Respiratory failure occurs due mainly either to lung failure resulting in hypoxaemia or pump failure resulting in alveolar hypoventilation and hypercapnia. Hypercapnic respiratory failure may be the result of mechanical defects, central nervous system depression, imbalance of energy demands and supplies and/or adaptation of central controllers.Hypercapnic respiratory failure may occur either acutely, insidiously or acutely upon chronic carbon dioxide retention. In all these conditions, pathophysiologically, the common denominator is reduced alveolar ventilation for a given carbon dioxide production.Acute hypercapnic respiratory failure is usually caused by defects in the central nervous system, impairment of neuromuscular transmission, mechanical defect of the ribcage and fatigue of the respiratory muscles.The pathophysiological mechanisms responsible for chronic carbon dioxide retention are not yet clear. The most attractive hypothesis for this disorder is the theory of “natural wisdom”. Patients facing a load have two options, either to push hard in order to maintain normal arterial carbon dioxide and oxygen tensions at the cost of eventually becoming fatigued and exhausted or to breathe at a lower minute ventilation, avoiding dyspnoea, fatigue and exhaustion but at the expense of reduced alveolar ventilation. Based on most recent work, the favoured hypothesis is that a threshold inspiratory load may exist, which, when exceeded, results in injury to the muscles and, consequently, an adaptive response is elicited to prevent and/or reduce this damage. This consists of cytokine production, which, in turn, modulates the respiratory controllers, either directly through the blood or probably the small afferents orviathe hypothalamic-pituitary-adrenal axis. Modulation of the pattern of breathing, however, ultimately results in alveolar hypoventilation and carbon dioxide retention.

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.

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%.

It has been suggested that in patients with adult respiratory distress syndrome (ARDS), intrinsic positive end-expiratory pressure (PEEPi) is generated by a disproportionate increase in expiratory flow resistance. Using the negative expiratory pressure (NEP) technique, we assessed whether expiratory flow limitation (EFL) and PEEPi were present at zero PEEP in 10 semirecumbent, mechanically ventilated ARDS patients. Because bronchodilators may decrease airway resistance, we also investigated the effect of nebulized salbutamol on EFL, PEEPi, and respiratory mechanics in these patients, and in seven patients we measured the latter variables in the supine position as well. In the semirecumbent position, eight of the 10 ARDS patients exhibited tidal EFL, ranging from 5 to 37% of the control tidal volume (Vt), whereas PEEPi was present in all 10 subjects, ranging from 0.4 cm H2O to 7.7 cm H2O. The onset of EFL was heralded by a distinct inflection point on the expiratory flow–volume curve, which probably reflected small-airway closure. Administration of salbutamol had no statistically significant effect on PEEPi, EFL (as %Vt), or respiratory mechanics. EFL (%Vt) and PEEPi were significantly higher in the supine position than in the semirecumbent position, whereas the other respiratory variables did not change. Our results suggest that in the absence of externally applied PEEP, most ARDS patients exhibit EFL associated with small-airway closure and a concomitant PEEPi.