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Splenectomy

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Last Update: May 6, 2024.

Continuing Education Activity

Splenectomy is a surgical procedure to remove the spleen that is typically performed to treat various clinical conditions such as hematologic disorders, trauma, and certain cancers. Splenectomy may be performed via open, laparoscopic, or robotic-assisted techniques. The spleen plays a crucial role in the immune system, filtering blood and fighting infections, but its removal is sometimes necessary due to disease or injury. Splenectomy carries risks, including bleeding, infection, and long-term complications such as an increased susceptibility to certain infections. However, when performed appropriately, splenectomy can significantly improve the quality of life and alleviate symptoms associated with underlying conditions.

This activity for healthcare professionals reviews the relevant anatomy and physiology, the indications for and contraindications to, surgical techniques, and complications of splenectomy. The activity also underscores the importance of the interprofessional team in improving outcomes for patients who require splenectomy. 

Objectives:

  • Identify patients who will benefit from splenectomy based on their clinical history and presentation.
  • Apply best practices when performing splenectomy via any surgical approach.
  • Assess and treat the commonly encountered complications of splenectomy using appropriate pharmacological and nonpharmacological interventions.
  • Develop and implement effective interprofessional team strategies to improve short- and long-term outcomes for patients undergoing splenectomy.
Access free multiple choice questions on this topic.

Introduction

Splenectomy is a surgical procedure performed to remove the spleen, an organ located in the upper left side of the abdomen. Once considered a vestigial organ, the spleen plays important roles in the immune system, including filtering pathogens from the bloodstream, removing old or damaged red blood cells, and producing antibodies to help fight infection.[1] Splenectomy is indicated in several clinical scenarios, including benign and malignant processes, as well as for anatomical reasons and traumatic injuries.[1][2]

Depending on the underlying condition and diagnosis, splenectomy can be performed using open, laparoscopic, or robotic-assisted techniques.[3] Each approach has advantages and considerations regarding recovery time, postoperative pain, and complication risks. Although laparoscopic splenectomy is favored in developed nations, open procedures remain common in the majority of resource-limited countries.[4]

Given the heightened risk of infections and other complications after a splenectomy, monitoring and medical follow-up are typically recommended to manage potential long-term effects and ensure continued well-being.

Anatomy and Physiology

A comprehensive understanding of the relevant anatomy is essential to effectively performing a splenectomy. The spleen is situated in the left upper quadrant of the abdomen, positioned beneath the left posterolateral aspects of the 9th to 11th ribs; its neighboring structures include the stomach, pancreas, colon, and left kidney. Despite individual variability, the adult spleen measures approximately 12 cm in length, 7 cm in width, and 3 cm in thickness, with an average weight of 150 grams.

The spleen is tethered to adjacent structures by various ligaments, notably the gastrosplenic and splenorenal ligaments. The gastrosplenic ligament runs from the greater curvature of the stomach to the hilum of the spleen and houses the short gastric arteries and the left gastroepiploic artery. The splenorenal ligament spans from the anterior surface of the left kidney to the splenic hilum, accommodating splenic arteries. These ligaments provide structural support and vascular connections critical for splenic function.

The splenic artery is the primary arterial supply to the spleen. Originating from the celiac trunk, the splenic artery traverses along the upper margin of the pancreatic body and tail. Upon reaching the splenic hilum, the artery divides into the short gastric artery, supplying the gastric fundus, and the left gastroepiploic artery, which runs along the greater curvature of the stomach. These branches ensure adequate blood flow to the spleen and adjacent gastric regions. Venous drainage occurs through tributaries that converge to form the splenic vein at the hilum. This vein courses posterior to the pancreas and merges with the superior mesenteric vein, ultimately contributing to the formation of the portal vein behind the pancreatic neck. The lymphatics of the spleen drain into the splenic hilar lymph nodes and the retropancreatic lymph nodes.[5]

Accessory spleens occur in 10% to 30% of individuals; most are located at the splenic hilum.[6] However, accessory spleens may be located near the pancreatic tail, gastrosplenic or splenorenal ligaments, and occasionally within the mesentery.[7] Instances of accessory spleens located below the peritoneal reflection are exceptionally rare.[8]

Indications

The most common indications for splenectomy include:

Congenital hemolytic anemias and hemoglobinopathies

  • Hereditary spherocytosis
  • Hereditary elliptocytosis
  • Pyruvate kinase deficiency
  • Drepanocytosis or sickle cell disease [1]
  • Thalassemia

Acquired immunological disorders 

  • Immune thrombocytopenic purpura
  • Autoimmune hemolytic anemia

Hematologic malignancies and myeloproliferative disorders

  • Various leukemias
  • Lymphoma [9]
  • Polycythemia vera
  • Myelofibrosis [10]

Hypersplenism

  • Metabolic storage disorders such as Gaucher or Niemann-Pick disease [11]
  • Infectious diseases including abscesses, schistosomiasis, malaria, and hydatid disease
  • Inflammatory disorders including Felty syndrome
  • Intrinsic splenic disorders such as cysts, hemangiomas, neoplasms, and splenic arterial aneurysms
  • Congestive disorders secondary to splenic or portal venous thrombosis or cirrhosis 

Anatomical necessity

  • En bloc with the distal pancreas for pancreatic disease involving the body and tail of the pancreas [2]
  • En bloc with the stomach in a radical gastrectomy [12] 

Trauma

  • The spleen is the most frequently affected organ in blunt abdominal trauma (35%–45% of cases) [13]
  • Splenic injury is a rare complication of colonoscopy [14][15]
  • Spontaneous rupture

Contraindications

While there are no absolute contraindications to splenectomy, certain factors warrant careful consideration, particularly in patients with splenomegaly or portal hypertension. When the spleen exceeds 1000 g to 2000 g, laparoscopic splenectomy may be challenging due to operative space restrictions, complicating dissection and specimen extraction. Research indicates prolonged operative times, increased blood loss, and a higher likelihood of conversion to open surgery in cases of splenomegaly compared to normal-sized spleens.[16] In such scenarios, if time allows, splenic artery embolization may be considered to reduce spleen size and facilitate laparoscopic intervention.[17]

Similarly, patients with portal hypertension face heightened bleeding risks attributable to esophagogastric varices and thrombocytopenia. Consequently, these individuals may experience prolonged operative times, elevated blood loss, and increased likelihood of requiring conversion to open surgery.[18]

Equipment

The equipment needed to perform a splenectomy varies depending on the surgical technique: open, laparoscopic, or robotic-assisted.

For an open splenectomy, the following equipment is typically required:

  • Scalpel 
  • Electrocautery device
  • Retractors 
  • Surgical instruments typical of a major laparotomy set
  • Ligature clips 
  • Sutures 
  • Suction irrigation system 
  • Surgical stapler or ligature device 
  • Sterile drapes, gowns, and gloves.

For a laparoscopic splenectomy, the necessary equipment typically includes:

  • Laparoscope (0° and 30°)
  • Monitors
  • Trocars 
  • Scalpel
  • Laparoscopic instruments, including graspers, scissors, suturing devices, and dissectors
  • Energy devices, such as electrocautery or ultrasonic dissectors
  • Endoscopic clips or ligating devices for vessel control
  • Specimen bag
  • Sutures
  • Pneumoperitoneum insufflation system 
  • CO2 gas insufflator to maintain pneumoperitoneum
  • Laparotomy tray in the room in case of conversion.

For a robotic-assisted splenectomy, the equipment typically includes:

  • A robotic surgical system consisting of a console, robotic arms, and a vision cart
  • Monitors 
  • Trocars 
  • Scalpel
  • Robotic arms equipped with specialized instruments for tissue manipulation and dissection
  • Endoscopic camera system
  • Energy devices integrated into the robotic instruments for cutting and coagulation
  • Endoscopic clips or ligating devices for vessel control
  • Sutures
  • Pneumoperitoneum insufflation system and
  • CO2 gas insufflator
  • Laparotomy tray in the room in case of conversion.

Personnel

For a splenectomy, the following personnel is required:

  • Operating surgeon
  • First assistant
  • Surgical technician or operating room nurse
  • Circulating or operating room nurse
  • Anesthesia provider.

Preparation

Preoperative assessment of spleen size and volume via abdominal ultrasonography is imperative for all patients scheduled for elective laparoscopic splenectomy. This evaluation not only aids in determining the appropriate surgical approach but also facilitates the detection of any coexisting conditions that may necessitate intraoperative evaluation, such as cholelithiasis in patients with hereditary spherocytosis. Additionally, patients with immune thrombocytopenic purpura or malignancies should undergo high-resolution computed tomography of the abdomen to identify any accessory spleens present, ensuring comprehensive surgical planning and optimal patient care.[19] 

Patients undergoing splenectomy must be vaccinated against polysaccharide-encapsulated organisms. Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the 3 most common organisms that are likely to cause overwhelming postsplenectomy infection (OPSI).[20] The overall lifetime risk for developing OPSI is approximately 5%; the mortality rate associated with OPSI is reported to be 38% to 70%. Patients undergoing elective splenectomy should receive vaccinations against these organisms approximately 2 weeks prior to surgery to allow an adequate immune response. Patients who undergo splenectomy for traumatic injuries or unplanned splenectomy during other abdominal procedures should receive vaccination approximately 2 weeks after surgery. However, individuals often receive vaccines before hospital discharge due to noncompliance and loss of follow-up.[19] 

Moreover, it is recommended that patients with autoimmune thrombocytopenia and a platelet count of less than 20 × 109/L  be preoperatively treated with corticosteroids or immunoglobulins to reduce intraoperative blood loss.[19] Additionally, platelets are not functional in patients with myelodysplastic disorders such as myelofibrosis and chronic granulocytic leukemia; a platelet transfusion should be considered despite a normal count.[9][21] Other medical issues such as uncontrolled comorbidities, nutritional deficiencies, anemia, thrombocytosis, and clotting or bleeding abnormalities should be assessed and optimized on a case-by-case basis. 

Technique or Treatment

Splenectomy can be accomplished via open, laparoscopic, and robotic-assisted techniques. Laparoscopic and robotic-assisted procedures are favored over open surgery due to their inherent advantages and lower complication rates.[22] The precision and stability afforded by robotic-assisted surgery, along with reduced manipulation of abdominal organs, are anticipated to decrease complication rates further, including those associated with splenectomy.[23] Consequently, minimally invasive approaches have become the standard for scheduled splenectomy, particularly in hematologic conditions where the procedure is warranted.

Patient Positioning

For an open splenectomy, the patient is supine; the positioning of patients during laparoscopic splenectomy is a topic of ongoing debate. Two approaches (using 3 patient positions) are commonly described: medial (anterior) and lateral (hemilateral and lateral). The superiority of one technique over the other is debatable since both approaches have well-known limitations.[24] The anterior position offers good visualization of the omental pouch and splenic hilum, facilitating concurrent procedures and potential conversion to open laparotomy if needed. However, dissection of ligament structures and dorsal vessels may be challenging, especially near the pancreatic tail. In contrast, the hemilateral position, where the patient is placed in the right lateral decubitus position, provides easier access to the posterior surface of the spleen and perisplenic ligaments, with simpler dissection and ligation of hilar vessels due to sparing the pancreatic tail. This position is favored by many surgeons for its adjustability and improved access to anatomic landmarks. The lateral position, with the abdomen vertical to the operating table, offers even easier dissection of ligaments and hilar landmarks, potentially reducing the risk of pancreatic injury. Comparative studies have shown the advantages of the lateral position, including shorter operative times, fewer complications, and shorter hospital stays.[25] However, repositioning for conversion to open laparotomy is required. Ultimately, the choice of patient position depends on the surgeon's preference.

Open Splenectomy

The patient is placed supine, and a time-out is conducted to verify the correct patient, procedure, site, and any additional information. Endotracheal intubation is performed, and adequate lines and tubes, including arterial lines, foley catheter, nasogastric or orogastric tube, and sequential compression devices, are placed. The abdomen is prepped and draped in a sterile fashion. A vertical midline incision is made extending from the xiphoid process to the pubic symphysis, or a left subcostal incision is made approximately 2 fingerbreadths below the costal margin extending from midline to the anterior axillary line and deepened through the skin, subcutaneous tissue, fascia layers, into the peritoneal cavity. All 4 quadrants of the abdomen are inspected, and a retractor is placed to aid in visualization.

Adhesiolysis is performed as needed, and the gastrocolic ligament is incised to enter the lesser sac. The gastrosplenic and splenocolic ligaments are divided and ligated, and the spleen is mobilized medially to expose the retroperitoneal attachments. The splenorenal and splenophrenic ligaments are divided and ligated, followed by ligation of the splenic artery and vein near the hilum using suture ligation or a vascular load stapler, with care taken to avoid injuries to the pancreatic tail. The spleen is carefully passed off the field to prevent spillage, and hemostasis is obtained. If pancreatic injuries are noted, a closed-suction drain may be placed. The abdomen is examined for accessory spleens, with the most common location being in the hilum, and any accessory spleens are resected. Finally, the fascia is closed, and the skin edges are reapproximated with staples or running subcuticular sutures.[25]

Laparoscopic Splenectomy

The patient is placed supine, and a time-out is conducted to verify the correct patient, procedure, site, and additional information. General anesthesia induction follows, and the patient can be positioned in either the supine or right lateral decubitus position, ensuring proper padding of all pressure points. Lines and tubes, including arterial lines, foley catheter, nasogastric or orogastric tube, and sequential compression devices, are correctly placed, and the abdomen is prepped and draped in a sterile fashion. The splenectomy procedure typically begins with obtaining abdominal access, commonly using an open cutdown technique, an optical trochar system, or a Veress needle. However, open cutdown is preferred in cases of massive splenomegaly, where the risk of injury is high.

Diagnostic laparoscopy is recommended before splenic mobilization to check for accessory spleens. Trocars are placed based on surgeon preference, typically 1 in the left subcostal position just off the midline/subxiphoid region, another in the left subcostal region in the anterior axillary line, and potentially an additional trocar laterally off the tip of the eleventh rib for cases of splenomegaly. Posterior avascular attachments and short gastric vessels are divided to retract the spleen and obtain access to the splenic hilum and pancreatic tail. The splenic hilum is then divided using an endoscopic stapler with a vascular load, ensuring hemostasis and controlling staple line bleeding with clips or hemostatic agents. In cases where the stapler is deemed unsafe, alternative methods such as electrothermal bipolar vessel sealers or ultrasonic coagulating shears can be used to divide the hilar vessels safely. The spleen is grasped and placed into a bag to avoid spillage of splenic tissue, especially in cases of malignancy. Morcellation is typically used for spleen removal, except in cases where intact removal is necessary. Drainage is generally not recommended except in cases of obvious or suspected pancreatic injury. The pneumoperitoneum is evacuated, and all trocars are removed. The fascial port sites are closed to prevent incisional hernias, and the skin incisions are reapproximated.[25]

Hand-Assisted Laparoscopic Splenectomy

This laparoscopic variation is an alternative to standard laparoscopic splenectomy, particularly in cases of massive splenomegaly where a conversion to open surgery may otherwise be necessary. Hand-assisted laparoscopic splenectomy (HALS) combines the advantages of both open and laparoscopic techniques, enabling the surgeon's nondominant hand to be inserted through hand-assist devices to maintain pneumoperitoneum and facilitate intraoperative maneuvers. An additional incision, typically no more than 7 cm to 8 cm in length and strategically positioned near the inferior pole of the enlarged spleen, allows for easier manipulation and removal of the spleen. Despite the additional incision, HALS has been associated with fewer intraoperative complications, lower conversion rates, shorter operative times, and, consequently, shorter hospital stays compared to open splenectomy. Notably, patients with smaller spleen sizes are not typically candidates for HALS, while those with massive splenomegaly (>22 cm) can benefit greatly from this approach, which combines the benefits of minimally invasive surgery with the technical advantages of hand assistance.[25]

Single-Incision Laparoscopic Splenectomy

The quest for minimally invasive and scarless surgical techniques has led to the development of single-incision laparoscopic procedures, including single-incision laparoscopic splenectomy (SILS). In SILS, a single port is utilized to insert working trocars into the abdominal cavity, typically through an umbilical or periumbilical incision. While SILS follows the basic principles of laparoscopy, it poses technical challenges due to the proximity of surgical tools, which are not specifically designed for SILS. Studies comparing SILS to standard laparoscopy have shown longer operative times and increased blood loss with SILS, which are attributed to these technical difficulties. However, SILS has comparable conversion, morbidity, and mortality rates to standard laparoscopy, with the added benefit of potentially less postoperative pain for patients. With further technological advancements and increased experience, SILS may become a more popular option for laparoscopic splenectomy.[25]

Robotic-Assisted Splenectomy

Since its introduction, robotic-assisted surgery has been hailed as an advanced iteration of laparoscopy, offering inherent benefits that have garnered widespread acceptance across various surgical specialties. This extends to splenectomy, where the robotic surgery platform is increasingly employed.[26] The reported advantages of robotics in splenectomy stem from its enhanced magnification and maneuverability. Traditionally, much importance is given to opening the lesser sac widely and dissecting the splenic vessels thoroughly. However, one study described a total lateral approach via robotic-assisted splenectomy using lateral ports with a technical modification where entering the lesser sac is wholly avoided.[27] Both techniques are described below: 

  • Robotic-assisted technique with opening of the lesser sac
    • In a robotic-assisted splenectomy, when the lesser sac is opened, the patient is typically positioned in a modified lithotomy position to allow optimal access to the abdomen. Following general anesthesia induction and proper positioning, the abdomen is prepped and draped in a sterile fashion. The surgeon makes small incisions for the robotic ports, typically placed in a configuration similar to laparoscopic splenectomy. The robotic arms and camera are inserted through these ports. Using the robotic system, the surgeon carefully dissects the peritoneal attachments to enter the lesser sac. The short gastric vessels are divided, allowing access to the spleen and hilum. The splenic artery and vein are meticulously dissected and ligated using robotic instruments. Care is taken to avoid injury to surrounding structures, including the pancreas. Once the splenic vessels are secured, the remaining attachments to the spleen are dissected using the robotic arms. The spleen is placed in an endoscopic retrieval bag and removed from the abdomen through one of the ports. If necessary, morcellation techniques may be employed to facilitate the extraction of the spleen. After confirming hemostasis and inspecting the surgical field, the robotic arms are removed, and port sites are closed in the traditional fashion.
  • Robotic-assisted technique without opening of the lesser sac
    • Patients are positioned in the right lateral decubitus position with the left arm abducted to expose the surgical field adequately. A flank cushion or bean bag is positioned beneath the right flank to elevate it from the iliac crest, creating adequate working space within the abdominal cavity. Ports are meticulously placed using the robotic system to ensure optimal access and visualization. The infraumbilical port is inserted first, with additional ports following in a diagonal line parallel to the splenic axis. The robot is then docked from the left side of the patient, targeting the splenic hilum for dissection. Dissection commences with the division of the splenocolic ligament, facilitated by the suspended spleen providing traction. Robotic instruments mobilize the inferior pole of the spleen, creating a window near the splenic capsule for the division of the short gastric vessels. Unlike traditional methods, the gastrocolic omentum remains intact. The splenic hilum is divided using a vascular endostapler, leaving the spleen free in the abdomen for retrieval. A retrieval bag introduced through the assistant port or lateral robotic arm port contains the spleen, which may be morcellated if necessary. Routine abdominal drainage is typically not required.[27]

Complications

Splenectomy has associated intra- and postoperative complications; postoperative complications may occur early, in the initial 3 postoperative months, or later.

Intraoperative Complications 

  • Bleeding: most commonly secondary to injury of the splenic capsule or short gastric vessels during mobilization. Conversion to laparotomy should be considered if adequate hemostasis cannot be achieved in a timely fashion. 
  • Injury to surrounding structures: the structures most commonly injured during splenectomy include the stomach, colon, and pancreas. Pancreatic injuries can lead to acute pancreatitis, pancreatic fluid collection, and possible pancreatic fistula.[28] Approximately 15% of laparoscopic splenectomies are complicated by pancreatic injuries. A drain should be placed when a pancreatic injury is suspected. 
  • Missed accessory spleen 
  • Splenic rupture and splenosis

Early Postoperative Complications in the Three Months Following Splenectomy

  • OPSI: suspected when a patient exhibits a sudden systemic infection characterized by a rapid and overwhelming onset following splenectomy, often accompanied by dermatorrhagia and disseminated intravascular coagulation, despite the absence of an identifiable infection site.[25] OPSI may begin as a simple respiratory infection that rapidly progresses to hyperpyrexia, headache, shivering, jaundice, anuria, septic shock, acute respiratory distress syndrome, multiple organ dysfunction syndrome, coma, and death.[25]
  • Bleeding
  • Intrabdominal abscess: most commonly in the subphrenic space and secondary to an infected hematoma or gastrointestinal tract injury. Drainage and antibiotics are typically required. These abscesses are more common in patients with immune thrombocytopenic purpura for reasons that are not well understood.[9]
  • Venous thromboembolism (VTE): abdominal VTE is reported in 6% to 11% of patients following splenectomy.[1] Portal vein thrombosis is a common and severe complication following splenectomy. The incidence is reported to be 5% to 55%, but a recent meta-analysis published in 2018 suggests an incidence of 8.1%.[29][30] Portosplenomesenteric venous thrombosis represents one of the most severe complications of this procedure.[10]
  • Pneumonia and atelectasis
  • Pancreatitis
  • Ileus
  • Abdominal wall infections
  • Abdominal wall hematomas
  • Abdominal wall hernias

Late Postoperative Complications

  • Infections: the lifetime risk of OPSI is approximately 1% to 3%.[1] Patients without a spleen have a 200-fold increased risk of death from septicemia compared to patients with a normally functioning spleen.[2] Asplenic patients are at risk for other bacterial and viral infections due to immunosuppression.[2]
  • Cancer: splenectomized patients have an increased risk of cancer, as well as increased cancer-related mortality. The risk for cancer development is greatest during the first 2 to 5 years after splenectomy. However, a persistent risk beyond 10 years after a splenectomy has been described.[1]
  • Abdominal wall hernias

Clinical Significance

The clinical significance of splenectomy lies in its therapeutic role in various medical conditions and its implications for long-term health and well-being. Splenectomy is performed for a range of indications, including both benign and malignant conditions such as hematologic disorders, splenic trauma, splenic cysts, and certain solid tumors. While splenectomy can alleviate symptoms, prevent complications, and improve overall patient outcomes, there are potential risks and long-term implications.

Patients undergoing splenectomy are at increased risk of infections, particularly from encapsulated bacteria, due to compromised immune defenses. Therefore, lifelong monitoring and preventive measures, such as vaccinations and antibiotic prophylaxis, are often necessary to mitigate these risks. Additionally, splenectomy may impact hematologic parameters, changing blood cell counts and potentially increasing the risk of thrombotic events.

Overall, while splenectomy can offer therapeutic benefits for certain medical conditions, clinicians must carefully weigh the potential risks and benefits and provide comprehensive postoperative care to optimize patient outcomes and minimize complications.

Enhancing Healthcare Team Outcomes

Regarding splenectomy, a multidisciplinary healthcare team collaborates to ensure comprehensive patient care, optimal outcomes, and safety. Physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals play distinct yet interconnected roles. Physicians and surgeons utilize their surgical expertise to perform the procedure effectively, employing the latest techniques, such as laparoscopic or robotic-assisted approaches, to minimize patient trauma and enhance recovery. Advanced practitioners, including physician assistants and nurse practitioners, contribute to patient care through preoperative evaluations, postoperative monitoring, and assisting in surgical procedures. Nurses are pivotal in patient advocacy, providing preoperative education, postoperative care, and monitoring for complications, including vigilance for signs of postsplenectomy infections. Pharmacists ensure appropriate medication management, including prophylactic antibiotics to reduce infection risk postoperatively, vaccinations to prevent infection, and educating patients about medication adherence and potential side effects.

Interprofessional communication and care coordination are essential components of patient-centered care in splenectomy. Effective communication among team members facilitates seamless care transitions, ensures timely interventions, and reduces the risk of errors. Care coordination involves integrating services across disciplines, ensuring patients receive holistic care from diagnosis to postoperative follow-up. Regular multidisciplinary team meetings allow for discussion of complex cases, shared decision-making, and coordination of care plans tailored to individual patient needs. By fostering collaboration and communication among healthcare professionals, splenectomy patients benefit from a cohesive, patient-centered approach that optimizes outcomes, enhances patient safety, and improves overall team performance.

Review Questions

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Disclosure: Slee Yi declares no relevant financial relationships with ineligible companies.

Disclosure: Jessica Buicko Lopez declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK560824PMID: 32809659

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