Multidisciplinary Management of Hepatic Hydrothorax in 2020: an Evidence-Based Review and Guidance

DR. BUBU A BANINI (Orcid ID : 0000-0002-2972-9263)

Article type : Review

Multidisciplinary Management of Hepatic Hydrothorax in 2020: An Evidence-Based Review and Guidance

Bubu A Banini1, Yahya Alwatari2, Madeline Stovall2, Nathan Ogden3, Evgeni Gershman4, Rachit D Shah2, Brian J Strife3, Samira Shojaee4, Richard K Sterling1

Author Institutional Affiliations: 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA 2. Division of Cardiothoracic Surgery, Department of Surgery, Virginia Commonwealth University, Richmond VA, USA. 3. Division of Interventional Radiology, Department of Radiology, Virginia Commonwealth University, Richmond, VA, USA. 4. Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

Author emails: Bubu A Banini [email protected] Yahya Alwatari [email protected] Madeline Stovall [email protected] Nathan Ogden [email protected] Evgeni Gershman [email protected] This article has been accepted for publication and undergone full peer review but has not been

throughAccepted Article the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/HEP.31434 This article is protected by copyright. All rights reserved Rachit D Shah [email protected] Brian J Strife [email protected] Samira Shojaee [email protected] Richard K Sterling [email protected]

Keywords: cirrhosis, pleural effusion, transjugular intrahepatic portosystemic shunt, indwelling pulmonary catheter, pleurodesis Accepted Article

This article is protected by copyright. All rights reserved Footnotes Page Corresponding author: Richard K Sterling, Division of Gastroenterology and Hepatology, Department of Internal Medicine, P.O. Box 980341, Richmond, VA, 23298, USA. [email protected]

List of abbreviations HH Hepatic hydrothorax SBEM Spontaneous bacterial empyema SBPL Spontaneous bacterial pleuritis LDH Lactate dehydrogenase SPAG Serum pleural fluid albumin gradient SAAG Serum ascites albumin gradient CT Computed tomography PMN Polymorphonuclear VATS Video-assisted thoracic surgery HE Hepatic encephalopathy RAA Renin angiotensin aldosterone HRS Hepatorenal syndrome TIPS Transjugular intrahepatic portosystemic shunt CTP Child-Turcotte-Pugh MELD Model for end-stage liver disease CPAP Continuous positive airway pressure IPC Indwelling pleural catheter MPE Malignant pleural effusion

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This article is protected by copyright. All rights reserved Abstract Hepatic hydrothorax is the formation of transudative pleural effusion as a consequence of portal hypertension. Only a minority of cases resolve after sodium restriction and diuretics. Despite the relatively low incidence of 5-15% among patients with cirrhotic portal hypertension, the high morbidity and serious clinical implications associated with hepatic hydrothorax necessitate a well- defined treatment strategy to guide patient care. Management is typically multidisciplinary, involving hepatologists, interventional pulmonologists, interventional radiologists, surgeons, and other specialties. In this manuscript, we assemble a multidisciplinary team to critically review the available literature and provide an evidence-based guidance for management of hepatic hydrothorax.

Introduction Hepatic hydrothorax (HH) is the presence of pleural effusion in a patient with cirrhosis without evidence of other cardiopulmonary disease. It occurs in 5-15% of patients with cirrhotic portal hypertension and is associated with high mortality (1, 2). Most patients present when the effusion is large, resulting in shortness of breath and orthopnea (1, 3). The exact mechanism by which HH develops is not fully understood, however, the prevailing theory is that peritoneal cavity ascitic fluid passes directly into the pleural cavity via diaphragmatic defects. Cirrhotic patients who develop HH are more likely to have acute kidney injury (AKI), hepatic encephalopathy (HE), septic shock and higher mortality. HH is notoriously difficult to treat. In this report, we review the pathophysiology, clinical presentation and diagnosis of HH and provide a practical and multidisciplinary treatment strategies comprising medical management, interventional radiology, pulmonology, and surgery. The management strategies are structured into 5 sections aimed at 1) Reduction of ascites fluid production; 2) Prevention of fluid transfer into pleural space; 3) Removal of fluid from pleural space; 4) Obliteration of pleural space; and 5) Liver transplantation.

Pathophysiology Cirrhotic ascites in the peritoneal space occurs as a result of portal hypertension, vasodilation of splanchnic and systemic arteries, and neurohormonal activation resulting in decreased sodium and water excretion (4, 5). It has been proposed that the combination of positive intraabdominal pressure and negative intrathoracic pressure facilitates movement of fluid from the peritoneal cavity into the pleural space through defects in the diaphragm (6). There are four types of diaphragmatic defects which can occur singly or in combination: type I, no obvious defect (9.1-31.7%); type II, blebs Accepted Article

This article is protected by copyright. All rights reserved on the diaphragm (36.4-41.3%); type III, broken defects or fenestrations in the diaphragm (20.6%- 72.7%); and type IV, multiple gaps in the diaphragm (1.6-9.1%) (5, 7). Due to the left side of the diaphragm being more muscular and thicker than the right, most cases of HH are right sided (59- 80%), with left sided (12-17%) and bilateral (8-24%) HH being less common (1, 8, 9).

Clinical presentation Most patients with HH have ascites, portal hypertension and stigmata of end-stage liver disease. The presence of symptoms associated with HH depends on the volume of the effusion, rate of fluid accumulation, and the presence of another cardiopulmonary disease (10). The most common presenting symptoms are dyspnea at rest (34%), cough (22%), nausea (11%) and pleuritic chest pain (8%) (1). In rare cases, HH can present with life-threatening acute tension hydrothorax (11). However, some patients are asymptomatic and HH is an incidental finding on imaging obtained for other reasons. Pleural space infection, referred to as spontaneous bacterial empyema (SBEM) or spontaneous bacterial pleuritis (SBPL), is an important potential complication which can occur as a result of bacterial peritonitis migrating into the pleural space or from invasion of microbes through pleural chest tubes, catheters or other thoracic instrumentation (12-14).

Diagnosis Diagnostic evaluation of HH should be pursued in patients with cirrhotic portal hypertension who present with pleural effusion confirmed on radiographic imaging. Since HH is a diagnosis of exclusion, other potential etiologies of pleural effusion including cardiac or pulmonary disease should be excluded. The workup generally includes echocardiogram to assess cardiac function and rule cardiac causes of pleural effusion; chest computed tomography (CT) to exclude mediastinal, pulmonary, or pleural lesions or malignancies; and abdominal ultrasound to evaluate for hepatic mass lesions, hepatic and portal venous flow, and ascites. Pleural fluid should be sampled via thoracentesis and sent for cell count, differential, gram stain, bacterial culture, protein, albumin, lactate dehydrogenase (LDH), fluid pH and bilirubin concentration. Similar to ascites, HH has transudative properties as determined through Light’s criteria (Table 1) (1, 3, 10, 15, 16). Total protein and albumin levels may be marginally higher in pleural fluid than in ascitic fluid due to greater efficiency of water absorption by the pleural surface (3, 10, 17). Pleural fluid to serum bilirubin ratio is usually <0.6 (18, 19). Some patients may be classified as having exudates based on Light’s criteria, when they would be expected to have transudates Accepted Article

This article is protected by copyright. All rights reserved based on clinical grounds. This can occur when the patient is on diuretics, resulting in contraction of extracellular fluid volume and increasing pleural fluid protein and LDH concentration. In such cases, the serum-pleural fluid albumin gradient (SPAG), analogous to the serum-ascites albumin gradient (SAAG), should be calculated, with a value >1.1 g/dL consistent with a transudative process (20-22). SBPL is typically diagnosed if pleural fluid polymorphonuclear (PMN) cell count is greater than 500 cells/µl, or greater than 250 cells/µl with positive culture, having excluded a parapneumonic effusion or empyema (Table 1) (14, 23-28). When the etiology of HH is uncertain, other analyses of pleural fluid such as polymerase chain reaction for mycobacterium, amylase concentration for pancreatic pleural effusion, cytology to rule out malignancy, and triglyceride level to assess chylothorax can be considered (8, 9, 12, 29, 30). When the presentation of HH is atypical, such as with a left-sided pleural effusion or in the absence of ascites, scintigraphic study with intraperitoneal injection of 99mTc-sulphur colloid or 99mTc-human serum albumin can be performed to confirm connections between the peritoneal and pleural cavities (20). Although not offered in all centers, scintigraphy can aid in the diagnosis as lack of migration of radioisotope into the pleural cavity suggests an alternate cause of pleural effusion (10, 17, 31). HH can also be diagnosed through direct visualization of diaphragmatic defects by Video-Assisted Thoracic Surgery (VATS), although this procedure is invasive and should be performed only if the diagnosis remains unclear or there is a plan to repair the defect. (5, 10).

Multidisciplinary management of hepatic hydrothorax 1. Reduction of ascitic fluid production a. Medical management i. Dietary sodium The first line treatment for HH relies on dietary sodium restriction (< 88mEq or 2g per day) and diuretic use (Figure 1 and Table 2), which result in a net negative sodium balance, decrease ascitic fluid production and ultimately reduce fluid movement from the peritoneal cavity to the pleural space (32). While adherence to low sodium diet has not been examined specifically in HH patients, several studies have shown poor patient adherence to dietary recommendations in cirrhotic patients with ascites. Morando et al (33) showed poor adherence to dietary sodium restriction among 120 cirrhotic patients with ascites, with only 37 patients following the recommended diet. Their study also showed that patients on low sodium diet had a 20% reduction in daily caloric intake, compared to those not adherent to the diet, suggesting that sodium restriction may lead to further energy and Accepted Article

This article is protected by copyright. All rights reserved nutritional deficiency in an already nutritionally vulnerable population (21). Therefore, it is not only important to advise sodium restriction in these patients, but also to emphasize consumption of high energy foods that are especially rich in protein.

ii. Diuretics Low sodium diet alone is usually insufficient to significantly reduce HH and prevent fluid re- accumulation, hence a combination of loop diuretics and an aldosterone receptor antagonist may be needed. Co-administration of oral furosemide 40mg and spironolactone 100mg daily (referred to as Step 1) is preferred, with goal fluid weight loss of 0.5 to 1.0 kg/day without electrolyte disturbance or renal dysfunction. Body weight, blood pressure, orthostatic symptoms, serum electrolyte and kidney function should be monitored. Inadequate weight loss should trigger assessment of a random spot urine sodium/ potassium ratio (34); a ratio ≥ 1 indicates that the patient is on adequate diuretics but is likely consuming more than the recommended dietary sodium, hence adherence to low sodium diet (< 2g per day) should be reinforced (34). Patients with inadequate weight loss and urine sodium/potassium ratio < 1 should have their diuretics up-titrated in a stepwise fashion to a maximum of furosemide 160mg and spironolactone 400mg daily (Step 4) in one- or two-week intervals in the absence of any contraindications until a stable and effective regimen is achieved. About 20-30% of cirrhotic patients with HH have persistent or recurrent pleural effusion despite dietary sodium restriction and diuretics and are considered as having diuretic-resistant HH (3, 35, 36). In certain cases, aggressive diuresis can be limited by electrolyte imbalance, renal insufficiency, hemodynamic instability, or precipitation of HE; these patients are considered as having diuretic-intractable HH (35). Both diuretic-resistant and diuretic-intractable HH should prompt consideration of other therapeutic modalities (Table 2).

iii. Other medical therapy: splanchnic and peripheral vasoconstrictors Medications targeting various steps in the formation of ascites may also have utility in the management of HH but should be used with caution. There are currently no large studies or randomized trials that have examined these medications in HH, and evidence is largely limited to case reports or case series (37-40). Splanchnic and peripheral vasoconstrictors including octreotide, midodrine, and terlipressin increase effective arterial volume and decrease activation of the renin– angiotensin-aldosterone (RAA) system, increasing renal sodium excretion. Accepted Article

This article is protected by copyright. All rights reserved Octreotide is a somatostatin analog that directly inhibits the RAA axis, improving effective renal plasma flow and natriuresis (41). In patients with renal failure, however, octreotide alone may have adverse effects on renal function hence its combination with the α-adrenergic agonist midodrine is recommended (37-40). In addition, octreotide can cause pulmonary and cardiac side-effects and is prone to tacchyphylaxis (42, 43) hence should be used only after a thorough assessment of the risk/benefit ratio. Terlipressin is a vasopressin analog used in the management of hepatorenal syndrome (HRS). In a patient with hepatitis B and D virus-associated cirrhosis with HH and HRS refractory to thoracentesis and octreotide, terlipressin and albumin administered for 5 days led to improvement of central volume and resolution of both HRS and HH (44). Further studies are needed to examine the role of splanchnic and peripheral vasoconstrictors in the management of HH. b. Transjugular intrahepatic portosystemic shunt (TIPS) Fluid accumulation in the setting of cirrhotic portal hypertension occurs when the portosystemic gradient (difference between the portal venous and right hepatic venous or inferior vena cava pressure) becomes significantly elevated, typically greater than 12 mmHg (normal ≤ 5 mmHg) (45). TIPS creation relieves portal hypertension by reducing the portosystemic gradient. Although TIPS does not treat the underlying cause of portal hypertension, reduction of the portosystemic gradient does effectively treat many of the complications of portal hypertension including acute and recurrent variceal bleeding, refractory ascites and refractory HH. The workup for TIPS includes comprehensive laboratory assessment (liver, kidney, electrolytes, coagulation), calculation of the Model for End-stage Liver Disease (MELD) score, evaluation of cardiac function with echocardiogram, and radiologic imaging to assess the hepatic parenchyma and vasculature. Often quoted contraindications to TIPS include bacteremia, heart failure, severe tricuspid regurgitation, pulmonary hypertension, uncontrolled systemic infection, untreated biliary obstruction, uncontrolled HE, uncorrectable coagulopathy, portal vein thrombosis, and underlying liver masses (46-48). A classic TIPS creates a low resistance intrahepatic shunt between a branch of the portal vein and a hepatic vein using a stent. A functioning TIPS should reduce the portosystemic gradient to less than 12mmHg (some may opt for a lower goal) (49). Many variations in TIPS technique exist, whether by operator choice or dictated by the patient’s underlying anatomy (50). Accepted Article

This article is protected by copyright. All rights reserved Studies directly examining the benefit of TIPS in the treatment of HH are limited, however, most series have found response rates between 70-80%. A retrospective study of 40 patients with Child-Turcotte-Pugh (CTP) class B or C cirrhosis and refractory HH found that 82% of patients who underwent TIPS had improvement of hydrothorax, and 71% had complete resolution (51). The same study found 1-year survival post-TIPS was 64%, although 50% of patients developed shunt insufficiency within 7 +/- 9 months. Shunt revision resulted in a secondary response rate of 82%. A recent meta-analysis which included 6 studies of TIPS for refractory HH (total of 198 patients) found the procedure relieved HH in 73% (complete relief 56%; partial relief 17%). The mean duration of follow-up was 10 months (52). Notably, most patients in these studies received uncovered or bare stents during TIPS creation, as covered stent grafts were not available for much of the study periods. Modern stent grafts, which are now considered the standard of care for TIPS creation, have demonstrated superior patency, improved symptom control, and reduced need for re-intervention when compared with uncovered stents (53-56). TIPS creation carries a low risk (2-4%) of major and minor immediate peri-procedural complications. Following a successful TIPS, a significant percentage of patients can be expected to develop medically controlled HE (15 to 25%) (57-60). In a small subset of patients, incapacitating post-TIPS encephalopathy can occur, necessitating shunt reduction or occlusion (61, 62). The incidence of post-TIPS encephalopathy can be minimized by dilating the shunt to 8 mm rather than 10 mm (63). Late complications include shunt stenosis or thrombosis requiring revision, although the incidence of these complications is decreasing with widespread adoption of covered stents over uncovered stents (53, 64). Risk of mortality after TIPS can be predicted by assessing one of many patient factors. In the elective setting, patients undergoing TIPS with MELD scores ≤ 17 have significantly improved survival at 3 months compared to those with MELD scores > 17 (50). Careful consideration should be given when offering TIPS to patients with elevated MELD scores. In addition, CTP class C status, presence of pre-TIPS encephalopathy, and serum bilirubin level >3mg/dl have been shown to independently predict post-TIPS mortality (65).

2. Prevention of fluid transfer to pleural space a. Continuous positive airway pressure (CPAP) CPAP increases air pressure in the thoracic cavity, thus decreasing the pressure gradient between the peritoneal and pleural cavities and decreasing fluid migration into the pleural space. In a patient with hepatitis B virus-associated cirrhosis who developed HH refractory to dietary sodium Accepted Article

This article is protected by copyright. All rights reserved restriction and diuretics, nasal CPAP during sleep resulted in improvement of HH (66). CPAP has also been used in conjunction with pleurodesis to enhance fluid movement from the pleural to the peritoneal space and allow time to achieve pleurodesis (67). It should be noted that cirrhotic patients with HE may not be amenable to a trial of CPAP given the increased risk of aspiration. Further studies are required to examine the utility of CPAP alone and in combination with other techniques for managing HH. b. Repair of diaphragmatic defects The surgical closure of transdiaphragmatic defects prevents unidirectional shifting of fluid into the thoracic cavity from the abdomen but is associated with high mortality in those with severely decompensated cirrhosis (CTP class C). During a median follow-up of 20 months after closure of diaphragmatic defects, the survival of patients with CTP class C (n=15) was worse at 53%, compared to those with CTP A (n=12) or CTP B (n=36) who had 80-85% survival (7). Surgical repair of diaphragmatic defects can be considered for management of refractory HH in a patient who is not a TIPS candidate (Figure 1) but otherwise a good surgical candidate (low MELD). The procedure can be performed via VATS or open thoracotomy with or without mesh, although open thoracotomy is rarely performed given significant associated morbidity and mortality. Abdominal approach via laparoscopic repair can also be considered. The type of diaphragmatic defect may influence the repair strategy. In a recent retrospective study, patients with type I defect were treated with mesh covering only; while those with types II, III or IV defects were treated with mesh with or without suturing (7). Diaphragmatic defect closure is limited by invasiveness and the need for general anesthesia with endotracheal intubation. Moreover, due to the large size of the diaphragm, visualization of diaphragm defects during VATS can be as low as 12%, thus underestimating the presence and number of defect (68). One- and three-month mortalities after defect closure have been reported to be 9.5% and 25.4%, respectively, due to septic shock, acute renal injury, gastrointestinal bleeding, HE and bowel ischemia (7). Due to these limitations, diaphragmatic defects closure is performed only in selected patients who have failed or have contraindication to other treatment strategies (Figure 1).

3. Removal of fluid from pleural space a. Repeated thoracentesis Accepted Article

This article is protected by copyright. All rights reserved In the setting of refractory HH in patients who are not TIPS or transplant candidates, or in patients awaiting transplant, repeated thoracentesis is considered a standard mode of symptom management (Figure 1). In a single center retrospective case-control study comparative study, repeated thoracentesis resulted in higher complication rate in the HH group compared to the non-HH group, with incremental rise of complications as the number of thoracentesis increased (13). On multivariable analysis, thrombocytopenia (platelet count <50,000) and rise in MELD score were independent predictors of hemothorax. Having a previous complication significantly increased the risk of future complications (OR=15; p<0.001) (13). b. Chest tube placement Multiple case series have shown that chest tube placement is associated with a very high complication rate (69). A retrospective study by Liu et al showed that chest tube for HH resulted in up to 88% complication rate including infectious complications, renal failure and electrolyte balance, with a 33% mortality rate secondary to empyema and sepsis (70). In a recent retrospective study of 140,573 with liver cirrhosis, among whom 1981 patients had HH requiring thoracentesis (1776) or chest tube (205), hospital length of stay and mortality for chest tube patients was twice higher than for thoracentesis patients (71). For these reasons, the AASLD Guidelines state that “Chest tube insertion is contraindicated in patients with hepatic hydrothorax” (32). Chest tube however, may be indicated in the management of infected pleural fluid (Table 1), preferably with smaller bore (< 20F) drain. The details of chest tube placement and management are beyond the scope of this review but could be of interest to the reader when infected pleural fluid is encountered (72-74). c. Indwelling pleural catheter (IPC) placement An IPC is a fenestrated catheter that is inserted and tunneled percutaneously into the pleural space to allow for intermittent drainage and facilitate pleurodesis. In the last decade, IPCs showed great palliative benefit in the management of symptomatic malignant pleural effusion (MPE). In 2017, the United States FDA approved the use of IPCs in non-MPE refractory to optimal medical management. Several studies demonstrate spontaneous pleurodesis after IPC placement, however, majority of patients in these studies also received liver transplant during the period between IPC placement and pleurodesis (75-77). Thus, the rate of spontaneous pleurodesis attributed to IPCs may be highly overestimated. In a prospective study of 24 patients who received IPC placement over Accepted Article

This article is protected by copyright. All rights reserved a 5-year period, successful pleurodesis and subsequent catheter removal occurred in 8 patients (33%), with mean time to pleurodesis of 131.8 days (75). In a retrospective review of 62 patients who underwent IPC placement, 33 (53%) were done as a bridge to liver transplant, 24 (39%) for palliation, and 5 for unclear intent (76). Complications were recorded in 22 (33%), with the most common complication being empyema. Nine patients (14.5%) had spontaneous pleurodesis over a mean time period of 180 days, all of them having received liver transplant. Finally, in a recent multicenter retrospective study of 79 patients from 8 medical centers, IPCs were placed in 21 (27%) as bridge to liver transplant, and the remaining 58 (73%) for palliation (77). Eight patients (10%) had pleural space infection; 2 (2.5%) died due to catheter-related empyema and sepsis. In this cohort, older age was predictive of mortality on multivariable analysis (77). Spontaneous pleurodesis with subsequent IPC removal occurred in 22 (28%) with median time to pleurodesis of 55 days; about half of these patients had received liver transplant in the interim. While IPCs appear promising for palliative management of symptomatic HH, their utility as a bridge to liver transplant needs to be further investigated in large multicenter prospective trials. Importantly, patient-centric outcomes such as quality of life, dyspnea score and quality adjusted life years should be the focus of further studies. d. Pleurovenous shunt A pleurovenous shunt is an indwelling catheter which shunts fluid directly from the pleural cavity into the systemic venous circulation. Although these catheters play a role in management of MPE, there has been relatively little study on their role in the management of refractory HH or other types of non-MPE. The most common catheter utilized is the Denver shunt, which was originally designed as a peritoneovenous shunt and is manually pumped at prescribed intervals. One published series of 12 patients with non-MPE, including 6 with HH, who underwent pleurovenous shunting found 100% clinical success (78). None of the patients required any further treatment for pleural effusion, although the follow-up period ranged from 1-40 months. In the 6 patients with HH, no shunt-related complications were experienced. One patient died 4 weeks after implantation due to liver failure. This limited series did not examine risk factors nor stratify the patients using any objective system (78). No randomized controlled trials have been performed which study the efficacy of pleurovenous shunting in non-MPE. No direct comparison of pleurovenous shunting to other forms Accepted Article

4. Obliteration of pleural space a. Surgical Pleurodesis Surgical pleurodesis is a procedure in which the space between the parietal and visceral pleura is obliterated using chemical irritant or mechanical abrasion to induce fibrosis and thus prevent recurrent effusion. Pleurodesis can be considered in carefully selected patients who are not candidates for TIPS or who are refractory to TIPS (Figure 1) and can serve as a bridge to liver transplant. Although pleurodesis can be achieved by chemical or mechanical methods, the latter is rarely used in HH patients due to underlying coagulopathy and high risk of bleeding. Case series of chemical pleurodesis via thoracoscopic insufflation of chemical irritant or slurry fusion via a thoracostomy tube have been reported in the literature. These studies however suffer from small numbers and significant selection bias and lack generalizability (Supplemental table 1). There are also small case series reporting thermal methods and argon beam in achieving pleurodesis (79). In one study of 21 patients, VATS and talc insufflation (13 patients) was more effective than talc slurry (8 patients) with success rate of 77% versus 37%, respectively (80). One meta-analysis of 180 patients from 20 case-reports and 13 case-series on the use of pleurodesis in HH demonstrated a pooled complete response rate of 72 % and complication rate of 82 % (81). This meta-analysis however included different methods of pleurodesis including mechanical and chemical with different pleurodesing agents (talc, Tetracycline, Minocycline among others) in a heterogeneous population with varying follow up period. Combination of chemical pleurodesis with suture repair of diaphragmatic defects or with mechanical pleurodesis can increase the response rate (67, 82). In addition, pre-operative thoracentesis/paracentesis, CPAP and somatostatin can increase the success rate of the pleurodesis (15). In a cohort of 11 patients with HH followed for a median of 16 weeks (range 2-52) after pleurodesis, survival was lower in those with CTP C compared to those with CTP B (22% vs. 50%) (83). Multiple pockets of pleural fluid may remain after pleurodesis that may be difficult to manage.

5. Liver transplantation Liver transplant is the definitive treatment for refractory HH. Patients with diuretic-resistant or diuretic-intractable HH, history of SBPL, or high MELD (>15) should be referred for evaluation at a Accepted Article

This article is protected by copyright. All rights reserved liver transplant center. Given the lack of evidence that HH confers excess waitlist mortality, there is no MELD exception points for this patient population. Post-transplant outcomes for patients with HH are similar to those of other liver transplant patients, with survival of 70% at 8 years (84, 85). A recent study that examined over 3,000 patients with cirrhosis and pleural effusion showed 30-day, 90-day, 1-year, and 3-year mortalities of 20.1%, 40.2%, 59.1%, and 75.9%, respectively (2). In the study, liver transplantation was the most important factor in determining both short- and long- term mortality. The 1-3 year mortality was 77.5% in the non- transplant group and 21.7% in the liver transplant group (3-year HR for transplantation: 0.17, 95% CI 0.11- 0.26, P < 0.001) (2). In another study of 41 cirrhotic patients with HH undergoing serial thoracentesis (n=11), pigtail drainage (n=16), surgery (n=10) or liver transplantation (n=4), the 12-month mortality rate was 18.2%, 87.5%, 70%, and 0%, respectively, for each modality (86). One obvious limitation of this study is the small number of patients in each arm, however, the considerably lower mortality of patients in the transplant arm compared to the other groups is nonetheless striking and underscores the potentially curative role of transplant in this disease entity.

Summary HH occurs in 5-15% of cirrhotic patients and carries a high morbidity and mortality rate. The current prevailing theory is that HH forms as a result of passage of ascitic fluid from the peritoneal cavity into the negatively pressured pleural cavity through diaphragmatic defects. Although HH is predominantly right-sided, left sided and bilateral effusions are not uncommon. Pleural fluid analysis is the cornerstone of HH diagnosis; the fluid should be sampled by thoracentesis and sent for analysis of LDH, fluid pH, protein, albumin, cell count with differential, gram stain, culture. First line of therapy for HH is medical management with low sodium diet and diuretics (Figure 1). However, roughly one-fourth of patients fail medical management and develop refractory HH. A comprehensive and multidisciplinary approach to management of HH should be formulated for any patient with refractory HH, and referral for liver transplant evaluation should be initiated. For patients who meet criteria for liver transplant listing and have an expected waitlist time less than three months, repeat paracentesis and thoracentesis should be used as a bridge to transplant. For patients with HH awaiting liver transplant with an anticipated waitlist time greater than 3 months, or for those who are not candidates for transplant, a variety of interventional radiology, pulmonary and surgical management options can be considered (Figure 1). TIPS placement should be performed in eligible patients. In those who are not eligible for TIPS, IPCs or pleurodesis with possible repair of Accepted Article

This article is protected by copyright. All rights reserved diaphragmatic defects can be considered. HH management is complex and necessitates a multidisciplinary and stream-lined approach to deliver the best patient outcomes.

Figure legend Figure 1. Treatment algorithm for hepatic hydrothorax. Abbreviations: CPAP, continuous positive airway pressure; IPC, indwelling pulmonary catheter; TIPS, transjugular intrahepatic portosystemic shunt; VATS, video-assisted thoracoscopic surgery

Accepted Article

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This article is protected by copyright. All rights reserved 54. Maleux G, Perez-Gutierrez NA, Evrard S, Mroue A, Le Moine O, Laleman W, Nevens F. Covered stents are better than uncovered stents for transjugular intrahepatic portosystemic shunts in cirrhotic patients with refractory ascites: a retrospective cohort study. Acta Gastroenterol Belg 2010;73:336-341. 55. Wang L, Xiao Z, Yue Z, Zhao H, Fan Z, Zhao M, He F, et al. Efficacy of covered and bare stent in TIPS for cirrhotic portal hypertension: A single-center randomized trial. Sci Rep 2016;6:21011. 56. Bercu ZL, Fischman AM, Kim E, Nowakowski FS, Patel RS, Schiano TD, Chang CY, et al. TIPS for refractory ascites: a 6-year single-center experience with expanded polytetrafluoroethylene-covered stent- grafts. AJR Am J Roentgenol 2015;204:654-661. 57. Sanyal AJ, Freedman AM, Shiffman ML, Purdum PP, 3rd, Luketic VA, Cheatham AK. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology 1994;20:46-55. 58. Riggio O, Merlli M, Pedretti G, Servi R, Meddi P, Lionetti R, Rossi P, et al. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Incidence and risk factors. Dig Dis Sci 1996;41:578-584. 59. Martinet JP, Fenyves D, Legault L, Roy L, Dufresne MP, Spahr L, Lafortune M, et al. Treatment of refractory ascites using transjugular intrahepatic portosystemic shunt (TIPS): a caution. Dig Dis Sci 1997;42:161-166. 60. Sanyal AJ, Freedman AM, Luketic VA, Purdum PP, 3rd, Shiffman ML, Cole PE, Tisnado J, et al. Transjugular intrahepatic portosystemic shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. A randomized, controlled trial. Ann Intern Med 1997;126:849-857. 61. Rowley MW, Choi M, Chen S, Hirsch K, Seetharam AB. Refractory Hepatic Encephalopathy After Elective Transjugular Intrahepatic Portosystemic Shunt: Risk Factors and Outcomes with Revision. Cardiovasc Intervent Radiol 2018;41:1765-1772. 62. Kochar N, Tripathi D, Ireland H, Redhead DN, Hayes PC. Transjugular intrahepatic portosystemic stent shunt (TIPSS) modification in the management of post-TIPSS refractory hepatic encephalopathy. Gut 2006;55:1617-1623. 63. Tang Y, Zheng S, Yang J, Bao W, Yang L, Li Y, Xu Y, et al. Use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative in transjugular intrahepatic portosystemic shunting: A retrospective study of 182 cirrhotic portal hypertension patients. Medicine (Baltimore) 2017;96:e8678. Accepted Article

This article is protected by copyright. All rights reserved 64. Bureau C, Garcia Pagan JC, Layrargues GP, Metivier S, Bellot P, Perreault P, Otal P, et al. Patency of stents covered with polytetrafluoroethylene in patients treated by transjugular intrahepatic portosystemic shunts: long-term results of a randomized multicentre study. Liver Int 2007;27:742-747. 65. Hung ML, Lee EW. Role of Transjugular Intrahepatic Portosystemic Shunt in the Management of Portal Hypertension: Review and Update of the Literature. Clin Liver Dis 2019;23:737-754. 66. Takahashi K, Chin K, Sumi K, Nakamura T, Matsumoto H, Niimi A, Ikai I, et al. Resistant hepatic hydrothorax: a successful case with treatment by nCPAP. Respir Med 2005;99:262-264. 67. Northup PG, Harmon RC, Pruett TL, Schenk WG, 3rd, Daniel TM, Berg CL. Mechanical pleurodesis aided by peritoneal drainage: procedure for hepatic hydrothorax. Ann Thorac Surg 2009;87:245-250. 68. Cerfolio RJ, Bryant AS. Efficacy of video-assisted thoracoscopic surgery with talc pleurodesis for porous diaphragm syndrome in patients with refractory hepatic hydrothorax. Ann Thorac Surg 2006;82:457- 459. 69. Orman ES, Lok AS. Outcomes of patients with chest tube insertion for hepatic hydrothorax. Hepatol Int 2009;3:582-586. 70. Liu LU, Haddadin HA, Bodian CA, Sigal SH, Korman JD, Bodenheimer HC, Jr., Schiano TD. Outcome analysis of cirrhotic patients undergoing chest tube placement. Chest 2004;126:142-148. 71. Ridha A, Al-Abboodi Y, Fasullo M. The Outcome of Thoracentesis versus Chest Tube Placement for Hepatic Hydrothorax in Patients with Cirrhosis: A Nationwide Analysis of the National Inpatient Sample. Gastroenterol Res Pract 2017;2017:5872068. 72. Laws D, Neville E, Duffy J, Pleural Diseases Group SoCCBTS. BTS guidelines for the insertion of a chest drain. Thorax 2003;58 Suppl 2:ii53-59. 73. Filosso PL, Guerrera F, Sandri A, Roffinella M, Solidoro P, Ruffini E, Oliaro A. Errors and Complications in Chest Tube Placement. Thorac Surg Clin 2017;27:57-67. 74. Chen CH, Shih CM, Chou JW, Liu YH, Hang LW, Hsia TC, Hsu WH, et al. Outcome predictors of cirrhotic patients with spontaneous bacterial empyema. Liver Int 2011;31:417-424. 75. Chen A, Massoni J, Jung D, Crippin J. Indwelling Tunneled Pleural Catheters for the Management of Hepatic Hydrothorax. A Pilot Study. Ann Am Thorac Soc 2016;13:862-866. 76. Kniese C, Diab K, Ghabril M, Bosslet G. Indwelling Pleural Catheters in Hepatic Hydrothorax: A Single- Center Series of Outcomes and Complications. Chest 2019;155:307-314. Accepted Article

This article is protected by copyright. All rights reserved 77. Shojaee S, Rahman N, Haas K, Kern R, Leise M, Alnijoumi M, Lamb C, et al. Indwelling Tunneled Pleural Catheters for Refractory Hepatic Hydrothorax in Patients With Cirrhosis: A Multicenter Study. Chest 2019;155:546-553. 78. Artemiou O, Marta GM, Klepetko W, Wolner E, Muller MR. Pleurovenous shunting in the treatment of nonmalignant pleural effusion. Ann Thorac Surg 2003;76:231-233. 79. Takayama T, Kurokawa Y, Kaiwa Y, Ansai M, Chiba T, Inoue T, Nakui M, et al. A new technique of thoracoscopic pleurodesis for refractory hepatic hydrothorax. Surg Endosc 2004;18:140-143. 80. Assouad J, Barthes Fle P, Shaker W, Souilamas R, Riquet M. Recurrent pleural effusion complicating liver cirrhosis. Ann Thorac Surg 2003;75:986-989. 81. Hou F, Qi X, Guo X. Effectiveness and Safety of Pleurodesis for Hepatic Hydrothorax: A Systematic Review and Meta-Analysis. Dig Dis Sci 2016;61:3321-3334. 82. Milanez de Campos JR, Filho LO, de Campos Werebe E, Sette H, Jr., Fernandez A, Filomeno LT, Jatene FB. Thoracoscopy and talc poudrage in the management of hepatic hydrothorax. Chest 2000;118:13-17. 83. Lee WJ, Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, Jeon WK, et al. Chemical pleurodesis for the management of refractory hepatic hydrothorax in patients with decompensated liver cirrhosis. Korean J Hepatol 2011;17:292-298. 84. Xiol X, Tremosa G, Castellote J, Gornals J, Lama C, Lopez C, Figueras J. Liver transplantation in patients with hepatic hydrothorax. Transpl Int 2005;18:672-675. 85. Serste T, Moreno C, Francoz C, Razek WA, Paugham C, Belghitti J, Valla D, et al. The impact of preoperative hepatic hydrothorax on the outcome of adult liver transplantation. Eur J Gastroenterol Hepatol 2010;22:207-212. 86. Yoon JH, Kim HJ, Jun CH, Cho SB, Jung Y, Choi SK. Various Treatment Modalities in Hepatic Hydrothorax: What Is Safe and Effective? Yonsei Med J 2019;60:944-951. Accepted Article

This article is protected by copyright. All rights reserved Table 1. Pleural fluid characteristics and management for uncomplicated hepatic hydrothorax, spontaneous bacterial pleuritis, uncomplicated and complicated parapneumonic effusion and empyema

Characteristic Hepatic Spontaneous Uncomplicated Complicated Empyema or feature of hydrothorax bacterial parapneumonic parapneumonic pleural fluid1 (HH) pleuritis effusion (UPPE) effusion (CPPE) (SBPL)2

Definition Pleural effusion Infected HH; Free-flowing Infected pleural Presence of pus, formed as a typically culture-negative effusion with or frank infection consequence of bacterial. pleural effusion septations and/or identified by cirrhotic portal often in the loculations and/or culture-positive hypertension setting of an thickened parietal fluid, in the underlying pleura on chest pleural space pneumonia imaging

Type of fluid Often, transudate Can be Exudate Exudate, Exudate, may be transudate or fibrinopurulent, purulent exudate; rarely or organizing purulent

pH > 7.3 > 7.3 > 7.2 < 7.2 < 7.2

Glucose level, >60 >60 > 40 < 40 < 40 mg/dL

Fluid/serum < 0.5 Variable, typically Variable, typically Variable, typically Variable, typically protein ratio < 0.5 > 0.5 > 0.5 > 0.5

LDH, IU/L < 200; typically Variable Typically Typically > 3 x Typically > 3 x < ⅔ x ULN for > ⅔ x but < 3 x ULN for serum ULN for serum serum LDH ULN for serum LDH, often > LDH, often > LDH 1000 1000

Fluid/serum < 0.6 Variable > 0.6 > 0.6 > 0.6 LDH ratio

Serum-to- > 1.1 g/dL NA NA NA NA pleural fluid albumin gradient

Gram stain and Negative Positive Negative Positive or Positive or culture Negative Negative

Management Refer to Antibiotics; may Antibiotics; may Tube Tube manuscript for need repeat need repeat thoracostomy + thoracostomy + HH management pleural US and pleural US and antibiotics; may antibiotics; may thoracentesis if thoracentesis if need tPA– need tPA– Accepted Article no clinical/ no clinical/ DNase; may DNase; may symptomatic symptomatic require VATS require VATS resolution. Also resolution and/or and/or

refer to text for decortication decortication HH management.

1 Pleural fluid characteristics listed in this table may help differentiate between infected and non-infected pleural space, however, the diagnosis of pleural space infections should rely on a combination of clinical presentation, pleural fluid analysis, and pleural space imaging. Further details on the diagnosis and management of pleural space infections are beyond the scope of this manuscript. 2 Historically called spontaneous bacterial empyema (SBEM).

Abbreviations: LDH, lactate dehydrogenase; NA, not available; US, ultrasound; tPA, tissue plasminogen activator; DNase, deoxyribonuclease; VATS, video-assisted thoracoscopic surgery

Accepted Article

Table 2. Strategies for treatment of hepatic hydrothorax

Category Modality Pros Cons

Reduction of Sodium restriction  Non-invasive  High rate of nonadherence ascitic fluid  Inexpensive  Risk of decreased nutritional production  Usually first line for HH intake/ sarcopenia  Limited use in refractory HH Diuretics  Non-invasive  Risk of kidney injury  Inexpensive  Risk of hypotension  Usually first line for HH  Limited utility in refractory HH Splanchnic and  Non-invasive  Risk of kidney injury peripheral  Inexpensive  Lack of robust data vasoconstrictors

TIPS  Usually first line for HH refractory  Post-TIPS encephalopathy of sodium restriction/diuretics  Shunt occlusion and thrombosis  High response rate  Post-TIPS cardiomyopathy  Secondary gains of resolving  Deterioration of liver function ascites and variceal bleeding  Minimally invasive

Prevention of CPAP  Non-invasive  Lack of data on effectiveness as fluid transfer to  Use as an adjunct in surgical sole treatment modality pleural space repair of diaphragmatic defects or obliteration of pleural space

Surgical repair of  Can be used when TIPS is  Invasive diaphragmatic contraindicated  Need for general anesthesia defects  Effective in reducing HH and  Limited visualization of defects achieving pleurodesis  May need repeated procedure  High complication rate

Removal of Thoracentesis  Fast symptom relief  Need for repeated procedure fluid from  Allows for pleural fluid analysis  Complications such as pleural space  Effective as a bridge to liver pneumothorax, hemothorax, transplant if wait time is short <3 expansion pulmonary edema months)

IPC  Effective for evacuating pleural  Complications such as leakage, space in a controlled manner dislodgement, empyema,  Can achieve pleurodesis pneumothorax  Effective for as-needed symptom

Accepted Article relief in a palliative setting

 Minimally invasive Pleurovenous  Effective for evacuating pleural  Risk of air embolism shunt space in a controlled manner  Chest pain  Minimally invasive

Obliteration of VATS and  Can be used when TIPS is  Invasive pleural space pleurodesis contraindicated  Need for repeated procedure  Allows for repair of diaphragmatic  Need for general anesthesia defects  Complications such as septic shock, empyema, bleeding

Liver Liver  Definitive management option  Invasive transplantation transplantation  Significantly decreases patient  Limited availability of organs mortality  Long waitlist time  Need for long-term immunosuppression

Abbreviations: CPAP, continuous positive airway pressure; HH, hepatic hydrothorax; IPC, indwelling pulmonary catheter; TIPS, transjugular intrahepatic portosystemic shunt; VATS, video-assisted thoracoscopic surgery Accepted Article

Resolved with 2g/day sodium restriction?

Yes No

Maintain sodium HH Recurs Resolved with restriction diuretics? 1

Yes No 2

Maintain sodium HH Recurs Resolved with restriction thoracentesis ± Titrate diuretics paracentesis? 3

Yes No

Monitor for HH Recurs Liver transplant recurrence candidate?

Yes

Expected waitlist time No < 3 months?

Yes No

Repeated thoracentesis ± paracentesis until TIPS candidate? transplant

Yes

No Resolved with TIPS?

Yes No

Monitor for recurrence HH Recurs Surgical candidate? or until transplant

Yes No

IPC; Surgical pleurodesis; IPC; Repeated thoracentesis Repair or diaphragmatic ± paracentesis; CPAP; defects Terlipressin; Octreotide

1. The starting diuretics regimen is typically furosemide 40mg/ spironolactone 100mg daily (Step 1). If necessary, titrate in a step-wise fashion to a maximum of furosemide 160mg/ spironolactone 400mg daily (Step 4), with serial monitoring of hemodynamic status, electrolytes and creatine. 2. The patient may have diuretic-resistant or diuretic-intractable hepatic hydrothorax. 3. Send fluid for cell count with differential, gram stain, culture, total protein , albumin, lactate dehydrogenase, fluid pH and bilirubin concentration.