Development of clinical tools to estimate the breathing effort during high-flow oxygen therapy: A multicenter cohort study.

INTRODUCTION AND OBJECTIVES: Quantifying breathing effort in non-intubated patients is important but difficult. We aimed to develop two models to estimate it in patients treated with high-flow oxygen therapy. PATIENTS AND METHODS: We analyzed the data of 260 patients from previous studies who received high-flow oxygen therapy. Their breathing effort was measured as the maximal deflection of esophageal pressure (ΔPes). We developed a multivariable linear regression model to estimate ΔPes (in cmH2O) and a multivariable logistic regression model to predict the risk of ΔPes being >10 cmH2O. Candidate predictors included age, sex, diagnosis of the coronavirus disease 2019 (COVID-19), respiratory rate, heart rate, mean arterial pressure, the results of arterial blood gas analysis, including base excess concentration (BEa) and the ratio of arterial tension to the inspiratory fraction of oxygen (PaO2:FiO2), and the product term between COVID-19 and PaO2:FiO2. RESULTS: We found that ΔPes can be estimated from the presence or absence of COVID-19, BEa, respiratory rate, PaO2:FiO2, and the product term between COVID-19 and PaO2:FiO2. The adjusted R2 was 0.39. The risk of ΔPes being >10 cmH2O can be predicted from BEa, respiratory rate, and PaO2:FiO2. The area under the receiver operating characteristic curve was 0.79 (0.73-0.85). We called these two models BREF, where BREF stands for BReathing EFfort and the three common predictors: BEa (B), respiratory rate (RE), and PaO2:FiO2 (F). CONCLUSIONS: We developed two models to estimate the breathing effort of patients on high-flow oxygen therapy. Our initial findings are promising and suggest that these models merit further evaluation.

Respiratory and peripheral muscular ultrasound characteristics in ICU COVID 19 ARDS patients.

PURPOSE: Severe cases of coronavirus disease 2019 develop ARDS requiring admission to the ICU. This study aimed to investigate the ultrasound characteristics of respiratory and peripheral muscles of patients affected by COVID19 who require mechanical ventilation. MATERIALS AND METHODS: This is a prospective observational study. We performed muscle ultrasound at the admission of ICU in 32 intubated patients with ARDS COVID19. The ultrasound was comprehensive of thickness and echogenicity of both parasternal intercostal and diaphragm muscles, and cross-sectional area and echogenicity of the rectus femoris. RESULTS: Patients who survived showed a significantly lower echogenicity score as compared with those who did not survive for both parasternal intercostal muscles. Similarly, the diaphragmatic echogenicity was significantly different between alive or dead patients. There was a significant correlation between right parasternal intercostal or diaphragm echogenicity and the cumulative fluid balance and urine protein output. Similar results were detected for rectus femoris echogenicity. CONCLUSIONS: The early changes detected by echogenicity ultrasound suggest a potential benefit of proactive early therapies designed to preserve respiratory and peripheral muscle architecture to reduce days on MV, although what constitutes a clinically significant change in muscle echogenicity remains unknown.

Reliability of transpulmonary pressure-time curve profile to identify tidal recruitment/hyperinflation in experimental unilateral pleural effusion.

The stress index (SI) is a parameter that characterizes the shape of the airway pressure-time profile (P/t). It indicates the slope progression of the curve, reflecting both lung and chest wall properties. The presence of pleural effusion alters the mechanical properties of the respiratory system decreasing transpulmonary pressure (Ptp). We investigated whether the SI computed using Ptp tracing would provide reliable insight into tidal recruitment/overdistention during the tidal cycle in the presence of unilateral effusion. Unilateral pleural effusion was simulated in anesthetized, mechanically ventilated pigs. Respiratory system mechanics and thoracic computed tomography (CT) were studied to assess P/t curve shape and changes in global lung aeration. SI derived from airway pressure (Paw) was compared with that calculated by Ptp under the same conditions. These results were themselves compared with quantitative CT analysis as a gold standard for tidal recruitment/hyperinflation. Despite marked changes in tidal recruitment, mean values of SI computed either from Paw or Ptp were remarkably insensitive to variations of PEEP or condition. After the instillation of effusion, SI indicates a preponderant over-distension effect, not detected by CT. After the increment in PEEP level, the extent of CT-determined tidal recruitment suggest a huge recruitment effect of PEEP as reflected by lung compliance. Both SI in this case were unaffected. We showed that the ability of SI to predict tidal recruitment and overdistension was significantly reduced in a model of altered chest wall-lung relationship, even if the parameter was computed from the Ptp curve profile.

Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial.

BACKGROUND: Critically ill patients suffer from physiological sleep deprivation and have reduced blood melatonin levels. This study was designed to determine whether nocturnal melatonin supplementation would reduce the need for sedation in patients with critical illness. METHODS: A single-center, double-blind randomized placebo-controlled trial was carried out from July 2007 to December 2009, in a mixed medical-surgical Intensive Care Unit of a University hospital, without any form of external funding. Of 1158 patients admitted to ICU and treated with conscious enteral sedation, 82 critically-ill with mechanical ventilation >48 hours and Simplified Acute Physiology Score II>32 points were randomized 1:1 to receive, at eight p.m. and midnight, melatonin (3+3mg) or placebo, from the third ICU day until ICU discharge. Primary outcome was total amount of enteral hydroxyzine administered. RESULTS: Melatonin treated patients received lower amount of enteral hydroxyzine. Other neurological indicators (amount of some neuroactive drugs, pain, agitation, anxiety, sleep observed by nurses, need for restraints, need for extra sedation, nurse evaluation of sedation adequacy) seemed improved, with reduced cost for neuroactive drugs. Post-traumatic stress disorder prevalence did not differ between groups, nor did ICU or hospital mortality. Study limitations include the differences between groups before intervention, the small sample size, and the single-center observation. CONCLUSION: Long-term enteral melatonin supplementation may result in a decreased need for sedation, with improved neurological indicators and cost reduction. Further multicenter evaluations are required to confirm these results with different sedation protocols.

Aerophagia increases the risk of ventilator-associated pneumonia in critically-ill patients.

BACKGROUND: Gastric residual volume in ventilated critically ill may complicate gut function. Over the years studies suggested to tolerate progressively higher residuals. The relationship between such volumes and the development of ventilator-associated pneumonia (VAP) is still under debate. No reports deal with the relevant anecdotal finding of air in the stomach. Aim of the present study is to test the role of air in the development of VAPs. METHODS: Prospective observational trial in consecutive patients with a predicted length of ICU stay >3 days. The first 8 days of stay were studied. Sedation was targeted to have awake/cooperative patients. Early enteral nutrition was attempted. Gastric content was measured every 4 hours by 60 mL-syringe suction. Upper digestive intolerance (UDI) was defined as >2 consecutive findings of liquid >200 mL, aerophagia was defined as >2 consecutive findings of air >150 mL. RESULTS: Three hundred sixty-four patients enrolled, 43 developed VAP (11.8%). Patients were sedated with enteral (76% total time), intravenous (6%) or both (28%) drugs. Conscious sedation was achieved in 54% of the observations. 326 patients began enteral nutrition during the first 24 hours (1000 kcal median calorie intake). 10% developed UDI, 15% had aerophagia. No association was found between VAP and UDI (P=0.78), while significant association was found between VAP and aerophagia (OR=2.88, P<0.01). A sensitivity analysis, excluding patients admitted with respiratory infection, confirmed the results. CONCLUSION: High volumes of air in the stomach significantly increased the risk of developing VAP, while gastric residual volumes were not associated with the incidence of pneumonia.

Performance assessment of a glucose control protocol in septic patients with an automated intermittent plasma glucose monitoring device.

BACKGROUND & AIMS: The optimal level and modality of glucose control in critically ill patients is still debated. A protocolized approach and the use of nearly-continuous technologies are recommended to manage hyperglycemia, hypoglycemia and glycemic variability. We recently proposed a pato-physiology-based glucose control protocol which takes into account patient glucose/carbohydrate intake and insulin resistance. Aim of the present investigation was to assess the performance of our protocol with an automated intermittent plasma glucose monitoring device (OptiScanner™ 5000). METHODS: OptiScanner™ was used in 6 septic patients, providing glucose measurement every 15' from a side-port of an indwelling central venous catheter. Target level of glucose was 80-150 mg/dL. Insulin infusion and kcal with nutritional support were also recorded. RESULTS: 6 septic patients were studied for 319 h (1277 measurements); 58 [45-65] hours for each patient (measurements/patient: 231 [172-265]). Blood glucose was at target for 93 [90-98]% of study time. Mean plasma glucose was 126 ± 11 mg/dL. Only 3 hypoglycemic episodes (78, 78, 69 mg/dL) were recorded. Glucose variability was limited: plasma glucose coefficient of variation was 11.7 ± 4.0% and plasma glucose standard deviation was 14.3 ± 5.5 mg/dL. CONCLUSIONS: The local glucose control protocol achieved satisfactory glucose control in septic patients along with a high degree of safeness. Automated intermittent plasma glucose monitoring seemed useful to assess the performance of the protocol.

Pleural effusion in ARDS.

Pleural effusion is a fluid collection within the pleural space and is a common finding in mechanically ventilated patients. It is frequently related to fluid overload, hyponcotic states, heart failure, and altered pleural pressure due to atelectasis or pneumonia. Recent literature has shown that its incidence within ARDS is increasing, even if, in most of cases, at least in the early phases, it seems of limited clinical relevance. Most of the knowledge of Pleural Effusion and of its interaction with lung/chest wall mechanics derives from a small number of experimental studies and from some clinical studies, in most of the cases performed with normal lung parenchyma. In ARDS, however, Pleural Effusion seems to have a little effect "per se" on tidal mechanics and oxygenation (increasing elastance and reducing PO2), that are already profoundly affected by the lung injury itself. To sum up all the observations, we can assume that Pleural Effusion alters regional transmural pressure, restricting more the inspiration phase, and creating an opening/closure effect that can be reverted by PEEP application in recruitable lungs. This restores volume and compliance only if the abdomen is normally expansible. Drainage of Pleural Effusion is frequently performed in ICU but the benefits and risks are not well established. Lung ultrasound is an effective technique with high sensitivity and specificity for both bedside diagnosis and drainage guidance. It may help to quantify and qualify the effusion and at the same time the grade of aeration of underling parenchyma. Aim of this review is to summarize the current evidence and opinions about the interaction between Pleural Effusion and positive pressure ventilation in the presence of ARDS, its impact on gas exchange and tidal mechanics, trying to figure out the best bedside management that is not available yet. The estimation of both lung and chest wall elastance may help in the clinical decision making whether to drain or not in order to improve respiratory mechanics and oxygenation. Further research is still needed to determine the effect of drainage on clinical outcome and to evaluate its application in the weaning strategies.

The consumption of glucose during ex vivo lung perfusion correlates with lung edema.

INTRODUCTION: Ex vivo lung perfusion (EVLP) has been recently proposed to recondition organs before transplantation from donors with marginal or unacceptable features. The aim of our investigation was to explore glucose consumption during EVLP. MATERIALS AND METHODS: We investigated 8 domestic pigs (mean weight, 21 ± 0.8 kg). After perfusion with Perfadex, retrieval, and back table surgery, we initiated EVLP. The lungs were perfused with Steen solution with added methylprednisolone, cefazoline, and heparin. The blood flow was gradually increased with a target of 40% of the estimated cardiac output (or less if the pulmonary artery pressure was >15 mm Hg), while keeping the left atrial pressure between 3 and 5 mm Hg. The temperature of the perfusate was increased from 25 °C to 37 °C. Once the temperature of the lung outflow was >32 °C, we began gas flow (4 L/min, 5%-8% CO(2) in air) and mechanical ventilation. EVLP parameters and blood gases were measured throughout the experiment; glucose consumption was calculated as (glucose initial-glucose final)/time. The wet to dry ratio was also calculated as an index of lung edema. RESULTS: When stratified by median glucose consumption (0.237 mg/min), high glucose consumers (0.588 ± 0.17) were characterized by worse lung function, as assessed by oxygenation (partial pressure of oxygen/inspiratory fraction of oxygen [PaO(2)/FiO(2)] 326 ± 63 mm Hg vs 218 ± 84; P=.083 low vs high, respectively), and lung edema (wet/dry ratio 6.5 ± 0.7 vs 8.6 ± 0.9; P=.012). Glucose consumption correlated with wet to dry ratio (R(2)=0.663; P=.014). CONCLUSIONS: We found that the worse the lung function, the greater the consumption of glucose during EVLP. This observation suggests the need to explore lung metabolism during EVLP to possibly obtain metrics for evaluation.

Daily monitoring of biomarkers of sepsis in complicated long-term ICU-patients: can it support treatment decisions?

BACKGROUND: Diagnosis/grading of infection and the systemic response to infection may be difficult on admission to the intensive care unit, but it is even more complicated for severely ill patients with long intensive care stays. The ACCP-SCCM criteria are difficult to apply for such patients, and objective, validated biomarkers would be of great use in this setting. METHODS: Long-term (>6 days) critically ill patients in the general ICU of University Hospital were prospectively enrolled in the study. All patients were assessed daily by the attending physician using the ACCP-SCCM classification. C-reactive protein (CRP, mg/dL), procalcitonin (PCT, ng/mL), and interleukin-6 (IL-6, pg/mL) of daily stored sera were measured after each patient's discharge. After discharge, an independent, overall clinical evaluation and an a posteriori ACCP-SCCM classification were chosen as the reference standard for all comparisons. The assessor was aware of the patient's clinical course but was blinded to levels of biomarkers. RESULTS: We studied clinical variables and biomarkers of 26 patients over a total of 592 patient days. The day-by-day ACCP-SCCM classification of the attending physician overestimated the severity of the inflammatory response to infection. The diagnostic discriminative ability of severe-sepsis/septic-shock for PCT was high (ROC area 0.952 [0.931-0.973]) and had a best threshold value of 1.58 (83.7% sensitivity, 94.6 % specificity). IL-6 had better discriminative ability than CRP, but both were worse than PCT. CONCLUSION: PCT > 0.43 ng/mL could add to the clinical propensity for sepsis vs. SIRS not related to infection. Values higher than 1.58 ng/mL may support the bedside clinical diagnosis of severe-sepsis. PCT between 0.5 and 1.0 suggest tight daily monitoring of clinical conditions and re-evaluation of PCT.

Time course of endogenous nitric oxide inhibitors in severe sepsis in humans.

AIM: Asymmetric and symmetric dimethylarginines (ADMA and SDMA, respectively) are protein breakdown markers; both compete with arginine for cellular transport and both are excreted in urine. Moreover, ADMA is a non-selective inhibitor of nitric oxide (NO) synthase that is metabolized by a specific hydrolase in which the activity during stress remains controversial. While an increase in ADMA is known to be associated with adverse events, little is known about SDMA. We investigated plasma ADMA and SDMA levels during ICU stay to reveal the time course of endogenous NO inhibition in patients with sepsis. METHODS: A post hoc analysis from a prospective random controlled trial conducted in three ICUs was performed to study the pathophysiological pathways of sepsis. ADMA, SDMA, the ratio of ADMA/SDMA (a marker of ADMA catabolism), arginine, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C reactive protein (CRP) were measured on days 1, 3, 6, 9, 12 and at discharge in 72 consecutive severely septic patients. RESULTS: Fasting basal glycemia, creatinine, IL-6, TNF-alpha, CRP, ADMA, and SDMA were higher than normal. The ADMA/SDMA ratio was decreased by 50%, and arginine levels were low. ADMA levels were related to the total Sequential Organ Failure Assessment (SOFA) scores and arginine levels, and inversely related to IL-6 and CRP levels. SDMA levels were related to Simplified Acute Physiologic Scores II (SAPS II), SOFA scores, blood urea, creatinine, and arginine levels. The ADMA/SDMA ratio was inversely related to IL-6 levels. In 58 ICU survivors, creatinine, IL-6, and CRP levels decreased over time; ADMA levels increased, SDMA levels remained stable, and the ADMA/SDMA ratio increased. In 14 non-survivors, creatinine, IL-6, TNF-alpha, CRP, and ADMA levels were stable, whereas the SDMA levels increased and the ADMA/SDMA ratio remained low. In both ICU survivors and non-survivors, the levels on the last ICU day confirmed the data trends. SDMA, but not ADMA, was associated with ICU mortality. CONCLUSION: ADMA catabolism appears to be activated by inflammation; its increase during the advanced septic phase in surviving patients may suggest an endogenous inhibition of NO synthesis during the full-blown septic phase. In severe sepsis, SDMA, but not ADMA, appears to be a marker of alterations in vital functions and mortality.

Sleep and delirium in the intensive care unit.

Intensive Care Unit (ICU) patients almost uniformly suffer from sleep disruption. Even though the role of sleep disturbances is not still adequately understood, they may be related to metabolic, immune, neurological and respiratory dysfunction and could worsen the quality of life after discharge. A harsh ICU environment, underlying disease, mechanical ventilation, pain and drugs are the main reasons that underlie sleep disruption in the critically ill. Polysomnography is the gold standard in evaluating sleep, but it is not feasible in clinical practice; therefore, other objective (bispectral index score [BIS] and actigraphy) and subjective (nurse and patient assessment) methods have been proposed, but their adequacy in ICU patients is not clear. Frequent evaluation of neurological status with validated tools is necessary to avoid excessive or prolonged sedation in order to better titrate patient-focused therapy. Hypnotic agents like benzodiazepines can increase total sleep time, but they alter the physiological progression of sleep phases, and decrease the time spent in the most restorative phases compared to the phases normally mediated by melatonin; melatonin production is decreased in critically ill patients, and as such, exogenous melatonin supplementation may improve sleep quality. Sleep disruption and the development of delirium are frequently related, both because of sleep scarcity and inappropriate dosing with sedatives. Delirium is strongly related to increased ICU morbidity and mortality, thus the resolution of sleep disruption could significantly contribute to improved ICU outcomes. An early evaluation of delirium is strongly recommended because of the potential to resolve the underlying causes or to begin an appropriate therapy. Further studies are needed on the effects of strategies to promote sleep and on the evaluation of better sleep in clinical outcomes, particularly on the development of delirium.