Br. J. Surg. Vol. 63 (1976) 392-396
Jaundice and wound healing : an experimental study I. BAYER A N D HAROLD ELLIS* SUMMARY
Obstructive jaundice was induced in rats by ligation and division of the common bile duct. The healing of a standard gastric incision and a parietal peritoneal defect in these animals showed histological evidence of delayed healing compared with controls. The bursting strength of the abdominal incision was also lowered, but not that oj the stomach, probably because of the adhesions which reinforced the gastric incisions. Angiography did, however, reveal delay in angiogenesis in the gastric wounds of jaundiced animals. The possible causes of this delay in healing and its clinical implications require further investigations.
EXPERIENCED surgeons will give their ‘clinical impression’ that there is impaired healing in patients with obstructive jaundice, yet the relationship between wound healing and jaundice has received little specific investigation (Lee, 1972). The present study investigates the effects of obstructive jaundice on the healing of abdominal wounds, gastric incisions and parietal peritoneal defects in the rat. Materials and methods The series included 140 adult female Sprague-Dawley rats whose weights ranged from 180 to 240 g. In the jaundiced group the operation comprised a standard laparotomy incision, ligation and division of the common bile duct, a standard gastric incision and a standard 1-cm2 parietal peritoneal defect. Both the abdominal wound and the gastric incision were sutured in a standard manner. In the control group the same procedure was performed apart from the bile duct ligation. All the operations were performed under sterile conditions, and ether was used as the anaesthetic agent. The gastric incision was made along the distal part of the greater curvature of the stomach for a length of 4cm, then repaired with a single layer of six interrupted 4/0 catgut sutures and covered with adjacent omentum. The 4-cm vertical midline laparotomy incision was closed with continuous 0 silk in two layers and protected by Nobecutane plastic spray. The animals were killed at 2, 4, 6 and 8 days, at which time they were weighed and blood samples were taken for full blood count, prothrombin time, serum electrolytes, total protein, urea and bilirubin estimations. At each 2-day interval, separate groups of both the jaundiced and control animals were used to estimate the bursting strength of the abdominal and gastric wounds, for histological studies of the peritoneal defects, abdominal and gastric incisions and for micro-angiography of the stomach incisions. 392
Bursting strength of the abdominal wall This was measured by the technique previously described from this laboratory by De Haan et al. (1974) as a modification of the method devised by Prudden et al. (1957). This comprised the insertion of a rubber condom into the peritoneal cavity through a defect made in the apex of the vagina. The balloon was connected to a cylinder of oxygen and inflated at a constant rate. The bursting strength was measured on a connecting mercury manometer at the time of wound disruption. The abdominal wall sutures were not removed before this procedure was carried out. Bursting strength of the stomach wall This was measured by inflating it under water by means of a catheter inserted through the oesophagus with the pylorus ligatured (Scheinin and Viljanto, 1966). During this procedure the sutures in the gastric incision and a n y adjacent adhesions to it were left undisturbed. Micro-angiography Micro-angiography was carried out by injection of between 15 and 20ml of Micro-opaque diluted to 50 per cent in normal saline via a cannula inserted into the abdominal aorta. Prior to the injection the vascular system was carefully washed out with heparinized saline. The injected animal was then immersed in 3 per cent formalin for 4 hours. The fixed stomach was subsequently removed for X-ray examination. Histology Histological studies of the gastric incisions and peritoneal defects were carried out on sections stained with haematoxylin and eosin and with van Gieson. A further separate group of 12 rats was submitted to common bile duct ligation and division without any other procedure in order to follow the biochemical changes and to assess survival in jaundiced rats.
Results All the rats subjected to bile duct division became obviously jaundiced within 48 hours, at which time the mean serum bilirubin level reached 8.6 f 3.25 mg per cent. Over the 8 days of the wound healing study the serum bilirubin level remained at a plateau. The animals remained healthy, and although there was loss of weight in the postoperative period this did not differ from the weight loss in the control group. The haemoglobin, haemocrit, white blood count, prothrombin time, serum electrolytes, total protein and
* Surgical Unit, Westminster Hospital, London.
Jaundice and wound healing
3 I 18
I2-
16-
108-
14-
6M
I
-:
4-
2-
I
,
Days
1
I2-
r Y
M
6
4
10
8
I2
Serum bilirubin (mg
10-
Ql -+?s
14 I
i,)
A .
M
Fig. 1 . Serum bilirubin levels following common bile duct ligation and division.
._ Y
: 8-
m
6401
T
/*I
LI
361
-
i
I 24-
i
I
,'
8
Control group
I
28
M
4-
I
4
1
I 8
T
I
-I
2
4
6
8
Jaundiced group Control P U P
1
10
Days
D
E
-
Fig. 3. Bursting strength of the healing stomach incision in jaundiced and control groups of rats. There is no significant difference between the groups.
E
L
'c 20c
e .A
.-
,? 3
m
Table I: SERUM BILIRUBIN IN JAUNDlCED RATS AFTER BILE DUCT LIGATION Serum bilirubin Day No. of animals (g, mean*s.d.) 2 12 8.63 1 3 . 2 5 4 12 9.07 5 1.49 10 11.06&1.76 6 8 12 9.71 +2.29 14 3 11.63 24 3 1 1.76 3 12.23 36 44/45 1-2 18.06
16-
':I 4
i
4
i
Days
6
~
Ib
Fig. 2. Bursting strength of the healing abdominal wall incision in jaundiced and control groups of rats. After 6 days there is a significant difference between the groups.
blood urea showed no change from the normal, and there was no difference between the jaundiced and the control groups. The separate group of 12 rats submitted to common bile duct ligation and division without any other procedure did not become obviously ill in a 5-week period of observation following the operation. Batches of 3 of these animals were killed at 14,24 and 36 days; the remaining 3 died, one at 44 days and 2 at 45 days. Post-mortem examination of these 3 rats showed that death was caused by rupture of the swollen proximal common bile duct, with biliary peritonitis. Unfortunately, blood was only obtained from one of these
Table 11: BURSTING STRENGTH OF THE HEALING ABDOMINAL WALL Jaundiced group Control group No. of Bursting No. of Bursting Day animals strength (mm Hg) animals strength (mm Hg) 2 5 1.40 i1.47 5 22201t 3.17 4 5 17.90& 1.55 5 21.3011.03 5 22,9050.74 5 19.16* 1.50 6 8 5 21.20+0.75 5 37.20 5 2.94 Table 111: BURSTING STRENGTH OF THE HEALING STOMACH WALL Jaundiced group Control group No. of Bursting No. of Bursting Day animals strength (mm Hg) animals strength (mm Hg) 5.9810.92 5 4.5050.70 2 5 4,9051.38 5 49010.97 4 5 15.245 1.47 5 14.35 & 1.03 6 5 17.45i1.71 8 5 17.38 1.90 5
+
393
I. Bayer and Harold Ellis
Fig. 4. Peritoneal defect in a control animal a t 8 days. Dense parallel collagen fibres and flattened fibroblasts are visible. ( x 80.)
Fig. 7. Gastric incision in a jaundiced animal at 8 days. N~~~the considerable delay i n healing, ( 32,)
6 and then showed a steep rise between the sixth and eighth days (Table 11, Fig. 2). Bursting strength of the stomach wall The bursting strength of the gastric incision showed a rapid increase from t h e fourth to the eighth day in both groups with no significant difference between the groups (Table III, Fig. 3).
Fig. 5. Peritoneal defect in a jaundiced animal at 8 days. The defect contains young fibroblasts with little collagen formation. 0.1 - . ( x8 ~~, ~
Histo1og.y Peritoneal defects : We have previously documented the normal healing process in peritoneal defects (Ellis et al., 1965). In the control group, defects on the fourth day demonstrated proliferating fibroblasts with commencing collagen deposition. By the eighth day dense collagen fibres were obvious ; these had orientated parallel to the surface of the wound and were interspersed with well-developed and flattened fibroblasts (Fig. 4). In the jaundiced rats the peritoneal defects demonstrated a delay of 48-72 hours in their healing process, so that at 8 days there was still a considerable cellular exudate containing young fibroblasts with minimal collagen formation (Fig. 5). Gastric incisions: In the control group, complete repair had occurred across the gastric wound at the eighth day (Fig. 6). In the jaundiced rats at 8 days the wound demonstrated granulation tissue in a loose stroma with necrotic tissue still present and only early fibroblast proliferation, demonstrating considerable histological delay in the healing process (Fig. 7).
animals dying at 45 days. The serum bilirubin levels are shown in Table I and Fig. 1.
Micro-angiography In the control group, new vessels could be seen crossing the gastric incision at 4 days, and by 8 days the vascular pattern of the stomach had virtually returned to normal (Fig. 8). However, in the jaundiced animals there was little new vessel formation across the wound at 8 days (Fig. 9).
Bursting strength of the abdominal wall There was no increase in the bursting strength of the abdominal wound in the jaundiced animals between thesecondand eighthdays. The burstingstrength in the control animals was significantly higher at days 4 and
Discussion Our studies have demonstrated that obstructive jaundice in the rat is associated with delay in healing of peritoneal wounds on histological study and in the healing of laparotomy incisions on bursting strength
Fig. 6. Gastric incision in a control animal at 8 days. The wound is virtually healed. ( x 32.)
394
Jaundice and wound healing measurements compared with controls. Although incisions of the stomach demonstrated delay in healing on microscopic examination, there was no difference between the bursting strength of the gastric wound in jaundiced and control animals. This may, however, be associated with the technique that we used in which the sutures were left ifl situ and, perhaps more important, t h e densely adherent omentum which invariably covered the serosal aspect of the incision and which considerably ‘reinforced’ the suture line was left intact. Jaundice had no apparent effect on this process of adhesion formation. The impairment in healing was correlated with delay in collagen deposition and, in the case of gastric wounds, with delay in the growth of blood vessels across the line of incision. Any experienced surgeon will have learned that wound dehiscence is particularly likely to occur in patients who are profoundly jaundiced, yet, surprisingly, we have been unable to find anything other than occasional anecdotal mention ofthis phenomenon in some of the many publications on wound healing and burst abdomen. Reitamo and Moller (1972) studied 49 patients with burst abdomen occurring in a group of 8226 laparotomies. These were compared with a control group obtained by taking the next patient of the same sex and of the same 10-year age group i n the series to undergo a laparotomy. They recorded 3 examples in a group comprising ‘uraemia, icterus and deranged liver function’ in the burst abdomen group compared with no examples of these complications amongst the controls. It is interesting that malignant disease, anaemia and hypoproteinaemia were twice as common in the burst abdomen group compared with the control group. In contrast, Keill et al. (1973), in a study of 47 abdominal wound dehiscences which they compared with 58 controls randomly selected from the 4242 operations in which the burst wounds occurred, found that 6 patients in each group were jaundiced, giving a completely comparable incidence. There is obviously need for further careful clinical studies of this situation. In practice, the problem IS a complicated one because patients with obstructive jaundice frequently have additional factors which themselves are associated with delay in healing-in particular, malignant disease, protein deficiency, infection, uraemia and anaemia. Clinical studies must therefore take into account the complex picture which is often associated with severe obstructive jaundice. In the experimental animal it is possible to dissect out each of these factors individually, and we have previously shown in this laboratory that malignant disease (Stewart, 1973), protein deficiency (Mott et al., 1969), infection, both distant and local (De Haan et al., 1974), and uraemia (Mott and Ellis, 1967), all in isolation, profoundly affect wound healing. We have not ourselves investigated the effects of anaemia. Careful studies by Bains et al. (1966) demonstrated a decrease in tensile strength of laparotomy wounds in anaemic rats compared with controls. It should be pointed out, however, that Hugo et al. (1969) found no
Pig. 8. Angiogram of a gastric incision at 8 days in a control animal. A leash of new vessels crosses the incision (its extremities are marked by the two arrows).
Fig. 9. Angiogram of a gastric incision at 8 days in a jaundiced animal. No vessels cross the line of the incision (its extremities are marked by the arrows).
effect of anaemia on the tensile strength of healing wounds in anaemic rabbits; similarly Trueblood et al. (1969) discovered no significant differences in t h e healing of colon anastomoses between anaemic and control rats. The effects of jaundice on healing have been sadly neglected in the laboratory. Indeed, only Karakantzas (1975) has previously investigated this phenomenon. Using ligation of the common bile duct in the rat in a pilot study in our laboratory, he was able to show that there was histological delay in the healing of parietal peritoneal defects. In our experimental model, hypoproteinaemia, anaemia and other complicating factors have been 395
I. Bayer and Harold Ellis excluded and yet healing was profoundly delayed. It would appear that bilirubin or some other substance in the retained bile has a profound inhibitory effect on fibroplasia and angiogenesis. This problem is being further investigated by cytokinetic studies in our laboratory. Tissue culture experiments might also shed light on the effects of jaundice on fibroblast function.
References BAINS J. W., CRAWFORD D. 1. and KETCHAM A. S.
(1966) Effect of chronic anaemia on wound tensile strength: correlation with blood volume, total red blood cell volume and proteins. Ann. Surg. 164, 243-246. ELLIS H., HARRISON W. and HUGH T. B. (1965) The healing of peritoneum under normal and abnormal conditions. Br. J. Surg. 52, 471-476. DE HAAN B. B., ELLIS H. and WILKS M. (1974) The role of infection on wound healing. Surg. Gynecol. Obstet. 138, 693-700. HUGO N. E., THOMPSON L. w., ZOOK E. G. and BENNETT J. E. (1969) Effect of chronic anemia on tensile strength of healing wounds. Surgery 66,741-745. KARAKANTZAS D. (1975) The effects of obstructive jaundice on wound healing: an experimental study. Thesis, University of Thessalonika, Greece. KEILL K. H., KEITZER F., NICHOLS w. K., HENZEL J. and DEWEESE M. s. (1973) Abdominal wound dehiscence. Arch. Surg. 106, 573-577.
396
(1972) The effect of obstructive jaundice on the migration of reticulo-endothelial cells and fibroblasts into early experimental granulomata. Br. J. Surg. 59, 875-877. MOTT T. J., ASHBY E. c., FLANNERY B. and ELLIS H. (1969) The effect of protein deficiency upon peritoneal healing and peritoneal wound contraction in the rat. Br. J. Nutr. 23, 497-504. MOTI T. J. and ELLIS H. (1967) A method of producing experimental uraemia in the rabbit with some observations on the influence of uraemia on peritoneal healing. Br. J. Urol. 39, 341-346. PRUDDEN J. F., NISHIHARA A. and BAKER L. (1957) The acceleration of wound healing with cartilage. Surg. Gynecol. Obstet. 105, 283-286. REITAMO J. and MOLLER c. (1972) Abdominal wound dehiscence. Acta Chir. Scand. 138, 170-1 75. SCHEININ T. M. and VILJANTO J. (1966) Bursting pressure of healing gastro-intestinal wounds in the rat. Ann. Med. Exp. Biol. Fenn. 44, 49-51. STEWART R. (1973) Influence of malignant cells on the healing of colonic anastomoses: experimental observations. Proc. R . Soc. Med. 66, 1089-1091. TRUEBLOOD H. w., NELSON T. s. and OBERHELMAN H. A. (1969) The effect of acute anemia and iron deficiency anemia on wound healing. Arch. Surg. 99, 113-1 16. LEE E.
Jaundice and wound healing : an experimental study I. BAYER A N D HAROLD ELLIS* SUMMARY
Obstructive jaundice was induced in rats by ligation and division of the common bile duct. The healing of a standard gastric incision and a parietal peritoneal defect in these animals showed histological evidence of delayed healing compared with controls. The bursting strength of the abdominal incision was also lowered, but not that oj the stomach, probably because of the adhesions which reinforced the gastric incisions. Angiography did, however, reveal delay in angiogenesis in the gastric wounds of jaundiced animals. The possible causes of this delay in healing and its clinical implications require further investigations.
EXPERIENCED surgeons will give their ‘clinical impression’ that there is impaired healing in patients with obstructive jaundice, yet the relationship between wound healing and jaundice has received little specific investigation (Lee, 1972). The present study investigates the effects of obstructive jaundice on the healing of abdominal wounds, gastric incisions and parietal peritoneal defects in the rat. Materials and methods The series included 140 adult female Sprague-Dawley rats whose weights ranged from 180 to 240 g. In the jaundiced group the operation comprised a standard laparotomy incision, ligation and division of the common bile duct, a standard gastric incision and a standard 1-cm2 parietal peritoneal defect. Both the abdominal wound and the gastric incision were sutured in a standard manner. In the control group the same procedure was performed apart from the bile duct ligation. All the operations were performed under sterile conditions, and ether was used as the anaesthetic agent. The gastric incision was made along the distal part of the greater curvature of the stomach for a length of 4cm, then repaired with a single layer of six interrupted 4/0 catgut sutures and covered with adjacent omentum. The 4-cm vertical midline laparotomy incision was closed with continuous 0 silk in two layers and protected by Nobecutane plastic spray. The animals were killed at 2, 4, 6 and 8 days, at which time they were weighed and blood samples were taken for full blood count, prothrombin time, serum electrolytes, total protein, urea and bilirubin estimations. At each 2-day interval, separate groups of both the jaundiced and control animals were used to estimate the bursting strength of the abdominal and gastric wounds, for histological studies of the peritoneal defects, abdominal and gastric incisions and for micro-angiography of the stomach incisions. 392
Bursting strength of the abdominal wall This was measured by the technique previously described from this laboratory by De Haan et al. (1974) as a modification of the method devised by Prudden et al. (1957). This comprised the insertion of a rubber condom into the peritoneal cavity through a defect made in the apex of the vagina. The balloon was connected to a cylinder of oxygen and inflated at a constant rate. The bursting strength was measured on a connecting mercury manometer at the time of wound disruption. The abdominal wall sutures were not removed before this procedure was carried out. Bursting strength of the stomach wall This was measured by inflating it under water by means of a catheter inserted through the oesophagus with the pylorus ligatured (Scheinin and Viljanto, 1966). During this procedure the sutures in the gastric incision and a n y adjacent adhesions to it were left undisturbed. Micro-angiography Micro-angiography was carried out by injection of between 15 and 20ml of Micro-opaque diluted to 50 per cent in normal saline via a cannula inserted into the abdominal aorta. Prior to the injection the vascular system was carefully washed out with heparinized saline. The injected animal was then immersed in 3 per cent formalin for 4 hours. The fixed stomach was subsequently removed for X-ray examination. Histology Histological studies of the gastric incisions and peritoneal defects were carried out on sections stained with haematoxylin and eosin and with van Gieson. A further separate group of 12 rats was submitted to common bile duct ligation and division without any other procedure in order to follow the biochemical changes and to assess survival in jaundiced rats.
Results All the rats subjected to bile duct division became obviously jaundiced within 48 hours, at which time the mean serum bilirubin level reached 8.6 f 3.25 mg per cent. Over the 8 days of the wound healing study the serum bilirubin level remained at a plateau. The animals remained healthy, and although there was loss of weight in the postoperative period this did not differ from the weight loss in the control group. The haemoglobin, haemocrit, white blood count, prothrombin time, serum electrolytes, total protein and
* Surgical Unit, Westminster Hospital, London.
Jaundice and wound healing
3 I 18
I2-
16-
108-
14-
6M
I
-:
4-
2-
I
,
Days
1
I2-
r Y
M
6
4
10
8
I2
Serum bilirubin (mg
10-
Ql -+?s
14 I
i,)
A .
M
Fig. 1 . Serum bilirubin levels following common bile duct ligation and division.
._ Y
: 8-
m
6401
T
/*I
LI
361
-
i
I 24-
i
I
,'
8
Control group
I
28
M
4-
I
4
1
I 8
T
I
-I
2
4
6
8
Jaundiced group Control P U P
1
10
Days
D
E
-
Fig. 3. Bursting strength of the healing stomach incision in jaundiced and control groups of rats. There is no significant difference between the groups.
E
L
'c 20c
e .A
.-
,? 3
m
Table I: SERUM BILIRUBIN IN JAUNDlCED RATS AFTER BILE DUCT LIGATION Serum bilirubin Day No. of animals (g, mean*s.d.) 2 12 8.63 1 3 . 2 5 4 12 9.07 5 1.49 10 11.06&1.76 6 8 12 9.71 +2.29 14 3 11.63 24 3 1 1.76 3 12.23 36 44/45 1-2 18.06
16-
':I 4
i
4
i
Days
6
~
Ib
Fig. 2. Bursting strength of the healing abdominal wall incision in jaundiced and control groups of rats. After 6 days there is a significant difference between the groups.
blood urea showed no change from the normal, and there was no difference between the jaundiced and the control groups. The separate group of 12 rats submitted to common bile duct ligation and division without any other procedure did not become obviously ill in a 5-week period of observation following the operation. Batches of 3 of these animals were killed at 14,24 and 36 days; the remaining 3 died, one at 44 days and 2 at 45 days. Post-mortem examination of these 3 rats showed that death was caused by rupture of the swollen proximal common bile duct, with biliary peritonitis. Unfortunately, blood was only obtained from one of these
Table 11: BURSTING STRENGTH OF THE HEALING ABDOMINAL WALL Jaundiced group Control group No. of Bursting No. of Bursting Day animals strength (mm Hg) animals strength (mm Hg) 2 5 1.40 i1.47 5 22201t 3.17 4 5 17.90& 1.55 5 21.3011.03 5 22,9050.74 5 19.16* 1.50 6 8 5 21.20+0.75 5 37.20 5 2.94 Table 111: BURSTING STRENGTH OF THE HEALING STOMACH WALL Jaundiced group Control group No. of Bursting No. of Bursting Day animals strength (mm Hg) animals strength (mm Hg) 5.9810.92 5 4.5050.70 2 5 4,9051.38 5 49010.97 4 5 15.245 1.47 5 14.35 & 1.03 6 5 17.45i1.71 8 5 17.38 1.90 5
+
393
I. Bayer and Harold Ellis
Fig. 4. Peritoneal defect in a control animal a t 8 days. Dense parallel collagen fibres and flattened fibroblasts are visible. ( x 80.)
Fig. 7. Gastric incision in a jaundiced animal at 8 days. N~~~the considerable delay i n healing, ( 32,)
6 and then showed a steep rise between the sixth and eighth days (Table 11, Fig. 2). Bursting strength of the stomach wall The bursting strength of the gastric incision showed a rapid increase from t h e fourth to the eighth day in both groups with no significant difference between the groups (Table III, Fig. 3).
Fig. 5. Peritoneal defect in a jaundiced animal at 8 days. The defect contains young fibroblasts with little collagen formation. 0.1 - . ( x8 ~~, ~
Histo1og.y Peritoneal defects : We have previously documented the normal healing process in peritoneal defects (Ellis et al., 1965). In the control group, defects on the fourth day demonstrated proliferating fibroblasts with commencing collagen deposition. By the eighth day dense collagen fibres were obvious ; these had orientated parallel to the surface of the wound and were interspersed with well-developed and flattened fibroblasts (Fig. 4). In the jaundiced rats the peritoneal defects demonstrated a delay of 48-72 hours in their healing process, so that at 8 days there was still a considerable cellular exudate containing young fibroblasts with minimal collagen formation (Fig. 5). Gastric incisions: In the control group, complete repair had occurred across the gastric wound at the eighth day (Fig. 6). In the jaundiced rats at 8 days the wound demonstrated granulation tissue in a loose stroma with necrotic tissue still present and only early fibroblast proliferation, demonstrating considerable histological delay in the healing process (Fig. 7).
animals dying at 45 days. The serum bilirubin levels are shown in Table I and Fig. 1.
Micro-angiography In the control group, new vessels could be seen crossing the gastric incision at 4 days, and by 8 days the vascular pattern of the stomach had virtually returned to normal (Fig. 8). However, in the jaundiced animals there was little new vessel formation across the wound at 8 days (Fig. 9).
Bursting strength of the abdominal wall There was no increase in the bursting strength of the abdominal wound in the jaundiced animals between thesecondand eighthdays. The burstingstrength in the control animals was significantly higher at days 4 and
Discussion Our studies have demonstrated that obstructive jaundice in the rat is associated with delay in healing of peritoneal wounds on histological study and in the healing of laparotomy incisions on bursting strength
Fig. 6. Gastric incision in a control animal at 8 days. The wound is virtually healed. ( x 32.)
394
Jaundice and wound healing measurements compared with controls. Although incisions of the stomach demonstrated delay in healing on microscopic examination, there was no difference between the bursting strength of the gastric wound in jaundiced and control animals. This may, however, be associated with the technique that we used in which the sutures were left ifl situ and, perhaps more important, t h e densely adherent omentum which invariably covered the serosal aspect of the incision and which considerably ‘reinforced’ the suture line was left intact. Jaundice had no apparent effect on this process of adhesion formation. The impairment in healing was correlated with delay in collagen deposition and, in the case of gastric wounds, with delay in the growth of blood vessels across the line of incision. Any experienced surgeon will have learned that wound dehiscence is particularly likely to occur in patients who are profoundly jaundiced, yet, surprisingly, we have been unable to find anything other than occasional anecdotal mention ofthis phenomenon in some of the many publications on wound healing and burst abdomen. Reitamo and Moller (1972) studied 49 patients with burst abdomen occurring in a group of 8226 laparotomies. These were compared with a control group obtained by taking the next patient of the same sex and of the same 10-year age group i n the series to undergo a laparotomy. They recorded 3 examples in a group comprising ‘uraemia, icterus and deranged liver function’ in the burst abdomen group compared with no examples of these complications amongst the controls. It is interesting that malignant disease, anaemia and hypoproteinaemia were twice as common in the burst abdomen group compared with the control group. In contrast, Keill et al. (1973), in a study of 47 abdominal wound dehiscences which they compared with 58 controls randomly selected from the 4242 operations in which the burst wounds occurred, found that 6 patients in each group were jaundiced, giving a completely comparable incidence. There is obviously need for further careful clinical studies of this situation. In practice, the problem IS a complicated one because patients with obstructive jaundice frequently have additional factors which themselves are associated with delay in healing-in particular, malignant disease, protein deficiency, infection, uraemia and anaemia. Clinical studies must therefore take into account the complex picture which is often associated with severe obstructive jaundice. In the experimental animal it is possible to dissect out each of these factors individually, and we have previously shown in this laboratory that malignant disease (Stewart, 1973), protein deficiency (Mott et al., 1969), infection, both distant and local (De Haan et al., 1974), and uraemia (Mott and Ellis, 1967), all in isolation, profoundly affect wound healing. We have not ourselves investigated the effects of anaemia. Careful studies by Bains et al. (1966) demonstrated a decrease in tensile strength of laparotomy wounds in anaemic rats compared with controls. It should be pointed out, however, that Hugo et al. (1969) found no
Pig. 8. Angiogram of a gastric incision at 8 days in a control animal. A leash of new vessels crosses the incision (its extremities are marked by the two arrows).
Fig. 9. Angiogram of a gastric incision at 8 days in a jaundiced animal. No vessels cross the line of the incision (its extremities are marked by the arrows).
effect of anaemia on the tensile strength of healing wounds in anaemic rabbits; similarly Trueblood et al. (1969) discovered no significant differences in t h e healing of colon anastomoses between anaemic and control rats. The effects of jaundice on healing have been sadly neglected in the laboratory. Indeed, only Karakantzas (1975) has previously investigated this phenomenon. Using ligation of the common bile duct in the rat in a pilot study in our laboratory, he was able to show that there was histological delay in the healing of parietal peritoneal defects. In our experimental model, hypoproteinaemia, anaemia and other complicating factors have been 395
I. Bayer and Harold Ellis excluded and yet healing was profoundly delayed. It would appear that bilirubin or some other substance in the retained bile has a profound inhibitory effect on fibroplasia and angiogenesis. This problem is being further investigated by cytokinetic studies in our laboratory. Tissue culture experiments might also shed light on the effects of jaundice on fibroblast function.
References BAINS J. W., CRAWFORD D. 1. and KETCHAM A. S.
(1966) Effect of chronic anaemia on wound tensile strength: correlation with blood volume, total red blood cell volume and proteins. Ann. Surg. 164, 243-246. ELLIS H., HARRISON W. and HUGH T. B. (1965) The healing of peritoneum under normal and abnormal conditions. Br. J. Surg. 52, 471-476. DE HAAN B. B., ELLIS H. and WILKS M. (1974) The role of infection on wound healing. Surg. Gynecol. Obstet. 138, 693-700. HUGO N. E., THOMPSON L. w., ZOOK E. G. and BENNETT J. E. (1969) Effect of chronic anemia on tensile strength of healing wounds. Surgery 66,741-745. KARAKANTZAS D. (1975) The effects of obstructive jaundice on wound healing: an experimental study. Thesis, University of Thessalonika, Greece. KEILL K. H., KEITZER F., NICHOLS w. K., HENZEL J. and DEWEESE M. s. (1973) Abdominal wound dehiscence. Arch. Surg. 106, 573-577.
396
(1972) The effect of obstructive jaundice on the migration of reticulo-endothelial cells and fibroblasts into early experimental granulomata. Br. J. Surg. 59, 875-877. MOTT T. J., ASHBY E. c., FLANNERY B. and ELLIS H. (1969) The effect of protein deficiency upon peritoneal healing and peritoneal wound contraction in the rat. Br. J. Nutr. 23, 497-504. MOTI T. J. and ELLIS H. (1967) A method of producing experimental uraemia in the rabbit with some observations on the influence of uraemia on peritoneal healing. Br. J. Urol. 39, 341-346. PRUDDEN J. F., NISHIHARA A. and BAKER L. (1957) The acceleration of wound healing with cartilage. Surg. Gynecol. Obstet. 105, 283-286. REITAMO J. and MOLLER c. (1972) Abdominal wound dehiscence. Acta Chir. Scand. 138, 170-1 75. SCHEININ T. M. and VILJANTO J. (1966) Bursting pressure of healing gastro-intestinal wounds in the rat. Ann. Med. Exp. Biol. Fenn. 44, 49-51. STEWART R. (1973) Influence of malignant cells on the healing of colonic anastomoses: experimental observations. Proc. R . Soc. Med. 66, 1089-1091. TRUEBLOOD H. w., NELSON T. s. and OBERHELMAN H. A. (1969) The effect of acute anemia and iron deficiency anemia on wound healing. Arch. Surg. 99, 113-1 16. LEE E.
