Boris Jung

Rapidly Progressive Diaphragmatic Weakness and Injury during Mechanical Ventilation in Humans

RATIONALE Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation (MV). Paradoxically, MV itself results in a rapid loss of diaphragmatic strength in animals. However, very little is known about the time course or mechanistic basis for such a phenomenon in humans. OBJECTIVES To determine in a prospective fashion the time course for development of diaphragmatic weakness during MV; and the relationship between MV duration and diaphragmatic injury or atrophy, and the status of candidate cellular pathways implicated in these phenomena. METHODS Airway occlusion pressure (TwPtr) generated by the diaphragm during phrenic nerve stimulation was measured in short-term (0.5 h; n = 6) and long-term (>5 d; n = 6) MV groups. Diaphragmatic biopsies obtained during thoracic surgery (MV for 2-3 h; n = 10) and from brain-dead organ donors (MV for 24-249 h; n = 15) were analyzed for ultrastructural injury, atrophy, and expression of proteolysis-related proteins (ubiquitin, nuclear factor-κB, and calpains). MEASUREMENTS AND MAIN RESULTS TwPtr decreased progressively during MV, with a mean reduction of 32 ± 6% after 6 days. Longer periods of MV were associated with significantly greater ultrastructural fiber injury (26.2 ± 4.8 vs. 4.7 ± 0.6% area), decreased cross-sectional area of muscle fibers (1,904 ± 220 vs. 3,100 ± 329 μm²), an increase of ubiquitinated proteins (+19%), higher expression of p65 nuclear factor-κB (+77%), and greater levels of the calcium-activated proteases calpain-1, -2, and -3 (+104%, +432%, and +266%, respectively) in the diaphragm. CONCLUSIONS Diaphragmatic weakness, injury, and atrophy occur rapidly in critically ill patients during MV, and are significantly correlated with the duration of ventilator support.

The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales

&NA; Unlike wards, where chronic and acute pain are regularly managed, comparisons of the most commonly used self‐report pain tools have not been reported for the intensive care unit (ICU) setting. The objective of this study was to compare the feasibility, validity and performance of the Visual Analog Scale (horizontal (VAS‐H) and vertical (VAS‐V) line orientation), the Verbal Descriptor Scale (VDS), the 0–10 oral Numeric Rating Scale (NRS‐O) and the 0–10 visually enlarged laminated NRS (NRS‐V) for pain assessment in critically ill patients. One hundred and eleven consecutive patients admitted into a medical‐surgical ICU were included as soon as they became alert and were able to follow simple commands. Pain was measured using the 5 scales in a randomized order upon enrollment‐(T1) and after‐(T2) administration of an analgesic or, in absence of pain upon enrollment, after a nociceptive procedure. The rate of any response obtained both at T1 and T2 (success rate) was significantly higher for NRS‐V (91%) compared with NRS‐O (83%), VDS (78%), VAS‐H (68%) and VAS‐V (66%). Pain intensity changed significantly between T1 and T2, showing a good validity and responsiveness for the 5 scales, which correlated well between each other. The negative predictive value calculated from true and false negatives defined by real and false absence of pain was highest for NRS‐V (90%). In conclusion, the NRS‐V should be the tool of choice for the ICU setting, because it is the most feasible and discriminative self‐report scale for measuring critically ill patients’ pain intensity.

Diaphragm Dysfunction on Admission to the Intensive Care Unit. Prevalence, Risk Factors, and Prognostic Impact—A Prospective Study

RATIONALE Diaphragmatic insults occurring during intensive care unit (ICU) stays have become the focus of intense research. However, diaphragmatic abnormalities at the initial phase of critical illness remain poorly documented in humans. OBJECTIVES To determine the incidence, risk factors, and prognostic impact of diaphragmatic impairment on ICU admission. METHODS Prospective, 6-month, observational cohort study in two ICUs. Mechanically ventilated patients were studied within 24 hours after intubation (Day 1) and 48 hours later (Day 3). Seventeen anesthetized intubated control anesthesia patients were also studied. The diaphragm was assessed by twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (Ptr,stim). MEASUREMENTS AND MAIN RESULTS Eighty-five consecutive patients aged 62 (54-75) (median [interquartile range]) were evaluated (medical admission, 79%; Simplified Acute Physiology Score II, 54 [44-68]). On Day 1, Ptr,stim was 8.2 (5.9-12.3) cm H2O and 64% of patients had Ptr,stim less than 11 cm H2O. Independent predictors of low Ptr,stim were sepsis (linear regression coefficient, -3.74; standard error, 1.16; P = 0.002) and Simplified Acute Physiology Score II (linear regression coefficient, -0.07; standard error, 1.69; P = 0.03). Compared with nonsurvivors, ICU survivors had higher Ptr,stim (9.7 [6.3-13.8] vs. 7.3 [5.5-9.7] cm H2O; P = 0.004). This was also true for hospital survivors versus nonsurvivors (9.7 [6.3-13.5] vs. 7.8 [5.5-10.1] cm H2O; P = 0.004). Day 1 and Day 3 Ptr,stim were similar. CONCLUSIONS A reduced capacity of the diaphragm to produce inspiratory pressure (diaphragm dysfunction) is frequent on ICU admission. It is associated with sepsis and disease severity, suggesting that it may represent another form of organ failure. It is associated with a poor prognosis. Clinical trial registered with www.clinicaltrials.gov (NCT 00786526).

The Effectiveness of Noninvasive Positive Pressure Ventilation to Enhance Preoxygenation in Morbidly Obese Patients: A Randomized Controlled Study

BACKGROUND: Noninvasive positive-pressure ventilation (NPPV) with pressure support-ventilation and positive end-expiratory pressure are effective in providing oxygenation during intubation in hypoxemic patients. We hypothesized administration of oxygen (O2) using NPPV would more rapidly increase the end-tidal O2 concentration (ETo2) than preoxygenation using spontaneous ventilation (SV) in morbidly obese patients. METHODS: Twenty-eight morbidly obese patients were enrolled in this prospective randomized study. Administration of O2 for 5 min was performed either with SV group or with NPPV (pressure support = 8 cm H2O, positive end-expiratory pressure = 6 cm H2O) (NPPV group). ETo2 was measured using the anesthesia breathing circuit, and is expressed as a fraction of atmospheric concentration. The primary end-point was the number of patients with an ETo2 >95% at the end of O2 administration. Secondary end-points included the time to reach the maximal ETo2 and the ETo2 at the conclusion of O2 administration. RESULTS: A larger proportion of patients achieved a 95% ETo2 at 5 min with NPPV than SV (13/14 vs 7/14, P = 0.01). The time to reach the maximal ETo2 was significantly less in the NPPV than in the SV group (185 ± 46 vs 222 ± 42 s, P = 0.02). The mean ETo2 at the conclusion of O2 administration was larger in the NPPV group than the SV group (96.9 ± 1.3 vs 94.1 ± 2.0%, P < 0.001). A modest, although significant, increase in gastric distension was observed in the NPPV group. No adverse effects were observed in either group. CONCLUSION: Administration of O2 via a facemask with NPPV in the operating room is safe, feasible, and efficient in morbidly obese patients. In this population NPPV provides a more rapid O2 administration, achieving a higher ETo2.

Mitochondrial Dysfunction and Lipid Accumulation in the Human Diaphragm during Mechanical Ventilation

RATIONALE Mechanical ventilation (MV) is associated with adverse effects on the diaphragm, but the cellular basis for this phenomenon, referred to as ventilator-induced diaphragmatic dysfunction (VIDD), is poorly understood. OBJECTIVES To determine whether mitochondrial function and cellular energy status are disrupted in human diaphragms after MV, and the role of mitochondria-derived oxidative stress in the development of VIDD. METHODS Diaphragm and biceps specimens obtained from brain-dead organ donors who underwent MV (15-176 h) and age-matched control subjects were compared regarding mitochondrial enzymatic function, mitochondrial DNA integrity, lipid content, and metabolic gene and protein expression. In addition, diaphragmatic force and oxidative stress after exposure to MV for 6 hours were evaluated in mice under different conditions. MEASUREMENTS AND MAIN RESULTS In human MV diaphragms, mitochondrial biogenesis and content were down-regulated, with a more specific defect of respiratory chain cytochrome-c oxidase. Laser capture microdissection of cytochrome-c oxidase-deficient fibers revealed mitochondrial DNA deletions, consistent with damage from oxidative stress. Diaphragmatic lipid accumulation and responses of master cellular metabolic sensors (AMP-activated protein kinase and sirtuins) were consistent with energy substrate excess as a possible stimulus for these changes. In mice, induction of hyperlipidemia worsened diaphragmatic oxidative stress during MV, whereas transgenic overexpression of a mitochondria-localized antioxidant (peroxiredoxin-3) was protective against VIDD. CONCLUSIONS Our data suggest that mitochondrial dysfunction lies at the nexus between oxidative stress and the impaired diaphragmatic contractility that develops during MV. Energy substrate oversupply relative to demand, resulting from diaphragmatic inactivity during MV, could play an important role in this process.

Postoperative noninvasive ventilation.

Thesemodificationsoftherespiratoryfunctionoccur early after surgery and are more often transient andcould lead to ARF. The clinical result (severity of theARF) is the product of perioperative-related ventilatoryimpairment and severity of the preoperative pulmonarycondition. Maintenance of adequate oxygenation in thepostoperative period is of major importance, especiallywhen pulmonary complications such as ARF occur. Al-though invasive endotracheal mechanical ventilation hasremained the cornerstone of ventilatory strategy for manyyearsforsevereARF,severalstudieshaveshownthatmor-tality associated with pulmonary disease is largely relatedto complications of postoperative reintubation and me-chanicalventilation.Therefore,majorobjectivesforanes-thesiologists are first to prevent the occurrence of postop-erative complications and second to ensure oxygenadministration and carbon dioxide removal while avoid-ing intubation if ARF occurs. Noninvasive ventilation(NIV) does not require an artificial airway (endotrachealtube or tracheotomy), and its use is well established toprevent ARF occurrence (prophylactic treatment) or totreat ARF to avoid reintubation (curative treatment) (fig.1). Studies show that patient-related risk factors, such aschronic obstructive pulmonary disease, age older than 60yr, American Society of Anesthesiologists class of II orhigher, obesity, functional dependence, and congestiveheart failure, increase the risk for postoperative pulmo-nary complications.

Pressure support ventilation attenuates ventilator-induced protein modifications in the diaphragm

IntroductionControlled mechanical ventilation (CMV) induces profound modifications of diaphragm protein metabolism, including muscle atrophy and severe ventilator-induced diaphragmatic dysfunction. Diaphragmatic modifications could be decreased by spontaneous breathing. We hypothesized that mechanical ventilation in pressure support ventilation (PSV), which preserves diaphragm muscle activity, would limit diaphragmatic protein catabolism.MethodsForty-two adult Sprague-Dawley rats were included in this prospective randomized animal study. After intraperitoneal anesthesia, animals were randomly assigned to the control group or to receive 6 or 18 hours of CMV or PSV. After sacrifice and incubation with 14C-phenylalanine, in vitro proteolysis and protein synthesis were measured on the costal region of the diaphragm. We also measured myofibrillar protein carbonyl levels and the activity of 20S proteasome and tripeptidylpeptidase II.ResultsCompared with control animals, diaphragmatic protein catabolism was significantly increased after 18 hours of CMV (33%, P = 0.0001) but not after 6 hours. CMV also decreased protein synthesis by 50% (P = 0.0012) after 6 hours and by 65% (P < 0.0001) after 18 hours of mechanical ventilation. Both 20S proteasome activity levels were increased by CMV. Compared with CMV, 6 and 18 hours of PSV showed no significant increase in proteolysis. PSV did not significantly increase protein synthesis versus controls. Both CMV and PSV increased protein carbonyl levels after 18 hours of mechanical ventilation from +63% (P < 0.001) and +82% (P < 0.0005), respectively.ConclusionsPSV is efficient at reducing mechanical ventilation-induced proteolysis and inhibition of protein synthesis without modifications in the level of oxidative injury compared with continuous mechanical ventilation. PSV could be an interesting alternative to limit ventilator-induced diaphragmatic dysfunction.

Early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the MACOCHA score in a multicenter cohort study.

RATIONALE Difficult intubation in the intensive care unit (ICU) is a challenging issue. OBJECTIVES To develop and validate a simplified score for identifying patients with difficult intubation in the ICU and to report related complications. METHODS Data collected in a prospective multicenter study from 1,000 consecutive intubations from 42 ICUs were used to develop a simplified score of difficult intubation, which was then validated externally in 400 consecutive intubation procedures from 18 other ICUs and internally by bootstrap on 1,000 iterations. MEASUREMENTS AND MAIN RESULTS In multivariate analysis, the main predictors of difficult intubation (incidence = 11.3%) were related to patient (Mallampati score III or IV, obstructive sleep apnea syndrome, reduced mobility of cervical spine, limited mouth opening); pathology (severe hypoxia, coma); and operator (nonanesthesiologist). From the β parameter, a seven-item simplified score (MACOCHA score) was built, with an area under the curve (AUC) of 0.89 (95% confidence interval [CI], 0.85-0.94). In the validation cohort (prevalence of difficult intubation = 8%), the AUC was 0.86 (95% CI, 0.76-0.96), with a sensitivity of 73%, a specificity of 89%, a negative predictive value of 98%, and a positive predictive value of 36%. After internal validation by bootstrap, the AUC was 0.89 (95% CI, 0.86-0.93). Severe life-threatening events (severe hypoxia, collapse, cardiac arrest, or death) occurred in 38% of the 1,000 cases. Patients with difficult intubation (n = 113) had significantly higher severe life-threatening complications than those who had a nondifficult intubation (51% vs. 36%; P < 0.0001). CONCLUSIONS Difficult intubation in the ICU is strongly associated with severe life-threatening complications. A simple score including seven clinical items discriminates difficult and nondifficult intubation in the ICU. Clinical trial registered with www.clinicaltrials.gov (NCT 01532063).

Effect of Statin Therapy on Mortality in Patients With Ventilator-AssociatedPneumonia: A Randomized Clinical Trial

IMPORTANCE Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality. OBJECTIVE To determine whether statin therapy can decrease day-28 mortality in patients with VAP. DESIGN, SETTING, AND PARTICIPANTS Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients. INTERVENTIONS Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first. MAIN OUTCOMES AND MEASURES Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14. RESULTS The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, -3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, -1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score. CONCLUSIONS AND RELEVANCE In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01057758.

Adaptive support ventilation prevents ventilator-induced diaphragmatic dysfunction in piglet: an in vivo and in vitro study.

Background:Contrary to adaptive support ventilation (ASV), prolonged totally controlled mechanical ventilation (CMV) results in the absence of diaphragm activity and causes ventilator-induced diaphragmatic dysfunction. Because main-taining respiratory muscles at rest is likely a major cause of ventilator-induced diaphragmatic dysfunction, ASV may prevent its occurrence in comparison with CMV. The aim of our study was to compare the effects of ASV with those of CMV on both in vivo and in vitro diaphragmatic properties. Methods:Two groups of six anesthetized piglets were ventilated during a 72-h period. Piglets in the CMV group (n = 6) were ventilated without spontaneous ventilation, and piglets in the ASV group (n = 6) were ventilated with spontaneous breaths. Transdiaphragmatic pressure was measured after bilateral, supramaximal transjugular stimulation of the two phrenic nerves. A pressure–frequency curve was drawn after stimulation from 20 to 120 Hz of the phrenic nerves. Diaphragm fiber proportions and mean sectional area were evaluated. Results:After 72 h of ventilation, transdiaphragmatic pressure decreased by 30% of its baseline value in the CMV group, whereas it did not decrease in the ASV group. Although CMV was associated with an atrophy of the diaphragm (evaluated by mean cross-sectional area of both the slow and fast myosin chains), atrophy was not detected in the ASV group. Conclusion:Maintaining diaphragmatic contractile activity by using the ASV mode may protect the diaphragm against the deleterious effect of prolonged CMV, as demonstrated both in vitro and in vivo, in healthy piglets.