Long-term Outcomes of Mechanical Ventilation L. D. Hudson, C. M. Lee, and J. R. Curtis

L. D. Hudson, C. M. Lee, and J. R. Curtis

Introduction

Traditionally, outcomes of mechanical ventilation for acute respiratory failure reported by investigators have been physiologic changes, mortality, duration of mechanical ventilation, and length of stay in both intensive care unit (ICU) and hospital. Various definitions for a mortality outcome have been used, often either an arbitrary period from acute disease onset such as 28 day mortality, or mortality at hospital discharge. Occasionally costs of the hospitalization have been included.

In recent years reports of longer term outcomes in patients with acute respira- tory failure (and especially in acute lung injury [ALI]/acute respiratory distress syndrome [ARDS]) have been published. These outcomes have included long-term survival, pulmonary function, and – more recently – quality of life and conditions or complications of acute respiratory failure that could affect quality of life. These complications or conditions include neurocognitive and neuropsychological ab- normalities and neuromuscular complaints and impairments.

The subject of this chapter is long-term outcomes after mechanical ventilation.

For the most part, we are unable to differentiate which outcomes in survivors of acute respiratory failure are related to the use of mechanical ventilation and which are due either to the underlying condition for which mechanical ventilation was being performed or a variety of other factors including co-morbidity and the effects of other therapies. We will approach this issue by first describing long-term outcomes associated with mechanical ventilation for acute respiratory failure in a general way. We will describe survival, emphasizing when available data on long term follow-up of these patients, and also quality of life and complications occur- ring in survivors. Mechanical ventilation may allow the occurrence or development of complications – but not be directly responsible for them. After a description of outcomes we will briefly discuss possible etiologic factors whenever data exist to allow this, including whether mechanical ventilation could be implicated. Most of the data will be reported separately for the differing underlying conditions or types of acute respiratory failure, mainly since the original papers most frequently report outcomes for particular disease cohorts, but also because the underlying condition is likely such an important determinant of outcome.

Why is it important that we know the long-term outcomes after mechanical

ventilation for acute respiratory failure? The answers vary depending on the

category of the outcomes being considered. Survival is important in order to know

prognosis, which could play a role in decision making for both the patient and his or her surrogates and the caregivers during the ICU admission. Knowledge of long-term survival may also be important in resource development and utilization planning. Objectively measured physiologic outcomes such as pulmonary function can help connect events and therapy during the acute illness with other more patient-centered outcomes. These measurements may provide information about mechanisms and also may have predictive value. Patient-centered outcomes such as quality of life and symptoms are what patients care about. Also, by under- standing the prevalence and severity of these outcomes, we can begin to link them with possible etiologic factors during the critical illness that are potentially modi- fiable. In this way we can begin to develop strategies for patient management both during the critical illness and in follow-up that may be able to prevent or minimize these adverse long-term outcomes.

Survival/Mortality

Hospital Mortality for Patients Receiving Mechanical Ventilation

Esteban and colleagues conducted an international prospective cohort study of adult patients admitted to ICUs and receiving mechanical ventilation for more than 12 consecutive hours during March, 1998 and reported their results in 2002 [1]. The study included 5183 patients in 361 ICUs in 20 countries. Mean duration of mechanical ventilation was 5.9 days and mean ICU length of stay was 11.2 days.

Overall mortality was 31%, 52% in patients receiving mechanical ventilation for ARDS and 22% receiving mechanical ventilation for an exacerbation of chronic obstructive pulmonary disease (COPD). This large study confirmed previous re- ports of higher mortality rates in patients with ARDS and lower mortality for COPD patients with acute respiratory failure.

Analysis of the types of patients and their conditions included in this cohort

provides important information about the practice of mechanical ventilation in the

broad international critical care community. It also helps inform us about the

relative magnitude of those populations in which long-term outcomes may be of

interest. Of the 5183 patients, 17% were being ventilated for coma, 2% for neuro-

muscular disease, 13% for acute respiratory failure or chronic pulmonary disease,

and 69% for acute respiratory failure without previous lung disease. Of those

patients with acute respiratory failure, about a third (21% of the total of mechani-

cally ventilated patients) were post-operative. Ten percent of the total had conges-

tive heart failure, 2% were post cardiac arrest. Thirty-eight percent had either

pneumonia (14%) or some other cause known to be associated with ALI (sepsis,

trauma, aspiration) although whether criteria for ALI were met is not known. Only

4.5% of the total carried a diagnosis of ARDS. In this chapter we will deal with

long-term outcomes in patients with acute respiratory failure superimposed on

chronic pulmonary disease (mainly COPD), ALI/ARDS, and will briefly mention

available data for mechanically ventilated patients with acute cardiogenic pulmo-

nary edema.

Hospital Mortality in Patients with COPD and Acute Respiratory Failure

Most series of patients with COPD and acute respiratory failure include both non-ventilated (usually the majority) and ventilated patients. Overall mortality rates are usually lower than or similar to the 22% in the Esteban study for ventilated patients. For example, Connors et al., in data from the multi-center SUPPORT study, found an 11% overall mortality rate for 1016 patients with exacerbations of COPD , of whom 348 were treated with mechanical ventilation [2]. They did not report hospital mortality rates stratified by mechanical ventilation. Seneff et al., in a prospective multi-center inception cohort study of 362 admissions to ICUs for an acute exacerbation of COPD, found an overall hospital mortality of 24% with the mortality in ventilated patients (n=170) being 31.8% compared to 16.7% in non- ventilated patients (n=192) [3]. When a multivariate analysis of potential variables to explain mortality was performed, the physiological measurements contained in the acute physiology score of the APACHE III score and the pre-ICU hospital length of stay were the two most important predictors of hospital mortality. After account- ing for these, the use of mechanical ventilation was not a statistically significant predictor of hospital mortality. Hospital mortality rates in these two multicenter studies are similar to those in previous reports since 1975 through the early 1990s [4].

Long-term Mortality Rates in Patients with COPD and Acute Respiratory Failure

Studies from the 1970s and 1980s suggested that once patients with COPD survive an episode of acute respiratory failure, their subsequent survival is similar to patients with the same degree of pulmonary dysfunction without an acute exacer- bation of COPD [5, 6]. In other words, the prognosis of a patient with COPD was dependent on their severity of COPD and was unaffected by a previous history of an episode of acute respiratory failure. Most patients in these studies were not treated with mechanical ventilation.

The studies by Connors et al. [2] and Seneff et al. [3] described above for hospital mortality also reported mortality at 6 months and one year (and two years for the Connors study). For the SUPPORT study cohort of 1016 patients reported by Connors, mortality rates increased from the 11% hospital mortality to 33%, 43%, and 49% respectively for 6 months, one and two years of follow-up. Approximately one-third of patients received mechanical ventilation (348/1016). Reduced survival was observed in patients who required mechanical ventilation – 43% mortality at 6 months compared to 28% in patients who were not ventilated.

In the study by Seneff and co-workers, specific longer-term survival data are

limited to those patients aged 65 years or older. Two hundred and sixteen of the

362 patients met these age criteria and complete data were available for 167 of those

216. Overall mortality was 30% at hospital discharge, 47% at 6 months, and 59% at

one year. Mortality figures for those receiving mechanical ventilation compared to

those who did not were, respectively, 37% vs. 23% at hospital discharge, 54% vs.

42% at 6 months, and 62% vs. 56% at one year. Thus, hospital mortality but not subsequent mortality was higher in those patients receiving mechanical ventilation (Fig. 1). When a multivariate analysis was performed to assess factors associated with mortality, however, mortality was explained by the physiologic abnormalities captured in the acute physiology score and by pre-ICU hospital length of stay and mechanical ventilation was not independently significant (Fig. 2).

Almagro and colleagues in Spain followed a cohort of 135 patients hospitalized for acute exacerbation of COPD for over two years [7]. Only eight of these patients were treated with mechanical ventilation. Hospital mortality is not described;

mortality at 6 months, 1, 2, and 2.5 years was 16%, 22%, 36% and 44%, respectively.

Separate analysis for patients receiving mechanical ventilation is not reported.

In summary, although hospital survival for patients with COPD and acute respiratory failure is relatively good, there is a high cumulative mortality over the next year. Ventilated patients have approximately twice the hospital mortality as non-ventilated patients but mechanical ventilation did not influence subsequent mortality. The multivariate analysis finding that respiratory physiology and sever- ity of baseline COPD predicts mortality is relatively more important for long-term than short-term outcome.

Fig. 1. Kaplan-Meier 1-year survival for 167 patients aged 65 years or older admitted to an ICU for acute exacerbation of COPD according to need for mechanical ventilation at ICU admission.

Adapted from [3] with permission

Hospital Mortality in ALI/ARDS

Values for 28 or 30-day mortality or hospital mortality in patients with ALI/ARDS vary considerably, ranging from about 30–60% [1, 4, 8, 9]. In the Esteban interna- tional study, the mortality listed for ARDS is 52% [1]. In a prospective cohort study from Sweden, Denmark and Iceland the 90 day mortality was 42% for ALI not fulfilling ARDS criteria and similar at 41% for ARDS [8]. In a recent one-year study of ALI in King County, Washington, USA in which all ventilated patients were systemically screened for the diagnosis of ALI, the overall mortality was 34% [9].

A number of variables affect the mortality rate including age and underlying etiology or risk condition of ALI, making comparisons between cohorts difficult without having detailed data on case-mix and comorbid states. Suntharalingam and colleagues reported a statistically insignificant trend of higher hospital mor- tality in patients with ARDS from a pulmonary (direct) etiology compared to those with ARDS from a non-pulmonary (indirect) etiology (47 vs. 28%, p=0.11) [10].

Our group at the University of Washington in Seattle, USA first reported on a

declining hospital mortality rate for patients with ARDS in 1995 [11]. Using data

from a registry of ARDS patients available since the early 1980s in which patients

were prospectively screened for a diagnosis of ARDS using the same criteria, we

showed a reduction in hospital mortality from greater than 60% in the 1980s to less

than 40% in the early 1990s. The hospital in which the study was performed,

Harborview Medical Center, is the major trauma referral center for a five state

region. Trauma as a risk condition for ALI or ARDS is known to be associated with

Fig. 2. Relative importance, as measured by % of explanatory power (x

) for predicting hospital

and 180-day mortality rates, of prognostic factors for 167 patients aged 65 years or older admitted

to an ICU for acute exacerbation of COPD. Adapted from [3]

a lower mortality than other common risk conditions, particularly sepsis, which may explain our relatively lower mortality compared to other studies. The reduc- tion in mortality rate over time, however, was related more to a decreased mortality in patients with sepsis as their ARDS risk. The severity of illness as judged by APACHE score was similar comparing the earlier years with a high mortality to later years with a lower mortality. The reduction was not affected after adjusting for frequency of risk conditions and age. Since our report, two other groups have reported a reduction in mortality rate over time, one report from England [12] and another from France [13].

Long-term Survival in ALI/ARDS

Although many have reported the hospital mortality associated with ARDS, there has only been one study that specifically investigated the effects of ARDS on long-term survival compared with a control group. Davidson and colleagues con- ducted a prospective, matched parallel cohort study following 127 survivors of ARDS related to trauma or sepsis, and 127 control survivors with sepsis or trauma without ARDS [14]. The control group was matched for severity of illness, using the Injury Severity Score for trauma patients, and the APACHE III score for those with sepsis. The median follow-up period for both subjects and controls was 753 days. This study found no difference in long-term mortality between the ARDS survivors and their matched controls (Fig. 3). Survival in both groups was corre- lated most significantly with risk factor, with a 3% late mortality in the trauma

Fig. 3. Kaplan-Meier survival plot of ARDS survivors and matched controls. Adapted from [14]

group compared to 22% in sepsis. Increased age and serious comorbidities in the sepsis patients were also associated with increased late mortality.

Long-term Mortality in Patients

with Acute Cardiogenic Pulmonary Edema

Wiener et al. reported survival data in 44 patients with acute cardiogenic pulmo- nary edema associated with coronary artery disease, of whom 26 had acute myo- cardial infarction (AMI) [15]. The authors do not describe the frequency of me- chanical ventilation. Hospital mortality was strongly influenced by the presence of AMI; 12 of 26 patients (46%) with AMI died in hospital compared to only 1 of 18 patients (6%) in its absence (p=0.006). Of the 30 hospital survivors, 8 of 30 (27%) had died at 1 year and 21 of 30 patients (70%) had died at 6 years. There was no significant difference in subsequent survival between those with and without AMI.

Adnet and coworkers followed a cohort of 79 patients with age > 75 years requiring endotracheal intubation and mechanical ventilation for acute cardio- genic pulmonary edema [16]. Hospital mortality was 26.6%. Independent predic- tors of increased ICU mortality from multiple logistic regression analysis were the presence of multiple organ failure, epinephrine use, length of ICU stay, and dura- tion of mechanical ventilation. The 58 hospital survivors were followed for a mean duration of 23 months (range 2–56 months) with 31 (53%) patients dying during the follow-up period. Overall 1 year mortality among hospital survivors was 30%.

The most common cause of long-term mortality was congestive heart failure.

Neither of these studies provide insight into the effect of mechanical ventilation on long-term survival from acute cardiogenic edema.

Long-term Outcome of Critically Ill Elderly Patients

Chelluri and colleagues reported long-term outcomes in critically ill patients aged 65 years and older, comparing those aged 75 years and older to those aged 65–74 years [17]: 97 patients were studied, 54 aged 75 years or older and 43 aged 65–74 years. Hospital mortality and mortality at one year did not differ between the two groups (39 vs. 40% and 63 vs. 58%, respectively). Neither did length of stay, hospital charges, and follow-up quality of life assessments. These authors concluded that age alone is not an adequate predictor of long-term survival and quality of life in critically ill elderly patients.

Long-term Follow-up of Diagnostic Studies

Serial diagnostic studies in the months after acute respiratory failure may provide

insight into the process and timing of lung repair. There is limited information

available about serial pulmonary function studies, and especially diagnostic imag-

ing and morphologic studies during recovery from acute respiratory failure treated

with mechanical ventilation.

Pulmonary Function Testing

Several studies have looked at the results of serial pulmonary function testing after survival from acute respiratory failure associated with ARDS or COPD. The studies of COPD patients benefit from baseline pulmonary function tests before onset of respiratory failure, and show that although recovery from mechanical ventilation is associated with an acute decrement of the forced expiratory volume in one second (FEV1), the majority of patients who survive the acute episode will return to their baseline pulmonary function [5, 6].

There have been two prospective studies of pulmonary function testing at uniform time points after recovery from ARDS [18, 19]. Unlike the studies in COPD, baseline pulmonary function tests were not available for survivors of ARDS, since most patients had no pre-morbid indication for testing. McHugh and associates enrolled 52 of 82 survivors of ARDS (63%), aiming to measure pulmonary function tests and self-perceived health scores at 2 weeks after extubation, and then again at 3 months, 6 months and one year [18]. The study showed that at extubation, forced vital capacity (FVC), total lung capacity (TLC) and diffusing capacity for carbon monoxide (DLCO) were all markedly reduced. There was significant improvement in pulmonary function tests between extubation and 3 months. Function improved a small amount more by 6 months, at which point the FVC was still reduced in 55%

of patients studied, the TLC was reduced in 45%, and the DLCO was reduced in 79%. As previously reported, the degree of persisting impairment was mild in the majority of patients. There was no additional improvement between 6 and 12 months. In a more recent study, Herridge et al. enrolled 109 ARDS survivors in a 12 months follow-up study that included pulmonary function testing [19]. Of the 97 survivors at 12 months, 83 were evaluated (86% follow-up). Results were similar to those found by McHugh: patients had a mild restrictive defect and a moderate reduction in diffusion capacity at three months, with return of spirometry to the normal range in most patients by six months (median values were within 80% of predicted values) and continued improvement in diffusion capacity at between six months and one year.

Pathology

The only studies providing information on the long-term effects of mechanical ventilation on lung histology are of four survivors of ARDS. These investigations are quite limited, likely due to the invasive nature of obtaining tissue for evaluation.

At 3 months, biopsies revealed interstitial fibrosis and infiltration of lymphocytes

and plasma cells in one patient [20]. Biopsies taken between 9 and 10 months

post-ARDS showed patchy interstitial fibrosis, hyperplasia of type II pneumocytes,

and increased numbers of alveolar macrophages and interstitial lymphocytes in

one subject, and relatively normal histology (except for residual alveolar wall

thickening) in a second subject [21]. A report of two sequential biopsies in the same

patient found that interstitial fibrosis was present early, and improved over time

[22]. If these reports are generalizable, it appears that the increased cellularity,

organization, and fibroblast proliferation with fibrosis described in the acute phase markedly improves in the recovery period.

Thoracic Imaging

There are few studies of the resolution of the radiographic changes coincident with acute respiratory failure in survivors of mechanical ventilation. These reports are limited to case series and prospective studies of patients recovering from ARDS. A review of 85 cases found that 19% of patients had persistent radiographic abnor- malities at 3 or more months after extubation; the most common findings were bibasilar interstitial infiltrates and reticular changes [23]. In Herridge’s et al.

follow-up study of over 100 ARDS survivors, 20% of patients had radiographic abnormalities at 1 year, with findings of linear fibrosis, small bullous cysts, and isolated areas of pleural thickening [19].

There is only one study of the evolution of computed tomography (CT) abnor- malities in survivors of ARDS. Following a protocol in which all patients with ARDS had chest CTs in the acute phase, Desai and colleagues performed follow-up CTs on 27 survivors, 110–267 days after intubation [24]. Investigators looked for four types of parenchymal changes, and visually quantified involvement to determine extent. Ground-glass opacities were identified in all patients in the acute phase of ARDS, with a median extent of 68%. Intense parenchymal opacification was also seen in all 27 patients in the acute phase, largely in dependent regions with a median extent of 13%. On follow-up CTs, ground glass opacities were seen in 17 of 27 patients but were not extensive (median extent of less than 1%). Twenty-three of 27 follow-up CTs demonstrated a coarse reticular pattern that distorted the under- lying parenchyma, mainly in small anterior regions of the lung.

What have we learned from studies of diagnostic tests after recovery from acute respiratory failure and mechanical ventilation? For the most part, the abnormalities found in acute ARDS by pulmonary function testing, histology and radiology improve over time and stabilize by 6 to 12 months. It is possible that the method of mechanical ventilation may have an impact on the timing and degree of lung repair, although no data are currently available to support this hypothesis. CT imaging may provide a sensitive and non-invasive surrogate for lung histology and may become a useful tool in future studies of lung recovery after acute respiratory failure.

Patient-centered Long-term Outcomes Health-related Quality of Life

There are an increasing number of studies that have examined the long-term effect

of ARDS or other critical illnesses requiring mechanical ventilation on the quality

of life and health status of survivors. McHugh and colleagues, using the Sickness

Impact Profile (SIP), demonstrated a significant decrement in health status among

survivors of ARDS and showed that health status improved during the first 3

months after discharge from the hospital but remained relatively stable thereafter [18]. Davidson and colleagues, using the Medical Outcomes Study Short Form-36 (SF-36) and the Saint George’s Respiratory Questionnaire, showed that there were significant decrements in most domains of health status among survivors of ARDS and that these decrements were significantly worse for patients with ARDS com- pared to patients with a comparable severity of illness from sepsis or trauma, but who did not meet criteria for ARDS [25] (Fig. 4). This study suggested decrements in physical function might be the most severe.

Similarly, in the largest and most complete follow-up study of ARDS survivors, Herridge found severe impairment in health status using the SF-36 at 3 months, with marked improvement at 6 months that continued to one year. Despite this improvement, at one year the median scores in all but one domain remained significantly reduced compared with age and gender matched controls [19]. Wein- ert and colleagues studied 24 survivors of ALI with the SF-36, also showing reduc- tions in many domains of health status and particularly severe reductions in social functioning and mental health domains [26]. Finally, Angus and colleagues used the Quality of Well Being questionnaire to assess health status in a cohort of 200 previously healthy patients who developed ARDS and showed marked decrements in many domains of health status at 6 months and no significant change from 6 to 12 months [27].

In addition to ARDS, studies have demonstrated reductions in health status for patients with other critical illnesses requiring prolonged mechanical ventilation,

Fig. 4. Symptom scores on the St. George’s Respiratory Questionnaire (SGRQ) of ARDS survivors,

matched controls and historical controls. Note: lower scores denote lesser symptoms. COPD

patients have a mean FEV1 of 1.3 L (45% predicted). From [23] with permission

including sepsis [28], multiple organ dysfunction [29], and general ICU patients [17, 30, 31]. Although results vary, these studies also suggest decrements in a wide range of the domains of health status.

A number of studies have attempted to define the predictors of decreased health status among survivors of ARDS or other critical illness. Several studies suggest that the health status prior to admission to the ICU is a strong predictor of the health status after discharge [32, 33]. A study by Wehler and colleagues showed that patients with the best health status prior to critical illness were more likely to have reductions in their health status while those patients with the lowest health status prior to admission to an ICU were actually more likely to improve from their baseline health status [32]. Similarly, Konopad and colleagues showed that among the very elderly, health status may actually increase from baseline after an ICU admission [34]. Severity of illness is also a significant predictor of health status after discharge from the ICU [18, 32, 33]. Increasing age predicts decreased health status after critical illness in some studies [32, 33], but other studies did not find age to be an important independent predictor of health status [17] and suggest that even those over the age of 70 who receive more than 30 days of intensive care are often satisfied with their health status and would choose to receive ICU care again if needed [30]. Schelling and colleagues showed that pulmonary function impairment predicted worse health status suggesting that treatment strategies designed to minimize lung injury may have diverse effects improving health status in ARDS survivors [35].

Exercise Tolerance

Exercise tolerance is another measure of functional ability. In the large follow-up study of ARDS survivors, Herridge evaluated the distance walked by subjects (the 6-minute walk test) at 3, 6 and 12 months post-ICU discharge [19]. Subjects’

exercise tolerance improved over one year, with median distance increasing from 281 meters at 3 months, to 396 meters at 6 months, to 422 meters at 12 months.

Despite this improvement, performance at one year remained markedly impaired, compared with the predicted distance of 640 meters. Most survivors assigned their exercise impairment to global muscle wasting and weakness; foot-drop, difficulty moving large joints and dyspnea were also cited.

Symptoms

Symptoms can be viewed as an additional patient-assessed outcome of import and

interest to patients and their families. There have been a few studies documenting

significant symptom burden for critically ill patients while in the ICU [36–38], but

relatively few studies explicitly examining the symptoms of survivors of critical

illness. Studies of health status among survivors of critical illness incorporate the

effect that these symptoms have on individuals’ lives, but it may also be important

for investigators to explicitly examine the specific symptoms that are troubling to

patients after a critical illness requiring mechanical ventilation as one way to

understand the potential ways to decrease the symptom burden and the effect these symptoms have on patients’ quality of life. For example, Angus and colleagues used the Quality of Well Being questionnaire to assess the quality of life of 132 ARDS survivors [27]. They found significant reductions in health status in the ARDS survivors and showed that the symptom domain of the Quality of Well Being questionnaire accounted for a larger decrement in quality of life than other do- mains including physical activity, social activity, and mobility. Symptoms ac- counted for approximately 70% of the reduction in health status seen in this study.

In the recent study involving comprehensive follow-up of ARDS patients, Her- ridge found that all subjects complained of muscle weakness and fatigue [19].

Similar to Herridge’s findings, Angus et al. [27] reported that the most common symptoms were musculoskeletal, with 70% of patients describing weakness, pain and fatigue. Other bothersome symptoms included lower respiratory tract symp- toms, as well as depression and anxiety, constitutional symptoms, and cognitive symptoms. These data provide some direction for investigators interested in de- creasing the symptom burden experienced by survivors of ARDS.

Neuropsychological Outcomes

There has been increasing interest in examining the effect of critical illness, and especially ARDS, on the cognitive, emotional, and psychological functioning of survivors. There is mounting evidence that suggests that patients who survive critical illness may be left with decreased functioning in these realms. Hopkins and colleagues examined the cognitive functioning of 55 ARDS survivors showing that at hospital discharge all 55 patients had significant impairment in cognitive and affective functioning [39]. However, much more concerning was the finding that at 1 year after discharge from the hospital, 30% of patients still had generalized cognitive dysfunction and 78% had decrements in one or more of the following areas: attention, memory, concentration, and mental processing speed [39]. These authors attempted to identify predictors of cognitive impairment and were limited by their small sample size and by the collinearity of many of the important potential predictors such as duration of mechanical ventilation, severity of underlying lung injury, severity of desaturations in the ICU, duration of desaturations in the ICU, duration and amount of sedation. Nonetheless, their analysis did show an associa- tion between the continuous oxygen saturation measurements and the severity of cognitive deficits [39]. Another study assessed cognitive function in 46 ARDS survivors sometime between 1 and 12 years after the ARDS (with a median of 6 years) and showed that 24% had mild or moderate cognitive impairment [40]. This study suggested significant impact of this impairment on patients’ lives by showing that 0 of 11 patients with cognitive impairment had returned to work while 27 of 35 patients without cognitive impairment had returned to work [40].

There has also been recent research looking at the prevalence and predictors of post-traumatic stress disorder (PTSD) after mechanical ventilation for ARDS.

Schelling and colleagues used a questionnaire called the Post Traumatic Stress

Syndrome 10-Questions Inventory (PTSS-10) with 80 survivors of ARDS with a

median time since ARDS of 4 years and excluded patients with head trauma or

pre-existing neurological or psychiatric diseases [40]. These authors found that 28% of the ARDS survivors had a PTSS-10 score above the cut-off for PTSD, a significantly higher proportion than two control groups: patients who had under- gone maxillofacial surgery and German United Nations soldiers who had experi- enced prolonged service in Cambodia [40]. These authors showed that if patients reported memories of traumatic experiences during their ICU stay, including memories of respiratory distress, feelings of anxiety, pain, or nightmares, they were more likely to have symptoms of PTSD.

It remains unclear exactly what aspects of mechanical ventilation or ALI predis- pose patients to long-term neuropsychological effects. Hopkins and colleagues provide some data suggesting it may correlate with desaturations [39]. Nelson and colleagues performed a cross-sectional study of 24 survivors of ALI that showed significant correlations between both symptoms of depression and symptoms of PTSD and a number of variables including days in the ICU, days on mechanical ventilation, and days of sedation [41]. Interestingly, these authors did not show a correlation between symptoms of either depression or PTSD and APACHE III score. In an interesting preliminary study, Schelling and colleagues performed a small retrospective case-control study comparing patients who received corticos- teroids for treatment of septic shock to similar patients who did not receive corticosteroids [42]. These authors found that the patients who received corticos- teroids had a significantly lower incidence of PTSD (5 of 27 compared to 16 of 27) and significantly higher scores on the mental health index of the SF-36. Although all of these studies are limited by their small numbers and their observational designs, these three studies provide intriguing preliminary data to suggest that the way patients are managed in the ICU may have important effects on their long-term mental health and cognitive function. Further studies are needed to attempt to identify the components of long-term mechanical ventilation or critical illness that predispose patients to neuropsychological deficits and to tease apart the potential causes that include desaturations or decreased cerebral perfusion pressure during critical illness, inflammation and bio-trauma of sepsis and ARDS, duration and amount of sedation, and traumatic experiences during an ICU stay. Since increas- ing severity of illness will portend increases in many of these variables, differenti- ating between the importance of these collinear potential causes will be challenging.

Furthermore, randomized controlled trials of different mechanical ventilation and sedation strategies should also examine the potential effects on these neuropsy- chological outcomes.

Return to Work after Mechanical Ventilation

For young survivors of critical illness, the ability to return to work is an important

outcome. This is particularly salient for survivors of ARDS, who tend to be under

age 50 (median age 39 in the Davidson study, and 45 years of age in the Herridge),

compared with a median age over 65 years among COPD survivors (mean age 66

in the Seneff study [3], and median age of 70 in the Connors report [2]). Few

follow-up studies have investigated return to work in ARDS survivors. At one year

after hospital discharge, McHugh found that only 44% of subjects had returned to

work [18]. Herridge’s results were similar: at one year, 49% of survivors had returned to work, most to their original positions [19]. The reasons that were reported for not returning to previous employment included weakness and fatigue, difficulty walking due to large joint immobility (from heterotopic ossification) and foot-drop, work stress and early retirement. Rothenhausler et al. showed that decreased cognitive function was an important predictor of inability to return to work after recovery from acute respiratory failure [40].

Method of Ventilation and Outcomes

While it is likely that most of the long-term outcomes after mechanical ventilation are directly related to the disease causing acute respiratory failure, the method of ventilation and ICU supportive care have also been shown to affect morbidity and mortality. Although uncommon, upper airway trauma may develop as a result of endotracheal intubation either via translaryngeal or tracheostomy tubes [43]. This trauma may lead to tracheolaryngeal malacia or stenosis, which may present with progressive shortness of breath and may lead to respiratory failure, or the devel- opment of a tracheo-innominate artery fistula which presents as life threatening hemoptysis [44]. Endotracheal intubation is also a risk factor for nosocomial pneumonia, which has a high associated mortality. The manner of ventilation is also associated with acute patient outcomes; in ARDS, failure to use low tidal volumes is associated with increased mortality [45], multiple organ dysfunction, and pulmonary barotrauma. Additionally, most critically ill patients requiring endotracheal intubation receive significant doses of sedative and analgesic medi- cations, drugs that are associated with hypotension, delirium, and increased ICU mortality.

Provision of ventilatory support without endotracheal intubation conceptually could reduce these complications of mechanical ventilation. There is convincing evidence from multiple randomized controlled multicenter trials of non-invasive positive pressure ventilation (NPPV) versus endotracheal intubation and mechani- cal ventilation in patients with acute respiratory failure from COPD that show improved mortality, morbidity, and shortened ICU and hospital stay [46]. NPPV may play a role in the support of patients with other causes of respiratory failure, including asthma, cardiogenic pulmonary edema, pneumonia, ARDS, and post- lung resection, but the data are still quite preliminary. To date, there are no studies of long-term outcomes of patients treated with NPPV, but it is conceivable that there would be a reduction in sequelae associated with intubation (airway trauma) and excessive sedation.

Conclusion

Most of the available data of long-term outcomes after mechanical ventilation deal

with the survivors of ALI/ARDS. Long-term survival of these patients appears to

be related more to the underlying risk condition (sepsis versus trauma) than to

occurrence of ALI. Similarly, the long-term survival in patients with COPD and

cardiogenic pulmonary edema is more related to the severity of the underlying condition than to the episode of acute respiratory failure itself.

In the last ten years, there has been an increasing amount of knowledge regard- ing long-term patient centered outcomes. Studies have revealed a significant im- pairment of health status, as assessed by a variety of methods, including measure- ments of health-related quality of life. Lung function in survivors of ALI shows substantial return towards normal function; impairment, when present, is typically mild-to-moderate and does not to appear to explain the reduced quality of life.

Recent studies point to neuromuscular, neurocognitive and neuropsychologic abnormalities, which persist at one year, as being the sequelae most troublesome to survivors.

It is extremely difficult to assign causation for the long-term sequelae in survi- vors of critical illness who have received mechanical ventilation based on our current limited knowledge. It is likely that most of the long-term complications after recovery are caused by the underlying disease process that leads to respiratory failure, but there are many ways in which ICU management, including the method of ventilation, may affect both short and long term outcomes. For example, in addition to increasing hospital mortality, failure to use lung protective ventilation with low tidal volumes may affect lung injury and the degree of successful repair.

It is also conceivable that the sustained systemic inflammation from injurious ventilation may affect end-organ function in the long-term as well as short-term, including central nervous system and neuromuscular function.

Studies are now needed to link the acute events occurring during the period of critical illness with the longer term sequelae in order to identify modifiable factors and allow strategies that will prevent or minimize these burdensome residua.

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