Current Respiratory Medicine Reviews - Volume 8, Issue 3, 2012

Therapeutic Hypothermia (TH) is a treatment approach that has made its way back to the guidelines for survivors of cardiac arrest in recent years [1, 2]. The use of this technique to preserve neurological function in patients who were successfully resuscitated after a cardiac arrest, is becoming a popular practice, or at least it is finally not seen as a “madscience experiment”, but as an evidence-based treatment option [3-5]. Other suggested indications for TH included: cerebrovascular accidents, spinal trauma and surgery, neonatal hypoxemia and seizures among others [6-8]. One indication that has a promising future, is the use of TH in patients with the Acute Respiratory Distress Syndrome (ARDS) [6, 9-11]. This is a common condition seen in Intensive Care Units (ICUs), which despite of aggressive therapies, still continues to have high rates of morbidity and mortality (35-50%) [12-17]. The only marginal improvement in the management of ARDS over the past two decades, is the one demonstrated by the ARDS-Net trial using lower tidal volumes in assisted mechanical ventilation [18]. Why do we suggest TH as a treatment for ARDS? This is an idea that has been surging over the past two decades. Villar and Slutsky published a pilot study in 1993 that evaluated this therapeutic intervention [9]. Nineteen patients were randomized to receive either conventional treatment or conventional treatment plus TH. A significant decrease in mortality rates was noted in the TH group (67% vs 100% p< 0.05) [9]. There are several theoretical benefits of using TH, the first one is that by decreasing core body temperature, the metabolic rate and oxygen requirements will be decreased [3, 8, 19]. Additionally there will be an improvement in the oxygen consumption/delivery equilibrium, thus improving the patient's respiratory function [20, 21]. There are also in vitro studies and animal models that have shown a significant decrease of bacterial dissemination and reduction of the exaggerated response of the immune system [10, 21, 22]. Both authors of this editorial have used TH in patients with ARDS demonstrating significant improvement in the Alveolar-arterial Oxygen gradient and survival (Varon J, Espina I, personal communication). Even though the science, theory and so-far-limited clinical evidence supporting TH for patients with ARDS is lacking, we believe that this therapeutic approach cannot be simply overlooked. The future of acute lung injury and ARDS management would benefit from a large-scale study assessing the impact of TH in the overall mortality and the clinical status of these patients....

This issue of Current Respiratory Medicine Reviews is dedicated to pulmonary infections in critical care and an ensemble of international experts have been brought together to review this important subject. Meeting new challenges in the management of pulmonary infections in the critically ill requires a greater understanding of pulmonary defence mechanisms, pathogenesis and diagnosis of infection, so that new strategies can be employed whilst at the same time making better use of currently available drugs. Nationwide trends demonstrate that an ever-increasing number of patients are being admitted to hospital with sepsis syndromes. Although absolute numbers of patients dying from sepsis are rising, this has been tempered by a reduction in mortality rates [1-3]. An ageing population with comorbid disease, more frequent use of indwelling medical devices and immunosuppression all contribute to the observation of an increase in sepsis. In the SOAP study, which examined sepsis in 198 European intensive care units, the most frequent site of infection was the lung and was present in two thirds of patients on arrival to critical care [4]. Community-acquired pneumonia remains an important reason for admission to both hospital and critical care and continues to rise, partly in response to an ageing population [5-7]. An additional burden on critical care capacity is posed by healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) which are frequently caused by organisms with bacterial resistance to multiple antibiotics and consequently higher treatment failure rates are often observed. Emergence of multidrug resistant organisms amongst community-acquired infections is a further area of concern [8]. New and emerging infections, which are often first identified in critically ill patients, pose an additional encumbrance [9, 10]. Erosion of the antimicrobial armamentarium is unfortunately set against a backdrop of a limited pipeline of new antimicrobial drugs coming into clinical practice. Wilkinson and colleagues review the complexity of pulmonary defence mechanisms that repel respiratory pathogens continually accessing the airway. They explore how an understanding of host immunity can improve vaccination strategies and lead to novel therapies. Williams et al. discuss the importance of the oral cavity in the pathogenesis of VAP and how an understanding of biofilm biology is fundamental to both the aetiology of VAP and developing new preventative therapies. Young and Doyle examine the central role of the endotracheal tube in VAP and how improvements in tube design may prevent its occurrence. Diagnosing VAP remains a challenge for the physician and the inability to accurately identify patients with VAP has undoubtedly hampered research in this area [11]. In their review Grover and colleagues discuss how established and novel biomarkers might enhance diagnostic certainty. Clinicians frequently focus on bacterial infections in the critically ill but are now realising that other organisms pose an increasing burden particularly in those with prolonged periods of ventilation. Linssen et al. discuss the impact of latent viral infections in mechanically ventilated patients, whilst Barnes reviews pulmonary fungal infections, which are often difficult to both diagnose and treat. The first influenza pandemic in over 40 years was caused by a novel influenza A strain, A(H1N1)pdm09 and this had a huge impact on critical care across the globe, including the postpandemic period. Dunning and Openshaw describe the clinical features of this disease and the treatment options available. Iannella and Luna consider the impact and aetiology of treatment failure in VAP including host, bacterial, and therapeutic factors. Complementary to this Dhanani and colleagues review how antibiotics may be optimally used including alternate modes of administration, continuous infusions, therapeutic drug monitoring and combination therapy. Poulakou et al. examine the burden and treatment options for Methicillin-resistant Staphylococcus aureus (MRSA), which is no longer limited to being a nosocomial pathogen. Notwithstanding the armamentarium available to physicians in modern healthcare systems, pulmonary infections will continue to present a challenge for critical care physicians and patients alike....

The lung has evolved an impressive array of strategies to sense and respond to foreign or dangerous material. This review uses an anatomical approach, from nose to alveoli, to detail our current understanding of these pulmonary defence mechanisms at the cellular and molecular level. Recent advances since the beginning of the 21st century have been given particular focus. The review initially focuses on individual host defence mechanisms of the upper airways including; the nose, sneeze, cough, the mucociliary apparatus, epithelial cells and dentritic cell network. Then we discuss individual mechanisms of the lower airways including the contribution of macrophages and opsonins to host defence. We then focus attention on the cellular interplay between the mechanisms discussed before finally presenting experimental and clinical evidence of advances that are based on our greater understanding of pulmonary defence mechanisms.

Ventilator-associated pneumonia (VAP) is the most prevalent infection in intensive care units (ICUs) and second only to urinary tract sepsis amongst hospital-acquired infections. The endotracheal tube is an important component in the pathogenesis of VAP, as it both subverts the normal defence mechanisms of the respiratory tract and offers a surface that can support biofilm growth, thereby providing a reservoir of potential respiratory pathogens. Traditionally recognized VAP pathogens include Staphylococcus aureus and Gram-negative bacteria such as Pseudomonas aeruginosa and members of the Enterobacteriaceae family. These microorganisms are not recognized as members of the normal oral microflora, but are thought to infect the lungs endogenously via the oropharyngeal route. Prior to entering the lower respiratory tract, there is evidence that the oral cavity does become colonised by respiratory pathogens. In this regard, it is probable that the normal oral microflora is an influencing factor for VAP, either through affecting recruitment of respiratory pathogens to oral plaque, or to biofilms that develop in the endotracheal tube. Indeed the ability of several Streptococcus species belonging to the normal oral microflora to promote recruitment of bacteria to plaque biofilm through production of extracellular glucans has long been recognised. Recent studies have indeed highlighted that poor oral hygiene is a risk factor for VAP and therefore the maintenance of adequate oral health care in ventilated patients represents an important preventative strategy.

The endotracheal tube, rather than the ventilator, is responsible for the vast majority of cases of ventilator associated pneumonia (VAP). Tracheal intubation should be avoided, or early extubation performed, if at all possible. With current high-volume low-pressure (HVLP) cuffs, pulmonary aspiration of microorganisms from the upper aerodigestive tract normally occurs and is frequently silent, until there is a clinical respiratory deterioration. Aspiration occurs by 3 mechanisms; channels within the HVLP cuff, in folding of the cuff upon movement and intermittent deflation of the cuff. This aspiration is the pivotal step in the development of VAP. The diagnosis of VAP is notoriously inaccurate and stifles the progress of research into prevention strategies. When treating bacteria present in the lung, the various paradigms of VAP diagnosis remain the only (and best) tools that we have to decide when the benefits of antibiotics outweigh the disadvantages. It is surprising, considering the accepted high mortality and cost of VAP, that until recently, there has been a massive under investment from industry in preventative technologies. New technologies should address the multiple factors implicated in the pathogenesis of VAP, including aspiration elimination by improved cuff designs. However, surrogate outcomes, such as pulmonary aspiration and tracheal colonisation (a more rigorous standard to aspire to), should be considered when evaluating preventative strategies. Pulmonary aspiration and/or tracheal colonisation by pathogenic organisms are undesirable and should be unacceptable. This review appraises the role of the endotracheal tube in both the development and prevention of VAP.

Ventilator Associated Pneumonia (VAP) is a common nosocomial infection in the ICU. Diagnosis based on best available criteria remains difficult. Current and novel biomarkers have the potential to speed up and improve the accuracy of its diagnosis. This review highlights the markers that have gained the most attention to date and aims to discuss the challenges faced in introducing them at the bedside.

Fungi are relatively rare causes of pulmonary infection and outside areas of endemic mycoses, infections are mainly opportunist caused by Pneumocystis and Aspergillus species. Invasive aspergillosis may be an undiagnosed problem in critically ill patients particularly those with end stage of lung and liver failure. The attributable mortality and impact of antifungal treatment are unknown. A raised index of clinical suspicion should lead to antigen testing on respiratory specimens from selected critical care patients to aid in earlier diagnosis. The high negative predictive value can be used to exclude diagnosis.

Cytomegalovirus (CMV), herpes simplex virus (HSV) type 1 (HSV-1) and type 2 (HSV-2), human herpes virus 6 (HHV-6) and 7 (HHV-7) and Epstein-Barr virus (EBV) all belong to the family of herpesviridae, are highly prevalent and ubiquitously distributed. In the immunocompetent adult host CMV and HSV infections usually have a benign course. As is the case with other herpesviridae, the initial infection is followed by a lifelong latent infection from which reactivation can occur. Asymptomatic viral shedding of CMV and/or HSV may occur in immunocompetent individuals. This viral shedding in patients without active viral disease makes it difficult to diagnose active disease in patients. In immunocompromised patients severe active disease due to these viruses is known to occur. However, critically ill patients admitted to the intensive care unit (ICU) are considered immunocompetent. Recent studies suggest that active infection with CMV, HSV, EBV or HHV-6 is also relatively common in ICU patients. Furthermore, an association between the presence of a CMV or HSV infection and increased mortality in critically ill patients was found. At present it is not clear whether this is intrinsically related to the micro-organism itself or merely an indication of the patients deteriorating physical condition leading to viral reactivation. To date the value of ganciclovir and acyclovir prophylaxis and/or treatment is unclear. The clinical relevance of active EBV or HHV-6 infection has not been established yet.

The first influenza pandemic in over 40 years was caused by a novel influenza A strain, A(H1N1)pdm09. Fortunately, most of those infected suffered mild disease. However, a significant minority of young adults and children exhibited severe illness, sometimes resulting in respiratory failure and even death. In the UK, A(H1N1)pdm09 influenza also caused a large disease burden the post-pandemic winter of 2010/11, stretching some healthcare resources to the limit. Although some pre-existing conditions increased the risk of severe disease, pregnant women and those with no underlying health problems contributed substantially to the total number of hospitalisations. Why outcomes of infection vary so widely is unknown and optimal personalised treatment strategies are yet to be developed. In this review, we give an overview of A(H1N1)pdm09 influenza in adults and the evidence supporting pharmacological interventions, with a focus on the use of antiviral agents.

The effective treatment of pneumonia in a critical care setting involves optimal administration of antibiotics. Various micro-organisms are responsible for causing pneumonia. As the pathogen may not always be evident, empiric broad spectrum antibiotic regimens are often used. There are various resources available to guide antibiotic therapy but unfortunately these have not been validated in critically ill patients. Of increasing concern, multidrug resistant bacteria are becoming more prevalent in the critical care units causing a paradigm shift for antibiotic therapy. In the context of a diminishing pipeline of antibiotic development, optimal use of available antibiotics is essential. Alternative modes of administration such as aerosolisation should be considered especially in nosocomial, multidrug resistant organisms. Further to this, de-escalation of antibiotics and antibiotic cycling are some of the strategies that can be utilised to reduce the emergence of multidrug resistant bacteria. Improvement of clinical outcomes for pneumonia in critical care may also be achieved through use of therapeutic drug monitoring and combination therapy. We advocate that the rational development of local antibiograms for critical care units to better guide the empiric antibiotic therapy in these patients.

Ventilator-associated pneumonia (VAP) is a severe, frequent and potentially fatal complication in the intensive care unit (ICU). Treatment failure (TF) in VAP is defined as the lack of improvement in clinical parameters and/or the persistence of the infecting microorganism, and is associated with a poor outcome. The prevalence of TF in VAP ranges from 30% to 62%, and there is general agreement that it is associated with increased mortality. TF may be related to host, bacterial, and therapeutic factors. Studies have focused on different approaches to monitor the evolution of patients with VAP, including the clinical pulmonary infection score (particularly the PaO2/FiO2 ratio), serum markers such as Creactive protein (CRP) and procalcitonin (PRC), or markers of systemic inflammatory response such as cytokines. The inappropriateness of initial antibiotic therapy is one of the main causes of clinical failure, so timely administration of appropriate antimicrobial therapy is essential. Complications of the original pneumonia and the presence of other extrapulmonary sites of infection may also be responsible for a lack of improvement in VAP and should be carefully ruled out. Rational de-escalation strategies, with or without the aid of novel biomarkers to guide the duration of antibiotic therapy, should allow for reduced antibiotic exposure. This may reduce the emergence of antibiotic resistance, related adverse events, and reduce costs without increasing the risk of TF.

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as an important nosocomial pathogen in recent decades, being responsible for an increasing proportion of patients with Hospital-Acquired Pneumonia (HAP) and Ventilator-Associated Pneumonia (VAP). On the other hand, many areas in the world have experienced an alarming emergence of infections and particularly pneumonias caused by the so-called Community-Acquired MRSA (CA-MRSA), a genetically distinct strain, which shares common clinical and microbiological features with nosocomial MRSA. This paper reviews the latest epidemiological and therapeutic data and discusses currently available and future treatment options. A recent significant epidemiological feature is the “creep” observed in vancomycin minimal inhibitory concentrations. As new clinical and PK data are available relating to the use of vancomycin and linezolid, which have both been first-line options in the treatment of MRSA pneumonia in the last decade, recently issued guidelines and arguments for their revision are discussed.