Incomplete fissures are associated with increased alveolar ventilation via spiracles in severe emphysema

Transcription

1 Interactive CardioVascular and Thoracic Surgery 25 (2017) doi: /icvts/ivx220 Advance Access publication 6 July 2017 THORACIC Cite this article as: Khauli S, Abston E, Sajjad H, Bolukbas S, Lopez JMA, Saad Jr R et al. Incomplete fissures are associated with increased alveolar ventilation via spiracles in severe emphysema. Interact CardioVasc Thorac Surg 2017;25: Incomplete fissures are associated with increased alveolar ventilation via spiracles in severe emphysema a b c d e Samih Khauli a,ericabston a, Hassan Sajjad b, Servet Bolukbas c, Julio Mott Ancona Lopez d, Roberto Saad Jr d, Surya P. Bhatt e and Michael Eberlein a,b, * Department of Internal Medicine, University of Iowa, Iowa City, IA, USA Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa, Iowa City, IA, USA Department of Thoracic Surgery, Helios University Hospital Wuppertal, University Witten/Herdecke, Wuppertal, Germany Faculdade de Ci^encias Médicas da Santa Casa de S~ao Paulo, S~ao Paulo, Brazil Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama, Birmingham, AL, USA * Corresponding author. Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, C33-GH, Iowa City, IA 52242, USA. Tel: ; fax: ; michael-eberlein@uiowa.edu (M. Eberlein). Received 8 January 2017; received in revised form 11 May 2017; accepted 4 June 2017 Abstract OBJECTIVES: In emphysema, air can flow preferentially via collateral pathways, which can connect an entire lung when incomplete fissures are present. Spiracles are openings through the chest wall into the lung parenchyma. We previously observed increased alveolar ventilation (VA) in subjects with severe emphysema, when spiracles occurred during lung transplant operations. In this study, we set out to identify a computed tomography (CT) imaging phenotype associated with improved VA via spiracles in severe emphysema. METHODS: We retrospectively reviewed 4 patients with severe emphysema who exhaled >_75% of the inhaled tidal volume via transpleural spiracles during a lung transplant operation. We used quantitative image analysis via VIDA VISION CT software to describe emphysema severity and distribution and fissure integrity from pretransplant CT scans of the chest. We analysed partial pressure of carbon dioxide and calculated estimates of VA at baseline and during spiracle ventilation. RESULTS: All 4 subjects demonstrated severe hyperinflation (total lung capacity 148 ± 24%predicted, residual volume 296 ± 79% predicted). On CT imaging, severe emphysema was present, with an average 38.7 ± 9% (range 28 50%) of lung parenchyma showing lowattenuation areas of Hounsfield units or less. Lung fissure integrity analysis demonstrated evidence of incomplete fissures (average detectable fissure integrity 67 ± 19%, range 40 ± ± 10%). During spiracle ventilation on unchanged ventilator settings, there was a significant reduction in partial pressure of carbon dioxide (61 ± 4 35 ± 4 mmhg, P < 0.001) and increase in estimated VA (2.1 ± ± 0.8 l/ min, P < 0.001). CONCLUSIONS: Incomplete lung fissures on quantitative CT analysis seem to be a key image phenotype associated with substantial improvements in VA during transpleural ventilation via spiracles in severe emphysema. Keywords: Chronic obstructive pulmonary disease Collateral ventilation Emphysema Lung transplant Computed tomography Physiology Spiracle Transpleural ventilation INTRODUCTION Collateral ventilation, defined as ventilation of alveolar spaces via non-anatomical air passages, plays an important role in severe emphysema [1, 2]. In severe emphysema, air can flow preferentially through collateral channels that bypass the normal airways, as the resistance in those collateral pathways is often lower than it is in the bronchi and bronchioles [2, 3]. In severe emphysema, collateral ventilation can connect alveolar spaces of an entire lung, if incomplete fissures are present [4 6]. Spiracles are openings through the chest wall into the lung parenchyma [1, 7 9]. If spiracles are created in severe emphysema, expiration can be partially or entirely transpleural via these spiracles [4, 5]. We have previously reported complete transpleural exhalation in a series of subjects with severe emphysema, when spiracles occurred inadvertently during the dissection of the emphysematous lung during bilateral lung transplant operations [4, 5]. We observed that transpleural ventilation via these spiracles substantially and significantly increased alveolar ventilation (VA) and lowered partial pressure of carbon dioxide [4, 5]. This observation suggested spiracles as a potential therapy in select patients with severe emphysema [4, 5]. In a previous pilot study, the creation of spiracles in subjects with emphysema was found to be safe and successful [7 9]. VC The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 852 S. Khauli et al. / Interactive CardioVascular and Thoracic Surgery However, it remains unclear, which emphysema imaging phenotype could be associated with an improvement in VA, when these spiracles are created. Identifying an imaging phenotype could play an important role in the selection of candidates for spiracles as a possible therapy for respiratory failure from severe emphysema. In this study, we performed a quantitative computed tomography (CT) image analysis to describe the imaging phenotype of subjects with emphysema, who had a substantial improvement in VA, when spiracles occurred during a lung transplant operation. We hypothesized that the imaging phenotype is characterized by incomplete fissures and homogenous distribution of severe emphysema. METHODS This is a retrospective cohort study of lung transplant recipients with effective spiracle ventilation (>_75% of the inhaled tidal volume was exhaled via transpleural spiracles) during lung transplant operations, as previously described [4, 5]. We obtained informed consent from the 4 subjects included in this case series. Patient demographics, pretransplant pulmonary function tests and arterial blood gas tests were extracted. Intraoperative anaesthesia records were reviewed for mechanical ventilator settings, and arterial blood gases results before and during spiracle ventilation and estimates of VA and dead-space ventilation (V d /V t ) were calculated, as previously described [4]. Pretransplant CT scans of the patient s chests were retrospectively analysed using VIDA VISION CT analysis software, (VIDA Diagnostics, Iowa City, IA, USA) as previously described [6, 10]. Percent emphysema was defined as the percentage of voxels in the lung fields with a density of less or equal to -950 Hounsfield units. A 15% difference in emphysema severity between lobes (left upper lobe versus left lower lobe and right upper lobe versus right middle plus right lower lobe) was used as a threshold to differentiate heterogeneous (>15% difference) disease from homogenous disease (<_15%). Fissure integrity was automatically generated. Because of the retrospective nature of the CT protocol, scans were sent to the VIDA Precision lab and edited by expert analysts at VIDA using an ISO certified quality control process. Analysts reviewed independently the fissure segmentation and fissure integrity score of all target lobes, as previously described [10]. Summary statistics are presented as mean and standard deviation. RESULTS The average age of the 4 subjects was 59 ± 6 years, and 50% were female. Preoperative lung function testing indicated severe GOLD Stage 4 chronic obstructive pulmonary disease, with a mean forced expiratory volume in 1 s 20 ± 10% predicted and forced expiratory volume in 1 s/forced vital capacity ratio of 0.29 ± All subjects demonstrated severe hyperinflation with a mean total lung capacity of 148 ± 24%, residual volume of 296 ± 79% predicted and a residual volume/total lung capacity ratio of 71 ± 13%. The diffusion capacity was severely reduced (20 ± 10% predicted). All subjects were hypercarbic (mean partial pressure of carbon dioxide 63 ± 6 mmhg) and had a mean oxygen requirement of 4 ± 2 l/min at rest. During spiracle ventilation, on unchanged settings of mechanical ventilation, all 4 subjects had significant reduction in partial pressure of carbon dioxide to an average of 35 ± 4 mmhg (P < compared with baseline). VA increased on average from 2.1 ± 0.5 to 3.8 ± 0.8 l/min (P < 0.001) and dead-space fraction was reduced from 0.6 ± 0.1 to 0.2 ± 0.1 (P < 0.001, Table 1). On CT imaging, all subjects had evidence of severe emphysema and 2 subjects had in addition bullous disease (Subjects 1 and 3, Fig. 1A). The quantitative chest computer tomographic analyses are summarized in Table 2 and Fig. 1B. Quantification of lobar lung density showed that on average 38.7 ± 9% (range 28 50%) of lobar lung parenchyma had densities less than -950 Hounsfield units, consistent with severe emphysema. With respect to emphysema distribution, only 1 of the 4 subjects (Subject 3) consistently met criteria for homogenous distribution of emphysema, when a 15% difference in emphysema severity between lobes was used as threshold to differentiate between homogenous and heterogeneous distribution. Lung fissure integrity analysis demonstrated evidence of incomplete fissures (average detectable fissure integrity 67 ± 19%, range 40 ± ± 10%, Fig. 1B). DISCUSSION In this study, subjects with effective spiracle ventilation had a quantitative CT image analysis phenotype characterized by incomplete pulmonary fissures and severe emphysema. The emphysema distribution was heterogeneous in distribution in Table 1: Parameters reflecting estimates of alveolar ventilation before (base) and during spiracle ventilation (spiracle) Subject 1 Subject 2 Subject 3 Subject 4 Mean ± SD P-value* Base Spiracle Base Spiracle Base Spiracle Base Spiracle Base Spiracle Transpleural ventilation (%) pco 2 (mmhg) ± 6 35 ± 4 <0.01 VA a (l/min) ± ± 0.8 <0.01 b V d /V t ± ± 0.1 <0.01 a VA = (VCO )/PaCO 2 ; VA is the estimate of alveolar ventilation [11]. b V d /V t = 1 - [(0.863 VCO 2 )/(MV PaCO 2 )]; V d /V t is the estimate of dead-space fraction [11]. VCO 2 is the estimated CO 2 production calculated from the Harris Benedict equation: VCO 2 = (HBpred 0.8)/ [11, 12]. HBpred is the predicted resting energy expenditure equation and is gender specific: for females, HBpred = [6.56 weight (kg)] + [1.85 height (cm)] - (4.56 age) [11] and for males, HBpred = [13.75 weight (kg)] + [5 height (cm)] - (6.76 age) [11]. *Comparison made using paired t-test. pco 2 : partial pressure of carbon dioxide; PaCO 2 : arterial pressure of carbon dioxide; MV: minute ventilation.

3 S. Khauli et al. / Interactive CardioVascular and Thoracic Surgery 853 Figure 1: (A) Pretransplant computer tomography of the chest. Top row shows representative axial cuts and bottom row shows representative coronal cuts. (B) Quantitative analysis of the computer tomography scans of the chest via VIDAjvision TM software. (I: top row) Summary schema showing the lobar distribution of emphysema. The size of the spheres is reflecting the extent of low attenuation area clusters, defined as lung parenchyma showing low-attenuation areas of Hounsfield units or less suggestive of emphysema, in each respective lobe. (II: bottom row) Fissure integrity analysis showing detectable fissures in dark blue, whereas the green areas represent fissure defects suggestive of incomplete fissures. The average detectable fissure integrity was 67 ± 19% (range 40 ± ± 10%). the majority of subjects. To the best of our knowledge, this is the first study that describes an imaging phenotype associated with effective spiracle ventilation. Severe emphysema and incomplete fissures seem to be the key features. The image phenotype of incomplete fissures in the severe emphysema is associated with the presence of interlobar collateral ventilation [6, 10, 13]; thus interlobar collateral ventilation seems to be the physiological principle allowing for effective transpleural ventilation via spiracles leading to improved VA in severe emphysema [4 6]. This finding is consistent with studies evaluating imaging predictors for the success of bronchoscopic lung volume reduction (BLVR) for emphysema [10, 13, 14]. BLVR is usually done by inserting endobronchial one-way valves to induce atelectasis and reduce hyperinflation [14]. One of the requirements for a BLVR success is the absence of interlobar collateral ventilation. Quantitative CT image fissure analysis showed that fissure defects predicted interlobar collateral ventilation [10]. A previous study suggested that interlobar collateral ventilation is associated with radiologically homogenous emphysema [15]. Higuchi et al. [15] described collateral ventilation in 15 of the 23 explanted lungs with severe emphysema. Preoperatively, they analysed the results of CT scans and classified the emphysema of each lung as homogenous or heterogeneous based on a visual assessment [15]. Significant collateral ventilation was present in all lungs with homogenous distribution of emphysema on a visual assessment, while only in 40% with heterogeneous emphysema [15]. In our study, which utilized validated software-based quantitative image analysis, only 1 of the 4 subjects (Subject 3) consistently met criteria for homogenous distribution of emphysema, when a 15% difference in emphysema severity between lobes was used as the threshold to differentiate between homogenous and heterogeneous distribution. The presence of homogenous emphysema by itself was however not associated with interlobar collateral ventilation in studies showing the feasibility of endobronchial valve treatment in select patients with severe homogeneous emphysema [16, 17]. In a study of subjects with <15% difference in emphysema destruction score between target and ipsilateral lobes, the presence of interlobar collateral ventilation was assessed via bronchoscopic measurements of collateral

4 854 S. Khauli et al. / Interactive CardioVascular and Thoracic Surgery Table 2: Quantitative image analysis of the computer tomography scans of the chest via VIDAjvision TM software Parameters Subject 1 Subject 2 Subject 3 Subject 4 Mean ± SD Fissure integrity Left oblique (%) ± 19 Right oblique-horizontal (%) ± 9 Right upper oblique (%) ± 36 Right lower oblique (%) ± 10 Right horizontal (%) ± 11 Right oblique (%) ± 10 LUL/LLL fissure (oblique) ± 19 RUL fissure (upper oblique and horizontal) ± 13 RLL fissure (oblique) ± 10 Emphysema (below -950 HU) Left lung (%) ± 11 Right lung (%) ± 13 Both (%) ± 9 LUL (%) ± 18 LLL (%) ± 13 RUL (%) ± 5 RML (%) ± 15 RLL (%) ± 24 Heterogeneity score (%) LUL (vs LLL) ± 26 RUL (vs RML + RLL) ± 16 Right lower (vs RML + RUL) ± 19 LUL: left upper lobe; LLL: left lower lobe; RUL: right upper lobe; RML: right middle lobe; RLL: right lower lobe; HU: Hounsfield units. airflow [16]. Of the 43 subjects with homogenous emphysema assessed, only 17 subjects (40%) had evidence of interlobar collateral ventilation [16]. Although the presence of interlobar collateral ventilation would represent a contraindication to BLVR in subjects with severe emphysema, it appears to be the factor associated with successful spiracle ventilation. Collateral airflow can be a passway of least resistance for air, as airway resistance often exceeds collateral resistance, causing air to flow preferentially through collateral pathways [2, 3]. Macklem [1] hypothesized in 1978 that if collateral flow resistance is less than airway resistance... ventilation...through openings directly through the chest wall into the parenchyma should bypass the obstruction, decrease work of breathing, increase alveolar ventilation and improve dyspnoea. Insects breathe through openings on their body surface called spiracles. Supportive of this spiracle hypothesis we have previously described and have extended this observation in this report that transpleural spiracle ventilation reproducibly and significantly increases VA and carbon dioxide elimination in subjects undergoing bilateral lung transplantation for severe emphysema during mechanical ventilation of the native lungs [4, 5]. The physiological mechanisms of improved VA and carbon dioxide elimination via spiracle ventilation likely are as follows: (a) in emphysema, air can flow preferentially via collateral pathways, which can connect an entire lung when incomplete fissures are present; (b) decompression of trapped alveolar gas via spiracles could transform alveolar dead space into functioning alveolar units, thus leading to more homogenous ventilation and (c) when the spiracles are formed and transpleural ventilation occurs, there is a one-way flow of gas through the anatomic dead space, washing out carbon dioxide from the anatomic dead space before the subsequent breath [4]. Furthermore, the feasibility and safety of creating spiracles were demonstrated in an important pilot study of 3 subjects with severe emphysema [7 9]. At 1 year following the procedure, all 3 subjects had substantial improvements in their pulmonary function tests and 6-min walk distance [8]. In the interim, Saad et al. [8] have performed spiracle placements on 9 subjects with severe emphysema and the first subject to undergo spiracle placement continues to do well now 8 years following the procedure (unpublished data). Limitations This study is limited by the retrospective design, small number of subjects and absence of a control group; however, observations were consistent between all subjects. The location and the number of spiracles that occurred in the study subjects could not be assessed, and further investigations are needed to define optimal number and location of spiracles. The spiracle ventilation observations are limited to the intraoperative-controlled positive pressure mechanical ventilation period during a lung transplant operation and cannot be generalized. However, the creation of spiracles reduced residual volume and increased forced expiratory volume in 1 s and 6-min walk distance in a pilot study of spontaneously breathing subjects with severe emphysema [8]. The quantitative CT imaging analysis is limited by different CT protocols, which were not optimal for quantitative imaging evaluation. All chest CT scans on the 4 subjects used 2-mm slices and high-frequency reconstructions (sharp) kernels per typical radiological visual standards, which is not the typical scan protocol recommended for quantitative CT [18, 19]. However, all the 4 subjects were CT scanned with the same parameters, so the results can be compared between subjects. In addition, there is no validated consensus regarding the definition of homogeneous emphysema; however, previous quantitative CT imaging analysis in emphysema subjects utilized the same thresholds as in this study [17].

5 S. Khauli et al. / Interactive CardioVascular and Thoracic Surgery 855 CONCLUSION Identifying subjects with severe emphysema and a quantitative CT analysis phenotype of incomplete fissures could inform the selection of subjects to include in future studies of spiracles as a possible therapy for a select group of patients with advanced emphysema. Conflict of interest: none declared. REFERENCES [1] Macklem PT. Collateral ventilation. N Engl J Med 1978;298: [2] Terry PB, Traystman RJ, Newball HH, Batra G, Menkes HA. Collateral ventilation in man. N Engl J Med 1978;298:10 5. [3] Morrell NW, Wignall BK, Biggs T, Seed WA. Collateral ventilation and gas exchange in emphysema. Am J Respir Crit Care Med 1994;150: [4] Chahla M, Larson CD, Parekh KR, Reed RM, Terry P, Schmidt GA et al. Transpleural ventilation via spiracles in severe emphysema increases alveolar ventilation. Chest 2016;149:e [5] Eberlein M, Larson CD, Parekh KR, Terry P et al. Complete transpleural exhalation during a bilateral lung transplant operation. Ann Am Thorac Soc 2015;12: [6] Khauli S, Bolukbas S, Reed RM, Eberlein M. Interlobar collateral ventilation in severe emphysema. Thorax 2016;71: [7] Lopez JM, Saad R Jr, Dorgan Neto V, Botter M, Goncalves R, Rivaben JH. Technical validation of pulmonary drainage for the treatment of severe pulmonary emphysema: a cadaver-based study. J Bras Pneumol 2013;39: [8] Saad R Jr, Dorgan Neto V, Botter M, Stirbulov R, Rivaben J, Goncalves R. Therapeutic application of collateral ventilation with pulmonary drainage in the treatment of diffuse emphysema: report of the first three cases. J Bras Pneumol 2009;35:14 9. [9] Saad R Jr, Dorgan Neto V, Botter M, Rivaben J, Goncalves R. Therapeutic application of collateral ventilation in diffuse pulmonary emphysema: study protocol presentation. J Bras Pneumol 2008;34: [10] Schuhmann M, Raffy P, Yin Y, Gompelman D, Oquz I, Eberhardt R et al. Computed tomography predictors of response to endobronchial valve lung reduction treatment. Comparison with Chartis. Am J Respir Crit Care Med 2015;191: [11] Siddiki H, Kojicic M, Li G, Yilmaz M, Thompson TB, Hubmayr RD et al. Bedside quantification of dead-space fraction using routine clinical data in patients with acute lung injury: secondary analysis of two prospective trials. Crit Care 2010;14:R141. [12] Roza AM, Shizgal HM. The Harris Benedict equation reevaluated: resting energy requirements and the body cell mass. Am J Clin Nutr 1984;40: [13] Koster TD, Slebos DJ. The fissure: interlobar collateral ventilation and implications for endoscopic therapy in emphysema. Int J Chron Obstruct Pulmon Dis 2016;11: [14] Klooster K, ten Hacken NH, Hartman JE, Kerstjens HA, van Rikxoort EM, Slebos DJ. Endobronchial valves for emphysema without interlobar collateral ventilation. N Engl J Med 2015;373: [15] Higuchi T, Reed A, Oto T, Holsworth L, Ellis S, Bailey MJ et al. Relation of interlobar collaterals to radiological heterogeneity in severe emphysema. Thorax 2006;61: [16] Valipour A, Slebos D-J, Herth F, Darwiche K, Wagner M, Ficker JH et al. Endobronchial valve therapy in patients with homogeneous emphysema: results from the IMPACT Study. Am J Respir Crit Care Med 2016;194: [17] Eberhardt R, Heussel CP, Kreuter M, Weinheimer O, Herth FJ. Bronchoscopic lung volume reduction in patients with severe homogeneous lung emphysema: a pilot study. Dtsch Med Wochenschr 2009;134: [18] Newell JD Jr, Sieren J, Hoffman EA. Development of quantitative computed tomography lung protocols. J Thorac Imaging 2013;28: [19] Sieren JP, Newell JD Jr, Barr RG, Bleecker ER, Burnette N, Carretta EE et al. SPIROMICS protocol for multicenter quantitative CT to phenotype the lungs. Am J Respir Crit Care Med 2016;194: