INT. I. HYPERTHERMIA,
1992,
VOL.
8,
NO.
5, 625-629
Risk of acute hypotension following epidural analgesia during deep regional hyperthermia: a case report
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
J. VAN DER ZEEtII, A. M. HOFFS, M . OUDKERKg, W. DE KOCKt, S. A . VAN DE MERWE* and P. C. DE JONGl Departments of tHyperthermia, $Medical Oncology, §Radiology and YAnaesthesiology, Dr Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands *Department of Experimental Radiotherapy, Erasmus University, Rotterdam, The Netherlands (Received 23 September 1991; revised and accepted 31 March 1992)
A potentially dangerous complication occurring during deep regional hyperthermia is described. A patient receiving epidural analgesics for pain caused by a large pelvic recurrent rectal tumour was treated by hyperthermia induced by electromagnetic radiation. The epidural infusion pump failed during heating and further analgesics were administered by bolus injections into the epidural space. Following the second bolus injection, a severe drop in arterial blood pressure was observed. The most likely multifactorial pathogenesis is discussed and measures to avoid such an event are recommended. Ke,y words: Deep hyperthermia, hypotension. epidural analgesia
1. Introduction In the Dr Daniel den Hoed Cancer Center, one of the reasons for applying deep regional hyperthermia is recurrent rectal cancer, causing severe, by oral medication uncontrollable pain, in patients for whom no effective standard treatment is left available. Hyperthermia is combined sequentially with intra-arterial chemotherapy (Estes er af. 1986). Both the feasibility and palliative effect of the combined treatment are the subject of an ongoing pilot study. Deep regional hyperthermia is induced by the recently installed BSD-2000 system (Turner and Schaefermeyer 1989). The treatment schedule, in combination with intraarterial chemotherapy, is as follows. Day 1 : (a) percutaneous introduction of catheters for thermometry under CT-guidance into the tumour; (b) introduction of balloon catheters through femoral arteries into both internal iliac arteries; and (c) hyperthermic treatment lasting 1 h (following a warming-up phase of maximum 30 min). Balloons of the intraarterial catheters are tilled 45 min before the start of hyperthermia to shut down circulation in order to induce a tumour pH decrease (van der Zee et al. 1989). Day 2: intra-arterial bolus injection of Mitomycin C, 10 mg/m2. Day 2-5: continuous intra-arterial infusion of 5FU, 1000 mg/m2 per 24 h. During the whole treatment procedure (total of 6 days), the patient has to remain in a supine position. Pain from recurrent rectal cancer is often aggravated by lying on one’s back. In order to make the treatment tolerable, an epidural catheter is introduced for administration of analgesic medication. In our institute, a solution of morphine plus bupivacaine is used (Hjortsa el al. 1986). Combination of the two drugs helps to prevent IlTo whom correspondence should be addressed. Presented at the 12th Conference of the European Society for Hyperthermic Oncology, Bergen, Norway, 26-29 June 1991. 0265-6736/92 $3 00 01992 Taylor & Francis Ltd
626
J . van der Zee et al.
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
the development of side effects and slows the development of tolerance. With continuous administration of this combination we have never observed hypotension. for either postoperative or chronic cancer pain.
2. Case report The patient, a 54-year-old woman, had been treated in 1988 by amputation for rectal cancer, classified Dukes' C1. In November 1989, she was treated for local recurrence with radiation, total dose 65 Gy in 35 fractions. However, in May 1990 the tumour, and thereby pain, again was progressive. Despite the use of morphine sulphate, 50 mg twice daily, pain was still prominent: 50-80 on a scale from 0 (no pain) to 100 (worst possible pain). The patient's general condition and cardiovascular function allowed treatment with regional deep hyperthermia. Treatment by intra-arterial chemotherapy plus hyperthermia was decided upon after informed consent. On day 1 an intravenous infusion line (saline infused at a rate of 500 ml in 12 h ) and a urinary bladder catheter were introduced. An epidural catheter was introduced at the level of L4/L5. Neither blood nor cerebrospinal fluid could be aspirated through the catheter. A bolus injection of 5 ml articaine 4% with 1 :200,000 adrenalin gave sufficient pain relief. This drug was chosen for its rapid onset: this dose however would have resulted in a solid nerve block to the thoracic level had it been injected inadvertently into the subarachnoid space. This trial dose did not cause any significant decrease in arterial blood pressure in spite of a partial motor paralysis involving the legs. Continuous infusion of 2 ml/h (1 mg morphine and 4 mg bupivacaine) was effective. Bupivacaine is approximately four times as potent as articaine. It was chosen for continuous administration because at the dosage used it generally does not result in motor weakness, yet it potentiates the analgesic effect of epidural morphine. Two intratumoural catheters for thermometry and two intra-arterial catheters were placed. The patient was installed in the BSD-2000 system, with temperature of thc water bolus set at 16"C, and treatment was started. Arterial blood pressure at start of heating was 127/70 mmHg. The standard procedure for hyperthermic treatment in our institute is to maintain tumour temperature > 42°C for 60 min, after a heating phase of maximum 30 min. In this case, the heating phase was interrupted several times for occurrence of local pain and it was decided to reposition the patient. During the first 30 min, power input was, therefore, relatively low (mean 309 W). After repositioning the patient, power input was continuous and increased steadily from 600 to lo00 W, with a time-averaged value of 738 W. After the second 30 min period, deep temperatures (tumour and vagina) had reached 40"C, and superficial temperatures, measured on the skin at the perineum and in the groins, had reached 39-42°C. Systemic temperature, measured orally had increased a few tenths of a degree from 36.9 to 37'2°C. Increase in heart rate (Figure 1) appears to reflect activity of the thermoregulatory response to the power input. The pain medication infusion pump failed during electromagnetic radiation and therefore was disconnected. After about 30 min, I ml of pain medication was administered epidurally as a bolus. Arterial blood pressure decreased after this administration, from 129/72 to 103/60 mmHg (Figure 2), but remained stable afterwards with the patient indicating no pathological symptoms. After 1 h, another 1 ml was administered. This time blood pressure dropped to 70/40 mmHg, while at the same time the patient indicated that she was feeling dyspnoeic. The waterbolus was emptied instantly, power shut off and the intravenous fluid infusion put at maximum rate. The patient felt better immediately, although blood pressure showed some improvement only slowly -to 100/50 over the period of 30 min that we left the patient on the treatment couch. Pulse pressure improved however. Continuous epidural
Acute hypotension during deep hyperthermia blood pressure
627
heart rate
~ ~ _ ~ ~ ~ _ _ _ _ _ _ _ _
.
1 140 1120
100
I . -
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
I$-
I-?
-.
~
40
h
401
f
BP syst.
I+
BP diast.
bolus inj.
1
heating period
*
heart rate
Figure 1. Course of arterial blood pressure during hyperthermic treatment. Following each epidural bolus injection of bupivacaine and morphine, a drop in arterial blood pressure was observed.
infusion of bupivacaine and morphine was started again. During the following days, she was treated with chemotherapy, according to protocol, without further events.
3. Discussion and conclusion At present, we have administered 145 regional deep hyperthermia treatments to 45 patients. Pretreatment eligibility check for treatment includes assessment of cardiovascular function. Standardly, patients are not hospitalized and measures to control hydration and perfusion status are not taken, except for monitoring heart rate and blood pressure at 5-min intervals. Cardiovascular failure as described in this case has not occurred during any of the other treatment sessions. The only difference in the treatment procedure described, in comparison to the standard procedure, was the epidural bolus administrationof analgesics. A bolus injection of bupivacaine into the epidural space may cause hypotension by the induction of a sympathetic nerve block (Cousins and Bromage 1988). However, dosage of bupivacaine (1 ml of a 0.2% solution) was not so great that one would expect such a sudden decrease in arterial blood pressure, even when taking into account that this was done shortly after continuous administration at a rate of 4 mg/h. However, the close temporal relationship between bolus administration and the hypotensive episode suggests strongly that epidural bupivacaine was at least partly implicated. The trial dose administered after epidural catheter insertion (5 ml of articaine 4 % with 1:200,000 adrenalin) did not result in a significant decrease in arterial blood pressure, though this dose was considerably more potent. Hypotension following an epidural bolus administration of 0.5 mg morphine is highly unlikely (Reiz and Westberg 1980). Although the possibility of inadvertant subarachnoid placement could be eliminated, the possibility of secondary catheter tip migration must be considered as a possible explanation of the hypotensive episode. Subsequent continuous administration through the epidural catheter was, however, uneventful. Had
J . van der Zee et al.
628
the catheter migrated to the subarachnoid space it would have resulted invariably in paralysis. Therefore, pathogenesis of the severe drop in blood pressure observed is most likely multifactorial. Other factors which may have contributed to this happening are the following:
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
(1) Regional hyperthermia may cause a decrease in blood pressure by vasodilation
both in the region treated, and systemically. Our present experience is that blood pressure may change during deep hyperthermia; generally no clinically relevant change is observed and if a decrease occurs it is mild and gradual. Similar experience has been reported by Samulski et al. (1987). Owing to problems during the first 30 min of hyperthermic treatment, regional temperatures in this patient were still relatively low and the systemic temperature had hardly changed. (2) Pressure excited by the water bolus may have caused aortocaval compression and thereby a failing venous return. (3) The patient had been fasting since the evening before and had drank only a little before hyperthermia had started. This, in combination with the accumulative fluid loss by sweating during the 1 h of hyperthermic treatment may have caused some degree of dehydration, which then could have contributed to the failing circulation (Cousins and Bromage 1988). Besides the danger of hypotension as a result of local anaesthetic nerve block, there is also the danger of reduced temperature perception. The patient’s ability to perceive temperature is essential during hyperthermia. Occurrence of power-dependent pain during the heating phase in this patient demonstrates that temperature perception was still present. Fortunately, the patient came through this event without any irreversible damage. However, this occurrence was a warning to us and is a warning to all clinicians applying deep regional hyperthermia. The most important message in this paper is that epidural administration of analgesics during regional deep hyperthermia carries the risk of circulatory failure, caused by a combination of factors, part of which are present but, apparently, compensated for during ‘standard treatment, provided that the patient has sufficient cardiovascular reserve. When a patient having an epidural catheter for control of pain is treated in the BSD-2000 system, the following measures are advised: ( I ) no epidural bolus injection of a drug which is known to result in sympathetic blockade during the hyperthermic treatment; (2) immediate access to a vein through an infusion line; (3) frequent monitoring of blood pressure; (4) care for the hydration status of the patient; ( 5 ) in order to minimize aortocaval compression, the patient is treated preferably in the prone position; (6) ephedrine solution ready for use.
Acknowledgement This work was financially supported by the Dutch Fund for Investigative Medicine, grant no. OG 89-32.
References COUSINS, M. J. and BROMAGE, P. R., 1988, Epidural neural blockade. In Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd Edn. Edited by M. J. Cousins and P. 0. Bridenbaugh (Philadelphia:J. B. Lippincott Co.), pp. 253-360.
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
Acute hypotension during deep hyperthermia
629
ESTES,N. C . , MORPHIS. J. G . , HORNBACK. N . B. and JEWELL. W . R . , 1986, Intra-arterial chemotherapy and hyperthermia for pain control in patients with recurrent rectal cancer. American Journal of Surgery, 152, 597-600. HJoRTS0, N. C., LUND,C., MOGENSEN,T., BIGLER,D. and KEHLET, H., 1986, Epidural morphine improves pain relief and maintains sensory analgesia during continuous epidural bupivacaine after abdominal surgery. Anesrhesiu and Analgesia, 65, 1033- 1036. REIZ, S . and WESTBERG,M . , 1980, Side-effects of epidural morphine. Lancer, ii, 203-204. SAMULSKI, T. V . , KAPP, D. S., FESSENDEN,P. and LOHRBACH,A., 1987, Heating deep seated eccentrically located tumors with an annular phased array system: a comparative clinical study using two annular array operating configurations. Inrernational Journal of Radiation Oncology, Biology and Physics, 13, 83-94. TURNER,P. F. and SCHAEFERMEYER, T., 1989, BSD-2000 approach for deep local and regional hyperthermia: clinical utility. Strahlentherupie und Onkologie. 165, 700-704. ZEE, J. VAN DER, BROEKMEYER-REURINK, M. P.,BERG,A. P. VAN DEN, GEEL,A. N.V A N , JANSEN, R. F. M . , KROON,B . B. R . , WWK,J . VAN, and HAGENBEEK,A., 1989, Temperature distribution and pH changes during hyperthemic regional isolation perfusion. European Journal of Cancer and Clinical Oncology, 8, 1 157- 1 163.
1992,
VOL.
8,
NO.
5, 625-629
Risk of acute hypotension following epidural analgesia during deep regional hyperthermia: a case report
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
J. VAN DER ZEEtII, A. M. HOFFS, M . OUDKERKg, W. DE KOCKt, S. A . VAN DE MERWE* and P. C. DE JONGl Departments of tHyperthermia, $Medical Oncology, §Radiology and YAnaesthesiology, Dr Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands *Department of Experimental Radiotherapy, Erasmus University, Rotterdam, The Netherlands (Received 23 September 1991; revised and accepted 31 March 1992)
A potentially dangerous complication occurring during deep regional hyperthermia is described. A patient receiving epidural analgesics for pain caused by a large pelvic recurrent rectal tumour was treated by hyperthermia induced by electromagnetic radiation. The epidural infusion pump failed during heating and further analgesics were administered by bolus injections into the epidural space. Following the second bolus injection, a severe drop in arterial blood pressure was observed. The most likely multifactorial pathogenesis is discussed and measures to avoid such an event are recommended. Ke,y words: Deep hyperthermia, hypotension. epidural analgesia
1. Introduction In the Dr Daniel den Hoed Cancer Center, one of the reasons for applying deep regional hyperthermia is recurrent rectal cancer, causing severe, by oral medication uncontrollable pain, in patients for whom no effective standard treatment is left available. Hyperthermia is combined sequentially with intra-arterial chemotherapy (Estes er af. 1986). Both the feasibility and palliative effect of the combined treatment are the subject of an ongoing pilot study. Deep regional hyperthermia is induced by the recently installed BSD-2000 system (Turner and Schaefermeyer 1989). The treatment schedule, in combination with intraarterial chemotherapy, is as follows. Day 1 : (a) percutaneous introduction of catheters for thermometry under CT-guidance into the tumour; (b) introduction of balloon catheters through femoral arteries into both internal iliac arteries; and (c) hyperthermic treatment lasting 1 h (following a warming-up phase of maximum 30 min). Balloons of the intraarterial catheters are tilled 45 min before the start of hyperthermia to shut down circulation in order to induce a tumour pH decrease (van der Zee et al. 1989). Day 2: intra-arterial bolus injection of Mitomycin C, 10 mg/m2. Day 2-5: continuous intra-arterial infusion of 5FU, 1000 mg/m2 per 24 h. During the whole treatment procedure (total of 6 days), the patient has to remain in a supine position. Pain from recurrent rectal cancer is often aggravated by lying on one’s back. In order to make the treatment tolerable, an epidural catheter is introduced for administration of analgesic medication. In our institute, a solution of morphine plus bupivacaine is used (Hjortsa el al. 1986). Combination of the two drugs helps to prevent IlTo whom correspondence should be addressed. Presented at the 12th Conference of the European Society for Hyperthermic Oncology, Bergen, Norway, 26-29 June 1991. 0265-6736/92 $3 00 01992 Taylor & Francis Ltd
626
J . van der Zee et al.
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
the development of side effects and slows the development of tolerance. With continuous administration of this combination we have never observed hypotension. for either postoperative or chronic cancer pain.
2. Case report The patient, a 54-year-old woman, had been treated in 1988 by amputation for rectal cancer, classified Dukes' C1. In November 1989, she was treated for local recurrence with radiation, total dose 65 Gy in 35 fractions. However, in May 1990 the tumour, and thereby pain, again was progressive. Despite the use of morphine sulphate, 50 mg twice daily, pain was still prominent: 50-80 on a scale from 0 (no pain) to 100 (worst possible pain). The patient's general condition and cardiovascular function allowed treatment with regional deep hyperthermia. Treatment by intra-arterial chemotherapy plus hyperthermia was decided upon after informed consent. On day 1 an intravenous infusion line (saline infused at a rate of 500 ml in 12 h ) and a urinary bladder catheter were introduced. An epidural catheter was introduced at the level of L4/L5. Neither blood nor cerebrospinal fluid could be aspirated through the catheter. A bolus injection of 5 ml articaine 4% with 1 :200,000 adrenalin gave sufficient pain relief. This drug was chosen for its rapid onset: this dose however would have resulted in a solid nerve block to the thoracic level had it been injected inadvertently into the subarachnoid space. This trial dose did not cause any significant decrease in arterial blood pressure in spite of a partial motor paralysis involving the legs. Continuous infusion of 2 ml/h (1 mg morphine and 4 mg bupivacaine) was effective. Bupivacaine is approximately four times as potent as articaine. It was chosen for continuous administration because at the dosage used it generally does not result in motor weakness, yet it potentiates the analgesic effect of epidural morphine. Two intratumoural catheters for thermometry and two intra-arterial catheters were placed. The patient was installed in the BSD-2000 system, with temperature of thc water bolus set at 16"C, and treatment was started. Arterial blood pressure at start of heating was 127/70 mmHg. The standard procedure for hyperthermic treatment in our institute is to maintain tumour temperature > 42°C for 60 min, after a heating phase of maximum 30 min. In this case, the heating phase was interrupted several times for occurrence of local pain and it was decided to reposition the patient. During the first 30 min, power input was, therefore, relatively low (mean 309 W). After repositioning the patient, power input was continuous and increased steadily from 600 to lo00 W, with a time-averaged value of 738 W. After the second 30 min period, deep temperatures (tumour and vagina) had reached 40"C, and superficial temperatures, measured on the skin at the perineum and in the groins, had reached 39-42°C. Systemic temperature, measured orally had increased a few tenths of a degree from 36.9 to 37'2°C. Increase in heart rate (Figure 1) appears to reflect activity of the thermoregulatory response to the power input. The pain medication infusion pump failed during electromagnetic radiation and therefore was disconnected. After about 30 min, I ml of pain medication was administered epidurally as a bolus. Arterial blood pressure decreased after this administration, from 129/72 to 103/60 mmHg (Figure 2), but remained stable afterwards with the patient indicating no pathological symptoms. After 1 h, another 1 ml was administered. This time blood pressure dropped to 70/40 mmHg, while at the same time the patient indicated that she was feeling dyspnoeic. The waterbolus was emptied instantly, power shut off and the intravenous fluid infusion put at maximum rate. The patient felt better immediately, although blood pressure showed some improvement only slowly -to 100/50 over the period of 30 min that we left the patient on the treatment couch. Pulse pressure improved however. Continuous epidural
Acute hypotension during deep hyperthermia blood pressure
627
heart rate
~ ~ _ ~ ~ ~ _ _ _ _ _ _ _ _
.
1 140 1120
100
I . -
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
I$-
I-?
-.
~
40
h
401
f
BP syst.
I+
BP diast.
bolus inj.
1
heating period
*
heart rate
Figure 1. Course of arterial blood pressure during hyperthermic treatment. Following each epidural bolus injection of bupivacaine and morphine, a drop in arterial blood pressure was observed.
infusion of bupivacaine and morphine was started again. During the following days, she was treated with chemotherapy, according to protocol, without further events.
3. Discussion and conclusion At present, we have administered 145 regional deep hyperthermia treatments to 45 patients. Pretreatment eligibility check for treatment includes assessment of cardiovascular function. Standardly, patients are not hospitalized and measures to control hydration and perfusion status are not taken, except for monitoring heart rate and blood pressure at 5-min intervals. Cardiovascular failure as described in this case has not occurred during any of the other treatment sessions. The only difference in the treatment procedure described, in comparison to the standard procedure, was the epidural bolus administrationof analgesics. A bolus injection of bupivacaine into the epidural space may cause hypotension by the induction of a sympathetic nerve block (Cousins and Bromage 1988). However, dosage of bupivacaine (1 ml of a 0.2% solution) was not so great that one would expect such a sudden decrease in arterial blood pressure, even when taking into account that this was done shortly after continuous administration at a rate of 4 mg/h. However, the close temporal relationship between bolus administration and the hypotensive episode suggests strongly that epidural bupivacaine was at least partly implicated. The trial dose administered after epidural catheter insertion (5 ml of articaine 4 % with 1:200,000 adrenalin) did not result in a significant decrease in arterial blood pressure, though this dose was considerably more potent. Hypotension following an epidural bolus administration of 0.5 mg morphine is highly unlikely (Reiz and Westberg 1980). Although the possibility of inadvertant subarachnoid placement could be eliminated, the possibility of secondary catheter tip migration must be considered as a possible explanation of the hypotensive episode. Subsequent continuous administration through the epidural catheter was, however, uneventful. Had
J . van der Zee et al.
628
the catheter migrated to the subarachnoid space it would have resulted invariably in paralysis. Therefore, pathogenesis of the severe drop in blood pressure observed is most likely multifactorial. Other factors which may have contributed to this happening are the following:
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
(1) Regional hyperthermia may cause a decrease in blood pressure by vasodilation
both in the region treated, and systemically. Our present experience is that blood pressure may change during deep hyperthermia; generally no clinically relevant change is observed and if a decrease occurs it is mild and gradual. Similar experience has been reported by Samulski et al. (1987). Owing to problems during the first 30 min of hyperthermic treatment, regional temperatures in this patient were still relatively low and the systemic temperature had hardly changed. (2) Pressure excited by the water bolus may have caused aortocaval compression and thereby a failing venous return. (3) The patient had been fasting since the evening before and had drank only a little before hyperthermia had started. This, in combination with the accumulative fluid loss by sweating during the 1 h of hyperthermic treatment may have caused some degree of dehydration, which then could have contributed to the failing circulation (Cousins and Bromage 1988). Besides the danger of hypotension as a result of local anaesthetic nerve block, there is also the danger of reduced temperature perception. The patient’s ability to perceive temperature is essential during hyperthermia. Occurrence of power-dependent pain during the heating phase in this patient demonstrates that temperature perception was still present. Fortunately, the patient came through this event without any irreversible damage. However, this occurrence was a warning to us and is a warning to all clinicians applying deep regional hyperthermia. The most important message in this paper is that epidural administration of analgesics during regional deep hyperthermia carries the risk of circulatory failure, caused by a combination of factors, part of which are present but, apparently, compensated for during ‘standard treatment, provided that the patient has sufficient cardiovascular reserve. When a patient having an epidural catheter for control of pain is treated in the BSD-2000 system, the following measures are advised: ( I ) no epidural bolus injection of a drug which is known to result in sympathetic blockade during the hyperthermic treatment; (2) immediate access to a vein through an infusion line; (3) frequent monitoring of blood pressure; (4) care for the hydration status of the patient; ( 5 ) in order to minimize aortocaval compression, the patient is treated preferably in the prone position; (6) ephedrine solution ready for use.
Acknowledgement This work was financially supported by the Dutch Fund for Investigative Medicine, grant no. OG 89-32.
References COUSINS, M. J. and BROMAGE, P. R., 1988, Epidural neural blockade. In Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd Edn. Edited by M. J. Cousins and P. 0. Bridenbaugh (Philadelphia:J. B. Lippincott Co.), pp. 253-360.
Int J Hyperthermia Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/01/14 For personal use only.
Acute hypotension during deep hyperthermia
629
ESTES,N. C . , MORPHIS. J. G . , HORNBACK. N . B. and JEWELL. W . R . , 1986, Intra-arterial chemotherapy and hyperthermia for pain control in patients with recurrent rectal cancer. American Journal of Surgery, 152, 597-600. HJoRTS0, N. C., LUND,C., MOGENSEN,T., BIGLER,D. and KEHLET, H., 1986, Epidural morphine improves pain relief and maintains sensory analgesia during continuous epidural bupivacaine after abdominal surgery. Anesrhesiu and Analgesia, 65, 1033- 1036. REIZ, S . and WESTBERG,M . , 1980, Side-effects of epidural morphine. Lancer, ii, 203-204. SAMULSKI, T. V . , KAPP, D. S., FESSENDEN,P. and LOHRBACH,A., 1987, Heating deep seated eccentrically located tumors with an annular phased array system: a comparative clinical study using two annular array operating configurations. Inrernational Journal of Radiation Oncology, Biology and Physics, 13, 83-94. TURNER,P. F. and SCHAEFERMEYER, T., 1989, BSD-2000 approach for deep local and regional hyperthermia: clinical utility. Strahlentherupie und Onkologie. 165, 700-704. ZEE, J. VAN DER, BROEKMEYER-REURINK, M. P.,BERG,A. P. VAN DEN, GEEL,A. N.V A N , JANSEN, R. F. M . , KROON,B . B. R . , WWK,J . VAN, and HAGENBEEK,A., 1989, Temperature distribution and pH changes during hyperthemic regional isolation perfusion. European Journal of Cancer and Clinical Oncology, 8, 1 157- 1 163.
