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Release Date: January 15, 2008
The lung can be injured by positive pressure ventilation (PPV) through several mechanisms. This injury is known as ventilator-induced lung injury (VILI). One such mechanism is overdistention injury when lung units are physically stretched beyond their normal maximums. This occurs when end-inspiratory transpulmonary pressures (and resulting end-inspiratory volumes) exceed the normal maximum of 30 to 35 cmH2O. Another injury occurs when collapsed lung units are subjected to shear stress when repetitively opened and closed during PPV. There may also be a tidal stretch injury that occurs with repetitive use of tidal volumes above the normal of 5 to 6 mL/kg, although this mechanism is more controversial. Of importance, these injuries likely occur predominantly in healthier regions of the lung, which receive the bulk of mechanical ventilatory support. Similarly, shear stress injury likely occurs in healthier regions immediately adjacent to sicker regions. The "art" of providing PPV is thus to support adequate gas exchange without causing regional VILI.
Using small (eg, 6 mL/kg) tidal volumes with plateau airway pressures less than 30 to 35 cmH2O is clearly the standard of care in patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Increasing, however, clinical data also suggest that this approach should also be applied to patients without ALI or ARDS to prevent their occurrence while the patient is receiving PPV. Indeed, a large observational trial from the Mayo Clinic has shown that a policy of small tidal volume ventilation in virtually everyone has resulted in marked reductions of ALI and ARDS developing in patients receiving PPV for other reasons.
The approaches to setting positive end-expiratory pressure (PEEP) have been studied in several large randomized clinical trials (RCTs) recently. All of these studies have focused on the question of whether, in the setting of small tidal volume ventilation to minimize shear stress open-close injury, aggressive vs conservative PEEP will further reduce VILI and improve outcomes. The argument for aggressive PEEP is that atelectasis will be further reduced. The argument for conservative PEEP is that this additional atelectasis reduction is not worth the accompanying increase in plateau pressure. The ARDS Network trial, which addressed this issue, showed better gas exchange and mechanics with aggressive PEEP this strategy had no effect on ventilator-free days or mortality. Two other recent large trials using small tidal volume strategies, one from Canada and one from Europe, have only been reported in form but also showed improved mechanics and blood gases with aggressive PEEP and no effect on mortality. Thus the decision to use aggressive vs conservative PEEP in the setting of low tidal volume mechanical ventilation rests on the clinician's judgment on the value of physiology improvements (without an associated mortality benefit) at the cost of higher plateau pressures.[3,4]
Two novel PPV strategies that have been proposed as lung protective for patients with severe oxygenation failure are airway pressure release ventilation (APRV) and high-frequency ventilation (HFV). APRV uses a long inflation period with superimposed spontaneous breathing. It is thus an alternative to tidal volume and PEEP to raise mean airway pressure. HFV uses very small tidal volumes and rapid breathing frequencies (up to 900 breaths/minute). Gas transport is thus by nonconvective flow, and substantial mean pressures can be provided with very small tidal distentions. Two RCTs reported several years ago evaluated APRV. One showed benefit (but with a seriously flawed control group strategy), and the other showed comparable outcomes to conventional ventilation. It must also be remembered that the end-inspiratory lung volume in APRV is the sum of both the ventilator-delivered inflation plus the spontaneous inflations. HFV in the adult has been evaluated in a single RCT conducted in the late 1990s, and the results showed only a "trend" in favor of HFV. More clinical trials are clearly needed to establish the role of these 2 modes before firm recommendations can be made.
Our understanding of patient-ventilator interactions has grown tremendously during the last 2 decades. Serious patient-ventilator dysynchrony is now known to frequently exist during all 3 phases of breath delivery: the trigger phase, the flow delivery phase, and the breath cycling off phase. This dysynchrony can create substantial imposed loads on the ventilatory muscles, which can lead to muscle fatigue, discomfort (with resulting sedation use), and unnecessary time on the ventilator.
Trigger dysynchrony is often a consequence of intrinsic PEEP (PEEPi). PEEPi develops in the setting of high minute ventilation, short expiratory times, and long expiratory time constants (ie, as occurs in obstructive airway disease). Under these conditions, the ventilatory muscles must first overcome the PEEPi before the ventilator senses an effort and delivers an assisted breath. This results in delayed triggering and even missed triggering -- both of which impose significant muscle loads. There are several approaches to improving breath triggering dysynchrony caused by PEEPi. Minute ventilation can be reduced, and expiratory time can be extended. This may be particularly important when using flow-cycled pressure support, which may have a prolonged inspiratory time in the presence of airway obstruction. Shortening the flow-cycling criteria or switching to pressure assist with a set inspiratory time may help this. Finally, applying PEEP in the circuit at levels below the PEEPi level can help equilibrate lung and circuit pressures to reduce the triggering load.
Triggering may also be an issue during sleep, when respiratory drive is reduced (or erratic). This may produce sleep disturbances, which can worsen psychological stress and further delay ventilator discontinuation. Sleep-induced triggering problems may require providing a certain backup rate capability during sleep.
Flow delivery dysynchrony occurs when ventilator-delivered flow is less than patient demand. Flow dysynchrony is often reduced when pressure-targeted, variable- flow breaths are used compared with the fixed-flow breaths of flow-volume targeted breaths. Two new developments may further improve flow (and cycle) dysynchrony: proportional assist ventilation (PAV) and neurally adjusted ventilatory assist (NAVA). PAV senses patient flow demand and puts a pressure and flow gain on this effort. This gain is set by the clinician as a proportion of the measured compliance/resistance characteristics of the patient. PAV has considerable conceptual appeal but no outcome studies have been performed to date. NAVA requires an array of electromyelogram sensors placed in the esophagus at the level of the diaphragm. This electromyelogram array detects inspiratory muscle activity and drives the pressure-flow output of the ventilator off of this. NAVA might thus be the ultimate patient-ventilator synchrony approach. Clinical adoption of NAVA, however, is likely to be driven by the logistic difficulties and the costs associated with the sensor array.
The ventilator discontinuation process continues to occupy a significant portion of a patient's need for mechanical ventilatory support. Several evidence-based guidelines have argued convincingly that daily spontaneous breathing trials (SBTs) are the most direct way to assess the ability of the patient recovering from respiratory failure to tolerate ventilator discontinuation. In patients passing an SBT (as judged by an integrated assessment of gas exchange, hemodynamics, ventilatory pattern, and subjective comfort), the likelihood of tolerating ventilator removal is high and, if airway protection is adequate, the likelihood of extubation success is also high.
Protocols run by nonphysician clinicians (eg, skilled respiratory therapists) can facilitate this discontinuation process. These clinicians are usually more readily available at the bedside to assess patients and to modify support strategies as needed. Of importance, these clinicians do not replace physician judgment -- instead they extend physician judgment through the use of physician-designed protocols.
In recent years, the role of excessive sedation hindering the ventilator discontinuation process has been increasingly appreciated. This has led to calls for daily spontaneous awakening trials (SATs) to be done in conjunction with SBTs. This approach has been met with some resistance because of the perception that abrupt sedation withdrawal can precipitate anxiety/delirium that may be difficult to bring under control.
Within this backdrop, the Awake and Breathe Controlled Trial (ABC Trial) was conducted and recently completed. In this trial 335 mechanically ventilated patients were randomized to management with a daily SBT (usual care + SBT group) or a daily SAT followed by an SBT (SAT + SBT group). The SAT strategy involved daily discontinuation of all sedation and following protocol rules to assure prompt responses to anxiety/delirium.
Compared with usual care plus SBTs, the SAT plus SBT strategy resulted in an average of 3.1 additional days breathing without assistance during the 28-day study period (14.7 vs 11.6; P = .02), discharge from the intensive care unit approximately 4 days earlier (median days, 9.1 vs 12.9; P = .01), and hospital discharge approximately 4 days earlier (median days, 14.9 vs 19.2; P = .04). More SAT plus SBT patients self-extubated (9.6% vs 3.6%; P = .03), but the number of patients who required reintubation after self-extubation was similar (3% vs 1.8%, P = .47) as were total reintubation rates (13.8% vs 12.5%, P = .73). During the 28-day study, 47 patients (28.1%) in the SAT plus SBT group died compared with 58 (34.5%) in the usual care plus SBT group (P = .21). There were trends toward less sedation use and brain dysfunction in the SAT plus SBT group.
These results strongly suggest that aggressive (but properly monitored) sedation reduction coupled with SBTs improve outcome in mechanically ventilated patients recovering from acute respiratory failure.
Ventilator-associated pneumonia (VAP) represents a common and serious nosocomial infection. Because of the implications of VAP for both healthcare systems and for patients, VAP is now a focus of attention to improve patient safety and outcomes. Several presentations and discussions at this year's CHEST meeting reviewed multiple recent advances in the area of VAP.
The first issues to address are the epidemiology, microbiology, outcomes, and diagnostics of VAP. Based on data from the National Nosocomial Infection Surveillance System, VAP represents the most common nosocomial infection seen in the intensive care unit (ICU), but the prevalence of VAP varies greatly based on ICU type. Burn ICUs have higher rates of VAP (approximately 12 cases per 1000 days of mechanical ventilation) whereas medical ICUs have a lower rate of VAP (3 cases per 1000 days of mechanical ventilation). This likely reflects differences in the underlying severity of illness of the patients in these ICUs, the antibiotic-prescribing patterns of the physicians practicing in these ICUs, and the use of mechanical ventilation in these different settings. VAP is caused by a diverse range of pathogens. Multiple studies document that the microbiology of VAP varies across ICUs and across hospitals. Despite these differences, several epidemiologic trends are apparent. Pseudomonas aeruginosa and Staphylococcus aureus occur with similar frequency and when pooled account for nearly 30% of all cases of VAP. In addition, this distribution of pathogens has not shifted much over the last decade. Finally, despite little change in the pathogens causing VAP, the antimicrobial susceptibilities of these organisms have evolved. Specifically, increasing rates of resistance are now reported for both Gram-negative and Gram-positive pathogens. For example, in the ICU, approximately 70% of S aureus sp are methicillin-resistant (MRSA). For P aeruginosa fewer than half of isolates show reliable susceptibility to fluoroquinolones and, nationally, 15% to 20% appear resistant to carbepenems. Understanding these changing patterns of resistance is central to efforts to improve outcomes. Clinicians must know about both the microbiology of VAP and the likely susceptibilities of the culprit pathogens to ensure that patients are given an antibiotic that has in vitro activity against the responsible bacteria.
From the perspective of cost, multiple studies document the extensive economic implications of VAP. In a large database analysis, Rello and colleagues observed that the attributable costs of VAP exceeded $40,000 per case. This excess cost was not driven by pharmacy charges. Rather VAP significantly prolonged both the duration of mechanical ventilation and the length of stay in the ICU. In a similar analysis, Warren and coworkers examined outcomes for VAP at a suburban nonacademic hospital. They also concluded after controlling for a number of potential confounders that VAP extensively added to hospital costs. These researchers estimated that the crude costs of VAP neared $50,000 per case. These financial outcomes reinforce why hospitals can potentially reap significant savings by implementing strategies to reduce rates of VAP. The mortality burden of VAP is less clear. It is often difficult to determine whether a patient died of VAP or with VAP. In an effort to elucidate this issue, Valles and colleagues compared predicted to observed mortality rates in critically ill patients with and without VAP. In patients in whom VAP never developed, the predicted and observed rates were equal, suggesting no excess mortality burden. In subjects with VAP, the observed mortality was 45% compared with a predicted mortality of 30%. This all seemed to be the result of more deaths in patients with late-onset VAP (VAP developing after more than 5 days of mechanical ventilation). In these individuals, the mortality rate was double what one would have predicted based on their severity of illness at time of admission to the ICU.
One of the biggest challenges with VAP remains its diagnosis. There is no gold standard for the diagnosis of VAP and controversy remains regarding whether all subjects require a lower airway culture to confirm the presence of infection. Because lower airway culturing may not be readily available and because it may be expensive, researchers have attempted to develop biomarkers to facilitate VAP diagnosis. In a study of soluble trigger receptor on myeloid cells (sTREM), Gibot and colleagues noted that this had an excellent sensitivity and specificity relative to a mini-bronchoalveolar lavage (BAL) . A small recent analysis of 23 patients, however, questioned the value of sTREM. In this study there seemed little difference in BAL levels of sTREM between those with VAP and those without VAP. It is unclear how many patients in this study actually had VAP because a positive lower airway culture was not required for the diagnosis of VAP. Measurement of procalcitonin is also an area of investigation for VAP diagnosis. Lyut and coworkers measured serial procalcitonin values over 7 days in mechanically ventilated subjects. This performed well in this early analysis. Nonetheless, experience with biomarkers is very limited and more studies are necessary before these technologies become commercially available.
The clinical pulmonary infection score (CPIS) represents an alternative approach to VAP diagnosis. In the CPIS, points are given based on x-ray results, white cell count, temperature, oxygenation, and purulence of secretions. Generally a score of less than 6 is thought to reliably exclude the diagnosis of VAP, and a higher score suggests VAP is more likely. Although attractive because it is simple, the CPIS may be prone to interobserver variability. More importantly, a recent meta-analysis concluded that the role for the CPIS is limited. The sensitivity and specificity for the CPIS varied substantially across the studies reviewed in this meta-analysis. The authors concluded that CPIS may provide suggestive evidence but not definitive evidence that VAP is either present or absent and urged clinicians to consider additional tests when faced with a patient who might have VAP.
Invasive lower airway testing remains a final option to facilitate the diagnosis of VAP. With the development of tools other than the traditional BAL to allow lower airway sampling (eg, mini-BAL), more effort has been placed on lower airway evaluation. The Canadian Critical Care Trials Group undertook a large multicenter, randomized trial to compare reliance on lower airway sampling with reliance on tracheal aspirates. The study included more than 740 subjects thought to have VAP. The final diagnosis of VAP was based on a blinded adjudication panel's conclusions. The 2 populations were similar at baseline. There was no difference in mortality based on the VAP diagnostic tool. Lower airway sampling also did not affect the use of antibiotics. The authors concluded that either paradigm is acceptable for the diagnosis of VAP. However, this analysis has several important limitations. The incidence of VAP in this trial was very low. Based on judgment, there was only one case of definitive VAP among all those evaluated. Furthermore, only 25% of those enrolled were judged to have probable VAP. In addition, the authors excluded patients thought to be at risk for multidrug- resistant pathogens such as MRSA and P aeruginosa. Overall approximately 5% of persons had such pathogens. This differs greatly from what is noted in the United States today. This discordance leads to questions about the generalizability of these findings if such concerning pathogens occur in patients who are at risk for VAP. Given that these organisms may account for 30% of what is seen in ICUs, one must interpret the study's findings with caution.
Marin Kollef, MD, of Washington University in St. Louis discussed the topic of prevention of VAP at this year's ACCP meeting. Before reviewing preventive options, Dr. Kollef briefly described the pathophysiologic development of VAP. By elucidating factors that promote the occurrence of VAP, value of various preventive interventions can be better appreciated. VAP requires the invasion of the lower airways by pathogenic organisms. Additionally, these organisms must gain entry to the lower airway first by colonizing the upper airway and digestive tract. In other words, the pathogenesis has 2 central aspects: colonization and aspiration. Unfortunately, the endotracheal tube (ETT) itself can promote both colonization and aspiration. The ETT impairs mucociliary clearance and limits sinus drainage. Additionally, biofilm can arise on the lumen of the ETT. This biofilm can serve as a direct point of entry of organisms into the lower airway. Dr. Kollef said that VAP should more properly be renamed ETT-associated pneumonia. Given this relationship between the ETT and VAP, it is not surprising that programs which foster earlier removal from mechanical ventilation or which avoid the need for ETT placement by using noninvasive ventilation overall show benefit in terms of reducing the risk for VAP.
Beyond preventing the need for ETT placement, other effective strategies for VAP prevention include keeping the head of the bed elevated to minimize silent aspiration and limiting antibiotic abuse. Less antibiotic exposure can help limit colonization with resistant pathogens that might later cause infection. At his own institution Dr. Kollef and colleagues implemented a VAP prevention bundle targeted at nurses and respiratory therapists. This program (entitled WHAP VAP) required education for all ICU caregivers about the pathophysiology and burden of VAP. It also emphasizes hand hygiene and infection control along with protocolized removal from ventilation and limited use of sedation. Oral care was addressed somewhat as was the issue of upper airway colonization by encouraging the use of orogastric tubes rather than nasogastric tubes. With this overall paradigm, Dr. Kollef and coworkers reduced VAP rates by more than 50%. They estimated they saved their institution millions of dollars over several years.
However, nurses and respiratory therapists cannot do it all. Thus simple and easy interventions dealing the ETT itself appear attractive. A modified ETT that facilitates the continuous suctioning of secretions that pool above the cuff of the ETT is available. This ETT is relatively expensive compared with standard tubes and has been shown in several trials to decrease the risk for VAP. Nonetheless, the benefit of this continuous aspiration ETT has only been demonstrated in early-onset VAP with low-virulence pathogens. Continuous aspiration has not been demonstrated to prevent VAP in patients requiring longer durations of mechanical ventilation or to prevent VAP caused by MRSA or P aeruginosa.
After providing this background, Dr. Kollef reviewed the findings of a recently completed large randomized trial that examined whether a silver-coated ETT could reduce VAP rates. Silver is a potent antimicrobial and active against Gram-positive and Gram-negative organisms. Silver has many clinical uses and is also impregnated onto central venous catheters to limit the potential for bloodstream infections. Animal data suggested that a silver-coated ETT could effective prevent VAP, and early human studies indicated this was a safe and viable alternative.[17,18]
In the large randomized trial, which was initially presented at the European Society of Intensive Care meeting in September, nearly 2000 persons were enrolled. Of these, more than 1600 were intubated for more than 48 hours and comprised the modified intent-to-treat population. The mean age of patients enrolled was approximately 61 years and the mean Acute Physiology and Chronic Health Evaluation II score measured 21. Approximately one quarter of the population was immunocompromised in some fashion. The overall rate of VAP was reduced from 7.5% to 4.8%. This 35% risk reduction was statistically significant (P = .0321). Limiting the analysis to persons in whom VAP developed within the first 10 days of ventilation confirmed the tube's efficacy (rate of VAP reduced from 6.7% to 3.5%, P = .0049). Kaplan-Meier analysis examining the time to onset of VAP also showed that the tube delayed VAP (P = .005). Microbiologically, the ETT, unlike other technologies, reduced VAP infections with both Gram-positive and Gram-negative infections including MRSA and Acinetobacter bumannii. Dr. Kollef suggested that for every 37 silver-coated ETT placed, 1 case of VAP is prevented. The silver-coated ETT did not alter mortality rates (30.4% vs 26.6%, P = .1106).
Although not commercially available, the silver-coated ETT represents a novel and potentially effective approach to VAP prevention. The key for clinicians will be to determine whether this ETT is cost-effective and which patients are appropriate candidates for placement of a silver-coated ETT.
Marcos Restrepo, MD, MSc, from the University of Texas Health Sciences Center in San Antonio, reviewed the contentious topic of empiric therapy for VAP. To comprehend the need for empiric therapy, Dr. Restrepo discussed the multiple studies which document that either delayed or inappropriate therapy for VAP increase the risk for death. Generally, inappropriate therapy is defined as the administration of an antibiotic to which the culprit pathogen is resistant in vitro. Inadequate dosing of an antimicrobial drug that might be active in vitro also represents a form of inappropriate therapy. To confirm the importance of appropriate therapy, Dr. Restrepo highlighted one typical study in which inappropriate or delayed therapy increased a patient's risk for death more than 5-fold.
Several factors complicate attempts to ensure appropriate therapy. The definitions for who is at risk for a resistant pathogen are evolving. The concept of healthcare-associated pneumonia (HCAP) was recently described. HCAP is pneumonia that occurs in a patient who, despite being an outpatient, is constantly in interaction with the healthcare system. Examples of such subjects include those from nursing homes and long-term care facilities and persons receiving wound care, immunosuppression therapy, or hemodialysis. In 1 report, the incidence of MRSA and P aeruginosa was significant in patients with HCAP, despite that these patients come to the emergency department. Hence clinicians must acknowledge that risk factors for infection with resistant pathogens have diffused beyond the confines of the hospital walls.
Dr. Restrepo then described the current empiric antibiotic recommendations from the American Thoracic Society and the Infectious Disease Society of America. In patients with HCAP or late-onset VAP (occurring after more than 5 days of ventilation), the guidelines recommend the use of 2 agents to cover resistant Gram-negative organisms and an additional agent for empiric anti-MRSA therapy. Problem pathogens include P aeruginosa, A bumannii, and extended beta-lactamase producing Klebsiella sp. Double coverage for Gram-negative organisms, Dr. Restrepo stressed, is not because 2 agents are necessarily better than 1 but because no single agent has reliable 100% activity against the bacteria of concern. A recent meta-analysis similarly concluded the only potential value for extended double Gram-negative coverage might be in P aeruginosa. This meta-analysis was limited because few studies were included.
With respect to individual agents, choices must be made based on local susceptibility data. For example, at a hospital where quinolones cover fewer than 50% of P aeruginosa isolates, there is little value to adding this drug as a second agent. Among other options, data are emerging to suggest that some agents may be preferred over others because of their pharmacokinetic and pharmacodynamic attributes. To illustrate this, Dr. Restrepo reviewed a recent trial of imipenem vs doripenem in nosocomial pneumonia. Both of these agents are active in vitro against P aeruginosa, but the susceptibilities of doripenem tend to be better than those of imipenem against P aeruginosa. In the clinical trial (n = 531) cure rates were similar between the 2 carbepenems. However in the subgroup of patients with documented P aeruginosa, the cure rate with doripenem was 80% vs 43% for imipenem (P = .03). For MRSA, a secondary analysis of 2 randomized, controlled trials comparing linezolid to vancomycin, both of which are active in vitro against MRSA, showed that randomization to linezolid was associated with both higher cure rates and improved survival. One limitation with this pooled analysis was that in each individual trial vancomycin was not aggressively dosed to trough levels of 15 micrograms/mL as is currently recommended. According to Dr. Restrepo, it is unclear whether more aggressive dosing will prove effective for vancomycin therapy for pneumonia. The central concern is that vancomycin has very poor lung penetration. Supporting his contention, Dr. Restrepo presented the results of a study that correlated vancomycin serum trough levels with survival in MRSA pneumonias. More aggressive dosing did not enhance cure rates or limit mortality.
In summary, presentations and discussions at CHEST reviewed multiple recent advances in the area of VAP. The literature in this field on topics ranging from diagnosis to prevention is rapidly changing. New diagnostic, preventive, and therapeutic options are available or soon will be available. Clinicians must keep abreast of these changes to make the best decisions for their patients.
The critical care management issues of organ transplant recipients is a growing area to which intensivists are increasingly being exposed, not only in the big academic institutions, but also in smaller community hospitals as more of these patients live longer and further from their "mother ships." Therefore it is becoming increasingly important for intensivists and pulmonologists to be familiar with the management nuances of these complicated patients. The management of organ transplant recipients was the topic of several discussions at the ACCP meeting. Debbie Levine, MD, from the University of Texas in San Antonio, addressed the intensive care unit (ICU) management of liver transplant candidates and recipients. Liver transplantation is the treatment of choice for various forms of end-stage liver disease, including viral liver disease, liver malignancies, acute liver failure, and certain metabolic derangements. What is also being seen in recent years is that sicker patients are undergoing transplantation. Sicker patients before transplant translates into sicker, more complicated patients after transplant. Frequently, these patients undergo transplantation when they have comorbidities and organ dysfunction. Dr. Levine alluded to the operating room experience being a "mere moment between 2 ICU stays" and that othotopic liver transplantation (OLTx) frequently involves extensive abdominal surgery on suboptimal surgical candidates.
For the patient with acute liver failure, there are several clinical consequences that extend into the posttransplant period. These include coagulation abnormalities, inadequate factor synthesis, fibrinolysis, and hypocalcemia. One needs to follow the coagulation abnormalities closely and aim for an international normalized ratio (INR) in the 1.5 to 2 range while keeping the platelet level above 50,000 and fibrinogen levels above 100 mg/dL. Sepsis is another major issue, with a high incidence of fungal infections in particular in patients with acute liver failure. After transplant, as with all forms of transplant, liver recipients are at continuous risk for infections. Neurological issues run the spectrum from encephalopathy to cerebral edema, which may require intracranial pressure monitoring.
Pulmonary problems after transplant include the need for prolonged mechanical ventilation. The cause is usually multifactorial with issues such as weakness, malnutrition, extensive upper abdominal surgery, pain, blood loss, marked vascular volume shifts, and sequelae of reperfusion injury all playing a role. In 1 report of OLTx recipients, 11% of 546 patients required ventilatory support beyond 24 hours. Acute respiratory distress syndrome in this setting has been reported in 4% to 25% of cases and carries with it a mortality rate as high as 80%. Pulmonary edema has been reported in 14% to 88% of cases and can be the result of overhydration and/or cardiac dysfunction. Perioperative pleural effusions may also occur and are usually right-sided or bilateral. These may enlarge over the first week after OLTx and about 10% ultimately require drainage.
The diaphragm may also be affected. In one study, 79% of 48 OLTx patients had delayed or absent phrenic nerve conduction on electromyography. This is mostly felt to be the result of crush injury by the subhepatic caval clamp. However in the context of liver transplantation, it is rarely associated with the need for prolonged mechanical ventilation. Drug-induced pulmonary dysfunction is seen mostly these days after the use of rapamycin, which has been reported to cause interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia, and diffuse alveolar hemorrhage. However, the onset of these is usually insidious and is generally not a perioperative problem.
Venous thromboembolism is seen rarely in patients with cirrhosis despite these patients receiving autoanticoagulation drugs. In one series, venous thromboembolism was found in 0.5% of 113 patients with an elevated INR and in another series of patients undergoing autopsy portal vein thrombosis was seen in more than 50%.
Pulmonary vascular disorders of liver disease run the spectrum from hepatopulmonary syndrome (HPS) to portopulmonary hypertension (portoPH). The former is primarily a disease of vasodilatation and might be caused by various mediators not being cleared appropriately by the liver. On the other end of the spectrum, portoPH is felt to be caused by an excess of vasoconstrictors such as thromboxane and endothelin. HPS tends to be a progressive disease with worsening hypoxemia. The 5-year survival of HPS is a dismal 20%. Transjugular intrahepatic portosystemic shunts do not affect the course of this disease, and the gold standard therapy is liver transplantation. The hypoxemia may take months to years to resolve after OLTx, but complete resolution will be seen in about 80% of patients.
PortoPH can occur with or without cirrhosis. Although it is usually associated with a high cardiac output, the prognosis is very poor and is worse than that of idiopathic pulmonary arterial hypertension or HIV-associated pulmonary hypertension. Patients will usually die of this before they succumb to their liver disease. The advent of effective therapies for pulmonary arterial hypertension has enabled patients with portoPH to be treated and to undergo successful transplant, whereas previously they would not have been regarded as appropriate candidates for OLTx. With regard to HPS and portoPH, liver transplantation allows the unique opportunity to reverse organ disease by transplanting another organ.
Dr. Wickii Vigneswaran, MD, Director of the Lung Transplant Program at the University of Chicago, addressed the perioperative care of the patient undergoing thoracic organ transplant. Dr. Vigneswaran underscored a few salient points to begin. Both heart and lungs are life-saving organs so we have "got to get it right." Both have limited ischemic times so no time can be wasted. Finally, the key to success is a multidisciplinary team approach.
Donor preparation and procurement includes avoiding high filling pressures and barotrauma. Ongoing monitoring of the lung through serial arterial blood gas measurement, chest x-rays, and a surveillance bronchoscopy is also essential. Organ preservation includes cold pulmonary flush with a pulmonary vasodilator, retrograde flushing to ensure the removal of all emboli, and cold solution for transportation.
For recipient preparation, it is important not to discontinue any therapy and to correct any anticoagulant therapy. Prospective cross-matching of the allograft is generally recommended for a panel-reactive antibody titer more than 10%. Such a recipient might also be treated with plasmaphoresis and/or intravenous immunoglobulin G.
A double lumen tube is inserted for lung recipients, preferably a left-sided tube to avoid occluding the right upper lobe. Cardiopulmonary bypass is necessary for patients with significant pulmonary hypertension and right ventricular dysfunction. Structures to avoid include the phrenic nerve, and it is also important to guard against venous or arterial anastamotic stenoses. Attention should be paid to hemostasis, preservation of the blood supply to the bronchial stump, and prevention of excess fluid accumulation. At the end of surgery the endotracheal tube should be changed and a bronchoscopic inspection of the anastamosis should be performed, with clearance of secretions and blood.
Postoperative care includes careful monitoring of the allograft. Primary graft dysfunction is the most common cause of early mortality. Filling pressures should be kept in the normal to low range. Among other factors, the lack of lymphatic drainage may predispose the patient to edema. Ventilator support should include low tidal volumes and low positive end-expiratory pressure (PEEP). PEEP should be avoided for patients with chronic obstructive pulmonary disease who receive a single lung to avoid dynamic hyperinflation of the native lung. Early extubation should be the goal where possible, but not in the operating room because patients might still manifest primary graft dysfunction. If the patient is still intubated for more than 48 hours, then a bronchoscopy prior to extubation is prudent. Early tracheostomy for failed extubation is advised because this will help with early mobilization and rehabilitation.
Postoperative care actually begins before the surgery in terms of education, discharge planning, nutrition, pulmonary rehabilitation, and patient/family education. This also allows for expectations to be managed. A multidisciplinary approach is the key, and collaborative team meetings are essential to ensuring that all team members are "on the same page."
Tim Whelan, MD, from the University of Minnesota, spoke about the medical ICU management of lung transplant recipients. He focused on common problems that might affect these patients and might result in them going to and being treated in a community ICU. The first condition addressed was that of bronchiolitis obliterans syndrome because this is responsible for most deaths beyond the first year. This physiologic entity is characterized by progressive airflow obstruction. Other conditions such as infection, acute rejection, disease recurrence, and airway complications need to be excluded.
Chronic renal disease is also a major long-term problem. This usually results from chronic calcineurin therapy. At 10 years posttransplant, about 50% of patients have a creatinine level more than 2.5, and at 5 years 3.2% of patients are on chronic hemodialysis.
For patients with acute respiratory failure, the differential diagnosis includes infection, acute rejection, congestive heart failure, volume overload, thromboembolic disease, and inflammatory lung disease (eg, rapamycin toxicity). Cytomegalovirus infection is seen in 13% to 75% of lung transplant recipients. It is often diagnosed in conjunction with another problem and clinicians need to be aware of ganciclovir-resistant strains (6% to 10% of cases). Other infections that might occur include community respiratory viruses and fungal infections, especially Aspergillus sp and Candida sp.
A high index of suspicion should always be maintained for venous thromboembolism and pulmonary emboli, which have a reported incidence of 6% to 8.6%
In addition, drug-drug interactions should always be considered, especially with the calcineurin inhibitors because these drugs may result in untoward side effects. Dr. Whelan ended with a sobering quotation that "lung transplant recipients can have as many diseases as they damn well please."
Kevin Chan, MD, from the University of Michigan, discussed ICU outcomes after hematopoietic stem cell transplantation (HSCT). There are about 16,000 HSCT procedures in the United States each year. Indications include hematologic malignancies, certain solid tumors, and some immune-mediated diseases. Prior to HSCT, patients receive some combination of ablative chemotherapy with or without radiation therapy. Pulmonary complications are seen in about 50% to 60% of patients. ICU admission is required in 30% to 40% and respiratory failure occurs in 10% to 25% of cases. The pulmonary problems that may be encountered include infections, acute graft host disease, diffuse alveolar hemorrhage, idiopathic pneumonitis, congestive heart failure, and bronchiolitis obliterans. In all, pulmonary complications account for 30% to 45% of deaths after HSCT.
Dr.Chan provided a historic perspective and through a series of temporarily sequential articles demonstrated a slow improvement in outcomes through the years in these patients. In one of the more recent papers, Soubani and associates reported that 11% of patients who underwent HSCT were admitted to the medical ICU, 61% were discharged from the ICU, and 41% were discharged home. Predictors of a poor outcome include high Acute Physiology and Chronic Health Evaluation scores, high lactate levels, positive blood cultures, need for pressors or mechanical ventilation, bilirubin level, and multiple organ system failure. It is important to discuss the patient's prognosis with both the patient and the patient's family to manage expectations, especially if the patient requires ICU admission.
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Neil MacIntyre, MD
Professor, Duke University Medical Center, Durham, North Carolina
Disclosure: Neil R. MacIntyre, MD, has disclosed no relevant financial relationships.
Steven D. Nathan, MD
Medical Director, Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia
Disclosure: Steven D. Nathan, MD, has disclosed that he has received grants for clinical research from Intermune, Actelion, and United Therapeutics. Dr. Nathan has also disclosed that he has served as an advisor or consultant to Intermune, Actelion, United Therapeutics, and Gilead, and has received grants for educational activities from Intermune and Actelion.
Andrew Shorr, MD, MPH
Associate Professor of Medicine, Department of Pulmonary & Critical Care Medicine, George Washington University, Washington, DC; Associate Chief, Department of Pulmonary & Critical Care Medicine, Washington Hospital Center, Washington, DC
Disclosure: Andrew F. Shorr, MD, MPH, FCCP, has disclosed that he has received grants for clinical research and/or educational activities from Pfizer, Ortho-McNeil, GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Shorr has also disclosed that he has served as an advisor or consultant to Pfizer and Ortho-McNeil.
Margaret A. Clark, RN, RRT-NPS
Editorial Director, Medscape Pulmonary Medicine and Allergy & Clinical Immunology
Disclosure: Margaret A. Clark, RN, RRT-NPS, has disclosed no relevant financial relationships.