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"...ALI and its more severe form,...ARDS, are devastating disorders of overwhelming pulmonary inflammation leading to hypoxemia and respiratory failure," write Adrienne G. Randolph, MD, MSc, from Perioperative and Pain Medicine, Children's Hospital and Harvard Medical School in Boston, Massachusetts. "There are detailed overviews of the diagnosis, epidemiology, pathogenesis, and treatment of adults with ALI/ARDS. This concise review is designed to focus on children, highlighting differences between children and adults in the epidemiology, diagnosis, prognosis, and evidence-base for management of pediatric ALI/ARDS."

Criteria for ALI and ARDS Diagnosis

Both in adults and in children, ALI and ARDS are most often diagnosed from criteria proposed by the American European Consensus Conference (AECC), with use of 4 clinical parameters. These parameters are (1) acute onset, (2) severe arterial hypoxemia not responding to use of inhaled oxygen alone (PaO₂/FIO₂ ratio ≤ 200 torr [≤ — kPa] for ARDS and PaO₂/FIO₂ ratio ≤ 300 torr [≤ — kPa] for ALI), (3) chest radiography showing bilateral infiltrates suggestive of diffuse pulmonary inflammation, and (4) absence of left atrial hypertension.

Although lung histology criteria for ARDS include evidence of diffuse alveolar damage, lung biopsy is seldom performed in children with ALI and ARDS. Children diagnosed by AECC criteria have prolonged duration of respiratory failure, requiring mechanical ventilation for 10 to 16 days, on average, and overall mortality rates are 10% to 40%.

The goal of this review was to offer clinicians a summary of the pertinent literature concerning pediatric management of ALI/ARDS by searching PubMed for clinical trials and performing a selected literature review of other relevant studies describing the epidemiology and diagnosis of ALI/ARDS.

Adults and children share common risk factors and pathophysiology of ALI/ARDS, with infection, particularly in the lower respiratory tract, being the most common trigger. In children, ALI and ARDS are associated with high morbidity rates, high death rates, and high healthcare costs. Reported population estimates suggest that the annual incidence of ALI in US children is 2500 to 9000, resulting in or contributing to 500 to 2000 deaths.

Clinical trials of ALI/ARDS are difficult to perform in children because of lower mortality rates as well as a relatively lower incidence of ALI/ARDS in this age group. The review author therefore relied, to some extent, on expert opinion.

Recommended Interventions

Expert opinion suggests that the following interventions be recommended:

1. Tidal volumes of more than 10-mL/kg body weight should be avoided.

2. Recommended ventilation parameters are plateau pressure of less than 30 centimeters H₂O, arterial pH of 7.35 to 7.45, and PaO₂ of 60 to 80 torr (— to — kPa; SpO₂ > 90%).

3. Supplementary pharmacotherapy should include sedation, analgesia, and stress ulcer prophylaxis.

4. In patients who are unstable because of shock or profound hypoxia, a 10-g/dL hemoglobin threshold is recommended for packed red blood cell transfusion. Once profound hypoxia and shock have resolved, evidence supports lowering the hemoglobin transfusion threshold to 7 g/dL.

"Untreated infection, necrosis of tissue, pancreatitis, and other persistent triggers of the inflammatory cascade will lead to unrelenting escalation of ARDS," Dr. Randolph writes. "Identification of the ARDS trigger source and achievement of source control are essential to optimize clinical outcomes. Because sepsis is commonly the trigger for ALI, early antibiotic therapy is recommended in those suspected of being infected."

Other Possible Treatments

For children with ALI/ARDS, there are no clear guidelines for beginning endotracheal intubation and ventilator support, except for loss of consciousness and inability to protect the airway. When intubation is needed in children, this should be performed by those with sufficient experience in intubating children, using appropriately sized equipment and endotracheal tubes. Delivery of adequate positive end-expiratory pressure when pulmonary compliance is low may best be achieved with use of cuffed endotracheal tubes.

Based on evidence from pediatric trials, promising treatments of pediatric ALI/ARDS include use of endotracheal surfactant; high-frequency oscillatory ventilation; noninvasive ventilation; and, as a rescue treatment, use of extracorporeal membrane oxygenation therapy.

Evidence from adult studies suggests that use of corticosteroids to treat lung inflammation and fibrosis, use of 4- to 6-mL/kg tidal volumes, and restrictive fluid management may be helpful. However, fluids should only be restricted once children have recovered sufficiently from septic shock.

In adults and children with respiratory failure and ALI/ARDS after hematopoietic stem cell transplant, mortality rate is 75% or more. Interventions for which potential benefits may outweigh the risks include continuous venovenous hemofiltration, bronchoalveolar lavage, etanercept, and/or lung biopsy in selected cases to identify undiagnosed, treatable conditions.

Treatments that should be studied further before recommending their use in children with ALI or ARDS include prone positioning, bronchodilator therapy, inhaled nitric oxide, tight glycemic control, and oxygen delivered by high-flow nasal cannula.

Treatment goals for management of ALI/ARDS in children include reducing mortality and morbidity rates, hastening recovery, and optimizing long-term cognitive and respiratory function.

"It is important to minimize profound hypoxia that leads to cell death and is damaging to the developing brain, and to minimize secondary damage to the injured lung and other organ systems that could prolong recovery," Dr. Randolph concludes. "In contrast to adults, severity of hypoxia at presentation is a fairly strong predictor of mortality in children with ALI/ARDS....Multiple organ failure is also a consistent mortality predictor in children with ALI/ARDS."

Dr. Randolph has consulted for Discovery Laboratories and has also served as a scientific advisory board member for a clinical trial of lucinactant.

"Among a large array of laboratory variables, procalcitonin has emerged as the leading one to indicate systemic infections with high accuracy," senior author Dr. Stefan Schroeder, from West Coast Hospital, Heide, Germany, told Reuters Health.

"There is extensive clinical evidence that procalcitonin allows reliable differentiation between systemic inflammatory response syndrome and bacterial or fungal sepsis and closely correlates with the systemic severity of infections in various diseases and medical disciplines," he added. "Moreover, some recent clinical studies have also shown that procalcitonin is a reliable means to guide antibiotic therapy in community acquired pneumonia and sepsis."

The goal of the present study was to determine if a procalcitonin-based algorithm could be used to guide antibiotic therapy in intensive care patients. Included in the investigation were 110 surgical intensive care patients who were receiving antibiotic therapy for confirmed or suspected high-grade bacterial infections. All of the subjects met at least two standard criteria for a systemic inflammatory response syndrome.

The subjects were randomized to receive antibiotic therapy for 8 consecutive days or as dictated by procalcitonin levels. In the procalcitonin group, if a patient had clinical improvements in signs and symptoms and if the procalcitonin level fell below 1 ng/mL or dropped by 25% to 35% from the initial value over 3 days, then antibiotic therapy could be discontinued.

The duration of antibiotic therapy was reduced by 2 days, on average, in the procalcitonin group compared to controls: 5.9 vs. 7.9 days (p <>

"Beyond a reduction of the length of antibiotic treatment, procalcitonin-guidance also had a favorable effect on the length of the intensive care stay," Dr. Schroeder said. The average length of stay was 15.5 days in the procalcitonin group compared with 17.7 days in the control group (p = 0.046).

The results clearly show that a procalcitonin-guided algorithm is a helpful approach to reduce the length of antibiotic therapy without negatively influencing the outcome of surgical intensive care patients, Dr. Schroeder said.

"Monitoring of procalcitonin is a valuable tool for therapeutic decision-making concerning the length of antibiotic treatment," he added. "However, adequate interpretation of procalcitonin concentrations always requires the background of clinical course and symptoms. This concept contributes to less extensive antibiotic treatment with positive effects on economical factors and the development of drug-resistances in intensive care medicine."

Regarding future research, Dr. Schroeder said that "our procalcitonin-based algorithm is certainly practicable and simple. However, procalcitonin cut-off points for antibiotic termination have not uniquely defined. Thus, procalcitonin-controlled antibiotic therapy must still be tested in heterogenous groups of patients, particularly the safety."

Crit Care. 2009;13:R83.

Clinical Context

Study Highlights

• Participants for study enrollment were all admitted to 1 surgical intensive care unit in Germany. All participants required antibiotic therapy based on confirmed or highly suspected bacterial infection along with at least 2 criteria for systemic inflammatory response syndrome.
• Participants were randomly assigned in the open-treatment study to receive either 8 days of antibiotics or a varying course of antibiotics based on procalcitonin levels. Antibiotics were discontinued among subjects in the procalcitonin-guided therapy group when the procalcitonin level decreased to less than 1, or when this value decreased by 25% to 35% of the initial value during 3 days.
• The type of antibiotic chosen was left to the discretion of the treating physician.
• The main outcomes of the study were the duration of antibiotic use, the duration of stay in the intensive care unit, and participants' clinical outcomes of hospitalization.
• 57 patients were assigned to the procalcitonin-guided therapy group, and 53 comprised the control group. The mean age of participants was 67 years old, and peritonitis and pneumonia accounted for the vast majority of admissions. The severity of illness between groups at baseline was similar.
• The most popular antibiotic choices for all patients were acylaminopenicillin plus a beta-lactamase inhibitor or nitroimidazole.
• Procalcitonin-guided therapy was associated with a significantly shorter duration of antibiotic treatment vs standard therapy (5.9 days vs 7.9 days, respectively).
• Procalcitonin-guided therapy was also associated with a shorter stay in the intensive care unit vs standard therapy (15.5 days vs 17.7 days, respectively).
• Disease severity scores remained similar between groups during the study, as did leukocyte counts and C-reactive protein concentrations.
• 14 participants in the control group died during hospitalization vs 15 subjects in the procalcitonin-guided therapy group. This difference between groups was not significant.

Clinical Implications

• Sepsis can be difficult to diagnose among critically ill patients, as common signs of sepsis are nonspecific in the setting of severe illness, and traditional laboratory tests may lag behind progression of infection.
• In the current study, antibiotic treatment guided by procalcitonin levels reduced the durations of antibiotic therapy and intensive care unit stay among critically ill surgical patients. Procalcitonin-guided therapy did not harm clinical outcomes vs standard therapy.

Abstract

The authors summarize the current applications of chest ultrasonography in the diagnosis and management of various pleural diseases. Ultrasound has been proved to be valuable for the evaluation of a wide variety of chest diseases, particularly when the pleural cavity is involved. Chest ultrasound can supplement other imaging modalities of the chest and guides a variety of diagnostic and therapeutic procedures. Pleural effusion, pleural thickening, pleural tumors, tumor extension into the pleura and even the chest wall, pleuritis, and pneumothorax can be detected easily and accurately with chest ultrasound. Many ultrasound features and signs of these diseases have been well characterized and widely applied in clinical practice. Under real-time ultrasound guidance the success rates of invasive procedures on pleural diseases increase significantly whereas the risks are greatly reduced. The advantages of low-cost, bedside availability and no radiation exposure have made ultrasound an indispensable diagnostic tool in modern pulmonary medicine.

Introduction

Advances in technology have greatly improved the imaging capabilities of ultrasound (US). US has been proved to be a reliable, efficient, and informative imaging modality for the evaluation of a wide variety of chest diseases^{[1**, 2-4, 5**]} and is particularly sensitive in imaging the chest wall, pleura, and pleural space because of their superficial locations.^{[6,7,8**,9,10]} Major advantages of US include the absence of radiation, low cost, flexibility and beside availability, and short examination time compared with computed tomography.

Invasive procedures such as aspiration, needle biopsy of the pleura, and closed tube placement for effusion drainage can be performed with more accuracy and safety under US guidance. US is notably helpful for critically ill patients because of its portability and simplicity.^[11] The indications and uses of chest US examination for pleural diseases are summarized as follows:

1. To clarify the nature of unknown pleural densities
2. To detect pleural effusion and guide thoracentesis and drainage, especially in minimal or loculated effusions
3. To differentiate subpulmonary effusion from subphrenic fluid accumulation and diaphragm paralysis in radiographically elevated hemidiaphragms
4. To localize pleural tumors or pleural thickening and guide needle biopsy of the pleura
5. To assist the evaluation of patients with pleuritic chest pain
6. To assess the invasion of tumors to the pleura and chest wall, and guide the transthoracic needle biopsy of the tumors
7. To recognize pneumothorax, especially for emergency situations, or when roentgenography equipment is not readily available

Techniques for Chest Ultrasound Examination and Normal Ultrasound Images of the Chest

The US equipment suitable for chest US imaging are those equipped with 3.5-, 5-, 7.5-, or 10-MHz linear, convex, and sector transducers. During chest US examination, patients can be scanned in a sitting or supine position. Bedridden patients can be examined by turning them to oblique or decubitus positions. The probe is moved in transverse or longitudinal positions along the intercostal spaces to avoid interference by bony ribs. Normal areas are also scanned for control comparisons. A higher frequency (5- or 7.5-MHz) transducer provides better resolutions of near structures, such as the chest wall and pleura. Otherwise, a 3.5-MHz transducer is more suitable for visualization of deeper lesions. A linear or convex transducer usually has a broad view of the field and is better than a sector scanner for screening. For lesions with a small US window or a very narrow intercostal space, however, a sector transducer is generally preferred.

Ultrasound images of the chest wall usually show soft-tissue echogenicity with multiple layers of muscle and fascia. When the transducer is oriented perpendicular to the intercostal space, normal ribs may appear as curvilinear echogenic interfaces with prominent acoustic shadow. Just beneath the chest wall, the parietal pleura lining the bony thorax and the visceral pleura covering the lungs are seen as two thin, bright echogenic lines. Normally, the two pleural lines are smooth and less than 2 mm in thickness. Between the parietal and visceral pleural lines is the pleural space, which usually measures only 0.3 to 0.4 mm. The two pleural lines normally glide with each other during respiratory movements in real-time US. This is termed the gliding sign of the pleura (Fig. 1). The gliding sign of the pleura comes from the movement of the pleura during lung excursion.

The underlying air-filled lung is a highly reflective interface that may block transmission of US into the lung parenchyma, so US images of the lung parenchyma display a pattern of repeated bright echoes caused by an acoustic reverberation artifact. These echoes are bright but formless, and diminish rapidly in intensity with increasing distance from the transducer. It is not always possible to visualize the two pleural lines and the pleural space between them. Instead, a highly echogenic line representing the pleura and pleuropulmonary surface is seen occasionally with reverberation echo artifacts beneath it. Back-and-forth movements of the echogenic pleural line during respiration (gliding sign) can still be observed in real-time US.

Both of the hemidiaphragms can be visualized just above the liver and spleen, and the respiratory movements of both hemidiaphragms can be observed in real-time US. During inspiration, the reverberation echoes of the lower lung descend progressively with lung excursion and appear like a curtain. The liver and fasted gallbladder can be used as tissue texture references for solid and fluid-containing regions. Hence, the echogenicity of a lesion is compared with that of the liver and is defined as hypoechoic, isoechoic, and hyperechoic accordingly.

Pleural Effusion

The value of US for diagnosis of pleural effusion is well documented. Even small amounts of pleural effusion can be detected accurately with US examination. The US image of pleural effusion is characterized by an echo-free space between the visceral and parietal pleura. This space may change in shape with respiration (Fig. 2A).^{[12*, 13]} The effusion can be free or encapsulated. The compressive atelectasis of the lungs in a large effusion can be seen as a tonguelike structure within the effusion. US is helpful in determining the nature of pleural opacity, identifying minimal or loculated effusion, and discriminating between subpulmonary and subphrenic effusions. If an abnormal elevation of a hemidiaphragm is noted on the chest radiograph, subpulmonary effusion can be differentiated from subphrenic fluid collection and diaphragm paralysis by defining the position of the diaphragm and by the real-time visualization of diaphragmatic motion.^[14] In the presence of hemithorax opacification on chest radiograph, US is also helpful in distinguishing between fluid-filled and solid lesions^[15].

Determining the Nature of Pleural Effusion by Ultrasound

Although the classification of transudate or exudate is not absolute, the distinction is helpful in suggesting further evaluation and possible diagnosis. The sonographic characteristics of effusion are helpful in differentiating transudates from exudates.^{[12*, 13]} According to the internal echogenicity, effusion can be subclassified as anechoic, complex nonseptated, complex septated, and homogenously echogenic. The effusion is defined as anechoic if totally echo-free spaces are present between the visceral and parietal pleura, complex nonseptated if echogenic materials are inside the anechoic effusions, complex septated if floating fibrin strands or septa are inside the effusions, and homogenously echogenic if homogenously echogenic spaces are present between the visceral and parietal pleura (Fig. 2B-E). In a study of 320 patients,^[12*] we found that transudates are anechoic, whereas an anechoic effusion can be either a transudate or an exudate. On the other hand, pleural effusion with complex nonseptated, complex septated, and homogenously echogenic patterns are always exudates. Homogenously echogenic effusions are typically seen in hemorrhagic effusion and empyema. These echogenic natures are probably the result of the presence of tissue debris, protein-rich particles, fibrins, or blood in the pleural fluid.

Other associated sonographic findings sometimes may also help to assess the nature of pleural effusion. For example, effusion with adjacent, thickened pleura is usually indicative of an exudate. The presence of a pulmonary consolidation, which is a parenchymal wedge-shaped hypoechoic lesion with air bronchograms, suggests an exudate of infectious origin (Fig. 2F).^[16] Pleural nodules may be seen in patients with malignant pleural effusion.(Fig. 2G)^{[17, 18]} It has also been reported that sonographic septation is a useful sign to predict the need for subsequent intrapleural fibrinolytic therapy and surgical intervention in cases of acute thoracic empyema.^[19]

Estimating the Volume of Pleural Effusion by Ultrasound

Several studies have been performed to measure the volume of pleural effusion by means of US.^{[20, 21]} We arbitrarily classify the volume of effusion as minimal if the echo-free space is seen within the costophrenic angle; small, if the space is greater than the costophrenic angle but still within a one-probe range; moderate, if the space is greater than a one-probe range but within a two-probe range; and large or massive, if the space is bigger than a two-probe range.

Differentiation of Minimal Effusion from Pleural Thickening

Although US is very powerful in the evaluation of pleural effusion, differentiating minimal pleural effusion from pleural thickening may sometimes be difficult. Both lesions can appear as anechoic on grayscale US, and thus "free of echoes" is not a reliable sign for fluid. It has been reported that nearly 20% of echo-free pleural lesions do not yield free fluid, whereas a significant percentage of complex-appearing lesions do.^[22] Therefore, predicting whether an echo-free or complex-appearing lesion is amenable to thoracentesis is not always possible with grayscale US.

Marks et al. ^[23] found that if a lesion changed shape with respiratory excursion and if it contained movable strands or echo densities, the lesion contained fluid and could be aspirated. These could be the best criteria to distinguish effusion from solid pleural lesions with grayscale US. However, these criteria still have limitations for detecting loculated and minimal fluid collection. Some pleural lesions do not change shape with respiration or have movable septa or echo densities, but are still amenable to aspiration.

It has been observed that true fluid in cases of loculated or minimal effusion may generate a color flow pattern during respiratory or cardiac cycles, and thus may display a turbulent color signal on color Doppler imaging.^{[24, 25*]} This is termed the fluid color sign of pleural effusion. Relatively high sensitivity (89.2%) and specificity (100%) of the fluid color sign in detecting minimal fluid collection have been shown in a study comprising 76 patients.^[25*] In brief, an echo-free space between the visceral and parietal pleura that changes shape with respiration or contains movable strands or echo densities on grayscale US, or displays a fluid color sign on color Doppler US, indicates the presence of fluid accumulation and is amenable to thoracentesis.

Pleural Thickenings And Pleural Tumors

Besides pleural effusion, many abnormal findings of the visceral and parietal pleura can be seen in the US images. Pleural thickenings are defined as focal echogenic lesions arising from the visceral or parietal pleura that are greater than 3 mm in width with or without irregular margins. Pleural thickening and adhesion are usually caused by putrid pleuritis, empyema, hemothorax, or iatrogenic pleurodesis. There are various echogenicities of thickened pleura. For instance, in putrid pleuritis resulting in pleural thickening, increasing echogenicity and septation of the pleural lesion may be seen with time as the pleural effusion becomes organized and solid, sometimes resulting in highly echogenic shadows indicative of calcification. It is important to differentiate minimal or loculated pleural effusion from pleural thickening before thoracentesis because both conditions may have similar US pictures.^[22] The US features useful to distinguish between minimal pleural effusion and pleural thickening have been described previously.^[23-25*]

In US, pleural tumors are well-defined, hypoechoic or echogenic solid nodular lesions located in the parietal or visceral pleura. Primary neoplasms of the pleura are rare except for benign and malignant mesothelioma. Metastatic pleural tumors or mesothelioma can appear as polypoid pleural nodules or sheetlike pleural thickening combined with pleural effusion (Fig. 3).^{[17, 18, 26]} Sometimes, differentiation between pleural fibrosis and pleural tumor is difficult by US. A US-guided core needle biopsy is very helpful for pathologic diagnosis of pleural tumors.^{[26, 27]}

Assessment of Pleural and Chest Wall Invasion by Lung Tumor A soft-tissue lesion extending to the surrounding pleura and chest wall is usually characteristic of malignancy. Rarely, inflammatory diseases such as actinomycosis and nocardiosis may spread in this manner (Fig. 4A and B). Evaluation of the extent of tumor invasion to the pleura and chest wall is important and may subsequently influence diagnosis and treatment. CT is usually recommended for determining the extent of pleural and chest wall extension in patients with lung cancer.[9, 10, 28] However, high-resolution, real-time US, particularly equipment with higher frequency (7.5-10-MHz) scanning probes, have also been found to be valuable in evaluating tumor invasion of the pleura and chest wall.[29*, 30] (Enlarge Image) Figure 4. Extension of inflammatory diseases (A, B) or tumors (C, D) to the pleura (A) Ultrasound (US) shows a chest wall abscess in a patient with liver cirrhosis as an ill-defined lesion with soft-tissue echogenicity that extends to the pleura. Puslike material was obtained with transthoracic aspiration under US guidance, which yielded Aeromonas hydrophila. (B) US shows an irregular and hypoechoic parenchymal lesion with involvement of the pleural cavity. Nocardiosis was proved microbiologically after transthoracic biopsy of the lesion under US guidance. (C) US shows a parenchymal tumor with posterior echo enhancement (PEE). Note that both of the visceral and parietal pleural lines are intact, fulfilling the criteria of ultrasound pattern 1 of Sugama et al..[29*] The respiratory movement of the tumor should be preserved in real-time US. (D) US shows a peripheral mass that extends beyond the pleura. The visceral pleural line is cut off, and the respiratory movement of the tumor is disturbed in real-time US. Invasion of the pleural cavity by the tumor is evident. A, abscess; P, pleura; L, lung; T, tumor; Pv, visceral pleural; Pp, parietal pleura. [ CLOSE WINDOW ] Figure 4. Extension of inflammatory diseases (A, B) or tumors (C, D) to the pleura (A) Ultrasound (US) shows a chest wall abscess in a patient with liver cirrhosis as an ill-defined lesion with soft-tissue echogenicity that extends to the pleura. Puslike material was obtained with transthoracic aspiration under US guidance, which yielded Aeromonas hydrophila. (B) US shows an irregular and hypoechoic parenchymal lesion with involvement of the pleural cavity. Nocardiosis was proved microbiologically after transthoracic biopsy of the lesion under US guidance. (C) US shows a parenchymal tumor with posterior echo enhancement (PEE). Note that both of the visceral and parietal pleural lines are intact, fulfilling the criteria of ultrasound pattern 1 of Sugama et al..[29*] The respiratory movement of the tumor should be preserved in real-time US. (D) US shows a peripheral mass that extends beyond the pleura. The visceral pleural line is cut off, and the respiratory movement of the tumor is disturbed in real-time US. Invasion of the pleural cavity by the tumor is evident. A, abscess; P, pleura; L, lung; T, tumor; Pv, visceral pleural; Pp, parietal pleura. Sugama et al. [29*] have defined the US criteria for the extent of tumor invasion. Ultrasound pattern (UP) 1 indicates that the tumor is in contact with the visceral pleura whereas UP2 means the tumor has extended beyond the visceral pleura and is in contact with the parietal pleura. Lastly, UP3 means that the tumor has extended to the chest wall through the visceral and parietal pleura. The visceral pleural lines are intact in UP1, but are invaded or interrupted in UP2 and UP3. Direct visualization of chest wall extension by the tumor is designed as UP3. The movement of the tumor with respiration is unaltered in UP1, disturbed in UP2, and vanished in UP3. Both UP2 and UP3 imply invasion of the tumor beyond the pleura. High-resolution, real-time US has the advantage of clearer discrimination of the various soft-tissue layers within the chest wall. When a tumor abutted to the chest wall is visualized with US, various layers of the chest wall, including the parietal and visceral pleura, pleural space, and muscle and fascia, can also be examined and the extent of tumor invasion can be determined (Fig. 4C and D). Disruption of the pleura, extension through the chest wall, and fixation of the tumor during breathing are indicators of pleural and chest wall involvement.[30] The accuracy of US in determining tumor invasion of the pleura and chest wall is better than chest CT. Transthoracic needle aspiration and biopsy of the tumor can be performed for pathologic diagnosis under real-time US guidance[1**, 2, 3, 31]. Pleuritic Chest Pain and Pleuritis Pleuritis is usually diagnosed clinically with the presentation of sharp chest pain magnified by breathing. Pleural effusion and consolidations may be suggestive findings on the chest radiographs. However, the chest radiographs may be normal because the inflamed pleura and small amounts of pleural effusion are not visible on chest radiographs. Gehmacher et al. [32] reported that abnormal US findings could be observed in 91% of the total 47 patients with clinical diagnosis of pleuritis and normal chest radiographs. The abnormal US features included interrupted pleural line in 42 (89%), irregularly formed and less demarcated subpleural hypoechoic consolidations in 30 (64%), localized pleural effusion in 35 (74%), and increased blood flow in 11 (23%) by color Doppler (Fig. 5A). Of course, the more apparent changes that can be found on chest radiographs may also be seen on US. (Enlarge Image) Figure 5. Ultrasound findings in patients with pleuritic chest pain and partial pneumothorax (A) Ultrasound (US) findings in a patient with pleuritic chest pain. The grayscale US reveals irregularity and interruption of the pleura. (B, C) Sonographic features in a patient with partial pneumothorax. Real-time US of the healthy side of the chest (B) shows normal gliding of the visceral and parietal pleura with respiration. On the other side with partial pneumothorax (C), the gliding sign of the pleura is absent in real-time US. Markedly enhanced comet-tail reverberation artifacts are seen compared with the US image of the healthy side. P, pleura; L, lung; Pv, visceral pleura; Pp, parietal pleura. Pneumothorax and Hydropneumothorax The majority of pneumothoraces are diagnosed by chest radiographs or CT, although US also may be helpful. Because of its simplicity and portability, US could be especially useful for emergency or clinical situations in which no roentgenographic equipment is readily available. In pneumothorax, loss of the gliding sign of pleura with respiration can be verified.[33] The reverberation comet-tail artifacts may be enhanced markedly in small pneumothorax (Fig. 5B and C), but the artifacts are occasionally absent in extensive pneumothorax.[7] US could be an accurate tool for diagnosis of clinically suspected pneumothorax. Targhetta et al. [33] reported the successful detection of the absence of gliding sign in 24 patients with radiographically confirmed pneumothorax. Although the extent of lung collapse and breadth of the pneumothorax could not be evaluated, it was possible to determine the areas of partial pneumothorax. The gliding sign of the pleura in real-time US comes from the movement of the pleura during respiratory excursion. Diaphragmatic paralysis or pleural adhesion may result in impaired lung excursion and, consequently, the absence of gliding sign may be misinterpreted as pneumothorax. However, paralysis of the diaphragm can be diagnosed easily by the disappearance of diaphragmatic kinetics in real-time US, whereas pleural thickening can be identified directly in patients with pleural adhesion. It would be better to compare the US findings suggestive of pneumothorax with those of the healthy side of the chest. In patients with hydropneumothorax, US can recognize the pneumothorax more easily by identifying the air-fluid boundary[34], which can move with respiration. The gliding sign above the air-fluid level is absent. Ultrasound-Guided Invasive Interventions Besides the imaging of various pleural diseases, another important use of chest US in pleural disease is that US can guide many invasive or interventional procedures, including diagnostic thoracentesis, closed tube drainage for pleural effusion, and needle biopsy of the pleura.[1**1, 2, 3, 35, 36] US guidance increases the success rates while decreasing the complications of these procedures. Compared with other imaging modalities, the advantage of the US-guided procedures is that the convenience and portability of US can easily provide complementary help for these procedures. Moreover, the lesions can be accurately visualized, located, and marked with US before the procedure is done, especially when the lesion is small. The lesion can even be monitored with dynamic images of real-time US during these procedures. The main contraindication to these procedures is hemorrhagic diathesis. Mild coagulation abnormalities, however, are acceptable for simple thoracentesis. Other contraindications include uncooperative patients who are unable to control breathing or cough on demand, especially when the lesion is small. The site of aspiration or biopsy should exclude the presence of local cutaneous lesions such as pyoderma or herpes zoster infection. Although the risk of complications decreases with US guidance, these procedures should still be performed with caution in patients with borderline respiratory failure. Thoracentesis and Closed Tube Drainage for Effusion For pleural effusion of unknown etiology, it is usually necessary to obtain the fluid for biochemical, cytologic, or microbiologic examinations. US is superior to chest radiographs in identifying the fluid and choosing the optimal site for diagnostic thoracentesis. The largest and most accessible area of fluid accumulation can be identified, and the depth for the needle to penetrate can be measured by chest US. With real-time US, direct visualization of the effusion during thoracentesis is applicable. All these US-guided measures help to improve the success rate of thoracentesis and avoid complications, such as pneumothorax. It is especially helpful when the effusion is minimal or loculated, when tedious radiographic study is not possible, or when safe thoracentesis is mandatory in a critically ill patient. The success rate of US-guided thoracentesis can be as high as 97%.[3] By differentiating minimal or loculated effusion from pleural thickening using the US criteria described earlier, US helps to predict the presence of fluid in an echo-free space and to decide whether it is amenable for thoracentesis.[23-25*] There are several clinical situations in which closed tube drainage for effusion is needed. These include huge effusion compromising the respiratory condition, complicated parapneumonic effusion and empyema, hemothorax, and malignant effusion preparing for pleurodesis. Complications related to these drainage procedures, such as laceration of the lung, diaphragm, liver, and spleen, could be disastrous. Malposition of the tube can result in failure of the drainage, particularly in loculated effusion. As with diagnostic thoracentesis, it is clear that US can decrease the risk of malposition and various complications by identifying the suitable site for the procedures. In cases of acute thoracic empyema, sonographic septation of the effusion is a useful sign to predict the need for subsequent intrapleural fibrinolytic therapy or for surgical intervention in addition to drainage.[19] Needle Biopsy of the Pleura Conventional closed pleural biopsy with the Cope or Abram needle must be performed in the presence of pleural effusion or pneumothorax. Chest US has some advantages in guiding pleural biopsy of focal pleural lesions. Hence, one advantage of US-guided pleural biopsy is in cases when the pleural involvement of various diseases may be focal. Because focal pleural thickening or pleural tumors can be identified clearly with US, the pleural biopsy can aim at the focal area with sonographic abnormalities. The chances of obtaining pleural tissues with significant pathologic findings will thus increase. Another advantage is that, with real-time US, the advance of the needle can be monitored, and overpenetration of the needle to the underlying lung parenchyma can be prevented. This is particularly true for patients with minimal pleural effusion or even without pleural effusion.[27] Conclusion Chest US is well documented as a valuable tool for pleural diseases. US helps to clarify the cause of pleural opacities, estimate the volume of pleural effusion, identify minimal or loculated pleural effusion, and differentiate between minimal pleural effusion and pleural thickening. US characteristics of effusion provide helpful information regarding the nature of the effusion. Variable pleural diseases, such as pleuritis, pleural fibrosis, pleural tumors, and pneumothorax, display different diagnostic US features. The extension of tumors to the pleura and chest wall can be assessed with US. Safe thoracentesis and drainage of effusion can be carried out under US guidance with a high success rate. Needle biopsy of the pleura can pinpoint the area with significant US abnormalities, thus increasing the diagnostic yield. With continuous monitoring of real-time US, overpenetration of the biopsy needle to the lung parenchyma can be avoided in patients with minimal effusion. References Yang PC: Ultrasound-guided transthoracic biopsy of the chest. Radiol Clin North Am 2000, 38:323-343. ** This review provides a detailed description of current applications of US as a diagnostic tool and the state-of-the-art use of US-guided interventional procedures in chest diseases. The indications and advantages, imaging techniques, diagnostic spectrum, biopsy procedures, and potential complications and contraindications are included. Yang PC: Ultrasound-guided transthoracic biopsy of peripheral lung, pleural, and chest wall lesions. J Thorac Imaging 1997, 12:272-284. Yang PC, Kuo SH, Luh KT: Ultrasonography and ultrasound-guided needle biopsy of chest diseases: indications, techniques, diagnostic yields and complications. J Med Ultrasound 1993, 1:53-63. Yang PC: Application of colour Doppler ultrasound in the diagnosis of chest diseases. Respirology 1997, 2:231-238. Beckh S, Bolcskei PL, Lessnau KD: Real-time chest ultrasonography: a comprehensive review for the pulmonologist. Chest 2002, 122:1759-1773. ** This article is also a comprehensive review of the clinical applications of real-time US in pulmonary and critical care medicine. Yang PC, Sheu JC, Luh KT: Clinical application of real-time ultrasonography in pleural and subpleural lesion. J Formos Med Assoc 1984, 83:646-657. Wernecke K: Ultrasound study of the pleura. Eur Radiol 2000, 10:1515-1523. Mathis G: Thoraxsonography-part I: chest wall and pleura. Ultrasound Med Biol 1997, 23:1131-1139. ** An overview of ultrasonographic examination in the chest wall and various pleural diseases. Muller NL: Imaging of the pleura. Radiology 1993, 186:297-309. McLoud TC, Flower CD: Imaging the pleura: sonography, CT, and MR imaging. AJR Am J Roentgenol 1991, 156:1145-1153. Yu CJ, Yang PC, Chang DB, et al.: Diagnostic and therapeutic use of chest sonography: value in critically ill patients. AJR Am J Roentgenol 1992, 159:695-701. Yang PC, Luh KT, Chang DB, et al.: Value of sonography in determining the nature of pleural effusion: analysis of 320 cases. AJR Am J Roentgenol 1992, 159:29-33. * This article presents the associations between the nature of pleural effusions and their US characteristics. US was proved to be informative in predicting the nature of pleural effusions in this study comprising 320 cases. Hirsch JH, Rogers JV, Mack LA: Real-time sonography of pleural opacities. AJR Am J Roentgenol 1981, 136:297-301. Ko JC, Yang PC, Chang DB, et al.: Ultrasonographic evaluation of peridiaphragmatic lesions: a prospective study. J Med Ultrasound 1994, 2:84-92. Yu CJ, Yang PC, Wu HD, et al.: Ultrasound study in unilateral hemithorax opacification. Image comparison with computed tomography. Am Rev Respir Dis 1993, 147:430-434. Yang PC, Luh KT, Chang DB, et al.: Ultrasonographic evaluation of pulmonary consolidation. Am Rev Respir Dis 1992, 146:757-762. Gorg C, Restrepo I, Schwerk WB: Sonography of malignant pleural effusion. Eur Radiol 1997, 7:1195-1198. Gorg C, Gorg K, Schwerk WB, et al.: Sonography of the diaphragmatic pleura in tumor patients. Ultraschall Med 1988, 9:274-278. Chen KY, Liaw YS, Wang HC, et al.: Sonographic septation: a useful prognostic indicator of acute thoracic empyema. J Ultrasound Med 2000, 19:837-843. Eibenberger KL, Dock WI, Ammann ME, et al.: Quantification of pleural effusions: sonography versus radiography. Radiology 1994, 191:681-684. Lorenz J, Borner N, Nikolaus HP: Sonographic volumetry of pleural effusions. Ultraschall Med 1988, 9:212-215. Laing FC, Filly RA: Problems in the application of ultrasonography for the evaluation of pleural opacities. Radiology 1978, 126:211-214. Marks WM, Filly RA, Callen PW: Real-time evaluation of pleural lesions: new observations regarding the probability of obtaining free fluid. Radiology 1982, 142:163-164. Wu RG, Yuan A, Liaw YS, et al.: Image comparison of real-time gray-scale ultrasound and color Doppler ultrasound for use in diagnosis of minimal pleural effusion. Am J Respir Crit Care Med 1994, 150:510-514. Wu RG, Yang PC, Kuo SH, et al.: Fluid color sign: a useful indicator for discrimination between pleural thickening and pleural effusion. J Ultrasound Med 1995, 14:767-769. This article shows that "fluid color" sign on color Doppler US is a useful diagnostic aid to grayscale US in detecting the presence of pleural fluid with relatively high sensitivity and specificity. Helio A, Stenwig AE, Solheim OP: Malignant pleural mesothelioma: US-guided histologic core-needle biopsy. Radiology 1999, 211:657-659. Chang DB, Yang PC, Luh KT, et al.: Ultrasound-guided pleural biopsy with Tru-Cut needle. Chest 1991, 100:1328-1333. Glazer HS, Duncan-Meyer J, Aronberg DJ, et al.: Pleural and chest wall invasion in bronchogenic carcinoma: CT evaluation. Radiology 1985, 157:191-194. Sugama Y, Tamaki S, Kitamura S, et al.: Ultrasonographic evaluation of pleural and chest wall invasion of lung cancer. Chest 1988, 93:275-279. * This article presents the role of US in evaluating tumor extension to the pleura and chest wall. The authors describe different UPs and features that indicate invasion of tumors into the pleural cavity and chest wall. Suzuki N, Saitoh T, Kitamura S: Tumor invasion of the chest wall in lung cancer: diagnosis with US. Radiology 1993, 187:39-42. Yang PC, Chang DB, Yu CJ, et al.: Ultrasound-guided core biopsy of thoracic tumors. Am Rev Respir Dis 1992, 146:763-767. Gehmacher O, Kopf A, Scheier M, et al.: Can pleurisy be detected with ultrasound? Ultraschall Med 1997, 18:214-219. Targhetta R, Bourgeois JM, Chavagneux R, et al.: Ultrasonic signs of pneumothorax: preliminary work. J Clin Ultrasound 1993, 21:245-250. Targhetta R, Bourgeois JM, Chavagneux R, et al.: Ultrasonographic approach to diagnosing hydropneumothorax. Chest 1992, 101:931-934. O'Moore PV, Mueller PR, Simeone JF, et al.: Sonographic guidance in diagnostic and therapeutic interventions in the pleural space. AJR Am J Roentgenol 1987, 149:1-5. Patel MC, Flower CD: Radiology in the management of pleural disease. Eur Radiol 1997, 7:1454-1462. Source : http://www.medscape.com/viewarticle/460444

Introduction

Noninvasive ventilation (NIV) can be defined as a ventilation modality that supports breathing without the need for intubation or surgical airway. Noninvasive ventilation is a popular method of adult respiratory management in both the emergency department and the intensive care unit (ICU), and it has gained increasing support in the care of pediatric patients. Besides avoiding the adverse effects of invasive ventilation, noninvasive ventilation has the added advantage of patient comfort. Noninvasive ventilation delivers mechanically assisted breaths without the placement of an artificial airway and has become an important mechanism of ventilator support both inside and outside the ICU.^1,2

Noninvasive ventilation is further subdivided into negative pressure ventilation (NPV) and noninvasive positive pressure ventilation (NIPPV); the latter includes continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP). This article addresses all of these methods and briefly discusses heliox therapy.

Indications

Neonates and infants

• Weaning from ventilator
• Preventing collapse of the lung
• Minimal need for respiratory support, with good respiratory drive
• Bronchiolitis

Pediatric

• Impending respiratory muscle fatigue
• Asthma
• Bronchiolitis
• Pneumonia
• Obstructive sleep apnea syndrome
• Chronic conditions (eg, Duchenne muscular dystrophy, other myopathies)
• Cystic fibrosis³

Adults

• Obstructive sleep apnea syndrome
• Chronic obstructive pulmonary disease with exacerbation
• Bilateral pneumonia
• Acute congestive heart failure with pulmonary edema
• Neuromuscular disorders
• Acute lung injury

Contraindications

Absolute contraindications

• Respiratory arrest or unstable cardiorespiratory status
• Uncooperative patients
• Inability to protect airway (impaired swallowing and cough)
• Trauma or burns involving the face
• Facial, esophageal, or gastric surgery
• Apnea (poor respiratory drive)
• Reduced consciousness
• Air leak syndrome

Relative contraindications

• Extreme anxiety
• Morbid obesity
• Copious secretions
• Need for continuous or nearly continuous ventilatory assistance
• Lack of respiratory drive
• Diseases with air trapping, such as asthma (In a child on continuous positive airway pressure (CPAP) therapy, periodic monitoring is required. If the clinical condition and arterial blood gases deteriorate despite CPAP support, intubation should be considered.)

Anesthesia

• Mild sedation and analgesia may be required to keep the patient comfortable.
• Anxiolytics may be helpful for patients experiencing claustrophobia due to the facial mask or for patients with increased respiratory rates secondary to anxiety.
• However, extreme caution must be exercised when using sedative agents in the setting of respiratory difficulty, as it may depress respiratory drive and lead to hypercarbia or respiratory failure, thereby requiring intubation. The respiratory effort of the patient must be maintained.
• Patients generally are cooperative and do well with explanation of the application procedure.

Equipment

• Available drivers/ventilators
  • Ventilators
    
    

    

    Bilevel positive airway pressure (BiPAP) vision ventilator.

    

    NIPPY ventilator (B&D Electromedical, Warwickshire, UK).

    
    
  • Negative pressure ventilator
• Interface appliances
  • Nasal/nasopharyngeal prongs
    
    

    

    Nasal and nasopharyngeal prongs for continuous positive airway pressure (CPAP).

    

    Nasal prongs.

    
    
  • Nasopharyngeal tube for continuous positive airway pressure (CPAP)
    
    

    

    Continuous positive airway pressure (CPAP) tubing.

    
    
  • Nasal mask
  • Face mask
  • Head mask
    
    

    

    Head mask as interface.

  • Cuirass
    
    

    

    Cuirass.

Positioning

Noninvasive Positive Pressure Ventilation (NIPPV) Setup

• Seat the patient in a bed or chair in a 30-90 º upright position.
• Position the mask so that the nasal portion of the mask fits just above the junction of the nasal bone and cartilage.
• A strap is needed to maintain correct position of most interfaces and is important for patient comfort. Simple disposable Velcro straps are most often used. Fasten the straps so that 1-2 fingers can pass between the headgear and the face. Take note that erosion of nasal bridge and nasal cartilage can occur with long-term use.

• Nasal prongs should fill the nasal openings completely without stretching the skin or putting undue pressure on the nares. The corrugated tubing should not be touching the patient’s skin.
• Make sure no lateral pressure is exerted on the septum; such pressure could pinch or twist the septum.

• Humidifier: Use a disposable humidifier top with a 1-L bag of water attached. Adequate humidity prevents drying of secretions.
• Oxygen flow: A gas flow of 6-10 L/min is delivered via a blender. This amount of gas flow provides adequate pressure to wash out carbon dioxide in the system, compensate for normal air leakage from tubing connections, and generate adequate pressure.
• Occlude the pressure line connection port with the white plug provided. This completes the NIPPV circuit.
• For continuous positive airway pressure (CPAP), set the default pressure at 4-6 cm H₂ O. Pressures of 10 cm H₂ O or greater may be used on an individual basis, depending on the patient's pathophysiology. Remember to check the water level and adjust for evaporation, as required.
• For bilevel positive airway pressure (BiPAP), common settings are inspiratory positive airway pressures (IPAP) of about 15 cm H₂ O and expiratory positive airway pressures (EPAP) of about 5 cm H₂ O. See the BiPAP section below for more details.
• Suction the airway, if needed, prior to application of facemask.

Technique

Noninvasive Positive Pressure Ventilation

• Ventilator mode
  • A continuous positive airway pressure (CPAP) ventilator delivers air at a constant pressure during inspiration and expiration.
  • The patient must be able to breathe spontaneously.
• Use
  • CPAP is mainly used for hypoxemic respiratory failure, such as in acute pulmonary edema. It prevents alveolar collapse and facilitates oxygen delivery to pulmonary capillaries. CPAP increases the functional residual capacity (FRC) and opens collapsed alveoli, which, in turn, enhances gas exchange and oxygenation.
  • CPAP reduces left ventricular transmural pressure, therefore increasing cardiac output. Hence, it is very effective for treatment of acute pulmonary edema and is considered the modality of first choice in these patients. Pressures usually are limited to 5-15 cm of H₂ O. Each patient’s requirements must be reviewed in light of his or her disease process and disease pathophysiology. Caution is advised in patients with borderline low blood pressure; they may become hemodynamically unstable, as one of the disadvantages of CPAP is reduced venous return.
  • In the ED and ICU, CPAP is generally administered using a facemask, creating a seal over the mouth and nose. However, a smaller mask can be used in some cases, covering just the nose. For patients who require CPAP at home on a nightly basis because of nocturnal hypoxemia due to episodes of obstructive sleep apnea, nasal prongs provide a pneumatic splint that holds the upper airway open. CPAP provides positive airway pressure throughout all phases of spontaneous ventilation.
    
    

    

    Continuous positive airway pressure (CPAP) administered on an adult patient.

    

    Continuous positive airway pressure (CPAP) administered on a child.

• Ventilator mode
  • Bilevel positive airway pressure (BiPAP) is pressure-limited ventilation. Predetermined inspiratory pressure is delivered, which can cause different tidal volumes, depending on the resistance of the respiratory system. BiPAP has the advantage of leak compensation. It is preferred for most short-term applications because pressure-limited modes are better tolerated than volume-limited modes.
  • BiPAP comes in the following 3 types:
    • Pressure support: The ventilator delivers air at a set pressure during inspiration each time a patient initiates a breath.
    • Pressure control: The ventilator automatically delivers a set number of breaths per minute at a set pressure.
    • Bilevel positive airway pressure: The ventilator delivers different pressures during inspiration and expiration. If necessary, this mode can fully ventilate the patient.
• Use
  • BiPAP provides 2 levels of positive pressure: inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP). This is highly beneficial in patients with respiratory fatigue or failure. During exhalation, pressure is variably positive. Airflow in the circuit is sensed by a transducer and is augmented to a preset level of ventilation. Cycling between inspiratory and expiratory modes may be triggered by the patient's breaths or may be preset. BiPAP helps in improving patient comfort.
  • BiPAP is a particularly effective respiratory modality when patients are not improving sufficiently on CPAP alone. Not only does it provide the benefit of CPAP by providing increased airway pressure during expiration, but it adds inspiratory assistance that may further reduce the work of breathing and assist with augmenting the ventilator in patients at risk for hypercapnea (eg, patients with COPD).
  • Patients may tire from breathing against resistance, even as it helps prevent alveoli from closing.
  • A common practice is to use initial IPAP settings of 10-12 cm H₂ O pressure and EPAP settings of 5-7 cm H₂ O, and then adjust IPAP to 15-20 cm H₂ O, depending upon the response over the next hour or so.
  • In conditions such as lung collapse or pulmonary edema, the initial EPAP may have to be high. However, an EPAP that is too high can lead to reduced preload. Hence, a balance in adjusting the ventilatory settings is desirable. Back-up rates can be chosen according to the age of the patient. The fraction of inspired oxygen (FiO₂) is another useful variable in titrating the response to oxygenation.

Volume-limited ventilation

• Ventilator mode
  • In volume-limited ventilation, a predetermined tidal volume or minute volume is delivered each time a patient takes a breath.
  • This leads to varying peak inspiratory pressures, depending on the resistance of the respiratory system.
• Use
  • In this mode, ventilators usually are set in assist-control mode with high tidal volume (10-15 mL/kg) to compensate for air leaks. Interfaces can be selected to suit the comfort of the patient.
  • This mode is suitable for obese patients or patients with chest wall deformities (ie, patients who need high inflation pressure) and for patients with neuromuscular diseases who need high tidal volumes for ventilation.

Negative Pressure Ventilation

The prototype negative pressure ventilation (NPV) was the iron lung, first used in 1928 but most famously used during the polio epidemics of 1950s.

Pearls

• Noninvasive ventilation should ensure maintenance of functional residual capacity.
• Noninvasive ventilation should be the first line of respiratory therapy in carefully selected clinical problems.
• Noninvasive ventilation helps avoid associated adverse side effects of invasive ventilation (eg, ventilator-associated pneumonias, excessive sedation, barotrauma, and volutrauma).
• Vital signs, clinical profile, and blood gases should be monitored carefully, especially in the first few hours after initiating noninvasive ventilation therapy. This allows early recognition of signs of lack of improvement and timely consideration of the need for intubation in selected cases.
• Negative pressure ventilation mimics physiological ventilation.
• Heliox therapy may be useful in patients with a selected group of obstructive airway diseases such as reactive airways disease.

Complications

• Noninvasive positive pressure ventilation (NIPPV) has relatively few complications when compared with invasive ventilation.
• Patients must be monitored carefully for worsening respiratory distress, tachypnea, and deteriorating blood gases.
• Inadequate clearance of respiratory secretions may pose a problem, especially since the seal must be maintained.
• Noninvasive ventilation (NIV) should be used with extreme caution in patients with pulmonary processes (eg, a lobar pneumonia) that affect only one side of the lungs.
  • In such cases, NIV primarily ventilates the good lung, producing increased pressure on that side, which leads to decreased blood flow to the healthy lung and increased pulmonary blood flow to the affected lung, or area of lower pressure.
  • This can lead to a relative decrease in gas exchange.
• As it is extremely important for the air seal to be tight, most complications are related to local skin effects, especially with long-term use.
  • These include ulceration and pressure necrosis at the application sites of appliances such as masks, straps, or nasal prongs.
  • Protective synthetic coverings (eg, CombiDERM ACD, ConvaTec DuoDERM CGF control gel formula dressing) may help prevent skin breakdown and ulceration on the bridge of the nose.
  • Eye irritation and pain or congestion of the nasal sinuses may occur.
• Distension of the stomach due to aerophagia and aspiration secondary to vomiting while on negative pressure ventilation (NPV) are additional concerns.
  • When gastric distension occurs, a nasogastric tube can be used to relieve the distension while still allowing the mask to seal.
  • Adverse hemodynamic effects from NPV are unusual, although preload reduction and hypotension may occur.^12,13

Noninvasive Ventilation and Heliox Adjunct Therapy

• The medical use of heliox as a breathable gas for respiratory disease was first introduced in 1934 by Barach. Since then, heliox has been studied in various upper and lower airway conditions by many investigators. Vineet et al conducted a computerized bibliographic search of available clinical material on the properties of helium and its applications in pediatric intensive care.¹⁴
• Noninvasive positive pressure ventilation (NIPPV) can be used to treat patients with upper airway obstructions such as those caused by glottic edema following extubation. In this situation, NIPPV can be combined with aerosolized medication and/or heliox.
• Heliox administration is most effective in conditions involving density-dependent increases in airway resistance, especially when used early in an acute disease process. Substituting helium for nitrogen in a gas mixture changes the physical properties of the inhaled gas, decreasing gas density and increasing laminar air flow in the airway.
• Heliox therapy also appears to be beneficial in chronic obstructive pulmonary disease (COPD) exacerbations. Jaber et al demonstrated that heliox during noninvasive pressure support ventilation improved pH level, PaCO₂ level (partial pressure of carbon dioxide in arterial gas), and work of breathing in patients with acute exacerbation of COPD.¹⁵ It may also improve clinical tolerance and potentially further reduce the need for invasive ventilation in selected patients.
• Gainnier et al reported that in their randomized, prospective study in adults, the helium-oxygen mixture decreases the work of breathing in patients with COPD who are mechanically ventilated.¹³ Hence, the helium-oxygen mixture may be useful in reducing the burden of ventilation.
• For effective results, heliox should be used in a combination ratio of 60 parts helium to 40 parts oxygen or 79 parts helium to 21 parts oxygen.
• Heliox can be administered as a nebulization or via ventilator, though not all ventilators have the ability to add heliox.
• Some of the medical conditions in which heliox may be useful include the following:
  • Croup
  • Bronchial asthma
  • COPD
  • Acute airway obstruction
  • Epiglottitis
  • Laryngitis
  • Tracheitis
  • Stridor
  • Foreign body aspiration
  • Tracheomalacia/stenosis
  • Cystic fibrosis
  • Bronchiectasis
• Continuing heliox therapy for hours has cost implications, as the heliox cylinders run out reasonably quickly. Any beneficial effect of heliox should become evident in a relatively short period.
  
  

  

  Heliox cylinders.

Abstract

Nosocomial lower respiratory tract infections are a common cause of morbidity and mortality in ICU patients receiving mechanical ventilation. Many studies have investigated the management and prevention of ventilator-associated pneumonia (VAP), but few have focused on the role of ventilator-associated tracheobronchitis (VAT). The pathogenesis of lower respiratory tract infections often begins with tracheal colonization that may progress to VAT, and in selected patients to VAP. Since there is no well-established definition of VAT, discrimination between VAT and VAP can be challenging. VAT is a localized disease with clinical signs (fever, leukocytosis, and purulent sputum), microbiologic information (Gram stain with bacteria and leukocytes, with either a positive semiquantitative or a quantitative sputum culture), and the absence of a new infiltrate on chest radiograph. Monitoring endotracheal aspirates has been used to identify and quantify pathogens colonizing the lower airway, to diagnose VAT or VAP, and to initiate early, targeted antibiotic therapy. Recent data suggest that VAT appears to be an important risk factor for VAP and that targeted antibiotic therapy for VAT may be a new paradigm for VAP prevention and better patient outcomes.

Introduction

"Man's mind, once stretched by a new idea, never regains its original dimension."

- Oliver Wendell Holmes

In comparison to ventilator-associated pneumonia (VAP), less data are available on ventilator-associated tracheobronchitis (VAT) and its management. VAT was not included in the 2005 American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines for the management of hospital-acquired pneumonia, health-care-associated pneumonia, and VAP,^[1] but two recent randomized, clinical trials^[2,3] of antibiotic therapy for VAT have stimulated interest.

VAT represents a spectrum of disease that has had different clinical definitions, and treatment options have been controversial.^[2-4] VAT should be suspected in intubated patients with clinical signs of lower respiratory tract infection (such as fever, leukocytosis, and purulent sputum) with a Gram stain demonstrating microorganisms and polymorphonuclear leukocytes (PMNLs), with either semiquantitative or quantitative cultures suggesting infection in the absence of a new or progressive infiltrate on chest radiography.^[3,5] Existing studies^[5-7] on VAT report a crude incidence rate that may vary from 2.7 to 10%. Common pathogens for VAT include Pseudomonas aeruginosa, Acinetobacter spp, and methicillin-resistant Staphylococcus aureus (MRSA).^[5,7,8]

This review summarizes current clinical data on the epidemiology, pathogenesis, and antibiotic management of VAT. A new paradigm for VAT treatment, VAP prevention, and improved outcomes in ICU patients receiving mechanical ventilation appears promising.^[2,3,9]

Epidemiology and Etiology

Several studies have looked at the incidence of VAT. A German multicenter study^[6] of 515 ICU patients found an incidence of 2.7%, among 161 multiple trauma patients in a single-center study^[7] in Spain the incidence was 3.7%, and it was 10% in a study^[5] of ICU patients receiving mechanical ventilation in France. The most frequent bacterial pathogens isolated have been P aeruginosa, followed by Acinetobacter baumannii and MRSA, Streptococcus pneumoniae (pneumococcus), Haemophilus influenza, Legionella pneumophila, and methicillin-sensitive S aureus. ^[5] Nonbacterial etiologies causing VAT are rare and also unlikely to cause VAP.^[10]

Medical and surgical patients with VAT appear to have a significantly longer length of ICU stay and duration of mechanical ventilation.^[5] By comparison, higher crude mortality rates ranging from 20 to 50% have been reported for VAP, and health-care cost for these patients has been estimated at $40,000 per episode.^[1,11,12]

Pathogenesis

Lower Respiratory Tract Colonization

Intubation and mechanical ventilation increase the risk of VAP by sixfold to 20-fold.^[1,11] Long-term mechanical ventilation with high airway pressures promotes lung injury, ARDS, and increases the risk for lung infection.^[13] Placement of an endotracheal tube (ETT) offers bacteria in the nasopharynx a convenient, easy, one-way path into the lower respiratory tract that results in greater colonization and risk for VAT.^[11,14] The presence of the ETT cuff acts as a barrier for bacteria and secretions to exit the lower airways. In addition, risk is increased by routine sedation and limited ETT suctioning that is needed to replace spontaneous coughing.

Lower-airway colonization can also result from endotracheal suctioning, inadvertently flushing of contaminated tubing condensate into the airways, contaminated "in-line" medication nebulizers (aerosol), or emboli from biofilm formations in the ETT lumen.^[14] Over time, bacterial concentrations and inflammation increase, resulting in a greater risk of progression to VAT or VAP (Figure 1).

(Enlarge Image)

Figure 1. Pathogenesis of bacterial lower respiration tract infections. Bacterial pathogens usually enter the lower respiratory tract from the oropharynx by leakage around the ETT tube cuff. Different prevention strategies for VAP are aimed at reducing number of bacteria entering the lower respiratory tract. The black arrow represents the "battle" between the bacterial pathogen and different host defenses. The three circles below represent potential patient outcomes that may occur over time.

Bacterial Risk Factors

The complex interactions between the patient's host defenses vs the quantity and virulence of the bacterial pathogen(s) entering the lower respiratory tract determines if colonization will progress to VAT, and in some cases to VAP (Figure 1).^[1,11,14] Bacterial virulence clearly varies between and within species. For example, infections caused by P aeruginosa isolates having exotoxin III are associated with a sevenfold-increased risk of death, when compared to other P aeruginosa isolates.^[15] Bacterial virulence also varies widely within Gram-positive species of MRSA.^[16]

Host Lung Defenses

Host defenses in the lung include three major groups: mechanical (cilia, mucous), cellular (PMNLs, macrophages, and their respective cytokines), and the humoral group (IgM, IgG, and IgA antibodies and complement). These marvelous defense systems are designed to contain or eliminate invading bacteria, and their efficacy will ultimately determine the clinical outcome of the patient.^[1,11,17,18]

Potential Patient Outcomes

If the outcome of this complex pathogen-host battle is favorable to the host, the infectious process will be halted, but tracheobronchial colonization can persist (Figure 2). If the host outcome is unfavorable, there may be increased numbers of lower respiratory tract pathogens and greater inflammation leading to purulent sputum as well as clinical signs and symptoms of infection and VAT, or possibly VAP may develop. VAP is usually associated with increased lung tissue damage, increased oxygenation demands, and a greater risk for complications such as empyema, lung abscess, secondary bacteremia, shock, and death.^[11] Therefore, the concept of halting the infectious progression to VAP at an earlier stage before tissue damage appears is an appealing strategy. Based on our current understanding of pathogenesis, appropriate treatment of VAT could represent such an opportunity.

(Enlarge Image)

Figure 2. Summary of changes in tracheal colonization over time in an intubated patient. Note increase in levels of colonization from the time of intubation until VAT (≥ 105-6 cfu/mL) was diagnosed on day 7. Targeted antibiotic therapy on day 7 resulted in a rapid decrease in tracheal colonization.

Diagnosis and Definitions

As previously mentioned, there is no consensus on diagnostic criteria for VAT. This is unfortunate because it leads to difficulty distinguishing between VAT and VAP, comparing clinical studies, and establishing treatment directives for VAT. Several definitions exist, and they are primarily differing in the need for microscopic confirmation. Further complicating the diagnosis is that it may be difficult or impossible to tell if there is a new and progressive infiltrate on a chest radiograph or CT lung scan that would confirm the diagnosis of VAP, as discussed below. In our opinion, the use of quantitative endotracheal aspirates with a pathogen at concentration of either 10^5-6 cfu/mL would be optimal to reduce confusion and controversy. In Table 1 , we compare a proposed definition of VAT with the accepted definition of VAP by ATS/IDSA. Both are based on clinical signs and symptoms, microbiologic data, and radiographic findings.

Microbiologic Confirmation of VAT or VAP

Intubated patients have ready access to specimens for Gram stain and culture that may help establish a diagnosis of lower respiratory tract infection and may help discriminate between VAT and VAP. Smears (Gram stains) of the endotracheal aspirates help establish the presence of inflammation based on numbers of PMNLs. The Gram stain may also provide information on morphology of the invading bacteria and when present correlates with a culture with ≥ 10⁵ organisms per milliliter.

Semiquantitative cultures of the endotracheal aspirate (ETA) are performed in most hospital microbiology laboratories, and moderate-to-heavy growth of a pathogen(s) is usually considered significant. Other laboratories have used quantitative ETA in which significant growth of a pathogen usually corresponds to ≥ 10^5-6 cfu/mL. We believe that microbiologic diagnosis of VAT and VAP is a "numbers game" and that quantitative criteria may provide a better standard for comparison and greater diagnostic specificity to discriminate between lower airway colonization and infection. However, the ETA will not help discriminate between VAT and VAP ( Table 1 ). The diagnosis of VAP can be confirmed with quantitative samples, obtained from the distal airways using bronchoscopic or nonbronchoscopic BAL specimens or protected specimen brush (PSB) criteria as shown in Table 1 .

Clinical signs and symptoms along with radiographic findings may be helpful for differentiating lower respiratory tract colonization from infection. As shown in Table 2 , quantitative microbiologic methods are also routinely used for processing urine cultures to help health-care providers discriminate between urinary tract colonization and infection (cystitis and pyelonephritis).

Biomarkers such as C-reactive protein, procalcitonin,^[19] soluble triggering receptor, elastin fiber, and BAL endotoxin have been used for the diagnosis of VAP and are summarized in a recent review article by Rea-Neto et al.^[20] These parameters offer an objective way to identify the presence of VAP.^[21] Povoa et al^[22] reported the identification of VAP as early as 4 days after the initiation of antibiotic treatment by repeatedly measuring C-reactive protein, there are no studies addressing the issue of biomarkers for VAT.

Radiographic Evaluation for VAP

In contrast to VAT, VAP requires the presence of a new or progressive infiltrate on chest radiograph or CT scan, which may be particularly difficult for the diagnosis of early VAP, which may not be identified on chest radiograph because pulmonary infiltrates are often the result of fluid, pus, or lung consolidation due to the host inflammatory response.^[23] In addition, the sensitivity and specificity for the diagnosis of VAP are limited in patients with preexisting infiltrates or concurrent disease due to congestive heart failure, atelectasis, prior pneumonia, or ARDS. For decades, it has been emphasized that use of the portable chest radiograph in critically ill ICU patients is often of poor quality and difficult to interpret.^[24,25] Nseir and coworkers^[2] reported that 38% of their ICU patients receiving mechanical ventilation had an abnormal chest radiograph finding at the time of admission to the ICU, and similar results have been reported by others.^[26]

Interpretation of chest infiltrates on chest radiographs may be improved with the use of CT lung scans. There are data suggesting that CT scan is likely to be a more sensitive and specific tool for diagnosing VAP in critically ill patients,^[27] but availability is limited, more difficult to perform, and infiltrates suggestive of VAP may be difficult to confirm or find consensus among blinded readers, especially in patients with diffuse infiltrates, pleural effusions, prior surgery, or ARDS.^[28] Although CT scans would be more expensive, if used, they would likely improve diagnostic accuracy.

Rationale for Antibiotic Therapy in VAT

Clinical Importance of VAT

A'Court and coworkers^[29] studied the natural history of tracheal colonization in 150 patients receiving mechanical ventilation, using serial quantitative, nonbronchoscopic, bronchial lavage samples. Increases in lower respiratory tract colonization occurred over time and appeared to peak approximately 2 days before the clinical signs of VAP, suggesting a window of opportunity for intervention.^[30]

In a prospective, observational cohort study^[5] of medical and surgical ICU patients, VAT was associated with increased length of ICU stay, more mechanical ventilator days, and higher mortality in medical but not surgical ICU patients. Patients with COPD who had VAT, when compared to "matched" control subjects, had significantly greater median days of mechanical ventilation and more ICU days. In this study,^[31] antibiotic therapy did not protect against VAP; but in a later prospective, observational case-control study^[32] of VAT, patients who were treated with antibiotics had significantly fewer days of mechanical ventilation and ICU stay.

Recent Randomized Clinical Trials of Antibiotic Therapy for VAT

The use of antibiotic therapy for VAT has been evaluated in two recently conducted, randomized trials. The first trial, by Palmer et al,^[3] was a double-blind, randomized, placebo-controlled study of medical and surgical ICU patients who received either targeted aerosolized antibiotic(s) treatment for 14 days or until extubation (n = 19) vs a saline solution placebo (n = 24). VAT was defined as the production ≥ 2 mL of purulent endotracheal secretions over a 4-h period with a Gram stain demonstrating bacteria. Aerosolized antibiotics included gentamicin sulfate if Gram-negative bacilli were present, vancomycin for Gram-positive bacteria, and both for those with mixed infections. Systemic antibiotics were administered at the discretion of treating physician, and were frequently prescribed in both groups. The aerosolized antibiotic group had significantly lower rates of clinical signs and symptoms of VAP, better weaning, reduced numbers of antibiotic-resistant organisms, and lower use of systemic antibiotics when compared to the placebo group (all end points, p <>[3] Notable limitations of this study included the concerns over the a definition of VAT without quantitative microbiologic evaluation of ETAs, high numbers of patients who had prior VAP, lack of data on radiographic signs of VAP, small numbers of patients studied, potential confounding by the use of systemic antibiotics, and possible risk of complications with the widespread or long-term use of aerosolized antibiotic therapy for 14 days.

The second study, by Nseir and coworkers,^[2] was a randomized, controlled, trial of patients who had monitored quantitative ETAs after intubation, to establish a diagnosis of VAT based on a pathogen in sputum (> 10⁶ cfu/mL), who were then randomized to receive either targeted antibiotic therapy vs no therapy. The results demonstrated that the antibiotic-treated group had a significant decrease in VAP episodes (p <>

(Enlarge Image)

Figure 3. Potential advantages of a model based on the diagnosis and early, targeted antibiotic treatment of VAT include reduction in VAP and improved patient outcomes. This model may also help in the management of early VAP (to early for chest radiograph changes) and possible VAP that includes patients with preexisting chest radiographs with prior diffuse infiltrates that prevent confirmation of new infiltrate needed to diagnose VAP.

VAT: A New Management Paradigm

The data from two, recent randomized clinical trials by Nseir and coworkers^[2] and Palmer et al^[3] underscore the importance of VAT and potential benefits of targeted antibiotic therapy to improve patient outcomes. Intuitively, reducing heavy bacterial colonization and associated inflammation in the lower respiratory tract also appears to be an important prevention strategy for VAP (Figure 3).^[2] Other prevention measures for VAP like oral decontamination with 2% chlorhexidine solution has proven to lower the incidence of VAP episodes supporting the colonization concept.^[33,34] In contrast to prevention strategies aimed at reducing oropharyngeal colonization with oral antiseptics or antibiotics, or specially designed ETTs that are used in all patients receiving mechanical ventilation, targeted antibiotic therapy for VAT would only be used in perhaps 5 to 10% of patients receiving mechanical ventilation.^[1-3,17,35]

Advantages of a model for managing lower airway colonization and infection similar to that of Nseir et al^[2] are shown in Figure 4. The focus of this model is based on the use of serial ETAs to help discriminate between lower airway colonization and VAT. This would allow earlier, targeted antibiotic therapy as a strategy improves the outcomes of ICU patients receiving mechanical ventilation, and reduce or prevent VAP. The risk-benefit ratio for using antibiotic therapy for VAT needs confirmation and further evaluation in clinical trials, but should be cost-effective if available incidence data suggesting VAT rates of 2.7 to 10% are correct.^[4,5] The potential risks and advantages of VAT therapy include selection of multidrug-resistant pathogens and complications such as Clostridium difficile colitis, but these need further evaluation and appear to be unlikely.^[3]

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Figure 4. A model based on the use of serial endotracheal sputum cultures for the early detection of VAT, and the initiation of timely, targeted antibiotic therapy, which has been demonstrated to reduce or prevent VAP and improve patient outcomes.[2,3]

The duration of targeted, antibiotic therapy for VAT has not been established, but VAT may respond to shorter courses of treatment because therapy is initiated early and before there is extensive tissue damage or when there are fewer bacteria. Singh and workers^[36] randomized 81 medical and surgical ICU patients with suspected pneumonia and a clinical pulmonary infection score ≤ 6 to a 3-day course of antibiotic therapy with ciprofloxacin compared to "routine care," which included combinations of antibiotics used for longer periods of treatment. The shorter-course group had significantly fewer superinfections and antibiotic-resistant pathogens (p < p =" 0.06).">[1] If confirmed effective, the use of aerosolized antibiotics for VAT may also decrease the need for systemic antibiotics and the development of antibiotic resistance.

Over the past 3 years, there has been greater emphasis directed at reducing health-care-associated infections by the Institute for Healthcare Improvement. Prevention of VAP has been a priority for hospitals that has achieved great success, but most critical care, infectious disease, and pulmonary providers do not believe that the use of the "VAP bundle" and checklists alone will produce a "zero-VAP infection" rate, especially in major referral hospitals caring for complicated patients.^[35] It is unlikely that all episodes of VAP can be prevented, eliminated, or considered a "medical error." Our goal should be to reduce rates, change culture, and aim for "zero VAP."^[21]

Several areas for future research on VAT have been identified, which include confirming these data, finding a common definition of VAT, a diagnostic threshold for quantitative endotracheal aspirates, and the duration of antibiotic therapy needed for VAT. We would also recommend a cost analysis of this strategy in comparison to other prevention strategies. In our opinion, this could be best achieved by the use of large, collaborative national and international networks for recruitment, with better designed clinical trials with independent data and statistical analysis. Such a network could save millions of dollars, provide more answers to our current questions, and provide a sound basis for future guidelines to manage lower respiratory tract infections.

Based on our current understanding of VAP pathogenesis, the use of serial quantitative ETAs should be a valuable thermometer to monitor the progress of the war between the invading host bacteria and host defenses as well as an intervention "flashpoint" for early, targeted antibiotic therapy for VAT. This model may have advantages over our current practice of early, empiric antibiotic therapy for VAP, followed by de-escalation and stopping antibiotics at 7 to 8 days.^[1-3] The benefits of using the VAT model as a strategy include a standard method and definition for benchmarking lower respiratory tract infection rates, a cost-effective alternative for VAP reduction and prevention, and several desired patient outcomes that include reduced antibiotic use and perhaps resistance, fewer days of mechanical ventilation, ICU stay, and reduced morbidity and mortality that should also decrease health-care costs. We believe that a paradigm targeting VAT has many attractive features, could improve our current management and prevention strategies, and is analogous to casting a stone into a still pond that creates ripples that will go on and on.^[2,3]