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Incidence and Risk of Aspiration in Mechanically Ventilated Patients
Abstract
Mechanical ventilation is essential for many patients with critical illness and respiratory failure, but places patients at risk of life-threatening complications termed ventilator-associated events (VAEs). VAEs occur in approximately 25% of mechanically ventilated patients. These increase duration of mechanical ventilation, intensive care unit (ICU) and hospital length of stay, healthcare costs, and risk of disability and death. Many VAEs are aspiration-associated events such as pneumonia and Acute Lung Injury (ALI); aspiration pneumonia in particular is the second most common diagnosis among hospitalized adult patients. However, the lack of standardized diagnostic methods to confirm suspicion of aspiration poses a barrier to diagnosis of aspiration-related events in mechanically ventilated patients. Therefore, development of biomarkers to detect the early occurrence of aspiration in mechanically ventilated patients is a national priority in the United States. These biomarkers would enable development of novel therapies and allow clinicians to institute such therapies early to attenuate the incidence of adverse events. Ongoing research aims to assess the sensitivity and specificity of specific biomarkers to detect occurrence of early aspiration events in adult and pediatric patients receiving mechanical ventilation. To this end, our research group is actively measuring pepsin and salivary amylase in tracheal aspirates from mechanically ventilated individuals as markers of gastric and oropharyngeal aspiration respectively. We hypothesize that aspiration events, identified by these markers, will correlate with incidence/time to VAEs and ICU outcomes including mortality, ventilator days, ICU days and hospital days. Accurate estimation of the incidence of aspiration and its impact on outcomes in mechanically ventilated patients will enable future trials of interventions to decrease morbidity/mortality from aspiration-associated pulmonary complications.
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Rationale:
The occurrence of ventilator-associated pneumonia (VAP) is linked to the aspiration of contaminated pharyngeal secretions around the endotracheal tube. Tubes with cuffs made of polyurethane rather than polyvinyl chloride or with a conical rather than a cylindrical shape increase tracheal sealing.
Objectives:
To test whether using polyurethane and/or conical cuffs reduces tracheal colonization and VAP in patients with acute respiratory failure.
Methods:
We conducted a multicenter, prospective, open-label, randomized study in four parallel groups in four intensive care units between 2010 and 2012. A cohort of 621 patients with expected ventilation longer than 2 days was included at intubation with a cuff composed of cylindrical polyvinyl chloride (n = 148), cylindrical polyurethane (n = 143), conical polyvinyl chloride (n = 150), or conical polyurethane (n = 162). We used Kaplan-Meier estimates and log-rank tests to compare times to events.
Measurements and main results:
After excluding 17 patients who secondarily refused participation or had met an exclusion criterion, 604 were included in the intention-to-treat analysis. Cumulative tracheal colonization greater than 10(3) cfu/ml at Day 2 was as follows (median [interquartile range]): cylindrical polyvinyl chloride, 0.66 (0.58-0.74); cylindrical polyurethane, 0.61 (0.53-0.70); conical polyvinyl chloride, 0.67 (0.60-0.76); and conical polyurethane, 0.62 (0.55-0.70) (P = 0.55). VAP developed in 77 patients (14.4%), and postextubational stridor developed in 28 patients (6.4%) (P = 0.20 and 0.28 between groups, respectively).
Conclusions:
Among patients requiring mechanical ventilation, polyurethane and/or conically shaped cuffs were not superior to conventional cuffs in preventing tracheal colonization and VAP. Clinical trial registered with clinicaltrials.gov (NCT01114022).
Laryngopharyngeal reflux is defined as the reflux of gastric content into larynx and pharynx. A large number of data suggest the growing prevalence of laryngopharyngeal symptoms in patients with gastroesophageal reflux disease. However, laryngopharyngeal reflux is a multifactorial syndrome and gastroesophageal reflux disease is not the only cause involved in its pathogenesis. Current critical issues in diagnosing laryngopharyngeal reflux are many nonspecific laryngeal symptoms and signs, and poor sensitivity and specificity of all currently available diagnostic tests. Although it is a pragmatic clinical strategy to start with empiric trials of proton pump inhibitors, many patients with suspected laryngopharyngeal reflux have persistent symptoms despite maximal acid suppression therapy. Overall, there are scant conflicting results to assess the effect of reflux treatments (including dietary and lifestyle modification, medical treatment, antireflux surgery) on laryngopharyngeal reflux. The present review is aimed at critically discussing the current treatment options in patients with laryngopharyngeal reflux, and provides a perspective on the development of new therapies.
Objectives:
Aspiration of oropharyngeal or gastric contents into the respiratory tract leads to a spectrum of disorders with high morbidity. Aspiration is a diagnostic dilemma, because clinical characteristics and diagnostic tests are not effective predicting or confirming aspiration. We sought to determine whether α-amylase, a protein secreted by salivary glands and the pancreas, is elevated in bronchoalveolar lavage specimens in patients with clinical risk factors for aspiration and whether bronchoalveolar lavage amylase predicts bacterial pneumonia.
Design:
Retrospective analysis.
Setting:
Five adult ICUs at a tertiary care urban medical center.
Patients:
Mechanically ventilated patients who underwent either bronchoscopic or nonbronchoscopic bronchoalveolar lavage within 72 hrs of endotracheal intubation between August 1, 2008 and June 30, 2010.
Measurements and main results:
A total of 296 bronchoalveolar lavage amylase results from 280 patients were included in the analysis, and 155 bronchoalveolar lavage amylase specimens were obtained from patients with at least one predefined preintubation risk factor (altered consciousness, swallowing dysfunction, difficult intubation, peri-intubation vomiting, or cardiac arrest). Bronchoalveolar lavage amylase concentration increased as the number of preintubation risk factors increased (p < 0.001). In addition, bronchoalveolar lavage amylase was elevated in patients with bacterial pneumonia (cfu/mL ≥ 10) (p < 0.001). The area under the receiver operator curve for the ability of bronchoalveolar lavage amylase to differentiate between positive and negative bronchoalveolar lavage culture was 0.67 (95% confidence interval, 0.60-0.75). The lower 95% confidence interval for bronchoalveolar lavage amylase in patients with at least one preintubation risk factor for aspiration was 125.9 units/L. In multivariate analysis, bronchoalveolar lavage amylase < 125 units/L was associated with significantly lower odds of bacterial pneumonia (odds ratio 0.39, 95% confidence interval 0.21-0.71, p = 0.002).
Conclusions:
Elevated bronchoalveolar lavage amylase is associated with risk factors for aspiration and may predict bacterial pneumonia. Bronchoalveolar lavage amylase may be useful as an early screening tool to guide management of patients suspected of aspiration.
Lipid-laden alveolar macrophages and pH monitoring have been used in the diagnosis of chronic aspiration in children with gastroesophageal reflux (GER). This study was conducted to prove a correlation between the detection of alimentary pulmonary fat phagocytosis and an increasing amount of proximal gastroesophageal reflux. It was assumed that proximal gastroesophageal reflux better correlates with aspiration than distal GER. Patients from 6 months to 16 years with unexplained recurrent wheezy bronchitis and bronchial hyperreactivity, or recurrent pneumonia with chronic cough underwent 24-hour double-channel pH monitoring and bronchoscopy with bronchoalveolar lavage (BAL). Aspiration of gastric content was determined by counting lipid laden alveolar macrophages from BAL specimens. There were no correlations between any pH-monitoring parameters and counts of lipid-laden macrophages in the whole study population, even when restricting analysis to those with abnormal reflux index expressing clinically significant GER. Quantifying lipid-laden alveolar macrophages from BAL in children with gastroesophageal-related respiratory disorders does not have an acceptable specificity to prove chronic aspiration as an underlying etiology. Therefore, research for other markers of pulmonary aspiration is needed.
Underinflation of the tracheal cuff frequently occurs in critically ill patients and represents a risk factor for microaspiration of contaminated oropharyngeal secretions and gastric contents that plays a major role in the pathogenesis of ventilator-associated pneumonia (VAP).
To determine the impact of continuous control of tracheal cuff pressure (P(cuff)) on microaspiration of gastric contents.
Prospective randomized controlled trial performed in a single medical intensive care unit. A total of 122 patients expected to receive mechanical ventilation for at least 48 hours through a tracheal tube were randomized to receive continuous control of P(cuff) using a pneumatic device (intervention group, n = 61) or routine care of P(cuff) (control group, n = 61).
The primary outcome was microaspiration of gastric contents as defined by the presence of pepsin at a significant level in tracheal secretions collected during the 48 hours after randomization. Secondary outcomes included incidence of VAP, tracheobronchial bacterial concentration, and tracheal ischemic lesions. The pneumatic device was efficient in controlling P(cuff). Pepsin was measured in 1,205 tracheal aspirates. Percentage of patients with abundant microaspiration (18 vs. 46%; P = 0.002; OR [95% confidence interval], 0.25 [0.11-0.59]), bacterial concentration in tracheal aspirates (mean ± SD 1.6 ± 2.4 vs. 3.1 ± 3.7 log(10) cfu/ml, P = 0.014), and VAP rate (9.8 vs. 26.2%; P = 0.032; 0.30 [0.11-0.84]) were significantly lower in the intervention group compared with the control group. However, no significant difference was found in tracheal ischemia score between the two groups.
Continuous control of P(cuff) is associated with significantly decreased microaspiration of gastric contents in critically ill patients.
We undertook to (1) obtain unequivocal evidence to confirm or rebut our initial observations that pepsin is taken up by hypopharyngeal epithelial cells by receptor-mediated endocytosis, (2) investigate whether uptake of pepsin at pH 7, in nonacidic refluxate, is of pathological significance, and 3) test our hypothesis that inactive but stable pepsin (<pH 8) taken up by hypopharyngeal epithelial cells causes damage by becoming reactivated inside the cell.
Human posterior cricoid biopsy specimens and cultured hypopharyngeal FaDu epithelial cells were used to perform competitive binding studies and to investigate colocalization of pepsin with clathrin, Rab-9, and TRG-46. FaDu cells were exposed to pepsin (both irreversibly and reversibly inactivated) in the presence and absence of wortmannin and dimethyl amiloride and analyzed by electron microscopy, MTT cytotoxicity assay, and Stress and Toxicity SuperArray.
Pepsin is unequivocally taken up by hypopharyngeal epithelial cells by receptor-mediated endocytosis. Uptake of pepsin at pH 7, in nonacidic refluxate, causes mitochondrial damage and changes the expression of several genes implicated in stress and toxicity. Irreversible, but not reversible, inhibition of peptic activity prevents these changes.
Pepsin, at pH 7, in nonacidic refluxate, causes damage by becoming reactivated inside the cell. Irreversible inhibitors of peptic activity hold promise as a new therapy for reflux.
To characterize the current economic burden of ventilator-associated pneumonia (VAP) and to determine which services increase the cost of VAP in North American hospitals.
We performed a retrospective, matched cohort analysis of mechanically ventilated patients enrolled in the North American Silver-Coated Endotracheal Tube (NASCENT) study, a prospective, randomized study conducted from 2002 to 2006 in 54 medical centers, including 45 teaching institutions (83.3%).
Case patients with microbiologically confirmed VAP (n = 30)were identified from 542 study participants with claims data and were matched by use of a primary diagnostic code, and subsequently by the Acute Physiology and Chronic Health Evaluation II score, to control patients without VAP (n = 90). Costs were estimated by applying hospital-specific cost-to-charge ratios based on all-payer inpatient costs associated with VAP diagnosis-related groups.
Median total charges per patient were $198,200 for case patients and $96,540 for matched control patients (P < .001); corresponding median hospital costs were $76,730 for case patients and $41,250 for control patients (P = .001). After adjusting for diagnosis-related group payments, median losses to hospitals were $32,140 for case patients and $19,360 for control patients (P = .151). The median duration of intubation was longer for case patients than for control patients (10.1 days vs 4.7 days; P < .001), as were the median duration of intensive care unit stay (18.5 days vs 8.0 days; P < .001) and the median duration of hospitalization (26.5 days vs 14.0 days; P < .001). Examples of services likely to be directly related to VAP and having higher median costs for case patients were hospital care (P < .05) and respiratory therapy (P < .05).
VAP was associated with increased hospital costs, longer duration of hospital stay, and a higher number of hospital services being affected, which underscores the need for bundled measures to prevent VAP.
NASCENT study ClinicalTrials.gov Identifier: NCT00148642.
Studies using combined multichannel intraluminal impedance with pH monitoring reveal a role for nonacidic reflux in laryngopharyngeal symptoms and injury. We have discovered that pepsin is taken up by laryngeal epithelial cells by receptor-mediated endocytosis. This finding reveals a novel mechanism by which pepsin could cause cell damage, potentially even in nonacidic refluxate. The objective of this study was to determine whether pepsin, at pH 7.4 and thus in nonacidic refluxate, causes cell damage.
Cultured hypopharyngeal epithelial (FaDu) cells were exposed to human pepsin (0.1 mg/mL) at pH 7.4 for either 1 hour or 12 hours at 37 degrees C and analyzed by electron microscopy, cytotoxicity assay, and SuperArray.
We report mitochondrial and Golgi complex damage in cells exposed to pepsin at neutral pH, observed by electron microscopy. We also report cell toxicity of pepsin at pH 7.4, measured by a cytotoxicity assay. Furthermore, using SuperArray, we found that pepsin at pH 7.4 significantly alters the expression levels of multiple genes implicated in stress and toxicity.
These findings are perhaps the first to explain why many patients have symptoms and injury associated with nonacidic reflux, and could have important implications for the development of new therapies for reflux, such as pepsin receptor antagonists and/or irreversible inhibitors of peptic activity.
The outcome of patients receiving mechanical ventilation for particular indications has been studied, but the outcome in a large number of unselected, heterogeneous patients has not been reported.
To determine the survival of patients receiving mechanical ventilation and the relative importance of factors influencing survival.
Prospective cohort of consecutive adult patients admitted to 361 intensive care units who received mechanical ventilation for more than 12 hours between March 1, 1998, and March 31, 1998. Data were collected on each patient at initiation of mechanical ventilation and daily throughout the course of mechanical ventilation for up to 28 days.
All-cause mortality during intensive care unit stay.
Of the 15 757 patients admitted, a total of 5183 (33%) received mechanical ventilation for a mean (SD) duration of 5.9 (7.2) days. The mean (SD) length of stay in the intensive care unit was 11.2 (13.7) days. Overall mortality rate in the intensive care unit was 30.7% (1590 patients) for the entire population, 52% (120) in patients who received ventilation because of acute respiratory distress syndrome, and 22% (115) in patients who received ventilation for an exacerbation of chronic obstructive pulmonary disease. Survival of unselected patients receiving mechanical ventilation for more than 12 hours was 69%. The main conditions independently associated with increased mortality were (1) factors present at the start of mechanical ventilation (odds ratio [OR], 2.98; 95% confidence interval [CI], 2.44-3.63; P<.001 for coma), (2) factors related to patient management (OR, 3.67; 95% CI, 2.02-6.66; P<.001 for plateau airway pressure >35 cm H(2)O), and (3) developments occurring over the course of mechanical ventilation (OR, 8.71; 95% CI, 5.44-13.94; P<.001 for ratio of PaO(2) to fraction of inspired oxygen <100).
Survival among mechanically ventilated patients depends not only on the factors present at the start of mechanical ventilation, but also on the development of complications and patient management in the intensive care unit.
Chronic pulmonary aspiration (CPA) in children is an important cause of recurrent pneumonia, progressive lung injury, respiratory disability and death. It is sporadic, intermittent and variable, and often occurs in children with complicated underlying medical conditions and syndromes that produce symptoms indistinguishable from CPA. For most types of aspiration there is no gold-standard diagnostic test. The diagnosis of CPA is currently made clinically with some supporting diagnostic evaluations, but often not until significant lung injury has been sustained. Despite multiple diagnostic techniques, the diagnosis or exclusion of CPA in children is challenging. This is of particular concern given the outcome of unrecognised progressive lung injury and the invasiveness of definitive therapies. Although new techniques have been introduced since the 1990s and significant advances in the understanding of dysphagia and gastro-oesophageal reflux have been made, characterisation of the aspirating child remains elusive.
Human lung transplantation is a therapeutic option for selected patients with advanced cardiopulmonary disease, but long-term survival is limited by chronic rejection. Persistent acute rejection and gastric aspiration have been implicated as risk factors but there is little or no evidence to date that they are associated.
We have tested the hypothesis that pepsin, a marker of gastric aspiration, is present in lung transplant recipients, and that high levels are associated with biopsy-diagnosed acute rejection and/or bronchiolitis obliterans syndrome.
Levels of bronchoalveolar lavage (BAL) pepsin were measured by ELISA in 36 lung transplant recipients, 4 normal volunteers, and 17 subjects with unexplained chronic cough.
Our primary finding was that, compared with control subjects, BAL pepsin levels were elevated in stable lung transplant recipients, subjects with acute rejection, and subjects with bronchiolitis obliterans syndrome. Our secondary finding was that the highest levels were found in recipients with acute vascular rejection grade > or = A2 (median, 11.2; range, 5.4 - 51.7 ng/ml; normal median, 1.1; range, 0-2.3 ng/ml; p = 0.004).
We have shown that elevated levels of pepsin, a biomarker of gastric aspiration, are consistently identified in the BAL of lung allografts. The highest levels were seen in patients with > or = grade A2 acute rejection. This provides further evidence supporting the possible role of aspiration in the development of overall allograft injury.
PurposeStudies on the impact of tapered-cuff tracheal tubes on rates of microaspiration and ventilator-associated pneumonia (VAP) in intubated patients have reported conflicting results. The aim of this study was to determine the influence of this shape of tracheal cuff on abundant microaspiration of gastric contents in critically ill patients. Methods
All patients intubated in the intensive care unit (ICU) and requiring mechanical ventilation for at least 48 h were eligible for this multicenter cluster-randomized controlled cross-over open-label study. The primary outcome was abundant microaspiration of gastric contents, defined by the presence of pepsin at significant level in >30% of tracheal aspirates. Quantitative measurement of pepsin and salivary amylase was performed in all tracheal aspirates during the 48 h following enrollment. ResultsA total of 326 patients were enrolled in the ten participating ICUs (162 in the PVC tapered-cuff group and 164 in the standard-cuff group). Patient characteristics were similar in the two study groups. The proportion of patients with abundant microaspiration of gastric contents was 53.5% in the tapered-cuff and 51.0% in the standard-cuff group (odds ratio 1.14, 95% CI 0.72–1.82). While abundant microaspiration of oropharyngeal secretions was not significantly different (77.4 vs 68.6%, p = 0.095), the proportion of patients with tracheobronchial colonization was significantly lower (29.6 vs 43.3%, p = 0.01) in the tapered-cuff than in the standard-cuff group. No significant difference between the two groups was found for other secondary outcomes, including ventilator-associated events and VAP. Conclusions
This trial showed no significant impact of tapered-cuff tracheal tubes on abundant microaspiration of gastric contents. Trial registrationClinicalTrials.gov, number NCT01948635.
▪ Objective: To determine if the semirecumbent position (45-degree angle) decreases aspiration of gastric contents to the airways in intubated and mechanically ventilated patients.
▪ Design: A randomized, two-period crossover trial.
▪ Setting: Respiratory intensive care unit.
▪ Patients: Nineteen patients requiring intubation and mechanical ventilation.
▪ Interventions: Patients were studied in the supine and semirecumbent positions on two separate days.
▪ Measurements: After technetium (Tc)-99m sulphur colloid labeling of gastric contents, sequential radioactive counts in endobronchial secretions were measured at 30-minute intervals over a 5-hour period. Samples of endobronchial secretions, gastric juice, and pharyngeal contents were obtained for qualitative bacterial cultures.
▪ Results: Mean radioactive counts in endobronchial secretions were higher in samples obtained while patients were in the supine position than in those obtained while patients were in the semirecumbent position (4154 cpm compared with 954 cpm; P = 0.036). Moreover, the aspiration pattern was time-dependent for each position: For the supine position, radioactivity was 298 cpm at 30 min and 2592 cpm at 300 min (P = 0.013); for the semirecumbent position, radioactivity was 103 cpm at 30 min and 216 cpm at 300 min (P = 0.04). The same microorganisms were isolated from stomach, pharynx, and endobronchial samples in 32% of studies done while patients were semirecumbent and in 68% of studies done while patients were in the supine position.
▪ Conclusions: We conclude that the supine position and length of time the patient is kept in this position are potential risk factors for aspiration of gastric contents. Elevating the head of the bed for patients who can tolerate the semirecumbent position may be a simple, no-cost prophylactic measure.
Unlabelled:
CF patients are often treated with proton pump inhibitors (PPIs) to reduce acidic gastro-esophageal reflux (GER) and bronchial aspiration of duodeno-gastric contents is common in CF. We have previously demonstrated that gastric juice (GJ) from patients "on" PPI can induce interleukin-8 (IL-8) production by bronchial epithelial cells in culture. We hypothesized that such effect would be more pronounced in CF patients known to have high inflammatory susceptibility. We aimed to evaluate the effect of GJ on IL-8 production by primary bronchial epithelial cells (PBEC), derived from a CF patient and a healthy subject.
Methods:
PBEC obtained from one donor (normal PBEC) and one receptor (CF-PBEC) for lung transplantation were stimulated with GJ from patients "off" and "on" PPI. IL-8 levels were measured in the supernatant.
Results:
GJ from patients "on" PPI provoked a significant higher IL-8 production compared to GJ from patients "off" PPI, both in normal PBEC [462 (200-1468) vs. 11 (4-28) pg/ml, p=0.0001] as in CF-PBEC [1468 (841-2449) vs. 85 (26-131) pg/ml, p<0.0001]. Exposure of the cells to GJ "off" PPI and "on" PPI provoked significantly higher IL-8 production in the CF-PBEC compared to the normal PBEC ["off" PPI 85 (26-131) vs. 11 (4-28) pg/ml, p=0.01; "on" PPI 1468 (841-2449) vs. 462 (200-1468) pg/ml, p=0.01]. Filtration (0.20 μm) of the GJ "on" PPI, to eliminate large particles and bacterial sub-products, resulted in a significant decrease of IL-8 production.
Conclusion:
Patients with CF, treated with PPIs, have GJ with high pH and high endotoxin levels. These patients often have GER and bronchial aspiration. The aspirated material (GJ "on" PPI) has a significantly enhanced inflammatory effect on CF bronchial epithelial cells in culture. As chronic PPI treatment in CF may result in a paradoxically increased inflammatory effect in the airways, alternative anti-reflux therapies should be considered in CF.
Objectives:
Extraesophageal symptoms are common manifestations of gastroesophageal reflux disease (GERD). Lack of a definitive diagnostic or treatment standards complicate management, which often leads to multiple specialty consultations, procedures, pharmaceuticals and diagnostic tests. The aim of this study was to determine the economic burden associated with extraesophageal reflux (EER).
Methods:
Direct costs of evaluation were estimated for patients referred with symptoms attributed to EER between 2007 and 2011. Medicare payment for evaluation and management and pharmaceutical prices was used to calculate first year and overall costs of evaluating and treating extraesophageal symptoms attributed to reflux.
Results:
Overall, 281 patients were studied (cough (50%), hoarseness (23%), globus/post-nasal drainage (15%), asthma (9%), and sore throat (3%)). Over a median (interquartile range) of 32 (16-46) months follow-up, patients had a mean (95% confidence interval) of 10.1 (9.4-10.9) consultations with specialists and underwent 6.4 (3-9) diagnostic procedures. Overall, the mean initial year direct cost was $5,438 per patient being evaluated for EER. Medical and non-medical components contributed $5,154 and $283. Of the overall cost, 52% were attributable to the use of proton pump inhibitors. During the initial year, direct costs were 5.6 times higher than those reported for typical GERD ($971). A total of 54% of patients reported improvement of symptoms. Overall cost per improved patient was $13,700.
Conclusions:
EER contributes substantially to health-care expenditures. In this cohort, the cost for initial year's evaluation and treatment of EER symptoms was quintuple that of typical GERD. Prescription costs and, in particular, proton pump inhibitors were the single greatest contributor to the cost of EER management.
Previous uncontrolled studies suggested a therapeutic benefit for treating gastroesophageal reflux disease (GERD) among patients with laryngitis. The present study is the first randomized, placebo-controlled, double-blind study of gastric acid suppression among patients with laryngitis in the United States.
Patients diagnosed with idiopathic chronic laryngitis were randomized to receive either lansoprazole 30 mg p.o. b.i.d. or a matching placebo for 3 months. Before randomization, all patients underwent upper endoscopy, dual probe ambulatory 24-h esophageal pH-metry, and laryngoscopy, as well as completing a symptom questionnaire for GERD and laryngitis. The primary outcome of treatment was the complete resolution of laryngeal symptoms.
A total of 22 patients with symptoms and signs of chronic laryngitis were enrolled, 20 of whom completed the study. At baseline, there were no significant differences between the two groups with regards to GERD symptoms, erosive esophagitis, proximal and distal esophageal pH-metry, or laryngeal signs and symptoms. In an intention-to-treat analysis, six patients in the lansoprazole group (50%) and only one patient (10%) in the placebo group achieved a complete symptomatic response, p = 0.04. Apart from receiving lansoprazole, there were no significant differences between responders and nonresponders in any of baseline esophageal or laryngeal signs and symptoms.
Empirical treatment with lansoprazole is efficacious in relieving symptoms of laryngitis compared to placebo. Such treatment can be considered as a first-line option in managing patients with idiopathic chronic laryngitis.
Objectives:
The subjectivity and complexity of surveillance definitions for ventilator-associated pneumonia preclude meaningful internal or external benchmarking and therefore hamper quality improvement initiatives for ventilated patients. We explored the feasibility of creating objective surveillance definitions for ventilator-associated pneumonia.
Design:
We identified clinical signs suitable for inclusion in objective definitions, proposed candidate definitions incorporating these objective signs, and then applied these definitions to retrospective clinical data to measure their frequencies and associations with adverse outcomes using multivariate regression models for cases and matched controls.
Setting:
Medical and surgical intensive care units in eight U.S. hospitals (four tertiary centers, three community hospitals, and one Veterans Affairs institution).
Patients:
Eight thousand seven hundred thirty-five consecutive episodes of mechanical ventilation for adult patients.
Interventions:
We evaluated 32 different candidate definitions composed of different combinations of the following signs: three thresholds for respiratory deterioration defined by sustained increases in daily minimum positive end-expiratory pressure or FIO2 after either 2 or 3 days of stable or decreasing ventilator settings, abnormal temperature, abnormal white blood cell count, purulent pulmonary secretions defined by neutrophils on Gram stain, and positive cultures for pathogenic organisms.
Measurements and main results:
Ventilator-associated pneumonia incidence, attributable ventilator days, hospital days, and hospital mortality. All candidate definitions were significantly associated with increased ventilator days and hospital days, but only definitions requiring objective evidence of respiratory deterioration were significantly associated with increased hospital mortality. Significant odds ratios for hospital mortality ranged from 1.9 (95% confidence interval 1.2-2.9) to 6.1 (95% confidence interval 2.2-17). Requiring additional clinical signs beyond respiratory deterioration alone decreased event rates, had little impact on attributable lengths of stay, and diminished sensitivity and positive predictive values for hospital mortality.
Conclusions:
Objective surveillance definitions that include quantitative evidence of respiratory deterioration after a period of stability strongly predict increased length of stay and hospital mortality. These definitions merit further evaluation of their utility for hospital quality and safety improvement programs.
Background Gastro-oesophageal reflux disease (GERD) is one of the commonest diseases of Western populations, affecting 20 to 30% of adults. GERD is multifaceted and the classical oesophageal symptoms such as heartburn and regurgitation often overlap with atypical symptoms that impact upon the respiratory system and airways. This is referred to as extra-oesophageal reflux disease (EERD), or laryngopharyngeal reflux (LPR), which manifests as chronic cough, laryngitis, hoarseness, voice disorders and asthma.
Aim The ‘Reflux and its consequences’ conference was held in Hull in 2010 and brought together a multidisciplinary group of experts all with a common interest in the many manifestations of reflux disease to present recent research and clinical progress in GERD and EERD. In particular new techniques for diagnosing reflux were showcased at the conference.
Methods Both clinical and non-clinical key opinion leaders were invited to write a review on key areas presented at the `Reflux and its consequences' conference for inclusion in this supplement.
Results and conclusion Eleven chapters contained in this supplement reflected the sessions of the conference and included discussion of the nature of the refluxate (acid, pepsin, bile acids and non-acid reflux); mechanisms of tissue damage and protection in the oesophagus, laryngopharynx and airways. Clinical conditions with a reflux aetiology including asthma, chronic cough, airway disease, LPR, and paediatric EERD were reviewed. In addition methods for diagnosis of reflux disease and treatment strategies, especially with reference to non-acid reflux, were considered.
Aliment Pharmacol Ther 2011; 33 (Suppl. 1), 1–71
To evaluate the economic impact of ventilator-associated pneumonia (VAP) on length of stay and hospital costs. Design. Retrospective matched cohort study.
Premier database of hospitals in the United States.
Eligible patients were admitted to intensive care units (ICUs), received mechanical ventilation for ≥2 calendar-days, and were discharged between October 1, 2008, and December 31, 2009.
VAP was defined by International Classification of Diseases, Ninth Revision (ICD-9), code 997.31 and ventilation charges for ≥2 calendar-days. We matched patients with VAP to patients without VAP by propensity score on the basis of demographics, administrative data, and severity of illness. Cost was based on provider perspective and procedural cost accounting methods.
Of 88,689 eligible patients, 2,238 (2.5%) had VAP; the incidence rate was 1.27 per 1,000 ventilation-days. In the matched cohort, patients with VAP ([Formula: see text]) had longer mean durations of mechanical ventilation (21.8 vs 10.3 days), ICU stay (20.5 vs 11.6 days), and hospitalization (32.6 vs 19.5 days; all [Formula: see text]) than patients without VAP ([Formula: see text]). Mean hospitalization costs were $99,598 for patients with VAP and $59,770 for patients without VAP ([Formula: see text]), resulting in an absolute difference of $39,828. Patients with VAP had a lower in-hospital mortality rate than patients without VAP (482/2,144 [22.5%] vs 630/2,144 [29.4%]; [Formula: see text]).
Our findings suggest that VAP continues to occur as defined by the new specific ICD-9 code and is associated with a statistically significant resource utilization burden, which underscores the need for cost-effective interventions to minimize the occurrence of this complication.
Gastroesophageal reflux disease is mediated principally by acid. Today, we recognise reflux reaches beyond the esophagus, where pepsin, not acid, causes damage. Extraesophageal reflux occurs both as liquid and probably aerosol, the latter with a further reach. Pepsin is stable up to pH 7 and regains activity after reacidification. The enzyme adheres to laryngeal cells, depletes its defences, and causes further damage internally after its endocytosis. Extraesophageal reflux can today be detected by recognising pharyngeal acidification using a miniaturised pH probe and by the identification of pepsin in saliva and in exhaled breath condensate by a rapid, sensitive, and specific immunoassay. Proton pump inhibitors do not help the majority with extraesophageal reflux but specifically formulated alginates, which sieve pepsin, give benefit. These new insights may lead to the development of novel drugs that dramatically reduce pepsinogen secretion, block the effects of adherent pepsin, and give corresponding clinical benefit.
“For now we see through a glass, darkly.”
—First epistle, Chapter 13, Corinthians
Some patients with idiopathic pulmonary fibrosis experience acute exacerbations in their respiratory status leading to substantial morbidity and mortality. Occult aspiration of gastric contents has been proposed as one possible mechanism leading to these acute exacerbations. We sought to determine whether pepsin, a marker of gastric aspiration, is elevated in bronchoalveolar lavage fluid obtained from patients during acute exacerbation of idiopathic pulmonary fibrosis, compared with that obtained in stable disease. Lavage samples were obtained in a case-control study of well-characterised patients. Acute exacerbation was defined using standard criteria. Levels of lavage pepsin were compared in cases and controls, and were correlated with clinical features and disease course. 24 cases with acute exacerbations and 30 stable controls were identified. There were no significant differences in baseline demographics between the two groups. Pepsin level was an indicator of acute exacerbation status (p=0.04). On average, pepsin appeared higher in patients with acute exacerbations compared with stable controls. This difference was driven by a subgroup of eight patients (33%) with pepsin levels ≥70 ng·mL(-1). Pepsin level was not an independent predictor of survival time. These results suggest occult aspiration may play a role in some cases of acute exacerbation of idiopathic pulmonary fibrosis.
The goal of this study was to determine, in lung transplant patients, if laparoscopic antireflux surgery (LARS) is an effective means to prevent aspiration as defined by the presence of pepsin in the bronchoalveolar lavage fluid (BALF).
Between September 2009 and November 2010, we collected BALF from 64 lung transplant patients at multiple routine surveillance assessments for acute cellular rejection, or when clinically indicated for diagnostic purposes. The BALF was tested for pepsin by enzyme-linked immunosorbent assay (ELISA). We then compared pepsin concentrations in the BALF of healthy controls (n = 11) and lung transplant patients with and without gastroesophageal reflux disease (GERD) on pH-monitoring (n = 8 and n = 12, respectively), and after treatment of GERD by LARS (n = 19). Time to the development of bronchiolitis obliterans syndrome was contrasted between groups based on GERD status or the presence of pepsin in the BALF.
We found that lung transplant patients with GERD had more pepsin in their BALF than lung transplant patients who underwent LARS (P = .029), and that pepsin was undetectable in the BALF of controls. Moreover, those with more pepsin had quicker progression to BOS and more acute rejection episodes.
This study compared pepsin in the BALF from lung transplant patients with and without LARS. Our data show that: (1) the detection of pepsin in the BALF proves aspiration because it is not present in healthy volunteers, and (2) LARS appears effective as a measure to prevent the aspiration of gastroesophageal refluxate in the lung transplant population. We believe that these findings provide a mechanism for those studies suggesting that LARS may prevent nonallogenic injury to the transplanted lungs from aspiration of gastroesophageal contents.
To critically discuss the attributable mortality of ventilator-associated pneumonia (VAP) and potential sources of variation.
The review will cover the available estimates (0-50%). It will also explore the source of variation because of definition of VAP (being lower if inaccurate), case-mix issues (being lower for trauma patients), the severity of underlying illnesses (being maximal when the severity of underlying illness is intermediate), and on the characteristics and the severity of the VAP episode. Another important source of variation is the use of poorly appropriate statistical models (estimates biased by lead time bias and competing events). New extensions of survival models which take into account the time dependence of VAP occurrence and competing risks allow less biased estimation as compared with traditional models.
Attributable mortality of VAP is about 6%. Accurate diagnostic methods are key to properly estimating it. Traditional statistical models should no longer be used to estimate it. Prevention efforts targeted on patients with intermediate severity may result in the most important outcome benefits.
Chronic passage of gastric and/or alimentary material into the airways is a frequent and difficult-to-diagnose condition. Because alveolar macrophages phagocytose aspirated material, it has been suggested that their identification is a useful diagnostic method. To know the usefulness of the lipid-laden alveolar macrophages (LLAM) index as a diagnostic tool for aspiration, children from 1 month to 16 years of age were included in three groups: G-I, children with pulmonary pathology and suspicion of aspiration by clinic or image evaluation; G-II, with pulmonary pathology without suspicion of aspiration; and G-III, without respiratory symptoms nor suspicion of aspiration. Bronchoalveolar lavage was obtained through bronchoscopy in G-I and G-II, and through endotracheal tube in G-III, and the LLAM index (0-400) was determined. A total of 112 patients (41, 30, and 41 in G-I to III, respectively) were studied. LLAM index (mean +/- SEM) was highest in G-I (233.2 +/- 5.5), as compared with G-II (187.8 +/- 11.6, P < 0.05), and G-III (108.5 +/- 13.5, P < 0.001). However, notable overlap of LLAM values was observed between G-I and G-II, and between G-II and G-III. When patients from G-I and G-III were jointly analyzed, the area under the ROC curve for diagnosing aspiration was 0.92, with a best cutoff value of >165 (98.6% sensitivity, 78.0% specificity, 87.8% overall accuracy). LLAM index, with a cutoff value of >165 is a useful diagnostic test for aspiration when there is suspicion of this condition. However, due to its low specificity, it does not discriminate other causes of chronic lung disease.
Objectives/hypothesis:
The utility of the lipid-laden macrophage index (LLMI) in the evaluation of airway inflammatory processes remains controversial. There is a paucity of normative data in both pediatric and adult populations, and there is wide variability in the reported cases. The goal of this project was to review the LLMI levels in a large series of patients with a wide range of well-documented pulmonary and airway diseases (cystic fibrosis, aspiration, tracheo/bronchomalacia, recurrent pneumonia, asthma, immunosuppressed conditions, and laryngeal clefts) to develop a better understanding of the clinical utility of the LLMI.
Study design:
This study is a retrospective analysis of patients who underwent initial bronchoscopy with broncheoalveolar lavage (BAL) and had specimens sent for determination of LLMI. This study was performed at a major pediatric tertiary care medical center from April 12, 2006 to July 13, 2009.
Methods:
Medical charts were reviewed for major diagnoses, indications for bronchoscopy, the side of lung (right versus left), documented aspiration, suspected aspiration, neutrophil counts, and patient age. These qualitative and quantitative variables were considered in relation to the LLMI.
Results:
The cohort of patients examined were 4.9 ± 4.3 years (4 days to 18 years of age). Forty-two percent were female and 58% were male. The highest median LLMI was in immunocompromised patients with a median of 78. Recurrent pneumonia, aspiration, tracheo/bronchomalacia, and cystic fibrosis had median LLMI levels of 55, 49, 40, and 50, respectively. There was a wide range of LLMI within each primary diagnosis. There was no significant correlation between neutrophils percentage in the BAL and LLMI. There were no significant differences between BAL specimens obtained from the right or left side.
Conclusions:
To our knowledge, this is the largest series of patients reported in the literature to have an LLMI compared with underlying diagnoses. Based on our data and analyses, there is wide variability between the range of LLMI and the primary diagnosis. As such, the diagnostic utility of the LLMI is limited and should be interpreted with caution.
Few contemporary population-based data exist about the incidence, patient characteristics, and outcomes of mechanical ventilation in acute care hospitals. We sought to describe the epidemiology of mechanical ventilation use in the United States.
Retrospective cohort study using year 2005 hospital discharge records from six states. National projections were generated from age-, race-, and sex-specific rates in the cohort.
Nonfederal acute care hospitals.
All discharges that included invasive mechanical ventilation identified using International Classification of Diseases, 9th Revision, Clinical Modification procedure codes (96.7x).
None.
Of 6,469,674 hospitalizations in the six states, 180,326 (2.8%) received invasive mechanical ventilation. There was a wide age distribution with 52.2% of patients <65 yrs of age. A total of 44.6% had at least one major comorbid condition. The most common comorbidities included diabetes (13.2%) and pulmonary disease (13.2%). Inhospital mortality was 34.5%, and only 30.8% of patients were discharged home from the hospital. Almost all patients received care in urban (73.5%) or suburban (23.6%) hospitals vs. rural hospitals (2.9%). Patients in urban hospitals experienced a higher number of organ dysfunctions, more dialysis and tracheostomies, and higher mortality compared with patients in rural hospitals. Projecting to national estimates, there were 790,257 hospitalizations involving mechanical ventilation in 2005, representing 2.7 episodes of mechanical ventilation per 1000 population. Estimated national costs were $27 billion representing 12% of all hospital costs. Incidence, mortality, and cumulative population costs rose significantly with age.
Mechanical ventilation use is common and accounts for a disproportionate amount of resource use, particularly in urban hospitals and in elderly patients. Mortality for mechanically ventilated patients is high. Quality improvement and cost-reduction strategies targeted at these patients are warranted.
To investigate the contribution of pepsin to inflammation attributed to nonacidic gastric reflux via analysis of inflammatory cytokine and cytokine receptor gene expression in pepsin-treated human hypopharyngeal epithelial cells in vitro.
Translational research.
This study was performed in an academic research laboratory.
Human hypopharyngeal epithelial cells were incubated with or without pepsin (0.1 mg/mL) at pH 7.4, 37 degrees C, overnight. Expression of 84 inflammatory cytokines and cytokine receptors was analyzed via RT(2) qPCR array.
Expression of a number of inflammatory cytokines and receptors was altered in human hypopharyngeal epithelial cells following overnight treatment with pepsin at neutral pH. Greater than 1.5-fold change in gene expression was detected for CCL20, CCL26, IL8, IL1F10, IL1A, IL5, BCL6, CCR6, and CXCL14 (P < 0.05).
Exposure of hypopharyngeal cells to pepsin in a nonacidic environment induces the expression of several pro-inflammatory cytokines and receptors, including those known to be involved in inflammation of esophageal epithelium in response to reflux and which contribute to the pathophysiology of reflux esophagitis. These data indicate that refluxed pepsin may contribute to laryngeal inflammation associated with nonacidic gastric reflux, including that experienced by patients despite maximal acid suppression therapy.
To determine whether peptic activity in bronchoalveolar fluid, due to the presence of the gastric proteolytic enzyme pepsin, could serve as a biochemical marker for pulmonary aspiration of gastric contents.
Prospective, experimental trial.
A university animal research laboratory.
Thirty-six New Zealand rabbits, weighing 2 to 4 kg.
New Zealand rabbits were anesthetized, intubated via tracheostomy, and mechanically ventilated. Pulmonary aspiration was induced by the intratracheal instillation of 2 mL/kg human gastric juice (pH 1.2 +/- 0.2; pepsin activity 0.02 +/- 0.006 microgram/mL; human gastric juice group, n = 24) or normal saline solution (pH 5.2 +/- 0.2; normal saline solution group; n = 12). Mechanical ventilation was continued. Bronchoalveolar lavage was performed at 15 mins (human gastric juice group, n = 8; normal saline solution group, n = 4), 30 mins (human gastric juice group, n = 8; normal saline solution group, n = 4), or 60 mins (human gastric juice group, n = 8; normal saline solution group, n = 4) postaspiration.
Peak airway pressure and PaO2 values were measured at baseline and 15 and 30 mins after aspiration. The pH of retrieved bronchoalveolar lavage fluid was measured and pepsin activity in sample fluid was determined. Changes from baseline in peak airway pressure and PaO2 were significant in human gastric juice animals at 15 and 30 mins when compared with normal saline solution animals (PaO2 -4% vs. -44%, peak airway pressure 20% vs. 36% at 15 mins; PaO2 -16% vs. -79%, peak airway pressure 28% vs. 69% at 30 mins; normal saline solution group vs. human gastric juice group, p < .02). Bronchoalveolar lavage fluid pH was not significantly different between groups at any time postaspiration (6.6 +/- 0.7 vs. 6.0 +/- 0.4 at 15 mins; 7.4 +/- 0.9 vs. 6.5 +/- 0.4 at 30 mins; 7.2 +/- 0.5 vs. 6.4 +/- 0.4 at 60 mins, normal saline solution group vs. human gastric juice group, p = NS). No peptic activity was present in bronchoalveolar lavage fluid from normal saline solution animals at any time. In the human gastric juice group, peptic activity was detected in postaspiration bronchoalveolar lavage fluid in eight of eight animals at 15 mins, six of eight animals at 30 mins, and five of eight animals at 60 mins (normal saline solution group vs. human gastric juice group; p < .001 at 15 mins, p < .01 at 30 mins, p = NS at 60 mins). Peptic activity of bronchoalveolar lavage fluid varied; mean values were greater at 15 mins than at 30 or 60 mins (pepsin activity: 0.004 +/- 0.002 microgram/mL vs. 0.002 +/- 0.001 microgram/mL vs. 0.0006 +/- 0.0001 microgram/mL, respectively, p < .05).
The results of this study suggest that peptic activity in bronchoalveolar lavage fluid can be detected up to 60 mins after induced, experimental gastric juice aspiration and may prove a clinically useful biochemical marker for episodes of occult pulmonary aspiration of gastric contents.
At present there is no test available which identifies children suffering from silent aspiration due to gastroesophageal reflux (GER). The purpose of this study was to determine whether lipid-laden alveolar macrophage (LLAM) scoring is a useful method to arrive at the diagnosis. We evaluated bronchoalveolar lavage fluid (BALF) from 68 children aged 6 months to 14 years (median 3.75 years) for the presence of lipid-laden alveolar macrophages. We compared children with chronic chest disease (CCD) and GER to healthy surgical controls without known lung disease, and to children with recurrent pneumonia without GER. By grading the amount of intracellular Sudan Red-positive material, we determined a semiquantitative lipid-laden macrophage (LLAM) score for each patient. Patients with chronic chest disease suspected to be caused by silent aspiration secondary to GER had a significantly higher LLAM score (median, 117; range, 10-956) than children with recurrent pneumonia due to other reasons (median, 29; range, 5-127; P < 0.01) and healthy controls (median, 37; range, 5-188; P < 0.01). We believe that simply observing lipid-laden macrophages is nonspecific, but quantitation of these cells is a useful method for diagnosing silent aspiration in children, especially when the score exceeds 200.
To investigate factors related to ventilator-associated pneumonia to assist in the development and implementation of prevention strategies.
A retrospective, descriptive design was used. Power analysis determined sample size. A consecutive sample of 120 patients admitted to the critical care units of a level I trauma center who were receiving mechanical ventilation was used. Data were obtained from clinical and financial databases. Variables included demographic data, causative organism of the pneumonia, medications, comorbid conditions, complications, duration of therapies, length of stay, and cost per case.
The average patient was a 49-year-old man. The sample was 54.9% trauma patients, and the prevalence of ventilator-associated pneumonia was 16.7%. Significant factors included duration of intubation (r = 0.28, P = .005), mechanical ventilation (r = 0.26, P = .005), and tube feeding (r = 0.30, P = .001); trauma (phi = 0.24, P = .009); and use of histamine2 receptor antagonists (phi = -0.25, P = .006). The only variable that significantly increased the odds ratio for ventilator-associated pneumonia was trauma. The only variable that significantly decreased the odds ratio was use of histamine2 receptor antagonists. Patients in whom ventilator-associated pneumonia developed had a 16-day increase in length of stay (t = -2.68, P = .008), and a $29,369 increase in cost per case (t = -3.649, P = .000).
These findings provide a baseline for discussions about potential changes in practice to help prevent ventilator-associated pneumonia.
Proton-pump inhibitors are often recommended in the treatment of laryngitis secondary to gastric reflux. Despite prospective treatment studies reporting high efficacy, only one previous report has been placebo-controlled and blinded. The objective of this study was to determine the efficacy of omeprazole in treating proven reflux laryngitis.
Prospective, placebo-controlled, randomized, double-blind clinical trial.
Fifty-three patients with one or more reflux laryngitis symptoms were recruited to undergo 24-hour dual-channel pH probe testing. Thirty patients with more than four episodes of laryngopharyngeal reflux were enrolled. By random assignment, 15 patients received 40 mg omeprazole twice a day and the other 15 received placebo for a period of 2 months. Symptoms (hoarseness, throat pain, lump in throat sensation, throat clearing, cough, excessive phlegm, dysphagia, odynophagia, and heartburn) and endoscopic laryngeal signs (erythema, edema, and mucus accumulation) were recorded initially, at 1 month, and 2 months.
In general, most symptom scores improved over time for both the omeprazole and placebo groups. Hoarseness, when patients begin with low hoarseness symptom scores, and throat clearing improved significantly more in patients on omeprazole than in those on placebo during the 2-month study. Throat pain, lump in throat sensation, excessive phlegm, difficulty swallowing, pain with swallowing, and heartburn showed improvement in both treatment arms, signifying the possibility of a placebo effect. Endoscopic laryngeal signs did not change significantly over the course of the study for either treatment group.
A placebo effect appears to exist in the treatment of reflux laryngitis. However, hoarseness, when initially scored low, and throat clearing resulting from reflux laryngitis are effectively treated by omeprazole.
Although assessment for aspiration of small volumes of gastric contents in tube-fed patients receiving mechanical ventilation is important, available methods for this purpose are not wholly satisfactory. A potential method is immunoassay of tracheal secretions for the gastric enzyme pepsin.
To determine the frequency with which pepsin in suctioned tracheal secretions from acutely ill, tube-fed patients receiving mechanical ventilation could be detected via an immunoassay.
A convenience sample of 136 specimens of suctioned tracheal secretions was collected from 30 acutely ill, tube-fed adults receiving mechanical ventilation. Multiple samples were obtained from 26 of the 30 patients (range, 2-11 per subject). An immunoassay with rooster polyclonal antibodies to purified human pepsin was used to detect pepsin in the secretions.
Fourteen specimens tested positive for pepsin. Secretions from 5 patients accounted for the 14 pepsin-positive results. A significant relationship was found between the position of the head of the bed and the presence of pepsin in tracheal secretions (P<.001). Of the 14 pepsin-positive specimens, 13 (92.9%) were obtained from subjects in a flat position.
A pepsin immunoassay can be used to detect pepsin in human tracheal secretions. If pepsin in tracheal secretions is considered an indicator of aspiration of gastric contents, aspiration occurred in 5 of the 30 subjects. A flat position is strongly associated with the presence of pepsin in tracheal secretions.
Aspiration of gastric contents is a relatively common cause of acute and chronic pulmonary disease. However, a reliable method of diagnosing recurrent aspiration is currently lacking. The aim of this study was to determine whether the presence of gastric pepsin in tracheal aspirates of infants and children might be used as a reliable marker of the microaspiration of refluxed gastric contents.
Ninety-eight children undergoing general anesthesia and tracheal intubation participated in the study. Sixty-four of 98 children underwent endoscopy for clinically significant gastroesophageal reflux. Thirty-four children from routine operative lists were nonreflux controls. These two groups were further subdivided based on the presence or absence of associated respiratory symptoms. After endotracheal intubation, tracheal aspirates were obtained and subsequently assayed for gastric pepsin using a fluoroscein isothiocyanate casein.
Pepsin was detected in 7 of 27 children with reflux symptoms alone and in 7 of 8 of those with chronic respiratory symptoms. In addition, pepsin was present in 31 of 37 children with a history of both reflux and chronic respiratory symptoms. Tracheal pepsin was not detected in any of the 26 children without gastroesophageal reflux or respiratory symptoms. Tracheal pepsin was found significantly more frequently in children with reflux symptoms than in those without, particularly in children with both reflux and respiratory problems.
Tracheal pepsin assay as a reliable marker of gastroesophageal reflux aspiration.
The detection of glucose in tracheal secretions has been used as an indicator of aspiration in mechanically ventilated, tube-fed children. Pepsin detection may be a more specific indicator. We determined the frequency of pepsin and glucose detection in tracheal secretions of mechanically ventilated children and studied the relationships between tracheal secretion pepsin and glucose and clinical evidence of gastroesophageal reflux.
Prospective observational study.
University teaching hospital.
A convenience sample of mechanically ventilated children.
Tracheal secretions were collected at the time of routine endotracheal tube suctioning. Tracheal aspirate glucose concentrations were assessed by using glucose oxidase reagent strips. Tracheal aspirate pepsin was detected by laboratory immunoassay.
One hundred tracheal aspirates were collected from 37 children. Pepsin (>or=1 microg/mL) was detected in nine aspirates, and glucose (>or=20 mg/dL) was detected in 59 aspirates. Overall, five (13.5%) patients had at least one pepsin-positive aspirate, and 33 (89%) had at least one glucose-positive aspirate. Patients with at least one pepsin-positive aspirate were more likely to have clinical evidence of gastroesophageal reflux than patients with pepsin-negative aspirates (5 of 5 vs. 9 of 32, p <.01, Fisher's exact test). Tracheal aspirate glucose positivity was unrelated to the administration of tube feedings and gastroesophageal reflux. No relationship between pepsin and glucose positivity was observed.
Pepsin is detectable in tracheal secretions of mechanically ventilated children at risk for aspiration. Elevated glucose concentrations in tracheal secretions can occur by mechanisms other than aspiration of glucose-rich formula. Pepsin may be a more specific marker for aspiration than glucose.
The optimal management of patients with reflux-associated laryngitis is unclear. We performed a placebo-controlled crossover trial in patients with proven reflux disease and associated laryngitis to determine the effect of pantoprazole and to gain information on the natural course of the disease.
Sixty-two consecutive non-smoking patients with hoarseness and proven laryngitis were examined. Scores with respect to the larynx and for subjective complaints were determined and 24-h pH-metry to assess acid reflux in the lower oesophagus and pharynx was performed. Patients with pathologic reflux were given the chance to enter a double-blinded randomized crossover trial with pantoprazole 40 mg b.i.d. and placebo for a duration of 3 months each, separated by a 2-week washout period.
Twenty-four of 62 patients showed pathological reflux; 21 patients were included in the study and 14 concluded all parts of the study. Both pantoprazole and placebo resulted in a marked improvement in laryngitis scores (decrease of 8.0 +/- 1.4 versus 5.6 +/- 2.6; no significant difference between the 2 treatments) and symptoms after the first 3 months (decrease of oesophageal symptom score of 2.2 +/- 1.4 versus 5.4 +/- 2.8; decrease of laryngeal scores of 8.3 +/- 3.6 versus 10.3 +/- 3.9; also no significant difference between the 2 treatments). A second pH-metry 2 weeks thereafter proved the persistence of reflux in most of these patients. Switching to pantoprazole led to a further improvement of scores. In the group switched to placebo there was recurrence only in a minority of patients. CONCLUSIONs: The self-limited nature of reflux-associated laryngitis in non-smokers is largely underestimated. Laryngitis improves despite the persistence of reflux. Pantoprazole may be helpful especially in relieving acute symptoms, but the advantage of long-term treatment over placebo has been greatly overestimated.
OBJECTIVE: Unsuccessful extubation from mechanical ventilation increases mortality and morbidity. Therefore, the identification of an accurate predictor of successful extubation is desirable. This study was designed to determine whether the results of easily performed respiratory measurements, particularly if reported as "combined extubation" indices, were better predictors of extubation failure in a pediatric population than were readily available clinical data. DESIGN: Prospective observational study. SETTING: Tertiary pediatric intensive care unit. PATIENTS: All children who required mechanical ventilation for >/=24 hrs during a 12-month period and whose parents gave informed written consent. INTERVENTIONS: Respiratory function measurements were made (on average) 7 hrs (range, 0.2-25.0 hrs) before extubation. Arterial blood gas results were obtained immediately before extubation. The values of each predictor associated with maximum sensitivity and specificity were determined, and the areas under receiver operator characteristic curves were compared to determine the most accurate predictor of successful extubation. MEASUREMENTS AND MAIN RESULTS: A total of 47 children (mean age, 3.90 yrs; range, 0.10-17.3 yrs) were studied; extubation failed in 7. A low tidal volume (<7.5 mL/kg) and a low minute volume (<250 mL/kg) had the highest sensitivities (86% and 71%, respectively) and specificities (61% and 71%, respectively) in predicting extubation failure. The a/A ratio performed least well in predicting extubation failure (area under the receiver operating characteristic curve, 0.51). CONCLUSIONS: Volume measurements during pediatric mechanical ventilation may facilitate successful extubation.
To describe and identify factors associated with mortality rate and quality of life 1 yr after prolonged mechanical ventilation.
Prospective, observational cohort study with patient recruitment over 26 months and follow-up for 1 yr.
Intensive care units at a tertiary care university hospital.
Adult patients receiving prolonged mechanical ventilation.
None.
We measured mortality rate and functional status, defined as the inability to perform instrumental activities of daily living (IADLs) 1 yr following prolonged mechanical ventilation. The study enrolled 817 patients. Their median age was 65 yrs, 46% were women, and 44% were alive at 1 yr. Median ages at baseline of 1-yr survivors and nonsurvivors were 53 and 71 yrs, respectively. At the time of admission to the hospital, survivors had fewer comorbidities, lower severity of illness score, and less dependence compared with nonsurvivors. Severity of illness on admission to the intensive care unit and prehospitalization functional status had a significant association with short-term mortality rate, whereas age and comorbidities were related to long-term mortality. Fifty-seven percent of the surviving patients needed caregiver assistance at 1 yr of follow-up. The odds of having IADL dependence at 1-yr among survivors was greater in older patients (odds ratio 1.04 for 1-yr increase in age) and those with IADL dependence before hospitalization (odds ratio 2.27).
Mortality rate after prolonged mechanical ventilation is high. Long-term mortality rate is associated with older age and poor prehospitalization functional status. Many survivors needed assistance after discharge from the hospital, and more than half still required caregiver assistance at 1 yr. Interventions providing support for caregivers and patients may improve the functional status and quality of life of both groups and thus need to be evaluated.
Acute respiratory failure requiring mechanical ventilation continues to contribute to mortality and affect long-term functional outcomes in patients admitted to the pediatric intensive care unit (ICU). Studies in adults with acute respiratory distress syndrome (ARDS) far outnumber those conducted in the pediatric age group, and pediatric intensivists are left with the task of carefully selecting and critically appraising relevant adult data and extrapolating results to their domain of practice.
The recent ARDSNet study reinforces the use of low tidal volumes. Administration of surfactant is safe, but once again its beneficial effect was not sustained in a randomized trial. Surfactant proteins A and D have been shown to be of prognostic value in cases of acute lung injury. The effect of inhaled nitric oxide (NO) in patients with ARDS can be enhanced by aggressive lung recruitment strategies such as can be achieved using high-frequency oscillatory ventilation (HFOV). A recent adult trial shows good response rates but no significant long-term outcome benefit from prone positioning in patients with ARDS. Routine scheduled assessments of readiness for weaning and extubation may be more important than specific weaning modes and weaning criteria for children. A recent meta-analysis suggests that prophylactic dexamethasone use may decrease postextubation stridor and possibly reduce the need for reintubation in selected patients. Outcome data in children requiring mechanical support is encouraging, especially for high-risk groups such as bone marrow transplant (BMT) recipients, and may guide ethically challenging decision-making for these patients.
Mechanical ventilation strategies aiming for optimal alveolar recruitment with the judicious use of positive end-expiratory pressure (PEEP) and low tidal volumes will remain the mainstay for managing respiratory failure in children. Dexamethasone may prevent postextubation stridor. Prone positioning, surfactant therapy, HFOV, and inhaled NO are used sporadically and need to be evaluated for their effect on mortality and duration of ventilation.
To determine the efficacy of proton-pump inhibitor (PPI) therapy for chronic laryngo-pharyngitis treated with lifestyle modification.
Double-blind, randomized trial comparing two-month Rabeprazole (20 mg b.i.d.) to placebo control.
Compared to baseline, both PPI and control patients had significant improvement in total reflux symptoms (P = 0.002 and P = 0.03 respectively), with significant improvement in "laryngo-pharyngeal" but not "typical" reflux symptoms. No significant difference was noted for change in reflux symptoms between PPI-treated and control patients (P = 0.44). Significant global improvement was noted by 50% of control and 53% of PPI-treated patients (P = 1.0). No significant differences were noted within or between treatment groups for change in health status or videostrobolaryngoscopy grade. Lifestyle modification compliance correlated significantly with global improvement.
Compared to baseline, lifestyle modification for 2 months significantly improved chronic laryngo-pharyngitis symptoms. When compared to control, treatment with a PPI failed to demonstrate significantly greater improvement in reflux symptoms, health status, or laryngeal appearance.
Prophylaxis is routinely provided for critically ill patients admitted to intensive care units (ICUs) who are at high risk for stress-related mucosal damage (SRMD), an erosive process of the gastroduodenum associated with abnormally high physiological demands. Traditionally, treatment options have included sucralfate, antacids and histamine H2 receptor antagonists (H2RAs). The H2RAs are currently the most widely used agents in prophylactic acid suppression; however, proton pump inhibitors (PPIs) have recently replaced H2RAs in the treatment of many acid-related conditions. PPIs achieve a more rapid and sustained increase in gastric pH and are not associated with the rapid tachyphylaxis seen with H2RAs. As a result, and after the introduction of intravenous formulations, PPIs are beginning to be used for the prophylaxis of SRMD in critically ill adults. The high prevalence of renal and hepatic impairment among the ICU population, as well as the need for multiple drug therapy in many patients, means that pharmacokinetic characteristics and the potential for drug interactions may be important considerations in the choice of prophylactic agent. This review seeks to present the pharmacological evidence that may inform decision-making about the prescription of drugs for prophylaxis of SRMD.
Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in critically ill patients. The clinical and economic consequences of VAP are unclear, with a broad range of values reported in the literature
To perform a systematic review to determine the incidence of VAP and its attributable mortality rate, length of stay, and costs.
Computerized PUBMED and MEDLINE search supplemented by manual searches for relevant articles, limited to articles published after 1990.
English-language observational studies and randomized trials that provided data on the incidence of VAP were included. Matched cohort studies were included for calculation of attributable mortality rate and length of stay.
Data were extracted on patient population, diagnostic criteria for VAP, incidence, outcome, type of intensive care unit, and study design.
The cumulative incidence of VAP was calculated by combining the results of several studies using standard formulas for combining proportions, in which the weighted average and variance are calculated. Results from studies comparing intensive care unit and hospital mortality due to VAP, additional length of stay, and additional days of mechanical ventilation were pooled using a random effects model, with assessment of heterogeneity.
Our findings indicate a) between 10% and 20% of patients receiving >48 hrs of mechanical ventilation will develop VAP; b) critically ill patients who develop VAP appear to be twice as likely to die compared with similar patients without VAP (pooled odds ratio, 2.03; 95% confidence interval, 1.16-3.56); c) patients with VAP have significantly longer intensive care unit lengths of stay (mean = 6.10 days; 95% confidence interval, 5.32-6.87 days); and d) patients who develop VAP incur > or = USD $10,019 in additional hospital costs.
Ventilator-associated pneumonia occurs in a considerable proportion of patients undergoing mechanical ventilation and is associated with substantial morbidity, a two-fold mortality rate, and excess cost. Given these findings, strategies that effectively prevent VAP are urgently needed.
A half decade has elapsed since the Institute of Medicine released 2 landmark reports on health care safety and quality, To Err Is Human1 and Crossing the Quality Chasm.2 Those studies helped articulate a broad agenda for quality improvement in health care, and examples of success on a small scale are numerous. However, the collective impact of improvement work has been far below the potential envisioned by the Institute of Medicine. Health care can benefit now from a new sense of urgency, with levels of discipline and pace akin to those of a political campaign.
To evaluate the efficacy of acid-suppressive therapy with the proton pump inhibitor esomeprazole on the signs and symptoms of chronic posterior laryngitis (CPL) in patients with suspected reflux laryngitis.
Prospective, multicenter, randomized, parallel-group trial that compared twice-daily esomeprazole 40 mg with placebo for 16 weeks.
Eligible patients had a history of one or more CPL symptoms (throat clearing, cough, globus, sore throat, or hoarseness) and laryngoscopic signs indicating reflux laryngitis based on CPL index (CPLI) scores measured during a screening laryngoscopy. Patients were randomized to treatment if their 7-day screening diary-card recordings showed a cumulative primary symptom score of 9 or higher and they had 3 or more days with moderately severe symptoms based on a 7-point scale. Efficacy was assessed by changes in symptoms as recorded by patients and investigators and by changes in CPLI scores based on laryngoscopic examinations.
The patients' primary CPL symptom at final visit (primary efficacy end point) was resolved in 14.7% (14/95) and 16.0% (8/50) of patients in the esomeprazole and placebo groups, respectively (P=.799). Esomeprazole and placebo were not significantly different for change from baseline to the final visit in mean total CPLI (-1.66+/-2.13 vs. -2.0+/-2.55, respectively; P=.446) or any other secondary efficacy end points based on patient diary card or investigator assessments.
This study provides no evidence of a therapeutic benefit of treatment with esomeprazole 40 mg twice daily for 16 weeks compared with placebo for signs and symptoms associated with CPL.
Gastro-oesophageal reflux (GOR)-related aspiration is associated with respiratory disease, but the current "gold standard" investigation, the lipid-laden macrophage index (LLMI), is flawed. A specific marker of GOR-related aspiration should originate in the stomach, but not the lung. An assay to detect gastric pepsin in the bronchoalveolar lavage (BAL) of children was developed and validated.
Gastro-oesophageal reflux was diagnosed in 33 children using intra-oesophageal pH monitoring. Thirteen asymptomatic negative controls requiring endotracheal intubation for elective surgery and 5 positive control patients with observed aspiration were recruited. All subjects received a BAL; the fluid obtained was analysed for the pepsin content and the LLMI.
All subjects in the negative control group were negative for pepsin. The positive control group had a significantly greater median pepsin level (P < .01) compared with negative controls. Patients with proximal oesophageal GOR and chronic cough also had significantly elevated pepsin levels (P = .04). The LLMI was not significantly elevated by the presence of cough or GOR.
This study suggests that GOR-related aspiration plays a role in chronic cough in children with known GOR. Detecting pepsin in BAL fluid may therefore become an important adjunct in patient selection for antireflux surgery.
Results of randomized treatment trials for laryngopharyngeal reflux (LPR) are mixed. The cause and effect between gastroesophageal reflux and laryngeal symptoms remain elusive.
To determine the efficacy of single-dose pantoprazole in newly diagnosed LPR and to correlate hypopharyngeal reflux with symptom improvement.
Randomized, double-blind, placebo-controlled trial was performed with a 2-wk run-in, 12-wk treatment period (pantoprazole 40 mg q.a.m. or placebo), and 4-wk follow-up. Study criteria were laryngeal complaints >3 days/wk and a positive triple-sensor pH test. Laryngeal exam was graded using a reflux finding score before and after treatment. Repeat pH test was performed on study drug at week 12. Weekly diaries were kept on symptom severity and global assessment. Total laryngeal symptom score was defined as the sum of six laryngeal symptoms. Mann-Whitney U, Wilcoxon, and Pearson tests were used.
Thirty-nine subjects (13 M/26 F, median age 39 yr) were randomized; 35 completed the study. During the treatment period, total laryngeal symptom scores significantly improved compared with pretreatment scores in both study groups, but there were no significant differences between them. Forty percent of pantoprazole group reported adequate relief at week 12, compared with 42% of placebo group (p= 0.89). No significant improvement in hypopharyngeal reflux was found in either study group. There were no significant correlations between laryngeal reflux finding scores and hypopharyngeal reflux episodes with symptom improvement.
Response was similar between single-dose pantoprazole and placebo in newly diagnosed LPR. Our results suggested that laryngeal exam was not useful in following treatment response. Hypopharyngeal reflux may represent acid reflux or artifacts, but is not likely the underlying cause.
Exposure of laryngeal epithelia to pepsin during extra-esophageal reflux causes depletion of laryngeal protective proteins, carbonic anhydrase isoenzyme III (CAIII), and squamous epithelial stress protein Sep70. The first objective of this study was to determine whether pepsin has to be enzymatically active to deplete these proteins. The second objective was to investigate the effect of pH on the activity and stability of human pepsin 3b under conditions that might be found in the human esophagus and larynx.
Prospective translational research study.
An established porcine in vitro model was used to examine the effect of active/inactive pepsin on laryngeal CAIII and Sep70 protein levels. The activity and stability of pepsin was determined by kinetic assay, measuring the rate of hydrolysis of a synthetic pepsin-specific substrate after incubation at various pH values for increasing duration.
Active pepsin is required to deplete laryngeal CAIII and Sep70. Pepsin has maximum activity at pH 2.0 and is inactive at pH 6.5 or higher. Although pepsin is inactive at pH 6.5 and above, it remains stable until pH 8.0 and can be reactivated when the pH is reduced. Pepsin is stable for at least 24 hours at pH 7.0, 37 degrees C and retains 79% +/- 11% of its original activity after re-acidification at pH 3.0.
Detectable levels of pepsin remain in laryngeal epithelia after a reflux event. Pepsin bound there would be enzymatically inactive because the mean pH of the laryngopharynx is pH 6.8. Significantly, pepsin could remain in a form that would be reactivated by a subsequent decrease in pH, such as would occur during an acidic reflux event or possibly after uptake into intracellular compartments of lower pH.