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(Chest. 2005;128:1209-1215.)
© 2005 American College of Chest Physicians

Effects of Acute on Chronic Respiratory Failure on Hypercapnia and 3-Month Survival*

Michele Vitacca, MD; Luca Bianchi, MD; Luca Barbano, MD; Mara Ziliani, MD and Nicolino Ambrosino, MD, FCCP

* From the Respiratory Department (Drs. Vitacca, Bianchi, Barbano, and Ziliani), Salvatore Maugeri Foundation, Istituto di Ricovero e Cura a Carattere Scientifico, Scientific Institute of Gussago, Gussago, Italy; and Pulmonary Unit (Dr. Ambrosino), Cardio-Thoracic Department, University Hospital of Pisa, Pisa, Italy.

Correspondence to: Michele Vitacca, MD, Foundation S. Margery, Istituto di Ricovero e Cura a Carattere Scientifico, Via Pinidolo 23, 25064 Gussago (BS), Italy; e-mail: mvitacca{at}fsm.it


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: There is a lack of information on respiratory function and mechanics after COPD exacerbations.

Study objectives: To find their role in short-term survival and occurrence of chronic hypercapnia after these events.

Patients and interventions: Seventy-three COPD patients recovering from a recent severe exacerbation underwent evaluation of breathing pattern, breathing mechanics, lung function, and arterial blood gas levels at the time of discharge from a respiratory ICU (RICU).

Results: The 3-month mortality rate after RICU discharge was 11%. The percent of ideal body weight (%IBW) [R = 6.04; p = 0.01] and occlusion pressure (R = 5.41; p = 0.02) provided significant distinction between deceased patients and survivors; the final discriminant equation showed that %IBW was able to predict patient death or survival with an accuracy of 90%. With decreasing order of power, the ratio of inspiratory time to total breathing cycle time (TI/TTOT) [R = 8.87; p = 0.003], pressure-time product of the inspiratory muscles (R = 7.12; p = 0.009), maximal esophageal pressure (R = 6.00; p = 0.01), esophageal pressure (R = 5.50; p = 0.02), PaO2/fraction of inspired oxygen (R = 4.72; p = 0.03), and pressure time index (PTI) [R = 4.57; p = 0.03] provided a significant distinction between hypercapnia and normocapnia at discharge. The discriminant equation, including TI/TTOT and PTI, could correctly separate hypercapnic or normocapnic patients with an accuracy of 76%.

Conclusions: In COPD patients who are recovering from a severe exacerbation, hypercapnia is strongly related to inspiratory muscle work, strength, and breathing pattern; and only body weight predicts short-term survival.

Key Words: acute exacerbations of COPD • lung function • respiratory failure • respiratory muscles


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The role of physiologic and clinical parameters, such as age,1 respiratory function,123 malnutrition,4 activity of daily life,4 or a recent multidimensional grading system, including body mass index, airflow obstruction, dyspnea, and exercise capacity,5 has been evaluated to predict the natural history of COPD. It has also been shown6 that the probability of developing chronic hypercapnia in severe, stable COPD increases with the severity of airway obstruction, obesity, and inspiratory muscle weakness. Malnutrition and the degree of airway obstruction were also associated with the failure of medical treatment and the related need for mechanical ventilation in severe exacerbations of COPD (ECOPDs).7 ECOPDs are frequent complications of the disease that may lead to acute respiratory failure and an associated high prevalence of reversible hypercapnia.8 Stable hypercapnia is often proposed as a negative prognostic factor for survival after discharge from an ICU, whereas "reversible" hypercapnia is associated with a similar prognosis to the prognosis of COPD patients undergoing nonhypercapnic acute respiratory failure.9 Critically ill patients with prolonged ICU stays may sometime present unplanned ICU readmission or even unexpected death.10 For this reason, strict clinical surveillance and monitoring of respiratory muscle function is recommended10 after patients are discharged from an ICU to the general ward. At the same time, after hospital discharge, the need for monitoring of hypercapnia, exacerbations with risks of death, or readmission to the ICU for COPD patients with therapeutic tools, such as comprehensive rehabilitation programs11 and, eventually, with long-term domiciliary mask ventilation,12 appears of great interest.

On the other hand, the role of respiratory muscles and mechanics in predicting the short-term survival and the presence of hypercapnia after a severe ECOPD needing a respiratory ICU (RICU) admission has been less studied. The aims of this study were as follows: (1) to measure breathing pattern, mechanics, lung function, and arterial blood gases in COPD patients recovering from a recent severe ECOPD; (2) to find an equation, if any, to discriminate chronic hypercapnic patients; and (3) to evaluate the predictive factors of 3-month survival immediately before RICU discharge.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The investigative protocol was approved by the Institutional Ethics Committee of the Salvatore Maugeri Foundation and was conducted according to the Declaration of Helsinki. Informed consent was obtained from all of the patients before their enrollment into the study.

Patients
This article reports on the results of a prospective, observational study that was carried out on patients known to be affected with COPD from January 1, 1995, to January 1, 1996. The diagnosis of COPD was according to the American Thoracic Society criteria13 based on the clinical history, physical examination, chest radiograph, and previous pulmonary function tests. Consecutive COPD patients who were discharged from the RICU of the Salvatore Maugeri Foundation in Gussago, Italy, were studied. The RICU of the Salvatore Maugeri Foundation is an ICU located in a rehabilitation hospital, which is a referral rehabilitation and chronic care center for a large geographic area in northern Italy. Among others, difficult-to-wean tracheotomized patients are also admitted to this institution to undergo either a program of progressive discontinuation from mechanical ventilation or to be discharged to a home program of long-term ventilatory assistance, if weaning from the ventilator fails. In addition, patients undergoing episodes of acute on chronic respiratory failure are admitted for treatment by noninvasive positive-pressure ventilation (NPPV).

Among the 110 patients admitted to our RICU in the study period, 27 (cardiosurgical sequelae, 11 patients; neuromuscular disease, 7 patients; neurologic disease, 6; ARDS, 3 patients) were non-COPD patients. Four COPD patients were excluded from the study because of concomitant cancer, and six were excluded because they refused evaluations. A total of 73 COPD patients were studied. No patients asked for a do-not-resuscitate order to be implemented during their RICU or hospital stay or during the 3 months of follow-up.

At the time of evaluation (1 to 3 days before RICU discharge), all of the patients had recovered from their exacerbation for ≥ 8 days (range, 8 to 21 days). They were in stable conditions as assessed by the following methods: (1) arterial pH > 7.35 during spontaneous breathing with an inspiratory oxygen fraction that was able to maintain arterial oxygen saturation > 90%; (2) absence of severe dyspnea or signs of respiratory distress-like abdominal paradox, use of accessory muscles, ratio of respiratory frequency to tidal volume < 95; and (3) hemodynamic stability (systolic arterial BP > 100 and < 150 mm Hg, with no need for IV vasopressor drugs); and (4) no use of nocturnal mechanical ventilation on the night before the RICU discharge.

Causes of RICU Admission
Twenty-four of 73 patients (33%) were difficult-to-wean tracheotomized patients. These 24 patients had been transferred to our RICU from the ICUs of other hospitals, because the caring physicians classified them as difficult-to-wean after some weaning attempts had failed and a tracheotomy had been performed. The causes of acute respiratory failure and consequent ICU admission were pneumonia in 10 patients, COPD exacerbation in 12 patients, and cardiogenic pulmonary edema in 2 patients. The time that elapsed from intubations to tracheotomy ranged from 6 to 10 days. The time from intubation to RICU admission ranged from 10 to 27 days. The weaning modalities were spontaneous breathing trial or decreasing levels of inspiratory pressure support, as described elsewhere.14

The other 49 patients (67%) had been treated in our RICU during an episode of acute respiratory failure. The causes of acute respiratory failure were pneumonia in 12 patients, ECOPD without pneumonia in 30 patients, cardiogenic pulmonary edema in 4 patients, and severe arrhythmia in 3 patients. Among these 49 patients, 4 were intubated in our RICU and successfully extubated, 23 patients were successfully treated with NPPV, and the other 22 patients were treated only with standard medical therapy.

In summary, 51 of 73 patients (70%) had been ventilated for a period of 4 to 15 days. Mechanical ventilation had been withdrawn 8 to 12 days before their enrollment into the study. Twenty patients (27%) were still tracheotomized, but they were breathing spontaneously at the time of the study.

The medical treatment of ECOPD had consisted of systemic steroids (76% of patients), inhaled bronchodilators (100%), and oxygen (100%). In their stable condition before the ECOPD, all of the patients were receiving treatment with inhaled bronchodilators but no with systemic or inhaled steroids. In their stable state before ECOPD, 69% of the patients were receiving long-term oxygen therapy, whereas 10.5% were receiving domiciliary long-term mechanical ventilation (90% with mask positive-pressure ventilation and the remaining through tracheotomy). Table 1 shows the RICU admission data for the patients in our study.


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  		Table 1.. RICU Admission Data According to Patient Groups*

 
Measurements and Monitoring
The following data were recorded: anthropometrics, nutritional status (percentage of ideal body weight [%IBW] and body mass index), percentage of patients needing mechanical ventilation (either invasive or noninvasive), ICU and hospital length of stay, and 3-month mortality rate.

One to 3 days before RICU discharge, all of the patients underwent the following measurements. For lung and respiratory muscle function, patients underwent dynamic and static lung volume measurements, which were carried out by means of a volume-constant body plethysmograph (CAD-NET system 1085; MedGraphics; St. Paul, MN). The predicted values of Quanjer et al15 were used. Arterial blood gas levels were assessed with an analyzer (ABL 300; Radiometer; Copenhagen, Denmark) on blood samples drawn from the radial artery while patients breathed room air. Maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) were assessed at the level of functional residual capacity and total lung capacity, respectively, according to the method of Black and Hyatt,16 using a respiratory module system (MedGraphics). Patients performed a minimum of three maneuvers, with at least a 1-min interval between efforts, until two acceptable values not differing from each other by > 5% were obtained. The best value was recorded. Predicted values were according to Bruschi et al.17 Despite the possibility to underestimate results because of leakage of air around the cannula and resistance created by the cannula itself, spirometry and respiratory muscle function were evaluated in tracheotomized patients through a mouthpiece with the simultaneous closure of the external hole of a fenestrated and uncuffed cannula.

For the experimental procedure of this study, flow and proximal airway pressure were measured by means of a pneumotachograph/pressure transducer (Bicore; Irvine, CA) inserted at the end of the tracheotomy cannula or connected to a mouthpiece as previously described.18 The volume was obtained by numerical integration of the flow signal. Changes in pleural pressure were estimated from changes in esophageal pressure (Pes), by means of the balloon-catheter technique, with an esophageal balloon catheter connected to a differential pressure transducer (± 140 cm H2O; Bicore). Transpulmonary pressure was obtained by the subtraction of Pes from proximal airway pressure.

All of the signals were digitized by an analog-to-digital converter and were sent to a personal computer at a sampling frequency of 100 Hz. The subsequent analysis was performed using a software package (ANADAT 5.1; RHT-Infodat; Montreal, QC, Canada), except for the inspiratory work of breathing, which was analyzed by means of a specific program (Computo; Elekton; Agliano Terme, Italy). Tidal volume, respiratory frequency, and minute ventilation were computed from the volume signal. The total breathing cycle time (TTOT), inspiratory time (TI), expiratory time, and TI/TTOT ratio, were calculated from the flow signal, as average values from 1-min continuous records of flow and volume. Dynamic intrinsic end-expiratory-positive pressure was measured as the negative deflection in Pes from the onset of inspiratory effort to the onset of inspiratory flow. Transpulmonary pressure was used to calculate inspiratory resistance at midinspiration and dynamic lung elastance according to the technique of Mead and Whittenberger.19 Dynamic compliance was calculated as the inverse of dynamic lung elastance. Changes in the magnitude of the effort of the inspiratory muscles were estimated from changes in Pes, as previously described.718 We measured Pes tidal swings, as well as the pressure-time product for the inspiratory muscles calculated over a period of 1 min (ie, pressure-time product minimum [PTPmin]). The inspiratory work of breathing (expressed as Joules per liter) was calculated from the area subtended by the Pes that was developed during inspiration and the relaxation curve of the chest wall (estimated chest wall compliance, 200 mL/cm H2O/L). Occlusion pressure was calculated as the difference in Pes prior to the onset of airflow of a patient’s initiated breath or measured as the change in Pes that occurs 100 ms before the start of flow. Starting from functional residual capacity, maximal Pes (Pesmax) was assessed by means of a Muller maneuver during a maximal inspiratory effort that was generated after manual occlusion of the flow transducer. The subjects were verbally encouraged to achieve maximal strength. The highest value (most-negative Pes) of three tests was considered in data analysis. Pressure time index (PTI) was calculated as Pes/Pesmax x TI/TTOT ratio.

Patients were studied during the day and were free to choose the most comfortable position so as to minimize their breathlessness. All of the patients adopted a semirecumbent position, and, after the application of topical anesthesia (xylocaine spray 10%), the balloon-tipped catheter was inserted through the nose into the middle third of the esophagus and, thereafter, was automatically inflated to 0.5 mL. The occlusion test was finally performed to check the proper functioning of the esophageal balloon: a pneumatic shutter was inserted in-line and proximally to the pneumotachograph only to perform this maneuver and was then removed. The occlusion test was satisfactory in every instance.

Statistical Analysis
Results are given as the mean (± SD). All of the tests and p values are two-tailed. The parametric variables were analyzed by unpaired or paired t tests, as appropriate, to test baseline differences in the 73 patients studied, according to %IBW (> 90 or < 90%), hypercapnia (> 48 or < 48 mm Hg), and age (> 70 or < 70 years). The level of hypercapnia was chosen higher than the reference value of 45 mm Hg to avoid a possible variability in the ABG data and < 50 mm Hg considered by the Global Initiative for Chronic Obstructive Lung Disease guideline20 as sign of hypercapnic respiratory failure. The cutoff point of 70 years was arbitrarily considered discriminant for aged COPD. The predictive models were developed using stepwise discriminant analysis. Multiple stepwise correlations were performed between all of the data recorded at patient discharge from the RICU to predict hypercapnia and 3-month follow-up for the 73 patients studied. To use the parametric discriminant analysis and correlation tests, the variables that were found to be nonparametric were logarithmically transformed. A p value of < 0.05 was considered to be statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Fifty-four of 73 patients (74%) in this study were hypercapnic (≥ 48 mm Hg) at discharge from the RICU. Table 1 shows anthropometric and demographic data, arterial blood gas levels, and the clinical characteristics of all of the patients in study, according to their presence of hypercapnia, age, and %IBW. As shown in Table 2 , the need for long-term oxygen therapy and home mechanical ventilation before admission to the RICU was statistically higher in hypercapnic patients than in nonhypercapnic patients.


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  		Table 2.. Anthropometric Data, Demographic Data, Arterial Blood Gas Levels, and Clinical Characteristics of Patients According to Hypercapnia, Age, and % IBW*

 
The overall 3-month mortality rate was 11%, with patients with an %IBW of < 90% showing a statistically (p = 0.019) higher mortality rate (32%) than patients with an %IBW of > 90% (2%). In addition, patients who were > 70 years of age showed a higher mortality rate than patients who were < 70 years of age, although the difference was not statistically significant. All eight of the deceased patients died from respiratory causes related to their underlying disease.

Patients who were > 70 years of age also showed statistically lower values of PEmax than patients < 70 years (49 ± 8 vs 72 ± 62 cm H2O, respectively; p = 0.0048). Undernourished patients showed lower PEmax values (48 ± 10 vs 73 ± 63 cm H2O; p = 0.008) and lower FEV1 values (29 ± 14 vs 38 ± 17% predicted; p = 0.048) than well-nourished patients.

Table 3 shows the breathing pattern, spirometric values, and characteristics of breathing mechanics according to the level of hypercapnia. In the 54 hypercapnic patients, the respiratory rate (p = 0.049), Pes swing (p = 0.046), inspiratory work of breathing (p = 0.043), PTPmin (p = 0.009), and PTI (p = 0.042) were statistically higher, whereas the FEV1 percent predicted (p = 0.009), the FVC percent predicted (p = 0.008), FEV1/FVC ratio (p = 0.046), PEmax (p = 0.044), and Pesmax (p = 0.044) were statistically lower than in normocapnic patients. Discriminant analysis showed that among all of the variables studied in decreasing order of power, TI/TTOT ratio (R = 8.87; p = 0.003), PTPmin (R = 7.12; p = 0.009), Pesmax (R = 6.00; p = 0.01), Pes (R = 5.50; p = 0.02), PaO2/fraction of inspired oxygen (R = 4.72; p = 0.03), and PTI (R = 4.57; p = 0.03) significantly provided distinction between the hypercapnic and normocapnic patients at discharge from the RICU. Table 4 shows that the discriminant equation, including TI/TTOT ratio and PTI, could correctly separate hypercapnic or normocapnic patients with an accuracy of 76%. Hypercapnia was found in 65 patients among 73 (89%) at RICU admission, whereas it was found in 54 of 73 patients (74%) at RICU discharge (in 75%, 85%, and 27%, respectively, of patients with prolonged weaning, NPPV, and medical therapy).


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  		Table 3.. Characteristics of Breathing Patterns, Spirometric Data, and Breathing Mechanics According to Hypercapnia*

 

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  		Table 4.. Classification Tables of Accuracy of Prediction and Equations for Survival and Hypercapnia

 
Discriminant analysis showed that among all of the studied parameters only %IBW (R = 6.04; p = 0.01) and occlusion pressure (R = 5.41; p = 0.02) provided significant distinction between deceased patients and survivors at 3 months after RICU discharge. Table 3 shows also the discriminant equation, including only %IBW able to predict patient death or survival with an accuracy of 90%. The presence of tracheotomy or the necessity of mechanical ventilation (irrespective of whether noninvasive mechanical ventilation or tracheotomy was used) was not found to be a risk factor in the predictive model for hypercapnia and death.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In COPD patients recovering from a severe ECOPD needing intensive care, we found that hypercapnia at RICU discharge is related to inspiratory work, respiratory muscle strength, and breathing pattern timing; and only body weight predicts the 3-month survival rate. Functional and clinical parameters have been advocated as related to long-term survival4 in COPD patients recovering from an ECOPD needing ICU assistance. Stable hypercapnia has been proposed as an important negative prognostic factor for survival after discharge from the ICU, whereas "reversible" hypercapnia was associated with survival rates similar to that of COPD patients undergoing nonhypercapnic acute respiratory failure.9 Mcnally et al8 suggested a high prevalence of reversible hypercapnia among patients hospitalized with ECOPD. The role of respiratory muscle function and mechanics in predicting the survival and occurrence of hypercapnia after a severe ECOPD exacerbation has been less well-studied; for this reason, we performed a study to find an equation that would be able to predict hypercapnia and the 3-month mortality rate after patients are discharged from an RICU.

The role of inspiratory muscles has been well-studied in patients with acute on chronic respiratory failure20 and in patients with chronic hypercapnia.6 Begin and Grassino6 showed that the probability of developing hypercapnia in patients with severe stable COPD increases with the degree of airway obstruction, obesity, and inspiratory muscle weakness. They showed that the failure of the respiratory muscular pump to perform sufficient work is the discriminant factor for a good alveolar ventilation and subsequent hypercapnia.6 These authors6 found that 102 hypercapnic patients (only 17 with PaCO2 levels of > 55 mm Hg), compared with normocapnic subjects, had to face a higher inspiratory muscle load with a lower PImax. In our study, we have confirmed, in a large group of patients with post-ECOPD severe hypercapnia, the relationship between hypercapnia and indexes of inspiratory muscular function like PTPmin and Pesmax. Also in our study, hypercapnic patients, when compared with normocapnic subjects, had to face a higher inspiratory muscle load with a lower PImax.

The relation between hypercapnia and a worse long-term survival rates,3 hypercapnia and a higher risk of ICU admission,21 and hypercapnia and a higher risk of lack of response to medical or NPPV therapy for ECOPD administered in the hospital722 have been extensively studied. Mcnally et al8 suggested a high prevalence of reversible hypercapnia among patients who had been hospitalized with ECOPD. Stable hypercapnia has also been proposed as an important negative prognostic factor for survival after discharge from an ICU, whereas "reversible" hypercapnia is associated with a similar prognosis to that of COPD patients undergoing nonhypercapnic acute respiratory failure.9 The results of our study strengthen the need to monitor and prevent severe exacerbations and admission to the ICU for COPD patients, with therapeutic tools for this purpose, like rehabilitation programs,11 and, eventually, with long-term domiciliary mask ventilation.12

The literature on COPD patients offers different conclusions about the prognostic indexes of long-term mortality in a wide range of variables. Age alone or in combination with other comorbidities2324 and the severity of airway obstruction24 were found to be negative predictive factors for survival after a severe ECOPD. Although in our study older patients showed higher mortality rates and lower FEV1 percent predicted values than patients who were < 70 years of age, our final equation had insufficient power to confirm these previous observations. Patients with chronic diseases have been found to be particularly prone to reduced inspiratory and expiratory muscle function67 with consequent severe limitation to mobility, sputum production, and cough efficacy; these conditions are often elicited in undernourished patients.4 The relationship between poor nutritional status and survival has been demonstrated in patients recovering from an ECOPD,4 as well as in patients with different etiologies.252627 For instance, Fiaccadori et al28 found that in patients with acute renal failure, a severe malnutrition was associated with a significant increase in hospital length of stay, morbidity, and death. The present study has confirmed that a poor nutritional status is a predictive negative factor for survival after RICU discharge, showing a risk of mortality five times greater in undernourished than in healthy, nourished patients. These data support the need to control nutritional status in these patients with appropriate supplementation.29

Some limitations of this study should be taken into account. Although the study population was admitted in the same unit because of similar severe relapse of their underling disease, it is not homogenous; in fact, the patients requiring either invasive or noninvasive mechanical ventilation and the patients requiring only medical therapy were considered as a whole, although their prognoses could be differently influenced. The measurements of PImax and PEmax, and spirometric values obtained through a mouthpiece in tracheotomized patients might lead to an underestimation of these data because of air leaks. In conclusion, in COPD patients recovering from a severe ECOPD needing intensive care hypercapnia is strongly related to respiratory muscle work strength and breathing pattern timing, and only body weight predicts 3-month survival.


   Footnotes
 
Abbreviations: ECOPD = exacerbation of COPD; %IBW = ideal body weight percentage; NPPV = noninvasive positive-pressure ventilation; PEmax = maximal expiratory pressure; Pes = esophageal pressure; Pesmax = maximal esophageal pressure; PImax = maximal inspiratory pressure; PTI = pressure time index; PTPmin = pressure-time product minimum; RICU = respiratory ICU; TI = inspiratory time; TTOT = total breathing cycle time

Received for publication December 7, 2004. Accepted for publication February 8, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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