Utility of augmented reality system in hepatobiliary surgery

Background/purpose

The aim of this study was to evaluate the utility of an image display system for augmented reality in hepatobiliary surgery under laparotomy.

Methods

An overlay display of organs, vessels, or tumor was obtained using a video see-through system as a display system developed at our institute. Registration between visceral organs and the surface-rendering image reconstructed by preoperative computed tomography (CT) was carried out with an optical location sensor. Using this system, we performed laparotomy for a patient with benign biliary stricture, a patient with gallbladder carcinoma, and a patient with hepatocellular carcinoma.

Results

The operative procedures performed consisted of choledochojejunostomy, right hepatectomy, and microwave coagulation therapy. All the operations were carried out safely using images of the site of tumor, preserved organs, and resection aspect overlaid onto the operation field images observed on the monitors. The position of each organ in the overlaid image closely corresponded with that of the actual organ. Intraoperative information generated from this system provided us with useful navigation. However, several problems such as registration error and lack of depth knowledge were noted.

Conclusion

The image display system appeared to be useful in performing hepatobiliary surgery under laparotomy. Further improvement of the system with individualized function for each operation will be essential, with feedback from clinical trials in the future.     

Intraoperative fluorescent imaging using indocyanine green for liver mapping and cholangiography

Background

Preoperative imaging is widely used and extremely helpful in hepatobiliary surgery. However, transfer of preoperative data to a intraoperative situation is very difficult. Surgeons need intraoperative anatomical information using imaging data for safe and precise operation in the field of hepatobiliary surgery. We have developed a new system for mapping liver segments and cholangiograms using intraoperative indocyanine green (ICG) fluorescence under infrared light observation.

Method

The imaging technique for mapping liver segments and cholangiogram based on ICG fluorescence used an infrared-based navigation system. Eighty one patients with liver tumors underwent hepatectomy from 2006, January to 2009, March. In liver surgery, 1 ml of ICG was injected via the portal vein under observation by the fluorescent imaging system. Fourteen patients were underwent laparoscopic cholecystectomy for chronic cholecystitis with gallstones. In laparoscopic cholecystectomy, 5 ml of ICG was administered intravenously just before operation and the bile duct was observed using the infrared-based navigation system.

Result

This new technique successfully identified stained subsegments and segments of the liver in 73 of 81 patients (90.1%). Moreover, clear mapping of liver segments was obtained even against a background of liver cirrhosis. Fluorescent cholangiography clearly showed the common bile duct and cystic duct in 10 of 14 patients (71.4%). No adverse reactions to the ICG were encountered.

Conclusion

Application of this technique allows intraoperative identification of anatomical landmark in hepatobiliary surgery.     

Natural orifice translumenal endoscopic surgery (NOTES) for innovation in hepatobiliary and pancreatic surgery: preface

Introduction

Natural orifice translumenal endoscopic surgery (NOTES) has captured the interest of interventional endoscopists and may represent the next stage of evolution of minimally invasive surgery. It provides the potential for performance of incisionless operations. It is gaining momentum both in the animal laboratory and in human case reports. Developments in the field of NOTES have led to the formation of the Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR) in 2006.

Materials and methods

In this special issue, the current trends in NOTES in the field of hepatobiliary and pancreatic surgery are featured, including NOTES cholecystectomy, hepatectomy splenectomy, pancreatic necrosectomy, and the future of NOTES. In this issue, we discuss the potential benefits of these procedures in hepatobiliary and pancreatic surgery.

Conclusion

We have just started the evaluation process for this new technology. The concept of NOTES is becoming established and is enormously advantageous for the patient. Both the surgeon and gastroenterologist should contribute to developing NOTES in making use of their specialties.     

Image overlay navigation by markerless surface registration in gastrointestinal, hepatobiliary and pancreatic surgery

Background

We applied a new concept of “image overlay surgery” consisting of the integration of virtual reality (VR) and augmented reality (AR) technology, in which dynamic 3D images were superimposed on the patient’s actual body surface and evaluated as a reference for surgical navigation in gastrointestinal, hepatobiliary and pancreatic surgery.

Methods

We carried out seven surgeries, including three cholecystectomies, two gastrectomies and two colectomies. A Macintosh and a DICOM workstation OsiriX were used in the operating room for image analysis. Raw data of the preoperative patient information obtained via MDCT were reconstructed to volume rendering and projected onto the patient's body surface during the surgeries. For accurate registration, OsiriX was first set to reproduce the patient body surface, and the positional coordinates of the umbilicus, left and right nipples, and the inguinal region were fixed as physiological markers on the body surface to reduce the positional error.

Results

The registration process was non-invasive and markerlesss, and was completed within 5 min. Image overlay navigation was helpful for 3D anatomical understanding of the surgical target in the gastrointestinal, hepatobiliary and pancreatic anatomies. The surgeon was able to minimize movement of the gaze and could utilize the image assistance without interfering with the forceps operation, reducing the gap from the VR. Unexpected organ injury could be avoided in all procedures. In biliary surgery, the projected virtual cholangiogram on the abdominal wall could advance safely with identification of the bile duct. For early gastric and colorectal cancer, the small tumors and blood vessels, which usually could not be found on the gastric serosa by laparoscopic view, were simultaneously detected on the body surface by carbon dioxide-enhanced MDCT. This provided accurate reconstructions of the tumor and involved lymph node, directly linked with optimization of the surgical procedures.

Conclusions

Our non-invasive markerless registration using physiological markers on the body surface reduced logistical efforts. The image overlay technique is a useful tool when highlighting hidden structures, giving more information.     

Integrated MR-laparoscopy system with respiratory synchronization for minimally invasive liver surgery

Purpose

The laparoscope has been invaluable in minimally invasive surgery, but provides only a surface view of target tissue; therefore it is lacking internal tissue information. In combination with the laparoscope for visualizing the cross-sectional view of the tissue, MRI is superior to ultrasonography or X-ray CT, because of its high soft-tissue contrast, arbitrary slice orientation and lack of radiation properties. Thus, we propose an integrated MR-laparoscopy system with a respiratory-synchronized navigation.

Methods

A transmit/receive RF coil for localized MR imaging with a 0.5?T open-MRI was mounted onto the tip of an MR-compatible laparoscope. The signal detection of the coil was examined with an excised porcine liver sample, an agar phantom and the abdominal wall of a healthy volunteer. A real-time navigation system to compensate for respiratory motion was developed, and examined with a healthy volunteer.

Results

The SNRs of the local MR images were 112, 62, and 62 in the liver sample, phantom, and volunteer. The navigation system successfully displayed the scope view, scope location and orientation, and MR images with respiratory-synchronized real time operation.

Conclusions

The MR-imaging and synchronization function of the proposed system seemed to be helpful for laparoscopic surgery.     

Augmented reality and image overlay navigation with OsiriX in laparoscopic and robotic surgery: not only a matter of fashion

Background

New technologies can considerably improve preoperative planning, enhance the surgeon’s skill and simplify the approach to complex procedures. Augmented reality techniques, robot assisted operations and computer assisted navigation tools will become increasingly important in surgery and in residents’ education.

Methods

We obtained 3D reconstructions from simple spiral computed tomography (CT) slides using OsiriX, an open source processing software package dedicated to DICOM images. These images were then projected on the patient's body with a beamer fixed to the operating table to enhance spatial perception during surgical intervention (augmented reality).

Results

Changing a window's deepness level allowed the surgeon to navigate through the patient's anatomy, highlighting regions of interest and marked pathologies. We used image overlay navigation for laparoscopic operations such cholecystectomy, abdominal exploration, distal pancreas resection and robotic liver resection.

Conclusions

Augmented reality techniques will transform the behaviour of surgeons, making surgical interventions easier, faster and probably safer. These new techniques will also renew methods of surgical teaching, facilitating transmission of knowledge and skill to young surgeons.     

Usefulness of intraoperative fluorescence imaging to evaluate local anatomy in hepatobiliary surgery

Background/Purpose

One of the major complications encountered in hepatobiliary surgery is the incidence of bile duct and blood vessel injuries. It is sometimes difficult during surgery to evaluate the local anatomy corresponding to hepatic arteries and bile ducts. We investigated the potential utility of an infrared camera system as a tool for evaluating local anatomy during hepatobiliary surgery.

Methods

An infrared camera system was used to detect indocyanine green fluorescence in vitro. We also employed this system for the intraoperative fluorescence imaging of the arteries and biliary system in a pig. Further, we evaluated blood flow in the hepatic artery, portal vein, and liver parenchyma during a human liver transplant and we investigated local anatomy in patients undergoing cholecystectomy.

Results

Fluorescence confirmed that indocyanine green was distributed in serum and bile. In the pig study, we confirmed the fluorescence of the biliary system for more than 1 h. In the liver transplant recipient, blood flow in the hepatic artery and portal vein was confirmed around the anastomosis. In most of the patients undergoing cholecystectomy, fluorescence was observed in the gallbladder, cystic and common bile ducts, and hepatic and cystic arteries.

Conclusions

Intraoperative fluorescence imaging in hepatobiliary surgery facilitates better understanding of the anatomy of arteries, the portal vein, and bile ducts.     

Robot-assisted laparoscopic pancreatic surgery

Background

In the field of gastroenterological surgery, laparoscopic surgery has advanced remarkably, and now accounts for most gastrointestinal operations. This paper outlines the current status of and future perspectives on robot-assisted laparoscopic pancreatectomy.

Methods

A review of the literature and authors’ experience was undertaken.

Results

The da Vinci Surgical System is a robot for assisting laparoscopy and is safer than conventional endoscopes, thanks to the 3-dimensional hi-vision images it yields, high articular function with the ability to perform 7 types of gripping, scaling function enabling 2:1, 3:1, and 5:1 adjustment of surgeon hand motion and forceps motions, a filtering function removing shaking of the surgeon’s hand, and visual magnification. By virtue of these functions, this system is expected to be particularly useful for patients requiring delicate operative manipulation.

Conclusions

Issues of importance remaining in robot-assisted laparoscopic pancreatectomy include its time of operation, which is longer than that of open surgery, and the extra time needed for application of the da Vinci compared with ordinary laparoscopic surgery. These issues may be resolved through accumulation of experience and modifications of the procedure. Robot-assisted laparoscopic pancreatectomy appears likely to become a standard procedure in the near future.     

Recent advances in visualization, imaging, and navigation in hepatobiliary and pancreatic sciences

Background/purpose

Recent introduction of multi-detector CT (MDCT) and high-speed magnetic resonance (MR) imaging have dramatically advanced visualization and imaging technology in diagnostic and therapeutic strategy in hepatobiliary pancreatic disease. However, image diagnostics have progressed with a background of the essence of anatomy, pathology, and physiology. It is important to object the reflection of the patient’s condition and pathology of each disease and remove pattern recognition in what they were depicted as an image. Visualization plays another important role in various medical diagnostics. Trends in scientific visualization will depend on advancements in molecular technology and computer hardware as well as trends in engineering disciplines.

Methods

In this special issue, the recent advances in visualization and imaging in the field of hepatobiliary and pancreatic sciences are featured including application of advanced visualization techniques, data management, data compression, feature extraction.

Results

We discuss the potential benefits of new technologies and procedures in hepatobiliary and pancreatic areas, that are circulating tumor cells, MR imaging for hepatocellular carcinoma, indocyanine green using fluorescence under infrared light observation, carbon dioxide enhanced MDCT virtual cholangiopancreatography, endoscopic ultrasonography-guided biliary drainage, natural orifice translumenal endoscopic surgery, MR-laparoscopy, and image overlay navigation surgery by OsiriX.

Conclusion

Some of the recent trends are discussed in terms of visualization and imaging in hapatobiliary and pancreatic sciences. The goal in using visualization is to assist existing scientific procedures by providing new insight through visual representation.     

Upgrade of an optical navigation system with a permanent electromagnetic position control

Introduction

The main problems of navigation in liver surgery are organ movement and deformation. With a combination of direct optical and indirect electromagnetic tracking technology, visualisation and positional control of surgical instruments within three-dimensional ultrasound data and registration of organ movements can be realised simultaneously.

Methods

Surgical instruments for liver resection were localised with an infrared-based navigation system (Polaris^®). Movements of the organ itself were registered using an electromagnetic navigation system (Aurora^®). The combination of these two navigation techniques and a new surgical navigation procedure focussed on a circumscribed critical dissection area were applied for the first time in liver resections.

Results

This new technique was effectively implemented. The position of the surgical instrument was localised continuously. Repeated position control with observation of the navigation screen was not necessary. During surgical resection, a sonic warning signal was activated when the surgical instrument entered a “no touch” area—an area of reduced safety margin.

Conclusion

Optical tracking of surgical instruments and simultaneous electromagnetic registration of organ position is feasible in liver resection.     

Lymph node navigation for pancreatic and biliary malignancy by NOTES

Background

Lymph node navigation and accurate staging of liver or peritoneal metastasis leads to better selection of the optimal treatment for patients with pancreatic and biliary malignancy. Less invasive techniques of detecting lymph node metastasis and distant metastasis would be valuable. Natural orifice translumenal endoscopic surgery (NOTES) is a new, evolving concept of minimally invasive surgery that may be useful for the staging of intraabdominal cancers.

Methods

Review of the literature regarding peritoneoscopy and lymph node mapping and biopsy by NOTES.

Results

NOTES peritoneoscopy for accurate diagnosis and staging of intraabdominal cancers is already in clinical use, and two case reports have shown the safety and feasibility of this technique. Previous experimental studies have also shown that lymph node mapping by NOTES is technically feasible with the currently available devices.

Conclusions

With the continued development of the techniques and technology of NOTES, peritoneoscopy and lymph node mapping by NOTES may become an alternative method for preoperative staging for patients with pancreatic and biliary malignancy.     

Evaluation for transvaginal and transgastric NOTES cholecystectomy in human and animal natural orifice translumenal endoscopic surgery

Background/purpose

Natural orifice translumenal endoscopic surgery (NOTES) is a novel concept using an endoscope via a translumenal access for abdominal surgery. This study was designed to evaluate the feasibility and technical aspects of NOTES cholecystectomy from our experience on humans and animals.

Methods

NOTES cholecystectomies were performed in 12 animal experiments, including 8 pigs (6 by transgastric and 2 by transvaginal accesses) and 4 dogs (4 transvaginal accesses), and a human female cadaver.

Results

The entire gallbladder could be removed under direct vision in all experiments. The average time was 60 min by transgastric and 40 min by transvaginal in animals. It was 87 min for human transvaginal cholecystectomy. In all animal and human procedures, there was no major complication concerning the operation.

Discussion

The transvaginal route may be the easiest route for abdominal NOTES. Percutaneous endoscopic gastrostomy (PEG) allowed the safe performance of a controlled gastric perforation and shortened the time. The hybrid method allowed performance of a safe procedure and shortened the time.

Conclusions

Transvaginal and transgastric NOTES cholecystectomy is technically feasible and safe in both humans and animals. New instrumentation needs to be developed to perform a pure NOTES cholecystectomy without transabdominal assistance.     

Robotic-assisted pancreatic surgery

Background

Pancreatic surgery is a challenging application of minimally invasive surgery. Due to the complexity of the surgical technique, requiring dissection along major abdominal vessels as well as delicate reconstruction involving biliary, pancreatic and enteric anastomoses, reports on laparoscopic pancreatic surgery have been scanty. With the advent of robotic-assisted surgery, however, the increased dexterity granted by endo-wristed instruments, the improved three-dimensional vision and the computer filtration of the surgeon’s movements have brought minimally invasive pancreatic surgery into a new era.

Methods

As the surgical group which has performed the highest number of robotic-assisted pancreatic procedures worldwide, we review the state of the art of minimally invasive robotic-assisted pancreatic surgery. Clinical results from all major robotic-assisted pancreatic surgery series are considered.

Results

Preliminary reports from the published major pancreatic surgery series show encouraging results, with morbidity and mortality comparable to open surgery. Preliminary data on cancer survival rates also appear to be similar to open series.

Conclusion

Robotic-assisted pancreatic surgery is safe and feasible for all pancreatic diseases. The complexity of pancreatic procedures warrant them to be carried out in specialised centres, where short- and long-term outcomes seem to be similar to the ones achieved in open surgery.     

Bezafibrate for the treatment of primary sclerosing cholangitis

Background

It is known that bezafibrate decreases serum alkaline phosphatase (ALP) in patients with hyperlipidemia, and the efficacy of this drug for the treatment of primary biliary cirrhosis has been confirmed. However, there has been little evidence of its efficacy for the treatment of primary sclerosing cholangitis (PSC).

Methods

Bezafibrate (400 mg/day) was orally administered to 7 consecutive patients with PSC, and we analyzed their clinical features and the drug efficacy in terms of the effect on hepatobiliary enzymes, including ALP, gamma-glutamyl transpeptidase (γ-GTP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) after 6 months. The latest hepatobiliary enzyme levels were also evaluated.

Results

In 3 patients (effective group), the levels of all hepatobiliary enzymes had decreased after 6 months. Mean ALP had decreased to approximately 40% of the baseline in this group. The efficacy of bezafibrate was observed for a long period (range, 8–27 months) in these 3 patients. There seemed to be no definite association between the efficacy of bezafibrate and the clinical features in the short term.

Conclusions

This study showed that bezafibrate could lower the levels of hepatobiliary enzymes in about half of a cohort of patients with PSC.     

Augmented reality technology for preoperative planning and intraoperative navigation during hepatobiliary surgery: A review of current methods

Background

Augmented reality (AR) technology is used to reconstruct three-dimensional (3D) images of hepatic and biliary structures from computed tomography and magnetic resonance imaging data, and to superimpose the virtual images onto a view of the surgical field. In liver surgery, these superimposed virtual images help the surgeon to visualize intrahepatic structures and therefore, to operate precisely and to improve clinical outcomes.

Robotic hepatobiliary and pancreatic surgery: a cohort study

Background

Robotic surgery has emerged as one of the most promising surgical advances since its launch at the turn of the millennium. Despite its worldwide acceptance in many different surgical specialties, the use of robotic assistance in the field of hepatobiliary and pancreatic (HBP) surgery remains relatively unexplored. This article aims to evaluate the efficacy and outcomes of robotic HBP surgery in a single surgical center.

Methods

Between May 2009 and December 2010, all patients admitted to our unit for robotic HBP surgery were evaluated. A retrospective analysis of a prospectively maintained database on clinical outcomes was performed.

Results

There were 55 robotic HBP operations performed during the study period. There were 27 robotic liver resections (left lateral sectionectomies n = 17, left hepatectomy n = 1, other segmentectomies n = 2 and wedge resections n = 7), 12 robotic pancreatic procedures (Whipple’s operations n = 8, spleen-preserving distal pancreatectomies n = 2, double bypass n = 1 and cystojejunostomy n = 1) and 16 biliary procedures (biliary enteric bypass n = 9, bile duct exploration and related procedures n = 7). The median postoperative hospital stays for robotic liver resections, biliary procedures and pancreatic operations were 5.5 days (range 3–11 days), 6 days (range 4–11 days) and 12 days (range 6–21 days), respectively. Morbidities for liver resection, biliary procedures and pancreatic operations were 7.4, 18 and 33%, respectively. There was no mortality in our series.

Conclusions

Robotic surgery is feasible and can be safely performed in patients with complicated HBP pathologies. Further evaluation with clinical trials is required to validate its real benefits.     

Role of adjuvant surgery for patients with initially unresectable pancreatic cancer with a long-term favorable response to non-surgical anti-cancer treatments: results of a project study for pancreatic surgery by the Japanese Society of Hepato-Biliary-Pancreatic Surgery

Purpose

A multicenter survey was conducted to explore the role of adjuvant surgery for initially unresectable pancreatic cancer with a long-term favorable response to non-surgical cancer treatments.

Methods

Clinical data including overall survival were retrospectively compared between 58 initially unresectable pancreatic cancer patients who underwent adjuvant surgery with a favorable response to non-surgical cancer treatments over 6 months after the initial treatment and 101 patients who did not undergo adjuvant surgery because of either unchanged unresectability, a poor performance status, and/or the patients’ or surgeons’ wishes.

Results

Overall mortality and morbidity were 1.7 and 47 % in the adjuvant surgery group. The survival curve in the adjuvant surgery group was significantly better than in the control group (p < 0.0001). The propensity score analysis revealed that adjuvant surgery was a significant independent prognostic variable with an adjusted hazard ratio (95 % confidence interval) of 0.569 (0.36–0.89). Subgroup analysis according to the time from initial treatment to surgical resection showed a significant favorable difference in the overall survival in patients who underwent adjuvant surgery over 240 days after the initial treatment.

Conclusion

Adjuvant surgery for initially unresectable pancreatic cancer patients can be a safe and effective treatment. The overall survival rate from the initial treatment is extremely high, especially in patients who received non-surgical anti-cancer treatment for more than 240 days.     

Image-guided hepatopancreatobiliary surgery using near-infrared fluorescent light

Background

Improved imaging methods and surgical techniques have created a new era in hepatopancreatobiliary (HPB) surgery. Despite these developments, visual inspection, palpation, and intraoperative ultrasound remain the most utilized tools during surgery today. This is problematic, though, especially in laparoscopic HPB surgery, where palpation is not possible. Optical imaging using near-infrared (NIR) fluorescence can be used for the real-time assessment of both anatomy (e.g., sensitive detection and demarcation of tumours and vital structures) and function (e.g., assessment of luminal flow and tissue perfusion) during both open and minimally invasive surgeries.

Methods

This article reviews the published literature related to preclinical development and clinical applications of NIR fluorescence imaging during HPB surgery.

Results

NIR fluorescence imaging combines the use of otherwise invisible NIR fluorescent contrast agents and specially designed camera systems, which are capable of detecting these contrast agents during surgery. Unlike visible light, NIR fluorescent light can penetrate several millimetres through blood and living tissue, thus providing improved detectability. Applications of this technique during HPB surgery include tumour imaging in liver and pancreas, and real-time imaging of the biliary tree.

Conclusions

NIR fluorescence imaging is a promising new technique that may someday improve surgical accuracy and lower complications.     

Management of postoperative arterial hemorrhage after pancreato-biliary surgery according to the site of bleeding: re-laparotomy or interventional radiology

Background/Purpose

Intra-abdominal arterial hemorrhage is still one of the most serious complications after pancreato-biliary surgery. We retrospectively analyzed our experiences with 15 patients in order to establish a therapeutic strategy for postoperative arterial hemorrhage following pancreato-biliary surgery.

Methods

Between August 1981 and November 2007, 15 patients developed massive intra-abdominal arterial bleeding after pancreato-biliary surgery. The initial surgery of these 15 patients were pylorus-preserving pancreatoduodenectomy (PPPD) (7 patients), hemihepatectomy and caudate lobectomy with extrahepatic bile duct resection or PPPD (4 patients), Whipple’s pancreatoduodenectomy (PD) (3 patients), and total pancreatectomy (1 patient). Twelve patients were managed by transcatheter arterial embolization and three patients underwent re-laparotomy.

Results

Patients were divided into two groups according to the site of bleeding: SMA group, superior mesenteric artery (4 patients); HA group, stump of gastroduodenal artery, right hepatic artery, common hepatic artery, or proper hepatic artery (11 patients). In the SMA group, re-laparotomy and coil embolization for pseudoaneurysm were performed in three and one patients, respectively, but none of the patients survived. In the HA group, all 11 patients were managed by transcatheter arterial embolization. None of four patients who had major hepatectomy with extrahepatic bile duct resection survived. Six of seven patients (85.7%) who had pancreatectomy survived, although hepatic infarction occurred in four.

Conclusions

Management of postoperative arterial hemorrhage after pancreato-biliary surgery should be done according to the site of bleeding and the initial operative procedure. Careful consideration is required for indication of interventional radiology for bleeding from SMA after pancreatectomy and hepatic artery after major hepatectomy with bilioenteric anastomosis.     

Clinical results of N-acetylcysteine after major hepatic surgery: a review

Background/Purpose

Ischemia/reperfusion injury is thought to play an important role in postoperative liver dysfunction and morbidity following major liver surgery. N-acetylcysteine may be protective by serving as a precursor to glutathione and replenishing intracellular stores, in addition to other mechanisms. The purpose of this review is to summarize the clinical evidence that N-acetylcysteine may reduce liver dysfunction and the postoperative complications following major liver surgery.

Methods

A PubMed (MEDLINE) search was performed using the search terms “N-acetylcysteine”, “Mucomyst”, “liver”, and “surgery” to identify all relevant articles published in English prior to February 2007.

Results

Seventy-three articles were identified, and of these, there were seven studies that involved human patients undergoing orthotopic liver transplantation (six randomized controlled trials and one retrospective study).

Conclusions

The evidence that routine use of N-acetylcysteine reduces ischemia/reperfusion injury and prevents complications after major liver surgery is not conclusive. The available studies may have been limited by small sample sizes, and heterogeneous outcome measures prevent conclusions being made across studies and prevent pooling of the data. Further study with more relevant clinical endpoints and larger sample sizes is warranted.