British Journal of Neurosurgery (1992) 6,333-342
ORIGINAL ARTICLE
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Pressure and blood flow in pituitary adenomas measured during transsphenoidal surgery ANDERS KRUSE,* JENS ASTRUP,* GEORG E. COLDt & HANS H. HANSENS
Departments of *Neurosurgery, fNeuroanaesthesiology and $Nuclear Medicine, Arhus Kommunehospital, 8000 h h u s C, Denmark
Abstract In 48 patients undergoing transsphenoidal surgery for pituitary adenoma, the intrasellar pressure was recorded during surgery. In 14 patients, adenoma blood flow was measured with the technique of local injection of 133xenon.Median intrasellar pressure was 30 mmHg (range 8-62), n=48, and median adenoma blood flow was 8 m1/100 g/min (range 0-37), n= 14. In two patients, blood flow in the anterior pituitary gland was measured, and values of 26 and 22 m1/100 g/min were obtained. The finding that intrasellar pressure is above central venous and intracranial pressure suggests the possibility that the adenoma and the anterior pituitary gland are supplied not only with venous blood, but receive an additional arterial supply at a less than normal arterial pressure. In three cases perfusion pressures that caused arrest of adenoma blood flow were found, and these observations are discussed with reference to pituitary apoplexy. Key words: Intrasellar pressure, pituitaly adenomas, pituitary apoplexy, pituitary blood Jaw, pituitaly gland, transsphenoidal surgery.
Introduction While it is generally accepted that the anterior pituitary gland in a number of species (e.g. rat, rabbit, dog) is supplied with only venous there is still doubt with respect to the blood supply of the human gland. Early reports have favoured an end-artery s~pply,37~ but after the elucidation of the venous portal system,5'6 some investigators have suggested a venous supply' and others a mixed venous-arterial supply.' A number of findings indicate a venous-arterial supply: therapeutic transsection of the pituitary stalk in patients with carcinoma of the breast or prostate does not cause an ischaemic infarction of the gland that corresponds in extent or topography to the venous h y p o t h e s i ~ ; l Patients * ~ ~ ~ with pituitary adenomas may have intrasellar pressure (IsP) values well above venous pressure and still
maintain an active adenoma and an intact anterior lobe function;1° arterial supply to pituitary adenomas has been demonstrated anatomically" and by angiography.12 In this study we correlate pituitary IsP with adenoma blood flow in order to define a critical intrasellar perfusion pressure (IsPP) that causes complete ischaemia. The observations are discussed in relation to the syndrome of pituitary apoplexy. Further, some observations of blood flow in the anterior pituitary gland were obtained.
Materials and methods
Patient population The study consecutively included 48 patients who underwent transsphenoidal surgery for
333
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lesions occupying intrasellar space: 23 men [median age 45 years (range 18-68)] and 25 women [median age 41 years (range 17-74)]. Twenty-six patients were operated upon for endocrine dysfunction (2 1 had acromegaly, three Cushings disease, two prolactinoma) and 22 patients presented with chiasma compression ( 17 had inactive adenoma, four craniopharyngioma and one was operated upon acutely because of pituitary apoplexy with ophthalmoplegia). Twenty patients had purely intrasellar adenomas, while 27 had variable degrees of suprasellar enlargement.
SuWY The operations were all performed under general anaesthesia using thiopental induction and maintenance with halothane, phentanyl and N20. Muscular relaxation was induced with atracurium. The patients were maintained slighly hypocapnic with PaC02 at 4.0-4.5 kP. The transseptal, transsphenoidal approach was used. The sphenoid air sinus was opened and mucosa removed. The bony floor of the sella was opened with a rongeur or drill and removed with a bone punch leaving the dura intact.
Intrasellar pressure measurements A 0.9 mm lumbar puncture needle was connected to a transducer through a polyethylene tube, and the system was filled with saline and calibrated to zero at the level of the adenoma. The needle was introduced into the adenoma and controlled on an image intensifier. IsP was recorded continuously. In all patients mean arterial blood pressure was recorded continuously by an intra-arterial line. In six patients the internal jugular vein was cannulated and a catheter was positioned in the jugular bulb to monitor intracranial pressure (ICP) indirectly. Jugular vein compression was performed to correlate changes in
ICP and IsP. Intrasellar pressure recording was completed in all 48 patients.
Adenoma blood-flow measurements The human pituitary gland is located within a bony grove. This makes blood-flow measurements with single photon emission technique (SPECT) or xenon-enhanced CT unreliable because of low signal-to-noise ratio. Owing to the debate of the origin of the blood supply to the anterior lobe, a clearance method of bloodflow measurements was chosen. The local injection technique of 133xenonwas used. This method is well established and has been used for measuring blood flow in various tissues such as brain, muscle and subcutaneous fat13-16 and it can be used intra-operatively. The flow determination is based on the washout of 133Xefrom the tissue. Blood-flow is calculated from the slope of the semilogarithmic transformed clearance curve. At equilibrium 133Xe will leave the tissue at a rate proportional to the blood-flow and the partition coefficient lambda: f l o ~ = l n 2 / t , ,x~ lambdax 100 (ml/min/100 g). tIl2was estimated from the clearance curvesY1'and lambda was arbitrarily set to 1. Using a Hamilton syringe with a 26 gauge needle we injected 50 pl of 133Xe(1 mCu/ml) into the adenoma during X-ray control. Air suction was established in the sinus, and a cadmium telluride detector mounted in the tip of a probe (2 mm diameter) and connected to a count-rate-meter through a flexible co-axial cable was inserted through the patient's nose and positioned externally on the dura (Fig. 1). The 133Xe clearance was recorded for approximately 5 min and displayed on a semilogarithmic graph (Fig. 2). Adenoma blood-flow measurements was consecutively performed in the final 20 patients. The two-sample rank sum test (Mann-Whitney test) was used for statistical comparison between the groups. Values of ~(0.05 were considered significant. The study was approved by the county ethical committee.
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Pressure in pituitary adenomas
FIG. 1. Peroperative X-ray showing the suction in the posterior part of the sphenoid air sinus (a), the pressure recording needle within the adenoma (b), the cadmium telluride probe positioned upon the dura (c), and the nasal speculum (d).
Results Intrasellar pressure The median IsP was 30 mmHg (range 8-62), n=48. In all patients, a pulsatile waveform was recorded. The median intrasellar pulse
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amplitude was 2.3 mmHg (range 1-14). There were no significant differences in median pressure between the clinical groups of patients. In the six patients with jugular vein cannulation, neck compression resulted in a net increase in jugular vein pressure of 10 mmHg (median; range 14-24) with a concomitant net increase in intrasellar pressure of 5 mmHg (median; range 32-37). This difference in net increase is not significant and indicates that changes in ICP modify IsP (Fig. 3). Assuming only arterial blood supply to the anterior pituitary gland and the adenoma, the mean IsPP can be estimated as the mean BP-mean IsP. The median IsPP was 58 mmHg (range 14-93), n=48. Adenoma blood-flow In five patients it was found that 133Xehad been injected into a large cyst within the adenoma. Consequently, there could be no flow-dependent xenon outwash, only clearance due to diffusion and redistribution. In three of these cases the clearance curves were flat (Fig. 4), and in two cases a small clearance comparable to a ‘flow’ of 2 m1/100 g/min was
8
FIG. 2. A semilogarithmic transformed clearance curve of 133xenon,comparable to a flow value of 16 m1/100 g/min.
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mmHg
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A
FIG. 3. Simultaneous rise in intrasellar pressure (A) and jugular bulb pressure (B) due to neck compression. Note the displacement and different calibration of the curves.
FIG.4. '33Xenonclearance curve from an intra-adenomatous cyst.
observed. Consequently, 'flow' values below 2 m1/100 g/min were considered equal to zero. In all patients the initial 1-1.5 min of the clearance curves showed a variable waveform before the mono-exponential washout set in (Figs. 2 and 4). The same phenomenon was observed in clearance curves from patients who had had xenon injected into a cyst, and it has therefore not been considered a flowdependent clearance. Presumably, it is caused by a rapid redistribution by diffusion of xenon within the adenoma. Exclusive of the five patients with xenon injection into a cyst, blood-flow measurements were completed in 15 patients. In one patient the xenon injection was accidentally performed within the pituitary gland. In the remaining 14 patients, who all had pituitary adenomas, median IsP was 27 mmHg (range 16-62),
which was not different from the median IsP of the whole series. The 133Xeinjection resulted in an increase of median IsP of 2 mmHg. The median IsPP was 55 mmHg (range 30-74), which was not different from the IsPP of the whole series. The median adenoma flow in the group was 8 mV100 g/min (range 0-37), n= 14. In three patients a rise in IsP was accompanied by a fall in adenoma blood-flow. In two of these patients initial flow measurements showed values of 8 and 37 m1/100 g/min at IsP of 40mmHg [mean arterial blood pressure (MaBP) 89 mmHg] and 22 mmHg (MaBP 77 mmHg). Haemorrhage in the adenoma, caused by positioning of the pressure recording needle in one case and 133Xeinjection in the other, was followed by IsP increases to 50 and 40 mmHg and concomitant flow value decreases
Pressure in pituitary adenomas
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to 5 and 0 m1/100 g/min, respectively (Fig. 5). MaBP remained constant during measuring. In the third patient MaBP was 66 mmHg, while IsP increased gradually from 22 to 32 mmHg and the clearance curve flattened. The increase in IsP was due to leak of saline from the pressure recording needle, which was then replaced. Thereafter IsP remained constant at 26 mmHg, and the clearance of 133Xeindicated a flow of 5 m1/100 g/min. The results are summarized in Table I.
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Pituitary gland Jow In the patient who received a '33Xe injection in the pituitary gland a blood-flow of 10 m1/100 g/min was found. The IsP was 44 mmHg with an IsPP of 40 mmHg. The patient suffered from a craniopharyngioma with chiasm compression but was without endocrine dysfunction. In two patients it was possible to measure flow in a well-defined pituitary gland after the
FIG.5. Increase in intrasellar pressure due to haemorrhage in the adenoma leading to a fall in blood-flow. Curve A constant intrasellar pressure of 22 mmHg, flow=37 m1/100 g/min. Curve B intrasellar pressure increase to 40 mmHg with concomitant fall in flow to zero.
TABLEI. Increases in intrasellar pressure (IsP) and concomitant changes in intrasellar perfusion pressure (IsPP) and flow in three patients IsP-2 mmHg
ISP-1
ISPP-1 IsPP-2 mmHg
Flow-1 Flow-2 m1/100 g/min
~
26
32
40
50 40
22
40 49
34 39
5
55
37
37
8
0 5 0
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adenoma had been removed. One was a 37year-old man with acromegaly and hypogonadism, but otherwise normal pituitary function. Adenoma blood-flow was 7 mV100 g/min at an IsP of 52 mmHg and an IsPP of 36 mmHg. Adenoma removal exposed a preserved pituitary gland in which a blood-flow of 26 m1/100 g/min was measured. The other patient was a 17-year-old woman with an inactive adenoma. She had presumably been a victim of pituitary apoplexy 3 months before surgery, but pituitary function was normal. IsP was 30 mmHg, but the adenoma was cystic with consequently no outwash of xenon. After removal of the tumour a flow of 22 m1/100 g/min was measured in the pituitary gland. Beside the above-mentioned haemorrhage in the adenoma due to xenon injection and replacement of the pressure recording needle, and IsP increase due to a leak of saline from the needle, there were no observed side effects or technical failures.
Discussion Our study confirms the high IsP values that Lees and Pickard’O have found associated with pituitary adenoma when the IsP was measured with patients in the supine position during transsphenoidal surgery. Lees and Pickard’s study suggests an association between elevated IsP and adenoma hyperprolactinaemia due to compression of the pituitary gland and pituitary stalk. Our study was not designed to investigate this possibility, and we have not observed correlations between IsP and type, size or extension of adenoma or pituitary function. Our only patient who was operated acutely because of pituitary apoplexy had an IsP of 60 mmHg. Median IsP for the whole group was 30 mmHg (range 8-62), n=48, which is comparable to the 27 mmHg (range 2-51) value found by Lees and Pickard.Io The syndrome of pituitary apoplexy and suggested high IsP causing adenoma and pituitary ischaemia and infarction, raise the question whether there is a critical IsPP associated with arrest of the blood-flow. Of interest in
this context is the controversy regarding the origin of the blood supply to the adenoma and pituitary, whether it is a1~erial,3.~J*mixed arterial and venous,’J 1*18 or solely venous.’ Although the IsPP proper may well be small -and our observations of critical intrasellar pressures indicate that it is-the pressure in the supplying vessels must of course be higher than the IsP. This applies not only to the adenoma, but in most cases, if not all, also to the pituitary gland, because it is located within the sella space. The clinical observation that the syndrome of pituitary apoplexy often includes hypopituitarism and diabetes insipidus supports this argument. An IsP of 30 mmHg is in our view not compatible with a blood-supply from only the venous and portal system. The observation of a jugular venous pressure of 14 mmHg supports this conclusion. The internal jugular vein pressure is probably a close estimate of ICP and hence of pressure in the portal system. In experiments with Rhesus monkeys, that have no arterial supply to the normal pituitary gland; Antunes has shown that a rise in airway pressure to 22 mmHg may be enough to arrest the portal vein The observations of critical IsPs of 32, 50 and 40 mmHg (Table I) associated with arrested or severely reduced adenoma blood flow indicate a perfusion pressure well below MaBP of 66, 89 and 73 mmHg, respectively. The explanation of these pressures that are far above venous but below arterial IsPP may be that the adenoma receives blood from resistance vessels in which some fall in pressure has already occurred. These observations strongly suggest that IsP of 40-50 mmHg may reduce the perfusion pressure to zero and cause adenoma ischaemia and infarction. The pituitary gland may have its own blood supply and a relatively higher perfusion pressure, and this may explain why the pituitary is sometimes spared in cases of pituitary apoplexy and adenoma infarction. The normal blood-flow values in the human pituitary have not yet been determined. Fundamental to the use of the xenon clearance method for measuring blood flow is the assumption of complete diffusion equilibrium between adenoma and blood. Xenon is highly
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lipophilic and diffuses freely across cell memRecently, using the laser-Doppler techbranes. It is almost completely removed from nique, Steinmeier et al. measured blood-flow the blood in the lungs which is why the in the human pituitary gland during transcalculations of blood flow are not influenced sphenoidal surgery for pituitary a d e n ~ r n a s . ~ ~ by recirculation.z0 Measuring blood-flow in absolute values Sooriyamoorthy and Livingston used the (ml/100 g/min) is not possible with this local xenon injection method for measuring method, but a correlation between flow meablood flow in the normal pituitary gland of the sured in absolute units and in the theoretical rabbit.z1 They found flow values of approxi- concept of flux has been suggested. In the mately 8 m1/100 g/min in the anterior lobe, anterior lobe a mean flow of 27 flux was found which is considerably lower than in other (95% confidence interval 8.1-65.4). It has not studies of pituitary blood-flow in animals. In yet been possible to differentiate between rats the pituitary blood-flow has been mea- adenoma blood-flow or anterior lobe bloodsured with the hydrogen washout technique flow with this method (Steinmeier, personal and by autoradiography and in dogs with the communication). thermodilution technique. These studies have We have found flow values of respectively yielded flow values around 50-90 m1/100 26 and 22 m1/100 g/min in the anterior g/min in the a d e n o h y p ~ p h y s i s . ~This ~ - ~may ~ pituitary gland of two patients after adenoma suggest a methodological error using the xenon removal. These values are comparable to the clearance method for measuring pituitary findings of Steinmeier et al., but are presumblood-flow. In the study by Sooriyamoorthy ably not representative of the normal blood and Livingston, the sodium iodide detector had flow in the human gland. In rats, using the a diameter of 2.5 cm and was placed “a few oestrogen-induced pituitary tumour model, inches away from the source”, probably out- Lees et al. have found a decrease in pituitary side the head of the rabbit, which is why the gland flow synchronous with tumour growth detector may too have sampled from expired and followed by appearance of spots of high 133Xein the pharynx, giving a slower clearance flow, presumably due to development of alterand therefore low flow values. This problem is native routes of tumour blood supply.z6 Anasolved in our study by placing the probe tomically it has been shown that oestrogendirectly upon the dura. When the local 133Xe induced tumours of the anterior pituitary gland injection method has been used in other in rats may be associated with the development compartments, e.g. the cerebral cortex, flow of a direct arterial supply.38 values have been comparable to findings with other methods (e.g. SPECT, ~ e n o n - C T ) . ’ ~ J ~ Most studies in animals on pituitary bloodConclusion flow are obtained in normal pituitary glands.19~z1~23~25~z7-30 In a few studies the oes- We have shown that pituitary adenomas have a trogen-induced tumour model has been used variable and in some cases a very high pressure and reduced flow values of approximately 25 that makes it unlikely that the blood supply is m1/100 g/min have been f o ~ n d . ~ ~ Jof~ solely , ~ ~ -venous ~ ~ origin. Our observations of Whether this method represents true neoplasia arrested blood flow at intrasellar pressures rather than hyperplasia is do~btful,3’*’~.~~ and below normal arterial pressure but above blood-flow measurements may not reflect flow venous pressure suggest that there is an in pituitary tumours. We have in our study additional arterial supply at a lower than found very low blood-flow values in human normal arterial pressure. This, in turn, suggests pituitary adenomas, but it is well known from that pituitary adenomas may have a critical other studies that blood-flow in human brain perfusion pressure well below normal arterial tumours may vary considerably, from zero to pressure. Consequently, a fall in arterial blood more than 100 ml/min/l00 g.36 pressurez0 or a small increase in intrasellar
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pressure (due to for example tumour growth or haemorrhage) may cause the perfusion pressure to fall below the critical threshold and produce the syndrome of pituitary apoplexy and adenoma infarction.
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Address for correspondence: Anders Kruse, Department of Neurosurgery, Rigshospitalet, Blegdamsvej 9,2100 Copenhagen, Denmark.
References 1 Gorczyca W, Hardy J. Arterial supply of the human pituitary gland. Neurosurgery 1987; 20:369-78. 2 Page RB. Pituitary blood flow. Am J Physiol 1982; 243:E427-E442. 3 Fumagalli Z.La vascolarizzazionedell’ipofisi umana. Z Anat EntwGesch 1942; 11 1:266-306. 4 Winterstein J. Zur Kenntnis der Hypophysenarterien. Anat Anzeiger 1939; 87275-92. 5 Green JD, Harris GW. The neurovascular link between the neurohypophysis and the adenohypophysis.J Endocrinol 1947; 5136-46. 6 Wislocki GB, King LS. The permeability of the hypophysis and the hypothalamus to vital dyes, with a study of the hypophysial vascular supply. Am J Anat 1936; 58: 421-72. 7 Xuereb GP, Prichard MML, Daniel PM. The arterial supply and venous drainage of the human hypophysis cerebri. Q J Exp Physiol 1954; 39199-217. 8 Adams JM, Daniels PM, Prichard MML. Transsection of the pituitary stalk in man: anatomical changes in the pituitary glands of 21 patients. J Neurol Neurosurg Psychiatry 1966;29545-55. 9 Sheehan HL, Davis JC. Pituitary necrosis. Br Med Bull 1968;2459-70. 10 Lees PD, Pickard JD. Hyperprolactinemia, intrasellar pituitary tissue pressure, and the pituitary stalk compression syndrome. J Neurosurg 1987; 62192-6. 1 1 Gorczyca W, Hardy J. Microadenomas of the human pituitary and their vascularization. Neurosurgery 1988; 221-6. 12 Powel DF, Baker HL, Laws ER. The primary angiographic &dings in pituitary adenomas. Radiology 1974; 110589-95. 13 Eintrei C, Leszniewski W, Carlsson C. Local application of 133Xenonfor measurement of regional cerebral blood flow (rCBF) during Halothane, Enflurane, and Isoflurance anesthesia in humans. Anesthesiology 1985; 63:391-4. 14 Eintrei C, Leszniewski W, 0”dman S, et al. Local applied 133Xenon for the measurement of regional cerebral blood flow (rCBF): an experimental study in the pig. Acta Physiol Scand 1985; 124261-7. 15 Lassen NA, Lmdbjerg IF, Munck 0. Measurement of blood flow through skeletal muscle by intramuscular injection of 133xenon.Lancet 1964; 1:686-9.
16 Sejersen P. Measurement of cutaneous blood flow by freely diffusible radioactive isotopes. Danish Med Bull 1971;SUppl 181-38. 17 Olesen J, Paulson OB, Lassen NA. Regional cerebral blood flow in man determined by the initial slope of the clearance of intra-arterially injected IJ3Xe. Stroke 1971;2519-40. 18 Stanfield JP. The blood supply of the human pituitary gland. J Anatomy 1960; 94:257-73. 19 Antunes JL, Muraszko K, Stark R, et al. Pituitary portal blood flow in primates: a Doppler study. Neurosurgery 1983; 12:492-5. 20 Jones NS, Finer N. Pituitary infarction and development of the empty sella syndrome after gastrointestinal haemorrhage. BMJ 1984; 289:661-2. 21 Sooriyamoorthy T, Livingston A. Blood flow changes in the pituitary neural lobe of the rabbit associated with neurohypophysial hormone-releasing stimuli. J Endocrinol 1973; 5775-85. 22 Kemeny AA, Jacubowski J, Stawowy A, et al. Changes of b l o i flow &I ostrogen-induced hyperplastic anterior pituitary lobe following bromocriptine administration. Br J Neurosurg 1987; 1:243-50. 23 Kemeny AA, Jacubowski J, Jefferson AA, et al. Blood flow and autoregulation in rat pituitary gland. J Neurosurg 1985; 63:116-19. 24 Kemeny AA,Jacubowski J, Pasztor E, et al. Reduction of blood flow in the adenohypophysis of rats by Bromocriptine. J Neurosurg 1985;63:120-4. 25 Kopaniky DR, Gann DS. Anterior pituitary vasodilation after hemorrhage in the dog. Endocrinology 1975; 97~630-5. 26 Lees PD, Richards HK, Lovick AHJ, et al. Autoradiographic measurements of regional pituitary blood flow and pituitary tumor perfusion in the conscious rat. J Cereb Blood Flow Metab 1987; 7 (Suppl 1):474. 27 Porter JC, Hines MFM, Smith KR, et al. Quantitative evaluation of local blood flow of the adenohypophysis in rats. Endocrinology 1967; 80583-98. 28 Goldmann H. Effect of acute stress on the pituitary gland endocrine gland blood flow. Endocrinology 1963; 72:588-91. 29 Takaoda Y, White RJ, Billiar RB, et al. Regional arterial blood flow in the primate pituitary gland. Surg Forum 1977; 28464-6. 30 Yates FEY Kirschman R, Olshen B. Analysis of adenohypophysial blood flow in the rat by radioisotope washout: estimate of the vasometer activity of vasopressin in the anterior pituitary. 31 Jacubowski J, Kemeny AA, Stawowy A, et al. Blood flow in diethylstilbestrol-induced anterior pituitary gland hyperplasia. Proc Soc Exp Biol Med 1986; 183:372-5. 32 Stawowy A, Kemeny AA, Jacubowski J. Changes of blood flow in the adenohypophysis of normal and estrogen pretreated Fischer rats by tamoxifen. Acta Endocrinol (Copenh) 1989; 121:821-6. 33 Tiboldi T, Nemessanyi 2, Csernay I, et al. Effect of estrogen on pituitary blood flow in rats. Endocrinol EXP 1967; 2~73-7. 34 Lloyd RV. Estrogen-induced hyperplasia and neoplasia in the rat anterior pituitary gland. Am J Pathol 1983; 1 13~198-206. 35 Trouillas J, Girod C. Animal models of human pituitary tumors. Path Res Pract 1988; 183:638-41.
Pressure in pituitay adenomas
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36 Lammertsma AA, Wise RJS, COX TCS, et al. Measurement of blood flow, oxygen utilisation, oxygen extraction ratio, and fractional blood volume in human brain tumours and surrounding tissue. Br J Radio1 1985; 58~725-34. 37 Steinmeier R, Fahlbusch R, Powers AD, et al. Pituitary microcirculation: physiological aspects and clinical
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implications. A laser-Doppler flow study during transsphenoidal adenomectomy. Neurosurgery 1991; 29:47-54. 38 Elias KA, Weiner RI. Direct arterial vascularization of estrogen-induced prolactin-secreting anterior pituitary tumors. Proc Natl Acad Sci USA 1984; 81:4549-53.
ORIGINAL ARTICLE
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Pressure and blood flow in pituitary adenomas measured during transsphenoidal surgery ANDERS KRUSE,* JENS ASTRUP,* GEORG E. COLDt & HANS H. HANSENS
Departments of *Neurosurgery, fNeuroanaesthesiology and $Nuclear Medicine, Arhus Kommunehospital, 8000 h h u s C, Denmark
Abstract In 48 patients undergoing transsphenoidal surgery for pituitary adenoma, the intrasellar pressure was recorded during surgery. In 14 patients, adenoma blood flow was measured with the technique of local injection of 133xenon.Median intrasellar pressure was 30 mmHg (range 8-62), n=48, and median adenoma blood flow was 8 m1/100 g/min (range 0-37), n= 14. In two patients, blood flow in the anterior pituitary gland was measured, and values of 26 and 22 m1/100 g/min were obtained. The finding that intrasellar pressure is above central venous and intracranial pressure suggests the possibility that the adenoma and the anterior pituitary gland are supplied not only with venous blood, but receive an additional arterial supply at a less than normal arterial pressure. In three cases perfusion pressures that caused arrest of adenoma blood flow were found, and these observations are discussed with reference to pituitary apoplexy. Key words: Intrasellar pressure, pituitaly adenomas, pituitary apoplexy, pituitary blood Jaw, pituitaly gland, transsphenoidal surgery.
Introduction While it is generally accepted that the anterior pituitary gland in a number of species (e.g. rat, rabbit, dog) is supplied with only venous there is still doubt with respect to the blood supply of the human gland. Early reports have favoured an end-artery s~pply,37~ but after the elucidation of the venous portal system,5'6 some investigators have suggested a venous supply' and others a mixed venous-arterial supply.' A number of findings indicate a venous-arterial supply: therapeutic transsection of the pituitary stalk in patients with carcinoma of the breast or prostate does not cause an ischaemic infarction of the gland that corresponds in extent or topography to the venous h y p o t h e s i ~ ; l Patients * ~ ~ ~ with pituitary adenomas may have intrasellar pressure (IsP) values well above venous pressure and still
maintain an active adenoma and an intact anterior lobe function;1° arterial supply to pituitary adenomas has been demonstrated anatomically" and by angiography.12 In this study we correlate pituitary IsP with adenoma blood flow in order to define a critical intrasellar perfusion pressure (IsPP) that causes complete ischaemia. The observations are discussed in relation to the syndrome of pituitary apoplexy. Further, some observations of blood flow in the anterior pituitary gland were obtained.
Materials and methods
Patient population The study consecutively included 48 patients who underwent transsphenoidal surgery for
333
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Anders Kruse et al.
lesions occupying intrasellar space: 23 men [median age 45 years (range 18-68)] and 25 women [median age 41 years (range 17-74)]. Twenty-six patients were operated upon for endocrine dysfunction (2 1 had acromegaly, three Cushings disease, two prolactinoma) and 22 patients presented with chiasma compression ( 17 had inactive adenoma, four craniopharyngioma and one was operated upon acutely because of pituitary apoplexy with ophthalmoplegia). Twenty patients had purely intrasellar adenomas, while 27 had variable degrees of suprasellar enlargement.
SuWY The operations were all performed under general anaesthesia using thiopental induction and maintenance with halothane, phentanyl and N20. Muscular relaxation was induced with atracurium. The patients were maintained slighly hypocapnic with PaC02 at 4.0-4.5 kP. The transseptal, transsphenoidal approach was used. The sphenoid air sinus was opened and mucosa removed. The bony floor of the sella was opened with a rongeur or drill and removed with a bone punch leaving the dura intact.
Intrasellar pressure measurements A 0.9 mm lumbar puncture needle was connected to a transducer through a polyethylene tube, and the system was filled with saline and calibrated to zero at the level of the adenoma. The needle was introduced into the adenoma and controlled on an image intensifier. IsP was recorded continuously. In all patients mean arterial blood pressure was recorded continuously by an intra-arterial line. In six patients the internal jugular vein was cannulated and a catheter was positioned in the jugular bulb to monitor intracranial pressure (ICP) indirectly. Jugular vein compression was performed to correlate changes in
ICP and IsP. Intrasellar pressure recording was completed in all 48 patients.
Adenoma blood-flow measurements The human pituitary gland is located within a bony grove. This makes blood-flow measurements with single photon emission technique (SPECT) or xenon-enhanced CT unreliable because of low signal-to-noise ratio. Owing to the debate of the origin of the blood supply to the anterior lobe, a clearance method of bloodflow measurements was chosen. The local injection technique of 133xenonwas used. This method is well established and has been used for measuring blood flow in various tissues such as brain, muscle and subcutaneous fat13-16 and it can be used intra-operatively. The flow determination is based on the washout of 133Xefrom the tissue. Blood-flow is calculated from the slope of the semilogarithmic transformed clearance curve. At equilibrium 133Xe will leave the tissue at a rate proportional to the blood-flow and the partition coefficient lambda: f l o ~ = l n 2 / t , ,x~ lambdax 100 (ml/min/100 g). tIl2was estimated from the clearance curvesY1'and lambda was arbitrarily set to 1. Using a Hamilton syringe with a 26 gauge needle we injected 50 pl of 133Xe(1 mCu/ml) into the adenoma during X-ray control. Air suction was established in the sinus, and a cadmium telluride detector mounted in the tip of a probe (2 mm diameter) and connected to a count-rate-meter through a flexible co-axial cable was inserted through the patient's nose and positioned externally on the dura (Fig. 1). The 133Xe clearance was recorded for approximately 5 min and displayed on a semilogarithmic graph (Fig. 2). Adenoma blood-flow measurements was consecutively performed in the final 20 patients. The two-sample rank sum test (Mann-Whitney test) was used for statistical comparison between the groups. Values of ~(0.05 were considered significant. The study was approved by the county ethical committee.
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Pressure in pituitary adenomas
FIG. 1. Peroperative X-ray showing the suction in the posterior part of the sphenoid air sinus (a), the pressure recording needle within the adenoma (b), the cadmium telluride probe positioned upon the dura (c), and the nasal speculum (d).
Results Intrasellar pressure The median IsP was 30 mmHg (range 8-62), n=48. In all patients, a pulsatile waveform was recorded. The median intrasellar pulse
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amplitude was 2.3 mmHg (range 1-14). There were no significant differences in median pressure between the clinical groups of patients. In the six patients with jugular vein cannulation, neck compression resulted in a net increase in jugular vein pressure of 10 mmHg (median; range 14-24) with a concomitant net increase in intrasellar pressure of 5 mmHg (median; range 32-37). This difference in net increase is not significant and indicates that changes in ICP modify IsP (Fig. 3). Assuming only arterial blood supply to the anterior pituitary gland and the adenoma, the mean IsPP can be estimated as the mean BP-mean IsP. The median IsPP was 58 mmHg (range 14-93), n=48. Adenoma blood-flow In five patients it was found that 133Xehad been injected into a large cyst within the adenoma. Consequently, there could be no flow-dependent xenon outwash, only clearance due to diffusion and redistribution. In three of these cases the clearance curves were flat (Fig. 4), and in two cases a small clearance comparable to a ‘flow’ of 2 m1/100 g/min was
8
FIG. 2. A semilogarithmic transformed clearance curve of 133xenon,comparable to a flow value of 16 m1/100 g/min.
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mmHg
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A
FIG. 3. Simultaneous rise in intrasellar pressure (A) and jugular bulb pressure (B) due to neck compression. Note the displacement and different calibration of the curves.
FIG.4. '33Xenonclearance curve from an intra-adenomatous cyst.
observed. Consequently, 'flow' values below 2 m1/100 g/min were considered equal to zero. In all patients the initial 1-1.5 min of the clearance curves showed a variable waveform before the mono-exponential washout set in (Figs. 2 and 4). The same phenomenon was observed in clearance curves from patients who had had xenon injected into a cyst, and it has therefore not been considered a flowdependent clearance. Presumably, it is caused by a rapid redistribution by diffusion of xenon within the adenoma. Exclusive of the five patients with xenon injection into a cyst, blood-flow measurements were completed in 15 patients. In one patient the xenon injection was accidentally performed within the pituitary gland. In the remaining 14 patients, who all had pituitary adenomas, median IsP was 27 mmHg (range 16-62),
which was not different from the median IsP of the whole series. The 133Xeinjection resulted in an increase of median IsP of 2 mmHg. The median IsPP was 55 mmHg (range 30-74), which was not different from the IsPP of the whole series. The median adenoma flow in the group was 8 mV100 g/min (range 0-37), n= 14. In three patients a rise in IsP was accompanied by a fall in adenoma blood-flow. In two of these patients initial flow measurements showed values of 8 and 37 m1/100 g/min at IsP of 40mmHg [mean arterial blood pressure (MaBP) 89 mmHg] and 22 mmHg (MaBP 77 mmHg). Haemorrhage in the adenoma, caused by positioning of the pressure recording needle in one case and 133Xeinjection in the other, was followed by IsP increases to 50 and 40 mmHg and concomitant flow value decreases
Pressure in pituitary adenomas
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to 5 and 0 m1/100 g/min, respectively (Fig. 5). MaBP remained constant during measuring. In the third patient MaBP was 66 mmHg, while IsP increased gradually from 22 to 32 mmHg and the clearance curve flattened. The increase in IsP was due to leak of saline from the pressure recording needle, which was then replaced. Thereafter IsP remained constant at 26 mmHg, and the clearance of 133Xeindicated a flow of 5 m1/100 g/min. The results are summarized in Table I.
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Pituitary gland Jow In the patient who received a '33Xe injection in the pituitary gland a blood-flow of 10 m1/100 g/min was found. The IsP was 44 mmHg with an IsPP of 40 mmHg. The patient suffered from a craniopharyngioma with chiasm compression but was without endocrine dysfunction. In two patients it was possible to measure flow in a well-defined pituitary gland after the
FIG.5. Increase in intrasellar pressure due to haemorrhage in the adenoma leading to a fall in blood-flow. Curve A constant intrasellar pressure of 22 mmHg, flow=37 m1/100 g/min. Curve B intrasellar pressure increase to 40 mmHg with concomitant fall in flow to zero.
TABLEI. Increases in intrasellar pressure (IsP) and concomitant changes in intrasellar perfusion pressure (IsPP) and flow in three patients IsP-2 mmHg
ISP-1
ISPP-1 IsPP-2 mmHg
Flow-1 Flow-2 m1/100 g/min
~
26
32
40
50 40
22
40 49
34 39
5
55
37
37
8
0 5 0
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adenoma had been removed. One was a 37year-old man with acromegaly and hypogonadism, but otherwise normal pituitary function. Adenoma blood-flow was 7 mV100 g/min at an IsP of 52 mmHg and an IsPP of 36 mmHg. Adenoma removal exposed a preserved pituitary gland in which a blood-flow of 26 m1/100 g/min was measured. The other patient was a 17-year-old woman with an inactive adenoma. She had presumably been a victim of pituitary apoplexy 3 months before surgery, but pituitary function was normal. IsP was 30 mmHg, but the adenoma was cystic with consequently no outwash of xenon. After removal of the tumour a flow of 22 m1/100 g/min was measured in the pituitary gland. Beside the above-mentioned haemorrhage in the adenoma due to xenon injection and replacement of the pressure recording needle, and IsP increase due to a leak of saline from the needle, there were no observed side effects or technical failures.
Discussion Our study confirms the high IsP values that Lees and Pickard’O have found associated with pituitary adenoma when the IsP was measured with patients in the supine position during transsphenoidal surgery. Lees and Pickard’s study suggests an association between elevated IsP and adenoma hyperprolactinaemia due to compression of the pituitary gland and pituitary stalk. Our study was not designed to investigate this possibility, and we have not observed correlations between IsP and type, size or extension of adenoma or pituitary function. Our only patient who was operated acutely because of pituitary apoplexy had an IsP of 60 mmHg. Median IsP for the whole group was 30 mmHg (range 8-62), n=48, which is comparable to the 27 mmHg (range 2-51) value found by Lees and Pickard.Io The syndrome of pituitary apoplexy and suggested high IsP causing adenoma and pituitary ischaemia and infarction, raise the question whether there is a critical IsPP associated with arrest of the blood-flow. Of interest in
this context is the controversy regarding the origin of the blood supply to the adenoma and pituitary, whether it is a1~erial,3.~J*mixed arterial and venous,’J 1*18 or solely venous.’ Although the IsPP proper may well be small -and our observations of critical intrasellar pressures indicate that it is-the pressure in the supplying vessels must of course be higher than the IsP. This applies not only to the adenoma, but in most cases, if not all, also to the pituitary gland, because it is located within the sella space. The clinical observation that the syndrome of pituitary apoplexy often includes hypopituitarism and diabetes insipidus supports this argument. An IsP of 30 mmHg is in our view not compatible with a blood-supply from only the venous and portal system. The observation of a jugular venous pressure of 14 mmHg supports this conclusion. The internal jugular vein pressure is probably a close estimate of ICP and hence of pressure in the portal system. In experiments with Rhesus monkeys, that have no arterial supply to the normal pituitary gland; Antunes has shown that a rise in airway pressure to 22 mmHg may be enough to arrest the portal vein The observations of critical IsPs of 32, 50 and 40 mmHg (Table I) associated with arrested or severely reduced adenoma blood flow indicate a perfusion pressure well below MaBP of 66, 89 and 73 mmHg, respectively. The explanation of these pressures that are far above venous but below arterial IsPP may be that the adenoma receives blood from resistance vessels in which some fall in pressure has already occurred. These observations strongly suggest that IsP of 40-50 mmHg may reduce the perfusion pressure to zero and cause adenoma ischaemia and infarction. The pituitary gland may have its own blood supply and a relatively higher perfusion pressure, and this may explain why the pituitary is sometimes spared in cases of pituitary apoplexy and adenoma infarction. The normal blood-flow values in the human pituitary have not yet been determined. Fundamental to the use of the xenon clearance method for measuring blood flow is the assumption of complete diffusion equilibrium between adenoma and blood. Xenon is highly
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Pressure in pituitary adenomas
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lipophilic and diffuses freely across cell memRecently, using the laser-Doppler techbranes. It is almost completely removed from nique, Steinmeier et al. measured blood-flow the blood in the lungs which is why the in the human pituitary gland during transcalculations of blood flow are not influenced sphenoidal surgery for pituitary a d e n ~ r n a s . ~ ~ by recirculation.z0 Measuring blood-flow in absolute values Sooriyamoorthy and Livingston used the (ml/100 g/min) is not possible with this local xenon injection method for measuring method, but a correlation between flow meablood flow in the normal pituitary gland of the sured in absolute units and in the theoretical rabbit.z1 They found flow values of approxi- concept of flux has been suggested. In the mately 8 m1/100 g/min in the anterior lobe, anterior lobe a mean flow of 27 flux was found which is considerably lower than in other (95% confidence interval 8.1-65.4). It has not studies of pituitary blood-flow in animals. In yet been possible to differentiate between rats the pituitary blood-flow has been mea- adenoma blood-flow or anterior lobe bloodsured with the hydrogen washout technique flow with this method (Steinmeier, personal and by autoradiography and in dogs with the communication). thermodilution technique. These studies have We have found flow values of respectively yielded flow values around 50-90 m1/100 26 and 22 m1/100 g/min in the anterior g/min in the a d e n o h y p ~ p h y s i s . ~This ~ - ~may ~ pituitary gland of two patients after adenoma suggest a methodological error using the xenon removal. These values are comparable to the clearance method for measuring pituitary findings of Steinmeier et al., but are presumblood-flow. In the study by Sooriyamoorthy ably not representative of the normal blood and Livingston, the sodium iodide detector had flow in the human gland. In rats, using the a diameter of 2.5 cm and was placed “a few oestrogen-induced pituitary tumour model, inches away from the source”, probably out- Lees et al. have found a decrease in pituitary side the head of the rabbit, which is why the gland flow synchronous with tumour growth detector may too have sampled from expired and followed by appearance of spots of high 133Xein the pharynx, giving a slower clearance flow, presumably due to development of alterand therefore low flow values. This problem is native routes of tumour blood supply.z6 Anasolved in our study by placing the probe tomically it has been shown that oestrogendirectly upon the dura. When the local 133Xe induced tumours of the anterior pituitary gland injection method has been used in other in rats may be associated with the development compartments, e.g. the cerebral cortex, flow of a direct arterial supply.38 values have been comparable to findings with other methods (e.g. SPECT, ~ e n o n - C T ) . ’ ~ J ~ Most studies in animals on pituitary bloodConclusion flow are obtained in normal pituitary glands.19~z1~23~25~z7-30 In a few studies the oes- We have shown that pituitary adenomas have a trogen-induced tumour model has been used variable and in some cases a very high pressure and reduced flow values of approximately 25 that makes it unlikely that the blood supply is m1/100 g/min have been f o ~ n d . ~ ~ Jof~ solely , ~ ~ -venous ~ ~ origin. Our observations of Whether this method represents true neoplasia arrested blood flow at intrasellar pressures rather than hyperplasia is do~btful,3’*’~.~~ and below normal arterial pressure but above blood-flow measurements may not reflect flow venous pressure suggest that there is an in pituitary tumours. We have in our study additional arterial supply at a lower than found very low blood-flow values in human normal arterial pressure. This, in turn, suggests pituitary adenomas, but it is well known from that pituitary adenomas may have a critical other studies that blood-flow in human brain perfusion pressure well below normal arterial tumours may vary considerably, from zero to pressure. Consequently, a fall in arterial blood more than 100 ml/min/l00 g.36 pressurez0 or a small increase in intrasellar
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pressure (due to for example tumour growth or haemorrhage) may cause the perfusion pressure to fall below the critical threshold and produce the syndrome of pituitary apoplexy and adenoma infarction.
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Address for correspondence: Anders Kruse, Department of Neurosurgery, Rigshospitalet, Blegdamsvej 9,2100 Copenhagen, Denmark.
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