Perioperative management - Endocystectomy for Echinococcus granulosus infection of the liver

Introduction

Human echinococcosis is a zoonosis caused by larval forms of Echinococcus tapeworms found in the small intestine of carnivores. Two species (E. granulosus and E. multilocularis) are of medical significance, causing cystic echinococcosis (CE) and alveolar echinococcosis (AE) in humans, respectively.

Alveolar echinococcosis is considered the most dangerous parasitic disease in Europe, while cystic echinococcosis is much milder. Due to the completely different growth behavior of the two diseases in humans, two different clinical pictures result. The appearance of AE resembles that of a malignancy, while the CE lesion appears benign due to the smooth-bordered pericyst.

According to WHO, cystic echinococcosis (CE) is the disease caused by the larval stage of Echinococcus granulosus (dog tapeworm). The actual tapeworm lives in the intestine of the definitive host (dog) and produces eggs that are excreted with the feces. The eggs are ingested by the intermediate/accidental host (human or animal). In the intestine, larvae (oncospheres) hatch from the eggs. These parasitic larvae penetrate the intestine and reach the liver or other organs via the portal vein system, where they transform into their second larval stage (metacestodes) and mature into cysts (hydatids). In the cyst, daughter cysts develop, in which protoscoleces (head structures of the future tapeworms) form. These protoscoleces can grow into adult tapeworms if larva-containing organs are consumed by a definitive host. Humans usually become infected by accidentally ingesting soil, water, or food contaminated with Echinococcus eggs from dog feces.

All age groups, including infants, children, and adolescents, are affected by cystic echinococcosis. The clinical course is highly variable and depends on the location of the cysts, their size, and the host reaction. The disease is characterized by slowly enlarging cysts (especially in the liver and lungs) that can remain asymptomatic for years and only become symptomatic due to their space-occupying effect, secondary bacterial infection of the cysts, cystobiliary or cystobronchial fistulas, or anaphylactic reactions after rupture. In most patients, only one organ is affected. Cysts are most commonly found in the liver (70%) and lungs (20%).

Epidemiology

Cystic echinococcosis (CE) is widespread worldwide. A particularly high prevalence is found in regions of South America, the Mediterranean coast, Eastern Europe, the Near and Middle East, East Africa, Central Asia, China, and Russia.

In Germany, the diagnosed cases almost exclusively involve patients from the aforementioned endemic areas.

In endemic areas, dogs are often fed with the viscera of slaughtered animals. Larva-containing offal causes adult tapeworms to develop in the main definitive host after consumption.

Infectiousness

The risk of infection is particularly high in hyperendemic areas where close contact with the main host (dog) occurs under poor hygienic conditions. There is no human-to-human transmission. Surgical material is not infectious.

Morphology

The cyst itself consists of the pericyst (periparasitic inflammatory reaction of the host tissue with the formation of a fibrous capsule) and the endocyst, the actual parasite's cyst component. The endocyst consists of an outer acellular and an inner germinative layer, where brood capsules with protoscoleces (head structures of the future adult worms), the so-called hooks, form.

Cyst Classification

Since 2003, there has been a standardized ultrasound classification according to WHO-IWGE (World Health Organization Informal Working Group on Echinococcosis), which is based on the division of cysts according to their sonographic morphology into active - transitional - inactive.

In this classification, 6 cyst stages are assigned to 3 clinical groups, with stage CL including an undifferentiated "cystic lesion" whose parasitic nature has not yet been definitively assessed.

Group 1: The active group includes unilocular cysts (CE1) or cysts with multiple daughter cysts (CE2).

Group 2: The transitional group includes cysts with a detached endocyst membrane ("water-lily" sign) (CE3a) and consolidated cysts with daughter cysts (CE3b). CE3a can solidify and become "inactive" or form daughter vesicles and transition to a CE2 stage.

Group 3: The "inactive" group shows involution with consolidation of the cyst content and increasing calcification and is considered avital in most cases.

In summary, CE1 and CE2 represent active cysts, CE3 is a transitional stage, with CE3b cysts considered biologically active. CE4 and CE5 are late inactive cyst stages.

Therapy

There is no standard therapy recommendation for the treatment of cystic echinococcosis. In principle, remissions without therapy are frequently observed and demonstrate the benign nature of this disease, as long as none of the risk constellations listed below are present.

The therapy of CE (cystic echinococcosis) depends on the cyst stage and is thus dependent on the morphology and vitality assessment. In principle, surgical removal is possible at all stages. However, there is a risk of overtreatment.

Due to the questionable inactivity, it is recommended to observe lesions in stages CE4 and CE5. In these stages, the lesion is monitored by imaging and serologically. If there is an increase in titer or size, surgical removal may be indicated.

In all other stages, a conservative therapy attempt with benzimidazoles albendazole or mebendazole for 3 to 6 months can be conducted for lesions up to about 5 cm, with a chance of healing in 60–70%.

For transhepatically puncturable cysts in stage CE1 or CE3a, which are smaller than 10 cm, puncture, aspiration, instillation, and reaspiration (so-called PAIR) is a promising and low-complication alternative to surgery, as the internal structure of these cysts is practically liquid. Here, the cyst is punctured and aspirated percutaneously or surgically (open or laparoscopically). Then, an anthelmintic or protoscolicidal substance is instilled, and this fluid is aspirated again after sufficient exposure time. The procedure is performed under albendazole protection to prevent secondary echinococcosis.

It should be noted that for cysts larger than 7-8 cm, the risk of a cystobiliary fistula increases (up to 80%). Since hypertonic NaCl (20%) or ethanol (95%), the two most commonly used protoscolicidal substances, can cause toxic cholangitis, a cystobiliary fistula must be definitively excluded by bilirubin determination in the cyst fluid and/or antegrade contrast imaging.

The surgical treatment is the first-choice therapy for

• Cysts > 10 cm
• Cysts in stage CE2 and CE3b with multiple daughter cysts, as the internal structure of the cysts is not suitable for PAIR.
• Cysts that are connected to the bile ducts.
• Cysts that compress organs or vessels.
• Cysts with the risk of rupture (traumatic or spontaneous) or already ruptured cysts.
• Cysts with a superficial location should not receive purely conservative therapy, as the wall of the cyst is thinned by the treatment, increasing the risk of cyst rupture, which can lead to secondary echinococcosis.
• Superinfected cysts when percutaneous treatment is not possible.

In the demonstrated case, there were three large echinococcal cysts of the liver in stage CE3b, one in the left and the other two, communicating with each other, in the right liver lobe. The endocystectomy aims to remove the entire endocyst with daughter cysts from the cyst cavity. In the vicinity of the cysts, massive adhesions to the surroundings are typically found.

• Patients with inoperable cysts in the liver and lung, multi-organ involvement, or peritoneal dissemination -> palliative drug therapy with anthelmintics.
• Inactive asymptomatic cysts -> lesions are monitored by imaging and serologically.
• Difficult-to-access cysts -> PAIR or drug therapy
• Very small cysts -> drug therapy
• Patients with a technically or functionally inoperable condition -> PAIR or drug therapy
• Patients for whom general contraindications for surgery apply -> PAIR or drug therapy

The diagnosis of a CE is mostly indirect and based on medical history, imaging, and serology.

The differential diagnoses are diverse and include:

• dysontogenetic cysts
• benign and malignant tumors
• abscesses
• tuberculosis and
• alveolar echinococcosis (cystic appearing necroses).

Medical History

The detailed medical history is the basis of diagnostics, especially for distinguishing from alveolar echinococcosis: contact with animals and agriculture, origin of the patient, lifelong travel history. Almost all cases of cystic echinococcosis are imported infections due to migration or prolonged stays abroad in countries with low hygiene standards for humans and animals. It is often an incidental finding.

Clinical Symptoms

Abdominal pain often appears as the first symptom. Larger liver cysts can be palpated as resistance in the right upper abdomen. Compression of bile ducts and the passage of cyst contents through cystobiliary fistulas into the bile ducts lead to bile duct obstruction, possibly accompanied by cholangitis. Leakage of hydatid fluid from a cyst, e.g., into the free abdominal cavity in the event of a cyst rupture, can range from mild allergic reactions to anaphylactic shock. The clinical symptoms of rare cyst locations (e.g., cerebral, spinal, cardiac, osseous) are organ-specific and varied.

Imaging

Ultrasound is the imaging method of choice for diagnosis, staging, and follow-up of hepatic cystic echinococcosis. It is superior to CT and MRI for staging. The sensitivity of ultrasound for assessing echinococcosis is 90-95% in the hands of experienced examiners.

Depending on the stage of the disease, an encapsulated cystic structure is observed, typically with a double wall ("double-line-sign") with or without internal structures. Septations, daughter cysts, and rarely calcifications can be observed.

Since 2003, there has been a consensus on the classification proposed by the WHO-IWGE (World Health Organization Informal Working Group on Echinococcosis), which allows classification of cysts into three relevant groups based on their sonomorphological appearance: active (CE1 and 2), transitional (CE3), and inactive (CE4 and 5). CE3 transitional cysts can be differentiated into CE3a (with detached endocyst) and CE3b (predominantly solidified with daughter vesicles).

This classification assigns 6 cyst stages to 3 clinical groups:

The CL category indicates a nonspecific cystic lesion that requires further investigation before a definitive decision about its parasitic nature can be made.

CE1 univesicular anechoic cyst, hydatid sand (sediment due to free protoscolices), "double line sign"

CE2 multivesicular/-septated cyst (daughter cysts), "rosette sign", "honeycomb sign"

CE3a univesicular cyst with detached floating endocyst membrane (“water-lily”-sign)

CE3b multivesicular cyst with signs of solid transformation (daughter cysts in solid matrix)

CE4 heterogeneous echogenicity of consolidated cyst contents without evidence of daughter cysts, solidified detached endocyst membrane (“ball of wool”-sign) as folded hypoechoic structure in a hyperechoic matrix

CE5 solid cyst contents, calcified cyst wall

Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) (T2-weighted with possibly cholangiopancreatography) are indicated in

(1) Sonographic uncertainty in the differential diagnosis of focal liver lesions

(2) Limitations of ultrasound examination due to restricted examination conditions

• in obesity
• meteorism
• subdiaphragmatic location

(3) disseminated disease

(4) extra-abdominal location (lung, bone)

(5) in complicated cysts (abscess, cystobiliary fistulas)

(5) Operation planning

(6) recurrent disease

Whenever possible, MRI imaging should be preferred over CT due to better visualization of fluid areas within the cyst matrix. It is the examination of choice for assessing the number, size, location of cysts, and their relationship to neighboring organs.

MR cholangiography is equivalent to ERCP in terms of sensitivity for clarifying cystobiliary connections. However, interventional procedures are only possible in conjunction with ERCP.

Serology

Serological tests are helpful to confirm an imaging suspicion. However, their significance is limited as they are associated with a high rate of false-negative results. Especially in early or late inactive cyst stages, where exposure of E. granulosus antigens to the host's immune system has not yet occurred or no longer occurs.

A two-step procedure is applied, initially using a sensitive antibody screening test (Enzyme-linked immunosorbent assay (ELISA), indirect hemagglutination test (IHA)) with an antigen from cyst fluid, followed by a confirmation test (immunoblot) using more specific antigens. False positive results due to cross-reactions with other helminths and gastrointestinal malignancies must also be considered.

Overall, the sensitivity and specificity of serological testing remain unsatisfactory, and up to 20% of cases of hepatic cystic echinococcosis show no measurable antibody response. A positive serology alone without a morphological correlate does not confirm cystic echinococcosis and does not require therapy.

Histology

The diagnosis can be made histologically from biopsy and surgical material. Punctures for aspiration of parasite material are only justified if the diagnosis remains unclear through imaging and serology. These should be performed under prophylaxis of secondary echinococcosis with, e.g., albendazole.

Routine preoperative cytology/histology is not recommended due to the risk of parasite dissemination or anaphylactic reactions upon cyst opening/rupture.

A confirmed infection is only present with histopathological evidence of echinococcus-typical structures (protoscolices/hooks in the cyst fluid) or typical macroscopic changes in the surgical resection.

• ERCP with bile duct stent in mechanical cholestasis or cholangitis due to compression or rupture of the cyst into the biliary system.
• To maximize the outcome for patients, secondary seeding of Echinococcus granulosus during surgical resection should be strictly avoided. Since the risk is present in a surgical procedure due to manipulation at the site of infection, an albendazole therapy (400mg/2x/d) should be started 24 hours before the operation.
• Blood group determination with sufficient transfusion reserve
• Increased cardiopulmonary risk requires clarification of the surgical risk through further diagnostics (stress ECG, heart echo, coronary angiography, lung function test).
• Adequate intensive care capacity for high-risk patients
• A mild laxative or enema is recommended the day before.
• Preoperative antibiotic administration as a single shot of a 2nd generation cephalosporin ½ hour before skin incision.

Standardized consent forms should be used for patient education. These also include appropriate anatomical drawings where the findings can be recorded. Alternatives and additional treatment options should be explained, especially extensions of the primary procedure should always be discussed.

Before any planned liver surgery, a cholecystectomy should also be discussed.

General Risks

• Bleeding and rebleeding
• Hematoma
• Need for transfusions with associated transfusion risks
• Thromboembolism
• Wound infection
• Abscess
• Injury to adjacent organs/structures (stomach, esophagus, spleen, diaphragm)
• Wound dehiscence
• Incisional hernia
• Follow-up surgery
• Mortality

Specific Risks

• Anaphylaxis
• Peritoneal seeding, secondary echinococcosis
• Liver parenchyma necrosis
• Bile fistula
• Bilioma
• Hemobilia
• Biliary peritonitis
• Pleural effusion
• Air embolism (due to unintentional or unnoticed opening of liver veins)
• Portal vein thrombosis
• Hepatic artery thrombosis
• Recurrence

Intubation anesthesia

Intra- and postoperative analgesia with epidural catheter

Follow the link here to PROSPECT (Procedure specific postoperative pain management) or to the current guideline Treatment of acute perioperative and post-traumatic pain.

In liver surgeries, anesthesia plays an important role in intraoperative blood-saving measures.
The pressure in the hepatic sinusoids depends on the pressure in the hepatic veins, which in turn depends on the central venous pressure (CVP). Therefore, during the preparation phase, the CVP should be lowered to 2-5 mmHg, which can significantly reduce intraoperative blood loss.
In the event of accidental opening of large hepatic veins or the vena cava, the PEEP should be temporarily increased to prevent impending air embolisms.

The positive end-expiratory pressure (PEEP, English positive end-expiratory pressure) is a parameter in artificial ventilation. It refers to a positive pressure in the lungs at the end of expiration. It is generated by a PEEP valve.

Supine position, both arms positioned alongside, slight hyperextension at the thoracolumbar junction

• Surgeon to the right of the patient
• 1st Assistant to the left of the patient
• 2nd Assistant to the right of the patient, towards the head of the surgeon
• Scrub nurse to the left of the patient, towards the feet of the 1st Assistant

• Gallbladder, vascular tray, or LTX tray
• Cable pull hook system
• Mercedes retractor
• Sealing/dissection instrument
• Ultrasound device
• Aids for focal hemostasis of the liver: e.g., clips, bipolar and monopolar coagulation
• Abdominal towels soaked with 20% NaCl
• Large-bore suction device
• Intravenously administered fat emulsion (Lipovenous®)
• Trocars 10 or 12 mm with preferably sharp conical obturator
• Closed wound drainage system (Blake® drains)

Postoperative Analgesia
Adequate pain management; for more severe pain, systemic analgesics in addition to the epidural catheter should be considered, taking into account potential hepatotoxicity. Follow the link to PROSPECT (Procedures Specific Postoperative Pain Management) or the link to the current guideline Treatment of Acute Perioperative and Posttraumatic Pain.

Medical Follow-up
If the drains do not produce bile by the 2nd postoperative day, a later bile fistula is extremely rare, so the drain can be removed on the 2nd/3rd day.

Follow-up with Albendazole 10-15 mg/kg body weight/day in 2 divided doses for 4 weeks. Administration must be with a high-fat meal to ensure absorption.

Removal of skin sutures around the 12th postoperative day

Postoperative follow-up should last at least 5 years with annual imaging using ultrasound or MRI.

Thrombosis Prophylaxis
In the absence of contraindications, due to the high risk of thromboembolism, low molecular weight heparin should be administered prophylactically, possibly in a weight- or risk-adapted dosage. Consider renal function, HIT II (history, platelet monitoring). Follow the link to the current guideline Prophylaxis of Venous Thromboembolism (VTE).

Mobilization
As early as possible, especially for pneumonia prophylaxis, which is essential in any liver surgery. Gradual resumption of physical activity until full load is achieved.

Physical and Respiratory Therapy
Pneumonia prophylaxis is vital and takes absolute priority in liver surgeries! For example, a breathing assistant (Bird) and/or Triflow exercise device and appropriate physical therapy.

Diet Advancement
Rapid diet advancement; on the 1st postoperative day, tea, soup, crackers. Full diet advancement should be completed by the 3rd postoperative day.

Bowel Regulation
From the 3rd day, the patient should be given a laxative, and bowel activity can be stimulated, for example, with an enema.

Incapacity for Work
In open procedures with median laparotomy extension into the right flank, the risk of postoperative incisional hernia is not insignificant, so the patient should adhere to postoperative rest for at least four to six weeks. Light work, especially office tasks, can be resumed earlier.