A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (TRANSFORM).

RATIONALE: Single-center randomized controlled trials of the Zephyr endobronchial valve (EBV) treatment have demonstrated benefit in severe heterogeneous emphysema. This is the first multicenter study evaluating this treatment approach. OBJECTIVES: To evaluate the efficacy and safety of Zephyr EBVs in patients with heterogeneous emphysema and absence of collateral ventilation. METHODS: This was a prospective, multicenter 2:1 randomized controlled trial of EBVs plus standard of care or standard of care alone (SoC). Primary outcome at 3 months post-procedure was the percentage of subjects with FEV1 improvement from baseline of 12% or greater. Changes in FEV1, residual volume, 6-minute-walk distance, St. George's Respiratory Questionnaire score, and modified Medical Research Council score were assessed at 3 and 6 months, and target lobe volume reduction on chest computed tomography at 3 months. MEASUREMENTS AND MAIN RESULTS: Ninety seven subjects were randomized to EBV (n = 65) or SoC (n = 32). At 3 months, 55.4% of EBV and 6.5% of SoC subjects had an FEV1 improvement of 12% or more (P < 0.001). Improvements were maintained at 6 months: EBV 56.3% versus SoC 3.2% (P < 0.001), with a mean ± SD change in FEV1 at 6 months of 20.7 ± 29.6% and -8.6 ± 13.0%, respectively. A total of 89.8% of EBV subjects had target lobe volume reduction greater than or equal to 350 ml, mean 1.09 ± 0.62 L (P < 0.001). Between-group differences for changes at 6 months were statistically and clinically significant: ΔEBV-SoC for residual volume, -700 ml; 6-minute-walk distance, +78.7 m; St. George's Respiratory Questionnaire score, -6.5 points; modified Medical Research Council dyspnea score, -0.6 points; and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, -1.8 points (all P < 0.05). Pneumothorax was the most common adverse event, occurring in 19 of 65 (29.2%) of EBV subjects. CONCLUSIONS: EBV treatment in hyperinflated patients with heterogeneous emphysema without collateral ventilation resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance, and quality of life, with an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT02022683).

Outcomes of single- versus multi-port video-assisted thoracoscopic surgery: Data from a multicenter randomized controlled trial of video-assisted thoracoscopic surgery versus thoracotomy for lung cancer.

Objectives: Surgery through a single port may be less painful because access is supplied by 1 intercostal nerve or more painful because multiple instruments are used in 1 port. We analyzed data collected from the video-assisted thoracoscopic surgery group of a randomized controlled trial to compare differences in pain up to 1 year. Methods: Groups were compared in a prespecified exploratory analysis using direct (regression) and indirect comparison (difference with respect to thoracotomy). In-hospital visual analogue scale pain scores were used, and analgesic ratios were calculated. After discharge, pain was evaluated using European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core 30 scores up to 1 year. Results: From July 2015 to February 2019, we randomized 503 participants. After excluding 50 participants who did not receive lobectomy, surgery was performed using a single port in 42 participants (predominately by a single surgeon), multiple ports in 166 participants, and thoracotomy in 245 participants. No differences were observed in-hospital between single- and multiple-port video-assisted thoracoscopic surgery when modeled using a direct comparison, mean difference of -0.24 (95% CI, -1.06 to 0.58) or indirect comparison, mean difference of -0.33 (-1.16 to 0.51). Mean analgesic ratio (single/multiple port) was 0.75 (0.64 to 0.87) for direct comparison and 0.90 (0.64 to 1.25) for indirect comparison. After discharge, pain for single-port video-assisted thoracoscopic surgery was lower than for multiple-port video-assisted thoracoscopic surgery (first 3 months), and corresponding physical function was higher up to 12 months. Conclusions: There were no consistent differences for in-hospital pain when lobectomy was undertaken using 1 or multiple ports. However, better pain scores and physical function were observed for single-port surgery after discharge.

LIONS PREY: A New Logistic Scoring System for the Prediction of Malignant Pulmonary Nodules.

OBJECTIVES: Classifying radiologic pulmonary lesions as malignant is challenging. Scoring systems like the Mayo model lack precision in predicting the probability of malignancy. We developed the logistic scoring system 'LIONS PREY' (Lung lesION Score PREdicts malignancY), which is superior to existing models in its precision in determining the likelihood of malignancy. METHODS: We evaluated all patients that were presented to our multidisciplinary team between January 2013 and December 2020. Availability of pathological results after resection or CT-/EBUS-guided sampling was mandatory for study inclusion. Two groups were formed: Group A (malignant nodule; n = 238) and Group B (benign nodule; n = 148). Initially, 22 potential score parameters were derived from the patients' medical histories. RESULTS: After uni- and multivariate analysis, we identified the following eight parameters that were integrated into a scoring system: (1) age (Group A: 64.5 ± 10.2 years vs. Group B: 61.6 ± 13.8 years; multivariate p-value: 0.054); (2) nodule size (21.8 ± 7.5 mm vs. 18.3 ± 7.9 mm; p = 0.051); (3) spiculation (73.1% vs. 41.9%; p = 0.024); (4) solidity (84.9% vs. 62.8%; p = 0.004); (5) size dynamics (6.4 ± 7.7 mm/3 months vs. 0.2 ± 0.9 mm/3 months; p < 0.0001); (6) smoking history (92.0% vs. 43.9%; p < 0.0001); (7) pack years (35.1 ± 19.1 vs. 21.3 ± 18.8; p = 0.079); and (8) cancer history (34.9% vs. 24.3%; p = 0.052). Our model demonstrated superior precision to that of the Mayo score (p = 0.013) with an overall correct classification of 96.0%, a calibration (observed/expected-ratio) of 1.1, and a discrimination (ROC analysis) of AUC (95% CI) 0.94 (0.92-0.97). CONCLUSIONS: Focusing on essential parameters, LIONS PREY can be easily and reproducibly applied based on computed tomography (CT) scans. Multidisciplinary team members could use it to facilitate decision making. Patients may find it easier to consent to surgery knowing the likelihood of pulmonary malignancy. The LIONS PREY app is available for free on Android and iOS devices.

Lung cancer resection in patients with underlying usual interstitial pneumonia: a meta-analysis.

OBJECTIVE: Patients with lung cancer with underlying idiopathic pulmonary fibrosis and usual interstitial pneumonia (UIP) pattern on CT represent a very high-risk group in terms of postoperative UIP acute exacerbations (AEs) and in-hospital mortality. We sought to investigate the outcomes in these patients. METHODS: We carried out a meta-analysis, searching four international databases from 1 January 1947 to 27 April 2022, for studies in any language reporting on the acute postoperative outcomes of patients with lung cancer undergoing surgical resection with underlying UIP (the primary outcome). Random effects meta-analyses (DerSimonian and Laird) were conducted. We analysed the difference in incidence of postoperative AE as well as the difference in long-term overall survival among subpopulations. These were stratified by the extent of surgical resection, with meta-regression testing (uniivariate and multivariate) according to the stage of disease, operative decision making and country of origin. This study was registered with PROSPERO (CRD42022319245). RESULTS: The overall incidence of AE of UIP postoperatively from 10 studies (2202 patients) was 14.6% (random effects model, 95% CI 9.8 to 20.1, I2=74%). Sublobar resection was significantly associated with a reduced odds of postoperative AE (OR 0.521 (fixed effects model), 95% CI 0.339 to 0.803, p=0.0031, I2=0%). The extent of resection was not significantly associated with overall survival following lung cancer resection in UIP patients (HR for sublobar resection 0.978 (random effects model), 95% CI 0.521 to 1.833, p=0.9351, I2=71%). CONCLUSIONS: With appropriate implementation of perioperative measures such as screening for high-risk cases, appropriate use of steroids, antifibrotics and employing sublobar resection in select cases, the risk of local recurrence versus in-hospital mortality from AEUIP can be balanced and long-term survival can be achieved in a super-selected group of patients. Further investigation in the form of a randomised study is warranted.

Feasibility study of a randomised controlled trial of preoperative and postoperative nutritional supplementation in major lung surgery.

OBJECTIVES: Malnutrition and weight loss are important risk factors for complications after lung surgery. However, it is uncertain whether modifying or optimising perioperative nutritional state with oral supplements results in a reduction in malnutrition, complications or quality of life. DESIGN: A randomised, open label, controlled feasibility study was conducted to assess the feasibility of carrying out a large multicentre randomised trial of nutritional intervention. The intervention involved preoperative carbohydrate-loading drinks (4×200 mL evening before surgery and 2×200 mL the morning of surgery) and early postoperative nutritional protein supplement drinks two times per day for 14 days compared with the control group receiving an equivalent volume of water. SETTING: Single adult thoracic centre in the UK. PARTICIPANTS: All adult patients admitted for major lung surgery. Patients were included if were able to take nutritional drinks prior to surgery and give written informed consent. Patients were excluded if they were likely unable to complete the study questionnaires, they had a body mass index <18.5 kg/m2, were receiving parenteral nutrition or known pregnancy. RESULTS: All patients presenting for major lung surgery were screened over a 6-month period, with 163 patients screened, 99 excluded and 64 (41%) patients randomised. Feasibility criteria were met and the study completed recruitment 5 months ahead of target. The two groups were well balanced and tools used to measure outcomes were robust. Compliance with nutritional drinks was 97% preoperatively and 89% postoperatively; 89% of the questionnaires at 3 months were returned fully completed. The qualitative interviews demonstrated that the trial and the intervention were acceptable to patients. Patients felt the questionnaires captured their experience of recovery from surgery well. CONCLUSION: A large multicentre randomised controlled trial of nutritional intervention in major lung surgery is feasible and required to test clinical efficacy in improving outcomes after surgery. TRIAL REGISTRATION NUMBER: ISRCTN16535341.

Targeting for cardioplegia: arresting agents and their safety.

Elective temporary cardiac arrest (cardioplegia) is often required during cardiac surgery. In the 1970 s, the development of hyperkalaemic cardioplegic solutions revolutionised cardiac surgery by offering effective chemically-induced cardiac arrest and myocardial protection during global ischaemia. Despite remaining the most widely-used cardioplegic technique, hyperkalaemia can have detrimental effects due to the Na and Ca loading of the cardiac cell induced by depolarisation of the cell membrane. Efforts over the last two decades to establish better cardioplegic agents have mainly remained limited to animal experiments. The failure of these approaches to progress to clinical trials may be due to a lack of clear criteria that a cardioplegic agent should meet at a cellular level and, more importantly, at a system level. In this review we attempt to define the criteria for the optimal cardioplegic agent. We also assess the suitability and clinical potential of previously-studied cardioplegic agents and suggest cellular targets, particularly those involved in cardiac excitation-contraction coupling, that may prove to be attractive options for the development of new cardioplegic drugs. Finally, we propose a multicellular target approach using a combination of pharmacological agents in order to offer better cardioplegic solutions.

Cardioplegia and cardiac surgery: pharmacological arrest and cardioprotection during global ischemia and reperfusion.

Since the start of cardiac surgery in the 1950s, multiple techniques have been used to protect the heart during the surgical requirement for elective global ischemia (and the still, relaxed, bloodless field that this provides the surgeon for repair of the lesion). Most of these techniques have been discarded. The current gold standard, established over 30 years ago, is hyperkalemic (moderately increased extracellular potassium) cardioplegia; this technique revolutionized cardiac surgery, allowing significant surgical advancement with relative safety. Hyperkalemic cardioplegia induces a rapid depolarized arrest that is readily reversible. Recent patient demographic changes, with surgeons operating on older, sicker patients who have more severe and diffuse disease, potentially requires a more prolonged elective ischemia; hence, an improved myocardial protection would be of benefit. Several areas of study have demonstrated that a new concept of myocardial protection--'polarized' arrest--may provide this additional protection. Many pharmacological agents have been shown (in experimental studies), to have the ability to induce a polarized arrest and to provide improved protection. However, the often-overlooked requirements of effect reversibility and systemic safety have meant that these agents usually remain experimental in nature. This review attempts to highlight the cellular components that can be targeted, within the excitation-contraction coupling cascade, to induce cardiac arrest, and to provide an explanation for the mechanism of action of these agents. In this context, the agents are discussed in terms of their clinical potential for use during cardiac surgery, with particular reference to the safety aspects of the agents.

Esmolol cardioplegia: the cellular mechanism of diastolic arrest.

AIMS: Esmolol, an ultra-short-acting beta-blocker, acts as a cardioplegic agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest. METHODS AND RESULTS: In unpaced Langendorff-perfused rat hearts, esmolol (0.03-3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Ca(tr)) in electrically-stimulated rat ventricular myocytes at 23 and 34 degrees C. The decrease in contraction (by 72% at 23 degrees C, from 0.16 +/- 0.01 to 0.04 +/- 0.01 microm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Ca(tr) (from 0.13 +/- 0.02 to 0.07 +/- 0.02, P < 0.001). There was no additional effect on myofilament Ca(2+) sensitivity. Esmolol's effects on contraction and Ca(tr) were not shared or altered by the beta-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current (I(Ca,L)) and the fast sodium current (I(Na)), with IC(50) values of 0.45 +/- 0.05 and 0.17 +/- 0.025 mmol/L, respectively. CONCLUSION: Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca(2+) channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na(+) channels.

Is ministernotomy superior to conventional approach for aortic valve replacement?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: is ministernotomy superior to conventional approach for aortic valve replacement (AVR)? Altogether, more than 115 papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that ministernotomy can be performed safely for AVR, without increased risk of death or other major complication; however, few objective advantages have been shown. Ministernotomy can be offered on the basis of patient choice and cosmesis rather than evident clinical benefit.

Does intermittent cross-clamp fibrillation provide equivalent myocardial protection compared to cardioplegia in patients undergoing bypass graft revascularisation?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: does intermittent cross-clamp fibrillation provide equivalent myocardial protection compared to cardioplegia in patients undergoing bypass graft revascularisation? Altogether, 58 papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We identified 13 studies, of which eight were randomised prospective trials. None of these studies found increased mortality, seven analyzed serum cardiac enzymes and showed that intermittent ischemic arrest provides equal or better protection compared to cardioplegic techniques. Two studies found an increased usage of inotropes and intra aortic balloon pump (IABP) in the intermittent ischemic arrest group. We conclude that intermittent cross-clamp fibrillation is a versatile and cost-effective method of myocardial protection, with the immediate postoperative outcome comparable to cardioplegic arrest in first-time coronary artery bypass graft (CABG). The ischaemic duration associated with intermittent cross-clamp fibrillation is invariably shorter than that associated with cardioplegic arrest, and this may be one explanation for the comparable outcomes. There may also be an element of preconditioning protection during the intermittent cross-clamp fibrillation method, as has been shown experimentally. During elective CABG in patients with no clinical evidence of aortic or cerebro-vascular disease, the incidence of peri-operative microemboli (ME) and postoperative neuropsychological disturbances are shown to be comparable with both techniques of myocardial preservation.

In patients with acute aortic intramural haematoma is open surgical repair superior to conservative management?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: in patients with acute aortic intramural haematoma (IMH) is open surgical repair superior to conservative management. IMH is defined as a clinical condition related to but pathologically distinct from aortic dissection. In this potentially lethal entity, there is haemorrhage into the aortic media in the absence of an intimal tear. Altogether more than 204 papers were found using the reported search terms, from which six systematic reviews represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. IMH represents 17% of all dissections, whereas in postmortem studies this condition is found in 4-13%. The 30-day mortality of IMH is 24% (36% with type A and 12% with type B IMH; P<0.05). With surgical repair, 30-day mortality of type A IMH was 14% for patients treated surgically and 36% for patients treated medically with a P-value of 0.02. Survival at 1, 2, 3, 5 and 10 years was respectively: 81+/-21%, 87+/-8%, 83+/-6%, 65+/-22% and 44+/-14%. In contrast, with 8% mortality associated with medical treatment, prognosis of type B IMH is more favourable without surgical intervention, the latter associated with a 30-day mortality of 33% (P<0.05). Symptomatic patients and those with rapid progression or overt dissection during follow-up need emergent surgery. Ascending aortic diameter of >50 mm or subadventitial haematoma thickness of >12 mm should be considered as the candidates for early surgery. Although IMH seems to have an improved prognosis over aortic dissection, survivors of IMH are at significant risk for progressive aortic abnormalities, including aortic rupture, aneurysm, and ulceration. We conclude that surgical treatment of aortic IMH involving the ascending aorta with open distal replacement of ascending aorta results in lower mortality and longer survival compared to conservative management. IMH affecting the descending aorta can be managed with medical or endovascular interventional approach. In this latter group, serial imaging of the aorta is recommended, as aneurysm formation is not uncommon.

Large subpectoral hematoma: possible complication of sternotomy post-cardiac surgery.

A 62-year-old female patient developed a significantly enlarged left breast 6 hours after sternotomy for a coronary artery bypass graft operation. This was the result of subpectoral bleeding caused by a sternal wire.

Is blood versus crystalloid cardioplegia relevant? Significantly improved protection may require new cardioplegic concepts!

The predominant method of myocardial protection during cardiac surgery is hyperkalaemic cardioplegia, inducing depolarised arrest. Since its development in the 1970s, the only real change has been to alter the vehicle to blood. Although blood cardioplegia was shown to be 'superior' to crystalloid cardioplegia, this advantage is marginal and might explain the continuous use of crystalloid cardioplegia by some surgeons. To achieve significant improvements in cardioplegic protection, more radical and conceptual changes in the solution, such as those potentially achieved by 'polarised' arrest, should be explored.