- Email: [email protected]
Feedback-controlled dextrose infusion during surgical management of insulinomas
CASE REPORTS
Feedback-Controlled Dextrose Infusion During Surgical Management of Insulinomas
JOHN H. KARAM, M.D. MARA LORENZI, M.D. CLINTON W. YOUNG, M.D.* ANNETTE D. BURNS, R.N. PETERMAN R. PROSSER. M.D. GEROLD M. GRODSKY, Ph.D. MAURICE GALANTE, M.D. PETER H. FORSHAM, M.D. San Francisco, California
From the Metabolic Research Unit and The Departments of Medicine, Surgery. and Biochemistry and Biophysics, University of California, San Francisco, California. This work was supported in part by Grant AM-12763(06) from the National Institutes of Health and by grants from the Levi J. and Marcy C. Skaggs Foundation of Oakland, California, and the Susan Greenwall Foundation of New York City. Pre- and postoperative evaluation was carried out in the General Clinical Research Center, University of California, San Francisco, with funds provided by the Division of Research Resources, RR-79. U.S. Public Health Service. Requests for reprints should be addressed to Dr. John H. Karam. Metabolic Research Unit, 1143 HSW, University of California, San Francisco, California 94143. Manuscript accepted August 30,1978. * Recipient of the Dorothy Frank Research Fellowship of the San Francisco Chapter of the American Diabetes Association.
Through the use of a feedback-controlled dextrose infusion system, we obtained continuous monitoring of the blood glucose level in a patient undergoing surgery for multiple pancreatic beta-cell tumors. In addition, this device infused dextrose at variable rates to matntain a predetermined euglycemic level of 90 mg/dl. Before locating the source of excessive insulin production, the maximum dextrose infusion rate of 400 mg/min was required; but after extirpation of multiple insulinomas, the dextrose-infusion rate declined whereas the blood glucose level rose ahove the preselected IeveLThemresults emphasize the usefulness of a monitoring and infusion system not only in protecting the patient from the haxard of hypoglycemia under anesthesia but also as an aid in determining whether all insulinsecreting tumors have been removed. Successful treatment of hyperinsulinism due to an insulin-producing, beta-cell adenoma of the pancreas involves localization and removal of the source of excessive insulin production. Although 90 per cent of insulinomas are solitary, as many as 8 to 14 per cent are reported to be multiple [1,2]. Technics to localize these tumors either preoperatively or at the time of surgery have been only partially successful, relying solely on the skill and experience of the surgeon. Recently a glucose-controlled insulin infusion system (GCIIS), the Biostator@, has been developed by Life Sciences Instruments (Miles Laboratories, Elkhart, Ind.) which displays continuous analysis of blood glucose and can be programmed to maintain euglycemia by infusing either dextrose or insulin [3]. This report describes the clinical usefulness of this instrument during the surgical management of a patient with hypoglycemia and hyperinsulinism due to multiple pancreatic beta-cell adenomas.
CASE REPORT A 67 year old female physician was seen in the emergency room of the University of California at San Francisco (UCSF) in a state of mental confusion and with a plasma,glucose level of 29 mg/dl. Mentation cleared after the intravenous administration of glucose. Over the previous five years she had had two admissions to UCSF for “transient ischemic” cerebral episodes associated with temporary confusion and slurred speech, which were not considered to be related to meals. Past work-up had revealed normal findings for brain scan, electroencephalogram, cerebral-spin&fluid examination, computer tomog raphy and cerebral arteriogram, A 5 hour, 100 g, oral glucose tolerance test performed five years before the present incident had resulted in the following blood glucose response: base line, 57 mg/dl; 1 hour, 59 mg/dl; 2 hours, 100
April 1879
The American Journal of Medicine
Volume 66
675
FEEDBACK-CONTROLLEDDEXTROSEINFUSION DURING INSULINOMA SURGERY-KARAM ET AL.
TABLE I
Preoperative Diagnostic Tests For lnsullnoma Fasting Plasma Glucoss’ Wdl)
Serum Immusoreactlve Insulin+ Wml)
0
81
33
10 20 30 45
62 46 32 27
280 295 -
Tlms Misutes Hours
Test 1 g tolbutamide intravenously+
Prolonged fast I
14 18 20 24
68 56 46 40
21 7 6 12
Prolonged fast II
13 18 20
77 50 50
22 19 9
75 92
435 495
1 mg glucagon intravenously*
5 10
*Glucose oxidase method [4].
%alt precipitation method of Grodsky and Forsham [5]. $1 g sodium tolbutamide dissolved in 20 ml sterile water given intravenously over 2 minutes after an overnight fast. 5 1 mg glucagon dissolved in 1 ml diluent given intravenously over 1 minute after 20 hours of fasting.
mg/dl; 3 hours, 68 mg/dl; 4 hours, 63 mg/dl; and 5 hours, 58 mg/dl. On six other occasions over the intervening five years, basal plasma glucose levels after an overnight fast were not in the grossly hypoglycemic range (65, 68, 80, 81, 68 and 77 mg/dl) and four nonfasting plasma glucose levels were also not subnormal (61,88,89 and 91 mg/dl). Sixteen years previously she had passed a single calcium oxalate stone after a period of intenserenal colic, but she has never been noted to have hypercalcemia on repeated determinations (9.4,9.3,8.9,9.1 and 8.7 mg/dl). She now has normal serum albumin, serum phosphorus, alkaline phosphatase and urinary calcium levels, normal bone density and has had no recurrence of renal colic. There has been no epigastric discomfort, headache or galactorrhea. In view of her documented hypoglycemia in the emergency room, she was admitted to LJCSF where the diagnosis of hyperinsulinism was documented. MATERIALS
AND METHODS
Determinations (Table I). The intravenous tolbutamide test induced mental confusion associated with sweatiness and tachycardia, accompanied by hypoglycemia and an exaggerated serum insulin response. (Average peak immunoreactive insulin [IRI] levels in nonobese, normal subjects are 110 MU/ml. with none exceeding 175 KU/ml.] Two complete fasts were undertaken for 24 and 20 hours, respectively, at which time the patient experienced mild
Preoperative
676
April 1979 The American Journal of Medicine
drowsiness associated with hypoglycemia. In both cases, the serum IRI tended to fall from initial levels; however, at the end of the first fast, an IRI value of 12 pU/ml showed a slight but inappropriate increase for a plasma glucose measurement of 40 mg/dl. At the end of the second fast, a rapid fnfusion of 1 mg glucagon raised the plasma glucose level to 92 mg/dl by 10 minutes and produced a profound increase in serum IRI to 495 ccU/ml. (Normal upper limits do not exceed 140 pU/ml in our laboratory.] As with the tolbutamide response, this was diagnostic of a pancreatic beta-cell tumor (Figure 1). Operative Procedures (Figure 2). Prior to surgery, an intravenous infusion of 10 per cent dextrose in water was administered at a rate of approximately 200 mg/min. While anesthesia was being administered in the operating room, the GCIIS was connected to the patient by inserting a 20-gauge MedicuP cannula through which venous blood was continuously withdrawn, via a double-lumen catheter. [The principle of the GCIIS is such that, after in-line mixing with a diluent, the blood sample is transferred to the electrochemical glucose sensor. This polarographically measures the hydrogen peroxide generated by the reaction between the glucose in the sample and the membrane-coupled [immobilized] glucose oxidase enzyme. The electrical output of the glucose sensor is converted in the analyzer module into a read-out of the glucose level [in mg/dl], which is continuously displayed.) The rate of blood withdrawal was only 2 ml/hour. A separate 21-gauge scalp vein needle coupled to a two-way adapter was connected on the same arm slightly proximal to the “analyzer” catheter, and this permitted infusion of either saline solution or 20 per cent dextrose solution. The computer was programmed by algorithm to infuse D-glucose [dextrose) at the necessary rate to maintain the patient’s blood glucose level at the preselected level of 90 mg/dl [3]. First inspection of the entire anterior surface of the pancreas, along with palpation of the mobilized head and the uncinate process, failed to reveal the presence of adenomas. For the initial 15 minutes of surgery, the GCIIS was infusing dextrose at the maximum pumping velocity of 2 ml/min. which delivered 400 mg/min. Despite the stress of surgery and the maximum dextrose-infusion rate from the Biostator, the patient’s blood glucose level was just barely maintained at 90 mg/dl, suggesting the presence of an endogenous source of hyperinsulinism. This was subsequently verified by a circulating IRI level of 108 pU/ml from this time. As the dissection was continued along the body and tailof the pancreas, three small tumors were identified in the tail as it projected into the hilum of the spleen. The largest of these was 1 cm in diameter, and the two smaller ones were 0.2 cm. After removing these three tumors, the blood glucose level remained at or below 90 mg/dl for 30 minutes, while dextrose continued to be infused from 260 to 400 mg/minute. In view of the pathologic verification of multiple adenomas, as well as the absence of hyperglycemia despite their resection, it was decided to perform a subtotal pancreatectomy, removing the entire body and tail of the pancreas as well as a portion of the head. Following this, the GCIIS soon ceased infusing dextrose as the blood glucose level ranged from 95 to 100 mg/dl. Pathologic examination of the body and tail revealed six small insulinomas, each measuring no more than 2 to 3 mm in di-
Volume 66
FEEDBACK-CONTROLLED
DEXTROSE
INFUSION
DURING INSULINOMA
SURGERY-KARAM
ET AL.
I.V Ggn.( I mg)o
pm- op
2 :
a 3
300
Patient 0.R
Glucagon Test
4
Pre-op TBA Test
250
I
0
5
I
IO
I
I
I
I5
20
25
1
30
Minutes Igure 1. Comparisonof serum insulin responseto standardintravenoustolbutamide and glucagontests before aridafter resection of multiple beta-cell tumors of the pancreas. Shadedarea represents the range of serum insulin response to 1 g tolbutamidegiven intravenouslyin seven nonobesenormalsubjects.A similar pattern occurs with glucagonstimulationin normal control subjects, except that the upper limit of serum insulinreach&l between 1 to 5 minutesdoes not exceed 140 /.&J/ml,Hiitha mean value of 86 j.&J/ml.
ameter. With saline solution alone, the patient’s blood glucose level stabilized at 100 mg/dl at the end of the operative procedure. Postotoperative Results(Figure3) AII intravenous drip of 5 per cent dextrose in water was begun in the recovery room, and the plasma glucose level was 363 mg/dl7 hours after surgery. Small supplements of regular insulin were administered for the first three postoperative days only. The patient’s elevated glucose level gradually declined during her hospitalization (see Figure 3), stabilizing at 120 to 125 mg/dl during the six weeks after discharge. Her serum IRI levels were initially quite low
on postoperative day 1, associated with evidence of pancreatitis in the remaining pancreatic segment. As this cleared, her fasting IRI levels rose in association with the hyperglycemic stimulus and declined to normal values as the hyperglycemia lessened. Repeat stimulation tests were carried out postoperatively with tolbutamide (1 g) and glucagon 11 rag), administered intravenously on days 12 and 13, respectively (see Figure 1). Fasting plasma glucosewas 130 mg/dl on day 12 just before tolbutamide was given and 120 mg/dl on day 13 at the time of the glucagon test. The patient had no symptoms of hyperglycemia during the repeat tolbutamide test [plasma glucose re-
April 1979
The American Journal of Medicine
Volume 66
677
FEEDBACK-CONTROLLED
DEXTROSE INFUSION DURING INSULINOMA
SURGERY-KARAM
ET AL.
IIO-
100 -
60 -
igure 2. Continuous monitoring of b!ocd glucose with feedback-controlled dextrose infusion dU0tIg exploration ana SurglGl removal of insulin-secreting tumors of the pancreas. BD refers to the preselected blood glucose level of 90 mg/dl, which the Biostator was programmed to maintain. Serum immunoreactive insulin measured during the procedure is represented by the boxed inserts.
mained above 90 mg/dl), and during the three months since her surgery she has remained essentially asymptomatic. COMMENT!3 Previous investigators have noted that a rise in the blood glucose level during surgery for an insulin-secreting, islet-cell tumor signals successful removal of the insulinoma [6,7]. However, the usefulness df this index has heretofore been undetermined by difficulties in monitoring glucose. Determinations could seldom be made fast enough to influence the surgeon’s decision and to alert the surgical team to institute changes in the rate of intravenous dextrose administration. In one instance, a surgeoq stopped the dextrose infusion to facilitate observation of the expected hyperglycemic rebound
678
April 1979 The American Journal of Medicine
following subtotal pancreatic resection, and an apparent hypoglycemic convulsion occurred [8]. With the GCIIS, glucose can be continuous1 monitored, and dextrose infused at variable rates to 1 aintain a preselected euglycemic level. In contrast to its more common use as an artificial beta cell designed to infuse insulin at variable rates in diabetic patients [9], we adapted the instrument to serve as an artificial liver in that it provided a glucose source to keep up with the excessive endogenous insulin production. In our patient, inspection and palpation of the entire anterior surface of the pancreas, as well as the mobilized head and uncinate process, failed to reveal an adenoma, yet the GCIIS’s maximum dextrose infusion rate (400 mg/min] was required to maintain blood glucose at 90
Volume 66
FEEDBACK-CONTROLLED DEXTROSE INFUSION DURING INSULINOMA SURGERY-KARAM
ET AL.
DISCHAROED
60 i
0
I
2
3 4
5 6
7
8 9
10 II I2 I3 14 I5 I6 I7 I8 IS 20 21
Postoperative
54
Day
lgure 3. Plasma glucose and serum insulin levels after subtotal pancreatectomy for multiple insulinomas. Samples were drawn after overnight fasting from postoperative day 6 on.
mg/dl-evidence supportive of insulinoma. Indeed, three small adenomas were subsequently identified and removed. When continuation of the maximum rate failed to raise the blood glucose level, the surgeon was encouraged to perform an additional pancreatic resection. Pathologic examination revealed six more 2 to 3 mm tumors, and the patient’s glucose level began to rise as the dextrose infusion terminated. Subsequent insulin responses to repeat stimulatory tests during the postoperative period have shown no evidence of residual tumor tissue, although the possibility of recurrence remains high since this patient had nine tumors scattered throughout the resected two thirds of her pancreas.
Thus, in addition to providing continuous glucose monitoring as a safeguard against potentially dangerous hypoglycemia during surgery, the programmed dextrose infusion capacity of the GCIIS was useful in suggesting the presence of residual tumor after the initial remova of three insulinomas. ADDENDUM
A case report of a patient with a single pancreatic insulinoma, whose surgical management was facilitated by a similar closed-loop controlled dextrose infusion, was published by Kudlow et al. [lo] after submission of this manuscript.
REFERENCES 1. Laurent 1, Debry G, Floquet 1: Hypoglycaemic Tumours. Amsterdam, Excerpta Medica Foundation, 1971. 2. Moss NH, Rhoads JE: Hyperinsulinism and islet cell tumors of the pancreas, chap 21. Surgical Diseases of the Pancreas (Howard JM, Jordan Cl Jr, eds], Philadelphia, J.B. Lippincott & Co., 1960. p 321. 3. Clemens AH, Chang PH. Kerner W. et al.: Development of an electrochemical bloocl glucose analyzer and new control algorithms for a lucose controlled insulin infusion system (artificial /3-cclP). Diabetes. Proceedings of the
4. 5. 6.
April 1979
IXth Congress of the International Diabetes Federation (Bajaj JS, ed), Amsterdam, Excerpta Medica Foundation, 1977, p 481. Glucose Analyzer Operational Manual. Fullerton, California, Beckman Instruments, July 1976. Grodsky GM, Forsham PH: An immunochemical assay of total extractable insulin in man. J Clin Invest 39: 1070, 1960. Landor JH, Klachko DM, Lie TH: Continuous monitoring of blood glucose during operation for islet cell adenomas. Ann
The American Journal of Medicine
Volume 66
679
FEEDBACK-CONTROLLED DEXTROSE INFUSION DURING INSULINOMA SURGERY-KARAM
9.
surg 171: 394,197o.
7. Schnelle N, Molnar GD, Ferris DO, et al.: Circulating glucose and insulin in surgery _ . for insulinomas. JAMA 217: 1072, 1971.
8.
660
Lemmer KE, quoted in Miller DR: Functioning adenomas of pancreas with hyperinsulinism: report of 13 patients. Arch Surg 90: 509,1965 [see p 520).
April 1676
The American Journal of Medicine
ET AL.
Clarke WL, Thomas L. Santiago JV: Clinical evaluation and preliminary studies on the use of an artificial pancreatic beta cell in juvenile diabetes mellitus. 1 Pediatr 91: 599, 1977. 10. Kudlow JE, Albisser AM, Angel A. et al.: Insulinoma resection facilitated by the artificial endocrine pancreas. Diabetes 27: 774, 1978.
Volume 66
Feedback-Controlled Dextrose Infusion During Surgical Management of Insulinomas
JOHN H. KARAM, M.D. MARA LORENZI, M.D. CLINTON W. YOUNG, M.D.* ANNETTE D. BURNS, R.N. PETERMAN R. PROSSER. M.D. GEROLD M. GRODSKY, Ph.D. MAURICE GALANTE, M.D. PETER H. FORSHAM, M.D. San Francisco, California
From the Metabolic Research Unit and The Departments of Medicine, Surgery. and Biochemistry and Biophysics, University of California, San Francisco, California. This work was supported in part by Grant AM-12763(06) from the National Institutes of Health and by grants from the Levi J. and Marcy C. Skaggs Foundation of Oakland, California, and the Susan Greenwall Foundation of New York City. Pre- and postoperative evaluation was carried out in the General Clinical Research Center, University of California, San Francisco, with funds provided by the Division of Research Resources, RR-79. U.S. Public Health Service. Requests for reprints should be addressed to Dr. John H. Karam. Metabolic Research Unit, 1143 HSW, University of California, San Francisco, California 94143. Manuscript accepted August 30,1978. * Recipient of the Dorothy Frank Research Fellowship of the San Francisco Chapter of the American Diabetes Association.
Through the use of a feedback-controlled dextrose infusion system, we obtained continuous monitoring of the blood glucose level in a patient undergoing surgery for multiple pancreatic beta-cell tumors. In addition, this device infused dextrose at variable rates to matntain a predetermined euglycemic level of 90 mg/dl. Before locating the source of excessive insulin production, the maximum dextrose infusion rate of 400 mg/min was required; but after extirpation of multiple insulinomas, the dextrose-infusion rate declined whereas the blood glucose level rose ahove the preselected IeveLThemresults emphasize the usefulness of a monitoring and infusion system not only in protecting the patient from the haxard of hypoglycemia under anesthesia but also as an aid in determining whether all insulinsecreting tumors have been removed. Successful treatment of hyperinsulinism due to an insulin-producing, beta-cell adenoma of the pancreas involves localization and removal of the source of excessive insulin production. Although 90 per cent of insulinomas are solitary, as many as 8 to 14 per cent are reported to be multiple [1,2]. Technics to localize these tumors either preoperatively or at the time of surgery have been only partially successful, relying solely on the skill and experience of the surgeon. Recently a glucose-controlled insulin infusion system (GCIIS), the Biostator@, has been developed by Life Sciences Instruments (Miles Laboratories, Elkhart, Ind.) which displays continuous analysis of blood glucose and can be programmed to maintain euglycemia by infusing either dextrose or insulin [3]. This report describes the clinical usefulness of this instrument during the surgical management of a patient with hypoglycemia and hyperinsulinism due to multiple pancreatic beta-cell adenomas.
CASE REPORT A 67 year old female physician was seen in the emergency room of the University of California at San Francisco (UCSF) in a state of mental confusion and with a plasma,glucose level of 29 mg/dl. Mentation cleared after the intravenous administration of glucose. Over the previous five years she had had two admissions to UCSF for “transient ischemic” cerebral episodes associated with temporary confusion and slurred speech, which were not considered to be related to meals. Past work-up had revealed normal findings for brain scan, electroencephalogram, cerebral-spin&fluid examination, computer tomog raphy and cerebral arteriogram, A 5 hour, 100 g, oral glucose tolerance test performed five years before the present incident had resulted in the following blood glucose response: base line, 57 mg/dl; 1 hour, 59 mg/dl; 2 hours, 100
April 1879
The American Journal of Medicine
Volume 66
675
FEEDBACK-CONTROLLEDDEXTROSEINFUSION DURING INSULINOMA SURGERY-KARAM ET AL.
TABLE I
Preoperative Diagnostic Tests For lnsullnoma Fasting Plasma Glucoss’ Wdl)
Serum Immusoreactlve Insulin+ Wml)
0
81
33
10 20 30 45
62 46 32 27
280 295 -
Tlms Misutes Hours
Test 1 g tolbutamide intravenously+
Prolonged fast I
14 18 20 24
68 56 46 40
21 7 6 12
Prolonged fast II
13 18 20
77 50 50
22 19 9
75 92
435 495
1 mg glucagon intravenously*
5 10
*Glucose oxidase method [4].
%alt precipitation method of Grodsky and Forsham [5]. $1 g sodium tolbutamide dissolved in 20 ml sterile water given intravenously over 2 minutes after an overnight fast. 5 1 mg glucagon dissolved in 1 ml diluent given intravenously over 1 minute after 20 hours of fasting.
mg/dl; 3 hours, 68 mg/dl; 4 hours, 63 mg/dl; and 5 hours, 58 mg/dl. On six other occasions over the intervening five years, basal plasma glucose levels after an overnight fast were not in the grossly hypoglycemic range (65, 68, 80, 81, 68 and 77 mg/dl) and four nonfasting plasma glucose levels were also not subnormal (61,88,89 and 91 mg/dl). Sixteen years previously she had passed a single calcium oxalate stone after a period of intenserenal colic, but she has never been noted to have hypercalcemia on repeated determinations (9.4,9.3,8.9,9.1 and 8.7 mg/dl). She now has normal serum albumin, serum phosphorus, alkaline phosphatase and urinary calcium levels, normal bone density and has had no recurrence of renal colic. There has been no epigastric discomfort, headache or galactorrhea. In view of her documented hypoglycemia in the emergency room, she was admitted to LJCSF where the diagnosis of hyperinsulinism was documented. MATERIALS
AND METHODS
Determinations (Table I). The intravenous tolbutamide test induced mental confusion associated with sweatiness and tachycardia, accompanied by hypoglycemia and an exaggerated serum insulin response. (Average peak immunoreactive insulin [IRI] levels in nonobese, normal subjects are 110 MU/ml. with none exceeding 175 KU/ml.] Two complete fasts were undertaken for 24 and 20 hours, respectively, at which time the patient experienced mild
Preoperative
676
April 1979 The American Journal of Medicine
drowsiness associated with hypoglycemia. In both cases, the serum IRI tended to fall from initial levels; however, at the end of the first fast, an IRI value of 12 pU/ml showed a slight but inappropriate increase for a plasma glucose measurement of 40 mg/dl. At the end of the second fast, a rapid fnfusion of 1 mg glucagon raised the plasma glucose level to 92 mg/dl by 10 minutes and produced a profound increase in serum IRI to 495 ccU/ml. (Normal upper limits do not exceed 140 pU/ml in our laboratory.] As with the tolbutamide response, this was diagnostic of a pancreatic beta-cell tumor (Figure 1). Operative Procedures (Figure 2). Prior to surgery, an intravenous infusion of 10 per cent dextrose in water was administered at a rate of approximately 200 mg/min. While anesthesia was being administered in the operating room, the GCIIS was connected to the patient by inserting a 20-gauge MedicuP cannula through which venous blood was continuously withdrawn, via a double-lumen catheter. [The principle of the GCIIS is such that, after in-line mixing with a diluent, the blood sample is transferred to the electrochemical glucose sensor. This polarographically measures the hydrogen peroxide generated by the reaction between the glucose in the sample and the membrane-coupled [immobilized] glucose oxidase enzyme. The electrical output of the glucose sensor is converted in the analyzer module into a read-out of the glucose level [in mg/dl], which is continuously displayed.) The rate of blood withdrawal was only 2 ml/hour. A separate 21-gauge scalp vein needle coupled to a two-way adapter was connected on the same arm slightly proximal to the “analyzer” catheter, and this permitted infusion of either saline solution or 20 per cent dextrose solution. The computer was programmed by algorithm to infuse D-glucose [dextrose) at the necessary rate to maintain the patient’s blood glucose level at the preselected level of 90 mg/dl [3]. First inspection of the entire anterior surface of the pancreas, along with palpation of the mobilized head and the uncinate process, failed to reveal the presence of adenomas. For the initial 15 minutes of surgery, the GCIIS was infusing dextrose at the maximum pumping velocity of 2 ml/min. which delivered 400 mg/min. Despite the stress of surgery and the maximum dextrose-infusion rate from the Biostator, the patient’s blood glucose level was just barely maintained at 90 mg/dl, suggesting the presence of an endogenous source of hyperinsulinism. This was subsequently verified by a circulating IRI level of 108 pU/ml from this time. As the dissection was continued along the body and tailof the pancreas, three small tumors were identified in the tail as it projected into the hilum of the spleen. The largest of these was 1 cm in diameter, and the two smaller ones were 0.2 cm. After removing these three tumors, the blood glucose level remained at or below 90 mg/dl for 30 minutes, while dextrose continued to be infused from 260 to 400 mg/minute. In view of the pathologic verification of multiple adenomas, as well as the absence of hyperglycemia despite their resection, it was decided to perform a subtotal pancreatectomy, removing the entire body and tail of the pancreas as well as a portion of the head. Following this, the GCIIS soon ceased infusing dextrose as the blood glucose level ranged from 95 to 100 mg/dl. Pathologic examination of the body and tail revealed six small insulinomas, each measuring no more than 2 to 3 mm in di-
Volume 66
FEEDBACK-CONTROLLED
DEXTROSE
INFUSION
DURING INSULINOMA
SURGERY-KARAM
ET AL.
I.V Ggn.( I mg)o
pm- op
2 :
a 3
300
Patient 0.R
Glucagon Test
4
Pre-op TBA Test
250
I
0
5
I
IO
I
I
I
I5
20
25
1
30
Minutes Igure 1. Comparisonof serum insulin responseto standardintravenoustolbutamide and glucagontests before aridafter resection of multiple beta-cell tumors of the pancreas. Shadedarea represents the range of serum insulin response to 1 g tolbutamidegiven intravenouslyin seven nonobesenormalsubjects.A similar pattern occurs with glucagonstimulationin normal control subjects, except that the upper limit of serum insulinreach&l between 1 to 5 minutesdoes not exceed 140 /.&J/ml,Hiitha mean value of 86 j.&J/ml.
ameter. With saline solution alone, the patient’s blood glucose level stabilized at 100 mg/dl at the end of the operative procedure. Postotoperative Results(Figure3) AII intravenous drip of 5 per cent dextrose in water was begun in the recovery room, and the plasma glucose level was 363 mg/dl7 hours after surgery. Small supplements of regular insulin were administered for the first three postoperative days only. The patient’s elevated glucose level gradually declined during her hospitalization (see Figure 3), stabilizing at 120 to 125 mg/dl during the six weeks after discharge. Her serum IRI levels were initially quite low
on postoperative day 1, associated with evidence of pancreatitis in the remaining pancreatic segment. As this cleared, her fasting IRI levels rose in association with the hyperglycemic stimulus and declined to normal values as the hyperglycemia lessened. Repeat stimulation tests were carried out postoperatively with tolbutamide (1 g) and glucagon 11 rag), administered intravenously on days 12 and 13, respectively (see Figure 1). Fasting plasma glucosewas 130 mg/dl on day 12 just before tolbutamide was given and 120 mg/dl on day 13 at the time of the glucagon test. The patient had no symptoms of hyperglycemia during the repeat tolbutamide test [plasma glucose re-
April 1979
The American Journal of Medicine
Volume 66
677
FEEDBACK-CONTROLLED
DEXTROSE INFUSION DURING INSULINOMA
SURGERY-KARAM
ET AL.
IIO-
100 -
60 -
igure 2. Continuous monitoring of b!ocd glucose with feedback-controlled dextrose infusion dU0tIg exploration ana SurglGl removal of insulin-secreting tumors of the pancreas. BD refers to the preselected blood glucose level of 90 mg/dl, which the Biostator was programmed to maintain. Serum immunoreactive insulin measured during the procedure is represented by the boxed inserts.
mained above 90 mg/dl), and during the three months since her surgery she has remained essentially asymptomatic. COMMENT!3 Previous investigators have noted that a rise in the blood glucose level during surgery for an insulin-secreting, islet-cell tumor signals successful removal of the insulinoma [6,7]. However, the usefulness df this index has heretofore been undetermined by difficulties in monitoring glucose. Determinations could seldom be made fast enough to influence the surgeon’s decision and to alert the surgical team to institute changes in the rate of intravenous dextrose administration. In one instance, a surgeoq stopped the dextrose infusion to facilitate observation of the expected hyperglycemic rebound
678
April 1979 The American Journal of Medicine
following subtotal pancreatic resection, and an apparent hypoglycemic convulsion occurred [8]. With the GCIIS, glucose can be continuous1 monitored, and dextrose infused at variable rates to 1 aintain a preselected euglycemic level. In contrast to its more common use as an artificial beta cell designed to infuse insulin at variable rates in diabetic patients [9], we adapted the instrument to serve as an artificial liver in that it provided a glucose source to keep up with the excessive endogenous insulin production. In our patient, inspection and palpation of the entire anterior surface of the pancreas, as well as the mobilized head and uncinate process, failed to reveal an adenoma, yet the GCIIS’s maximum dextrose infusion rate (400 mg/min] was required to maintain blood glucose at 90
Volume 66
FEEDBACK-CONTROLLED DEXTROSE INFUSION DURING INSULINOMA SURGERY-KARAM
ET AL.
DISCHAROED
60 i
0
I
2
3 4
5 6
7
8 9
10 II I2 I3 14 I5 I6 I7 I8 IS 20 21
Postoperative
54
Day
lgure 3. Plasma glucose and serum insulin levels after subtotal pancreatectomy for multiple insulinomas. Samples were drawn after overnight fasting from postoperative day 6 on.
mg/dl-evidence supportive of insulinoma. Indeed, three small adenomas were subsequently identified and removed. When continuation of the maximum rate failed to raise the blood glucose level, the surgeon was encouraged to perform an additional pancreatic resection. Pathologic examination revealed six more 2 to 3 mm tumors, and the patient’s glucose level began to rise as the dextrose infusion terminated. Subsequent insulin responses to repeat stimulatory tests during the postoperative period have shown no evidence of residual tumor tissue, although the possibility of recurrence remains high since this patient had nine tumors scattered throughout the resected two thirds of her pancreas.
Thus, in addition to providing continuous glucose monitoring as a safeguard against potentially dangerous hypoglycemia during surgery, the programmed dextrose infusion capacity of the GCIIS was useful in suggesting the presence of residual tumor after the initial remova of three insulinomas. ADDENDUM
A case report of a patient with a single pancreatic insulinoma, whose surgical management was facilitated by a similar closed-loop controlled dextrose infusion, was published by Kudlow et al. [lo] after submission of this manuscript.
REFERENCES 1. Laurent 1, Debry G, Floquet 1: Hypoglycaemic Tumours. Amsterdam, Excerpta Medica Foundation, 1971. 2. Moss NH, Rhoads JE: Hyperinsulinism and islet cell tumors of the pancreas, chap 21. Surgical Diseases of the Pancreas (Howard JM, Jordan Cl Jr, eds], Philadelphia, J.B. Lippincott & Co., 1960. p 321. 3. Clemens AH, Chang PH. Kerner W. et al.: Development of an electrochemical bloocl glucose analyzer and new control algorithms for a lucose controlled insulin infusion system (artificial /3-cclP). Diabetes. Proceedings of the
4. 5. 6.
April 1979
IXth Congress of the International Diabetes Federation (Bajaj JS, ed), Amsterdam, Excerpta Medica Foundation, 1977, p 481. Glucose Analyzer Operational Manual. Fullerton, California, Beckman Instruments, July 1976. Grodsky GM, Forsham PH: An immunochemical assay of total extractable insulin in man. J Clin Invest 39: 1070, 1960. Landor JH, Klachko DM, Lie TH: Continuous monitoring of blood glucose during operation for islet cell adenomas. Ann
The American Journal of Medicine
Volume 66
679
FEEDBACK-CONTROLLED DEXTROSE INFUSION DURING INSULINOMA SURGERY-KARAM
9.
surg 171: 394,197o.
7. Schnelle N, Molnar GD, Ferris DO, et al.: Circulating glucose and insulin in surgery _ . for insulinomas. JAMA 217: 1072, 1971.
8.
660
Lemmer KE, quoted in Miller DR: Functioning adenomas of pancreas with hyperinsulinism: report of 13 patients. Arch Surg 90: 509,1965 [see p 520).
April 1676
The American Journal of Medicine
ET AL.
Clarke WL, Thomas L. Santiago JV: Clinical evaluation and preliminary studies on the use of an artificial pancreatic beta cell in juvenile diabetes mellitus. 1 Pediatr 91: 599, 1977. 10. Kudlow JE, Albisser AM, Angel A. et al.: Insulinoma resection facilitated by the artificial endocrine pancreas. Diabetes 27: 774, 1978.
Volume 66