Management of chronic pleural effusions in the neonate

INTRODUCTION — Pleural effusion occurs as a result of an abnormal fluid collection within the pleural space. Once a pleural effusion has been diagnosed in the neonate, management decisions are based on the effusion's effect on the respiratory status of the patient, which is primarily based on the size of the effusion and the cause and chronicity of the condition.

The management of chronic neonatal pleural effusions will be reviewed here. The etiology, presentation, and acute management of neonatal pleural effusions are discussed separately. (See "Approach to the neonate with pleural effusions".)

OUR APPROACH — The management of recurrent and chronic effusions is primarily dependent on the likelihood and rapidity of resolution when the underlying cause is treated. Most cases of neonatal pleural effusions are transient and do not need further intervention. The following is our approach to managing a neonate following the initial acute management, which is discussed separately. (See "Approach to the neonate with pleural effusions", section on 'Initial acute management'.)

●In patients who continue to be symptomatic, needle aspiration is repeated two or three times until it is clear that the effusion(s) will either clear or continue. In general, recurrent effusions caused by hydrops or other nonchylous etiologies can usually be treated with serial needle aspirations over a relatively brief period of time as the underlying condition is treated or spontaneously resolves.

●In patients with chronic effusions, defined as those requiring repeated needle aspirations to relieve respiratory distress, we place a chest tube for slow continuous drainage of fluid using an underwater seal system. In our center, we typically use pigtail catheters of 8.5 French or greater. We monitor chest tube output and serum electrolytes frequently and replace volume and adjust electrolyte infusions based on the composition and volume of the drainage. After initial chest radiographs confirm appropriate chest tube placement, they are repeated only if there is increased respiratory distress or if a sudden decrease in output occurs. (See 'Tube thoracostomy' below.)

●Infants with continued non-chylous drainage (transudate) primarily have fluid and electrolyte losses. In these infants, hydration and electrolyte status are monitored at least daily. Volume losses greater than approximately 6 mL/kg per hour are replaced with normal saline and appropriate amounts of potassium, depending on the composition of the drainage, over an hour or two, every six to twelve hours. For infants with significant ongoing protein losses, the use of protein-containing replacement fluid should be considered so that the patient does not become hypo-proteinemic (eg, fresh frozen plasma instead of normal saline).

●Chylous pleural effusions are the most frequent cause of chronic neonatal pleural effusions. They are associated with continued and persistent accumulation of large volumes of pleural fluid. Prolonged drainage of chylothorax may lead to significant losses of fluid, electrolytes, proteins (including immunoglobulins), and lymphocytes. Depletion of immunoglobulins and lymphocytes may cause clinically significant immunosuppression. Because of the complexity of management of infants requiring prolonged drainage, we recommend transfer of such infants to tertiary centers with staff who have expertise in the care of these infants.

Management approach for chylous effusion — For neonates with chronic chylothorax, we use the following step-wise management approach:

●Our initial intervention is the use of a formula with a high concentration of medium-chain triglycerides. If drainage of chyle continues for more than a week, a trial of total parenteral nutrition (TPN) and nothing by mouth is administered. However, if possible, we prefer to continue enteral feeds due to the long-term complications of TPN. (See 'Dietary management' below.)

●For infants who fail to respond within one to two weeks of dietary measures with continued chest tube output, octreotide is offered after discussion with the parent(s) or legal guardian of the infant regarding the risk and uncertainty of benefits. Of note, other centers do not use octreotide due to concern for adverse effects and data that report limited benefit. However, for infants with prolonged chest tube drainage despite dietary measures, we provide octreotide with parenteral at an initial dose of 1 mcg/kg per hour and increased by 1 mcg/kg per hour per day until a response is noted or the infusion rate reaches a maximum of 10 mcg/kg per hour. A positive response is considered to be at least a 25 percent reduction in output. Once a response is obtained, we usually continue infusion at the same rate for 7 to 10 days before beginning a slow taper over another week. If chest tube drainage increases, we increase the octreotide infusion rate and maintain it for at least another week before tapering and discontinuation. (See 'Pharmacologic management' below.)

If maximal octreotide dosing does reduce chest tube output after two or three days, we rapidly taper octreotide over a day or two and consider chemical pleurodesis or surgical intervention.

●In patients with chylothorax and prolonged drainage, serum albumin and clotting studies are measured once or twice weekly, and replacement therapy is administered as needed. Intravenous immune globulin (IVIG) therapy is considered for patients with hypoimmunoglobulinemia due to severe and prolonged loss. (See 'Protein loss' below.)

●When the drainage has ceased, we remove the tubes and wait at least a week (and often longer) before starting to feed mother or donor human milk to the infant. If human milk is not available, a standard formula is provided. We continue to monitor the patient for another week or more for recurrence of a pleural effusion.

INTERVENTIONS

Tube thoracostomy — In the neonate with persistent pleural effusion(s) that continue to cause respiratory distress despite serial needle aspirations, placement of a chest tube(s) with underwater seal system can slowly drain pleural fluid on an ongoing basis, resulting in improved respiratory function [1]. In neonates, chest tubes in a size range of 10 to 12 French, or pigtail catheters of 8.5 French or greater should be used. We prefer pigtail catheters as they seem to remain in place longer.

Similar to the insertion site used for needle aspiration, the tube should be inserted under sterile conditions with the infant in the supine position in the midaxillary line in the 5^th or 6^th intercostal space and directed posteriorly. The tube should be sutured in place and covered with an airtight occlusive dressing. The distal end is then connected to a closed system calibrated suction device with 10 to 15 cm water negative pressure. Proper position of the tube should be verified with a chest radiograph. Initially, the volume of drainage should be measured every six to eight hours after the initial volume has been drained. As the volume decreases, the measurement interval can be increased. Bilateral chest tube placement may be necessary if the effusions are large on both sides.

Continued drainage of pleural fluid either by repeated aspiration or chest tube drainage can lead to significant loss of fluid and electrolytes. (See 'Volume and electrolyte loss management' below.)

For chylous effusion, chronic drainage can lead to depletion of serum proteins, especially albumin and immunoglobulins, and lymphocytes. (See 'Chylous effusions' below.)

In neonates, persistent effusions are rarely due to infectious causes. The management of pediatric parapneumonic effusions and empyema, including the indications for chest tube placement, are discussed separately. (See "Management and prognosis of parapneumonic effusion and empyema in children", section on 'Chest tubes'.)

Volume and electrolyte loss management — Significant volume and electrolyte loss can occur with chronic chest tube drainage. The electrolyte content of pleural effusions is similar to that of plasma. Thus, large amounts of water and electrolytes (especially sodium) can be lost with ongoing drainage. Daily assessments of weight and electrolytes are therefore essential in the early management of continuous chest tube output. The need for replacement of losses will depend on the magnitude of the losses and changes in serum electrolytes. The decision to replace lost volume depends on the infant's daily fluid and electrolyte intake. Volume loss should be calculated every 8 to 12 hours and, if greater than 6 mL/kg per hour, replacement with normal saline or other appropriate solution should be given intravenously over one to two hours, every six to twelve hours.

Protein loss — In some cases, protein loss may also be significant depending on the composition of the pleural fluid. Analysis of the fluid will provide the protein concentration and will guide whether serum albumin levels should be monitored and if (when) protein replacement therapy (eg, fresh frozen plasma) is needed.

Pleurodesis — Pleurodesis is a procedure that obliterates the pleural space to prevent a recurrent pleural effusion following pleural drainage. After draining the effusion, a chemical irritant that induces inflammation and fibrosis is instilled into the pleural space (ie, chemical pleurodesis). Various agents have been used for chemical pleurodesis. Many of these, especially chemotherapeutic agents, are contraindicated in neonates and young infants because of potential toxicities. (See "Chemical pleurodesis for the prevention of recurrent pleural effusion".)

Data are limited in infants and include case reports, primarily in patients with persistent chylous effusions, using the following agents:

●Talc [2]

●Iodopovidone [3-6]

●Tetracycline derivatives (doxycycline) [5,7]

●Fibrin glue [8-14]

●Streptococcus pyogenes A3 (OK-432) [15,16]

The use of these agents need further study to determine efficacy and safety in the treatment of neonatal pleural effusions. As a result, these interventions cannot be recommended for routine use.

Nevertheless, an infant with persistent unilateral chylous effusion was successfully managed with pleurodesis using doxycycline at our center. The decision to use pleurodesis should be made by knowledgeable clinicians on a case-by-case basis.

Surgical management — Infants who continue to have chronic pleural effusions despite all attempts at medical therapy may require surgical intervention. Discussion of these options, which include mechanical pleurodesis, pleuroperitoneal shunt [17-19], and ligation of the thoracic duct [13,14,20-22], is beyond the scope of this review.

CHYLOUS EFFUSIONS

Overview — Management of infants with chylous effusions is challenging, as there are significant losses from pleural fluid drainage of fluid and electrolytes; proteins including albumin, clotting factors, and immunoglobulins; and, in addition to humoral components, cellular elements of immunity, particularly lymphocytes [23,24]. However, based on retrospective data from large case series, comprehensive management with ventilatory support, and dietary management focused on decreasing thoracic duct lymph flow (parenteral nutrition and the use of medium-chain triglycerides [MCT]) have improved the outcome of neonates with chylothorax [25,26].

Replacement therapy

Protein loss — Because chyle contains significant amounts of protein, ongoing drainage can lead to significant loss of:

●Albumin – Serum albumin concentrations should be followed once or twice weekly, and replacement should be given to maintain levels above 2 to 2.5 g/dL.

●Coagulation factors – Coagulation factors, especially fibrinogen and factor VII, can be lost in clinically significant amounts. Periodic clotting studies should be obtained and fresh frozen plasma given as needed to normalize the values. Although there are no specific guidelines, we provide replacement therapy to maintain coagulation studies at a threshold of no less than 1.5 times normal values.

●Immunoglobulin – Although there are no published guidelines regarding the management of immunoglobulin loss, there is a significant loss of immunoglobulins with ongoing chyle drainage, which may result in severe hypoimmunoglobulinemia [27-29]. Older studies in animals have demonstrated that thoracic duct cannulation and drainage for as little as five days can produce a significant humoral and cellular immune defect [30]. As a result, we monitor serum immunoglobulin G (IgG) levels on a weekly basis and begin replacement dosing with intravenous immunoglobulin (IVIG) to maintain a targeted trough level of 500 mg/dL, which is the mean IgG level for a one-month-old infant and the replacement trough level used in the care of patients with primary immune deficiencies [31]. Initial dosing of IVIG for immune replacement is 400 to 600 mg/kg. The normal half-life of IgG is approximately three weeks; however, with high rates of drainage, the replacement dose and interval will need to be adjusted to maintain the IgG level at or above the target level. (See "Immune globulin therapy in inborn errors of immunity", section on 'Trough levels'.)

Lymphocyte depletion — Profound cellular deficiency occurs with prolonged chylous drainage, based on data from patients undergoing organ transplantation for whom 14 days of chylous drainage resulted in lymphocyte depletion to a degree associated with clinically significant immunosuppression. In order to avoid significant lymphocyte depletion, measures to reduce chyle production (eg, dietary measures) are initiated in patients who require chronic drainage. (See 'Reduction of chyle drainage' below.)

The potential complications of such lymphocyte depletion were illustrated in a large case series of 178 infants with chylous effusions, among whom a low absolute lymphocyte count was associated with culture-positive sepsis [26].

Reduction of chyle drainage

Dietary management — Dietary management is focused on decreasing thoracic duct lymph flow and includes the following:

●The use of formula with a high concentration of MCT and a low concentration of long-chain fatty acids has been shown to be effective in decreasing chyle flow with resolution of chylous effusions [20,21,26,32,33]. Fat-free human milk produced by centrifugation and supplemented with MCT or total parenteral nutrition (TPN) has also been reported to be successful in the management of both congenital and postoperative chylothorax [34]. The mechanism of decreased chyle flow appears to be due to MCT being directly absorbed into the portal vein system, thereby bypassing the lymphatic system and resulting in a reduction in the volume and lipid concentration of the pleural fluid [35].

●Because enteral feeds stimulate thoracic duct lymph flow, withholding feeds (nothing by mouth) with administration of TPN decreases chylous flow. The regimen of nothing by mouth/TPN decreased chyle flow in patients who failed to respond to MCT [21,32].

Although the optimal approach is controversial, most centers, including our own, advocate an initial noninvasive trial of MCT-enriched formula, as most patients will respond with a decrease in chyle flow/drainage (defined as a 25 percent reduction in drainage) and resolution of the effusion, and TPN is associated with significant complications including cholestasis and central line infections. However, nothing by mouth/TPN is initiated for patients who fail to respond with an adequate decrease in drainage with MCT-enriched formula [21,36].

For infants responsive to dietary measures, the chest tube(s) are removed after the drainage ceases. Feeds with human milk are initiated in one to two weeks. If human milk is not available, standard formula is used.

Pharmacologic management — Octreotide is a synthetic analogue of somatostatin, a regulatory hormone that reduces intestinal blood flow and can decrease the production rate of chyle (see "Physiology of somatostatin and its analogues"). Octreotide has been reported to be beneficial in the treatment of chronic chylothorax in adults. However, we do not routinely use octreotide in neonates with chylothorax because it has significant adverse effects and data remain uncertain about whether it is beneficial in the management of chronic neonatal chylothorax. (See "Management of chylothorax", section on 'Adjunctive therapies'.)

We reserve the use of octreotide for refractory cases of chronic neonatal chylothorax after a thorough discussion with the parent/caregiver of the infant regarding the uncertainty of risk and benefits. If given, octreotide can be administered either subcutaneously or intravenously. We prefer a continuous intravenous infusion starting at 1 mcg/kg per hour and increasing the dose once daily to a maximum of 10 mcg/kg per hour depending on the patient's response. Because octreotide blunts insulin release, close monitoring of serum glucose values should be performed during the induction phase with spacing of measurements as a stable infusion rate is achieved. If intravenous access is lost, octreotide can be given subcutaneously at the same dose at six- to eight-hour intervals until intravenous access is restored.

Adverse effects of octreotide have been reported in approximately 14 percent of neonates treated for chylothorax [37]. Reported significant complications of octreotide for patients with chylothorax and other conditions (eg, congenital hyperinsulinism and enterocutaneous fistulas) include persistent pulmonary hypertension of the newborn (PPHN) and necrotizing enterocolitis (NEC) [38-43].

Data are uncertain about whether octreotide is beneficial in the management of chronic neonatal chylothorax that is resistant to dietary management. In neonates, there are no clinical trials studying the effect of octreotide in the treatment of chylothorax. Evidence is limited to case reports, and data from observational studies are contradictory. A systematic review of 753 infants with congenital chylothorax reported that of the 138 infants treated with octreotide, approximately 78 percent had resolution of chylothorax without the need for surgical intervention [44]. An earlier systematic review reported that octreotide is a safe and relatively effective intervention with decrease or cessation of chylous drainage in approximately 50 percent of cases [37].

In a large case series of 178 infants with chylous effusions that was not included in either review, 172 were initially managed medically with chest tube drainage and nutritional measures (eg, MCT enteral feeding, total parental feeds, and withholding of feeds) and 6 patients received no treatment [26]. Additional interventions included pharmacologic treatment with octreotide for 45 patients and surgery for 21 patients. In this cohort, the administration of octreotide was not associated with additional benefit over dietary measures. In contrast, a small case series reported octreotide was safe and effective in treating refractory chylothorax in patients following surgery for congenital heart disease [45].

Other interventions — Other interventions that have been used in neonates with chylothorax include the following; however, these interventions should not be used routinely, as the evidence of demonstrated benefit is inadequate. They should only be considered on a case-by-case basis for neonates that fail to respond to routine management.

●High-frequency ventilation and high end-expiratory pressure in patients on mechanical ventilation – In patients who are mechanically ventilated, high-frequency ventilation [46] and high end-expiratory pressure [47] have been reported to be beneficial in the management of infants with chylothorax.

●Inhaled nitric oxide – A single case report noted a reduction in chyle flow with inhaled nitric oxide (iNO) in an infant with postoperative chylothorax and pulmonary hypertension [48].

●Etilefrine – A report of two cases noted a significant reduction of chyle output after starting treatment with continuous infusion of etilefrine, a sympathomimetic agent with both alpha and beta adrenergic stimulation [49]. Both heart rate and blood pressure increased during the infusion but returned to basal values after etilefrine was discontinued.

●Glucocorticoids – There are also reports that glucocorticoid therapy may be helpful in the management of postoperative chylothorax [50,51].

●Propranolol – A limited number of reports suggest that propranolol may be effective in treating chylothorax [52-55]. Evidence is insufficient to recommend its use.

●Sildenafil – A single case report indicated successful treatment of an octreotide-resistant congenital chylothorax with the phosphodiesterase inhibitor sildenafil [56].

●Interventional cardiac catheterization – Chylothorax resulting from occlusion or stenosis of the left innominate vein may be successfully remedied by balloon dilation in the cardiac catheterization laboratory [57].

Follow-up management — After resolution of chylothorax, long-term immunologic follow-up of patients depends on how rapidly T cell lymphocyte and immunoglobulin levels recover. Retrospective data from small cases series have failed to establish the beneficial effects of intravenous immune globulin (IVIG) for patients with chylothorax and hypoimmunoglobulinemia [27-29,58]. Nevertheless, we continue to provide IVIG to patients with persistent T cell lymphopenia and hypoimmunoglobulinemia until there is more definitive evidence of the lack of efficacy.

For patients who have recovery of T cell lymphocytes and immunoglobulins to normal or near normal concentrations by the time of discharge, no further follow-up is necessary beyond the usual discharge management based on the patient's neonatal intensive care hospitalization. (See "Discharge planning for high-risk newborns" and "Care of the neonatal intensive care unit graduate".)

SUMMARY AND RECOMMENDATIONS

●Initial management of chronic pleural effusions in the neonate – Chronic pleural effusions are defined as those that require repeated needle aspirations to relieve respiratory distress. In neonates with chronic pleural effusions, we suggest chest tube placement for slow continuous drainage of fluid using an underwater seal system (Grade 2C). (See 'Our approach' above.)

•Losses associated with ongoing drainage – These include significant losses of water and electrolytes, and depending on the composition of the fluid, protein. As a result, daily assessments of weight and electrolytes are needed to determine the need of fluid replacement, including determination of volume and content. (See 'Our approach' above and 'Tube thoracostomy' above.)

●Management of chylothorax drainage – Chylous drainage can persist over a considerable time period and be associated with significant losses of fluid, electrolytes, protein including albumin, clotting factors and immunoglobulins, and cellular elements of immunity, particularly lymphocytes. We manage these losses by replacement and by using measures to reduce chyle drainage (see 'Protein loss' above and 'Lymphocyte depletion' above):

•Replacing losses – We replace fluid and electrolyte losses depending on the magnitude of the losses and changes in serum electrolytes. (See 'Volume and electrolyte loss management' above.)

We replace protein losses as follows (see 'Protein loss' above):

-Albumin – We suggest administering intravenous infusions of albumin to maintain serum albumin concentrations above 2 to 2.5 g/dL (Grade 2C).

-Clotting factors – We suggest administering an intravenous infusion of fresh frozen plasma to correct abnormal clotting studies to below 1.5 times the upper limit of normal (Grade 2C).

-Immunoglobulins – For patients with severe hypoimmunoglobulinemia, we suggest administering intravenous immune globulin (IVIG) to maintain a threshold level of immunoglobulin of 500 mg/dL. (See 'Follow-up management' above.)

•Reducing chyle drainage – In patients with chronic chylothorax, we use a step-wise approach to reduce chyle flow (see 'Our approach' above):

-Dietary management – We suggest an initial trial of formula with a high concentration of medium-chain triglycerides (MCT) and a low concentration of long-chain fatty acids (Grade 2B). (See 'Dietary management' above.)

In patients who fail to respond to MCT-enriched formula, we suggest stopping oral feeds (nothing by mouth) and administering total parental nutrition (TPN) (Grade 2B). (See 'Dietary management' above.)

-Pharmacologic management not routinely used – We suggest not routinely using octreotide for neonates with chronic chylothorax (Grade 2B). In our center, octreotide is reserved on a case-by-case basis for patients who fail to respond to dietary measures. Data remain uncertain on its benefits in neonates. (See 'Pharmacologic management' above.)

●Measures not routinely used – We do not routinely use the following measures to treat persistent neonatal pleural effusions: chemical pleurodesis and surgical interventions (ie, mechanical pleurodesis, pleuroperitoneal shunt, ligation of the thoracic duct for patients with chylothorax). However, infants who continue to have chronic effusions despite all attempts at medical therapy may require surgical intervention. (See 'Pleurodesis' above and 'Surgical management' above.)