British Journal ofPlastic Surgery (1991), 44.299-301 0 1991 The Trustees of British Association of Plastic Surgeons
experimental study on the effect of nifedipine on ischaemic skin flap survival in rats
An
S.Pal*,
R. K. Khazanchi* and K. Moudgilt
*Division of Reconstructive Surgery and Renal Transplantation, Department of Surgical Disciplines, and TDepartment of Biochemistry, All India Institute of Medical Sciences, New Delhi, India SUMMAR Y. Vasodilators have been employed previously in an attempt to improve survival of ischaemic rat skin flaps. The effect of nifediphre, a calcium channel blocker, on skin flap survival was studied using a standard experimental rat model. The control group had a mean flap necrosis of 37.009~0. Rats treated by nifedipine starting 1 day preoperatively and continued for 1 week postoperatively had a mean necrosis of 10.0953%. Rats treated by nifedipine started postoperatively and continued for 1 week had a mean flap necrosis of 12.289%. Treated groups had signiflcantly lower flap necrosis in comparison to untreated controls. There was no significant difference in flap necrosis between the two treated groups. This study shows that nifedipine improves survival in standard ischaemic rat skin flaps.
its individual source of water and standard rat food. All cages were housed in an airconditioned room.
The problem of skin flap necrosis, especially of random skin flaps, is all pervasive. Previous studies both clinical and experimental using various pharmacologic agents like vasodilators (Myers and Cherry, 1968 ; Wexler et al., 1975 ; Kerrigan and Daniel, 1982) blood rheology modifiers (Roth et al., 1988) and fluorocarbons (Ramasastry et al., 1984) have not yielded consistent results. Vasodilators ranging from alpha receptor blockers, beta blockers, guanethidine and 6-hydroxy dopamine have been tried with varied success (Wexler et al., 1975; Finseth and Adelberg, 1978). A study using verapamil (Stein et al., 1989), a calcium channel blocker, has shown that it improves survival of rat island skin flaps with occluded venous another calcium channel drainage. Nifedipine, blocker, is an effective arteriolar smooth muscle relaxant (Katzung, 1987). Being a potent vasodilator, theoretically it can improve the blood supply in ischaemic skin flaps. The pharmacokinetics of the drug allow it to be absorbed almost totally by the oral and sublingual route enabling optimal and consistent blood levels. Previous studies with nifedipine (Miller et al., 1985; Emery et al., 1990) have failed to demonstrate its potential to salvage ischaemic skin flaps.
Surgical technique
Rats were anaesthetised using sodium pentothal 30 mg/kg intraperitoneally. The dorsum of each rat was then shaved from sacral to scapular region and painted with betadine after cleaning with Savlon. Caudally based 3 x 10 cm skin flaps (Khouri et al., 1986) were raised approximately 1 cm from the base of the tail so that the free (cephalad) edge of the flap generally lay about 0.5 cm from the scapular tips. The flap consisted of skin and panniculus camosus. Care was taken to keep the paired sacral pedicles at the flap base totally intact. The raised pedicle flap was reapproximated to the skin edges with 4-O nylon atraumatic continuous sutures. No electrocautery or haemostatic agents were used. For all animals the flaps were assessed at the end of the 1st postoperative week. Flap necrosis is known to stabilise at 1 week postoperatively (Roth et al., 1988). Under anaesthesia the flaps were traced on acetate paper and area of necrosis marked. The area of necrosis and total flap area were measured by using a polar planimeter (Ramasastry et al., 1985). The surface area of flap necrosis, represented by the blackened and indurated area of the cephalad part of the flap, was calculated using the planimeter and the result for each rat expressed as percentage necrosis (i.e., necrotic flap area/total flap area x 100). Three separate measurements were made for each flap and a mean value obtained for each of the rats.
Materials and methods
The experimental animals used were male Wistar rats weighing 275-375 g. The rats (N=45) were divided into 3 groups as follows: Group A-Control group (n = 15); Group B-Started on nifedipine orally 1 day preoperatively and continued until the 7th postoperative day (n= 15); Group C-Started on nifedipine orally in the immediate postoperative period and continued until the 7th postoperative day. The rats were housed in separate cages. Each had
Drug dosage and delivery
Nifedipine (DEPIN-Cipla India Limited) capsule contents were instilled in the oral cavity of each rat 299
300
British Journal of Plastic Surgery dependent channels much like the sodium channels of nerve but relatively selective for calcium ions. Most types of smooth muscles are dependent on transmembrane calcium influx for normal resting tone and contractile responses. These cells are relaxed by calcium channel inhibitors. Vascular smooth muscle is most sensitive to this inhibition. In the vascular system arteriolar smooth muscle appears to be more sensitive than that in veins. Besides vasodilatation nifedipine results in a fall in blood pressure and tachycardia. Ishii et al. (1980) and Nagao et al. (1985) have studied this effect in normotensive and spontaneously hypertensive Wistar rats. Significant falls in blood pressure were observed in hypertensive rats. Normotensive rats also had hypotension and tachycardia which was dose dependent. The fall in blood pressure was more and lasted longer with increasing dosages of nifedipine from 0.2 mg to 5 mg/kg (Ischii et al., 1980). Clapham (1984) also found a dose dependent hypotensive effect in hypertensive rats. According to this study, nifedipine in low doses is effective in decreasing flap necrosis in a standard ischaemic rat skin flap. Though the mechanism of action has not been studied vasodilation seems plausible. Some other mechanisms may also be responsible. Calcium channel blockers prevent deleterious calcium influx into an ischaemic cell thereby retarding and preventing cell death (Stein et al., 1989). Calcium is involved in various steps of oxygen radical release and oxygen radical injury to cell components (Manson et al., 1983). Experimental studies in rabbits have also shown that calcium channel blockers inhibit platelet aggregation (Katzung, 1987). The pharmacokinetics of nifedipine allow it to be almost totally absorbed orally and sublingually. In
(post incisural fossa in the lower jaw) using an insulin syringe. One drop of Depin was administered every 12 hours. The resultant dosage administered to each rat (weight range 275-375 g) ranged between 0.30.5 mg/kg/day. Results In the control group A the range of flap necrosis was 82.558%-45.283% with a mean of 37.009% f 4.293% SD. In group B (n = 15) rats the range of flap necrosis was 7.124x--14.59% with a mean of 10.095%+ 2.314% SD. In Group C (n=l5) rats the range was 10.15x-15.00% with a mean of 12.289%fl.306% SD. Using one way analysis of variance and multiple range test the nifedipine treated animals (Groups B and C) had a statistically significant (p
experimental study on the effect of nifedipine on ischaemic skin flap survival in rats
An
S.Pal*,
R. K. Khazanchi* and K. Moudgilt
*Division of Reconstructive Surgery and Renal Transplantation, Department of Surgical Disciplines, and TDepartment of Biochemistry, All India Institute of Medical Sciences, New Delhi, India SUMMAR Y. Vasodilators have been employed previously in an attempt to improve survival of ischaemic rat skin flaps. The effect of nifediphre, a calcium channel blocker, on skin flap survival was studied using a standard experimental rat model. The control group had a mean flap necrosis of 37.009~0. Rats treated by nifedipine starting 1 day preoperatively and continued for 1 week postoperatively had a mean necrosis of 10.0953%. Rats treated by nifedipine started postoperatively and continued for 1 week had a mean flap necrosis of 12.289%. Treated groups had signiflcantly lower flap necrosis in comparison to untreated controls. There was no significant difference in flap necrosis between the two treated groups. This study shows that nifedipine improves survival in standard ischaemic rat skin flaps.
its individual source of water and standard rat food. All cages were housed in an airconditioned room.
The problem of skin flap necrosis, especially of random skin flaps, is all pervasive. Previous studies both clinical and experimental using various pharmacologic agents like vasodilators (Myers and Cherry, 1968 ; Wexler et al., 1975 ; Kerrigan and Daniel, 1982) blood rheology modifiers (Roth et al., 1988) and fluorocarbons (Ramasastry et al., 1984) have not yielded consistent results. Vasodilators ranging from alpha receptor blockers, beta blockers, guanethidine and 6-hydroxy dopamine have been tried with varied success (Wexler et al., 1975; Finseth and Adelberg, 1978). A study using verapamil (Stein et al., 1989), a calcium channel blocker, has shown that it improves survival of rat island skin flaps with occluded venous another calcium channel drainage. Nifedipine, blocker, is an effective arteriolar smooth muscle relaxant (Katzung, 1987). Being a potent vasodilator, theoretically it can improve the blood supply in ischaemic skin flaps. The pharmacokinetics of the drug allow it to be absorbed almost totally by the oral and sublingual route enabling optimal and consistent blood levels. Previous studies with nifedipine (Miller et al., 1985; Emery et al., 1990) have failed to demonstrate its potential to salvage ischaemic skin flaps.
Surgical technique
Rats were anaesthetised using sodium pentothal 30 mg/kg intraperitoneally. The dorsum of each rat was then shaved from sacral to scapular region and painted with betadine after cleaning with Savlon. Caudally based 3 x 10 cm skin flaps (Khouri et al., 1986) were raised approximately 1 cm from the base of the tail so that the free (cephalad) edge of the flap generally lay about 0.5 cm from the scapular tips. The flap consisted of skin and panniculus camosus. Care was taken to keep the paired sacral pedicles at the flap base totally intact. The raised pedicle flap was reapproximated to the skin edges with 4-O nylon atraumatic continuous sutures. No electrocautery or haemostatic agents were used. For all animals the flaps were assessed at the end of the 1st postoperative week. Flap necrosis is known to stabilise at 1 week postoperatively (Roth et al., 1988). Under anaesthesia the flaps were traced on acetate paper and area of necrosis marked. The area of necrosis and total flap area were measured by using a polar planimeter (Ramasastry et al., 1985). The surface area of flap necrosis, represented by the blackened and indurated area of the cephalad part of the flap, was calculated using the planimeter and the result for each rat expressed as percentage necrosis (i.e., necrotic flap area/total flap area x 100). Three separate measurements were made for each flap and a mean value obtained for each of the rats.
Materials and methods
The experimental animals used were male Wistar rats weighing 275-375 g. The rats (N=45) were divided into 3 groups as follows: Group A-Control group (n = 15); Group B-Started on nifedipine orally 1 day preoperatively and continued until the 7th postoperative day (n= 15); Group C-Started on nifedipine orally in the immediate postoperative period and continued until the 7th postoperative day. The rats were housed in separate cages. Each had
Drug dosage and delivery
Nifedipine (DEPIN-Cipla India Limited) capsule contents were instilled in the oral cavity of each rat 299
300
British Journal of Plastic Surgery dependent channels much like the sodium channels of nerve but relatively selective for calcium ions. Most types of smooth muscles are dependent on transmembrane calcium influx for normal resting tone and contractile responses. These cells are relaxed by calcium channel inhibitors. Vascular smooth muscle is most sensitive to this inhibition. In the vascular system arteriolar smooth muscle appears to be more sensitive than that in veins. Besides vasodilatation nifedipine results in a fall in blood pressure and tachycardia. Ishii et al. (1980) and Nagao et al. (1985) have studied this effect in normotensive and spontaneously hypertensive Wistar rats. Significant falls in blood pressure were observed in hypertensive rats. Normotensive rats also had hypotension and tachycardia which was dose dependent. The fall in blood pressure was more and lasted longer with increasing dosages of nifedipine from 0.2 mg to 5 mg/kg (Ischii et al., 1980). Clapham (1984) also found a dose dependent hypotensive effect in hypertensive rats. According to this study, nifedipine in low doses is effective in decreasing flap necrosis in a standard ischaemic rat skin flap. Though the mechanism of action has not been studied vasodilation seems plausible. Some other mechanisms may also be responsible. Calcium channel blockers prevent deleterious calcium influx into an ischaemic cell thereby retarding and preventing cell death (Stein et al., 1989). Calcium is involved in various steps of oxygen radical release and oxygen radical injury to cell components (Manson et al., 1983). Experimental studies in rabbits have also shown that calcium channel blockers inhibit platelet aggregation (Katzung, 1987). The pharmacokinetics of nifedipine allow it to be almost totally absorbed orally and sublingually. In
(post incisural fossa in the lower jaw) using an insulin syringe. One drop of Depin was administered every 12 hours. The resultant dosage administered to each rat (weight range 275-375 g) ranged between 0.30.5 mg/kg/day. Results In the control group A the range of flap necrosis was 82.558%-45.283% with a mean of 37.009% f 4.293% SD. In group B (n = 15) rats the range of flap necrosis was 7.124x--14.59% with a mean of 10.095%+ 2.314% SD. In Group C (n=l5) rats the range was 10.15x-15.00% with a mean of 12.289%fl.306% SD. Using one way analysis of variance and multiple range test the nifedipine treated animals (Groups B and C) had a statistically significant (p
