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(1) Background: Acute kidney injury (AKI) is common among critically ill COVID-19 patients, but its temporal association with prone positioning (PP) is still unknown, and no data exist on the possibility of predicting PP-associated AKI from bedside clinical variables. (2) Methods: We analyzed data from 93 COVID-19-related ARDS patients who underwent invasive mechanical ventilation (IMV) and at least one PP cycle. We collected hemodynamic variables, respiratory mechanics, and circulating biomarkers before, during, and after the first PP cycle. PP-associated AKI (PP-AKI) was defined as AKI diagnosed any time from the start of PP to 48 h after returning to the supine position. A t -test for independent samples was used to test for the differences between groups, while binomial logistical regression was performed to assess variables independently associated with PP-associated AKI. (3) Results: A total of 48/93 (52%) patients developed PP-AKI, with a median onset at 24 [13.5-44.5] hours after starting PP. No significant differences in demographic characteristics between groups were found. Before starting the first PP cycle, patients who developed PP-AKI had a significantly lower cumulative fluid balance (CFB), even when normalized for body weight ( p = 0.006). Central venous pressure (CVP) values, measured before the first PP (OR 0.803, 95% CI [0.684-0.942], p = 0.007), as well as BMI (OR 1.153, 95% CI = [1.013-1.313], p = 0.031), were independently associated with the development of PP-AKI. In the multivariable regression analysis, a lower CVP before the first PP cycle was independently associated with ventilator-free days (OR 0.271, 95% CI [0.123-0.936], p = 0.011) and with ICU mortality (OR:0.831, 95% CI [0.699-0.989], p = 0.037). (4) Conclusions: Acute kidney injury occurs frequently in invasively ventilated severe COVID-19 ARDS patients undergoing their first prone positioning cycle. Higher BMI and lower CVP before PP are independently associated with the occurrence of AKI during prone positioning.

Background: Patients with acute respiratory failure (ARF) may need mechanical ventilation (MV), which can lead to diaphragmatic dysfunction and muscle wasting, thus making difficult the weaning from the ventilator. Currently, there are no biomarkers specific for respiratory muscle and their function can only be assessed trough ultrasound or other invasive methods. Previously, the fast and slow isoform of the skeletal troponin I (fsTnI and ssTnI, respectively) have shown to be specific markers of muscle damage in healthy volunteers. We aimed therefore at describing the trend of skeletal troponin in mixed population of ICU patients undergoing weaning from mechanical ventilation and compared the value of fsTnI and ssTnI with diaphragmatic ultrasound derived parameters. Methods: In this prospective observational study we enrolled consecutive patients recovering from acute hypoxemic respiratory failure (AHRF) within 24 h from the start of weaning. Every day an arterial blood sample was collected to measure fsTnI, ssTnI, and global markers of muscle damage, such as ALT, AST, and CPK. Moreover, thickening fraction (TF) and diaphragmatic displacement (DE) were assessed by diaphragmatic ultrasound. The trend of fsTnI and ssTnI was evaluated during the first 3 days of weaning. Results: We enrolled 62 consecutive patients in the study, with a mean age of 67 ± 13 years and 43 of them (69%) were male. We did not find significant variations in the ssTnI trend ( p = 0.623), but fsTnI significantly decreased over time by 30% from Day 1 to Day 2 and by 20% from Day 2 to Day 3 ( p < 0.05). There was a significant interaction effect between baseline ssTnI and DE [ F (2) = 4.396, p = 0.015], with high basal levels of ssTnI being associated to a higher decrease in DE. On the contrary, the high basal levels of fsTnI at day 1 were characterized by significant higher DE at each time point. Conclusions: Skeletal muscle proteins have a distinctive pattern of variation during weaning from mechanical ventilation. At day 1, a high basal value of ssTnI were associated to a higher decrease over time of diaphragmatic function while high values of fsTnI were associated to a higher displacement at each time point., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Spadaro, Dalla Corte, Scaramuzzo, Grasso, Cinnella, Rosta, Chiavieri, Alvisi, Di Mussi, Volta, Bellini and Trentini.)

Background: Expiratory flow limitation (EFL) is characterised by a markedly reduced expiratory flow insensitive to the expiratory driving pressure. The presence of EFL can influence the respiratory and cardiovascular function and damage the small airways; its occurrence has been demonstrated in different diseases, such as COPD, asthma, obesity, cardiac failure, ARDS, and cystic fibrosis. Our aim was to evaluate the prevalence of EFL in patients requiring mechanical ventilation for acute respiratory failure and to determine the main clinical characteristics, the risk factors and clinical outcome associated with the presence of EFL., Methods: Patients admitted to the intensive care unit (ICU) with an expected length of mechanical ventilation of 72 h were enrolled in this prospective, observational study. Patients were evaluated, within 24 h from ICU admission and for at least 72 h, in terms of respiratory mechanics, presence of EFL through the PEEP test, daily fluid balance and followed for outcome measurements., Results: Among the 121 patients enrolled, 37 (31%) exhibited EFL upon admission. Flow-limited patients had higher BMI, history of pulmonary or heart disease, worse respiratory dyspnoea score, higher intrinsic positive end-expiratory pressure, flow and additional resistance. Over the course of the initial 72 h of mechanical ventilation, additional 21 patients (17%) developed EFL. New onset EFL was associated with a more positive cumulative fluid balance at day 3 (103.3 ml/kg) compared to that of patients without EFL (65.8 ml/kg). Flow-limited patients had longer duration of mechanical ventilation, longer ICU length of stay and higher in-ICU mortality., Conclusions: EFL is common among ICU patients and correlates with adverse outcomes. The major determinant for developing EFL in patients during the first 3 days of their ICU stay is a positive fluid balance. Further studies are needed to assess if a restrictive fluid therapy might be associated with a lower incidence of EFL.

Background: The pressure-volume (P-V) curve has been suggested as a bedside tool to set mechanical ventilation; however, it reflects a global behavior of the lung without giving information on the regional mechanical properties. Regional P-V (PVr) curves derived from electrical impedance tomography (EIT) could provide valuable clinical information at bedside, being able to explore the regional mechanics of the lung. In the present study, we hypothesized that regional P-V curves would provide different information from those obtained from global P-V curves, both in terms of upper and lower inflection points. Therefore, we constructed pressure-volume curves for each pixel row from non-dependent to dependent lung regions of patients affected by acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS)., Methods: We analyzed slow-inflation P-V maneuvers data from 12 mechanically ventilated patients. During the inflation, the pneumotachograph was used to record flow and airway pressure while the EIT signals were recorded digitally. From each maneuver, global respiratory system P-V curve (PVg) and PVr curves were obtained, each one corresponding to a pixel row within the EIT image. PVg and PVr curves were fitted using a sigmoidal equation, and the upper (UIP) and lower (LIP) inflection points for each curve were mathematically identified; LIP and UIP from PVg were respectively called LIPg and UIPg. From each measurement, the highest regional LIP (LIPr MAX ) and the lowest regional UIP (UIPr MIN ) were identified and the pressure difference between those two points was defined as linear driving pressure (ΔP LIN )., Results: A significant difference (p < 0.001) was found between LIPr MAX (15.8 [9.2-21.1] cmH 2 O) and LIPg (2.9 [2.2-8.9] cmH 2 O); in all measurements, the LIPr MAX was higher than the corresponding LIPg. We found a significant difference (p < 0.005) between UIPr MIN (30.1 [23.5-37.6] cmH 2 O) and UIPg (40.5 [34.2-45] cmH 2 O), the UIPr MIN always being lower than the corresponding UIPg. Median ΔP LIN was 12.6 [7.4-20.8] cmH 2 O and in 56% of cases was < 14 cmH 2 O., Conclusions: Regional inflection points derived by EIT show high variability reflecting lung heterogeneity. Regional P-V curves obtained by EIT could convey more sensitive information than global lung mechanics on the pressures within which all lung regions express linear compliance., Trial Registration: Clinicaltrials.gov, NCT02907840 . Registered on 20 September 2016.

Background: The rapid shallow breathing index (RSBI), which is the ratio between respiratory rate (RR) and tidal volume (VT), is one of the most widely used indices to predict weaning outcome. Whereas the diaphragm plays a fundamental role in generating VT, in the case of diaphragmatic dysfunction the inspiratory accessory muscles may contribute. If this occurs during a weaning trial, delayed weaning failure is likely since the accessory muscles are more fatigable than the diaphragm. Hence, we hypothesised that the traditional RSBI could be implemented by substituting VT with the ultrasonographic evaluation of diaphragmatic displacement (DD). We named the new index the diaphragmatic-RSBI (D-RSBI). The aim of this study was to compare the ability of the traditional RSBI and D-RSBI to predict weaning failure in ready-to-wean patients., Methods: We performed a prospective observational study. During a T-tube spontaneous breathing trial (SBT) we simultaneously evaluated right hemidiaphragm displacement (i.e., DD) by using M-mode ultrasonography as well as the RSBI. Outcome of the weaning attempt, length of mechanical ventilation, length of intensive care unit and hospital stay, and hospital mortality were recorded. Receiver operator characteristic (ROC) curves were used to evaluate the diagnostic accuracy of D-RSBI and RSBI., Results: We enrolled 51 patients requiring mechanical ventilation for more than 48 h who were ready to perform a SBT. Most of the patients, 34 (66 %), were successfully weaned from mechanical ventilation. When considering the 17 patients that failed the weaning attempt, 11 (64 %) had to be reconnected to the ventilator during the SBT, three (18 %) had to be re-intubated within 48 h of extubation, and three (18 %) required non-invasive ventilation support within 48 h of extubation. The areas under the ROC curves for D-RSBI and RSBI were 0.89 and 0.72, respectively (P = 0.006)., Conclusions: D-RSBI (RR/DD) was more accurate than traditional RSBI (RR/VT) in predicting the weaning outcome., Trial Registration: Our clinical trial was retrospectively registered with ClinicalTrials.gov (identifier: NCT02696018 ). ClinicalTrials.gov processed our record on 25 February 2016.

Objectives and Design: We investigated the effect of balanced (BS) and unbalanced (UBS) solutions in the absence or presence of hydroxyethyl starch (HES) on neutrophil functionality, evaluating the release of matrix metalloproteinase (MMP)-9, myeloperoxidase (MPO), and MMP-8., Materials and Methods: Neutrophils were isolated by gradient centrifugation and dextran sedimentation and incubated in BS or UBS without or with HES, in the absence or presence of Interleukin-8 (IL-8) or Lipopolysaccharide (LPS). MMP-9, MPO, and MMP-8 were assayed by commercially available ELISA kits., Results: There was not any influence of volume replacement solutions on the release of the enzymes from resting neutrophils. After IL-8 stimulation, the release of MMP-9 was higher in BS than in UBS or RPMI-1640, whereas HES enhanced its release regardless of the composition. After LPS stimulation, the release of MMP-9 was higher in both UBS and BS than RPMI-1640, but HES brought its release back to physiological conditions. No difference was found in the release of MPO and MMP-8 after stimulation with IL-8 or LPS., Conclusion: Volume replacement solutions might have an impact on the release of MMP-9 depending on the inflammatory milieu, suggesting that the use of balanced or unbalanced solutions is not a neutral choice.

Background: Administration of normal saline might increase circulating levels of pro-inflammatory cytokines and may cause variation of plasmatic electrolytic and hyperchloremic acidosis, which in turn can impair renal function. Hence the use of balanced solutions could influence the inflammatory cascade triggered by the surgical procedures, the plasmatic electrolyte concentration, the acid-base equilibrium, and the renal function., Methods: This is a double blind randomized trial. Forty patients undergoing major abdominal surgery (bowel cancer) were allocated in two groups, the balanced solution (BS) group in which the fluids administered were balanced solutions (colloids and crystalloids); and the unbalanced solution (UBS) group in which the fluids administered were unbalanced solutions (colloids and crystalloids). Measurements were performed after anaesthesia induction (T0), at the end of surgery (T1), within 2 h after surgery (T2) and 24 h after the beginning of surgery (T3). The following data were collected: 1) active matrix metalloproteinase 9 (MMP-9) and its tissue inhibitor (TIMP-1), IL-6, IL-8, IL-10; 2) blood gases variables; 3) electrolytes, albumin, total serum protein and the strong ion difference; 4) neutrophil gelatinase-associated lipocalin (NGAL) from urinary sample., Results: The BS group exhibited higher circulating level of IL-10 and TIMP-1 and lower level of active MMP-9. The UBS group experienced hypercloremia, hypocalcemia, hypomagnesemia, worse acid-base equilibrium and higher level of NGAL., Conclusions: The use of balanced solutions was responsible of less alteration of plasmatic electrolytes, acid-base equilibrium, kidney function and it might be associated with an early anti-inflammatory mechanisms triggering., Trial Registration: ClinicalTrials.gov (Ref: NCT01320891).

Objective: To identify the nature of the changes of respiratory mechanics in patients with middle cervical spinal cord injury (SCI) and their correlation with posture., Design: Clinical trial., Setting: Acute SCI unit., Participants: Patients with SCI (N=34) at C4-5 level studied within 6 months of injury., Interventions: Patients were assessed by the negative expiratory pressure test, maximal static respiratory pressure test, and standard spirometry., Main Outcome Measures: The following respiratory variables were recorded in both the semirecumbent and supine positions: (1) tidal expiratory flow limitation (TEFL); (2) airway resistances; (3) mouth occlusion pressure developed 0.1 seconds after occluded inspiration at functional residual capacity (P(0.1)); (4) maximal static inspiratory pressure (MIP) and maximal static expiratory pressure (MEP); and (5) spirometric data., Results: TEFL was detected in 32% of the patients in the supine position and in 9% in the semirecumbent position. Airway resistances and P(0.1) were much higher compared with normative values, while MIP and MEP were markedly reduced. The ratio of forced expiratory volume in 1 second to forced vital capacity was less than 70%, while the other spirometric data were reduced up to 30% of predicted values., Conclusions: Patients with middle cervical SCI can develop TEFL. The presence of TEFL, associated with increased airway resistance, could increase the work of breathing in the presence of a reduced capacity of the respiratory muscles to respond to the increased load. The semirecumbent position and the use of continuous positive airway pressure can be helpful to (1) reduce the extent of TEFL and avoid the opening/closure of the small airways; (2) decrease airway resistance; and (3) maintain the expiratory flow as high as possible, which aids in the removal of secretions., (Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Excessive production of matrix metalloproteinase 9 (MMP-9) is linked to tissue damage and anastomotic leakage after large bowel surgery. Hence, the aim of this study was to verify whether different strategies of fluids administration can reduce MMP-9 expression., Methods: In the in vitro experiment, the authors tested the hypothesis of a direct inhibition of MMP-9 by the fluids used perioperatively, i.e., lactated Ringer's solution, 3.4% poligeline, and hydroxyethyl starch 130/0.4. In the in vivo experiment, 36 patients undergoing surgery for colon cancer were randomly assigned to three groups to receive lactated Ringer's solution, poligeline, or hydroxyethyl starch. MMP-9 and tissue inhibitor of metalloproteinases were measured from venous blood samples; the MMP-9/tissue inhibitor of metalloproteinases ratio was calculated as an index of equilibrium between the action of MMP-9 and its inhibition., Results: In the in vitro experiment, the presence of hydroxyethyl starch 130/0.4 in the MMP-9 assay system showed a strong inhibition of the enzymatic activity compared with lactated Ringer's solution. In the in vivo experiment, MMP-9 and tissue inhibitor of metalloproteinases plasma levels did not differ among the three groups at baseline, whereas those levels increased significantly at the end of surgery. At that time, the MMP-9 plasma levels and the MMP-9/tissue inhibitor of metalloproteinases ratio were significantly higher in the lactated Ringer's solution and poligeline groups than in the hydroxyethyl starch group. These results were confirmed 72 h after surgery., Conclusions: This study demonstrates that hydroxyethyl starch 130/04 decreases the circulating levels of MMP-9 in patients undergoing abdominal surgery.

Objective: To evaluate the acute effect of hyperoxemia on the comfort and the respiratory variables in patients undergoing pressure support ventilation (PSV) for acute respiratory failure (ARF)., Design and Setting: Prospective, observational study performed in the intensive care unit of a university hospital., Patients: Thirteen semirecumbent patients were ventilated in PSV mode, the setting of which was established by the treating physician who was blinded to the study., Measurements: The variables measured at different levels (21-80%) of FiO(2) randomly applied were: minute volume (V (E)), respiratory frequency (f) and the pressure develing during the first 100 ms of an occluded breath (P(0.1)). These variables were firstly measured at the level of FiO(2) chosen by the treating physician. Severity of dyspnea was rated using the visual analogue scale 15' after each FiO(2) variation., Results: Modulation of FiO(2) was able to vary significantly the respiratory variables, since a FiO(2) increase was associated with a decrease in dyspnea, P(0.1), f, and V (E). While valuable variations were detected at both lower and higher values of FiO(2) than those established by the treating physician, a significant improvement in the respiratory variables was detected at FiO(2) 60%. The reduction in respiratory drive was statistically related to an amelioration of dyspnea (R(2)=0.89) even at values of FiO(2) higher than 60%., Conclusions: During PSV the respiratory drive can be heavily modulated by varying the FiO(2) since even at FiO(2) greater than 0.6 dyspnea and respiratory variables continued to improve.

Objective: Elective abdominal aneurysm repair can be performed by using the transperitoneal or the retroperitoneal approach. The latter has been described as having a better outcome, reducing the impairment of respiratory function or the incidence of lung complications. Hence, the retroperitoneal approach has been proposed for treatment of medically high-risk patients. However, the superiority of one technique or the other in preserving pulmonary function has not been conclusively demonstrated. The aim of this study was to ascertain whether the retroperitoneal and the transperitoneal approaches affect respiratory function differently., Design: A prospective randomized study., Setting: Two four-bed surgical-medical ICUs of a University hospital., Patients: Twenty-three consecutive patients undergoing abdominal aortic aneurysm repair were randomized to the retroperitoneal (12 patients) and transperitoneal approach (11 patients). They were studied: a). within 30 min the end of surgery; b). 8 h after the end of surgery; and c). during a T-piece tube-weaning trial., Measurements: The comparison between the two groups was based on respiratory mechanics, partitioned between lung and chest wall components, basic spirometry, tension-time index of the inspiratory muscle, weaning indexes, and length of stay both in ICU and hospital., Results: The two surgical techniques do not differ in their impact on either respiratory mechanics or inspiratory muscle function or weaning indexes. However, there was a tendency for retroperitoneal patients to stay for less time both in ICU and in the hospital., Conclusions: During the first 24 h after surgery, the postoperative impairment of respiratory function is independent of the surgical approach.

Study Objectives: (1) To determine the incidence of expiratory flow limitation (FL) at ICU admission, at the time of extubation, and at ICU discharge in intubated patients with COPD receiving mechanical ventilation for acute respiratory failure (ARF); and (2) to assess the feasibility of inspiratory capacity (IC) as an indication of pulmonary dynamic hyperinflation in this setting., Design: Prospective, observational pilot study with physiologic measurements performed at ICU admission and during the weaning process driven by the clinician. A 60-min T-tube trial was initiated once criteria for weaning were present. The decision to extubate or reventilate patients was made by the clinician at the end of this session. Assessment of failure or success of T-tube trials was performed independently., Setting: A 25-bed ICU of a tertiary teaching university hospital., Patients: Over a 13-month period, 25 intubated patients with COPD receiving mechanical ventilation for ARF were included., Interventions: None., Measurements and Results: At ICU admission, FL assessed by the negative expiratory pressure test was measured under passive ventilatory conditions at the baseline ventilatory settings, on zero end-expiratory pressure, and in a semirecumbent position. During weaning, FL, respiratory pattern, and IC were measured during T-tube trials, before extubation, 1 h after extubation, and at ICU discharge. At ICU admission, 24 of 25 patients presented FL with, on average, 73 +/- 22% of the tidal volume. Ten patients were unavailable for follow-up due to death (n = 6) unplanned extubation (n = 3), or refusal (n = 1), so that only 15 patients completed the whole protocol (all 15 patients were extubated). For these 15 patients, the incidence of FL was 93% at ICU admission, 47% before extubation, and 40% at ICU discharge. IC was significantly greater at ICU discharge than before extubation (36 +/- 11% predicted vs 44 +/- 12% predicted, p < 0.01) and in successful T-tube trials compared with unsuccessful T-tube trials (38 +/- 13% predicted vs 24 +/- 8% predicted, p < 0.01)., Conclusions: The incidence of expiratory FL is high in patients with COPD receiving mechanical ventilation, and is reduced during aggressive therapy when the patient is placed on mechanical ventilatory support and the time that weaning begins during the ICU stay. IC was lower in patients in whom weaning was unsuccessful. Further large-scale studies are required to confirm these preliminary results.

Study Objectives: Supplemental oxygen is used in hypoxemic patients with chronic airways obstruction (CAO) because it reduces pulmonary artery pressure and prolongs life. The purpose of this study was to assess at rest the effects of 30% oxygen inhalation on dyspnea, breathing pattern, neuromuscular inspiratory drive based on measurement of mouth occlusion pressure (P(0.1)), and dynamic hyperinflation (DH), as reflected by changes in inspiratory capacity (IC)., Methods: Ten patients with stable CAO receiving long-term oxygen were studied at rest, before and after 5, 15, and 25 min of oxygen administration. Severity of dyspnea was rated using the visual analog scale (VAS). Breathing pattern parameters, P(0.1), IC, and tidal expiratory flow limitation (EFL), were measured sequentially., Results: Eight patients exhibited EFL under baseline condition. During 30% oxygen breathing, the VAS score significantly decreased, associated with a concurrent increase of IC (11%). There was also a significant reduction of minute ventilation and tidal volume (11% and 12%, respectively), which was due to a significant decrease of mean inspiratory flow. Although not significantly, P(0.1) decreased by 13%. Finally, two patients reverted from EFL to no EFL., Conclusion: Patients with CAO receiving long-term oxygen may benefit from hyperoxic breathing at rest, since it decreases the ventilation and the degree of DH, with concurrent improvement of dyspnea sensation.

Objective: Although computerized methods of analyzing respiratory system mechanics such as the least squares fitting method have been used in various patient populations, no conclusive data are available in patients with chronic obstructive pulmonary disease (COPD), probably because they may develop expiratory flow limitation (EFL). This suggests that respiratory mechanics be determined only during inspiration., Setting: Eight-bed multidisciplinary ICU of a teaching hospital., Patients: Eight non-flow-limited postvascular surgery patients and eight flow-limited COPD patients., Intervention: Patients were sedated, paralyzed for diagnostic purposes, and ventilated in volume control ventilation with constant inspiratory flow rate., Measurements: Data on resistance, compliance, and dynamic intrinsic positive end-expiratory pressure (PEEPi,dyn) obtained by applying the least squares fitting method during inspiration, expiration, and the overall breathing cycle were compared with those obtained by the traditional method (constant flow, end-inspiratory occlusion method)., Results and Conclusion: Our results indicate that (a) the presence of EFL markedly decreases the precision of resistance and compliance values measured by the LSF method, (b) the determination of respiratory variables during inspiration allows the calculation of respiratory mechanics in flow limited COPD patients, and (c) the LSF method is able to detect the presence of PEEPi,dyn if only inspiratory data are used.