Antonia Koutsoukou

Patterns of dynamic hyperinflation during exercise and recovery in patients with severe chronic obstructive pulmonary disease

Background: Not all patients with severe chronic obstructive pulmonary disease (COPD) progressively hyperinflate during symptom limited exercise. The pattern of change in chest wall volumes (Vcw) was investigated in patients with severe COPD who progressively hyperinflate during exercise and those who do not. Methods: Twenty patients with forced expiratory volume in 1 second (FEV1) 35 (2)% predicted were studied during a ramp incremental cycling test to the limit of tolerance (Wpeak). Changes in Vcw at the end of expiration (EEVcw), end of inspiration (EIVcw), and at total lung capacity (TLCVcw) were computed by optoelectronic plethysmography (OEP) during exercise and recovery. Results: Two significantly different patterns of change in EEVcw were observed during exercise. Twelve patients had a progressive significant increase in EEVcw during exercise (early hyperinflators, EH) amounting to 750 (90) ml at Wpeak. In contrast, in all eight remaining patients EEVcw remained unchanged up to 66% Wpeak but increased significantly by 210 (80) ml at Wpeak (late hyperinflators, LH). Although at the limit of tolerance the increase in EEVcw was significantly greater in EH, both groups reached similar Wpeak and breathed with a tidal EIVcw that closely approached TLCVcw (EIVcw/TLCVcw 93 (1)% and 93 (3)%, respectively). EEVcw was increased by 254 (130) ml above baseline 3 minutes after exercise only in EH. Conclusions: Patients with severe COPD exhibit two patterns during exercise: early and late hyperinflation. In those who hyperinflate early, it may take several minutes before the hyperinflation is fully reversed after termination of exercise.

Inflammation and Immune Response in COPD: Where Do We Stand?

Increasing evidence indicates that chronic inflammatory and immune responses play key roles in the development and progression of COPD. Recent data provide evidence for a role in the NLRP3 inflammasome in the airway inflammation observed in COPD. Cigarette smoke activates innate immune cells by triggering pattern recognition receptors (PRRs) to release “danger signal”. These signals act as ligands to Toll-like receptors (TLRs), triggering the production of cytokines and inducing innate inflammation. In smokers who develop COPD there appears to be a specific pattern of inflammation in the airways and parenchyma as a result of both innate and adaptive immune responses, with the predominance of CD8+ and CD4+ cells, and in the more severe disease, with the presence of lymphoid follicles containing B lymphocytes and T cells. Furthermore, viral and bacterial infections interfere with the chronic inflammation seen in stable COPD and exacerbations via pathogen-associated molecular patterns (PAMPs). Finally, autoimmunity is another novel aspect that may play a critical role in the pathogenesis of COPD. This review is un update of the currently discussed roles of inflammatory and immune responses in the pathogenesis of COPD.

Effects of rehabilitation on chest wall volume regulation during exercise in COPD patients

In order to investigate underlying mechanisms, the present authors studied the effect of pulmonary rehabilitation on the regulation of total chest wall and compartmental (ribcage, abdominal) volumes during exercise in patients with chronic obstructive pulmonary disease. In total, 20 patients (forced expiratory volume in one second, mean±sem 39±3% predicted) undertook high-intensity exercise 3 days·week-1 for 12 weeks. Before and after rehabilitation, the changes in chest wall (cw) volumes at the end of expiration (EEV) and inspiration (EIV) were computed by optoelectronic plethysmography during incremental exercise to the limit of tolerance (Wpeak). Rehabilitation significantly improved Wpeak (57±7 versus 47±5 W). In the post-rehabilitation period and at identical work rates, significant reductions were observed in minute ventilation (35.1±2.7 versus 38.4±2.7 L·min-1), breathing frequency (26±1 versus 29±1 breaths·min-1) and EEVcw and EIVcw (by 182±79 and 136±37 mL, respectively). Inspiratory reserve volume was significantly increased (by 148±70 mL). Volume reductions were attributed to significant changes in abdominal EEV and EIV (by 163±59 and 125±27 mL, respectively). The improvement in Wpeak was similar in patients who progressively hyperinflated during exercise and those who did not (24 and 26%, respectively). In conclusion, pulmonary rehabilitation lowers chest wall volumes during exercise by decreasing the abdominal volumes. The improvement in exercise capacity following rehabilitation is independent of the pattern of exercise-induced dynamic hyperinflation.

Expiratory flow limitation in morbidly obese postoperative mechanically ventilated patients

Although obesity promotes tidal expiratory flow limitation (EFL), with concurrent dynamic hyperinflation (DH), intrinsic PEEP (PEEPi) and risk of low lung volume injury, the prevalence and magnitude of EFL, DH and PEEPi have not yet been studied in mechanically ventilated morbidly obese subjects.

Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen

Abstract Serological, molecular and phylogenetic analyses of a recently imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) in Greece are reported. Although MERS-CoV remained detectable in the respiratory tract secretions of the patient until the fourth week of illness, viraemia was last detected 2 days after initiation of triple combination therapy with pegylated interferon, ribavirin and lopinavir/ritonavir, administered from Day 13 of illness. Phylogenetic analysis of the virus showed close similarity with other human MERS-CoVs from the recent Jeddah outbreak in Saudi Arabia. Immunoglobulin G (IgG) titres peaked 3 weeks after the onset of illness, whilst IgM levels remained constantly elevated during the follow-up period (second to fifth week of illness). Serological testing confirmed by virus neutralisation assay detected an additional case that was a close contact of the patient.

Intrinsic positive end-expiratory pressure in mechanically ventilated patients with and without tidal expiratory flow limitation.

ObjectiveTo assess static intrinsic positive end-expiratory pressure (PEEPi,st) and expiratory flow limitation (FL) in 32 consecutive mechanically ventilated patients with acute respiratory failure (ARF), using a commercial ventilator with an incorporated device that allows the application of a negative expiratory pressure (NEP). DesignProspective clinical study. SettingMultidisciplinary intensive care unit of a university hospital. PatientsThirty-two consecutive ventilated patients with ARF of various etiologies. InterventionsEvaluation of respiratory mechanics, PEEPi,st, and FL from pressure, flow, and volume traces provided by the ventilator. MeasurementsPeak airway pressure, PEEPi,st, dynamic elastance, and interrupter resistance were measured in relaxed patients in a supine position. Comparison of tidal flow–volume curves before and during the application of an NEP of 5 cm H2O was used to assess tidal expiratory FL. ResultsTwelve of 32 patients studied exhibited tidal expiratory FL, which was detected by the absence of increase in expiratory flow despite application of an NEP over the entire or part of the baseline expiratory flow–volume curve. All patients exhibited PEEPi,st, which amounted to 1.2 ± 0.9 cm H2O (mean ± sd) in the 20 non-FL patients and 7.1 ± 2.8 cm H2O in the 12 FL patients (p < 0.00001). The majority of patients with ARF resulting from underlying lung disease (11 of 13) had FL and a PEEPi,st > 4 cm H2O, whereas in patients with ARF of extrapulmonary origin, PEEPi,st was always < 4 cm H2O and only one grossly obese patient exhibited FL. Based on multiple regression analysis, in non-FL patients, PEEPi,st correlated significantly only with minute ventilation, whereas in FL patients PEEPi,st correlated significantly with peak airway pressure. ConclusionsBecause all the patients exhibited PEEPi,st and 12 of 32 patients (38%) also had FL, the authors conclude that the assessment of these variables at the bedside could provide useful information concerning respiratory mechanics in mechanically ventilated patients.

Acute effects of combined high-frequency oscillation and tracheal gas insufflation in severe acute respiratory distress syndrome.

Objective:In acute respiratory distress syndrome (ARDS), high-frequency oscillation (HFO) improves oxygenation relative to conventional mechanical ventilation (CMV). Alveolar ventilation is improved by adding tracheal gas insufflation (TGI) to CMV. We hypothesized that combined HFO and TGI (HFO-TGI) might result in improved gas exchange relative to both standard HFO and CMV according to the ARDS Network protocol. Design:Prospective, randomized, crossover study. Setting:A 30-bed university intensive care unit. Patients:A total of 14 patients with early (<72 hrs in duration), severe (Pao2/Fio2 of <150 mm Hg and prerecruitment oxygenation index of 22.8 ± 1.9 [mean ± sem]), primary ARDS. Interventions:Patients were ventilated with HFO without (60 mins) and combined with TGI (6.1 ± 0.1 L/min, 60 mins) in random order. HFO sessions were repeated in inverse order within 24 hrs. HFO sessions were preceded and followed by ARDS Network CMV. Four recruitment maneuvers were performed during the study period. During HFO sessions, mean airway pressure was set at 1 cm H2O above the point of maximal curvature of the respiratory system expiratory pressure–volume curve. Measurements and Main Results:Gas exchange and hemodynamics were determined before, during, and after HFO sessions. HFO-TGI improved Pao2/Fio2 relative to HFO and CMV (174.5 ± 10.4 vs. 136.0 ± 10.0 and 105.0 ± 3.7 mm Hg, respectively, p < .05 for both) and oxygenation index relative to HFO (17.1 ± 1.3 vs. 22.3 ± 1.7, respectively p < .05). Pao2/Fio2 returned to baseline within 3 hrs after HFO. During HFO-TGI, shunt fraction and mixed venous oxygen saturation improved relative to CMV (0.36 ± 0.01 vs. 0.45 ± 0.01 and 77.8% ± 1.2% vs. 71.8% ± 1.3%, respectively, p < .05 for both). Paco2 and hemodynamics were unaffected by HFO sessions. Respiratory mechanics remained unchanged throughout the study period. Conclusions:In early onset, primary, severe ARDS, short-term HFO-TGI improves oxygenation relative to standard HFO and ARDS Network CMV.

Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

ABSTRACT Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.

Chest wall volume regulation during exercise in COPD patients with GOLD stages II to IV

The present study investigated how end-expiratory ribcage and abdominal volume regulation during exercise is related to the degree of dynamic chest wall hyperinflation in patients with different spirometric severity of chronic obstructive pulmonary disease (COPD) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. In total, 42 COPD patients and 11 age-matched healthy subjects were studied during a ramp-incremental cycling test to the limit of tolerance (Wpeak). Volume variations of the chest wall (at end expiration (EEVcw) and end inspiration) and its compartments (ribcage (Vrc) and abdominal (Vab)) were computed by optoelectronic plethysmography. At Wpeak, only patients in GOLD stages III and IV exhibited a significant increase in EEVcw (increase of 454±509 and 562±363 mL, respectively). These patients did not significantly reduce end-expiratory Vab, whereas patients in GOLD stage II resembled healthy subjects with significantly reduced end-expiratory Vab (decrease of 287±350 mL). In patients, the greater the increase in EEVcw at Wpeak, the smaller the reductions in end-expiratory Vab and the greater the increase in end-expiratory Vrc. In chronic obstructive pulmonary disease patients with different spirometric disease severity, greater degrees of exercise-induced dynamic chest wall hyperinflation were accompanied by lower degrees of end-expiratory abdominal volume displacement and larger increases in end-expiratory ribcage volume.

Effects of exercise-induced arterial hypoxaemia and work rate on diaphragmatic fatigue in highly trained endurance athletes

Diaphragmatic fatigue occurs in highly trained athletes during exhaustive exercise. Since approximately half of them also exhibit exercise‐induced arterial hypoxaemia (EIAH) during high‐intensity exercise, the present study sought to test the hypothesis that arterial hypoxaemia contributes to exercise‐induced diaphragmatic fatigue in this population. Ten cyclists (: 70.0 ± 1.6 ml kg−1 min−1; mean ±s.e.m.) completed, in a balanced ordering sequence, one normoxic (end‐exercise arterial O2 saturation (S  a,O 2 ): 92 ± 1%) and one hyperoxic (F  I,O 2: 0.5% O2; S  a,O 2 : 97 ± 1%) 5 min exercise test at intensities equal to 80 ± 3 and 90 ± 3% of maximal work rate (WRmax), respectively, producing the same tidal volume (VT) and breathing frequency (f) throughout exercise. Cervical magnetic stimulation was used to determine reduction in twitch transdiaphragmatic pressure (Pdi,tw) during recovery. Hyperoxic exercise at 90% WRmax induced significantly (P= 0.022) greater post‐exercise reduction in Pdi,tw (15 ± 2%) than did normoxic exercise at 80% WRmax (9 ± 2%), despite the similar mean ventilation (123 ± 8 and 119 ± 8 l min−1, respectively), breathing pattern (VT: 2.53 ± 0.05 and 2.61 ± 0.05 l, f: 49 ± 2 and 46 ± 2 breaths min−1, respectively), mean changes in Pdi during exercise (37.1 ± 2.4 and 38.2 ± 2.8 cmH2O, respectively) and end‐exercise arterial lactate (12.1 ± 1.4 and 10.8 ± 1.1 mmol l−1, respectively). The difference found in diaphragmatic fatigue between the hyperoxic (at higher leg work rate) and the normoxic (at lower leg work rate) tests suggests that neither EIAH nor lactic acidosis per se are likely predominant causative factors in diaphragmatic fatigue in this population, at least at the level of S  a,O 2 tested. Rather, this result leads us to hypothesize that blood flow competition with the legs is an important contributor to diaphragmatic fatigue in heavy exercise, assuming that higher leg work required greater leg blood flow.