INTRODUCTION

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Cystic fibrosis (CF) causes abnormal ion transport in airway epithelial cells and alters the clearance of airway secretions (1). Subsequent chronic infection leads to inflammation, mucus hypersecretion, and bronchoconstriction that obstruct airways and cause bronchiectasis. The progressive airways disease is complicated by increased ventilatory requirements, air trapping, and respiratory muscle weakness, and leads to respiratory failure, the cause of death in more than 90% of CF patients (2). A 1978 survey documented poor outcomes for CF patients requiring mechanical ventilation, and palliative care has been suggested for CF patients with respiratory failure caused by advanced lung disease (3). However, a 1989 review of five infants with CF with acute respiratory failure demonstrated 100% recovery and long-term survival comparable to that of age- and sex-matched CF controls (4).

Several developments prompted reconsideration of the use of intensive care units (ICUs) and mechanical ventilation for adults with CF. Lung transplantation provides an opportunity for dramatic improvement of respiratory function and quality of life for such patients, but uncompensated respiratory failure may occur during the long waiting period for donor organs (currently > 2 yr) (5). The incidence of some life-threatening but reversible complications of CF that can precipitate respiratory failure (e.g., pneumothorax, massive hemoptysis) increases with age (6). The growing number of adults with CF (more than 7,750 in the United States) and the increasing median survival of persons with CF (32.3 yr in 1998) (6) have significantly increased ICU use at some centers. To measure acute and long-term survival in CF, and to identify factors that may influence these outcomes, we retrospectively evaluated all adults with CF who were admitted to the medical ICU at the University of North Carolina (UNC) Hospitals during the 9 yr after the development of a lung transplant program at that medical center.

	METHODS

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All adults with CF who were admitted to the medical or respiratory ICUs at the UNC Hospitals between January 1990 and December 1998 were identified from admission records. CF was diagnosed on the basis of characteristic pulmonary and gastrointestinal disease plus an abnormal sweat chloride test result or cystic fibrosis transmembrane regulator (CFTR) genotype (7). Patients admitted after lung transplantation were excluded. Demographic data (age, sex), severity of disease (body mass index [BMI], FEV₁), primary admitting diagnosis, interventions (number of days in the ICU, mask or intubated ventilator days), complications (pneumothorax, renal failure, nosocomial infections), and outcomes were recorded from medical records. The outcomes were survival to ICU discharge, survival to lung transplantation, death, and survival at 1 yr after discharge from the ICU. All analyses were based on number of episodes, since 28 patients (37%) had multiple admissions for CF. The relation of survival to FEV₁ was evaluated with Fisher's exact test.

Hemoptysis and Antibiotic Desensitization

Management of major hemoptysis (> 240 ml/24 h) was done according to published guidelines (8). All patients received intravenous antibiotics chosen on the basis of the sensitivities of the patients' most recent sputum bacterial isolates. Drugs that could have interfered with coagulation were discontinued and coagulation defects corrected. Exercise and chest physiotherapy were temporarily discontinued and bronchial artery embolization was performed when indicated (9, 10). Antibiotic desensitization for patients with known or suspected hypersensitivity reactions was done according to standard protocols (11, 12). Whenever feasible, the antibiotics were prepared immediately before ICU admission.

Pulmonary Exacerbations

Standard care. Obstructive airway exacerbations complicated by respiratory failure were treated with intense standard care as previously described (13). Antibiotic selection was based on the patients' most recent sputum bacterial isolates. Airway clearance was augmented by chest physiotherapy and other methods under the guidance of physical therapists, using nurses, family, and other personnel as needed. Enteral nutrition with adequate pancreatic enzyme supplementation was initiated as early as possible. Corticosteroids were not used except for patients with allergic bronchopulmonary aspergillosis (ABPA) and patients known to be corticosteroid-responsive or with severe hypercapnia that was refractory to other treatments (14, 15). When needed, methylprednisolone (1 to 2 mg/kg/d) was given for 2 to 4 d and tapered rapidly to 7.5 to 10 mg/d. Physical rehabilitation to maintain musculoskeletal fitness and augment airway clearance was continued, even for patients who required assisted ventilation.

Mucolytic agents. Nebulized N-acetylcysteine has been advocated as a mucolytic agent for CF but was rarely used for the patients in our study. Bronchoscopy and bronchial lavage with 0.16 g/dl N-acetylcysteine in normal saline was performed in three individuals with severe hypercapnic respiratory failure (arterial carbon dioxide tension [Pa_CO2] > 108 mm Hg) and tracheal intubation. Copious purulent secretions were removed, but mucosal erythema and edema increased and the patients' Pa_CO2 increased for 6 to 10 h after each procedure, despite continued mechanical ventilation. After 1994, recombinant human deoxyribonuclease (DNase) was used in most patients (16, 17). Normal (0.9 g/dl) or hypertonic (3 g/dl) saline was administered by nebulization or direct tracheal instillation just before chest physiotherapy, particularly after 1992 (18).

Ventilatory support. Some patients with progressive hypercapnic respiratory failure despite intensive standard therapy were treated with assisted ventilation. Bilevel positive airway pressure applied via a nasal or face mask was increasingly used as initial therapy, to avoid the adverse effects of tracheal intubation (21, 22). Inspiratory and expiratory pressures were set at 8 and 4 cm H₂O, and were titrated upward as tolerated to achieve a pH > 7.25. Supplemental oxygen was started at 6 to 12 L/m and titrated to maintain an arterial oxygen tension (Pa_O2) > 60 mm Hg. When adequate gas exchange could not be maintained or the patient was unable to tolerate mask ventilation, positive pressure ventilation via an endotracheal tube was initiated. The use of volume cycled (assist-control or synchronized intermittent mandatory ventilation) ventilatory modes evolved to constant inspiratory pressure (pressure support or pressure control) modes over the study period. Low levels (5 to 10 cm H₂O) of positive end expiratory pressure (PEEP) were usually added to minimize airway closure. High frequency ventilatory modes were used transiently in six patients to reduce airway pressures and help clear airway secretions.

	RESULTS

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Seventy-six adults with CF (41 females ranging in age from 16 to 42 yr [mean: 26 yr] and 35 males ranging in age from 18 to 45 [mean: 30 yr]) had 136 ICU admissions over the 9-yr study period. Sixty-five admissions (48%) were for exacerbations of CF with respiratory failure (Table 1), 33 (24%) were for massive hemoptysis, 30 (22%) were for antibiotic desensitization, three (2%) were for pneumothorax, and five (4%) were for other reasons (two suicide attempts, one pulmonary artery catheterization, one following thoracotomy, and one for severe portal hypertension). The numbers of adults with CF followed at UNC Hospitals and requiring ICU care each year are shown in Table 1. About 6% of these adults required ICU admission in any given year (range: 2.5 to 9.9%), and there was no trend in this rate over time.

Thirty-three admissions for massive hemoptysis occurred among 15 patients, and 23 episodes involving 12 patients were treated with bronchial artery embolization (BAE). Two patients died of persistent hemoptysis despite BAE. The average ICU stay for hemoptysis was 2 d (range: 1 to 7 d). Eleven patients (73%) were alive 1 yr after ICU discharge. Two others died from respiratory failure at 1 and 3 mo after ICU discharge, respectively.

There were 30 admissions for antibiotic desensitization, involving 13 patients. Two patients had serious reactions, and the average ICU stay for desensitization was 1.2 d (range: 1 to 3 d). All 13 patients were alive at 1 yr after discharge. Three admissions for pneumothorax complicated by respiratory failure occurred, involving three patients. All were treated with closed-tube drainage. One patient required intubation and one required mask ventilation. All three improved and were discharged after an average ICU stay of 1.6 d. All were alive 1 yr after discharge, including two who received double lung transplants. There were two admissions for suicide attempts; in one case the patient was discharged from the ICU and was alive 1 yr later. One patient admitted for massive ascites resulting from portal hypertension survived to ICU discharge but died 2 mo later. One patient was admitted for elective right heart catheterization, and one other patient was of status postthoracotomy for an aborted lung transplantation. Both were discharged, and the latter patient was alive 1 yr later, after a successful double lung transplantation.

There were 65 admissions for CF exacerbation and respiratory failure, involving 42 patients. All received intensive standard therapy, and in 50 episodes (37 patients) ventilatory support was required. The outcomes were analyzed on the basis of type of ventilatory support given (none, mask, or endotracheal; Table 2). Eight patients, each of whom had from two to five admissions (total: 21 episodes), required different modes of ventilatory support. Fifteen episodes involving 12 patients were managed with intensive standard therapy but no ventilatory support. In three of these episodes the patient died, and 12 episodes involving the remaining nine patients resulted in ICU discharge. Three patients were readmitted to the ICU during the same hospital admission in which the first ICU discharge occurred, and two of these patients required intubation. Three patients subsequently received lung transplants and one was alive 1 yr later without a lung transplant. The mean ICU stays were 2.5 d (range: 2 to 9 d) for survivors and 1.3 d (range: 1 to 2 d) for nonsurvivors. Eighteen episodes involving 12 patients were managed with mask ventilation. In four of these episodes the patient died and 14 episodes resulted in ICU discharge. Four patients (33%) received lung transplants. The mean durations of ventilatory support were 5.6 d (range: 1 to 21 d) for survivors and 10.0 d (range: 1 to 26 d) for nonsurvivors. The mean ICU stays were 6.7 d (range: 2 to 26 d) for survivors and 10.4 d (range: 1 to 26 d) for nonsurvivors.

Thirty-two episodes of ICU admission, involving 30 patients, required tracheal intubation and mechanical ventilation. Among these patients were five for whom a trial of mask ventilation had failed. Twelve of the 30 patients died, and 20 episodes resulted in ICU discharge. Ten patients (33%) underwent successful lung transplantation, of whom eight were still being ventilated and two who received transplants within 6 mo of ICU discharge. Two patients were alive without a transplant at 1 yr after ICU discharge. The mean durations of ventilatory support for the 30 patients requiring tracheal intubation were 9.9 d (range: 5 to 45 d) for survivors and 7.3 d (range: 1 to 17 d) for nonsurvivors. The mean ICU stays were 14.6 d (range: 4 to 45 d) for survivors and 10.5 d (range: 1 to 37 d) for nonsurvivors. The severity of lung disease did not significantly predict outcomes. Twenty-one of the 30 patients (22 episodes) had an FEV₁ < 30% predicted (7% to 28% predicted). In eight episodes the patient died and 14 episodesincluding five in which cadaveric transplants and three in which living donor lobar transplants were done while the patient was ventilator-dependentresulted in an ICU discharge. Two others had transplants within 6 mo of ICU discharge, and one was alive at 1 yr without a transplant. The mean duration of ventilatory support for patients who received transplants while ventilated was 10.1 d (range: 1 to 17 d).

In summary, 17 of the 42 patients admitted with hypercapnic respiratory failure received lung transplants and 14 were alive 1 yr later. Three patients survived for more than 1 yr without transplantation, and three died within 6 mo of ICU discharge. Nineteen of the 42 patients died in the ICU. Nine of these patients had worsening hypercapnia and acidosis, three died of sepsis and renal failure, and supportive measures were discontinued in the case of seven patients. There were no pneumothoraces or nosocomial infections.

There were no clear predictors of survival for the patients with CF exacerbations and respiratory failure. Baseline FEV₁ (Figure 1) and BMI (Figure 2) showed no significant correlations with survival. Survival was similar for both sexes, with 15 (63%) of 24 women (31 episodes) and eight (44%) of 18 men (34 episodes) surviving. Survival in this series was not clearly affected by respiratory bacteria. Twenty-six patients infected with antibiotic-sensitive Pseudomonas aeruginosa accounted for 39 episodes, and 15 (58%) of these patients survived. Twelve patients infected with multiply antibiotic-resistant P. aeruginosa (23) accounted for 18 episodes, and five (42%) of these patients survived. Eight patients infected with Burkholderia cepacia accounted for 18 episodes, and four (50%) survived. Staphylococcus aureus concomitantly infected three patients with P. aeruginosa, infections, one with multiply antibiotic- resistant P. aeruginosa, and one with B. cepacia, and four of these five patients (80%) survived.

View larger version (16K): [in this window] [in a new window]   Figure 1.   ICU outcomes of respiratory failure episodes caused by exacerbations of CF, versus baseline pulmonary function.

View larger version (16K): [in this window] [in a new window]   Figure 2.   ICU outcomes of respiratory failure episodes caused by exacerbations of CF, versus baseline (BMI).

	DISCUSSION

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The ICU outcomes in this study for adults with CF and the potentially reversible complications of pneumothorax-induced respiratory failure or massive hemoptysis extend findings reported by Garland and coworkers (4) for infants with CF. All three patients with pneumothorax recovered, and 13 of 15 patients with massive hemoptysis (33 admissions) survived. Therefore, ICU care is appropriate and effective for adults with CF and acutely reversible complications.

ICU care for adults with CF who have respiratory failure as a consequence of progressive disease has significant efficacy. Seventeen of forty-two patients (65 episodes) admitted with respiratory failure had successful lung transplantations and three were alive without lung transplants at 1 yr after ICU discharge. Ventilatory support may be appropriate for patients when lung transplantation is imminent. Thirty-seven patients received ventilatory support (50 episodes), and 14 (38%) of the 37 had successful lung transplantations. Live donor lobar transplants may be an option when cadaveric lungs are unavailable for listed patients. Four of the 14 patients with successful transplants received live donor lobar transplants.

The choice of ventilatory mode for patients with complications of CF has evolved with experience and the availability of newer methods, particularly bilevel positive airway pressure ventilation via mask (21, 22). Nasal or face mask ventilation enables cough and facilitates clearance of secretions. Verbal communication is preserved and intermittent use is feasible. Constant inspiratory pressure (pressure support) has largely replaced volume cycled (assist-control and synchronized intermittent mandatory ventilation) modes. High-frequency modes have been used to improve clearance of airway secretions, but the results have been variable.

Corticosteroids can reduce airway inflammation, but may increase the risk of disseminating infection with panresistant bacteria. High-dose corticosteroid treatment is a relative contraindication to lung transplantation in many centers. Corticosteroids were only used for patients who failed to respond to intensive standard therapy and who understood the risks of these drugs. Nevertheless, a subset of the patients in our series improved dramatically with such therapy.

CF causes progressive respiratory failure and death in most patients, and mechanical ventilation for complications of CF has been discouraged because of poor outcomes. The development of effective lung transplantation stimulated reconsideration of the use of ICU care and mechanical ventilation in this setting. On the basis of the experience of 76 patients admitted to the UNC Hospital's medical or respiratory ICUs over a period of 9 yr, we conclude that ICU care is appropriate for some complications of CF in adults. The outcomes with acute reversible complications, such as massive hemoptysis and complicated pneumothorax, are excellent. Progressive respiratory failure of reversible cause or for which lung transplantation is an imminent option can often be managed successfully. Mask ventilation can provide effective respiratory support for periods ranging from weeks to years, with relatively minor complications. Ventilation and oxygenation can be sustained for several weeks with tracheal intubation and a positive pressure ventilator, but cough and secretion clearance are impaired and lung function is frequently worsened. Baseline FEV₁, BMI, sex, and type of respiratory tract bacteria did not predict the outcomes in our study. With two exceptions, ventilatory support of more than 2 wk duration was associated with poor outcomes.

Our study involved a select group of patients at a large CF center with an active lung transplantation program. Within the United States, transplantation is available only at a limited number of locations and the candidacy criteria vary, for which reason the results will not be universally applicable. However, some key principles for managing CF are widely relevant, and many clinical approaches may be useful in other settings. Data clearly support the intensive treatment of acutely reversible complications of CF, even in the setting of advanced lung disease. For patients who are not transplant candidates and have progressive respiratory failure, it can be difficult to decide whether to offer tracheal intubation and mechanical ventilation. Potentially reversible aspects of disease, short-term goals, and the patient's and family's wishes are important considerations. Ideally, these issues will have been addressed earlier. In our study, a few patients with prolonged intubation did well, but extended positive pressure ventilation was generally associated with poor outcomes. Evaluation for lung transplantation while a patient is intubated is impractical, since the waiting time for organs is usually long and in some programs the requirement for positive pressure ventilation contraindicates transplantation. The effective use of ICU care and assisted ventilation for adults with CF requires an understanding of the potential benefits and limitations of such therapy, and the education and involvement of the patient and patient's family in these major medical decisions.