Imipenem/cilastatin sodium (IPM/CS) as an embolic agent for transcatheter arterial embolisation: a preliminary clinical study of gastrointestinal bleeding from neoplasms

Control of tumour bleeding is a compelling need for physicians. Anticancer therapy, including resection, chemotherapy, and radiation, can be a solution for bleeding from neoplasms. Transcatheter arterial embolisation (TAE) may be selected as rescue therapy for patients in whom haemostasis is not achievable with these treatments.

Various embolic materials including metallic coils, gelatin sponges, n-butyl 2-cyanoac\rylate, polyvinyl alcohol (PVA), and microspheres have been used for TAE for intestinal bleeding (Kramer et al. 2000; Defreyne et al. 2001). When the bleeding origin vessel is well visualised and superselectively accessible, coil embolisation will be selected (Defreyne et al. 2001; Gordon et al. 1997; Horiguchi et al. 2003; Ledermann et al. 1999). However, it may be difficult to identify culprit vessels of tumour bleeding on angiography because tumour bleeding is likely to be attributed to fine vessels (Chuang et al. 1979). Additionally, tumour bleeding is sometimes intermittent, and extravasation may not be observed at the time of angiography. In these situations, superselective embolisation using coils will not be feasible, and use of gelatin sponges or PVA may be considered. However, embolisation with these agents may cause ischaemic complications of neighbouring intact structures, particularly for small and large intestinal bleeding, because of relatively poor collateral blood supply (Defreyne et al. 2001; Guy et al. 1992; Rosenkrantz et al. 1982). Pancreatitis and duodenal stricture have been reported as complications after superselective TAE of the gastroduodenal artery, mostly using glue and a gelatin sponge (Lang 1992; Loffroy & Guiu 2009).

In 1999, two Japanese studies reported introduction of imipenem/cilastatin sodium (IPM/CS) as an embolic agent for chemoembolisation in an animal model, in which IPM/CS particles in a mixture with iodine contrast material were revealed as small in size, around 10 to 70 μm, and demonstrated a transient embolic effect (Aihara 1999a; Aihara 1999b). Based on these characteristics of IPM/CS, we assumed the usefulness of IPM/CS as an embolic agent for intestinal bleeding from neoplasms. In clinical practice, we performed embolotherapy using IPM/CS for patients who needed haemostasis for bleeding from neoplasms, and who were poor candidates for other therapeutic options such as endoscopic, surgical haemostasis and embolotherapy with other embolic materials because of the possibility of ischemic complication. Arterial introduction of IPM/CS as a prophylactic antibiotic for acute pancreatitis has been performed (Buchler et al. 2000), indicating the safety of arterial introduction of IPM/CS.

The purpose of the present study was to evaluate the feasibility and usefulness of IPM/CS as an embolic material for intestinal bleeding from neoplasms.

A summary of the clinical course of the seven patients (11 procedures) is shown in Table 1. Angiography revealed tumour staining in all patients (Figure 1). Extravasation was observed in three of the eleven procedures. However, bleeding origin vessels accessible by microcatheter were not found in any of the three procedures (Figure 1). All 11 procedures showed encased arteries, proliferation of blood vessels, and prolonged staining with contrast enhancement at locations of the known tumours, which were strongly assumed to be origins of bleeding.

Pt. no	Age	Sex	Disease	Outcome	Proc no.	Extravasation	Embolized artery	IPM/CS (g)	Rebleeding (day)
1	53	M	Pancreatic cancer	Died at day 247	1	+	PA	0.5	-
2	59	M	Malignat lymphoma	Died at day 163	2	+	JA	2.2	0
					3		JA	0.6	-
3	68	M	Pancreatic lymphoma	Died at day 48	4		IA	0.5	21
					5		IA	1.0	1
4	73	M	Pancreatic cancer	Transferred at day 44	6		PA	1.5	10
					7		PA	1.4	-
5	64	M	Metastasis to the pancreas	Died at day 224	8		PA	0.9	-
6	46	F	Invasion of cervical cancer to the rectum	Transferred at day 339	9 10		IRA	0.4	0
							SRA	0.4	-
7	43	F	Colon cancer	Died at day 37	11	+	LCA		-

Pt. no., patient number; Proc. no., procedure number; PA, pancreatic arcade; JA, jejunal artery; IA, ileal artery; RCC, renal cell carcinoma; IRA, inferior rectum artery; SRA, superior rectum artery; LCA; left colic artery.

The positions of the microcatheter during embolisation were at the main trunk of the pancreatic arcade (4 procedures), at a site proximal to the arterial arcade of the jejunal artery (2 procedures), at a site proximal to the arterial arcade of the ileal artery (2 procedures), at a site proximal to the marginal artery of the left colic artery (1 procedure), at the main trunk of superior rectal artery (1 procedure), and at the main trunk of the inferior rectal artery (1 procedure). Disappearance of extravasation or blood flow to the tumour during the procedure was obtained in all procedures. Thus, the technical success rate was 100%. No complication was observed relating to the TAE technique. The median amount of IPM/CS used for TAE was 0.6 g (range: 0.2–1.5 g).

Bleeding recurred for five procedures (45%) in four patients at 0, 0, 1, 10, and 21 days after TAE. TAE was repeated after four of the five procedures and was successful in all procedures. During all these repeat TAE procedures, recanalisation of the arteries that were embolised at the first TAE was observed (Figure 1c). For the other patient suffering from rebleeding, haemostasis occurred without repeat TAE. No conversion to surgical haemostasis occurred.

No clinical sign or symptom of ischaemia after TAE was observed. The mean WBC, LDH, and CPK before and after TAE were as follows; WBC (μl): 8637 ± 3243, 10212 ± 3490, LDH (IU/l): 275 ± 250, 285 ± 244, CPK (IU/l): 33 ± 20, 38 ± 30. No significant difference in WBC, LDH, or CPK was found before and after TAE . In the patient who had two TAE procedures and endoscopies after each TAE (patient 3), no sign of rebleeding or ischaemic change was noted.

No death directly relevant to tumour bleeding or embolisation occurred. Five patients died because of progression of the original diseases 37 to 247 days (median: 163 days) after TAE.

We experienced no adverse event related to arterial introduction of IPM/CS, suggesting the safety of IPM/CS as an embolic material. The 100% technical success rate indicated the feasibility of TAE using IPM/CS for bleeding from neoplasms. The effectiveness of TAE using IPM/CS was suggested by stabilisation of blood haemoglobin after TAE with a decreased volume of blood transfusion. Lack of haemorrhagic death further supports the effectiveness of TAE. Our preliminary experiences indicated that TAE using IPM/CS may contribute to reduce the blood transfusion.

Proximal embolisation using a gelatin sponge and metallic coil is not recommended because of the possibility of ischaemic complications (Gordon et al. 1997). In our series, although IPM/CS was introduced from the proximal site of the artery to cover the tumour staining, no major ischaemic complication was suggested based on physical examinations and laboratory data. Although some previous studies have shown successful embolisation using PVA introduced from the proximal site for gastrointestinal bleeding (Defreyne et al. 2001; Loffroy et al. 2010), the risk of causing an ischaemic event has been demonstrated in another report (Guy et al. 1992). Recently, Okuno et al. presented an evaluation of feasibility and effects of TAE using IPM/CS as an embolic agent to treat tendinopathy and enthesopathy (Okuno et al. 2013). In this study, IPM/CS with the same concentration as our study was introduced from relatively proximal point of the branches feeding the target site. Nevertheless, there was no adverse event relating to IPM/CS embolization. Although, the embolized organs are different, Okuno’s study may support the safety of IPM/CS as an embolic agent. The absence of ischaemic complication after proximal IPM/CS embolisation in our study was considered due to the transient embolic effect of IPM/CS, which was demonstrated in our study based on the findings of recanalisation on repeat TAE.

IPM/CS is an antibiotic agent, and it is slightly soluble in water. Therefore, IPM/CS ought to dissolve over time. The transient embolic effect of IPM/CS maybe responsible for rebleeding. Rebleeding occurred in four patients in the present study. The rebleeding ratio in our study was higher than that in previous reports using PVA, glue, a gelatin sponge, and a metallic coil for gastrointestinal bleeding (Defreyne et al. 2001; Guy et al. 1992). However, all repeat TAE procedures after rebleeding were successful in our series. Because safety should be a compelling priority in the treatment of chronic tumour bleeding, transient embolisation with IPM/CS may be one of the viable therapeutic options if repetition is acceptable. Additionally, because of the small particle size of IPM/CS, it would be difficult to stop massive bleeding using IPM/CS, and its application should be restricted to the mild, oozing type of bleeding.

A major limitation of our study is the small number of patients studied.

Another limitation is no proof of macroscopic hemostasis because the patients did not receive operations or endoscopy. The superiority of IPM/CS over other embolic materials as an embolic material for bleeding from neoplasms was not evaluated in this study because of the nature of retrospective study. A further study to compare between IPM/CS and other embolic materials is needed.

In conclusion, our preliminary observations suggest the feasibility of TAE using IPM/CS as an embolic material for oozing from the tumour at the duodenum as well as the small and large intestines. The favourable result of the present preliminary, retrospective study warrants a prospective investigation in a larger population to determine the safety and effectiveness of TAE using IPM/CS.