THE EFFICACY OF MAGNESIUM SULFATE ON RESOLVING SURGICALLY PROVOKED VASOSPASM OF THE FLAP PEDICLE IN AN EXPERIMENT

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Autoři: P. Hýža ¹; J. Veselý ¹; D. Schwarz ²; A. Vašků ³; L. Streit ¹; U. Choudry ⁴; A. Sukop ⁵
Působiště autorů: Department of Plastic and Aesthetic Surgery, Masaryk University, Brno ¹; Institute of Biostatistics and Analyses, Masaryk University, Brno ²; Department of Pathological Physiology, Masaryk University, Brno, Czech Republic ³; Department of Surgery, Division of Plastic Surgery, University of Minnesota, MN, USA, and ⁴; Department of Plastic Surgery, 3rd Faculty of Medicine, Charles University, Prague Czech Republic ⁵
Vyšlo v časopise: ACTA CHIRURGIAE PLASTICAE, 51, 1, 2009, pp. 15-19

INTRODUCTION

Vasospasm is a common problem in microvascular surgery. This undesirable condition frequently accompanies manipulation of small vessels during free flap surgeries and replantations. Often it causes only temporary and incomplete obstruction of the vessels. In some cases, however, a prolonged vasospasm may cause complete obstruction of the vessel and result in formation of thrombus (14, 16, 36, 29).

The vasospasm may develop in the flap pedicle, but more importantly it can affect small arteries and veins inside the flap. The latter manifests as flap non-perfusion with no apparent obstruction in the flap pedicle and anastomoses (53). Surgical treatment of vasospasm is usually ineffective, in which case pharmacologic therapy should be administered. A number of vasoactive substances have been studied and used clinically for the treatment of vasospasm. However, the ideal chemical is still being sought (4, 6, 8, 10, 12, 17, 18, 20–22, 25–26, 28, 33, 35, 45, 52, 54).

The purpose of this experimental study was to evaluate the effect of magnesium sulphate on vasospasm provoked by surgical manipulation (axial tension) on the flap pedicle. Tension of the flap pedicle commonly appears during surgical manipulation of the vessel, and therefore it can serve as a stimulus in the experimental model. This kind of surgical manipulation of the vessel cannot be studied in a clinical environment without putting flap viability into risk. From this point of view, the animal experimental model was necessary.

MATERIAL AND METHODS

The study was approved by the ethical committee at St. Anne University Hospital, Brno. 40 male Wistar rats weighing around 300 g each were classified in two experimental groups (n=20 in each). In the treatment group (group A) Magnesium Sulphuricum 10% (Biotika, Czech Republic) was applied; the second group (group B) served as the control.

The rats were anesthetized by intramuscular application of a mixture of ketamine (100 mg/kg) and xylazine (10 mg/kg). The surgery was conducted under standard temperature conditions (25°C) and the laser-Doppler probe holder was placed in the right groin and the island skin flap nourished by superficial inferior epigastric vessels was raised. The flap measured 2 x 2 cm. Dissection of the flap was sharp at the margins of the flap, and the tissue was clamped with hemostat before being transsected to ensure an absolutely bloodless operating field. The pedicle was exposed from the branching point of the femoral artery to about 5 mm distal by removing the perivascular tissue with microscissors under operating microscope. The perivascular tissue was elevated as two flaps, and the 6-0 nylon suture was sutured and tied to the flaps. This suture was later used for an attachment of the weight. Then the flap was left resting for 25 minutes before the laser-Doppler probe (PeriFlux system 5000, small straight probe 407-1, Perimed, Jarfalla, Sweden) was attached and continuous recording of the perfusion signal began. After another 10 minutes of leaving the flap resting (this time point was assigned as t=0), a 15g weight was attached to the nylon suture and hung on the block for 5 minutes. The weight produced consistent tension on the pedicle in the direction of the vessel. In the treatment group A the vessels were immersed in Magnesium Sulphate (Fig. 1) for the period of the tension on the flap pedicle (5 minutes) and continued for next 2 minutes after the tension was relieved (t=+7 minutes). In the control group B the tension alone was applied for 5 minutes, and no chemicals were administered. After the tension was released (t= +5 minutes), the recording of the perfusion signal continued for following 30 minutes.

Fig. 1. The vasospasm vas provoked by pulling the pedicle of the groin flap for 5 minutes. At the same time the pedicle was immersed with magnesium sulphate 10%. After the tension on the pedicle was relieved, the pedicle was further washed with magnesium sulphate 10% for 2 minutes

The perfusion recording signals were exported from the control software package of the laser-Doppler flowmeter into ASCII format files. Graphic representations of blood flow were created from these files. The signals were corrupted by impulse noise, making it impossible to properly detect the important time points and signal amplitudes. Therefore a Savitzky-Golay polynomial filter was employed to smooth the signals. Then two important time periods “t_B” and “t_C” were extracted from the signals by using Matlab scripts. The time period “t_B” represents the period between t=+5[s] and the time point on the graph when perfusion began to increase after a period of poor perfusion secondary to the exposure of the pedicle to tension. The time period “t_C” represents the period between t=+5[s] and the time when the re-perfusion reached its maximal value (Fig. 2).

Fig. 2. The average perfusion curve obtained from laser-Doppler recording. Values tB and tC were automatically detected on the curve. tB represented a period from the time t+5 minutes (stimulus ended) till the time when the perfusion of the flap began to increase; and tC represented a period from the time t+5 minutes (stimulus ended) till the perfusion of the flap reached its maximum

The above-mentioned signal characteristics “t_B” and “t_C” were analysed. The Kruskal-Wallis and Wilcoxon rank-sum test were used to assess significance of differences between the groups. A p-value of <0.01 was considered significant.

RESULTS

The tension applied on the flap pedicle caused significant vasospasm. After the period of very low perfusion, the perfusion began increase at the time t(B) and gradually reached its maximum value at the time t(C). The mean values of t(B) and t(C) are shown in Table 1, and graphical representation of the values can be seen from Figures 3A and 3B. Statistical comparison of the groups shows a significant difference between therapeutic and control groups in both t(B) and t(C) at p=0.01.

Fig. 3. Box and whisker plots comparing groups Aand B for variables “t<sub>B</sub>” (Fig. 3a) and “t<sub>C</sub>” (Fig. 3b). The transverse lines through the boxes are at the 25<sup>th</sup>, 50<sup>th</sup> and 75<sup>th</sup> quartiles. The dashed “whiskers” extend 1.5 times the inter-quartile range. The “+” sign signifies data outliers 3a) The axis Y is represented by the values of time tB – duration of the vasospasm before re-perfusion of the flap began 3b) Axis Y is represented by the values of tC – time to maximum of the flap perfusion after vasospasm

DISCUSSION

Vasospasm is a common complication in microvascular surgery which may cause serious problems. The vasospasm can be provoked by mechanical stress, removing perivascular tissues, cold, bleeding, low blood pressure or vasoconstricting chemical substances (29). The animal model used in this study was based on our previous experiments (the results will be published elsewhere) which showed that tension exerted in the axis of the flap pedicle produced the most consistent and long-lasting vasospasm, suitable for studying the effect of topically administered chemical agents. It has been shown that stretching the arterial smooth muscle to 1.2 times its resting length resulted in maximal phopsphorylation of myosin light chains, which is the key to smooth muscle contraction (59).

Various animal models which differ in both the way vasospasm was provoked and the manner of objective documentation have been used by some authors (1, 23–32). Temporary ischemia of the flap (13–15, 41, 56–57), cooling of the vessels (7, 58), clamping of the vessels (15, 19, 55, 57) and vascular anastomosis (14) have been used. The duration of the vasospasm was usually assessed by measuring the diameter of the vessels (7, 15, 55–57), distribution of the blood in the peripheral tissue nourished by the studied vessel (13, 40, 41), transonic Doppler (14) or laser-Doppler (19). The advantages of our experimental model are that the model was based on a precisely-defined surgical manipulation, which was constant in its strength and location. The model is also easily repeatable and consistently reproducible. The level of the blood-flow was precisely measured in the peripheral tissue of the flap by laser-Doppler. This flap was nourished exclusively by the pedicle vessels; thus the value of perfusion measured on the flap reflects the status of the pedicle vessels. Moreover, the vasospasm of small arteries and arterioles inside the flap, if this appeared, or the effect of the chemical on these vessels could have been detected.

The mode of the action of magnesium sulphate is still not clear. The vasodilator properties of Mg²⁺ are well documented both in vitro (1–3, 31, 38, 49, 51) and in vivo (9, 11, 29–30, 37, 39, 43, 46–47). One of the mechanisms for the vasorelaxant effect of magnesium ions is likely to be related to calcium inhibition (5, 15, 23, 48). Some reports suggested competitive inhibition between magnesium and calcium ions for binding sites on the myosin light chain kinase regulatory protein, calmodulin (50). Then Calcium is unable to activate myosin light chain kinase when Mg²⁺ ion is bound to calmodulin. This results in lower tension of smooth muscle in the presence of magnesium ions. Mg²⁺ induced relaxation is also thought to be due to conformational changes in the actomyosin ATP-ase, rendering it less active in a dose-dependent manner (24, 34). Other putative mode of action of magnesium ions includes inhibition of the release of excitatory amino acids and blockade of the N-methyl-D-aspartate-glutamate receptor (27, 44). A recent report suggested that magnesium therapy may be more effective if the magnesium is administered as a preventative measure to protect against vasospasm rather than after the onset of vasospasm (42).

Magnesium sulphate is a readily available, inexpensive substance used for treatment of a number of conditions including vasospasm secondary to subarachnoid hemorrhage in neurosurgery, pre-eclampsia in obstetrics (32) and acute myocardial infarction in cardiology (60). It has proved its efficacy in several experimental and clinical studies. However, to our knowledge, no clinical or experimental study has as yet proven its efficacy in resolving vasospasm of the flap pedicle.

CONCLUSION

Topical application of magnesium sulphate 10% significantly shortens the duration of the vasospasm provoked by tension on the vascular pedicle of the axial groin flap in rats. Further study on higher animals is needed to prove the effect of this chemical, but our finding is in correlation with our clinical observations. Moreover, the anticipated physiologic mechanism supports the use of magnesium sulphate for the treatment of surgically provoked vasospasm.

Acknowledgment:

This work was supported by Grant IGA NR-8368-5.

Address for correspondence:

Petr Hýža, M.D.

Berkova 34

612 00 Brno

Czech Republic

E-mail: petr.hyza@fnusa.cz

Zdroje

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