Abstract
Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) requiring invasive mechanical ventilation (IMV) are associated with significant morbidity and mortality. Extracorporeal carbon dioxide removal (ECCO2R) may facilitate extubation and ambulation in these patients and potentially improve outcomes.
Objectives: We assessed the feasibility of achieving early extubation and ambulation in subjects requiring IMV for exacerbations of COPD using single-site ECCO2R.
Methods: Five subjects with exacerbations of COPD with uncompensated hypercapnia requiring IMV were enrolled in this single-center, prospective, feasibility trial using a protocol of ECCO2R, extubation, and physical rehabilitation. The primary endpoint was extubation within 72 hours of starting ECCO2R.
Measurements and Main Results: Mean preintubation pH and PaCO2 were 7.23 ± 0.05 and 81.6 ± 15.9 mm Hg, respectively. All subjects met the primary endpoint (median duration, 4 h; range, 1.5–21.5 h). Mean duration of extracorporeal support was 193.0 ± 76.5 hours. Mean time to ambulation after extracorporeal initiation was 29.4 ± 12.6 hours. Mean maximal ambulation on extracorporeal support was 302 feet (range, 70–600). Four subjects were discharged home, and one underwent planned lung transplantation. Two minor bleeding complications occurred. There were no complications from mobilization on extracorporeal support.
Conclusions: ECCO2R facilitates early extubation and ambulation in exacerbations of COPD requiring IMV and has the potential to serve as a new paradigm for the management of a select group of patients. Rigorous clinical trials are needed to corroborate these results and to investigate the effect on long-term outcomes and cost effectiveness over conventional management.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, with acute exacerbations of COPD accounting for a large proportion of the morbidity, mortality, and healthcare costs associated with the disease (1–4). Despite the increasing use of noninvasive ventilation in managing acute exacerbations of COPD, a substantial number of patients fail this intervention and require invasive mechanical ventilation (IMV) for hypercapnic respiratory failure, with an associated in-hospital mortality rate of 30% (5, 6). Although the goal of IMV is to provide adequate gas exchange and decrease the workload of the respiratory system, IMV in COPD may have several deleterious consequences, including dynamic hyperinflation and elevated intrinsic positive end-expiratory pressure (PEEP), ventilator-associated pneumonia, impaired delivery of aerosolized medications, immobility, and deconditioning, all of which may significantly affect morbidity and mortality (5, 7–14).
Extracorporeal CO2 removal (ECCO2R) may eliminate the need for IMV in hypercapnic respiratory failure, which could offer a new option in the management of acute exacerbations of COPD. Modern extracorporeal circuits are very efficient at CO2 removal, requiring significantly lower extracorporeal blood flow rates than are required to support oxygenation, and advances in technology have improved their risk profile. Prior studies demonstrated the potential for ECCO2R as a means of “lung rest” in patients with the acute respiratory distress syndrome, although these studies involved older extracorporeal technology with higher rates of complications (15–17). Recent reports of ECCO2R as an adjunct to IMV to improve ventilatory parameters or as a way to avoid IMV in acute exacerbations of COPD have suggested a potential role for ECCO2R in this population (18–24). However, no study has combined venovenous ECCO2R, endotracheal extubation, and physical rehabilitation, including ambulation while receiving ECCO2R, in the management of hypercapnic respiratory failure from COPD. We hypothesize that institution of venovenous ECCO2R with an upper-body configuration in patients requiring IMV for hypercapnic respiratory failure due to acute exacerbations of COPD will result in rapid extubation and improved respiratory mechanics, allowing for early mobilization. We report the result of a prospective pilot study of five subjects using this strategy.
This was a prospective, unblinded, interventional trial of ECCO2R to facilitate early endotracheal extubation and early physical therapy in subjects on IMV for acute hypercapnic respiratory failure due to exacerbations of COPD. Subjects were screened from all admissions into the medical intensive care units (ICUs) at the Columbia College of Physicians and Surgeons/New York-Presbyterian Hospital from January through November 2012.
Patients between 45 and 85 years of age were eligible for enrollment if they met all of the following inclusion criteria: clinical exacerbation of COPD (defined by acute onset, change in the patient's baseline dyspnea, cough, or sputum production beyond day-to-day variation in a patient with underlying COPD), respiratory failure with an ongoing requirement for IMV, and a preintubation arterial blood gas (ABG) with pH ≤ 7.35 and PaCO2 ≥ 55 mm Hg. Exclusion criteria included any condition that could limit recovery from respiratory failure, such as NYHA Class IV functional status or evidence of decompensated congestive heart failure, advanced malignancy, body mass index greater than 31.1 kg/m2 for men or greater than 32.2 kg/m2 for women, acquired immunodeficiency syndrome or other severely immunocompromised condition, PaO2 to FiO2 ratio consistently less than 250, history of intracranial bleeding, known or suspected pregnancy, history of complications from extracorporeal support, inability to receive blood products, known hypersensitivity to heparin or history of heparin-induced thrombotic thrombocytopenia, and inability to ambulate within 7 days before hospital admission. Other exclusion criteria that could potentially limit recovery from respiratory failure and that were determined at the discretion of the study physicians included anatomic abnormalities that would preclude catheter placement in the neck, severe bleeding diathesis, severe malnutrition or cachexia, and severely debilitated state.
After enrollment, subjects were brought to the operating room for percutaneous insertion of a bicaval dual-lumen cannula (MAQUET Cardiovascular, LLC, Rastatt, Germany) into the right internal jugular vein under fluoroscopic and transesophageal echocardiographic guidance (25). The cannula was connected to the extracorporeal circuit consisting of a CARDIOHELP System (MAQUET Cardiovascular, LLC). After the patient was returned to the ICU, sedation was discontinued, and ventilator settings were decreased to an FiO2 of 0.4 and a PEEP of 5 cm of water with SpO2 greater than 87%. Once those settings were achieved, a spontaneous breathing trial was performed with pressure support ventilation with 5 cm of water and a PEEP of 5 cm of water or with a T-piece trial. Subjects with an intact mental status and who met established clinical criteria on a spontaneous breathing trial were extubated to supplemental oxygen via facemask. Supplemental oxygen was weaned to nasal cannula, using the lowest oxygen flow necessary to maintain oxygen saturation of hemoglobin greater than 87% and greater than 94% in patients with known coronary artery disease (Figure 1).
Figure 1. Outline of study procedures. aPTT = activated partial thromboplastin time; SpO2 = oxygen saturation by pulse oximetry.
[More] [Minimize]The extracorporeal circuit was managed collaboratively by a team of perfusionists, thoracic surgeons, nurses, nurse practitioners, and intensivists. The fraction of delivered oxygen via the circuit was maintained at 1.0, and sweep gas flow rate was adjusted to achieve a pH between 7.34 and 7.42 based on ABG data measured every 3 to 6 hours. The extracorporeal blood flow was started at 1 L/min and was increased as tolerated to a maximum negative pressure in the venous limb of −70 mm Hg. Intravenous heparin was administered as a bolus dose of 2,000 to 5,000 units (depending upon the patient's weight and baseline activated partial thromboplastin time [aPTT]) at the time of cannulation, and a continuous infusion was maintained to achieve an aPTT between 40 and 60 seconds. Packed red blood cells were transfused for a hemoglobin level less than 7 g/dl, for active bleeding, or if there was evidence of end-organ dysfunction that was attributable to anemia. When less than 1 L/min of sweep gas flow was needed to maintain pH between 7.34 and 7.42, the sweep gas was discontinued (no gas exchange via the oxygenator) with subsequent assessment of respiratory status and an ABG. If there was no increase in dyspnea or work of breathing or if there was evidence of uncompensated respiratory acidosis on ABG analysis after 1 hour, ECCO2R was discontinued and the subject underwent bedside decannulation. Heparin was held for 1 hour, after which subjects were placed in slight Trendelenburg position and the cannula was removed during exhalation under positive intrathoracic pressure. Manual compression was performed at the cannulation site for 30 minutes to achieve hemostasis.
Medical management of the subject’s COPD exacerbation (corticosteroids, inhaled bronchodilators, and antibiotics) was at the discretion of the ICU attending.
During the course of ECCO2R support, subjects were assessed by a dedicated team of physical and occupational therapists in the medical ICU. Subjects received active physiotherapy daily with the goal of daily ambulation while in the ICU.
Modified Borg dyspnea scores, on a scale of 0 to 10, with 0 representing no dyspnea and 10 representing maximal dyspnea, were obtained before ECCO2R initiation and then daily for the duration of the hospitalization.
The primary outcome was the number of subjects successfully extubated within 72 hours of ECCO2R initiation. Secondary outcomes included ICU length of stay, hospital length of stay, time to ambulation, longest distance walked on extracorporeal support, changes in spirometric data, changes in dyspnea as assessed by modified Borg dyspnea score, in-hospital mortality, rate of discharge to home, and rate of adverse events related to ECCO2R.
Descriptive statistics (mean, median, standard deviation for continuous variables, frequency and percentage for categorical variables) were used to analyze baseline demographics and outcomes.
MAQUET Cardiovascular, LLC provided the extracorporeal circuit components (CARDIOHELP System) and the bicaval dual-lumen cannulae. They did not have any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
This study was approved by the Columbia University Institutional Review Board, IRB#AAAI1221. Informed consent was obtained from the subject’s legal surrogate before enrollment, and reconfirmation of consent was obtained from the subject once decision-making capacity was regained after extubation.
Ten subjects met inclusion criteria. Five of these subjects met all inclusion and exclusion criteria and were enrolled. Five additional subjects who met inclusion criteria were evaluated and excluded: two who did not meet BMI criteria and three who were expected to be rapidly weaned from IMV. The mean age of the enrolled subjects was 73 ± 8.7 years (Table 1). All subjects who met clinical criteria for an exacerbation of COPD had a previously documented history of severe to very severe COPD, a history of acute exacerbations requiring hospitalization (average, 2.5 exacerbations per year), and evidence of chronic respiratory acidosis. Three subjects had previously been intubated for exacerbations, with the duration of IMV ranging from 5 to 12 days. Before initiation of ECCO2R, all five subjects failed noninvasive ventilation (median, 6.5 h; range, 2–48 h) due to worsened hypercapnia, increased somnolence, or increased work of breathing, with mean preintubation pH of 7.23 ± 0.05, PaCO2 of 81.6 ± 15.9 mm Hg, and a PaO2 to FiO2 ratio of 256 ± 58. The mean duration of IMV before ECCO2R initiation was 16.5 ± 5.9 hours (Table 2). Although subject 4 had a more modest increase in PaCO2, she had a history of prolonged intubation for COPD exacerbations and had failed noninvasive ventilation with increased work of breathing and somnolence.
| Subject | Age (yr) | Sex | Baseline FEV1 (L, % predicted) | Baseline FEV1/FVC | BMI |
|---|---|---|---|---|---|
| 1 | 64 | M | — | — | 20.7 |
| 2 | 79 | F | — | — | 22.1 |
| 3 | 63 | F | 0.22, 10 | 19 | 15.8 |
| 4 | 80 | F | 0.81, 50 | — | 23.6 |
| 5 | 79 | M | 0.90, 26 | 30 | 20.7 |
| Subject | Duration of NIV (h) | Preintubation pH | Preintubation PaCO2 (mm Hg) | Preintubation PaO2:FiO2 ratio | Duration of pre-ECCO2R IMV (h) |
|---|---|---|---|---|---|
| 1 | 6.5 | 7.19 | 75 | 205 | 15 |
| 2 | 2 | 7.18 | 94 | 238 | 11 |
| 3 | 48 | 7.22 | 95 | 229 | 26 |
| 4 | 3.5 | 7.30 | 57 | 253 | 12.5 |
| 5 | 12 | 7.24 | 87 | 355 | 18 |
ECCO2R access was obtained via the right internal jugular vein with a 20-Fr bicaval dual-lumen cannula in all but one subject, in whom a 23-Fr cannula was used due to unavailability of the 20-Fr cannula (Table 3). The extracorporeal blood flow rate varied by subject but was maintained between 1 and 1.7 L/min for all subjects. Sweep gas flow rates ranged between 1 and 7 L/min with a pH range of 7.34 to 7.48, with a subsequent decrease in flow rates as subjects were weaned from ECCO2R support. The fraction of delivered oxygen in the ECCO2R circuit was maintained at 1.0 throughout the study in all subjects. The mean aPTT across all subjects was 43.3 ± 5.1 seconds.
| Subject | Cannula Size (Fr) | Blood Flow Rate (L/min) | Sweep Gas Flow Rate (L/min) | pH on ECCO2R | PaCO2 on ECCO2R | Supplemental Oxygen |
|---|---|---|---|---|---|---|
| 1 | 23 | 1.0–1.5 | 1.0–1.5 | 7.36–7.47 | 48–54 | None |
| 2 | 20 | 1.0–1.6 | 2.0–4.5 | 7.34–7.48 | 50–59 | NC 1–5 L/min |
| 3 | 20 | 1.5–1.7 | 1.5–2.0 | 7.42–7.48 | 39–63 | HFNC 35–50% |
| 4 | 20 | 1.0–1.3 | 1.3–7.0 | 7.36–7.46 | 43–68 | HFNC 40–100% |
| 5 | 20 | 1.5–1.6 | 0.5–2.0 | 7.38–7.41 | 54–69 | NC 3–6 L/min |
All subjects were treated with antibiotics, corticosteroids, and short- and long-acting inhaled bronchodilators. There were no significant differences in treatment regimens among subjects.
The primary outcome, endotracheal extubation within 72 hours of ECCO2R initiation, was achieved in all subjects (100%), with a median duration of 4 hours (range, 1.5–21.5 h) (Table 4). All but one subject were extubated within 5 hours of ECCO2R initiation, with one subject requiring 21.5 hours before extubation due to the residual effects of sedation given for cannulation. The mean duration of ECCO2R was 193.0 ± 76.5 hours. Mean time from ECCO2R initiation to ambulation was 29.4 ± 12.6 hours, with a mean maximal ambulation while receiving ECCO2R of 302 feet (range, 70–600 ft).
| Subject | Duration of ECCO2R (h) | Time from ECCO2R Initiation to Extubation (h) | Time from ECCO2R Initiation to Mobilization (h) | Maximal Ambulation on ECCO2R (ft) | ICU LOS (d) | Hospital LOS (d) |
|---|---|---|---|---|---|---|
| 1 | 91 | 2 | 18.5 | 150 | 7 | 8 |
| 2 | 140 | 21.5 | 26.5 | 450 | 8 | 10 |
| 3 | 280 | 1.5 | 45 | 70 | 12* | 30† |
| 4 | 240 | 5 | 40 | 240 | 12 | 15 |
| 5 | 214 | 4 | 17 | 600 | 12 | 15 |
The mean ICU length of stay was 10.2 ± 2.5 days, and the mean hospital length of stay was 15.6 ± 8.6 days. There was 100% survival to both ICU and hospital discharge. Four of the five subjects were bridged to recovery from their acute exacerbations, all of whom were discharged directly to home. The subject who was bridged to planned lung transplantation received ECCO2R for 280 hours until the time of transplant, with a total hospital length of stay of 30 days. She was subsequently discharged to acute rehabilitation and then home. Mean hospital length of stay, excluding the patient bridged to transplant, was 12.0 ± 3.6 days.
Varying degrees of supplemental oxygen were needed to achieve oxygen saturation goals (Table 3). High-flow nasal cannula was used in two subjects to meet oxygenation goals; the subject with end-stage COPD who was awaiting lung transplantation and one subject who developed a significant amount of atelectasis from mucus plugging that improved with chest physical therapy.
Modified Borg dyspnea scores went from a pre-ECCO2R mean value of 9.8 ± 0.5 to 0.9 ± 1.4 after 2 days of ECCO2R, correlating with improvements in pH and PaCO2 (Figures 2 and 3), and remained at that level after discontinuation of ECCO2R. One subject was unable to report dyspnea scores due to difficulty in comprehension of the scale.
Bedside spirometry showed variable changes in airflow obstruction during the course of ECCO2R, with FEV1 remaining stable or increasing during the hospitalization (Figure 4).
There were two clinically relevant nonmajor bleeding events: epistaxis in one subject and recurrent hemoptysis presumed to be related to underlying bronchiectasis in another subject. Anticoagulation was temporarily held for each bleeding episode, with subsequent resumption at lower doses, with an aPTT goal of 40 seconds. Neither event required transfusion of packed red blood cells or the premature discontinuation of ECCO2R. One subject required transfusion of one unit of packed red blood cells for a hemoglobin of 6.4 g/dl on ECCO2R Day 2 in the absence of overt hemorrhage, with an appropriate rise in hemoglobin. There were no instances of cannula malposition, device malfunction, hospital-acquired pneumonia, venous thrombosis, or decubitus ulcer formation. There were no complications related to mobilization on ECCO2R.
In this study, venovenous ECCO2R facilitated endotracheal extubation and ambulation of subjects with hypercapnic respiratory failure. Endotracheal extubation occurred within 6.8 ± 8.3 hours of ECCO2R initiation. Dyspnea was dramatically reduced once CO2 and pH were returned to near baseline with ECCO2R in the setting of decreased work of breathing required to maintain adequate gas exchange. The pH range of 7.34 to 7.42 was chosen because patients who were hypercapnic at baseline were likely to return to a similar baseline, and we did not want them to significantly decrease their chronic renal bicarbonate buffer. We were generally successful in reaching our targeted pH (actual range, 7.34–7.48), although pH was ultimately dependent on both the ECMO sweep gas flow and the patient’s native lung ventilation because spontaneously breathing patients exert considerable control over their pH regardless of device intervention. The two adverse events potentially related to ECCO2R involved bleeding, and both were managed conservatively without the need for cessation of ECCO2R or transfusion of packed red blood cells. Despite conservative anticoagulation goals, we did not see any evidence of venous thrombosis. Because the ability to oxygenate at lower extracorporeal blood flows is limited, the need for supplemental oxygen was common, and adequate oxygen saturations were achieved in all subjects. Full ambulation while receiving ECCO2R was performed in all subjects under the guidance of a dedicated physical therapy team within the ICU.
IMV is necessary for the management of many patients with acute exacerbations of COPD (5). Although gas exchange abnormalities and respiratory muscle fatigue may be ameliorated with positive-pressure IMV, there are multiple adverse potential consequences. The combination of positive pressure ventilation and high airway resistance frequently leads to dynamic hyperinflation and elevated intrinsic PEEP, which can potentiate hemodynamic instability and increase the risk of pneumothorax and pneumomediastinum (8). The delivery of aerosolized medications is compromised by excess dead space from the endotracheal tube and ventilator circuit (9). As many as 25% of patients receiving IMV in the ICU may develop ventilator-associated pneumonia, and acute exacerbations of COPD are associated with deconditioning and higher rates of long-term disability, which is compounded by the use of sedatives (10–12, 14). All of these factors contribute to an in-hospital mortality of 22% and a 5-year mortality of 76% for patients with acute exacerbations of COPD requiring IMV (5, 13). Strategies that reduce the need for IMV in COPD may play a crucial role in improving short- and long-term outcomes. ECCO2R offers an opportunity to do just that; however, this concept is not entirely new.
In the 1970s and 1980s, Gattinoni and colleagues first applied the principle of ECCO2R to patients with severe hypoxemic respiratory failure as a means of providing “lung rest” in an effort to minimize ventilator-associated lung injury (15–17). In patients with severe hypoxemic respiratory failure, extracorporeal blood flow rates accounting for a high percentage of the cardiac output are often needed to achieve adequate oxygenation (26). In contrast, CO2 removal can be achieved with much lower rates of blood flow (27). The use of ECCO2R as an adjunct to IMV in an acute exacerbation of COPD has been reported by Cardenas and colleagues, using a dual-lumen venous cannula in the internal jugular vein of a single patient (19). A blood flow rate of 800 ml per minute was sufficient to remove the majority of CO2 produced. Tidal volume and respiratory rate were minimized on the ventilator, reversing dynamic hyperinflation and reducing airway pressures, and the patient was weaned from ECCO2R and endotracheally extubated within 48 hours of decannulation. Two recent studies reported on the use of a pumpless femoral arteriovenous extracorporeal circuit to prevent endotracheal intubation in patients with acute exacerbations of COPD whose hypercapnic respiratory failure was progressing despite noninvasive ventilation (20, 21). In the study by Brederlau and colleagues, two of the three subjects were successfully managed with arteriovenous CO2 removal and noninvasive ventilation, but the third subject failed this strategy due to progressive hypoxemic respiratory failure (20). In the study by Kluge and colleagues, 19 of 21 (90%) patients avoided endotracheal intubation after initiation of arteriovenous CO2 removal. Of the two patients who required endotracheal intubation, one developed severe hypoxemia, and the other had a major catheter-related bleeding complication requiring discontinuation of the circuit (21). The most recent case series by Burki and colleagues demonstrated the feasibility of pump-driven venovenous ECCO2R via a femoral or an internal jugular dual-lumen cannula in patients with COPD exacerbations to rescue from noninvasive ventilation, avoid intubation, or facilitate extubation, with variable success (24). These studies demonstrate the feasibility of using an extracorporeal circuit for removing CO2 to avoid endotracheal intubation or to minimize the need for IMV; however, they also highlight major limitations that we address in our study. Although femoral cannulation is not an absolute contraindication to mobilization (28), such configurations raise greater concerns for cannula dislodgement or interruption of flow with ambulation than upper-body configurations. These risks may change with the development of smaller cannulae. With the equipment that is currently available, our use of an upper-body venous configuration via a dual-lumen cannula not only facilitates extubation but also simplifies early mobilization and active physiotherapy, which are of paramount importance in this vulnerable population (29, 30). The ability to actively participate in rehabilitation while receiving ECCO2R accomplished two objectives: those who were bridged to recovery were able to return home after discharge, and transplant candidacy was maintained in the subject who was bridged to transplantation. With an upper-body configuration, ambulation on ECCO2R may be achieved safely and reliably, though in our experience this has required a coordinated effort by physical therapists, perfusionists, intensive care nurses, and physicians, with appropriate attention paid to cannula position and circuit integrity. An additional benefit of avoiding femoral arterial cannulation is the lack of concern for limb ischemia and compartment syndrome, which has previously been documented with femoral arteriovenous circuits (31).
Despite the success in achieving early endotracheal extubation and ambulation, there are limitations to the interpretation of this pilot study. The subjects met strict inclusion and exclusion criteria, including restrictions on body mass index to avoid a concomitant or confounding diagnosis of obesity hypoventilation syndrome as the etiology of the hypercapnia. To maximize the likelihood of successful ambulation on ECCO2R, subjects were excluded if not ambulatory within a week before their presentation. Additionally, patients with severe hypoxemia were excluded. With the cannula sizes that were used, blood flow rates could have been increased to correct for a greater degree of hypoxemia, but the particular focus of this trial was to demonstrate the ability to manage primarily hypercapnic respiratory failure at relatively low blood flow rates. As smaller, unicaval, coaxial cannulae are developed, which are likely to be more easily inserted, safer, and more limited in their blood flow rates, they will not have the capacity to support severely hypoxemic patients. We therefore sought subjects representative of a population that would still benefit in those circumstances. Randomized controlled trials are needed to define the optimal patient population that might benefit from ECCO2R.
This is a feasibility pilot study. Before any recommendation can be made regarding the application of ECCO2R, these results should be corroborated in larger, randomized trials that can also assess whether ECCO2R can decrease the high in-hospital and long-term mortality rates observed among patients with COPD exacerbations. Given the expense of providing extracorporeal support balanced against the potential decrease in the incidence of ventilator-associated complications and the use of post–hospital discharge resources, future trials should include a cost-benefit analysis to evaluate the economic impact of this approach.
We report the feasibility of venovenous ECCO2R in facilitating early endotracheal extubation and ambulation in acute exacerbations of COPD requiring IMV. This protocolized use of ECCO2R has the potential to serve as a new paradigm for the future management of hypercapnic respiratory failure in this population. Randomized, controlled trials are needed to confirm these findings and to define whether there is an ideal patient population in whom there are consistent clinical advantages to ECCO2R over conventional IMV in managing acute exacerbations of COPD.
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Author Contributions: All authors contributed to literature search, figures, study design, data collection, data analysis, data interpretation, and writing.
* These authors contributed equally to this work.
Author disclosures are available with the text of this article at www.atsjournals.org.
