an impaired cellular oxygen utilization during sepsis. Respiratory complex IV, or cytochrome c oxidase, was only previously studied in muscle biopsies of 16 surviving and 12 nonsurviving septic patients. We hypothesized that higher activities and quantities of this enzyme complex could be associated with septic patient survival. The objective was to evaluate the relationship between cytochrome c oxidase activities and quantities and 6-month survival in a larger series of septic patients using a less invasive method (circulating platelets). DESIGN: Prospective, multicenter, observational study. SETTING: The study was carried out in six Spanish intensive care units. PATIENTS: We included 96 septic patients. INTERVENTIONS: We determined the cytochrome c oxidase activity per citrate synthase activity ratio and cytochrome c oxidase quantity per citrate synthase activity ratio in circulating platelets at the time of diagnosis and related them to 6-month survival. The written informed consent from the family members was obtained. MEASUREMENTS AND MAIN RESULTS: Survivor patients (n = 54) showed higher cytochrome c oxidase activity per citrate synthase activity ratio (p = .04) and cytochrome c oxidase quantity per citrate synthase activity ratio (p = .006) than nonsurvivors (n = 42). Logistic regression analyses confirmed that the cytochrome c oxidase activity per citrate synthase activity ratio (p = .04) and cytochrome c oxidase quantity per citrate synthase activity ratio (p = .02) were independent predictors of 6-month survival. The area under the curve to predict 6-month survival was 0.62 (95% confidence interval 0.51-0.74; p = .04) for the cytochrome c oxidase activity per citrate synthase activity ratio and 0.67 (95% confidence interval 0.56-0.76; p = .003) for the cytochrome c oxidase quantity per citrate synthase activity ratio. A negative correlation was found between the cytochrome c oxidase quantity per citrate synthase activity ratio and Sepsis-Related Organ Failure Assessment score (p = .04). CONCLUSIONS: Platelet cytochrome c oxidase activity and quantity were independent predictors of 6-month survival and could be used as biomarkers of sepsis mortality. This is a rapid, easy, and less invasive protocol to assess mitochondrial function. Patients with lower cytochrome c oxidase activity and quantity could benefit from drugs that improve mitochondrial function.

International consensus on the monitoring of cerebral oxygen tissue pressure in neurocritical patients. / Consenso internacional sobre la monitorización de la presión tisular cerebral de oxígeno en pacientes neurocríticos.

Continuous monitoring of cerebral oxygenation and its application to the management of the severe neurological patient is a challenge for the management of patients with acute critical brain damage. Although several techniques have been described for monitoring brain, brain tissue oxygen monitoring provides relevant information about oxygen levels of brain tissue. However, the development of this technique has been associated with the need to answer not only some technical aspects of it as well as the meaning of the changes of the cerebral oxygenation in the neurocritical patient. The consensus document responds to various questions related to the monitoring of cerebral oxygenation by means of a cerebral oxygen tissue pressure sensor. For this purpose, a list of questions was prepared and a reviewed of the medical literature was made. The quality of the evidence and the degree of recommendation was evaluated using the GRADE methodology.

Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis.

INTRODUCTION: Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. METHODS: This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. RESULTS: Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). CONCLUSIONS: The novel findings of our study on patients with severe sepsis (to our knowledge, the largest series reporting data about MMP levels in sepsis) are that reduced MMP-9/TIMP-1 ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that TIMP-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis.

Pathophysiology and Management of Intracranial Hypertension and Tissular Brain Hypoxia After Severe Traumatic Brain Injury: An Integrative Approach.

Monitoring intracranial pressure in comatose patients with severe traumatic brain injury (TBI) is considered necessary by most experts. Acute intracranial hypertension (IHT), when severe and sustained, is a life-threatening complication that demands emergency treatment. Yet, secondary anoxic-ischemic injury after brain trauma can occur in the absence of IHT. In such cases, adding other monitoring modalities can alert clinicians when the patient is in a state of energy failure. This article reviews the mechanisms, diagnosis, and treatment of IHT and brain hypoxia after TBI, emphasizing the need to develop a physiologically integrative approach to the management of these complex situations.

Prognostic value of changes in brain tissue oxygen pressure before and after decompressive craniectomy following severe traumatic brain injury.

OBJECTIVE In severe traumatic brain injury (TBI), the effects of decompressive craniectomy (DC) on brain tissue oxygen pressure (PbtO2) and outcome are unclear. The authors aimed to investigate whether changes in PbtO2 after DC could be used as an independent prognostic factor. METHODS The authors conducted a retrospective, observational study at 2 university hospital ICUs. The study included 42 patients who were admitted with isolated moderate or severe TBI and underwent intracranial pressure (ICP) and PbtO2 monitoring before and after DC. The indication for DC was an ICP higher than 25 mm Hg refractory to first-tier medical treatment. Patients who underwent primary DC for mass lesion evacuation were excluded. However, patients were included who had undergone previous surgery as long as it was not a craniectomy. ICP/PbtO2 monitoring probes were located in an apparently normal area of the most damaged hemisphere based on cranial CT scanning findings. PbtO2 values were routinely recorded hourly before and after DC, but for comparisons the authors used the first PbtO2 value on ICU admission and the number of hours with PbtO2 < 15 mm Hg before DC, as well as the mean PbtO2 every 6 hours during 24 hours pre- and post-DC. The end point of the study was the 6-month Glasgow Outcome Scale; a score of 4 or 5 was considered a favorable outcome, whereas a score of 1-3 was considered an unfavorable outcome. RESULTS Of the 42 patients included, 26 underwent unilateral DC and 16 bilateral DC. The median Glasgow Coma Scale score at the scene of the accident or at the initial hospital before the patient was transferred to one of the 2 ICUs was 7 (interquartile range [IQR] 4-14). The median time from admission to DC was 49 hours (IQR 7-301 hours). Before DC, the median ICP and PbtO2 at 6 hours were 35 mm Hg (IQR 28-51 mm Hg) and 11.4 mm Hg (IQR 3-26 mm Hg), respectively. In patients with favorable outcome, PbtO2 at ICU admission was higher and the percentage of time that pre-DC PbtO2 was < 15 mm Hg was lower (19 ± 4.5 mm Hg and 18.25% ± 21.9%, respectively; n = 28) than in those with unfavorable outcome (12.8 ± 5.2 mm Hg [p < 0.001] and 59.58% ± 38.8% [p < 0.001], respectively; n = 14). There were no significant differences in outcomes according to the mean PbtO2 values only during the last 12 hours before DC, the hours of refractory intracranial hypertension, the timing of DC from admission, or the presence/absence of previous surgery. In contrast, there were significant differences in PbtO2 values during the 12- to 24-hour period before DC. In most patients, PbtO2 increased during the 24 hours after DC but these changes were more pronounced in patients with favorable outcome than in those with unfavorable outcome (28.6 ± 8.5 mm Hg vs 17.2 ± 5.9 mm Hg, p < 0.0001; respectively). The areas under the curve for the mean PbtO2 values at 12 and 24 hours after DC were 0.878 (95% CI 0.75-1, p < 0.0001) and 0.865 (95% CI 0.73-1, p < 0.0001), respectively. CONCLUSIONS The authors' findings suggest that changes in PbtO2 before and after DC, measured with probes in healthy-appearing areas of the most damaged hemisphere, have independent prognostic value for the 6-month outcome in TBI patients.

Association between serum tissue inhibitor of matrix metalloproteinase-1 levels and mortality in patients with severe brain trauma injury.

OBJECTIVE: Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a role in neuroinflammation after brain trauma injury (TBI). Previous studies with small sample size have reported higher circulating MMP-2 and MMP-9 levels in patients with TBI, but no association between those levels and mortality. Thus, the aim of this study was to determine whether serum TIMP-1 and MMP-9 levels are associated with mortality in patients with severe TBI. METHODS: This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of TIMP-1, MMP-9 and tumor necrosis factor (TNF)-alpha, and plasma levels of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 plasma were measured in 100 patients with severe TBI at admission. Endpoint was 30-day mortality. RESULTS: Non-surviving TBI patients (n = 27) showed higher serum TIMP-1 levels than survivor ones (n = 73). We did not find differences in MMP-9 serum levels. Logistic regression analysis showed that serum TIMP-1 levels were associated 30-day mortality (OR = 1.01; 95% CI = 1.001-1.013; P = 0.03). Survival analysis showed that patients with serum TIMP-1 higher than 220 ng/mL presented increased 30-day mortality than patients with lower levels (Chi-square = 5.50; P = 0.02). The area under the curve (AUC) for TIMP-1 as predictor of 30-day mortality was 0.73 (95% CI = 0.624-0.844; P<0.001). An association between TIMP-1 levels and APACHE-II score, TNF- alpha and TF was found. CONCLUSIONS: The most relevant and new findings of our study, the largest series reporting data on TIMP-1 and MMP-9 levels in patients with severe TBI, were that serum TIMP-1 levels were associated with TBI mortality and could be used as a prognostic biomarker of mortality in TBI patients.

An early PEEP/FIO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome.

RATIONALE: Current American-European Consensus Conference definitions for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are inadequate for inclusion into clinical trials due to the lack of standardization for measuring the oxygenation defect. OBJECTIVES: We questioned whether an early assessment of oxygenation on specific ventilator settings would identify patients with established ARDS (persisting over 24 h). METHODS: At the time of meeting ARDS criteria (Day 0) and 24 hours later (Day 1), arterial blood gases were obtained on standard ventilator settings, Vt 7 ml/kg predicted body weight plus the following positive end-expiratory pressure (PEEP) and Fi(O(2)) settings in sequence: (1) PEEP >or= 5 cm H(2)O and Fi(O(2)) >or= 0.5, (2) PEEP >or= 5 cm H(2)O and Fi(O(2)) 1.0, (3) PEEP >or= 10 cm H(2)O and Fi(O(2))>or=0.5, and (4) PEEP >or= 10 cm H(2)O and Fi(O(2)) 1.0. MEASUREMENTS AND MAIN RESULTS: One hundred seventy patients meeting ARDS criteria (Pa(O(2))/Fi(O(2)) 128 +/- 33 mm Hg) were enrolled. Overall hospital mortality was 34.1%. The standard ventilator settings that best identified patients with established ARDS and predicted differences in intensive care unit (ICU) mortality were PEEP >or= 10 cm H(2)O and Fi(O(2)) >or= 0.5 at Day 1 (P = 0.0001). Only 99 (58.2%) patients continued to meet ARDS criteria (Pa(O(2))/Fi(O(2)), 155.8 +/- 29.8 mm Hg; ICU mortality, 45.5%), whereas 55 patients were reclassified as having ALI (Pa(O(2))/Fi(O(2)), 246.5 +/- 25.6 mm Hg; ICU mortality, 20%) and 16 patients as having acute respiratory failure (Pa(O(2))/Fi(O(2)), 370 +/- 54 mm Hg; ICU mortality, 6.3%) (P = 0.0001) on these settings. CONCLUSIONS: Patients meeting current American-European Consensus Conference ARDS criteria may have highly variable levels of lung injury and outcomes. A systematic method of assessing severity of lung injury is required for enrollment of patients with ARDS into randomized controlled trials. Clinical trial registered with www.clinicaltrials.gov (NCT 00435110).