Chronic Intrapericardial Catheterization for Repeated Drug Delivery: Technical Feasibility Study in the Göttingen Minipig

Abstract: Background. A minimally invasive pericardial access and chronic catheterization may enhance the therapeutic effects of intrapericardial drug delivery. We aimed to evaluate the technical feasibility of percutaneous intrapericardial implantation of a drug port system for chronic local drug delivery. Methods and Results. Under fluoroscopic guidance, a percutaneous subxiphoid access to the pericardial space was obtained with fine needle and micropuncture set in 6 Göttingen minipigs. A 6.4 Fr silicone tube and its drug port were implanted into the pericardial space and a subcutaneous pocket. One animal was euthanized immediately after procedure for acute macroscopic study. The other 5 animals were followed monthly for 2 months and then euthanized for chronic macroscopic study. Technical success was obtained in all animals. The mean procedure duration was 55.3 ± 9.6 minutes and the mean radiation exposure time was 7.9 ± 1.9 minutes. Acute macroscopic study showed no pericardial laceration at the entry site and no gross injury to the nearby epicardium. Follow-ups demonstrated that the pericardial space was intact and silicone catheters kept patent in all cases. No migration of the catheter tip out of the pericardial space or leakage of contrast was observed. All the catheters were easily removed at the end of study. Infection of the subcutaneous tunnel as a major complication was found in 1 pig. Small scattered adhesions of the pericardial space were observed in 2 pigs at chronic macroscopic study. Conclusions. Percutaneous intrapericardial catheterization for chronic local drug delivery is technically feasible and of potential for clinical trial.

J INVASIVE CARDIOL 2012;24(5):210-214

Key words: cardiovascular pharmacology, arrhythmias-basic studies, angiogenesis, gene therapy, animal models of human disease

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The pericardial space has long been respected as an ideal reservoir for local drug delivery to the heart, allowing therapeutic agents to directly attack the diseased epicardium, myocardium, coronary vasculature, autonomic nerves, and conducting tissues.^1,2 Due to its natural barrier action, the pericardium delays and lessens systemic absorption as compared with oral or intravascular approach of delivery. This enables the use of smaller doses of therapeutic agents to obtain higher local concentration with prolonged drug exposure and increased specificity to act on target tissues while minimizing untoward systemic side effects.³ Clinical implications of intrapericardial drug administration have also been underscored by numerous animal experiments in regard to anti-ischemia, antiarrhythmia, reduction of luminal narrowing after coronary angioplasty, and angiogenic therapies for myocardial infarction.^4-9 More recently, intrapericardial delivery of stem cells for cardiac regenerative therapies has gained increasing interest.^10-14 To accomplish the above intrapericardial therapies, a percutaneous access to the normal pericardial space is needed. Several techniques of percutaneous pericardial access, although technically challengeable, have been reported by means of various approaches such as subxiphoid and anterior mediastinal, transatrial, and transventricular access.^2,9,15-18 However, all these techniques are limited to a single dose administration following each procedure of pericardial access. To enhance therapeutic effects of the intrapericardial therapies, a chronic intrapericardial catheter indwelling is required for repeated delivery of drugs. The purpose of the study was to evaluate the technical feasibility of percutaneous intrapericardial implantation of a drug port system for repeated local drug delivery.

Methods

Six female Göttingen minipigs (Ellegaard Göttingen Minipigs A/S) with body weight 25-34 kg were used in this study. One animal was euthanized immediately after implantation of the intrapericardial catheter-port system for early evaluation on the technical safety. Other animals were followed for 8 weeks after implantation procedures. Animal care and all experimental procedures were carried out in accordance with guidelines of the European Communities Council Directive (86/609/EEC). Protocols were approved by the Ethics Committee for Animal Research of the local government.

After being fasted for 24 hours, each pig was premedicated with diazepam 0.1 mg/kg, ketamine 10 mg/kg, and atropine 0.01 mg/kg intramuscularly. Intravenous hydration with normal saline was established by catheterization of the auricular vein with 18-22 gauge needles (Abbott Ireland) and maintained during procedures. Induction of anesthesia was performed with propofol 2 mg/kg intravenously. After the pig was endotracheally intubated, the tube was connected to the anesthesia system (Ohmeda Excel 210 Se; Madison, Boc Group, Inc) and mechanical ventilator (Ohmeda 7800; Madison, Boc Group Inc). Anesthesia was maintained with halothane 2%-2.5%; Electrocardiography (ECG) was monitored closely throughout the procedure. The pigs were fixed at operating table in supine position with cranial and caudal extension of the limbs. The thorax, upper abdomen, and left subaxillary area were prepped and draped in a sterile fashion.

Percutaneous subxiphoid pericardial access was obtained by the use of the micropuncture set as described previously.¹⁸ Briefly, under fluoroscopic guidance (BV Pulsera; Philips Medical Systems) in lateral projection, a 21 gauge two-part trocar needle was inserted subcutaneously and advanced in the midline direction along the posterior surface of the sternum into the anterior mediastinal space. The entry site of the pericardium was targeted at the anterior heart wall approximately 2 cm cranially to the heart apex. When the tip of the needle punctured the pericardium and myocardium, self-limiting premature ventricular contractions were usually noticed with ECG monitor. The correct needle position was indicted by pulsatile motion of the needle tip. After removal of the stylet of the needle, a 0.018˝ micro guidewire from micropuncture set (5 Fr Micro Access Kit, AngioDynamics) was gently inserted through the needle cannula into the pericardial space as confirmed by the wire remaining within the cardiac silhouette during fluoroscopy in various projections (Figure 1). The needle cannula was removed and the coaxial micropuncture dilators were placed over the guidewire into the pericardial space. Through the outer dilator of the coaxial system, 5 mL of diluted contrast agent (Urografin 76%; Schering, Inc) with saline solution was injected to verify the dilator inside the pericardial space.

Next a 0.035˝, Rosen heavy-duty guidewire (William Cook Europe) was used to exchange the dilator of micropuncture set with a 7 Fr introducer sheath (Radifocus, Terumo Corporation). Through the introducer sheath, a 0.016˝ guidewire (Radifocus) was inserted into the pericardial space. The guidewire was looped superiorly and then inferiorly around the heart until the nearby region of the apex. Then a 6.4 Fr user attachable silicone catheter from a vascular access port set (ImPort, Medtronic, Inc) was placed over the guidewire to the guidewire tip. The guidewire and the sheath were removed, leaving the silicone catheter in place. A subcutaneous tunnel was established from the subxiphoid skin entry site to the left subaxillary area. The silicone catheter was placed through the tunnel and connected to a low profile port. A small incision was made and a subcutaneous pocket was created with blunt dissection. The port connected to the silicone catheter was placed in the pocket (Figure 2). The skin was closed. Fluoroscopy was performed when 5 mL of diluted contrast medium with saline solution was injected through the subcutaneous port to document the subcutaneous course and intrapericardial location of the silicone tube (Figure 3). The contrast medium injected into the pericardial space was immediately drained from the port. The color of contrast medium drained from the port was inspected to exclude the potential hemopericardium as a procedure-related complication. Chest fluoroscopy was also performed to check for occurrence of the pneumothorax.

Five of the 6 pigs were allowed to recover from anesthesia for subsequent follow-ups. After procedures, the pigs were given amoxicillin trihydrate plus potassium clavulanate (Synulox; Pfizer) intramuscularly at 20 mg/kg daily for 5 days and carprofen (Rimadyl; Pfizer) orally at 4 mg/kg twice a day for 3 days. One pig was euthanized immediately after implantation and necropsy was carried out to evaluate the technical safety.

Follow-ups were carried out at 1 and 2 months after interventions, respectively. The animal was anesthetized by using the same protocol described above. Upon injection of 5 mL of diluted contrast medium into the percutaneous port, chest fluoroscopy was performed to check for location of the silicone catheter inside the pericardial space and the subcutaneous tunnel, patency of the catheter, and possible leakage of contrast medium from the entry site at the pericardium. After the contrast medium was injected in the pericardial space, chest fluoroscopy was performed with the animal in both supine and abdominal prone position at the operating table. The contrast medium was then drained from the port. In the follow-up at week 8, the silicone catheter was removed after chest fluoroscopy and the animals were then euthanized by intravenous injection of potassium chloride solution.

Necropsy was performed immediately after euthanasia. The heart was first examined in situ. After removal of the heart, the pericardial space was opened. Gross visual inspection was focused on possible complications associated with the procedures and potential damages to the pericardium, epicardium, and surrounding structures in the mediastinum.

Results

Percutaneous pericardial access and subsequent silicone catheter implantation was successfully achieved in all 6 animals. The mean procedure duration was 55.3 ± 9.6 minutes and the mean radiation exposure time was 7.9 ± 1.9 minutes. Except for occasional premature ventricular contractions, no other complications, such as pneumothorax, hemopericardium, and fatal arrhythmia were encountered during the procedures. In the pig that was euthanized immediately after silicone catheter implantation, neither laceration of the pericardium at the entry site of the pericardial space nor gross injury of the nearby epicardium was noticed (Figure 4).

Chest fluoroscopic follow-ups at 1 and 2 months after implantation suggested that the pericardial space was intact and all the silicone catheters kept patent without kinking or rupture. Although the segments of catheters inside the pericardial space showed changes in position, no migration of the catheter tip out of the pericardial space was observed. No leakage of contrast medium out of the pericardial space was found. All catheters were easily removed at the end of study.

Infection of the subcutaneous tunnel was found in 1 pig, which was excluded from the study after 1-month follow-up. At necropsy after 2-month follow-up, pericardial effusion was not found in any pigs. However, small scattered adhesions of the pericardial space were observed in 2 pigs (Figure 5).

Discussion

Technically, the procedure includes two major steps: (1) percutaneous subxiphoid pericardial access; and (2) implantation of the silicone catheter into the pericardial space and the vascular access port subcutaneously. In the former, we used a newly modified technique focusing on the feature of minimal invasion in order to improve the technical safety; in the latter, some technical issues were addressed to facilitate selective pericardial implantation of the silicone catheter.

The technique of percutaneous subxiphoid access to the normal pericardial space, which was first described by Sosa and colleagues,¹⁹ is commonly used in epicardial radiofrequency catheter ablation for arrhythmias. One common complication associated with this technique is hemopericardium mostly due to right ventricle perforation. Even in experienced hands, its occurrence has been reported in about 10%-20%.^20,21

Recently, we described a modified technique for percutaneous subxiphoid access by the use of micropuncture set.¹⁸ Compared with the conventional technique by Sosa, our modified technique has several advantages improving the technical safety during the procedure.

First, we used the low-profile device for pericardial access.The puncture needle that we used was 21-gauge with outer diameter of 0.8 mm, and the micro guidewire was 0.018˝ in diameter. By contrast, Sosa and colleagues used a 17-gauge Tuohy needle with an outer diameter of 1.5 mm and a regular guidewire that was 0.035˝ in diameter. According to Sosa’s report, although the right ventricle is perforated with the guidewire, these perforations are usually “dry,” ie, no hemopericardium occurs because of the small width.^15,20 Thus, it seems reasonable that the use of a lower-profile needle and guidewire might be associated with less occurrence of hemopericardium.

Second, the use of a low-profile needle is potentially of less damage to the pericardium at the entry site of pericardial space. During the procedure, it usually occurs that after the pericardium is punctured with the needle, the guidewire fails to be introduced into the pericardial space through the needle. Thus, the needle and guidewire are removed and a new attempt is made. When the pericardial access is finally obtained after several attempts, the pericardium nearby the entry site will be damaged with some small holes due to previous attempts of puncture. The larger diameter needle used, the more damage will occur to the pericardium. This might lead to subsequent leakage of therapeutic agents from the pericardial space after implantation of the catheter port system and administration of drugs for therapeutic purpose. Although previous studies^22,23 described the use of a 21-gauge needle with a dedicated device to puncture (PerDucer Comedicus), the large profile of the PerDucer requires a 19 Fr (6.3 mm in diameter) introducer to be placed subcutaneously in the anterior mediastinum. This necessitates a large incision at the skin entry site and produces a substantial invasion in the anterior mediastinum. Insertion of a large dilator or introducer may be severely painful in some patients, so intravenous administration of analgesics has to be applied.^18,23,24 In contrast, our technique has the feature of minimal invasion because we used a 4-5 Fr coaxial micropuncture set with diameter of 1.3-1.67 mm.

Third, during the pericardial access procedure, we used fluoroscopic guidance in the lateral projection instead of the left anterior oblique projection, as used by Sosa and colleagues. The strength of the lateral view projection at fluoroscopic guidance has also been proved by another study because it more clearly defines the desired needle pathway and maximally separates the mediastinal, pericardial, and myocardial planes without any intervening structures.²⁵ More important, the use of fluoroscopy in lateral projection can clearly depict the guidewire hugging the cardiac silhouette if placed correctly inside the pericardial space, so that it provides assurance that the guidewire is not within the right ventricle. This is an essential and reliable sign to demonstrate successful access to the pericardial space.

The purpose of the present study was to evaluate the technical feasibility of intrapericardial implantation of a drug port system for repeated local drug delivery. In addition to the technical success of implantation without major complications during procedure, the system implanted inside the pericardium and buried subcutaneously should stay patent during a period of time for intrapericardial therapy. The intrapericardial segment of the silicone catheter should also stay in place, without migration out of the pericardial space. The pericardium should be intact without perforation due to the heartbeat-induced chronic friction between the pericardium and the long-term dwelling silicone catheter. Finally, the silicone catheter should be easily and safely removed at the end of study. The results of our studies met all the criteria above, supporting the technical feasibility of percutaneous intrapericardial implantation for a drug port system for repeated local drug delivery.

However, infection of the subcutaneous tract and pocket was observed in one animal. Since the subcutaneous tunnel and pocket were filled with pus, the pig was excluded from the study after 1 month of follow-up. Although animals are more likely to get infection after procedure due to difficulties of postoperative animal care, catheter-related infection is a potential complication if applied in humans.

It is worth noting that the pericardium is prone to injury and inflammation due to various stimuli, such as infections, inflammations, transmural infarction, radiation, and thoracotomy. Thus, the pericardium is generally considered as a structure best left undisturbed.²⁶ It has been observed that after epicardial radiofrequency ablation for cardiac arrhythmias, pericarditis occurs in virtually all patients to some extent as the result of local inflammatory response.²⁷ In theory, long-term placement of a catheter in the pericardial space may induce a cascade of inflammatory pathways and wound healing events not only as a result of foreign-body response to the implanted catheter, but also due to chronic friction with the catheter that constantly moves with the heartbeat. Once the cascade of inflammatory pathways was elicited, constrictive pericarditis would likely be the final clinical sequelae. Furthermore, if extensive intrapericardial adhesions or fibrosis occurs after implantation of infusion catheter, subsequent local drug deliveries and therapies might be adversely affected.

In the present study, 4 pigs underwent necropsy and macroscopic study after 2-month follow-up. In 2 pigs, small scattered adhesions were found, which appeared loose and filmy and were easily broken by gentle blunt dissection; in the other 2 pigs, the pericardium was intact. Our findings suggested that the pericardial inflammation secondary to implantation of catheter, albeit minimal, might pose a concern over technical safety. In a study reported by Kolettis et al,28 the PerDucer was used to implant intrapericardial 4 Fr hydrophilic catheters in 5 pigs. The animals were euthanized 6 months after procedures and histopathological studies revealed a moderate inflammatory infiltration and fibrosis of the pericardium adjacent to the catheter. The discrepancy between the two studies suggests that the intensity of intrapericardial inflammation may correlate with the duration of catheter indwelling.

More recently, Bartoli et al²⁹ used a canine model to evaluate technical safety on intrapericardial catheterization. In their study, thoracotomy was performed in 7 anesthetized dogs and a 5 Fr silicone catheter was inserted into the pericardial space. Microscopic histopathological examinations at an average of 213 days after operation showed minimum chronic inflammation at catheter entry site, surrounding pericardium, and myocardium. Compared with the study by Kolettis et al, although the mean duration for catheter indwelling in the pericardial space was longer than 6 months, the intensity of the pericardial inflammation was much less severe. One of the reasons for this discordance would be a species-related difference in the intensity of the pericardial response to the indwelling catheter. Furthermore, d’Avila et al also observed that swine manifested a more intense pericardial inflammatory reaction than seen clinically in humans after epicardial ablation procedures.²⁷ More important, d’Avila et al demonstrated that intrapericardial instillation of 2 mg/kg of intermediate-acting corticosteroids effectively prevented postprocedure inflammatory adhesion formation in a swine model.²⁷ This would have a potential clinical implication if the chronic intrapericardial catheterization is applied in humans.

Study limitations. The major limitation of this study was the small sample size of animals. Evaluation of technical success as well as associated complications in more animals is needed. Since the present study focused on development of a new technique and its technical feasibility, the safety issues, eg, prevention of catheter-related infection and pericardial inflammation, remain to be addressed in the future.

Conclusion

We described a new technique of chronic percutaneous intrapericardial catheterization for repeated local drug delivery, which has a great clinical implication. This technique is technically feasible and minimally invasive. Further study is needed in a large animal population to address the technical safety of long-term indwelling catheter in the pericardial sac. The authors believe that this technique also holds much potential for preclinical studies with pericardial local drug delivery and therapies.

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From the ¹Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain, ²Department of Cardiology, San Pedro de Alcántara Hospital, Cáceres, Spain, and ³Department of Endovascular Therapy, Hospiten Rambla, Santa Cruz de Tenerife, Spain.
Funding: This work was supported in part by grant PRI08A042 (to Dr FS) from FundeSalud (Fundación para la Formación y la Investigación de los Profesionales de la Salud de Extremadura).
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted November 29, 2011, provisional acceptance given January 9, 2012, final version accepted January 18, 2012.
Address for correspondence: Fei Sun, MD, Jesús Usón Minimally Invasive Surgery Centre; Carretera N-521, km. 41.8, 10071 Cáceres, Spain. Email: feisun@ccmijesususon.com