Splenic arterial embolization has been gaining momentum owing to its increasing application in managing various medical and surgical conditions, in addition to its well-established role in managing splenic trauma. For instance, the splenic artery can be compromised by nearby inflammatory processes in the pancreas or at the surgical bed after major hepatobiliary surgery, resulting in pseudoaneurysm formation, which often requires early intervention. In rare cases, the spleen may rupture without trauma and cause catastrophic hemorrhage (i.e., atraumatic splenic rupture). Partial splenic embolization has also been discussed for its role in improving hematological parameters in patients with hypersplenism or in those receiving high-dose chemotherapy or immunosuppressants.

Herein, we report 6 cases of splenic artery embolization performed at our center between April 2011 and October 2023. Cases with different indications and underlying pathologies are included (Table 1), with rationale and techniques employed in each case discussed.

Table 1 . Demographics, endovascular treatment, and technical and clinical outcomes of six patients who received splenic artery embolization.

Case	Age (y)/Sex	Presentation	Diagnosis	Treatment & site (splenic artery or branch)	Technical success	Clinical outcome
1	45/M	Polytrauma	Traumatic splenic artery pseudoaneurysm; splenic laceration	Coil embolization at the superior terminal branch of the splenic artery for pseudoaneurysm; Gelfoam embolization at the proximal splenic artery	Yesa	No clinical evidence of rebleeding, uneventful recovery and discharge
2	56/M	Abdominal pain, hypovolemic shock	Pseudoaneurysm complicating pancreatic pseudocyst	Trapping of the proximal splenic artery involved by pseudoaneurysm	Yesa	Same day open removal of clot and cystogastrostomy for pseudocyst, uneventful recovery and discharge
3	55/M	Post-Whipple operation fresh blood output from abdominal drain	Procedure-related pseudoaneurysm	Trapping of the mid splenic artery involved by pseudoaneurysm	Yesa	Death 2 days after further major hepatobiliary operation
4	71/F	Abdominal pain, hypovolemic shock	Atraumatic splenic rupture (primary splenic angiosarcoma)	NBCA glue embolization of tumor feeder from the inferior terminal branch of the splenic artery	Yesa	Death due to abdominal compartment syndrome, bowel ischemia despite multiple operations 2 days after the index procedure
5	73/M	Abdominal pain, hypovolemic shock	Atraumatic splenic rupture (B cell lymphoma relapse)	Gelatin sponge embolization at the mid splenic artery	Yesa	Death due to refractory hemodynamic shock 1 day after index procedure
6	72/F	N/A (elective procedure)	Hypersplenism from hematological disorders	PVA particle embolization of the inferior terminal branch of the splenic artery	Yesb	Favorable hematological parameters response

M, male; F, female; NBCA, N-butyl cyanoacrylate; PVA, polyvinyl alcohol; N/A, not available..

^aTechnical success is defined as successful angiographic exclusion of bleeder(s) from the parent artery..

^bIn this case, technical success is defined as angiographic success in achieving planned devascularized territory..

The study was approved by the Hospital Authority NTWC Cluster Research Ethics Committee (IRB-2024-091).

1) Case 1: Blunt splenic trauma with concomitant trauma-related pseudoaneurysm and splenic laceration

Patient 1 was a 45-year-old man who presented with polytrauma. Computed tomography (CT) revealed an American Association for the Surgery of Trauma Organ Injury Scale (AAST-OIS) grade IV splenic injury with laceration and a 2 cm trauma-related splenic pseudoaneurysm (Fig. 1A). The patient was hemodynamically stable. Non-operative management with splenic embolization was performed.

Figure 1. Images for case 1. (A) CT scan shows a 2 cm pseudoaneurysm within the splenic parenchyma. (B, C) Pretreatment splenic artery angiogram confirms pseudoaneurysm arising from the superior terminal branch, with no evidence of contrast extravasation. (D) Angiography after NBCA glue embolization of pseudoaneurysm reveals several foci of initially occult angiographic contrast stasis, indicating coexisting multifocal parenchymal injuries (red arrows). With multiple parenchymal lesions, proximal embolization was performed to reduce arterial pressure. (E) Angiographic success was achieved after Gelfoam embolization with dampen splenic arterial flow. The greater pancreatic artery is seen preserved. (F) Follow-up CT scan at 1 month shows preserved mid-lower pole splenic parenchymal perfusion. CT, computed tomography; NBCA, N-butyl cyanoacrylate.

Angiography confirmed a pseudoaneurysm arising from the superior terminal branch of the splenic artery with no contrast extravasation (Fig. 1B). The feeding terminal branch was superselectively cannulated (Fig. 1C) and embolized with N-butyl cyanoacrylate (NBCA) glue (25% concentration), with successful obliteration of the pseudoaneurysm.

Post-embolization angiogram of the distal splenic artery showed several foci of initially occult angiographic contrast stasis, indicating coexisting multifocal parenchymal injuries (Fig. 1D, red arrows). Adjuvant proximal embolization with Gelfoam slurry was performed with successfully dampened splenic arterial flow (Fig. 1E). The patient recovered well with no clinical evidence of recurrent bleeding. Follow-up CT at 1 month showed preserved mid-lower pole splenic perfusion, with an infarct at the superior pole attributed to prior glue embolization (Fig. 1F).

2) Case 2: Pseudoaneurysm complicating pancreatic pseudocyst

Patient 2 was a 56-year-old man with a previous history of biliary pancreatitis complicated with a 8 cm pseudocyst. The patient presented with acute abdominal pain and hypovolemic shock. CT revealed a 14 cm hematoma centered at the pancreatic body with active contrast extravasation, indicating a bleeding pseudocyst (Fig. 2A).

Figure 2. Images for case 2. (A) CT scan shows a large hematoma centered at the pancreatic body, with active internal contrast extravasation. (B) Pre-treatment celiac artery angiogram confirms a pseudoaneurysm arising from the proximal splenic artery. (C) Post-coil and tissue glue embolization angiogram obtained using sandwich technique shows successful obliteration of the bleeder with no non-target embolization to the left gastric artery and common hepatic artery. (D, E) Follow-up CT scan obtained at 3 months shows preserved splenic perfusion. Note the intervally hypertrophied artery coursing from the gastric fundus to the splenic hilum via the gastrosplenic ligament, which was not observed previously, representing a short gastric artery reconstituting splenic perfusion (E, red arrow). CT, computed tomography.

Angiography confirmed a 3.5 cm pseudoaneurysm arising from the proximal splenic artery with contrast extravasation (Fig. 2B). Coil embolization was performed using sandwich technique to eliminate all inflows through the pancreatic collateral network. This was later reinforced by glue injection (tissue glue, 33%) because of the patient’s unstable hemodynamics. Post-embolization celiac angiogram confirmed successful elimination of the bleeder with no non-target embolization (Fig. 2C).

The patient’s condition temporarily stabilized. Laparotomy was subsequently performed, with drainage of 3 L of intraabdominal blood clots and cystogastrostomy done. The patient’s postoperative recovery was uneventful. A follow-up CT performed 3 months later showed resolved hematoma and pancreatic pseudocyst. The splenic perfusion was preserved (Fig. 2D).

3) Case 3: Iatrogenic or procedure-related pseudoaneurysm

Patient 3 was a 55-year-old man who underwent Whipple operation for a pancreatic uncinate-process neuroendocrine tumor. Postoperative CT on day 13 suggested a pancreaticogastrostomy (PG) leak (Fig. 3A, B). On day 15, the patient’s condition deteriorated acutely with hemodynamic shock and fresh blood output from the abdominal drain. CT showed a new fusiform splenic artery pseudoaneurysm and adjacent large hematoma (Fig. 3C). Angiography confirmed a pseudoaneurysm arising from the proximal-mid splenic artery without active contrast extravasation (Fig. 3D). Coil embolization of the splenic artery was performed using sandwich technique. Completion angiography revealed technical success with complete obliteration of the pseudoaneurysm, and the distal splenic artery was supplied by collaterals (Fig. 3E).

Figure 3. Images for case 3. (A, B) Postoperative day 13 CT scan shows fluid collection surrounding the pancreaticogastrostomy, which raised the suspicion of anastomotic leak. (C) A repeat postoperative day 15 CT scan shows acute blood within the intervally enlarged collection and a new splenic artery pseudoaneurysm (red arrow). (D) Pre-treatment splenic artery angiogram confirms a fusiform proximal-mid splenic artery pseudoaneurysm at the level distal to dorsal pancreatic artery origin. (E) Coil embolization using sandwich technique led to successful exclusion of the pseudoaneurysm from the parent splenic artery. Note the preserved dorsal pancreatic artery reconstituting the splenic arterial supply. CT, computed tomography.

The patient’s condition temporarily stabilized. Further surgery confirmed a 7 mm PG anastomotic dehiscence. Complete total pancreatectomy and revision gastrojejunostomy were performed, which were complicated by aberrant hepatic artery injury. The patient’s condition further deteriorated despite endovascular stenting and maximum medical support, and the patient succumbed 2 days postoperatively.

4) Case 4: Atraumatic splenic rupture (ruptured primary splenic angiosarcoma)

Patient 4 was a 71-year old woman with an unremarkable medical history, presented with acute abdominal pain and hypovolemic shock. CT revealed hemoperitoneum with a heterogeneous arterial hyperenhancing tumor at the splenic lower pole and multifocal bilobar hepatic arterial hyperenhancing lesions (Fig. 4A, B). Clotting profile revealed disseminated intravascular coagulation (DIC). Urgent embolization was performed as part of the stabilizing measures prior to definitive total splenectomy in view of the high risk of bleeding.

Figure 4. Images for case 4. (A, B) CT scans show hemoperitoneum and a heterogeneously hyperenhancing mass at the lower pole of the spleen, with splenic capsule disruption over the inferolateral aspect. Multiple hyperenhancing hepatic lesions of similar enhancement pattern are also seen. (C) Pre-treatment splenic artery angiogram confirms a hypervascular lower splenic mass supplied by the hypertrophied inferior terminal branch of the splenic artery. Contrast extravasation is seen. (D) Considering the known impaired clotting profile and the need of rapid hemostasis, glue embolization was selected for this case. Post-NBCA glue embolization celiac angiogram shows successful elimination of the tumor stain and active bleeder. CT, computed tomography; NBCA, N-butyl cyanoacrylate.

Angiography revealed a hypervascular tumor occupying the lower pole of the spleen, supplied by the inferior terminal branch of the splenic artery, with contrast extravasation (Fig. 4C). Selective glue embolization with NBCA glue (20% concentration) was performed at the tumor feeder, with successful elimination of the tumor stain and active bleeder from the parent splenic artery (Fig. 4D).

Upon close observation in the intensive care unit after embolization, the patient developed abdominal compartment syndrome with intraabdominal pressure of 60 mmHg. The patient underwent emergency laparotomy and total splenectomy. Intraoperative findings confirmed a 4 cm rupture at the lower pole of the spleen, with no evidence of rebleeding. The patient remained in a critical condition postoperatively, with worsening DIC and severe metabolic acidosis, and subsequently developed diffuse bowel ischemia. The patient died 2 days after the procedure and surgery. Pathological examination of the splenic specimen revealed a primary splenic angiosarcoma.

5) Case 5: Atraumatic splenic rupture (ruptured splenic lymphoma)

Patient 5 was a 73-year-old man with a history of diffuse large B cell lymphoma, with recent note of new cervical and groin lymphadenopathies. The patient presented with acute abdominal pain and hypovolemic shock. CT revealed hemoperitoneum with foci of active contrast extravasation from the enlarged spleen (up to 19.7 cm in length). Hepatomegaly and multiple enlarged intraabdominal and iliac lymphadenopathies were also observed (Fig. 5A-C). Clinically and radiologically, there was evidence of a lymphoma relapse.

Figure 5. Images for case 5. (A, B, C) CT scans show the presence of hemoperitoneum with hepatosplenomegaly and multiple enlarged paraaortic lymph nodes. Several foci of active contrast extravasation are noted in the enlarged spleen. (D) Pre-treatment celiac angiogram confirms multiple foci of contrast extravasation within the spleen arising from the superior, middle, and inferior terminal branches (red arrows). Considering the multiplicity of bleeders, proximal splenic embolization was preferred for this case to decrease splenic perfusion pressure. CT, computed tomography.

Angiography revealed at least three foci of active contrast extravasation from the superior, middle, and inferior branches of the splenic artery (Fig. 5D, red arrows). Proximal splenic embolization with Gelfoam slurry was performed, with successful exclusion of bleeders from the parent artery. The patient’s condition remained critical postoperatively, with DIC, acute renal failure, and severe metabolic acidosis. Despite receiving maximal medical support in the intensive care unit, the patient died the following day.

6) Case 6: Partial splenic embolization (PSE) for hypersplenism

Patient 6 was a 72-year-old woman, in whom multiple lines of medical therapy for autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenia purpura (ITP) failed. She had multiple comorbidities and was considered unfit for total splenectomy. Partial splenic embolization was offered as an alternative to surgery.

The treatment goal was set at 50% embolization volume. Splenic artery angiography was performed. The inferior terminal branch of the splenic artery was selectively cannulated, with parenchymal phase angiogram delineating the predicted embolization territory (Fig. 6C), followed by polyvinyl alcohol (PVA) particle embolization. Post-embolization angiogram demonstrated technical success (Fig. 6D). The patient developed fever and left upper abdominal pain on day 4 postoperatively. CT showed no evidence of complication and confirmed a successful planned embolization volume at approximately 50% (Fig. 6E). The symptoms subsided with supportive treatment. Subsequent clinical success was confirmed by gradual normalization of the platelet count in 3 weeks and stable hemoglobin level, without the need for transfusion during 3 months postoperatively (compared with monthly transfusion before).

Figure 6. Images for case 6. (A, B) Pre-treatment angiography was performed to delineate the vascular anatomy. Parenchymal phase angiogram shows the size of the spleen for treatment planning. (C) The lower half of the spleen (50%) was selected as the embolization target to minimize post-procedural pleurisy and pleural effusion. Selective cannulation of the inferior terminal branch was performed, with angiogram estimating the planned embolization territory with the current catheter position. (D) Post-embolization splenic artery angiogram confirms successful devascularization of the lower half of the spleen while preserved flow in the upper half. (E) Follow-up computed tomography scan obtained after 4 days confirms successfully planned devascularized volume.

Through the aforementioned cases, we highlighted four different indications for splenic artery embolization (blunt splenic trauma, splenic artery pseudoaneurysms, atraumatic splenic rupture, and hypersplenism), underscoring the role of splenic artery embolization. The evidence for clinical practice and technical considerations for each indication have been discussed below.

1) Embolization for blunt splenic trauma

Over the past few decades, the approach for managing splenic trauma has shifted from operative to non-operative management (NOM), which involves close clinical monitoring with or without splenic artery embolization. The advantages of NOM include fewer intraabdominal complications, lower transfusion needs, preservation of splenic function, and avoidance of overwhelming post-splenectomy infection (OPSI). A multicenter study by Banerjee et al. [1] suggested that centers with a higher use of splenic artery embolization have a higher splenic salvage rate and a lower failure rate of NOM. This is consistent with the findings of Requarth et al. [2], who stated that NOM has a higher failure rate in observational management without splenic artery embolization and that splenic artery embolization is associated with a higher splenic salvage rate in AAST-OIS grade 4 and 5 splenic injuries.

Three techniques of splenic artery embolization have been described for blunt splenic trauma. Proximal embolization is defined as the placement of embolic agent in the splenic artery proximal to its dividing branches and distal to the dorsal pancreatic artery. Technical success is determined by the cessation of arterial flow at the packed point while distal flow is provided by collaterals. Proximal embolization aims to dampen splenic perfusion pressure, which is typically achieved by coil packing; though vascular plugs and absorbable gelatin has also been used. Distal embolization is defined as the placement of embolic agent in the segmental branches of the splenic artery within the parenchyma, targeting ischemia within a limited vascular territory, where technical success is defined as the cessation of distal flow without collateral supply. Absorbable gelatin, particles, and coils can be employed in distal embolization either alone or in combination [3]. Combined embolization is defined as the combined use of the above two techniques, in which additional proximal embolization after successful distal embolization may help eliminate possible occult injuries on the initial angiogram which may cause delayed rebleeding. In general, proximal embolization is performed in cases of multifocal splenic injury, whereas distal embolization is performed for focal vascular injury. Proximal embolization may require a shorter procedure time, enable quicker hemostasis, and reduce radiation dose to both the patient and operator [4].

Case 1 illustrates two manifestations of blunt splenic trauma—vascular injury and parenchymal injury. The presence of vascular injury including traumatic pseudoaneurysm signifies an AAST-OIS grade IV injury. The management of pseudoaneurysm has been discussed in the next section. In this case, hemostasis was achieved by proximal embolization of multifocal splenic parenchymal injuries using absorbable gelatin.

To date, no randomized controlled trials have been conducted to compare proximal and distal embolization, and conflicting findings exist in the literature regarding the clinical outcomes of different embolization locations. Schnüriger et al. [5] conducted a meta-analysis comparing proximal and distal embolization in terms of efficacy and complications and reported no significant difference between the two techniques in terms of major splenic infarctions, infections, and major rebleeding. Conversely, Rong et al. [6] reported that proximal embolization is associated with a significantly lower rate of severe complications (complications that are life-threatening or require further surgery) than those with the distal and combined techniques.

2) Embolization for splenic artery pseudoaneurysms

Various etiologies of splenic artery pseudoaneurysms have been reported. The most common cause is acute pancreatitis, followed by abdominal trauma; less commonly pseudoaneurysms may be iatrogenic or may occur secondary to peptic ulcer disease and pancreatic neoplasm invasion [7]. Splenic artery pseudoaneurysms are more likely to occur in blunt abdominal trauma than in penetrating abdominal trauma and are more often intrasplenic in location (as in case 1) than occurring in the main splenic artery. Enzymatic activity from leaked digestive excretions (e.g., proteolytic enzymes in pseudocysts in case 2) can cause autodigestion of the vessel walls and form pseudoaneurysms. Inadvertent vascular wall disruption can also occur in complex surgery, either by direct vessel injury or by postoperative perivascular inflammation, as observed in case 3.

For managing splenic artery pseudoaneurysms, prompt treatment is needed regardless of the presence of symptoms and pseudoaneurysm sizes according to the recently published Cardiovascular and Interventional Radiological Society of Europe standards of practice in late 2023 [8]. The aim of endovascular treatment is to exclude pseudoaneurysms from the arterial circulation. The etiology of splenic artery pseudoaneurysms is not considered a factor for determining the indication for treatment.

Endovascular treatment considerations for splenic artery pseudoaneurysms differ from those for hepatic and renal pseudoaneurysms, in which preserving organ perfusion is crucial. A constructive approach (e.g., the use of covered stents) is considered for the liver and kidneys whenever technically and anatomically feasible. In contrast, the spleen is more forgiving in adopting a destructive approach, where part of the splenic artery is expendable because distal organ perfusion can be achieved by collaterals. Coils are the most widely used agents for pseudoaneurysm embolization, and various techniques have been described. For pseudoaneurysms with collateral inflow vessels, sandwich technique is required to block both the efferent and afferent arteries. Stent graft deployment is another option for treating splenic artery pseudoaneurysms. However, additional considerations for stent grafts include the availability of delivery systems, necessity of periprocedural antithrombotics to maintain patency, as well as additional time, cost, and expertise required compared with other endovascular options.

In cases 2 and 3, a destructive approach with sandwich technique was implemented to the proximal and mid splenic artery. The landing zone of the last coil should be carefully planned such that the dorsal pancreatic artery maintains splenic perfusion via the collaterals. If a pseudoaneurysm arises at a site located more proximal to the origin of the pancreatic branches (as observed in case 2), the destructive approach will inevitably sacrifice the pancreatic branches. In case 2, splenic perfusion was reconstituted by the gastric collateral network, suggesting that sacrificing the pancreatic branches may not necessarily jeopardize splenic perfusion.

3) Atraumatic splenic rupture (ASR)

ASR is a rare entity with a poorly defined incidence and prognosis owing to the heterogeneity of available data. The three proposed mechanisms of ASR include increased intrasplenic tension due to cellular hyperplasia/engorgement or underlying infiltrative processes, splenic compression by the abdominal musculature during physiological activities, and vascular occlusion resulting in thrombosis and infarction. These may lead to interstitial and subcapsular hemorrhages, splenic capsular distension, and eventually rupture [9].

Renzulli et al. [10] suggested six major etiology groups, including neoplastic, infectious, inflammatory noninfectious, drug- and treatment-related, mechanical, and idiopathic. Neoplastic and infectious disorders are the most common. Among neoplastic disorders, malignant hematological disorder is the most common. Cases 4 and 5 presented with ASR of neoplastic etiology (malignant hematological and primary neoplastic disorders). Neoplastic causes are significantly associated with fatal outcomes. Additionally, splenomegaly and age >40 years are significantly associated with increased ASR-related mortality. In general, patients with ASR of neoplastic etiology undergo total splenectomy, although in some circumstances, transarterial embolization (TAE) may be considered as a temporary stabilizing measure (as observed in case 5) or as a preoperative technique to reduce anticipated intraoperative blood loss (as observed in case 4). Different techniques were employed in both cases. In case 4, distal embolization targeted the tumor feeder, whereas in case 5, proximal embolization was performed using a temporary occlusive agent in view of multiple bleeders. Technical success was achieved in both cases.

To date, no widely accepted treatment guideline is available for managing ASR. Direct application of treatment guidelines for blunt splenic injury and ASR is not recommended because the latter often involves a pathological spleen. Case reports are available describing the success of TAE in initial stabilization and as part of the non-operative management of ASR; however, evidence remains insufficient for conclusive recommendation. In our center, the management of ASR is based on case-by-case discussions among surgeons, intensivists, and interventional radiologists, and TAE is only performed in carefully selected cases.

4) Partial splenic embolization (PSE) for hypersplenism

By functionally removing a part of the spleen and decreasing its consumptive activity, PSE is considered a less invasive alternative to total splenectomy for managing surgically unfit patients with hypersplenism. PSE can improve hematological parameters in patients with hypersplenism from various hematological disorders, as well as cytopenia induced by chemotherapy [11]. The advantages of PSE over splenectomy include retention of splenic immunological function and reduced risk of OPSI. Case 6 illustrates successful improvement in hematological parameters in a patient with AIHA/ITP. Miyazaki et al. [12] reported a complete or partial response rate of platelet increase after PSE in more than 70% of patients with ITP who were refractory to steroids. Kimura et al. [13] also concluded that repeated PSE may be an effective alternative to splenectomy for treating chronic ITP.

In PSE for hypersplenism, most interventional radiologists aim to embolize 50%-70% of the splenic parenchyma to balance procedural efficacy and safety [3], where hematological response and complication severity were found to correlate with the embolized volume [11]. Harned et al. [14] reported that a smaller embolization volume at 30%-40% showed lower efficacy in improving hematological parameter despite significantly reduced morbidity.

“Selective partial embolization” and “non-selective partial embolization” are the two PSE techniques that have been described. The former targets and embolizes the distal branches of the splenic artery (often the mid-lower pole to minimize post-procedural pleurisy and pleural effusion, as performed in case 6) guided by intermittent parenchymal phase angiograms, whereas the latter involves the deployment of embolic agents at the main splenic artery beyond the pancreatic branch origins until the splenic parenchymal blush is reduced. Gelatin sponge pledgets and particles are the embolic agents of choice. Coils are not preferred because distal permeative embolization is required to induce parenchymal ischemia. Zaitoun et al. [15] investigated the clinical, laboratory, and radiological outcomes of PSE using gelatin sponges, calibrated microparticles and PVA particles and reported significantly better outcomes with particles than with gelatin sponges in improving leukocyte and platelet counts over 1 year after PSE. Although these permanent agents have shown promising results, they are associated with greater and longer post-procedure abdominal pain. Occasionally, as observed in case 6, differentiating between post-embolization syndrome and splenic abscess in the setting of post-procedure fever and abdominal pain can be clinically challenging. If the clinical suspicion of procedure-related major complications remains high, CT should be made readily available to guide clinical management.

5) Conclusion

Splenic artery embolization can be used to treat various medical conditions, not limited to facilitating non-operative management of blunt splenic trauma. This minimally invasive procedure is a safe and effective modality for treating splenic artery pseudoaneurysms and may have potential as a temporary stabilizing measure or preoperative technique for managing patients with atraumatic splenic rupture. Partial splenic embolization can be considered an alternative to splenectomy in patients with hypersplenism who are contraindicated for surgery. Interventional radiologists should be aware of these indications and understand their corresponding technical considerations and existing evidence for practice.

None.

The authors have nothing to disclose.

Concept and design: CHC, YSL, JCWS. Analysis and interpretation: all authors. Data collection: CHC, YSL. Writing the article: CHC. Critical revision of the article: YSL, PLC, CHH, JCWS. Final approval of the article: all authors. Statistical analysis: none. Obtained funding: none. Overall responsibility: CHC.