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Ann Thorac Surg 2006;82:1976-1981
© 2006 The Society of Thoracic Surgeons
a Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
b Division of Cardiothoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
c Department of Pulmonary Medicine, Wroclaw Medical University, Wroclaw, Poland
Accepted for publication June 19, 2006.
* Address correspondence to Dr Kuzniar, Sleep Disorders Center, Mayo Clinic, 200 First St SW, Rochester, MN 55902 (Email: kuzniar.tomasz{at}mayo.edu).
| General thoracic surgery:
The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.
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Abstract |
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METHODS: Charts of patients who underwent talc pleurodesis at Northwestern Memorial Hospital between January 1, 1997 and December 31, 2003 were retrospectively reviewed. We sought variables associated with the development of postoperative ALI or severe hypoxemia, defined as an increase in fraction of the inspired oxygen by more than 0.15 within 24 hours after the surgery. The analysis included 84 patients (58 women, 26 men) who underwent VATS talc pleurodesis for malignant (n = 74) or benign (n = 10) indications.
RESULTS: ALI developed in 5 patients (5.9%), severe hypoxemia developed in 25 (29.8%), and 54 (64.3%) did not have postoperative complications. In multivariate analysis, the presence of peripheral edema before pleurodesis (p = 0.005), any preoperative requirement for supplemental oxygen (p = 0.032), and chemotherapy within 14 days before pleurodesis (p = 0.04) were identified as predictors of ALI or severe postoperative hypoxemia.
CONCLUSIONS: Oxygen supplementation, recent chemotherapy, and presence of peripheral edema were independent predictors of a combined outcome of ALI or severe hypoxemia after VATS talc pleurodesis. Patients with these characteristics might be at risk for adverse outcomes of talc pleurodesis and should be considered for alternative therapy for their effusions.
Accumulation of pleural effusion frequently accompanies disseminated malignancies and causes significant symptoms and impairment in these patients’ quality of life [1, 2]. Pleurodesis is a procedure intended to obliterate the pleural cavity to alleviate symptoms and improve quality of life in these patients [3]. In addition, pleurodesis is performed in a number of nonmalignant conditions, including recurrent pneumothorax and recalcitrant pleural effusions due to myriad conditions such as congestive heart failure, cirrhosis, yellow nail syndrome, systemic lupus erythematosus, and chylothorax.
Among many agents that have been used to induce irritation of the pleural surfaces and obliterate the pleural space, talc is one of the most effective [4]. Pain and dyspnea are the most common complications of talc pleurodesis [5]; however, serious talc initiated inflammatory responses such as systemic inflammatory response syndrome (SIRS), acute respiratory failure [6–8], and acute lung injury (ALI) all occur with disturbing frequency after talc pleurodesis. Patients undergoing pleurodesis for malignancy typically have life spans limited to months; therefore, serious complications and prolonged hospitalizations caused by "palliative" interventions cannot be tolerated. The aim of this study was to elucidate the predictors of ALI and severe hypoxemia in patients undergoing talc pleurodesis through a video-assisted thoracic surgery (VATS).
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Material and Methods |
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Outcomes
The three outcomes defined for the purpose of this study were ALI, severe hypoxemia, and no complications. Postpleurodesis ALI was defined in a standard way as the presence of bilateral pulmonary infiltrates on chest roentgenogram and partial pressure of oxygen in the arterial blood/fraction of inspired oxygen (PaO
2/FIO
2) ratio of less than 300 requiring mechanical ventilation within 24 hours of the procedure. Because ALI is a relatively infrequent outcome, we defined a second outcome that may represent the lesser magnitude of the same pathophysiologic process as ALI. We thus defined severe hypoxemia as hypoxemia requiring an increase in FIO
2 by 0.15 on two consecutive measurements taken within 6 hours of each other, in 24 hours after pleurodesis. All other patients not fulfilling the criteria for ALI or severe hypoxemia were defined as a no complication group.
Variables
A list of variables/putative predictors of VATS talc pleurodesis-related ALI was formulated from discussions among authors after a review of the literature. These were divided into:
Indication and the type of malignancy were recorded based on the admission records, previous oncology clinic notes, and in-hospital oncology notes. Temperature was recorded as peak temperature within 24 hours before pleurodesis and within 24 hours after the procedure.
Oxygen saturation was calculated as a mean of the measurements taken within the 24-hour period before pleurodesis. The FIO 2 was recorded as a mean of the measurements taken in the 24-hour period before or after the pleurodesis. To allow comparison between patients receiving supplemental oxygen by the nasal cannula and those with the Venturi mask, it was assumed that each 1 L/min of supplemental oxygen by nasal cannula led to an increase in FIO 2 that was approximately equivalent to 0.03, up to 6 L/min [9, 10].
The presence of peripheral edema was ascertained by physical examination notes within 24 hours before pleurodesis. Complete blood count values were recorded from the last analysis preceding the pleurodesis, if obtained within 24 hours before the procedure. Data on liver and kidney function tests and albumin were recorded from the last analysis preceding the pleurodesis, if obtained within 7 days before the procedure. Performance status was determined from the last oncologist’s clinical note before pleurodesis. The volume of pleural effusion drained at the time of pleurodesis, the dose of talc used, and the presence of macroscopic pleural metastases were recorded from the intraoperative report. Length of stay was calculated as total number of days of hospital admission after the pleurodesis took place. Patients who died during the same hospital admission were excluded from analysis of length of stay.
Talc Preparation
Two preparations of talc were used in patients included in this study. Talc A was supplied by the Central Admixture Pharmacy Services Inc (Sterile talc, Chicago, IL) and talc B was supplied by Bryan Corporation (Sterile talc powder, Woburn, MA). Talc particles were measured using a Stereoscan 180 scanning microscope (Cambridge Instruments, Cambridge, MA). Samples were pressed to double-sided adhesive disks and covered with gold particles. Images were obtained with the accelerating voltage of 20 kV.
Statistical Analysis
To validate the choice of our variables, t test with the Welch correction was used for comparison of ALI and severe hypoxemia groups. Continuous variables were described as mean ± SD or medians and interquartile (IRQ) range. Using 
2 for discrete variables or one-way analysis of variance (ANOVA) for continuous variables in univariate analyses, we identified variables associated with ALI, severe hypoxemia, or either ALI or severe hypoxemia. Using variables thus identified, we then performed a forward stepwise multiple regression analysis. Variables included in this analysis were required to have a p 
0.15 in univariate analysis for either "ALI" or "severe hypoxemia." The Student t test was used to compare sizes of talc particles. SPSS 10.0 software (SPSS Inc, Chicago, IL) was used to analyze the data.
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Results |
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Demographic data of the study population are presented in Table 1. Two thirds of the patients were women, and 74 (88%) of 84 underwent the procedure to control a malignant effusion. Breast cancer and lung cancer were the most common malignancies in our patient population, followed by gastrointestinal cancers, lymphoma, genitourinary cancers, carcinoma of unknown primary, mesothelioma, and melanoma. Among 10 patients who had pleurodesis for nonmalignant indication, 4 had pneumothorax. The dose of talc that was used for pleurodesis could be established in 54 patients. The median dose (IQR) was 8 (5 to 10) g.
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For patients undergoing a palliative procedure, complications that worsen symptoms, prolong hospital stays, create additional morbidity, or cause mortality are clearly poor outcomes. As defined in our study, severe hypoxemia is not a commonly used outcome, and its influence on other better-known outcomes is not known. To validate the importance of this outcome, we analyzed the length of stay of patients with severe hypoxemia and compared them with lengths of stay of two other groups. Owing to the low number of 4 patients in the ALI group (excluding a patient who died postoperatively), the difference in median (IQR) length of stay between patients with ALI (29 [21 to 47] days), and either patients with severe hypoxemia (8 [7 to 14] days) or those without complications (3 [5 to 10] days) was not statistically significant (p = 0.20 and p = 0.17, respectively). There was a trend towards longer stay in patients with hypoxemia versus patients without complications, although this did not reach statistical significance (p = 0.0533).
Because patients may be placed on supplemental oxygen for a number of poorly defined clinical criteria, the FIO 2 may not be an accurate indicator of increased oxygen requirement. We therefore compared postoperative pulse oximetry oxyhemoglobin saturation (SpO 2) in the patients with severe hypoxemia and those without complications (Fig 1). Despite receiving higher FIO 2 (0.42% ± 0.13% versus 0.26% ± 0.04%, p < 0.0001), patients in the severe hypoxemia group had significantly lower SpO 2 (90.9% ± 1.0%) than patients without complications (95.1% ± 0.3%, p = 0.0005). Thus, the increased oxygen administration to the severe hypoxemia patients was based on a truly increased need and was not a finding based on a patient-triggered or nurse-triggered increase in the FIO 2.
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Comment |
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The cause of talc pleurodesis-related ALI is unknown. In their retrospective review of 89 cases of slurry and poudrage pleurodesis, Rehse and colleagues [6] did not find any predictors of the development of respiratory complications that they defined as dyspnea, hypoxia, reexpansion pulmonary edema, acute respiratory distress syndrome (ARDS), or death. These broad criteria led to "respiratory complications" in 48 (53.9%) of 89 patients. Smaller talc particles have been shown to be associated with more prominent gas exchange abnormalities and hypoxemia in a recent randomized trial [17].
In this review, we identified several conditions associated with the postoperative development of ALI and severe hypoxemia. Requirement for oxygen supplementation before pleurodesis was identified as a predictor of ALI or severe hypoxemia in multivariate analysis. Although it is difficult to explain directly this relationship from our retrospective data, we believe that poor general status, cachexia, presence of micrometastases, and drug-related or deconditioning-related atelectasis may all play a role in poor tolerance of the procedure by hypoxemic patients.
We also examined the effects of the intensity of SIRS on the incidence of ALI and severe hypoxemia. Intrapleural talc instillation is known to produce clinical symptoms of SIRS (fever, leukocytosis, tachycardia and tachypnea) with accompanying high concentrations of interleukin-8 and monocyte chemotactic protein-1 in pleural fluid [11, 18]. There was no relationship between preprocedure and postprocedure body temperature or white blood cell count and the development of hypoxemia/ALI in our patients. The oncologic patients representing the bulk of our study group had advanced malignancies that may have blunted the inflammatory response to pleurodesis.
Generalized problems with fluid transudation before pleurodesis, as suggested by the presence of peripheral edema on the physical examination, was the strongest independent predictor of ALI or severe hypoxemia in our study. Lack of association between the albumin level and the development of ALI or severe hypoxemia suggests that low oncotic pressure, which may promote increased lung edema formation, is not the sole cause of these complications (Table 2).
Hypoxemia or ALI were more likely to develop in patients who recently underwent chemotherapy. Several chemotherapeutic agents have been implicated in causing ARDS/ALI clinical picture [19–22]. The pathogenesis of this injury varies depending on a drug class, but may involve direct cytotoxic effect on pneumocytes, endothelial cells, or a cytokine-mediated response. Although data are conflicting on the direct effect of chemotherapy on perioperative outcomes [23, 24], we believe that the higher incidence of complications in patients who recently received chemotherapy may be merely a marker of an advanced malignancy and generally poor condition.
Acute lung injury was significantly more common in patients who had chest tube drainage before pleurodesis (4/13) than in patients who went into surgery without a chest tube (1/71). We believe that patient selection bias may have accounted for the difference in the observed rate of adverse outcomes. Patients who had chest tubes placed before pleurodesis were typically those with large effusions where reexpansion pulmonary edema was a concern, or patients who presented in extremis necessitating urgent chest tube placement.
It has been shown that size of talc particles may influence the systemic deposition of talc [16] and the prevalence of postprocedure hypoxemia [17]. Montes and colleagues [25] have also reported that the use of higher dose of talc produces higher systemic deposition of talc particles. Our patients were treated with talc obtained from two manufacturers. Scanning microscopy examination proved that these talc formulations differed significantly in terms of median size of the particles. Because of the retrospective character of this study, we were not able to ascertain in most patients the brand of talc preparation used. In those patients (28/84) in whom the brand of talc preparation could be determined, there was no difference in incidence of ALI and severe hypoxemia between the two preparations of talc.
Finally, 4 (80%) of 5 patients with ALI had right-sided procedures, and the fifth patient with ALI underwent bilateral pleurodesis (Table 2). This apparent predominance of complications after right-sided procedures was most likely due to the small number of patients included in the study. Others, however, have also reported a similar higher incidence of postprocedure ALI on the right side [5, 6, 8].
The main limitation of this study is its retrospective character, which may lead to lack of information on some putative factors decreasing the number of analyzable subjects. Specifically, the strong association of the talc particle size and dose, as suggested by several studies, and the development of ALI would have been better explored in a randomized prospective study [16, 17, 25].
Second, to increase the number of patients included in the study, we analyzed patients undergoing pleurodesis for malignant and benign indications together. We believed that most procedure-related and some patient-related factors are common to both these groups. However, we cannot rule out that the mechanism of talc pleurodesis-related ALI might be different between malignant and benign pleural effusions. Specifically, cachexia and chemotherapy may have affected patients with malignant, but not with benign, pleural effusions. We believed that performing a multiple regression analysis on the combined groups does not increase a likelihood of detecting a nonexisting relationship, although it may lead to not detecting a relationship when it truly exists.
Finally, because the list of putative predictors was prepared based on current limited knowledge of pathogenesis of talc-induced ALI, we cannot exclude that there are important factors that were omitted in our study.
In summary, ALI and severe hypoxemia are frequent complications of VATS talc pleurodesis and their cause is likely multifactorial. Patients requiring preoperative oxygen supplementation, who have received recent chemotherapy or have peripheral edema may be at increased risk for severe postoperative hypoxia. Although talc pleurodesis remains a highly effective treatment method for palliating malignant pleural effusions in patients who are relatively well compensated, alternative management of pleural effusions in patients with characteristics predisposing to ALI/severe hypoxemia may be warranted.
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This article has been cited by other articles:
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  A. V. Gonzalez, V. Bezwada, J. F. Beamis Jr, and A. G. Villanueva Lung Injury Following Thoracoscopic Talc Insufflation: Experience of a Single North American Center Chest, June 1, 2010; 137(6): 1375 - 1381. [Abstract] [Full Text] [PDF]
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 M. Liberman, A. Muzikansky, C. D. Wright, J. C. Wain, D. M. Donahue, J. S. Allan, H. A. Gaissert, C. R. Morse, D. J. Mathisen, and M. Lanuti Incidence and Risk Factors of Persistent Air Leak After Major Pulmonary Resection and Use of Chemical Pleurodesis Ann. Thorac. Surg., March 1, 2010; 89(3): 891 - 898. [Abstract] [Full Text] [PDF]
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R. D. Baron, R. Milton, and J. A.C. Thorpe Pleurodesis Using Small Talc Particles Results in an Unacceptably High Rate of Acute Lung Injury and Hypoxia Ann. Thorac. Surg., December 1, 2007; 84(6): 2136 - 2136. [Full Text] [PDF]
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