Frank Van Haren

Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries

IMPORTANCE Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%); of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%); and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02010073.

Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study

Rationale: Noninvasive ventilation (NIV) is increasingly used in patients with acute respiratory distress syndrome (ARDS). The evidence supporting NIV use in patients with ARDS remains relatively sparse. Objectives: To determine whether, during NIV, the categorization of ARDS severity based on the PaO2/FiO2 Berlin criteria is useful. Methods: The LUNG SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) study described the management of patients with ARDS. This substudy examines the current practice of NIV use in ARDS, the utility of the PaO2/FiO2 ratio in classifying patients receiving NIV, and the impact of NIV on outcome. Measurements and Main Results: Of 2,813 patients with ARDS, 436 (15.5%) were managed with NIV on Days 1 and 2 following fulfillment of diagnostic criteria. Classification of ARDS severity based on PaO2/FiO2 ratio was associated with an increase in intensity of ventilatory support, NIV failure, and intensive care unit (ICU) mortality. NIV failure occurred in 22.2% of mild, 42.3% of moderate, and 47.1% of patients with severe ARDS. Hospital mortality in patients with NIV success and failure was 16.1% and 45.4%, respectively. NIV use was independently associated with increased ICU (hazard ratio, 1.446 [95% confidence interval, 1.159‐1.805]), but not hospital, mortality. In a propensity matched analysis, ICU mortality was higher in NIV than invasively ventilated patients with a PaO2/FiO2 lower than 150 mm Hg. Conclusions: NIV was used in 15% of patients with ARDS, irrespective of severity category. NIV seems to be associated with higher ICU mortality in patients with a PaO2/FiO2 lower than 150 mm Hg. Clinical trial registered with www.clinicaltrials.gov (NCT 02010073).

Fluid resuscitation in human sepsis: Time to rewrite history?

Fluid resuscitation continues to be recommended as the first-line resuscitative therapy for all patients with severe sepsis and septic shock. The current acceptance of the therapy is based in part on long history and familiarity with its use in the resuscitation of other forms of shock, as well as on an incomplete and incorrect understanding of the pathophysiology of sepsis. Recently, the safety of intravenous fluids in patients with sepsis has been called into question with both prospective and observational data suggesting improved outcomes with less fluid or no fluid. The current evidence for the continued use of fluid resuscitation for sepsis remains contentious with no prospective evidence demonstrating benefit to fluid resuscitation as a therapy in isolation. This article reviews the historical and physiological rationale for the introduction of fluid resuscitation as treatment for sepsis and highlights a number of significant concerns based on current experimental and clinical evidence. The research agenda should focus on the development of hyperdynamic animal sepsis models which more closely mimic human sepsis and on experimental and clinical studies designed to evaluate minimal or no fluid strategies in the resuscitation phase of sepsis.

What's new in volume therapy in the intensive care unit?

The administration of intravenous fluid to critically ill patients is one of the most common but also one of the most fiercely debated interventions in intensive care medicine. During the past decade, a number of important studies have been published which provide clinicians with improved knowledge regarding the timing, the type and the amount of fluid they should give to their critically ill patients. However, despite the fact that many thousands of patients have been enrolled in these trials of alternative fluid strategies, consensus remains elusive and practice is widely variable. Early adequate resuscitation of patients in shock followed by a restrictive strategy may be associated with better outcomes. Colloids such as modern hydroxyethyl starch are more effective than crystalloids in early resuscitation of patients in shock, and are safe when administered during surgery. However, these colloids may not be beneficial later in the course of intensive care treatment and should best be avoided in intensive care patients who have a high risk of developing acute kidney injury. Albumin has no clear benefit over saline and is associated with increased mortality in neurotrauma patients. Balanced fluids reduce the risk of hyperchloraemic acidosis and possibly kidney injury. The use of hypertonic fluids in patients with sepsis and acute lung injury warrants further investigation and should be considered experimental at this stage. Fluid therapy impacts relevant patient-related outcomes. Clinicians should adopt an individualized strategy based on the clinical scenario and best available evidence. One size does not fit all.

Sleep Monitoring Techniques within Intensive Care

Sleep is an essential biological function that provides important restorative psycho-physiological processes. Patients in the Intensive Care Unit are highly vulnerable to sleep disturbance which can protract their recovery. Despite sleep disturbance being widely acknowledged amongst this patient cohort, the ability to make significant changes to minimise the burden of sleep deprivation remains a challenge. This is further compounded by the difficulties faced by clinicians to identify and implement accurate and feasible sleep monitoring techniques in the intensive care. Whilst objective, behavioural and subjective methods of sleep assessment exist, all have specific limitations when applied to critically ill patients. In an attempt to illuminate these issues, current sleep monitoring techniques are appraised.

An Ovine Model of Hyperdynamic Endotoxemia and Vital Organ Metabolism

Background: Animal models of endotoxemia are frequently used to understand the pathophysiology of sepsis and test new therapies. However, important differences exist between commonly used experimental models of endotoxemia and clinical sepsis. Animal models of endotoxemia frequently produce hypodynamic shock in contrast to clinical hyperdynamic shock. This difference may exaggerate the importance of hypoperfusion as a causative factor in organ dysfunction. This study sought to develop an ovine model of hyperdynamic endotoxemia and assess if there is evidence of impaired oxidative metabolism in the vital organs. Methods: Eight sheep had microdialysis catheters implanted into the brain, heart, liver, kidney, and arterial circulation. Shock was induced with a 4 h escalating dose infusion of endotoxin. After 3 h vasopressor support was initiated with noradrenaline and vasopressin. Animals were monitored for 12 h after endotoxemia. Blood samples were recovered for hemoglobin, white blood cell count, creatinine, and proinflammatory cytokines (IL-1Beta, IL-6, and IL-8). Results: The endotoxin infusion was successful in producing distributive shock with the mean arterial pressure decreasing from 84.5 ± 12.8 mm Hg to 49 ± 8.03 mm Hg (P < 0.001). Cardiac index remained within the normal range decreasing from 3.33 ± 0.56 L/min/m2 to 2.89l ± 0.36 L/min/m2 (P = 0.0845). Lactate/pyruvate ratios were not significantly abnormal in the heart, brain, kidney, or arterial circulation. Liver microdialysis samples demonstrated persistently high lactate/pyruvate ratios (mean 37.9 ± 3.3). Conclusions: An escalating dose endotoxin infusion was successful in producing hyperdynamic shock. There was evidence of impaired oxidative metabolism in the liver suggesting impaired splanchnic perfusion. This may be a modifiable factor in the progression to multiple organ dysfunction and death.

Inspiratory Muscle Rehabilitation in Critically Ill Adults. A Systematic Review and Meta-Analysis

Rationale: Respiratory muscle weakness is common in critically ill patients; the role of targeted inspiratory muscle training (IMT) in intensive care unit rehabilitation strategies remains poorly defined. Objectives: The primary objective of the present study was to describe the range and tolerability of published methods for IMT. The secondary objectives were to determine whether IMT improves respiratory muscle strength and clinical outcomes in critically ill patients. Methods: We conducted a systematic review to identify randomized and nonrandomized studies of physical rehabilitation interventions intended to strengthen the respiratory muscles in critically ill adults. We searched the MEDLINE, Embase, HealthSTAR, CINAHL, and CENTRAL databases (inception to September Week 3, 2017) and conference proceedings (2012 to 2017). Data were independently extracted by two authors and collected on a standardized report form. Results: A total of 28 studies (N = 1,185 patients) were included. IMT was initiated during early mechanical ventilation (8 studies), after patients proved difficult to wean (14 studies), or after extubation (3 studies), and 3 other studies did not report exact timing. Threshold loading was the most common technique; 13 studies employed strength training regimens, 11 studies employed endurance training regimens, and 4 could not be classified. IMT was feasible, and there were few adverse events during IMT sessions (nine studies; median, 0%; interquartile range, 0‐0%). In randomized trials (n = 20), IMT improved maximal inspiratory pressure compared with control (15 trials; mean increase, 6 cm H2O; 95% confidence interval [CI], 5‐8 cm H2O; pooled relative ratio of means, 1.19; 95% CI, 1.14‐1.25) and maximal expiratory pressure (4 trials; mean increase, 9 cm H2O; 95% CI, 5‐14 cm H2O). IMT was associated with a shorter duration of ventilation (nine trials; mean difference, 4.1 d; 95% CI, 0.8‐7.4 d) and a shorter duration of weaning (eight trials; mean difference, 2.3 d; 95% CI, 0.7‐4.0 d), but confidence in these pooled estimates was low owing to methodological limitations, including substantial statistical and methodological heterogeneity. Conclusions: Most studies of IMT in critically ill patients have employed inspiratory threshold loading. IMT is feasible and well tolerated in critically ill patients and improves both inspiratory and expiratory muscle strength. The impact of IMT on clinical outcomes requires future confirmation.

Personalised fluid resuscitation in the ICU: still a fluid concept?

The administration of intravenous fluid to critically ill patients is one of the most common, but also one of the most fiercely debated, interventions in intensive care medicine. Even though many thousands of patients have been enrolled in large trials of alternative fluid strategies, consensus remains elusive and practice is widely variable. Critically ill patients are significantly heterogeneous, making a one size fits all approach unlikely to be successful.New data from basic, animal, and clinical research suggest that fluid resuscitation could be associated with significant harm. There are several important limitations and concerns regarding fluid bolus therapy as it is currently being used in clinical practice. These include, but are not limited to: the lack of an agreed definition; limited and short-lived physiological effects; no evidence of an effect on relevant patient outcomes; and the potential to contribute to fluid overload, specifically when fluid responsiveness is not assessed and when targets and safety limits are not used.Fluid administration in critically ill patients requires clinicians to integrate abnormal physiological parameters into a clinical decision-making model that also incorporates the likely diagnosis and the likely risk or benefit in the specific patient’s context. Personalised fluid resuscitation requires careful attention to the mnemonic CIT TAIT: context, indication, targets, timing, amount of fluid, infusion strategy, and type of fluid.The research agenda should focus on experimental and clinical studies to: improve our understanding of the physiological effects of fluid infusion, e.g. on the glycocalyx; evaluate new types of fluids; evaluate novel fluid minimisation protocols; study the effects of a no-fluid strategy for selected patients and scenarios; and compare fluid therapy with other interventions. The adaptive platform trial design may provide us with the tools to evaluate these types of interventions in the intrinsically heterogeneous intensive care unit population, accounting for the explicit assumption that treatment effects may be heterogeneous.

Immunocompromised patients with acute respiratory distress syndrome: Secondary analysis of the LUNG SAFE database

BackgroundThe aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients.MethodsWe performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents.ResultsOf 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p < 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p < 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio.ConclusionsImmunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge.Trial registrationClinicalTrials.gov, NCT02010073. Registered on 12 December 2013.

Unintended Consequences: Fluid Resuscitation Worsens Shock in an Ovine Model of Endotoxemia

Rationale: Fluid resuscitation is widely considered a life‐saving intervention in septic shock; however, recent evidence has brought both its safety and efficacy in sepsis into question. Objectives: In this study, we sought to compare fluid resuscitation with vasopressors with the use of vasopressors alone in a hyperdynamic model of ovine endotoxemia. Methods: Endotoxemic shock was induced in 16 sheep, after which they received fluid resuscitation with 40 ml/kg of 0.9% saline or commenced hemodynamic support with protocolized noradrenaline and vasopressin. Microdialysis catheters were inserted into the arterial circulation, heart, brain, kidney, and liver to monitor local metabolism. Blood samples were recovered to measure serum inflammatory cytokines, creatinine, troponin, atrial natriuretic peptide, brain natriuretic peptide, and hyaluronan. All animals were monitored and supported for 12 hours after fluid resuscitation. Measurements and Main Results: After resuscitation, animals that received fluid resuscitation required significantly more noradrenaline to maintain the same mean arterial pressure in the subsequent 12 hours (68.9 mg vs. 39.6 mg; P = 0.04). Serum cytokines were similar between groups. Atrial natriuretic peptide increased significantly after fluid resuscitation compared with that observed in animals managed without fluid resuscitation (335 ng/ml [256‐382] vs. 233 ng/ml [144‐292]; P = 0.04). Cross‐sectional time‐series analysis showed that the rate of increase of the glycocalyx glycosaminoglycan hyaluronan was greater in the fluid‐resuscitated group over the course of the study (P = 0.02). Conclusions: Fluid resuscitation resulted in a paradoxical increase in vasopressor requirement. Additionally, it did not result in improvements in any of the measured microcirculatory‐ or organ‐specific markers measured. The increase in vasopressor requirement may have been due to endothelial/glycocalyx damage secondary to atrial natriuretic peptide‐mediated glycocalyx shedding.