Extrapulmonary Ventilation for Unresponsive Severe Acute Respiratory Distress Syndrome After Pulmonary Resection

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1 Extrapulmonary Ventilation for Unresponsive Severe Acute Respiratory Distress Syndrome After Pulmonary Resection Manuela Iglesias, MD, Elisabeth Martinez, MD, Joan Ramon Badia, MD, PhD, and Paolo Macchiarini, MD, PhD Departments of General Thoracic Surgery and Pulmonary Medicine, Fundatió Clinic, and Institut d Investigations Biomèdiques August Pi i Sunyer (IDIBABS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain Background. The purpose of this study was to evaluate the feasibility of integrating an artificial, pumpless extracorporeal membrane ventilator (Novalung) to near static mechanical ventilation and its efficacy in patients with severe postresectional acute respiratory distress syndrome (ARDS) unresponsive to optimal conventional treatment. Methods. Indications were severe postresectional and unresponsive acute respiratory distress syndrome, hemodynamic stability, and no significant peripheral arterial occlusive disease or heparin-induced thrombocytopenia. Management included placement of the arteriovenous femoral transcutaneous interventional lung-assist membrane ventilator, lung rest at minimal mechanical ventilator settings, and optimization of systemic oxygen consumption and delivery. Results. Among 239 pulmonary resections performed between 2005 and 2006, 7 patients (2.9%) experienced, days after 5 pneumonectomies and 2 lobectomies, a severe (Murray score, ) acute respiratory distress syndrome unresponsive to 4 2 days of conventional therapy. The interventional lung-assist membrane ventilator was left in place days, and replaced only once for massive clotting. During this time, 29% 0.3% or L/min of the cardiac output perfused the device, without hemodynamic impairment. Using a sweep gas flow of L/min, the device allowed an extracorporeal carbon dioxide removal of ml/ min, lung(s) rest (tidal volume, ml/kg; respiratory rate, 6 2 beats/min; fraction of inspired oxygen, ), early (<24 hours) significant improvement of respiratory function, and reduction of plasmatic interleukin-6 levels (p < 0.001) and Murray score ( ; p < 0.003). All but 1 patient (14%) who died of multiorgan failure were weaned from mechanical ventilation 8 3 days after removal of the interventional lung-assist membrane ventilator, and all of them were discharged from the hospital. Conclusions. The integration of this device to near static mechanical ventilation of the residual native lung(s) is feasible and highly effective in patients with severe and unresponsive acute respiratory distress syndrome after pulmonary resection. (Ann Thorac Surg 2008;85:237 44) 2008 by The Society of Thoracic Surgeons Despite recent advances in pathophysiology, anesthesia, ventilatory support, antibiotic therapy, and critical care, mortality from acute respiratory distress syndrome (ARDS) after pulmonary resections remains high at approximately 40% to 60% in contemporary series [1 5]. Early support of gas exchange with mechanical ventilation (MV) is vital in such patients [6]. Unfortunately, MV is a double-edged sword because by forcing the failing lung(s) to work with unphysiologic positive pressure instead of being allowed to rest and heal, it promotes further barotrauma, volutrauma, and biotrauma (ventilatory-induced lung injury). This vicious circle can, however, be prevented when protective respiratory settings are used, eg, low (6 ml/kg) tidal volumes Accepted for publication June 1, Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29 31, Address correspondence to Dr Macchiarini, Department of General Thoracic Surgery, Hospital Clinic of Barcelona, University of Barcelona, 170 Villaroel, E-30889, Barcelona; pmacchiarini@clinic.ub.es. (Vt), most likely because of the reduced injurious lung stretch and release of inflammatory mediators [7]. The interventional lung-assist membrane ventilator (ila, Novalung, Hechingen, Germany) is a pumpless device that provides passive complete carbon dioxide removal by means of a peripheral arteriovenous shunt using only the heart as the driving force. Because it temporarily takes over the ventilation function of the residual lung(s), one may postulate that the mechanical ventilator settings can be reduced to achieve rest or nondamaging settings, opening the door to advanced lung protection protocols. This study was conducted to evaluate the feasibility and efficacy of this concept in patients with severe and unresponsive ARDS after lung resections. Patients and Methods All eligible patients undergoing pulmonary resection between January 1, 2005, and December 31, 2006, who exhibited a severe ARDS unresponsive to optimal con by The Society of Thoracic Surgeons /08/$34.00 Published by Elsevier Inc doi: /j.athoracsur

2 238 IGLESIAS ET AL Ann Thorac Surg POSTRESECTIONAL ACUTE RESPIRATORY FAILURE 2008;85: ventional therapy entered a prospective study evaluating the feasibility and efficacy of the ila device in such patients. The study was approved by the local institutional review board and ethics committee of the University of Barcelona. All patients were receiving optimal conventional treatment, sedated, and ventilated at maximum levels at the time of the decision for device implantation. Informed consent was obtained from patients surrogates. Eligibility Criteria Patients who underwent pulmonary resection were eligible for the study if they met the severity score [8] and ARDS criteria established by the American-European Consensus Conference for ARDS [9, 10], were unresponsive to optimal conventional treatment, hemodynamically stable (mean arterial blood pressure 60 mm Hg with minimal vasopressor agents), and had no peripheral arterial occlusive disease impairing the limb perfusion after cannulation or heparin-induced thrombocytopenia. The ARDS criteria were (1) sudden onset of acute respiratory insufficiency requiring mechanical ventilation; (2) diffuse pulmonary infiltrates on the chest radiograph consistent with alveolar edema; (3) ratio (Pao 2 /Fio 2 ratio) of partial pressure of arterial oxygen (Pao 2 ) to the fraction of inspired oxygen (Fio 2 ) less than 200 mm Hg (oxygenation index); and (4) absence of hydrostatic pulmonary edema as a result of left heart failure or fluid overload, on the basis of pulmonary arterial catheterization, echocardiogram, laboratory data (creatine kinase-mb, troponin T, and so forth), clinical evaluation, or a combination of these. Patients initially presenting with aspiration of gastric contents or pleural fluid after bronchopleural fistula, major atelectasis, bronchopneumonia, or pulmonary embolism who later experienced noncardiogenic pulmonary edema were classified as secondary ARDS; primary ARDS included the remaining cases. The severity of the ARDS was calculated according to Murray and associates [8], which evaluates radiographic consolidation, hypoxemia, level of positive endexpiratory pressure (PEEP), and static lung compliance, in which ARDS may be classified as mild (1 to 2.5) or severe ( 2.5). Failure of optimal conventional treatment included unresponsiveness to early intubation and MV using protective ventilation strategies (Vt of 6 to 8 ml/kg), forced diuresis, broad-spectrum antibiotics, aggressive pulmonary toilet consisting of aspiration bronchoscopy and postural changes, inhaled nitric oxide (20 ppm), and intravenous steroid therapy (48 hours) [6]. Preoperative, Anesthetic, and Postoperative Management Preoperative evaluation included a complete history, physical examination, blood cell count, biochemical profile, chest roentgenogram, electrocardiogram, pulmonary function tests, and computed tomographic scan of the chest and abdomen. Patients with a forced expiratory volume in 1 second of less than 60% of predicted value or impaired exercise tolerance underwent a differential lung ventilation and perfusion scan, a cardiopulmonary exercise test, or both. Surgical candidates were selected to undergo pneumonectomy if the calculated postoperative forced expiratory volume in 1 second was 0.8 L or greater (or 40% of the predicted value), and carbon monoxide diffusion capacity was 60% or greater than the predicted value. Further cardiac testing was performed in patients with risk factors for coronary artery disease or cardiac insufficiency. Before surgery, a thoracic epidural catheter was routinely inserted, except in cases of patients refusal, coagulation disorders, acute neurologic problems, local or systemic infection, or technical failure. Prophylactic antibiotics (ceftriaxone, 2 g) were given intravenously at 20 to 90 minutes before anesthesia induction. Anesthesia was induced with remifentanil, propofol, and cisatracurium, followed by insertion of a double-lumen tube under endoscopic view. During one-lung ventilation, ventilatory settings (respiratory frequency of 15 to 18 breaths/min; Vt of6to10ml kg 1 min 1 ; inspiratory to expiratory ratio of 1:2 to 1:2.5; Fio 2 of 0.50 to 1.00; pressure-control versus volume-control; continuous positive airway pressure in operated lung and PEEP in dependent lung) were adjusted to achieve an arterial partial pressure of carbon dioxide of 30 to 45 mm Hg and a peripheral arterial oxygen saturation of 90% or more while avoiding increased peak airway inspiratory pressure ( 40 cm H 2 O) and gas trapping at end-expiration (persistent expiratory flow). Anesthesia was maintained with a target-controlled infusion of propofol to keep the bispectral index between 40 and 60. Intraoperative analgesia was provided with continuos infusion of remifentanil (0.2 to 0.3 g kg min 1 ), a bolus of fentanyl (250 to 500 g) at skin incision, and epidural administration of ropivacaine 2% (5 to 10 ml) at chest closure. During surgery, ventilatory variables (Vt, respiratory frequency, peak airway inspiratory pressure, Fio 2, and arterial oxygen saturation) and duration of one-lung ventilation were recorded to calculate a ventilatory hyperpressure index (product of inspiratory plateau pressure 10 cm H 2 O and the duration of one-lung ventilation). Hemoglobin level was maintained greater than 9 g/dl. After surgery, laboratory data included serial measurements of oxygenation index ratio, biochemical profile, and blood cell counts, and cultures of blood and tracheobronchial secretions. During and after surgery, the use of vasoactive drugs was recorded, as was urine output, chest drainage, and amount of fluid intake (colloids, crystalloids, homologous blood units, fresh-frozen plasma, and beverages). All patients were monitored for at least 6 hours either in the postanesthesia care unit, intermediate care, or the intensive care unit to provide respiratory care and early mobilization. Oral feeding was resumed within 24 hours after surgery, and total fluid intake was limited to compensate for the volume of blood loss with colloids and crystalloids. The analgesic regimen was continued for 2 to 4 days by using either intravenous patient-controlled analgesia pump of morphine or epidural patient-controlled analgesia of ropivacaine 0.1% and fentanyl (2.2 g/ml), or both. Arterial blood sam-

3 Ann Thorac Surg IGLESIAS ET AL 2008;85: POSTRESECTIONAL ACUTE RESPIRATORY FAILURE 239 Table 1. Preoperative, Perioperative, and Postoperative Patient Characteristics Variables Numbers a Preoperative Age (y) Sex (males vs. females) 7 vs 1 Body weight (kg)/height (cm) 61 10/161 9 Chronic alcohol consumption 3 (43%) Smoking habits (packs/day) 1.5 Diabetes mellitus 1 (14%) Chronic obstructive pulmonary disease 4 (57%) ASA class III/IV 6/1 ppfev 1 (L/%) / predicted Dlco (%) Perioperative Indication: (lung cancer vs trauma) 6 vs 1 Type of operation: lobectomy vs 2vs5 pneumonectomy TNM stages (IB/IIa/IIIa) 3/2/1 Duration of surgery (min) Duration of one-lung ventilation (min) Tidal volume (ml/kg) Static lung compliance (%) Plateau inspiratory pressure (cm H 2 O) Positive end-expiratory pressure (cm H 2 O) Ventilatory hyperpressure index Epidural thoracic anesthesia 5 (71%) Fluid infusion during anesthesia (L) Postoperative Extubated (yes vs no) 6 vs 1 Pao 2 /Fio 2 on arrival in ICU/PACU Fluid infusion, first 24 h (L) Fluid balance, first 24 h (ml) Cumulated intraoperative and postoperative fluid infusion (L) a Numbers, when not specified, refer to numbers of patients. ASA American Society of Anesthesiologists; Chronic alcohol consumption consumption of 100 g/d (at least five drinks) for several months or years; Dlco lung diffusion for carbon monoxide; ICU intensive care unit; Lung cancer surgery included a complete nodal dissection; PACU postanesthesia care unit; Pao 2 /Fio 2 ratio of arterial oxygen pressure and inspiratory oxygen fraction; ppfev 1 postoperative predicted forced expiratory volume in 1 second in %; Static lung compliance [tidal volume/(plateau pressure positive end-expiratory pressure)]; TNM tumor, nodal, and metastasis involvement. plings and chest radiograms were routinely performed at arrival in the intensive care unit or postanesthesia care unit, on the first day after surgery, and in any case of clinical deterioration. Placement of Interventional Lung-Assist Membrane Ventilator Before placement of the ila device, an ultrasound examination was made to measure the internal diameter of the common femoral artery and rule out atheromatous or calcified abnormalities and any venous abnormalities. The selected arterial cannula was at least 20% smaller than the internal artery diameter, and the venous cannula was one size bigger than the arterial cannula to be used. The arterial and venous cannulas were placed, in the intensive care unit, over a guidewire using a standard transcutaneous Seldinger technique, cannulating first the femoral artery and then the contralateral vein. Cannulas were advanced maximally, flushed with a bolus of about 50 ml of heparinized saline solution (heparin doses 10 to 20 IU/kg body weight), and clamped proximally. The deaired and filled (240 ml of saline solution) ila device was then connected to both previously placed cannulas while an assistant flooded the two open ends with saline solution to eliminate any residual air as the connection was completed. Before unclamping, all connections were secured. Device unclamping was performed gently and progressively for 1 to 2 minutes to minimize the hemodynamic effects of the induced arteriovenous shunt. A line connected to an oxygen source (sweep gas) was then attached to the labeled oxygen inflow port at an initial flow rate of 1 L/min to provide a pressure gradient inside the ila membrane and therefore to enhance gaseous diffusion. Blood flow through the ila device was monitored by a specially designed flowmeter (Novalung Emtec) placed at the outflow venous line. Table 2. Hemodynamic Effects of Interventional Lung Assisted Support a Variables Standard Anti-ARDS Therapy ila Support p Value Cardiac output (L/min) Mean arterial pressure (mm Hg) Mean pulmonary arterial pressure (mm Hg) Systemic vascular resistance 1, , (dyne/cm 5 ) Pulmonary vascular resistance (dyne/cm 5 ) Pulmonary capillary wedge pressure (mm Hg) Central venous pressure (mm Hg) Stroke volume (ml/kg per beat) Left ventricular stroke work index (gm M/m 2 per beat) a Values are expressed as mean standard deviation of n number of observations. ila numbers reflect the mean values observed during the entire period of device support. ila interventional lung assist device; LVSWI left ventricular stroke work index (stroke volume index [stroke volume/body surface area] (mean pulmonary arterial pressure pulmonary capillary wedge pressure) ; Stroke volume (cardiac output 1000 ml/l/ heart rate).

4 240 IGLESIAS ET AL Ann Thorac Surg POSTRESECTIONAL ACUTE RESPIRATORY FAILURE 2008;85: Ventilatory Variables While on Interventional Lung-Assist Membrane Ventilator Patient management during ila targeted stepwise reduction of the MV settings to rest or nondamaging settings (Fio to 0.8, respiratory frequency 6 to 10 beats/min, pressure control ventilation with peak inspiratory pressures of 20 cm H 2 O, and PEEP 10 cm H 2 O). Basically, the first step was to decrease the minute volume by approximately 10%, increase the PEEP by 2 to 3cmH 2 O, and load the sweep gas flow at the initial rate of 1 L/min. After 20 minutes of observation, control arterial blood gases were taken to avoid acute and excessive arterial carbon dioxide partial pressure reduction impairing cerebral perfusion, while the mean arterial pressure ( 10 mm Hg) was kept constant. Additional reductions of the mechanical ventilator settings were made gradually, but within 2 hours, to reach the targeted rest or nondamaging settings. Interventional Lung-Assist Membrane Ventilator Monitoring and Removal Peripheral pulses and leg temperature were assessed and documented hourly to monitor ischemia, especially at the site of the arterial cannula. After ila connection, a continuous heparin infusion was started at a dose of 5 to 10 IU/kg body weight to reduce thrombotic risks, maintaining an activated partial thromboplastin time of 55 seconds while on anticoagulation. Fibrinogen was also checked, particularly in patients with an active infection, and, if abnormally elevated, the heparin dose was increased to reach an activated partial thromboplastin time of 70 to 80 seconds. To optimize blood flow through the ila, hematocrit was held at less than 30%. Systemic mean arterial blood pressures was constantly kept at least at 60 mm Hg and adjusted with volume substitution or, preferentially, vasoactive drugs (eg, norepinephrine Table 3. Difference in Ventilatory Variables During Initial Protective Ventilation and Interventional Lung Assist Support in Patients With Refractory Acute Respiratory Distress Syndrome After Lung Resections a Fig 1. Evolution of the oxygenation index (ratio of partial pressure of arterial oxygen [Pao 2 ] to the fraction of inspired oxygen [Fio 2 ]) and arterial carbon dioxide (Paco 2 ) as a function of time. Oxygen delivery (ml O 2 /min) was calculated according to the following formula: cardiac output (L/min) Hb (hemoglobin) concentration (g/l) 1.31 (ml O 2 /g Hb) % saturation (Sao 2 ). (ila interventional assist device.) or dopamine). The device itself was closely observed for the presence of air or water, or clotting, and, if malfunctioning, was removed and changed. Patients undergoing treatment with ila were allowed routine nursing care and were suitable for transport. By clinical, radiologic, and functional improvements (arterial oxygen saturation 95% at Fio 2 at 0.5 or less), the ila weaning was initiated. Initially, the sweep gas flow was stopped for at least 3 hours and the respiratory function was reassessed. The ila was removed only if the respiratory status remained constant during this entire time, and heparin was discontinued at least 4 hours before. Decannulation was accomplished after any transcutaneous technique principles. After successful wean- Mechanical Ventilation Variables Initial Protective Ventilation ila Support p Value Tidal volume (ml/kg) Respiratory rate (breaths/min) Plateau inspiratory pressure (cm H 2 O) PEEP (cm H 2 O) Fraction inspired oxygen (Fio 2 ) Static lung compliance (ml/cm H 2 O) a Values are expressed as mean standard deviation of n number of observations. ila numbers reflect the mean values observed during the entire period of device support. ila interventional lung assist device; PEEP positive end-expiratory pressure; Static lung compliance [(tidal volume/plateau pressure) positive end-expiratory pressure)]. Fig 2. Plasma concentration of interleukin-6 (IL-6) as a function of time. (ila interventional assist device.)

5 Ann Thorac Surg IGLESIAS ET AL 2008;85: POSTRESECTIONAL ACUTE RESPIRATORY FAILURE 241 Fig 3. Radiologic evolution as a function of time in a patient having had a postpneumonectomy stump carinal resection with primary end-to-end trachea-to-right main bronchus anastomosis and experiencing a severe unresponsive acute respiratory distress syndrome. The severity of the acute respiratory distress syndrome was calculated according to Murray and colleagues [8], which evaluates radiographic consolidation, hypoxemia, level of positive end-expiratory pressure, and static lung compliance, whereby acute respiratory distress syndrome may be mild (1 to 2.5) or severe ( 2.5). (ila interventional assist device.) ing from ila, patients remained on MV until standard extubation criteria were met. Patients were discharged from the intensive care unit when they were stable off MV. Plasma Interleukin-6 Concentrations Blood samples were obtained from the last 4 patients before the start of extrapulmonary ventilation with ila implantation and every 6 hours thereafter to measure plasma interleukin-6 (R & D Systems, Minneapolis, MN) [11]. Statistical Analysis Mortality was defined as any death occurring during the hospital stay. Data are presented as mean standard deviation, using either absolute numbers or percentages. All values were calculated and tested with a commercial statistical package (SPSS 7.0, SPSS Inc, Chicago, IL). Two-tailed paired Student s t tests with multiple comparison adjustments were used to compare values recorded during treatment with those recorded at baseline, and differences were considered significant at a 95% level (p 0.05). Results Among 239 pulmonary resections, 9 patients exhibited an acute lung injury or ARDS, and 2 of them were successfully treated with conventional treatment. The residual 7 patients (2.9%), however, had at days postoperatively a severe (Murray score, ) ARDS, and their preoperative, perioperative, and postoperative characteristics are depicted in Table 1. The cause was primary in 6 (86%) and secondary to a bronchopleural fistula after carinal resection and reconstruction for a postpneumonectomy stump tumor recurrence in 1. After 4 2 days of unresponsiveness to conventional ARDS treatment, the ila was implanted in all but 1 of them transcutaneously. The ila was left in place days (range, 2 to 9 days), and a replacement of the lung membrane was necessary in only one case because of massive clotting. During this time, an average of 29% 0.3% or L/min of the cardiac output perfused the device, without resulting in a significant hemodynamic impairment or need of massive vasopressors (Table 2). Using an average Fig 4. Radiologic evolution as a function of time in a patient having had a lower lobe lobectomy and experiencing a severe unresponsive acute respiratory distress syndrome. The severity of the acute respiratory distress syndrome was calculated according to Murray and colleagues [8], as described for Figure 3.(iLA interventional assist device.)

6 242 IGLESIAS ET AL Ann Thorac Surg POSTRESECTIONAL ACUTE RESPIRATORY FAILURE 2008;85: sweep gas flow of L/min, the device allowed an arteriovenous extracorporeal carbon dioxide removal of ml/min, a minimal ventilation of the residual native lung(s) (Table 3), and a significant improvement of the respiratory function (Fig 1), especially within the first 24 hours. The mean plasma interleukin-6 values decreased from pg/ml before ila placement to pg/ml on day 4 (p 0.001; Fig 2), and the Murray score decreased to (p 0.003) by the time of the ila removal (Figs 3, 4). All but 1 patient (14%) who died on ila for multiorgan failure could be weaned 8 3 days after ila removal. This last patient was a 63-year-old man with a previous coronary artery bypass graft surgery whose severe ARDS improved only during the first 24 hours while on ila; he ultimately died of septic shock and multiorgan failure. The device removal was uncomplicated in all but 1 patient (14%) requiring distal arterial embolectomy and patch plasty of the cannulated femoral communis artery. None of the 6 surviving patients required permanent MV or supplemental oxygen supply. Comment Acute respiratory distress syndrome still occurs in less than 3% of patients undergoing lung resections [5], and its standard treatment consists of early intubation and mechanical ventilation, diuresis to improve fluid balance, broad-spectrum antibiotic coverage, aggressive pulmonary toilet including aspiration bronchoscopy and frequent position changes of the patient, and intravenous steroid therapy (48 hours) [6]. Unfortunately, mortality remains high at 40% to 60%, and is related to the severe comorbidity including multiple-organ failure, sepsis, stroke, myocardial infarction [1, 3 6], or, in some cases, progressive irreversible pulmonary failure caused by the ventilator-induced lung injury to the residual aerated and potentially recruitable lung regions. There is, therefore, a clear need for therapeutic innovations in these patients. Protective ventilation strategies with low Vt are, probably, the approach most rapidly gaining acceptance. In effect, a number of landmark clinical trials including the Acute Respiratory Distress Syndrome Network have shown an improved clinical outcome when using low (6 ml/kg) Vt to reduce lung stretch [12, 13]. Unfortunately, in clinical reality protective ventilation has not been established as the standard of care it should be, and this may be related to the fear that low Vt strategies may not only cause alveolar hypoventilation, hypercapnia, and acidosis triggering increased intracranial pressure and pulmonary hypertension [14] but also require higher Fio 2 and PEEP levels to maintain minimal acceptable arterial oxygenation levels, which by themselves could contribute to oxidant-induced lung injury. Another strategy would be extracorporeal life support systems. They focus on carbon dioxide removal and oxygen exchange, avoid high Vt and airway pressure, and provide temporary or permanent respiratory life support even in the absence of native pulmonary function [15]. Extracorporeal membrane oxygenator technology is the most known and used so far clinically [16], and involves placing patients on a venovenous or venoarterial life support circuit with a membrane oxygenator to temporarily take over the gas exchange function of the lung. While on extracorporeal life support, the mechanical ventilator settings can be reduced to such an extent to achieve nondamaging settings, thereby minimizing ventilator-induced lung injury and maximizing both the recruitment of functional residual lung capacity and the rest and healing of the residual injured lungs. It has become the standard treatment for neonatal and pediatric respiratory failure unresponsive to other modes of treatment [17 19]. Although Hemmila and colleagues [20] have very recently provided definitive evidence that extracorporeal life support is a successful therapeutic option even for adult patients with severe (Pao 2 /Fio 2 100) ARDS unresponsive to conventional mechanical ventilator strategies, their use has not gained wide acceptance, probably because of lack of evidence and randomized trials, fear about the related complications that are the rule and not the exception, team training, and costs [16]. In a retrospective evaluation of patients undergoing pneumonectomy between 2001 and 2004 at our department, postoperative severe ARDS occurred in 9 of 71 patients (12.6%), and, among them, 7 or 77% of these patients died despite optimal conventional treatment. This frustrating scenario prompted us to consider an extracorporeal life support for any future patients experiencing severe and unresponsive ARDS based on the recent evidence made by the University of Michigan in 2004 [20] that native lung recovery can occur despite total loss of lung function for days or weeks when supported with extracorporeal life support, and the recent commercial availability of the ila membrane ventilator. There were three potential clinical advantages of using the ila in our patient population, namely the (1) pumpless nature of the ila, and the possibility of (2) using a near static, nondamaging MV beyond the Acute Respiratory Distress Syndrome Network guidelines, and (3) putting the residual lung(s) at rest to give them time to heal. First, the ila has a very low-resistance (approximately 7 mm Hg at a blood flow of 0.5 to 2.5 L/min) gas exchanger that requires only 20% to 30% of the cardiac output as the sole driving force when placed through a simple peripheral percutaneous arteriovenous shunt to achieve extracorporeal near-total carbon dioxide removal. Therefore, any roller pump and substantial portion of the tubing and extracorporeal membrane oxygenation-related components are unnecessary, and potential related deleterious effects of foreign surface areas and priming fluid and blood transfusion volumes [16] can be avoided. Second and third, inasmuch as the ila allows an extracorporeal near-total carbon dioxide removal, the lungs are not required to supply any additional ventilatory function and can therefore be minimally ventilated (eg, 4 mg/ ml/kg). This is a condition sine qua non not only to obtain a minimal but sufficient native oxygenation by means of apneic oxygenation but also to put the damaged

7 Ann Thorac Surg IGLESIAS ET AL 2008;85: POSTRESECTIONAL ACUTE RESPIRATORY FAILURE 243 lungs at rest and give time to heal, according to the rationales behind extracorporeal carbon dioxide removal and apneic oxygenation elaborated by Kolobow and coworkers [21] and Gattinoni and associates [22]. The results presented here demonstrate that the application of the ila is feasible and efficacious in the study population. The vascular accesses were easy achieved by a simple transcutaneous Seldinger technique of the femoral artery and vein, and even the clamp release maneuvers and opening of the arteriovenous peripheral shunt was not associated with further impairment of left ventricular function, a particular fear in pneumonectomy patients. The fall in cardiac output was usually compensated with peripheral vasopressors to avoid fluid overload to the resting lung, and the amount of drugs required was minimal. The nursing management was straightforward and did not require a specialized education, and patient compliance was not affected because routine nursing care could be provided. Only 1 patient required exchange of the device as a result of massive clotting, and the same patient had as well a distal arterial embolic discharge requiring open surgery. This complication, already reported in a larger series of nonsurgical ARDS patients [23], might be prevented by the insertion of a smaller arterial cannula that would allow an improved distal arterial perfusion while keeping adequate blood flow through the ila. The observed early blood gas exchange improvement, especially the oxygenation index, was frankly unexpected given the known limited oxygenation capacity of the ila in comparison with pump-driven extracorporeal membrane oxygenation. One may postulate that the oxygenation improvement took place because the more protective ventilation to the diseased lungs spared them any mechanical function while oxygenation was provided by the minimal but still recovering residual lung parenchyma. The results of this study are particularly attractive because they indirectly demonstrate that even the most damaged postresectional ARDS lungs can provide minimal but lifesaving oxygenation and temporary and definitive recovery, provided they do not exercise ventilatory function. These benefits occurred despite the higher requirements for PEEP necessary to maintain a minimal functional residual capacity of the residual lung(s) while on ila. Indirectly, they do show that even those patient populations can hemodynamically tolerate high PEEP levels. These results, coupled with the significant reductions in plasma interleukin-6 concentrations, suggest that the combination of ila and near-static ventilation induced less lung inflammation, reduced the systemic inflammatory response to lung injury, and contributed to the lower mortality in our patients (7). In conclusion, the present study suggests that the implantation of a pumpless extracorporeal lung membrane is feasible, efficiently provides complete carbon dioxide removal, and avoids any further ventilator-induced lung injury. Oxygenation is a limitation of the ila device but can be obtained by means of apneic oxygenation generated from the recovering lungs. This resting status induced less lung inflammation, reduced the systemic inflammatory response to lung injury, and may explain the lower mortality observed in our patients. The authors highly acknowledge the excellent care contributions of Samuel Garcia Reina, MD, David Sanchez, MD, Albert Rodriguez, MD, Irene Rovira, MD, Carmen Gomar, MD, Abel Gómez-Caro, MD, Miguel Catalan, MD, Josep Maria Gimferrer, MD, and Elisabeth Zavala, MD. References 1. Kutlu CA, Williams CA, Evans EA, Pastorino U, Goldstraw P. Acute lung injury and acute respiratory distress syndrome after pulmonary resection. Ann Thorac Surg 2000;69: Jordan S, Mitchell JA, Quinlan GJ, Goldstraw P, Evans TW. The pathogenesis of lung injury following pulmonary resection. Eur Respir J 2000;15: Ruffini E, Parola A, Papalia E, et al. Frequency and mortality of acute lung injury and acute respiratory distress syndrome after pulmonary resection for bronchogenic carcinoma. Eur J Cardiothorac Surg 2001;20: Licker M, de Perrot M, Spiliopoulus A, et al. Risk factors for acute lung injury after thoracic surgery for lung cancer. Anesth Analg 2003;97: Dulu A, Pastores SM, Park B, Riedel E, Rusch V, Halpern NA. Prevalence and mortality of acute lung injury and ARDS after lung resection. Chest 2006;130: Mathisen DJ, Kuo EY, Hahn C, et al. Inhaled nitric oxide for adult respiratory distress syndrome after pulmonary resection. Ann Thorac Surg 1998;66: Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282: Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988;138: Bernard GR, Artigas A, Brigham KL, et al. The American- European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149: Matthay MA. Conference summary: acute lung injury. Chest 1999;116(Suppl):119S 26S. 11. Arons MM, Wheeler AP, Bernard GR, et al. Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 1999;27: [No authors listed] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342: Laffely JG, Kavanagh BP. Ventilation with lower tidal volumes as compared with traditional tidal volumes in lung injury. N Engl J Med 2000;343: Bidani A, Tzouanakis AE, Cardenas VJ, et al. Permissive hypercapnia in acute respiratory failure. JAMA 1994;272: Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressure controlled inverse ration ventilation and extracorporeal CO 2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med 1994;149: Alpard SK, Zwischenberger JB. Extracorporeal membrane oxygenation for severe respiratory failure. 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8 244 IGLESIAS ET AL Ann Thorac Surg POSTRESECTIONAL ACUTE RESPIRATORY FAILURE 2008;85: Bartlett RH, Roloff DW, Custer JR, et al. Extracorporeal life support: the University of Michigan experience. JAMA 2000; 283: Swaniker F, Kolla S, Moler F, et al. Extracorporeal life support outcome for 128 pediatric patients with respiratory failure. J Pediatr Surg 2000;35: Hemmila MR, Rowe SA, Boules TN, et al. Extracorporeal life support for severe acute respiratory distress syndrome in adults. Ann Surg 2004;240: DISCUSSION DR SCOTT J. SWANSON (New York, NY): What were the weaning criteria, or how did you determine when you could come off the machine? DR MACCHIARINI: Basically it was the Pao 2 /Fio 2 ratio (oxygenation index; arterial partial pressure of oxygen divided by fraction of inspired oxygen) and the clinical evaluation. So far we do not consider the interleukin-6 response a criteria for weaning off the ila (interventional lung-assist ventilatory membrane). DR DAVID H. HARPOLE (Durham, NC): When your P/F (Pao 2 /Fio 2 ratio) was greater than 200, which is normal, it seemed like it was after a few days, and you would? DR MACCHIARINI: Basically, yes. We just wanted to not be in a condition of ARDS (acute respiratory distress syndrome) but in between ARDS and acute lung injury, which can be theoretically better managed through ventilation. DR ARA VAPORCIYAN (Houston, TX): I enjoyed the talk very much, and it s these sorts of novel techniques that we need to be experimenting with, exactly like your group is doing. I have a couple of questions. First, the conventional group had a PEEP (positive end-expiratory pressure) of 6, whereas you turned up the PEEP once the patient was placed on the ila, so I was wondering, is it standard to use low PEEP in your ARDS patients, or was this a separate group for which higher PEEP was not utilized during conventional ventilation? DR MACCHIARINI: Well, to recruit nonventilated regions of the lung, you can do it either through an open lung procedure by increasing the PEEP or using other maneuvers. We did not like to use higher PEEPs than shown here simply because the majority of the patients were pneumonectomy. But this study clearly shows that even PEEPs more than 15 can be tolerated very well in these patients, and therefore one might argue that higher levels of PEEP as well as higher levels of inspiratory pressure could be used in the conventional treatment, but, on the other hand, what is conventional? DR VAPORCIYAN: And that was my second question. Did you think that some of the results were due to the increase in PEEP that you used in the ila group compared to the conventional group? DR MACCHIARINI: Well, one major advantage that you have here in the United States is that you take care of your own patients in the intensive care unit and we did not have this in Barcelona. We do as of right now. But if you transfer a patient into the intensive care unit, which is conducted by intensivists or other types of people, they change their mind and use PEEP or they use peak inspiratory pressure above 30 or whatever. So it s very difficult to define this question. 21. Kolobow T, Gattinoni L, Tomlinson T, et al. An alternative to breathing. J Thorac Cardiovasc Surg 1978;58: Gattinoni L, Pesanti A, Mascheroni D, et al. Lowfrequency positive-pressure ventilation with extracorporeal CO 2 removal in severe acute respiratory failure. JAMA 1986;256: Bein T, Weber F, Philipp A, et al. A new pumpless extracorporeal interventional lung assist in critical hypoxemia/ hypercapnia. Crit Care Med 2006;34: DR YOUNG TAE KIM (Seoul, South Korea): For the CO 2 (carbon dioxide) removal, one of the most important factors would be the blood flow through the cannula. What size of cannula did you use? Second, was there any need to maintain blood pressure at a certain level? Third, what would be the air flow through the membrane? How do you manage the air flow? What is the usual flow of the air through the membrane? DR MACCHIARINI: Concerning the first question, the arterial and venous cannulas were, respectively, I think each time a 13F and a 15F cannula. With great respect, I would disagree that the CO 2 is dependent on the blood flow. Oxygenation is dependent on the blood flow. CO 2 removal was never a problem, because the consensus of this gas exchanger is so that it just removes the CO 2. I m sorry, the last question? DR KIM: I agree that blood flows have only a little effect on the CO 2 removal. I am saying the ventilation of the membrane. What degree of air flow do you use through the membrane? DR MACCHIARINI: You could theoretically use this gas exchange device without any sweep gas flow, but by putting sweep gas flow in the sense of putting simply oxygen in between 1 and 15 L, you increase the diffusing capacity of the CO 2 and your oxygen. How we did it, we just placed the ila and then increased stepwise, 1 to 4, 4 to 8, 8 to 12 oxygen per minute of sweep gas flow. DR HYUN-SUNG LEE (Koyang, South Korea): In ARDS, the performance status after discharge is important as well as survival. I wonder about your patients performance status after discharge. This is my first question. Second, I think extracorporeal devices can lead to an increase of serum cytokine or inflammatory mediator. What do you think about the reason for the decrease of cytokine in your data? DR MACCHIARINI: As I showed in I think the second to last slide, all surviving patients did not need any sort of mechanical ventilation or oxygen supply. So they went well. But this is in line with the major clinical experience of ARDS patients from the University of Michigan. Concerning the second question, I do not think that the cytokine response that we observed has something to do with the ila. I think it s just simply a reflection of the fact that you put the lungs at rest, they do not work, and by that time, they improve significantly. Our group will present experimental data at the AATS (American Association for Thoracic Surgery) this year showing clearly that during ila and putting the lung at rest, you can recover completely surfactant and other molecules that might be important in the genesis of ARDS.