Prevention and Control of Nosocomial Pneumonia

Published on 22/03/2015 by admin

Filed under Critical Care Medicine

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1263 times

126 Prevention and Control of Nosocomial Pneumonia

Richard G. Wunderink

Preventing pneumonia in the critically ill is a daunting task, and even controlling the incidence is difficult. Despite this, many in the patient safety movement have suggested that nosocomial pneumonia should be a “never” event. While complete prevention of nosocomial pneumonia is unlikely, substantial progress has been made in reducing the incidence.

Pneumonia is the most common nosocomial infection in the intensive care unit (ICU).1 The frequency of ventilator-associated pneumonia (VAP) varies from 8% to 28%.2 A large 1-day point prevalence study of pneumonia demonstrated that nearly 10% of ICU patients were being treated for pneumonia.1 However, rather than overall rates, the incidence per day of mechanical ventilation is a more legitimate description. The National Nosocomial Infection Surveillance program reports VAPs/1000 ventilator days. However, the risk of VAP also does not remain static throughout the duration of ICU stay. The greatest risk is early in the course of mechanical ventilation, dropping from a daily hazard rate of 3.3% at day 5 to a 1.3% rate at day 15.3 The incidence also varies significantly among different types of ICU patients. Postoperative patients, especially those undergoing cardiothoracic and trauma-related surgery, appear to have the highest rates. Coronary care unit patients appear to have the lowest rates; medical, respiratory, and other surgical patients demonstrate intermediate rates.

The influence of endotracheal intubation is so dominant that ICU-acquired pneumonia is almost synonymous with VAP. Endotracheal intubation increases the rate of nosocomial pneumonia between 3- and 21-fold.2 Research on hospital-acquired pneumonia has been dominated by VAP, and very little is known about pneumonia in nonintubated ICU patients. Because the effect of nosocomial pneumonia on morbidity and mortality in nonintubated patients is minor compared with that of VAP, concentration on VAP is appropriate.

A distinction should be made between prevention of all nosocomial pneumonia and prevention of life-threatening nosocomial pneumonia. The latter is almost exclusively VAP. The crude mortality rate for VAP ranges from 24% to 76%, with an estimated attributable mortality of 20% to 30%.2,4 Early-onset VAP (within 5-7 days of intubation) has a minimal effect on mortality if any. The greatest crude and attributable mortality rates are associated with late-onset multidrug resistant (MDR) microorganisms such as Pseudomonas aeruginosa, Acinetobacter spp., and methicillin-resistant Staphylococcus aureus (MRSA). Unfortunately, the most effective and well-documented strategies to prevent pneumonia work predominantly or exclusively in early-onset VAP and therefore have not resulted in a significant improvement in mortality. Conversely, one of the most consistent adverse effects of VAP (including early onset) is a prolonged duration of mechanical ventilation. Because duration of ICU stay is the principal determinant of cost of care, prevention measures may be cost-effective even if they do not result in improved mortality.

image Pathogenesis

The key to effective prevention and control strategies is a clear understanding of the underlying pathogenesis of nosocomial pneumonia. The essence of nosocomial pneumonia pathogenesis involves three basic steps:

1 Colonization of the oropharynx with pathogenic microorganisms
2 Aspiration
3 Overwhelming of the lower respiratory tract’s host defense mechanisms

Effective prevention and control measures can be analyzed by their effect on one or more of these steps.

Despite the convenience of this simple analysis, to assume that the pathogenesis of all types of nosocomial pneumonia and VAP is the same would be naive and incorrect. An example is the role of gastric colonization preceding oropharyngeal colonization, the basis for attention to enteral feedings and stress ulcer prophylaxis in VAP prevention. Although possibly an important factor for pneumonia due to Enterobacteriaceae, gastric and enteric colonization has no role in the pathogenesis of S. aureus or P. aeruginosa pneumonia, the two most common causes of VAP. Conversely, daily chlorhexidine baths did not prevent VAP in a trauma population but did significantly decrease VAP from MRSA.5 Therefore, prevention strategies should be individualized to the pathogens and mechanisms prevalent in a specific ICU.

Colonization with Pathogenic Microorganisms

The antecedent event to most nosocomial pneumonias is colonization of the oropharynx with pathogenic bacteria. The oropharynx is not sterile normally, but the character of the normal flora is remarkably constant. A variety of factors alter the normal flora, allowing more pathogenic microorganisms to appear and increase in number.

Time of exposure to these selective forces is a critical issue. Early-onset pneumonia, even early-onset VAP, tends to be caused by less pathogenic microorganisms such as streptococci, Hemophilus influenzae, or methicillin-sensitive S. aureus. Most of these selective forces are introduced in the hospital environment itself, rather than specifically in the ICU. Therefore, patients who develop pneumonia during the first few days of ICU admission or mechanical ventilation are at risk for MDR pathogens if the ICU admission was preceded by a 3- to 5-day hospital stay. Many of the same factors also operate in skilled-care nursing home facilities, blurring the distinction between hospital- and community-acquired pneumonia, and have led to a new designation of healthcare-associated pneumonia (HCAP).

Previously, colonization of the oropharynx by gram-negative enteric bacilli, generally from the Enterobacteriaceae family, was the major concern. These microorganisms are part of the normal bowel flora. Oropharyngeal colonization occurred by one of two main routes. The first is reflux of bacteria into the stomach from the duodenum, with subsequent gastroesophageal reflux into the esophagus and oropharynx. Colonization and proliferation in the stomach are critical intermediate steps in this pathway. Therefore, many prevention strategies logically target the stomach. The other route is self-inoculation by the fecal-oral route, through contamination of equipment or the hands of healthcare providers or the patient.

S. aureus is now the most common microorganism causing ICU-acquired pneumonia, with P. aeruginosa the next most common. In addition, Acinetobacter species have become a common cause of VAP in many institutions. None of these three microorganisms has a typical colonization pattern like that of the Enterobacteriaceae. S. aureus is a normal colonizer of the skin and the nasopharynx. Antegrade colonization of the oropharynx from the nose, especially with the use of nasogastric tubes in many critically ill patients, can occur quite easily. Similarly, Acinetobacter is found on moist body surfaces and in the gingival crevices of patients with poor oral hygiene. P. aeruginosa is usually not part of normal bowel flora but is ubiquitous in the environment. One of the unique aspects of Pseudomonas VAP is the appearance of tracheal colonization before oropharyngeal colonization.6 Because colonization of the stomach is not an important intermediary step for these pathogens, prevention measures directed at the stomach are not likely to affect pneumonia caused by these microorganisms. Both MRSA and Acinetobacter colonization can be decreased with the use of chlorhexidine whole-body bathing.5

Avoidance of Antibiotics

The most important factor that leads to increased colonization of the oropharynx with pathogenic microorganisms is the use of systemic antibiotics, especially broad-spectrum antibiotics.7 Antibiotic therapy results in alteration of the oropharyngeal flora and gives pathogens a selection advantage. The broader the antibiotic spectrum, the greater the likelihood normal flora will be affected. At the same time, some pathogens are also eliminated. For this reason, antibiotics function more as amplifying agents rather than as true causes of colonization. The pathogenic microorganisms must still reside in the area normally, such as nasopharyngeal carriage of S. aureus, or be transferred from other sites including the environment to colonize. Thus pneumonia can still occur despite avoidance of antibiotics. However, the causative microorganisms are more likely to be less virulent pathogens or even normal flora, such as α-hemolytic streptococci, and less likely to lead to life-threatening pneumonia.

Diagnostic strategies for fever in the ICU that result in the use of fewer antibiotics have been associated with lower mortality.8 Shorter courses and fewer antibiotics for documented infections in critically ill patients have also been associated with a decreased risk of superinfection.9–11 Although avoiding antibiotics may have only a small effect on the risk of developing the first episode of pneumonia, limiting their usage has a major effect on secondary pneumonia and infection-related death in the ICU.

Use of Topical Antibacterial Agents

In contrast to systemic antibiotics, the use of topical antibiotics for the prevention of colonization may be beneficial. In general, strategies rely on controlling pathogenic microorganisms at specific sites, despite the effect on normal flora. Topical agents generally do not have the toxicity of systemic agents, and although the use of topical antibiotics can lead to MDR isolates, the risk may not be as great as with systemic antibiotics.

Selective Digestive Tract Decontamination

By far the most extensively studied and most aggressive form of topical antibiotic strategy to prevent colonization is selective digestive tract decontamination. Although the specific agents used in different studies vary, the major focus is on controlling oropharyngeal colonization by almost sterilizing the bowel. Therefore, the antibiotics used are directed primarily at gram-negative bacilli (usually polymyxin B and an aminoglycoside) and Candida (usually amphotericin B). Most regimens include two components—topical antibiotics in the oropharynx, and nonabsorbable antibiotics via a gastric tube. Some also include an initial short course of systemic antibiotics.

Despite more than 40 randomized controlled trials and several meta-analyses,12–13 the benefit of selective digestive tract decontamination remains unclear. However, several patterns have emerged. Selective digestive tract decontamination fairly consistently decreases the incidence of VAP when systemic antibiotics are used for the first 48 to 72 hours.14 The rationale for the use of systemic antibiotics is to prevent incipient endogenous infections until sterilization of the bowel occurs. However, an equivalent benefit has been found with a short course of prophylactic antibiotics alone.15

The efficacy of selective digestive tract decontamination in preventing life-threatening late-onset VAP is less clear. Most studies do not demonstrate lower mortality in the treated group, despite lower rates of VAP. Treatment is directed primarily against the Enterobacteriaceae and yeast in the gastrointestinal tract, but because these microorganisms do not cause the majority of cases of VAP in the ICU, its benefit in preventing VAP due to these microorganisms may be diluted by the many cases of pneumonia caused by organisms that are not specifically addressed by the regimen.

The major criticism of selective digestive tract decontamination is the potential for promoting antibiotic resistance. This theoretical risk has not been clearly demonstrated, even in ICUs that have used the regimen for prolonged periods.14 However, recent data which look at the whole ICU and non-ICU ecosystem suggest this may be an issue.16 The major determining factor is probably not the selective decontamination, but rather the concomitant systemic antibiotics. If selective digestive tract decontamination truly decreases the incidence of VAP (and possibly other nosocomial infections), the resultant decrease in systemic antibiotic use may cancel out the risk of selecting for resistant isolates.

Because the major benefit of selective digestive tract decontamination appears to be in preventing VAP due to Enterobacteriaceae, this strategy is probably best reserved for patient populations at increased risk for VAP due to these microorganisms. Postsurgical, trauma, and solid organ transplant patients are in this category. In addition, this approach appears to be very effective as part of the management of epidemics of antibiotic-resistant clones.

Topical Oropharyngeal Agents

Controlling colonization of the oropharynx alone has also generated interest. In a randomized controlled trial of open heart surgery patients, use of a chlorhexidine oral rinse lowered the risk of VAP from 9.4% to 2.9%, with the major effect being on gram-negative bacteria.17–18 This primary finding was accompanied by decreases in all nosocomial infections, fewer nonprophylactic antibiotic prescriptions, and a trend toward lower mortality. Subsequent studies have confirmed the benefit of chlorhexidine topical oral treatments on risk of VAP.19 One advantage of oral decontamination only is no disruption of the normal bowel flora by treating only the primary area of concern. Conversely, chlorhexidine may not be able to prevent infection with MDR pathogens such as Pseudomonas and Acinetobacter.20 Oral decontamination with other agents such as antimicrobial peptides21 has not been demonstrated to be of benefit.

Aerosolized Antibiotics

The earliest studied form of topical colonization prevention was aerosolized antibiotics. In the early era of mechanical ventilation, daily aerosolized polymyxin B resulted in a dramatic decrease in the rate of gram-negative VAP.22 Not surprisingly, routine use was soon complicated by the emergence of antibiotic-resistant microorganisms. This issue, combined with a lack of mortality benefit, led to abandonment of this strategy. Recently, aerosolized ceftazidime was not shown to decrease VAP rates in trauma patients, but also did not increase MDR pathogen colonization.23 A recent variation is to use aerosolized antibiotics for purulent tracheobronchitis, thought to be a precursor to VAP.24

Avoidance of Increased Gastric pH

The normally acidic environment of the gastric lumen is extremely effective in preventing colonization with either swallowed oropharyngeal flora or refluxed enteric flora. Several prevention strategies focus on this aspect of prevention of VAP.

Stress Ulcer Prophylaxis

At one time, gastrointestinal bleeding from stress ulceration was a substantial problem in ventilated patients and a major cause of death. Prophylaxis against stress ulceration was thus considered critical for ventilated patients. However, the incidence of stress mucosal ulceration has decreased markedly as a result of better hemodynamic resuscitation, improved ventilatory strategies, and earlier use of enteral nutrition.

The debate regarding optimal gastrointestinal bleeding prophylaxis has therefore evolved over the last few decades. Initially, antacids were found to be inferior to histamine type 2 blockers (H2 blockers). In addition to increasing gastric pH, antacids increase gastric volume, which is probably an independent risk factor for VAP. Subsequently sucralfate was hypothesized to be superior to H2 blockers because it did not affect gastric pH and might have intrinsic antibacterial properties. No clear-cut benefit of sucralfate over H2 blockers in reducing VAP has been found, while a slight but consistent increase in gastrointestinal bleeding has been documented.25 Proton pump inhibitors are also used frequently despite more limited data.

The major issue is whether stress ulcer prophylaxis is needed at all in most mechanically ventilated patients.25 The few placebo-controlled trials suggest both H2 blockers and sucralfate may lead to an increased risk of VAP. Several multivariate analyses found proton pump inhibitors to be associated with increased pneumonia rates, including HAP/VAP,26 HCAP, and even community-acquired pneumonia. Ironically, use of gastrointestinal prophylaxis is actually encouraged as part of a ventilator/VAP bundle in many institutions. A subgroup of patients at increased risk for gastrointestinal hemorrhage can be identified and patients without these high risk factors may not need prophylaxis.27

Enteral Nutrition Strategies

Malnutrition is clearly associated with an increased risk of pneumonia and increased mortality in the critically ill.28 In addition to classic effects on cell-mediated immunity, an effect specific to pneumonia is increased binding of gram-negative bacilli, including Pseudomonas, to epithelial cells.6

Enteral administration of nutrition is the preferred route for treating and preventing malnutrition in the critically ill, although parenteral nutrition in high risk patients is preferable to no nutrition.28 Meta-analysis has suggested that patients can even be fed soon after gastrointestinal surgery.29–30 However, continuous enteral nutrition infusions may increase both gastric pH and gastric volume and theoretically increase VAP risk. Several multivariate studies have suggested that this potential risk is real.31–32 A randomized trial found that the risk of VAP was increased with early aggressive feedings compared with low-level enteral nutrition (approximately 20% of goal feeding rate).33 The lower rate was chosen to avoid atrophy of the microvilli of the enteric mucosa, a potential source of nosocomial infection. The increased risk of VAP was attributed to an increased risk of aspiration, which is also seen in surgical series.30 Despite this, meta-analyses of early versus delayed enteral nutrition suggest a mortality benefit and probable decreased risk of VAP with early feedings.34 A balance between potential risks would be early initiation of enteral feeding but avoidance of aggressive infusions that might cause high gastric residuals and gastric distention.

Several strategies have been tried to provide enteral feeding yet prevent increased gastric colonization with pathogenic microorganisms. Theoretically, bolus feedings allow intermittent lowering of the gastric pH, potentially sterilizing the stomach between doses. However, one randomized controlled trial found that bolus feedings did not decrease the risk of VAP, and fewer patients achieved their goal feeding rates.35 Acidification of enteral feedings not only did not improve VAP rates but also caused adverse consequences from the resultant metabolic acidosis.36

Modified Endotracheal Tubes

Attention has recently focused on colonization of the endotracheal tube itself. Many bacteria can adhere to the polyvinyl chloride surface of endotracheal tubes through secretion of a glycocalyx. Protected from systemic antibiotics and host defense mechanisms, microorganisms in this glycocalyx can become a source of re-inoculation of the lower respiratory tract. This mechanism may explain the high recurrent VAP rates, particularly for Pseudomonas. Early tracheostomy may also get around this problem,37 at least temporarily. A silver-impregnated endotracheal tube has been demonstrated to lower the incidence of VAP and delay onset in those who do develop VAP,21 although cost remains a barrier to routine use. Other treatments of endotracheal tubes may be developed which kill bacteria, prevent glycocalyx, or prevent quorum sensing.

Cross-Infection

The role of cross-contamination in the ICU should never be underestimated. Cross-contamination can cause colonization with specific pathogenic bacteria in a patient who has no other risk factors for that microorganism. In particular, P. aeruginosa and MRSA appear to have the greatest potential to cause cross-contamination and subsequent infection.

By far the most important factor in cross-infection is handwashing among caregivers. Multiple studies have documented the poor infection control practices of medical personnel, including physicians and bedside nurses. The risk of poor handwashing increases with the intensity of care needed for an individual patient and with the number of patients per nurse. The use of an alcohol-based, self-drying hand wash appears to be effective and to increase compliance with handwashing.38–39

Avoiding cross-contamination via medical equipment is also important. Contaminated equipment is still a major cause of epidemic outbreaks of nosocomial pneumonia. Any clustering of VAP, especially when caused by an unusual agent, should raise this possibility. Respiratory therapy equipment is particularly suspect, and adherence to standards for the sterilization of ventilators, bronchoscopes, and other reusable equipment should be rigorous.

Probably the best strategy is a continuous, multifaceted, multidisciplinary program of infection control.40 An important component of this program is monitoring VAP rates and providing feedback to individual units on infection rates. Although such a program is costly to develop, the substantial cost benefit of avoiding pneumonia usually justifies the expense.

Aspiration

Evidence from a variety of sources documents the importance of aspiration in nosocomial pneumonia, although the definition of aspiration may vary.

Large-Volume Aspiration

Large-volume aspiration is clearly a risk factor in nonintubated ICU patients. Although the aspirated material itself may not be infectious, such as enteral feedings, aspiration of a large bolus clearly predisposes to pneumonia. Large-volume aspiration may result in ARDS, which is by itself associated with an increased risk of VAP. Predisposing factors for this type of aspiration are gastrointestinal, such as protracted vomiting from bowel obstruction or gastrointestinal bleeding, and neurologic, including seizures, induction of anesthesia, and alcohol intoxication.

Appropriate use of endotracheal intubation is actually a protective factor for this type of aspiration. Once large-volume aspiration has occurred, selective use of bronchoscopy to extract solid material that might occlude a bronchus and cause a postobstructive pneumonia is one of the few preventive measures of benefit. Empirical antibiotics, especially prolonged courses, do not clearly prevent pneumonia but do select for more virulent microorganisms.

A form of large-volume aspiration unique to ventilated patients is the inadvertent instillation of ventilator tubing condensate. The condensate in tubing closest to the endotracheal tube frequently contains high levels (>105 organisms/mL) of pathogenic microorganisms. If this condensate is accidentally spilled back into the patient’s tracheobronchial tree, VAP is very likely. This may be one explanation for the increased risk of VAP associated with patient transport out of the ICU.41

Small-Volume Aspiration

Aspiration of a smaller volume of secretions is also associated with an increased risk of pneumonia in both intubated and nonintubated patients. Neurologic disease with inability to protect the upper airway is consistently documented as a risk factor for pneumonia. In this situation, aspiration occurs before or in conjunction with endotracheal intubation. The bolus can be either oropharyngeal secretions or gastric secretions. In the former situation, a large inoculum of oropharyngeal flora can reach the lower respiratory tract, and clinical pneumonia usually occurs within 48 to 72 hours.

Prevention of pneumonia from small-volume aspiration is probably best achieved by prophylactic antibiotics. Prospective observational studies have suggested that antibiotics early in the course of mechanical ventilation are associated with a lower incidence of pneumonia.3,31 However, the best evidence is a prospective randomized trial of short-course cephalosporin prophylaxis (two doses) in patients intubated for nontraumatic coma.15 The incidence of VAP was only 23% in the prophylaxis group, compared with 66% in the control group that did not receive any antibiotic. The findings of this randomized controlled trial are corroborated by many studies of selective decontamination of the digestive tract which found a decreased incidence of pneumonia only if a short course of systemic antibiotics was included with the topical antibiotics.

Prophylactic antibiotics have clearly been demonstrated to be of benefit only in the initial intubation of patients not previously hospitalized for a significant period. The efficacy of the short course is dependent on the fact that the aspirated bolus contains mainly normal oral flora rather than a high concentration of MDR pathogens. These conditions may apply to patient groups other than those with nontraumatic coma, such as respiratory failure from non-bronchitic exacerbations of chronic obstructive lung disease, but the benefit must still be determined.

This prevention strategy seems to contradict the importance of avoiding unnecessary antibiotics, discussed earlier. One very real risk is that preventing early-onset pneumonia, which does not have an attributable mortality, may increase the risk of more lethal late-onset VAP. Two aspects of this strategy outweigh the potential downside of increased risk of oropharyngeal colonization with more pathogenic bacteria. First, the antibiotics are continued for only 24 hours. Second, the 40% lower risk of pneumonia in patients given prophylaxis avoids a longer course of antibiotics, often with a wider spectrum.

Microaspiration

Microaspiration is by far the most important form of aspiration in endotracheally intubated patients. Oropharyngeal secretions pool above the cuff of the endotracheal tube in most intubated patients. Extremely small volumes of secretions can pass below the cuff during small movements of the endotracheal tube associated with head repositioning, coughing, and other activities. Because oropharyngeal secretions contain 106 to 1010 colony-forming units per milliliter of secretions, even 0.1 mL of secretions can present a significant challenge to the host defenses of the lower respiratory tract. In addition, the endotracheal tube itself may become colonized with viable bacteria encrusted in the glycocalyx and deposited on the polyvinyl chloride surface of the tube. Subsequent suctioning or other manipulations of the endotracheal tube can reintroduce bacteria into the lower respiratory tract. Simply suctioning the patient prior to repositioning may decrease the rate of VAP. Several other preventive therapies are directed at stopping or limiting this type of aspiration.

Shorter Duration of Endotracheal Intubation

Epidemiologic studies have demonstrated that the risk of VAP is not linear. The greatest risk occurs early, with a 3% per day risk in the first week, 2% per day in the second week, and 1% per day subsequently.3 In addition, early-onset VAP (within the first 5-7 days of mechanical ventilation) has the lowest attributable mortality.2,4 Therefore, the sooner the patient is extubated, the lower the cumulative risk of pneumonia and the lower the risk of lethal nosocomial pneumonia.

Probably the best strategy is avoiding intubation completely. Management of many patients with noninvasive ventilation is now standard practice in most ICUs. However, patients who fail noninvasive ventilation appear to have an increased duration of subsequent endotracheal intubation and thus an increased risk of VAP. Careful selection of candidates for noninvasive ventilation and early abandonment of this treatment in unsuccessful cases are critical to decreasing the pneumonia risk.

Even when patients are intubated, variations in the duration of mechanical ventilation for the same type and severity of critical illness suggest that efforts to shorten this duration are a viable approach to preventing VAP. Several strategies have demonstrated a significant benefit, including daily interruption of sedation42–43 and daily assessment of ability to wean.44 The overall benefit is partially attributable in part to lower VAP rates.

The downside of an aggressive extubation strategy is the association between reintubation and increased risk of VAP. Several studies have demonstrated that reintubation increases the risk of VAP threefold.41,45 The need for reintubation reexposes the patient to the risk of small-volume aspiration discussed earlier. In addition, colonization of the oropharyngeal secretions by pathogenic bacteria is more likely because of the prior episode of intubation. Therefore, although avoiding or shortening the duration of mechanical ventilation is clearly a laudable goal, an increase in the risk of VAP may occur with an overly aggressive approach.

Early Tracheostomy

The benefit of early tracheostomy remains unsettled.37,46 Tracheostomy has some potential benefits in the prevention of VAP. The glottis is not held open by the endotracheal tube, and the vocal cords can be opposed, decreasing the risk of aspiration significantly. Routine tracheostomy may be one explanation for the leveling off of the incidence of VAP after several weeks of mechanical ventilation. Probably just as important is that the security of a tracheostomy may allow greater mobilization of the patient and a greater amount of time spent in the upright position. Early reports of an increased risk of pneumonia with tracheostomy were compromised by lack of adjustment for prior duration of mechanical ventilation, inaccurate diagnosis (with some tracheostomy site infections classified as pneumonia), and variable surgical techniques. Early tracheostomy performed with the percutaneous dilatational technique may be more beneficial,37 but more data are needed.

Semirecumbent Positioning

Elegant clinical experiments have demonstrated that the degree of gastroesophageal reflux is significantly greater in supine patients than in semirecumbent patients.47 Not only was reflux greater, but bowel flora colonized the oropharynx and bronchial tree in 68% of patients ventilated in the supine position, compared with only 32% in the semirecumbent position.

A prospective randomized trial clearly demonstrated that both clinically suspected and microbiologically confirmed cases of VAP were more common in patients ventilated in the supine position (8% of clinically suspected VAPs versus 34% for semirecumbent).32 Supine body position (odds ratio 6.8) and enteral nutrition (odds ratio 5.7) were both independent risk factors for VAP, with the highest frequency in patients receiving enteral nutrition in the supine position (14 of 28; 50%). This finding suggests that gastric distention, whether caused by feedings or increased gastric secretions, may have an amplifying effect in the supine position.

Avoiding the supine position as much as possible is a simple and effective preventive measure that should be practiced in all ICUs. However, compliance with elevation of the head of the bed to 45 degrees is difficult, and achieving lower degrees of elevation are not associated with decreased VAP rates.48 In patients who are unable to be placed in the semirecumbent position, continuous lateral rotation with specialized beds may have a beneficial effect.49

Avoidance of Ventilator Tubing Manipulation

Several lines of evidence suggest that minimizing the number of manipulations of the ventilator tubing can decrease the incidence of VAP, possibly by decreasing the incidence of small-volume or microaspiration. Condensation of exhaled gas in the expiratory limb of the tubing or from humidifiers in the inspiratory limb can become heavily colonized with bacteria. Instillation of this liquid bolus into the patient’s airway during manipulation of the tubing or movement of the patient can present a significant bacterial challenge to the lower respiratory tract defenses.

The use of heat and moisture exchangers rather than heater-humidifiers would theoretically alleviate some of this risk. A meta-analysis of eight randomized controlled trials suggested a 30% reduction in VAP rates, especially if the patient was ventilated for more than 7 days.50 This benefit is partially offset by increased rates of endotracheal tube occlusion secondary to inspissated secretions with the use of heat and moisture exchangers. Because the rate of VAP is clearly not increased with heat and moisture exchangers, other considerations determine the frequency of their use, especially cost.

The most consistent evidence that ventilator tube manipulation may increase the risk of VAP is that increasing the interval between changes of the ventilator tubing decreases the incidence of VAP. A series of studies progressively increased the duration of time between changes and found equivalent or less VAP with longer intervals. Most institutions no longer change ventilator tubing unless gross contamination is present.

Transporting patients outside the ICU, usually for diagnostic procedures, has also been associated with an increased risk of VAP.41 In a prospective study, 24% of patients requiring transport outside of the ICU developed VAP, compared with only 4% of patients who did not. Unfortunately, more than half of ventilated patients required transport at least once. The need for bagging, changing ventilators, moving the patient out of bed, and other aspects of the process all increase the possibility of inadvertent introduction of condensate from the ventilator tubing into the patient. In addition, unintentional extubation is greater when transferring ventilated patients.

Routine chest physiotherapy, even in a high risk neurologic population, does not prevent VAP.51 However, use of saline instillation when suctioning ventilated patients52 and suctioning prior to repositioning in bed may decrease VAP risk slightly.

Continuous Aspiration of Subglottic Secretions

A specially modified endotracheal tube allows continuous aspiration of subglottic secretions pooled above the endotracheal tube cuff. This tube has an extra channel with the lumen on the dorsal surface, just above the level of the inflatable cuff. Studies of continuous aspiration of subglottic secretions have variably demonstrated lower VAP rates53–54 but mainly in early-onset VAP, usually due to H. influenzae and streptococci. No decrease in VAP due to MDR microorganisms and no mortality differences have been demonstrated. Consistent with this pattern, the benefit is obviated if the patient receives antibiotics early in the course of mechanical ventilation,55 similar to the benefit of prophylactic antibiotics in early-onset VAP.15 Pneumonia can also occur if the system malfunctions, usually due to plugging of the lumen or low cuff pressures allowing secretions to drain into the distal trachea rather than collecting above the cuff. These factors and the high cost have limited the use of this modality.

Avoidance of Gastric Overdistention

Unfortunately, even when in the semirecumbent position, many patients still have gastroesophageal reflux and microaspiration when given enteral feedings. The major issue is overdistention of the stomach. The adverse effect of increased gastric volume may cancel out the beneficial effect of bolus feedings on gastric pH, contributing to this strategy’s lack of benefit. Two strategies have been studied to address this problem. The first is use of nasoenteric tubes rather than nasogastric tubes. Although this strategy is attractive theoretically, meta-analysis of eleven randomized controlled trials did not show a benefit of postpyloric feeding compared with nasogastric feeding.56 The major limitation is the difficulty in placing feeding tubes in the small bowel. The second strategy is the use of gastric prokinetic agents such as metoclopramide. An additional benefit is that these agents increase the tone of the lower esophageal sphincter, potentially decreasing the risk of reflux while increasing gastric emptying. Once again, a randomized controlled trial failed to confirm the benefit of using metoclopramide to decrease the risk of VAP.39 However, the ability of these agents to increase the tolerance of enteral nutrition warrants their continued use, despite no demonstrated effect on VAP.

Overwhelming Lower Respiratory Host Defenses

An underappreciated fact about nosocomial pneumonia is that despite aspiration of oropharyngeal secretions documented to contain pathogenic bacteria, only a minority of colonized patients actually develop pneumonia. In the classic study of Johanson et al., only 23% of patients with gram-negative colonization of the oropharynx subsequently developed pneumonia.57 Others have shown that quantitative culture levels of microorganisms equivalent to those found in pneumonia can transiently appear in routine non-bronchoscopic bronchoalveolar lavage samples without the subsequent clinical VAP.58 Thus, the two steps described earlier—colonization by pathogens and aspiration—are necessary but not sufficient causes of nosocomial pneumonia.

The third step in the pathogenesis of nosocomial pneumonia, the overwhelming of lower respiratory tract defenses, is the least studied or understood. One major reason may be that the causes are heterogeneous and patient dependent, rather than the stereotypical steps of colonization and aspiration. As infection control and patient safety efforts become more effective in limiting these risk factors, the remaining patients who do develop VAP are likely to have significant defects in host immunity.

Patients who develop VAP should generally be considered to have a form of acquired immunosuppression.59 The more frequent occurrence of other nosocomial infections in patients with VAP supports this concept. In addition, a subgroup of VAP patients develop multiple separate episodes of VAP,60 suggesting even greater compromise of their lower respiratory tract defenses.

Many of the causes of compromised lower respiratory tract defenses are due to the underlying disease or critical illness precipitating ICU admission and the need for mechanical ventilation. However, several are generic to most ICU patients and may be targets for prevention strategies.

Malnutrition

The overall rate of VAP appears to have decreased since early in the era of mechanical ventilation. Although a variety of factors may explain this finding, one important change is the aggressive use of nutritional support. In addition to increasing the risk of oropharyngeal colonization, malnutrition blunts many of the inflammatory responses to the bacterial challenge. The need for aggressive early nutrition may be somewhat debatable, but provision of nutrition after 48 hours of mechanical ventilation is clearly the standard of care. Specialized immune-enhancing formulas have not been proven to significantly impact the risk of infection.

Corticosteroids

Systemic corticosteroids have well documented antiinflammatory effects that can clearly influence immune function. The difficulty in determining the effect of corticosteroids on risk of VAP is the competing beneficial effect on other risk factors for VAP. An example is use of corticosteroids may allow earlier extubation of a patient intubated for an exacerbation of asthma, thereby lowering the risk of VAP. This dual effect probably holds true for most cases in which corticosteroids are used acutely for critically ill patients. The potential benefits begin to be outweighed by clear adverse consequences after more prolonged courses.

Transfusions

A common cause of immunosuppression is the use of red blood cell transfusions. This effect of transfusions has been known for several decades and was used therapeutically in pretransplantation management of patients with end-stage renal disease. Because the trigger for red blood cell transfusion varies widely among institutions and even among individual practitioners,61 a more restrictive transfusion policy may avoid compromising host immunity. Hebert and colleagues demonstrated that a conservative transfusion policy was associated with equivalent mortality to more liberal transfusions in most ICU patients.62 A more conservative transfusion practice in trauma patients was associated with decreased VAP rates.63 A complementary policy of routinely using leukoreduction filters with all blood transfusions decreased the incidence of posttransfusion fever as well as overall antibiotic use,64 potentially decreasing the risk of pneumonia via several mechanisms.

Key Points

1 The influence of endotracheal intubation is so dominant that ICU-acquired pneumonia is almost synonymous with ventilator-associated pneumonia (VAP).
2 A distinction should be made between prevention of all nosocomial pneumonia and prevention of life-threatening nosocomial pneumonia, usually late-onset VAP.
3 The pathogenesis of nosocomial pneumonia can be broken down into three basic steps: colonization of the oropharynx with pathogenic microorganisms, aspiration, and overwhelming of the lower respiratory tract’s host defense mechanisms.
4 The most important factor in colonization of the oropharynx with pathogenic microorganisms is the use of systemic antibiotics, especially broad-spectrum antibiotics.
5 The risk of VAP is time dependent, so any maneuver that decreases the duration of mechanical ventilation will decrease pneumonia rates.
6 Avoiding the supine position as much as possible in ventilated patients is a simple and effective preventive measure for nosocomial pneumonia; it should be practiced in all ICUs.
7 Several lines of evidence suggest that minimizing the number of manipulations of the ventilator tubing will decrease the incidence of VAP.
8 Causes of the relative immunocompromised state that allows bacteria to overwhelm local host defenses in the lung are heterogeneous and patient dependent, unlike the stereotypical steps of colonization and aspiration.

Annotated References

Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: A randomised trial. Lancet. 1999;354:1851-1858.

This randomized controlled trial of body positioning clearly demonstrated a decreased risk with the semirecumbent position, providing strong evidence of the role of microaspiration in the pathogenesis of VAP.

Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371:126-134.

The combination of daily awakening from sedation and spontaneous breathing trials resulted in earlier extubation, shorter ICU length of stay, and lower mortality than the group with attempts at spontaneous breathing trials without specified sedation holds.

de Jonge E, Schultz MJ, Spanjaard L, et al. Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet. 2003;362:1011-1016.

Parent multicenter randomized trial of SDD and selective decontamination of the oropharynx which demonstrated a small mortality benefit. Subsequent publiched substudies found selection for cephalosporin resistance by SDD and an increased incidence of infections once patients were transferred to the floor.

Sirvent JM, Torres A, El Ebiary M, et al. Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Respir Crit Care Med. 1997;155:1729-1734.

Randomized controlled trial of true prophylactic antibiotic use to prevent VAP in a defined subgroup illustrated the two-edged sword of antibiotics—decreasing the risk of early pneumonia while selecting for more pathogenic microorganisms and possibly increasing the risk of late-onset VAP.

Valles J, Artigas A, Rello J, et al. Continuous aspiration of subglottic secretions in preventing ventilator-associated pneumonia. Ann Intern Med. 1995;122:179-186.

Randomized trial demonstrating the decreased risk of early-onset VAP with a manipulation that decreases the amount of microaspiration. Even if the practical use of continuous aspiration of subglottic secretions is limited, the study illustrated the problem of secretions pooling above the cuff of the endotracheal tube and its role in VAP.

References

1 Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA. 1995;274:639-644.

2 Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med. 2002;165:867-903.

3 Cook DJ, Walter SD, Cook RJ, et al. Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients. Ann Intern Med. 1998;129:433-440.

4 Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

5 Evans HL, Dellit TH, Chan J, Nathens AB, Maier RV, Cuschieri J. Effect of chlorhexidine whole-body bathing on hospital-acquired infections among trauma patients. Arch Surg. 2010;145:240-246.

6 Niederman MS, Mantovani R, Schoch P, Papas J, Fein AM. Patterns and routes of tracheobronchial colonization in mechanically ventilated patients. The role of nutritional status in colonization of the lower airway by Pseudomonas species. Chest. 1989;95:155-161.

7 Trouillet JL, Chastre J, Vuagnat A, et al. Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am J Respir Crit Care Med. 1998;157:531-539.

8 Fagon JY, Chastre J, Wolff M, et al. Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. A randomized trial. Ann Intern Med. 2000;132:621-630.

9 Soo Hoo GW, Wen YE, Nguyen TV, Goetz MB. Impact of clinical guidelines in the management of severe hospital-acquired pneumonia. Chest. 2005;128:2778-2787.

10 Ibrahim EH, Ward S, Sherman G, Schaiff R, Fraser VJ, Kollef MH. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med. 2001;29:1109-1115.

11 Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000;162:505-511.

12 Meta-analysis of randomised controlled trials of selective decontamination of the digestive tract. Selective Decontamination of the Digestive Tract Trialists’ Collaborative Group. BMJ. 1993;307:525-532.

13 Kollef MH. The role of selective digestive tract decontamination on mortality and respiratory tract infections. A meta-analysis. Chest. 1994;105:1101-1108.

14 de Jonge E, Schultz MJ, Spanjaard L, et al. Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet. 2003;362:1011-1016.

15 Sirvent JM, Torres A, El-Ebiary M, Castro P, de Batlle J, Bonet A. Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Respir Crit Care Med. 1997;155:1729-1734.

16 Oostdijk EA, de Smet AM, Blok HE, et al. Ecological effects of selective decontamination on resistant gram-negative bacterial colonization. Am J Respir Crit Care Med. 2010;181:452-457.

17 DeRiso AJ2nd, Ladowski JS, Dillon TA, Justice JW, Peterson AC. Chlorhexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic systemic antibiotic use in patients undergoing heart surgery. Chest. 1996;109:1556-1561.

18 Chlebicki MP, Safdar N. Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. Crit Care Med. 2007;35:595-602.

19 Koeman M, van der Ven AJ, Hak E, et al. Oral decontamination with chlorhexidine reduces the incidence of ventilator-associated pneumonia. Am J Respir Crit Care Med. 2006;173:1348-1355.

20 Fourrier F, Dubois D, Pronnier P, et al. Effect of gingival and dental plaque antiseptic decontamination on nosocomial infections acquired in the intensive care unit: a double-blind placebo-controlled multicenter study. Crit Care Med. 2005;33:1728-1735.

21 Kollef MH, Afessa B, Anzueto A, et al. Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia: the NASCENT randomized trial. JAMA. 2008;300:805-813.

22 Klick JM, du Moulin GC, Hedley-Whyte J, Teres D, Bushnell LS, Feingold DS. Prevention of gram-negative bacillary pneumonia using polymyxin aerosol as prophylaxis. II. Effect on the incidence of pneumonia in seriously ill patients. J Clin Invest. 1975;55:514-519.

23 Claridge JA, Edwards NM, Swanson J, et al. Aerosolized ceftazidime prophylaxis against ventilator-associated pneumonia in high-risk trauma patients: results of a double-blind randomized study. Surg Infect (Larchmt). 2007;8:83-90.

24 Palmer LB, Smaldone GC, Chen JJ, et al. Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit. Crit Care Med. 2008;36:2008-2013.

25 Cook D, Guyatt G, Marshall J, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med. 1998;338:791-797.

26 Herzig SJ, Howell MD, Ngo LH, Marcantonio ER. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA. 2009;301:2120-2128.

27 Cook D, Heyland D, Griffith L, Cook R, Marshall J, Pagliarello J. Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. Crit Care Med. 1999;27:2812-2817.

28 Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr. 2001;74:534-542.

29 Mazaki T, Ebisawa K. Enteral versus parenteral nutrition after gastrointestinal surgery: a systematic review and meta-analysis of randomized controlled trials in the English literature. J Gastrointest Surg. 2008;12:739-755.

30 Lewis SJ, Andersen HK, Thomas S. Early enteral nutrition within 24 h of intestinal surgery versus later commencement of feeding: a systematic review and meta-analysis. J Gastrointest Surg. 2009;13:569-575.

31 George DL, Falk PS, Wunderink RG, et al. Epidemiology of ventilator-acquired pneumonia based on protected bronchoscopic sampling. Am J Respir Crit Care Med. 1998;158:1839-1847.

32 Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Nogue S, Ferrer M. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999;354:1851-1858.

33 Ibrahim EH, Mehringer L, Prentice D, et al. Early versus late enteral feeding of mechanically ventilated patients: results of a clinical trial. JPEN J Parenter Enteral Nutr. 2002;26:174-181.

34 Doig GS, Heighes PT, Simpson F, Sweetman EA, Davies AR. Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials. Intensive Care Med. 2009;35:2018-2027.

35 Bonten MJ, Gaillard CA, van der Hulst R, et al. Intermittent enteral feeding: the influence on respiratory and digestive tract colonization in mechanically ventilated intensive-care-unit patients. Am J Respir Crit Care Med. 1996;154:394-399.

36 Heyland DK, Cook DJ, Schoenfeld PS, Frietag A, Varon J, Wood G. The effect of acidified enteral feeds on gastric colonization in critically ill patients: results of a multicenter randomized trial. Canadian Critical Care Trials Group. Crit Care Med. 1999;27:2399-2406.

37 Rumbak MJ, Newton M, Truncale T, Schwartz SW, Adams JW, Hazard PB. A prospective, randomized, study comparing early percutaneous dilational tracheotomy to prolonged translaryngeal intubation (delayed tracheotomy) in critically ill medical patients. Crit Care Med. 2004;32:1689-1694.

38 Doebbeling BN, Stanley GL, Sheetz CT, et al. Comparative efficacy of alternative hand-washing agents in reducing nosocomial infections in intensive care units. N Engl J Med. 1992;327:88-93.

39 Gordin FM, Schultz ME, Huber RA, Gill JA. Reduction in nosocomial transmission of drug-resistant bacteria after introduction of an alcohol-based handrub. Infect Control Hosp Epidemiol. 2005;26:650-653.

40 Zack JE, Garrison T, Trovillion E, et al. Effect of an education program aimed at reducing the occurrence of ventilator-associated pneumonia. Crit Care Med. 2002;30:2407-2412.

41 Kollef MH, Von Harz B, Prentice D, et al. Patient transport from intensive care increases the risk of developing ventilator-associated pneumonia. Chest. 1997;112:765-773.

42 Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342:1471-1477.

43 Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371:126-134.

44 Ely EW, Baker AM, Dunagan DP, et al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med. 1996;335:1864-1869.

45 Torres A, Gatell JM, Aznar E, et al. Re-intubation increases the risk of nosocomial pneumonia in patients needing mechanical ventilation. Am J Respir Crit Care Med. 1995;152:137-141.

46 Terragni PP, Antonelli M, Fumagalli R, et al. Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial. JAMA. 2010;303:1483-1489.

47 Torres A, Serra-Batlles J, Ros E, et al. Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position. Ann Intern Med. 1992;116:540-543.

48 van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et al. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med. 2006;34:396-402.

49 Staudinger T, Bojic A, Holzinger U, et al. Continuous lateral rotation therapy to prevent ventilator-associated pneumonia. Crit Care Med. 2010;38:486-490.

50 Kola A, Eckmanns T, Gastmeier P. Efficacy of heat and moisture exchangers in preventing ventilator-associated pneumonia: meta-analysis of randomized controlled trials. Intensive Care Med. 2005;31:5-11.

51 Patman S, Jenkins S, Stiller K. Physiotherapy does not prevent, or hasten recovery from, ventilator-associated pneumonia in patients with acquired brain injury. Intensive Care Med. 2009;35:258-265.

52 Caruso P, Denari S, Ruiz SA, Demarzo SE, Deheinzelin D. Saline instillation before tracheal suctioning decreases the incidence of ventilator-associated pneumonia. Crit Care Med. 2009;37:32-38.

53 Bouza E, Perez MJ, Munoz P, Rincon C, Barrio JM, Hortal J. Continuous aspiration of subglottic secretions in the prevention of ventilator-associated pneumonia in the postoperative period of major heart surgery. Chest. 2008;134:938-946.

54 Lorente L, Lecuona M, Jimenez A, Mora ML, Sierra A. Influence of an endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia. Am J Respir Crit Care Med. 2007;176:1079-1083.

55 Rello J, Sonora R, Jubert P, Artigas A, Rue M, Valles J. Pneumonia in intubated patients: role of respiratory airway care. Am J Respir Crit Care Med. 1996;154:111-115.

56 Ho KM, Dobb GJ, Webb SA. A comparison of early gastric and post-pyloric feeding in critically ill patients: a meta-analysis. Intensive Care Med. 2006;32:639-649.

57 Johanson WGJr, Pierce AK, Sanford JP, Thomas GD. Nosocomial respiratory infections with gram-negative bacilli. The significance of colonization of the respiratory tract. Ann Intern Med. 1972;77:701-706.

58 Garrard CS, A’Court CD. The diagnosis of pneumonia in the critically ill. Chest. 1995;108:17S-25S.

59 Wunderink RG. Nosocomial pneumonia, including ventilator-associated pneumonia. Proc Am Thorac Soc. 2005;2:440-444.

60 Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290:2588-2598.

61 Hebert PC, Wells G, Martin C, et al. Variation in red cell transfusion practice in the intensive care unit: a multicentre cohort study. Crit Care. 1999;3:57-63.

62 Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340:409-417.

63 Earley AS, Gracias VH, Haut E, et al. Anemia management program reduces transfusion volumes, incidence of ventilator-associated pneumonia, and cost in trauma patients. J Trauma. 2006;61:1-5. discussion

64 Hebert PC, Fergusson D, Blajchman MA, et al. Clinical outcomes following institution of the Canadian universal leukoreduction program for red blood cell transfusions. JAMA. 2003;289:1941-1949.

Related posts:

Indirect Calorimetry Basic Ethical Principles in Critical Care Central Nervous System Infections Fluids and Electrolytes in Children Teaching Critical Care Pathophysiology and Classification of Shock States