A laparoscopic cholecystectomy


With the widespread usage of laparoscopic cholecystectomy ( LC ) , the incidence of iatrogenic gall canal hurt ( BDI ) has increased over the past decennary. Despite the expertness gained worldwide in executing this process, the overall incidence of hurt to the gall canal is about twice every bit high as that following unfastened cholecystectomy [ 1-3 ] . Because BDI sustained during LC is known to happen more proximally compared with unfastened cholecystectomy and misidentification of the anatomy is non entirely restricted to the bilious tree, a higher incidence of attendant hepatic arteria hurt ( HAI ) can be anticipated [ 4-6 ] .HAI hurt may attach to BDI, the commonest affecting the right hepatic arteria in association with an excisional hurt of the common hepatic canal, due to the propinquity of the arteria and the canal.

This association was noted by Meyers and co-workers in the early 1990s [ 7 ] , and recent articles have expanded our cognition of this complication [ 8-19 ] . Although coincident hurt to the common gall canal and hepatic arteria is an progressively recognized complication of LC, the clinical significance of the associated vascular hurt remains controversial. Break of the hepatic arterial flow is normally tolerated in an otherwise healthy patient. However, the sensitiveness of the bilious tree to the want of arterial blood supply is good known and might explicate the pathogenesis of bilious leaks and stricture after Reconstruction of a transected common gall canal [ 20 ] .The purpose of this reappraisal is to turn to the issue of attendant vascular hurts with accent to its clinical relevancy.

Best services for writing your paper according to Trustpilot

Premium Partner
From $18.00 per page
4,8 / 5
Writers Experience
Recommended Service
From $13.90 per page
4,6 / 5
Writers Experience
From $20.00 per page
4,5 / 5
Writers Experience
* All Partners were chosen among 50+ writing services by our Customer Satisfaction Team


An on-line hunt of the Medline database was undertaken utilizing the keywords ‘bile canal hurt ‘ , ‘vascular hurt ‘ , ‘laparoscopic cholecystectomy ‘ , and ‘outcome ‘ in assorted combinations.

Boolean operators AND, OR and NOT were used. No day of the month or linguistic communication limitation was used. Manual cross-referencing was performed.


The incidence of HAI in association with BDI is hard to determine, as few studies on BDI reference the topic, and most series include extremely selected patient populations in the context of BDI [ 8-19 ] .

In add-on, it is frequently hard to find the position of the right hepatic arteria ( RHA ) during operations to mend a BDI, because the arteria is frequently encased in redness ensuing from tissue harm, bile aggregations, or infection [ 16 ] . Furthermore, everyday arterial imagination is non common topographic point in the appraisal of such hurts. As a effect, the existent incidence of attendant vascular hurt is likely underestimated.In a multi-institutional aggregation of 77,604 laparoscopic cholecystectomies, Deziel et Al. reported 44 instances ( 12 % ) of hepatic arterial hurt in 365 patients with major gall canal hurts [ 21 ] .

In selected series the presence of attendant hurt of the hepatic arteria has been reported in 12 – 47 per cent of patients with LC-related iatrogenic BDI [ 7,16,19,21-22 ] . This considerable variableness in the rate of HAI seems in portion related to the type of preoperative probe used, with the diagnosing of HAI being higher in series where mesenteric angiography has been routinely performed [ 17 ] . The most common vascular construction injured during dissection of Calot ‘s trigon is the RHA ( 90 % ) . Damage to the chief hepatic arteria is the 2nd highest superior hurt ( 8 % ) , while the portal vena ( normally in combination with hepatic artery hurt ) is the 3rd highest superior hurt, although it is well less common ( 4 % ) [ 16-17 ] .


HAI must be suspected in any patient with BDI referred for primary fix or refashioning of an unsuccessful primary fix. Modern magnetic resonance or computed imaging angiography are normally equal to except hurt to either the arterial or portal venous systems, or to place the presence of a pseudoaneurysm that may follow sepsis or traumatic hurt [ 23 ] .

Non-enhancement of the right hepatic lobe during the arterial stage of a contrast CT scan is normally the most common radiological characteristic proposing an HAI [ 16 ] ( Figure 1 ) . Duplex echography is frequently undependable, but is utile in the intraoperative appraisal of the hepatic vasculature [ 19 ] .Although some writers support the everyday usage of preoperative mesenteric angiography in patients with BDI [ 17 ] , most Centres now limit the usage of this invasive probe to patients with arterial occlusion suspected by non-invasive diagnostic processs [ 13-16,19 ] ( Figure 2 ) . Vascular appraisal is peculiarly of import if there has been a old effort at fix and in the direction of more proximal hurts, which may be associated with harm to the RHA [ 23 ] .Initial symptoms may be nonspecific ; typically related to the effects of bilious leak or bilious obstructor instead than due to vascular-related complications [ 23 ] . The clinical presentation of patients with and without arterial hurts is comparable [ 17,19 ] .

Alves et Al. reported that about one tierce of patients had their HAI identified at the clip of cholecystectomy ( normally after transition ) [ 17 ] , with the staying patients holding the hurt identified in the early postoperative period if there was a bile leak, or subsequently if they presented with icterus. Showing symptoms, timing of diagnosing and figure of old efforts at intervention were comparable in patients with and without an arterial hurt.Specific early symptoms related to arterial hurt have been reported periodically and may include hemorrhage, haemobilia, acute hepatic inadequacy, and sepsis related to right lobe wasting, mortification and abscess formation [ 11-14 ] . Macroscopic ischaemic alterations of the liver can be noticed every bit early as the 4th twenty-four hours after the arterial hurt [ 19 ] . Development of hepatic ischemia was reported in 11-67 per cent of patients with coincident RHA and BDI in recent surveies [ 11-18 ] .Hepatic arteria pseudoaneurysm is a rare complication of LC, variably happening in the early or late postoperative period and may do GI or intraperitoneal hemorrhage [ 24 ] . Pseudoaneurysm perplexing LC often affects the RHA, but may be confined to the cystic arteria leftover.

However, these lesions are normally conformable to angiographic direction, with low related morbidity and favorable long-run consequences [ 25 ] .Several categorizations of bile canal hurt have been proposed, but there is no universally accepted criterion. However, the lone categorization of laparoscopic bile canal hurts which incorporates attendant vascular hurt harmonizing to the mechanism of hurt is the Stewart-Way categorization [ 16 ] .

Mechanisms of hurt and bar

A high hazard of coincident vascular hurt in patients with proximal gall canal hurt has been confirmed in recent analyses of LC-related complications [ 12-18 ] . The RHA is at hazard during LC, as it is present in Calot ‘s trigon in 82 % of occasions, and may hence be mistaken for the cystic arteria and therefore ligated [ 26 ] .Stewart et Al.

depict how the right hepatic canal could be mistaken for the cystic canal, and the RHA for the cystic arteria, which accounts for the most common form of hurt [ 16 ] . During operations that result in hurt of the common hepatic canal or right hepatic canal, the RHA is in a place to be injured or, if the arteria is seen, it may be misidentified as the cystic arteria. The common gall canal ( mistaken for the cystic canal ) can be clipped and mobilized, exposing the RHA, which lies behind the common hepatic canal [ 16 ] .

The sawbones is led to believe that the RHA is really a posterior cystic arteria, and it is frequently clipped based on that erroneous premise. Factors that influence the happening of HAI include the degree of the common hepatic canal hurt and the point where the RHA crosses the common hepatic canal. Similar mechanisms could ensue in RHA with right hepatic canal hurts because of either calculated ligation or hurt during a dissection that is excessively close to the right hepatic canal. These factors emphasize the importance of placing the cystic arteria, following its class to the gall bladder wall, and niping it near to the gall bladder, even if this entails niping anterior and posterior subdivisions of the cystic arteria individually.Three forms of arterial hurt are noted: transection, occlusion by cartridge holders and thrombosis of the vas [ 19 ] . The most common type of arterial hurt is transection of the RHA, normally being mistaken as the cystic arteria. The hepatic arteria may be injured unwittingly while trying to command bleeding during the class of dissection. Bleeding encountered during LC should be addressed by tamponage instead than blindly seeking to use cartridge holders, so the shed blooding vas should be isolated and a secure cartridge holder placed exactly.

If these tactics are unsuccessful, transition is indicated. Another possible cause of vessel occlusion is thrombosis of the hepatic arteria, frequently secondary to bilious peritoneal inflammation.Surgeons who are referred patients for bilious Reconstruction with stenosis, hepatic mortification, or abscess should reexamine prior operative notes and question the primary sawbones specifically with respect to intraoperative hemorrhage and how this was managed intra-operatively.

Consequences of Vascular Injury

Two arterial retes play an of import function in keeping equal vascularisation of the extrahepatic biliary system [ 27-28 ] . One is the arterial rete on the surface of the common gall canal and the common hepatic canal, linking the posterosuperior pancreaticoduodenal arteria and the RHA. The other is at the hilar home base on the inferior surface of the hilus of the liver.

It is formed by the collateral vass coming from the RHA and the left hepatic arteria. In patients with a major BDI and coincident HAI, the arterial rete on the gall canal is wholly transected, but in add-on the arterial blood supply to the right liver lobe may be impaired and the hilar home base rete might be jeopardized.Experimental surveies provide relevant information. Even though the hepatic parenchymal blood supply comes preponderantly from the portal circulation, and hepatic arteria ligation is normally tolerated without clinical sequelae [ 29-32 ] , bilious obstructor in add-on to RHA hurt may predispose to the development of hepatic mortification. Doppman et al. [ 33 ] demonstrated hepatic mortification and infarction in liver sections with bilious obstructor following hepatic artery embolization.

Similarly, Yoshidome et Al. [ 34 ] noted increased susceptibleness to hepatic ischaemia with clogging icterus. Okada [ 35 ] and Soares and co-workers [ 36 ] noted that hepatic artery occlusion in the scene of clogging icterus caused hepatic mortification. These informations may explicate the development of hepatic ischaemia, mortification, and abscess formation in patients with relentless bilious obstructor.Early studies suggest that BDI associated with HAI typically produces terrible effects [ 11,14-15,18 ] . Buell et Al.

in a series of 49 bile canal hurts, reported a mortality rate of 38 % in patients with HAI compared to 3 % in patients with stray bile canal hurts [ 14 ] . Similarly, Gupta et Al. [ 11 ] and Bachellier et Al.

[ 12 ] demonstrated that attendant arterial hurt is a important hazard factor for postoperative liver mortification, liver abscess formation, stricture of the hepaticojejunostomy and late stenosis within the intrahepatic bilious piece of land.Schmidt et al reported that six of 11 patients ( 54.5 % ) with combined BDI and RHA hurts had bilious complications [ 18 ] . Aside from these little series, there are anecdotal studies of patients with combined bile canal and RHA hurts during LC ensuing in high mortality and terrible bilious complications.However, two important surveies do non back up these findings [ 16, 17 ] . Stewart et al. , in a series of 84 patients with combined BDI and HAI out of a sum of 345 patients with BDI, reported that complications such as hemorrhage, haemobilia, hepatic abscess formation, hepatic ischaemia, and need for hepatectomy were more common in patients with HAI compared with those without HAI.

Nevertheless, the overall incidence of morbidity was lower ( 54 % ) than what might hold been expected from the earlier surveies cited above. For illustration, merely 11 % of the patients with HAI developed hepatic ischaemia, and merely 5 % required right hepatic resections. Furthermore, the mortality rate and incidence of secondary bilious cirrhosis were unaffected by HAI. Postoperative complications were significantly more common ( 41 % ) if the bilious fix was undertaken by the primary sawbones instead than a hepatobiliary specializer ( 3 % ) , back uping the position that specific surgical experience is the chief determiner of surgical result.Similary, Alves and co-workers evaluated prospectively a series of 55 patients, by coeliac and superior mesenteric angiography, but failed to show a negative influence of attendant arterial hurts in the short or long term result after bilious hurt [ 17 ] . Neither of these surveies showed any difference in anastomotic stenosis rate between patients who had an stray BDI and those who had a combined vascular and bilious hurt although the Numberss of patients studied was non big.

Bilious complications in earlier series occurred in up to 60 per cent of patients with combined bilious and arterial hurts undergoing biliary-enteric inosculation without arterial Reconstruction [ 8,11-13 ] . In more recent series, where the fix was fashioned by using the left hepatic canal attack, an overall success rate of 93 per cent has been achieved [ 16-17 ] .Overall there is grounds that HAI associated with BDI may increase morbidity, but in footings of long-run anastomotic stenosis formation, there is no strong grounds to back up a negative impact of a attendant vascular hurt ; this is particularly true when the fix is performed in a specialist hepatobiliary unit. In patients who are unable to undergo early fix, proximal extension of an ischemic stenosis may do fix technically more hard.Coexisting portal vena hurts have been periodically reported and are associated with peculiarly lay waste toing hurts as a normal portal circulation is prerequisite for convalescence of the dearterialized liver parenchyma [ 37 ] . Portal vein thrombosis may take to cavernous transmutation of the portal vena. This increases the trouble of subsequently fix and may itself take to bile canal compaction.


Management depends on the timing of acknowledgment of the arterial hurt and whether there is grounds of liver hurt. There is argument in the literature about whether fix of the right hepatic arteria should be done. However, the limited figure of patients who have had RHA Reconstruction ( merely 7 patients in the series analyzed ) , does non let unequivocal decisions to be drawn. With intraoperative or early acknowledgment ( within 4 yearss ) of RHA hurt, some writers suggest arterial Reconstruction to avoid hepatic mortification, biliary-enteric anastomotic escape and late bilious stenosis [ 11-12, 19 ] .

Reanastomosis utilizing an end-to-end technique is normally possible merely if the hurt is related to a partial or complete transectional hurt of the vas, and is undertaken following immediate transition to laparotomy. Vascular Reconstruction utilizing autologous venous transplant or homograft has besides been described [ 12,19 ] . If revascularization is non technically executable but where the meeting of the right and left canals is integral, a Hepp-Couinaud Reconstruction utilizing the extrahepatic part of the left hepatic canal to guarantee equal blood supply to the hepatico-jejunostomy represents the most effectual technique to avoid development of anastomotic stenosis [ 16-17 ] .Other writers have suggested non trying Reconstruction of the injured arteria, as RHA ligation in a non-cholestatic liver is normally tolerated without clinical sequelae owing to the portal flow and the supply of arterial blood from collateral vass [ 16-17, 38 ] . Similarly, the excisional hurt to the arteria may render revascularisations impossible.When a hepatic arteria hurt is identified late, HAI may act upon the determination to execute liver resection at the clip of bilious fix or revisional surgery if liver wasting is present. Alves et Al.

reported that right hepatectomy was inevitable in 12 of 26 patients with vascular hurt, 20 of whom had break of the RHA [ 17 ] . The precise mechanism of wasting is non known but may be related to the combination of arterial hurt with systemic or portal hypotension seen in some patients with bile canal hurt in the early post-cholecystectomy period, when sepsis or bleeding is ill controlled. However, unrecognised hurt to the right ductal system or hapless initial fix may take to chronic bilious obstructor, which may in bend lead to wasting of the affected liver, peculiarly if it is associated with arterial hurt.

The absence of right lobe wasting may mean the presence of a important cross-circulation between the left and right hepatic arteriaPortal vena hurts are normally managed by sutura fix or occasional Reconstruction of the occluded portal vena at the clip of bilious Reconstruction [ 8 ] . These types of hurts are exceptionally rare but can be associated with fatal complications and as most mentions refer merely to scarce instance studies instead than series of patients, it is hard to pull steadfast decisions sing their direction.In terrible vascular injures, the vascular constituent may go the prevailing characteristic of the hurt with mortification of the intrahepatic biliary system, similar to that seen when the hepatic arteria thromboses after liver organ transplant, or even hepatic infarction. Infarct of the intrahepatic bilious tree requires liver organ transplant, while hepatic infarction may take to the demand for hepatic resection or organ transplant [ 39-40 ] . Difficult right hepatic canal fix when bilious hurt is associated with RHA harm may account for the much higher rate of complications affecting the right liver and may hence be best treated by right hepatectomy [ 39 ] . Based on the available informations, a general intervention algorithm is proposed in Figure 3.


In the laparoscopic epoch, BDI tend to be located more proximally compared to those observed in unfastened surgical epoch and vascular hurts occur more frequently than believed in the yesteryear. The early reported association between failure of bilious fix and arterial hurts may merely reflect that HAI is more common among high bilious hurts, and high bilious hurts are besides more hard to mend.

However, as patients with an arterial hurt are more likely to hold ischaemic bilious mucous membrane, there is a higher hazard of stenosis formation if the inosculation is performed below the bilious meeting. Long term result of patients with and without hepatic arteria hurt is comparable every bit long as the Hepp-Couinaud technique is used to execute the bilious fix at the hilar degree and onto the left hepatic canal. The find of a simple break of the right subdivision of the hepatic arteria should non impact direction if a Hepp-Couinaud bilious fix is performed. Evidence of wasting of the right liver lobe or terrible stricturing of the right hepatic canal preventing fix, may bespeak the demand for right hepatic resection. When the HAI is identified early, there may be an option for fix, although this is controversial ; in delayed instances it seems sensible to disregard the vascular hurt. Early referral to a specializer hepatobiliary Centre, without trying fix, is recommended.


  1. Roslyn JJ, Binns GS, Hughes EF, et Al. Open cholecystectomy: a modern-day analysis of 42 474 patients. Ann Surg 1993 ; 218: 129-137.
  2. Fletcher DR, Hobbs MST, Tan P, Valinsky LJ, et Al. Complications of cholecystectomy: hazards of the laparoscopic attack and protective effects of operative cholangiography: a population-based survey. Ann Surg 1999 ; 229: 449-457.
  3. Adamsen S, Hansen OH, Funch-Jensen P, et al..

    Bile canal hurt during laparoscopic cholecystectomy: a prospective countrywide series. J AmColl Surg 1997 ; 184: 571-578.

  4. Strasberg SM, Hertl M, Soper NJ. An analysis of the job of bilious hurt during laparoscopic cholecystectomy. J Am Coll Surg 1995 ; 189:101- 25.
  5. Chaudhary A, Manisegran M, Chandra A, et al..

    How make bile canal hurts sustained during laparoscopic cholecystectomy differ from those during unfastened cholecystectomy? J Laparoendosc Adv Surg Tech 2001 ; 4:187-91.

  6. Bergman JJ, new wave lair Brink GR, Rauws EAJ, , et Al. Treatment of bile canal lesions after laparoscopic cholecystectomy. Gut 1996 ; 38: 141-7.

  7. Davidoff AM, Pappas TN, Murray EA, et Al. Mechanisms of major bilious hurt during laparoscopic cholecystectomy Ann Surg 1992 ; 215: 196-202.
  8. Madariaga JR, Dodson SF, Selby R, et Al. Corrective intervention and anatomic considerations for laparoscopic cholecystectomy hurts. J Am Coll Surg 1994 ; 179: 321-325.
  9. Holbert BL, Baron RL, Dodd GD.

    Hepatic infarction caused by arterial inadequacy: spectrum and development of CT findings. Am J Gastroenterol 1996 ; 166: 815.

  10. Smith GS, Birnbaum BA, Jacobs JE. Hepatic infarction secondary to arterial inadequacy in native livers: CT findings in 10 patients. Radiology 1998 ; 208: 223-229.
  11. Gupta N, Solomon H, Fairchild R, Kaminski D: Management and result of patients with combined bile canal and hepatic arteria hurts.

    Arch Surg 1998 ; 133: 176-181.

  12. Bachellier P, Nakano H, Weber JC, et al.. Surgical fix after bile canal and vascular hurts during laparoscopic cholecystectomy: when and how? World J Surg 2001 ; 25: 1335-1345.
  13. Koffron A, Ferrario M, Parsons W, et Al.

    Failed primary direction of iatrogenic bilious hurt: incidence and significance of attendant hepatic arterial break. Surgery 2001 ; 130: 722-731.

  14. Buell JF, Cronin DC, Funaki B, , et Al: Devastating and fatal complications associated with combined vascular and bile canal hurts. Arch Surg 2002 ; 137: 703-710.

  15. Bilge O, Bozkiran S, Ozden I, et Al. The consequence of accompaniment vascular break in patients with iatrogenic bilious hurts. Langenbecks Arch Surg 2003 ; 388: 265-269.
  16. Stewart L, Robinson TN, Lee CM, et Al. Right hepatic hurt associated with laparoscopic gall canal hurt: Incidence, mechanism and effects.

    J Gastrointest Surg 2004 ; 8: 523-531.

  17. Alves A, Farges O, Nicolet J, et Al. Incidence and effect of an hepatic arteria hurt in patients with postcholecystectomy bile canal stenosiss. Ann Surg 2003 ; 238: 93-96.

  18. Schmidt SC, Settmacher U, Langrehr JM, Neuhaus P. Management and result of patients with combined bile canal and hepatic arterial hurts after laparoscopic cholecystectomy. Surgery 2004 ; 135: 613-618.
  19. Li J, Frilling A, Nadalin S, et Al. Management of attendant hepatic arteria hurt in patients with iatrogenic major gall canal hurt after laparoscopic cholecystectomy. Br J Surg. 2008 ; 95 ( 4 ) :460-5
  20. Terblanche J, Allison HF, Northover JMA. An ischaemic footing for bilious stenosiss.

    Surgery 1993 ; 94:52-7.

  21. Deziel DJ, Millikan KW, Economou SG, et Al. Complications of laparoscopic cholecystectomy: A national study of 4,292 infirmaries and an analysis of 77,704 instances. Am J Surg 1993 ; 165:9-14.
  22. Chapman WC, Halevy A, Blumgart LH, Benjamin IS. Postcholecystectomy bile canal stenosiss.

    Management and result in 130 patients. Arch Surg 1995 ; 130: 597-602.

  23. Connor S, Garden OJ. Bile canal hurt in the epoch of laparoscopic cholecystectomy. Br J Surg 2006 ; 93: 158-168.

  24. Nicholson T, Travis S, Ettles D, et Al. Hepatic arteria angiography and embolization for hemobilia following laparoscopic cholecystectomy. Cardiovasc Intervent Radiol 1999 ; 22: 20.

  25. Tessier DJ, Fowl RJ, Stone WM, et Al. Iatrogenic hepatic arteria pseudoaneurysms: an uncommon complication after hepatic, bilious, and pancreatic processs. Ann Vasc Surg. 2003 Nov ; 17 ( 6 ) :663-9.

  26. Gray S, Skandalakis J. Atlas of Surgical Anatomy for General Surgeons. Baltimore: Williams & A ; Wilkins, 1985.
  27. Stapleton GN, Hickman R, Terblanche J. Blood supply of the right and left hepatic canals.

    Br J Surg 1998 ; 85: 202-207.

  28. Vellar ID. The blood supply of the bilious ductal system and its relevancy to vasculobiliary hurts following cholecystectomy. Aust N Z J Surg 1999 ; 69: 816-820.
  29. Allison DJ, Jordan H, Hennessy O. Curative embolisation of the hepatic arteria: A reappraisal of 75 processs.

    Lancet 1985 ; 1:595-599.

  30. Sheldon GF, Rutledge R. Hepatic injury. Adv Surg 1989 ; 22: 179-193.
  31. Say hey kids ET, Wheeler CS.

    Presentation of indirect arterial flow after break of hepatic arterias in adult male. N Engl J Med 1974 ; 290:993-996.

  32. Bengmark S, Rosengren K.

    Angiographic survey of the collateral circulation to the liver after ligation of the hepatic arteria in adult male. Am J Surg 1970 ; 119:620-624.

  33. Doppman JL, Girton M, Vermess M. The hazard of hepatic arteria embolization in the presence of clogging icterus.

    Radiology 1982 ; 143:37-43.

  34. Yoshidome H, Miyazaki M, Shimizu H, et Al. Clogging icterus impairs hepatic sinusoidal endothelial cell map and renders liver susceptible to hepatic ischemia/reperfusion. J Hepatol 2000 ; 33:59-67.
  35. Okada Y. Experimental survey on the break of hepatic blood flow in clogging icterus, with particular mention to the causes of decease and drawn-out icterus after bilious decompression.

    Nippon Geka Hokan 1989 ; 58:275-288.

  36. Soares AF, Castro e Silva Junior O, Ceneviva R, et Al. Biochemical and morphological alterations in the liver after hepatic arteria ligation in the presence or absence of extrahepatic acholia. Int J Exp Pathol 1993 ; 74:367-370.

  37. Frilling A, Li J, Weber F, et Al. Major bile canal hurts after laparoscopic cholecystectomy: a third centre experience. J Gastrointest Surg 2004 ; 8: 679-685.

  38. Halasz NA: Cholecystectomy and hepatic arteria hurt. Arch Surg 1991 ; 126: 137-138.
  39. Thomson BN, Parks RW, Madhavan KK, Garden OJ. Liver resection and organ transplant in the direction of iatrogenic bilious hurt.

    World J Surg. 2007 Dec ; 31 ( 12 ) :2363-9.